CN104693194B - 3‑(2‑丙烯酸酯)‑3ˊ‑硝基异噁唑氧化吲哚化合物及其制备方法及应用 - Google Patents
3‑(2‑丙烯酸酯)‑3ˊ‑硝基异噁唑氧化吲哚化合物及其制备方法及应用 Download PDFInfo
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- CN104693194B CN104693194B CN201510049705.7A CN201510049705A CN104693194B CN 104693194 B CN104693194 B CN 104693194B CN 201510049705 A CN201510049705 A CN 201510049705A CN 104693194 B CN104693194 B CN 104693194B
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- compound
- acrylate
- nitro
- isoxazole
- oxoindole
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- -1 nitro isoxazole Oxoindole compounds Chemical class 0.000 title claims abstract description 6
- 238000002360 preparation method Methods 0.000 title claims description 11
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 title abstract description 5
- 239000003814 drug Substances 0.000 claims abstract description 18
- 238000003379 elimination reaction Methods 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 61
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- PMQFLWLYAXYFHG-UHFFFAOYSA-N 3,5-dimethyl-4-nitro-1,2-oxazole Chemical class CC1=NOC(C)=C1[N+]([O-])=O PMQFLWLYAXYFHG-UHFFFAOYSA-N 0.000 claims description 5
- FYGHSUNMUKGBRK-UHFFFAOYSA-N 1,2,3-trimethylbenzene Chemical compound CC1=CC=CC(C)=C1C FYGHSUNMUKGBRK-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 2
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 1
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
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- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 abstract 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- 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
Abstract
本发明公开了一种3‑(2‑丙烯酸酯)‑3ˊ‑硝基异噁唑氧化吲哚化合物，本发明以不同取代的3‑(2‑丙烯酸酯)‑3‑OBoc氧化吲哚和3,5‑二甲基‑4‑硝基异噁唑，经有机碱直接催化加成消除反应，合成了3‑(2‑丙烯酸酯)‑3ˊ‑硝基异噁唑氧化吲哚化合物，该类骨架包含潜在的生物活性含异噁唑基团和丙烯酸酯类基团，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三种肿瘤细胞株进行肿瘤生长抑制活性筛选，证明这些衍生物发现具有一定的抑制肿瘤细胞生长活性，可预期作为抗肿瘤药物用途。
Description
技术领域
本发明涉及化学技术领域，尤其是一种3-(2-丙烯酸酯)-3ˊ-硝基异噁唑氧化吲哚化合物及其制备方法及应用。
背景技术
把具有生物活性基团拼接到一个分子骨架中在有机化学和医药化学中是极其重要的研究领域。（1）氧化吲哚是一类重要的杂环化合物，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，3-季碳氧化吲哚是其中很重要的一种，很多天然产物中的3-季碳氧化吲哚都具有很好的生物活性。其中，3-季碳硫取代氧化吲哚也存在于生物活性分子和药物分子中。例如，化合物spirobrassinin和methoxyspirobrassinin具有抗肿瘤、抗菌和产卵兴奋剂等生物活性。（2）异噁唑基团也普遍存在天然产物和药物分子中。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。（3）丙烯酸酯基团也存在于一些活性分子中，例如，甲氧基丙烯酸酯类杀菌剂是一种仿生杀菌剂，是继苯并咪唑和三唑类之后的一个里程碑式的农药杀菌剂；作为化学中间体原料的甲基丙烯酸月桂酯和甲基丙烯酸异冰片酸酯也包含丙烯酸酯基团。鉴于3,3'-双取代氧化吲哚骨架化合物具有潜在的生物活性，异噁唑基团和丙烯酸酯类基团属于潜在的生物活性官能团。因此，把异噁唑基团和丙烯酸酯类基团拼接到氧化吲哚骨架，合成一系列新的潜在多活性官能团的氧化吲哚衍生物，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3-(2-丙烯酸酯)-3ˊ-硝基异噁唑氧化吲哚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：3-(2-丙烯酸酯)-3ˊ-硝基异噁唑氧化吲哚化合物，该化合物具有如下通式（Ⅰ）的结构：
