PEG化吲哚菁染料偶联紫杉醇前药型化合物及其制备和应用

专利名称：PEG化吲哚菁染料偶联紫杉醇前药型化合物及其制备和应用

专利类型：发明专利

专利申请号：CN202310022430.2

专利申请（专利权）人：沈阳药科大学
权利人地址：辽宁省本溪市高新技术产业开发区华佗大街26号

专利发明（设计）人：王钝,李彦峰,毕洪书,方彦生

专利摘要：本发明属于药学领域，具体涉及一种基于氧化还原敏感键连接的靶向肿瘤PEG化吲哚菁染料偶联紫杉醇前药型化合物及其制备方法和在制备抗肿瘤药物的应用化合物为具有通式(I)所示的PEG化吲哚菁染料偶联紫杉醇前药型化合物及其药学上可接受的盐、溶剂化物，该化合物体外肿瘤细胞生长抑制试验证明该类化合物对前列腺肿瘤细胞具有良好的抑制效果。#imgabs0#

主权利要求：
1.一种PEG化吲哚菁染料偶联紫杉醇前药型化合物及其药学上可接受的盐，其特征在于：化合物为具有通式（I）所示的结构：其中：
R1选自氢、C1‑C5烷基、磺酸基、卤素；
R2选自氢、C1‑C5烷基；
X选自以下连接链：
‑
Y为卤素负离子；
1≤m≤5；2≤p≤6；1≤n≤45。
2.按权利要求1所述的PEG化吲哚菁染料偶联紫杉醇前药型化合物及其药学上可接受
的盐，其特征在于：化合物为具有通式（I）所示的结构：
R1选自氢、C1‑C3烷基、磺酸基、卤素；
R2选自氢、C1‑C3烷基；
X选自以下连接链：
‑
Y为溴或碘；
1≤m≤5；2≤p≤6；1≤n≤45。
3.按权利要求2所述的PEG化吲哚菁染料偶联紫杉醇前药型化合物及其药学上可接受
的盐，其特征在于：所述化合物为
苯丙酸,β‑(苯甲酰氨基)‑α‑[3‑[2‑[3‑[2‑[3‑[1‑[5‑[甲氧基聚乙二醇氨基羰基]戊基]‑1,3‑二氢‑3,3‑二‑甲基‑2H‑吲哚‑2‑甲叉基亚乙基]‑2‑氯‑1‑环己烯‑1‑基]乙烯基]‑
3,3‑二甲基‑3H‑吲哚‑1‑基丙基氨基羰基]乙基]硫代甲基乙叉基硫基]丙酰氧基‑6,12b‑双(乙酰氧基)‑12‑(苯甲酰氧基)‑2a,3,4,4a,5,6,9,10,11,12,12a,12b‑十二氢‑4,11‑二羟基‑4a,8,13,13‑四甲基‑5‑氧代‑7,11‑亚甲基‑1H‑环癸并[3,4]苯并[1,2‑b]氧杂丁环‑9‑基酯,[2aR‑[2aα,4β,4aβ,6β,9α(αR*,βS*),11α,12α,12aα,12bα]]；
苯丙酸,β‑(苯甲酰氨基)‑α‑[3‑[2‑[3‑[2‑[3‑[1‑[5‑[甲氧基聚乙二醇氨基羰基]戊基]‑1,3‑二氢‑3,3‑二‑甲基‑2H‑吲哚‑2‑甲叉基亚乙基]‑2‑氯‑1‑环己烯‑1‑基]乙烯基]‑
3,3‑二甲基‑3H‑吲哚‑1‑基丙基氨基羰基]乙基]硫基]丙酰氧基‑6,12b‑双(乙酰氧基)‑
12‑(苯甲酰氧基)‑2a,3,4,4a,5,6,9,10,11,12,12a,12b‑十二氢‑4,11‑二羟基‑4a,8,13,13‑四甲基‑5‑氧代‑7,11‑亚甲基‑1H‑环癸并[3,4]苯并[1,2‑b]氧杂丁环‑9‑基酯,[2aR‑[2aα,4β,4aβ,6β,9α(αR*,βS*),11α,12α,12aα,12bα]]；
苯丙酸,β‑(苯甲酰氨基)‑α‑[3‑[2‑[3‑[2‑[3‑[1‑[5‑[甲氧基聚乙二醇氨基羰基]戊基]‑1,3‑二氢‑3,3‑二‑甲基‑2H‑吲哚‑2‑甲叉基]亚乙基]‑2‑氯‑1‑环己烯‑1‑基]乙烯基]‑
3,3‑二甲基‑3H‑吲哚‑1‑基丙基氨基羰基]乙基]二硫基]丙酰氧基‑6,12b‑双(乙酰氧基)‑
12‑(苯甲酰氧基)‑2a,3,4,4a,5,6,9,10,11,12,12a,12b‑十二氢‑4,11‑二羟基‑4a,8,13,13‑四甲基‑5‑氧代‑7,11‑亚甲基‑1H‑环癸并[3,4]苯并[1,2‑b]氧杂丁环‑9‑基酯,[2aR‑[2aα,4β,4aβ,6β,9α(αR*,βS*),11α,12α,12aα,12bα]]；
苯丙酸,β‑(苯甲酰氨基)‑α‑[4‑[3‑[3‑[2‑[3‑[1‑[5‑[甲氧基聚乙二醇氨基羰基]戊基]‑1,3‑二氢‑3,3‑二‑甲基‑2H‑吲哚‑2‑甲叉基]亚乙基]‑2‑氯‑1‑环己烯‑1‑基]乙烯基]‑
3,3‑二甲基‑3H‑吲哚‑1‑基丙基氨基羰基]乙基]二硫基]丁酰氧基‑6,12b‑双(乙酰氧基)‑
12‑(苯甲酰氧基)‑2a,3,4,4a,5,6,9,10,11,12,12a,12b‑十二氢‑4,11‑二羟基‑4a,8,13,13‑四甲基‑5‑氧代‑7,11‑亚甲基‑1H‑环癸并[3,4]苯并[1,2‑b]氧杂丁环‑9‑基酯,[2aR‑[2aα,4β,4aβ,6β,9α(αR*,βS*),11α,12α,12aα,12bα]]；
苯丙酸,β‑(苯甲酰氨基)‑α‑[3‑[2‑[3‑[1‑[5‑[甲氧基聚乙二醇氨基羰基]戊基]‑1,
3‑二氢‑3,3‑二‑甲基‑2H‑吲哚‑2‑甲叉基]亚乙基]‑2‑氯‑1‑环己烯‑1‑基]乙烯基]‑3,3‑二甲基‑5‑磺酸基‑3H‑吲哚‑1‑基丙基氨基羰基]甲基硫基]乙酰氧基‑6,12b‑双(乙酰氧基)‑
12‑(苯甲酰氧基)‑2a,3,4,4a,5,6,9,10,11,12,12a,12b‑十二氢‑4,11‑二羟基‑4a,8,13,13‑四甲基‑5‑氧代‑7,11‑亚甲基‑1H‑环癸并[3,4]苯并[1,2‑b]氧杂丁环‑9‑基酯,[2aR‑[2aα,4β,4aβ,6β,9α(αR*,βS*),11α,12α,12aα,12bα]]；
苯丙酸,β‑(苯甲酰氨基)‑α‑[3‑[2‑[3‑[1‑[5‑[甲氧基聚乙二醇氨基羰基]戊基]‑1,
3‑二氢‑3,3‑二‑甲基‑2H‑吲哚‑2‑甲叉基]亚乙基]‑2‑氯‑1‑环己烯‑1‑基]乙烯基]‑3,3‑二甲基‑5‑磺酸基‑3H‑吲哚‑1‑基丙基氨基羰基]甲基二硫基]乙酰氧基‑6,12b‑双(乙酰氧基)‑12‑(苯甲酰氧基)‑2a,3,4,4a,5,6,9,10,11,12,12a,12b‑十二氢‑4,
11‑二羟基‑4a,8,13,13‑四甲基‑5‑氧代‑7,11‑亚甲基‑1H‑环癸并[3,4]苯并[1,2‑b]氧杂丁环‑9‑基酯,[2aR‑[2aα,4β,4aβ,6β,9α(αR*,βS*),11α,12α,12aα,12bα]]；
苯丙酸,β‑(苯甲酰氨基)‑α‑[3‑[2‑[3‑[2‑[3‑[1‑[5‑[甲氧基聚乙二醇氨基羰基]戊基]‑1,3‑二氢‑3,3‑二‑甲基‑2H‑吲哚‑2‑甲叉基]亚乙基]‑2‑氯‑1‑环己烯‑1‑基]乙烯基]‑
3,3‑二甲基‑5‑磺酸基‑3H‑吲哚‑1‑基丙基氨基羰基]乙基]硫代]甲基乙叉基硫基]丙酰氧基‑6,12b‑双(乙酰氧基)‑12‑(苯甲酰氧基)‑2a,3,4,4a,5,6,9,10,11,12,12a,
12b‑十二氢‑4,11‑二羟基‑4a,8,13,13‑四甲基‑5‑氧代‑7,11‑亚甲基‑1H‑环癸并[3,
4]苯并[1,2‑b]氧杂丁环‑9‑基酯,[2aR‑[2aα,4β,4aβ,6β,9α(αR*,βS*),11α,12α,12aα,12bα]]；
苯丙酸,β‑（苯甲酰氨基）‑α‑[3‑[2‑[3‑[2‑[3‑[1‑[5‑[甲氧基聚乙二醇氨基羰基]戊基]‑1,3‑二氢‑3,3‑二‑甲基‑2H‑吲哚‑2‑甲叉基]亚乙基]‑2‑氯‑1‑环己烯‑1‑基]乙烯基]‑
3,3‑二甲基‑5‑磺酸基‑3H‑吲哚‑1‑基丙基氨基羰基]乙基]硫基]丙酰氧基‑6,12b‑双(乙酰氧基)‑12‑(苯甲酰氧基)‑2a,3,4,4a,5,6,9,10,11,12,12a,12b‑十二氢‑4,
11‑二羟基‑4a,8,13,13‑四甲基‑5‑氧代‑7,11‑亚甲基‑1H‑环癸并[3,4]苯并[1,2‑b]氧杂丁环‑9‑基酯,[2aR‑[2aα,4β,4aβ,6β,9α(αR*,βS*),11α,12α,12aα,12bα]]；
苯丙酸,β‑（苯甲酰氨基）‑α‑[3‑[2‑[3‑[2‑[3‑[1‑[5‑[甲氧基聚乙二醇氨基羰基]戊基]‑1,3‑二氢‑3,3‑二‑甲基‑2H‑吲哚‑2‑甲叉基]亚乙基]‑2‑氯‑1‑环己烯‑1‑基]乙烯基]‑
3,3‑二甲基‑5‑磺酸基‑3H‑吲哚‑1‑基丙基氨基羰基]乙基]二硫基]丙酰氧基‑6,12b‑双(乙酰氧基)‑12‑(苯甲酰氧基)‑2a,3,4,4a,5,6,9,10,11,12,12a,12b‑十二氢‑4,11‑二羟基‑4a,8,13,13‑四甲基‑5‑氧代‑7,11‑亚甲基‑1H‑环癸并[3,4]苯并[1,2‑b]氧杂丁环‑9‑基酯,[2aR‑[2aα,4β,4aβ,6β,9α(αR*,βS*),11α,12α,12aα,12bα]]；
苯丙酸,β‑(苯甲酰氨基)‑α‑[4‑[3‑[3‑[2‑[3‑[1‑[5‑[甲氧基聚乙二醇氨基羰基]戊基]‑1,3‑二氢‑3,3‑二‑甲基‑2H‑吲哚‑2‑甲叉基]亚乙基]‑2‑氯‑1‑环己烯‑1‑基]乙烯基]‑
3,3‑二甲基‑5‑磺酸基‑3H‑吲哚‑1‑基丙基氨基羰基]乙基]二硫基]丁酰氧基‑6,12b‑双(乙酰氧基)‑12‑(苯甲酰氧基)‑2a,3,4,4a,5,6,9,10,11,12,12a,12b‑十二氢‑4,11‑二羟基‑4a,8,13,13‑四甲基‑5‑氧代‑7,11‑亚甲基‑1H‑环癸并[3,4]苯并[1,2‑b]氧杂丁环‑9‑基酯,[2aR‑[2aα,4β,4aβ,6β,9α(αR*,βS*),11α,12α,12aα,12bα]]苯丙酸,β‑(苯甲酰氨基)‑α‑[3‑[2‑[3‑[1‑[5‑[甲氧基聚乙二醇氨基羰基]戊基]‑1,3‑二氢‑3,3‑二‑甲基‑2H‑吲哚‑2‑甲叉基]亚乙基]‑2‑氯‑1‑环己烯‑1‑基]乙烯基]‑
3,3‑二甲基‑5‑氯‑3H‑吲哚‑1‑基丙基氨基羰基]甲基]硫基]乙酰氧基‑6,12b‑双(乙酰氧基)‑12‑(苯甲酰氧基)‑2a,3,4,4a,5,6,9,10,11,12,12a,12b‑十二氢‑4,11‑二羟基‑4a,8,13,13‑四甲基‑5‑氧代‑7,11‑亚甲基‑1H‑环癸并[3,4]苯并[1,2‑b]氧杂丁环‑9‑基酯,[2aR‑[2aα,4β,4aβ,6β,9α(αR*,βS*),11α,12α,12aα,12bα]]；
苯丙酸,β‑(苯甲酰氨基)‑α‑[3‑[2‑[3‑[2‑[3‑[1‑[5‑[甲氧基聚乙二醇氨基羰基]戊基]‑1,3‑二氢‑3,3‑二‑甲基‑2H‑吲哚‑2‑甲叉基]亚乙基]‑2‑氯‑1‑环己烯‑1‑基]乙烯基]‑
3,3‑二甲基‑5‑氯‑3H‑吲哚‑1‑基丙基氨基羰基]乙基]硫代甲基乙叉基硫基]丙酰氧基‑6,
12b‑双(乙酰氧基)‑12‑(苯甲酰氧基)‑2a,3,4,4a,5,6,9,10,11,12,12a,12b‑十二氢‑4,11‑二羟基‑4a,8,13,13‑四甲基‑5‑氧代‑7,11‑亚甲基‑1H‑环癸并[3,4]苯并[1,2‑b]氧杂丁环‑9‑基酯,[2aR‑[2aα,4β,4aβ,6β,9α(αR*,βS*),11α,12α,
12aα,12bα]]；
苯丙酸,β‑(苯甲酰氨基)‑α‑[3‑[2‑[3‑[2‑[3‑[1‑[5‑[甲氧基聚乙二醇氨基羰基]戊基]‑1,3‑二氢‑3,3‑二‑甲基‑2H‑吲哚‑2‑甲叉基]亚乙基]‑2‑氯‑1‑环己烯‑1‑基]乙烯基]‑
3,3‑二甲基‑5‑氯‑3H‑吲哚‑1‑基丙基氨基羰基]乙基]硫基]丙酰氧基‑6,12b‑双(乙酰氧基)‑12‑(苯甲酰氧基)‑2a,3,4,4a,5,6,9,10,11,12,12a,12b‑十二氢‑4,
11‑二羟基‑4a,8,13,13‑四甲基‑5‑氧代‑7,11‑亚甲基‑1H‑环癸并[3,4]苯并[1,2‑b]氧杂丁环‑9‑基酯,[2aR‑[2aα,4β,4aβ,6β,9α(αR*,βS*),11α,12α,12aα,12bα]]；
苯丙酸,β‑(苯甲酰氨基)‑α‑[3‑[2‑[3‑[2‑[3‑[1‑[5‑[甲氧基聚乙二醇氨基羰基]戊基]‑1,3‑二氢‑3,3‑二‑甲基‑2H‑吲哚‑2‑甲叉基]亚乙基]‑2‑氯‑1‑环己烯‑1‑基]乙烯基]‑
3,3‑二甲基‑5‑氯‑3H‑吲哚‑1‑基丙基氨基羰基]乙基]二硫基]丙酰氧基‑6,12b‑双(乙酰氧基)‑12‑(苯甲酰氧基)‑2a,3,4,4a,5,6,9,10,11,12,12a,12b‑十二氢‑4,
11‑二羟基‑4a,8,13,13‑四甲基‑5‑氧代‑7,11‑亚甲基‑1H‑环癸并[3,4]苯并[1,2‑b]氧杂丁环‑9‑基酯,[2aR‑[2aα,4β,4aβ,6β,9α(αR*,βS*),11α,12α,12aα,12bα]]；
苯丙酸,β‑(苯甲酰氨基)‑α‑[4‑[3‑[3‑[2‑[3‑[1‑[5‑[甲氧基聚乙二醇氨基羰基]戊基]‑1,3‑二氢‑3,3‑二‑甲基‑2H‑吲哚‑2‑甲叉基]亚乙基]‑2‑氯‑1‑环己烯‑1‑基]乙烯基]‑
3,3‑二甲基‑5‑氯‑3H‑吲哚‑1‑基丙基氨基羰基]乙基]二硫基]丁酰氧基‑6,12b‑双(乙酰氧基)‑12‑(苯甲酰氧基)‑2a,3,4,4a,5,6,9,10,11,12,12a,12b‑十二氢‑4,
11‑二羟基‑4a,8,13,13‑四甲基‑5‑氧代‑7,11‑亚甲基‑1H‑环癸并[3,4]苯并[1,2‑b]氧杂丁环‑9‑基酯,[2aR‑[2aα,4β,4aβ,6β,9α(αR*,βS*),11α,12α,12aα,12bα]]。
4.一种权利要求1所述的PEG化吲哚菁染料偶联紫杉醇前药型化合物及其药学上可接
受的盐的制备方法，其特征在于：
（1）连有取代基R1的2,3,3‑三甲基吲哚与烃化剂Y‑(CH2)mCOOH反应制得季铵盐1，取代吲哚与烃化剂的摩尔比1:1 1:4；
~
（2）连有取代基的R2的2,3,3‑三甲基‑3‑取代吲哚与烃化剂Y‑(CH2)pNH2·HBr反应制得季铵盐2，取代吲哚与烃化剂的摩尔比1:1 1:4；
~
（3）将步骤（2）制得的季铵盐2与Boc酸酐反应，制得季胺盐3，季胺盐2与Boc酸酐的摩尔比1:1 1:3；
~
（4）将步骤（1）制得的季铵盐1、步骤（3）制得的季铵盐3，与N‑[(3‑(苯胺基亚甲基)‑2‑氯‑1‑环己烯‑1‑基)亚甲基]苯胺盐酸盐4反应制得吲哚七甲川菁化合物5；
