CN116478149A - 13-杂环-β-榄香烯一氧化氮供体型衍生物及其制备和应用 - Google Patents
13-杂环-β-榄香烯一氧化氮供体型衍生物及其制备和应用 Download PDFInfo
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- CN116478149A CN116478149A CN202211406506.3A CN202211406506A CN116478149A CN 116478149 A CN116478149 A CN 116478149A CN 202211406506 A CN202211406506 A CN 202211406506A CN 116478149 A CN116478149 A CN 116478149A
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- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen 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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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/08—1,2,5-Oxadiazoles; Hydrogenated 1,2,5-oxadiazoles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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Abstract
本发明公开了一种13‑杂环‑β‑榄香烯一氧化氮供体型衍生物及其制备和应用。本发明提供了结构如通式(I)所示的一种13‑杂环‑β‑榄香烯一氧化氮供体型衍生物，或其可药用盐，或溶剂化物，或其对映异构体、非对映异构体。本发明衍生物在设计策略上优于以往的β‑榄香烯一氧化氮供体型衍生物，引入了可提高体内抗肿瘤活性的含氮环状结构和NO供体，极大地改善了β‑榄香烯母核的理化性质，且能够应用于治疗临床上缺乏有效治疗药物的白血病等。
Description
技术领域
本发明涉及药物化学和新药研发领域，具体涉及13-杂环-β-榄香烯一氧化氮供体型衍生物及其制备和应用。
背景技术
榄香烯是从莪术中提取分离的倍半萜天然产物，是一个不含蒽环、环氧、硝基等毒性基团的抗癌植物药。榄香烯口服乳和注射液经国家食品药品监督管理总局(NMPA)批准，作为广谱抗癌药物已经应用于临床多年。榄香烯提取物中包含多种同分异构体，其中β-榄香烯发挥最主要的抗肿瘤活性。β-榄香烯属于小分子化合物，结构中只含有碳、氢两种元素。这导致其水溶性差，生物利用度低，需要使用较大剂量才能发挥作用，使其临床应用受到了限制。因此，对榄香烯进行结构优化具有重要的研究意义。
一氧化氮(NO)作为内源性气体分子，参与抗炎、抗肿瘤等多种生理、病理过程。与正常细胞对比，肿瘤细胞对NO更加敏感，低浓度的NO能促进肿瘤细胞生长，但高浓度的NO逆转肿瘤细胞的耐药性、抑制肿瘤发生与转移。NO半衰期短，分子小又具有亲脂性，能快速透过细胞膜，但存在不易定量和运输的缺点。因此，临床上使用NO供体作为NO代替物。
相比于传统硝酸酯类NO供体，呋咱类NO供体的优势是在大多数组织或器官中通过非酶催化途径释放NO而产生生物活性。绝大部分小分子NO供体型药物稳定性差，在体内血液循环过程中催化分解掉，到达靶细胞或把组织时浓度不够，反而起到促进肿瘤细胞生长的作用，适得其反。因此，将NO供体直接用于治疗血液性癌症(如白血病)，具有更好的针对性，可能取得更好的疗效。
此外，我们研究发现，在β-榄香烯结构中引入含氮杂环结构，如吡唑和N-乙基哌嗪，可以显著提升其抗肿瘤活性。同时，在β-榄香烯14位我们选择引入含有氨基和醇羟基的醇胺连接臂，醇羟基部分再与呋咱类NO供体相连。因此，本发明基于药效团融合的原理，将β-榄香烯与NO药效团和含氮杂环药效团融合在β-榄香烯分子中，可显著改善β-榄香烯的理化和成药性，得到抗肿瘤效果更强的β-榄香烯衍生物。
发明内容
本发明的第一个目的是针对现有技术的不足，提供一种13-杂环-β-榄香烯一氧化氮供体型衍生物，在榄香烯13位引入含氮环状基团，然后在14位榄香烯以醇胺和酸酐为连接臂与呋咱一氧化氮供体连接，最终制备得到具有新型连接臂的β-榄香烯一氧化氮供体型衍生物，具有优异抗肿瘤活性。
一种13-杂环-β-榄香烯一氧化氮供体型衍生物，或其可药用盐，或溶剂化物，或其对映异构体、非对映异构体，所述13-杂环-β-榄香烯一氧化氮供体型衍生物具有如下通式(I)：
其中：
R1为含有氮、氧或硫的环状结构；
R2为含氮和氧原子的直链或环状醇胺结构；
R3、R4分别独立选自C1-10链烷基、C3-12环烷基、C6-12芳基、5-10元环杂芳基、C2-10烯基、C2-10炔基或C2-10烷氧基。
作为优选，式(I)中：
R1为C2-8的含有氮、氧或硫的环状结构；
R2为C2-5的含氮和氧原子的直链醇胺结构或C5-8的环状醇胺结构；
R3、R4分别独立选自C2-6的链烷基、C2-6的烯基、C2-6的炔基。
作为优选，式(I)中：
R1选自
R2选自 其中氧原子与羰基相连；
R3、R4分别独立选自-CH2CH2-、-CH＝CH-、-CH2CH2CH2-、-CH2CH＝CH-、-CH＝CHCH2-、-CH2C≡C-、-C≡CCH2-、-CH2CH2CH2CH2-、-CH2CH2CH＝CH-、-CH2CH＝CHCH2-、-CH＝CHCH2CH2-、-CH2C≡CCH2-、-CH2CH2CH2CH2CH2-、-CH2C≡CCH2CH2-、-CH2CH2C≡CCH2-、-CH2CH2C≡CCH2CH2-，其按照从左到右分别与两端结构相连。
作为优选，式(I)中：
R1为
R2选自 其中氧原子与羰基相连；
R3、R4分别独立选自-CH2CH2-、-CH＝CH-、-CH2CH2CH2-、-CH2CH＝CH-、-CH＝CHCH2-、-CH2C≡C-、-C≡CCH2-、-CH2CH2CH2CH2-、-CH2CH2CH＝CH-、-CH2CH＝CHCH2-、-CH＝CHCH2CH2-、-CH2C≡CCH2-、-CH2CH2CH2CH2CH2-、-CH2C≡CCH2CH2-、-CH2CH2C≡CCH2-、-CH2CH2C≡CCH2CH2-，其按照从左到右的顺序分别与两端结构相连。
作为优选，所述13-杂环-β-榄香烯一氧化氮供体型衍生物选自如下结构所示的化合物1～36：
本发明的第二个目的是提供上述13-杂环-β-榄香烯一氧化氮供体型衍生物的制备方法，采用如下技术方案：
(1)β-榄香烯A-1进行13、14位烯丙位氯代反应得到中间体A-2；
(2)含有氮杂原子官能团的R1结构片段A-3通过选择性亲核取代到中间体A-2的13位上，得到中间体A-4；
(3)含有氮杂原子官能团的R2结构片段A-5通过选择性亲核取代到中间体A-4的14位上，得到中间体A-6；
(4)苯巯基乙酸A-7经过30％H2O2氧化处理，又经发烟硝酸处理闭环得到中间体A-8；
(5)含有羟基官能团的R3结构片段A-9通过选择性亲核取代到中间体A-10上，得到中间体A-10；
(6)含有羰基官能团的R4结构片段A-11与中间体A-10酯化得到中间体A-11；
(7)中间体A-6和中间体A-11进行分子间酰胺缩合，得到通式(I)所示的衍生物；
其合成路线如下：
本发明的第三个目的是提供所述的13-杂环-β-榄香烯一氧化氮供体型衍生物，或其可药用盐，或溶剂化物，或其对映异构体、非对映异构体在制备抗肿瘤药物中的应用。
作为优选，所述肿瘤包括白血病、黑色素瘤等。
本发明的第四个目的是提供一种抗肿瘤药物，含有安全有效量的所述的13-杂环-β-榄香烯一氧化氮供体型衍生物，或其可药用盐，或溶剂化物，或其对映异构体、非对映异构体。
作为优选，所述抗肿瘤药物还可以包括药理上可接受的盐及药理上可以接受的赋形剂或载体。
本发明所述“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有5-1000mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组分能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
在本发明中，13-杂环-β-榄香烯的合成路线如反应式1所示。
本发明与现有技术相比，采用13-杂环-β-榄香烯作为抗肿瘤活性骨架，具有如下重要优势：1)在β-榄香烯氯化反应中，13,14-双氯-榄香烯是作为主产物生成，单取代榄香烯产率很少，原子利用率极大地提高，后续的分离、纯化较单取代榄香烯更容易，更加适合工业化的大生产，为后续此类药物研发提供了便利；2)13,14-双氯-β-榄香烯的抗肿瘤活性与13-氯-β-榄香烯、14-氯-β-榄香烯和β-榄香烯相当，一方面，双氯代化合物极性会比单取代化合物大，另一方面，13,14位氯代的化合物可以引入不同的基团，发挥不同的生物活性，表现出了更好的类药性。
同时，本发明引入了可提高体内抗肿瘤活性的含氮杂环和NO供体作为药效基团，改善了榄香烯母体的理化性质；因此，本发明公开的β-榄香烯一氧化氮供体型衍生物易于制备分离，长期用药安全性更优，且能在血液中快速释放出NO，对白血病等血液类疾病表现出更好的靶向性和治疗活性，具有很好的创新性和新颖性。
具体实施方式
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的操作方法，通常按照常规条件，或按照制造厂商所建议的条件。
(一)中间体2的制备
在0℃条件下，向含β-榄香烯(29.4mmol)的二氯甲烷(40mL)和乙酸(35mL)混合溶液中，加入TBAF(1.0minTHF，0.5mL)，使用微量注射泵加入NaClO(40mL)，在0℃下反应5h。反应结束时，用饱和碳酸氢钠淬灭，用乙酸乙酯萃取，合并有机相，依次用水和饱和食盐水洗涤，无水硫酸钠干燥，减压蒸馏除去溶剂，残留物经硅胶柱层析分离(纯石油醚)，得到无色液体化合物，即中间体2，产率为25％。
1HNMR(500MHz,CDCl3)δ5.79(dd,J＝17.2,11.0Hz,1H),5.28(s,1H),5.18(s,1H),5.04(s,1H),4.97–4.89(m,3H),4.11(s,3H),3.97(d,J＝11.7Hz,1H),2.35–2.22(m,2H),1.77–1.42(m,9H),0.99(s,3H).13CNMR(125MHz,CDCl3)δ149.51,148.95,147.44,116.29,113.33,111.42,50.88,47.63,47.56,41.01,39.72,39.61,33.76,26.97,15.73.
(二)中间体3-4的制备
反应式2：中间体3-4和5-10的合成路线。试剂和条件：(a)Cs2CO3，DMF，r.t.，
12h；(b)Cs2CO3，DMF，60℃。
如反应式2所示，向含有中间体2(1.0mmol)的DMF(6mL)中，加入Cs2CO3(2.0mmol)，室温条件下搅拌20min。向混合溶液中加入吡唑(2.0mmol)室温搅拌12h。反应结束时，向混合溶液加水稀释，用乙酸乙酯萃取，合并有机液，依次用水和饱和食盐水洗涤，无水硫酸钠干燥后，残留物经硅胶柱层析分离(二氯甲烷：甲醇体积比100：1)，得到无色透明液体，即中间体3(67％)。
1HNMR(500MHz,CDCl3)δ7.52(d,J＝1.6Hz,1H),7.40(d,J＝2.2Hz,1H),6.28(t,J＝2.0Hz,1H),5.74(dd,J＝10.9,17.3Hz,1H),5.25(s,1H),5.02(s,1H),4.94–4.86(m,3H),4.78(s,3H),4.06(d,J＝12.5Hz,1H),3.94(d,J＝11.7Hz,1H),2.22(dd,J＝3.6,12.4Hz,1H),1.95(td,J＝3.5,11.7Hz,1H),1.65–1.44(m,6H),0.96(s,3H).13CNMR(125MHz,CDCl3)δ149.5,149.0,147.4,139.3,129.5,116.4,111.8,111.5,105.9,56.3,51.0,47.6,41.9,39.8,39.6,33.7,26.8,15.8.MS(ESI)m/z:305.2[M+H]+.
按照相同的方法，更换反应物，制得中间体4。
1-(2-((1R,3R,4S)-3-(3-氯丙-1-烯-2-基)-4-甲基-4-乙烯基环己基)烯丙基)-4-乙基哌嗪(4)
无色透明液体,产率59％,1HNMR(500MHz,CDCl3)δ5.71–5.64(m,1H),5.16(s,1H),4.82(dd,J＝3.6,15.5Hz,5H),3.99(d,J＝12.2Hz,1H),3.86(d,J＝11.7Hz,1H),2.86–2.79(m,2H),2.36(q,J＝7.2Hz,11H),2.19–2.15(m,1H),2.04–1.98(m,1H),1.54–1.33(m,6H),1.00(d,J＝7.2Hz,3H),0.87(s,3H).13CNMR(125MHz,CDCl3)δ150.8,149.4,147.8,116.2,111.2,110.9,63.5,53.3,53.1,52.5,51.1,47.9,42.3,39.9,39.9,34.0,27.1,15.9,12.1.MS(ESI)m/z:351.2[M+H]+.
