CN110964078B - 具有抗肺癌作用的常春藤皂苷元类化合物h-x及其制备方法和应用 - Google Patents
具有抗肺癌作用的常春藤皂苷元类化合物h-x及其制备方法和应用 Download PDFInfo
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Abstract
本发明提供了一类具有抗肿瘤作用的常春藤皂苷元类化合物H‑X及其制备方法和应用,其结构通式1如下。本发明大部分衍生物对肿瘤细胞A549、MCF‑7和HepG2的抑制作用明显,其中化合物常春藤皂苷元‑2,6‑二甲基吡嗪(H‑08)在肿瘤与正常之间都表现出较好的选择性,尤其是对肺癌A549细胞。其对A549、MCF‑7、HepG2、MDCK及H9c2的IC50分别是3.45±0.59μM,8.73±1.49μM,8.71±0.38μM,14.11±0.04μM,16.69±0.12μM,其对A549细胞的抑制作用类似于阳性药顺铂(IC50为3.85±0.63μM),但对MDCK及H9c2的毒性明显低于顺铂。
Description
技术领域
本发明涉及一种化合物及其制备方法和应用,具体一种具有显著抗肺癌活性的化合物及其制备方法和应用,属于药物化学领域。
背景技术
恶性肿瘤是目前严重威胁人类生命和健康的重大疾病之一,据美国癌症协会在CA:A Cancer Journal for Clinicians杂志上发表的2018年癌症统计:在美国,2018年新增癌症患者1735350人,609640人死于癌症,其中肺癌患者的死亡数目最高,达到154050人。同时,中国国家癌症中心主任陈万青指出肺癌在中国是众多癌症之中的头号杀手。目前,手术、放疗和化疗是治疗肿瘤的常用方法。放疗、化疗在杀伤肿瘤细胞的同时也杀伤正常细胞,对人体副作用大,因此寻找高效低毒、选择性强的肿瘤治疗方法一直是肿瘤研究的热点。
常春藤皂苷元属β-香树脂烷型五环三萜类化合物,广泛分布于川续断科、忍冬科、毛茛科、五加科、败酱科等多种植物,如续断、威灵仙、白头翁、金银花等。研究表明常春藤皂苷元具有抗肿瘤、抗抑郁、抗菌抗炎、抗糖尿病等多种药理作用,但是常春藤皂苷元由于溶解性差,生物利用度低,口服给药效果差等特点,临床应用也受到相应限制。课题组前期借鉴中药配伍原则和药物化学拼合原理,辅以计算机辅助药物设计方法,在中药中的抗肿瘤活性成分中引入川芎嗪和碳链,通过初步药效学评价发现所合成的部分化合物的抗肿瘤作用及选择性得到明显增强,因此,本发明应用药物拼合,选取常春藤皂苷元、碳链及川芎嗪相拼合,以期获得选择性高、抗肿瘤作用强、毒副作用小的药物。
本发明以常春藤皂苷元为原料,运用药物化学的相关合成方法在常春藤皂苷元中引入碳链及川芎嗪,合成了本发明化合物(24种常春藤皂苷元-碳链-川芎嗪衍生物);对该类化合物的活性评价主要围绕抗肿瘤(尤其肺癌)方面展开,分别测试了类似物对3种癌症细胞系(A549、MCF-7、HepG2)和正常细胞系(H9c2、MDCK)的细胞毒活性。
发明内容
本发明的目的之一是提供一种具有结构通式1的化合物及其制备方法。
本发明的目的之二是提供通式1的化合物在制备抗肿瘤药物中的应用。
本发明的目的之三是提供一种具有显著性抗肺癌作用的化合物。
本发明的目的是通过如下技术方案实现的:
具有通式1结构的化合物或其药学上可接受的盐,
注明:通式1中虚线代表α构型;
进一步,本发明化合物编号及结构式如下:
进一步,所述化合物可加入制剂领域常规辅料制成片剂、胶囊剂、颗粒剂、散剂、口服液、注射剂等常规剂型。
本发明所述化合物的制备方法包括如下步骤:
本发明化合物按如下方法制备:
化合物H-01的制备方法:将常春藤皂苷元溶于有机溶剂,与2-氯甲基吡嗪在催化剂作用下生成H-01;
