CN108912127A - 一种基于靛红骨架的苯并[b,e]氮杂卓化合物及其制备方法 - Google Patents
一种基于靛红骨架的苯并[b,e]氮杂卓化合物及其制备方法 Download PDFInfo
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- CN108912127A CN108912127A CN201810979889.0A CN201810979889A CN108912127A CN 108912127 A CN108912127 A CN 108912127A CN 201810979889 A CN201810979889 A CN 201810979889A CN 108912127 A CN108912127 A CN 108912127A
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Communicable Diseases (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供了一个基于靛红骨架的苯并[b,e]氮杂卓化合物，该化合物的独特骨架结构使其具有良好的抗菌活性。本发明还发展了一种路易斯酸催化的吡咯烷扩环合成苯并[b,e]氮杂卓的制备方法。利用4‑吡咯烷靛红和多种苯酚化合物作为底物，利用一步法合成复杂结构的多环胺，同时扩展了吡咯烷合成多元杂环化合物的合成策略。本发明的合成方法底物方便易得，操作方便，反应活性较高，原料转化完全，具有绿色经济性。
Description
技术领域
本发明属于药物化学技术领域，本发明涉及一种基于靛红骨架的苯并[b,e]氮杂卓化合物及其制备方法。
背景技术
七元氮杂环是一类特殊的化合物，主要由杂环化合物中的卓类化合物组成；其七元环的特殊结构具有显著的生理和药理作用，对这些化合物的潜在药理性质探究主要在对抗癌类和对抗菌类方面。例如竞争性抗利尿激素受体阻断剂Tolvaptan，以及作为八大主要抗抑郁药之一的Mirtazapine。
目前，人们合成七元氮杂环1-苯并氮杂卓的反应策略包括Pictet-Spengler反应、NHC/Pd催化环化、Ichikawa重排和闭环反应等。1895年，“叔胺效应”首次被发现。该效应中叔胺发挥了双重作用(一方面极化并且削弱C-H键，通过超共轭作用增加氢原子周围负电子的密度从而促进氢负离子的生成；另一方面是在氢迁移的基础上通过与杂原子上的孤电子对的p-p共轭作用增加在原位置生成的正离子的稳定性)，使得α-碳原子容易发生氢迁移。而[1,5]氢迁移环化反应是最为高效的C(sp3)-H键活化的方法之一，也被越来越多的人应用在环状化合物的合成中。
2017年，Dae Young Kim及其同事利用环丙烷三元环张力引发的[1，5]-氢迁移环化反应，实现苯并氮杂卓的合成(Org.Lett.2017,19,1334-1337)。该反应虽然实现了该类化合物的构建，但由于其底物的构建较为复杂，不利于该合成策略的实际应用。
利用环烷烃进行扩环反应是合成多元环状化合物的策略之一，例如上述合成策略。目前，四氢吡咯烷是合成氮杂环类化合物的常用底物，但是，利用四氢吡咯烷的开环扩环反应，所获得的环状产物都是六元环、八元环及九元环，而无法获得七元环状化合物。
因此，为了克服现有技术中的上述问题，获得更好的七元氮杂环类化合物的反应路径，促进该类天然产物分子的性能研究和应用扩展，需要一种新的苯并[b,e]氮杂卓化合物合成转化的策略，以改善反应的原子经济性、步骤经济性和环境友好性。
发明内容
本发明的目的在于提供一种基于靛红骨架的苯并[b,e]氮杂卓化合物及其制备方法。本发明提供的骨架化合物分子是一类重要的医药中间体和药物类似物，对药物筛选和制药行业具有重要的应用价值。本发明操作简单实用，产率好，且反应具有绿色经济性，对环境友好。
为实现上述目的，本发明采取的技术方案如下：
一种基于靛红骨架的苯并[b,e]氮杂卓化合物，其特征在于：结构如式Ⅰ所示：
式Ⅰ中，虚线表示任选的单键；
R1选自C1-C3烷基、苯基、C1-C3烷基取代苯基、苄基、环丙烷基、环丙基乙基、烯丙基任意一种；并且
