CN111171041A - 20位取代的喜树碱衍生物及其制备方法和应用 - Google Patents
20位取代的喜树碱衍生物及其制备方法和应用 Download PDFInfo
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- CN111171041A CN111171041A CN201811340402.0A CN201811340402A CN111171041A CN 111171041 A CN111171041 A CN 111171041A CN 201811340402 A CN201811340402 A CN 201811340402A CN 111171041 A CN111171041 A CN 111171041A
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- C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
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- A—HUMAN NECESSITIES
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Abstract
本发明提供一种20位取代的喜树碱衍生物，具有式(I)所示结构的化合物、其异构体、其药学上可接受的盐、其制备方法以及包含所述化合物的药物组合物。本发明所述化合物及其药物组合物在制备预防和/或治疗癌症的药物中的应用。本发明所述化合物具有极好的体外细胞毒活性和优秀的体内抗肿瘤效果，所述化合物的制备方法简单、原料易得。因此，本发明化合物具有广泛的药用前景。
Description
技术领域
本发明属于医药技术领域，具体涉及一类新型的喜树碱衍生物及其制备方法和应用。
背景技术
喜树碱衍生物被誉为20世纪90年代抗癌药物的三大发现之一，显示了广谱的抗肿瘤活性和巨大的研究与应用价值。早期的喜树碱类化合物其作用机制是与Top I和DNA形成三元复合物，阻断DNA的复制和转录，具有选择性低和毒副作用大等缺点。随着科技的发展，分子靶向性的抗肿瘤药物已经成为了近年来的研究热点，这类药物能够选择性的作用于与肿瘤细胞分化增殖相关的信号转导通路，本发明以10,11-亚甲二氧基喜树碱为起始化合物，对其进行结构改造来开发更加高效低毒的抗肿瘤候选化合物。
发明内容
本发明提供了一种喜树碱衍生物及其制备方法及在抗肿瘤上的应用，可以解决现有技术存在的选择性低和毒副作用大等缺点，可用于制备预防或治疗肿瘤的药物。
为解决上述技术问题，本发明一方面提供一种具有式(I)所示结构的化合物、其异构体和药学上可接受的盐：
式中X为-(CH2)n-、-(CH2)nO-、-(CH2)nNH-、-(CH2)nCONH-、-(CH2)nNHCO(CH2)m-、(CH2)n-(CH＝CH)p-(CH2)m-、-(CH2)n-(CH＝CH)p-(CH2)mO-、-O(CH2)nSS(CH2)mO-或-O(CH2)nSS(CH2)mOCOY-；
Y为-(CH2)n-或-(CH2)nCONH-；
n和m各自独立地为0或者正整数，优选地，n和m各自独立地为正整数，更为优选地，n和m各自独立地为1、2、3、4、5、6、7、8、9或10；
p为正整数，优选地，p为1或2；
R选自于氢原子、取代或未取代的磺酰胺基、取代或未取代的碱基、取代或未取代的饱和含氮杂环和取代或未取代的烷基中的任意一种；优选地，所述R为取代或未取代的磺酰胺基、取代或未取代的碱基、取代或未取代的饱和含氮杂环和取代或未取代的烷基中的任意一种。
当所述基团为取代的基团时，该取代基选自于氢原子、卤原子、羟基、硝基、氨基、烷基、取代的烷基、烷氧基、取代的烷氧基、芳基、取代的芳基、杂芳基和取代的杂芳基中的任意一种。
在一个较佳的实施例中，式(I)中X为-(CH2)nNH-，n为1，R为氢或烷基，优选地，式(I)化合物为化合物2或化合物3。
在一个较佳的实施例中，式(I)中X为-(CH2)nNH-，n为1，R为取代或未取代的磺酰胺基，并且R具有式(II)所示结构：
其中，
R1为烷基、芳基、取代的芳基、杂芳基或取代的杂芳基；优选地R1为C1-C4烷基，更优选地R1为甲基、乙基、正丙基或正丁基；同样优选地R1可以为苯基、取代的苯基、萘基、噻吩或吡啶，更优选地R1为对位氟取代、氯取代、硝基取代、甲基取代或者甲氧基取代的苯基；
R2为苯基或取代的苯基，优选地为对位氟取代或者甲氧基取代的苯基；
特别优选地，式(I)化合物为w-1、w-2、w-3、w-4、w-5、w-6、w-7、w-8、w-9、w-10、w-11、w-12、w-13、w-14、w-15、w-16、w-17、w-18、w-19、w-20、w-21、w-22、w-23或w-24。
这类化合物的制备方法包含以下步骤：
1)以胡椒醛为起始原料，经过浓硝酸硝化、氢气钯碳还原两步反应得到了6-氨基-3,4-亚甲二氧基苯甲醛，再和5′(S)-1,5-二氧代-(5′-乙基-5′-羟基-2′H,5′H,6′H-6-氧代吡喃)-[3′,4′,f]-Δ6(8)-四氢中氮茚在对甲苯磺酸的催化下，发生弗里德兰德缩合反应，所得反应物通过硅胶柱层析进行纯化得到10,11-亚甲二氧基喜树碱；
2)10,11-亚甲二氧基喜树碱在缩合剂催化下和Boc保护的甘氨酸发生酰化反应，得到的产物在三氟乙酸条件下脱掉Boc保护基，得到20位甘氨酸修饰的10,11-亚甲二氧基喜树碱；
3)该20位甘氨酸修饰的10,11-亚甲二氧基喜树碱在碘化亚铜催化下和含不同取代基的苯磺酰基叠氮、炔基一锅法反应得到所述化合物。
在另一个较佳的实施例中，式(I)中X为-(CH2)nNHCO(CH2)m-，n和m均为1，R为取代或未取代的尿嘧啶，并且R具有式(III)所示结构：
其中，R3为H、F或Cl。
特别优选地，式(I)化合物为w-25、w-26或w-27。
在另一优选例中，所述的R、X、Y、R1、R2、R3为实施例中各具体化合物中相应基团。
这类化合物的制备方法包含以下步骤：
1)以胡椒醛为起始原料，经过浓硝酸硝化、氢气钯碳还原两步反应得到了6-氨基-3,4-亚甲二氧基苯甲醛，再和5′(S)-1,5-二氧代-(5′-乙基-5′-羟基-2′H,5′H,6′H-6-氧代吡喃)-[3′,4′,f]-Δ6(8)-四氢中氮茚在对甲苯磺酸的催化下，发生弗里德兰德缩合反应，所得反应物通过硅胶柱层析进行纯化得到10,11-亚甲二氧基喜树碱；
2)10,11-亚甲二氧基喜树碱在缩合剂催化下和Boc保护的甘氨酸发生酰化反应，得到的产物在三氟乙酸条件下脱掉Boc保护基，得到20位甘氨酸修饰的10,11-亚甲二氧基喜树碱；
3)上述得到20位甘氨酸修饰的10,11-亚甲二氧基喜树碱，与不同取代基修饰的尿嘧啶乙酸在缩合剂的催化下发生酰化反应，得到所述化合物。
在另一个较佳的实施例中，式(I)中X为-(CH2)nNHCO(CH2)m-，n为1，m为0，R为取代或未取代的饱和含氮杂环；优选地，式(I)化合物为w-28、w-29、w-30、w-31、w-32或w-33。
这类化合物的制备方法包含以下步骤：
1)以胡椒醛为起始原料，经过浓硝酸硝化、氢气钯碳还原两步反应得到了6-氨基-3,4-亚甲二氧基苯甲醛，再和5′(S)-1,5-二氧代-(5′-乙基-5′-羟基-2′H,5′H,6′H-6-氧代吡喃)-[3′,4′,f]-Δ6(8)-四氢中氮茚在对甲苯磺酸的催化下，发生弗里德兰德缩合反应，所得反应物通过硅胶柱层析进行纯化得到10,11-亚甲二氧基喜树碱；
2)10,11-亚甲二氧基喜树碱在缩合剂催化下和Boc保护的甘氨酸发生酰化反应，得到的产物在三氟乙酸条件下脱掉Boc保护基，得到20位甘氨酸修饰的10,11-亚甲二氧基喜树碱；
3)以上述得到20位甘氨酸修饰的10,11-亚甲二氧基喜树碱，在三乙胺催化下和羰基二咪唑、杂环胺发生酰化反应，得到所述化合物。
在另一个较佳的实施例中，式(I)中X为-(CH2)n-或-(CH2)nCONH-，n为2，R为取代或未取代的烷基；优选地，式(I)化合物为z-1-9或z-2-5。
这类化合物的制备方法包含以下步骤：
1)以胡椒醛为起始原料，经过浓硝酸硝化、氢气钯碳还原两步反应得到了6-氨基-3,4-亚甲二氧基苯甲醛，再和5′(S)-1,5-二氧代-(5′-乙基-5′-羟基-2′H,5′H,6′H-6-氧代吡喃)-[3′,4′,f]-Δ6(8)-四氢中氮茚在对甲苯磺酸的催化下，发生弗里德兰德缩合反应，所得反应物通过硅胶柱层析进行纯化得到10,11-亚甲二氧基喜树碱；
2)以上述得到10,11-亚甲二氧基喜树碱，在缩合剂催化下和羟基被TBDMS保护的2S-(4′-丁酸酰胺)-3R-十九烷醇发生酰化反应，得到的产物在三氟乙酸条件下脱掉TBDMS保护基，得到化合物z-1-9；10,11-亚甲二氧基喜树碱在缩合剂的催化下和(4E,8E,12E,16E)-4,8,12,16,2021-五甲基-4,8,12,16,20-五烯-二十二碳五烯酸发生酰化反应，得到化合物z-2-5。
在另一个较佳的实施例中，式(I)中X为-O(CH2)nSS(CH2)mOCOY-，Y为-(CH2)n-或-(CH2)nCONH-；n和m均为2，R为取代或未取代的烷基；优选地，式(I)化合物为z-3-3、z-4-2、z-5-1、z-6-1、z-7-1或z-8-1。
这类化合物的制备方法包含以下步骤：
1)以胡椒醛为起始原料，经过浓硝酸硝化、氢气钯碳还原两步反应得到了6-氨基-3,4-亚甲二氧基苯甲醛，再和5′(S)-1,5-二氧代-(5′-乙基-5′-羟基-2′H,5′H,6′H-6-氧代吡喃)-[3′,4′,f]-Δ6(8)-四氢中氮茚在对甲苯磺酸的催化下，发生弗里德兰德缩合反应，所得反应物通过硅胶柱层析进行纯化得到10,11-亚甲二氧基喜树碱；
2)将上述得到10,11-亚甲二氧基喜树碱在DMAP催化下和三光气与双(2-羟基乙基)二硫醚发生反应，得到20位含有二硫键及碳酸酯修饰的10,11-亚甲二氧基喜树碱，该化合物和胺基上不同取代的4-胺基氧代丁酸在DMAP、DIC和EDCI催化下发生酰化反应，得到所述化合物。
在又一个较佳的实施例中，式(I)中X为-CH2NH-或-OCH2CH2SSCH2CH2O-，R为H。
本发明另一方面还提供一种药物组合物，包含治疗有效剂量的上述化合物、其异构体或者药学上可接受的盐，以及药学上可接受的载体。
本发明再一方面还提供上述化合物、其异构体或者药学上可接受的盐或者上述药物组合物在用于制备预防和/或治疗癌症的药物中的应用。优选地，所述癌症为肺癌或结肠癌。
本发明的喜树碱衍生物对肿瘤组织的选择性要显著高于传统的喜树碱类化合物，抗肿瘤活性和母体化合物相比显著提高，同时保持着较小的毒性，可应用于制备预防或治疗肿瘤的药物。本发明的喜树碱衍生物结构特征清晰，合成方便，纯化方式简便快捷，具有良好的生物活性，因此此类化合物在预防或治疗肿瘤方面有着广泛的前景。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1.化合物z-1-9灌胃给药对小鼠A549移植瘤生长的影响。
图2.化合物z-1-9灌胃给药对A549移植瘤小鼠体重的影响。
图3.化合物w-31灌胃给药对小鼠A549移植瘤生长的影响。
图4.化合物w-31灌胃给药对A549移植瘤小鼠体重的影响。
具体实施方式
本发明的方法与技术通常依据本领域已知的传统方法进行，除非另有说明。与本文中描述的生物学、药理学、及医学与医药化学相关的命名法，及实验方法与技术是本领域已知且常用的。化学合成方法、化学分析方法、医药制备方法、制剂与给药方法、及患者的治疗方法均采用标准技术。
除非另有说明，否则本文中所使用的科学与技术术语应具有那些本领域普通技术人员通常理解的含义。但下列术语具有如下定义：