化合物H-02的制备方法:将常春藤皂苷元溶于有机溶剂,与2-氯甲基-6-甲基吡嗪在催化剂作用下生成H-02;
化合物H-03的制备方法:将常春藤皂苷元溶于有机溶剂,与2-氯甲基-5-甲基吡嗪在催化剂作用下生成H-03;
化合物H-04的制备方法:将常春藤皂苷元溶于有机溶剂,与2-氯甲基-3-甲基吡嗪在催化剂作用下生成H-04;
化合物H-05的制备方法:将常春藤皂苷元溶于有机溶剂,与2-氯甲基-5,6-二甲基吡嗪在催化剂作用下生成H-05;
化合物H-06的制备方法:将常春藤皂苷元溶于有机溶剂,与川芎嗪在催化剂作用下生成H-06;
化合物H-07的制备方法:将常春藤皂苷元溶于有机溶剂,分两步反应与2-溴乙醇及吡嗪酸在催化剂作用下生成H-07;
化合物H-08的制备方法:将常春藤皂苷元溶于有机溶剂,分两步反应与2-溴乙醇及6-甲基吡嗪酸在催化剂作用下生成H-08;
化合物H-09的制备方法:将常春藤皂苷元溶于有机溶剂,分两步反应与2-溴乙醇及5-甲基吡嗪酸在催化剂作用下生成H-09;
化合物H-10的制备方法:将常春藤皂苷元溶于有机溶剂,分两步反应与2-溴乙醇及3-甲基吡嗪酸在催化剂作用下生成H-10;
化合物H-11的制备方法:将常春藤皂苷元溶于有机溶剂,分两步反应与2-溴乙醇及5,6-二甲基吡嗪酸在催化剂作用下生成H-11;
化合物H-12的制备方法:将常春藤皂苷元溶于有机溶剂,分两步反应与2-溴乙醇及川芎嗪酸在催化剂作用下生成H-12;
化合物H-13的制备方法:将常春藤皂苷元溶于有机溶剂,分两步反应与4-氯-1丁醇及吡嗪酸在催化剂作用下生成H-13;
化合物H-14的制备方法:将常春藤皂苷元溶于有机溶剂,分两步反应与4-氯-1丁醇及6-甲基吡嗪酸在催化剂作用下生成H-14;;
化合物H-15的制备方法:将常春藤皂苷元溶于有机溶剂,分两步反应与4-氯-1丁醇及5-甲基吡嗪酸在催化剂作用下生成H-15;;
化合物H-16的制备方法:将常春藤皂苷元溶于有机溶剂,分两步反应与4-氯-1丁醇及3-甲基吡嗪酸在催化剂作用下生成H-16;
化合物H-17的制备方法:将常春藤皂苷元溶于有机溶剂,分两步反应与4-氯-1丁醇及5,6-二甲基吡嗪酸在催化剂作用下生成H-17;
化合物H-18的制备方法:将常春藤皂苷元溶于有机溶剂,分两步反应与4-氯-1丁醇及川芎嗪酸在催化剂作用下生成H-18;
化合物H-19的制备方法:将常春藤皂苷元溶于有机溶剂,分两步反应与4-氯-1丁醇及吡嗪酸在催化剂作用下生成H-19;
化合物H-20的制备方法:将常春藤皂苷元溶于有机溶剂,分两步反应与4-氯-1丁醇及6-甲基吡嗪酸在催化剂作用下生成H-20;
化合物H-21的制备方法:将常春藤皂苷元溶于有机溶剂,分两步反应与4-氯-1丁醇及5-甲基吡嗪酸在催化剂作用下生成H-21;
化合物H-22的制备方法:将常春藤皂苷元溶于有机溶剂,分两步反应与4-氯-1丁醇及3-甲基吡嗪酸在催化剂作用下生成H-22;
化合物H-23的制备方法:将常春藤皂苷元溶于有机溶剂,分两步反应与4-氯-1丁醇及5,6-二甲基吡嗪酸在催化剂作用下生成H-23;
化合物H-24的制备方法:将常春藤皂苷元溶于有机溶剂,分两步反应与4-氯-1丁醇及川芎嗪酸在催化剂作用下生成H-24;
本发明反应路线:
路线1 H-01-H-06的合成
反应条件和试剂:(1)NCS,BPO,CCl4,N2,60℃,8h(2)DMF,K2CO3,85℃,4h.
路线2 H-07-H-13的合成
反应条件和试剂:(1)2-Bromoethanol,DMF,K2CO3,85℃,4h(2)KMnO4,H2O,75℃,2h(3)CH2Cl2EDCI,DMAP,rt,12h.
