CN116730994A - 一种泽兰林素7位磺酰化衍生物的制备方法 - Google Patents
一种泽兰林素7位磺酰化衍生物的制备方法 Download PDFInfo
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- KLAOKWJLUQKWIF-UHFFFAOYSA-N eupatorin Chemical compound C1=C(O)C(OC)=CC=C1C1=CC(=O)C2=C(O)C(OC)=C(OC)C=C2O1 KLAOKWJLUQKWIF-UHFFFAOYSA-N 0.000 claims abstract description 12
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- 238000005694 sulfonylation reaction Methods 0.000 claims abstract description 12
- DTPRTOXMYKYSIJ-UHFFFAOYSA-N eupatorin Natural products C1=C(O)C(OC)=CC=C1C1=CC(=O)C2=CC(OC)=C(OC)C=C2O1 DTPRTOXMYKYSIJ-UHFFFAOYSA-N 0.000 claims abstract description 10
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- 238000006243 chemical reaction Methods 0.000 claims description 10
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- 238000000034 method Methods 0.000 claims description 6
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- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 3
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- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
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- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
本发明涉及一种泽兰林素7位磺酰化衍生物的制备方法，包括如下步骤：有机溶剂中，泽兰林素与磺酰氯
Description
技术领域
本发明属于药物化学领域，具体涉及一种泽兰林素7位磺酰化衍生物的制备方法。
背景技术
泽兰林素是韩国Estee East制药研发的一种治疗胃炎和消化性溃疡的药物。本发明通过对其7位羟基进行磺酰化修饰获得了系列7位磺酰化衍生物，黄酮结构是泽兰林素发挥药理作用的骨架，本发明在7位引入芳环(或杂芳环)磺酰基药效团，显著增强了泽兰林素的抗炎活性。本发明提供上述泽兰林素7位磺酰化衍生物的制备方法。
发明内容
本发明提供一种式I结构的泽兰林素7位磺酰化衍生物的制备方法，其特征在于包括如下步骤：
有机溶剂中，泽兰林素与磺酰氯反应，得到式I结构的泽兰林素7位磺酰化衍生物；其中A环选自任选被一个或多个R1取代的5-6元杂环基或6-10元芳基；所述R1选自C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、卤素、硝基、氰基、氨基、羟基、C1-C6烷氧羰基。
所述有机溶剂优选二氯甲烷、氯仿、乙腈、苯、甲苯、THF、乙醚、乙二醇二甲醚、DMF、二氧六环、丙酮等中的一种或几种。
上述制备方法中，优选在反应中加入碱性试剂，所述碱性试剂包括有机碱、无机碱，所述碱性试剂进一步优选碱金属碳酸盐(如Li2CO3、Na2CO3、K2CO3)、三乙胺、吡啶、醋酸钠、喹啉、咪唑、二甲基苯胺、DMAP(二甲基氨基吡啶)、2,6-二甲基吡啶中的一种或几种混合。
本发明的另一实施方案提供一种上述式I结构的泽兰林素7位磺酰化衍生物的制备方法，其特征在于所述5-6元杂环基选自吡啶基、噻吩基、呋喃基、吡喃基、噻唑基、咪唑基、咪唑啉基、吡唑基、吡唑啉基、三氮唑基；所述6-10元芳基选自苯基、萘基；所述C1-C6烷基选自甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、正戊基、异戊基、2,2-二甲基丙基、正己基、2-甲基戊基、2,2-二甲基丁基、3-甲基戊基、2,3-二甲基丙基；所述C1-C6烷氧基选自甲氧基、乙氧基、正丙氧基、异丙氧基、叔丁氧基、环丙氧基；所述C1-C6卤代烷基选自三氟甲基、三氯甲基、三溴甲基、二氟甲基、一氟甲基、六氟乙基；所述C1-C6卤代烷氧基选自三氟甲氧基、二氟甲氧基、一氟甲氧基、六氟乙氧基；所述C1-C6烷氧羰基选自甲氧基羰基、乙氧基羰基、叔丁氧基羰基；所述卤素选自氟、氯、溴、碘。
