CN114230630B - 雷公藤甲素衍生物及其应用 - Google Patents
雷公藤甲素衍生物及其应用 Download PDFInfo
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- CN114230630B CN114230630B CN202111356992.8A CN202111356992A CN114230630B CN 114230630 B CN114230630 B CN 114230630B CN 202111356992 A CN202111356992 A CN 202111356992A CN 114230630 B CN114230630 B CN 114230630B
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- Prior art keywords
- hydroxy
- triptolide
- phenylbutanol
- carbamate
- sulphonamido
- Prior art date
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- DFBIRQPKNDILPW-CIVMWXNOSA-N Triptolide Chemical class O=C1OCC([C@@H]2C3)=C1CC[C@]2(C)[C@]12O[C@H]1[C@@H]1O[C@]1(C(C)C)[C@@H](O)[C@]21[C@H]3O1 DFBIRQPKNDILPW-CIVMWXNOSA-N 0.000 title claims abstract description 21
- 150000001875 compounds Chemical class 0.000 claims abstract description 19
- 239000003814 drug Substances 0.000 claims abstract description 6
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 69
- -1 sulphonamido Chemical group 0.000 claims description 56
- 238000002360 preparation method Methods 0.000 claims description 38
- 229940079593 drug Drugs 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 2
- 241000830536 Tripterygium wilfordii Species 0.000 claims 1
- 235000015398 thunder god vine Nutrition 0.000 claims 1
- 150000003839 salts Chemical class 0.000 abstract description 11
- 230000000694 effects Effects 0.000 abstract description 9
- 108010016183 Human immunodeficiency virus 1 p16 protease Proteins 0.000 abstract description 8
- 239000002243 precursor Substances 0.000 abstract description 7
- 208000030507 AIDS Diseases 0.000 abstract description 5
- 238000001647 drug administration Methods 0.000 abstract description 2
- 230000002401 inhibitory effect Effects 0.000 abstract description 2
- IMIQIWQBJKROCN-LEWJYISDSA-N n-[(2r,3s)-3-amino-2-hydroxy-4-phenylbutyl]-4-methoxy-n-(2-methylpropyl)benzenesulfonamide Chemical compound C1=CC(OC)=CC=C1S(=O)(=O)N(CC(C)C)C[C@@H](O)[C@@H](N)CC1=CC=CC=C1 IMIQIWQBJKROCN-LEWJYISDSA-N 0.000 description 16
- 239000011734 sodium Substances 0.000 description 16
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- YKUJZZHGTWVWHA-UHFFFAOYSA-N triptolide Natural products COC12CC3OC3(C(C)C)C(O)C14OC4CC5C6=C(CCC25C)C(=O)OC6 YKUJZZHGTWVWHA-UHFFFAOYSA-N 0.000 description 5
- WCKQPPQRFNHPRJ-UHFFFAOYSA-N 4-[[4-(dimethylamino)phenyl]diazenyl]benzoic acid Chemical compound C1=CC(N(C)C)=CC=C1N=NC1=CC=C(C(O)=O)C=C1 WCKQPPQRFNHPRJ-UHFFFAOYSA-N 0.000 description 4
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
- C07J73/001—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom
- C07J73/003—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom by oxygen as hetero atom
-
- 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
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
Abstract
本发明涉及雷公藤甲素衍生物及其应用，可有效解决艾滋病的用药问题，其解决的技术方案是，雷公藤甲素衍生物及其药学上可接受的盐或前体物，其结构如通式(I)所示：
Description
技术领域
本发明涉及医药领域，特别是一种雷公藤甲素衍生物及其应用。
背景技术
获得性免疫缺陷综合征，是人类因感染免疫缺陷病毒(Human ImmunodeficiencyVirus， HIV)而导致免疫缺陷，并引发一系列机会性感染及肿瘤的综合征。
目前， HIV/AIDS的治疗仍采用药物治疗。但是，随着各种抗HIV药物的频繁使用，越来越多的药物产生了耐药性，从而限制了其临床应用。HIV-1PR是由HIV基因编码的一种特异性天冬氨酰蛋白酶，抑制蛋白酶的活性可使被感染的细胞只能产生不成熟、不具有感染性的病毒。因此，HIV-1PR是研发抗HIV药物的重要靶点。
发明内容
针对上述情况，为解决现有技术之缺陷，本发明之目的就是提供一种雷公藤甲素衍生物及其应用，可有效解决艾滋病的用药问题。
本发明解决的技术方案是，雷公藤甲素衍生物及其药学上可接受的盐或前体物，其结构如通式(I)所示：
式中：
R1选自：-H、-C1-4烷基、-C3-6环烷基、6-10元芳基、5-10元杂芳基，所述杂芳基和杂环基含有1-3个选自O、N和S的杂原子，且R1任选1-3个R11取代；
R11为1-3个相同或不同的选自氢、卤素、羟基、氨基、三氟甲基、三氟甲氧基、巯基、-C1-4烷基、-C1-4烷硫基、-C1-4烷氧基甲基的取代基；
R2选自：-H、卤素、-CN、-CF3、-OCF3、-OR21、-CH2OR21、-SR21、-CH2SR21、-NR21R22、 -C1-4烷基、-C3-6环烷基；
R21、R22相同或不同，独立的选自：-H、C1-4烷基。
具体的，本发明优选提供定义如下的通式(I)所述的雷公藤甲素类衍生物及其药学上可接受的盐或前体物，R1选自：-H、
R2选自：-H、卤素、-CN、-CF3、-OCF3、-OR21、-SR21、-NR21R22；
R21、R22相同或不同，独立的选自：-H、C1-4烷基。
本发明上述的雷公藤甲素类衍生物及药学上可接受的盐或前药，可以优选为下述化合物中的一种或两种以上，但下述化合物并不意味着对本发明的任何限制；其中下述化合物分别与本申请说明书表一中的化合物1至30相对应，具体列举如下：