路线3 H-14-H-20的合成
反应条件和试剂:(1)KMnO4,H2O,75℃,2h(2)CH2Cl24-chlorobutanol,EDCI,DMAP,rt,12h(3)DMF K2CO3,75℃,4h
路线4 H-21-H-26的合成
反应条件和试剂:(1)DMF,K2CO3,4-chlorobutanol,75℃,4h(2)CH2Cl2,EDCI,DMAP,rt,12h.
本发明还提供式1化合物在制备抗肿瘤药物中的应用。
进一步,所述肿瘤为肺癌、乳腺癌、肝癌细胞系。
本发明还提供一种药物组合物,该组合物包含以治疗有效量存在的式1化合物或其药学可接受的盐与至少一种药学可接受的赋形剂的混合物。
进一步,所述组合物还包含至少一种常规抗癌药。
更进一步,所述抗癌药选自环磷酰胺、5-氟尿嘧啶、紫杉醇、阿霉素、依托泊苷、伊立替康、奥沙利铂、顺铂或健择。
本发明还提供治疗癌症的方法,包括给予患者给药有效量的式1化合物或其药学上可接受的盐。
为使上述剂型能够实现,需在制备这些剂型时加入药学可接受的赋形剂,例如填充剂、崩解剂、润滑剂、助悬剂、粘合剂、甜味剂、矫味剂、防腐剂等,填充剂包括:淀粉、预胶化淀粉、乳糖、甘露醇、甲壳素、微晶纤维素、蔗糖等,崩解剂包括:淀粉、预胶化淀粉、微晶纤维素、羧甲基淀粉钠、交联聚乙烯吡咯烷酮、低取代羟丙纤维素、交联羧甲基纤维素钠等,润滑剂包括:硬脂酸镁、十二烷基硫酸钠、滑石粉、二氧化硅等,助悬剂包括:聚乙烯吡咯烷酮、微晶纤维素、蔗糖、琼脂、羟丙基甲基纤维素等,粘合剂包括,淀粉浆、聚乙烯吡咯烷酮、羟丙基甲基纤维素等,甜味剂包括:糖精钠、阿斯帕坦、蔗糖、甜蜜素、甘草次酸等,矫味剂包括:甜味剂及各种香精,防腐剂包括:尼泊金类、苯甲酸、苯甲酸钠、山梨酸及其盐类、苯扎溴铵、醋酸氯乙定、桉叶油等。
本发明所述“药学可接受的”表示化合物或组合物必须在化学上和/或毒理学上与制剂中包含的其他成分相容。
所述“治疗有效量”表示本发明化合物治疗或预防特定疾病或症状;减弱、改善或消除特定疾病的一种或多种症状;或预防或延迟特定疾病或症状的发作的量。
本发明化合物具有明显抑制肿瘤细胞系(A549、MCF-7、HepG-2)生长的活性但对H9c2,MDCK毒性较小。化合物H-08在肿瘤与正常之间都表现出较高的选择性。其对肺癌(A549)的抑制作用最强,其半数抑制浓度为3.45±0.59μM,与顺铂(DDP)类似(IC50为3.85±0.63μM),但毒性较低。
实验例1 MTT法观察本发明化合物H-X对肿瘤细胞和正常细胞增殖影响
1.仪器与材料
Thermo 3111型CO2培养箱;HFsafe生物安全柜;Multiskan GO酶标仪;京立牌LD5-2B型台式低速离心机;Olympus IX71倒置荧光显微镜改良型RPMI-1640、DMEM培养基、胎牛血清、0.25%胰蛋白酶溶液、噻唑蓝、磷酸盐缓冲液(赛默飞世尔生物化学制品北京有限公司);二甲基亚砜(DMSO);
人肺癌细胞系A549;人乳腺癌细胞系MCF-7;人肝癌细胞系HepG2;大鼠心肌细胞H9c2,犬肾细胞系MDCK。
实验药物:本发明化合物H-X1-24(分别按实施例5-27制备);阳性药物顺铂。
2.方法
2.1不同细胞株的培养
A549、MCF-7、HepG2和MDCK细胞培养在含10%胎牛血清的DMEM培养液中,放置于37℃、5%的CO2培养箱中温育。细胞均呈贴壁状态生长,在倒置显微镜下观察生长状况,待细胞数量适量时传代培养。
H9c2细胞培养在含10%胎牛血清的1640培养液中,放置于37℃、5%的CO2培养箱中温育。细胞均呈贴壁状态生长,在倒置显微镜下观察生长状况,待细胞数量适量时传代培养。
2.2初筛细胞抑制率
取对数生长期的A549、MCF-7、HepG2、MDCK以及H9c2细胞进行试验,胰蛋白酶消化后轻轻吹打制成单细胞悬液,计数后调整细胞浓度为3×104cells·mL-1,以每孔100μL细胞液的数量接种于96孔培养板中,随后置于含5%CO2的37℃培养箱中培养24h使细胞贴壁。每孔分别加入100μL用新鲜培养基稀释好的待测化合物,使药物最终浓度为50μM、25μM、12.5μM、6.25μM、3.125μM。设置细胞对照组及空白对照组,药物组每浓度设置4个复孔,细胞对照组和空白对照组设置12个复孔。培养箱中继续培养72h后,将培养液吸出,加入200μL新鲜培养液,再每孔加20μL5mg·mL-1MTT继续孵育4h,弃去上清,再加150μLDMSO,振荡10min,酶标仪490nm波长测得吸光度值并记录结果,抑制率%=[1-(A给药-A空白)/(A正常-A空白)]×100%。本部分实验重复三次。
