CN114539249B - 一类鬼臼毒素衍生物微管蛋白抑制剂及其制备方法和医药用途 - Google Patents
一类鬼臼毒素衍生物微管蛋白抑制剂及其制备方法和医药用途 Download PDFInfo
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- CN114539249B CN114539249B CN202210173908.7A CN202210173908A CN114539249B CN 114539249 B CN114539249 B CN 114539249B CN 202210173908 A CN202210173908 A CN 202210173908A CN 114539249 B CN114539249 B CN 114539249B
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- compound
- methoxy
- podophyllotoxin derivative
- pharmaceutically acceptable
- represents oxygen
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Abstract
本发明公开了结构如式I所示的鬼臼毒素衍生物或药学上可接受的盐或溶剂合物。本发明还公开了所述的鬼臼毒素衍生物或药学上可接受的盐或溶剂合物在制备微管蛋白抑制剂的用途，在细胞水平上可以抑制肿瘤细胞的增殖，在动物水平上可以抑制裸鼠移植瘤的生长，可用于治疗各种癌症；且本发明鬼臼毒素衍生物具有较低的毒副作用，对正常细胞几乎没有明显的毒性，提高了安全性。
Description
技术领域
本发明涉及药物化学领域，具体涉及一类鬼臼毒素衍生物的制备方法及其医药用途。该类化合物作为微管蛋白抑制剂，在细胞水平上可以抑制肿瘤细胞的增殖，在动物水平上可以抑制裸鼠移植瘤的生长，可应用于治疗各种肿瘤或癌症等疾病。
背景技术
当前，恶性肿瘤严重威胁着人类的生命和健康，其死亡率高居不下。现如今，化学药物治疗肿瘤被认为是最有效的治疗方法之一。但是，临床上，越来越多的肿瘤出现了多药耐药性(MDR)问题，直接导致药物化疗的失败。
微管广泛存在于真核细胞中，在肿瘤细胞有丝分裂初期，为形成纺锤体，微管处于解聚和重新聚合的动态平衡。癌细胞异常活跃的分裂繁殖过程与微管/微管蛋白这种解聚和聚合的动态平衡密切相关。因此，微管蛋白抑制剂通过与微管蛋白上的特定位点结合，影响和干扰微管蛋白的聚合和解聚的动力学行为，进而阻断有丝分裂过程中M期纺锤体的形成，使肿瘤细胞生长停滞于G2/M期，从而抑制肿瘤细胞的生长、增殖，诱导肿瘤细胞调亡。目前在微管上已明确的有四个微管蛋白抑制剂结合位点，分别是紫杉醇结合位点、laulimalide结合位点、长春碱结合位点和秋水仙碱结合位点。作用于秋水仙碱位点的微管蛋白聚合抑制剂，不仅能克服微管蛋白其他三个结合位点剂抑制带来的如伴有显著骨髓抑制、神经毒性等副作用，还能克服由P-糖蛋白介导的耐药机制，对多药耐药肿瘤细胞可维持不变的细胞毒活性，具有抗肿瘤耐药作用等优点，同时还具有可以不同程度的抑制肿瘤组织中的血管生成等多重功能的作用。
鬼臼毒素(Podophyllotoxin，PPT)是一种具有显著抗肿瘤作用的天然木脂素类活性物质。它通过抑制微管蛋白的聚合从而阻止微管的形成而发挥抗肿瘤作用。但鬼臼毒素存在水溶性差、抗癌谱较窄以及较严重的骨髓抑制与胃肠道反应等明显的毒副作用，限制了其在临床上的应用。国内外研究者对其做了大量的结构修饰和改造，虽然获得的衍生物依托泊苷(VP-16)和替尼泊苷(VM-26)已用于临床抗肿瘤应用，但这些药物仍存在多药耐药、选择性差和毒副作用等问题，极大的限制了其在临床上的发挥。
发明内容
本发明的目的在于提供一系列鬼臼毒素衍生物，并将其作为具有多功能的微管蛋白聚合抑制剂，在细胞水平上可以抑制肿瘤细胞的增殖，在动物水平上可以抑制裸鼠移植瘤的生长，可用于治疗各种癌症；且本发明鬼臼毒素衍生物具有较低的毒副作用，对正常细胞几乎没有明显的毒性，提高了安全性。本发明鬼臼毒素衍生物不仅能充分开发活性天然产物，还具有良好的市场前景。
本发明的目的是通过以下技术方案实现的：
结构如式I所示的鬼臼毒素衍生物或药学上可接受的盐或溶剂合物：
其中，X代表亚甲基或羰基；Y代表氧或氮；Z代表氧或硫；
R1、R2分别独立的选自氢、甲基、乙基，或者R1、R2互相连接与苯环共同形成含两个氧原子的5～7元杂环；所述的含两个氧原子的五～七元杂环包括二氧五环、二氧六环、二氧七环；
R3、R4、R5分别独立的选自氢、羟基、甲氧基、二氟甲氧基、三氟甲氧基、卤素、氰基、硝基，或者R3、R4互相连接与苯环共同形成含两个氧原子的5～7元杂环，或者R4、R5互相连接与苯环共同形成含两个氧院子的5～7元杂环；
Y代表氮时，R6选自氢、C1-C6烷基；Y代表氧，R6代表共价键。
优选的，R1、R2分别独立的选自甲基，或者R1、R2互相连接与苯环共同形成含两个氧原子的5～7元杂环；
R3、R4、R5分别的独立选自氢、羟基、甲氧基、二氟甲氧基、三氟甲氧基、卤素、氰基、硝基，或者R3、R4互相连接与苯环共同形成含两个氧原子的5～7元杂环，或者R4、R5互相连接与苯环共同形成含两个氧院子的5～7元杂环；
Y代表氮时，R6选自氢、C1-C3烷基。
进一步优选的，X代表亚甲基或羰基；Y代表氧或氮；Z代表氧；
R1、R2互相连接与苯环共同形成二氧五环或二氧六环；
R3选自甲氧基、氟、氯、溴、硝基，R4选自甲氧基、氟、溴，R5选自甲氧基、氟、氯、溴，但R3、R4、R5不能同时为甲氧基，或者R3、R5不能同时为氟；
Y代表氮时，R6选自氢；Y代表氧，R6代表共价键。
作为本发明最优选的技术方案，鬼臼毒素衍生物的结构如式Ia所示：
X代表亚甲基或羰基；Y代表氧或氮；Z代表氧；
R1、R2互相连接与苯环共同形成二氧六环；
R3选自甲氧基、氟、氯、溴，R4选自甲氧基，R5选自甲氧基、氯、溴，但R3、R4、R5不能同时为甲氧基；
Y代表氮时，R6选自氢；Y代表氧，R6代表共价键。
具体的，本发明所示的鬼臼毒素衍生物选自如下化合物：
药学上可接受的盐为所述的鬼臼毒素衍生物的盐酸盐、氢溴酸盐、硫酸盐、磷酸盐、甲磺酸盐、乙酸盐、乳酸盐、琥珀酸盐、富马酸盐、马来酸盐、柠檬酸盐、苯甲酸盐、对甲苯磺酸盐或碱性金属阳离子盐。
溶剂合物是指所述的鬼臼毒素衍生物与药学上可接受的溶剂分子缔合形成的物质，药学上可接受的溶剂分子包括丙酮、二甲亚砜、水等。
本发明的另一个目的是提供所述的鬼臼毒素衍生物的制备方法，根据X，Y，Z，R6的不同，包括：
当X代表亚甲基，Y代表氧，Z代表氧时，合成路线如下：
其中，甲基化反应：左旋多巴和二氯亚砜的摩尔比为1:3，反应溶剂为甲醇，反应温度为室温(25±5℃)；酰基化反应：化合物2和碳酸二叔丁酯的摩尔比为1:1.5，反应溶剂为1,4-二氧六环和1M氢氧化钠水溶液体积比1:1的混合溶剂，反应温度为80℃；烷基化反应：化合物3和选自硫酸二甲酯或二碘甲烷或1,2-二溴乙烷或1,3-二溴丙烷任一种的摩尔比为1:1.5，化合物3和碳酸钾的摩尔比为1:2，反应溶剂为乙腈，反应温度为100℃；还原反应：化合物4和硼氢化钠的摩尔比为1:5，反应溶剂为四氢呋喃和甲醇体积比1:1的混合溶剂，反应温度为室温；环合反应1：化合物5和氯化亚砜的摩尔比为1:5，反应溶剂为四氢呋喃，反应温度为室温；环合反应2：化合物6与式所示的醛的摩尔比为1:1，反应溶剂为二氯甲烷，化合物6与浓硫酸(以H2SO4计)为1:2，反应温度为室温。