术语“异构体”包括构象异构体、光学异构体(如对映异构体和非对映异构体)和几何异构体(如顺反异构体)。这些异构体或其组合可以作为外消旋的混合物(消旋体)、单独的对映异构体、单独的非对映异构体、非对映异构体混合物、顺式或反式异构体存在。
术语“药学上可接受的盐”指式(I)化合物的任何药物可接受的盐，优选指化合物的酸加成盐。优选的药物可接受的盐的例子是药物可接受的无机或有机酸的酸加成盐，例如氢卤酸、硫酸、磷酸或脂肪族或芳香族羧酸或磺酸，例如乙酸、琥珀酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、烟酸、甲磺酸、对甲苯磺酸或萘磺酸。其他优选的药物可接受的盐的例子是碱金属盐(钠或钾)、碱土金属盐(钙或镁)或者从氨或诸如C1-C7烷基胺、环己基胺、三乙醇胺、乙二胺或三(羟甲基)氨基甲烷的药物可接受的有机胺衍生的铵盐。
术语“磺酰胺基”是指具有-SO2N-结构的化合物基团的合称，特别优选地是指具有下式(II)结构的化学基团的合称，
其中R1为烷基、芳基、取代的芳基、杂芳基或取代的杂芳基，R2为芳基或取代的芳基。
术语“碱基”包含取代的或未取代的天然碱基以及人工合成碱基；优选地，为取代的或未取代的天然碱基，包括但不限于取代的或未取代的腺嘌呤、取代的或未取代的鸟嘌呤、取代的或未取代的尿嘧啶、取代的或未取代的胸腺嘧啶和取代的或未取代的胞嘧啶；更优选地为取代的或未取代的尿嘧啶，例如5-氟尿嘧啶。
术语“饱和含氮杂环”优选地为4-6元含氮杂环，包括但不限于取代或未取代的四氢吡咯、取代或未取代的吗啉、取代或未取代的哌啶、取代或未取代的哌嗪以及取代或未取代的硫代吗啉等。
术语“烷基”指任意直链或支链、取代或未取代的饱和烃基，其中碳原子数为1-10的烃基包括但不限于甲基、乙基、正丙基、异丙基、环丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、叔戊基、2,4,4-三甲基戊基、环戊基、正己基、异己基、环己基、正庚基、环庚基、正辛基、2-乙基己基、环辛基、正壬基、环壬基或正癸基。其他具有更多碳原子数的长链烷基包括但不限于角鲨烯、十九烷醇等。典型地，“烷基”指C1-20烷基，较佳地C1-10烷基。
术语“卤原子”指任一元素周期表第7列的放射稳定的原子，即氟、氯、溴或碘，优选氟和氯。
术语“芳基”、“取代的芳基”、“杂芳基”和“取代的杂芳基”指芳香族烃环，优选具有5、6或7个原子，最优选具有6个原子构成所述环。“杂芳基”和“取代的杂芳基”指环中具有至少一个杂原子(例如氧、硫或氮原子)和至少一个碳原子的芳香族烃环。所述“芳基”包括但不限于取代的或未取代的下列基团：苯基、邻甲基苯基、间甲苯基、二甲苯基、萘基或蒽基。典型地，“芳基”指C6-20芳基，“杂芳基”指C2-18杂芳基，较佳地C3-15杂芳基。
术语“取代的”指任意至少一个氢原子被取代基所替代的基团，所述取代基选自卤原子、烷基、取代的烷基、烷氧基、取代的烷氧基、环烷基、取代的环烷基、环烯基、取代的环烯基、酰基、酰基氨基、酰氧基、氨基、取代的氨基、氨基酰基、氨基酰氧基、氧酰基氨基、氰基、羟基、羧基、羧基烷基、酮基、硫代酮基、硫醇基、硫代烷氧基、取代的硫代烷氧基、芳基、芳氧基、杂芳基、杂芳基氧基、杂环基、杂环基氧基、羟基氨基、烷氧基氨基、硝基、-SO-烷基、-SO-取代的烷基、-SO-芳基、-SO-杂芳基、-SO2-烷基、-SO2-取代的烷基、-SO2-芳基和-SO2-杂芳基。
术语“治疗有效剂量”是指药物的任何如下所述的量，当单独使用或与另一种治疗剂组合使用该量的药物时，可促进疾病消退，疾病消退表现为疾病症状的严重度降低、无疾病症状期的频率和持续时间增加、或者防止由患病导致的障碍或失能。本发明药物的“治疗有效剂量”也包括“预防有效剂量”，“预防有效剂量”是药物的任何如下所述的量，当将该量的药物单独施用或者与另一种治疗剂组合施用于具有发生疾病的风险或者遭受疾病复发的受试者时，可抑制疾病的发生或复发。
如对本领域所属技术人员显而易见地，有效的体内给药剂量及具体的给药方式会根据所治疗的哺乳动物种类、体重和年龄，所使用的具体化合物及使用这些化合物的具体目的而变化。本领域所属技术人员根据常规的药理学方法可确定有效剂量水平(即达到所需效果所必需的剂量水平)。通常，产物的人体临床应用从较低的剂量水平开始，随后不断提高剂量水平直到达到所需的效果。可选择地，可通过现有的药理学方法采用可接受的体外研究来建立本方法鉴定的组合物的有用剂量和给药途径。
本发明“药物组合物”可以制成片剂、胶囊、粉剂、颗粒、锭剂、栓剂、口服液或无菌胃肠外悬液等液体制剂形式，以及大或小容量注射剂、冻干粉剂等针剂形式。上述剂型的药物均可按照药学领域的常规方法制备。
本发明所述的“药学上可接受的载体”包括药学领域常规的稀释剂、填充剂、粘合剂、湿润剂、吸收促进剂、表面活性剂、吸附载体、润滑剂等。
术语“癌症”是指一大类以异常细胞在体内不受控制地生长为特征的各种疾病。不受控制的细胞分裂和生长分裂和生长导致形成恶性肿瘤或细胞，它们侵入邻近组织，还可以通过淋巴系统或血流转移到身体的远端部分。在本发明中“治疗癌症”的另一种等同的描述是“治疗肿瘤”或者“抗癌”或者“抗肿瘤”。
癌症是不受控制的妨碍身体器官和系统的正常功能的细胞生长的病症。患有癌症的受试者是具有客观可测量的存在于受试者机体内的癌症细胞的受试者。处于发展癌症的危险中的受试者是易于发展癌症(例如基于家族史、遗传倾向)的受试者、接触放射或其他引起癌症的试剂的受试者。
本发明化合物及其药物组合物可用于预防或治疗多种癌症。这种癌症的例子包括乳腺癌、前列腺癌、肺癌、卵巢癌、宫颈癌、皮肤癌、黑素瘤、结肠癌、胃癌、肝癌、食道癌、肾癌、咽喉癌、甲状腺癌、胰腺癌、睾丸癌、脑癌、骨癌和血癌(如白血病、慢性淋巴细胞性白血病)等。其他的癌症包括但不限于基底细胞癌、胆道癌、膀胱癌、骨癌、脑和中枢神经系统(CNS)癌、宫颈癌、绒毛膜癌、结肠直肠癌、结缔组织癌、消化系统癌、子宫内膜癌、食道癌、眼癌、头颈癌、上皮内肿瘤、喉癌、肺癌(小细胞、大细胞)、淋巴瘤(包括霍奇金淋巴瘤和非霍奇金淋巴瘤)、黑素瘤、神经母细胞瘤、口腔癌(例如唇、舌头、口和咽)、视网膜母细胞瘤、横纹肌肉瘤、呼吸系统癌、肉瘤、子宫癌、泌尿系统癌以及其他癌和肉瘤。本发明化合物及其组合物优选地可用于结肠癌和/或肺癌。
本发明化合物、其异构体、其药学上可接受的盐、或包含所述化合物的药物组合物的施用方式没有特别限制。代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)等。本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。可以选用与达沙替尼相同或相近的给药方式，其中包括(但并不限于)：口服、经皮、静脉内、肌內、局部给药等。
本发明还提供了一种预防和/或治疗癌症的方法，所述方法包括向患者施用治疗有效剂量的如前所述具有式(I)所示结构的化合物、其异构体或其药学上可接受的盐，或者包含所述化合物的药物组合物。优选地，所述癌症为肺癌或结肠癌。
一些本发明的化合物的实例包括表A所示的化合物(尤其是除了编号2和3之外的化合物)：
表A
本发明化合物在没有特别说明的情况下一般可以运用10,11-亚甲二氧基喜树碱经过多步反应合成获得。
所述的10,11-亚甲二氧基喜树碱又可以通过以下方法来制备：以胡椒醛为起始原料，经过浓硝酸硝化、氢气钯碳还原两步反应得到了6-氨基-3,4-亚甲二氧基苯甲醛，再和5′(S)-1,5-二氧代-(5′-乙基-5′-羟基-2′H,5′H,6′H-6-氧代吡喃)-[3′,4′,f]-Δ6(8)-四氢中氮茚在对甲苯磺酸的催化下，发生弗里德兰德缩合反应，所得反应物通过硅胶柱层析进行纯化得到10,11-亚甲二氧基喜树碱。
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实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数是重量百分比和重量份数。
实施例1 20位磺酰脒基取代的喜树碱衍生物的制备
本发明20位磺酰脒基取代的喜树碱衍生物的制备可以通过如下通式来进行。
反应条件:(a)DMAP,DIC,EDCI,DCM；(b)CF3COOD,CH2Cl2.；(c)R1SO2N3,alkynes,Et3N,CuI,DCM.
概括地讲，本发明20位磺酰脒基取代的喜树碱衍生物的制备包括以下步骤：
1)10,11-亚甲二氧基喜树碱在缩合剂催化下和Boc保护的甘氨酸发生酰化反应，得到的产物在三氟乙酸条件下脱掉Boc保护基，得到20位甘氨酸修饰的10,11-亚甲二氧基喜树碱；
2)该20位甘氨酸修饰的10,11-亚甲二氧基喜树碱在碘化亚铜催化下和含不同取代基的苯磺酰基叠氮、炔基一锅法反应得到所述20位磺酰脒基取代的喜树碱衍生物。
具体的合成方法如下：
1.10,11-亚甲二氧基-20(S)-O-(Boc-甘氨酸)喜树碱(化合物2)的制备
在100mL的茄形瓶中加入20(S)-10,11-亚甲二氧基喜树碱(200mg,0.5mmol)，用无水二氯甲烷(45mL)溶解，再加入EDCI(0.84g,4.4mmol)，DMAP(124mg,1.02mmol)，Boc-甘氨酸(105mg,0.6mmol)，氮气保护下常温反应12h。TLC检测反应完全后，降至室温，加入二氯甲烷(100mL)稀释，依次用0.1M的稀盐酸，蒸馏水，饱和食盐水洗三次，旋蒸浓缩得到黄色油状液体，硅胶柱层析(二氯甲烷:丙酮＝8:1)分纯，得到棕色固体0.26g，收率95％，即化合物2。mp 241-242℃；HRMS(ESI):calcd for C28H27N3O9 550.5360,found 550.1806.
1H NMR(500MHz,DMSO)δ8.34(s,1H),7.36(s,2H),7.02(d,J＝70.1Hz,1H),6.24(s,2H),5.45(s,2H),5.08(d,J＝25.9Hz,2H),3.87(dd,J＝54.0,17.3Hz,2H),2.10(s,2H),1.32(d,6H),0.94(d,6H).
13C NMR(125MHz,DMSO)δ169.98,167.64,157.03,156.29,151.82,149.97,149.09,146.81,146.63,145.88,130.60,128.58,125.99,118.23,104.79,103.46,103.07,95.30,79.08,76.70,66.61,50.46,42.34,41.06,30.69,28.20,23.63,7.93.
2. 10,11-亚甲二氧基-20(S)-O-甘氨酸喜树碱(化合物3)的制备
在100mL的茄形瓶中加入化合物2(200mg,0.36mmol)，用无水二氯甲烷(45mL)溶解，再加入CF3COOH(6mL)，氮气保护下常温反应12h。TLC检测反应完全后，旋蒸浓缩得到黄色油状液体，硅胶柱层析(二氯甲烷:丙酮＝8:1)分纯，得到棕色固体0.15g，收率95％，即化合物3。mp>250℃；HRMS(ESI):calcd for C23H19N3O7 450.4190,found 450.1288.
1H NMR(500MHz,DMSO)δ8.44(s,1H),7.45(s,1H),7.40(s,1H),7.16(s,1H),6.25(s,2H),5.48(d,J＝16.5Hz,2H),5.16(d,J＝20.9Hz,2H),4.26(d,J＝17.9Hz,1H),4.06(d,J＝17.9Hz,1H),2.21–2.09(m,2H),0.98–0.89(m,3H).
13C NMR(125MHz,DMSO)δ167.34,167.15,156.99,151.97,149.97,149.22,146.89,146.86,145.20,130.85,128.80,126.18,118.33,104.77,103.62,103.12,95.17,78.01,66.75,50.61,30.57,23.63,7.93.