本发明的另一实施方案提供一种上述式I结构的泽兰林素7位磺酰化衍生物的制备方法，其特征在于所述A环选自2-甲基苯基、3-甲基苯基、4-甲基苯基、2-甲氧基苯基、4-甲氧基苯基、2-三氟甲基苯基、3-三氟甲基苯基、4-三氟甲基苯基、2-三氟甲氧基苯基、3-三氟甲氧基苯基、4-三氟甲氧基苯基、2-氟苯基、3-氟苯基、4-氟苯基、2-氯苯基、3-氯苯基、4-氯苯基、2-溴苯基、3-溴苯基、4-溴苯基、2-硝基苯基、3-硝基苯基、4-硝基苯基、2-甲氧羰基苯基、4-甲氧羰基苯基、3-氰基苯基、4-氰基苯基、苯基、3-吡啶基、2-噻吩基、4-叔丁基苯基。
本发明上述制备方法制备的式I结构的泽兰林素7位磺酰化衍生物在制备抗炎药物中的应用。
本发明所述5-6元杂环基选自含有1-3个杂原子的5-6元杂环基，所述杂原子选自N、O、S；所述5-6元杂环基进一步优选吡啶基、噻吩基、呋喃基、吡喃基、噻唑基、咪唑基、咪唑啉基、吡唑基、吡唑啉基、三氮唑基。所述6-10元芳基选自苯基、萘基。所述C1-C6烷基是指含有1至6个碳原子的直链、支链烷基或环烷基，优选甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、正戊基、异戊基、2,2-二甲基丙基、正己基、2-甲基戊基、2,2-二甲基丁基、3-甲基戊基、2,3-二甲基丙基。所述C1-C6烷氧基是指含有1至6个碳原子的直链、支链烷氧基或环烷氧基，优选甲氧基、乙氧基、正丙氧基、异丙氧基、叔丁氧基、环丙氧基。所述C1-C6卤代烷基是指被一个或多个卤素取代的含有1至6个碳原子的直链、支链烷基或环烷基，优选三氟甲基、三氯甲基、三溴甲基、二氟甲基、一氟甲基、六氟乙基等。所述C1-C6卤代烷氧基是指被一个或多个卤素取代的含有1至6个碳原子的直链、支链烷氧基或环烷氧基，优选三氟甲氧基、二氟甲氧基、一氟甲氧基、六氟乙氧基等。所述C1-C6烷氧羰基是指含有1至6个碳原子的直链、支链烷氧羰基或环烷氧基羰基，优选甲氧基羰基、乙氧基羰基、叔丁氧基羰基等。所述的“卤素”优选氟、氯、溴、碘等。
应理解，在本发明范围内，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
与现有技术相比，本发明的优点在于：本发明提供了一种泽兰林素7位磺酰化衍生物的制备方法，制备步骤简单、反应条件温和、收率较高。此外，本发明制备的泽兰林素7位磺酰化衍生物，结构新颖、药理活性优异。
附图说明
图1是一氧化氮的标准曲线图；
图2是对照组、模型组及个别受试组对一氧化氮释放图；
图3是IL-6的标准曲线图；
图4是对照组、模型组及个别受试组的IL-6释放量图。
具体实施方式
为了便于对本发明的进一步理解，下面提供的实施例对其做了更详细的说明。但是这些实施例仅供更好的理解发明而并非用来限定本发明的范围或实施原则，本发明的实施方式不限于以下内容。
实施例1制备泽林兰素衍生物1～31
合成化合物1
取泽兰林素(0.14mmol)加入100mL三颈烧瓶中，向其中加入50mL三氯甲烷将其溶解，加入K2CO3(0.22mmol)、2-甲苯磺酰氯(0.22mmol)，加热至回流温度，回流3h后，TLC检测反应完全，加适量水淬灭反应，氯仿萃取，有机层经无水硫酸钠干燥、过滤、浓缩后经硅胶柱层析(乙酸乙酯：石油醚＝1：2)分离得化合物1(65.6mg)。
合成化合物2
取泽兰林素(0.1mmol)溶于40mL二氯甲烷中，加入三乙胺(0.2mmol)、3-甲苯磺酰氯(0.2mmol)、催化量的DMAP，30℃下反应5h后，TLC检测反应完全，加适量水淬灭反应，二氯甲烷萃取，有机层经无水硫酸钠干燥、过滤、浓缩后经硅胶柱层析(乙酸乙酯：石油醚＝1：2)分离得化合物2(47.4mg)。
合成化合物3
取泽兰林素(0.1mmol)溶于30mL丙酮中，加入吡啶(0.3mmol)、4-甲苯磺酰氯(0.2mmol)，室温下反应过夜后，TLC检测反应完全，加适量水淬灭反应，二氯甲烷萃取，有机层经无水硫酸钠干燥、过滤、浓缩后经硅胶柱层析(乙酸乙酯：石油醚＝1：2)分离得化合物3(47.3mg)。
按照上述合成化合物1、2、3的类似方法，使用泽兰林素，在有机溶剂(二氯甲烷、氯仿、乙腈、苯、甲苯、THF、乙醚、乙二醇二甲醚、DMF、二氧六环
二甲基苯胺、DMAP(二甲基氨基吡啶)、2,6-二甲基吡啶中的一种或几种混合】反应(室温至回流温度)，可以以下表中的收率得到相应的泽兰林素衍生物(化合物4-31)。
化合物1-31的NMR、MS数据如下：
化合物1的结构表征数据为：1H NMR(400MHZ,CHCl3)δ12.99(s,1H),7.91(d,J＝7.87Hz,1H),7.55(q,J＝8.35Hz,2H),7.43(d,J＝7.58Hz,1H),7.31(q,J＝7.21Hz,2H),7.09(s,1H),6.99(d,J＝8.44Hz,1H),6.63(s,1H),3.99(d,J＝8.34Hz,6H),3.66(s,3H),2.85(s,3H)；13C NMR(101MHz,CHCl3)δ183.01,165.07,154.08,152.70,151.03,149.41,146.75,139.55,136.32,134.48,132.78,130.21,126.11,123.18,120.46,111.21,110.10,108.75,104.26,102.23,60.79,56.18,20.60；HRMS m/z:499.09452[M+H]+。
