CN113105395B - 4-苯基磺酰基-1-三羟基苯甲酰基哌嗪-2-羧酰胺衍生物及其制备方法与应用 - Google Patents
4-苯基磺酰基-1-三羟基苯甲酰基哌嗪-2-羧酰胺衍生物及其制备方法与应用 Download PDFInfo
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- CN113105395B CN113105395B CN202110436413.4A CN202110436413A CN113105395B CN 113105395 B CN113105395 B CN 113105395B CN 202110436413 A CN202110436413 A CN 202110436413A CN 113105395 B CN113105395 B CN 113105395B
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 87
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 42
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- 239000007787 solid Substances 0.000 claims description 31
- 238000006243 chemical reaction Methods 0.000 claims description 23
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Abstract
本发明提供了一种4‑苯基磺酰基‑1‑三羟基苯甲酰基哌嗪‑2‑羧酰胺衍生物，具有如下通式IA或IB所示的结构。本发明还涉及该类衍生物的制备方法及其作为HIV抑制剂在制备抗艾滋病药物中的应用。
Description
技术领域
本发明涉及一种衍生物及其制备方法，具体涉及4-苯基磺酰基-1-三羟基苯甲酰基哌嗪-2-羧酰胺衍生物的制备及其在抗HIV药物领域的应用，属于有机合成与医药应用技术领域。
背景技术
艾滋病是获得性免疫缺陷综合征(Acquired immunodeficiency syndrome，AIDS)的简称，主要由感染人类免疫缺陷病毒1(Human immunodeficiency virus 1，HIV-1)引起。HIV通过攻击人体免疫系统中最重要的CD4+T淋巴细胞，使人体丧失免疫功能，从而出现多种感染，后期常常发生恶性肿瘤等并发症，最终导致全身衰竭而死亡。“高效抗逆转录病毒疗法”(Highly Active Antiretroviral Therapy，HAART)的普及为艾滋病患者带来福音，通过联合使用三种或三种以上靶向病毒不同复制时期的抗HIV-1药物，最大程度上降低艾滋病患者体内的病毒载量，从而降低艾滋病的发病率和死亡率。但是，由于HIV-1基因的高突变性，使其极易产生耐药性，加之HAART的长期使用导致费用高昂、药物蓄积毒性和药物依从性，不能彻底清除病毒从根本上治愈患者，从而限制了该疗法的广泛应用。因此，开发具有新靶点、新机制、新骨架的HIV-1抑制剂具有重要意义。
HIV-1逆转录酶(Reverse Transcriptase，RT)是病毒生命周期的关键酶，具有两种功能上不同的酶活性，即负责RNA依赖的、DNA依赖的DNA聚合酶活性(RDDP和DDDP)和RNase H活性，它们在病毒基因组RNA产生双链DNA过程中起协同作用。HIV-1RNase H裂解RNA/DNA杂合体的RNA链的同时，在正链DNA合成过程中降解引物tRNA，并降解多聚嘌呤束(PPTs)从而促进正链DNA的合成。RNase H的活性位点通常含有四个带负电荷的氨基酸残基，称为“DEDD”基序(由D443、E478、D498和D549催化性氨基酸残基组成)，而额外存在的组氨酸残基可以进一步提高催化效率，带负电荷的保守残基通过结合二价金属离子(Mg2+或Mn2+)从而发挥其催化活性。HIV-1RNase H作为新颖的HIV-1靶标，近年来得到了越来越多药物化学家的青睐。
为发现新一代HIV抑制剂，本发明公开了一类全新结构的4-苯基磺酰基-1-三羟基苯甲酰基哌嗪-2-羧酰胺衍生物类HIV-1RNase H抑制剂，现有技术中未见相关报道。
发明内容
本发明提供了4-苯基磺酰基-1-三羟基苯甲酰基哌嗪-2-羧酰胺衍生物及其制备方法，本发明还提供了上述化合物的部分活性筛选结果及其制药用途。
本发明的技术方案如下：
一、4-苯基磺酰基-1-三羟基苯甲酰基哌嗪-2-羧酰胺衍生物
本发明的4-苯基磺酰基-1-三羟基苯甲酰基哌嗪-2-羧酰胺衍生物，具有如下通式IA或IB所示的结构：
其中，
R1为氨基或氰基；R2为取代甲胺基、取代乙胺基或氮杂螺壬烷基，所述的取代基选自苯基、甲基-苯基、4-甲氧基苯基、呋喃基、噻吩基、联苯基、萘基。
根据本发明优选的，通式IA或IB中，R1为氨基或氰基；R2为N-苯基、N-甲基-N-苯基、N-4-甲氧基苄基、N-呋喃-2-基甲基、N-噻吩-2-基甲基、N-[[1,1'-联苯]-4-基甲基]、N-萘-2-基甲基、2,7-二氮杂螺[4.4]壬烷基。
进一步优选的，4-苯基磺酰基-1-三羟基苯甲酰基哌嗪-2-羧酰胺衍生物，是下列之一：
二、4-苯基磺酰基-1-三羟基苯甲酰基哌嗪-2-羧酰胺衍生物的制备方法
本发明4-苯基磺酰基-1-三羟基苯甲酰基哌嗪-2-羧酰胺衍生物的制备方法，以3,4,5-三苄氧基苯甲酸为初始原料，与1-Boc-3-甲基哌嗪-1,3-二羧酸酯或1-Boc-2-甲基哌嗪-1,2-二羧酸酯经酰化反应制得中间体，利用三氟乙酸和二氯甲烷溶液将Boc保护基脱去，然后经亲核取代反应、水解反应、酸胺缩合，最后在氢气和钯碳条件下脱去苄基得到目标化合物IA和IB。
化合物IA合成路线如下：
反应试剂与反应条件：i)1-Boc-3-甲基哌嗪-1,3-二羧酸酯，1-乙基-3(3-二甲基丙胺)碳二亚胺，1-羟基苯并三唑，三乙胺，N,N-二甲基甲酰胺，室温；ii)三氟乙酸、二氯甲烷，室温；iii)取代磺酰氯，三乙胺，二氯甲烷，室温；iv)氢氧化锂，水，四氢呋喃；v)2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯，N,N-二异丙基乙胺，0℃转室温；vi)氢气，钯碳，甲醇、二氯甲烷，室温。