3.化合物w-1的制备
在50mL的茄形瓶中加入化合物3(30mg,0.07mmol)，用无水二氯甲烷(25mL)溶解，再加入2滴三乙胺，搅拌反应10min，直到反应液澄清。氮气保护下依次加入苯乙炔(7.32μL,0.07mmol)，4-甲基苯磺酰基叠氮(19mg,0.084mmol)，碘化亚铜(1.2mg,0.007mmol)，氮气保护下常温反应12h。TLC检测反应完全后，加入饱和氯化铵溶液(3mL),继续搅拌30min。加入二氯甲烷(50mL)稀释，有机层依次用蒸馏水和饱和食盐水洗涤3次，无水MgSO4干燥有机层。旋蒸浓缩得到黄色油状液体，硅胶柱层析(二氯甲烷:丙酮＝8:1)分纯，得到黄色固体38mg，收率76％，即化合物w-1。mp 151-152℃；HRMS(ESI):calcd for C38H32N4O9S 721.7530,found 721.1970.
1H NMR(500MHz,DMSO)δ8.43(s,1H),7.53(d,J＝8.0Hz,1H),7.48(s,1H),7.43(d,J＝7.4Hz,1H),7.39(s,1H),7.27(d,J＝7.3Hz,2H),7.22–7.14(m,3H),7.03(d,J＝7.9Hz,2H),6.97(s,1H),6.26(d,J＝1.8Hz,2H),5.48(s,2H),5.18(s,2H),4.35(dd,J＝17.9,5.7Hz,1H),4.26(dd,J＝17.8,5.8Hz,1H),4.09(s,2H),2.36(s,1H),2.21(s,2H),2.10(dt,J＝13.9,6.9Hz,2H),0.84(t,J＝7.2Hz,3H).
13C NMR(125MHz,DMSO)δ168.19,167.41,167.13,156.95,151.73,150.11,149.12,146.97,145.15,141.82,141.22,135.23,130.51,129.31,129.22,128.73,127.10,126.16,126.09,118.53,105.07,103.54,103.03,94.63,77.09,66.82,50.61,42.84,38.29,30.79,21.45,21.25,7.91.
4.化合物w-2的制备
制备和纯化方法同化合物w-1，用4-氟苯磺酰基叠氮代替4-甲基苯磺酰基叠氮，得到黄色粉末状固体41mg，收率81％，即化合物w-2。mp 156-157℃；HRMS(ESI):calcd forC37H29FN4O9S 725.7164,found 725.1712.
1H NMR(500MHz,DMSO)δ9.17(t,J＝5.8Hz,1H),8.43(s,1H),7.66(dd,J＝8.6,5.3Hz,2H),7.48(s,1H),7.38(s,1H),7.25(d,J＝7.4Hz,2H),7.21–7.14(m,3H),7.01(t,J＝8.8Hz,2H),6.97(s,1H),6.26(d,J＝3.5Hz,2H),5.49(s,2H),5.18(s,2H),4.38(dd,J＝17.9,5.7Hz,1H),4.29(dd,J＝17.9,5.9Hz,1H),4.10(s,2H),2.10(dq,J＝13.0,6.5Hz,2H),0.84(t,J＝7.4Hz,3H).
13C NMR(125MHz,DMSO)δ168.15,167.44,167.41,162.79,156.95,151.75,150.10,149.13,146.98,146.93,145.14,140.30,134.99,130.55,129.24,129.02,128.94,128.78,128.74,127.15,126.11,118.54,115.78,115.61,105.02,103.56,103.04,94.59,77.14,66.82,50.63,42.94,38.27,30.77,7.92.
5.化合物w-3的制备
制备和纯化方法同化合物w-1，用4-氯苯磺酰基叠氮代替4-甲基苯磺酰基叠氮，得到黄色粉末状固体39mg，收率75％，即化合物w-3。mp 160-161℃；HRMS(ESI):calcd forC37H29ClN4O9S 741.1680,found 741.1416.
1H NMR(500MHz,DMSO)δ8.42(s,1H),7.58(d,J＝8.6Hz,2H),7.47(s,1H),7.38(s,1H),7.23(dd,J＝7.5,6.0Hz,3H),7.16(dt,J＝20.0,6.9Hz,3H),7.00(d,J＝8.4Hz,1H),6.97(s,1H),6.26(d,J＝2.7Hz,2H),5.49(s,2H),5.17(s,2H),4.39(dd,J＝17.9,5.7Hz,1H),4.30(dd,J＝17.9,5.9Hz,1H),4.10(s,2H),2.10(dq,J＝14.2,7.1Hz,2H),0.84(t,J＝7.4Hz,3H).
13C NMR(125MHz,DMSO)δ168.14,167.57,167.46,156.95,151.75,150.08,149.13,146.98,146.93,145.14,142.72,136.50,134.93,130.53,129.70,129.23,128.74,128.58,127.98,127.93,127.14,126.10,118.52,105.03,103.56,103.03,94.59,77.16,66.82,50.62,42.97,38.29,30.75,7.92.
6.化合物w-4的制备
制备和纯化方法同化合物w-1，用4-硝基苯磺酰基叠氮代替4-甲基苯磺酰基叠氮，得到黄色粉末状固体42mg，收率81％，即化合物w-4。mp 166-167℃；HRMS(ESI):calcd forC37H29N5O11S 752.7230,found 752.1655.
1H NMR(500MHz,DMSO)δ8.40(d,J＝8.9Hz,1H),8.14(d,J＝8.8Hz,1H),7.92(d,J＝8.7Hz,1H),7.74(d,J＝8.7Hz,1H),7.44(s,1H),7.33(s,1H),7.29–7.24(m,1H),7.22(d,J＝7.2Hz,2H),7.15(t,J＝7.0Hz,2H),7.12–7.08(m,1H),6.97(s,1H),6.25(s,2H),5.49(s,2H),5.13(t,J＝13.2Hz,2H),4.45(dd,J＝18.0,5.7Hz,1H),4.36(dd,J＝17.9,5.9Hz,1H),4.12(d,J＝6.8Hz,1H),3.58(s,1H),2.12(td,J＝13.8,7.0Hz,2H),0.86(t,J＝7.3Hz,3H).
13C NMR(125MHz,DMSO)δ170.38,168.16,168.10,167.49,156.94,151.75,150.68,150.03,149.19,149.12,148.95,146.96,146.88,145.14,134.65,130.48,129.75,129.65,129.22,128.74,127.45,127.19,124.88,123.87,118.52,104.95,103.52,103.04,94.56,77.25,66.83,50.59,43.09,42.50,38.37,30.73,7.94.
7.化合物w-5的制备
制备和纯化方法同化合物w-1，用β-萘磺酰基叠氮代替4-甲基苯磺酰基叠氮，得到黄色粉末状固体39mg，收率73％，即化合物w-5。mp 165-166℃；HRMS(ESI):calcd forC41H32N4O9S 757.7860,found 757.1960.
1H NMR(500MHz,DMSO)δ9.21(t,J＝5.9Hz,1H),8.30(s,1H),8.09(s,1H),7.75(s,1H),7.68(d,J＝8.2Hz,1H),7.59–7.53(m,2H),7.49–7.44(m,1H),7.42(s,1H),7.32(d,J＝13.3Hz,1H),7.28(d,J＝7.6Hz,2H),7.12(t,J＝7.6Hz,2H),7.04(t,J＝7.3Hz,1H),6.92(s,1H),6.25(d,J＝9.4Hz,2H),5.49(t,J＝10.0Hz,2H),5.07(d,J＝19.1Hz,1H),4.91(d,J＝19.1Hz,1H),4.45(dd,J＝17.8,5.9Hz,1H),4.31(dd,J＝17.8,5.9Hz,1H),4.15(s,2H),2.06(td,J＝14.7,7.2Hz,2H),0.81(t,J＝7.4Hz,3H).
13C NMR(125MHz,DMSO)δ168.31,167.66,167.49,156.88,151.58,149.80,149.04,146.90,146.87,145.33,140.89,135.07,133.86,131.73,130.24,129.29,129.05,128.63,128.48,128.37,127.86,127.19,127.08,125.98,125.89,122.47,118.25,105.15,103.46,102.98,94.56,77.25,66.76,50.47,43.03,38.24,30.64,7.92.
8.化合物w-6的制备
制备和纯化方法同化合物w-1，用乙磺酰基叠氮代替4-甲基苯磺酰基叠氮，得到淡黄色粉末状固体35mg，收率75％，即化合物w-6。mp 161-162℃；HRMS(ESI):calcd forC33H30N4O9S 659.6820,found 659.1810.
1H NMR(500MHz,DMSO)δ8.43(d,J＝18.1Hz,1H),7.48(d,J＝12.4Hz,2H),7.38(d,J＝7.3Hz,2H),7.32–7.26(m,2H),7.12(s,1H),7.06(s,1H),7.03(s,1H),6.26(d,J＝4.9Hz,2H),5.50(t,J＝7.7Hz,2H),5.20(d,J＝11.7Hz,2H),3.98(s,1H),3.91(d,J＝16.3Hz,1H),3.58–3.51(m,1H),3.48(s,1H),2.19–2.10(m,2H),1.21(d,J＝2.3Hz,3H),1.11(t,J＝7.1Hz,2H),0.95–0.89(m,3H).
13C NMR(125MHz,DMSO)δ168.21,167.42,166.77,156.94,151.87,150.07,149.19,146.93,145.28,135.56,130.64,129.44,128.85,128.78,127.21,126.13,118.52,104.98,103.58,103.08,94.40,77.17,76.97,66.80,50.63,49.03,47.25,42.73,38.48,30.86,8.60,8.43,7.95.
9.化合物w-7的制备
制备和纯化方法同化合物w-1，用3-吡啶磺酰基叠氮代替4-甲基苯磺酰基叠氮，得到黄色粉末状固体35mg，收率70％，即化合物w-7。mp 156-157℃；HRMS(ESI):calcd forC36H29N5O9S 708.7140,found 708.1756.
1H NMR(500MHz,DMSO)δ9.37(t,J＝5.8Hz,1H),8.40(s,1H),7.88(d,J＝7.9Hz,1H),7.45(d,J＝5.6Hz,1H),7.38(s,1H),7.25(d,J＝7.4Hz,2H),7.15(dt,J＝23.8,7.2Hz,5H),6.95(s,1H),6.25(d,J＝3.6Hz,2H),5.48(s,2H),5.17(s,2H),4.43(dd,J＝17.9,5.8Hz,1H),4.30(dd,J＝17.9,5.8Hz,1H),4.13(s,2H),2.10(dt,J＝14.0,6.9Hz,2H),0.85(t,J＝7.4Hz,3H).
13C NMR(125MHz,DMSO)δ168.05,167.78,167.39,156.94,152.18,151.71,150.08,149.10,147.01,146.89,146.45,145.19,134.79,133.81,130.47,129.23,128.76,127.24,126.06,123.68,118.42,105.04,103.52,103.02,94.49,77.18,66.79,50.60,43.06,41.78,38.38,30.75,26.89,7.94.
10.化合物w-8的制备
制备和纯化方法同化合物w-1，用甲磺酰基叠氮代替4-甲基苯磺酰基叠氮，得到黄色粉末状固体33mg，收率73％，即化合物w-8。mp 175-176℃；HRMS(ESI):calcd forC32H28N4O9S 645.6550,found 645.1644.
1H NMR(500MHz,DMSO)δ8.82(t,J＝5.6Hz,1H),8.44(s,1H),7.49(s,1H),7.41(s,1H),7.35(d,J＝7.5Hz,2H),7.26(t,J＝7.5Hz,3H),7.21–7.17(m,1H),6.95(s,1H),6.26(s,2H),5.47(s,2H),5.18(t,J＝11.0Hz,2H),4.29(dd,J＝18.0,5.9Hz,1H),4.15(dd,J＝17.9,5.8Hz,1H),4.05(dd,J＝31.7,14.7Hz,2H),2.80(s,3H),2.10(dt,J＝23.2,7.1Hz,2H),0.87(t,J＝7.3Hz,3H).
13C NMR(125MHz,DMSO)δ168.20,167.44,166.53,156.96,151.87,150.07,149.19,146.91,146.87,145.47,135.44,130.63,129.47,128.88,128.81,127.24,126.15,118.36,104.98,103.58,103.06,94.42,77.09,66.71,50.65,43.55,42.83,38.38,30.70,8.01.
11.化合物w-9的制备
制备和纯化方法同化合物w-1，用丙磺酰基叠氮代替4-甲基苯磺酰基叠氮，得到黄色粉末状固体35mg，收率75％，即化合物w-9。mp 143-144℃；HRMS(ESI):calcd forC34H32N4O9S 673.7090,found 673.1955.
1H NMR(500MHz,DMSO)δ8.42(s,1H),7.78(t,J＝6.1Hz,1H),7.47(s,2H),7.42(s,1H),7.39–7.31(m,2H),7.32–7.20(m,2H),7.04(s,1H),6.27(d,J＝4.2Hz,2H),5.47(d,J＝7.5Hz,2H),5.17(s,2H),4.20(dd,J＝18.9,6.2Hz,1H),4.07–3.95(m,1H),2.95–2.85(m,2H),2.18–2.07(m,2H),1.61(dd,J＝14.8,7.3Hz,2H),0.92(t,J＝7.2Hz,3H),0.88–0.83(m,2H),0.78(t,J＝7.3Hz,3H).