R1’选自H原子或多取代苯酚。
作为优选的，上述基于靛红骨架的苯并[b,e]氮杂卓化合物结构如式Ⅱ所示：
式Ⅱ中，虚线表示任选的单键；
R1选自C1-C3烷基、苯基、C1-C3烷基取代苯基、苄基、环丙烷基、环丙基乙基、烯丙基任意一种；并且
R2、R3各自独立地选自C1-C3烷基、羟基、C1-C3烷氧基、苄氧基中任意一种。
一种制备上述式Ⅰ或式Ⅱ所示基于靛红骨架的苯并[b,e]氮杂卓化合物的合成方法，利用4-吡咯烷靛红类化合物与苯酚类化合物，在催化剂作用下，反应生成上述基于靛红骨架的苯并[b,e]氮杂卓化合物。
上述4-吡咯烷靛红类化合物为式Ⅲ所示化合物，上述苯酚类化合物为式Ⅳ所示化合物：
式Ⅲ、式Ⅳ中，虚线表示任选的单键；
R1选自C1-C3烷基、苯基、C1-C3烷基取代苯基、苄基、环丙烷基、环丙基乙基、烯丙基任意一种；并且
R2、R3各自独立地选自C1-C3烷基、羟基、C1-C3烷氧基、苄氧基中任意一种。
在上述化合物的定义中，所用专业术语不论单独使用或者使用在复合词中，代表如下取代基：
烷基：指直链烷基或者支链烷基；
烷氧基、苄氧基：指烷基、苄基与氧原子连结后的官能团。
上述催化剂为甲磺酸、三氟甲磺酸、三氟甲磺酰胺、三氟甲磺酸钐、三氟甲磺酸钪、三氟甲磺酸铱、三氟甲磺酸钆、樟脑磺酸、氯化锌中任意一种。
上述反应在溶剂中进行，溶剂为对该反应惰性的溶剂。溶剂为甲苯、三氯甲烷、1,2-二氯乙烷、二氯甲烷、四氢呋喃、六氟异丙醇、乙腈中任意一种。
上述4-吡咯烷靛红类化合物与苯酚类化合物的摩尔比为1:3；上述催化剂的用量为20mol％；上述溶剂的用量为每摩尔4-吡咯烷靛红类化合物添加20L溶剂。
上述反应的反应温度为80℃-120℃，上述反应在纯N2气氛、纯O2气氛或空气气氛中进行。
本发明涉及的化合物可以以一种或者多种立体异构体的形式存在。各种异构体包括对映异构体、非对映异构体、几何异构体。这些异构体包括这些异构体的混合物均在本发明的保护范围内。
本发明提供了一种上述式Ⅰ或式Ⅱ所示基于靛红骨架的苯并[b,e]氮杂卓化合物的用途，用于制备一种制剂或药物，所述制剂或药物用于
(1)抑制或杀灭白色念珠菌；
(2)治疗由白色念珠菌引起的感染性疾病；
(3)抑制或杀灭海洋污损菌；
(4)治理由海洋污损菌形成的生物污损层。
本发明还提供了一种含有上述式Ⅰ或式Ⅱ所示基于靛红骨架的苯并[b,e]氮杂卓化合物的制剂，所述制剂含有药学上可接受的载体或助剂。
本发明的技术方案取得了如下有益效果：在路易斯酸的协助下，4-吡咯烷基靛红经过[1,5]-氢迁移形成两性离子中间体，随后进行分子间Pictet-Spengler反应，生成的3-羟基靛红衍生物迅速被氧化；吡咯环的氮作为路易斯碱，与路易斯酸结合，作为离去基团离去，形成了邻亚甲基苯醌这种瞬态活性中间体，最后邻亚甲基苯醌通过亲核加成生成最终产物苯并[b，e]氮杂卓。
靛红及其衍生物具有多种生物活性，其在抗肿瘤、抗病毒、神经保护等方面的活性非常有意义。苯并杂卓是一类具有多种生理和药理活性的七元杂环化合物，在新药开发中占有中药的地位，其中某些化合物已经作为药物应用于临床，例如用于治疗精神疾病的奥氮平、阿普唑仑和卡马西平以及治疗心血管疾病的地儿硫卓等，临床效果很好。本发明提供的苯并[b,e]氮杂卓化合物具有的独特结构，是具有良好应用价值的抗真菌和细菌的先导化合物，用于治疗细菌感染引起的疾病，以及海洋生物污损的治理领域。
本发明还发展了一种路易斯酸催化的吡咯烷扩环合成苯并[b,e]氮杂卓的合成方法。利用4-吡咯烷靛红和多种苯酚化合物作为底物，利用一步法合成复杂结构的多环胺。扩展了吡咯烷合成多元杂环化合物的合成策略。并且该方法反应底物吡咯烷衍生物方便易得，底物普适性好，底物取代基可以是吸电子基或供电子基，且取代基的位置对反应产率没有明显的影响。操作方便，经济高效；反应活性较高，原料转化完全；产物分离方便，且反应具有绿色经济性，对环境友好。
具体实施方式
通过以下实施例提供的具体实施方案，对本发明的上述内容进行进一步详细说明，对于本研究领域的技术人员而言，不应将此理解为本发明上述主题的范围仅限于以下实例；凡基于本发明上述内容所实现的技术均属于本发明的范围。