化合物IB合成路线如下：
反应试剂与反应条件：i)1-Boc-2-甲基哌嗪-1,2-二羧酸酯，1-乙基-3(3-二甲基丙胺)碳二亚胺，1-羟基苯并三唑，三乙胺，N,N-二甲基甲酰胺，室温；ii)三氟乙酸，二氯甲烷，室温；iii)取代磺酰氯，三乙胺，二氯甲烷，室温；iv)氢氧化锂，水，四氢呋喃；v)2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯，N,N-二异丙基乙胺，0℃转室温；vi)氢气，钯碳，甲醇、二氯甲烷，室温。
其中，R1、R2如上述通式IA或IB中所述。
本发明4-苯基磺酰基-1-三羟基苯甲酰基哌嗪-2-羧酰胺衍生物的制备方法，以目标化合物IA为例，具体步骤如下：
(1)在冰浴条件下，将3,4,5-三苄氧基苯甲酸、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、1-羟基苯并三唑、三乙胺共称于250mL烧瓶中，加入适量N,N-二甲基甲酰胺溶解，搅拌15min后，撤去冰浴，室温搅拌1h。最后向加入1-Boc-3-甲基哌嗪-1,3-二羧酸酯，反应过夜，柱层析分离纯化得白色中间体1-(叔丁基)3-甲基4-(3,4,5-三(苄氧基)苯甲酰基)哌嗪-1,3-二羧酸酯(IA-b)；
(2)将IA-b溶于5mL二氯甲烷中，然后慢慢地加入三氟乙酸，室温搅拌6h。加入10mL水，用饱和的碳酸氢钠溶液调pH，二氯甲烷萃取，干燥，快速柱层析，得淡黄色1-(3,4,5-三(苄氧基)苯甲酰基)哌嗪-2-羧酸甲酯(IA-c)；
(3)在冰浴条件下，将1-(3,4,5-三(苄氧基)苯甲酰基)哌嗪-2-羧酸甲酯、三乙胺和相应的酰氯取代基共称于25mL烧瓶中，加入适量二氯甲烷溶解，移除冰浴，室温搅拌12h。用乙酸乙酯萃取，干燥，过滤，浓缩得淡黄色4-((4-硝基苯基)磺酰基)-1-(3,4,5-三(苄氧基)苯甲酰基)哌嗪-2-羧酸甲酯(IA-d)；
(4)将4-((4-硝基苯基)磺酰基)-1-(3,4,5-三(苄氧基)苯甲酰基)哌嗪-2-羧酸甲酯、一水合氢氧化锂共称于25mL烧瓶中，加入适量四氢呋喃和水(1:1)溶解，室温搅拌1.5h，TLC监测。调pH至5左右，有固体析出，抽滤，干燥得淡黄色4-((4-氨基苯基)磺酰基)-1-(3,4,5-三(苄氧基)苯甲酰基)哌嗪-2-羧酸(IA-e)；
(5)将4-((4-氨基苯基)磺酰基)-1-(3,4,5-三(苄氧基)苯甲酰基)哌嗪-2-羧酸和2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐共称于25mL烧瓶中，冰浴条件下加入适量二氯甲烷溶解，活化30min，然后向反应液中加入相应的取代胺和N,N-二异丙基乙胺，移除冰浴，室温搅拌8h。用乙酸乙酯萃取，干燥，浓缩得白色4-((4-硝基苯基)磺酰基)-N-苯基-1-(3,4,5-三(苄氧基)苯甲酰基)哌嗪-2-羧酰胺(IA-f)；
(6)将4-((4-硝基苯基)磺酰基)-N-苯基-1-(3,4,5-三(苄氧基)苯甲酰基)哌嗪-2-羧酰胺置于50mL圆底烧瓶中，加入适量二氯甲烷和甲醇(1:1)溶解，加入10％钯碳。通氢气，室温反应12h。硅藻土过滤，减压浓缩，重结晶得到目标产物IA。
所得目标化合物IA和IB结构见表1。
表1目标化合物的结构式
三、4-苯基磺酰基-1-三羟基苯甲酰基哌嗪-2-羧酰胺衍生物的应用
抑酶活性测试结果表明，4-苯基磺酰基-1-三羟基苯甲酰基哌嗪-2-羧酰胺衍生物是一系列结构新颖的HIV-1RNase H抑制剂，6个目标化合物表现出显著的HIV-1RNase H抑制活性，其中，化合物IA-6(IC50＝0.067±0.02μM)活性最优，说明该类化合物具有进一步研究的价值。
因此，本发明所提供的4-苯基磺酰基-1-三羟基苯甲酰基哌嗪-2-羧酰胺衍生物可作为HIV-1RNase H抑制剂用于制备抗艾滋病药物。
一种抗HIV-1的药物组合物，含有上述的4-苯基磺酰基-1-三羟基苯甲酰基哌嗪-2-羧酰胺衍生物及其药学上可接受的盐与药用辅料，制成不同剂型的药物。
具体实施方式
下面结合实施例对本发明做进一步说明，所有目标化合物的编号与表1相同，所述百分比数均为质量百分比。
实施例1：中间体1-(叔丁基)3-甲基4-(3,4,5-三(苄氧基)苯甲酰基)哌嗪-1,3-二羧酸酯(IA-b)的制备
称取3,4,5-三苄氧基苯甲酸(2.0180g，4.52mmol)置于250mL烧瓶中，加入50mL N,N-二甲基甲酰胺溶解，冰浴条件下加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(0.9322g，4.89mmol)，1-羟基苯并三唑(0.6425g，4.97mmol)，三乙胺(1.25mL，10.06mmol)，搅拌15min后，撤去冰浴，室温条件下搅拌1h。最后向烧瓶中加入1-Boc-3-甲基哌嗪-1,3-二羧酸酯或1-Boc-2-甲基哌嗪-1,2-二羧酸酯(1.0925g，5.51mmol)，反应过夜。反应毕，向反应液中加入150mL水，产生白色浑浊，混匀后转移至分液漏斗，用乙酸乙酯萃取(3×50mL)，合并有机相，依次用1N盐酸溶液和饱和碳酸氢钠溶液各洗涤2-3次，最后用饱和氯化钠溶液洗涤1-2次。将有机相转移至250mL锥形瓶中，加入适量的无水硫酸钠，干燥、过滤、浓缩得粗品。硅胶干法拌样，湿法装柱，柱层析分离纯化，浓缩得白色粉末状固体，产率：75％，mp：101-104℃。1H NMR(400MHz,DMSO-d6)δ7.42(t,J＝6.7Hz,6H),7.35(dd,J＝7.1,1.1Hz,3H),7.39–7.25(m,6H),6.95(s,2H),5.16(s,6H),4.78(t,J＝5.2Hz,1H),4.03(m,6H),3.67(s,3H),1.45(s,9H).ESI-MS:m/z 667.40(M+1).C39H42N2O8[666.77].