式中，R1为烷基；R2为烷基或H；R3为烷基或卤素。
3-(2-丙烯酸酯)-3ˊ-硝基异噁唑氧化吲哚化合物的制备方法，由相应的3-(2-丙烯酸酯)-3-OBoc氧化吲哚化合物与3,5-二甲基-4-硝基异噁唑在碱性有机催化剂条件下，按摩尔比为4:3的比例在有机溶剂中进行加成消除反应，获得3-(2-丙烯酸酯)-3ˊ-硝基异噁唑氧化吲哚化合物。
所述的有机碱为DABCO或β-ICD (β-6’-羟基异辛克宁)及其衍生的有机碱，碱性催化剂的加入量为氧化吲哚摩尔量的1-100%。
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3,5-二甲基-4-硝基异噁唑反应温度为25-100℃，反应时间为0.1-10小时。
本发明的反应原理如下：
通过采用上述技术方案，以不同取代的3-(2-丙烯酸酯)-3-OBoc氧化吲哚与3,5-二甲基-4-硝基异噁唑，经有机碱直接催化加成消除反应，合成了3-(2-丙烯酸酯)-3ˊ-硝基异噁唑氧化吲哚化合物，该类骨架包含潜在的生物活性异噁唑基团和丙烯酸酯类基团，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，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3a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3b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3c的核磁谱图数据。
具体实施方式
本发明的实施例1：3-(2-丙烯酸酯)-3ˊ-硝基异噁唑氧化吲哚化合物的制备， 在圆底烧瓶中，先加入5毫升有机溶剂二氯甲烷，再依次加入3-(2-丙烯酸甲酯)-3-OBoc-N-苯基氧化吲哚0.3mmol（122.7 mg），3,5-二甲基-4-硝基异噁唑0.4 mmol（56.8 mg），DABCO3.4 mg（10 mol%），室温搅拌反应12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, 即化合物3a。产率78%, 核磁共振和高分辨质谱测试等结果如下：熔点：102.8-103.1；核磁共振和高分辨质谱测试等结果如下：1H NMR (CDCl3, 400 MHz) δ: 1.10 (t, J = 5.7 Hz, 3H), 2.37 (s, 3H), 3.21(s, 3H), 3.78 (d, J = 10.1 Hz, 1H), 4.00-4.05 (m, 2H), 4.33 (d, J = 11.1 Hz,1H), 6.16 (s, 1H), 6.64 (s, 1H), 6.73 (d, J = 6.3 Hz, 1H), 6.91-6.94 (m, 1H),7.11-7.12 (m, 1H), 7.20-7.24 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ: 11.4, 13.7,26.5, 32.1, 53.9, 61.2, 108.1, 122.5, 123.2, 127.9, 129.0, 129.2, 138.5,143.6, 155.0, 164.6, 169.3, 175.9; HRMS (ESI-TOF) m/z: Calcd. for C19H19N3NaO6 [M+Na]+: 408.1172; Found: 408.1178.
化合物3b-3q的制备方法同化合物3a，投料比与化合物3a相同，可得到化合物3b-3q，反应产率和反应时间见表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3b: 黄色固体，产率65%, 熔点：76.3-76.8 oC；核磁共振和高分辨质谱测试等结果如下：1H NMR (CDCl3, 400 MHz) δ: 1.071 (t, J = 14.4 Hz,3H), 2.38 (s, 3H), 3.91-4.01 (m, 2H), 4.07-4.15 (m, 1H), 4.29-4.37 (m, 1H),4.80 (d, J = 15.6 Hz, 1H), 5.00 (d, J = 16.1 Hz, 1H), 6.16 (s, 1H), 6.60-6.64(m, 2H), 6.89-6.93 (m, 1H), 7.08-7.12 (m, 1H), 7.16-7.18 (m, 1H), 7.25-7.36(m, 5H); 13C NMR (CDCl3, 100 MHz) δ: 11.5, 13.8, 32.1, 44.6, 54.0, 61.2,109.4, 122.7, 123.5, 127.5, 127.6, 128.0, 128.7, 129.0, 129.1, 135.5, 138.6,142.9, 164.7, 169.3, 176.0; HRMS (ESI-TOF) m/z: Calcd. for C25H23N3NaO6 [M+Na]+:484.1485; Found: 484.1479.
本实施例制备化合物3c: 黄色固体，产率79%, 熔点：135.7-136.2 oC。核磁共振和高分辨质谱测试等结果如下：1H NMR (CDCl3, 400 MHz) δ: 1.10 (t, J = 10.7 Hz, 3H),2.23 (s, 3H), 2.37 (s, 3H), 3.18 (s, 3H), 3.76 (d, J = 11.1 Hz, 1H), 4.00-4.07 (m, 2H), 4.28 (d, J = 11.1 Hz, 1H), 6.14 (s, 1H), 6.61 (d, J = 6.3 Hz,1H), 6.63 (s, 1H), 6.915-6.911 (m, 1H), 7.00-7.02 (m, 1H); 13C NMR (CDCl3, 100MHz) δ: 11.3, 13.7, 20.9, 26.6, 32.2, 54.0, 61.1, 107.8, 124.0, 127.8, 129.0,129.4, 132.1, 138.5, 141.1, 154.9, 164.7, 169.3, 175.8; HRMS (ESI-TOF) m/z:Calcd. for C20H21N3NaO6 [M+Na]+: 422.1328; Found: 422.1329.