3.结果
H-01~H-24以及阳性药(DDP)对3种肿瘤细胞系(A549、MCF-7和HepG2)和正常细胞系(MDCK,H9c2)的IC50值如表1所示。
由表1可以看出,大部分衍生物对肿瘤细胞A549、MCF-7和HepG2的抑制作用均强于常春藤皂苷元,其中化合物H-08(常春藤皂苷元-2,6-二甲基吡嗪)在肿瘤与正常之间都表现出较好的选择性,尤其是对A549细胞。其对A549、MCF-7、HepG2、MDCK和H9c2的IC50分别是3.45±0.59μM、8.73±1.49nM、8.71±0.38μM、14.11±0.04μM、16.69±0.12μM。
表1 常春藤皂苷元衍生物H-X对不同肿瘤细胞株、MDCK、H9c2细胞的IC50值
4.结论
本发明化合物表现出抑制肿瘤细胞系(A549、MCF-7和HepG2)增殖的活性。其中,化合物H-08对A549表现出较好的选择性,抗肿瘤活性类似于阳性药DDP,对大鼠心肌细胞(H9c2)以及犬肾细胞(MDCK)毒性低于DDP,表明该类化合物可用于抗肿瘤药物的研究。
实验例2 Annexin V-FITC/PI双染法观察本发明化合物P-02对肿瘤细胞凋亡影响
1.仪器与材料
Thermo 3111型CO2培养箱;HFsafe生物安全柜:京立牌LD5-2B型台式低速离心机;Olympus IX71倒置荧光显微镜;流式细胞仪;改良型RPMI-1640、DMEM培养基、胎牛血清、0.25%胰蛋白酶溶液、磷酸盐缓冲液(赛默飞世尔生物化学制品北京有限公司);AnnexinV-F1TC/PI试剂盒(索莱宝生物技术有限公司)。
人肺癌细胞系A549;
实验药物:本发明化合物H-08。
2.方法
2.1不同细胞株的培养
A549细胞培养在含10%胎牛血清的DMEM培养液中,放置于37℃、5%的CO2培养箱中温育。细胞均呈贴壁状态生长,在倒置显微镜下观察生长状况,待细胞数量适量时传代培养。
2.2Annexin V-FITC/PI双染法检测化合物H-08对A549凋亡影响
取对数生长期的A549细胞进行试验,胰蛋白酶消化后轻轻吹打制成单细胞悬液,计数后调整细胞浓度为3×104cells·mL-1,以每孔1.6mL细胞液的数量接种于6孔培养板中,随后置于含5%CO2的37℃培养箱中培养24h使细胞贴壁。每孔分别加入1.6mL用新鲜培养基稀释好的待测化合物,使药物最终浓度为2μM、5μM、10μM。设置细胞对照组,对照组、药物组每浓度设置3个复孔。培养箱中继续培养72h后,将培养液及细胞收集,2400r/min离心10min,弃去上清液,加入1mLPBS重悬细胞,2400r/min离心10min,弃去上清液,加入1mLbinding buffer重悬细胞,2400r/min离心10min,弃去上清液,加入200μLbindingbuffer重悬细胞,加入5μL Annexin V-FITC混匀,室温孵育10min,再加入5μLPI混匀,室温孵育5min,流式细胞仪检测。
3.结果
H-08对A549不同浓度下的凋亡情况如表2所示。由表2可知,H-08对A549的凋亡呈现浓度依赖关系,随着给药浓度的增加(2、5、10μM),凋亡率逐渐增加,由对照组的3.7%逐渐上升到17.4%、90.9%、94.5%;化合物H-08可诱发A549细胞凋亡。
表2;H-08对A549不同浓度下的凋亡情况
注明:Q1区代表机械损伤;Q2区代表晚期凋亡;Q3区代表正常;Q4区代表早期凋亡。
4.结论
本发明化合物H-08可诱发A549细胞凋亡,表明该化合物可用于抗肿瘤药物的研究。
实验例3 PI单染法观察本发明化合物H-08对肿瘤细胞和正常细胞周期影响
1.仪器与材料
Thermo 3111型CO2培养箱;HFsafe生物安全柜;京立牌LD5-2B型台式低速离心机;Olympus IX71倒置荧光显微镜;流式细胞仪;改良型RPMI-1640、DMEM培养基、胎牛血清、0.25%胰蛋白酶溶液、磷酸盐缓冲液(赛默飞世尔生物化学制品北京有限公司);周期试剂盒(碧云天生物技术有限公司)。