当X代表羰基，Y代表氮，Z代表氧时，合成路线如下：
其中，甲基化反应：左旋多巴和二氯亚砜的摩尔比为1:3，反应溶剂为甲醇，反应温度为室温(25±5℃)；酰基化反应：化合物2和碳酸二叔丁酯的摩尔比为1:1.5，反应溶剂为1,4-二氧六环和1M氢氧化钠水溶液体积比1:1的混合溶剂，反应温度为80℃；烷基化反应：化合物3和选自硫酸二甲酯或二碘甲烷或1,2-二溴乙烷或1,3-二溴丙烷任一种的摩尔比为1:1.5，化合物3和碳酸钾的摩尔比为1:2，反应溶剂为乙腈，反应温度为100℃；脱保护反应：反应溶剂为三氟乙酸，反应温度为室温；酰化反应：化合物7和异氰酸钾的摩尔比为1:5，反应溶剂为冰醋酸，反应温度为室温；环合反应1：反应溶剂为5M盐酸，反应温度为60℃；环合反应2：化合物9与式所示的醛的摩尔比为1:1，反应溶剂为二氯甲烷，化合物9与浓硫酸(以H2SO4计)为1:2，反应温度为室温。
当X代表羰基，Y代表氮，Z代表氧或硫时，合成路线如下：
其中，甲基化反应：左旋多巴和二氯亚砜的摩尔比为1:3，反应溶剂为甲醇，反应温度为室温(25±5℃)；酰基化反应：化合物2和碳酸二叔丁酯的摩尔比为1:1.5，反应溶剂为1,4-二氧六环和1M氢氧化钠水溶液体积比1:1的混合溶剂，反应温度为80℃；烷基化反应：化合物3和选自硫酸二甲酯或二碘甲烷或1,2-二溴乙烷或1,3-二溴丙烷任一种的摩尔比为1:1.5，化合物3和碳酸钾的摩尔比为1:2，反应溶剂为乙腈，反应温度为100℃；脱保护反应：反应溶剂为三氟乙酸，反应温度为室温；脱水反应：化合物7与式所示的醛的摩尔比为1:1，反应溶剂为二氯甲烷和异丙醇体积比2:1的混合溶剂，反应温度为室温；环合反应1：反应溶剂为三氟乙酸，反应温度为50℃；环合反应2：化合物11和不同的异氰酸酯的摩尔比为1:2，反应溶剂为二氯甲烷，三乙胺，反应温度为室温。
本发明所述的鬼臼毒素衍生物能够通过抑制微管蛋白的聚合，在细胞水平上可以抑制肿瘤细胞的增殖，在动物水平上可以抑制裸鼠移植瘤的生长；本发明所述的鬼臼毒素衍生物抗癌谱较宽，可以用于治疗包括但不限于乳腺癌、结肠癌、非小细胞肺癌、白血病、前列腺癌、胃癌、肝癌等疾病。
因此，本发明的另一个目的是提供所述的鬼臼毒素衍生物或药学上可接受的盐或溶剂合物在制备微管蛋白抑制剂的用途。
本发明的另一个目的是提供所述的鬼臼毒素衍生物或药学上可接受的盐或溶剂合物在制备抗肿瘤药物的用途。
所述的肿瘤为乳腺癌、非小细胞肺癌、结肠癌、前列腺癌、胃癌、肝癌、白血病。
本发明的另一个目的是提供一种药物组合物，它是以所述的鬼臼毒素衍生物或药学上可接受的盐或溶剂合物为有效成分或主要有效成分，与可药用的载体、稀释剂或赋形剂制成的。
本发明所述的鬼臼毒素衍生物或药学上可接受的盐或溶剂合物或者药用组合物可以采用口服、静脉注射等给药方式。在临床上可用于单药治疗，也可以和其他临床上使用的化疗药物及放疗等治疗手段联合用于前述癌症的治疗。本发明的所述的鬼臼毒素衍生物或药学上可接受的盐或溶剂合物临床所用剂量为0.01mg-1000mg/天，也可根据病情的轻重或剂型的不同偏离此范围。
附图说明
图1是化合物I24和I24微管蛋白聚合抑制实验荧光曲线。
图2是化合物I24和I24对人乳腺癌MCF-7细胞裸鼠移植瘤的生长抑制作用。
图3是化合物I24和I24对人非小细胞肺癌A549细胞裸鼠移植瘤的生长抑制作用。
具体实施方式
以下通过实施例对本发明的技术方案进行进一步的详细说明，但不应当将此理解为本发明的保护范围仅限于以下的实施例。
实施例1
步骤一：化合物4a的制备
以左旋多巴(化合物1，10g，50mmol)为起始原料，溶解在甲醇(200ml中)中，滴入氯化亚砜(150mmol)，室温反应6小时，减压浓缩，得到化合物2，浅黄色固体，产率98％。
将化合物2(10.5g，50mmol)置于1,4-二氧六环(70ml)中，缓慢加入1M氢氧化钠水溶液(70ml)，随后加入碳酸二叔丁酯(16g，1.5eq)，80℃回流反应8h，加入盐酸调节pH为5，乙酸乙酯萃取三次，合并乙酸乙酯层，无水硫酸钠除水，得到油状物(化合物3)，化合物3直接用于下一步。将化合物3(73.3mmol)溶于乙腈，加入碳酸钾(20.7g，150mmol)及硫酸二甲酯(10.4ml，110mmol)，100℃回流反应10h，减压旋干乙腈，加入水及乙酸乙酯分液，乙酸乙酯萃取水层三次，合并乙酸乙酯层，经硅胶柱层析(洗脱剂为乙酸乙酯:石油醚＝1:3V/V)得到化合物4a(R1＝R2＝CH3)，淡黄色油状物，12.1g，产率71％。
步骤二：(5R,10aS)-2-乙基-7,8-二甲氧基-5-(3,4,5-三甲氧基苯基)-10,10a-二氢咪唑并[1,5-b]异喹啉-1,3(2H,5H)-二酮(化合物I1)的制备
将化合物4a(239mg，1mmol)溶解于5ml三氟乙酸中，室温反应1小时，用碳酸钾调反应溶液节pH至10，乙酸乙酯萃取，无水硫酸钠除水，浓缩得到淡黄色固体(化合物7a)，直接用于下一步。将化合物7a溶解于二氯甲烷与异丙醇混合溶剂(6ml，二氯甲烷:异丙醇＝2:1V/V)，加入3,4,5-三甲氧基苯甲醛(196mg，1eq)，室温反应过夜，减压浓缩得到白色固体(化合物10a)，将化合物10a溶解在三氟乙酸中，50℃回流反应1小时，加入反应液5倍体积的二氯甲烷稀释，用碳酸钾调节pH至10，二氯甲烷萃取，无水硫酸钠除水，经硅胶柱层析(洗脱剂为乙酸乙酯:石油醚＝1:1V/V)得到无色粉末状固体(化合物11a)271mg，产率65％。取化合物11a(41.7mg，1mmol)溶解于二氯甲烷中，加入三乙胺，然后加入异氰酸乙酯(140mg，2eq)，室温反应过夜，反应液直接减压浓缩拌样，硅胶柱层析(洗脱剂为乙酸乙酯:石油醚＝1:1V/V)得到化合物I1，无色固体，产率71％。1H NMR(500MHz,CDCl3)δ6.68(s,1H),6.48(s,3H),6.12(s,1H),4.12(dd,J＝11.4,5.3Hz,1H),3.91(s,3H),3.84(s,3H),3.78(s,6H),3.74(s,3H),3.57(dq,J＝13.6,7.2Hz,2H),3.25(dd,J＝15.9,5.3Hz,1H),2.88(dd,J＝15.8,11.5Hz,1H),1.22(t,J＝7.2Hz,3H).13C NMR(126MHz,CDCl3)δ172.96,154.71,153.58,148.77,148.38,138.04,137.64,125.53,123.95,111.40,111.19,105.91,60.97,56.40,56.24,56.11,54.84,52.30,33.92,30.27,13.66.HRMS(ESI)m/z:479.1787,calcdfor:C24H28N2O7Na[M+Na]+479.1789.