本实施例制备化合物3d: 黄色固体，产率80%, 熔点：44.6-45.1 oC。核磁共振和高分辨质谱测试等结果如下：1H NMR (CDCl3, 400 MHz) δ: 1H NMR (CDCl3, 400 MHz) δ:1.08 (t, J = 11.4 Hz, 3H), 2.20 (s, 3H), 2.37 (s, 3H), 3.90 (d, J = 11.1 Hz,1H), 3.95-4.0 (m, 1H), 4.08-4.15 (m, 1H), 4.29 (d, J = 11.1 Hz, 1H), 4.75 (d,J = 12.6 Hz, 1H), 4.98 (d, J = 12.5 Hz, 1H), 6.14 (s, 1H), 6.48 (d, J = 6.4Hz, 1H), 6.63 (s, 1H), 6.89 (t, J = 6.4 Hz, 1H), 6.96 (s, 1H), 7.23-7.26 (m,1H), 7.29-7.34 (m, 4H); 13C NMR (CDCl3, 100 MHz) δ: 11.4, 13.8, 20.9, 32.2,44.6, 54.1, 61.2, 109.1, 124.2, 127.4, 127.6, 127.8, 128.6, 129.1, 129.3,132.2, 132.3, 135.6, 138.7, 140.5, 155.0 164.8, 169.3, 175.8; HRMS (ESI-TOF)m/z: Calcd. for C26H25N3NaO6 [M+Na]+: 498.1641; Found: 498.1644.
本实施例制备化合物3e: 黄色固体，产率76%, 熔点：113.9-114.4 oC。核磁共振和高分辨质谱测试等结果如下：1H NMR (CDCl3, 400 MHz) δ: 1H NMR (CDCl3, 400 MHz) δ: 1H NMR (CDCl3, 400 MHz) δ: 1.16 (t, J = 14.4 Hz, 3H), 2.41 (s, 3H), 3.21 (s,3H), 3.83 (d, J = 14.4 Hz, 1H), 4. 04-4. 11 (m, 2H), 4.27 (d, J = 14.4 Hz,1H), 6.17 (s, 1H), 6.67 (s, 1H), 6.68-6.71 (m, 1H), 6.92-6.97 (m, 2H); 13C NMR(CDCl3, 100 MHz) δ: 11.4, 13.8, 26.7, 32.0, 54.1, 61.3, 108.7 (d, J CF = 8.0Hz), 111.8 (d, J CF = 25.1 Hz), 115.5 (d, J CF = 23.4 Hz), 128.6, 137.8, 139.7,155.1, 158.9 (d, J CF = 240.2 Hz), 164.5, 168.9, 175.6; HRMS (ESI-TOF) m/z:Calcd. for C19H18FN3NaO6 [M+Na]+: 426.1077; Found: 426.1068.
本实施例制备化合物3f: 黄色固体，产率67%, 熔点：80.7-81.2 oC。核磁共振和高分辨质谱测试等结果如下：1H NMR (CDCl3, 400 MHz) δ: 1.15 (t, J = 14.4 Hz, 3H),2.42 (s, 3H), 3.97 (d, J = 14.4 Hz, 1H), 4.01-4.09 (m, 1H), 4.11-4.17 (m,1H), 4.3 (d, J = 14.4 Hz, 1H), 4.81 (d, J = 16.1 Hz, 1H), 4.96 (d, J = 15.6Hz, 1H), 6.15 (s, 1H), 6.52-6.56 (m, 1H), 6.65 (s, 1H), 6.79-6.84 (m, 1H),6.99-7.02 (m, 1H), 7.26-7.35 (m, 5H); 13C NMR (CDCl3, 100 MHz) δ: 11.5, 13.9,32.0, 44.7, 54.2, 61.4, 110.0 (d, J CF = 8.7 Hz), 112.0 (d, J CF = 26.4 Hz),115.4 (d, J CF = 23.1 Hz), 127.4, 127.7, 128.6, 128.8, 135.1, 138.0, 138.9,155.1, 158.9 (d, J CF = 241.0 Hz), 164.6, 168.9, 175.7; HRMS (ESI-TOF) m/z:Calcd. for C25H22FN3NaO6 [M+Na]+: 502.1390; Found: 502.1392.