(三)中间体5-10的制备
向含有3(1.0mmol)的DMF(5mL)溶液中，依次加入N-甲基-2-羟基乙胺(1.5mmol)和DIPEA(2.0mmol)，60℃反应12h。反应结束后，加入水稀释，用乙酸乙酯萃取，合并有机相，依次用水和饱和食盐水洗涤，无水硫酸钠干燥，减压蒸馏除去溶剂，残留物经硅胶层析(二氯甲烷：甲醇体积比60：1)得到中间体5(51％)。
1HNMR(500MHz,CDCl3)δ7.50(d,J＝1.5Hz,1H),7.39(d,J＝2.1Hz,1H),6.26(t,J＝2.0Hz,1H),5.74(dd,J＝17.8,10.5Hz,1H),5.01(d,J＝17.9Hz,2H),4.90–4.85(m,2H),4.79–4.70(m,4H),3.62–3.54(m,2H),3.13(d,J＝13.4Hz,1H),2.67–2.54(m,2H),2.35(dt,J＝12.4,4.8Hz,1H),2.15(s,4H),1.92–1.82(m,1H),1.60–1.39(m,6H),0.96(s,3H).13CNMR(125MHz,CDCl3)δ149.7,149.6,148.5,139.2,129.4,114.6,111.5,110.5,105.8,66.1,58.6,58.5,56.3,47.6,41.9,41.8,39.7,39.6,33.8,26.8,15.9.MS(ESI)m/z:344.2[M+H]+.
按相同的方法，更换反应物，制得中间体6-10。
(1-(2-((1R,2S,5R)-5-(3-(1H-吡唑-1-基)丙-1-烯-2-基)-2-甲基-2-乙烯基环己基)烯丙基)哌啶-4-基)甲醇(6)
淡黄色液体，产率46％，1HNMR(500MHz,CDCl3)δ7.51(d,J＝1.4Hz,1H),7.39(d,J＝1.8Hz,1H),6.27(t,J＝2.0Hz,1H),5.79(dd,J＝10.8,17.5Hz,1H),5.03(d,J＝18.8Hz,2H),4.89–4.83(m,2H),4.80–4.72(m,4H),3.55–3.45(m,2H),3.09–2.95(m,1H),2.92–2.76(m,2H),2.62(s,1H),2.24–2.12(m,1H),2.08–1.86(m,2H),1.75–1.63(m,3H),1.50(dddd,J＝12.2,23.2,34.2,44.0Hz,9H),0.96(s,3H).13CNMR(125MHz,CDCl3)δ149.8,149.7,148.3,139.1,129.4,113.5,111.5,110.2,105.7,67.6,66.6,56.2,54.4,52.7,47.9,41.9,39.7,38.7,33.6,29.7,28.9,28.8,26.9,15.9.MS(ESI)m/z:384.2[M+H]+.
2-(4-(2-((1R,2S,5R)-5-(3-(1H-吡唑-1-基)丙-1-烯-2-基)-2-甲基-2-乙烯基环己基)烯丙基)哌嗪-1-基)乙烷-1-醇(7)
铜绿色液体，产率80％，1HNMR(500MHz,CDCl3)δ7.49(d,J＝1.5Hz,1H),7.37(d,J＝2.1Hz,1H),6.25(t,J＝2.0Hz,1H),5.75(dd,J＝10.8,17.5Hz,1H),5.00(d,J＝9.4Hz,2H),4.89–4.82(m,2H),4.75(s,4H),3.60(t,J＝5.4Hz,2H),3.00(d,J＝13.7Hz,1H),2.63–2.22(m,12H),2.14(dd,J＝3.4,12.6Hz,1H),1.93–1.84(m,1H),1.61–1.38(m,6H),0.95(s,3H).13CNMR(125MHz,CDCl3)δ149.9,149.8,148.2,139.3,129.4,113.9,111.6,110.3,105.8,66.2,59.5,57.8,56.4,53.1,47.9,41.9,39.8,33.7,27.1,16.0.MS(ESI)m/z:399.2[M+H]+.
2-((2-((1R,2S,5R)-5-(3-(4-乙基哌嗪-1-基)丙-1-烯-2-基)-2-甲基-2-乙烯基环己基)烯丙基)(甲基)氨基)乙-1-醇(8)
淡黄色液体，产率66％，1HNMR(500MHz,CDCl3)δ5.71–5.64(m,1H),5.16(s,1H),4.82(dd,J＝3.6,15.5Hz,5H),3.99(d,J＝12.2Hz,1H),3.86(d,J＝11.7Hz,1H),2.86–2.79(m,2H),2.36(q,J＝7.2Hz,11H),2.19–2.15(m,1H),2.04–1.98(m,1H),1.54–1.33(m,6H),1.00(d,J＝7.2Hz,3H),0.87(s,3H).13CNMR(125MHz,CDCl3)δ150.9,150.1,149.1,114.3,110.9,110.4,66.3,63.7,59.0,58.6,53.3,53.0,52.4,48.0,42.4,41.9,40.0,39.9,34.3,27.2,16.0,12.1.MS(ESI)m/z:390.4[M+H]+.
(1-(2-((1R,2S,5R)-5-(3-(4-乙基哌嗪-1-基)丙-1-烯-2-基)-2-甲基-2-乙烯基环己基)烯丙基)哌啶-4-基)甲醇(9)
无色透明液体，产率64％，1HNMR(500MHz,CDCl3)δ5.81(dd,J＝10.8,17.5Hz,1H),5.03(s,1H),4.95–4.83(m,4H),4.77(s,1H),3.49(d,J＝6.4Hz,2H),3.04–
2.82(m,5H),2.66–2.32(m,10H),2.22(dd,J＝3.2,12.7Hz,1H),2.12–1.91(m,3H),1.75–1.39(m,11H),1.10(t,J＝7.2Hz,3H),0.99(s,3H).13CNMR(125MHz,CDCl3)δ151.1,150.3,149.0,113.2,110.7,110.0,67.9,66.8,63.6,54.5,53.2,53.0,52.8,52.4,48.3,42.4,40.1,40.0,38.9,34.1,29.1,29.0,27.3,16.1,12.0.MS(ESI)m/z:430.4[M+H]+.
2-(4-(2-((1R,2S,5R)-5-(3-(4-乙基哌嗪-1-基)丙-1-烯-2-基)-2-甲基-2-乙烯基环己基)烯丙基)哌嗪-1-基)乙烷-1-醇(10)
淡黄色液体，产率76％，1HNMR(500MHz,CDCl3)δ5.81(dd,J＝10.8,17.5Hz,1H),5.03(s,1H),4.95–4.83(m,4H),4.77(s,1H),3.49(d,J＝6.4Hz,2H),3.04–2.82(m,5H),2.66–2.32(m,10H),2.22(dd,J＝3.2,12.7Hz,1H),2.12–1.91(m,3H),1.75–1.39(m,11H),1.10(t,J＝7.2Hz,3H),0.99(s,3H).13CNMR(125MHz,CDCl3)δ151.0,150.2,148.5,113.6,110.7,110.1,66.3,63.6,59.5,57.8,53.2,53.1,53.0,52.4,48.2,42.4,40.0,39.9,34.1,27.2,16.0,12.0.MS(ESI)m/z:445.4[M+H]+.
(四)中间体13-15的制备
反应式3.中间体13-15和13a-b、14a-b、15a-b的合成路线。试剂和条件：(a)15％
NaOH，THF，r.t.，2h；(b)DMAP，DCM，r.t.，12h。
在0℃条件下，向含有3,4-双(苯磺酰基)-1,2,5-噁二唑-2-氧化物(2.0mmol)的四氢呋喃溶液中，缓慢滴加15％NaOH水溶液(0.4mmol)，滴加完毕后，继续搅拌10min，加入反应物乙二醇(20.0mmol)，室温条件下反应4h。减压蒸馏除去溶剂，加入水稀释，用二氯甲烷萃取，合并有机相，依次用水和饱和食盐水洗涤，无水硫酸钠干燥，减压蒸馏除去溶剂，残留物经硅胶层析(二氯甲烷：甲醇体积比100：1)得到中间体13(77％)。
m.p.128-130℃.1HNMR(400MHz,CDCl3)δ8.07(d,J＝8.2Hz,2H),7.77(t,J＝
7.5Hz,1H),7.63(t,J＝7.8Hz,2H),4.59–4.49(m,2H),4.08–4.02(m,2H).13CNMR(100MHz,CDCl3)δ159.1,137.8,135.9,129.9,128.7,110.7,73.0,60.5.HRMS(ESI)calcdforC10H10N2NaO6S309.0152[M+Na]+,found309.0142.
按照反应式3和上述相同的方法，更换反应物，制得中间体14、15。
4-(3-羟基丙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(14)
白色固体，产率73％，m.p.109-110℃.1HNMR(500MHz,CDCl3)δ8.05(dd,J＝8.5,1.1Hz,2H),7.78–7.73(m,1H),7.64–7.60(m,2H),4.59(t,J＝6.0Hz,2H),3.87(t,J＝5.8Hz,2H),2.13(p,J＝5.9Hz,2H).13CNMR(125MHz,CDCl3)δ159.0,135.8,129.8,110.6,69.4,59.4,31.4.MS(ESI)m/z:323.0[M+Na]+.
4-((4-羟基丁基2-炔-1-基)氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(15)
白色固体，产率59％，m.p.116-118℃.1HNMR(400MHz,CDCl3)δ8.07(d,J＝7.7Hz,2H),7.76(t,J＝7.4Hz,1H),7.63(t,J＝7.7Hz,2H),5.10(s,2H),4.34(s,2H).13CNMR(100MHz,CDCl3)δ158.2,138.0,135.9,129.8,128.8,110.8,88.3,77.7,59.0,51.1.HRMS(ESI)calcdforC12H10N2NaO6S333.0512[M+Na]+,found333.0512.
(五)中间体13a、13b、14a、14b、15a、15b的制备
向含有中间体13(2.0mmol)的二氯甲烷(10mL)溶液中，依次加入反应物丁二酸酐(2.2mmol)和DMAP(1.0mmol)，在30℃条件下搅拌3h，采用薄层色谱法检测反应。用二氯甲烷稀释反应混合物。有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，减压蒸馏除去溶剂，残留物经硅胶柱层析分离(二氯甲烷：甲醇体积比100：1)得到白色固体，即中间体13a(58％)。
m.p.118-120℃.1HNMR(400MHz,CDCl3)δ8.13–8.06(m,2H),7.82–7.76(m,1H),7.65(t,J＝7.9Hz,2H),4.65(dd,J＝5.4,3.4Hz,2H),4.56(dd,J＝5.4,3.4Hz,2H),2.73(t,J＝2.7Hz,4H).13CNMR(100MHz,CDCl3)δ176.9,171.9,158.8,138.2,135.8,129.8,128.8,110.6,69.0,61.6,29.0,28.9.HRMS(ESI)calcdforC14H14N2NaO9S409.0312[M+Na]+,found409.0295.
按照上述相同的方法，更换反应物，制得中间体13b、14a、14b、15a、15b。
中间体13b、14a、14b、15a、15b的1HNMR
4-(2-((4-羧基丁酰基)氧基)乙氧基)-3-(苯磺酰基)-1,2,5-噁二唑-2-氧化物(13b)
白色固体，产率63％，m.p.91-93℃.1HNMR(500MHz,CDCl3)δ8.06(dd,J＝8.5,1.2Hz,2H),7.78–7.73(m,1H),7.62(td,J＝7.6,1.7Hz,2H),4.65–4.61(m,2H),4.51(dd,J＝5.4,3.7Hz,2H),2.47(dt,J＝8.3,7.3Hz,4H),1.99(p,J＝7.2Hz,2H).13CNMR(100MHz,CDCl3)δ178.6,172.7,158.8,138.0,135.8,129.8,128.8,110.6,69.0,61.3,33.0,32.9,19.7.HRMS(ESI)calcdforC15H16N2NaO9S423.0469[M+Na]+,found423.0465.
4-(3-((3-羧基丙酰基)氧基)丙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(14a)
白色固体，产率77％，m.p.104-105℃,1HNMR(500MHz,CDCl3)δ8.05(dd,J＝8.5,1.2Hz,2H),7.78–7.73(m,1H),7.65–7.59(m,2H),4.50(t,J＝6.1Hz,2H),4.31(t,J＝6.1Hz,2H),2.70–2.60(m,4H),2.22(p,J＝6.1Hz,2H).13CNMR(125MHz,CDCl3)δ178.0,172.2,159.0,138.1,135.8,129.8,128.6,110.6,67.9,60.7,28.9,28.0.MS(ESI)m/z:423.0[M+Na]+.
4-(3-((4-羧基丁酰基)氧基)丙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(14b)
白色固体，产率77％,m.p.96-98℃,1HNMR(500MHz,CDCl3)δ8.06(dd,J＝8.4,1.1Hz,2H),7.79–7.74(m,1H),7.63(t,J＝7.9Hz,2H),4.51(t,J＝6.1Hz,2H),4.28(t,J＝6.1Hz,2H),2.43(td,J＝7.3,1.4Hz,4H),2.22(p,J＝6.1Hz,2H),1.96(p,J＝7.3Hz,2H).13CNMR(125MHz,CDCl3)δ178.6,172.9,159.0,138.1,135.8,129.8,128.7,110.6,68.1,60.5,33.1,33.0,28.0,19.9.MS(ESI)m/z:437.0[M+Na]+.