雷公藤甲素-((2S,3R)-3-羟基-4-((N-异丁基-4-甲氧基苯基)磺酰胺基)-1-苯基丁醇-2-基)氨基甲酸酯、
雷公藤甲素-((2S,3R)-3-羟基-4-((N-异丁基-4-硝基苯基)磺酰胺基)-1-苯基丁醇-2-基)氨基甲酸酯、
雷公藤甲素-((2S,3R)-3-羟基-4-((N-异丁基-4-胺基苯基)磺酰胺基)-1-苯基丁醇-2-基)氨基甲酸酯、
雷公藤甲素-((2S,3R)-3-羟基-4-((N-异丁基-4-氟苯基)磺酰胺基)-1-苯基丁醇-2-基)氨基甲酸酯；
雷公藤甲素-((2S,3R)-3-羟基-4-((N-异丁基-4-氰基苯基)磺酰胺基)-1-苯基丁醇-2-基)氨基甲酸酯、
雷公藤甲素-((2S,3R)-3-羟基-4-((N-异丁基-4-三氟甲基苯基)磺酰胺基)-1-苯基丁醇-2-基)氨基甲酸酯、
雷公藤甲素-((2S,3R)-3-羟基-4-((N-异丁基-4-甲巯基苯基)磺酰胺基)-1-苯基丁醇-2-基)氨基甲酸酯、
雷公藤甲素-((2S,3R)-3-羟基-4-((N-异丁基-4-溴苯基)磺酰胺基)-1-苯基丁醇-2-基)氨基甲酸酯、
雷公藤甲素-((2S,3R)-3-羟基-4-((N-((R)-2-羟丙基)-4-甲氧基苯基)磺酰胺基)-1-苯基丁醇-2-基) 氨基甲酸酯、
雷公藤甲素-((2S,3R)-3-羟基-4-((N-((R)-2-羟丙基)-4-硝基苯基)磺酰胺基)-1-苯基丁醇-2-基)氨基甲酸酯、
雷公藤甲素-((2S,3R)-3-羟基-4-((N-((R)-2-羟丙基)-4-胺基苯基)磺酰胺基)-1-苯基丁醇-2-基)氨基甲酸酯、
雷公藤甲素-((2S,3R)-3-羟基-4-((N-((R)-2-羟丙基)-4-三氟甲基苯基)磺酰胺基)-1-苯基丁醇-2-基) 氨基甲酸酯、
雷公藤甲素-((2S,3R)-3-羟基-4-((N-((S)-2-羟丙基)-4-甲氧基苯基)磺酰胺基)-1-苯基丁醇-2-基) 氨基甲酸酯、
雷公藤甲素-((2S,3R)-3-羟基-4-((N-((S)-2-羟丙基)-4-硝基苯基)磺酰胺基)-1-苯基丁醇-2-基)氨基甲酸酯、
雷公藤甲素-((2S,3R)-3-羟基-4-((N-((S)-2-羟丙基)-4-胺基苯基)磺酰胺基)-1-苯基丁醇-2-基)氨基甲酸酯、
雷公藤甲素-((2S,3R)-3-羟基-4-((N-((S)-2-羟丙基)-4-三氟甲基苯基)磺酰胺基)-1-苯基丁醇-2-基) 氨基甲酸酯、
雷公藤甲素-((2S,3R)-3-羟基-4-((N-正丙基-4-甲氧基苯基)磺酰胺基)-1-苯基丁醇-2-基)氨基甲酸酯、
雷公藤甲素-((2S,3R)-3-羟基-4-((N-正丙基-4-硝基苯基)磺酰胺基)-1-苯基丁醇-2-基)氨基甲酸酯、
雷公藤甲素-((2S,3R)-3-羟基-4-((N-正丙基-4-胺基苯基)磺酰胺基)-1-苯基丁醇-2-基)氨基甲酸酯、
雷公藤甲素-((2S,3R)-3-羟基-4-((N-正丙基-4-氟苯基)磺酰胺基)-1-苯基丁醇-2-基)氨基甲酸酯、
雷公藤甲素-((2S,3R)-3-羟基-4-((N-正丙基-4-三氟甲基苯基)磺酰胺基)-1-苯基丁醇-2-基)氨基甲酸酯、
雷公藤甲素-((2S,3R)-3-羟基-4-((N-环丙基-4-硝基苯基)磺酰胺基)-1-苯基丁醇-2-基)氨基甲酸酯、
雷公藤甲素-((2S,3R)-3-羟基-4-((N-环丙基-4-胺基苯基)磺酰胺基)-1-苯基丁醇-2-基)氨基甲酸酯、
雷公藤甲素-((2S,3R)-3-羟基-4-((N-环丙基-4-氟苯基)磺酰胺基)-1-苯基丁醇-2-基)氨基甲酸酯、
雷公藤甲素-((2S,3R)-3-羟基-4-((N-环丙基-4-三氟甲基苯基)磺酰胺基)-1-苯基丁醇-2-基)氨基甲酸酯、
雷公藤甲素-((2S,3R)-3-羟基-4-((N-异丙基-4-硝基苯基)磺酰胺基)-1-苯基丁醇-2-基)氨基甲酸酯、
雷公藤甲素-((2S,3R)-3-羟基-4-((N-异丙基-4-胺基苯基)磺酰胺基)-1-苯基丁醇-2-基)氨基甲酸酯、
雷公藤甲素-((2S,3R)-3-羟基-4-((N-异丙基-4-氟苯基)磺酰胺基)-1-苯基丁醇-2-基)氨基甲酸酯、
雷公藤甲素-((2S,3R)-3-羟基-4-((N-异丙基-4-三氟甲基苯基)磺酰胺基)-1-苯基丁醇-2-基)氨基甲酸酯、
雷公藤甲素-((2S,3R)-3-羟基-4-((N-异丙基-4-氟苯基)磺酰胺基)-1-苯基丁醇-2-基)氨基甲酸酯。
按照本发明所属领域的常规方法，本发明通式(I)所示的雷公藤甲素类衍生物可以与酸生成药学上可接受的盐。可药用加成盐包括无机酸和有机酸加成盐，与下列酸加成的盐特别优选的是：盐酸、氢溴酸、硫酸、磷酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘二磺酸、乙酸、丙酸、乳酸、三氟乙酸、马来酸、柠檬酸、富马酸、草酸、酒石酸、苯甲酸等。
此外，本发明还包括雷公藤甲素类衍生物的前体物(前药)，本发明衍生物的前药是通式 (I)的衍生物，它们自身可能具有较弱的活性甚至没有活性，但是给药后，在生理条件下(例如通过代谢、溶剂分解或另外的方式)被转化成相应的生物活性形式。
本发明中“卤素”是指氟、氯、溴或碘代；“环烷基”是指取代或未取代的环烷基；“芳基”是指无取代基或连有取代基的单环或多环的环状芳香体系；“杂芳基”是指含有一个或多个选自N、O、S杂原子的单环或多环的环状体系。
本发明还提供了上述的雷公藤甲素类衍生物、或其药学上可接受的盐或前体物在制备抗艾滋病药物中的应用，其还可以用作HIV-1蛋白激酶抑制剂。本发明提供了上述雷公藤甲素类衍生物的药理活性实验，检测了其对HIV-1蛋白酶的抑制活性，试验结果表明，部分化合物对HIV-1蛋白酶有较好的抑制活性，具有重要的进一步研究价值。
进一步的，本发明提供了以上述的雷公藤甲素类衍生物、或其药学上可接受的盐或前体物为有效成份，与药学上可接受的一种或多种载体组成的药物组合物。
本发明还提供了上述的药物组合物在制备抗艾滋病药物中的应用，该药物组合物还可以用作HIV-1蛋白酶抑制剂。
具体实施方式
以下结合实施例对本发明的技术方案作进一步地详细介绍，但本发明的保护范围并不局限于此。
本发明通式(I)所示衍生物可参照下述合成路线进行制备。制备过程中所用原料可通过下述合成路线中描述的方式、或采用本领域普通技术人员熟知的方法制备、或直接商购获得。
本发明通式(I)所示衍生物，可按照上述路线合成，重要中间体D采用常规的化学工作者周知的方法合成，该路线首先由雷公藤甲素与氯甲酸对硝基苯酯缩合，随后在三乙胺作碱的条件下与中间体D经酰化反应得到目标化合物，所发生的反应均为常规化学反应。
以下实施例在合成方法上具有代表性，本发明通式(I)所示衍生物(尤其是表一中的化合物1至31)均可参照合成路线以及实施例的制备方法合成得到。
实施例1化合物1的制备：雷公藤甲素-((2S,3R)-3-羟基-4-((N-异丁基-4-甲氧基苯基)磺酰胺基)-1-苯基丁醇-2-基)氨基甲酸酯
步骤A：雷公藤甲素-(4-硝基苯基)甲酸酯的制备
将雷公藤甲素(0.30g，0.83mmol)加入含有15mL二氯甲烷的50mL茄型瓶中，冰浴下缓慢滴加氯甲酸对硝基苯酯(0.25g，1.25mmol)，随后缓慢加入吡啶(0.13mL，1.66mmol)，加毕后转移至室温反应2小时，TLC检测反应完毕，分3次加入45mL水，有机相合并，减压浓缩除去二氯甲烷，粗品经柱层析(流动相正己烷：乙酸乙酯＝1:1)后得到目标产品，白色固体0.32g(73.4％)。
1H NMR(400MHz,Chloroform-d)δ8.29(d,J＝9.0Hz,2H),7.44(d,J＝9.0Hz,2H),4.91 (s,1H),4.75–4.66(m,2H),3.88(d,J＝3.0Hz,1H),3.61(d,J＝3.0Hz,1H),3.56(d,J＝5.4Hz,1H),2.73(d,J＝12.8Hz,1H),2.37–2.32(m,1H),2.26–2.16(m,2H),2.07–1.93(m,2H),1.68 (s,1H),1.63–1.59(m,1H),1.11(s,3H),1.03(d,J＝7.0Hz,3H),0.91(d,J＝7.0Hz,3H)；
13C NMR(101MHz,Chloroform-d)δ173.17,159.70,155.45,152.50,145.41,125.71,125.27, 121.72,69.98,63.39,62.78,61.53,59.61,55.33,55.18,40.30,35.66,29.83,28.25,23.36,17.52,17.05,16.67,13.82；
LC-MS(ESI)[M+H]+m/z 525.2.