（5）吲哚七甲川菁化合物5与甲氧基聚乙二醇胺（PEG‑NH2）在缩合剂催化下发生缩合反应得到PEG化的吲哚七甲川菁6；
（6）吲哚七甲川菁化合物6在酸性条件下脱去Boc保护基得到吲哚七甲川菁7；
（7）吲哚七甲川菁7与紫杉醇衍生物发生缩合反应得到具有结构通式(I)化合物；
。
5.按权利要求4所述的方法，其特征在于：所述步骤（1）中Y‑(CH2)mCOOH为含有1~6碳原子的卤代羧酸；
所述步骤（2）中Y‑(CH2)pNH2·HBr为含有2~6碳原子的卤代烷基胺的氢溴酸盐。
6.按权利要求4所述的方法，其特征在于：所述步骤（1）和（2）在溶剂存在下进行反应，反应时间4 40小时，反应温度60 148℃；其中，溶剂选自甲苯、二甲苯、二氯苯、乙醇、甲醇或~ ~乙腈。
7.按权利要求4所述的方法，其特征在于：所述步骤（4）中季铵盐1、季铵盐3，与N‑[(3‑(苯胺基亚甲基)‑2‑氯‑1‑环己烯‑1‑基)亚甲基]苯胺盐酸盐4的摩尔配比是1:1:1；
所述步骤（4）在溶剂/催化剂体系下进行，其中，溶剂/催化剂为乙醇/醋酸钠，催化剂与季铵盐1的配比为0.3:1 3:1。
~
8.一种药用组合物，其特征在于：组合物含具有权利要求1中通式（I）所示的PEG化吲哚菁染料偶联紫杉醇前药型化合物及其药学上可接受的盐和药学上可接受的载体。
9.一种权利要求1所述化合物的应用，其特征在于：具有通式（I）所示的PEG化吲哚菁染料偶联紫杉醇前药型化合物及其药学上可接受的盐或权利要求8所述药用组合物在制备抗肿瘤药物中的应用。 说明书 : PEG化吲哚菁染料偶联紫杉醇前药型化合物及其制备和应用技术领域[0001] 本发明属于药学领域，具体涉及一种基于氧化还原敏感键连接的靶向肿瘤PEG化吲哚菁染料偶联紫杉醇前药型化合物及其制备方法和在制备抗肿瘤药物的应用。背景技术[0002] 紫杉醇(Paclitaxel，PTX)是一种二萜类抗肿瘤药物，可有效治疗乳腺癌、非小细胞肺癌、卵巢癌、胃癌等实体肿瘤[1,2]。PTX具有独特的抗肿瘤机制，通过诱导和促使微管蛋白聚合成微管，同时抑制所形成微管解聚，微管束不能和微管组织中心相互连接，癌细胞的有丝分裂异常或停留在G2/M期，导致癌细胞无法复制，最终导致癌细胞死亡[3,4]。[0003] 尽管PTX具有良好的抗肿瘤效果，但其在水中的溶解度极低，1mL水中仅溶解0.25μg[5]。为解决这个问题，第一个上市的PTX注射剂泰素 是将PTX溶解于由非离子表面活性剂聚氧乙烯蓖麻油(Polyoxyethylenecastoroil，CremophorEL)和无水乙醇同比例组成的混合溶媒中。CremophorEL被认为与紫杉醇临床常见的毒性反应—过敏反应、神经毒性和肾毒性有关：CremophorEL在体内降解时可使肥大细胞脱颗粒，释放组胺，或激活补体导致严重的过敏反应[6,7]；而且，CremophorEL导致动物的外周神经元肿胀，神经细胞内颗粒释放及脱髓鞘改变，引起神经毒性。此外，最近有报道，紫杉醇制剂中使用CremophorEL会降低其抗肿瘤疗效[8]。[0004] 的缺陷促使各大制药公司继续研发PTX新型制剂，多种PTX纳米制剂相继问世，如紫杉醇脂质体制剂力朴素 白蛋白结合型紫杉醇制剂 胶束聚合物紫杉醇制剂 等；但这些制剂也各有其缺点：力朴素具有泰素相似的过敏反应，Abraxane价格昂贵，Genexol‑PM有神经肌肉毒性和骨髓抑制。因此，在针对紫杉醇的研究中，为提高PTX的溶解性并增强其肿瘤靶向性，除了开发新型药物递送系统以外，设计性质改良的紫杉醇前药也是紫杉醇研究的另一主要热点。发明内容[0005] 本发明的目的是提供一种基于氧化还原敏感键连接的靶向肿瘤PEG化吲哚菁染料偶联紫杉醇前药型化合物及其制备方法和在制备抗肿瘤药物的应用。[0006] 为实现上述目的，本发明的技术方案为：[0007] 一种PEG化吲哚菁染料偶联紫杉醇前药型化合物，化合物为具有通式(I)所示的PEG化吲哚菁染料偶联紫杉醇前药型化合物及其药学上可接受的盐、溶剂化物：[0008][0009] 其中：[0010] R1和R2可相同或不同自独立选自氢、C1‑C5烷基、C1‑C5烷氧基、磺酸基、卤素、苯基；且，R1和/或R2还可与相邻的C形成芳基或杂芳基(即，R1和/或R2与苯基上相邻的C形成苯并[e]吲哚)；[0011] X选自以下连接链：[0012][0013] Y‑为卤素负离子；[0014] 1≤m≤5；2≤p≤6；1≤n≤45。[0015] 优选，化合物为具有通式(I)所示的PEG化吲哚菁染料偶联紫杉醇前药型化合物及其药学上可接受的盐、溶剂化物：[0016] R1和R2可相同或不同自独立选自为氢、C1‑C3烷基、C1‑C3烷氧基、磺酸基、卤素、苯基；且，R1和/或R2还可与相邻的C形成芳基或杂芳基(即，R1和/或R2与苯基上相邻的C形成苯并[e]吲哚)；[0017] X选自以下连接链：[0018][0019] Y‑为溴或碘；[0020] 1≤m≤5；2≤p≤6；1≤n≤45。[0021] 进一步优选，所述化合物为[0022] 苯丙酸,β‑(苯甲酰氨基)‑α‑[3‑[2‑[3‑[2‑[3‑[1‑[5‑[甲氧基聚乙二醇氨基羰基]戊基]‑1,3‑二氢‑3,3‑二‑甲基‑2H‑吲哚‑2‑甲叉基亚乙基]‑2‑氯‑1‑环己烯‑1‑基]乙烯基]‑3,3‑二甲基‑3H‑吲哚‑1‑基丙基氨基羰基]乙基]硫代甲基乙叉基硫基]丙酰氧基‑6,12b‑双(乙酰氧基)‑12‑(苯甲酰氧基)‑2a,3,4,4a,5,6,9,10,11,12,12a,12b‑十二氢‑4,11‑二羟基‑4a,8,13,13‑四甲基‑5‑氧代‑7,11‑亚甲基‑1H‑环癸并[3,4]苯并[1,2‑b]氧杂丁环‑9‑基酯,[2aR‑[2aα,4β,4aβ,6β,9α(αR*,βS*),11α,12α,12aα,12bα]]；[0023] 苯丙酸,β‑(苯甲酰氨基)‑α‑[3‑[2‑[3‑[2‑[3‑[1‑[5‑[甲氧基聚乙二醇氨基羰基]戊基]‑1,3‑二氢‑3,3‑二‑甲基‑2H‑吲哚‑2‑甲叉基亚乙基]‑2‑氯‑1‑环己烯‑1‑基]乙烯基]‑3,3‑二甲基‑3H‑吲哚‑1‑基丙基氨基羰基]乙基]硫基]丙酰氧基‑6,12b‑双(乙酰氧基)‑12‑(苯甲酰氧基)‑2a,3,4,4a,5,6,9,10,11,12,12a,12b‑十二氢‑4,11‑二羟基‑4a,8,13,13‑四甲基‑5‑氧代‑7,11‑亚甲基‑1H‑环癸并[3,4]苯并[1,2‑b]氧杂丁环‑9‑基酯,[2aR‑[2aα,4β,4aβ,6β,9α(αR*,βS*),11α,12α,12aα,12bα]]；[0024] 苯丙酸,β‑(苯甲酰氨基)‑α‑[3‑[2‑[3‑[2‑[3‑[1‑[5‑[甲氧基聚乙二醇氨基羰基]戊基]‑1,3‑二氢‑3,3‑二‑甲基‑2H‑吲哚‑2‑甲叉基]亚乙基]‑2‑氯‑1‑环己烯‑1‑基]乙烯基]‑3,3‑二甲基‑3H‑吲哚‑1‑基丙基氨基羰基]乙基]二硫基]丙酰氧基‑6,12b‑双(乙酰氧基)‑12‑(苯甲酰氧基)‑2a,3,4,4a,5,6,9,10,11,12,12a,12b‑十二氢‑4,11‑二羟基‑4a,8,13,13‑四甲基‑5‑氧代‑7,11‑亚甲基‑1H‑环癸并[3,4]苯并[1,2‑b]氧杂丁环‑9‑基酯,[2aR‑[2aα,4β,4aβ,6β,9α(αR*,βS*),11α,12α,12aα,12bα]]；[0025] 苯丙酸,β‑(苯甲酰氨基)‑α‑[4‑[3‑[3‑[2‑[3‑[1‑[5‑[甲氧基聚乙二醇氨基羰基]戊基]‑1,3‑二氢‑3,3‑二‑甲基‑2H‑吲哚‑2‑甲叉基]亚乙基]‑2‑氯‑1‑环己烯‑1‑基]乙烯基]‑3,3‑二甲基‑3H‑吲哚‑1‑基丙基氨基羰基]乙基]二硫基]丁酰氧基‑6,12b‑双(乙酰氧基)‑12‑(苯甲酰氧基)‑2a,3,4,4a,5,6,9,10,11,12,12a,12b‑十二氢‑4,11‑二羟基‑4a,8,13,13‑四甲基‑5‑氧代‑7,11‑亚甲基‑1H‑环癸并[3,4]苯并[1,2‑b]氧杂丁环‑9‑基酯,[2aR‑[2aα,4β,4aβ,6β,9α(αR*,βS*),11α,12α,12aα,12bα]]；[0026] 苯丙酸,β‑(苯甲酰氨基)‑α‑[3‑[2‑[3‑[1‑[5‑[甲氧基聚乙二醇氨基羰基]戊基]‑1,3‑二氢‑3,3‑二‑甲基‑2H‑吲哚‑2‑甲叉基]亚乙基]‑2‑氯‑1‑环己烯‑1‑基]乙烯基]‑3,3‑二甲基‑5‑磺酸基‑3H‑吲哚‑1‑基丙基氨基羰基]甲基硫基]乙酰氧基‑6,12b‑双(乙酰氧基)‑12‑(苯甲酰氧基)‑2a,3,4,4a,5,6,9,10,11,12,12a,12b‑十二氢‑4,11‑二羟基‑4a,8,13,13‑四甲基‑5‑氧代‑7,11‑亚甲基‑1H‑环癸并[3,4]苯并[1,2‑b]氧杂丁环‑9‑基酯,[2aR‑[2aα,4β,4aβ,6β,9α(αR*,βS*),11α,12α,12aα,12bα]]；[0027] 苯丙酸,β‑(苯甲酰氨基)‑α‑[3‑[2‑[3‑[1‑[5‑[甲氧基聚乙二醇氨基羰基]戊基]‑1,3‑二氢‑3,3‑二‑甲基‑2H‑吲哚‑2‑甲叉基]亚乙基]‑2‑氯‑1‑环己烯‑1‑基]乙烯基]‑3,3‑二甲基‑5‑磺酸基‑3H‑吲哚‑1‑基丙基氨基羰基]甲基二硫基]乙酰氧基‑6,12b‑双(乙酰氧基)‑12‑(苯甲酰氧基)‑2a,3,4,4a,5,6,9,10,11,12,12a,12b‑十二氢‑4,11‑二羟基‑4a,8,13,13‑四甲基‑5‑氧代‑7,11‑亚甲基‑1H‑环癸并[3,4]苯并[1,2‑b]氧杂丁环‑9‑基酯,[2aR‑[2aα,4β,4aβ,6β,9α(αR*,βS*),11α,12α,12aα,12bα]]；[0028] 苯丙酸,β‑(苯甲酰氨基)‑α‑[3‑[2‑[3‑[2‑[3‑[1‑[5‑[甲氧基聚乙二醇氨基羰基]戊基]‑1,3‑二氢‑3,3‑二‑甲基‑2H‑吲哚‑2‑甲叉基]亚乙基]‑2‑氯‑1‑环己烯‑1‑基]乙烯基]‑3,3‑二甲基‑5‑磺酸基‑3H‑吲哚‑1‑基丙基氨基羰基]乙基]硫代]甲基乙叉基硫基]丙酰氧基‑6,12b‑双(乙酰氧基)‑12‑(苯甲酰氧基)‑2a,3,4,4a,5,6,9,10,11,12,12a,12b‑十二氢‑4,11‑二羟基‑4a,8,13,13‑四甲基‑5‑氧代‑7,11‑亚甲基‑1H‑环癸并[3,4]苯并[1,2‑b]氧杂丁环‑9‑基酯,[2aR‑[2aα,4β,4aβ,6β,9α(αR*,βS*),11α,12α,12aα,12bα]]；[0029] 苯丙酸,β‑(苯甲酰氨基)‑α‑[3‑[2‑[3‑[2‑[3‑[1‑[5‑[甲氧基聚乙二醇氨基羰基]戊基]‑1,3‑二氢‑3,3‑二‑甲基‑2H‑吲哚‑2‑甲叉基]亚乙基]‑2‑氯‑1‑环己烯‑1‑基]乙烯基]‑3,3‑二甲基‑5‑磺酸基‑3H‑吲哚‑1‑基丙基氨基羰基]乙基]硫基]丙酰氧基‑6,12b‑双(乙酰氧基)‑12‑(苯甲酰氧基)‑2a,3,4,4a,5,6,9,10,11,12,12a,12b‑十二氢‑4,11‑二羟基‑4a,8,13,13‑四甲基‑5‑氧代‑7,11‑亚甲基‑1H‑环癸并[3,4]苯并[1,2‑b]氧杂丁环‑9‑基酯,[2aR‑[2aα,4β,4aβ,6β,9α(αR*,βS*),11α,12α,12aα,12bα]]；[0030] 苯丙酸,β‑(苯甲酰氨基)‑α‑[3‑[2‑[3‑[2‑[3‑[1‑[5‑[甲氧基聚乙二醇氨基羰基]戊基]‑1,3‑二氢‑3,3‑二‑甲基‑2H‑吲哚‑2‑甲叉基]亚乙基]‑2‑氯‑1‑环己烯‑1‑基]乙烯基]‑3,3‑二甲基‑5‑磺酸基‑3H‑吲哚‑1‑基丙基氨基羰基]乙基]二硫基]丙酰氧基‑6,12b‑双(乙酰氧基)‑12‑(苯甲酰氧基)‑2a,3,4,4a,5,6,9,10,11,12,12a,12b‑十二氢‑4,11‑二羟基‑4a,8,13,13‑四甲基‑5‑氧代‑7,11‑亚甲基‑1H‑环癸并[3,4]苯并[1,2‑b]氧杂丁环‑9‑基酯,[2aR‑[2aα,4β,4aβ,6β,9α(αR*,βS*),11α,12α,12aα,12bα]]；[0031] 苯丙酸,β‑(苯甲酰氨基)‑α‑[4‑[3‑[3‑[2‑[3‑[1‑[5‑[甲氧基聚乙二醇氨基羰基]戊基]‑1,3‑二氢‑3,3‑二‑甲基‑2H‑吲哚‑2‑甲叉基]亚乙基]‑2‑氯‑1‑环己烯‑1‑基]乙烯基]‑3,3‑二甲基‑5‑磺酸基‑3H‑吲哚‑1‑基丙基氨基羰基]乙基]二硫基]丁酰氧基‑6,12b‑双(乙酰氧基)‑12‑(苯甲酰氧基)‑2a,3,4,4a,5,6,9,10,11,12,12a,12b‑十二氢‑4,11‑二羟基‑4a,8,13,13‑四甲基‑5‑氧代‑7,11‑亚甲基‑1H‑环癸并[3,4]苯并[1,2‑b]氧杂丁环‑9‑基酯,[2aR‑[2aα,4β,4aβ,6β,9α(αR*,βS*),11α,12α,12aα,12bα]]苯丙酸,β‑(苯甲酰氨基)‑α‑[3‑[2‑[3‑[1‑[5‑[甲氧基聚乙二醇氨基羰基]戊基]‑1,3‑二氢‑3,3‑二‑甲基‑2H‑吲哚‑2‑甲叉基]亚乙基]‑2‑氯‑1‑环己烯‑1‑基]乙烯基]‑3,3‑二甲基‑5‑氯‑3H‑吲哚‑1‑基丙基氨基羰基]甲基]硫基]乙酰氧基‑6,12b‑双(乙酰氧基)‑12‑(苯甲酰氧基)‑2a,3,4,4a,5,6,9,10,11,12,12a,12b‑十二氢‑4,11‑二羟基‑4a,8,13,13‑四甲基‑5‑氧代‑7,11‑亚甲基‑1H‑环癸并[3,4]苯并[1,2‑b]氧杂丁环‑9‑基酯,[2aR‑[2aα,4β,4aβ,6β,9α(αR*,βS*),11α,12α,12aα,12bα]]；[0032] 苯丙酸,β‑(苯甲酰氨基)‑α‑[3‑[2‑[3‑[2‑[3‑[1‑[5‑[甲氧基聚乙二醇氨基羰基]戊基]‑1,3‑二氢‑3,3‑二‑甲基‑2H‑吲哚‑2‑甲叉基]亚乙基]‑2‑氯‑1‑环己烯‑1‑基]乙烯基]‑3,3‑二甲基‑5‑氯‑3H‑吲哚‑1‑基丙基氨基羰基]乙基]硫代甲基乙叉基硫基]丙酰氧基‑6,12b‑双(乙酰氧基)‑12‑(苯甲酰氧基)‑2a,3,4,4a,5,6,9,10,11,12,12a,12b‑十二氢‑4,11‑二羟基‑4a,8,13,13‑四甲基‑5‑氧代‑7,11‑亚甲基‑1H‑环癸并[3,4]苯并[1,2‑b]氧杂丁环‑9‑基酯,[2aR‑[2aα,4β,4aβ,6β,9α(αR*,βS*),11α,12α,12aα,12bα]]；[0033] 