4-((4-((3-羧基丙酰基)氧基)丁-2-炔-1-基)氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(15a)
白色固体，产率60％，m.p.106-108℃.1HNMR(400MHz,CDCl3)δ8.11–8.04(m,2H),7.77(t,J＝7.5Hz,1H),7.63(t,J＝7.9Hz,2H),5.10(t,J＝1.6Hz,2H),4.81–
4.73(m,2H),2.74–2.65(m,4H).13CNMR(100MHz,CDCl3)δ177.2,171.4,158.1,138.1,135.9,129.9,128.8,110.8,83.9,78.8,58.8,52.3,28.8,28.8.HRMS(ESI)calcdforC16H14N2NaO9S433.0312[M+Na]+,found433.0317.
4-(4-((4-羧基丁酰)氧基)丁-2-炔-1-基氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(15b)
白色固体,产率76％,m.p.94-96℃.1HNMR(400MHz,CDCl3)δ8.07(d,J＝7.6Hz,2H),7.77(t,J＝7.5Hz,1H),7.63(t,J＝7.8Hz,2H),5.10(s,2H),4.74(s,2H),2.46(td,J＝7.3,4.9Hz,4H),1.97(p,J＝7.3Hz,2H).13CNMR(100MHz,CDCl3)δ179.0,172.1,158.0,137.7,135.8,129.8,128.7,110.6,83.9,78.6,58.6,52.0,32.8,19.6.HRMS(ESI)calcdforC16H14N2NaO9S447.0469[M+Na]+,found447.0486.
(六)β-榄香烯一氧化氮供体型衍生物终产物16a-f、17a-f、18a-f、19a-f、20a-f和21a-f的制备
反应式4.β-榄香烯一氧化氮供体型衍生物终产物16a-f、17a-f、18a-f、19a-f、20a-f和21a-f的合成路线。试剂和条件：EDCI，DMAP，DCM，r.t.，12h。
如反应式4所示，将榄香烯中间体5-10(0.2mmol)、NO供体中间体13a、13b、14a、14b、15a和15b(0.2mmol)、EDCI(0.2mmol)和催化量的DMAP在无水二氯甲烷(3mL)中在室温下搅拌12h。采用LC-MS法检测反应。加水淬灭反应，用二氯甲烷萃取反应混合物。有机层依次用水和盐水洗涤，无水硫酸钠干燥，减压蒸馏除去溶剂，残留物通过柱层析(二氯甲烷：甲醇体积比100:1)纯化，使产物为液体。
所采用的各中间体均可按上述(一)～(五)进行制备，在此不再赘述。
实施例1：制备化合物1(16a)
4-(2-((4-(2-((2-((1R,2S,5R)-5-(3-(1H-吡唑-1-基)丙-1-烯-2-基))-2-甲基-2-乙烯基环己基)烯丙基)(甲基)氨基)乙氧基)-4-氧代丁酰基)氧基)乙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物的制备。
向含有中间体5(0.2mmol)的二氯甲烷(3mL)溶液中，依次加入中间体13a(0.2mmol)、EDCI(0.2mmol)和DMAP(0.01mmol)，室温搅拌12h。加二氯甲烷稀释，依次用水和饱和食水洗涤，无水硫酸钠干燥，减压蒸馏除去溶剂，残留物经硅胶柱层析分离(二氯甲烷：甲醇体积比100：1)，无色透明液体，产率65％。
1HNMR(500MHz,CDCl3)δ8.06–8.01(m,2H),7.77–7.71(m,1H),7.61(t,J＝7.9Hz,2H),7.49–7.46(m,1H),7.38(d,J＝2.2Hz,1H),6.24(t,J＝2.1Hz,1H),5.75(dd,J＝17.4,10.9Hz,1H),5.00(d,J＝16.7Hz,2H),4.88–4.81(m,2H),4.73(d,J＝15.3Hz,4H),4.62–4.58(m,2H),4.49(dt,J＝8.7,4.5Hz,2H),4.19–4.09(m,J＝6.1Hz,2H),3.11(d,J＝13.5Hz,1H),2.70–2.58(m,5H),2.44–2.37(m,2H),2.19–2.11(m,4H),1.92(t,J＝10.9Hz,1H),1.60–1.37(m,6H),0.94(s,3H).13CNMR(125MHz,CDCl3)δ172.2,172.2,158.8,150.0,149.9,149.0,139.3,138.1,135.8,129.8,129.5,128.7,114.1,111.5,110.5,110.4,105.8,69.0,66.1,62.8,61.5,56.3,55.3,47.2,42.8,42.0,39.9,39.8,33.6,29.1,29.0,27.1,15.8.HRMS(ESI)m/z:calcdforC35H45N5O9S[M+H]+,712.3011；found,712.3034.
实施例2：制备化合物2(16b)
4-(2-((5-(2-((2-((1R,2S,5R)-5-(3-(1H-吡唑-1-基)丙-1-烯-2-基))-2-甲基-2-乙烯基环己基)烯丙基)(甲基)氨基)乙氧基)-5-氧代戊酰基)氧基)乙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物的制备方法基本同实施例1，区别在于，将(五)中的丁二酸酐替换为戊二酸酐。
本实施例中制得无色透明液体，产率73％。
1HNMR(500MHz,CDCl3)δ8.08–8.03(m,2H),7.76(t,J＝7.5Hz,1H),7.62(t,J＝7.8Hz,2H),7.50(d,J＝1.7Hz,1H),7.40(s,1H),6.26(t,J＝1.8Hz,1H),5.77(dd,J＝11.1,17.2Hz,1H),5.02(d,J＝17.7Hz,2H),4.89–4.83(m,2H),4.74(d,J＝15.1Hz,4H),4.64–4.60(m,2H),4.52–4.48(m,2H),4.22–4.07(m,2H),3.11(d,J＝13.4Hz,1H),2.63(s,2H),2.43(dt,J＝7.3,23.3Hz,5H),2.15(s,3H),1.98(p,J＝7.3Hz,3H),1.72(s,1H),1.61–1.39(m,6H),0.95(s,3H).13CNMR(125MHz,CDCl3)δ172.8,172.7,158.7,149.9,149.9,148.9,139.3,138.1,135.7,129.8,129.5,128.7,114.0,111.5,110.5,110.4,105.8,69.0,66.0,62.4,61.2,56.3,55.4,47.2,42.7,42.0,39.9,39.8,33.6,33.2,33.1,27.0,20.0,15.8.HRMS(ESI)m/z:calcdforC36H47N5O9S[M+H]+,726.3167；found,726.3158.
实施例3：制备化合物3(16c)
4-(3-((4-(2-((2-((1R,2S,5R)-5-(3-(1H-吡唑-1-基)丙-1-烯-2-基))-2-甲基-2-乙烯基环己基)烯丙基)(甲基)氨基)乙氧基)-4-氧代丁酰基)氧基)丙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物制备方法基本同实施例1，区别在于，将(四)中的乙二醇替换为丙二醇。
本实施例中制得无色透明液体，产率67％。
1HNMR(500MHz,CDCl3)δ8.03(d,J＝7.7Hz,2H),7.73(t,J＝7.5Hz,1H),7.60(t,J＝7.8Hz,2H),7.49–7.46(m,1H),7.38(d,J＝2.1Hz,1H),6.24(t,J＝2.1Hz,1H),5.75(dd,J＝10.8,17.5Hz,1H),5.00(d,J＝16.0Hz,2H),4.87–4.82(m,2H),4.75–4.69(m,4H),4.48(t,J＝6.1Hz,2H),4.27(t,J＝6.1Hz,2H),4.16–4.06(m,J＝6.3Hz,2H),3.10(d,J＝13.6Hz,1H),2.61(d,J＝29.4Hz,6H),2.40(dt,J＝5.4,12.3Hz,1H),2.21–2.12(m,6H),1.91(t,J＝9.6Hz,1H),1.60–1.37(m,6H),0.93(s,3H).13CNMR(125MHz,CDCl3)δ172.2,158.9,149.9,149.8,148.9,139.2,138.0,135.7,129.7,129.4,128.6,114.0,111.4,110.5,110.3,105.7,68.0,66.0,62.6,60.5,56.2,55.2,47.1,42.7,41.9,39.8,39.7,33.5,29.1,29.0,27.9,27.0,15.8.HRMS(ESI)m/z:calcdforC36H47N5O9S[M+H]+,726.3167；found,726.3157.
实施例4：制备化合物4(16d)
4-(3-((5-(2-((2-((1R,2S,5R)-5-(3-(1H-吡唑-1-基)丙-1-烯-2-基))-2-甲基-2-乙烯基环己基)烯丙基)(甲基)氨基)乙氧基)-5-氧代戊酰基)氧基)丙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物制备方法基本同实施例2，区别在于，将(四)中的乙二醇替换为丙二醇。
本实施例中制得无色透明液体，产率62％。
1HNMR(500MHz,CDCl3)δ8.05(dd,J＝8.5,1.1Hz,2H),7.77–7.73(m,1H),7.64–7.60(m,2H),7.50(d,J＝1.5Hz,1H),7.39(d,J＝1.9Hz,1H),6.26(t,J＝2.0Hz,1H),5.77(dd,J＝17.5,10.8Hz,1H),5.02(d,J＝18.7Hz,2H),4.89–4.83(m,2H),4.74(d,J＝13.5Hz,4H),4.50(t,J＝6.1Hz,2H),4.26(t,J＝6.1Hz,2H),4.20–4.08(m,2H),3.18–3.06(m,1H),2.62(d,J＝12.5Hz,2H),2.38(dt,J＝11.6,7.4Hz,5H),2.23–2.12(m,6H),1.96–1.93(m,2H),1.82–1.67(m,1H),1.60–1.38(m,6H),0.95(s,3H).13CNMR(125MHz,CDCl3)δ172.8,172.8,158.9,149.9,149.9,148.9,139.2,138.1,135.7,129.8,129.5,128.6,114.0,111.5,110.5,110.4,105.8,68.0,66.0,62.4,60.3,56.3,55.4,47.2,42.7,42.0,39.8,39.8,33.6,33.3,33.2,28.0,27.0,20.1,15.8.HRMS(ESI)m/z:calcdforC37H49N5O9S[M+H]+,740.3324；found,740.3329.
实施例5：制备化合物5(16e)
4-((4-((4-(2-((2-((1R,2S,5R)-5-(3-(1H-吡唑-1-基)丙-1-烯-2-基))-2-甲基-2-乙烯基环己基)烯丙基)(甲基)氨基)乙氧基)-4-氧代丁酰基)氧基)丁-2-炔基-1-基)氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物制备方法基本同实施例1，区别在于，将(四)中的乙二醇替换为1,4-丁炔二醇。
本实施例中制得无色透明液体，产率60％。
1HNMR(500MHz,CDCl3)δ8.07(dd,J＝8.5,1.2Hz,2H),7.79–7.74(m,1H),7.66–7.60(m,2H),7.50(d,J＝1.5Hz,1H),7.43–7.36(m,1H),6.26(t,J＝2.1Hz,1H),5.77(dd,J＝17.4,10.9Hz,1H),5.11–4.99(m,4H),4.90–4.84(m,2H),4.79–4.72(m,6H),4.24–4.09(m,2H),3.12(d,J＝13.2Hz,1H),2.66(tt,J＝9.3,4.7Hz,6H),2.48–2.38(m,1H),2.18(d,J＝19.3Hz,4H),1.98–1.88(m,1H),1.63–1.41(m,6H),0.96(s,3H).13CNMR(125MHz,CDCl3)δ172.1,171.5,158.0,149.9,149.9,149.0,139.3,137.9,135.8,129.8,129.5,128.7,114.1,111.5,110.6,110.4,105.8,83.9,78.7,66.0,62.7,58.7,56.3,55.3,52.2,47.2,42.7,42.0,39.9,39.8,33.6,29.0,28.9,27.0,15.8.HRMS(ESI)m/z:calcdfor C37H45N5O9S[M+H]+,736.3011；found,736.3013.
实施例6：制备化合物6(16f)
4-((4-((5-(2-((2-((1R,2S,5R)-5-(3-(1H-吡唑-1-基)丙-1-烯-2-基))-2-甲基-2-乙烯基环己基)烯丙基)(甲基)氨基)乙氧基)-5-氧代戊酰基)氧基)丁-2-炔基-1-基)氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物制备方法基本同实施例2，区别在于，将(四)中的乙二醇替换为1,4-丁炔二醇。
本实施例中制得无色透明液体，产率87％。
1HNMR(500MHz,CDCl3)δ8.06–8.03(m,2H),7.77–7.72(m,1H),7.61(t,J＝7.9Hz,2H),7.48(d,J＝1.7Hz,1H),7.38(d,J＝2.1Hz,1H),6.24(t,J＝2.0Hz,1H),5.75(dd,J＝10.8,17.5Hz,1H),5.07(t,J＝1.5Hz,2H),5.00(d,J＝16.6Hz,2H),4.87–4.82(m,2H),4.75–4.71(m,6H),4.13(tt,J＝6.3,14.0Hz,2H),3.11(d,J＝13.6Hz,1H),2.67–2.57(m,2H),2.40(dt,J＝7.3,24.0Hz,5H),2.16(d,J＝15.9Hz,4H),1.94(td,J＝5.7,11.5,13.1Hz,3H),1.61–1.37(m,6H),0.94(s,3H).13CNMR(125MHz,CDCl3)δ172.8,172.1,158.0,149.9,149.8,148.9,139.2,137.9,135.8,129.8,129.4,128.7,114.0,111.5,110.6,110.4,105.8,84.0,78.6,66.0,62.4,58.7,56.3,55.4,51.9,47.2,42.7,42.0,39.8,39.7,33.6,33.2,32.9,27.0,20.0,15.8.HRMS(ESI)m/z:calcdforC38H47N5O9S[M+H]+,750.3167；found,750.3174.