本实施例制备化合物3g: 黄色固体，产率69%, 熔点：134.7-135.8 oC。核磁共振和高分辨质谱测试等结果如下：1H NMR (CDCl3, 400 MHz) δ: 1H NMR (CDCl3, 400 MHz)δ: 1.16 (t, J = 11.5 Hz, 3H), 2.42 (s, 3H), 3.20 (s, 3H), 3.82 (d, J = 11.5Hz, 1H), 4.04-4.11 (m, 2H), 4.23 (d, J = 11.4 Hz, 1H), 6.18 (s, 1H), 6.67 (s,1H), 6.69 (d, J = 6.6 Hz, 1H), 7.14 (d, J = 1.9 Hz, 1H), 7.21-7.23 (m, 1H);13C NMR (CDCl3, 100 MHz) δ: 11.5, 13.8, 26.7, 32.0, 53.8, 61.4, 109.1, 123.9,127.9, 128.6, 129.1, 130.9, 137.7, 142.3, 155.2, 164.4, 168.8, 175.5; HRMS(ESI-TOF) m/z: Calcd. for C19H18ClN3NaO6 [M+Na]+: 442.0782; Found: 442.0782.
本实施例制备化合物3h: 黄色固体，产率60%, 熔点：48.5-48.7 oC。核磁共振和高分辨质谱测试等结果如下：1H NMR (CDCl3, 400 MHz) δ: 1.16 (t, J = 14.4 Hz, 3H),2.43 (s, 3H), 3.96 (d, J = 14.4 Hz, 1H), 4.01-4.10 (m, 1H), 4.13-4.2 (m, 1H),4.24-4.29 (m, 1H), 4.81 (d, J = 16.1 Hz, 1H), 4.97 (d, J = 16.1 Hz, 1H), 6.18(s, 1H), 6.54 (d, J = 8.4 Hz, 1H), 6.68 (s, 1H), 7.08-7.10 (m, 1H), 7.19 (d,J = 2.0 Hz, 1H), 7.26-7.35 (m, 5H); 13C NMR (CDCl3, 100 MHz) δ: 11.5, 13.9,32.0, 44.7, 54.0, 61.5, 110.4, 124.1, 127.4, 127.7, 128.0, 128.6, 128.8,129.0, 130.9, 135.0, 137.9, 141.6, 155.2, 164.5, 168.8, 175.5; HRMS (ESI-TOF)m/z: Calcd. for C25H22ClN3NaO6 [M+Na]+: 518.1095; Found: 518.1095.
本实施例制备化合物3i: 黄色固体，产率61%, 熔点：105.1-106.6 oC。核磁共振和高分辨质谱测试等结果如下：1H NMR (CDCl3, 400 MHz) δ: 1H NMR (CDCl3, 400 MHz) δ:1.13 (t, J = 11.3 Hz, 3H), 2.42 (s, 3H), 3.57 (s, 3H), 3.77 (d, J = 11.2 Hz,1H), 4.00-4.08 (m, 2H), 4.26 (d, J = 11.2 Hz, 1H), 6.19 (s, 1H), 6.68 (s,1H), 6.83-6.87 (m, 1H), 6.99-7.00 (m, 1H), 7.15-7.17 (m, 1H); 13C NMR (CDCl3,100 MHz) δ: 11.4, 13.8, 30.0, 32.3, 53.6, 61.4, 115.5, 121.7, 123.2, 128.3,131.5, 131.8, 138.2, 139.7, 155.1, 164.4, 168.7, 176.2; HRMS (ESI-TOF) m/z:Calcd. for C19H18ClN3NaO6 [M+Na]+: 442.0782; Found: 442.0786.
本实施例制备化合物3j: 黄色固体，产率64%, 熔点：133.4-133.6 oC。核磁共振和高分辨质谱测试等结果如下：1H NMR (CDCl3, 400 MHz) δ: 2.42 (s, 3H), 3.22 (s,3H), 3.67 (s, 3H), 3.85 (d, J = 11.5 Hz, 1H), 4.28 (d, J = 11.5 Hz, 1H), 6.18(s, 1H), 6.64 (s, 1H), 6.69-6.72 (m, 1H), 6.94-6.98 (m, 2H); 13C NMR (CDCl3,100 MHz) δ: 11.4, 26.8, 31.9, 52.4, 54.2, 109.0 (d, J CF = 8.1 Hz), 111.8 (d,J CF = 24.4 Hz), 115.5 (d, J CF = 25.1 Hz), 128.7, 130.6, 137.6, 139.7, 155.1,158.6 (d, J CF = 242.1 Hz), 165.0, 168.9, 175.5; HRMS (ESI-TOF) m/z: Calcd. forC18H16FN3NaO6 [M+Na]+: 412.0921; Found: 412.0914.
