CN116903511A - 一种吡咯类生物碱衍生物及其在制备具有抗炎作用的药物中的应用 - Google Patents
一种吡咯类生物碱衍生物及其在制备具有抗炎作用的药物中的应用 Download PDFInfo
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- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/333—Radicals substituted by oxygen or sulfur atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/337—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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Abstract
本发明涉及药物化学技术领域，具体公开了一种吡咯类生物碱衍生物及其在制备具有抗炎作用的药物中的应用。所述的吡咯类生物碱衍生物，其具有式Ⅰ所示的结构。研究表明，本发明所述的吡咯类生物碱衍生物具有抗炎作用；因此，将本发明所述的吡咯类生物碱衍生物作为活性成分用于制备具有抗炎作用的药物，具有重要的应用价值。
Description
技术领域
本发明涉及药物化学技术领域，具体涉及一种吡咯类生物碱衍生物及其在制备具有抗炎作用的药物中的应用。
背景技术
生物碱是一类含氮的碱性有机化合物，有似碱的性质；大多数生物碱具有复杂的环状结构，氮素多包含在环内。目前，按照生物碱的基本结构分类，大致可分为60类左右。研究表明，不同结构类的生物碱具有的生物活性是不同的。
炎症，是机体对于刺激的一种防御反应，表现为红、肿、热、痛和功能障碍；其可以是感染引起的感染性炎症，也可以不是由于感染引起的非感染性炎症。抗炎药是用于治疗组织受到损伤后所发生的反应炎症的药物。目前，抗炎药物主要分为两类，一类是甾体抗炎药，另一类是非甾体抗炎药。如常见的抗炎药物有阿司匹林、对乙酰氨基酚、吲哚美辛、萘普生等；但是现有的抗炎药并不适用于所有的病例；并且长期服用都具有不同的副作用。因此，开发一种全新的具有抗炎作用的化合物，具有重要的应用价值。
发明内容
为了克服现有技术中存在的至少之一的技术问题，本发明首先提供了一种吡咯类生物碱衍生物。
本发明所要解决的上述技术问题，通过以下技术方案予以实现：
一种吡咯类生物碱衍生物，其具有式Ⅰ所示的结构：
其中，R1独立地选自：氢、羟基、C1-10烷氧基、C1-10烷基、C6-10芳基、5-10元杂芳基、芳氧基、卤代的C1-10烷基、C1-10烷酰基、3-10元杂环烷基、3-10元杂环烷氧基、卤素、硝基或氰基；
R2独立地选自：氢、羟基、C1-10烷氧基、C1-10烷基、C6-10芳基、5-10元杂芳基、芳氧基、卤代的C1-10烷基、C1-10烷酰基、3-10元杂环烷基、3-10元杂环烷氧基、卤素、硝基或氰基。
优选地，R1独立地选自：氢、羟基、C1-50烷氧基、C1-5烷基、C6-8芳基、5-8元杂芳基、芳氧基、卤代的C1-5烷基、C1-5烷酰基、4-8元杂环烷基、4-8元杂环烷氧基、卤素、硝基或氰基。
优选地，R2独立地选自：氢、羟基、C1-50烷氧基、C1-5烷基、C6-8芳基、5-8元杂芳基、芳氧基、卤代的C1-5烷基、C1-5烷酰基、4-8元杂环烷基、4-8元杂环烷氧基、卤素、硝基或氰基。
优选地，R1独立地选自：氢、C1-5烷氧基、C1-5烷基、芳氧基、卤代的C1-5烷基、卤素或氰基。
优选地，R2独立地选自：氢、C1-5烷氧基、C1-5烷基、芳氧基、卤代的C1-5烷基、卤素或氰基。
优选地，R1和R2中所述的C1-10烷氧基选自甲氧基。
优选地，R1和R2中所述的卤素选自氟和氯；所述的卤代的C1-10烷基选自三氟甲基。