实施例7：制备化合物7(17a)
4-(2-((4-((1-(2-((1R,2S,5R)-5-(3-(1H-吡唑-1-基)丙-1-烯-2-基))-2-甲基-2-乙烯基环己基)烯丙基)哌啶-4-基)甲氧基)-4-氧代丁酰基)氧基)乙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物制备方法基本同实施例1，区别在于，将(三)中的N-甲基-2-羟基乙胺替换为4-羟甲基哌啶。
本实施例中制得无色透明液体，产率61％。
1HNMR(500MHz,CDCl3)δ8.05(dd,J＝8.5,1.2Hz,2H),7.76–7.72(m,1H),7.61(td,J＝7.6,1.7Hz,2H),7.49(d,J＝1.8Hz,1H),7.38(d,J＝1.9Hz,1H),6.25(t,J＝2.1Hz,1H),5.75(dd,J＝17.5,10.8Hz,1H),5.00(d,J＝6.8Hz,2H),4.87–4.81(m,2H),4.76–4.70(m,4H),4.61(dd,J＝5.4,3.7Hz,2H),4.50(dd,J＝5.9,3.1Hz,2H),3.97–
3.89(m,2H),2.98(d,J＝13.8Hz,1H),2.77(d,J＝9.5Hz,2H),2.69–2.64(m,4H),2.59(d,J＝13.9Hz,1H),2.14(dd,J＝12.5,3.2Hz,1H),1.91(q,J＝11.5Hz,2H),1.73–1.29(m,12H),0.95(s,3H).13CNMR(125MHz,CDCl3)δ172.2,172.1,158.8,149.9,149.9,148.5,139.3,138.1,135.7,129.8,129.4,128.7,113.5,111.5,110.5,110.3,105.8,69.3,68.9,66.5,61.5,56.4,54.1,52.5,47.9,41.9,39.8,39.8,35.5,33.6,29.0,29.0,28.9,27.1,15.9.HRMS(ESI)m/z:calcdforC38H49N5O9S[M+H]+,752.3324；found,752.3317.
实施例8：制备化合物8(17b)
4-(2-((5-((1-(2-((1R,2S,5R)-5-(3-(1H-吡唑-1-基)丙-1-烯-2-基)-2-甲基-2-乙烯基环己基)烯丙基)哌啶-4-基)甲氧基)-5-氧代戊酰基)氧基)乙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物制备方法基本同实施例7，区别在于，将(五)中的丁二酸酐替换为戊二酸酐。
本实施例中制得无色透明液体，产率58％。
1HNMR(500MHz,CDCl3)δ8.05(dd,J＝1.1,8.4Hz,2H),7.78–7.72(m,1H),7.64–7.60(m,2H),7.50(d,J＝1.7Hz,1H),7.38(d,J＝2.1Hz,1H),6.26(t,J＝2.0Hz,1H),5.76(dd,J＝10.8,17.5Hz,1H),5.00(d,J＝6.4Hz,2H),4.88–4.82(m,2H),4.75(d,J＝4.8Hz,4H),4.62(dd,J＝3.7,5.4Hz,2H),4.52–4.48(m,2H),3.93(d,J＝6.2Hz,2H),2.98(d,J＝12.7Hz,1H),2.82–2.72(m,2H),2.59(d,J＝13.3Hz,1H),2.42(dt,J＝7.3,22.1Hz,4H),2.15(d,J＝11.2Hz,1H),2.04–1.84(m,5H),1.75–1.66(m,1H),1.67–1.38(m,10H),0.95(s,3H).13CNMR(125MHz,CDCl3)δ173.0,172.7,158.8,150.0,149.9,148.6,139.3,138.1,135.8,129.8,129.5,128.7,113.5,111.5,110.5,110.3,105.8,69.1,69.0,66.5,61.2,56.4,54.2,52.5,47.9,42.0,39.9,39.8,35.5,33.7,33.3,33.2,29.1,27.1,20.1,16.0.HRMS(ESI)m/z:calcdforC39H51N5O9S[M+H]+,766.348；found,766.3478.
实施例9：制备化合物9(17c)
4-(3-((4-((1-(2-((1R,2S,5R)-5-(3-(1H-吡唑-1-基)丙-1-烯-2-基))-2-甲基-2-乙烯基环己基)烯丙基)哌啶-4-基)甲氧基)-4-氧代丁酰基)氧基)丙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物制备方法基本同实施例7，区别在于，将(四)中的乙二醇替换为丙二醇。
本实施例中制得无色透明液体，产率68％。
1HNMR(500MHz,CDCl3)δ8.08–8.01(m,2H),7.75(t,J＝7.5Hz,1H),7.62(t,J＝7.8Hz,2H),7.52–7.46(m,1H),7.38(s,1H),6.26(t,J＝1.9Hz,1H),5.77(dd,J＝10.8,17.4Hz,1H),5.00(s,2H),4.89–4.81(m,2H),4.75(d,J＝4.1Hz,4H),4.50(t,J＝6.1Hz,2H),4.30(t,J＝6.1Hz,2H),3.90(d,J＝6.1Hz,2H),2.97(d,J＝12.9Hz,1H),2.82–2.72(m,2H),2.63(s,5H),2.25–2.10(m,3H),2.04–1.75(m,3H),1.75–1.35(m,11H),0.96(s,3H).13CNMR(125MHz,CDCl3)δ172.4,172.3,159.0,150.0,149.9,148.6,139.3,
138.1,135.7,129.8,129.5,128.7,113.5,111.5,110.6,110.3,105.8,69.3,68.0,66.5,60.6,56.4,54.1,52.5,47.9,42.0,39.9,39.8,35.5,33.7,29.1,29.0,28.0,27.1,16.0.HRMS(ESI)m/z:calcdforC39H51N5O9S[M+H]+,766.348；found,766.3496.
实施例10：制备化合物10(17d)
4-(3-((5-((1-(2-((1R,2S,5R)-5-(3-(1H-吡唑-1-基)丙-1-烯-2-基))-2-甲基-2-乙烯基环己基)烯丙基)哌啶-4-基)甲氧基)-5-氧代戊酰基)氧基)丙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物制备方法基本同实施例8，区别在于，将(四)中的乙二醇替换为丙二醇。
本实施例中制得无色透明液体，产率56％。
1HNMR(500MHz,CDCl3)δ8.04(dd,J＝1.1,8.4Hz,2H),7.77–7.72(m,1H),7.65–7.59(m,2H),7.49(d,J＝1.7Hz,1H),7.38(d,J＝2.1Hz,1H),6.25(t,J＝2.0Hz,1H),5.76(dd,J＝10.8,17.5Hz,1H),5.00(d,J＝7.5Hz,2H),4.88–4.81(m,2H),4.74(d,J＝3.9Hz,4H),4.49(t,J＝6.1Hz,2H),4.26(t,J＝6.1Hz,2H),3.95–3.89(m,2H),2.98(d,J＝13.4Hz,1H),2.83–2.72(m,2H),2.59(d,J＝13.6Hz,1H),2.38(dt,J＝7.4,10.7Hz,4H),2.23–2.12(m,3H),2.05–1.80(m,5H),1.68(s,1H),1.67–1.36(m,10H),0.95(s,3H).13CNMR(125MHz,CDCl3)δ173.0,172.8,158.9,149.9,149.9,148.5,139.3,138.1,135.8,129.8,129.4,128.6,113.4,111.5,110.5,110.3,105.8,69.0,68.0,66.5,60.3,56.4,54.1,52.5,47.9,41.9,39.8,39.8,35.5,33.7,33.3,33.2,29.0,28.0,27.1,20.2,16.0.HRMS(ESI)m/z:calcdforC40H53N5O9S[M+H]+,780.3637；found,780.3634.
实施例11：制备化合物11(17e)
4-((4-((4-((1-(2-((1R,2S,5R)-5-(3-(1H-吡唑-1-基)丙-1-烯-2-基))-2-甲基-2-乙烯基环己基)烯丙基)哌啶-4-基)甲氧基)-4-氧代丁酰基)氧基)丁-2-炔基-1-基)氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物制备方法基本同实施例7，区别在于，将(四)中的乙二醇替换为1,4-丁炔二醇。
本实施例中制得无色透明液体，产率49％。
1HNMR(500MHz,CDCl3)δ8.06(dd,J＝1.2,8.5Hz,2H),7.79–7.72(m,1H),7.65–7.59(m,2H),7.49(d,J＝1.4Hz,1H),7.38(d,J＝2.1Hz,1H),6.25(t,J＝2.1Hz,1H),5.76(dd,J＝10.8,17.5Hz,1H),5.08(t,J＝1.7Hz,2H),5.00(d,J＝8.2Hz,2H),4.87–
4.81(m,2H),4.74(d,J＝4.6Hz,6H),3.95(d,J＝5.9Hz,2H),2.99(d,J＝13.6Hz,1H),2.78(d,J＝8.4Hz,2H),2.71–2.56(m,5H),2.15(d,J＝10.4Hz,1H),1.96–1.85(m,2H),1.72–1.31(m,12H),0.95(s,3H).13CNMR(125MHz,CDCl3)δ172.1,171.6,158.0,150.0,149.9,148.5,139.3,137.9,135.8,129.8,129.4,128.7,113.5,111.5,110.7,110.3,105.8,83.9,78.7,69.4,66.5,58.7,56.4,54.1,52.5,52.2,47.9,41.9,39.8,39.8,35.5,33.7,29.0,29.0,27.1,16.0.HRMS(ESI)m/z:calcdforC40H49N5O9S[M+H]+,776.3324；found,776.3298.
实施例12：制备化合物12(17f)
4-((4-((5-((1-(2-((1R,2S,5R)-5-(3-(1H-吡唑-1-基)丙-1-烯-2-基))-2-甲基-2-乙烯基环己基)烯丙基)哌啶-4-基)甲氧基)-5-氧代戊酰基)氧基)丁-2-炔-1-基)氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物制备方法基本同实施例8，区别在于，将(四)中的乙二醇替换为1,4-丁炔二醇。
本实施例中制得无色透明液体，产率25％。
1HNMR(500MHz,CDCl3)δ8.09–8.04(m,2H),7.79–7.74(m,1H),7.63(t,J＝7.9Hz,2H),7.50(d,J＝1.5Hz,1H),7.40–7.37(m,1H),6.26(t,J＝2.0Hz,1H),5.77(dd,J＝10.8,17.4Hz,1H),5.09(t,J＝1.6Hz,2H),5.00(s,2H),4.88–4.82(m,2H),4.77–4.72(m,6H),3.94(d,J＝6.0Hz,2H),2.98(d,J＝13.1Hz,1H),2.83–2.73(m,2H),2.60(d,J＝13.5Hz,1H),2.41(dt,J＝7.4,21.6Hz,4H),2.15(d,J＝11.0Hz,1H),1.95(dp,J＝8.4,9.4,19.4Hz,5H),1.68(s,1H),1.66–1.37(m,10H),0.96(s,3H).13CNMR(125MHz,CDCl3)δ172.9,172.2,158.0,150.0,149.9,148.6,139.3,138.0,135.8,129.8,129.5,128.8,113.4,111.5,110.7,110.3,105.8,84.1,78.6,69.1,66.5,58.7,56.4,54.2,52.5,52.0,47.9,42.0,39.8,35.5,33.7,33.2,33.1,29.1,27.1,20.1,16.0.HRMS(ESI)m/z:calcdfor C41H51N5O9S[M+H]+,790.348；found,790.3474.
实施例13：制备化合物13(18a)
4-(2-((4-(2-(4-(2-((1R,2S,5R)-5-(3-(1H-吡唑-1-基)丙-1-烯-2-基))-2-甲基-2-乙烯基环己基)烯丙基)哌嗪-1-基)乙氧基)-4-氧代丁酰基)氧基)乙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物制备方法基本同实施例1，区别在于，将(三)中的N-甲基-2-羟基乙胺替换为1-(2-羟乙基)哌嗪。
本实施例中制得无色透明液体，产率54％。
1HNMR(500MHz,CDCl3)δ8.11–8.02(m,2H),7.76(t,J＝7.5Hz,1H),7.63(t,J＝7.9Hz,2H),7.50(s,1H),7.39(s,1H),6.28–6.23(m,1H),5.77(dd,J＝10.8,17.1Hz,1H),5.02(d,J＝17.6Hz,2H),4.85(dd,J＝6.6,13.6Hz,2H),4.75(s,4H),4.65–4.59(m,2H),4.54–4.48(m,2H),4.23(t,J＝5.4Hz,2H),3.08–2.96(m,1H),2.67(d,J＝16.7Hz,8H),2.57–2.48(m,3H),2.42(d,J＝19.9Hz,2H),2.20–2.10(m,1H),1.93–1.86(m,1H),1.85–1.68(m,2H),1.61–1.40(m,6H),0.96(s,3H).13CNMR(125MHz,CDCl3)δ172.2,172.2,158.8,149.9,149.9,147.9,139.3,138.1,135.8,129.8,129.5,128.8,113.9,111.6,110.5,110.4,105.9,69.0,66.2,62.4,61.5,56.7,56.4,53.6,53.0,47.9,42.0,39.9,39.9,33.7,29.1,29.0,27.1,16.0.HRMS(ESI)m/z:calcdforC38H50N6O9S[M+H]+,767.3433；found,767.343.