下面实施例中所使用的实验方法如无特殊说明，均为常规方法；下述实施例中所用的试剂、材料、仪器等，如无特殊说明，均可从商业途径得到。
实施例1
取0.1mmol的1-苄基-4-吡咯烷基靛红于反应瓶中，依次加入2mL溶剂，向瓶中竖直滴入0.3mmol对甲基苯酚，最后再加入催化剂。控制体系温度，持续搅拌，通过薄层色谱板点样跟踪反应至原料反应完全。
待反应完成后，使用硅胶柱进行分离纯化，将纯化后的产品旋蒸得目标产物。
利用上述反应式，设立19组平行试验组，使用不同的催化剂、溶剂和反应时间。催化剂分别为甲磺酸MsOH、三氟甲磺酸TfOH、三氟甲磺酰胺Tf2NH、三氟甲磺酸钐Sm(OTf)3、三氟甲磺酸钪Sc(OTf)3、三氟甲磺酸铱Y(OTf)3、三氟甲磺酸钆Gd(OTf)3、樟脑磺酸(+)-CSA、氯化锌ZnCl2。溶剂分别为甲苯、三氯甲烷、1,2-二氯乙烷DCE、二氯甲烷DCM、四氢呋喃THF、六氟异丙醇HFIP、乙腈MeCN。试验组具体使用的催化剂、溶剂种类和浓度如表1所示：
表1.1-苄基-4-吡咯烷基靛红与对甲基苯酚反应产率表
注：产率为分离产率；第18组中在纯N2气氛下进行反应，第19组在纯O2气氛下进行反应。
根据以上平行试验结果分析，
下列实施例2-17中，按照实施例1的操作步骤，反应体系中，原料4-吡咯烷靛红与苯酚类化合物分别为0.1mmol、0.3mmol，在0.02mmol三氟甲磺酸钪催化下，以2mL DCE作溶剂，在100℃温度下持续搅拌反应至原料反应完全。
实施例2
原料：1-苄基-4-吡咯烷基靛红，对甲基苯酚
产物：化学式：C26H25N2O3
分子量：412.49
结构式：
产率：59％
1H NMR(500MHz,CDCl3)δ7.52(s,1H),7.40–7.16(m,5H),6.97–6.85(m,2H),6.72(d,J＝8.0Hz,1H),6.54(d,J＝7.7Hz,1H),5.76(d,J＝7.7Hz,1H),5.28(s,1H),4.77(q,J＝15.6Hz,2H),4.58(dd,J＝10.5,2.3Hz,1H),3.74(ddd,J＝12.8,7.8,3.5Hz,1H),3.46–3.31(m,1H),2.45(ddd,J＝16.4,12.2,5.9Hz,1H),2.25(s,3H),2.13–2.04(m,1H),2.04–1.90(m,2H)；13C NMR(125MHz,CDCl3)δ181.43,160.84,152.20,150.95,147.20,139.31,135.57,130.15,130.07,129.48,128.80,128.29,127.83,127.53,127.39,115.91,103.65,98.72,44.11,43.88,40.30,31.02,27.17,20.71.
实施例3
原料：1-(4-甲基苄基)-4-吡咯烷基靛红，对甲基苯酚
产物：化学式：C27H26N2O3
分子量：426.52
结构式：
产率：45％
1H NMR(500MHz,CDCl3)δ7.51(s,1H),7.15(d,J＝7.5Hz,2H),7.09(d,J＝7.5Hz,2H),6.93(d,J＝7.9Hz,1H),6.89(s,1H),6.70(d,J＝8.0Hz,1H),6.54(d,J＝7.6Hz,1H),5.78(d,J＝7.6Hz,1H),5.05(s,1H),4.81–4.66(m,2H),4.57(d,J＝10.2Hz,1H),3.81–3.66(m,1H),3.47–3.33(m,1H),2.44(dd,J＝19.5,8.7Hz,1H),2.29(s,3H),2.25(s,3H),2.13–2.04(m,1H),1.97(s,2H)；13C NMR(125MHz,CDCl3)δ181.59,160.80,152.16,150.90,147.30,139.30,137.60,132.54,130.19,130.13,129.48,128.30,127.57,127.24,115.86,103.65,98.79,44.12,43.64,40.31,30.98,27.15,21.12,20.74.