苯丙酸,β‑(苯甲酰氨基)‑α‑[3‑[2‑[3‑[2‑[3‑[1‑[5‑[甲氧基聚乙二醇氨基羰基]戊基]‑1,3‑二氢‑3,3‑二‑甲基‑2H‑吲哚‑2‑甲叉基]亚乙基]‑2‑氯‑1‑环己烯‑1‑基]乙烯基]‑3,3‑二甲基‑5‑氯‑3H‑吲哚‑1‑基丙基氨基羰基]乙基]硫基]丙酰氧基‑6,12b‑双(乙酰氧基)‑12‑(苯甲酰氧基)‑2a,3,4,4a,5,6,9,10,11,12,12a,12b‑十二氢‑4,11‑二羟基‑4a,8,13,13‑四甲基‑5‑氧代‑7,11‑亚甲基‑1H‑环癸并[3,4]苯并[1,2‑b]氧杂丁环‑9‑基酯,[2aR‑[2aα,4β,4aβ,6β,9α(αR*,βS*),11α,12α,12aα,12bα]]；[0034] 苯丙酸,β‑(苯甲酰氨基)‑α‑[3‑[2‑[3‑[2‑[3‑[1‑[5‑[甲氧基聚乙二醇氨基羰基]戊基]‑1,3‑二氢‑3,3‑二‑甲基‑2H‑吲哚‑2‑甲叉基]亚乙基]‑2‑氯‑1‑环己烯‑1‑基]乙烯基]‑3,3‑二甲基‑5‑氯‑3H‑吲哚‑1‑基丙基氨基羰基]乙基]二硫基]丙酰氧基‑6,12b‑双(乙酰氧基)‑12‑(苯甲酰氧基)‑2a,3,4,4a,5,6,9,10,11,12,12a,12b‑十二氢‑4,11‑二羟基‑4a,8,13,13‑四甲基‑5‑氧代‑7,11‑亚甲基‑1H‑环癸并[3,4]苯并[1,2‑b]氧杂丁环‑9‑基酯,[2aR‑[2aα,4β,4aβ,6β,9α(αR*,βS*),11α,12α,12aα,12bα]]；[0035] 苯丙酸,β‑(苯甲酰氨基)‑α‑[4‑[3‑[3‑[2‑[3‑[1‑[5‑[甲氧基聚乙二醇氨基羰基]戊基]‑1,3‑二氢‑3,3‑二‑甲基‑2H‑吲哚‑2‑甲叉基]亚乙基]‑2‑氯‑1‑环己烯‑1‑基]乙烯基]‑3,3‑二甲基‑5‑氯‑3H‑吲哚‑1‑基丙基氨基羰基]乙基]二硫基]丁酰氧基‑6,12b‑双(乙酰氧基)‑12‑(苯甲酰氧基)‑2a,3,4,4a,5,6,9,10,11,12,12a,12b‑十二氢‑4,11‑二羟基‑4a,8,13,13‑四甲基‑5‑氧代‑7,11‑亚甲基‑1H‑环癸并[3,4]苯并[1,2‑b]氧杂丁环‑9‑基酯,[2aR‑[2aα,4β,4aβ,6β,9α(αR*,βS*),11α,12α,12aα,12bα]]。[0036] 一种PEG化吲哚菁染料偶联紫杉醇前药型化合物的制备方法，[0037] (1)连有取代基R1的2,3,3‑三甲基吲哚与烃化剂Y‑(CH2)mCOOH反应制得季铵盐1，取代吲哚与烃化剂的摩尔比1:1～1:4；[0038][0039] (2)连有取代基的R2的2,3,3‑三甲基‑3‑取代吲哚与烃化剂Y‑(CH2)pNH2·HBr反应制得季铵盐2，取代吲哚与烃化剂的摩尔比1:1～1:4；[0040][0041] (3)将步骤(2)制得的季铵盐2与Boc酸酐反应，制得季胺盐3，季胺盐2与Boc酸酐的摩尔比1:1～1:3；[0042][0043] (4)将步骤(1)制得的季铵盐1、步骤(3)制得的季铵盐3，与N‑[(3‑(苯胺基亚甲基)‑2‑氯‑1‑环己烯‑1‑基)亚甲基]苯胺盐酸盐4反应制得吲哚七甲川菁化合物5；[0044][0045] (5)吲哚七甲川菁化合物5与甲氧基聚乙二醇胺(PEG‑NH2)在缩合剂催化下发生缩合反应得到PEG化的吲哚七甲川菁6；[0046][0047] (6)吲哚七甲川菁化合物6在酸性条件下脱去Boc保护基得到吲哚七甲川菁7；[0048][0049] (7)吲哚七甲川菁7与紫杉醇衍生物发生缩合反应得到具有结构通式(I)化合物；[0050][0051] 所述步骤(1)中Y‑(CH2)mCOOH为含有1～6碳原子的卤代羧酸；[0052] 所述步骤(2)中Y‑(CH2)pNH2·HBr为含有2～6碳原子的卤代烷基胺的氢溴酸盐。[0053] 所述步骤(1)和(2)在溶剂存在下进行反应，反应时间4～40小时，反应温度60～148℃；其中，溶剂选自甲苯、二甲苯、二氯苯、乙醇、甲醇或乙腈。[0054] 所述步骤(4)中季铵盐1、季铵盐3，与N‑[(3‑(苯胺基亚甲基)‑2‑氯‑1‑环己烯‑1‑基)亚甲基]苯胺盐酸盐4的摩尔配比是1:1:1；[0055] 所述步骤(4)在溶剂/催化剂体系下进行，其中，溶剂/催化剂为乙醇/醋酸钠或醋酐/醋酸钠，催化剂与季铵盐1的配比为0.3:1～3:1。[0056] 一种药用组合物，组合物含具有通式(I)所示的PEG化吲哚菁染料偶联紫杉醇前药型化合物及其药学上可接受的盐、溶剂化物和药学上可接受的载体。[0057] 本发明所述的“药用可接受的盐”主要是指带有电荷的有机或无机基团，并且可以与其它药用试剂一起给药，比如在盐中作为配对阳离子和配对阴离子。比如阳离子盐，阴离子盐，两性离子盐。所述的阳离子有钠离子、钾离子、镁离子、钙离子、锌离子、季铵盐，但并不局限于此；阴离子有氯离子、醋酸根离子、甲基苯磺酸离子、柠檬酸盐、碳酸盐和碳酸氢盐，同样阴离子盐也不局限于此。[0058] 一种所述化合物的应用，具有通式(I)所示的PEG化吲哚菁染料偶联紫杉醇前药型化合物及其药学上可接受的盐或所述药用组合物在制备抗肿瘤药物中的应用[0059] 本发明所具有的优点：[0060] 本发明利用分子杂合原理将PEG化衍生物甲氧基聚乙二醇胺与特异性靶向肿瘤细胞线粒体的近红外吲哚七甲川菁染料共价结合，再通过对肿瘤高氧化还原态敏感的化学键偶联紫杉醇，设计不同结构的PEG化菁染料偶联氧化还原响应型紫杉醇前药化合物，该类化合物兼具肿瘤靶向与肿瘤治疗的功能。具体实施方式[0061] 以下通过实施例的具体实施方式再对本发明内容作进一步详细说明，所述是对本发明的解释而不是限定。在不脱离本发明的精神和原则之内所做的任何修改应包括在本发明的保护范围内。[0062] 实施例1[0063] 苯丙酸,β‑(苯甲酰氨基)‑α‑[3‑[2‑[3‑[2‑[3‑[1‑[5‑[甲氧基聚乙二醇氨基羰基]戊基]‑1,3‑二氢‑3,3‑二‑甲基‑2H‑吲哚‑2‑甲叉基亚乙基]‑2‑氯‑1‑环己烯‑1‑基]乙烯基]‑3,3‑二甲基‑3H‑吲哚‑1‑基丙基氨基羰基]乙基]硫代甲基乙叉基硫基]丙酰氧基‑6,12b‑双(乙酰氧基)‑12‑(苯甲酰氧基)‑2a,3,4,4a,5,6,9,10,11,12,12a,12b‑十二氢‑4,11‑二羟基‑4a,8,13,13‑四甲基‑5‑氧代‑7,11‑亚甲基‑1H‑环癸并[3,4]苯并[1,2‑b]氧杂丁环‑9‑基酯,[2aR‑[2aα,4β,4aβ,6β,9α(αR*,βS*),11α,12α,12aα,12bα]](Z‑1)的合成[0064] (1)1‑(5‑羧戊基)‑2,3,3‑三甲基‑3H‑吲哚鎓溴盐(化合物1‑1)的合成[0065][0066] 2,3,3‑三甲基‑3H‑吲哚(10g,62.8mmol)和6‑溴己酸(30.6g,314.5mmol)加入500mL的茄形瓶中，加入350mL的乙腈，升温至78℃，反应72h。反应结束后，减压浓缩除去乙腈，加入500mL乙酸乙酯搅拌，析出粉红色固体，抽滤，将得到的固体用乙酸乙酯洗涤，真空+干燥箱干燥得粉红色粉末状固体15.0g,收率67.6％。MS(ESI)m/z：274.1[M]。[0067] (2))1‑(3‑氨基丙基)‑2,3,3‑三甲基‑3H‑吲哚鎓溴盐(化合物1‑2)的制备[0068][0069] 2,3,3‑三甲基‑3H‑吲哚(10g,62.8mmol)和3‑溴丙胺(27g,125mmol)加入1000mL的茄形瓶中，加入500mL的乙腈，升温至78℃，反应72h。反应结束后，放置过夜待固体全部析出，过滤，滤饼用乙腈打浆2h，抽滤，减压干燥得灰白色固体15.0g，收率80.6％。MS(ESI)m/+z：217.1[M]。[0070] (3)1‑[3‑(叔丁氧基羰基氨基)丙基]‑2,3,3‑三甲基‑3H‑吲哚溴鎓盐(化合物1‑3)的合成[0071][0072] 室温下将化合物1‑2(10g,33.7mmol)和Boc2O(22.1g,101.3mmol)加入到400mL氯仿溶液中，化合物1‑2不溶，缓慢滴加三乙胺(13.6g,135.1mmol)后使其全部溶解，升温至60℃搅拌反应4h，反应结束，用饱和食盐水洗涤3次，无水硫酸钠干燥过夜，抽滤浓缩得粉红色+液体11.0g，收率82.3％。MS(ESI)m/z：317.2[M]。[0073] (4)2‑[2‑[3‑[1‑(5‑羧戊基)‑3,3‑二甲基吲哚‑2‑甲叉基亚乙基]‑2‑氯‑1‑环己烯‑1‑基]乙烯基]‑3,3‑二甲基‑1‑[3‑(叔丁氧基羰基氨基)丙基]‑3H‑吲哚溴鎓盐(化合物1‑5)的制备[0074][0075] 化合物1‑3(10g,25.2mmol)、N‑[(3‑(苯胺基亚甲基)‑2‑氯‑1‑环己烯‑1‑基)亚甲基]苯胺盐酸盐(化合物4)(8.1g,25.2mmol)以及化合物1‑1(6.9g,25.2mmol)加入到250mL的茄形瓶中，加入100mL的无水乙醇和无水乙酸钠(65.4mg,0.8mmol)，升温至78℃搅拌反应，反应8h，反应液浓缩至干，残留物经柱层析纯化(二氯甲烷：甲醇＝35：1)，得1.2g绿色固+体，收率18.7％，MS(ESI)m/z：726.4[M]。[0076] (5)[2‑[3‑[1‑[5‑[[甲氧基聚(氧‑1,2‑乙二基)]氨基羰基]戊基]‑1,3‑二氢‑3,3‑二甲基‑2H‑吲哚‑2‑甲叉基亚乙基]‑2‑氯‑1‑环己烯‑1‑基]乙烯基]‑3,3‑二甲基‑1‑[3‑(叔丁氧基羰基氨基)丙基]‑3H‑吲哚溴鎓盐(化合物1‑6)的合成[0077][0078] 冰盐浴条件下，将中间体1‑5(500mg,0.69mmol)加入干燥的二氯甲烷中，待完全溶解后，滴加EDCI(420mg,2.20mmol)和NHS(198mg,1.72mmol)，搅拌过夜至原料完全转化为活性酯，然后加入甲氧基聚乙二醇胺(1.38g,1.38mmol)。TLC监测反应，待反应结束后，减压浓缩除去溶剂，经薄层层析纯化后，得680mg绿色固体，产率51.2％。MS(FT‑ICR)m/z：976.1012+[M++Na] 。[0079] (6)中间体[2‑[3‑[1‑[5‑[[甲氧基聚(氧‑1,2‑乙二基)]氨基羰基]戊基]‑1,3‑二氢‑3,3‑二甲基‑2H‑吲哚‑2‑甲叉基亚乙基]‑2‑氯‑1‑环己烯‑1‑基]乙烯基]‑3,3‑二甲基‑1‑(3‑氨基丙基)‑3H‑吲哚溴鎓盐(化合物1‑7)的合成[0080][0081] 冰浴条件下，将化合物1‑6(500mg,0.25mmol)用10mL二氯甲烷全部溶解，缓慢滴加10mL三氟乙酸，保温搅拌反应5小时，反应完毕减压浓缩除去溶剂，经柱层析纯化后得350mg+ 2+绿色固体，产率75.7％。MS(FT‑ICR)m/z：893.044[M+H] 。[0082] (7)5β,20‑环氧‑1,2α,4,7β,10β,13α‑六羟基紫杉烷‑11‑烯‑9‑酮‑4,10‑二乙酸酯‑2‑苯甲酸酯‑13‑[(2’R,3’S)N‑苯甲酰‑3’‑苯基‑2’‑[α‑(羧基乙基乙叉基二硫基)丙酰氧基]异丝氨酸酯](中间体PTX‑1)的合成[0083][0084] N2保护下，将3,3’‑(丙烷‑2,2‑二基双(硫烷二基))二丙酸(252mg,1.00mmol)加入到25mL的茄形瓶中，并用3mL乙酸酐溶解，室温下搅拌过夜。反应结束，将18mL甲苯分三次加入体系中，并进行减压蒸馏得白色固体。将所得固体直接溶于10mL二氯甲烷中，并加入紫杉醇(853mg,1.00mmol)和催化量的DMAP，室温条件下搅拌过夜，反应结束后，薄层层析纯化得‑白色固体600mg，收率55.2％MS(ESI)m/z：1086.1[M‑H]。[0085] (8)化合物Z‑1的合成[0086][0087] 冰盐浴条件下，将化合物PTX‑1(500mg,0.46mmol)溶解于10mL干燥的二氯甲烷中，搅拌状态下滴加EDCI(175mg,0.92mmol)和催化量的DMAP，30min后加入化合物1‑7(821mmol,0.46mmol)。TLC检测反应进程，反应完毕后，减压浓缩除去溶剂，经柱层析纯化+ 2+ 1后，得250mg绿色固体，产率20.3％。