化合物2的结构表征数据为：1H NMR(400MHZ,CHCl3)δ13.00(s,1H),7.82(s,1H),7.77(d,J＝7.80Hz,1H),7.52(q,J＝7.26Hz,2H),7.44(t,J＝7.72Hz,1H),7.35(s,1H),7.26(d,J＝0.60Hz,1H),7.10(s,1H),6.99(d,J＝8.20Hz,1H),6.64(s,1H),3.99(d,J＝8.88Hz,6H),3.71(s,3H),2.45(s,3H).13C NMR(101MHz,CHCl3)δ183.03,154.16,146.84,139.61,135.40,129.05,128.71,125.60,120.47,123.19,111.22,110.20,108.77,104.29,102.16,60.85,56.20,21.35；HRMS m/z:499.09842[M+H]+。
化合物3的结构表征数据为：1H NMR(400MHZ,CHCl3)δ12.98(s,1H),7.85(d,J＝7.91Hz,2H),7.53(d,J＝8.54Hz,1H),7.35(d,J＝6.97Hz,3H),7.11(s,1H),6.99(d,J＝8.48Hz,1H),6.64(s,1H),3.99(d,J＝8.98Hz,6H),3.72(s,3H),2.46(s,3H)；13C NMR(101MHz,CHCl3)δ183.02,165.08,154.14,152.72,151.10,149.44,146.96,145.83,136.36,132.63,129.85,128.51,123.20,120.47,111.23,110.17,108.78,104.28,102.12,60.90,56.19,21.81；HRMS m/z:499.10611[M+H]+。
化合物4的结构表征数据为：1H NMR(400MHZ,CHCl3)δ12.96(s,1H),7.89(d,J＝7.85Hz,1H),7.64(q,J＝7.83Hz,1H),7.53(q,J＝8.46Hz,1H),7.34(s,1H),7.10(d,J＝9.51Hz,2H),7.02(m,J＝7.72Hz,2H),6.63(s,1H),3.99(d,J＝9.22Hz,9H),3.76(s,3H)；13CNMR(101MHz,CHCl3)δ183.02,165.06,158.20,154.07,152.69,151.11,149.42,147.57,136.47,131.48,123.24,120.45,120.14,112.57,111.21,109.99,108.78,104.27,102.41,60.98,56.25；HRMS m/z:515.10078[M+H]+。
化合物5的结构表征数据为：1H NMR(400MHZ,CHCl3)δ12.98(s,1H),7.89(d,J＝8.26Hz,2H),7.53(q,J＝8.47Hz,1H),7.35(s,1H),7.11(s,1H),7.00(d,J＝8.24Hz,2H),6.63(s,1H),3.99(d,J＝9.00Hz,6H),3.89(s,3H),3.74(s,3H)；13CNMR(101MHz,CHCl3)δ183.00,165.05,164.43,154.12,152.71,151.10,149.42,147.03,136.38,130.81,126.80,123.17,120.46,114.40,60.94,56.18,55.77,29.71,29.33,14.14；HRMS m/z:515.10089[M+H]+。
化合物6的结构表征数据为：1H NMR(400MHZ,CHCl3)δ13.01(s,1H),7.99(d,J＝7.92Hz,2H),7.75(q,J＝7.92Hz,2H),7.53(q,J＝7.36Hz,2H),7.42(q,J＝7.64Hz,1H),7.35(s,1H),7.08(s,1H),6.99(d,J＝8.44Hz,1H),6.64(s,1H),3.99(d,J＝7.44Hz,6H),3.73(s,3H)；13C NMR(101MHz,CHCl3)δ182.99,165.14,154.22,152.75,151.09,149.43,147.19,136.35,136.22,131.66,128.36,126.32,123.14,120.43,111.23,110.34,108.76,104.28,102.60,60.90,56.17；HRMS m/z:445.22787[M+H]+。
化合物7的结构表征数据为：1H NMR(400MHZ,CHCl3)δ13.04(s,1H),7.91(d,J＝7.76Hz,1H),7.86(s,1H),7.63(q,J＝8.00Hz,1H),7.55(q,J＝8.52Hz,2H),7.35(s,1H),7.06(s,1H),7.00(d,J＝8.48Hz,1H),6.65(s,1H),3.99(d,J＝7.40Hz,6H),3.73(s,3H)；13CNMR(101MHz,CHCl3)δ182.97,165.17,154.30,152.79,151.08,149.46,149.24,146.39,137.59,136.28,130.90,127.06,126.79,123.10,121.12,120.50,111.24,110.44,108.77,104.31,102.20,60.81,56.18；HRMS m/z:445.22797[M+H]+.