实施例2
(5R,9aS)-8-乙基-5-(3,4,5-三甲氧基苯基)-9a,10-二氢-[1,3]二氧杂环[4,5-g]咪唑并[1,5-b]异喹啉-7,9(5H,8H)-二酮(化合物I2)的制备
制备方法同实施例1，将制备化合物4a使用的硫酸二甲酯替换为二碘甲烷(制得化合物4b，R1、R2相互连接与苯环共同形成二氧五环)，其他条件均不变，得到化合物I2，白色固体，产率68％。1H NMR(600MHz,CDCl3)δ6.68(s,1H),6.46(s,2H),6.45(s,1H),6.03(s,1H),5.96(d,J＝1.0Hz,1H),5.94(d,J＝1.0Hz,1H),4.14(dd,J＝11.4,5.2Hz,1H),3.83(s,3H),3.80(s,6H),3.56(qd,J＝13.8,7.2Hz,2H),3.23(dd,J＝15.8,5.2Hz,1H),2.84(dd,J＝15.8,11.5Hz,1H),1.21(t,J＝7.2Hz,3H).13C NMR(151MHz,CDCl3)δ173.05,154.93,153.79,147.64,147.35,138.17,137.77,127.18,125.12,108.81,108.57,105.94,101.70,61.17,56.59,55.54,52.63,34.14,30.94,13.86.HRMS(ESI)m/z:463.1474,calcd for:C23H24N2O7Na[M+Na]+463.1476.
实施例3
(6R,10aS)-9-乙基-6-(3,4,5-三甲氧基苯基)-2,3,10a,11-四氢-[1,4]二氧杂环[2,3-g]咪唑并[1,5-b]异喹啉-8,10(6H,9H)-二酮(化合物I3)的制备
制备方法同实施例1，将制备化合物4a使用的硫酸二甲酯替换为1,2-二溴乙烷(制得化合物4c，R1、R2相互连接与苯环共同形成二氧六环)，其他条件均不变，得到化合物I3，无色固体，产率73％。1H NMR(500MHz,CDCl3)δ6.73(s,1H),6.51(s,1H),6.45(s,2H),6.01(s,1H),4.23(dd,J＝14.0,4.3Hz,4H),4.14(dd,J＝11.6,5.1Hz,1H),3.56(dq,J＝13.7,7.2Hz,2H),3.21(dd,J＝15.8,5.1Hz,1H),2.81(dd,J＝15.6,11.6Hz,1H),1.20(t,J＝7.2Hz,3H).13C NMR(126MHz,CDCl3)δ172.67,154.61,153.28,142.97,142.64,137.74,137.52,126.60,124.30,116.83,116.80,105.57,64.28,64.20,60.67,56.14,54.78,52.54,33.64,29.95,13.36.HRMS(ESI)m/z:477.1634,calcd for:C24H26N2O7Na[M+Na]+477.1632.
实施例4
(5R,10aS)-7,8-二甲氧基-2-甲基-3-硫氧基-5-(3,4,5-三甲氧基苯基)-2,3,10,10a-四氢咪唑并[1,5-b]异喹啉-1(5H)-酮(化合物I4)的制备
制备方法同实施例1，仅将步骤二中异氰酸乙酯替换为异硫氰酸甲酯，其他条件均不变，得到化合物I4，亮黄色固体，产率61％。1H NMR(500MHz,CDCl3)δ6.80(s,1H),6.67(s,1H),6.65(s,2H),6.48(s,1H),4.25(dd,J＝11.7,5.6Hz,1H),3.89(s,3H),3.81(s,3H),3.75(s,6H),3.74(s,3H),3.30(dd,J＝16.0,5.6Hz,1H),3.25(s,3H),3.25(s,3H),2.93(dd,J＝15.7,11.9Hz,1H).13C NMR(126MHz,CDCl3)δ180.17,173.48,153.40,148.77,148.53,138.22,136.62,125.46,123.11,111.00,110.96,106.37,77.16,60.86,57.88,56.35,56.15,56.05,54.50,30.24,27.95.HRMS(ESI)m/z:481.1399,calcd for:C23H26N2NaO6S[M+Na]+481.1404.
实施例5
(5R,9aS)-8-甲基-7-硫氧基-5-(3,4,5-三甲氧基苯基)-7,8,9a,10-四氢-[1,3]二氧杂环[4,5-g]咪唑并[1,5-b]异喹啉-9(5H)-酮(化合物I5)的制备
制备方法同实施例1，将制备化合物4a使用的硫酸二甲酯替换为二碘甲烷(制得化合物4b)，将步骤二中异氰酸乙酯替换为异硫氰酸甲酯，其他条件均不变，得到化合物I5，亮黄色固体，产率52％。1H NMR(600MHz,CDCl3)δ6.73(s,1H),6.67(s,1H),6.64(s,2H),6.48(s,1H),5.96(dd,J＝15.4,1.1Hz,2H),4.28(dd,J＝11.8,5.5Hz,1H),3.82(s,3H),3.79(s,6H),3.29(dd,J＝16.0,5.5Hz,1H),3.26(s,3H),2.92(dd,J＝15.9,11.8Hz,1H).13C NMR(126MHz,CDCl3)δ180.28,173.41,153.50,147.59,147.38,138.37,136.52,126.97,124.22,108.31,106.50,101.58,60.94,58.39,56.46,54.63,30.70,29.84,28.00.HRMS(ESI)m/z:465.1090,calcd for:C22H22N2O6SNa[M+Na]+465.1091.
实施例6
(6R,10aS)-9-甲基-8-硫氧基-6-(3,4,5-三甲氧基苯基)-2,3,8,9,10a,11-六氢-[1,4]二氧基][2,3-g]咪唑并[1,5-b]异喹啉-10(6H)-酮(化合物I6)的制备
制备方法同实施例1，将制备化合物4a使用的硫酸二甲酯替换为1,2-二溴乙烷(制得化合物4c)，将步骤二中异氰酸乙酯替换为异硫氰酸甲酯，其他条件均不变，得到化合物I6，亮黄色固体，产率67％。1H NMR(500MHz,CDCl3)δ6.73(d,J＝2.4Hz,2H),6.62(s,2H),6.55(s,1H),4.31–4.27(m,1H),4.24(dd,J＝11.7,4.6Hz,4H),3.82(s,3H),3.79(s,6H),3.31–3.26(m,1H),3.26(s,3H),2.89(dd,J＝15.8,11.9Hz,1H).13C NMR(126MHz,CDCl3)δ180.37,173.52,153.43,143.34,143.14,138.27,136.80,126.79,123.84,117.04,116.86,106.49,64.56,64.47,60.94,58.10,56.45,54.93,30.16,28.00.ESI-MS m/z:457.1,calcdfor:C23H24N2O6S[M+H]+457.2.
实施例7
(5R,10aS)-2-乙基-7,8-二甲氧基-3-硫氧基-5-(3,4,5-三甲氧基苯基)-2,3,10,10a-四氢咪唑并[1,5-b]异喹啉-1(5H)-酮(化合物I7)的制备
制备方法同实施例1，仅将步骤二中异氰酸乙酯替换为异硫氰酸乙酯，其他条件均不变，得到化合物I7，亮黄色固体，产率57％。1H NMR(500MHz,CDCl3)δ6.81(s,1H),6.67(s,1H),6.65(s,2H),6.48(s,1H),4.23(dd,J＝11.7,5.6Hz,1H),3.92–3.85(m,5H),3.82(s,3H),3.76(s,6H),3.74(s,3H),3.30(dd,J＝16.0,5.7Hz,1H),2.93(dd,J＝15.8,11.9Hz,1H),1.22(t,J＝7.2Hz,3H).13C NMR(126MHz,CDCl3)δ179.69,173.36,153.40,148.78,148.52,138.19,136.70,125.53,123.14,111.02,111.00,106.39,77.16,60.88,57.75,56.36,56.17,56.07,54.39,36.71,30.31,13.14.HRMS(ESI)m/z:495.1557,calcd for:C24H28N2NaO6S[M+Na]+495.1560.