优选地，R1和R2中所述的C1-10烷基选自甲基或叔丁基。
优选地，所述的吡咯类生物碱衍生物，选自如下任一结构的化合物：
本发明还提供了一种上述吡咯类生物碱衍生物在制备具有抗炎作用的药物中的应用。
优选地，所述的药物的剂型为片剂、胶囊剂、颗粒剂、注射剂或口服液。
有益效果：本发明提供了一种全新的吡咯类生物碱衍生物；研究表明，所述的吡咯类生物碱衍生物具有抗炎作用；因此，将本发明所述的吡咯类生物碱衍生物作为活性成分用于制备具有抗炎作用的药物，具有重要的应用价值。
发明人在进一步研究中发现，在本发明母核结构中，R1和R2被不同的取代基取代得到的吡咯类生物碱衍生物，其抗炎作用是不同的，效果的差别甚至是巨大的。发明在进一步研究中惊奇的发现，在本发明实验范围内，R1和R2被氰基取代得到的吡咯类生物碱衍生物其抗炎效果最佳，其抗炎效果要优于阳性对照药吲哚美辛；R1和R2被三氟甲基取代得到的吡咯类生物碱衍生物其抗炎效果次之，其抗炎效果和阳性对照药吲哚美辛相当；二者具有十分优异的抗炎效果，其抗炎效果要远远高于R1和R2被其它取代基取代得到的吡咯类生物碱衍生物。
附图说明
图1为本发明吡咯类生物碱衍生物的合成路径图。
具体实施方式
以下结合具体实施例来进一步解释本发明，但实施例对本发明不做任何形式的限定。
图1合成路径图的具体方法为：在氮气氛围无水乙腈中，将化合物4-32(1eq.)与碳酸钾(2.1eq.)混合，逐滴加入溴乙酸乙酯(2eq.)，然后将反应混合物在室温下搅拌18小时。加水淬灭反应，乙酸乙酯萃取。有机相用盐水洗涤，无水硫酸钠干燥，过滤，真空浓缩。所得残渣经柱层析得到化合物4-2—32-2。
实施例1
按照图1和成路径图中所示的通用方法，以化合物2(1g,4mmol)和4-甲氧基苯硼酸(1.8g,12mmol)为原料，合成化合物4。通过硅胶色谱法进行纯化(石油醚:乙酸乙酯＝12:1→8:1)，产率81％，黄色固体。TLC:Rf＝0.3(石油醚:乙酸乙酯＝4:1)。1H NMR(300MHz,DMSO)δ12.28(s,1H),9.50(s,1H),7.34(d,J＝8.8Hz,2H),7.15(d,J＝8.7Hz,2H),7.08(d,J＝2.5Hz,1H),6.91(d,J＝8.9Hz,2H),6.86(d,J＝8.8Hz,2H),3.74(d,J＝7.9Hz,6H).13C NMR(75MHz,DMSO)δ178.69(s),159.15(s),157.89(s),136.06(s),132.09(s),129.84(s),129.34(s),127.64(s),123.53(d,J＝15.3Hz),113.92(d,J＝4.2Hz),55.08(d,J＝10.6Hz).
以化合物4(257mg,0.84mmol)和溴乙酸乙酯(0.12mL,0.93mmol)为原料，合成化合物4-2。通过硅胶色谱法进行纯化(石油醚:乙酸乙酯＝12:1→8:1)，产率96％，黄色油状液体。TLC:Rf＝0.4(石油醚:乙酸乙酯＝4:1)。1H NMR(300MHz,DMSO)δ9.55(s,1H),7.36(s,1H),7.17(d,J＝8.8Hz,2H),7.05(dd,J＝12.8,8.8Hz,4H),6.79(d,J＝8.9Hz,2H),4.84(s,2H),4.11(q,J＝7.1Hz,2H),3.79(s,3H),3.69(s,3H),1.15(t,J＝7.1Hz,3H).13C NMR(75MHz,DMSO)δ179.76(s),168.39(s),159.83(s),157.75(s),139.37(s),131.74(s),131.07(s),128.43(s),126.56(s),123.76(s),121.50(s),114.53(s),113.84(s),61.02(s),55.05(d,J＝16.4Hz),47.33(s),13.97(s).