实施例2：中间体1-(3,4,5-三(苄氧基)苯甲酰基)哌嗪-2-羧酸甲酯(IA-c)的制备
称取IA-b(1.2305g，2.51mmol)溶于5mL二氯甲烷中，然后慢慢地向其中加入三氟乙酸(2.12mL，30mmol)，室温条件下搅拌6h。TLC检测反应完毕，向反应液中加入10mL水，用饱和的碳酸氢钠溶液调pH为9，二氯甲烷萃取三次，饱和氯化钠溶液洗涤2-3次，合并有机层，无水硫酸钠干燥。然后经快速柱层析，乙酸乙酯-石油醚体系中重结晶得淡黄色固体，产率：81％，mp：156-158℃。1H NMR(400MHz,DMSO-d6)δ7.42(t,J＝6.7Hz,6H),7.35(dd,J＝7.1,1.1Hz,3H),7.39–7.25(m,6H),6.95(s,2H),5.16(s,6H),4.78(t,J＝5.2Hz,1H),4.03(m,6H),3.67(s,3H),1.08(s,1H,NH).ESI-MS:m/z 565.13(M-1).C34H34N2O6[566.77].
实施例3：中间体4-((4-硝基苯基)磺酰基)-1-(3,4,5-三(苄氧基)苯甲酰基)哌嗪-2-羧酸甲酯(IA-d-1)的制备
称取中间体IA-c(1.5012g，0.18mmol)加入到50mL烧瓶中，加入20mL二氯甲烷溶解，冰浴条件下依次向反应瓶中加入三乙胺(0.75mL，0.36mmol)和对硝基苯磺酰氯(0.9212g，0.27mmol)，30min后移除冰浴，室温搅拌12h。TLC检测反应完毕，将反应液浓缩，用乙酸乙酯萃取三次，合并有机相，依次用1N盐酸溶液和饱和碳酸氢钠溶液各洗涤2-3次，最后用饱和氯化钠溶液洗涤1-2次。将有机相转移至250mL锥形瓶中，加入适量的无水硫酸钠，干燥、过滤、浓缩得淡黄色粉末状固体，产率：77％，mp：78-81℃。1H NMR(400MHz,DMSO-d6)δ8.49(d,J＝8.7Hz,2H),8.04(d,J＝8.5Hz,2H),7.39(d,J＝6.8Hz,6H),7.37–7.31(m,3H),7.28(d,J＝7.0Hz,6H),6.70(s,2H),5.14(s,6H),4.18(s,1H),3.74(s,3H),3.29–3.21(m,6H).ESI-MS:m/z 750.09(M-1).C40H37N3O10S[751.81].
实施例4：中间体4-((4-氨基苯基)磺酰基)-1-(3,4,5-三(苄氧基)苯甲酰基)哌嗪-2-羧酸(IA-e-1)的制备
称取中间体IA-d(1.015g，0.21mmol)加入到25mL烧瓶中，加入50mL四氢呋喃和水(1:1)溶解，再加入一水合氢氧化锂(0.2018g，0.53mmol)，室温搅拌1.5h。TLC检测反应完毕，减压除去多余溶剂，调pH至5左右，有浅黄色固体析出，抽滤，干燥得淡黄色固体，产率：96％，mp：123.5-126.5℃。1H NMR(400MHz,DMSO-d6)δ12.31(s,1H,COOH),8.49(d,J＝8.7Hz,2H),8.04(d,J＝8.5Hz,2H),7.39(d,J＝6.8Hz,6H),7.37–7.31(m,3H),7.28(d,J＝7.0Hz,6H),6.70(s,2H),5.14(s,6H),4.18(s,1H),3.29–3.21(m,6H).ESI-MS:m/z736.19(M-1).C39H35N3O10S[737.20]
实施例5：中间体4-((4-硝基苯基)磺酰基)-N-苯基-1-(3,4,5-三(苄氧基)苯甲酰基)哌嗪-2-羧酰胺(IA-f-1)的制备
称取中间体IA-e(0.1028g，0.28mmol)和HATU(0.0215g，0.42mmol)于25mL烧瓶中，冰浴条件下加入15mL二氯甲烷溶解，冰浴活化30min，然后向反应液中加入苯胺(0.0224g，0.42mmol)和DIEA(68μL，0.84mmol)，移除冰浴，室温搅拌8h。TLC检测反应完毕，减压除去多余溶剂，用乙酸乙酯萃取三次，合并有机相，无水硫酸钠干燥，浓缩得白色粗品0.08g，产率：73％，mp：105-108℃。1H NMR(400MHz,DMSO-d6)δ9.33(s,1H),8.32(d,J＝8.8Hz,2H),7.92(d,J＝8.9Hz,2H),7.54–7.49(m,2H),7.42(dd,J＝7.1,1.1Hz,6H),7.35(tt,J＝7.1,1.3Hz,8H),7.32–7.26(m,3H),7.08(tt,J＝7.0,1.2Hz,1H),6.97(s,2H),5.14–5.05(m,6H),4.91(t,J＝5.0Hz,1H),3.95(ddd,J＝12.5,6.7,4.6Hz,1H),3.87–3.79(m,2H),3.68(dd,J＝12.4,5.0Hz,1H),3.29–3.21(m,2H).ESI-MS:m/z 812.14(M-1).C45H40N4O9S[813.25].
实施例6：终产物IA的通用制法
称取中间体IA-f约0.1g于50mL圆底烧瓶中，加入适量二氯甲烷和甲醇(1:1)溶解，加两倍量的10％钯碳。反应体系通氢气，室温反应12h。反应液经硅藻土过滤，减压浓缩，重结晶得到目标产物IA。
4-((4-氨基苯基)磺酰基)-N-苯基-1-(3,4,5-三羟基苯甲酰基)哌嗪-2-羧酰胺(IA-1).由中间体IA-f-1脱苄基得，经乙酸乙酯洗涤得白色粉末状固体0.08g，产率：67％，mp：120-123℃。1H NMR(400MHz,DMSO-d6)δ10.08(s,1H),9.33(s,2H),8.78(s,1H),8.06(d,J＝7.9Hz,2H),7.88(d,J＝8.2Hz,2H),7.54(d,J＝7.9Hz,2H),7.19(d,J＝7.5Hz,1H),7.12(d,J＝7.5Hz,2H),6.48(s,2H),6.15(s,2H,NH2),4.04(q,J＝7.1Hz,1H),3.34–2.82(m,6H).13C NMR(100MHz,DMSO-d6)δ171.04,169.87,152.95,146.19,138.75,138.17,131.67,129.08,128.36,128.35,124.70,120.96,114.30,106.67,52.88,48.53,45.92,45.81.ESI-MS:m/z 511.18(M-1),535.11[M+23].C24H24N4O7S[512.54].