MS(FT‑ICR)m/z：1439.267[M+Na] ；H‑NMR(600MHz,DMSO‑d6)δ9.27(t,J＝8.6Hz,1H),8.28(d,J＝14.0Hz,1H),8.23(d,J＝13.8Hz,1H),8.16(d,J＝5.8Hz,1H),7.99–7.95(m,2H),7.87(s,1H),7.84(dd,J＝12.1,6.1Hz,2H),7.73(t,J＝7.3Hz,1H),7.68–7.59(m,4H),7.53(t,J＝7.3Hz,1H),7.47(dd,J＝8.0,2.3Hz,3H),7.44(dd,J＝5.9,2.8Hz,6H),7.43–7.39(m,2H),7.32–7.25(m,2H),7.17(tt,J＝5.7,3.0Hz,1H),6.35(d,J＝14.2Hz,1H),6.29(q,J＝4.7Hz,2H),5.82(d,J＝9.0Hz,1H),5.54(t,J＝8.9Hz,1H),5.39(dd,J＝14.7,8.1Hz,2H),4.90(dq,J＝9.6,3.8,2.5Hz,2H),4.62(s,1H),4.21(d,J＝7.7Hz,4H),4.10(dd,J＝11.5,6.1Hz,1H),4.00(q,J＝8.3Hz,2H),3.61(d,J＝4.8Hz,1H),3.57(d,J＝7.2Hz,1H),3.49(dq,J＝6.7,2.3Hz,128H),3.42(dd,J＝5.9,3.6Hz,3H),3.23(s,3H),3.21–3.17(m,2H),3.15(d,J＝5.8Hz,2H),2.75(d,J＝6.7Hz,2H),2.73–2.70(m,4H),2.70(s,3H),2.35(t,J＝7.5Hz,2H),2.22(s,3H),2.09(s,3H),2.06(t,J＝7.3Hz,2H),1.90(d,J＝6.1Hz,1H),1.89–1.83(m,3H),1.78(s,4H),1.76–1.69(m,3H),1.66(d,J＝3.7Hz,11H),1.56–1.52(m,3H),1.49(s,4H),1.44(s,6H),1.35(p,J＝7.7Hz,132H),1.23(d,J＝5.2Hz,1H),1.02(s,3H),0.99(s,3H)；C‑NMR(151MHz,DMSO‑d6)δ202.39,172.76,172.00,171.79,170.90,170.53,169.68,169.16,168.80,166.40,165.25,148.13,143.50,142.69,142.07,142.01,141.21,140.99,139.38,137.28,134.22,133.54,133.42,131.50,129.96,129.60,128.73,128.60,128.31,128.26,127.69,127.50,126.36,126.15,125.44,125.04,122.56,111.77,111.24,102.12,101.14,83.62,80.26,76.73,75.30,74.74,74.71,74.50,71.30,70.85,70.44,69.80,69.60,69.17,58.07,57.42,55.83,54.07,49.17,48.89,46.09,43.84,42.95,41.73,38.43,36.52,36.12,35.23,34.99,34.38,34.03,30.51,30.47,27.51,27.46,27.09,26.85,26.34,25.88,25.86,25.74,25.59,24.87,24.65,22.60,21.38,20.67,20.42,13.93,9.77。[0088] 实施例2[0089] 苯丙酸,β‑(苯甲酰氨基)‑α‑[3‑[2‑[3‑[2‑[3‑[1‑[5‑[甲氧基聚乙二醇氨基羰基]戊基]‑1,3‑二氢‑3,3‑二‑甲基‑2H‑吲哚‑2‑甲叉基亚乙基]‑2‑氯‑1‑环己烯‑1‑基]乙烯基]‑3,3‑二甲基‑3H‑吲哚‑1‑基丙基氨基羰基]乙基]硫基]丙酰氧基‑6,12b‑双(乙酰氧基)‑12‑(苯甲酰氧基)‑2a,3,4,4a,5,6,9,10,11,12,12a,12b‑十二氢‑4,11‑二羟基‑4a,8,13,13‑四甲基‑5‑氧代‑7,11‑亚甲基‑1H‑环癸并[3,4]苯并[1,2‑b]氧杂丁环‑9‑基酯,[2aR‑[2aα,4β,4aβ,6β,9α(αR*,βS*),11α,12α,12aα,12bα]](Z‑2)的合成[0090] (1)5β,20‑环氧‑1,2α,4,7β,10β,13α‑六羟基紫杉烷‑11‑烯‑9‑酮‑4,10‑二乙酸酯‑2‑苯甲酸酯‑13‑[(2’R,3’S)N‑苯甲酰‑3’‑苯基‑2’‑[α‑(羧基乙基硫基)丙酰氧基]异丝氨酸酯](化合物PTX‑2)的合成[0091][0092] 采用化合物PTX‑1相同的合成方法，以3,3’‑硫代二丙酸(178.0mg,1.00mmol)和紫杉醇(853mg,1.00mmol)为原料，反应制得白色固体600mg，收率59.2％。MS(ESI)m/z：1012.4‑[M‑H]。[0093] (2)化合物Z‑2的合成[0094][0095] 采用实施例1化合物Z‑1相同的合成方法，将化合物1‑7和化合物PTX‑2反应，得Z‑2+ 3+ 1为绿色固体，得量260mg，收率20.3％。MS(FT‑ICR)m/z：957.1574[M +H+Na] ；H‑NMR(600MHz,DMSO‑d6)δ9.31(d,J＝8.6Hz,1H),8.30–8.22(m,3H),7.99–7.96(m,1H),7.88–7.82(m,3H),7.73(t,J＝7.4Hz,1H),7.64(ddd,J＝22.6,12.4,7.2Hz,4H),7.56–7.39(m,10H),7.33–7.24(m,2H),7.20–7.16(m,1H),6.38–6.26(m,3H),5.81(t,J＝9.0Hz,1H),5.55(t,J＝8.7Hz,1H),5.40(dd,J＝10.8,8.1Hz,2H),4.92–4.88(m,1H),4.63(s,1H),4.22(dq,J＝9.3,5.3,4.6Hz,4H),4.13–4.07(m,1H),4.00(q,J＝8.3Hz,1H),3.61(d,J＝4.9Hz,1H),3.59(s,1H),3.57(d,J＝7.1Hz,1H),3.53–3.46(m,128H),3.42(dd,J＝5.9,3.7Hz,3H),3.36(dt,J＝5.9,2.9Hz,3H),3.24–3.13(m,9H),2.92–2.81(m,6H),2.71(td,J＝6.8,2.9Hz,5H),2.47(s,1H),2.23(s,2H),2.09–2.05(m,4H),1.91–1.70(m,11H),1.67(d,J＝2.0Hz,8H),1.66(s,4H),1.55(td,J＝7.5,4.0Hz,2H),1.49(s,2H),1.36(dp,J＝9.2,3.5,133.0Hz,2H),1.23(s,1H),1.07–0.82(m,6H)；C‑NMR(151MHz,DMSO‑d6)δ202.63,173.00,172.23,172.05,171.91,170.90,170.43,169.93,169.41,169.05,166.73,165.51,148.37,143.74,142.95,142.33,142.28,141.48,141.25,139.65,137.53,134.49,133.79,133.68,131.76,130.22,129.86,128.98,128.87,128.58,128.50,127.95,127.76,126.62,126.40,125.69,125.29,122.85,122.81,112.03,111.53,102.38,101.40,83.88,80.52,76.98,75.56,75.04,75.00,74.76,71.56,71.13,70.70,70.06,69.86,69.43,58.32,57.67,54.30,51.81,49.42,49.16,46.35,44.10,43.21,42.01,38.68,36.78,36.43,36.38,35.25,35.22,35.19,34.63,33.99,33.96,33.56,33.27,32.93,32.46,27.77,27.72,27.33,27.11,26.61,26.15,26.12,26.00,25.13,22.86,22.37,21.63,20.93,20.69,14.22,14.19,10.03.[0096] 实施例3[0097] 苯丙酸,β‑(苯甲酰氨基)‑α‑[3‑[2‑[3‑[2‑[3‑[1‑[5‑[甲氧基聚乙二醇氨基羰基]戊基]‑1,3‑二氢‑3,3‑二‑甲基‑2H‑吲哚‑2‑甲叉基]亚乙基]‑2‑氯‑1‑环己烯‑1‑基]乙烯基]‑3,3‑二甲基‑3H‑吲哚‑1‑基丙基氨基羰基]乙基]二硫基]丙酰氧基‑6,12b‑双(乙酰氧基)‑12‑(苯甲酰氧基)‑2a,3,4,4a,5,6,9,10,11,12,12a,12b‑十二氢‑4,11‑二羟基‑4a,8,13,13‑四甲基‑5‑氧代‑7,11‑亚甲基‑1H‑环癸并[3,4]苯并[1,2‑b]氧杂丁环‑9‑基酯,[2aR‑[2aα,4β,4aβ,6β,9α(αR*,βS*),11α,12α,12aα,12bα]](Z‑3)的合成：[0098] (1)5β,20‑环氧‑1,2α,4,7β,10β,13α‑六羟基紫杉烷‑11‑烯‑9‑酮‑4,10‑二乙酸酯‑2‑苯甲酸酯‑13‑[(2’R,3’S)N‑苯甲酰‑3’‑苯基‑2’‑[α‑(羧基乙基二硫基)丙酰氧基]异丝氨酸酯](化合物PTX‑3)的制备[0099][0100] 采用化合物PTX‑1相同的合成方法，以3,3’‑二硫代二丙酸(210mg,1.00mmol)和紫杉醇(853mg,1.00mmol)为原料反应制得白色固体620mg，收率60.3％。MS(ESI)m/z：1045.3‑[M‑H]。[0101] (3)化合物Z‑3的合成[0102][0103] 采用实施例1化合物Z‑1相同的合成方法，将化合物1‑7和化合物PTX‑3反应，制得3+ 1化合物Z‑3绿色固体，得量260mg，收率20.4％。MS(FT‑ICR)m/z：982.155[M+H+H] ；H‑NMR(600MHz,DMSO‑d6)δ9.3(d,J＝8.5Hz,1H),8.31–8.20(m,3H),8.00–7.95(m,2H),7.90–7.82(m,3H),7.73(t,J＝7.4Hz,1H),7.60(ddd,J＝22.5,12.3,7.2Hz,4H),7.54(t,J＝7.3Hz,1H),7.50–7.40(m,9H),7.33–7.24(m,2H),7.18(tq,J＝6.3,3.2,2.3Hz,1H),6.39–6.25(m,3H),5.82(t,J＝9.0Hz,1H),5.55(t,J＝8.7Hz,1H),5.40(dd,J＝10.8,8.1Hz,2H),4.93–4.88(m,1H),4.63(s,1H),4.27–4.17(m,4H),4.14–4.06(m,1H),4.00(q,J＝8.3Hz,2H),3.60(s,1H),3.58(s,1H),3.50(d,J＝2.2Hz,124H),3.42(dd,J＝5.8,3.7Hz,2H),3.36(dd,J＝6.0,3.2Hz,2H),3.24(s,6H),3.17–3.14(m,2H),2.94–2.80(m,6H),2.71(td,J＝6.9,3.0Hz,5H),2.35–2.27(m,1H),2.23(s,2H),2.11–2.04(m,5H),1.88(ddt,J＝17.4,11.1,5.8Hz,4H),1.78(s,3H),1.76–1.70(m,3H),1.67(t,J＝2.5Hz,13H),1.58–1.47(m,6H),131.36(td,J＝7.7,3.8Hz,2H),1.23(s,2H),1.01(d,J＝19.4Hz,4H)；C‑NMR(151MHz,DMSO‑d6)δ202.36,172.73,171.95,171.77,171.63,170.62,170.16,169.66,169.14,168.77,166.45,165.23,148.09,143.46,142.67,142.05,142.00,141.20,140.97,139.38,137.25,134.21,133.51,133.41,131.48,129.95,129.58,128.70,128.60,128.30,128.23,127.67,127.49,126.34,126.12,125.41,125.01,122.57,122.53,111.76,111.25,102.11,101.12,83.60,80.24,76.70,75.28,74.76,74.72,74.48,71.28,70.85,70.43,69.78,69.58,69.15,58.05,57.39,54.02,51.53,49.15,48.88,46.07,43.82,42.94,41.73,39.94,39.80,39.66,39.52,39.38,39.24,39.10,38.41,36.51,36.15,36.10,34.97,34.94,34.91,34.35,33.71,33.68,33.28,32.99,32.66,32.19,31.29,29.01,27.49,27.44,27.05,26.84,26.33,25.87,25.84,25.72,24.85,22.58,22.09,21.35,20.65,20.41,13.94,13.91,9.76..[0104] 实施例4[0105] 苯丙酸,β‑(苯甲酰氨基)‑α‑[4‑[3‑[3‑[2‑[3‑[1‑[5‑[甲氧基聚乙二醇氨基羰基]戊基]‑1,3‑二氢‑3,3‑二‑甲基‑2H‑吲哚‑2‑甲叉基]亚乙基]‑2‑氯‑1‑环己烯‑1‑基]乙烯基]‑3,3‑二甲基‑3H‑吲哚‑1‑基丙基氨基羰基]乙基]二硫基]丁酰氧基‑6,12b‑双(乙酰氧基)‑12‑(苯甲酰氧基)‑2a,3,4,4a,5,6,9,10,11,12,12a,12b‑十二氢‑4,11‑二羟基‑4a,8,13,13‑四甲基‑5‑氧代‑7,11‑亚甲基‑1H‑环癸并[3,4]苯并[1,2‑b]氧杂丁环‑9‑基酯,[2aR‑[2aα,4β,4aβ,6β,9α(αR*,βS*),11α,12α,12aα,12bα]](Z‑4)的合成：[0106] (1)5β,20‑环氧‑1,2α,4,7β,10β,13α‑六羟基紫杉烷‑11‑烯‑9‑酮‑4,10‑二乙酸酯‑2‑苯甲酸酯‑13‑[(2’R,3’S)N‑苯甲酰‑3’‑苯基‑2’‑[α‑(羧基丙基硫基)丁酰氧基]异丝氨酸酯](化合物PTX‑4)的合成[0107][0108] 采用化合物PTX‑1相同的合成方法，以4,4’‑二硫代二丁酸(238mg,1.00mmol)、紫杉醇(853mg,1.00mmol)为原料反应制得白色固体650mg，收率60.5％。MS(ESI)m/z：1072.4‑[M‑H]。[0109] (2)化合物Z‑4的合成[0110][0111] 采用实施例1化合物Z‑1相同的合成方法，将化合物1‑7和化合物PTX‑4反应，制得1化合物Z‑4，为绿色固体，得量250mg，收率19.8％。