实施例4
原料：1-苯基-4-吡咯烷基靛红，对甲基苯酚
产物：化学式：C25H22N2O3
分子量：398.46
结构式：
产率：52％
1H NMR(500MHz,CDCl3)δ7.68(s,1H),7.46(t,J＝7.5Hz,2H),7.36(d,J＝7.6Hz,3H),6.94(d,J＝8.2Hz,2H),6.70(d,J＝7.8Hz,1H),6.63(d,J＝7.7Hz,1H),5.88(d,J＝7.7Hz,1H),4.90(s,1H),4.62(d,J＝10.0Hz,1H),3.84–3.69(m,1H),3.46(dd,J＝13.6,5.0Hz,1H),2.61–2.44(m,1H),2.26(s,3H),2.17–1.94(m,3H)；13C NMR(125MHz,CDCl3)δ180.97,159.92,152.46,150.84,147.96,139.46,133.43,130.24,129.53,128.32,128.17,127.34,126.06,115.78,103.75,99.12,44.21,40.55,30.84,27.07,20.74.
实施例5
原料：1-甲基-4-吡咯烷基靛红，对甲基苯酚
产物：化学式：C20H20N2O3
分子量：336.39
结构式：
产率：69％
1H NMR(500MHz,CDCl3)δ7.45(s,1H),7.03–6.88(m,2H),6.78(d,J＝8.0Hz,1H),6.65(d,J＝7.5Hz,1H),5.84(d,J＝7.5Hz,1H),5.61(s,1H),5.30(s,2H),4.62(d,J＝10.2Hz,1H),3.85–3.64(m,1H),3.40(dd,J＝13.3,4.9Hz,1H),3.09(s,3H),2.58–2.41(m,1H),2.27(s,3H),2.17–1.90(m,3H)；13C NMR(125MHz,CDCl3)δ181.83,160.79,152.01,150.84,148.26,139.34,130.26,130.23,129.61,128.32,127.23,115.82,103.41,97.64,77.29,77.03,76.78,44.20,40.65,30.90,27.06,26.04,20.76.
实施例6
原料：1-乙基-4-吡咯烷基靛红，对甲基苯酚
产物：化学式：C21H22N2O3
分子量：350.42
结构式：
产率：56％
1H NMR(500MHz,DMSO)δ9.21(s,1H),7.56(s,1H),6.92(d,J＝9.0Hz,2H),6.78(d,J＝7.9Hz,1H),6.62(d,J＝7.7Hz,1H),6.17(d,J＝7.7Hz,1H),4.64(d,J＝9.2Hz,1H),3.68(dd,J＝9.7,3.4Hz,1H),3.63(dd,J＝14.4,7.2Hz,2H),3.51(dd,J＝13.8,4.1Hz,1H),2.53–2.43(m,1H),2.23(s,3H),1.94(ddd,J＝15.0,8.9,5.4Hz,2H),1.86(dd,J＝12.7,8.5Hz,1H),1.17(t,J＝7.1Hz,3H)；13C NMR(125MHz,DMSO)δ181.94,160.09,152.73,152.06,147.08,139.51,130.27,130.19,128.17,127.75,115.53,103.14,98.16,55.39,43.85,34.61,30.78,27.09,20.88,13.48.
实施例7
原料：1-环丙基-4-吡咯烷基靛红，对甲基苯酚
产物：化学式：C22H22N2O3
分子量：362.43
结构式：
产率：49％
1H NMR(500MHz,CDCl3)δ7.46(s,1H),7.01–6.89(m,2H),6.71(t,J＝8.6Hz,2H),6.16(d,J＝7.7Hz,1H),4.85(s,1H),4.59(d,J＝9.8Hz,1H),3.76–3.65(m,1H),3.41(dd,J＝13.6,5.3Hz,1H),2.58(s,1H),2.49(dt,J＝15.6,5.9Hz,1H),2.28(s,3H),2.10(dd,J＝13.0,7.3Hz,1H),1.98(d,J＝5.2Hz,2H),0.98(d,J＝6.0Hz,2H),0.88(s,2H),0.85(d,J＝6.8Hz,1H)；13C NMR(125MHz,CDCl3)δ181.85,161.23,151.84,150.85,148.62,139.52,130.29,130.22,129.65,128.31,126.78,115.84,103.59,99.04,44.26,40.72,30.97,29.72,27.10,21.93,20.76,5.94,0.02.