实施例8
(5R,9aS)-8-乙基-7-硫氧基-5-(3,4,5-三甲氧基苯基)-7,8,9a,10-四氢-[1,3]二氧杂环[4,5-g]咪唑并[1,5-b]异喹啉-9(5H)-酮(化合物I8)的制备
制备方法同实施例1，将制备化合物4a使用的硫酸二甲酯替换为二碘甲烷(制得化合物4b)，将步骤二中异氰酸乙酯替换为异硫氰酸乙酯，其他条件均不变，得到化合物I8，亮黄色固体，产率51％。1H NMR(500MHz,CDCl3)δ6.74(s,1H),6.67(s,1H),6.64(s,2H),6.48(s,1H),5.96(dd,J＝12.6,1.2Hz,2H),4.25(dd,J＝12.3,5.5Hz,1H),3.88(q,J＝7.2Hz,2H),3.83(s,3H),3.79(s,6H),3.28(dd,J＝15.6,5.5Hz,1H),2.90(dd,J＝15.5,12.3Hz,1H),1.23(t,J＝7.2Hz,3H).13C NMR(126MHz,CDCl3)δ179.77,173.28,153.48,147.56,147.34,138.31,136.59,127.02,124.22,108.32,108.30,106.52,101.56,60.94,58.25,56.45,54.50,36.77,30.75,13.18.HRMS(ESI)m/z:479.1246,calcd for:C23H24N2O6SNa[M+Na]+479.1247.
实施例9
(6R,10aS)-9-乙基-8-硫氧基-6-(3,4,5-三甲氧基苯基)-2,3,8,9,10a,11-六氢-[1,4]二氧杂环[2,3-g]咪唑并[1,5-b]异喹啉-10(6H)-酮(化合物I9)的制备
制备方法同实施例1，将制备化合物4a使用的硫酸二甲酯替换为1,2-二溴乙烷(制得化合物4c)，将步骤二中异氰酸乙酯替换为异硫氰酸乙酯，其他条件均不变，得到化合物I9，亮黄色固体，产率65％。1H NMR(600MHz,CDCl3)δ6.73(s,2H),6.62(s,2H),6.54(s,1H),4.28-4.23(m,5H),3.88(q,J＝7.2Hz,2H),3.82(s,3H),3.78(s,6H),3.28(dd,J＝16.0,5.5Hz,1H),2.87(dd,J＝16.0,11.9Hz,1H),1.22(t,J＝7.2Hz,3H).13C NMR(151MHz,CDCl3)δ179.79,173.37,153.36,143.27,143.07,138.08,136.85,126.80,123.81,117.01,116.82,106.39,64.54,64.45,60.94,57.93,56.40,54.78,36.74,30.19,13.20.ESI-MS m/z:471.2,calcd for:C24H26N2O6S[M+H]+471.2.
实施例10
(5R,9aS)-5-(3,4,5-三甲氧基苯基)-9a,10-二氢-[1,3]二氧杂[4,5-g]咪唑并[1,5-b]异喹啉-7,9(5H,8H)-二酮(化合物I10)的制备
将化合物4b(3.39g，10mmol)溶解于二氯甲烷(25ml)中，滴加三氟乙酸(25ml)，室温反应1小时，加入二氯甲烷稀释，用碳酸钾调节pH至10，二氯甲烷层经无水硫酸钠除水后，减压浓缩得到淡黄色固体(化合物7b)1.91g，产率90％。取化合物7b(446mg，2mmol)溶解于冰醋酸中，加入异氰酸钾810mg(5eq)，室温反应过夜，加入二氯甲烷稀释，碳酸钾调节pH至10，二氯甲烷萃取，减压浓缩，得到的油状物(化合物8b)溶解于5M盐酸中，60℃回流反应1小时，二氯甲烷稀释，用碳酸钾调节pH至中性，二氯甲烷萃取，硅胶柱层析(洗脱剂为EtAc:PE＝2:1V/V)得到无色粉末固体(化合物9b)251mg，产率53.6％。取化合物9b(30mg，0.126mmol)溶解于二氯甲烷中，加入3,4,5-三甲氧基苯甲醛(50mg)，加入浓硫酸(130μL)，室温反应4h，用碳酸氢钠调节pH至10，二氯甲烷萃取，除水，减压浓缩，硅胶柱层析(洗脱剂为EtAc:PE＝1:1V/V)，即得化合物I10，白色固体33.9mg，56.5％。1H NMR(600MHz,CDCl3)δ8.06(s,1H),6.69(s,1H),6.46(s,1H),6.45(s,2H),6.02(s,1H),5.97(d,J＝1.1Hz,1H),5.95(d,J＝1.1Hz,1H),4.20(dd,J＝11.5,5.2Hz,1H),3.83(s,3H),3.80(s,6H),3.22(dd,J＝15.9,5.2Hz,1H),2.94(dd,J＝15.8,11.5Hz,1H).13C NMR(151MHz,CDCl3)δ172.97,153.92,153.60,147.51,147.22,138.07,137.25,126.63,124.76,108.63,108.36,105.74,101.54,60.97,56.42,55.15,53.60,30.56.HRMS(ESI)m/z:435.1159,calcd for:C21H20N2O7Na[M+Na]+435.1163.
实施例11
(6R,10aS)-6-(3,4,5-三甲氧基苯基)-2,3,10a,11-四氢-[1,4]二氧杂环[2,3-g]咪唑并[1,5-b]异喹啉-8,10(6H,9H)-二酮(化合物I11)的制备
制备方法同实施例10，仅将化合物4b替换为化合物4c，其他条件均不变，得到化合物I11，白色固体，产率52％。1H NMR(500MHz,CDCl3)δ8.15(s,1H),6.79(s,1H),6.58(s,1H),6.49(s,2H),6.06(s,1H),4.34–4.27(m,4H),4.24(d,J＝5.1Hz,1H),3.87(s,3H),3.84(s,6H),3.26(dd,J＝15.5,5.1Hz,1H),2.96(dd,J＝15.5,11.8Hz,1H).13C NMR(126MHz,CDCl3)δ173.12,154.12,153.58,143.31,142.99,138.12,137.50,126.53,124.40,117.16,117.09,105.85,64.56,64.47,60.95,56.45,54.86,53.98,30.04.HRMS(ESI)m/z:449.1319,calcd for:C22H22N2O7Na[M+Na]+449.1319
实施例12
(7R,11aS)-7-(3,4,5-三甲氧基苯基)-3,4,7,11,11a,12-六氢-2H，9H-[1,4]二氧并[2,3-g]恶唑并[3,4-b]异喹啉-9-酮(化合物I12)的制备
将制备化合物4a使用的硫酸二甲酯替换为1,3-二溴丙烷(制得化合物4d，R1、R2相互连接与苯环共同形成二氧七环)；在四氢呋喃和甲醇1:1(40ml:40ml)的混合溶剂中，加入硼氢化钠(27.8g)及氯化锂(34g)，搅拌10min，加入化合物4d(5g，14.7mmol)，室温反应1h，过滤，滤液减压浓缩后加入乙酸乙酯溶解，减压浓缩得到无色透明油状物(化合物5d)，直接用于下一步。将化合物5d(2g，6.4mmol)溶解于四氢呋喃中，加入氯化亚砜(13ml)，室温反应2h，碳酸氢钠中和，二氯甲烷萃取三次，硅胶柱层析(洗脱剂为EtAc/PE＝1:1V/V)得到淡黄色固体(化合物6d)，910mg，产率60.2％。将化合物6d(30mg，0.126mmol)溶解于二氯甲烷中，加入3,4,5-三甲氧基苯甲醛(196mg，1mmol)，加入浓硫酸(130μL)，室温反应4h，碳酸氢钠调节pH为10，二氯甲烷萃取，减压浓缩，硅胶柱层析(洗脱剂为EtAc/PE＝1：2V/V)即得到白色固体即I12为20.9mg，40.5％。1HNMR(500MHz,CDCl3)δ6.82(s,1H),6.66(s,1H),6.45(s,2H),5.86(s,1H),4.48(t,J＝8.3Hz,1H),4.32–4.26(m,1H),4.27–4.20(m,1H),4.13–4.00(m,4H),3.83(s,3H),3.78(s,6H),2.93(dd,J＝15.5,4.5Hz,1H),2.85(dd,J＝15.5,10.9Hz,1H),2.19(dddd,J＝20.6,14.6,9.1,4.0Hz,2H).13C NMR(126MHz,CDCl3)δ156.75,153.40,150.66,150.28,138.01,137.75,128.75,127.49,121.61,121.57,106.08,70.86,68.54,60.96,56.42,56.26,48.51,33.82,31.99.HRMS(ESI)m/z:450.1523,calcd for:C23H25NNaO7[M+Na]+450.1523.