人肺癌细胞系A549;
实验药物:本发明化合物H-08。
2.方法
2.1不同细胞株的培养
A549细胞培养在含10%胎牛血清的DMEM培养液中,放置于37℃、5%的CO2培养箱中温育。细胞均呈贴壁状态生长,在倒置显微镜下观察生长状况,待细胞数量适量时传代培养。
2.2PI单染法检测化合物H-08对A549周期影响
取对数生长期的A549细胞进行试验,胰蛋白酶消化后轻轻吹打制成单细胞悬液,计数后调整细胞浓度为3×104cells·mL-1,以每孔1.6mL细胞液的数量接种于6孔培养板中,随后置于含5%CO2的37℃培养箱中培养24h使细胞贴壁。每孔分别加入1.6mL用新鲜培养基稀释好的待测化合物,使药物最终浓度为2μM、5μM、10μM。设置细胞对照组,对照组、药物组每浓度设置3个复孔。培养箱中继续培养72h后,将培养液及细胞收集,2400r/min离心10min,弃去上清液,加入1mLPBS重悬细胞,2400r/min离心10min,弃去上清液,再加入1mL70%冷乙醇重悬细胞,4℃固定12h,2400r/min离心10min,弃去上清液,加入1mLPBS重悬细胞,2400r/min离心10min,弃去上清液,加入500μL PI染液混匀,37℃孵育30min,流式细胞仪检测。
3.结果
H-08对A549不同浓度下的周期影响情况如表3所示。由表3可知,随着给药浓度增高(2、5、10μM),A549细胞的S期值明显上升,从16.67%上升到60.46%,而G0/G1和G2/M降低,说明H-08能阻碍A549的S期,抑制细胞增殖。
表3:H-08对A549不同浓度下的周期影响情况
4.结论
本发明化合物H-08在A549可通过促进细胞凋亡,阻滞肿瘤细胞有丝分裂的方式抑制肿瘤细胞的生长,与前期实验结果相符,表明该化合物可用于抗肿瘤药物的研究。
具体实施方式
实施例1 氯甲基吡嗪的制备
将2-甲基吡嗪(10.63mmol),NCS(1.42g,10.63mmol)和BPO(0.26g,1.06mmol)加入到CCl4(40mL)的溶液中,于室温光照下搅拌2小时。氮气保护下回流加热8小时,冷却后将混合物在冰浴中搅拌1小时,抽滤,用10mL四氯化碳洗涤,减压下蒸馏,得刺激性黄色油状液体。该产物不经处理待用。其它类型吡嗪(2,3-二甲基吡嗪,2,5-二甲基吡嗪,2,6-二甲基吡嗪,2,3,5-三甲基吡嗪和2,3,5,6-四甲基吡嗪),依照上法处理。
实施例2 吡嗪酸的制备
将粉末状高锰酸钾(3.3g,20.90mmol)溶于水(50mL)中,然后在20分钟内将其滴入甲基吡嗪的水溶液中。75℃下搅拌反应2小时。TLC监测直至反应结束。冷却,过滤,用50mL水洗涤,用硝酸将滤液调至pH 1.5,缓慢升温至50℃,保持10分钟,然后冷却,用3×20mL乙酸乙酯萃取,无水硫酸钠除水,减压蒸馏并干燥。该产品未经处理待用。其它甲基吡嗪包括2,3-二甲基吡嗪,2,6-二甲基吡嗪,2,3,5-三甲基吡嗪和2,3,5,6-四甲基吡嗪以2,6-二甲基吡嗪进行。
实施例3 常春藤皂苷元醇的制备
将常春藤皂苷元(1.246g,2.64mmol),K2CO3(728mg,5.28mmol)加入到含2-溴乙醇(1.649g,13.20mmol)的DMF(20mL)溶液中,85℃下搅拌4小时。然后将反应混合物用乙酸乙酯(30mL)与饱和NaCl水溶液萃取,取乙酸乙酯层,无水硫酸钠干燥,并通过柱色谱法纯化,得到白色粉末。Yield:95%(after chromatograph with DCM/MeOH,1%-2%)as a whitepowder,m.p.:246.6℃.1H NMR(400MHz,CDCl3)δ5.28(s,1H,H-12),4.05(t,J=5.9Hz,2H,H-31),3.72(d,J=10.2Hz,1H,H-23a),3.63(t,J=7.7Hz,1H,H-3),3.56(t,J=6.3Hz,2H,H-32),3.43(d,J=9.9Hz,1H,H-23a),2.90-2.82(m,1H,H-18),1.12(s,3H,-CH3),0.96-0.88(m,12H,4×-CH3),0.73(s,3H,-CH3).13C