化合物8的结构表征数据为：1H NMR(400MHZ,CHCl3)δ13.04(s,1H),8.05(d,J＝8.11Hz,2H),7.53(d,J＝8.46Hz,1H),7.39(q,J＝8.36Hz,2H),7.35(s,1H),7.06(s,1H),6.99(d,J＝8.47Hz,1H),6.65(s,1H),3.99(d,J＝7.14Hz,6H),3.73(s,3H)；13C NMR(101MHz,CHCl3)δ182.96,165.13,154.25,153.54,152.79,151.07,149.45,146.48,136.24,133.88,130.80,123.08,120.81,120.49,111.23,110.38,108.76,104.28,102.19,60.81,56.17,121.46,118.87,29.71；HRMS m/z:569.07306[M+H]+.
化合物9的结构表征数据为：1H NMR(400MHZ,CHCl3)δ13.00(s,1H),8.12(d,J＝7.96Hz,1H),8.00(d,J＝7.83Hz,1H),7.83(q,J＝7.64Hz,1H),7.71(q,J＝7.70Hz,1H),7.54(d,J＝8.47Hz,1H),7.35(s,1H),7.10(s,1H),6.99(d,J＝8.31Hz,1H),3.99(d,J＝8.21Hz,6H),3.66(s,3H)；13C NMR(101MHz,CHCl3)δ182.98,165.18,154.29,152.77,151.12,149.44,146.66,136.27,134.53,134.31,132.39,132.23,128.72,128.66,123.09,123.70,120.50,111.23,110.39,108.75,104.27,102.78,60.80,56.18；HRMS m/z:553.06445[M+H]+.
化合物10的结构表征数据为：1H NMR(400MHZ,CHCl3)δ13.05(s,1H),8.30(s,1H),8.15(d,J＝7.85Hz,1H),7.97(q,J＝7.76Hz,1H),7.73(q,J＝7.84Hz,1H),7.54(d,J＝8.36Hz,1H),7.35(s,1H),7.07(s,1H),7.00(d,J＝8.40Hz,1H),6.65(s,1H),3.99(d,J＝8.21Hz,6H),3.66(s,3H)；13C NMR(101MHz,CHCl3)δ182.97,165.19,154.30,152.81,151.10,149.47,146.30,137.03,136.19,131.63,131.11,129.99,125.73,123.09,120.51,111.25,110.48,108.79,104.33,102.32,60.77,56.18；HRMS m/z:553.07703[M+H]+.
化合物11的结构表征数据为：1H NMR(400MHZ,CHCl3)δ13.06(s,1H),8.13(d,J＝8.11Hz,2H),7.85(d,J＝8.12Hz,2H),7.54(q,J＝8.47Hz,1H),7.35(s,1H),7.06(s,1H),7.00(d,J＝8.44Hz,1H),6.65(s,1H),3.99(d,J＝6.73Hz,6H),3.72(s,3H)；13C NMR(101MHz,CHCl3)δ149.47,146.38,129.05,126.37,123.08,120.51,111.25,108.77,104.33,102.14,60.85,56.19；HRMS m/z:553.07373[M+H]+.
化合物12的结构表征数据为：1H NMR(400MHZ,CHCl3)δ13.00(s,1H),7.86(t,J＝7.18Hz 1H),7.71(q,J＝6.66Hz,1H),7.54(d,J＝8.40Hz,1H),7.32(q,J＝6.66Hz,3H),7.11(s,1H),6.99(d,J＝8.42Hz,1H),6.64(s,1H),3.99(d,J＝8.41Hz,6H),3.76(s,3H)；13CNMR(101MHz,CHCl3)δ183.00,165.16,154.24,152.75,151.11,149.43,146.69,56.20,61.01,102.63,104.30,108.77,110.37,111.22,117.42,117.63,120.50,123.13,124.34,131.07,136.38,137.04；HRMS m/z:503.06891[M+H]+.
化合物13的结构表征数据为：1H NMR(400MHZ,CHCl3)δ13.04(s,1H),7.77(d,J＝7.81Hz,1H),7.71(d,J＝7.71Hz,1H),7.56(q,J＝8.49Hz,2H),7.41(t,J＝8.30Hz 1H),7.35(s,1H),7.08(s,1H),7.00(d,J＝8.51Hz 1H),6.65(s,1H),3.99(d,J＝8.45Hz,6H),3.74(s,3H).13C NMR(101MHz,CHCl3)δ182.99,165.17,154.26,131.06,124.33,121.83,120.51,116.02,111.24,108.80,104.33,102.16,60.89,56.18；HRMS m/z:503.08005[M+H]+.