13C NMR(125MHz,DMSO)δ169.59,167.62,156.96,151.86,150.12,149.16,146.94,146.87,145.54,130.62,129.66,129.44,129.01,128.82,128.78,126.11,118.30,105.00,103.56,103.08,94.76,77.19,66.69,54.47,50.58,43.90,30.55,17.49,17.33,17.16,13.49,12.93,7.99.
12.化合物w-10的制备
制备和纯化方法同化合物w-1，用丁磺酰基叠氮代替4-甲基苯磺酰基叠氮，得到黄色粉末状固体37mg，收率76％，即化合物w-10。mp 128-129℃；HRMS(ESI):calcd forC35H34N4O9S 687.7360,found 687.2113.
1H NMR(500MHz,DMSO)δ8.84(t,J＝5.8Hz,1H),8.45(s,1H),7.50(s,1H),7.43(s,1H),7.35(t,J＝7.3Hz,2H),7.26(t,J＝7.5Hz,2H),7.18(t,J＝7.4Hz,1H),6.96(s,1H),6.27(d,J＝1.6Hz,2H),5.47(s,2H),5.20(s,2H),4.30(dd,J＝17.8,5.9Hz,1H),4.17(dd,J＝17.9,5.8Hz,1H),4.06(t,J＝6.8Hz,2H),2.76(ddd,J＝20.9,13.5,8.9Hz,2H),2.10(td,J＝13.9,6.9Hz,2H),1.44–1.37(m,2H),1.03(dt,J＝14.6,7.3Hz,2H),0.86(dd,J＝14.3,6.9Hz,3H),0.61(t,J＝7.3Hz,3H).
13C NMR(125MHz,DMSO)δ168.22,167.36,166.68,156.95,151.82,150.11,149.17,146.93,145.33,135.59,130.64,129.44,128.78,127.21,126.17,118.49,105.04,103.59,103.07,94.44,76.98,66.75,54.29,50.64,42.79,38.33,30.81,25.61,21.16,13.80,7.96.
13.化合物w-11的制备
制备和纯化方法同化合物w-1，用甲磺酰基叠氮和对氟苯乙炔代替4-甲基苯磺酰基叠氮和苯乙炔，得到黄色粉末状固体34mg，收率73％，即化合物w-11。mp 174-175℃；HRMS(ESI):calcd for C32H27FN4O9S 663.6454,found 663.1552.
1H NMR(500MHz,DMSO)δ8.83(t,J＝5.7Hz,1H),8.43(s,1H),7.48(s,1H),7.42–7.37(m,3H),7.10(t,J＝8.8Hz,2H),6.96(s,1H),6.27(s,2H),5.48(s,2H),5.23–5.13(m,2H),4.30(dd,J＝17.9,5.8Hz,1H),4.15(dd,J＝17.9,5.7Hz,1H),4.04(dd,J＝28.9,14.7Hz,2H),2.84(s,3H),2.15–2.08(m,2H),0.88(t,J＝7.3Hz,3H).
13C NMR(125MHz,DMSO)δ168.19,167.44,166.43,162.63,160.70,156.97,151.89,150.05,149.19,146.91,145.48,131.50,131.43,130.64,128.86,126.15,118.36,115.65,115.48,104.97,103.57,103.07,94.42,77.11,66.72,50.64,43.61,42.82,37.62,36.24,30.69,8.00.
14.化合物w-12的制备
用对甲氧基苯磺酰基叠氮代替4-甲基苯磺酰基叠氮，制备和纯化方法同化合物w-1，得到黄色粉末状固体40mg，收率78％，即化合物w-12。mp 139-141℃；HRMS(ESI):calcdfor C38H32N4O10S 737.7520,found 737.1908.
1H NMR(500MHz,DMSO)δ8.97(t,J＝5.6Hz,1H),8.39(s,1H),7.53(t,J＝9.3Hz,2H),7.45(s,1H),7.38(s,1H),7.25(d,J＝7.4Hz,2H),7.19(t,J＝7.1Hz,2H),7.16–7.12(m,1H),6.96(s,1H),6.70(d,J＝8.7Hz,2H),6.25(d,J＝2.2Hz,2H),5.47(s,2H),5.14(s,2H),4.34(dd,J＝17.9,5.6Hz,1H),4.24(dd,J＝17.9,5.8Hz,1H),4.08(s,1H),3.82(s,1H),3.66(d,J＝18.4Hz,3H),2.14–2.04(m,2H),0.83(t,J＝7.3Hz,3H).
13C NMR(125MHz,DMSO)δ168.23,167.42,166.91,161.69,156.93,151.72,149.10,146.94,146.92,145.16,135.97,135.24,130.49,129.28,129.11,128.81,128.72,128.18,127.10,126.05,118.51,114.25,113.82,105.04,103.50,103.03,94.63,77.07,66.81,56.07,55.81,50.57,42.82,41.77,38.16,30.77,26.89,7.92.
15.化合物w-13的制备
用2-噻吩磺酰基叠氮和对氟苯乙炔代替4-甲基苯磺酰基叠氮和苯乙炔，制备和纯化方法同化合物w-1，得到黄色粉末状固体37mg，收率73％，即化合物w-13。mp 178-179℃；HRMS(ESI):calcd for C35H27FN4O9S2 731.7384,found 731.1271.
1H NMR(500MHz,DMSO)δ9.24(t,J＝5.7Hz,1H),8.41(s,1H),7.55(d,J＝4.8Hz,1H),7.47(d,J＝10.9Hz,1H),7.39(s,1H),7.31(t,J＝5.7Hz,3H),7.04(t,J＝8.8Hz,2H),6.97(d,J＝12.1Hz,1H),6.83–6.79(m,1H),6.25(d,J＝2.5Hz,2H),5.47(s,2H),5.17(s,2H),4.42(dd,J＝17.9,5.8Hz,1H),4.29(dd,J＝17.9,5.8Hz,1H),4.08(s,2H),2.10(tt,J＝14.1,7.1Hz,2H),0.84(t,J＝7.3Hz,3H).
13C NMR(125MHz,DMSO)δ168.05,167.35,167.23,156.93,151.75,150.08,149.13,146.97,146.93,145.38,145.06,131.36,131.29,131.23,131.19,131.17,130.53,130.19,128.76,127.14,126.08,118.56,115.61,115.44,105.07,103.53,103.04,94.68,77.14,66.84,50.60,42.88,37.46,30.84,7.90.
16.化合物w-14的制备
用对甲氧基苯磺酰基叠氮和对氟苯乙炔代替4-甲基苯磺酰基叠氮和苯乙炔，制备和纯化方法同化合物w-1,粉末状固体40mg，收率75％，即化合物w-14。mp 221-222℃；HRMS(ESI):calcd for C38H31FN4O10S 755.7424,found 755.1798.
1H NMR(500MHz,DMSO)δ9.07(t,J＝5.7Hz,1H),8.41(s,1H),7.52(d,J＝8.1Hz,2H),7.46(s,1H),7.38(s,1H),7.29(dd,J＝8.1,5.8Hz,2H),7.02(dd,J＝9.8,8.3Hz,4H),6.97(s,1H),6.26(d,J＝2.8Hz,2H),5.50(d,J＝14.0Hz,2H),5.16(s,2H),4.36(dd,J＝17.9,5.7Hz,1H),4.26(dd,J＝17.9,5.8Hz,1H),4.07(s,2H),2.21(s,3H),2.10(dt,J＝19.5,6.5Hz,2H),0.84(t,J＝7.4Hz,3H).
13C NMR(125MHz,DMSO)δ168.21,167.42,167.06,162.56,160.63,156.95,151.74,150.08,149.12,146.96,146.93,145.15,141.85,141.15,131.29,131.23,130.51,129.20,128.72,126.13,126.08,118.54,115.54,115.37,105.05,103.52,103.05,94.61,77.11,66.82,50.60,42.83,37.48,30.78,21.24,7.91.
17.化合物w-15的制备
用对氯苯磺酰基叠氮和对氟苯乙炔代替4-甲基苯磺酰基叠氮和苯乙炔，制备和纯化方法同化合物w-1，得到黄色粉末状固体41mg，收率77％，即化合物w-15。mp 165-167℃；HRMS(ESI):calcd for C37H28ClFN4O9S 759.1584,found 759.1310.
1H NMR(500MHz,DMSO)δ9.27(t,J＝5.8Hz,1H),8.43(s,1H),7.58(d,J＝8.5Hz,2H),7.48(s,1H),7.38(s,1H),7.29–7.21(m,4H),7.01(t,J＝8.8Hz,2H),6.97(s,1H),6.26(d,J＝2.9Hz,2H),5.49(s,2H),5.19(s,2H),4.40(dd,J＝18.0,5.8Hz,1H),4.30(dd,J＝17.8,5.9Hz,1H),4.08(s,2H),2.15–2.08(m,2H),0.85(t,J＝7.4Hz,3H).
13C NMR(125MHz,DMSO)δ168.16,167.51,167.47,160.66,156.95,151.75,150.07,149.14,146.99,146.93,145.13,142.68,136.52,131.25,131.19,130.96,130.54,128.76,128.73,127.94,126.12,118.53,115.57,115.40,105.04,103.56,103.03,94.58,77.19,66.83,50.64,42.97,37.51,30.75,7.91.
18.化合物w-16的制备
用对甲苯磺酰基叠氮和对甲氧基苯乙炔代替4-甲基苯磺酰基叠氮和苯乙炔，制备和纯化方法同化合物w-1，得到黄色粉末状固体39mg，收率75％，即化合物w-16。mp 158-160℃；HRMS(ESI):calcd for C39H34N4O10S 751.7790,found 751.2076.
1H NMR(500MHz,DMSO)δ8.88(t,J＝5.8Hz,1H),8.39(s,1H),7.55(t,J＝8.2Hz,2H),7.44(s,1H),7.38(s,1H),7.18(d,J＝8.5Hz,2H),7.04(d,J＝8.1Hz,2H),6.97(s,1H),6.75(d,J＝8.6Hz,2H),6.26(d,J＝2.7Hz,2H),5.48(s,2H),5.14(s,2H),4.34(dd,J＝17.9,5.8Hz,1H),4.24(dd,J＝17.9,5.9Hz,1H),4.00(s,2H),3.64(s,3H),2.22(s,3H),2.15–2.06(m,2H),0.85(t,J＝7.4Hz,3H).
13C NMR(125MHz,DMSO)δ168.22,167.67,167.41,158.59,156.94,151.73,150.07,149.11,146.95,146.93,145.19,141.75,141.30,130.58,130.49,129.20,128.69,126.82,126.15,126.06,118.52,114.19,105.05,103.50,103.04,94.63,77.08,66.81,55.41,50.58,42.82,37.50,30.79,21.25,7.92.
19.化合物w-17的制备
用对氯苯磺酰基叠氮和对甲氧基苯乙炔代替4-甲基苯磺酰基叠氮和苯乙炔，制备和纯化方法同化合物w-1，得到黄色粉末状固体39mg，收率73％，即化合物w-17。mp 145-146℃；HRMS(ESI):calcd for C38H31ClN4O10S 771.1940,found 771.1504.
1H NMR(500MHz,DMSO)δ9.13(t,J＝5.8Hz,1H),8.42(s,1H),7.56(d,J＝8.5Hz,2H),7.47(s,1H),7.38(s,1H),7.22(d,J＝8.4Hz,2H),7.14(d,J＝8.5Hz,2H),6.97(s,1H),6.72(d,J＝8.5Hz,2H),6.26(d,J＝2.7Hz,2H),5.49(s,2H),5.18(s,2H),4.38(dd,J＝17.9,5.7Hz,1H),4.28(dd,J＝18.0,5.9Hz,1H),4.01(s,2H),3.64(s,3H),2.11(dq,J＝14.1,7.1Hz,2H),0.85(t,J＝7.4Hz,3H).
13C NMR(125MHz,DMSO)δ168.17,168.12,167.47,158.61,156.95,151.74,150.08,149.13,146.99,146.93,145.17,142.79,136.38,130.53,130.48,128.76,128.68,127.94,126.45,126.11,118.51,114.17,105.05,103.56,103.03,94.59,77.16,66.82,55.41,50.63,42.95,37.48,30.75,7.93.
20.化合物w-18的制备
用对硝基苯磺酰基叠氮和对氟苯乙炔代替4-甲基苯磺酰基叠氮和苯乙炔，制备和纯化方法同化合物w-1，得到黄色粉末状固体41mg，收率76％，即化合物w-18。mp 217-218℃；HRMS(ESI):calcd for C37H28FN5O11S 770.7134,found 770.1548.