实施例2
按照图1合成路径图中所示的通用方法，以化合物2(500mg,2mmol)和4-叔丁基苯硼酸(1.01g,6mmol)为原料，合成化合物6。通过硅胶色谱法进行纯化(石油醚:乙酸乙酯＝20:1→12:1)，产率75％，浅黄色固体。TLC:Rf＝0.3(石油醚:乙酸乙酯＝6:1)。1H NMR(300MHz,DMSO)δ12.29(s,1H),9.52(s,1H),7.38(s,4H),7.32(d,J＝8.4Hz,2H),7.20(d,J＝8.3Hz,2H),7.13(d,J＝2.5Hz,1H),1.28(s,8H),1.27(s,6H).13C NMR(75MHz,DMSO)δ178.89(s),150.64(s),148.61(s),135.97(s),132.34(d,J＝2.0Hz),128.53(s),128.10(s),127.72(s),125.21(s),123.78(s),34.31(d,J＝17.1Hz),31.09(d,J＝8.4Hz).
以化合物6(300mg,0.83mmol)和溴乙酸乙酯(0.2mL,1.66mmol)为原料，合成化合物6-2。通过硅胶色谱法进行纯化(石油醚:乙酸乙酯＝12:1→8:1)，产率91％，浅黄色固体。TLC:Rf＝0.3(石油醚:乙酸乙酯＝8:1)。1H NMR(300MHz,DMSO)δ9.57(s,1H),7.51(d,J＝8.4Hz,2H),7.42(s,1H),7.21(dd,J＝8.4,7.1Hz,4H),7.09(d,J＝8.5Hz,2H),4.81(s,2H),4.09(q,J＝7.1Hz,2H),1.31(s,9H),1.22(s,9H),1.12(t,J＝7.1Hz,3H).13C NMR(75MHz,DMSO)δ179.94(s),168.27(s),151.86(s),148.50(s),139.55(s),131.18(d,J＝2.5Hz),130.07(s),126.78(d,J＝6.4Hz),125.80(s),125.11(s),123.73(s),60.96(s),47.35(s),34.54(s),34.10(s),31.01(d,J＝4.3Hz),26.33(s),13.97(s).
实施例3
按照图1合成路径图中所示的通用方法，以化合物2(500mg,2mmol)和4-苯氧基苯硼酸(1.28g,6mmol)为原料，合成化合物7。通过硅胶色谱法进行纯化(石油醚:乙酸乙酯＝20:1→12:1)，产率45％，白色固体。TLC:Rf＝0.4(石油醚:乙酸乙酯＝4:1)。1H NMR(300MHz,DMSO)δ12.41(s,1H),9.53(s,1H),7.41(t,J＝8.2Hz,6H),7.25(d,J＝8.5Hz,2H),7.15(s,3H),7.06(d,J＝8.7Hz,2H),7.02(d,J＝8.5Hz,2H),6.94(t,J＝8.7Hz,4H).13C NMR(75MHz,DMSO)δ178.97(s),156.94(s),156.47(s),155.84(s),155.32(s),135.60(s),132.36(s),130.95–129.37(m),126.03(s),124.01(s),123.40(d,J＝17.2Hz),119.30(s),118.64(d,J＝17.0Hz),117.91(s).