4-((4-氨基苯基)磺酰基)-N-甲基-N-苯基-1-(3,4,5-三羟基苯甲酰基)哌嗪-2-羧酰胺(IA-2).由中间体IA-f-2脱苄基，经乙酸乙酯洗涤得白色粉末状固体0.15g，产率：83％，mp：138-141℃。1H NMR(400MHz,DMSO-d6)δ9.33(s,2H),8.78(s,1H),8.06(d,J＝7.9Hz,2H),7.88(d,J＝8.2Hz,2H),7.54(d,J＝7.9Hz,2H),7.19(d,J＝7.5Hz,1H),7.12(d,J＝7.5Hz,2H),6.48(s,2H),6.15(s,2H,NH2),4.04(q,J＝7.1Hz,1H),3.42(s,3H),3.34–2.82(m,6H).13C NMR(100MHz,DMSO-d6)δ169.84,168.95,152.95,146.19,142.07,138.75,131.67,129.08,128.89,128.36,126.45,123.98,114.30,106.67,52.62,49.21,45.87,32.86.ESI-MS:m/z 549.61(M+23).C25H26N4O7S[526.56].
4-((4-氰基苯基)磺酰基)-N-苯基-1-(3,4,5-三羟基苯甲酰基)哌嗪-2-羧酰胺(IA-3).由中间体IA-f-3脱苄基，经乙酸乙酯洗涤得白色固体粉末0.08g，产率：67％，mp：126-129℃。1H NMR(400MHz,DMSO-d6)δ10.35(s,1H),10.08(s,1H),9.33(s,1H),8.78(s,1H),8.06(d,J＝7.9Hz,2H),7.88(d,J＝8.2Hz,2H),7.54(d,J＝7.9Hz,2H),7.19(d,J＝7.5Hz,1H),7.12(d,J＝7.5Hz,2H),6.48(s,2H),4.04(q,J＝7.1Hz,1H),3.34–2.82(m,6H).13C NMR(100MHz,DMSO-d6)δ171.04,169.87,146.19,141.40,138.75,138.17,132.78,129.08,128.36,127.89,124.70,120.96,118.27,116.35,106.67,52.88,48.53,45.92,45.81.ESI-MS:m/z 521.14(M-1).C25H22N4O7S[522.53].
4-((4-氰基苯基)磺酰基)-N-甲基-N-苯基-1-(3,4,5-三羟基苯甲酰基)哌嗪-2-羧酰胺(IA-4).由中间体IA-f-4脱苄基，经乙酸乙酯洗涤得白色固体粉末0.12g，产率：75％，mp：186-189℃。1H NMR(400MHz,DMSO-d6)δ9.33(s,2H),8.78(s,1H),8.06(d,J＝7.9Hz,2H),7.88(d,J＝8.2Hz,2H),7.54(d,J＝7.9Hz,2H),7.19(d,J＝7.5Hz,1H),7.12(d,J＝7.5Hz,2H),6.48(s,2H),4.04(q,J＝7.1Hz,1H),3.42(s,3H),3.34–2.82(m,6H).13C NMR(100MHz,DMSO-d6)δ169.84,168.95,146.19,142.07,141.40,138.75,132.78,128.89,128.36,127.89,126.45,123.98,118.27,116.35,106.67,52.62,49.21,45.93,45.81,32.86.ESI-MS:m/z 535.14(M-1).C26H24N4O7S[536.56].
4-((4-氨基苯基)磺酰基)-N-(4-甲氧基苄基)-1-(3,4,5-三羟基苯甲酰基)哌嗪-2-羧酰胺(IA-5).由中间体IA-f-5脱苄基，经乙酸乙酯洗涤得白色固体粉末0.13g，产率：86％，mp：192-195℃。1H NMR(400MHz,DMSO-d6)δ10.25(s,1H),10.08(s,1H),9.11(s,2H),7.33(d,J＝8.4Hz,2H),7.20(s,2H),6.88(d,J＝8.5Hz,2H),6.65(s,2H),6.28(d,J＝12.0Hz,2H),6.15(s,2H,NH2),4.27(s,2H),4.04(q,J＝7.1Hz,1H),3.74(s,3H),3.34–2.82(m,6H).13C NMR(100MHz,DMSO-d6)δ170.44,169.87,158.96,152.95,146.19,138.75,134.12,131.67,129.16,129.08,128.36,114.30,113.92,106.67,55.32,52.88,48.62,45.87,45.82,43.71.ESI-MS:m/z 555.34(M-1).C26H28N4O8S[556.59].
4-((4-氨基苯基)磺酰基)-N-(呋喃-2-基甲基)-1-(3,4,5-三羟基苯甲酰基)哌嗪-2-羧酰胺(IA-6).由中间体IA-f-6脱苄基，经乙酸乙酯洗涤得白色固体粉末0.14g，产率：82％，mp：181-184℃。1H NMR(400MHz,DMSO-d6)δ9.77(s,1H),9.08(s,2H),8.48(s,1H),8.03(dt,J＝12.2,5.8Hz,1H),7.44–7.27(m,2H),6.66(d,J＝7.4Hz,2H),6.35(d,J＝7.4Hz,2H),6.26(s,2H),6.13(s,2H,NH2),4.03(q,J＝7.1Hz,1H),3.84(s,2H),3.23–3.06(m,6H).13C NMR(100MHz,DMSO-d6)δ170.45,169.87,153.82,152.95,146.19,142.29,138.75,131.67,129.08,128.36,114.30,110.56,107.58,106.67,52.88,48.61,45.87,28.98.ESI-MS:m/z 515.23(M-1).C23H24N4O8S[516.53].
4-((4-氰基苯基)磺酰基)-N-(4-甲氧基苄基)-1-(3,4,5-三羟基苯甲酰基)哌嗪-2-羧酰胺(IA-7).由中间体IA-f-7脱苄基，经乙酸乙酯洗涤得白色固体颗粒0.25g，产率：63％，mp：201-204℃。1H NMR(400MHz,DMSO-d6)δ10.05(s,1H),9.21(s,1H),8.66(s,1H),8.45(s,1H),8.09(d,J＝8.4Hz,2H),7.82(d,J＝8.3Hz,2H),7.34(d,J＝6.6Hz,2H),7.30(d,J＝6.7Hz,2H),6.41(s,2H),4.19(s,2H),3.65(s,3H),3.58–3.51(m,1H),3.11–3.08(m,6H).13C NMR(100MHz,DMSO-d6)δ170.44,169.87,158.96,146.19,141.39,138.75,134.12,132.78,129.16,128.36,127.89,118.27,116.35,113.92,106.67,55.32,52.88,48.62,45.87,45.82,43.71.ESI-MS:m/z 565.26(M-1).C27H26N4O8S[566.59].