1H NMR(500MHz,DMSO)δ9.50(t,J＝5.8Hz,1H),8.40(s,1H),7.94(d,J＝8.6Hz,2H),7.75(d,J＝8.6Hz,2H),7.46(s,1H),7.33(s,1H),7.25(dd,J＝8.2,5.6Hz,2H),7.00–6.95(m,3H),6.26(s,2H),5.50(s,2H),5.20–5.09(m,2H),4.46(dd,J＝17.9,5.7Hz,1H),4.35(dd,J＝17.9,5.9Hz,1H),4.08(t,J＝11.3Hz,2H),2.16–2.09(m,2H),0.86(t,J＝7.3Hz,3H).
13C NMR(125MHz,DMSO)δ168.12,167.50,162.61,160.68,156.95,151.76,150.03,149.16,148.95,146.97,146.89,145.13,131.27,130.73,130.49,128.69,127.43,126.07,123.87,118.53,115.59,115.42,104.96,103.53,103.04,94.56,77.27,66.83,56.48,50.60,43.09,37.61,30.72,19.01,7.93.
21.化合物w-19的制备
用对氟苯磺酰基叠氮和对氟苯乙炔代替4-甲基苯磺酰基叠氮和苯乙炔，制备和纯化方法同化合物w-1，得到黄色粉末状固体43mg，收率82％，即化合物w-19。mp 163-164℃；HRMS(ESI):calcd for C37H28F2N4O9S 743.7068,found 743.1610.
1H NMR(500MHz,DMSO)δ9.21(t,J＝5.8Hz,1H),8.42(s,1H),7.66(dd,J＝8.5,5.4Hz,2H),7.47(s,1H),7.38(s,1H),7.28(dd,J＝8.2,5.7Hz,2H),7.02(dd,J＝8.7,7.1Hz,4H),6.97(s,1H),6.26(d,J＝3.6Hz,2H),5.49(s,2H),5.17(s,2H),4.38(dd,J＝17.9,5.7Hz,1H),4.29(dd,J＝17.9,5.9Hz,1H),4.08(s,2H),2.15–2.08(m,2H),0.85(t,J＝7.4Hz,3H).
13C NMR(125MHz,DMSO)δ168.17,167.44,167.34,164.79,162.80,162.57,160.63,156.95,151.75,150.07,149.13,146.98,145.14,140.26,131.19,131.04,130.54,128.91,128.75,126.10,118.54,115.77,115.56,115.39,105.01,103.54,103.03,94.57,77.16,66.82,56.48,50.61,42.93,37.49,30.77,19.01,7.91.
22.化合物w-20的制备
用对硝基苯磺酰基叠氮和对甲氧基苯乙炔代替4-甲基苯磺酰基叠氮和苯乙炔，制备和纯化方法同化合物w-1，得到黄色粉末状固体41mg，收率75％，即化合物w-20。mp 195-196℃；HRMS(ESI):calcd for C38H31N5O12S 782.7490,found 782.1746.
1H NMR(500MHz,DMSO)δ9.41(t,J＝5.7Hz,1H),8.39(s,1H),7.89(d,J＝8.6Hz,2H),7.70(d,J＝8.6Hz,2H),7.45(s,1H),7.33(s,1H),7.10(d,J＝8.5Hz,2H),6.97(s,1H),6.66(d,J＝8.5Hz,2H),6.25(s,2H),5.50(s,2H),5.13(t,J＝14.5Hz,2H),4.45(dd,J＝17.9,5.7Hz,1H),4.34(dd,J＝17.9,5.9Hz,1H),4.02(q,J＝14.6Hz,2H),3.59(s,3H),2.13(tt,J＝13.9,7.0Hz,2H),0.87(t,J＝7.3Hz,3H).
13C NMR(125MHz,DMSO)δ168.76,168.15,167.52,158.63,156.95,151.74,150.02,149.26,149.12,148.81,146.97,146.88,145.19,130.49,128.69,127.38,126.10,126.06,123.75,118.50,114.13,104.98,103.52,103.03,94.57,77.27,66.82,55.34,50.60,43.07,37.53,30.71,7.95.
23.化合物w-21的制备
用对氟苯磺酰基叠氮和对甲氧基苯乙炔代替4-甲基苯磺酰基叠氮和苯乙炔，制备和纯化方法同化合物w-1，得到黄色粉末状固体41mg，收率78％，即化合物w-21。mp 159-160℃；HRMS(ESI):calcd for C38H31FN4O10S 755.7424,found 755.1798.
1H NMR(500MHz,DMSO)δ9.04(t,J＝5.8Hz,1H),8.41(s,1H),7.66(dd,J＝8.6,5.4Hz,2H),7.46(s,1H),7.38(s,1H),7.16(d,J＝8.5Hz,2H),7.01(t,J＝8.8Hz,2H),6.97(s,1H),6.74(d,J＝8.6Hz,2H),6.26(d,J＝3.4Hz,2H),5.49(s,2H),5.16(s,2H),4.36(dd,J＝17.9,5.7Hz,1H),4.27(dd,J＝17.9,5.9Hz,1H),4.02(s,2H),3.64(s,3H),2.15–2.08(m,2H),0.85(t,J＝7.4Hz,3H).
13C NMR(125MHz,DMSO)δ168.17,167.94,167.44,162.75,158.60,156.95,151.75,150.06,149.12,146.96,145.17,140.41,130.51,128.99,128.91,128.73,126.56,126.09,118.52,115.74,115.56,114.20,105.01,103.53,103.03,94.59,77.12,66.81,56.48,55.41,50.60,42.92,37.49,30.78,19.01,7.92.
24.化合物w-22的制备
用β-萘磺酰基叠氮和对甲氧基苯乙炔代替4-甲基苯磺酰基叠氮和苯乙炔，制备和纯化方法同化合物w-1，得到黄色粉末状固体38mg，收率70％，即化合物w-22。mp 169-171℃；HRMS(ESI):calcd for C42H34FN4O10S 787.8120,found 787.2058.
1H NMR(500MHz,DMSO)δ9.13(t,J＝5.7Hz,1H),8.29(s,1H),8.00(s,1H),7.74(d,J＝8.2Hz,1H),7.64(d,J＝8.2Hz,1H),7.58–7.50(m,3H),7.46(t,J＝7.4Hz,1H),7.41(s,1H),7.33(s,1H),7.16(d,J＝8.5Hz,2H),6.92(s,1H),6.61(d,J＝8.5Hz,2H),6.25(d,J＝9.1Hz,2H),5.49(t,J＝10.1Hz,2H),5.06(d,J＝19.0Hz,1H),4.89(d,J＝19.0Hz,1H),4.45(dd,J＝17.8,5.9Hz,1H),4.30(dd,J＝17.7,5.8Hz,1H),4.09–4.01(m,2H),3.49(s,3H),2.08(tt,J＝14.4,7.2Hz,2H),0.83(t,J＝7.3Hz,3H).
13C NMR(125MHz,DMSO)δ168.35,168.20,167.50,158.41,156.89,151.56,149.78,149.03,146.90,146.86,145.38,140.85,133.79,131.69,130.50,130.21,129.00,128.47,128.35,128.27,127.81,127.11,126.49,125.96,125.83,122.44,118.21,114.02,105.17,103.45,102.97,94.57,77.27,66.75,55.21,50.47,42.98,37.37,30.62,7.94.
25.化合物w-23的制备
用β-萘磺酰基叠氮和对氟苯乙炔代替4-甲基苯磺酰基叠氮和苯乙炔，制备和纯化方法同化合物w-1，得到黄色粉末状固体39mg，收率72％，即化合物w-23。mp 170-171℃；HRMS(ESI):calcd for C41H31FN4O9S 775.7764,found 775.1896.
1H NMR(500MHz,DMSO)δ9.28(t,J＝5.9Hz,1H),8.28(s,1H),8.03(s,1H),7.74(t,J＝9.8Hz,1H),7.65(d,J＝8.2Hz,1H),7.58–7.51(m,3H),7.50–7.43(m,1H),7.41(s,1H),7.32(d,J＝7.7Hz,1H),7.29(dd,J＝8.4,5.6Hz,2H),6.92–6.85(m,3H),6.26(t,J＝7.1Hz,2H),5.49(t,J＝10.3Hz,2H),5.06(d,J＝19.1Hz,1H),4.89(d,J＝19.1Hz,1H),4.47(dd,J＝17.8,5.9Hz,1H),4.32(dd,J＝17.8,5.9Hz,1H),4.16–4.07(m,2H),2.08(tt,J＝14.4,7.2Hz,2H),0.83(t,J＝7.4Hz,3H).
13C NMR(125MHz,DMSO)δ168.34,167.60,167.50,162.43,160.50,156.88,151.57,149.76,149.04,146.86,145.34,140.75,133.81,131.66,131.27,131.20,131.02,130.21,128.96,128.46,128.42,128.35,127.84,127.19,125.96,125.83,122.38,118.23,115.42,115.25,105.15,103.44,102.97,94.54,77.30,66.75,50.46,43.01,37.39,30.62,7.92.
26.化合物w-24的制备
用3-吡啶磺酰基叠氮和对氟苯乙炔代替4-甲基苯磺酰基叠氮和苯乙炔，制备和纯化方法同化合物w-1，得到黄色粉末状固体39mg，收率77％，即化合物w-24。mp 173-175℃；HRMS(ESI):calcd for C36H28FN5O9S 726.7044,found 726.1655.
1H NMR(500MHz,DMSO)δ9.39(t,J＝5.8Hz,1H),8.65(s,1H),8.46(s,1H),8.42(s,1H),7.88(d,J＝8.0Hz,1H),7.48(s,1H),7.38(s,1H),7.28(dd,J＝8.4,5.7Hz,2H),7.17(dd,J＝8.0,4.7Hz,1H),7.00(t,J＝8.8Hz,2H),6.95(s,1H),6.26(d,J＝3.6Hz,2H),5.49(s,2H),5.20(s,2H),4.44(dd,J＝17.9,5.9Hz,1H),4.30(dd,J＝17.8,5.8Hz,1H),4.09(d,J＝14.5Hz,2H),2.14–2.07(m,2H),0.85(t,J＝7.4Hz,3H).
13C NMR(125MHz,DMSO)δ168.07,167.72,167.40,162.57,160.64,156.95,152.17,151.71,150.09,149.11,147.03,146.90,146.38,145.17,133.80,131.26,131.19,130.81,130.49,128.78,126.08,123.65,118.43,115.61,115.44,105.05,103.55,103.02,94.49,77.21,66.79,50.63,43.05,37.59,30.74,7.93.
实施例2 20位为尿嘧啶基修饰的10,11-亚甲二氧基喜树碱衍生物的制备
本发明20位为尿嘧啶基修饰的10,11-亚甲二氧基喜树碱衍生物可以通过如下通式进行制备。
反应条件:(a)DMAP,DIC,EDCI,DCM；(b)CF3COOD,CH2Cl2；(c)5'-substituteduracil 1'(N)-acetic acid,DMAP,DIC,EDCI,DCM.
概括地讲，所述20位为尿嘧啶基修饰的10,11-亚甲二氧基喜树碱衍生物的制备步骤包括：
1)10,11-亚甲二氧基喜树碱在缩合剂催化下和Boc保护的甘氨酸发生酰化反应，得到的产物在三氟乙酸条件下脱掉Boc保护基，得到20位甘氨酸修饰的10,11-亚甲二氧基喜树碱；
2)上述得到20位甘氨酸修饰的10,11-亚甲二氧基喜树碱，与不同取代基修饰的尿嘧啶乙酸在缩合剂的催化下发生酰化反应，得到所述20位为尿嘧啶基修饰的10,11-亚甲二氧基喜树碱衍生物。
具体化合物的制备方法如下：
1.化合物w-25的制备
50mL茄型瓶中加入化合物3(60mg，0.13mmol)，2-(2,4-二氧代嘧啶-1-基)乙酸(180mg，1.1mmol)，用二氯甲烷以及甲醇混合溶剂溶解至反应液澄清，依次加入DIC，DMAP，EDCI，氮气保护，反应24h，TLC检测反应毕，停止反应，旋蒸除去溶剂，硅胶柱层析分离纯化(二氯甲烷:甲醇＝40：1)，得到浅黄色粉末状固体60mg，收率为77％，即化合物w-25。mp>250℃；HRMS(ESI):calcd for C29H23N5O10 602.5280,found 602.1506.
1H NMR(500MHz,DMSO)δ11.21(s,1H),8.71(s,1H),8.38(s,1H),7.46(d,J＝31.5Hz,3H),7.01(s,1H),6.26(s,2H),5.46(s,3H),5.11(s,2H),4.35(s,2H),4.22(s,1H),4.09(s,1H),2.15(s,2H),0.89(s,3H).
13C NMR(125MHz,DMSO)δ169.16,167.91,167.52,164.22,156.91,151.84,151.37,150.10,149.12,146.86,145.38,130.58,128.75,127.84,126.08,118.48,114.29,105.07,103.50,103.05,101.07,94.70,76.84,66.79,50.51,49.67,30.86,7.97.
2.化合物w-26的制备
用2-(2,4-二氧代嘧啶-5-氯-1-基)乙酸代替2-(2,4-二氧代嘧啶-1-基)乙酸，制备和纯化方法同化合物w-25，得到黄色粉末状固体65mg，收率79％，即化合物w-26。mp 242-243℃；HRMS(ESI):calcd for C29H22ClN5O10 636.9700,found 636.1151.