实施例8
原料：1-烯丙基-4-吡咯烷基靛红，对甲基苯酚
产物：化学式：C22H22N2O3
分子量：362.43
结构式：
产率：56％
1H NMR(500MHz,CDCl3)δ7.51(s,1H),7.00–6.90(m,2H),6.73(d,J＝8.0Hz,1H),6.64(d,J＝7.7Hz,1H),5.88(d,J＝7.7Hz,1H),5.78(ddd,J＝22.5,10.6,5.5Hz,1H),5.21(dd,J＝19.3,13.9Hz,2H),5.08(s,1H),4.60(dd,J＝10.4,2.5Hz,1H),4.23(d,J＝5.3Hz,2H),3.74(ddd,J＝12.8,8.0,3.7Hz,1H),3.42(ddd,J＝13.7,10.0,5.8Hz,1H),2.49(ddd,J＝16.3,12.1,6.0Hz,1H),2.27(s,3H),2.16–2.07(m,1H),2.03–1.90(m,2H)；13C NMR(125MHz,CDCl3)δ181.55,160.46,152.19,150.94,147.36,139.38,131.35,130.21,130.12,129.52,128.31,127.22,118.05,115.87,103.59,98.58,44.18,42.41,40.45,30.95,27.11,20.76.
实施例9
原料：1-苄基-4-(1-全氢异吲哚基)靛红，对甲基苯酚
产物：化学式：C30H30N2O3
分子量：466.58
结构式：
产率：63％
1H NMR(500MHz,CDCl3)δ7.44(d,J＝7.1Hz,1H),7.31–7.22(m,6H),7.03(s,1H),6.94(d,J＝8.1Hz,1H),6.70(d,J＝8.1Hz,1H),6.51(d,J＝7.7Hz,1H),5.72(d,J＝7.7Hz,1H),5.02(s,1H),4.75(q,J＝15.6Hz,2H),4.18(d,J＝10.4Hz,1H),4.04–3.94(m,1H),3.13(dd,J＝13.7,7.9Hz,1H),2.38(d,J＝5.6Hz,2H),2.30(s,3H),1.72(d,J＝12.5Hz,1H),1.58(d,J＝4.2Hz,3H),1.50(d,J＝9.7Hz,1H),1.13(dd,J＝20.0,12.0Hz,3H)；13C NMR(125MHz,CDCl3)δ181.39,160.95,151.66,151.41,147.07,138.20,135.62,130.18,129.96,128.79,128.34,127.81,127.54,126.49,125.70,116.32,103.51,98.38,46.45,43.83,41.15,37.05,32.26,29.20,25.53,22.20,20.83.
实施例10
原料：1-苄基-4-吡咯烷基靛红，1,4-苯二酚
产物：化学式：C25H22N2O4
分子量：414.46
结构式：
产率：40％
1H NMR(500MHz,DMSO)δ8.68(s,1H),8.58(s,1H),7.54(s,1H),7.32(d,J＝2.9Hz,4H),7.26(d,J＝3.6Hz,1H),6.66–6.52(m,3H),6.45(d,J＝8.5Hz,1H),6.41(s,1H),6.03(d,J＝7.6Hz,1H),4.78(s,2H),4.52(d,J＝9.2Hz,1H),3.57(d,J＝8.0Hz,1H),3.54–3.42(m,3H),2.37(d,J＝5.0Hz,1H),1.86(t,J＝13.8Hz,2H),1.77(s,1H)；13C NMR(125MHz,DMSO)δ181.46,160.56,152.16,150.15,147.37,147.22,139.86,136.80,131.13,129.12,127.96,127.93,127.88,116.54,116.22,114.03,103.32,98.82,44.04,43.27,30.57,26.86.
实施例11
原料：1-苄基-4-吡咯烷基靛红，4-苄氧基苯酚
产物：化学式：C32H28N2O4
分子量：504.59
结构式：
产率：42％
1H NMR(500MHz,CDCl3)δ7.41(s,1H),7.38–7.11(m,10H),6.67(s,2H),6.64(s,1H),6.49(d,J＝7.4Hz,1H),5.70(d,J＝7.3Hz,1H),4.89(s,2H),4.80(s,1H),4.72(s,2H),4.49(d,J＝9.8Hz,1H),3.56(s,1H),3.29(d,J＝9.9Hz,1H),2.34(s,1H),1.98(d,J＝8.6Hz,1H),1.86(s,2H)；13C NMR(125MHz,CDCl3)δ180.44,159.75,151.83,151.15,146.33,146.16,138.49,136.07,134.50,129.95,127.81,127.52,126.88,126.84,126.48,126.44,125.91,115.96,115.53,112.59,102.66,97.76,69.66,43.20,42.84,39.67,29.70,25.82.