本实施例制备化合物3k: 黄色固体，产率90%, 熔点：136.4-137.0 oC。核磁共振和高分辨质谱测试等结果如下：1H NMR (CDCl3, 400 MHz) δ: 2.24 (s, 3H), 2.38 (s,3H), 3.19 (s, 3H), 3.63 (s, 3H), 3.77 (d, J = 11.3 Hz, 1H), 4.29 (d, J = 11.3Hz, 1H), 6.17 (s, 1H), 6.61-6.63 (m, 2H), 6.91-6.92 (m, 1H), 7.01-7.03 (m,1H); 13C NMR (CDCl3, 100 MHz) δ: 11.4, 20.9, 26.6, 32.1, 52.2, 54.0, 108.0,124.1, 128.0, 129.0, 129.5, 131.1, 132.2, 138.3, 141.2, 155.0, 165.1, 169.3,175.8; HRMS (ESI-TOF) m/z: Calcd. for C19H19N3NaO6 [M+Na]+: 408.1172; Found:408.1176.
本实施例制备化合物3l: 黄色固体，产率67%, 熔点：44.9-45.4 oC。核磁共振和高分辨质谱测试等结果如下：1H NMR (CDCl3, 400 MHz) δ: 2.38 (s, 3H), 3.59 (s, 3H),3.91 (d, J = 11.3 Hz, 1H), 4.35 (d, J = 11.3Hz, 1H), 4.77 (d, J = 12.6 Hz,1H),5.04 (d, J = 12.3 Hz, 1H), 6.18 (s, 1H), 6.61 (d, J = 6.2 Hz, 1H), 6.64(s, 1H), 6.89-6.93 (m, 1H), 7.09-7.12 (m, 1H), 7.16-7.17 (m, 1H), 7.25-7.28(m, 1H), 7.31-7.36 (m, 4H); 13C NMR (CDCl3, 100 MHz) δ: 11.4, 32.1, 44.6,52.2, 54.0, 109.4, 122.7, 123.5, 127.5, 127.6, 128.2, 128.7, 128.9, 129.2,135.5, 138.3, 142.9, 155.1, 165.2, 169.2, 175.9; HRMS (ESI-TOF) m/z: Calcd.for C24H21N3NaO6 [M+Na]+: 470.1328; Found: 470.1335.
本实施例制备化合物3m: 黄色固体，产率70%, 熔点：121.6-122.2 oC。核磁共振和高分辨质谱测试等结果如下：1H NMR (CDCl3, 400 MHz) δ: 1.17 (t, J = 14.2 Hz, 3H),2.42 (s, 3H), 3.20 (s, 3H), 3.82 (d, J = 14.1 Hz, 1H), 4.05-4.10 (m, 2H),4.22 (d, J = 14.3 Hz, 1H), 6.18 (s, 1H), 6.65 (d, J = 8.3 Hz, 1H), 6.67 (s,1H), 7.27 (s, 1H), 7.36-7.38 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ: 11.4, 13.8,26.7, 32.1, 53.8, 61.4, 109.6, 115.1, 126.6, 128.5, 131.3, 132.1, 137.8,142.8, 155.2, 164.5, 168.8, 175.4; HRMS (ESI-TOF) m/z: Calcd. forC19H18BrN3NaO6 [M+Na]+: 486.0277; Found: 486.0271.
本实施例制备化合物3n: 黄色固体，产率65%, 熔点：50.1-50.5 oC。核磁共振和高分辨质谱测试等结果如下：1H NMR (CDCl3, 400 MHz) δ: 1.16 (t, J = 14.4 Hz, 3H),2.43 (s, 3H), 3.95 (d, J = 14.4 Hz, 1H), 4.02-4.09 (m, 1H), 4.12-4.19 (m,1H), 4.25 (d, J = 14.4 Hz, 1H), 4.78 (d, J = 15.8 Hz, 1H), 4.96 (d, J = 15.8Hz, 1H), 6.18 (s, 1H), 6.49 (d, J = 8.4 Hz, 1H), 6.67 (s, 1H), 7.23-7.33 (m,7H); 13C NMR (CDCl3, 100 MHz) δ: 11.5, 13.9, 32.0, 44.7, 54.0, 61.5, 110.9,115.3, 126.9, 127.4, 127.8, 128.5, 128.8, 131.3, 132.0, 135.0, 138.0, 142.1,155.2, 164.5, 168.8 175.5; HRMS (ESI-TOF) m/z: Calcd. for C25H22BrN3NaO6 [M+Na]+: 562.0590; Found: 562.0596.