实施例14：制备化合物14(18b)
4-(2-((5-(2-(4-(2-((1R,2S,5R)-5-(3-(1H-吡唑-1-基)丙-1-烯-2-基))-2-甲基-2-乙烯基环己基)烯丙基)哌嗪-1-基)乙氧基)-5-氧代戊酰基)氧基)乙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物制备方法基本同实施例13，区别在于，将(五)中的丁二酸酐替换为戊二酸酐。
本实施例中制得无色透明液体，产率45％。
1HNMR(500MHz,CDCl3)δ8.06(dd,J＝1.2,8.5Hz,2H),7.79–7.74(m,1H),7.62(td,J＝1.7,7.6Hz,2H),7.50(d,J＝1.4Hz,1H),7.39(d,J＝1.9Hz,1H),6.26(t,J＝2.1Hz,1H),5.77(dd,J＝10.8,17.4Hz,1H),5.02(d,J＝13.7Hz,2H),4.89–4.82(m,2H),4.76(s,4H),4.62(dd,J＝3.7,5.4Hz,2H),4.50(dd,J＝3.7,5.4Hz,2H),4.21(t,J＝5.9Hz,2H),3.07–2.94(m,1H),2.64(t,J＝5.6Hz,3H),2.56–2.50(m,2H),2.44(dt,J＝7.3,23.1Hz,7H),2.30(d,J＝16.2Hz,1H),2.19–2.12(m,1H),1.98(p,J＝7.3Hz,2H),1.94–1.86(m,1H),1.83–1.66(m,2H),1.62–1.40(m,6H),0.96(s,3H).13CNMR(125MHz,CDCl3)δ172.9,172.7,158.8,149.9,149.9,148.1,139.3,138.1,135.8,129.8,129.4,128.7,113.9,111.5,110.5,110.3,105.8,69.0,66.2,62.0,61.2,56.7,56.4,53.5,53.0,47.9,41.9,39.8,39.8,33.6,33.2,33.1,27.1,20.0,15.9.HRMS(ESI)m/z:calcdforC39H52N6O9S[M+H]+,781.3589；found,781.3541.
实施例15：制备化合物15(18c)
4-(3-((4-(2-(4-(2-((1R,2S,5R)-5-(3-(1H-吡唑-1-基)丙-1-烯-2-基))-2-甲基-2-乙烯基环己基)烯丙基)哌嗪-1-基)乙氧基)-4-氧代丁酰基)氧基)丙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物制备方法基本同实施例13，区别在于，将(四)中的乙二醇替换为丙二醇。
本实施例中制得淡黄色液体，产率80％。
1HNMR(500MHz,CDCl3)δ8.07–8.04(m,2H),7.78–7.73(m,1H),7.65–7.60(m,2H),7.52–7.49(m,1H),7.40(d,J＝2.0Hz,1H),6.27(t,J＝2.0Hz,1H),5.77(dd,J＝10.8,17.5Hz,1H),5.03(d,J＝24.5Hz,2H),4.89–4.82(m,2H),4.81–4.72(m,4H),4.51(t,J＝6.1Hz,2H),4.30(t,J＝6.1Hz,2H),4.20(t,J＝5.8Hz,2H),3.06(d,J＝15.5Hz,1H),2.68–2.41(m,14H),2.21(q,J＝6.1Hz,4H),1.91(dd,J＝7.9,18.0Hz,1H),1.60–1.40(m,6H),0.96(s,3H).13CNMR(125MHz,CDCl3)δ172.3,158.9,149.9,149.8,147.9,139.2,138.0,135.7,129.8,129.4,128.6,114.1,111.5,110.5,110.4,105.8,68.0,66.1,62.1,60.6,56.5,56.4,53.3,52.8,47.9,41.9,39.8,39.8,33.6,29.1,29.0,28.0,27.0,15.9.HRMS(ESI)m/z:calcdforC39H52N6O9S[M+H]+,781.3589；found,781.357.
实施例16：制备化合物16(18d)
4-(3-((5-(2-(4-(2-((1R,2S,5R)-5-(3-(1H-吡唑-1-基)丙-1-烯-2-基))-2-甲基-2-乙烯基环己基)烯丙基)哌嗪-1-基)乙氧基)-5-氧代戊酰基)氧基)丙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物制备方法基本同实施例14，区别在于，将(四)中的乙二醇替换为丙二醇。
本实施例中制得无色透明液体，产率68％。
1HNMR(500MHz,CDCl3)δ8.06(d,J＝8.0Hz,2H),7.76(t,J＝7.5Hz,1H),7.63(t,J＝7.9Hz,2H),7.51(s,1H),7.40(s,1H),6.27(s,1H),5.77(dd,J＝10.8,16.6Hz,1H),5.02(d,J＝13.6Hz,2H),4.89–4.82(m,2H),4.76(s,4H),4.50(t,J＝6.1Hz,2H),4.24(dt,J＝5.8,27.0Hz,4H),3.01(d,J＝21.1Hz,1H),2.65(s,3H),2.57–2.50(m,2H),2.43–2.36(m,5H),2.35–2.27(m,1H),2.21(p,J＝6.1Hz,2H),2.18–2.10(m,1H),1.94(tt,J＝7.7,13.8Hz,3H),1.73–1.39(m,10H),0.96(s,3H).13CNMR(125MHz,CDCl3)δ172.9,158.9,149.9,149.9,148.1,139.3,138.1,135.8,129.8,129.5,128.6,113.9,111.6,110.5,110.3,105.8,68.1,66.2,62.0,60.4,56.8,56.4,53.6,53.0,47.9,42.0,39.9,39.8,33.7,33.3,33.2,28.0,27.1,20.2,15.9.HRMS(ESI)m/z:calcdforC40H54N6O9S[M+H]+,795.3746；found,795.3701.
实施例17：制备化合物17(18e)
4-((4-((4-(2-(4-(2-((1R,2S,5R)-5-(3-(1H-吡唑-1-基)丙-1-烯-2-))基)-2-甲基-2-乙烯基环己基)烯丙基)哌嗪-1-基)乙氧基)-4-氧代丁酰基)氧基)丁-2-炔-1-基)氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物制备方法基本同实施例13，区别在于，将(四)中的乙二醇替换为1,4-丁炔二醇。
本实施例中制得无色透明液体，产率45％。
1HNMR(500MHz,CDCl3)δ8.08(d,J＝8.0Hz,2H),7.77(t,J＝7.5Hz,1H),7.63(t,J＝7.7Hz,2H),7.51(s,1H),7.39(s,1H),6.27(s,1H),5.77(dd,J＝10.7,17.4Hz,1H),5.12–4.99(m,4H),4.88–4.73(m,8H),4.24(t,J＝5.7Hz,2H),3.08–2.97(m,1H),2.66(d,J＝12.3Hz,7H),2.56–2.50(m,2H),2.43(dt,J＝7.4,15.7Hz,2H),2.35–2.28(m,1H),2.19–2.12(m,1H),1.90(d,J＝7.3Hz,1H),1.75–1.66(m,3H),1.61–1.41(m,6H),0.96(s,3H).13CNMR(125MHz,CDCl3)δ172.1,171.6,158.0,149.9,149.9,148.1,139.3,137.9,135.8,129.8,129.4,128.7,113.9,111.6,110.7,110.3,105.8,83.9,78.8,66.2,62.4,58.7,56.7,56.4,53.5,53.0,52.2,47.9,41.9,39.8,39.8,33.6,29.0,28.9,27.1,15.9.HRMS(ESI)m/z:calcdforC40H50N6O9S[M+H]+,791.3433；found,791.3423.
实施例18：制备化合物18(18f)
4-((4-((5-(2-(4-(2-((1R,2S,5R)-5-(3-(1H-吡唑-1-基)丙-1-烯-2-基)-2-甲基-2-乙烯基环己基)烯丙基)哌嗪-1-基)乙氧基)-5-氧代戊酰基)氧基)丁-2-炔-1-基)氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物制备方法基本同实施例14，区别在于，将(四)中的乙二醇替换为1,4-丁炔二醇。
本实施例中制得无色透明液体，产率56％。
1HNMR(500MHz,CDCl3)δ8.07(d,J＝7.8Hz,2H),7.77(t,J＝7.5Hz,1H),7.63(t,J＝7.8Hz,2H),7.53–7.49(m,1H),7.40(s,1H),6.27(t,J＝1.8Hz,1H),5.77(dd,J＝
11.3,17.3Hz,1H),5.05(d,J＝45.6Hz,4H),4.89–4.83(m,2H),4.80–4.72(m,6H),4.23(t,J＝5.4Hz,2H),3.09–2.95(m,1H),2.65(s,3H),2.55(d,J＝14.3Hz,3H),2.43(dt,J＝7.3,22.7Hz,6H),2.34–2.27(m,1H),2.22–2.12(m,1H),1.97(p,J＝7.3Hz,3H),1.77–1.67(m,2H),1.60–1.41(m,6H),0.96(s,3H).13CNMR(125MHz,CDCl3)δ172.8,172.2,158.0,149.9,149.9,148.1,139.3,137.9,135.8,129.8,129.4,128.7,114.0,111.6,
110.7,110.4,105.8,84.1,78.6,66.2,61.9,58.7,56.7,56.4,53.5,53.0,51.9,47.9,41.9,39.8,39.8,33.6,33.2,33.0,27.1,20.0,15.9.HRMS(ESI)m/z:calcdforC41H52N6O9S[M+H]+,805.3589；found,805.3593.
实施例19：制备化合物19(19a)
4-(2-((4-(2-((2-((1R,2S,5R)-5-(3-(4-乙基哌嗪-1-基)丙-1-烯-2-基))-2-甲基-2-乙烯基环己基)烯丙基)(甲基)氨基)乙氧基)-4-氧代丁酰基)氧基)乙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物制备方法基本同实施例1，区别在于，将(二)中的吡唑替换为N-乙基哌嗪。
本实施例中制得无色透明液体，产率49％。
1HNMR(500MHz,CDCl3)δ8.09–8.03(m,2H),7.75(tt,J＝1.2,7.2Hz,1H),7.66–7.59(m,2H),5.79(dd,J＝10.8,17.5Hz,1H),5.03(s,1H),4.94–4.83(m,4H),4.77(s,1H),4.64–4.60(m,2H),4.53–4.49(m,2H),4.17(td,J＝3.3,6.0Hz,2H),3.13(d,J＝13.7Hz,1H),2.95–2.88(m,2H),2.71–2.61(m,7H),2.60–2.27(m,10H),2.23–2.16(m,4H),2.12–2.02(m,1H),1.66–1.57(m,2H),1.51–1.37(m,4H),1.10(t,J＝7.2Hz,3H),0.97(s,3H).13CNMR(125MHz,CDCl3)δ172.2,172.2,158.8,150.9,150.3,149.3,138.2,135.8,129.8,128.8,113.9,110.9,110.5,110.2,69.0,66.1,63.5,62.9,61.5,55.4,53.0,52.9,52.4,47.6,42.9,42.5,40.1,40.0,34.0,29.1,29.0,27.3,15.9,11.9.HRMS(ESI)m/z:calcdforC38H55N5O9S[M+H]+,758.3793；found,758.3749.
实施例20：制备化合物20(19b)
4-(2-((5-(2-((2-((1R,2S,5R)-5-(3-(4-乙基哌嗪-1-基)丙-1-烯-2-基))-2-甲基-2-乙烯基环己基)烯丙基)(甲基)氨基)乙氧基)-5-氧代戊酰基)氧基)乙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物制备方法基本同实施例19，区别在于，将(五)中的丁二酸酐替换为戊二酸酐。
本实施例中制得无色透明液体，产率58％。
1HNMR(500MHz,CDCl3)δ8.04(dd,J＝1.1,8.5Hz,2H),7.77–7.72(m,1H),7.64–7.58(m,2H),5.78(dd,J＝10.8,17.5Hz,1H),5.03(s,1H),4.94–4.82(m,4H),4.76(s,1H),4.61(dd,J＝3.8,5.4Hz,2H),4.49(dd,J＝3.2,5.9Hz,2H),4.15(td,J＝3.5,6.0Hz,2H),3.12(d,J＝13.7Hz,1H),2.95–2.88(m,2H),2.71–2.34(m,17H),2.22–2.15(m,4H),2.07(d,J＝7.8Hz,1H),1.97(p,J＝7.4Hz,2H),1.65–1.56(m,2H),1.50–1.36(m,4H),1.09(t,J＝7.2Hz,3H),0.96(s,3H).13CNMR(125MHz,CDCl3)δ172.9,172.7,158.8,150.9,150.3,149.3,138.1,135.8,129.8,128.7,113.8,110.9,110.5,110.2,69.0,66.1,63.5,62.5,61.2,55.5,53.0,52.9,52.4,47.5,42.9,42.5,40.1,39.9,34.0,33.2,33.1,27.3,20.0,15.9,11.9.HRMS(ESI)m/z:calcdforC39H57N5O9S[M+H]+,772.395；found,772.3926.