实施例12
原料：1-苄基-4-吡咯烷基靛红，4-异丙基苯酚
产物：化学式：C28H28N2O3
分子量：440.54
结构式：
产率：46％
1H NMR(500MHz,CDCl3)δ7.54(s,1H),7.34–7.20(m,5H),7.00(dd,J＝8.2,2.2Hz,1H),6.95(d,J＝2.1Hz,1H),6.72(d,J＝8.2Hz,1H),6.54(d,J＝7.7Hz,1H),5.78(d,J＝7.7Hz,1H),4.83(s,1H),4.79(d,J＝5.8Hz,1H),4.59(dd,J＝10.6,2.7Hz,1H),3.77(ddt,J＝12.8,8.9,3.6Hz,1H),3.41(dtd,J＝13.9,5.9,3.9Hz,1H),2.82(dt,J＝13.8,6.9Hz,1H),2.52–2.39(m,1H),2.10(dtd,J＝10.4,7.4,3.0Hz,1H),1.19(dd,J＝6.9,2.7Hz,6H)；13C NMR(125MHz,CDCl3)δ181.53,160.79,152.11,150.98,147.28,141.51,139.14,135.57,129.31,128.80,127.82,127.78,127.49,127.19,125.44,115.75,103.66,98.70,44.12,43.86,40.56,33.42,31.02,27.20,24.34,24.20,1.04.
实施例13
原料：1-苄基-4-吡咯烷基靛红，2,6-二异丙基苯酚
产物：化学式：C31H34N2O3
分子量：482.62
结构式：
产率：78％
1H NMR(500MHz,CDCl3)δ7.55(s,1H),7.39–7.19(m,6H),6.82(s,2H),6.57(d,J＝7.7Hz,1H),5.79(d,J＝7.7Hz,1H),4.88(d,J＝15.8Hz,1H),4.81–4.69(m,2H),4.24(dd,J＝9.8,2.6Hz,1H),3.60(ddd,J＝18.0,10.1,5.9Hz,1H),3.35(dq,J＝13.9,5.4Hz,1H),3.14(tt,J＝13.7,6.8Hz,2H),2.37(ddd,J＝15.6,11.6,5.8Hz,1H),2.16(dtd,J＝10.8,7.9,2.9Hz,1H),2.01–1.88(m,2H),1.27–1.17(m,12H)；13C NMR(125MHz,CDCl3)δ181.53,160.86,152.17,148.50,147.19,140.47,135.66,135.59,133.80,128.85,128.79,128.31,127.78,127.45,127.37,123.35,103.52,98.41,46.05,43.88,43.83,31.73,27.35,26.70,22.78.
实施例14
原料：1-乙基-4-吡咯烷基靛红，2,6-二异丙基苯酚
产物：化学式：C26H32N2O3
分子量：420.55
结构式：
产率：55％
1H NMR(500MHz,CDCl3)δ7.51(s,1H),6.87(s,2H),6.68(d,J＝7.7Hz,1H),5.91(d,J＝7.7Hz,1H),4.76(s,1H),4.28(dd,J＝9.6,2.5Hz,1H),3.69(tq,J＝14.2,7.3Hz,2H),3.58(ddd,J＝11.4,10.1,5.7Hz,1H),3.35(dq,J＝13.9,5.5Hz,1H),3.17(dq,J＝13.7,6.8Hz,2H),2.40(tt,J＝9.9,5.8Hz,1H),2.19(dtd,J＝10.6,7.9,2.9Hz,1H),2.02–1.91(m,2H),1.24(dt,J＝8.6,4.3Hz,16H)；13C NMR(125MHz,CDCl3)δ182.08,160.44,152.22,148.47,147.21,140.49,135.72,133.80,128.10,123.34,103.35,97.46,46.06,43.81,34.77,31.65,27.35,26.67,22.82,13.23.
实施例15
原料：1-环丙基-4-吡咯烷基靛红，2,6-二异丙基苯酚
产物：化学式：C27H32N2O3
分子量：432.56
结构式：
产率：65％
1H NMR(500MHz,CDCl3)δ7.48(s,1H),6.86(s,2H),6.70(d,J＝7.7Hz,1H),6.17(d,J＝7.7Hz,1H),4.76(s,1H),4.28(dd,J＝9.6,2.5Hz,1H),3.57(ddd,J＝11.6,10.0,5.5Hz,1H),3.38–3.27(m,1H),3.16(dt,J＝13.7,6.8Hz,2H),2.66–2.55(m,1H),2.40(tt,J＝9.9,5.8Hz,1H),2.18(dtd,J＝10.6,7.9,3.0Hz,1H),2.00–1.88(m,2H),1.25(dd,J＝6.8,4.8Hz,13H),0.98(t,J＝7.4Hz,2H),0.93–0.84(m,2H)；13C NMR(125MHz,CDCl3)δ181.81,161.32,151.87,148.47,148.42,140.68,135.78,133.79,127.90,123.34,103.35,98.65,46.06,43.83,31.64,27.35,26.68,22.83,21.93,5.95,5.93.