4-((4-氨基苯基)磺酰基)-N-(噻吩-2-基甲基)-1-(3,4,5-三羟基苯甲酰基)哌嗪-2-羧酰胺(IA-8).由中间体IA-f-8脱苄基，经乙酸乙酯洗涤得白色固体粉末0.25g，产率：68％，mp：179-181℃。1H NMR(400MHz,DMSO-d6)δ9.65(s,1H),9.14(s,1H),8.78(s,1H),8.66(s,1H),7.50(d,J＝8.5Hz,2H),7.39(s,3H),7.28(s,2H),6.95(d,J＝8.4Hz,2H),6.74(s,2H,NH2),4.52(s,2H),4.40–4.14(m,1H),3.60–3.43(m,6H).13C NMR(100MHz,DMSO-d6)δ170.33,169.87,152.95,146.19,142.20,138.75,131.67,129.08,128.36,125.84,125.75,125.05,114.30,106.67,52.88,48.62,45.87,45.82,39.26.ESI-MS:m/z 531.35(M-1).C23H24N4O7S2[532.60].
N-([[1,1'-联苯]-4-基甲基]-4-((4-氨基苯基)磺酰基)-1-(3,4,5-三羟基苯甲酰基)哌嗪-2-羧酰胺(IA-9).由中间体IA-f-9脱苄基，经乙酸乙酯洗涤得白色固体颗粒0.16g，产率：62％，mp：193-196℃。1H NMR(400MHz,DMSO-d6)δ9.12(s,2H),8.60(s,1H),8.52(s,1H),7.68–7.65(m,2H),7.62(d,J＝8.1Hz,2H),7.48–7.34(m,7H),6.67(d,J＝8.7Hz,2H),6.31(s,2H),6.15(s,2H,NH2),4.40(s,2H),4.13–3.99(m,1H),3.60–3.51(m,6H).13CNMR(100MHz,DMSO-d6)δ171.33,168.89,153.91,146.19,140.48,139.12,135.31,130.11,129.40,128.06,127.77,127.08,127.05,119.31,113.28,106.67,52.88,48.62,45.87,42.48.ESI-MS:m/z 603.74(M+1).C31H30N4O7S[602.68].
N-([[1,1'-联苯]-4-基甲基]-4-((4-氰基苯基)磺酰基)-1-(3,4,5-三羟基苯甲酰基)哌嗪-2-羧酰胺(IA-10).由中间体IA-f-10脱苄基，经乙酸乙酯洗涤得白色固体颗粒0.29g，产率：74％，mp：197-200℃。1H NMR(400MHz,DMSO-d6)δ9.13(s,2H),8.65(s,1H),8.57(s,1H),8.16(d,J＝8.4Hz,2H),7.90(d,J＝8.4Hz,2H),7.64–7.58(m,7H),7.47(s,2H),7.37(d,J＝6.0Hz,2H),4.39(s,2H),4.26–3.99(m,1H),3.67–3.59(m,6H).13C NMR(100MHz,DMSO-d6)δ171.22,146.19,140.45,139.16,135.35,134.16,129.08,128.74,127.58,127.07,118.12,116.26,54.05,48.62,42.42.ESI-MS:m/z 611.13(M-1).C32H28N4O7S[612.66].
4-((4-氰基苯基)磺酰基)-N-(呋喃-2-基甲基)-1-(3,4,5-三羟基苯甲酰基)哌嗪-2-羧酰胺(IA-11).由中间体IA-f-11脱苄基，经乙酸乙酯洗涤得白色固体颗粒0.37g，产率：88％，mp：169-172℃。1H NMR(400MHz,DMSO-d6)δ9.77(s,1H),9.08(s,2H),8.48(s,1H),8.03(dt,J＝12.2,5.8Hz,1H),7.44–7.27(m,2H),6.66(d,J＝7.4Hz,2H),6.35(d,J＝7.4Hz,2H),6.26(s,2H),4.03(q,J＝7.1Hz,1H),3.84(s,2H),3.23–3.06(m,6H).13C NMR(100MHz,DMSO-d6)δ170.45,169.87,153.82,146.19,142.29,141.39,138.75,132.78,128.36,127.89,118.27,116.35,110.56,107.58,106.67,52.88,48.61,45.87,45.82,36.39.ESI-MS:m/z 525.55(M-1).C24H22N4O8S[526.52].
4-((4-氰基苯基)磺酰基)-N-(萘-2-基甲基)-1-(3,4,5-三羟基苯甲酰基)哌嗪-2-羧酰胺(IA-12).由中间体IA-f-12脱苄基，经乙酸乙酯洗涤得白色固体颗粒0.24g，产率：82％，mp：178-181℃。1H NMR(400MHz,DMSO-d6)δ9.15(s,2H),8.54(s,1H),8.48(s,1H),7.99–7.81(m,3H),7.59–7.51(m,2H),7.41(p,J＝9.2,8.5Hz,4H),6.60(d,J＝8.7Hz,2H),6.29(s,2H),4.36(s,2H),4.03(q,J＝7.1Hz,1H),3.57–3.46(m,6H).13C NMR(100MHz,DMSO-d6)δ170.44,169.87,146.19,141.39,138.75,137.95,134.22,133.44,132.78,128.42,128.36,128.30,127.89,127.74,127.59,126.80,126.50,126.43,118.27,116.35,106.67,52.88,48.62,45.87,45.82,44.02.ESI-MS:m/z 585.95(M-1).C30H26N4O7S[586.62].
化合物IB合成与IA类似，所不同的是采用1-Boc-2-甲基哌嗪-1,2-二羧酸酯为原料。各步骤中间体及终产物结构信息如下：
中间体1-(叔丁基)2-甲基4-(3,4,5-三(苄氧基)苯甲酰基)哌嗪-1,2-二羧酸酯(IB-b):白色粉末状固体，产率：75％，mp：109-112℃。1H NMR(400MHz,DMSO-d6)δ7.42(t,J＝6.7Hz,6H),7.36(dd,J＝7.1,1.1Hz,3H),7.32–7.25(m,3H),7.14(s,2H),6.94(s,3H),5.14(s,6H),4.73(t,J＝5.1Hz,1H),4.00–3.89(m,6H),3.66(s,3H),1.46(s,9H).ESI-MS:m/z667.40(M+1).C39H42N2O8[666.77].
中间体4-(3,4,5-三(苄氧基)苯甲酰基)哌嗪-2-羧酸甲酯(IB-c):白色固体，产率80％，mp：78-81℃。1H NMR(400MHz,DMSO-d6)δ7.42(t,J＝6.7Hz,6H),7.36(dd,J＝7.1,1.1Hz,3H),7.32–7.25(m,3H),7.14(s,2H),6.94(s,3H),5.14(s,6H),4.73(t,J＝5.1Hz,1H),4.00–3.89(m,6H),3.66(s,3H),1.07(s,1H,NH).ESI-MS:m/z 565.04(M-1),567.10(M+1).C34H34N2O6[566.77].