实施例13
(6R,10aS)-6-(7-甲氧基苯并[d][1,3]二氧基-5-基)-2,3,10a,11-四氢-[1,4]二氧基[2,3-g]咪唑并[1,5-b]异喹啉-8,10(6H,9H)-二酮(化合物I13)的制备
制备方法同实施例10，将制备化合物4b替换为化合物4c，将3,4,5-三甲氧基苯甲醛替换为7-甲氧基胡椒醛，其他条件均不变，得到化合物I13，深褐色固体，产率37％。1H NMR(500MHz,CDCl3)δ7.84(s,1H),6.73(s,1H),6.58(s,1H),6.51(s,1H),6.27(s,1H),5.99(s,1H),5.94(s,2H),4.24(dd,J＝10.6,3.3Hz,4H),4.24(dd,J＝11.7,5.2Hz,1H),3.89(s,3H),3.19(dd,J＝15.8,5.2Hz,1H),2.89(dd,J＝15.8,11.7Hz,1H).13C NMR(126MHz,CDCl3)δ172.97,153.84,149.19,143.76,143.34,142.99,136.54,135.18,126.57,124.37,117.15,117.06,108.90,102.45,101.75,64.55,64.48,56.97,54.53,53.81,29.97.HRMS(ESI)m/z:411.1187,calcd for:C21H19N2O7[M+H]+411.1187.
实施例14
(6R,10aS)-6-(3,4-双(二氟甲氧基)苯基)-2,3,6,10,10a,11-六氢-8H-[1,4]二氧杂环[2,3-g]恶唑[3,4-b]异喹啉-8-酮(化合物I14)的制备
制备方法同实施例12，将化合物4d替换成化合物4c，3,4,5-三甲氧基苯甲醛替换为3,4-双(二氟甲氧基)苯甲醛，其他条件均不变，得到化合物I14，白色固体，产率69％。1HNMR(500MHz,CDCl3)δ7.20(d,J＝8.9Hz,1H),7.16(d,J＝5.6Hz,2H),6.70(s,1H),6.51(t，J＝73.4Hz,2H),6.43(s,1H),5.89(s,1H),4.49(t,J＝8.4Hz,1H),4.28–4.19(m,4H),4.12(dd,J＝8.4,4.4Hz,1H),3.99(m,1H),2.92(dd,J＝15.4,4.4Hz,1H),2.85(dd,J＝15.4,11.3Hz,1H).13C NMR(126MHz,CDCl3)δ156.73,143.38,142.94,142.43,142.10,141.21,126.91,125.83,125.44,122.71,122.48,117.99,117.95,117.32,116.82,115.90,115.86,113.82,113.77,68.68,64.56,64.47,55.29,48.52,33.82.HRMS(ESI)m/z:478.0884,calcdfor:C21H17F4NNaO6[M+Na]+478.0884.
实施例15
(6R,10aS)-6-(3,5-双(三氟甲基)苯基)-2,3,6,10,10a,11-六氢-8H-[1,4]二氧杂氮[2,3-g]恶唑[3,4-b]异喹啉-8-酮(化合物I15)的制备
制备方法同实施例12，将化合物4d替换成化合物4c，3,4,5-三甲氧基苯甲醛替换为3,5-三氟甲基苯甲醛，其他条件均不变，得到化合物I15，白色固体，产率75％。1H NMR(500MHz,CDCl3)δ7.88(s,1H),7.78(s,2H),6.79(s,1H),6.42(s,1H),6.06(s,1H),4.57(t,J＝8.4Hz,1H),4.33–4.26(m,4H),4.21(dd,J＝8.8,4.2Hz,1H),4.05(m,1H),3.01(dd,J＝15.5,4.5Hz,1H),2.93(dd,J＝15.4,11.0Hz,1H).13C NMR(126MHz,CDCl3)δ156.84,144.78,143.65,143.16,132.34,132.08,128.72,128.70,125.55,124.94,122.33,117.61,116.66,68.70,64.55,64.47,55.51,48.77,33.71.HRMS(ESI)m/z:482.0797,calcd for:C21H15F6NNaO4[M+Na]+482.0797.
实施例16
(6R,10aS)-6-(4-氟-3-甲氧基苯基)-2,3,6,10,10a,11-六氢-8H-[1,4]二氧杂环[2,3-g]恶唑并[3,4-b]异喹啉-8-酮(化合物I16)的制备
制备方法同实施例12，将化合物4d替换成化合物4c，3,4,5-三甲氧基苯甲醛替换为3-甲氧基-4-氟苯甲醛，其他条件均不变，得到化合物I16，白色固体，产率69％。1H NMR(500MHz,CDCl3)δ7.03(dd,J＝8.2,1.9Hz,1H),6.96(dd,J＝11.1,8.3Hz,1H),6.68(s,1H),6.59(ddd,J＝8.2,4.2,2.1Hz,1H),6.46(s,1H),5.87(s,1H),4.45(t,J＝8.4Hz,1H),4.22(ddd,J＝6.5,3.7,1.7Hz,4H),4.09(dd,J＝8.4，3.7Hz,1H),3.99(m,1H),3.86(s,3H),2.90(dd,J＝13.3,4.7Hz,1H),2.84(dd,J＝13.3,8.6Hz,1H).13C NMR(151MHz,CDCl3)δ156.75,152.99,151.36,147.84,147.76,143.17,142.77,138.69,138.67,126.56,125.44,120.71,120.66,117.10,116.97,115.98,115.86,114.34,114.33,68.63,64.56,64.46,56.52,55.71,48.37,33.90.HRMS(ESI)m/z:394.1064,calcd for:C20H18FNNaO5[M+Na]+394.1061.
实施例17
(6R,10aS)-6-(3,5-二溴-4-甲氧基苯基)-2,3,6,10,10a,11-六氢-8H-[1,4]二氧杂环[2,3-g]恶唑[3,4-b]异喹啉-8-酮(化合物I17)的制备
制备方法同实施例12，将化合物4d替换成化合物4c，3,4,5-三甲氧基苯甲醛替换为4-甲氧基-3,5-二溴苯甲醛，其他条件均不变，得到化合物I17，白色固体，产率64％。1HNMR(600MHz,CDCl3)δ7.40(s,2H),6.70(s,1H),6.42(s,1H),5.80(s,1H),4.50(t,J＝8.4Hz,1H),4.29–4.22(m,4H),4.12(dd,J＝8.4,4.2Hz,1H),4.04–3.99(m,1H),3.88(s,3H),2.91(dd,J＝15.3,4.4Hz,1H),2.84(dd,J＝15.3,11.1Hz,1H).13C NMR(151MHz,CDCl3)δ156.70,154.00,143.43,142.97,140.82,132.71,125.62,125.40,118.53,117.33,116.82,68.63,64.54,64.46,60.75,54.85,48.52,33.72.HRMS(ESI)m/z:531.9365,calcdfor:C20H17Br2NNaO5[M+Na]+531.9366.