实施例16
原料：1-环丙基亚甲基-4-吡咯烷基靛红，2,6-二异丙基苯酚
产物：化学式：C28H34N2O3
分子量：446.59
结构式：
产率：74％
1H NMR(500MHz,CDCl3)δ7.53(s,1H),6.87(s,2H),6.68(d,J＝7.6Hz,1H),5.96(d,J＝7.6Hz,1H),4.76(s,1H),4.28(d,J＝8.7Hz,1H),3.59(dd,J＝13.5,4.8Hz,1H),3.56–3.45(m,2H),3.35(dd,J＝13.7,5.6Hz,1H),3.16(dt,J＝13.4,6.7Hz,2H),2.40(dt,J＝14.7,7.3Hz,1H),2.26–2.14(m,1H),2.02–1.92(m,2H),1.61(s,1H),1.35–1.17(m,14H),0.51(d,J＝7.5Hz,2H),0.36(d,J＝4.2Hz,2H)；13C NMR(125MHz,CDCl3)δ182.06,160.80,152.20,148.48,147.80,140.48,135.73,133.80,128.06,123.36,103.36,97.79,46.07,44.41,43.83,31.70,27.35,26.69,22.82,9.97,4.02,3.93.
实施例17
原料：1-烯丙基-4-吡咯烷基靛红，2,6-二异丙基苯酚
产物：化学式：C27H32N2O3
分子量：432.56
结构式：
产率：43％
1H NMR(500MHz,CDCl3)δ7.53(s,1H),7.53(s,1H),6.86(s,2H),6.86(s,2H),6.65(d,J＝7.7Hz,1H),6.65(d,J＝7.7Hz,1H),5.90(d,J＝7.7Hz,1H),5.90(d,J＝7.7Hz,1H),5.81(ddd,J＝22.5,10.5,5.4Hz,1H),5.81(ddd,J＝22.5,10.5,5.4Hz,1H),5.22(dd,J＝19.6,13.8Hz,2H),4.75(s,1H),4.36–4.18(m,3H),3.59(ddd,J＝16.4,10.2,5.9Hz,1H),3.35(dq,J＝13.9,5.5Hz,1H),3.21–3.08(m,2H),2.40(tt,J＝10.0,5.8Hz,1H),2.18(dtd,J＝10.7,7.9,2.9Hz,1H),1.96(dq,J＝12.2,6.0Hz,2H),1.24(dd,J＝6.8,4.1Hz,13H)；13CNMR(125MHz,CDCl3)δ181.58,160.50,152.17,148.48,147.28,140.52,135.66,133.79,131.43,128.21,123.34,117.91,103.40,98.21,46.05,43.84,42.37,31.66,27.34,26.67,22.81.