步骤B：化合物1的制备
将中间体7(0.15g,0.29mmol)，Et3N(0.12ml,0.87mmol)，N-((2R,3S)-3-胺基-2-羟基-4- 苯基丁基)-N-异丁基-4-甲氧基苯磺酰胺(0.12g,0.29mmol)加入到含有10mL乙腈的50mL 茄形瓶中，室温反应2小时，TLC检测反应完毕，反应体系减压浓缩除去多余的乙腈后用30 mL(3×10mL)乙酸乙酯萃取，有机相用无水硫酸钠干燥，选用CH2Cl2：MeOH＝50:1的流动相硅胶柱层析，得到白色固体化合物1 0.13g(57.5％)。
1H NMR(600MHz,CDCl3)δ7.74(d,J＝8.4Hz,2H),7.26–7.23(m,4H),7.19(d,J＝6.6Hz,1H),6.98(d,J＝8.4Hz,2H),4.68–4.61(m,2H),3.88–3.84(m,3H),3.87(s,3H),3.78(d,J＝2.4Hz,1H),3.43(s,1H),3.36(d,J＝5.4Hz,1H),3.23(dd,J＝15.0,8.0Hz,1H),3.16(d,J＝ 14.4Hz,1H),3.10(d,J＝14.4Hz,1H),2.99(dd,J＝13.2,8.4Hz,1H),2.83–2.74(m,2H),2.64(d,J＝11.4Hz,1H),2.30(d,J＝17.4Hz,1H),2.14–2.09(m,2H),1.89(dt,J＝13.8,6.6Hz,1H), 1.80(t,J＝13.8Hz,1H),1.55–1.50(m,2H),1.21–1.16(m,1H),1.01(s,3H),0.91(d,J＝6.6Hz,3H),0.85(d,J＝6.6Hz,3H),0.76(d,J＝6.6Hz,3H),0.71(d,J＝6.6Hz,3H)；
13C NMR(151MHz,CDCl3)δ173.2,163.0,159.9,155.8,137.7,130.2,129.6,129.5,128.4, 126.4,125.6,114.3,72.9,71.7,69.9,63.6,63.5,61.0,59.6,58.6,55.6,55.5,55.3,54.9,53.7,40.3,36.0,35.7,29.8,28.0,27.2,23.5,20.2,19.9,17.5,17.1,16.7,13.8.
HRMS(ESI)m/z calcd.for C42H52N2O11S([M+Na]+):815.3190,found 815.3202.
实施例2化合物2的制备：雷公藤甲素-((2S,3R)-3-羟基-4-((N-异丁基-4-硝基苯基)磺酰胺基)-1- 苯基丁醇-2-基)氨基甲酸酯
制备方法参照实施例1，其中，步骤B中将N-((2R,3S)-3-胺基-2-羟基-4-苯基丁基)-N-异丁基-4-甲氧基苯磺酰胺替换为N-((2R,3S)-3-胺基-2-羟基-4-苯基丁基)-N-异丁基-4-硝基苯磺酰胺。
1H NMR(600MHz,CDCl3)δ8.35(d,J＝8.6Hz,2H),8.00(d,J＝8.6Hz,2H),7.28–7.26(m,2H),7.23–7.20(m,3H),4.76(s,1H),4.67(brs,2H),3.84(brs,1H),3.80(d,J＝3.0Hz,1H),3.44(d,J＝2.4Hz,1H),3.39(d,J＝5.4Hz,1H),3.31–3.27(m,2H),3.15(dd,J＝13.6,2.4Hz, 1H),3.00(d,J＝7.2Hz,2H),2.73(dd,J＝14.4,9.0Hz,1H),2.66(d,J＝11.4Hz,1H),2.31(d,J＝16.2Hz,1H),2.17–2.11(m,2H),1.96–1.92(m,1H),1.87–1.82(m,1H),1.55–1.49(m,2H), 1.26(d,J＝4.2Hz,1H),1.22–1.17(m,1H),1.01(s,3H),0.90(d,J＝6.6Hz,3H),0.87(d,J＝6.6Hz,3H),0.76(d,J＝6.6Hz,3H),0.71(d,J＝6.6Hz,3H)；
13C NMR(151MHz,CDCl3)δ173.2,159.9,155.9,150.0,144.9,137.3,129.3,128.6,128.5, 126.6,125.6,124.4,72.5,72.0,70.0,63.7,63.4,61.1,59.7,57.7,55.7,55.6,54.8,52.9,40.3,36.1,35.7,29.8,28.1,26.9,23.4,20.0,19.9,17.4 17.0,16.7,13.8.
HRMS(ESI)m/z calcd.for C41H49N3O12S([M+Na]+):830.2935,found 830.2976.
实施例3化合物3的制备：雷公藤甲素-((2S,3R)-3-羟基-4-((N-异丁基-4-胺基苯基)磺酰胺基)-1- 苯基丁醇-2-基)氨基甲酸酯
制备方法参照实施例1，其中，步骤B中将N-((2R,3S)-3-胺基-2-羟基-4-苯基丁基)-N-异丁基-4-甲氧基苯磺酰胺替换为N-((2R,3S)-3-胺基-2-羟基-4-苯基丁基)-N-异丁基-4-胺基苯磺酰胺。
1H NMR(600MHz,CDCl3)δ7.57(d,J＝8.0Hz,2H),7.25(d,J＝6.6Hz,4H),7.20–7.18(m,1H),6.68(d,J＝8.0Hz,2H),4.75(s,1H),4.68–4.62(m,2H),3.83(d,J＝7.2Hz,2H),3.44 (s,1H),3.36(d,J＝5.4Hz,1H),3.23(dd,J＝15.0,8.4Hz,1H),3.15(d,J＝13.2Hz,1H),3.08(d,J＝15.0Hz,1H),2.97(dd,J＝13.2,8.4Hz,1H),2.79–2.74(m,2H),2.64(d,J＝12.0Hz,1H), 2.30(d,J＝15.0Hz,1H),2.13–2.08(m,2H),1.90–1.86(m,1H),1.80(t,J＝14.0Hz,1H),1.55–1.50(m,2H),1.26(brs,1H),1.21–1.16(m,1H),1.01(s,3H),0.91(d,J＝6.6Hz,3H),0.85(d,J ＝6.6Hz,3H),0.76(d,J＝6.6Hz,3H),0.72(d,J＝6.6Hz,3H)；
13C NMR(151MHz,CDCl3)δ173.3,160.0,155.7,150.7,137.8,129.6,129.5,128.4,126.6, 126.4,125.6,114.2,72.9,71.7,70.0,63.7,63.5,61.0,59.6,58.7,55.5,55.3,54.9,53.7,40.3,36.0,35.7,29.8,28.0,27.2,23.4,20.2,19.9,17.5,17.1,16.7,13.8.