1H NMR(500MHz,DMSO)δ11.79(s,1H),8.74(s,1H),8.38(s,1H),8.03(s,1H),7.42(s,2H),7.01(s,1H),6.26(s,2H),5.46(s,2H),5.11(s,2H),4.36(s,2H),4.24(dd,J＝18.3,5.5Hz,1H),4.09(dd,J＝17.9,5.3Hz,1H),2.19–2.09(m,2H),0.90(t,J＝7.1Hz,3H).
13C NMR(125MHz,DMSO)δ169.11,167.61,167.51,159.95,156.91,151.84,150.51,150.09,149.12,146.90,146.86,145.39,144.01,130.55,128.74,126.07,118.45,106.38,105.08,103.48,103.04,94.70,76.86,66.79,50.50,49.99,40.72,30.85,7.97.
3.化合物w-27的制备
用2-(2,4-二氧代嘧啶-5-氟-1-基)乙酸代替2-(2,4-二氧代嘧啶-1-基)乙酸，制备和纯化方法同化合物w-25，得到黄色粉末状固体60mg，收率74％，即化合物w-27。mp 242-243℃；HRMS(ESI):calcd for C29H22FN5O10 620.5184,found 620.1409.
1H NMR(500MHz,DMSO)δ8.73(s,1H),8.37(s,1H),7.97(d,J＝6.4Hz,1H),7.41(s,2H),7.01(s,1H),6.26(s,2H),5.46(s,2H),5.09(s,2H),4.29(d,J＝18.1Hz,2H),4.26–4.17(m,1H),4.11–4.02(m,1H),2.19–2.07(m,2H),0.90(t,J＝6.8Hz,3H).
13C NMR(125MHz,DMSO)δ169.12,167.68,167.51,156.91,151.84,150.07,150.04,149.11,146.90,146.84,145.40,140.65,131.35,131.07,130.54,128.70,126.05,118.46,105.04,103.47,103.05,94.71,76.85,66.79,50.48,49.86,40.72,30.86,7.97.
实施例3 20位为杂环酰胺修饰的10,11-亚甲二氧基喜树碱衍生物的制备
本发明20位为杂环酰胺修饰的10,11-亚甲二氧基喜树碱衍生物可通过如下通式进行制备。
反应条件:(a)DMAP,DIC,EDCI,DCM；(b)CF3COOH,CH2Cl2；(c)CDI,合适的仲胺(2°amine),Et3N,DCM,0℃.
概括地讲，所述20位为杂环酰胺修饰的10,11-亚甲二氧基喜树碱衍生物的制备步骤包括：
1)10,11-亚甲二氧基喜树碱在缩合剂催化下和Boc保护的甘氨酸发生酰化反应，得到的产物在三氟乙酸条件下脱掉Boc保护基，得到20位甘氨酸修饰的10,11-亚甲二氧基喜树碱；
2)以上述得到20位甘氨酸修饰的10,11-亚甲二氧基喜树碱，在三乙胺催化下和羰基二咪唑、杂环胺发生酰化反应，得到所述化合物。
具体化合物的制备方法如下：
1.化合物w-28的制备
在50mL茄型瓶中加入3(50mg,0.11mmol),三乙胺3滴和二氯甲烷(10mL),放入冰浴中反应，待反应温度降至0℃，加入CDI(23.4mg,0.14mmol)反应1h，加入吗啉(15μL，0.154mmol),升至室温,反应过夜。TLC检测反应完全后，加入二氯甲烷(50mL)稀释，有机层依次用蒸馏水、饱和食盐水洗涤3次，无水MgSO4干燥有机层。旋蒸浓缩得到黄色油状液体，硅胶柱层析(二氯甲烷:丙酮＝8:1)分纯，得到黄色固体48mg，收率78％，即化合物w-28。mp>250℃；HRMS(ESI):calcd for C28H26N4O9 563.5350,found 563.1758.
1H NMR(500MHz,DMSO)δ8.42(s,1H),7.46(s,1H),7.42(s,1H),7.14(t,J＝5.7Hz,1H),7.05(s,1H),6.27(d,J＝4.8Hz,2H),5.45(s,2H),5.15(s,2H),4.02(dd,J＝17.7,5.7Hz,1H),3.90(dd,J＝17.8,5.8Hz,1H),3.48(t,J＝4.7Hz,4H),3.25(dt,J＝13.5,6.6Hz,4H),2.12(td,J＝13.8,7.0Hz,2H),0.89(t,J＝7.3Hz,3H).
13C NMR(125MHz,DMSO)δ170.50,167.64,157.76,156.94,151.85,150.20,149.12,146.92,146.68,145.54,130.58,128.76,126.05,118.48,105.01,103.53,103.06，95.08,76.45,66.76,66.35,50.49,44.21,42.44,30.93,7.93.
2.化合物w-29的制备
用四氢吡咯代替吗啉，制备和纯化方法同化合物w-28，得到黄色固体46mg，收率76％，即化合物w-29。mp>250℃；HRMS(ESI):calcd for C28H26N4O8 547.5360,found547.1809.
1H NMR(500MHz,DMSO)δ8.45(s,1H),7.47(d,J＝22.2Hz,2H),7.03(s,1H),6.64(s,1H),6.27(s,2H),5.45(s,2H),5.20(s,2H),3.98(s,1H),3.90(d,J＝17.9Hz,1H),3.17(d,J＝7.5Hz,4H),2.12(s,2H),1.74(s,4H),0.87(t,J＝7.1Hz,3H).
13C NMR(125MHz,DMSO)δ170.76,167.64,156.97,156.57,151.86,150.24,149.16,146.97,146.75,145.45,135.04,130.65,128.86,126.13,120.43,118.63,105.09,103.61,103.06,95.00,76.34,66.82,50.56,45.72,42.16,31.04,25.45,7.89.
3.化合物w-30的制备
用哌嗪代替吗啉，制备和纯化方法同化合物w-28，得到黄色固体23mg，收率36％，即化合物w-30。mp 243-244℃；HRMS(ESI):calcd for C29H29N5O8 576.5780,found576.2073.
1H NMR(500MHz,DMSO)δ8.36(s,1H),7.37(s,1H),7.34(s,1H),7.10(s,1H),6.21(d,J＝2.3Hz,2H),5.42(q,J＝16.8Hz,2H),5.05(s,2H),4.03(d,J＝17.9Hz,1H),3.92(d,J＝17.9Hz,1H),3.36(s,4H),2.59(s,4H),2.36(s,3H),2.08(dt,J＝24.0,7.0Hz,2H),0.89(t,J＝7.3Hz,3H).
13C NMR(125MHz,DMSO)δ170.45,167.84,157.51,157.15,151.99,149.78,149.17,146.67,146.48,146.10,130.94,128.51,126.09,118.22,104.60,103.48,103.11,66.58,53.86,53.63,45.17,44.38,42.33,42.24,30.70,7.86.
4.化合物w-31的制备
用2-甲基哌啶代替吗啉，制备和纯化方法同化合物w-28，得到黄色固体49mg，收率78％，即化合物w-31。mp 240-242℃；HRMS(ESI):calcd for C30H30N4O8 575.5900,found575.2121.
1H NMR(500MHz,DMSO)δ8.28(d,J＝3.2Hz,1H),7.32–7.28(m,1H),7.25(d,J＝10.6Hz,1H),7.13(d,J＝8.0Hz,1H),6.20(d,J＝5.0Hz,2H),5.41(dd,J＝30.3,16.6Hz,2H),4.94(dd,J＝22.9,12.8Hz,2H),4.07–3.97(m,1H),3.97–3.85(m,1H),3.71(d,J＝14.6Hz,1H),2.69(dt,J＝26.3,12.7Hz,1H),2.14–2.01(m,2H),1.87–1.79(m,1H),1.53–1.30(m,5H),0.98(dd,J＝21.3,6.8Hz,3H),0.93–0.83(m,3H).
13C NMR(125MHz,DMSO)δ172.97,170.74,157.28,156.98,151.79,150.51,150.40,149.09,147.02,146.36,130.61,128.86,126.05,118.53,105.27,103.56,103.03,96.34,76.40,72.86,65.69,55.37,50.62,45.60,38.35,30.68,18.75,15.74,8.24.
5.化合物w-32的制备
用硫代吗啉代替吗啉，制备和纯化方法同化合物w-28，得到黄色固体45mg，收率70％，即化合物w-32。mp>250℃；HRMS(ESI):calcd for C28H26N4O8S 579.5860,found579.1544.
1H NMR(500MHz,DMSO)δ8.43(s,1H),7.47(s,1H),7.42(s,1H),7.17(t,J＝5.8Hz,1H),7.09(d,J＝5.9Hz,1H),6.27(d,J＝4.9Hz,2H),5.46(s,2H),5.17(d,J＝9.6Hz,2H),4.01(dd,J＝17.7,5.7Hz,1H),3.89(dd,J＝17.7,5.7Hz,1H),3.59(ddd,J＝12.9,9.1,4.3Hz,3H),3.29–3.25(m,1H),2.84–2.80(m,1H),2.46(t,J＝4.9Hz,3H),2.13(tt,J＝14.2,7.2Hz,2H),0.91(t,J＝7.4Hz,3H).
13C NMR(125MHz,DMSO)δ170.56,167.66,157.18,156.97,151.85,150.23,149.13,146.94,146.69,145.65,130.58,128.78,126.05,118.42,105.03,103.55,103.06,95.20,76.49,66.74,50.52,46.54,45.21,42.70,30.91,26.55,24.08,7.97.
6.化合物w-33的制备
用哌啶代替吗啉，制备和纯化方法同化合物w-28，得到黄色固体51mg，收率74％，即化合物w-33。mp 240-242℃；HRMS(ESI):calcd for C29H28N4O8 560.5580,found560.2821.
1H NMR(500MHz,DMSO)δ8.28(d,J＝3.2Hz,1H),7.32–7.28(m,1H),7.25(d,J＝10.6Hz,1H),7.13(d,J＝8.0Hz,1H),6.20(d,J＝5.0Hz,2H),5.41(dd,J＝30.3,16.6Hz,2H),4.94(dd,J＝22.9,12.8Hz,2H),4.07–3.97(m,1H),3.97–3.85(m,1H),3.71(d,J＝14.6Hz,1H),2.69(dt,J＝26.3,12.7Hz,1H),2.14–2.01(m,2H),1.87–1.79(m,1H),1.53–1.30(m,5H),0.98(dd,J＝21.3,6.8Hz,3H),0.93–0.83(m,3H).
13C NMR(125MHz,DMSO)δ172.97,170.74,157.28,156.98,151.79,150.51,150.40,149.09,147.02,146.36,130.61,128.86,126.05,118.53,105.27,103.56,103.03,96.34,76.40,72.86,65.69,55.37,50.62,45.60,38.35,30.68,18.75,15.74,8.24.
实施例4 20位为羧酸修饰的10,11-亚甲二氧基喜树碱衍生物
1.化合物z-1-9的制备
本发明化合物z-1-9可以通过以下反应来进行制备。
反应:(a)DMAP,DIC,EDCI,DCM；(b)CF3COOH,CH2Cl2.
具体的，在100mL的茄形瓶中加入20(S)-10,11-亚甲二氧基喜树碱(200mg,0.5mmol)，用无水二氯甲烷(45mL)溶解，再加入EDCI(0.84g,4.4mmol)，DMAP(124mg,1.02mmol)，2S-(4′-丁酸酰胺)-3R-叔丁基二甲基硅基十九烷醇(1.81g,4.4mmol)，氮气保护下常温反应12h。TLC检测反应完全后，降至室温，加入二氯甲烷(100mL)稀释，依次用0.1M的稀盐酸，蒸馏水，饱和食盐水洗三次，旋蒸浓缩得到黄色油状液体，硅胶柱层析(二氯甲烷:丙酮＝20:1)分纯，得到黄色固体0.27g，收率60％，即化合物4。mp 223-224℃；HRMS(ESI):calcd for C51H75N3O8Si 885.5341,found 885.2656.
1H NMR(500MHz,dmso)δ8.45(s,1H),7.55(d,J＝6.2Hz,1H),7.50(s,1H),7.45(s,1H),7.00(s,1H),6.26(s,2H),5.44(s,2H),5.19(s,2H),3.01(s,2H),2.99–2.93(m,1H),2.74(s,2H),2.64(d,J＝21.2Hz,2H),2.11(s,3H),1.99(s,2H),1.19(t,J＝14.5Hz,34H),0.88(t,J＝7.3Hz,3H),0.84–0.80(m,4H),0.75(d,J＝10.1Hz,9H),-0.04(t,J＝13.3Hz,6H).