实施例21：制备化合物21(19c)
4-(3-((4-(2-((2-((1R,2S,5R)-5-(3-(4-乙基哌嗪-1-基)丙-1-烯-2-基))-2-甲基-2-乙烯基环己基)烯丙基)(甲基)氨基)乙氧基)-4-氧代丁酰基)氧基)丙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物制备方法基本同实施例19，区别在于，将(四)中的乙二醇替换为丙二醇。
本实施例中制得无色透明液体，产率42％。
1HNMR(500MHz,CDCl3)δ8.06(dd,J＝1.1,8.4Hz,2H),7.80–7.72(m,1H),7.66–7.60(m,2H),5.80(dd,J＝10.8,17.5Hz,1H),5.04(s,1H),4.96–4.84(m,4H),4.78(s,1H),4.51(t,J＝6.1Hz,2H),4.30(t,J＝6.1Hz,2H),4.14(td,J＝3.3,6.0Hz,2H),3.14(d,J＝13.7Hz,1H),2.99–2.88(m,2H),2.71–2.61(m,7H),2.59–2.41(m,8H),2.24–2.16(m,6H),2.13–2.01(m,2H),2.02–1.91(m,1H),1.61(q,J＝12.9Hz,2H),1.52–1.39(m,4H),1.14(t,J＝7.2Hz,3H),0.98(s,3H).13CNMR(125MHz,CDCl3)δ172.3,172.3,159.0,150.9,150.3,149.3,138.1,135.8,129.8,128.7,113.9,110.9,110.6,110.2,68.0,66.1,63.4,62.8,60.6,55.4,52.9,52.4,47.5,42.8,42.5,40.1,40.0,34.0,29.1,29.1,28.0,27.3,15.9,11.8.HRMS(ESI)m/z:calcdforC39H57N5O9S[M+H]+,772.395；found,772.3937.
实施例22：制备化合物22(19d)
4-(3-((5-(2-((2-((1R,2S,5R)-5-(3-(4-乙基哌嗪-1-基)丙-1-烯-2-基))-2-甲基-2-乙烯基环己基)烯丙基)(甲基)氨基)乙氧基)-5-氧代戊酰基)氧基)丙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物制备方法基本同实施例20，区别在于，将(四)中的乙二醇替换为丙二醇。
本实施例中制得无色透明液体，产率43％。
1HNMR(500MHz,CDCl3)δ8.05(dd,J＝1.1,8.4Hz,2H),7.78–7.72(m,1H),7.66–7.60(m,2H),5.79(dd,J＝10.8,17.5Hz,1H),5.04(s,1H),4.95–4.84(m,4H),4.77(s,1H),4.50(t,J＝6.1Hz,2H),4.27(t,J＝6.1Hz,2H),4.15(tt,J＝4.0,7.7Hz,2H),3.14(d,J＝13.6Hz,1H),2.98–2.89(m,2H),2.66(td,J＝7.0,13.5,14.0Hz,3H),2.60–2.34(m,13H),2.23–2.16(m,6H),2.01(dp,J＝7.4,8.1,62.7Hz,4H),1.61(q,J＝12.8Hz,2H),1.51–1.38(m,4H),1.15(t,J＝7.2Hz,3H),0.98(s,3H).13CNMR(125MHz,CDCl3)δ172.9,172.9,158.9,150.9,150.3,149.3,138.1,135.8,129.8,128.7,113.9,110.9,110.6,110.2,68.1,66.1,63.5,62.5,60.4,55.5,52.9,52.9,52.4,47.5,42.9,42.5,40.1,40.0,34.0,33.3,33.2,28.1,27.3,20.2,15.9,11.8.HRMS(ESI)m/z:calcdforC40H59N5O9S[M+H]+,786.4106；found,786.4089.
实施例23：制备化合物23(19e)
4-((4-((4-(2-((2-((1R,2S,5R)-5-(3-(4-乙基哌嗪-1-基)丙-1-烯-2-基))-2-甲基-2-乙烯基环己基)烯丙基)(甲基)氨基)乙氧基)-4-氧代丁酰基)氧基)丁-2-炔-1-基)氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物制备方法基本同实施例19，区别在于，将(四)中的乙二醇替换为1,4-丁炔二醇。
本实施例中制得无色透明液体，产率32％。
1HNMR(500MHz,CDCl3)δ8.09–8.04(m,2H),7.78–7.74(m,1H),7.63(td,J＝1.7,7.6Hz,2H),5.79(dd,J＝10.8,17.5Hz,1H),5.09(t,J＝1.7Hz,2H),5.03(s,1H),4.94–4.84(m,4H),4.79–4.74(m,3H),4.17(tt,J＝4.1,7.7Hz,2H),3.13(d,J＝13.6Hz,1H),2.97–2.88(m,2H),2.72–2.36(m,17H),2.23–2.15(m,4H),2.10–2.02(m,1H),1.61(q,J＝12.9Hz,2H),1.51–1.39(m,4H),1.11(t,J＝7.2Hz,3H),0.97(s,3H).13CNMR(125MHz,CDCl3)δ172.1,171.6,158.0,151.0,150.3,149.3,138.0,135.8,129.8,128.8,113.9,110.8,110.7,110.2,83.9,78.8,66.1,63.5,62.9,58.7,55.4,53.1,53.0,52.4,52.2,47.5,42.8,42.5,40.1,40.0,34.0,29.0,28.9,27.3,15.9,11.9.HRMS(ESI)m/z:calcd forC40H55N5O9S[M+H]+,782.3793；found,782.3796.
实施例24：制备化合物24(19f)
4-((4-((5-(2-((2-((1R,2S,5R)-5-(3-(4-乙基哌嗪-1-基)丙-1-烯-2-基))-2-甲基-2-乙烯基环己基)烯丙基)(甲基)氨基)乙氧基)-5-氧代戊酰基)氧基)丁-2-炔-1-基)氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物制备方法基本同实施例20，区别在于，将(四)中的乙二醇替换为1,4-丁炔二醇。
本实施例中制得无色透明液体，产率53％。
1HNMR(500MHz,CDCl3)δ8.04(dd,J＝1.1,8.4Hz,2H),7.77–7.73(m,1H),7.64–7.59(m,2H),5.79(dd,J＝10.8,17.5Hz,1H),5.03(s,1H),4.94–4.82(m,4H),4.77(s,1H),4.49(t,J＝6.1Hz,2H),4.26(t,J＝6.1Hz,2H),4.18–4.10(m,2H),3.13(d,J＝13.7Hz,1H),2.96–2.86(m,2H),2.65(td,J＝7.2,13.5,14.1Hz,3H),2.51–2.35(m,12H),2.22–2.15(m,6H),2.07(t,J＝11.5Hz,1H),1.94(p,J＝7.4Hz,2H),1.66–1.56(m,2H),1.50–1.37(m,4H),1.09(t,J＝7.2Hz,3H),0.97(s,3H).13CNMR(125MHz,CDCl3)δ172.8,172.1,158.0,151.0,150.3,149.3,138.0,135.8,129.8,128.8,113.8,110.8,110.7,110.2,84.1,78.6,66.1,63.5,62.5,58.7,55.5,53.1,53.0,52.4,51.9,47.5,42.9,42.5,40.1,39.9,33.9,33.2,33.0,27.3,20.0,15.9,11.9.HRMS(ESI)m/z:calcdforC41H57N5O9S[M+H]+,796.395；found,796.3958.
实施例25：制备化合物25(20a)
4-(2-((4-((1-(2-((1R,2S,5R)-5-(3-(4-乙基哌嗪-1-基)丙-1-烯-2-基))-2-甲基-2-乙烯基环己基)烯丙基)哌啶-4-基)甲氧基)-4-氧代丁酰基)氧基)乙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物制备方法基本同实施例1，区别在于，将(三)中的N-甲基-2-羟基乙胺替换为4-羟甲基哌啶。
本实施例中制得无色透明液体，产率50％。
1HNMR(500MHz,CDCl3)δ8.08–8.03(m,2H),7.75(t,J＝7.5Hz,1H),7.62(t,J＝7.9Hz,2H),5.79(dd,J＝10.8,17.5Hz,1H),5.01(s,1H),4.93–4.82(m,4H),4.76(d,J＝2.1Hz,1H),4.64–4.59(m,2H),4.54–4.48(m,2H),3.93(d,J＝6.2Hz,2H),2.94(dt,J＝13.6,41.4Hz,4H),2.81(t,J＝11.0Hz,2H),2.69–2.59(m,6H),2.55–2.36(m,8H),2.18(dd,J＝3.1,12.7Hz,1H),2.06(t,J＝11.5Hz,1H),1.96–1.90(m,1H),1.70(d,J＝11.6Hz,1H),1.65–1.55(m,5H),1.52–1.30(m,6H),1.08(t,J＝7.2Hz,3H),0.98(s,3H).13CNMR(125MHz,CDCl3)δ172.3,172.2,158.8,151.0,150.3,148.8,138.1,135.8,129.8,128.7,113.4,110.8,110.5,110.1,69.4,69.0,66.7,63.6,61.5,54.2,53.1,52.9,52.6,52.4,48.3,42.4,40.1,40.0,35.5,34.1,29.1,29.0,29.0,27.3,16.1,11.9.HRMS(ESI)m/z:calcdforC41H59N5O9S[M+H]+,798.4106；found,798.4096.
实施例26：制备化合物26(20b)
4-(2-((5-((1-(2-((1R,2S,5R)-5-(3-(4-乙基哌嗪-1-基)丙-1-烯-2-基))-2-甲基-2-乙烯基环己基)烯丙基)哌啶-4-基)甲氧基)-5-氧代戊酰基)氧基)乙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物制备方法基本同实施例25，区别在于，将(五)中的丁二酸酐替换为戊二酸酐。
本实施例中制得无色透明液体，产率29％。
1HNMR(500MHz,CDCl3)δ8.06(d,J＝7.5Hz,2H),7.76(t,J＝7.5Hz,1H),7.63(t,J＝7.9Hz,2H),5.80(dd,J＝10.8,17.5Hz,1H),5.03(s,1H),4.94–4.84(m,4H),4.78(s,1H),4.65–4.59(m,2H),4.53–4.48(m,2H),3.93(d,J＝6.3Hz,2H),3.04–2.88(m,4H),2.86–2.80(m,2H),2.64(d,J＝13.9Hz,2H),2.55–2.38(m,12H),2.20(d,J＝12.6Hz,1H),2.07(s,1H),1.98(dt,J＝7.3,14.6Hz,4H),1.72(s,1H),1.61(d,J＝12.3Hz,4H),1.56–1.39(m,6H),1.13(t,J＝7.2Hz,3H),0.99(s,3H).13CNMR(125MHz,CDCl3)δ173.0,172.7,158.8,150.9,150.3,148.7,138.1,135.8,129.8,128.7,113.5,111.0,110.5,110.1,69.1,69.0,66.6,63.5,61.2,54.2,52.8,52.7,52.6,52.3,48.3,42.4,40.1,40.0,35.5,34.1,33.3,33.2,29.1,29.0,27.3,20.1,16.1,11.7.HRMS(ESI)m/z:calcdforC42H61N5O9S[M+H]+,812.4263；found,812.4261.
实施例27：制备化合物27(20c)
4-(3-((4-((1-(2-((1R,2S,5R)-5-(3-(4-乙基哌嗪-1-基)丙-1-烯-2-基))-2-甲基-2-乙烯基环己基)烯丙基)哌啶-4-基)甲氧基)-4-氧代丁酰基)氧基)丙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物制备方法基本同实施例25，区别在于，将(四)中的乙二醇替换为丙二醇。
本实施例中制得无色透明液体，产率52％。
1HNMR(500MHz,CDCl3)δ8.06(dd,J＝1.1,8.5Hz,2H),7.79–7.73(m,1H),7.63(td,J＝1.6,7.7Hz,2H),5.80(dd,J＝10.8,17.5Hz,1H),5.04(s,1H),4.95–4.83(m,4H),4.78(s,1H),4.51(t,J＝6.1Hz,2H),4.30(t,J＝6.1Hz,2H),3.90(d,J＝6.4Hz,2H),2.92(tt,J＝11.2,41.2Hz,6H),2.63(s,6H),2.59–2.39(m,8H),2.22(p,J＝6.2Hz,4H),2.07(t,J＝11.5Hz,1H),1.96(t,J＝13.4Hz,1H),1.72(t,J＝11.6Hz,1H),1.68–1.39(m,
10H),1.14(t,J＝7.2Hz,3H),0.99(s,3H).13CNMR(125MHz,CDCl3)δ172.4,172.3,
159.0,150.9,150.3,148.7,138.1,135.8,129.8,128.7,113.5,110.9,110.6,110.1,69.3,68.0,66.6,63.5,60.6,54.2,52.8,52.8,52.6,52.3,48.2,42.4,40.1,40.0,35.5,34.1,32.0,29.1,29.0,28.9,28.0,27.3,16.0,11.7.HRMS(ESI)m/z:calcdforC42H61N5O9S[M+H]+,812.4263；found,812.4269.