以化合物7(600mg,1.39mmol)和溴乙酸乙酯(0.31mL,2.78mmol)为原料，合成化合物7-2。通过硅胶色谱法进行纯化(石油醚:乙酸乙酯＝25:1→10:1)，产率50％，白色油状液体。TLC:Rf＝0.3(石油醚:乙酸乙酯＝7:1)。1H NMR(300MHz,DMSO)δ9.58(s,1H),7.43(s,1H),7.38(dd,J＝14.2,7.7Hz,4H),7.26(d,J＝8.7Hz,2H),7.16(dd,J＝13.3,4.5Hz,4H),7.08(dd,J＝8.1,4.4Hz,4H),6.99(d,J＝7.6Hz,2H),6.87(d,J＝8.7Hz,2H),4.89(s,2H),4.11(q,J＝7.1Hz,2H),1.15(t,J＝7.1Hz,3H).13C NMR(75MHz,DMSO)δ180.04(s),168.32(s),157.78(s),156.35(s),155.67(s),155.26(s),139.05(s),132.28(s),131.26(s),130.12(d,J＝11.8Hz),129.23(s),128.87(s),124.09(d,J＝13.7Hz),123.51(d,J＝9.5Hz),119.37(s),118.82(s),118.44(d,J＝13.6Hz),61.07(s),47.44(s),13.99(s).
实施例4
按照图1合成路径图中所示的通用方法，以化合物2(1.5g,6mmol)和4-甲基苯硼酸(12.45g,18mmol)为原料，合成化合物8。通过硅胶色谱法进行纯化(石油醚:乙酸乙酯＝25:1→12:1)，产率49％，白色固体。TLC:Rf＝0.4(石油醚:乙酸乙酯＝5:1)。1H NMR(300MHz,DMSO)δ12.36(s,1H),9.52(s,1H),7.29(d,J＝8.0Hz,2H),7.11(dt,J＝12.5,8.1Hz,7H),2.28(d,J＝7.6Hz,6H).13C NMR(75MHz,DMSO)δ178.95(s),137.62(s),136.26(s),135.45(s),132.35(s),129.05(d,J＝5.3Hz),128.42(s),128.08(s),123.92(s),20.78(d,J＝10.1Hz).
以化合物8(600mg,2.18mmol)和溴乙酸乙酯(0.5mL,4.36mmol)为原料，合成化合物8-2。通过硅胶色谱法进行纯化(石油醚:乙酸乙酯＝16:1→12:1)，产率81％，白色固体。TLC:Rf＝0.4(石油醚:乙酸乙酯＝8:1)。1H NMR(300MHz,DMSO)δ9.56(s,1H),7.40(s,1H),7.27(d,J＝7.9Hz,2H),7.12(d,J＝8.1Hz,2H),7.01(s,4H),4.83(s,2H),4.10(q,J＝7.1Hz,2H),2.35(s,3H),2.21(s,3H),1.14(t,J＝7.1Hz,3H).13C NMR(75MHz,DMSO)δ179.96(s),168.35(s),139.71(s),138.93(s),135.39(s),131.24(d,J＝0.8Hz),130.21(s),129.69(s),128.99(s),127.26(s),126.63(s),123.97(s),61.06(s),47.40(s),20.94(s),20.59(s),14.00(s).
实施例5
按照图1合成路径图中所示的通用方法，以化合物2(1.5g,5.9mmol)和4-三氟甲基苯硼酸(3.38g,17.8mmol)为原料，合成化合物9。通过硅胶色谱法进行纯化(石油醚:乙酸乙酯＝20:1→6:1)，产率44％，黄色固体。TLC:Rf＝0.3(石油醚:乙酸乙酯＝5:1)。1H NMR(300MHz,DMSO)δ12.79(s,1H),9.62(s,1H),7.75(d,J＝8.2Hz,2H),7.67(d,J＝8.2Hz,2H),7.60(d,J＝8.1Hz,2H),7.45(d,J＝8.0Hz,2H),7.31(d,J＝2.2Hz,1H).13C NMR(75MHz,DMSO)δ179.82(s),139.02(d,J＝1.4Hz),134.80(d,J＝1.4Hz),133.42(d,J＝0.6Hz),129.42(s),128.76(d,J＝3.7Hz),127.20(s),126.78(s),126.04(d,J＝16.8Hz),125.76–125.28(m),123.42(s),122.43(d,J＝17.1Hz).