化合物14的结构表征数据为：1H NMR(400MHZ,CHCl3)δ13.02(s,1H),8.00(q,J＝4.21Hz,1H),7.54(d,J＝8.40Hz,1H),7.35(s,1H),7.23(d,J＝8.20Hz 1H),7.08(s,1H),7.00(d,J＝8.48Hz 1H),6.65(s,1H),3.99(d,J＝8.45Hz,6H),3.74(s,3H)；13C NMR(101MHz,CHCl3)δ182.98,165.14,154.25,152.79,151.12,149.46,146.66,136.28,131.44,123.13,120.49,116.75,116.52,111.24,110.33,108.78,104.30,102.22,60.91,56.19；HRMS m/z:503.07880[M+H]+.
化合物15的结构表征数据为：1H NMR(400MHZ,CHCl3)δ13.00(s,1H),8.00(d,J＝7.93Hz,1H),7.63(m,J＝7.16Hz,2H),7.53(d,J＝8.43Hz,1H),7.41(t,J＝7.50Hz 1H),7.34(s,1H),7.07(s,1H),6.99(d,J＝8.51Hz 1H),6.63(s,1H),3.99(d,J＝7.62Hz,6H),3.74(s,3H)；13C NMR(101MHz,CHCl3)δ182.99,165.14,154.27,152.74,151.07,149.42,146.81.136.39,135.27,134.32,133.85,132.22,131.85,126.96,123.14,120.49,111.21,110.33,108.77,104.29 102.66,61.08,56.19；HRMS m/z:519.04724[M+H]+.
化合物16的结构表征数据为：1H NMR(400MHZ,CHCl3)δ13.04(s,1H),8.00(s,1H),7.86(d,J＝7.80Hz,1H),7.68(d,J＝8.4Hz,1H),7.52(m,J＝5.41Hz,2H),7.34(d,J＝7.64Hz,1H),7.26(s,1H),7.07(s,1H),6.99(q,J＝7.60Hz 1H),6.65(s,1H),3.99(d,J＝8.76Hz,6H),3.74(s,3H)；13C NMR(101MHz,CHCl3)δ183.00,165.17,154.26,152.78,151.09,149.45,146.46,137.35,136.27,135.46,134.72,130.45,128.50,126.55,123.12,120.51,111.24,110.41,108.77,104.33,102.22,60.88,56.18,29.72；HRMS m/z:519.04755[M+H]+.
化合物17的结构表征数据为：1H NMR(400MHZ,CHCl3)δ13.03(s,1H),7.91(d,J＝7.80Hz,2H),7.54(d,J＝8.36Hz,3H),7.35(s,1H),7.07(s,1H),7.00(d,J＝8.44Hz,1H),6.65(s,1H),3.99(d,J＝8.28Hz,6H),3.74(s,3H)；13C NMR(101MHz,CHCl3)δ182.97,165.14,154.26,152.77,151.11,149.44,146.60,141.44,136.25,134.11,129.90,129.59,123.10,120.50,111.22,110.36,108.74,104.31,102.18,60.93,56.19；HRMS m/z:519.04773[M+H]+.。
5-化合物18的结构表征数据为：1H NMR(400MHZ,CHCl3)δ13.00(s,1H),8.03(d,J＝7.7Hz,1H),7.87(d,J＝7.80Hz,1H),7.49(M,J＝7.94Hz,3H),7.34(s,1H),7.06(s,1H),6.99(d,J＝8.36Hz,1H),6.64(s,1H),3.99(d,J＝7.40Hz,6H),3.74(s,3H)；13C NMR(101MHz,CHCl3)δ182.99,165.13,154.27,152.73,151.05,149.41,146.79,136.39,136.22,135.78,135.14,132.10,127.56,123.13,121.60,120.49,111.21,110.32,108.76,104.29,102.65,61.14,56.18；HRMS m/z:564.99518[M+H]+.。
化合物19的结构表征数据为：1H NMR(400MHZ,CHCl3)δ13.05(s,1H),8.16(s,1H),7.90(d,J＝7.96Hz,1H),7.83(d,J＝7.96Hz,1H),7.54(d,J＝8.40Hz 1H),7.45(t,J＝7.96Hz 1H),7.35(s,1H),7.07(s,1H),7.00(s,J＝8.48Hz,1H),6.65(s,1H),3.99(d,J＝8.80Hz,6H),3.75(s,3H)；13C NMR(101MHz,CHCl3)δ130.63,126.97,123.10,120.51,111.24,110.41,108.77,104.32,102.23,60.88,56.20；HRMS m/z:564.98511[M+H]+.