NMR(100MHz,CDCl3)δ178.2,144.1,122.3,76.8,72.1,66.1,61.4,49.8,47.6,46.9,45.8,41.8,41.8,41.5,39.3,38.1,36.9,33.8,33.1,32.5,32.5,30.7,27.6,26.7,25.9,23.6,23.4,23.0,18.5,17.1,15.7,11.4.HRMS(ESI)m/z:[M-H2O]+499.3790,calculated.for C32H50O4499.3782.
实施例4 氯代常春藤皂苷元的制备
将常春藤皂苷元(1.236g,2.64mmol)和K2CO3(730mg,5.28mmol)加入到含4-氯丁醇(1.43g,13.20mmol)的DMF(20mL)溶液中,在85℃下加热搅拌4h。然后将反应混合物用乙酸乙酯(30mL)与饱和NaCl水溶液萃取,取乙酸乙酯层,无水硫酸钠干燥,并通过柱色谱法纯化,得到白色粉末。Yield:54%(after chromatograph with DCM/MeOH,1%-2%)as awhite powder,m.p.:170.2℃.1H NMR(400MHz,CDCl3)δ5.28(s,1H,H-12),3.72(d,J=10.2Hz,1H,H-23a),3.63(t,J=7.6Hz,1H,H-3),3.42(d,J=10.2Hz,1H,H-23b),2.89-2.80(m,1H,H-18),1.12(s,3H,-CH3),0.95(s,3H,-CH3),0.93-0.88(m,9H,3×-CH3),0.73(d,J=8.5Hz,3H,-CH3).13C NMR(100MHz,CDCl3)δ177.7,143.8,122.4,76.9,72.2,63.3,49.8,47.6,46.7,45.9,44.5,41.8,41.7,41.3,39.3,38.1,36.9,33.9,33.1,32.5,32.5,30.7,29.4,27.6,26.8,26.1,25.9,23.6,23.4,23.0,18.5,17.1,15.7,11.4.HRMS(ESI)m/z:[M-H2O+H]+545.3752,calculated.for C34H54ClO3545.3756.
实施例5 H-01的制备
将常春藤皂苷元(282.2mg,0.6mmol),2-氯甲基吡嗪(153.6mg,约0.6mmol,制备为实施例1)和K2CO3(248.4mg,1.8mmol)加入到20ml DMF中,85℃下搅拌4小时。然后将反应混合物用乙酸乙酯(20mL)稀释,饱和NaCl水溶液洗涤,经无水硫酸钠干燥,并通过柱色谱法纯化,得到白色粉末,即H-01。Yield:40%(after chromatograph with DCM/MeOH,1%-1.5%)as a white powder,m.p.:146.8℃.1H NMR(400MHz,CDCl3)δ8.68(s,1H,-N=C-H),8.53(d,J=9.0Hz,2H,2×-N=C-H),5.31(s,1H,H-12),5.22(q,J=13.9Hz,2H,H-31),3.71(d,J=10.3Hz,1H,H-23a),3.65-3.59(m,1H,H-3),3.41(d,J=10.3Hz,1H,H-23b),2.91(m,1H,H-18),1.12(s,3H,-CH3),0.93-0.89(m,9H,3×-CH3),0.87(s,3H,-CH3),0.59(s,3H,-CH3).13C NMR(100MHz,CDCl3)δ177.3,152.2,144.2,144.0,143.9,143.6,122.8,77.0,72.2,64.8,49.9,47.7,47.1,45.9,41.9,41.9,41.5,39.4,38.2,37.0,33.9,33.2,32.6,32.6,30.8,27.8,26.9,26.0,23.8,23.5,23.2,18.6,17.0,15.8,11.5.HRMS(ESI)m/z:[M+H]+565.4003,calculated.for C35H53N2O4565.4000.