H‑NMR(600MHz,DMSO‑d6)δ9.23(d,J＝8.4Hz,1H),8.26(d,J＝13.8Hz,2H),8.04(t,J＝5.7Hz,1H),7.99–7.96(m,2H),7.87–7.80(m,4H),7.74(t,J＝7.3Hz,1H),7.69–7.62(m,4H),7.55(t,J＝7.3Hz,1H),7.50–7.41(m,8H),7.39(d,J＝8.4Hz,1H),7.29(ddd,J＝8.0,5.4,2.8Hz,1H),7.18(ddt,J＝6.4,4.7,2.2Hz,1H),6.35–6.28(m,3H),5.81(t,J＝9.1Hz,1H),5.76(s,1H),5.53(t,J＝8.8Hz,1H),5.41(d,J＝7.2Hz,1H),5.36(d,J＝9.1Hz,1H),4.90(dd,J＝8.4,4.3Hz,2H),4.62(s,1H),4.21(q,J＝7.3,6.8Hz,3H),4.10(dt,J＝11.2,7.0Hz,1H),4.01(q,J＝8.3Hz,2H),3.59(dd,J＝26.0,6.1Hz,2H),3.52–3.47(m,88H),3.42(dd,J＝5.9,3.7Hz,2H),3.36(t,J＝6.0Hz,2H),3.24(s,3H),3.18(dq,J＝17.2,6.2Hz,4H),2.73–2.63(m,8H),2.24–2.17(m,5H),2.08(d,J＝21.4Hz,5H),1.92–1.80(m,9H),1.78(s,4H),1.72(t,J＝7.6Hz,2H),1.67(s,12H),1.55(q,J＝7.4Hz,2H),1.49(s,4H),1.34(dd,J＝14.9,7.4Hz,2H),1.23(s,1H),131.01(d,J＝19.2Hz,6H).；C‑NMR(151MHz,DMSO‑d)δ202.20,172.43,172.04,171.82,171.77,171.38,169.52,169.17,168.63,166.23,165.08,148.02,145.71,142.91,141.88,141.85,140.95,140.35,139.17,137.16,134.06,133.38,133.30,131.36,129.80,129.44,128.59,128.55,128.45,128.19,128.09,127.47,127.29,126.28,126.15,125.05,122.44,119.79,111.19,110.57,101.82,101.36,83.46,80.11,76.55,75.13,74.56,74.44,74.34,71.14,70.74,70.27,69.64,69.44,69.01,57.90,57.25,54.78,53.90,48.88,45.92,43.70,42.79,41.67,38.28,37.00,36.36,36.03,35.93,34.85,34.22,33.58,31.44,27.32,27.26,27.00,26.61,26.18,25.69,25.59,24.72,24.42,23.71,22.42,21.22,20.51,20.25,13.72,9.62.[0112] 实施例5[0113] 苯丙酸,β‑(苯甲酰氨基)‑α‑[3‑[2‑[3‑[1‑[5‑[甲氧基聚乙二醇氨基羰基]戊基]‑1,3‑二氢‑3,3‑二‑甲基‑2H‑吲哚‑2‑甲叉基]亚乙基]‑2‑氯‑1‑环己烯‑1‑基]乙烯基]‑3,3‑二甲基‑5‑磺酸基‑3H‑吲哚‑1‑基丙基氨基羰基]甲基硫基]乙酰氧基‑6,12b‑双(乙酰氧基)‑12‑(苯甲酰氧基)‑2a,3,4,4a,5,6,9,10,11,12,12a,12b‑十二氢‑4,11‑二羟基‑4a,8,13,13‑四甲基‑5‑氧代‑7,11‑亚甲基‑1H‑环癸并[3,4]苯并[1,2‑b]氧杂丁环‑9‑基酯,[2aR‑[2aα,4β,4aβ,6β,9α(αR*,βS*),11α,12α,12aα,12bα]](Z‑5)的合成：[0114] (1)5β,20‑环氧‑1,2α,4,7β,10β,13α‑六羟基紫杉烷‑11‑烯‑9‑酮‑4,10‑二乙酸酯‑2‑苯甲酸酯‑13‑[(2’R,3’S)N‑苯甲酰‑3’‑苯基‑2’‑[α‑(羧基甲基硫基)乙酰氧基]异丝氨酸酯](PTX‑5)的制备[0115] 采用化合物PTX‑1相同的合成方法，以2,2’‑硫代二乙酸(150mg,1.00mmol)和紫杉醇(853mg,1.00mmol)为原料，反应制得粗品采用薄层层析纯化得白色固体600mg，收率‑60.9％。MS(ESI)m/z：984.2[M‑H]。[0116][0117] (3)[2‑[3‑[1‑[5‑[[甲氧基聚(氧‑1,2‑乙二基)]氨基羰基]戊基]‑1,3‑二氢‑3,3‑二甲基‑5‑磺酸基‑2H‑吲哚‑2‑甲叉基亚乙基]‑2‑氯‑1‑环己烯‑1‑基]乙烯基]‑3,3‑二甲基‑1‑(3‑氨基丙基)‑3H‑吲哚溴鎓盐(化合物1‑8)的制备[0118][0119] 采用实施例1中化合物1‑7相同的合成方法，将4‑磺酸基苯肼为起始原料，制得化2+合物1‑8，产率70.0％，MS(FT‑ICR)m/z：866.965[M+H+H] 。[0120] (4)化合物Z‑5的合成[0121][0122] 采用实施例1化合物Z‑1相同的合成方法，将化合物1‑8和化合物PTX‑5反应，制得3+ 1化合物Z‑5绿色固体，得量270mg，收率19.8％。MS(FT‑ICR)m/z:981.7754[M+H+H+Na] ；H‑NMR(600MHz,DMSO‑d6)δ9.25(d,J＝8.3Hz,1H),8.26(dd,J＝13.9,4.7Hz,2H),8.21(t,J＝5.6Hz,1H),7.98–7.95(m,2H),7.85–7.83(m,2H),7.82–7.79(m,2H),7.75–7.71(m,1H),7.66(dd,J＝8.3,6.8Hz,3H),7.63(d,J＝7.3Hz,1H),7.51(td,J＝7.0,1.4Hz,1H),7.47–7.40(m,8H),7.39(d,J＝8.4Hz,1H),7.28(ddd,J＝7.9,5.6,2.7Hz,1H),7.16(tt,J＝6.5,2.1Hz,1H),6.35–6.27(m,3H),5.80(t,J＝9.1Hz,1H),5.52(t,J＝8.8Hz,1H),5.39(dd,J＝11.2,8.2Hz,2H),4.89(d,J＝7.1Hz,2H),4.61(s,1H),4.21(d,J＝9.4Hz,4H),4.09(dt,J＝10.6,7.1Hz,1H),4.03–3.96(m,2H),3.64–3.59(m,2H),3.58–3.55(m,1H),3.52–3.46(m,84H),3.42(dd,J＝5.9,3.7Hz,2H),3.36(t,J＝6.0Hz,2H),3.24(d,J＝12.3Hz,5H),3.20(q,J＝7.5,6.6Hz,2H),3.15(q,J＝5.9Hz,2H),2.69(t,J＝6.0Hz,4H),2.23(s,3H),2.09(s,2H),2.05(t,J＝7.3Hz,2H),1.86(dt,J＝21.9,6.3Hz,4H),1.80–1.75(m,4H),1.72(t,J＝7.5Hz,2H),1.67(s,12H),1.53(q,J＝7.5Hz,2H),1.49(s,3H),1.34(td,J＝8.2,5.3Hz,132H),1.23(d,J＝5.1Hz,1H),1.00(d,J＝20.4Hz,6H).；C‑NMR(151MHz,DMSO‑d6)δ202.33,172.68,172.06,171.94,169.66,169.42,169.07,168.76,168.62,166.36,165.23,148.17,145.91,143.15,142.98,142.01,141.97,141.05,140.51,139.27,137.25,134.15,133.52,133.47,131.47,129.93,129.59,128.74,128.69,128.62,128.28,127.59,127.44,126.47,126.33,125.14,122.58,119.93,111.28,110.76,102.05,101.38,83.59,80.24,76.68,75.27,75.12,74.69,74.48,71.28,70.96,70.42,69.78,69.58,69.15,58.04,57.40,54.11,49.06,48.97,46.05,43.87,42.92,41.67,38.41,36.49,36.37,34.99,34.33,34.30,32.55,27.48,27.39,27.03,26.76,26.31,25.83,25.73,24.85,22.60,21.34,20.65,20.36,13.86,9.75.[0123] 实施例6[0124] 苯丙酸,β‑(苯甲酰氨基)‑α‑[3‑[2‑[3‑[1‑[5‑[甲氧基聚乙二醇氨基羰基]戊基]‑1,3‑二氢‑3,3‑二‑甲基‑2H‑吲哚‑2‑甲叉基]亚乙基]‑2‑氯‑1‑环己烯‑1‑基]乙烯基]‑3,3‑二甲基‑5‑磺酸基‑3H‑吲哚‑1‑基丙基氨基羰基]甲基二硫基]乙酰氧基‑6,12b‑双(乙酰氧基)‑12‑(苯甲酰氧基)‑2a,3,4,4a,5,6,9,10,11,12,12a,12b‑十二氢‑4,11‑二羟基‑4a,8,13,13‑四甲基‑5‑氧代‑7,11‑亚甲基‑1H‑环癸并[3,4]苯并[1,2‑b]氧杂丁环‑9‑基酯,[2aR‑[2aα,4β,4aβ,6β,9α(αR*,βS*),11α,12α,12aα,12bα]](Z‑6)的合成：[0125] (1)(1)5β,20‑环氧‑1,2α,4,7β,10β,13α‑六羟基紫杉烷‑11‑烯‑9‑酮‑4,10‑二乙酸酯‑2‑苯甲酸酯‑13‑[(2’R,3’S)N‑苯甲酰‑3’‑苯基‑2’‑[α‑(羧基甲基二硫基)乙酰氧基]异丝氨酸酯](化合物PTX‑6)的制备[0126][0127] 采用化合物PTX‑1相同的合成方法，以2,2’‑二硫代二乙酸(182mg,1.00mmol)和紫杉醇(853mg,1.00mmol)为原料反应制得白色固体620mg，收率60.3％。MS(ESI)m/z：1016.3‑[M‑H]。[0128] (2)化合物Z‑6的制备[0129][0130] 采用实施例1化合物Z‑1相同的合成方法，将化合物1‑8和化合物PTX‑6反应，制得3+ 1化合物Z‑6绿色固体，得量280mg，收率20.7％。MS(FT‑ICR)m/z：963.085[M+H+H+Na] ；H‑NMR(600MHz,DMSO‑d6)δ9.29(d,J＝8.2Hz,1H),8.35(dd,J＝10.7,5.5Hz,1H),8.26(d,J＝14.2Hz,2H),7.99–7.95(m,2H),7.88–7.79(m,4H),7.75–7.71(m,1H),7.69–7.61(m,4H),7.53(t,J＝7.3Hz,1H),7.48–7.36(m,9H),7.28(q,J＝7.0Hz,1H),7.16(tt,J＝6.0,2.9Hz,1H),6.35–6.27(m,3H),5.79(t,J＝8.9Hz,1H),5.50(t,J＝8.9Hz,1H),5.41(dd,J＝16.1,8.3Hz,2H),4.90(dd,J＝8.5,3.8Hz,2H),4.60(s,1H),4.26–4.17(m,4H),4.10(td,J＝7.3,3.7Hz,1H),4.03–3.97(m,2H),3.86(d,J＝4.9Hz,2H),3.63(s,1H),3.56(d,J＝7.2Hz,1H),3.51–3.47(m,92H),3.42(dd,J＝5.9,3.7Hz,2H),3.37–3.34(m,2H),3.23(s,5H),3.16(ddt,J＝8.4,6.0,2.4Hz,3H),2.70(d,J＝7.8Hz,4H),2.34–2.28(m,1H),2.22(s,2H),2.07(d,J＝19.6Hz,5H),1.90(q,J＝7.5,5.2Hz,2H),1.85(q,J＝6.4Hz,2H),1.77(t,J＝3.1Hz,3H),1.72(d,J＝8.8Hz,3H),1.67(d,J＝3.3Hz,12H),1.56–1.52(m,2H),1.49(s,3H),1.3413(dq,J＝8.8,4.7Hz,2H),1.25–1.21(m,1H),0.100(d,J＝21.0Hz,6H)；C‑NMR(151MHz,DMSO‑d6)δ202.35,172.57,172.18,171.97,169.68,169.09,168.81,168.77,167.82,166.33,165.25,148.17,145.81,143.07,142.02,141.99,141.08,140.50,139.30,137.24,134.23,133.54,133.45,131.48,129.93,129.59,128.73,128.70,128.30,127.69,127.48,126.47,126.39,126.29,125.19,122.58,119.92,111.36,110.72,101.98,101.51,83.60,80.22,76.67,75.28,75.22,74.71,74.48,71.28,70.92,70.42,69.78,69.58,69.16,58.05,57.40,54.23,52.21,49.01,46.05,43.85,42.92,41.77,38.42,36.50,35.00,34.31,27.48,27.41,26.97,26.76,26.33,25.84,25.74,24.86,22.65,21.35,20.65,20.38,13.90,9.76.