化合物20的结构表征数据为：1H NMR(400MHZ,CHCl3)δ13.04(s,1H),7.84(d,J＝7.75Hz 2H),7.71(d,J＝7.61Hz,2H),7.54(d,J＝8.44Hz,1H),7.35(s,1H),7.07(s,1H),7.00(d,J＝8.43Hz,1H),6.65(s,1H),7.00(s,J＝8.48Hz,1H),6.65(s,1H),3.99(d,J＝8.21Hz,6H),3.74(s,3H)；13C NMR(101MHz,CHCl3)δ182.97,165.14,154.26,152.78,151.10,149.45,146.59,136.25,134.70,132.57,130.04,129.90,123.11,120.50,111.24,110.36,108.76,104.31,102.15,60.92,56.20；HRMS m/z:564.99500[M+H]+.
化合物21的结构表征数据为：1H NMR(400MHZ,CHCl3)δ13.05(s,1H),8.12(d,J＝7.72Hz,1H),7.92(d,J＝7.79Hz,2H),7.86(t,J＝7.57Hz,1H),7.76(t,J＝7.57Hz,1H),7.54(d,J＝8.38Hz,1H),7.36(s,1H),7.11(s,1H),7.00(d,J＝8.30Hz,1H),6.66(s,1H),3.99(d,J＝7.91Hz,6H),3.74(s,3H)；13C NMR(101MHz,CHCl3)δ183.00,165.27,154.38,151.18,149.45,146.62,136.24,135.46,132.35,131.78,129.53,125.07,123.07,120.55,111.23,108.77,104.32,61.10,56.19；HRMS m/z:530.07159[M+H]+.
化合物22的结构表征数据为：1H NMR(400MHZ,CHCl3)δ13.07(s,1H),8.86(s,1H),8.55(d,J＝8.20Hz,2H),8.28(d,J＝7.78Hz,1H),7.80(t,J＝8.05Hz,1H),7.55(d,J＝8.51Hz,1H),7.36(s,1H),7.11(s,1H),7.00(d,J＝8.39Hz,1H),6.66(s,1H),3.99(d,J＝9.10Hz,6H),3.75(s,3H)；13C NMR(101MHz,CHCl3)δ182.94,165.28,154.37,152.85,151.18,149.48,137.75,133.88,130.54,128.95,123.94,120.56,111.26,108.80,104.36,102.38,60.95,56.21；HRMS m/z:530.07164[M+H]+.
化合物23的结构表征数据为：1H NMR(400MHZ,CHCl3)δ13.07(s,1H),8.41(d,J＝8.11Hz 2H),8.18(d,J＝8.20Hz,2H),7.54(d,J＝8.09Hz,1H),7.35(s,1H),7.08(s,1H),7.00(d,J＝8.42Hz,1H),6.66(s,1H),3.99(d,J＝7.29Hz,6H),3.72(s,3H)；13C NMR(101MHz,CHCl3)δ182.97,165.14,154.26,152.77,151.11,149.44,146.60,141.44,136.25,134.11,129.90,129.59,123.10,120.50,111.22,110.36,108.74,104.31,102.18,60.93,56.19；HRMS m/z:530.07166[M+H]+.
化合物24的结构表征数据为：1H NMR(400MHZ,CHCl3)δ13.00(s,1H),8.04(d,J＝7.94Hz,1H),7.76(s,2H),7.64(q,J＝4.47Hz,1H),7.53(d,J＝8.42Hz,1H),7.34(s,1H),7.05(s,1H),6.99(d,J＝8.44Hz,1H),3.98(d,J＝8.45Hz,8H),3.73(s,2H)；13C NMR(101MHz,CHCl3)δ183.00,166.81,165.11,154.30,152.74,151.10,149.44,147.01,136.46,134.27,133.32,130.92,130.28,129.76,123.17,120.48,111.23,110.30,108.81,104.31,102.44,60.97,56.19,53.33；HRMS m/z:563.98109[M+H]+.
化合物25的结构表征数据为：1H NMR(400MHZ,CHCl3)δ13.03(s,1H),8.22(d,J＝7.79Hz,2H),8.05(d,J＝7.81Hz,2H),7.54(q,J＝8.57Hz,1H),7.35(s,1H),7.08(s,1H),7.00(d,J＝8.40Hz,1H),6.65(s,1H),3.99(d,J＝8.94Hz,9H),3.70(s,3H)；13C NMR(101MHz,CHCl3)δ182.97,165.23,154.26,152.78,149.44,146.54,139.49,130.29,128.53,123.11,120.52,135.48,111.23,110.40,108.76,104.32,102.20,60.88,56.19,52.86；HRMS m/z:543.08360[M+H]+.
化合物26的结构表征数据为：1H NMR(400MHZ,CHCl3)δ13.07(s,1H),8.28(s,1H),8.19(d,J＝8.02Hz,1H),7.98(q,J＝7.69Hz,1H),7.73(q,J＝7.83Hz,1H),7.54(d,J＝8.26Hz,1H),7.35(s,1H),7.08(s,1H),7.00(d,J＝8.48Hz,1H),6.66(s,1H),3.99(d,J＝8.58Hz,6H),3.73(s,3H)；13C NMR(101MHz,CHCl3)δ182.94,165.27,154.35,152.83,151.16,149.46,146.17,137.55,137.42,132.36,132.06,130.27,123.03,120.56,116.70,113.92,111.24,110.58,108.76,104.36,102.32,60.92,56.20；HRMS m/z:508.06812[M+H]+.