以化合物9(300mg,0.78mmol)和溴乙酸乙酯(0.17mL,1.56mmol)为原料，合成化合物9-2。通过硅胶色谱法进行纯化(石油醚:乙酸乙酯＝12:1→8:1)，产率83％，白色固体。TLC:Rf＝0.3(石油醚:乙酸乙酯＝4:1)。1H NMR(300MHz,DMSO)δ9.66(s,1H),7.87(d,J＝8.1Hz,2H),7.60(t,J＝4.1Hz,3H),7.51(d,J＝8.0Hz,2H),7.32(d,J＝8.1Hz,2H),4.93(s,2H),4.10(q,J＝7.1Hz,2H),1.13(t,J＝7.1Hz,3H).13C NMR(75MHz,DMSO)δ180.67(s),168.15(s),138.44(s),137.97(d,J＝1.4Hz),133.33(d,J＝1.4Hz),132.02(s),131.46(s),130.04(s),129.61(s),128.08(s),127.07(s),126.65(s),126.46–125.91(m),125.90–125.24(m),123.56(s),123.08(s),122.44(s),122.16(s),61.20(s),47.64(s),13.91(s).
实施例6
按照图1合成路径图中所示的通用方法，以化合物2(1g,3.95mmol)和4-氟苯硼酸(1.66g,11.85mmol)为原料，合成化合物10。通过硅胶色谱法进行纯化(石油醚:乙酸乙酯＝20:1→8:1)，产率86％，黄色固体。TLC:Rf＝0.3(石油醚:乙酸乙酯＝4:1)。1H NMR(300MHz,DMSO)δ12.50(s,1H),9.54(s,1H),7.41(dd,J＝8.9,5.5Hz,2H),7.25(d,J＝5.6Hz,2H),7.23–7.18(m,2H),7.18–7.15(m,2H),7.13–7.10(m,1H).13C NMR(75MHz,DMSO)δ179.22(s),163.60(s),162.64(s),160.34(s),135.19(s),132.51(s),131.40(d,J＝3.2Hz),130.80(d,J＝8.4Hz),130.08(d,J＝8.0Hz),127.49(d,J＝3.3Hz),123.08(s),115.47(dd,J＝21.5,7.3Hz).
以化合物10(920mg,3.25mmol)和溴乙酸乙酯(0.72mL,6.5mmol)为原料，合成化合物10-2。通过硅胶色谱法进行纯化(石油醚:乙酸乙酯＝20:1→10:1)，产率80％，浅黄色固体。TLC:Rf＝0.5(石油醚:乙酸乙酯＝4:1)。1H NMR(300MHz,DMSO)δ9.59(s,1H),7.44(s,1H),7.33(d,J＝3.7Hz,2H),7.30(d,J＝1.2Hz,2H),7.14(dd,J＝9.0,5.6Hz,2H),7.07(t,J＝8.9Hz,2H),4.88(s,2H),4.10(q,J＝7.1Hz,2H),1.14(t,J＝7.1Hz,3H).13C NMR(75MHz,DMSO)δ180.20(s),168.23(s),164.22(s),162.46(s),160.94(s),159.23(s),138.57(s),132.78(d,J＝8.7Hz),131.33(s),130.35(d,J＝3.1Hz),129.24(d,J＝8.1Hz),125.64(d,J＝3.3Hz),123.24(s),116.42(s),116.14(s),115.43(s),115.14(s),61.08(s),47.38(s),13.92(s).
实施例7
按照图1合成路径图中所示的通用方法，以化合物2(500mg,2mmol)和4-氰基苯硼酸(882mg,6mmol)为原料，合成化合物14。通过硅胶色谱法进行纯化(石油醚:乙酸乙酯＝10:1→2:1)，产率49％，黄色固体。TLC:Rf＝0.2(石油醚:乙酸乙酯＝2:1)。1H NMR(300MHz,DMSO)δ12.85(s,1H),9.62(s,1H),7.86(d,J＝8.3Hz,2H),7.78(d,J＝8.3Hz,2H),7.55(d,J＝8.3Hz,2H),7.41(d,J＝8.3Hz,2H),7.33(d,J＝1.7Hz,1H).13C NMR(75MHz,DMSO)δ179.97(s),139.62(s),135.20(s),134.72(s),133.65(s),132.56(d,J＝8.1Hz),129.52(s),128.95(s),123.56(s),118.88(s),118.58(s),110.84(s),109.13(s).