实施例28：制备化合物28(20d)
4-(3-((5-((1-(2-((1R,2S,5R)-5-(3-(4-乙基哌嗪-1-基)丙-1-烯-2-基))-2-甲基-2-乙烯基环己基)烯丙基)哌啶-4-基)甲氧基)-5-氧代戊酰基)氧基)丙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物制备方法基本同实施例26，区别在于，将(四)中的乙二醇替换为丙二醇。
本实施例中制得无色透明液体，产率44％。
1HNMR(500MHz,CDCl3)δ8.06(dt,J＝1.5,8.6Hz,2H),7.76(tt,J＝1.2,7.2Hz,1H),7.63(td,J＝1.7,7.6Hz,2H),5.80(dd,J＝10.8,17.5Hz,1H),5.03(s,1H),4.95–4.83(m,4H),4.77(s,1H),4.50(t,J＝6.1Hz,2H),4.27(t,J＝6.1Hz,2H),3.92(d,J＝6.2Hz,2H),3.03–2.87(m,3H),2.83(t,J＝10.6Hz,2H),2.66–2.43(m,8H),2.38(dt,J＝7.4,12.3Hz,5H),2.21(dq,J＝4.9,5.5,11.2Hz,3H),2.07(t,J＝11.5Hz,1H),1.95(p,J＝7.3Hz,3H),1.86–1.39(m,14H),1.11(t,J＝7.2Hz,3H),0.99(s,3H).13CNMR(125MHz,CDCl3)δ173.0,172.9,158.9,151.0,150.3,148.9,138.1,135.8,129.8,128.6,113.3,110.8,110.5,110.1,69.1,68.0,66.7,63.6,60.4,54.2,53.2,52.9,52.6,52.4,48.2,42.4,40.1,39.9,35.5,34.1,33.3,33.2,29.1,29.1,28.0,27.3,20.2,16.1,12.0.HRMS(ESI)m/z:calcdforC43H63N5O9S[M+H]+,826.4419；found,826.4469.
实施例29：制备化合物29(20e)
4-((4-((4-((1-(2-((1R,2S,5R)-5-(3-(4-乙基哌嗪-1-基)丙-1-烯-2-基))-2-甲基-2-乙烯基环己基)烯丙基)哌啶-4-基)甲氧基)-4-氧代丁酰基)氧基)丁-2-炔基-1-基)氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物制备方法基本同实施例25，区别在于，将(四)中的乙二醇替换为1,4-丁炔二醇。
本实施例中制得无色透明液体，产率31％。
1HNMR(500MHz,CDCl3)δ8.09–8.04(m,2H),7.79–7.74(m,1H),7.66–7.61(m,2H),5.80(dd,J＝10.8,17.5Hz,1H),5.09(t,J＝1.6Hz,2H),5.02(s,1H),4.94–4.83(m,4H),4.79–4.73(m,3H),3.95(d,J＝6.2Hz,2H),3.00(d,J＝13.8Hz,1H),2.92(q,J＝13.4Hz,2H),2.82(t,J＝10.4Hz,2H),2.70–2.36(m,15H),2.19(dd,J＝3.1,12.8Hz,1H),2.07(t,J＝11.5Hz,1H),1.94(t,J＝11.5Hz,1H),1.75–1.57(m,6H),1.52–1.41(m,4H),1.10(t,J＝7.2Hz,3H),0.98(s,3H).13CNMR(125MHz,CDCl3)δ172.1,171.6,158.0,151.0,150.3,148.8,138.0,135.8,129.8,128.8,113.4,110.8,110.7,110.1,83.9,78.8,69.4,66.7,63.6,58.7,54.2,53.0,52.9,52.6,52.4,52.2,48.2,42.4,40.1,40.0,35.5,34.1,29.0,29.0,29.0,27.3,16.1,11.9.HRMS(ESI)m/z:calcdforC43H59N5O9S[M+H]+,822.4106；found,822.4107.
实施例30：制备化合物30(20f)
4-((4-((5-((1-(2-((1R,2S,5R)-5-(3-(4-乙基哌嗪-1-基)丙-1-烯-2-基))-2-甲基-2-乙烯基环己基)烯丙基)哌啶-4-基)甲氧基)-5-氧代戊酰基)氧基)丁-2-炔-1-基)氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物制备方法基本同实施例26，区别在于，将(四)中的乙二醇替换为1,4-丁炔二醇。
本实施例中制得无色透明液体，产率55％。
1HNMR(500MHz,CDCl3)δ8.07(d,J＝8.1Hz,2H),7.77(t,J＝7.5Hz,1H),7.63(t,J＝7.6Hz,2H),5.80(dd,J＝10.8,17.4Hz,1H),5.10(s,2H),5.03(s,1H),4.94–4.83(m,4H),4.76(d,J＝16.1Hz,3H),3.93(d,J＝5.8Hz,2H),2.93(ddt,J＝11.4,38.2,51.7Hz,6H),2.64(d,J＝13.9Hz,2H),2.55–2.34(m,11H),2.20(d,J＝12.3Hz,1H),2.09–2.04(m,1H),1.99–1.91(m,3H),1.75–1.33(m,13H),1.12(t,J＝6.9Hz,3H),0.99(s,3H).13CNMR(125MHz,CDCl3)δ172.9,172.2,158.0,151.0,150.3,148.8,138.0,135.8,129.8,128.8,113.4,110.8,110.7,110.1,84.1,78.7,69.1,66.7,63.6,58.7,54.2,53.1,52.9,52.6,52.4,52.0,48.3,42.4,40.1,40.0,35.5,34.1,33.2,33.1,29.1,29.1,27.3,20.1,16.1,11.9.HRMS(ESI)m/z:calcdforC44H61N5O9S[M+H]+,836.4263；found,836.4268.
实施例31：制备化合物31(21a)
4-(2-((4-(2-(4-(2-((1R,2S,5R)-5-(3-(4-乙基哌嗪-1-基)丙-1-烯-2-基))-2-甲基-2-乙烯基环己基)烯丙基)哌嗪-1-基)乙氧基)-4-氧代丁酰基)氧基)乙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物制备方法基本同实施例1，将(三)中的N-甲基-2-羟基乙胺替换为1-(2-羟乙基)哌嗪。
本实施例中制得无色透明液体，产率52％。
1HNMR(500MHz,CDCl3)δ8.05(dd,J＝1.2,8.5Hz,2H),7.77–7.72(m,1H),7.61(td,J＝1.7,7.6Hz,2H),5.78(dd,J＝10.8,17.5Hz,1H),5.02(s,1H),4.93–4.81(m,4H),4.76(s,1H),4.63–4.60(m,2H),4.50(dd,J＝3.7,5.4Hz,2H),4.20(t,J＝6.0Hz,2H),3.00(d,J＝13.8Hz,1H),2.95–2.87(m,2H),2.72–2.59(m,9H),2.57–2.36(m,14H),2.35–2.30(m,1H),2.24–2.01(m,3H),1.62–1.38(m,6H),1.10(t,J＝7.2Hz,3H),0.97(s,3H).13CNMR(125MHz,CDCl3)δ172.2,172.1,158.8,150.9,150.2,148.4,138.1,135.8,129.8,128.7,113.6,110.9,110.5,110.2,68.9,66.3,63.5,62.4,61.5,56.7,53.6,53.1,52.9,52.4,48.3,42.4,40.1,40.0,34.0,29.1,29.0,27.3,16.0,11.8.HRMS(ESI)m/z:calcd forC41H60N6O9S[M+H]+,813.4215；found,813.4222.
实施例32：制备化合物32(21b)
4-(2-((5-(2-(4-(2-((1R,2S,5R)-5-(3-(4-乙基哌嗪-1-基)丙-1-烯-2-基))-2-甲基-2-乙烯基环己基)烯丙基)哌嗪-1-基)乙氧基)-5-氧代戊酰基)氧基)乙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物制备方法基本同实施例31，区别在于，将(五)中的丁二酸酐替换为戊二酸酐。
本实施例中制得无色透明液体，产率38％。
1HNMR(500MHz,CDCl3)δ8.08–8.04(m,2H),7.78–7.74(m,1H),7.62(td,J＝1.7,7.6Hz,2H),5.79(dd,J＝10.8,17.5Hz,1H),5.03(s,1H),4.94–4.82(m,4H),4.77(s,1H),4.64–4.61(m,2H),4.50(dd,J＝3.7,5.4Hz,2H),4.20(t,J＝6.0Hz,2H),3.01(d,J＝13.8Hz,1H),2.92(q,J＝13.4Hz,2H),2.67–2.58(m,4H),2.55–2.27(m,20H),2.18(dd,J＝3.1,12.8Hz,1H),2.10–2.03(m,2H),2.00–1.95(m,2H),1.64–1.56(m,2H),1.52–1.38(m,4H),1.10(t,J＝7.2Hz,3H),0.98(s,3H).13CNMR(125MHz,CDCl3)δ172.9,172.7,158.8,150.9,150.2,148.4,138.1,135.8,129.8,128.7,113.6,110.9,110.5,110.2,69.0,66.3,63.5,61.9,61.2,56.8,53.6,53.1,52.9,52.8,52.4,48.3,42.4,40.1,40.0,34.0,33.2,33.1,27.3,20.1,16.0,11.8.HRMS(ESI)m/z:calcdforC42H62N6O9S[M+H]+,827.4372；found,827.4323.
实施例33：制备化合物33(21c)
4-(3-((4-(2-(4-(2-((1R,2S,5R)-5-(3-(4-乙基哌嗪-1-基)丙-1-烯-2-基))-2-甲基-2-乙烯基环己基)烯丙基)哌嗪-1-基)乙氧基)-4-氧代丁酰基)氧基)丙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物制备方法基本同实施例31，区别在于，将(四)中的乙二醇替换为丙二醇。
本实施例中制得无色透明液体，产率70％。
1HNMR(500MHz,CDCl3)δ8.08–8.04(m,2H),7.78–7.73(m,1H),7.63(t,J＝7.9Hz,2H),5.80(dd,J＝10.8,17.5Hz,1H),5.04(s,1H),4.95–4.83(m,4H),4.78(s,1H),4.51(t,J＝6.1Hz,2H),4.30(t,J＝6.1Hz,2H),4.18(t,J＝6.0Hz,2H),3.02(d,J＝13.8Hz,1H),2.98–2.89(m,2H),2.71–2.28(m,24H),2.21(qd,J＝3.6,11.3Hz,4H),2.08(d,J＝11.6Hz,1H),1.60(dd,J＝8.0,12.1Hz,2H),1.53–1.38(m,4H),1.15(t,J＝7.2Hz,3H),0.99(s,3H).13CNMR(125MHz,CDCl3)δ172.3,172.3,158.9,150.9,150.2,148.4,138.1,135.7,129.8,128.7,113.6,110.8,110.6,110.1,68.0,66.3,63.5,62.3,60.6,56.7,53.6,53.1,53.0,52.9,52.4,48.3,42.4,40.1,39.9,34.0,29.1,29.1,28.0,27.2,16.0,11.8.HRMS(ESI)m/z:calcdforC42H62N6O9S[M+H]+,827.4372；found,827.4326.
实施例34：制备化合物34(21d)
4-(3-((5-(2-(4-(2-((1R,2S,5R)-5-(3-(4-乙基哌嗪-1-基)丙-1-烯-2-基))-2-甲基-2-乙烯基环己基)烯丙基)哌嗪-1-基)乙氧基)-5-氧代戊酰基)氧基)丙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物制备方法基本同实施例32，区别在于，将(四)中的乙二醇替换为丙二醇。
本实施例中制得无色透明液体，产率58％。
1HNMR(500MHz,CDCl3)δ8.05–8.03(m,2H),7.77–7.72(m,1H),7.62(td,J＝1.7,7.6Hz,2H),5.78(dd,J＝10.8,17.5Hz,1H),5.02(s,1H),4.93–4.82(m,4H),4.77(s,1H),4.49(t,J＝6.1Hz,2H),4.26(t,J＝6.1Hz,2H),4.18(t,J＝6.0Hz,2H),3.01(d,J＝13.8Hz,1H),2.96–2.88(m,2H),2.67–2.57(m,5H),2.57–2.34(m,19H),2.26–2.17(m,4H),2.03(s,1H),1.95–1.91(m,2H),1.64–1.56(m,2H),1.51–1.39(m,4H),1.12(t,J＝7.2Hz,3H),0.97(s,3H).13CNMR(125MHz,CDCl3)δ172.9,158.9,150.8,150.2,148.4,138.1,135.8,129.8,128.6,113.7,111.0,110.5,110.2,68.1,66.3,63.4,61.9,60.4,56.8,53.6,53.1,52.7,52.6,52.3,48.3,42.4,40.0,40.0,34.0,33.3,33.2,28.0,27.3,20.1,16.0,11.6.HRMS(ESI)m/z:calcdforC43H64N6O9S[M+H]+,841.4528；found,841.4536.