抑菌活性测定：
分别将上述实施例2、5、15、16制备得到的产物采用微量稀释法测定其对白色念珠菌Canidia Albicans和海洋污损菌，得到其最低抑菌浓度MIC(μM)值，并分别以环丙沙星(白色念珠菌)、Seanine211(海洋污损菌)的活性做对照。检测海洋污损菌为AS42(Aeromonas salmonicida)和ZJ028(Pseudomonas aeruginosa)。
具体测定方法如下：将细菌接到LB液体培养基中，25℃下，160rpm摇晃培养24h，使用时将菌液稀释到500倍。将待测化合物用二甲基亚砜DMSO溶解，初始浓度为100μmol/L，环丙沙星/Seanine211为阳性对照，DMSO为阴性对照，细菌培养液为空白对照。在96孔板中，在竖排中首先加入100μL菌液，然后第一排中加入98μL菌液和2μL浓度为100μmol/L的化合物溶液，混匀，取100μL混合液加入第二排孔中，依次取上面孔中100μL混合液加入下面一个孔，设置6-10个浓度梯度，最后将每个孔用细菌混悬液补充至200μL。每个浓度设置2个平行对照，环丙沙星/Seanine211、DMSO和细菌混悬液分别作为阳性、阴性，空白对照，25℃恒温培养24h,使用全自动酶标仪在405nm下测定吸光度数值，进而获得最低抑菌浓度值。测定结果如表2所示，表2为本发明应用实施例2、5、15、16得到的抑菌活性测试结果：
表2.实施例2、5、15、16合成化合物的抑菌活性测试结果表
实施例15合成化合物显示出较强的抗白色念珠菌、AS42及ZJ028活性，稍弱于阳性药；其他实施例所合成产品显示出抗白色念珠菌活性，它们所共有的苯并[b,e]氮杂卓化合物的独特结构，具有用作抑制细菌和真菌的药物或中间体的巨大潜力。
以上所述，仅是本发明的较佳实施例而已，并非是对本发明作其它形式的限制，任何熟悉本专业的技术人员可能利用上述揭示的技术内容加以变更或改型为等同变化的等效实施例。但是凡是未脱离本发明技术方案内容，依据本发明的技术实质对以上实施例所作的任何简单修改、等同变化与改型，仍属于本发明技术方案的保护范围。
Claims (10)
1.一种基于靛红骨架的苯并[b,e]氮杂卓化合物，其特征在于：结构如式Ⅰ所示：
式Ⅰ中，虚线表示任选的单键；
R1选自C1-C3烷基、苯基、C1-C3烷基取代苯基、苄基、环丙烷基、环丙基乙基、烯丙基任意一种；并且
R1’选自H原子或多取代苯酚。
2.根据权利要求1所述的化合物，其特征在于：结构如式Ⅱ所示：
式Ⅱ中，虚线表示任选的单键；
R1选自C1-C3烷基、苯基、C1-C3烷基取代苯基、苄基、环丙烷基、环丙基乙基、烯丙基任意一种；并且
R2、R3各自独立地选自C1-C3烷基、羟基、C1-C3烷氧基、苄氧基中任意一种。
3.一种制备权利要求1或2所述基于靛红骨架的苯并[b,e]氮杂卓化合物的合成方法，其特征在于：
4-吡咯烷靛红类化合物与苯酚类化合物，在催化剂作用下，反应生成所述基于靛红骨架的苯并[b,e]氮杂卓化合物。
4.根据权利要求3所述的合成方法，其特征在于：
所述4-吡咯烷靛红类化合物为式Ⅲ所示化合物，所述苯酚类化合物为式Ⅳ所示化合物：
式Ⅲ、式Ⅳ中，虚线表示任选的单键；
R1选自C1-C3烷基、苯基、C1-C3烷基取代苯基、苄基、环丙烷基、环丙基乙基、烯丙基任意一种；并且
R2、R3各自独立地选自C1-C3烷基、羟基、C1-C3烷氧基、苄氧基中任意一种。
5.根据权利要求4所述的合成方法，其特征在于：所述催化剂为甲磺酸、三氟甲磺酸、三氟甲磺酰胺、三氟甲磺酸钐、三氟甲磺酸钪、三氟甲磺酸铱、三氟甲磺酸钆、樟脑磺酸、氯化锌中任意一种。
6.根据权利要求5所述的合成方法，其特征在于：所述反应在溶剂中进行，溶剂为甲苯、三氯甲烷、1,2-二氯乙烷、二氯甲烷、四氢呋喃、六氟异丙醇、乙腈中任意一种。
7.根据权利要求6所述的合成方法，其特征在于：所述4-吡咯烷靛红类化合物与苯酚类化合物的摩尔比为1:3；所述催化剂的用量为20mol％；所述溶剂的用量为每摩尔4-吡咯烷靛红类化合物添加20L溶剂。
8.根据权利要求7所述的合成方法，其特征在于：所述反应温度为80℃-120℃，所述反应在纯N2气氛、纯O2气氛或空气气氛中进行。
9.权利要求1或2所述基于靛红骨架的苯并[b,e]氮杂卓化合物的用途，其特征在于：用于制备一种制剂或药物，所述制剂或药物用于
(1)抑制或杀灭白色念珠菌；
(2)治疗由白色念珠菌引起的感染性疾病；
(3)抑制或杀灭海洋污损菌；
(4)治理由海洋污损菌形成的生物污损层。
10.一种含有权利要求1或2所述基于靛红骨架的苯并[b,e]氮杂卓化合物的制剂，其特征在于：所述制剂含有药学上可接受的载体或助剂。
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| EP0529636A1 (en) * | 1991-08-28 | 1993-03-03 | Neurosearch A/S | Novel isatinoxime derivatives, their preparation and use |
| US5436250A (en) * | 1991-08-28 | 1995-07-25 | Neurosearch A/S | Isatineoxime derivatives, their preparation and use |
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