中间体1-((4-硝基苯基)磺酰基)-4-(3,4,5-三(苄氧基)苯甲酰基)哌嗪-2-羧酸甲酯(IB-d):无色透明油状液体，产率：62％。1H NMR(400MHz,DMSO-d6)δ8.44(d,J＝8.8Hz,2H),8.08(d,J＝8.9Hz,2H),7.50–7.40(m,6H),7.40–7.32(m,6H),7.29(d,J＝7.1Hz,3H),6.70(s,2H),5.00(s,6H),4.04(q,J＝7.1Hz,1H),3.75(s,3H),3.34–2.82(m,6H).ESI-MS:m/z750.91(M+1).C40H37N3O10S[751.22].
中间体1-((4-硝基苯基)磺酰基)-4-(3,4,5-三(苄氧基)苯甲酰基)哌嗪-2-羧酸(IB-e):淡黄色固体颗粒，产率：94％，mp：115-118℃。1H NMR(400MHz,DMSO-d6)δ12.32(s,1H,COOH),8.44(d,J＝8.8Hz,2H),8.08(d,J＝8.9Hz,2H),7.50–7.40(m,6H),7.40–7.32(m,6H),7.29(d,J＝7.1Hz,3H),6.70(s,2H),5.00(s,6H),4.04(q,J＝7.1Hz,1H),3.34–2.82(m,6H).ESI-MS:m/z 736.13(M-1).C39H35N3O10S[737.78].
中间体1-((4-硝基苯基)磺酰基)-N-苯基-4-(3,4,5-三(苄氧基)苯甲酰基)哌嗪-2-羧酰胺(IB-f-1):白色固体粉末，产率：84％，mp：153-156℃。1H NMR(400MHz,DMSO-d6)δ9.43(s,1H),8.35(d,J＝8.8Hz,2H),8.06(d,J＝8.9Hz,2H),7.55–7.49(m,2H),7.42(dd,J＝7.1,1.1Hz,6H),7.35(tt,J＝7.1,1.2Hz,8H),7.32–7.26(m,3H),7.08(tt,J＝7.0,1.2Hz,1H),6.94(s,2H),5.14–5.05(m,6H),4.61(t,J＝5.4Hz,1H),3.89–3.77(m,3H),3.64–3.58(m,2H),3.56–3.48(m,1H).ESI-MS:m/z 812.14(M-1).C45H40N4O9S[813.25].
1-((4-氨基苯基)磺酰基)-N-苯基-4-(3,4,5-三羟基苯甲酰基)哌嗪-2-羧酰胺(IB-1).由中间体IB-f-1脱苄基，经乙酸乙酯洗涤得白色固体颗粒0.25g，产率：75％，mp：173-176℃。1H NMR(400MHz,DMSO-d6)δ10.03(s,1H),9.07(s,2H),8.43(s,1H),7.37(d,J＝8.4Hz,4H),7.28(t,J＝7.8Hz,2H),7.05(t,J＝7.3Hz,1H),6.53(d,J＝8.5Hz,2H),6.24(s,2H),6.02(s,2H,NH2),3.75(q,J＝7.1Hz,1H),3.71–3.45(m,6H).13C NMR(100MHz,DMSO-d6)δ170.16,168.03,153.52,146.06,138.75,135.13,129.41,129.07,125.50,124.02,123.67,120.37,113.14,106.74,54.87,42.26,34.85.ESI-MS:m/z 511.22(M-1).C24H24N4O7S[512.54].
1-((4-氨基苯基)磺酰基)-N-甲基-N-苯基-4-(3,4,5-三羟基苯甲酰基)哌嗪-2-羧酰胺(IB-2).由中间体IB-f-2脱苄基得，经乙酸乙酯洗涤得白色固体颗粒0.08g，产率：61％，mp：172-175℃。1H NMR(400MHz,DMSO-d6)δ9.23(s,2H),9.02(s,1H),7.61(d,J＝8.5Hz,2H),7.38–7.32(m,5H),6.89(d,J＝8.7Hz,2H),6.62(d,J＝8.1Hz,2H),6.09(s,2H,NH2),5.12(s,3H),4.97–4.89(m,1H),4.04(t,J＝5.7Hz,2H),3.01(s,4H).13C NMR(100MHz,DMSO-d6)δ169.77,169.45,152.90,146.20,142.18,138.75,131.13,129.16,128.89,128.35,126.45,123.98,114.23,106.89,55.57,46.55,45.49,45.10,32.79.ESI-MS:m/z525.57(M-1).C25H26N4O7S[526.56].
1-((4-氨基苯基)磺酰基)-N-(4-甲氧基苄基)-4-(3,4,5-三羟基苯甲酰基)哌嗪-2-羧酰胺(IB-3).由中间体IB-f-3脱苄基，经乙酸乙酯洗涤得白色固体颗粒0.09g，产率：69％，mp：202-205℃。1H NMR(400MHz,DMSO-d6)δ9.08(s,2H),8.49(s,1H),8.25(s,1H),7.37(d,J＝8.4Hz,2H),7.06(s,2H),6.86(d,J＝8.2Hz,2H),6.59(d,J＝8.5Hz,2H),6.25(s,2H),6.04(s,2H,NH2),4.31(s,2H),4.10(dd,J＝14.5,5.6Hz,1H),3.73(s,3H),3.68–3.43(m,6H).13C NMR(100MHz,DMSO-d6)δ170.26,169.00,158.72,153.50,146.01,135.20,131.22,129.48,129.11,125.62,124.00,114.16,113.14,106.95,55.53,54.68,42.07,40.45.ESI-MS:m/z 555.79(M-1).C26H28N4O8S[556.59].
1-((4-氨基苯基)磺酰基)-N-(呋喃-2-基甲基)-4-(3,4,5-三羟基苯甲酰基)哌嗪-2-羧酰胺(IB-4).由中间体IB-f-4脱苄基，经乙酸乙酯洗涤得白色固体颗粒0.07g，产率：58％，mp：195-198℃。1H NMR(400MHz,DMSO-d6)δ9.77(s,1H),9.08(s,2H),8.48(s,1H),8.03(dt,J＝12.2,5.8Hz,1H),7.44–7.27(m,2H),6.66(d,J＝7.4Hz,2H),6.35(d,J＝7.4Hz,2H),6.26(s,2H),6.13(s,2H,NH2),4.03(q,J＝7.1Hz,1H),3.84(s,2H),3.23–3.06(m,6H).13C NMR(100MHz,DMSO-d6)δ170.71,169.45,153.75,152.90,146.20,142.29,138.75,131.08,129.16,128.35,114.23,110.56,107.58,106.89,58.18,46.74,45.49,45.05,36.39.ESI-MS:m/z 515.43(M-1).C23H24N4O8S[516.53].