本实施例制备化合物3o: 黄色固体，产率64%, 熔点：149.7-150.7 oC。核磁共振和高分辨质谱测试等结果如下：1H NMR (CDCl3, 400 MHz) δ: 2.40 (s, 3H), 3.25 (s,3H), 3.65 (s, 3H), 3.82 (d, J = 10.0 Hz, 1H), 4.84 (d, J = 10.0 Hz, 1H), 6.22(s, 1H), 6.66 (s, 1H), 6.78 (d, J = 10.0 Hz, 1H), 6.95-6.98 (m, 1H), 7.15-7.16 (m ,1H), 7.24-7.27 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ: 11.5, 26.7, 32.1,52.3, 54.0, 108.3, 122.6, 123.3, 128.2, 128.9, 129.3, 138.2, 143.6, 155.1,165.1, 169.3, 175.9; HRMS (ESI-TOF) m/z: Calcd. for C18H17N3NaO6 [M+Na]+:394.1015; Found: 394.1014.
本实施例制备化合物3p: 黄色固体，产率67%, 熔点：121.6-122.1 oC。核磁共振和高分辨质谱测试等结果如下：1H NMR (CDCl3, 400 MHz) δ: 1.37 (s, 9H), 2.42 (s,3H), 3.99 (d, J = 15.0 Hz, 1H), 4.22 (d, J = 15.0 Hz, 1H), 4.84 (d, J = 15.0Hz, 1H), 4.91 (d, J = 15.0 Hz, 1H), 6.05 (s, 1H), 6.50 (s, 1H), 6.56 (d, J =10.0 Hz, 1H), 7.09-7.11 (m, 1H), 7.24-7.32 (m, 6H); 13C NMR (CDCl3, 100 MHz)δ: 11.5, 26.7, 32.1, 52.3, 54.0, 108.3, 122.6, 123.3, 128.2, 128.9, 129.3,138.2, 143.6, 155.1, 165.1, 169.3, 175.9; HRMS (ESI-TOF) m/z: Calcd. forC27H26ClN3NaO6 [M+Na]+: 546.1408; Found: 546.1413.
本实施例制备化合物3q: 黄色固体，产率61%, 熔点：203.1-203.5 oC。核磁共振和高分辨质谱测试等结果如下：1H NMR (CDCl3, 400 MHz) δ: 2.43 (s, 3H), 3.94 (d, J =12.0 Hz, 1H), 4.26 (d, J = 9.0 Hz, 1H), 4.69 (d, J = 9.0 Hz, 1H), 5.05 (d, J= 12.0 Hz, 1H), 6.27 (br s, 1H), 6.52 (d, J = 8.0 Hz, 1H), 6.78 (s, 1H),7.08-7.10 (m, 1H), 7.16 (s, 1H), 7.26-7.31 (m, 6H); 13C NMR (CDCl3, 100 MHz)δ: 11.5, 32.1, 44.1, 53.9, 110.6, 123.6, 124.2, 127.3, 127.8, 128.3, 128.8,129.3, 130.5, 134.9, 141.5, 147.5, 155.3, 168.6, 175.6; HRMS (ESI-TOF) m/z:Calcd. for C23H18ClN3NaO6 [M+Na]+: 490.0782; Found: 490.0779.