HRMS(ESI)m/z calcd.for C41H51N3O10S([M+Na]+):800.3193,found 800.3214.
实施例4化合物6的制备：雷公藤甲素-((2S,3R)-3-羟基-4-((N-异丁基-4-三氟甲基苯基)磺酰胺基)-1-苯基丁醇-2-基)氨基甲酸酯
制备方法参照实施例1，其中，步骤B中将N-((2R,3S)-3-胺基-2-羟基-4-苯基丁基)-N-异丁基-4-甲氧基苯磺酰胺替换为N-((2R,3S)-3-胺基-2-羟基-4-苯基丁基)-N-异丁基-4-三氟甲基苯磺酰胺。
1H NMR(600MHz,CDCl3)δ7.94(d,J＝8.4Hz,2H),7.78(d,J＝8.4Hz,2H),7.27(d,J＝ 7.2Hz,2H),7.25–7.23(m,2H),7.21–7.19(m,1H),4.76(s,1H),4.65(q,J＝17.6Hz,2H),3.84(brs,2H),3.79(d,J＝2.8Hz,1H),3.44(d,J＝2.4Hz,1H),3.36(d,J＝5.6Hz,1H),3.28–3.23 (m,2H),3.20–3.16(m,1H),3.00(dd,J＝13.6,8.0Hz,1H),2.91(dd,J＝13.6,7.2Hz,1H),2.75(dd,J＝14.0,9.2Hz,1H),2.65(d,J＝12.8Hz,1H),2.30(d,J＝16.8Hz,1H),2.15–2.11(m,2H), 1.92(dt,J＝13.6,6.8Hz,1H),1.78(t,J＝14.0Hz,1H),1.55–1.52(m,2H),1.21–1.16(m,1H),1.01(s,3H),0.90(d,J＝6.6Hz,3H),0.85(d,J＝6.6Hz,3H),0.76(d,J＝6.8Hz,3H),0.71(d,J＝ 6.8Hz,3H)；
13C NMR(151MHz,CDCl3)δ173.2,159.9,155.9,142.4,137.5,129.4,128.5,127.9,126.5, 126.3,126.2,125.6,72.7,71.9,69.9,63.6,63.4,61.0,59.7,58.2,55.5,54.9,53.4,40.3,36.1,35.6,29.8,28.1,27.0,23.4,20.1,19.9,17.4,17.0,16.7,13.8.
HRMS(ESI)m/z calcd.for C42H49F3N2O10S([M+Na]+):853.2958,found 853.2946.
实施例5化合物7的制备：雷公藤甲素-((2S,3R)-3-羟基-4-((N-异丁基-4-甲巯基苯基)磺酰胺基)-1-苯基丁醇-2-基)氨基甲酸酯
制备方法参照实施例1，其中，步骤B中将N-((2R,3S)-3-胺基-2-羟基-4-苯基丁基)-N-异丁基-4-甲氧基苯磺酰胺替换为N-((2R,3S)-3-胺基-2-羟基-4-苯基丁基)-N-异丁基-4-甲硫基苯磺酰胺。
1H NMR(400MHz,CDCl3)δ7.72(d,J＝8.4Hz,2H),7.34(d,J＝8.4Hz,2H),7.31–7.26(m,4H),7.25–7.20(m,1H),4.79(s,1H),4.69(brs,2H),3.86(d,J＝6.0Hz,2H),3.81(d,J＝2.4 Hz,1H),3.47(d,J＝2.4Hz,1H),3.39(d,J＝5.6Hz,1H),3.31–3.22(m,2H),3.19–3.17(m,1H),3.03(dd,J＝13.2,8.4Hz,1H),2.87–2.77(m,2H),2.68(d,J＝12.4Hz,1H),2.56(s,3H), 2.34(d,J＝16.0Hz,1H),2.19–2.13(m,2H),1.93(dt,J＝13.8,6.8Hz,1H),1.82(t,J＝14.0Hz,1H),1.55(dd,J＝13.2,6.8Hz,2H),1.25–1.18(m,1H),1.04(s,3H),0.95(d,J＝6.6Hz,3H), 0.88(d,J＝6.6Hz,3H),0.80(d,J＝6.6Hz,3H),0.75(d,J＝6.6Hz,3H)；
13C NMR(101MHz,CDCl3)δ173.2,160.0,155.8,145.8,137.7,134.2,129.5,128.5,127.8, 126.5,125.6,125.5,72.8,71.7,70.0,63.6,63.5,61.0,59.7,58.6,55.5,55.4,54.9,53.8,40.3,36.1,35.7,29.8,28.1,27.2,23.5,20.2,19.9,17.5,17.1,16.7,14.8,13.8.
HRMS(ESI)m/z calcd.for C42H52N2O10S2([M+Na]+):831.2961,found 831.2966.
实施例6化合物9的制备：雷公藤甲素-((2S,3R)-3-羟基-4-((N-((R)-2-羟丙基)-4-甲氧基苯基) 磺酰胺基)-1-苯基丁醇-2-基)氨基甲酸酯
制备方法参照实施例1，其中，步骤B中将N-((2R,3S)-3-胺基-2-羟基-4-苯基丁基)-N-异丁基-4-甲氧基苯磺酰胺替换为N-((2R,3S)-3-胺基-2-羟基-4-苯基丁基)-N-((R)-2-羟丙基)-4-甲氧基苯磺酰胺。
1H NMR(600MHz,CDCl3)δ7.73(d,J＝8.8Hz,2H),7.25–7.21(m,4H),7.19–7.16(m,1H),6.96(d,J＝8.8Hz,2H),4.78(s,1H),4.68–4.62(m,2H),4.22–4.18(m,1H),4.08(t,J＝6.6Hz,1H),3.92–3.89(m,1H),3.86(s,3H),3.80(d,J＝3.0Hz,1H),3.55(dd,J＝14.4,1.8Hz,1H), 3.45(d,J＝5.4Hz,1H),3.43(d,J＝3.0Hz,1H),3.29(dd,J＝14.4,2.4Hz,1H),3.10(dd,J＝14.0,4.0Hz,1H),2.95(dd,J＝14.8,9.0Hz,1H),2.85(dd,J＝14.4,9.0Hz,1H),2.71(dd,J＝14.0, 10.2Hz,1H),2.64(d,J＝13.2Hz,1H),2.29(d,J＝16.2Hz,1H),2.18–2.08(m,2H),1.87(t,J＝14.0Hz,1H),1.56–1.49(m,2H),1.23–1.18(m,1H),1.16(d,J＝6.6Hz,3H),1.02(s,3H),0.74 (d,J＝6.8Hz,3H),0.70(d,J＝6.8Hz,3H)；
13C NMR(151MHz,CDCl3)δ173.2,163.1,160.0,155.6,137.9,129.8,129.5,128.3,126.3, 125.6,114.4,74.5,71.6,70.0,68.3,63.7,63.5,61.2,59.9,59.4,56.0,55.7,55.6,55.0,54.7,40.3,35.9,35.7,29.8,27.9,23.4,20.5,17.5,17.1,16.8,13.8.
HRMS(ESI)m/z calcd.for C41H50N2O12S([M+Na]+):817.2982,found 817.3020.