1-((4-氨基苯基)磺酰基)-N-(萘-1-基甲基)-4-(3,4,5-三羟基苯甲酰基)哌嗪-2-羧酰胺(IB-5).由中间体IB-f-5脱苄基，经乙酸乙酯洗涤得白色固体颗粒0.12g，产率：67％，mp：189-192℃。1H NMR(400MHz,DMSO-d6)δ9.15(s,2H),8.54(s,1H),8.48(s,1H),7.99–7.81(m,3H),7.59–7.51(m,2H),7.41(p,J＝9.2,8.5Hz,4H),6.60(d,J＝8.7Hz,2H),6.29(s,2H),6.13(s,2H,NH2),4.36(s,2H),4.03(q,J＝7.1Hz,1H),3.57–3.46(m,6H).13CNMR(100MHz,DMSO-d6)δ170.40,169.21,153.52,146.06,135.19,134.24,133.68,131.34,129.47,128.93,128.09,126.84,126.29,125.92,124.01,123.86,113.12,106.89,60.24,54.59,21.24.ESI-MS:m/z575.86(M-1).C29H28N4O8S[576.17].
1-((4-氨基苯基)磺酰基)-N-(噻吩-2-基甲基)-4-(3,4,5-三羟基苯甲酰基)哌嗪-2-羧酰胺(IB-6).由中间体IB-f-6脱苄基，经乙酸乙酯洗涤得白色固体颗粒0.13g，产率：72％，mp：213-216℃。1H NMR(400MHz,DMSO-d6)δ9.08(s,1H),8.74(s,1H),8.18(s,2H),7.53(dd,J＝5.1,1.3Hz,1H),7.46–7.32(m,4H),7.28(t,J＝3.6Hz,2H),7.13(s,1H),7.03(dd,J＝5.1,3.5Hz,1H),6.70(s,2H),5.08(q,J＝5.6,4.0Hz,2H),4.56(d,J＝5.4Hz,2H),4.47–4.27(m,1H),3.63–3.60(m,2H),3.14(d,J＝3.2Hz,2H).13C NMR(100MHz,DMSO-d6)δ161.03,140.45,128.89,128.61,128.54,128.36,128.07,127.56,127.27,126.77,74.77,70.76,54.08,43.14,42.31.ESI-MS:m/z 531.84(M-1).C23H24N4O7S2[532.59].
N-([[1,1'-联苯]-4-基甲基]-1-((4-氨基苯基)磺酰基)-4-(3,4,5-三羟基苯甲酰基)哌嗪-2-羧酰胺(IB-7).由中间体IB-f-7脱苄基，经乙酸乙酯洗涤得白色固体颗粒0.12g，产率：67％，mp：192-195℃。1H NMR(400MHz,DMSO-d6)δ9.11(s,2H),8.52(s,1H),8.42(s,1H),7.66(d,J＝7.1Hz,2H),7.59(d,J＝8.1Hz,2H),7.48–7.34(m,5H),7.23(s,2H),6.61(d,J＝8.8Hz,2H),6.28(s,2H),6.06(s,2H,NH2),4.41(s,2H),4.21(t,J＝7.4Hz,2H),4.03(q,J＝7.1Hz,1H),3.69(d,J＝11.9Hz,2H),3.54–3.40(m,2H).13C NMR(100MHz,DMSO-d6)δ171.22,146.19,140.45,139.16,135.35,134.16,129.08,128.74,127.58,127.07,118.12,116.26,54.05,48.62,42.42.ESI-MS:m/z 601.5(M-1).C31H30N4O7S[602.18].
7-(1-(((4-氨基苯基)磺酰基)-4-(3,4,5-三羟基苯甲酰基)哌嗪-2-羰基)-2,7-二氮杂螺[4.4]壬烷-2-羧酸叔丁酯(IB-8).由中间体IB-f-8脱苄基，经乙酸乙酯洗涤得白色固体颗粒0.04g，产率：66％，mp：254-257℃。1H NMR(400MHz,DMSO-d6)δ9.10(s,2H),8.42(s,1H),7.42(d,J＝8.4Hz,2H),7.31(s,2H),6.67–6.61(m,2H),6.08(s,2H,NH2),4.36–4.29(m,2H),3.88–3.78(m,1H),3.75–3.71(m,1H),3.71–3.63(m,2H),3.61–3.36(m,9H),1.90–1.78(m,2H),1.73(dddd,J＝12.3,8.0,4.8,3.1Hz,2H),1.47(s,9H).13C NMR(100MHz,DMSO-d6)δ169.84,169.45,155.75,152.90,146.20,138.75,131.15,129.16,128.35,114.23,106.89,79.75,59.60,59.06,57.54,49.16,47.29,47.15,46.60,45.49,45.10,37.71,37.66,28.39.ESI-MS:m/z644.86(M-1).C30H39N5O9S[645.25].
实施例7：核糖核酸酶H(RNase H)抑制活性测试实验
实验材料：
由大肠杆菌表达并经纯化的野生型HIV-1BH10逆转录酶；合成寡核苷酸31Trna(5′-UUUUUUUUUAGGAUACAUAUGGUUAAAGUAU-3′)和21P(5′-ATACTTTAACCATATG TATCC-3′)(购买自Sigma)。
实验步骤：
核糖核酸酶H活性经由模板-引物31Trna/21P测定。模板RNA5’末端由[γ-32P]ATP((购买自Perkin Elmer)和T4多核苷酸激酶((购买自New England Biolabs)标记，然后经小型Quick SpinTM柱((购买自Roche)纯化。标记好的模板在含50mM NaCl的50mM Tris-HCl(pH 8.0)中退火至21-nt引物(21P)。在30μL的50mM Tris-HCl(pH 8.0)、50mM NaCl、5mMMgCl2、25nM 32P-labeled模板-引物(31Trna/21P)，及5％二甲基亚砜(DMSO)溶液中，20-40nM HIV-1逆转录酶在37℃下进行核糖核酸酶H裂解测定4分钟。化合物的稀释液在37℃下于逆转录酶缓冲液中与逆转录酶进行预孵育，之后加入标记的模板-引物使反应开始。在适当的时间取出少许并以等量样品缓冲液[10mM EDTA的90％甲酰胺(包含二甲苯蓝FF(3mg/mL)和溴酚蓝(3mg/mL))溶液]淬灭后，进行变性聚丙烯酰胺凝胶电泳分析。