本发明的式（1）化合物具有重要的生物活性，体外对人前列腺（PC-3）, 人肺癌细胞（A549）以及人白血病细胞（K562）共三株肿瘤细胞的细胞毒性试验表明：此类式（1）所示的结构的3-(2-丙烯酸酯)-3ˊ-硝基异噁唑氧化吲哚化合物对肿瘤细胞生长具有抑制作用，有可能发展成为新的防治肿瘤药物。
药理实施例1：化合物3a-3q对PC-3细胞的细胞毒性
PC-3（人前列腺癌）细胞用RPMI-1640培养基培养，培养基中含10%的胎牛血清，100U/mL 青霉素及100U/mL的链霉素。细胞以每孔5000个细胞的浓度加入到96孔中，在37oC 含5% CO2潮湿空气的培养箱中培养24小时。
细胞存活率的测定用改良MTT法。细胞经过24小时的孵育后，分别将新配的化合物3a-3q的二甲基亚砜溶液以浓度梯度加入到各孔中，使孔中化合物最终浓度分别为5 μmol/L, 10 μmol/L, 20 μmol/L, 40 μmol/L 和80 μmol/L。48小时后，每孔加入10 μL MTT （5mg/mL) 的磷酸盐缓冲液，再继续在37 oC 培养4小时后，离心5分钟除去未转化的MTT，每孔中加入150 μL 二甲基亚砜。以溶解还原的MTT 晶体甲臜（formazan），用酶标仪在490 nm波长测定OD值。其中化合物3a-3q对PC-3细胞半抑制浓度IC50由spss软件(19版本)分析得到。化合物3a对PC-3肿瘤细胞的IC50为42.9 μmol/L；化合物3b对PC-3肿瘤细胞的IC50为23.5 μmol/L；化合物3c对PC-3肿瘤细胞的IC50为71.4 μmol/L；化合物3d对PC-3肿瘤细胞的IC50为54.9 μmol/L；化合物3e对PC-3肿瘤细胞的IC50为90.5 μmol/L；化合物3f对PC-3肿瘤细胞的IC50为33.9 μmol/L；化合物3g对PC-3肿瘤细胞的IC50为17.1 μmol/L；化合物3h对PC-3肿瘤细胞的IC50为12.4 μmol/L；化合物3i对PC-3肿瘤细胞的IC50为23.2 μmol/L；化合物3j对PC-3肿瘤细胞的IC50为23.5 μmol/L；化合物3k对PC-3肿瘤细胞的IC50为68.7 μmol/L；化合物3l对PC-3肿瘤细胞的IC50为25.8 μmol/L; 化合物3m对PC-3肿瘤细胞的IC50为17.3 μmol/L; 化合物3n对PC-3肿瘤细胞的IC50为39.0 μmol/L; 化合物3o对PC-3肿瘤细胞的IC50为25.8 μmol/L; 化合物3p对PC-3肿瘤细胞的IC50为大于100 μmol/L；化合物3q对PC-3肿瘤细胞的IC50为大于100 μmol/L；而阳性照顺铂对PC-3肿瘤细胞的IC50为27.1 μmol/L。
实验结论：PC-3细胞是测试化合物对肿瘤细胞的细胞毒性的有效工具和评价指标。本实验表明此类式（1）所示的3-(2-丙烯酸酯)-3ˊ-硝基异噁唑氧化吲哚化合物对PC-3细胞具有较强的细胞毒性，有可能发展成新的具有抗肿瘤作用的药物。
药理实施例2：化合物3a-3q对A549细胞的细胞毒性
A549（人非小细胞肺癌肺癌）用DMEM培养基培养，培养基中含10%的胎牛血清，100U/mL的青霉素和100U/mL链霉素。细胞以每孔4000个细胞的浓度加入到96孔中，在37℃含5%CO2潮湿空气的培养箱中培养24小时。
细胞存活率的测定用改良MTT法。具体方法如药理实施例1。化合物3a对A549肿瘤细胞的IC50为31.7 μmol/L；化合物3b对A549肿瘤细胞的IC50为40.7 μmol/L；化合物3c对A549肿瘤细胞的IC50为80.9 μmol/L；化合物3d对A549肿瘤细胞的IC50为41.4 μmol/L；化合物3e对A549肿瘤细胞的IC50大于100.0 μmol/L；化合物3f对A549肿瘤细胞的IC50为54.1 μmol/L；化合物3g对A549肿瘤细胞的IC50为31.4 μmol/L；化合物3h对A549肿瘤细胞的IC50为37.9 μmol/L；化合物3i对A549肿瘤细胞的IC50为37.1 μmol/L；化合物3j对A549肿瘤细胞的IC50为42.0 μmol/L；化合物3k对A549肿瘤细胞的IC50为78.9 μmol/L；化合物3l对A549肿瘤细胞的IC50为52.7 μmol/L; 化合物3m对PC-3肿瘤细胞的IC50为37.3 μmol/L; 化合物3n对PC-3肿瘤细胞的IC50为69.1 μmol/L; 化合物3o对A549肿瘤细胞的IC50为41.8 μmol/L; 化合物3p对A549肿瘤细胞的IC50为大于100 μmol/L；化合物3q对A549肿瘤细胞的IC50为大于100 μmol/L；而阳性对照顺铂对A549肿瘤细胞的IC50为23.4 μmol/L。