实施例18
(7R,11aS)-7-(7-甲氧基苯并[d][1,3]二氧基-5-基)-3,4,7,11,11a,12-六氢-2H，9H-[1,4]二氧基[2,3-g]恶唑并[3,4-b]异喹啉-9-酮(化合物I18)的制备
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制备方法同实施例12，将3,4,5-三甲氧基苯甲醛替换为7-甲氧基胡椒醛，其他条件均不变，得到化合物I18，深褐色固体，产率32％。1H NMR(500MHz,CDCl3)δ6.79(s,1H),6.63(s,1H),6.61(s,1H),6.25(s,1H),5.94(s,2H),5.82(s,1H),4.47(t,J＝8.1Hz,1H),4.27–4.24(m,1H),4.20(s,1H),4.09(t,J＝22.6Hz,4H),3.88(s,3H),2.93–2.79(m,2H),2.31–2.15(m,2H).13C NMR(126MHz,CDCl3)δ156.67,150.62,150.26,148.97,143.67,136.76,135.05,128.82,127.36,121.52,121.46,108.96,102.60,101.69,70.78,70.75,68.58,56.89,56.03,48.39,33.80,31.93.HRMS(ESI)m/z:412.1388,calcd for:C22H22NO7[M+H]+412.1391.
实施例19
(6R,10aS)-6-(3,5-二溴-4-氰基苯基)-2,3,6,10,10a,11-六氢-8H-[1,4]二氧杂环[2,3-g]恶唑[3,4-b]异喹啉-8-酮(化合物I19)的制备
制备方法同实施例12，将化合物4d替换成化合物4c，3,4,5-三甲氧基苯甲醛替换为3,5-二溴-4-氰基苯甲醛，其他条件均不变，得到化合物I19，浅黄色固体，产率43％。1HNMR(500MHz,CDCl3)δ6.99(d,J＝8.4Hz,2H),6.71(s,1H),6.37(s,1H),5.86(s,1H),4.51(t,J＝8.2Hz,1H),4.24(d,J＝9.4Hz,4H),4.14(dd,J＝7.9,3.8Hz,1H),3.96(d,J＝2.7Hz,1H),2.98–2.89(m,1H),2.87–2.78(m,1H).13C NMR(126MHz,CDCl3)δ164.34,162.22,156.71,143.84,143.15,125.46,123.87,117.66,116.50,112.51,112.35,109.04,68.79,64.51,64.43,55.23,48.64,33.55.ESI-MS m/z:507.2,calcd for:C20H15Br2N2O4[M+H]+507.3.
实施例20
(6R,10aS)-6-(4-溴-3,5-二甲氧基苯基)-2,3,6,10,10a,11-六氢-8H-[1,4]二氧杂环[2,3-g]恶唑[3,4-b]异喹啉-8-酮(化合物I20)的制备
制备方法同实施例12，将化合物4d替换成化合物4c，3,4,5-三甲氧基苯甲醛替换为4-溴-3,5-二甲氧基苯醛，其他条件均不变，得到化合物I20，棕黄色固体，产率52.4％。1HNMR(500MHz,CDCl3)δ6.70(s,1H),6.50(s,1H),6.47(s,2H),5.87(s,1H),4.49(s,1H),4.24(d,J＝11.9Hz,4H),4.11(dd,J＝8.2,4.0Hz,1H),4.02(dd,J＝6.5,3.1Hz,1H),3.82(s,6H),2.94–2.81(m,2H).13C NMR(126MHz,CDCl3)δ157.31,156.78,143.26,142.97,142.86,126.23,125.48,117.16,116.98,105.37,100.85,77.16,68.53,64.59,64.45,56.73,56.23,48.67,33.89.ESI-MS m/z:463.3,calcd for:C21H21BrNO6[M+H]+463.3
实施例21
(6R,10aS)-6-(3-氯-4,5-二甲氧基苯基)-2,3,10a,11-四氢-[1,4]二氧杂环[2,3-g]咪唑并[1,5-b]异喹啉-8,10(6H,9H)-二酮(化合物I21)的制备
制备方法同实施例10，仅将化合物4b替换为化合物4c，3,4,5-三甲氧基苯甲醛替换为5-氯-3,4-二甲氧基苯甲醛，其他条件均不变，得到化合物I21，色固体，产率61％。1HNMR(500MHz,CDCl3)δ8.13(s,1H),6.90(d,J＝1.7Hz,1H),6.75(s,1H),6.65(d,J＝1.8Hz,1H),6.49(s,1H),6.00(s,1H),4.27–4.23(m,4H),4.18(dd,J＝11.6,5.2Hz,1H),3.86(s,3H),3.85(s,3H),3.21(dd,J＝15.8,5.2Hz,1H),2.90(dd,J＝15.6,11.6Hz,1H).13C NMR(126MHz,CDCl3)δ172.95,154.19,154.16,145.44,143.50,143.08,138.37,128.64,125.86,124.42,121.38,117.31,116.99,111.80,64.55,64.49,60.81,56.44,54.19,53.83,29.94.HRMS(ESI)m/z:453.0824,calcd for:C21H19ClN2NaO6[M+Na]+453.0824.
实施例22
(6R,10aS)-6-(3,5-二氯-4-氟苯基)-2,3,10a,11-四氢-[1,4]二氧杂环[2,3-g]咪唑并[1,5-b]异喹啉-8,10(6H,9H)-二酮(化合物I22)的制备
制备方法同实施例10，仅将化合物4b替换为化合物4c，3,4,5-三甲氧基苯甲醛替换为3,5-二氯-4-氟苯甲醛，其他条件均不变，得到化合物I22，白色固体，产率73％。1H NMR(500MHz,CDCl3)δ8.01(s,1H),7.22(s,1H),7.21(s,1H),6.77(s,1H),6.42(s,1H),6.00(s,1H),4.26(d,J＝9.7Hz,4H),4.16(dd,J＝11.6,5.1Hz,1H),3.21(dd,J＝15.8,5.1Hz,1H),2.90(dd,J＝15.6,11.6Hz,1H).13C NMR(126MHz,CDCl3)δ172.39,154.93,154.02,152.92,143.62,143.13,139.01,138.97,128.80,124.88,124.30,122.88,122.74,117.40,116.68,77.01,64.40,64.34,53.75,53.32,31.58,29.75,22.65,14.11.HRMS(ESI)m/z:445.0132,calcd for:C19H13Cl2FN2NaO4[M+Na]+445.0129.
实施例23
(6R,10aS)-6-(3-氟-4,5-二甲氧基苯基)-2,3,6,10,10a,11-六氢-8H-[1,4]二氧杂环[2,3-g]恶唑[3,4-b]异喹啉-8-酮(化合物I23)的制备
制备方法同实施例10，仅将化合物4b替换为化合物4c，3,4,5-三甲氧基苯甲醛替换为5-氟-3,4-二甲氧基苯甲醛，其他条件均不变，得到化合物I23，白色固体，产率62％。1HNMR(500MHz,CDCl3)δ8.12(s,1H),6.78(s,1H),6.75(s,1H),6.50(s,1H),6.42(dd,J＝11.0,1.4Hz,1H),6.02(s,1H),4.28–4.22(m,4H),4.17(dd,J＝11.5,5.2Hz,1H),3.90(s,3H),3.86(s,3H),3.20(dd,J＝15.8,5.2Hz,1H),2.90(dd,J＝15.6,11.5Hz,1H).13C NMR(126MHz,CDCl3)δ172.93,156.92,154.96,154.12,154.02,153.98,143.49,143.05,137.32,137.26,137.14,137.03,125.92,124.44,117.29,117.00,109.00,108.83,108.51,108.50,77.16,64.56,64.49,61.58,61.55,56.61,54.20,54.19,53.80,29.92.HRMS(ESI)m/z:437.1120,calcd for:C21H19FN2NaO6[M+Na]+437.1119.
实施例24
(6R,10aS)-6-(3,5-二溴-4-甲氧基苯基)-2,3,10a,11-四氢-[1,4]二氧杂环[2,3-g]咪唑并[1,5-b]异喹啉-8,10(6H,9H)-二酮(化合物I24)的制备
制备方法同实施例10，将化合物4b替换为4c，3,4,5-三甲氧基苯甲醛替换为4-甲氧基-3,5-二溴苯甲醛，其他条件均不变，得到化合物I24，白色固体，产率59％。1H NMR(600MHz,CDCl3)δ8.09(s,1H),7.39(s,2H),6.76(s,1H),6.43(s,1H),5.97(s,1H),4.28–4.22(m,4H),4.18(dd,J＝11.6,5.1Hz,1H),3.87(s,3H),3.21(dd,J＝15.8,5.1Hz,1H),2.89(dd,J＝15.8,11.6Hz,1H).13C NMR(151MHz,CDCl3)δ172.77,154.17,154.16,143.62,143.18,140.40,132.56,125.36,124.38,118.75,117.45,116.88,77.16,64.52,64.47,60.76,53.90,53.30,29.91.HRMS(ESI)m/z:546.9297,calcd for:C20H16Br2N2NaO5[M+Na]+546.9299.