实施例35：制备化合物35(21e)
4-((4-((4-(2-(4-(2-((1R,2S,5R)-5-(3-(4-乙基哌嗪-1-基)丙-1-烯-2-)基)-2-甲基-2-乙烯基环己基)烯丙基)哌嗪-1-基)乙氧基)-4-氧代丁酰基)氧基)丁-2-炔-1-基)氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物制备方法基本同实施例31，区别在于，将(四)中的乙二醇替换为1,4-丁炔二醇。
本实施例中制得无色透明液体，产率37％。
1HNMR(500MHz,CDCl3)δ8.06(dd,J＝1.1,8.4Hz,2H),7.78–7.73(m,1H),7.66–7.59(m,2H),5.79(dd,J＝10.8,17.5Hz,1H),5.09(t,J＝1.6Hz,2H),5.02(s,1H),4.94–4.81(m,4H),4.78–4.73(m,3H),4.21(t,J＝6.0Hz,2H),3.01(d,J＝13.8Hz,1H),2.91(q,J＝13.4Hz,2H),2.69–2.59(m,8H),2.56–2.24(m,17H),2.21–2.15(m,1H),2.06(t,J＝12.1Hz,1H),1.63–1.55(m,2H),1.51–1.38(m,4H),1.08(t,J＝7.2Hz,3H),0.98(s,3H).13CNMR(125MHz,CDCl3)δ172.1,171.6,158.0,151.0,150.3,148.5,138.0,135.8,129.8,128.8,113.6,110.9,110.7,110.2,83.9,78.8,66.3,63.6,62.4,58.7,56.7,53.6,53.2,53.0,52.9,52.4,52.2,48.3,42.4,40.1,40.0,34.1,29.0,28.9,27.3,16.1,11.9.HRMS(ESI)m/z:calcdforC43H60N6O9S[M+H]+,837.4215；found,837.4232.
实施例36：制备化合物36(21f)
4-((4-((5-(2-(4-(2-((1R,2S,5R)-5-(3-(4-乙基哌嗪-1-基)丙-1-烯-2-)基)-2-甲基-2-乙烯基环己基)烯丙基)哌嗪-1-基)乙氧基)-5-氧代戊酰基)氧基)丁-2-炔-1-基)氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物制备方法基本同实施例32，区别在于，将(四)中的乙二醇替换为1,4-丁炔二醇。
本实施例中制得无色透明液体，产率52％。
1HNMR(500MHz,CDCl3)δ8.09–8.03(m,2H),7.79–7.72(m,1H),7.66–7.58(m,2H),5.78(dd,J＝10.8,17.5Hz,1H),5.09(t,J＝1.7Hz,2H),5.02(s,1H),4.93–4.82(m,4H),4.77(d,J＝1.9Hz,1H),4.73(t,J＝1.6Hz,2H),4.19(t,J＝5.9Hz,2H),3.01(d,J＝13.8Hz,1H),2.95–2.87(m,2H),2.66–2.58(m,4H),2.57–2.26(m,21H),2.17(dd,J＝3.1,12.8Hz,1H),2.05(t,J＝10.5Hz,1H),1.98–1.92(m,2H),1.59(dd,J＝7.1,12.5Hz,2H),1.51–1.39(m,4H),1.10(t,J＝7.2Hz,3H),0.97(s,3H).13CNMR(125MHz,CDCl3)δ172.8,172.2,158.0,150.9,150.2,148.4,137.9,135.8,129.8,128.7,113.6,110.9,110.7,110.2,84.1,78.6,66.3,63.5,61.9,58.7,56.8,53.6,53.1,52.9,52.8,52.4,51.9,48.3,42.4,40.1,40.0,34.0,33.2,33.0,27.3,20.0,16.0,11.8.HRMS(ESI)m/z:calcdfor C44H62N6O9S[M+H]+,851.4372；found,851.4381.
药效学实验
1.一氧化氮体外释放试验
1.1实验设备与试剂
仪器
多功能酶标仪(美国MDSpectramacM3)
超净工作台(中国苏州净化SW-CJ-1FD)
试剂
一氧化碳(NO)测定试剂盒(中国南京建成生物工程研究所A013-2-1)
1.2实验方法
1样本前处理：将样品稀释至100μM，充分混匀，取160μL操作。
2操作表：
计算方法：
组织样本中NO含量计算公式：
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1.3试验结果
表1.实施例1-36制得β-榄香烯一氧化氮供体型衍生物的NO体外释放结果
由表1中数据可以看出，除实施例12、18的NO释放量较高外，其余化合物的NO释放量均较低。两种化合物的NO释放量均呈时间依赖性，30min后显著升高。此外，13-吡唑-β-榄香烯类化合物的NO含量高于13-N-乙基哌嗪-β-榄香烯类化合物。这两种化合物较高的NO释放水平也反映在随后更强的抗增殖活性上。
2.体外抗肿瘤活性评价试验
2.1实验设备
超净工作台(苏州净化SW-CJ-1FD)；
CO2培养箱(SANYOXD-101)；
生物倒置显微镜(OLYMPUSIX51)；
酶标仪(BioTekInstrumentsEL-x800)；
2.2实验方法
1)将细胞消化、计数，配制细胞悬液(K562，CCRF-CEM5×105个/mL，其余3.5×104个/mL)，96孔细胞培养板中每孔加入100μL细胞悬液；
2)96孔细胞培养板置于37℃，5％CO2培养箱中培养24h；
3)用培养基稀释药物至所需工作液浓度，每孔加入100μL相应的含药培养基，同时设立阴性对照组；
4)96孔细胞培养板置于37℃，5％CO2培养箱中培养72h；
5)将96孔板进行CCK-8染色，λ＝450nm，测定OD值；
1)每孔加入10μLCCK-8，在培养箱继续培养1-2h；
2)摇床10min轻轻地混匀，去除96孔板中气泡；
3)λ＝450nm，酶标仪读出每孔的OD值，计算抑制率。
6)计算各组别抑制率。
2.3实验结果
表2.实施例1-36化合物对4种人类癌细胞株抗增殖活性的抑制率(1和10μM)
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由表2可知，所有化合物的抗增殖活性强于β-榄香烯，说明NO供体的引入进一步提高了β-榄香烯的抗增殖活性。此外，在1和10μM浓度下，大多数化合物对K562和CCRF-CEM细胞的抑制作用明显强于对A375和SK-MEL-2细胞的抑制作用。这可能是由于β-榄香烯NO供体衍生物的代谢物仍然存在于血液中，具有抗肿瘤作用。因此，它们对K562和CCRF-CEM细胞株的敏感性高于对A375和SK-MEL-2细胞株的敏感性。
表3.实施例1-18化合物对2种人类癌细胞株抗增殖活性的IC50(μM)
结果如表3所示，所有化合物的抗增殖活性均强于β-榄香烯，部分化合物的IC50值甚至小于1μM。其中，实施例12(17f)、18(18f)对K562和CCRF-CEM细胞的抑制活性分别是β-榄香烯的100倍和90倍以上。活性较好的实施例12(17f)、18(18f)也表现出较高的NO释放水平，表现出协同抗肿瘤作用。这些结果表明，NO供体的引入可能会增强β-榄香烯的抗肿瘤活性。
3.抗人白血病细胞K562裸鼠移植瘤的体内抗肿瘤活性
3.1受试动物与实验设备
来源、种系、品系：balb/c裸鼠，上海灵畅生物科技有限公司提供。
日龄：6-8周
性别：雌性
动物数：每组6只，共3组，共18只
实验仪器：
电子称(常熟市双杰测试仪器厂T1000型)；
分析天平(Mettler Toledo ME204)；
3.2分组与给药方案
模型组：尾静脉注射等量溶媒，100μL/10g，每天一次，持续观察28天
β-榄香烯组：尾静脉注射，30mg/kg，100μL/10g，每天一次，持续观察28天
实施例18(18f)组：尾静脉注射，30mg/kg，100μL/10g，每天一次，持续观察28天
3.3模型的制备
收集培养的人白血病细胞K562细胞悬液，浓度为5×107个/mL，以每只0.1mL接种于小鼠右侧腋窝皮下。
3.4分组与给药
小鼠移植瘤用游标卡尺测量移植瘤直径，肿瘤生长至50-100mm3时将动物随机分组。同时，各组小鼠开始给药，给药方案见组别与给药方案。实验结束后，随即处死小鼠，手术剥取瘤块称重。
3.5实验结果
在给药4周内，模型组、β-榄香烯组和实施例18(18f)组的体重随着治疗时间的增加而逐渐增加，说明β-榄香烯和实施例18(18f)组没有明显的毒性。然而，在实验结束时称量肿瘤后发现，模型组肿瘤体积的增长随着治疗时间的增加而被严重夸大。相反，β-榄香烯组和实施例18(18f)组肿瘤体积的生长没有受到明显的抑制。此外，β-榄香烯组和实施例18(18f)组的肿瘤重量明显低于模型组，说明它们都有效地抑制了肿瘤的生长。正如预期的那样，实施例18(18f)组的抗肿瘤效果好于β-榄香烯组。在抑制肿瘤生长方面，虽然两者都能抑制肿瘤生长，但实施例18(18f)的抑制作用比β-榄香烯强约20％。
以上结果表明含氮基团和NO供体的引入有效增强了β-榄香烯在体内的抗肿瘤作用，是基于β-榄香烯抗肿瘤药物研发的可行策略。
此外应理解，在阅读了本发明的上述描述内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (10)
1.一种13-杂环-β-榄香烯一氧化氮供体型衍生物，或其可药用盐，或溶剂化物，或其对映异构体、非对映异构体，其特征在于，所述13-杂环-β-榄香烯一氧化氮供体型衍生物的结构如式(I)所示：
其中：
R1为含有氮、氧或硫的环状结构；
R2为含氮和氧原子的直链或环状醇胺结构；
R3、R4分别独立选自C1-10的链烷基、C3-12的环烷基、C6-12的芳基、5-10的元环杂芳基、C2-10的烯基、C2-10的炔基或C2-10的烷氧基。
2.根据权利要求1所述的一种13-杂环-β-榄香烯一氧化氮供体型衍生物，其特征在于，式(I)中：
R1为C2-8的含有氮、氧或硫的环状结构；
R2为C2-5的含氮和氧原子的直链醇胺结构或C5-8的环状醇胺结构；
R3、R4分别独立选自C2-6的链烷基、C2-6的烯基、C2-6的炔基。
3.根据权利要求2所述的一种13-杂环-β-榄香烯一氧化氮供体型衍生物，其特征在于，式(I)中：
R1选自
R2选自 其中氧原子与羰基相连；
R3、R4分别独立选自-CH2CH2-、-CH＝CH-、-CH2CH2CH2-、-CH2CH＝CH-、-CH＝CHCH2-、-CH2C≡C-、-C≡CCH2-、-CH2CH2CH2CH2-、-CH2CH2CH＝CH-、-CH2CH＝CHCH2-、-CH＝CHCH2CH2-、-CH2C≡CCH2-、-CH2CH2CH2CH2CH2-、-CH2C≡CCH2CH2-、-CH2CH2C≡CCH2-、-CH2CH2C≡CCH2CH2-，其按照从左到右的顺序分别与两端结构相连。
4.根据权利要求3所述的一种13-杂环-β-榄香烯一氧化氮供体型衍生物，其特征在于，式(I)中：
R1为
R2选自 其中氧原子与羰基相连；
R3、R4分别独立选自-CH2CH2-、-CH＝CH-、-CH2CH2CH2-、-CH2CH＝CH-、-CH＝CHCH2-、-CH2C≡C-、-C≡CCH2-、-CH2CH2CH2CH2-、-CH2CH2CH＝CH-、-CH2CH＝CHCH2-、-CH＝CHCH2CH2-、-CH2C≡CCH2-、-CH2CH2CH2CH2CH2-、-CH2C≡CCH2CH2-、-CH2CH2C≡CCH2-、-CH2CH2C≡CCH2CH2-，其按照从左到右分别与两端结构相连。
5.根据权利要求4所述的一种13-杂环-β-榄香烯一氧化氮供体型衍生物，其特征在于，所述13-杂环-β-榄香烯一氧化氮供体型衍生物选自如下结构所示的化合物1～36：
6.一种制备如权利要求1-5任一项所述的13-杂环-β-榄香烯一氧化氮供体型衍生物的方法，其特征在于，包括以下步骤：
(1)β-榄香烯A-1进行13、14位烯丙位氯代反应得到中间体A-2；
(2)含有氮杂原子官能团的R1结构片段A-3通过选择性亲核取代到中间体A-2的13位上，得到中间体A-4；
(3)含有氮杂原子官能团的R2结构片段A-5通过选择性亲核取代到中间体A-4的14位上，得到中间体A-6；
(4)苯巯基乙酸A-7经过30％H2O2氧化处理，又经发烟硝酸处理闭环得到中间体A-8；
(5)含有羟基官能团的R3结构片段A-9通过选择性亲核取代到中间体A-10上，得到中间体A-10；
(6)含有羰基官能团的R4结构片段A-11与中间体A-10酯化得到中间体A-11；
(7)中间体A-6和中间体A-11进行分子间酰胺缩合，得到通式(I)所示的衍生物；
其合成路线如下：
7.根据权利要求1-5任一项所述的13-杂环-β-榄香烯一氧化氮供体型衍生物，或其可药用盐，或溶剂化物，或其对映异构体、非对映异构体在制备抗肿瘤药物中的应用。
8.根据权利要求7所述的应用，其特征在于所述肿瘤包括白血病和黑色素瘤。
9.一种抗肿瘤药物，含有安全有效量的所述的13-杂环-β-榄香烯一氧化氮供体型衍生物，或其可药用盐，或溶剂化物，或其对映异构体、非对映异构体。
10.根据权利要求7所述的抗肿瘤药物，其特征在于，还包括药理上可接受的盐及药理上可以接受的赋形剂或载体。
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| CN (1) | CN116478149A (zh) |
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2022
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