实验结果：
对表1所示20个化合物进行抗HIV-1RNase H活性筛选，其HIV-1RNase H抑制活性数据见表2。阳性对照药为β-侧柏酚(β-thujaplicinol)。
表2目标化合物对野生型HIV-1RNase H的抑制活性
a体外抑制50％RNase H活性的浓度。
b溶解性差，未测试。
如表2所示，6个目标化合物对于HIV-1RNase H表现出较强的抑制活性，IC50值在0.067～0.56μM之间。其中，尤其以化合物IA-6的活性最高(IC50＝0.067±0.02μM)，约为阳性对照β-thujaplicinol(IC50＝1.98±0.22μM)的30倍。
Claims (7)
1.4-苯基磺酰基-1-三羟基苯甲酰基哌嗪-2-羧酰胺衍生物，具有如下通式IA或IB所示的结构：
其中，
R1为氨基或氰基；R2为N-苯基、取代甲胺基、取代乙胺基或氮杂螺壬烷基，所述的取代基选自苯基、甲基-苯基、4-甲氧基苯基、呋喃基、噻吩基、联苯基、萘基。
2.如权利要求1所述的4-苯基磺酰基-1-三羟基苯甲酰基哌嗪-2-羧酰胺衍生物，其特征在于，通式IA或IB中，R1为氨基或氰基；R2为N-苯基、N-甲基-N-苯基、N-4-甲氧基苄基、N-呋喃-2-基甲基、N-噻吩-2-基甲基、N-[[1,1'-联苯]-4-基甲基]、N-萘-2-基甲基、2,7-二氮杂螺[4.4]壬烷基。
3.4-苯基磺酰基-1-三羟基苯甲酰基哌嗪-2-羧酰胺衍生物，其特征在于，化合物为下列之一：
4.如权利要求1或2所述的4-苯基磺酰基-1-三羟基苯甲酰基哌嗪-2-羧酰胺衍生物的制备方法，其特征在于，包括步骤：
以3,4,5-三苄氧基苯甲酸为初始原料，与1-Boc-3-甲基哌嗪-1,3-二羧酸酯或1-Boc-2-甲基哌嗪-1,2-二羧酸酯经酰化反应制得中间体，利用三氟乙酸和二氯甲烷溶液将Boc保护基脱去，然后经亲核取代反应、水解反应、酸胺缩合，最后在氢气和钯碳条件下脱去苄基得到目标化合物IA和IB；
化合物IA合成路线如下：
反应试剂与反应条件：i)1-Boc-3-甲基哌嗪-1,3-二羧酸酯，1-乙基-3(3-二甲基丙胺)碳二亚胺，1-羟基苯并三唑，三乙胺，N,N-二甲基甲酰胺，室温；ii)三氟乙酸、二氯甲烷，室温；iii)取代磺酰氯，三乙胺，二氯甲烷，室温；iv)氢氧化锂，水，四氢呋喃；v)2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯，N,N-二异丙基乙胺，0℃转室温；vi)氢气，钯碳，甲醇、二氯甲烷，室温；
化合物IB合成路线如下：
反应试剂与反应条件：i)1-Boc-2-甲基哌嗪-1,2-二羧酸酯，1-乙基-3(3-二甲基丙胺)碳二亚胺，1-羟基苯并三唑，三乙胺，N,N-二甲基甲酰胺，室温；ii)三氟乙酸，二氯甲烷，室温；iii)取代磺酰氯，三乙胺，二氯甲烷，室温；iv)氢氧化锂，水，四氢呋喃；v)2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯，N,N-二异丙基乙胺，0℃转室温；vi)氢气，钯碳，甲醇、二氯甲烷，室温；
其中，R1、R2如权利要求1或2中通式IA或IB中所述。
5.如权利要求4所述的4-苯基磺酰基-1-三羟基苯甲酰基哌嗪-2-羧酰胺衍生物的制备方法，化合物IA的具体制备步骤如下：
(1)在冰浴条件下，将3,4,5-三苄氧基苯甲酸、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、1-羟基苯并三唑和三乙胺共称于250mL烧瓶中，加入适量N,N-二甲基甲酰胺溶解，搅拌15min后，撤去冰浴，室温搅拌1h；最后加入1-Boc-3-甲基哌嗪-1,3-二羧酸酯，反应过夜，柱层析分离纯化得白色中间体1-(叔丁基)3-甲基4-(3,4,5-三(苄氧基)苯甲酰基)哌嗪-1,3-二羧酸酯(IA-b)；
(2)将IA-b溶于5mL二氯甲烷中，然后慢慢地加入三氟乙酸，室温搅拌6h；加入10mL水，用饱和的碳酸氢钠溶液调pH，二氯甲烷萃取，干燥，快速柱层析，得淡黄色1-(3,4,5-三(苄氧基)苯甲酰基)哌嗪-2-羧酸甲酯(IA-c)；
(3)在冰浴条件下，将1-(3,4,5-三(苄氧基)苯甲酰基)哌嗪-2-羧酸甲酯、三乙胺和相应的酰氯取代基共称于25mL烧瓶中，加入适量二氯甲烷溶解，移除冰浴，室温搅拌12h；用乙酸乙酯萃取，干燥，过滤，浓缩得淡黄色4-((4-硝基苯基)磺酰基)-1-(3,4,5-三(苄氧基)苯甲酰基)哌嗪-2-羧酸甲酯(IA-d)；
(4)将4-((4-硝基苯基)磺酰基)-1-(3,4,5-三(苄氧基)苯甲酰基)哌嗪-2-羧酸甲酯、一水合氢氧化锂共称于25mL烧瓶中，加入适量1:1的四氢呋喃和水溶解，室温搅拌1.5h；TLC监测反应，调pH至5左右，有固体析出，抽滤，干燥得淡黄色4-((4-氨基苯基)磺酰基)-1-(3,4,5-三(苄氧基)苯甲酰基)哌嗪-2-羧酸(IA-e)；
(5)将4-((4-氨基苯基)磺酰基)-1-(3,4,5-三(苄氧基)苯甲酰基)哌嗪-2-羧酸和2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐共称于25mL烧瓶中，冰浴条件下加入适量二氯甲烷溶解，活化30min，然后向反应液中加入相应的取代胺和N,N-二异丙基乙胺，移除冰浴，室温搅拌8h；用乙酸乙酯萃取，干燥，浓缩得白色4-((4-硝基苯基)磺酰基)-N-苯基-1-(3,4,5-三(苄氧基)苯甲酰基)哌嗪-2-羧酰胺(IA-f)；
(6)将4-((4-硝基苯基)磺酰基)-N-苯基-1-(3,4,5-三(苄氧基)苯甲酰基)哌嗪-2-羧酰胺置于50mL圆底烧瓶中，加入1:1的二氯甲烷和甲醇溶解，加入10％钯碳；通氢气，室温反应12h；硅藻土过滤，减压浓缩，重结晶得到目标产物IA。
6.如权利要求1-3任一所述的4-苯基磺酰基-1三羟基苯甲酰基哌嗪-2-羧酰胺衍生物在制备抗艾滋病药物中的应用。
7.一种抗HIV药物组合物，其特征在于，包括权利要求1-3任一所述的4-苯基磺酰基-1-三羟基苯甲酰基哌嗪-2-羧酰胺衍生物或其可药用盐和一种或多种药学上可接受载体或赋形剂。
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