实施例6 H-02的制备
将常春藤皂苷元(282.2mg,0.6mmol),6-甲基-2-氯甲基吡嗪(153.6mg,约0.6mmol,制备为实施例1)和K2CO3(248.4mg,1.8mmol)加入到20ml DMF中,85℃下搅拌4小时。然后将反应混合物用乙酸乙酯(20mL)稀释,饱和NaCl水溶液洗涤,经无水硫酸钠干燥,并通过柱色谱法纯化,得到白色粉末,即H-02。Yield:35%(after chromatograph withDCM/MeOH,1%-1.5%)as a white powder,m.p.:107.0℃.1H NMR(400MHz,CDCl3)δ8.47(s,1H,-N=C-H),8.39(s,1H,-N=C-H),5.30(s,1H,H-12),5.18(q,J=13.8Hz,2H,H-31),3.71(d,J=10.3Hz,1H,H-23a),3.62(t,J=7.9Hz,1H,H-3),3.41(d,J=10.3Hz,1H,H-23b),2.91(m,1H,H-18),2.56(s,3H,-CH3),1.12(s,3H,-CH3),0.93-0.90(m,9H,3×-CH3),0.88(s,3H,-CH3),0.58(s,3H,-CH3).13C NMR(100MHz,CDCl3)δ177.3,153.4,150.9,143.7,143.6,140.4,122.7,77.0,72.3,64.9,49.9,47.7,47.0,46.0,41.9,41.8,41.5,39.4,38.2,37.0,33.9,33.2,32.6,32.6,30.8,27.8,27.1,26.9,26.1,23.8,23.5,23.2,21.6,18.6,17.0,15.8,11.5.HRMS(ESI)m/z:[M+H]+579.4142,calculated.forC36H55N2O4579.4156.
实施例7 H-03的制备
将常春藤皂苷元(282.2mg,0.6mmol),5-甲基-2-氯甲基吡嗪(153.6mg,约0.6mmol,制备为实施例1)和K2CO3(248.4mg,1.8mmol)加入到20ml DMF中,85℃下搅拌4小时。然后将反应混合物用乙酸乙酯(20mL)稀释,饱和NaCl水溶液洗涤,经无水硫酸钠干燥,并通过柱色谱法纯化,得到白色粉末,即H-03。Yield:60%(after chromatograph withDCM/MeOH,1%-1.5%)as a white powder,m.p.:170.3℃.1H NMR(400MHz,CDCl3)δ8.45(m,2H,2×-N=C-H),5.30(d,J=2.7Hz,1H,H-12),3.71(d,J=10.3Hz,1H,H-23a),3.41(d,J=10.3Hz,1H,H-23b),2.90(m,1H,H-18),2.57(d,J=6.7Hz,3H,-CH3),1.12(s,3H,-CH3),0.91(d,J=6.6Hz,9H,3×-CH3),0.88(s,3H,-CH3),0.57(s,3H,-CH3).13C NMR(100MHz,CDCl3)δ177.4,153.1,148.8,143.9,143.7,142.7,122.7,77.0,72.3,,64.7,49.9,47.7,47.0,45.9,41.9,41.8,41.5,39.4,38.2,37.0,33.9,33.2,32.6,32.6,30.8,27.8,26.9,26.1,23.8,23.5,23.2,21.4,18.6,17.0,15.8,11.5.HRMS(ESI)m/z:[M+H]+579.4142,calculated.for C36H55N2O4579.4156.