实施例25
(6R,10aS)-6-(3-溴-4,5-二甲氧基苯基)-2,3,6,10,10a,11-六氢-8H-[1,4]二氧基[2,3-g]恶唑并[3,4-b]异喹啉-8-酮(化合物I25)的制备
制备方法同实施例12，将化合物4d替换成化合物4c，3,4,5-三甲氧基苯甲醛替换为3,4-二甲氧基-5-溴苯甲醛，其他条件均不变，得到化合物I19，白色固体，产率51％。1HNMR(500MHz,CDCl3)δ7.00(s,1H),6.77(s,1H),6.69(s,1H),6.48(s,1H),5.83(s,1H),4.48(t,J＝8.3Hz,1H),4.25(d,J＝10.0Hz,4H),4.10(dd,J＝8.6,4.3Hz,1H),4.05–3.98(m,1H),2.92(dd,J＝15.1,4.4Hz,1H),2.84(dd,J＝15.1,11.2Hz,1H).13C NMR(126MHz,CDCl3)δ156.74,153.88,146.31,143.32,142.87,139.40,126.14,125.43,124.15,117.78,117.18,116.94,112.93,68.65,64.57,64.48,60.68,56.40,55.63,48.43,33.86.HRMS(ESI)m/z:484.0367,calcd for:
C21H20BrNNaO6[M+Na]+484.0366.
实施例26
(6R,10aS)-6-(3,5-二氯-4-甲氧基苯基)-2,3,6,10,10a,11-六氢-8H-[1,4]二氧杂环[2,3-g]恶唑[3,4-b]异喹啉-8-酮(化合物I26)的制备
制备方法同实施例12，将化合物4d替换成化合物4c，3,4,5-三甲氧基苯甲醛替换为4-甲氧基-3,5-二氯苯甲醛，其他条件均不变，得到化合物I26，白色固体，产率55％。1HNMR(500MHz,CDCl3)δ7.20(s,2H),6.70(s,1H),6.43(s,1H),5.80(s,1H),4.50(t,J＝8.4Hz,1H),4.25(dd,J＝11.6,3.5Hz,4H),4.12(dd,J＝8.7,4.3Hz,1H),4.01(ddd,J＝12.4,8.6,4.3Hz,1H),3.89(s,3H),2.91(dd,J＝15.3,4.5Hz,1H),2.84(dd,J＝15.3,11.0Hz,1H).13C NMR(126MHz,CDCl3)δ156.71,152.21,143.48,143.00,139.70,129.69,129.01,125.65,125.43,117.35,116.85,68.65,64.57,64.49,60.84,55.08,48.56,33.76,0.13.ESI-MS m/z:444.0376calcd for:C20H17Cl2NNaO5[M+Na]+444.0376.
实施例27
(6R,10aS)-6-(3-硝基-4,5-二甲氧基苯基)-2,3,6,10,10a,11-六氢-8H-[1,4]二氧杂环[2,3-g]恶唑[3,4-b]异喹啉-8-酮(化合物I27)的制备
制备方法同实施例10，仅将化合物4b替换为化合物4c，3,4,5-三甲氧基苯甲醛替换为3-硝基-4,5-二甲氧基苯甲醛，其他条件均不变，得到化合物I27，黄色固体，产率71％。1HNMR(600MHz,CDCl3)δ8.02(s,1H),7.25(d,J＝1.9Hz,1H),6.95(s,1H),6.77(s,1H),6.46(s,1H),6.07(s,1H),4.32–4.23(m,4H),4.24–4.20(m,1H),4.17(dd,J＝11.6,5.1Hz,1H),3.96(d,J＝7.9Hz,3H),3.95–3.89(m,3H),3.22(dd,J＝15.8,5.1Hz,1H),2.91(dd,J＝15.7,11.7Hz,1H).13C NMR(126MHz,CDCl3)δ173.00,154.68,154.53,145.01,143.73,143.20,142.73,138.08,125.00,124.55,117.54,116.83,116.69,115.13,77.16,64.53,64.47,62.11,56.78,53.96,53.84,29.86.ESI-MS m/z:442.4,calcd for:C21H20N3O8[M+H]+442.4.
实施例28
(6R,10aS)-6-(3,5-二氯-4-甲氧基苯基)-2,3,10a，11-四氢-[1,4]二氧杂环[2,3-g]咪唑并[1,5-b]异喹啉-8,10(6H,9H)-二酮(化合物I28)的制备
制备方法同实施例10，仅将化合物4b替换为化合物4c，3,4,5-三甲氧基苯甲醛替换为3,5-二氯-4-甲氧基苯甲醛，其他条件均不变，得到化合物I27，白色到浅黄色固体，51％。1HNMR(500MHz,CDCl3)δ7.19(s,2H),6.76(s,1H),6.44(s,1H),5.98(s,1H),4.26(d,J＝9.9Hz,4H),4.18(dd,J＝11.7,5.1Hz,1H),3.89(s,3H),3.21(dd,J＝15.8,5.1Hz,1H),2.90(dd,J＝15.6,11.7Hz,1H).13C NMR(126MHz,CDCl3)δ172.62,154.07,152.19,143.50,143.05,139.14,129.77,128.70,125.22,124.28,117.32,116.74,64.40,64.35,60.71,53.76,53.37,29.77.HRMS(ESI)m/z:457.0327,calcd for:C20H16Cl2N2NaO5[M+Na]+457.0328.
实施例29
(6R,10aS)-6-(3-氟-4,5-二甲氧基苯基)-2,3,6,10,10a，11-六氢-8H-[1,4]二氧杂环[2,3-g]恶唑[3,4-b]异喹啉-8-酮(化合物I29)的制备
制备方法同实施例12，将化合物4d替换成环合物4c，3,4,5-三甲氧基苯甲醛替换为5-氟-3,4-二甲氧基苯甲醛，其他条件均不变，得到化合物I29，白色固体，产率64％。1HNMR(600MHz,CDCl3)δ6.84(s,1H),6.69(s,1H),6.48(s,1H),6.38(dd,J＝11.1,1.8Hz,1H),5.84(s,1H),4.48(t,J＝8.7Hz,1H),4.25(td,J＝6.5,3.8Hz,4H),4.11(dd,J＝8.7,4.5Hz,1H),4.01(m,1H),3.91(s,3H),3.87(s,3H),2.91(dd,J＝15.5,4.5Hz,1H),2.84(dd,J＝15.5,11.0Hz,1H).13CNMR(151MHz,CDCl3)δ156.74,156.62,154.99,153.83,153.80,143.26,142.80,137.77,137.72,136.89,136.80,126.16,125.43,117.14,116.94,108.97,108.83,108.71,108.70,77.16,68.65,64.56,64.47,61.60,61.57,56.56,55.67,48.39,33.84.HRMS(ESI)m/z:424.1169,calcd for:C21H20FNNaO6[M+Na]+424.1169.