实施例7化合物10的制备：雷公藤甲素-((2S,3R)-3-羟基-4-((N-((R)-2-羟丙基)-4-硝基苯基)磺酰胺基)-1-苯基丁醇-2-基)氨基甲酸酯
制备方法参照实施例1，其中，步骤B中将N-((2R,3S)-3-胺基-2-羟基-4-苯基丁基)-N-异丁基-4-甲氧基苯磺酰胺替换为N-((2R,3S)-3-胺基-2-羟基-4-苯基丁基)-N-((R)-2-羟丙基)-4-硝基苯磺酰胺。
1H NMR(600MHz,CDCl3)δ8.35(d,J＝8.8Hz,2H),7.99(d,J＝8.8Hz,2H),7.24(t,J＝ 7.2Hz,2H),7.21–7.17(m,3H),4.78(s,1H),4.68(brs,2H),4.29–4.25(m,1H),4.05(t,J＝7.2Hz,1H),3.90–3.85(m,1H),3.82(d,J＝3.0Hz,1H),3.67(d,J＝13.8Hz,1H),3.48(d,J＝6.0Hz,1H),3.44(d,J＝3.0Hz,1H),3.40(dd,J＝14.4,1.8Hz,1H),3.16(dd,J＝14.4,3.6Hz,1H), 2.94(dd,J＝14.8,9.6Hz,1H),2.83(dd,J＝14.8,9.6Hz,1H),2.65(dd,J＝14.4,10.8Hz,2H),2.30(d,J＝16.2Hz,1H),2.22(dt,J＝14.6,6.0Hz,1H),2.13–2.09(m,1H),1.95(t,J＝14.2Hz, 1H),1.55(dd,J＝12.0,5.4Hz,1H),1.45–1.41(m,1H),1.22(dd,J＝12.0,6.0Hz,1H),1.18(d,J＝6.6Hz,3H),1.04(s,3H),0.72(d,J＝6.8Hz,3H),0.68(d,J＝6.8Hz,3H).
13C NMR(151MHz,CDCl3)δ173.3,160.0,155.7,150.1,143.8,137.6,129.4,128.6,128.4, 126.4,125.6,124.6,74.7,71.8,70.1,68.5,63.7,63.5,61.3,60.1,59.3,56.2,55.8,55.1,54.6,40.3,36.2,35.7,29.9,27.7,23.3,20.6,17.4,17.1,16.7,13.9.
HRMS(ESI)m/z calcd.for C40H47N3O13S([M+Na]+):832.2727,found 832.2725.
实施例8化合物12的制备：雷公藤甲素-((2S,3R)-3-羟基-4-((N-((R)-2-羟丙基)-4-三氟甲基苯基)磺酰胺基)-1-苯基丁醇-2-基)氨基甲酸酯
制备方法参照实施例1，其中，步骤B中将N-((2R,3S)-3-胺基-2-羟基-4-苯基丁基)-N-异丁基-4-甲氧基苯磺酰胺替换为N-((2R,3S)-3-胺基-2-羟基-4-苯基丁基)-N-((R)-2-羟丙基)-4-三氟甲基苯磺酰胺。
1H NMR(600MHz,CDCl3)δ7.83(d,J＝8.2Hz,2H),7.68(d,J＝8.2Hz,2H),7.14(d,J＝ 7.2Hz,2H),7.12(d,J＝7.2Hz,2H),7.09(t,J＝7.2Hz,1H),4.69(s,1H),4.59–4.52(m,2H),4.14(dd,J＝12.8,6.0Hz,1H),4.00(t,J＝7.2Hz,1H),3.82–3.77(m,1H),3.71(d,J＝3.0Hz, 1H),3.53(d,J＝14.4Hz,1H),3.37(d,J＝5.6Hz,1H),3.33(d,J＝2.4Hz,1H),3.25(d,J＝13.2Hz,1H),3.03(dd,J＝14.2,4.0Hz,1H),2.87(dd,J＝14.8,9.0Hz,1H),2.77(dd,J＝15.0,9.6Hz, 1H),2.62–2.54(m,2H),2.21(d,J＝16.0Hz,1H),2.08(dt,J＝14.8,6.0Hz,1H),2.03–2.00(m,1H),1.76(t,J＝14.0Hz,1H),1.45(dd,J＝13.2,6.0Hz,1H),1.39(dt,J＝13.8,6.6Hz,1H),1.11 (dd,J＝12.0,6.0Hz,1H),1.08(d,J＝6.6Hz,3H),0.92(s,3H),0.64(d,J＝6.8Hz,3H),0.60(d,J＝6.8Hz,3H).
13C NMR(151MHz,CDCl3)δ173.2,159.8,155.7,141.7,137.7,129.4,128.4,127.9,126.5, 126.4,125.6,74.6,71.8,70.0,68.4,63.7,63.5,61.3,60.0,59.4,56.1,55.8,55.1,54.7,40.3,36.1,35.7,29.9,27.9,23.4,20.6,17.4,17.1,16.8,13.8.
HRMS(ESI)m/z calcd.for C41H47F3N2O11S([M+Na]+):855.2750,found 855.2732.
实施例9化合物13的制备：N-(1-甲基-3-(4-乙酰基哌啶-1-基)-1H-吡唑-4-基)-3-((4-甲基哌嗪-1- 羰基)甲基)-苯甲酰胺
制备方法参照实施例1，其中，步骤B中将N-((2R,3S)-3-胺基-2-羟基-4-苯基丁基)-N-异丁基-4-甲氧基苯磺酰胺替换为N-((2R,3S)-3-胺基-2-羟基-4-苯基丁基)-N-((S)-2-羟丙基)-4-甲氧基苯磺酰胺。
1H NMR(600MHz,CDCl3)δ7.75(d,J＝8.8Hz,2H),7.24(t,J＝6.0Hz,4H),7.20–7.18(m,1H),6.99(d,J＝8.8Hz,2H),4.78(s,1H),4.69–4.62(m,2H),4.19–4.17(m,1H),3.95(d,J＝5.4Hz,1H),3.87(s,3H),3.81(d,J＝3.0Hz,1H),3.44(dd,J＝13.2,4.2Hz,2H),3.33(dd,J＝ 14.4,7.2Hz,1H),3.27(t,J＝11.4Hz,1H),3.15(d,J＝15.0Hz,1H),3.10–3.06(m,2H),2.95(dd,J＝14.4,9.0Hz,2H),2.81(dd,J＝13.8,9.6Hz,1H),2.66(d,J＝13.0Hz,1H),2.30(d,J＝16.8 Hz,1H),2.16–2.12(m,2H),1.84(t,J＝14.0Hz,1H),1.56–1.53(m,1H),1.21–1.19(m,1H),1.17(d,J＝6.6Hz,3H),1.02(s,3H),0.76(d,J＝6.8Hz,3H),0.72(d,J＝6.8Hz,3H)；
13C NMR(151MHz,CDCl3)δ173.2,163.1,160.0,155.8,137.8,129.6,129.5,129.3,128.4, 126.4,125.6,114.4,72.7,71.5,70.0,67.1,63.6,61.4,60.0,58.2,55.9,55.8,55.6,54.7,54.3,54.0,40.3,36.6,35.6,29.8,27.8,23.4,20.9,17.4,17.1,16.7,13.9.
HRMS(ESI)m/z calcd.for C41H50N2O12S([M+Na]+):817.2982,found 817.2957.