[0131] 实施例7[0132] 苯丙酸,β‑(苯甲酰氨基)‑α‑[3‑[2‑[3‑[2‑[3‑[1‑[5‑[甲氧基聚乙二醇氨基羰基]戊基]‑1,3‑二氢‑3,3‑二‑甲基‑2H‑吲哚‑2‑甲叉基]亚乙基]‑2‑氯‑1‑环己烯‑1‑基]乙烯基]‑3,3‑二甲基‑5‑磺酸基‑3H‑吲哚‑1‑基丙基氨基羰基]乙基]硫代]甲基乙叉基硫基]丙酰氧基‑6,12b‑双(乙酰氧基)‑12‑(苯甲酰氧基)‑2a,3,4,4a,5,6,9,10,11,12,12a,12b‑十二氢‑4,11‑二羟基‑4a,8,13,13‑四甲基‑5‑氧代‑7,11‑亚甲基‑1H‑环癸并[3,4]苯并[1,2‑b]氧杂丁环‑9‑基酯,[2aR‑[2aα,4β,4aβ,6β,9α(αR*,βS*),11α,12α,12aα,12bα]](Z‑7)的合成：[0133][0134] 采用实施例1化合物Z‑1相同的合成方法，将化合物1‑8和化合物PTX‑1反应，得Z‑73+ 1为绿色固体，得量290mg，收率21.4％。MS(FT‑ICR)m/z：986.443[M+H+H+Na] ；H‑NMR(600MHz,DMSO‑d6)δ9.22(d,J＝8.5Hz,1H),8.26(d,J＝13.7Hz,2H),8.10(t,J＝5.6Hz,1H),7.99–7.96(m,2H),7.87–7.84(m,2H),7.84–7.80(m,2H),7.75–7.71(m,1H),7.69–7.61(m,4H),7.55–7.52(m,1H),7.48–7.40(m,8H),7.38(d,J＝8.4Hz,1H),7.28(td,J＝7.1,1.5Hz,1H),7.18(hept,J＝3.9Hz,1H),6.35–6.27(m,3H),5.84–5.79(m,1H),5.54(t,J＝8.8Hz,1H),5.39(dd,J＝23.1,8.1Hz,2H),4.92–4.88(m,2H),4.62(s,1H),4.21(dt,J＝14.8,7.6Hz,4H),4.10(dt,J＝10.8,7.1Hz,1H),4.00(q,J＝8.3Hz,2H),3.59(dd,J＝26.4,5.9Hz,2H),3.53–3.45(m,84H),3.42(dd,J＝5.9,3.7Hz,2H),3.36(t,J＝6.0Hz,2H),3.23(s,3H),3.22–3.14(m,4H),2.76(t,J＝7.3Hz,2H),2.72(d,J＝7.6Hz,3H),2.70(s,4H),2.34(t,J＝7.4Hz,2H),2.22(s,3H),2.07(d,J＝19.9Hz,5H),1.91–1.83(m,4H),1.81–1.77(m,4H),1.72(t,J＝7.4Hz,2H),1.68–1.65(m,12H),1.56–1.51(m,2H),1.49(s,3H),1.44(d,J＝1.7Hz,6H),1.34(td,J＝8.9,8.5,4.9Hz,2H),1.23(d,J＝4.4Hz,1H),1.01(d,J＝1320.2Hz,6H)；C‑NMR(151MHz,DMSO‑d6)δ202.31,172.54,172.13,171.92,170.85,170.44,169.61,169.07,168.73,166.34,165.18,148.13,145.81,143.02,141.96,141.05,140.45,139.31,137.21,134.17,133.48,133.38,131.44,129.91,129.54,128.68,128.55,128.26,128.20,127.62,127.43,126.40,126.29,125.15,122.54,119.89,111.32,110.68,101.92,101.49,83.56,80.21,76.67,75.24,74.68,74.64,74.45,71.24,70.79,70.39,69.75,69.54,69.12,58.01,57.36,55.77,53.98,48.98,48.96,46.04,43.80,42.90,41.77,39.90,39.77,39.62,39.49,39.35,39.21,39.07,38.38,36.47,36.06,35.17,34.96,34.33,33.97,30.46,30.42,28.99,27.43,27.37,27.10,26.72,26.29,25.82,25.78,25.69,25.52,24.82,24.60,22.54,21.32,20.62,20.35,13.87,9.72.[0135] 实施例8[0136] 苯丙酸,β‑(苯甲酰氨基)‑α‑[3‑[2‑[3‑[2‑[3‑[1‑[5‑[甲氧基聚乙二醇氨基羰基]戊基]‑1,3‑二氢‑3,3‑二‑甲基‑2H‑吲哚‑2‑甲叉基]亚乙基]‑2‑氯‑1‑环己烯‑1‑基]乙烯基]‑3,3‑二甲基‑5‑磺酸基‑3H‑吲哚‑1‑基丙基氨基羰基]乙基]硫基]丙酰氧基‑6,12b‑双(乙酰氧基)‑12‑(苯甲酰氧基)‑2a,3,4,4a,5,6,9,10,11,12,12a,12b‑十二氢‑4,11‑二羟基‑4a,8,13,13‑四甲基‑5‑氧代‑7,11‑亚甲基‑1H‑环癸并[3,4]苯并[1,2‑b]氧杂丁环‑9‑基酯,[2aR‑[2aα,4β,4aβ,6β,9α(αR*,βS*),11α,12α,12aα,12bα]](Z‑8)的合成：[0137][0138] 采用实施例1化合物Z‑1相同的合成方法，将化合物1‑8和化合物PTX‑2反应，得Z‑83+ 1为绿色固体，得量250mg，收率18.4％。MS(FT‑ICR)m/z：976.441[M+H+H+Na] ；H‑NMR(600MHz,DMSO‑d6)δ9.23(d,J＝8.6Hz,1H),8.26(d,J＝13.8Hz,2H),8.09(t,J＝5.6Hz,1H),7.99–7.96(m,2H),7.86–7.80(m,4H),7.73(t,J＝7.4Hz,1H),7.68–7.61(m,4H),7.54(t,J＝7.3Hz,1H),7.49–7.37(m,9H),7.28(t,J＝6.8Hz,1H),7.18(p,J＝4.3Hz,1H),6.36–6.27(m,3H),5.82(t,J＝9.0Hz,1H),5.55(t,J＝8.8Hz,1H),5.41(d,J＝7.2Hz,1H),5.36(d,J＝8.9Hz,1H),4.92–4.89(m,2H),4.63(s,1H),4.21(dt,J＝14.4,7.4Hz,4H),4.09(q,J＝8.5,6.3Hz,1H),4.01(q,J＝8.3Hz,2H),3.63–3.55(m,2H),3.50(dd,J＝6.9,3.7Hz,88H),3.42(dd,J＝5.9,3.6Hz,2H),3.36(t,J＝6.0Hz,3H),3.23(s,3H),3.20(d,J＝6.2Hz,2H),3.16(t,J＝5.6Hz,3H),2.70(d,J＝10.3Hz,7H),2.65(t,J＝7.2Hz,2H),2.33(t,J＝7.4Hz,2H),2.23(s,2H),2.09(s,3H),2.06(t,J＝7.3Hz,2H),1.91–1.83(m,4H),1.78(s,4H),1.72(t,J＝7.6Hz,2H),1.67(s,11H),1.53(q,J＝7.3Hz,3H),1.49(s,3H),1.35(q,J＝137.8Hz,2H),1.23(s,2H),1.00(d,J＝20.6Hz,6H)；C‑NMR(151MHz,DMSO‑d6)δ202.35,172.58,172.18,171.96,170.96,170.52,169.65,169.11,168.78,166.45,165.23,148.15,145.84,143.05,142.00,141.08,140.49,139.37,137.26,134.23,133.51,133.41,131.49,129.94,129.58,128.71,128.32,128.24,127.64,127.45,126.44,126.32,125.19,122.57,119.93,111.37,110.71,101.96,101.52,83.60,80.26,76.70,75.28,74.72,74.67,74.49,71.28,70.83,70.44,69.78,69.58,69.15,58.05,57.41,53.99,49.03,49.00,48.60,46.07,43.84,42.94,41.80,38.42,36.50,36.10,35.66,34.99,34.37,33.98,29.02,27.47,27.41,27.13,26.87,26.75,26.33,25.94,25.84,25.73,24.86,22.57,22.08,21.35,20.66,20.37,13.90,9.76.[0139] 实施例9[0140] 苯丙酸,β‑(苯甲酰氨基)‑α‑[3‑[2‑[3‑[2‑[3‑[1‑[5‑[甲氧基聚乙二醇氨基羰基]戊基]‑1,3‑二氢‑3,3‑二‑甲基‑2H‑吲哚‑2‑甲叉基]亚乙基]‑2‑氯‑1‑环己烯‑1‑基]乙烯基]‑3,3‑二甲基‑5‑磺酸基‑3H‑吲哚‑1‑基丙基氨基羰基]乙基]二硫基]丙酰氧基‑6,12b‑双(乙酰氧基)‑12‑(苯甲酰氧基)‑2a,3,4,4a,5,6,9,10,11,12,12a,12b‑十二氢‑4,11‑二羟基‑4a,8,13,13‑四甲基‑5‑氧代‑7,11‑亚甲基‑1H‑环癸并[3,4]苯并[1,2‑b]氧杂丁环‑9‑基酯,[2aR‑[2aα,4β,4aβ,6β,9α(αR*,βS*),11α,12α,12aα,12bα]](Z‑9)的合成：[0141][0142] 采用实施例1化合物Z‑1相同的合成方法，将化合物1‑8和化合物PTX‑3反应，，得Z‑3+ 19为绿色固体，得量260mg，收率19.1％。MS(FT‑ICR)m/z：987.103[M+H+H+Na] ；H‑NMR(600MHz,DMSO‑d6)δ9.22(d,J＝8.6Hz,1H),8.26(dd,J＝13.9,4.4Hz,2H),8.14(t,J＝5.6Hz,1H),7.99–7.96(m,2H),7.86–7.79(m,4H),7.72(d,J＝7.4Hz,1H),7.68–7.61(m,4H),7.53(d,J＝7.5Hz,1H),7.47(t,J＝7.6Hz,2H),7.45–7.42(m,6H),7.39(d,J＝8.4Hz,1H),7.28(td,J＝6.9,6.2,2.3Hz,1H),7.19(q,J＝4.3Hz,1H),6.35–6.28(m,3H),5.82(t,J＝9.0Hz,1H),5.56(t,J＝8.7Hz,1H),5.41(d,J＝7.2Hz,1H),5.36(d,J＝8.9Hz,1H),4.92–4.88(m,2H),4.63(s,1H),4.21(q,J＝8.4Hz,4H),4.10(dt,J＝11.0,7.0Hz,1H),4.01(q,J＝8.3Hz,2H),3.59(dd,J＝25.3,6.1Hz,2H),3.51–3.47(m,104H),3.42(dd,J＝5.9,3.6Hz,2H),3.36(t,J＝6.0Hz,2H),3.23(s,5H),3.16(q,J＝5.8Hz,2H),2.90(t,J＝6.9Hz,2H),2.84(dt,J＝17.7,6.4Hz,4H),2.70(t,J＝6.5Hz,4H),2.46(t,J＝7.1Hz,2H),2.31(tt,J＝8.1,4.9Hz,1H),2.23(s,3H),2.09(s,3H),2.06(t,J＝7.3Hz,2H),1.91–1.83(m,4H),1.78(s,4H),1.72(t,J＝7.5Hz,2H),1.67(s,5H),1.67(s,5H),1.54(q,J＝6.9,6.4Hz,3H),1.4913(s,3H),1.35(q,J＝7.9Hz,2H),1.23(s,1H),1.01(d,J＝20.0Hz,6H)；C‑NMR(151MHz,DMSO‑d6)δ202.35,172.63,172.13,171.95,170.64,170.14,169.64,169.07,168.78,166.49,165.23,148.16,145.87,143.11,143.01,141.99,141.07,140.50,139.34,137.21,134.23,133.51,133.43,131.50,129.95,129.58,128.73,128.70,128.60,128.32,128.24,127.62,127.45,126.45,126.30,125.17,122.57,119.93,111.34,110.73,102.01,101.46,83.60,80.26,76.70,75.28,74.74,74.71,74.49,71.28,70.86,70.43,69.78,69.58,69.15,58.04,57.41,53.95,49.04,48.99,46.07,43.85,42.93,41.79,38.42,36.51,36.15,34.99,34.94,34.36,33.63,32.97,32.15,29.01,28.69,27.47,27.40,27.11,26.76,26.33,25.85,25.73,24.86,22.57,21.35,20.66,20.38,13.90,9.75.[0143] 实施例10[0144] 苯丙酸,β‑(苯甲酰氨基)‑α‑[4‑[3‑[3‑[2‑[3‑[1‑[5‑[甲氧基聚乙二醇氨基羰基]戊基]‑1,3‑二氢‑3,3‑二‑甲基‑2H‑吲哚‑2‑甲叉基]亚乙基]‑2‑氯‑1‑环己烯‑1‑基]乙烯基]‑3,3‑二甲基‑5‑磺酸基‑3H‑吲哚‑1‑基丙基氨基羰基]乙基]二硫基]丁酰氧基‑6,12b‑双(乙酰氧基)‑12‑(苯甲酰氧基)‑2a,3,4,4a,5,6,9,10,11,12,12a,12b‑十二氢‑4,11‑二羟基‑4a,8,13,13‑四甲基‑5‑氧代‑7,11‑亚甲基‑1H‑环癸并[3,4]苯并[1,2‑b]氧杂丁环‑9‑基酯,[2aR‑[2aα,4β,4aβ,6β,9α(αR*,βS*),11α,12α,12aα,12bα]](Z‑10)的合成：[0145][0146] 采用实施例1化合物Z‑1相同的合成方法，将化合物1‑8和化合物PTX‑4反应，得Z‑110为绿色固体，得量280mg，收率20.5％。