以化合物14(100mg,0.34mmol)和溴乙酸乙酯(0.08mL,0.68mmol)为原料，合成化合物14-2。通过硅胶色谱法进行纯化(石油醚:乙酸乙酯＝8:1→2:1)，产率73％，浅黄色固体。TLC:Rf＝0.3(石油醚:乙酸乙酯＝2:1)。1H NMR(300MHz,DMSO)δ9.65(s,1H),7.99(d,J＝8.1Hz,2H),7.71(d,J＝8.2Hz,2H),7.62(s,1H),7.48(d,J＝8.1Hz,2H),7.27(d,J＝8.2Hz,2H),4.91(s,2H),4.10(q,J＝7.1Hz,2H),1.14(t,J＝7.2Hz,3H).13C NMR(75MHz,DMSO)δ180.77(s),180.77(s),168.07(s),138.45(d,J＝7.1Hz),133.80(s),133.20(s),132.54(s),132.18(s),131.52(s),128.17(s),122.93(s),118.78(s),118.35(s),112.41(s),108.95(s),61.26(s),47.67(s),13.97(s).
实施例8
按照图1合成路径图中所示的通用方法，以化合物2(800mg,3.2mmol)和4-氯苯硼酸(1.5g,9.6mmol)为原料，合成化合物15。通过硅胶色谱法进行纯化(石油醚:乙酸乙酯＝16:1→8:1)，产率60％，黄色固体。TLC:Rf＝0.3(石油醚:乙酸乙酯＝7:1)。1H NMR(300MHz,DMSO)δ12.57(s,1H),9.56(s,1H),7.46–7.31(m,6H),7.24(s,1H),7.20(d,J＝7.3Hz,2H).13C NMR(75MHz,DMSO)δ179.39(s),134.96(s),133.79(s),132.97(d,J＝16.4Hz),131.23(s),130.36(s),129.81(d,J＝11.0Hz),128.61(s),123.08(s).
以化合物15(400mg,1.27mmol)和溴乙酸乙酯(0.28mL,2.54mmol)为原料，合成化合物15-2。通过硅胶色谱法进行纯化(石油醚:乙酸乙酯＝20:1→10:1)，产率93％，白色固体。TLC:Rf＝0.5(石油醚:乙酸乙酯＝4:1)。1H NMR(300MHz,DMSO)δ9.60(s,1H),7.56(d,J＝8.4Hz,2H),7.48(s,1H),7.29(t,J＝8.7Hz,4H),7.13(d,J＝8.6Hz,2H),4.89(s,2H),4.10(q,J＝7.1Hz,2H),1.14(t,J＝7.1Hz,3H).13C NMR(75MHz,DMSO)δ180.33(s),168.20(s),138.43(s),134.47(s),132.75(s),132.26(s),131.62(s),131.10(s),129.24(d,J＝17.3Hz),128.51(s),128.03(s),123.03(s),61.14(s),47.49(s),13.95(s).