实施例10化合物14的制备：雷公藤甲素-((2S,3R)-3-羟基-4-((N-((S)-2-羟丙基)-4-硝基苯基) 磺酰胺基)-1-苯基丁醇-2-基)氨基甲酸酯
制备方法参照实施例1，其中，步骤B中将N-((2R,3S)-3-胺基-2-羟基-4-苯基丁基)-N-异丁基-4-甲氧基苯磺酰胺替换为N-((2R,3S)-3-胺基-2-羟基-4-苯基丁基)-N-((S)-2-羟丙基)-4-硝基苯磺酰胺。
1H NMR(600MHz,CDCl3)δ8.37(d,J＝8.8Hz,2H),8.00(d,J＝8.8Hz,2H),7.25(t,J＝ 7.2Hz,2H),7.20(dd,J＝14.0,7.2Hz,3H),4.76(s,1H),4.69(s,2H),4.16–4.13(m,1H),4.00–3.97(m,1H),3.91(ddd,J＝15.6,10.0,5.4Hz,1H),3.82(d,J＝3.0Hz,1H),3.45(d,J＝3.0Hz, 1H),3.43(d,J＝6.0Hz,1H),3.31(dd,J＝14.4,2.4Hz,1H),3.24(dd,J＝14.6,8.8Hz,1H),3.20–3.11(m,2H),2.99(dd,J＝14.4,2.4Hz,1H),2.73–2.67(m,2H),2.31(d,J＝16.2Hz,1H),2.19 (dt,J＝14.8,6.0Hz,1H),2.13–2.07(m,1H),1.93–1.89(m,1H),1.54(dd,J＝12.0,5.0Hz,1H),1.47(dt,J＝13.8,7.0Hz,1H),1.22(dd,J＝12.0,6.0Hz,1H),1.19(d,J＝6.6Hz,3H),1.02(s, 3H),0.74(d,J＝6.8Hz,3H),0.69(d,J＝6.8Hz,3H).
13C NMR(151MHz,CDCl3)δ173.3,160.0,155.9,150.1,143.7,137.5,129.3,128.7,128.5, 126.5,125.6,124.5,72.7,71.9,70.1,66.1,63.8,63.5,61.3,60.0,57.5,55.8,55.7,54.7,53.8,40.3,36.8,35.7,29.9,27.7,23.3,20.6,17.4,17.0,16.7,13.9.
HRMS(ESI)m/z calcd.for C40H47N3O13S([M+Na]+):832.2727,found 832.2728.
实施例11化合物17的制备：雷公藤甲素-((2S,3R)-3-羟基-4-((N-正丙基-4-甲氧基苯基)磺酰胺基)-1-苯基丁醇-2-基)氨基甲酸酯
制备方法参照实施例1，其中，步骤B中将N-((2R,3S)-3-胺基-2-羟基-4-苯基丁基)-N-异丁基-4-甲氧基苯磺酰胺替换为N-((2R,3S)-3-胺基-2-羟基-4-苯基丁基)-N-正丙基-4-甲氧基苯磺酰胺。
1H NMR(400MHz,CDCl3)δ7.78(d,J＝8.8Hz,2H),7.30–7.28(m,4H),7.23(dd,J＝6.0, 2.0Hz,1H),7.01(d,J＝8.8Hz,2H),4.80(s,1H),4.73–4.64(m,2H),3.91(s,3H),3.84–3.82(m,2H),3.48(d,J＝2.0Hz,1H),3.41(d,J＝5.6Hz,1H),3.25–3.16(m,4H),3.11–3.04(m,1H), 2.82(dd,J＝14.0,9.2Hz,1H),2.68(d,J＝12.0Hz,1H),2.33(d,J＝16.0Hz,1H),2.19–2.22(m,2H),1.86(d,J＝14.0Hz,1H),1.75(dd,J＝14.8,7.0Hz,1H),1.58–1.55(m,3H),1.48(dd,J＝ 15.0,7.6Hz,1H),1.26–1.18(m,1H),1.04(s,3H),0.87(t,J＝7.0Hz,3H),0.80(d,J＝7.0Hz, 3H),0.76(d,J＝7.0Hz,3H)；
13C NMR(101MHz,CDCl3)δ173.3,163.0,160.0,155.7,137.7,131.0,129.5,129.4,128.9, 128.4,126.4,114.4,72.8,71.7,70.0,65.6,63.5,61.0,59.7,55.7,55.5,55.2,54.9,52.6,52.1,40.3,35.7,30.6,29.8,28.1,23.4,21.8,19.2,17.5,16.8,13.8,11.2.
HRMS(ESI)m/z calcd.for C41H50N2O11S([M+Na]+):801.3033,found 801.3024.
实施例12化合物18的制备：雷公藤甲素-((2S,3R)-3-羟基-4-((N-正丙基-4-硝基苯基)磺酰胺基)-1-苯基丁醇-2-基)氨基甲酸酯
制备方法参照实施例1，其中，步骤B中将N-((2R,3S)-3-胺基-2-羟基-4-苯基丁基)-N-异丁基-4-甲氧基苯磺酰胺替换为N-((2R,3S)-3-胺基-2-羟基-4-苯基丁基)-N-正丙基-4-硝基苯磺酰胺。
1H NMR(400MHz,CDCl3)δ8.40(d,J＝8.8Hz,2H),8.05(d,J＝8.8Hz,2H),7.34–7.32(m,2H),7.28–7.24(m,3H),4.81(s,1H),4.71(brs,2H),3.90–3.89(m,2H),3.84(d,J＝2.8Hz,1H),3.48(d,J＝2.4Hz,1H),3.43(d,J＝5.6Hz,1H),3.34–3.30(m,2H),3.23–3.18(m,3H), 2.80(dd,J＝14.0,9.2Hz,1H),2.70(d,J＝12.4Hz,1H),2.36(d,J＝16.4Hz,1H),2.23–2.16(m,2H),1.89(t,J＝14.0Hz,1H),1.64–1.55(m,4H),1.28–1.20(m,1H),1.06(s,3H),0.89(t,J＝ 7.2Hz,3H),0.81(d,J＝6.8Hz,3H),0.76(d,J＝6.8Hz,3H)；
13C NMR(101MHz,CDCl3)δ173.2,159.9,155.9,150.0,145.1,137.3,129.4,128.6,128.5, 126.7,125.7,124.5,72.7,72.0,70.0,63.6,63.4,61.1,59.8,55.5,55.4,54.9,52.3,51.9,40.3,36.1,35.7,29.9,28.1,23.4,21.7,17.5,17.1,16.7,13.8,11.1.
HRMS(ESI)m/z calcd.for C40H47N3O12S([M+Na]+):816.2778,found 816.2763.
实施例13化合物22的制备：雷公藤甲素-((2S,3R)-3-羟基-4-((N-环丙基-4-甲氧基苯基)磺酰胺基)-1-苯基丁醇-2-基)氨基甲酸酯
制备方法参照实施例1，其中，步骤B中将N-((2R,3S)-3-胺基-2-羟基-4-苯基丁基)-N-异丁基-4-甲氧基苯磺酰胺替换为N-((2R,3S)-3-胺基-2-羟基-4-苯基丁基)-N-环丙基-4-甲氧基苯磺酰胺。
1H NMR(400MHz,CDCl3)δ7.82(d,J＝8.6Hz,2H),7.31–7.28(m,4H),7.24–7.22(m,1H),7.02(d,J＝8.6Hz,2H),4.80(s,1H),4.74–4.64(m,2H),4.04–4.00(m,1H),3.98–3.94(m, 4H),3.83(s,1H),3.49(s,1H),3.42(d,J＝4.8Hz,1H),3.29(t,J＝8.8Hz,2H),3.18(dd,J＝14.0,3.6Hz,1H),2.81(dd,J＝14.0,9.6Hz,1H),2.69(d,J＝10.8Hz,1H),2.34(d,J＝16.8Hz,1H), 2.18–2.10(m,3H),1.86(t,J＝14.0Hz,1H),1.59–1.56(m,2H),1.25–1.21(m,1H),1.05(s,3H),0.99(dd,J＝13.2,5.6Hz,2H),0.90(dd,J＝18.8,6.4Hz,2H),0.80(d,J＝7.0Hz,3H),0.76 (d,J＝7.0Hz,3H)；
13C NMR(101MHz,CDCl3)δ173.3,163.2,160.1,155.7,137.8,130.0,129.5,129.0,128.4, 126.4,125.6,114.3,72.6,71.7,70.0,63.7,63.5,60.9,59.7,55.7,55.6,55.4,55.2,54.9,40.4,35.8,35.7,32.4,29.8,28.0,23.5,17.5,17.1,16.8,13.8,7.5,7.4.