在100mL的茄形瓶中加入化合物4(100mg,0.11mmol)，用CF3COOH溶解，常温反应12h。TLC检测反应完全后，旋蒸浓缩得到黄色油状液体，硅胶柱层析(二氯甲烷:丙酮＝5:1)分纯，得到淡黄色固体0.07g，收率90％，即化合物z-1-9。mp 240-241℃；HRMS(ESI):calcdfor C44H59N3O9 773.4351,found 773.2159.
1H NMR(500MHz,CDCl3)δ8.23(s,1H),7.62(s,1H),7.17(s,1H),6.21(s,2H),5.67(d,J＝16.9Hz,1H),5.38(d,J＝17.1Hz,1H),5.21(s,2H),3.25–3.14(m,2H),2.96–2.84(m,2H),2.63–2.53(m,2H),2.30–2.07(m,4H),1.25(s,47H),0.98(t,J＝7.0Hz,3H),0.88(t,J＝6.7Hz,4H).
2.化合物z-2-5的制备
本发明化合物z-2-5可以通过以下反应来进行制备。
反应条件:(a)DMAP,DIC,EDCI,DCM.
具体地，在100mL的茄形瓶中加入20(S)-10,11-亚甲二氧基喜树碱(200mg,0.5mmol)，用无水二氯甲烷(45mL)溶解，再加入EDCI(0.84g,4.4mmol)，DMAP(124mg,1.02mmol)，(4E,8E,12E,16E)-4,8,12,16,2021-五甲基-4,8,12,16,20-五烯-二十二碳五烯酸(1.76g,4.4mmol)，氮气保护下常温反应12h。TLC检测反应完全后，降至室温，加入二氯甲烷(100mL)稀释，依次用0.1M的稀盐酸，蒸馏水，饱和食盐水洗三次，旋蒸浓缩得到黄色油状液体，硅胶柱层析(二氯甲烷:丙酮＝15:1)分纯，得到棕色固体0.25g，收率65％，即化合物z-2-5。mp 223-224℃；HRMS(ESI):calcd for C48H58N2O7 774.4251,found 774.3124.
1H NMR(500MHz,CDCl3)δ8.17(s,1H),7.48(s,1H),7.16(s,1H),7.12(s,1H),6.19(s,2H),5.67(d,J＝17.1Hz,1H),5.40(d,J＝17.1Hz,1H),5.22–5.05(m,6H),3.50(s,2H),2.65–2.54(m,2H),2.37–2.23(m,3H),2.21–2.11(m,2H),2.11–1.88(m,14H),1.71–1.55(m,15H),1.53(s,3H),0.97(t,J＝7.5Hz,3H).
实施例5 20位为碳酸酯修饰的10,11-亚甲二氧基喜树碱衍生物的制备
1.化合物z-3-3的制备
本发明化合物z-3-3可以通过以下反应来进行制备。
反应条件:(a)Triphosgene,CH2Cl2,DMAP,2,2'-dithiobis-Ethanol；(b)DMAP,DIC,EDCI,DCM；(c)CF3COOH,CH2Cl2.
具体地，N2保护下，0℃条件下将无水DCM溶解的三光气(0.45g，1.53mmol)滴加到无水DCM溶解的20(S)-10,11-亚甲二氧基喜树碱(1.5g，3.82mmol)和DMAP(1.4g,4.59mmol)中，室温搅拌1h后，加入无水THF溶解的双(2-羟基乙基)二硫醚(11.7g,76.3mmol)，氮气保护下室温反应12h。反应完毕，停止反应，降至室温，旋蒸浓缩除去溶剂，硅胶柱层析(二氯甲烷:丙酮＝10:1)分离纯化，得到黄褐色粉末状固体1.3g，收率67％，即化合物5。mp 211-212℃；HRMS(ESI):calcd for C26H24N2O9S2 572.0952,found 572.0142.
1H NMR(500MHz,dmso)δ8.43(s,1H),7.48(d,J＝4.2Hz,1H),6.95(s,1H),6.27(s,2H),5.47(d,J＝17.2Hz,2H),5.19(d,J＝4.7Hz,2H),4.32(t,J＝6.1Hz,2H),3.55(t,J＝6.4Hz,2H),2.98(dd,J＝13.7,7.5Hz,2H),2.80–2.72(m,2H),2.15(tq,J＝14.2,7.0Hz,2H),0.90(dd,J＝16.4,9.0Hz,3H).
在100mL的茄形瓶中加入化合物5(100mg,0.17mmol)，用无水二氯甲烷(45mL)溶解，再加入EDCI(0.84g,4.4mmol)，DMAP(124mg,1.02mmol)，2S-(4′-丁酸酰胺)-3R-叔丁基二甲基硅基十九烷醇(1.81g,4.4mmol)，氮气保护下常温反应12h。TLC检测反应完全后，降至室温，加入二氯甲烷(100mL)稀释，依次用0.1M的稀盐酸，蒸馏水，饱和食盐水洗三次，旋蒸浓缩得到黄色油状液体，硅胶柱层析(二氯甲烷:丙酮＝20:1)分纯，得到黄色固体0.17g，收率65％，即化合物6。mp 254-255℃；HRMS(ESI):calcd for C55H81N3O12S2Si 1067.5124,found 1067.1245.
1H NMR(500MHz,dmso)δ8.42(s,1H),7.55(s,1H),7.46(s,1H),7.44(s,1H),6.93(d,J＝4.9Hz,1H),6.24(d,J＝20.3Hz,2H),5.46(d,J＝19.1Hz,2H),5.17(s,2H),4.30(dd,J＝16.7,10.8Hz,2H),4.15(s,2H),3.16(d,J＝13.7Hz,1H),3.07–3.02(m,2H),3.01–2.96(m,2H),2.91(t,J＝6.2Hz,2H),2.45–2.41(m,2H),2.34(d,J＝6.3Hz,2H),2.14(dt,J＝22.2,7.3Hz,2H),1.33–1.11(m,31H),1.06(s,3H),0.90(t,J＝7.3Hz,3H),0.82–0.78(m,9H),-0.00(dd,J＝25.7,6.1Hz,6H).
在100mL的茄形瓶中加入化合物6(100mg,0.09mmol)，用CF3COOH溶解，常温搅拌12h。TLC检测反应完全后，真空旋蒸浓缩得到黄色油状液体，硅胶柱层析(二氯甲烷:丙酮＝5:1)分纯，得到淡黄色固体0.08g，收率90％，即化合物z-3-3。mp 251-252℃；HRMS(ESI):calcd for C49H67N3O12S2 953.4215,found 953.3215.
1H NMR(500MHz,dmso)δ8.43(s,1H),7.62(s,1H),7.46(d,J＝14.0Hz,2H),6.94(s,1H),6.26(s,2H),5.48(s,2H),5.18(s,2H),4.31(s,2H),4.15(s,2H),2.97(s,4H),2.90(t,J＝6.1Hz,2H),2.42(d,J＝6.6Hz,2H),2.35(d,J＝6.5Hz,2H),2.14(dd,J＝14.5,7.0Hz,2H),1.21(d,J＝23.7Hz,30H),0.90(dd,J＝15.8,8.6Hz,6H),0.82(t,J＝6.5Hz,3H).
2.化合物z-4-2的制备
本发明化合物z-4-2可以通过以下反应来进行制备。
反应条件:(a)Triphosgene,CH2Cl2,DMAP,2,2'-dithiobis-Ethanol；(b)DMAP,DIC,EDCI,DCM.
具体地，N2保护下，0℃条件下将无水DCM溶解的三光气(0.45g，1.53mmol)滴加到无水DCM溶解的20(S)-10,11-亚甲二氧基喜树碱(1.5g，3.82mmol)和DMAP(1.4g,4.59mmol)中，室温搅拌1h后，加入无水THF溶解的双(2-羟基乙基)二硫醚(11.7g,76.3mmol)，氮气保护下室温反应12h。反应完毕，停止反应，降至室温，旋蒸浓缩除去溶剂，硅胶柱层析(二氯甲烷:丙酮＝10:1)分离纯化，得到黄褐色粉末状固体1.3g，收率67％，即化合物5。mp 211-212℃；HRMS(ESI):calcd for C26H24N2O9S2 572.0952,found 572.0142.
1H NMR(500MHz,dmso)δ8.43(s,1H),7.48(d,J＝4.2Hz,1H),6.95(s,1H),6.27(s,2H),5.47(d,J＝17.2Hz,2H),5.19(d,J＝4.7Hz,2H),4.32(t,J＝6.1Hz,2H),3.55(t,J＝6.4Hz,2H),2.98(dd,J＝13.7,7.5Hz,2H),2.80–2.72(m,2H),2.15(tq,J＝14.2,7.0Hz,2H),0.90(dd,J＝16.4,9.0Hz,3H).
在100mL的茄形瓶中加入5(100mg,0.17mmol)，用无水二氯甲烷(45mL)溶解，再加入EDCI(0.84g,4.4mmol)，DMAP(124mg,1.02mmol)，(4E,8E,12E,16E)-4,8,12,16,21-五甲基-4,8,12,16,20-五烯-二十二碳酸(1.76g,4.4mmol)，氮气保护下常温搅拌12h。TLC检测反应完全后，降至室温，加入二氯甲烷(100mL)稀释，依次用0.1M的稀盐酸，蒸馏水，饱和食盐水洗三次，真空旋蒸浓缩得到黄色油状液体，硅胶柱层析(二氯甲烷:丙酮＝20:1)分纯，得到黄色固体0.17g，收率67％，即化合物z-4-2。mp 254-255℃；HRMS(ESI):calcd forC53H66N2O10S2 954.4219,found 954.3258.
1H NMR(500MHz,dmso)δ8.44(s,1H),7.48(s,1H),7.44(s,1H),6.94(s,1H),6.26(d,J＝4.6Hz,2H),5.47(t,J＝9.4Hz,2H),5.19(s,2H),5.04(d,J＝7.5Hz,4H),4.30(dd,J＝9.8,4.1Hz,2H),4.15(t,J＝6.1Hz,2H),2.99(t,J＝6.0Hz,2H),2.91(t,J＝6.2Hz,2H),2.29(t,J＝7.6Hz,2H),2.17–2.08(m,4H),1.94(ddd,J＝37.3,14.3,6.9Hz,13H),1.59(d,J＝6.1Hz,3H),1.53–1.48(m,12H),0.89(t,J＝7.4Hz,3H).
3.化合物z-5-1的制备
本发明化合物z-5-1可以通过以下反应来进行制备。
反应条件:(a)Triphosgene,CH2Cl2,DMAP,2,2'-dithiobis-Ethanol；(b)DMAP,DIC,EDCI,DCM.
具体地，N2保护下，0℃条件下将无水DCM溶解的三光气(0.45g，1.53mmol)滴加到无水DCM溶解的20(S)-10,11-亚甲二氧基喜树碱(1.5g，3.82mmol)和DMAP(1.4g,4.59mmol)中，室温搅拌1h后，加入无水THF溶解的双(2-羟基乙基)二硫醚(11.7g,76.3mmol)，氮气保护下室温反应12h。反应完毕，停止反应，降至室温，旋蒸浓缩除去溶剂，硅胶柱层析(二氯甲烷:丙酮＝10:1)分离纯化，得到黄褐色粉末状固体1.3g，收率67％，即化合物5。mp 211-212℃；HRMS(ESI):calcd for C26H24N2O9S2 572.0952,found 572.0142.
1H NMR(500MHz,dmso)δ8.43(s,1H),7.48(d,J＝4.2Hz,1H),6.95(s,1H),6.27(s,2H),5.47(d,J＝17.2Hz,2H),5.19(d,J＝4.7Hz,2H),4.32(t,J＝6.1Hz,2H),3.55(t,J＝6.4Hz,2H),2.98(dd,J＝13.7,7.5Hz,2H),2.80–2.72(m,2H),2.15(tq,J＝14.2,7.0Hz,2H),0.90(dd,J＝16.4,9.0Hz,3H).
在100mL的茄形瓶中加入5(100mg,0.17mmol)，用无水二氯甲烷(45mL)溶解，再加入EDCI(0.84g,4.4mmol)，DMAP(124mg,1.02mmol)，9-十八烯酸(1.23g,4.4mmol)，氮气保护下常温反应12h。TLC检测反应完全后，降至室温，加入二氯甲烷(100mL)稀释，依次用0.1M的稀盐酸，蒸馏水，饱和食盐水洗三次，旋蒸浓缩得到黄色油状液体，硅胶柱层析(二氯甲烷:丙酮＝20:1)分纯，得到黄色固体0.23g，收率70％，即化合物z-5-1。mp 223-225℃；HRMS(ESI):calcd for C44H56N2O10S2 836.5119,found 836.3258.
1H NMR(500MHz,dmso)δ8.44(s,1H),7.48(s,1H),7.44(s,1H),6.94(s,1H),6.26(d,J＝4.6Hz,2H),5.47(t,J＝9.4Hz,2H),5.19(s,2H),5.04(d,J＝7.5Hz,4H),4.30(dd,J＝9.8,4.1Hz,2H),4.15(t,J＝6.1Hz,2H),2.99(t,J＝6.0Hz,2H),2.91(t,J＝6.2Hz,2H),2.29(t,J＝7.6Hz,2H),2.17–2.08(m,4H),1.59(d,J＝6.1Hz,3H),1.53–1.48(m,12H),0.89(t,J＝7.4Hz,3H).