化合物27的结构表征数据为：1H NMR(400MHZ,CHCl3)δ13.07(s,1H),8.01(d,J＝7.89Hz,2H),7.87(d,J＝7.97Hz,2H),7.54(q,J＝8.48Hz,1H),7.34(s,1H),7.06(s,1H),7.00(d,J＝8.45Hz,1H),6.65(s,1H),3.99(d,J＝7.28Hz,6H),3.71(s,3H)；13C NMR(101MHz,CHCl3)δ182.92,165.23,154.35,152.85,151.13,149.46,146.24,139.87,136.05,132.89,129.11,123.00,120.53,118.25,116.92,111.24.110.54,108.75,104.33,102.25,60.90,56.20；HRMS m/z:508.06709[M+H]+.
化合物28的结构表征数据为：1H NMR(400MHZ,CHCl3)δ13.00(s,1H),7.98(d,J＝7.79Hz,2H),7.70(d,J＝7.43Hz,1H),7.56(m,J＝5.61Hz,3H),7.35(s,1H),7.10(s,1H),6.99(d,J＝8.24Hz,1H),6.64(s,1H),3.99(d,J＝8.87Hz,6H),3.70(s,3H)；13C NMR(101MHz,CHCl3)δ183.02,165.10,154.17,152.73,151.08,149.43,146.80,136.36,135.70,134.61,129.23,128.47,123.17,120.48,111.22,110.24,108.76,104.29,102.18,60.86,56.19,2.12；HRMS m/z:485.0936[M+H]+.
化合物29的结构表征数据为：1H NMR(400MHZ,CHCl3)δ13.05(s,1H),9.16(s,1H)，8.91(d,J＝4.41Hz,1H),8.25(d,J＝7.55Hz,1H),7.53(q,J＝5.20Hz,2H),7.35(s,1H),7.10(s,1H),7.00(d,J＝8.24Hz,1H),6.65(s,1H),3.99(d,J＝8.67Hz,6H),3.72(s,3H)；13CNMR(101MHz,CHCl3)δ182.95,165.21,154.91,154.31,152.82,151.13,149.46,149.09,146.27,136.10,123.72,123.06,120.53,111.25,110.52,108.79,104.33,102.34,60.88,56.20；HRMS m/z:485.0827[M+H]+.
化合物30的结构表征数据为：1H NMR(400MHZ,CHCl3)δ13.01(s,1H),7.77(d,J＝4.86Hz,2H),7.54(d,J＝8.49Hz,1H),7.35(s,1H),7.15(d,J＝4.23Hz,1H),7.10(s,1H),7.00(d,J＝8.46Hz,1H),6.65(s,1H),3.99(d,J＝8.56Hz,6H),3.78(s,3H)；13C NMR(101MHz,CHCl3)δ183.01,165.15,154.20,152.77,149.45,146.77,136.48,135.72,135.16,127.69,123.16,120.50,111.23,110.36,108.80,104.31,102.18,61.05,56.20；HRMS m/z:491.04691[M+H]+.
化合物31的结构表征数据为：1H NMR(400MHZ,CHCl3)δ13.00(s,1H),7.91(d,J＝7.92Hz,2H),7.58(d,J＝7.88Hz,2H),7.53(d,J＝8.48Hz,1H),7.35(s,1H),7.09(s,1H),6.99(d,J＝8.48Hz,1H),6.64(s,1H),3.99(d,J＝7.53Hz,6H),3.70(s,3H),1.35(s,9H)；13CNMR(101MHz,CHCl3)δ183.03,165.04,158.74,154.10,152.71,151.04,149.43,146.85,136.39,132.68,128.35,126.27,123.19,120.45,111.21,110.15,108.76,104.25,102.08,60.77,56.18,35.42,31.01,29.71；HRMS m/z:541.15295[M+H]+.