HRMS(ESI)m/z calcd.for C41H48N2O11S([M+Na]+):799.2877,found 799.2872.
实施例14化合物23的制备：雷公藤甲素-((2S,3R)-3-羟基-4-((N-环丙基-4-硝基苯基)磺酰胺基)-1-苯基丁醇-2-基)氨基甲酸酯
制备方法参照实施例1，其中，步骤B中将N-((2R,3S)-3-胺基-2-羟基-4-苯基丁基)-N-异丁基-4-甲氧基苯磺酰胺替换为N-((2R,3S)-3-胺基-2-羟基-4-苯基丁基)-N-环丙基-4-硝基苯磺酰胺。
1H NMR(400MHz,CDCl3)δ8.42(d,J＝8.6Hz,2H),8.10(d,J＝8.6Hz,2H),7.34–7.32(m,2H),7.28–7.23(m,3H),4.81(s,1H),4.72(s,2H),4.02–3.97(m,1H),3.95–3.90(m,1H),3.84(d,J＝2.4Hz,1H),3.49(d,J＝2.4Hz,1H),3.45(d,J＝5.6Hz,1H),3.37(dd,J＝14.8,5.2 Hz,2H),3.22(dd,J＝14.0,4.0Hz,1H),2.77(dd,J＝14.0,10.0Hz,1H),2.74–2.70(m,1H),2.36(d,J＝16.4Hz,1H),2.24–2.16(m,3H),1.93(t,J＝14.0Hz,1H),1.61–1.52(m,2H),1.27– 1.21(m,1H),1.07(s,3H),1.02–0.96(m,2H),0.91(d,J＝7.2Hz,1H),0.85(d,J＝6.0Hz,1H), 0.80(d,J＝6.8Hz,3H),0.76(d,J＝6.8Hz,3H)；
13C NMR(101MHz,CDCl3)δ173.2,159.9,155.8,150.2,143.4,137.4,129.4,129.1,128.6, 126.6,125.6,124.3,72.4,72.0,70.0,63.7,63.5,61.1,59.8,55.6,55.5,55.3,54.9,40.4,36.2,35.7,32.1,29.9,28.0,23.4,17.5,17.1,16.8,13.8,8.13,7.39.
HRMS(ESI)m/z calcd.for C40H45N3O12S([M+Na]+):814.2622,found 814.2627.
实施例15化合物30的制备：雷公藤甲素-((2S,3R)-3-羟基-4-((N-异丙基-4-三氟甲基苯基)磺酰胺基)-1-苯基丁醇-2-基)氨基甲酸酯
制备方法参照实施例1，其中，步骤B中将N-((2R,3S)-3-胺基-2-羟基-4-苯基丁基)-N-异丁基-4-甲氧基苯磺酰胺替换为N-((2R,3S)-3-胺基-2-羟基-4-苯基丁基)-N-异丙基-4-三氟甲基苯磺酰胺。
1H NMR(400MHz,CDCl3)δ8.02(d,J＝8.0Hz,2H),7.81(d,J＝8.0Hz,2H),7.32–7.26(m,4H),7.24–7.23(m,1H),4.80(s,1H),4.66(q,J＝17.2Hz,2H),4.20–4.13(m,1H),3.95–3.88(m,1H),3.82–3.79(m,2H),3.47(d,J＝2.4Hz,1H),3.41–3.38(m,2H),3.31(dd,J＝14.0, 3.6Hz,1H),3.23(dd,J＝15.8,8.4Hz,1H),2.76(dd,J＝14.0,10.0Hz,1H),2.67(d,J＝12.4Hz,1H),2.32(d,J＝16.4Hz,1H),2.18–2.11(m,2H),1.78(t,J＝14.0Hz,1H),1.59–1.54(m,2H), 1.23(dd,J＝12.0,5.6Hz,1H),1.15(d,J＝6.8Hz,3H),1.00(s,3H),0.97(d,J＝6.8Hz,3H),0.78(d,J＝6.8Hz,3H),0.75(d,J＝6.8Hz,3H)；
13C NMR(101MHz,CDCl3)δ173.2,159.9,155.7,143.5,137.6,129.4,128.5,127.9,126.5, 126.4,126.3,125.6,74.8,71.7,70.0,63.6,63.4,61.0,59.8,55.5,55.4,54.9,50.9,47.1,40.3,36.7,35.6,29.8,28.3,23.4,22.0,19.6,17.5,17.0,16.7,13.7.
HRMS(ESI)m/z calcd.for C41H47F3N2O10S([M+Na]+):839.2801,found 839.2832.
实施例16化合物31的制备：雷公藤甲素-((2S,3R)-3-羟基-4-((N-异丙基-4-氟苯基)磺酰胺基)-1- 苯基丁醇-2-基)氨基甲酸酯
制备方法参照实施例1，其中，步骤B中将N-((2R,3S)-3-胺基-2-羟基-4-苯基丁基)-N-异丁基-4-甲氧基苯磺酰胺替换为N-((2R,3S)-3-胺基-2-羟基-4-苯基丁基)-N-环丙基-4-氟苯磺酰胺。
1H NMR(400MHz,CDCl3)δ7.90(dd,J＝8.4,5.2Hz,2H),7.32–7.26(m,4H),7.25–7.20 (m,3H),4.80(s,1H),4.72–4.62(m,2H),4.16–4.12(m,2H),3.95–3.87(m,1H),3.81(d,J＝2.8Hz,1H),3.77(d,J＝7.2Hz,1H),3.47(d,J＝2.4Hz,1H),3.41–3.38(m,1H),3.32–3.28(m,1H),3.21(dd,J＝16.0,8.4Hz,1H),2.76(dd,J＝14.0,10.0Hz,1H),2.67(d,J＝12.4Hz,1H), 2.33(d,J＝16.0Hz,1H),2.18–2.11(m,2H),1.80(t,J＝14.0Hz,1H),1.58–1.55(m,2H),1.23(dd,J＝12.0,5.6Hz,1H),1.15(d,J＝6.8Hz,3H),1.01(s,3H),0.94(d,J＝6.8Hz,3H),0.78(d,J ＝7.0Hz,3H),0.76(d,J＝6.8Hz,3H)；
13C NMR(101MHz,CDCl3)δ173.2,166.4,163.9,159.9,155.7,137.7,136.0,135.9,130.1, 130.0,129.5,128.5,126.5,125.6,116.6,116.4,75.0,71.6,70.0,63.6,63.4,61.0,59.8,55.5,55.3,54.9,50.7,46.9,40.3,36.7,35.6,29.8,28.3,23.4,22.0,19.4,17.5,17.1,16.7,13.7.
HRMS(ESI)m/z calcd.for C40H47FN2O10S([M+Na]+):789.2833,found 789.2808.