实验例吡咯类生物碱衍生物抗炎实验
取小鼠单核巨噬细胞白血病细胞(RAW264.7)，以按照每孔1×104个的添加量加入到96孔板中，放入37℃含5％CO2的培养箱中培养24h；然后加入倍比稀释的不同浓度的含待测药物溶液，继续培养1h后，加入的LPS溶液，使得其终浓度为500ng/mL，继续培养24h后每孔取100μL上清液放入新的96孔板中，接着每孔加入浓度为50mg/L的Griess试剂，混匀后用酶标仪测定540nm波长下每孔的吸光度；计算NO抑制率；并绘制化合物浓度—抑制率曲线图；进一步计算吡咯类生物碱衍生物对小鼠单核巨噬细胞白血病细胞产生NO的IC50值；测试结果见表1。
待测药物为实施例1～8制备得到的吡咯类生物碱衍生物。阳性对照组的加入药物为吲哚美辛，阴性对照组加入的为DMSO。
NO抑制率(％)＝(A2-A1)/(A2-A0)×100％；其中，A0、A1、A2分别为空白对照组(不加LPS)、实验组、阴性对照组的吸光值。
表1.吡咯类生物碱衍生物抗炎实验结果
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从表1实验数据可以看出，本发明所述的吡咯类生物碱衍生物均显示出一定的抗炎作用；只不过，在本发明母核结构中，R1和R2被不同取代基取代后得到的吡咯类生物碱衍生物，其抗炎作用是不同的，差别甚至是巨大的。上述实验数据表明：R1和R2被氰基取代得到的吡咯类生物碱衍生物(实施例7制备得到的吡咯类生物碱衍生物)其抗炎效果最佳，其抗炎效果要显著优于阳性对照药吲哚美辛；R1和R2被三氟甲基取代得到的吡咯类生物碱衍生物(实施例5制备得到的吡咯类生物碱衍生物)其抗炎效果次之，其抗炎效果和阳性对照药吲哚美辛相当；二者具有十分优异的抗炎效果，其抗炎效果要远远高于R1和R2被其它取代基取代得到的吡咯类生物碱衍生物。
Claims (10)
1.一种吡咯类生物碱衍生物，其特征在于，具有式Ⅰ所示的结构：
其中，R1独立地选自：氢、羟基、C1-10烷氧基、C1-10烷基、C6-10芳基、5-10元杂芳基、芳氧基、卤代的C1-10烷基、C1-10烷酰基、3-10元杂环烷基、3-10元杂环烷氧基、卤素、硝基或氰基；
R2独立地选自：氢、羟基、C1-10烷氧基、C1-10烷基、C6-10芳基、5-10元杂芳基、芳氧基、卤代的C1-10烷基、C1-10烷酰基、3-10元杂环烷基、3-10元杂环烷氧基、卤素、硝基或氰基。
2.根据权利要求1所述的吡咯类生物碱衍生物，其特征在于，R1独立地选自：氢、羟基、C1-50烷氧基、C1-5烷基、C6-8芳基、5-8元杂芳基、芳氧基、卤代的C1-5烷基、C1-5烷酰基、4-8元杂环烷基、4-8元杂环烷氧基、卤素、硝基或氰基。
3.根据权利要求1所述的吡咯类生物碱衍生物，其特征在于，R2独立地选自：氢、羟基、C1-50烷氧基、C1-5烷基、C6-8芳基、5-8元杂芳基、芳氧基、卤代的C1-5烷基、C1-5烷酰基、4-8元杂环烷基、4-8元杂环烷氧基、卤素、硝基或氰基。
4.根据权利要求1所述的吡咯类生物碱衍生物，其特征在于，R1独立地选自：氢、C1-5烷氧基、C1-5烷基、芳氧基、卤代的C1-5烷基、卤素或氰基。
5.根据权利要求1所述的吡咯类生物碱衍生物，其特征在于，R2独立地选自：氢、C1-5烷氧基、C1-5烷基、芳氧基、卤代的C1-5烷基、卤素或氰基。
6.根据权利要求1所述的吡咯类生物碱衍生物，其特征在于，R1和R2中所述的C1-10烷氧基选自甲氧基。
7.根据权利要求1所述的吡咯类生物碱衍生物，其特征在于，R1和R2中所述的卤素选自氟和氯；所述的卤代的C1-10烷基选自三氟甲基。
8.根据权利要求1所述的吡咯类生物碱衍生物，其特征在于，R1和R2中所述的C1-10烷基选自甲基或叔丁基。
9.根据权利要求1所述的吡咯类生物碱衍生物，其特征在于，选自如下任一结构的化合物：
10.权利要求1～9任一项所述的吡咯类生物碱衍生物在制备具有抗炎作用的药物中的应用。
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