4.化合物z-6-1的制备
用9,12-二烯十八酸代替9-十八烯酸，制备和纯化方法同化合物z-5-1，得到黄色固体200mg，收率71％，即化合物z-6-1。mp 238-240℃；HRMS(ESI):calcd for C44H56N2O10S2836.1200,found 836.2121.
1H NMR(500MHz,dmso)δ8.44(s,1H),7.48(s,1H),7.44(s,1H),6.94(s,1H),6.26(d,J＝4.6Hz,2H),5.47(t,J＝9.4Hz,2H),5.19(s,2H),5.04(d,J＝7.5Hz,4H),4.30(dd,J＝9.8,4.1Hz,2H),4.15(t,J＝6.1Hz,2H),2.99(t,J＝6.0Hz,2H),2.91(t,J＝6.2Hz,2H),2.29(t,J＝7.6Hz,1H),2.17–2.08(m,4H),1.59(d,J＝6.1Hz,3H),1.53–1.48(m,12H),0.89(t,J＝7.4Hz,3H).
5.化合物z-7-1的制备
本发明化合物z-7-1可以通过以下反应来进行制备。
反应条件:(a)Triphosgene,CH2Cl2,DMAP,2,2'-dithiobis-Ethanol；(b)DMAP,DIC,EDCI,DCM.
具体地，N2保护下，0℃条件下将无水DCM溶解的固体三光气(0.45g，1.53mmol)滴加到无水DCM溶解的20(S)-10,11-亚甲二氧基喜树碱(1.5g，3.82mmol)和DMAP(1.4g,4.59mmol)中，室温搅拌1h后，加入无水THF溶解的双(2-羟基乙基)二硫醚(11.7g,76.3mmol)，氮气保护下室温反应12h。反应完毕，停止反应，降至室温，旋蒸浓缩除去溶剂，硅胶柱层析(二氯甲烷:丙酮＝10:1)分离纯化，得到黄褐色粉末状固体1.3g，收率67％，即化合物5。mp 211-212℃；HRMS(ESI):calcd for C26H24N2O9S2 572.0952,found 572.0142.
1H NMR(500MHz,dmso)δ8.43(s,1H),7.48(d,J＝4.2Hz,1H),6.95(s,1H),6.27(s,2H),5.47(d,J＝17.2Hz,2H),5.19(d,J＝4.7Hz,2H),4.32(t,J＝6.1Hz,2H),3.55(t,J＝6.4Hz,2H),2.98(dd,J＝13.7,7.5Hz,2H),2.80–2.72(m,2H),2.15(tq,J＝14.2,7.0Hz,2H),0.90(dd,J＝16.4,9.0Hz,3H).
在100mL的茄形瓶中加入5(100mg,0.17mmol)，用无水二氯甲烷(45mL)溶解，再加入EDCI(0.84g,4.4mmol)，DMAP(124mg,1.02mmol)，6(1.82g,4.4mmol)，氮气保护下常温反应12h。TLC检测反应完全后，降至室温，加入二氯甲烷(100mL)稀释，依次用0.1M的稀盐酸，蒸馏水，饱和食盐水洗三次，旋蒸浓缩得到黄色油状液体，硅胶柱层析(二氯甲烷:丙酮＝20:1)分纯，得到黄色固体0.31g，收率70％，即化合物z-7-1。mp 250-252℃；HRMS(ESI):calcd for C42H43N5O14S4 969.1519,found 969.3258.
6.化合物z-8-1的制备
用6化合物的苯环3位溴代的化合物带起化合物6，制备和纯化方法同化合物z-7-1，得到黄色固体320mg，收率69％，即化合物z-8-1。mp 252-254℃；HRMS(ESI):calcd forC42H42BrN2O14S4 1047.1430,found 1047.2131.
实施例6本发明的10,11-亚甲二氧基喜树碱衍生物体外抗肿瘤活性测试
为了初步评价20位修饰的喜树碱衍生物的细胞毒活性，按照本领域常规的测试方法测定了化合物2、3及w-1-w-33在50nM浓度对人肺癌A549细胞的抑制率。
实验结果如表1所示，在50nM浓度下，20位以甘氨酸为连接臂的磺酰脒修饰的化合物w-1-w-24，20位以甘氨酸为连接臂的尿嘧啶修饰的化合物w-25-w-27和20位以甘氨酸为连接臂的杂环酰胺修饰的化合物w-28-w-33对A549细胞的抑制率均在50％以上，表现出了良好的细胞毒活性，且显著优于伊立替康。
表1 A549细胞筛选结果1
表2部分化合物对体外细胞株A549、HCT-116和NCI-H1975的IC50值
我们另外按照本领域常规的测试方法测定了化合物w-25-w-32对人肺腺癌细胞株A549、人结肠癌细胞株HCT-116和人非小细胞肺腺癌细胞株NCI-H1975的细胞毒活性(表2)，结果表明20位修饰的衍生物具有很强的抗肿瘤活性，A549、HCT-116和NCI-H1975细胞对化合物w-25、w-27、w-30和w-31都非常敏感，其中20位为2-甲基哌啶酰胺修饰的化合物w-31对A549细胞的抑制活性(IC50＝9.76nM)优于伊立替康1000倍(IC50＝9.14uM)。
表3部分化合物对体外细胞株SW620、HCT-8、NCI-H446的IC50值
注：a表格中表示伊立替康10uM下对相应细胞株的抑制率。
我们另外按照本领域常规的测试方法测定了化合物w-31、z-1-9、z-2-5、z-3-3、和z-4-2对人结肠癌细胞SW620、人结肠癌细胞HCT-8和人小细胞肺癌细胞NCI-H446的细胞毒活性(表3)，数据表明SW620、HCT-8、NCI-H446细胞对化合物w-31非常敏感，IC50可以达到0.11nM，其活性高于伊立替康，其他四个化合物的活性也高于伊立替康。
实施例7体内抗肿瘤活性测试
运用本领域公知的技术，本发明人通过小鼠移植瘤模型对本发明化合物z-1-9的体内抗肿瘤活性进行了测试。
测试方法包括：
人肺癌A549细胞体外培养至所需数量，收集细胞离心，去上清，PBS洗1次，用PBS重悬细胞，皮下接种于BALB/c-nu小鼠右前肢腋下，每只接种8×106个细胞。待小鼠腋下瘤体积生长至100mm3左右时，将小鼠按瘤体积随机分为3组，溶剂对照组、z-1-9高剂量组和低剂量组。z-1-9高剂量组和低剂量组分别灌胃给予24mg/kg以及12mg/kg的z-1-9，每2天给药1次。每周三次记录小鼠体重变化情况以及瘤体积大小。
结果观察：
BALB/c-nu小鼠皮下接种A549细胞后，约10天左右，肿瘤体积达到100mm3，随机分组给药。第19天，溶剂对照组肿瘤组织生长至1157.21±370.81mm3，处死小鼠，剥取肿瘤组织，冻存于-80℃。其余各组停止给药，继续观察，记录肿瘤体积，于给药后第28天处死全部小鼠，剥取肿瘤组织，冻存于-80℃。
以给药天数为横坐标，绘制肿瘤体积生长曲线，如图1所示。与溶剂对照组相比，z-1-9化合物高剂量和低剂量给药均能明显抑制小鼠A549移植瘤的生长，且具有一定的剂量依赖性，给药19天后抑瘤率分别为73.79％和54.66％。
表4.化合物对小鼠A549移植瘤生长的影响
注：*p<0.01vs溶剂对照组
a根据给药19天后数据计算
以给药天数为横坐标，绘制小鼠体重变化曲线，结果见图2。溶剂对照组小鼠体重呈逐渐增高趋势。z-1-9给药后，高、低剂量组小鼠体重均明显下降。5天后逐渐恢复，但是仍低于对照组小鼠体重，其中高剂量组尤为明显，提示其具有一定的毒副作用，轻微的毒副作用是喜树碱类化合物普遍存在的问题。
运用类似的测试方法，我们测试了化合物w-31对小鼠A549移植瘤的生长抑制作用。
人肺癌A549细胞皮下接种于小鼠右前肢腋下，待生长至100mm3左右时，分组给药，w-31高、中、低剂量组分别灌胃给予20mg/kg、10mg/kg和5mg/kg化合物w-31，每周2次，溶剂对照组灌胃等体积溶剂。每周三次测量小鼠体重。给药19天后，处死对照组小鼠。其余各组小鼠停止给药，继续测量至28天，处死小鼠。
表5.化合物31对小鼠A549移植瘤生长的影响
注：*p<0.01vs溶剂对照组
a根据给药19天后数据计算
结果显示表5、图3和图4，化合物w-31对小鼠A549实体瘤的生长有明显抑制作用，且呈剂量依赖性；5、10mg/kg剂量给药对小鼠体重无明显影响，20mg/kg剂量给药对小鼠体重有一定影响，毒副作用相较同类化合物有一定改善。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，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 (17)
1.一种具有式(I)所示结构的化合物、其异构体或其药学上可接受的盐：
式中，X为-(CH2)n-、-(CH2)nO-、-(CH2)nNH-、-(CH2)nCONH-、-(CH2)nNHCO(CH2)m-、(CH2)n-(CH＝CH)p-(CH2)m-、-(CH2)n-(CH＝CH)p-(CH2)mO-、-O(CH2)nSS(CH2)mO-或-O(CH2)nSS(CH2)mOCOY-；
Y为-(CH2)n-或-(CH2)nCONH-；
n和m各自独立地为0或者正整数；
p为正整数；
R选自于氢原子、取代或未取代的磺酰胺基、取代或未取代的碱基、取代或未取代的饱和含氮杂环和取代或未取代的烷基中的任意一种；
当所述基团为取代的基团时，该取代基选自于氢原子、卤原子、羟基、硝基、氨基、烷基、取代的烷基、烷氧基、取代的烷氧基、芳基、取代的芳基、杂芳基和取代的杂芳基中的任意一种。
2.根据权利要求1所述的化合物，其特征在于，X为-(CH2)nNH-，n为1，R为取代或未取代的磺酰胺基，并且R具有式(II)所示结构：
其中，
R1为烷基、芳基、取代的芳基、杂芳基或取代的杂芳基；
R2为芳基或取代的芳基。
3.根据权利要求2所述的化合物，其特征在于，R1为C1-C4烷基，优选地为甲基、乙基、正丙基或正丁基。
4.根据权利要求2所述的化合物，其特征在于，R1为苯基、取代的苯基、萘基、噻吩或吡啶，优选地为对位氟取代、氯取代、硝基取代、甲基取代或者甲氧基取代的苯基。
5.根据权利要求2所述的化合物，其特征在于，R2为苯基或取代的苯基，优选地为对位氟取代或者甲氧基取代的苯基。
6.根据权利要求2所述的化合物，其特征在于，所述化合物为w-1、w-2、w-3、w-4、w-5、w-6、w-7、w-8、w-9、w-10、w-11、w-12、w-13、w-14、w-15、w-16、w-17、w-18、w-19、w-20、w-21、w-22、w-23或w-24。
7.根据权利要求1所述的化合物，其特征在于，X为-(CH2)nNHCO(CH2)m-，n和m均为1，R为取代或未取代的尿嘧啶，并且R具有式(III)所示结构：
其中，R3为H、F或Cl。
8.根据权利要求7所述的化合物，其特征在于，所述化合物为w-25、w-26或w-27。
9.根据权利要求1所述的化合物，其特征在于，X为-(CH2)nNHCO(CH2)m-，n为1，m为0，R为取代或未取代的饱和含氮杂环。
10.根据权利要求9所述的化合物，其特征在于，所述化合物为w-28、w-29、w-30、w-31、w-32或w-33。
11.根据权利要求1所述的化合物，其特征在于，X为-(CH2)n-或-(CH2)nCONH-，n为2，R为取代或未取代的烷基。
12.根据权利要求11所述的化合物，其特征在于，所述化合物为z-1-9或z-2-5。
13.根据权利要求1所述的化合物，其特征在于，
X为-O(CH2)nSS(CH2)mOCOY-，Y为-(CH2)n-或-(CH2)nCONH-；
n和m均为2，R为取代或未取代的烷基。
14.根据权利要求13所述的化合物，其特征在于，所述化合物为z-3-3、z-4-2、z-5-1、z-6-1、z-7-1或z-8-1。
15.根据权利要求1所述的化合物，其特征在于，X为-CH2NH-或-OCH2CH2SSCH2CH2O-，R为H。
16.一种药物组合物，包含治疗有效剂量的权利要求1-15任一所述的化合物、其异构体，或其药学上可接受的盐，以及药学上可接受的载体。
17.根据权利要求1-15任一所述的化合物、其异构体或其药学上可接受的盐，或者权利要求16所述的药物组合物在用于制备预防和/或治疗癌症的药物中的应用。
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