应用试验：本发明通式I所示衍生物的药理活性测试
本发明所述化合物采用的底物为(Arg-Glu(EDANS)-Ser-Gln-Asn-Tyr-Pro- Ile-Val-Gln-Lys(DABCYL)-Arg)(AnaSpec)，底物切点两侧分别标记Edans和Dabcyl发色团。Edans的荧光发色光谱与Dabcyl的吸收光谱重叠，在足够近的距离内通过荧光共振能量转移产生荧光淬灭，使完整的底物几乎没有荧光。当荧光底物经HIV蛋白酶切后，Edans发色团远离了Dabcyl基团，荧光淬灭条件小时，这时Edans就在340nm的激发光下于490nm处产生荧光，加入待测化合物后，化合物对酶抑制活性强时则底物产物减少，荧光强度降低，反之荧光强度增加。
HIV-1蛋白酶在大肠杆菌中表达并纯化，蛋白酶使用PD-10柱脱盐。活性测定在PH4.7 的缓冲溶液中进行，缓冲溶液用0.1M醋酸钠、1M氯化钠、1mM EDTA、1mM DTT，2％DMSO和1mg/mL牛血清白蛋白配置。
用96孔板对样品进行HIV-1蛋白酶抑制活性的测定，每孔加入底物(5μM)和缓冲液185μL，加入5μL样品溶液，测定空白吸收，加入10μL HIV-1蛋白酶，孵育5min后测定 490nm波长的吸光度，计算出各个浓度下样品的抑制率，用Graphpad软件计算得到IC50值。
表一中的初步药理活性结果显示：所设计的部分雷公藤甲素类化合物具有较好的HIV-1 蛋白酶抑制活性，其中化合物13的IC50值为84.75nM。鉴于目前尚未见将雷公藤甲素引入 HIV-1蛋白酶的设计中的研究报道，因此通式I的化合物具有良好的进一步研发前景。
表一：化合物1-31HIV-1蛋白酶抑制药理活性测试结果
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Claims (4)
1.雷公藤甲素衍生物，其特征在于，包括以下化合物中的一种或两种以上：
雷公藤甲素-((2S,3R)-3-羟基-4-((N-异丁基-4-硝基苯基)磺酰胺基)-1-苯基丁醇-2-基)氨基甲酸酯；
雷公藤甲素-((2S,3R)-3-羟基-4-((N-异丁基-4-胺基苯基)磺酰胺基)-1-苯基丁醇-2-基)氨基甲酸酯；
雷公藤甲素-((2S,3R)-3-羟基-4-((N-异丁基-4-氟苯基)磺酰胺基)-1-苯基丁醇-2-基)氨基甲酸酯；
雷公藤甲素-((2S,3R)-3-羟基-4-((N-异丁基-4-氰基苯基)磺酰胺基)-1-苯基丁醇-2-基)氨基甲酸酯；
雷公藤甲素-((2S,3R)-3-羟基-4-((N-异丁基-4-三氟甲基苯基)磺酰胺基)-1-苯基丁醇-2-基)氨基甲酸酯；
雷公藤甲素-((2S,3R)-3-羟基-4-((N-异丁基-4-甲巯基苯基)磺酰胺基)-1-苯基丁醇-2-基)氨基甲酸酯；
雷公藤甲素-((2S,3R)-3-羟基-4-((N-异丁基-4-溴苯基)磺酰胺基)-1-苯基丁醇-2-基)氨基甲酸酯；
雷公藤甲素-((2S,3R)-3-羟基-4-((N-((R)-2-羟丙基)-4-硝基苯基)磺酰胺基)-1-苯基丁醇-2-基)氨基甲酸酯；
雷公藤甲素-((2S,3R)-3-羟基-4-((N-((R)-2-羟丙基)-4-胺基苯基)磺酰胺基)-1-苯基丁醇-2-基)氨基甲酸酯；
雷公藤甲素-((2S,3R)-3-羟基-4-((N-((R)-2-羟丙基)-4-三氟甲基苯基)磺酰胺基)-1-苯基丁醇-2-基)氨基甲酸酯；
雷公藤甲素-((2S,3R)-3-羟基-4-((N-((S)-2-羟丙基)-4-甲氧基苯基)磺酰胺基)-1-苯基丁醇-2-基)氨基甲酸酯；
雷公藤甲素-((2S,3R)-3-羟基-4-((N-正丙基-4-胺基苯基)磺酰胺基)-1-苯基丁醇-2-基)氨基甲酸酯；
雷公藤甲素-((2S,3R)-3-羟基-4-((N-正丙基-4-氟苯基)磺酰胺基)-1-苯基丁醇-2-基)氨基甲酸酯；
雷公藤甲素-((2S,3R)-3-羟基-4-((N-正丙基-4-三氟甲基苯基)磺酰胺基)-1-苯基丁醇-2-基)氨基甲酸酯；
雷公藤甲素-((2S,3R)-3-羟基-4-((N-环丙基-4-甲氧基苯基)磺酰胺基)-1-苯基丁醇-2-基)氨基甲酸酯；
雷公藤甲素-((2S,3R)-3-羟基-4-((N-环丙基-4-硝基苯基)磺酰胺基)-1-苯基丁醇-2-基)氨基甲酸酯；
雷公藤甲素-((2S,3R)-3-羟基-4-((N-环丙基-4-胺基苯基)磺酰胺基)-1-苯基丁醇-2-基)氨基甲酸酯；
雷公藤甲素-((2S,3R)-3-羟基-4-((N-环丙基-4-氟苯基)磺酰胺基)-1-苯基丁醇-2-基)氨基甲酸酯；
雷公藤甲素-((2S,3R)-3-羟基-4-((N-环丙基-4-三氟甲基苯基)磺酰胺基)-1-苯基丁醇-2-基)氨基甲酸酯；
雷公藤甲素-((2S,3R)-3-羟基-4-((N-异丙基-4-硝基苯基)磺酰胺基)-1-苯基丁醇-2-基)氨基甲酸酯；
雷公藤甲素-((2S,3R)-3-羟基-4-((N-异丙基-4-胺基苯基)磺酰胺基)-1-苯基丁醇-2-基)氨基甲酸酯；
雷公藤甲素-((2S,3R)-3-羟基-4-((N-异丙基-4-甲氧基苯基)磺酰胺基)-1-苯基丁醇-2-基)氨基甲酸酯；
雷公藤甲素-((2S,3R)-3-羟基-4-((N-异丙基-4-三氟甲基苯基)磺酰胺基)-1-苯基丁醇-2-基)氨基甲酸酯；
雷公藤甲素-((2S,3R)-3-羟基-4-((N-异丙基-4-氟苯基)磺酰胺基)-1-苯基丁醇-2-基)氨基甲酸酯。
2.权利要求1所述的化合物在制备抗艾滋病药物中的应用。
3.一种药物组合物以权利要求1所述的雷公藤类衍生物为有效成份与药学上可接受的一种或多种载体组成。
4.权利要求3所述的药物组合物在制备抗艾滋病药物中的应用。
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102755335A (zh) * | 2012-07-13 | 2012-10-31 | 中国科学院武汉病毒研究所 | 一种雷公藤甲素在制备治疗或预防艾滋病毒药物中的应用 |
| CN104478830A (zh) * | 2014-12-31 | 2015-04-01 | 中国医学科学院医药生物技术研究所 | 一组叔胺类拟肽衍生物及其在抑制hiv-1蛋白酶中的应用 |
| WO2015085447A1 (zh) * | 2013-12-11 | 2015-06-18 | 香港浸会大学 | 新的雷公藤甲素衍生物及其制备方法和用途 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102755335A (zh) * | 2012-07-13 | 2012-10-31 | 中国科学院武汉病毒研究所 | 一种雷公藤甲素在制备治疗或预防艾滋病毒药物中的应用 |
| WO2015085447A1 (zh) * | 2013-12-11 | 2015-06-18 | 香港浸会大学 | 新的雷公藤甲素衍生物及其制备方法和用途 |
| CN104478830A (zh) * | 2014-12-31 | 2015-04-01 | 中国医学科学院医药生物技术研究所 | 一组叔胺类拟肽衍生物及其在抑制hiv-1蛋白酶中的应用 |
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| HIV-1蛋白酶抑制剂研发新进展;杨志衡等;《中国新药杂志》;第23卷(第19期);2246-2254, 2260 * |
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