实验结论：A549细胞是测试化合物对肿瘤细胞的细胞毒性的有效工具和评价指标。本实验表明此类式（1）所示的3-(2-丙烯酸酯)-3ˊ-硝基异噁唑氧化吲哚化合物对A549细胞具有较强的细胞毒性，有可能发展成新的具有抗肿瘤作用的药物。
药理实施例3：化合物3a-3q对K562细胞的细胞毒性
K562（人慢性髓系白血病细胞）用RPMI-1640培养基培养，培养基中含10%的胎牛血清，100 U/mL的青霉素和100 U/mL链霉素。细胞以每孔5000个细胞的浓度加入到96孔中，在37℃含5% CO2潮湿空气的培养箱中培养24小时。
细胞存活率的测定用改良MTT法。具体方法如药理实施例1。化合物3a对K562肿瘤细胞的IC50为35.1 μmol/L；化合物3b对K562肿瘤细胞的IC50为11.8 μmol/L；化合物3c对K562肿瘤细胞的IC50为43.7 μmol/L；化合物3d对K562肿瘤细胞的IC50为12.3 μmol/L；化合物3e对K562肿瘤细胞的IC50为23.3 μmol/L；化合物3f对K562肿瘤细胞的IC50为9.1 μmol/L；化合物3g对K562肿瘤细胞的IC50为8.8 μmol/L；化合物3h对K562肿瘤细胞的IC50为7.8 μmol/L；化合物3i对K562肿瘤细胞的IC50为11.7 μmol/L；化合物3j对K562肿瘤细胞的IC50为25.2 μmol/L；化合物3k对K562肿瘤细胞的IC50为54.7 μmol/L；化合物3l对K562肿瘤细胞的IC50为15.7 μmol/L; 化合物3m对K562肿瘤细胞的IC50为9.2 μmol/L;化合物3n对K562肿瘤细胞的IC50为12.7 μmol/L; 化合物3o对K562肿瘤细胞的IC50为33.3 μmol/L; 化合物3q对K562肿瘤细胞的IC50为大于100 μmol/L；化合物3q对K562肿瘤细胞的IC50为大于100 μmol/L；而阳性对照顺铂对K562肿瘤细胞的IC50为21.6 μmol/L。
实验结论：K562细胞是测试化合物对肿瘤细胞的细胞毒性的有效工具和评价指标。本实验表明此类式（1）所示的3-(2-丙烯酸酯)-3ˊ-硝基异噁唑氧化吲哚化合物对K562细胞具有较强的细胞毒性，有可能发展成新的具有抗肿瘤作用的药物。
从以上药理实施例中我们可以看出这些化合物对这三株肿瘤细胞都显示有一定的细胞毒性。可见这些化合物具有开发成为抗肿瘤药物的潜力，值得继续深入研究下去。
Claims (5)
1.一种3-(2-丙烯酸酯)-3ˊ-硝基异噁唑氧化吲哚化合物，其特征在于：该化合物具有如通式(Ⅰ)所示的结构：
式中，R1为Me或Bn；R2为甲基、乙基、叔丁基或H；R3为CH3、F、Cl或Br。
2.一种如权利要求1所述的3-(2-丙烯酸酯)-3ˊ-硝基异噁唑氧化吲哚化合物的制备方法，其特征在于：将3-(2-丙烯酸酯)-3-OBoc氧化吲哚化合物与3,5-二甲基-4-硝基异噁唑在碱性有机催化剂条件下，按摩尔比为4:3的比例在有机溶剂中进行加成消除反应，获得3-(2-丙烯酸酯)-3ˊ-硝基异噁唑氧化吲哚化合物。
3.根据权利要求2所述的3-(2-丙烯酸酯)-3ˊ-硝基异噁唑氧化吲哚化合物的制备方法，其特征在于：所述的有机溶剂为乙腈、甲醇、乙醇、丙醇、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3-(2-丙烯酸酯)-3ˊ-硝基异噁唑氧化吲哚化合物的制备方法，其特征在于：3-(2-丙烯酸酯)-3-OBoc氧化吲哚化合物和3,5-二甲基-4-硝基异噁唑反应温度为25-100℃，反应时间为0.1-10小时。
5.一种如权利要求1所述的3-(2-丙烯酸酯)-3ˊ-硝基异噁唑氧化吲哚化合物在制备防治肿瘤疾病药物的应用。
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