实施例2
本发明通过LPS诱导细胞建立炎症模型(图2)，本发明泽兰林素衍生物1-31及泽兰林素在100μM浓度下，作用于RAW164.7细胞，均能显著降低一氧化氮释放水平，相对于模型组(LPS)，化合物1-31在100μM浓度下均可降低50％以上的一氧化氮释放水平。其中，在100μM浓度下，泽兰林素与化合物14(J14)的活性相当(图中未列出)。在此，申请人仅列出化合物7(图中标记为J7)、9(图中标记为J9)、11(图中标记为J11)、12(图中标记为J12)、13(图中标记为J13)、14(图中标记为J14)、22(图中标记为J22)、26(图中标记为J26)对一氧化氮释放水平的抑制作用，具体试验情况如下：
通过LPS诱导细胞建立炎症模型，在不同浓度(0、25、50、100、150、200μM)作用于RAW164.7细胞，使用一氧化氮试剂盒测试八个化合物在不同浓度的细胞上清液中一氧化氮含量的变化，得出标准曲线如图2。由于吸光度与一氧化氮的释放量成正比，因此可以通过吸光度来推断一氧化氮的释放量。
实施例3
本发明泽兰林素衍生物1-31及泽兰林素对IL-6释放水平的抑制作用
申请人仅列出化合物7(图中标记为J7)、9(图中标记为J9)、11(图中标记为J11)、12(图中标记为J12)、13(图中标记为J13)、14(图中标记为J14)、22(图中标记为J22)、26(图中标记为J26)对IL-6放水平的抑制作用，具体试验情况如下：
建立炎症模型后，将化合物7、9、11、12、13、14、22、26八种化合物以50μmol和100μmol的药物浓度作用于细胞，使用ELISA试剂盒测试细胞上清液中IL-6的含量，作出标准曲线如图3。由于吸光度与IL-6的释放量成正比，因此可以通过吸光度来推断IL-6的释放量。其中，在100μM浓度下，泽兰林素与化合物14(J14)的活性相当(图中未列出)。
由图4的活性结果可见，与LPS组相比，随着药物浓度的增大，化合物7、9、11、12、13、14、22、26释放IL-6的含量皆降低，说明化合物都有抗炎作用。
Claims (8)
1.一种式I结构的泽兰林素7位磺酰化衍生物的制备方法，其特征在于包括如下步骤：
有机溶剂中，泽兰林素与磺酰氯反应，得到式I结构的泽兰林素7位磺酰化衍生物；其中A环选自任选被一个或多个R1取代的5-6元杂环基或6-10元芳基；所述R1选自C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、卤素、硝基、氰基、氨基、羟基、C1-C6烷氧羰基。
2.权利要求1所述的制备方法，其特征在于所述5-6元杂环基选自吡啶基、噻吩基、呋喃基、吡喃基、噻唑基、咪唑基、咪唑啉基、吡唑基、吡唑啉基、三氮唑基；所述6-10元芳基选自苯基、萘基；所述C1-C6烷基选自甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、正戊基、异戊基、2,2-二甲基丙基、正己基、2-甲基戊基、2,2-二甲基丁基、3-甲基戊基、2,3-二甲基丙基；所述C1-C6烷氧基选自甲氧基、乙氧基、正丙氧基、异丙氧基、叔丁氧基、环丙氧基；所述C1-C6卤代烷基选自三氟甲基、三氯甲基、三溴甲基、二氟甲基、一氟甲基、六氟乙基；所述C1-C6卤代烷氧基选自三氟甲氧基、二氟甲氧基、一氟甲氧基、六氟乙氧基；所述C1-C6烷氧羰基选自甲氧基羰基、乙氧基羰基、叔丁氧基羰基；所述卤素选自氟、氯、溴、碘。
3.权利要求1所述的制备方法，其特征在于所述A环选自2-甲基苯基、3-甲基苯基、4-甲基苯基、2-甲氧基苯基、4-甲氧基苯基、2-三氟甲基苯基、3-三氟甲基苯基、4-三氟甲基苯基、2-三氟甲氧基苯基、3-三氟甲氧基苯基、4-三氟甲氧基苯基、2-氟苯基、3-氟苯基、4-氟苯基、2-氯苯基、3-氯苯基、4-氯苯基、2-溴苯基、3-溴苯基、4-溴苯基、2-硝基苯基、3-硝基苯基、4-硝基苯基、2-甲氧羰基苯基、4-甲氧羰基苯基、3-氰基苯基、4-氰基苯基、苯基、3-吡啶基、2-噻吩基、4-叔丁基苯基。
4.权利要求1-3任一项所述的制备方法，其特征在于所述有机溶剂优选二氯甲烷、氯仿、乙腈、苯、甲苯、THF、乙醚、乙二醇二甲醚、DMF、二氧六环、丙酮等中的一种或几种。
5.权利要求1-4任一项所述的制备方法，其特征在于优选在反应中加入碱性试剂，所述碱性试剂包括有机碱、无机碱。
6.权利要求5所述的制备方法，其特征在于所述碱性试剂进一步优选碱金属碳酸盐、三乙胺、吡啶、醋酸钠、喹啉、咪唑、二甲基苯胺、DMAP(二甲基氨基吡啶)、2,6-二甲基吡啶中的一种或几种混合。
7.权利要求6所述的制备方法，其特征在于所述碱金属碳酸盐优选Li2CO3、Na2CO3、K2CO3中的一种或几种。
8.权利要求1-7任一项所述制备方法制备的式I结构的泽兰林素7位磺酰化衍生物或其药学上可接受的盐在制备抗炎药物中的应用。
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