H‑NMR(600MHz,DMSO‑d6)δ9.23(d,J＝8.4Hz,1H),8.26(d,J＝13.8Hz,2H),8.04(t,J＝5.7Hz,1H),7.99–7.96(m,2H),7.87–7.80(m,4H),7.74(t,J＝7.3Hz,1H),7.68–7.62(m,4H),7.54(t,J＝7.3Hz,1H),7.48(t,J＝7.6Hz,2H),7.45–7.41(m,6H),7.38(d,J＝8.4Hz,1H),7.28(ddd,J＝8.0,5.4,2.8Hz,1H),7.18(ddt,J＝6.4,4.7,2.2Hz,1H),6.35–6.27(m,3H),5.80(t,J＝9.1Hz,1H),5.75(s,1H),5.52(t,J＝8.8Hz,1H),5.41(d,J＝7.2Hz,1H),5.36(d,J＝9.1Hz,1H),4.90(dd,J＝8.4,4.3Hz,2H),4.62(s,1H),4.21(p,J＝6.9Hz,4H),4.10(dt,J＝11.2,7.0Hz,1H),4.00(q,J＝8.3Hz,2H),3.59(dd,J＝26.0,6.1Hz,2H),3.52–3.46(m,88H),3.42(dd,J＝5.9,3.7Hz,2H),3.36(t,J＝6.0Hz,2H),3.23(s,3H),3.17(dq,J＝17.2,6.2Hz,4H),2.72–2.63(m,8H),2.31(qd,J＝8.2,5.4,3.4Hz,1H),2.24–2.16(m,5H),2.07(d,J＝21.4Hz,5H),1.91–1.81(m,8H),1.78(s,3H),1.72(t,J＝7.6Hz,2H),1.67(s,12H),1.54(t,J＝7.5Hz,2H),1.49(s,3H),1.35(q,13J＝8.0,7.4Hz,2H),1.23(s,1H),1.00(d,J＝19.2Hz,6H)；C‑NMR(151MHz,DMSO‑d6)δ202.34,172.57,172.18,171.96,171.91,171.52,169.66,169.31,168.77,166.36,165.22,148.16,145.85,143.05,142.02,141.99,141.09,140.49,139.31,137.30,134.20,133.52,133.44,131.50,129.94,129.58,128.73,128.69,128.59,128.33,128.23,127.61,127.43,126.42,126.29,125.19,122.58,119.93,111.33,110.71,101.96,101.50,83.60,80.25,76.69,75.27,74.70,74.58,74.48,71.28,70.87,70.41,69.78,69.58,69.15,58.04,57.39,54.92,54.04,49.02,46.06,43.84,42.93,41.81,39.94,39.80,39.66,39.52,39.38,39.24,39.10,38.42,37.14,36.50,36.17,36.07,34.99,34.36,33.72,31.58,29.02,27.46,27.40,27.14,26.75,26.32,25.83,25.73,24.86,24.56,23.85,22.56,21.36,20.65,20.39,13.86,9.76.[0147] 实施例11[0148] 苯丙酸,β‑(苯甲酰氨基)‑α‑[3‑[2‑[3‑[1‑[5‑[甲氧基聚乙二醇氨基羰基]戊基]‑1,3‑二氢‑3,3‑二‑甲基‑2H‑吲哚‑2‑甲叉基]亚乙基]‑2‑氯‑1‑环己烯‑1‑基]乙烯基]‑3,3‑二甲基‑5‑氯‑3H‑吲哚‑1‑基丙基氨基羰基]甲基]硫基]乙酰氧基‑6,12b‑双(乙酰氧基)‑12‑(苯甲酰氧基)‑2a,3,4,4a,5,6,9,10,11,12,12a,12b‑十二氢‑4,11‑二羟基‑4a,8,13,13‑四甲基‑5‑氧代‑7,11‑亚甲基‑1H‑环癸并[3,4]苯并[1,2‑b]氧杂丁环‑9‑基酯,[2aR‑[2aα,4β,4aβ,6β,9α(αR*,βS*),11α,12α,12aα,12bα]](Z‑11)的合成：[0149] (1)[2‑[3‑[1‑[5‑[[甲氧基聚(氧‑1,2‑乙二基)]氨基羰基]戊基]‑1,3‑二氢‑3,3‑二甲基‑5‑氯‑2H‑吲哚‑2‑甲叉基亚乙基]‑2‑氯‑1‑环己烯‑1‑基]乙烯基]‑3,3‑二甲基‑1‑(3‑氨基丙基)‑3H‑吲哚溴鎓盐(化合物1‑9)的制备[0150][0151] 采用实施例1中化合物1‑7相同的合成方法，将4‑氯苯肼为起始原料，制得化合物+ 2+1‑9，产率76.4％。MS(FT‑ICR)m/z:821.539[M+H] 。[0152] (2)化合物Z‑11的合成[0153][0154] 采用实施例1化合物Z‑1相同的合成方法，将化合物1‑9和化合物PTX‑5反应，得Z‑111为绿色固体，得量280mg，收率21.5％。H‑NMR(600MHz,DMSO‑d6)δ9.26(d,J＝8.3Hz,1H),8.29–8.20(m,3H),8.00–7.97(m,2H),7.86–7.80(m,4H),7.75–7.72(m,1H),7.69–7.63(m,4H),7.52(td,J＝7.0,1.4Hz,1H),7.47–7.38(m,9H),7.28(ddd,J＝7.9,5.6,2.7Hz,1H),7.17(tt,J＝6.5,2.1Hz,1H),6.35–6.28(m,3H),5.81(t,J＝9.1Hz,1H),5.53(t,J＝8.8Hz,1H),5.40(dd,J＝11.2,8.2Hz,2H),4.90(d,J＝7.1Hz,2H),4.62(s,1H),4.22(d,J＝9.4Hz,4H),4.10(dt,J＝10.6,7.1Hz,1H),4.03–3.98(m,2H),3.65–3.56(m,4H),3.52–3.47(m,84H),3.43(dd,J＝5.9,3.7Hz,2H),3.37(t,J＝6.0Hz,2H),3.25(d,J＝12.3Hz,5H),3.21(q,J＝7.5,6.6Hz,2H),3.16(q,J＝5.9Hz,2H),2.70(t,J＝6.0Hz,3H),2.24(s,3H),2.10(s,3H),2.06(t,J＝7.3Hz,2H),1.87(dt,J＝21.9,6.3Hz,4H),1.79–1.76(m,4H),1.73(t,J＝7.5Hz,2H),1.68(s,11H),1.54(q,J＝7.5Hz,2H),1.50(s,3H),1.37–1.32(m,2H),1.2413(d,J＝5.1Hz,1H),1.01(d,J＝20.4Hz,6H).；C‑NMR(151MHz,DMSO‑d6)δ202.47,172.82,172.20,172.08,169.80,169.56,169.21,168.90,168.76,166.50,165.37,148.31,146.05,143.29,143.12,142.15,142.11,141.19,140.65,139.41,137.39,134.29,133.66,133.61,131.61,130.07,129.73,128.88,128.83,128.76,128.42,127.73,127.58,126.61,126.47,125.28,122.72,120.07,111.42,110.90,102.19,101.52,83.73,80.38,76.82,75.41,75.26,74.83,74.62,71.42,71.10,70.56,69.92,69.72,69.29,58.18,57.54,54.25,49.20,49.11,46.19,44.01,43.06,41.80,38.55,36.63,36.51,35.13,34.47,34.44,32.69,27.62,27.53,27.17,26.90,26.45,25.97,25.87,24.99,22.74,21.48,20.79,20.50,14.00,9.89.[0155] 实施例12[0156] 苯丙酸,β‑(苯甲酰氨基)‑α‑[3‑[2‑[3‑[2‑[3‑[1‑[5‑[甲氧基聚乙二醇氨基羰基]戊基]‑1,3‑二氢‑3,3‑二‑甲基‑2H‑吲哚‑2‑甲叉基]亚乙基]‑2‑氯‑1‑环己烯‑1‑基]乙烯基]‑3,3‑二甲基‑5‑氯‑3H‑吲哚‑1‑基丙基氨基羰基]乙基]硫代甲基乙叉基硫基]丙酰氧基‑6,12b‑双(乙酰氧基)‑12‑(苯甲酰氧基)‑2a,3,4,4a,5,6,9,10,11,12,12a,12b‑十二氢‑4,11‑二羟基‑4a,8,13,13‑四甲基‑5‑氧代‑7,11‑亚甲基‑1H‑环癸并[3,4]苯并[1,2‑b]氧杂丁环‑9‑基酯,[2aR‑[2aα,4β,4aβ,6β,9α(αR*,βS*),11α,12α,12aα,12bα]](Z‑12)的合成[0157][0158] 采用实施例1化合物Z‑1相同的合成方法，将化合物1‑9和化合物PTX‑1反应，，得Z‑1 112为绿色固体，得量280mg，收率21.2％。H‑NMR(600MHz,DMSO‑d6) HNMR(600MHz,)δ9.23(d,J＝8.5Hz,1H),8.26(d,J＝14.3Hz,2H),8.10(t,J＝5.6Hz,1H),7.99–7.97(m,2H),7.88–7.80(m,4H),7.76–7.72(m,1H),7.69–7.62(m,4H),7.56–7.52(m,1H),7.49–7.38(m,9H),7.29(td,J＝7.1,1.5Hz,1H),7.19(p,J＝4.3Hz,1H),6.35–6.28(m,3H),5.84–5.79(m,1H),5.55(t,J＝8.8Hz,1H),5.40(dd,J＝23.1,8.1Hz,2H),4.93–4.89(m,2H),4.63(s,1H),4.22(dt,J＝15.3,7.7Hz,4H),4.13–4.08(m,1H),4.01(q,J＝8.3Hz,2H),3.60(dd,J＝26.3,6.0Hz,2H),3.52–3.48(m,84H),3.43(dd,J＝5.9,3.7Hz,2H),3.37(t,J＝6.0Hz,2H),3.24(s,5H),3.17(q,J＝5.9,5.5Hz,2H),2.78–2.68(m,10H),2.35(t,J＝7.4Hz,2H),2.23(s,3H),2.08(d,J＝19.9Hz,5H),1.92–1.83(m,4H),1.81–1.76(m,4H),1.73(t,J＝7.7Hz,2H),1.69–1.65(m,12H),1.57–1.52(m,3H),1.50(s,3H),1.45(d,J＝1.7Hz,6H),1.38–1.3213(m,2H),1.25–1.23(m,1H),1.01(d,J＝20.2Hz,6H)；C‑NMR(151MHz,DMSO‑d6)δ202.48,172.71,172.31,172.09,171.02,170.61,169.78,169.24,168.91,166.51,165.36,148.30,145.98,143.19,142.13,141.22,140.62,139.48,137.38,134.34,133.65,133.55,131.61,130.08,129.71,128.85,128.73,128.43,128.37,127.79,127.60,126.57,126.46,125.33,122.72,120.06,111.49,110.85,102.09,101.66,83.73,80.38,76.84,75.41,74.85,74.81,74.62,71.42,70.96,70.56,69.92,69.72,69.30,58.19,57.54,55.94,54.15,49.15,49.13,46.21,43.98,43.07,41.95,38.55,36.64,36.23,35.35,35.13,34.50,34.15,30.63,30.59,27.60,27.54,27.27,26.89,26.46,26.00,25.96,25.87,25.69,24.99,24.77,22.71,21.50,20.79,20.52,14.04,9.89.[0159] 实施例13[0160] 苯丙酸,β‑(苯甲酰氨基)‑α‑[3‑[2‑[3‑[2‑[3‑[1‑[5‑[甲氧基聚乙二醇氨基羰基]戊基]‑1,3‑二氢‑3,3‑二‑甲基‑2H‑吲哚‑2‑甲叉基]亚乙基]‑2‑氯‑1‑环己烯‑1‑基]乙烯基]‑3,3‑二甲基‑5‑氯‑3H‑吲哚‑1‑基丙基氨基羰基]乙基]硫基]丙酰氧基‑6,12b‑双(乙酰氧基)‑12‑(苯甲酰氧基)‑2a,3,4,4a,5,6,9,10,11,12,12a,12b‑十二氢‑4,11‑二羟基‑4a,8,13,13‑四甲基‑5‑氧代‑7,11‑亚甲基‑1H‑环癸并[3,4]苯并[1,2‑b]氧杂丁环‑9‑基酯,[2aR‑[2aα,4β,4aβ,6β,9α(αR*,βS*),11α,12α,12aα,12bα]](Z‑13)的合成[0161][0162] 采用实施例1化合物Z‑1相同的合成方法，将化合物1‑9和化合物PTX‑2反应，，得Z‑113为绿色固体，得量270mg，收率20.4％。