实施例30
一、对肿瘤细胞的抗增殖实验
测试本发明化合物对肿瘤细胞：乳腺癌细胞MCF-7、结肠癌细胞HT29、结肠癌细胞HCT116、非小细胞肺癌细胞A549、三阴性乳腺癌细胞MDA-MB-231、白血病细胞K562的抗增殖活性。
方法：细胞消化、计数、制成浓度为5×104个/mL的细胞悬液，96孔板中每孔加入100μL细胞悬液(每孔3-5×103个细胞)。96孔板置于37℃、5％CO2培养箱中培养24小时。用完全培养基(RPMI1640培养基+10％胎牛血清+1％双抗)稀释药物至所需浓度，每孔加入100μL相应的含药培养基。96孔板置于37℃、5％CO2培养箱中培养48小时。每孔加入20μL MTT(5mg/mL)，在培养箱继续培养4小时。弃去培养基，每孔加入150μL DMSO溶解，摇床10分钟轻轻混匀。λ＝570nm，酶标仪读出每孔的OD值。测试结果用Graphpad Prism 6分析。化合物的测试结果见表1。
结果表明，大部分代表性化合物对这几株癌细胞都有增殖抑制活性，特别是化合物I17、I21、I24、I25、I26和I28，对上述癌细胞具有显著的增殖抑制活性，其活性比阳性对照药紫杉醇和CA-4好，而且与母体化合物鬼臼毒素相比，活性提高了近10倍。
表1.代表性化合物抗细胞增殖活性
二、对正常细胞的毒性实验
测试本发明化合物对正常细胞293T(人源胚胎肾细胞)的毒性。
方法：细胞消化、计数、制成浓度为5×104个/mL的细胞悬液，96孔板中每孔加入100μL细胞悬液(每孔3～5×103个细胞)。96孔板置于37℃、5％CO2培养箱中培养24小时。用完全培养基(RPMI1640培养基+10％胎牛血清+1％双抗)稀释药物至所需浓度，每孔加入100μL相应的含药培养基。96孔板置于37℃、5％CO2培养箱中培养48小时。每孔加入20μL MTT(5mg/mL)，在培养箱继续培养4小时。弃去培养基，每孔加入150μL DMSO溶解，摇床10分钟轻轻混匀。λ＝570nm，酶标仪读出每孔的OD值。测试结果用Graphpad Prism 6分析。化合物的测试结果见表2。
结果表明，鬼臼毒素、CA-4和紫杉醇对正常细胞293T(人源胚胎肾细胞)的毒性比较大，而本发明绝大多数化合物对正常细胞293T(人源胚胎肾细胞)几乎没有明显的毒性。
表2.代表性化合物对正常细胞的毒性
三、对微管蛋白的聚合抑制实验
测试化合物I24、I28对微管蛋白的聚合抑制活性。
方法：将化合物分别设置为5个浓度不等的梯度，每个浓度生物学重复3次。将2mg/mL微管蛋白(细胞骨架)重新悬浮于PEM缓冲液[80mM PIPES(pH6.9),0.5mM EGTA,2mMMgCl2]和15％甘油中，然后在冰上与化合物或溶剂DMSO预孵育5分钟。在检测微管蛋白聚合反应之前，加入含有GTP(三磷酸鸟苷)的PEG至终浓度为3mg/mL。通过多功能荧光酶标仪，激发光波长为360，每分钟检测一次，在450nm波长处持续检测荧光60分钟。设置空白对照组(0.1％DMSO+PEM)，Graphpad Prism 6分析测试结果。测试结果见表3及图1。
结果表明，本发明中的化合物I24和I28能很好的抑制微管蛋白的集合，其抑制活性与阳性对照药CA-4相当，进一步说明化合物I24和I28的作用靶点为微管蛋白秋水仙碱位点。
表3.化合物的微管蛋白聚合抑制
四、化合物I24和I28对乳腺癌MCF-7细胞裸鼠移植瘤的生长抑制活性
雌性Balb/c裸鼠(南京集萃药康实验动物有限责任公司)，周龄为五周，体重18-20g，64只。收集培养的乳腺癌MCF-7细胞，计数、调整使细胞悬液浓度为1×107个/ml，于裸鼠右侧腋窝皮下每只接种0.2ml。用游标卡尺测量裸鼠移植瘤的直径，接种肿瘤细胞10天后，肿瘤长至100mm3左右时，按照图2将裸鼠随机分为8组，每组8只。将紫杉醇、化合物I24、化合物I28分别溶于88％生理盐水、10％DMF和2％吐温80的混合溶剂中，空白对照组(Control)腹腔注射等量溶媒，每两天腹腔注射1次，持续21天；阳性对照组(PTX)腹腔注射10mg/kg紫杉醇，每两天注射1次，持续21天；实验组腹腔注射5mg/kg，10mg/kg，20mg/kg化合物I24和I28。每两天注射1次，持续21天；给药21天结束后处死裸鼠，通过手术剥取瘤块，称重。计算肿瘤生长抑制率(％)，用Graphpad Prism 6对结果进行分析，组间用t检验进行统计学分析处理。
实验结果如图2所示，表明，化合物I24和I28能很好的抑制裸鼠体内肿瘤的生长，使肿瘤体积显著减少，在5mg/kg、10mg/kg和20mg/kg给药剂量下，化合物I24的抑瘤率分别为20.79％、73.21％、78.91％；化合物I2的抑瘤率分别为41.04％、70.15％、85.12％。
五、化合物I24和I28对非小细胞肺癌A549细胞裸鼠移植瘤的生长抑制活性
Balb/c裸鼠(南京集萃药康实验动物有限责任公司)，周龄为五周，体重为18-20g，共40只，雌雄各半。收集培养的非小细胞肺癌A549细胞，计数、调整使细胞悬液浓度为5×107个/ml，于裸鼠右侧腋窝皮下每只接种0.2ml。用游标卡尺测量裸鼠移植瘤的直径，接种肿瘤细胞10天后，肿瘤长至100mm3左右时，按照图3将裸鼠随机分为5组，每组8只。将紫杉醇、CA-4、化合物I24及化合物I28分别溶于88％生理盐水、10％DMF和2％吐温80的混合溶剂中，空白对照组(Control)腹腔注射等量溶媒，每两天腹腔注射1次，持续21天；阳性对照组(PTX)腹腔注射10mg/kg紫杉醇，每两天注射1次，持续21天；实验组分别腹腔注射20mg/kgCA-4、化合物I24和I28。每两天注射1次，持续21天；给药21天结束后处死裸鼠，通过手术剥取瘤块，称重。计算肿瘤生长抑制率(％)，用Graphpad Prism 6对结果进行分析，组间用t检验进行统计学分析处理。
实验结果如图3所示，表明，化合物I24及I28能很好的抑制裸鼠体内肿瘤的生长，使肿瘤体积显著减少，在20mg/kg给药剂量下，化合物I24的抑瘤率为27.93％；化合物I28的抑瘤率为61.03％。
Claims (8)
1.结构如式I所示的鬼臼毒素衍生物或药学上可接受的盐：
其中，X代表亚甲基或羰基；Y代表氧或氮；Z代表氧；
R1、R2互相连接与苯环共同形成二氧五环或二氧六环；
R3选自甲氧基、氟、氯、溴、硝基，R4选自甲氧基、氟、溴，R5选自甲氧基、氟、氯、溴，但R3、R4、R5不能同时为甲氧基，或者R3、R5不能同时为氟；
Y代表氮时，R6选自氢；Y代表氧，R6代表共价键。
2.结构如式Ia所示的鬼臼毒素衍生物或药学上可接受的盐：
X代表亚甲基或羰基；Y代表氧或氮；Z代表氧；
R1、R2互相连接与苯环共同形成二氧六环；
R3选自甲氧基、氟、氯、溴，R4选自甲氧基，R5选自甲氧基、氯、溴，但R3、R4、R5不能同时为甲氧基；
Y代表氮时，R6选自氢；Y代表氧，R6代表共价键。
3.鬼臼毒素衍生物或药学上可接受的盐，其特征在于：鬼臼毒素衍生物选自如下化合物：
4.权利要求1所述的鬼臼毒素衍生物的制备方法，其特征在于：当X代表亚甲基，Y代表氧，Z代表氧时，合成路线如下：
当X代表羰基，Y代表氮，Z代表氧时，合成路线如下：
当X代表羰基，Y代表氮，Z代表氧时，合成路线如下：
5.权利要求1-3任一项所述的鬼臼毒素衍生物或药学上可接受的盐在制备微管蛋白抑制剂的用途。
6.权利要求1-3任一项所述的鬼臼毒素衍生物或药学上可接受的盐在制备抗肿瘤药物的用途。
7.根据权利要求6所述的用途，其特征在于：所述的肿瘤为乳腺癌、非小细胞肺癌、结肠癌、前列腺癌、胃癌、肝癌、白血病。
8.一种药物组合物，其特征在于：它是以权利要求1-3任一项所述的鬼臼毒素衍生物或药学上可接受的盐为有效成分或主要有效成分，与可药用的载体、稀释剂或赋形剂制成的。
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