H‑NMR(600MHz,DMSO‑d6)δ9.24(d,J＝8.6Hz,1H),8.26(d,J＝13.8Hz,2H),8.09(t,J＝5.6Hz,1H),7.99–7.96(m,2H),7.86–7.80(m,4H),7.73(t,J＝7.4Hz,1H),7.68–7.62(m,4H),7.54(t,J＝7.3Hz,1H),7.49–7.37(m,10H),7.28(t,J＝6.8Hz,1H),7.20–7.17(m,1H),6.35–6.28(m,3H),5.82(t,J＝9.0Hz,1H),5.55(t,J＝8.8Hz,1H),5.41(d,J＝7.2Hz,1H),5.36(d,J＝8.9Hz,1H),4.92–4.89(m,2H),4.64(s,1H),4.21(dt,J＝14.4,7.4Hz,3H),4.11(dd,J＝10.2,6.1Hz,2H),4.01(q,J＝8.3Hz,2H),3.63–3.56(m,2H),3.50(dd,J＝6.9,3.7Hz,88H),3.42(dd,J＝5.9,3.6Hz,2H),3.36(t,J＝6.0Hz,2H),3.24–3.14(m,9H),2.71(d,J＝10.3Hz,7H),2.65(t,J＝7.2Hz,2H),2.33(t,J＝7.4Hz,2H),2.23(s,3H),2.10(s,3H),2.06(t,J＝7.3Hz,2H),1.91–1.82(m,4H),1.78(s,3H),1.67(s,11H),1.52(d,J＝27.8Hz,7H),1.37–1.32(m,2H),1.23(s,1H),1.01(d,J＝1320.6Hz,6H)；C‑NMR(151MHz,DMSO‑d6)δ202.49,172.71,172.32,172.10,171.10,170.66,169.79,169.25,168.92,166.59,165.37,148.29,145.98,143.18,142.14,141.22,140.63,139.51,137.39,134.37,133.65,133.54,131.63,130.08,129.72,128.85,128.46,128.37,127.78,127.59,126.58,126.46,125.33,122.71,120.07,111.51,110.85,102.10,101.65,83.74,80.40,76.84,75.42,74.86,74.81,74.62,71.42,70.96,70.57,69.92,69.72,69.29,58.18,57.55,54.13,49.16,49.14,48.74,46.21,43.98,43.07,41.94,38.56,36.64,36.24,35.79,35.13,34.50,34.12,27.61,27.54,27.27,27.01,26.89,26.47,26.08,25.98,25.87,25.00,22.71,21.49,20.80,20.51,14.04,9.90.[0163] 实施例14[0164] 苯丙酸,β‑(苯甲酰氨基)‑α‑[3‑[2‑[3‑[2‑[3‑[1‑[5‑[甲氧基聚乙二醇氨基羰基]戊基]‑1,3‑二氢‑3,3‑二‑甲基‑2H‑吲哚‑2‑甲叉基]亚乙基]‑2‑氯‑1‑环己烯‑1‑基]乙烯基]‑3,3‑二甲基‑5‑氯‑3H‑吲哚‑1‑基丙基氨基羰基]乙基]二硫基]丙酰氧基‑6,12b‑双(乙酰氧基)‑12‑(苯甲酰氧基)‑2a,3,4,4a,5,6,9,10,11,12,12a,12b‑十二氢‑4,11‑二羟基‑4a,8,13,13‑四甲基‑5‑氧代‑7,11‑亚甲基‑1H‑环癸并[3,4]苯并[1,2‑b]氧杂丁环‑9‑基酯,[2aR‑[2aα,4β,4aβ,6β,9α(αR*,βS*),11α,12α,12aα,12bα]](Z‑14)的合成[0165][0166] 采用实施例1化合物Z‑1相同的合成方法，将化合物1‑9和化合物PTX‑3反应，，得Z‑114为绿色固体，得量250mg，收率18.9％。H‑NMR(600MHz,DMSO‑d6)δ9.23(d,J＝8.6Hz,1H),8.26(dd,J＝13.9,4.4Hz,2H),8.14(t,J＝5.6Hz,1H),7.99–7.96(m,2H),7.86–7.80(m,4H),7.73(t,J＝7.4Hz,1H),7.69–7.61(m,4H),7.54(t,J＝7.4Hz,1H),7.49–7.38(m,9H),7.28(td,J＝6.9,6.2,2.3Hz,1H),7.19(p,J＝4.3Hz,1H),6.37–6.27(m,3H),5.82(t,J＝9.0Hz,1H),5.56(t,J＝8.7Hz,1H),5.41(d,J＝7.2Hz,1H),5.37(d,J＝8.9Hz,1H),4.92–4.88(m,2H),4.63(s,1H),4.21(q,J＝8.4Hz,3H),4.10(dt,J＝11.0,7.0Hz,1H),4.01(q,J＝8.3Hz,2H),3.60(dd,J＝25.3,6.1Hz,2H),3.52–3.46(m,100H),3.43(dd,J＝5.9,3.6Hz,2H),3.36(t,J＝6.0Hz,2H),3.24(s,5H),3.16(q,J＝5.8Hz,2H),2.92–2.81(m,6H),2.71(t,J＝6.5Hz,3H),2.46(t,J＝7.1Hz,2H),2.23(s,3H),2.08(d,J＝21.7Hz,5H),1.91–1.81(m,4H),1.79(s,4H),1.73(q,J＝7.7Hz,2H),1.67(d,J＝2.2Hz,11H),1.57–1.48(m,7H),131.34(p,J＝7.9Hz,2H),1.23(s,1H),1.01(d,J＝20.0Hz,6H)；C‑NMR(151MHz,DMSO‑d6)δ202.49,172.77,172.26,172.09,170.78,170.28,169.78,169.21,168.92,166.62,165.37,148.30,146.01,143.25,143.14,142.13,141.21,140.64,139.48,137.35,134.37,133.65,133.57,131.63,130.08,129.72,128.87,128.84,128.74,128.46,128.38,127.76,127.59,126.58,126.44,125.31,122.71,120.07,111.47,110.87,102.15,101.59,83.73,80.40,76.84,75.42,74.88,74.85,74.62,71.42,71.00,70.57,69.92,69.72,69.29,58.18,57.54,54.09,49.18,49.13,46.21,43.99,43.07,41.93,38.56,36.65,36.29,35.13,35.08,34.50,33.77,33.11,32.28,29.15,28.83,27.61,27.54,27.25,26.90,26.47,25.98,25.87,25.00,22.71,21.49,20.79,20.52,14.04,9.89[0167] 实施例15[0168] 苯丙酸,β‑(苯甲酰氨基)‑α‑[4‑[3‑[3‑[2‑[3‑[1‑[5‑[甲氧基聚乙二醇氨基羰基]戊基]‑1,3‑二氢‑3,3‑二‑甲基‑2H‑吲哚‑2‑甲叉基]亚乙基]‑2‑氯‑1‑环己烯‑1‑基]乙烯基]‑3,3‑二甲基‑5‑氯‑3H‑吲哚‑1‑基丙基氨基羰基]乙基]二硫基]丁酰氧基‑6,12b‑双(乙酰氧基)‑12‑(苯甲酰氧基)‑2a,3,4,4a,5,6,9,10,11,12,12a,12b‑十二氢‑4,11‑二羟基‑4a,8,13,13‑四甲基‑5‑氧代‑7,11‑亚甲基‑1H‑环癸并[3,4]苯并[1,2‑b]氧杂丁环‑9‑基酯,[2aR‑[2aα,4β,4aβ,6β,9α(αR*,βS*),11α,12α,12aα,12bα]](Z‑15)的合成[0169][0170] 采用实施例1化合物Z‑1相同的合成方法，将化合物1‑9和化合物PTX‑4反应，，得Z‑115为绿色固体，得量240mg，收率18.2％。H‑NMR(600MHz,DMSO‑d6)δ9.23(d,J＝8.4Hz,1H),8.26(d,J＝13.8Hz,2H),8.04(t,J＝5.7Hz,1H),8.00–7.96(m,2H),7.86–7.80(m,4H),7.74(t,J＝7.3Hz,1H),7.68–7.62(m,4H),7.55(t,J＝7.3Hz,1H),7.50–7.42(m,8H),7.39(d,J＝8.4Hz,1H),7.29(ddd,J＝8.0,5.4,2.8Hz,1H),7.18(ddt,J＝6.4,4.7,2.2Hz,1H),6.35–6.28(m,3H),5.80(d,J＝9.2Hz,1H),5.76(s,1H),5.53(t,J＝8.8Hz,1H),5.41(d,J＝7.2Hz,1H),5.36(d,J＝9.1Hz,1H),4.90(dd,J＝8.4,4.3Hz,2H),4.62(s,1H),4.21(q,J＝7.3,6.8Hz,3H),4.10(dt,J＝11.2,7.0Hz,1H),4.01(q,J＝8.3Hz,2H),3.59(dd,J＝26.0,6.1Hz,2H),3.52–3.47(m,88H),3.42(dd,J＝5.9,3.7Hz,2H),3.36(t,J＝6.0Hz,2H),3.24(s,3H),3.18(dt,J＝15.3,6.2Hz,4H),2.73–2.63(m,8H),2.23(s,3H),2.19(t,J＝7.4Hz,2H),2.10(s,3H),2.06(t,J＝7.3Hz,2H),1.91–1.80(m,9H),1.78(s,3H),1.72(t,J＝7.6Hz,2H),1.67(s,12H),1.52(d,J＝29.7Hz,6H),1.34(p,J＝8.0,7.6Hz,2H),1.23(s,131H),1.01(d,J＝19.2Hz,6H).；C‑NMR(151MHz,DMSO‑d6)δ202.48,172.71,172.31,172.09,172.05,171.66,169.80,169.45,168.91,166.50,165.36,148.30,145.98,143.19,142.15,142.13,141.23,140.63,139.45,137.44,134.34,133.66,133.58,131.64,130.08,129.71,128.87,128.83,128.73,128.47,128.37,127.75,127.56,126.56,126.43,125.32,122.72,120.07,111.47,110.85,102.09,101.64,83.74,80.38,76.83,75.41,74.84,74.72,74.62,71.42,71.01,70.55,69.92,69.72,69.29,58.18,57.53,55.06,54.17,49.16,46.20,43.97,43.07,41.95,38.55,37.28,36.64,36.31,36.21,35.13,34.49,33.86,31.72,29.16,27.60,27.54,27.28,26.89,26.46,25.97,25.87,25.00,24.70,23.99,22.70,21.50,20.79,20.53,14.00,9.89.[0171] 应用例[0172] MTT的化学名为3‑(4,5‑二甲基噻唑‑2)‑2,5‑二苯基四氮唑溴盐，是一种黄颜色的染料，商品名为噻唑蓝。MTT法可用于药物体外细胞毒性的测定，检测原理为活细胞线粒体中的NADPH(还原型辅酶II)能使外源性MTT还原为水不溶性的蓝紫色结晶甲瓒(Formazan)并沉积在细胞中，而死细胞无此功能。二甲基亚砜能溶解细胞中的甲瓒，用酶标仪在490nm或570nm波长处测定其光密度(opticaldensity，OD)值，在一定细胞数范围内，其光密度值与活细胞指数成正相关。本专利采用MTT法对上述各实施例制备所得目标化合物的体外抗前列腺癌活性进行考察。由于紫杉醇对乳腺癌、非小细胞肺癌、卵巢癌、胃癌等实体肿瘤效果显著，因此选择人乳腺癌细胞MCF‑7、人胃癌SGC‑7901和人结肠癌HCT‑116细胞株评估目标化合物的抗肿瘤效果，以紫杉醇为阳性对照。具体操作如下：对需要传代的细胞进行消化4以制成细胞悬液，用新鲜培养液将其稀释至适宜的细胞密度(3.0×10 cells/mL)，混匀并加入100μL细胞悬液在96孔板的各孔中，于培养箱中培养过夜使其贴壁。第二天，等细胞贴壁后便可加药。溶液剂的配制：先将药物用甲醇进行溶解，然后再用细胞培养液进行稀释。然后在96孔板的每个孔中加入200μL的含药培养液，每个浓度设置4个平行孔；对照组只加100μL的新鲜培养液。然后于培养箱中培养48h，取出96孔板，吸走旧培养液，每孔补加100μL新鲜培养液，然后每孔加入5mg/mLMTT溶液20μL，置培养箱中培养4h后吸走培养液，每孔加入200μLDMSO，在振荡器上振荡10min以溶解甲瓒。将酶标仪的吸收波长设置为570nm，测定该波长下的吸光度值。CellInhibitionRate(％)＝(1–A/Ac)×100％，其中，A：给药孔的吸光度值；Ac：对照孔的吸光度值。再利用GraphPadPrism5.0软件计算IC50。[0173] 对本发明中基于氧化还原敏感键连接的靶向肿瘤PEG化吲哚菁染料偶联紫杉醇前药型化合物进行体外抗肿瘤活性测定，并以紫杉醇为阳性对照，结果如Table1所示。[0174] Table1TheIC50(μM)oftestcompoundsinMCF‑7,SGC‑7901andHCT‑116celllines[0175][0176] 由上述可见，本发明基于氧化还原敏感键连接的靶向肿瘤PEG化吲哚菁染料偶联紫杉醇前药型化合物均表现出了一定的细胞毒性，这种细胞毒性质是化合物自身具备的还是化合物进入细胞后氧化还原敏感键断裂，释放出紫杉醇而发挥细胞毒作用，因未进行前药化合物释放研究，因此尚无法定论；但细胞毒试验的初步结果说明了该设计思路值得展开进一步研究。[0177] 在测试化合物中，Z‑5和Z‑6的活性更高，IC50值与PTX接近，我们推测这可能与这2个化合物的原药释放速度有关。这2个化合物共同的结构特点是氧化还原敏感键中的硫原子均位于紫杉醇2’‑OH所成酯键羰基的α‑位，这个位置的桥连键不仅具有氧化还原双敏感性，而且更易断裂，从而促进邻位碳相连酯键的解离，因此能够更快地释放出原形药物；同时也说明了硫原子均位于紫杉醇2’‑OH所成酯键羰基的α‑位比β‑位和γ‑位更容易断裂。

专利地区：辽宁

专利申请日期：2023-01-07

专利公开日期：2024-11-01

专利公告号：CN116178700B