实施例8 H-04的制备
将常春藤皂苷元(282.2mg,0.6mmol),3-甲基-2-氯甲基吡嗪(153.6mg,约0.6mmol,制备为实施例1)和K2CO3(248.4mg,1.8mmol)加入到20ml DMF中,85℃下搅拌4小时。然后将反应混合物用乙酸乙酯(20mL)稀释,饱和NaCl水溶液洗涤,经无水硫酸钠干燥,并通过柱色谱法纯化,得到白色粉末,即H-04。Yield:36%(after chromatograph withDCM/MeOH,1%-1.5%)as a white powder,m.p.:170.4℃.1H NMR(400MHz,CDCl3)δ8.41(s,1H,-N=C-H),8.38(s,1H,-N=C-H),5.22(m,3H,H-12,H-31a,H-32b),3.71(d,J=10.3Hz,1H,H-23a),3.64-3.59(m,1H,H-3),3.41(d,J=10.3Hz,1H,H-23b),2.85(m,1H,H-18),2.63(s,3H,-CH3),1.10(s,3H,-CH3),0.93-0.88(m,12H,4×-CH3),0.57(s,3H,-CH3).13C NMR(100MHz,CDCl3)δ177.4,153.1,148.9,143.9,143.7,142.7,122.7,77.0,72.3,,64.7,49.9,47.7,47.0,45.93,41.9,41.8,41.5,39.4,38.2,37.0,33.9,33.2,32.6,32.6,30.8,27.8,26.9,26.1,23.8,23.5,23.2,21.4,18.6,17.0,15.8,11.5.HRMS(ESI)m/z:[M+H]+579.4145,calculated.for C36H55N2O4579.4156.
实施例9 H-05的制备
将常春藤皂苷元(282.2mg,0.6mmol),5,6-二甲基-2-氯甲基吡嗪(153.6mg,约0.6mmol,制备为实施例1)和K2CO3(248.4mg,1.8mmol)加入到20ml DMF中,85℃下搅拌4小时。然后将反应混合物用乙酸乙酯(20mL)稀释,饱和NaCl水溶液洗涤,经无水硫酸钠干燥,并通过柱色谱法纯化,得到白色粉末,即H-05。Yield:approximately 40%(afterchromatograph with methanol/dichloromethane,1%-1.5%)as a white solid,m.p.>200℃.1H NMR(400MHz,CDCl3)δ8.24(d,J=13.0Hz,1H,-N=C-H),5.22-5.09(m,3H,H-12,H-31),3.67(d,J=10.1Hz,1H,H-23a),3.62-3.57(m,1H,H-3),3.37(d,J=10.1Hz,1H,H-23b),2.83(m,1H,H-18),2.59-2.49(m,6H,2×-CH3),1.07(s,3H,-CH3),0.90-0.85(m,12H,4×-CH3),0.52(d,J=5.4Hz,3H,-CH3).13C NMR(100MHz,CDCl3)δ177.3,152.4,149.9,146.3,143.5,141.2,122.6,76.8,72.0,65.0,49.9,47.6,47.0,45.9,41.8,41.7,41.4,39.3,38.2,37.0,33.9,33.1,32.6,32.5,30.8,27.7,26.6,26.0,23.7,23.4,23.1,21.4,21.2,18.5,16.9,15.7,11.6.HRMS(ESI)m/z:[M+H]+593.4295,calculated.forC37H57N2O4593.4313.
实施例10 H-06的制备
将常春藤皂苷元(282.2mg,0.6mmol),氯代川芎嗪(153.6mg,约0.6mmol,制备为实施例1)和K2CO3(248.4mg,1.8mmol)加入到20ml DMF中,85℃下搅拌4小时。然后将反应混合物用乙酸乙酯(20mL)稀释,饱和NaCl水溶液洗涤,经无水硫酸钠干燥,并通过柱色谱法纯化,得到白色粉末,即H-06。Yield:90%(after chromatograph with DCM/MeOH,1%-1.5%)as a white powder,m.p.:127.8℃.1H NMR(400MHz,CDCl3)δ5.24-5.08(m,3H,H-12,H-31a,H-31b),3.72(d,J=10.2Hz,1H,H-23a),3.62(t,J=7.8Hz,1H,H-3),3.41(d,J=10.3Hz,1H,H-23b),2.85(m,1H,H-18),2.55-2.48(m,9H,3×-CH3),1.09(s,3H,-CH3),0.93-0.88(m,12H,4×-CH3),0.53(s,3H,-CH3).13C NMR(100MHz,CDCl3)δ177.3,151.1,149.3,148.9,145.5,143.7,122.5,77.0,72.3,65.0,50.0,47.7,47.0,46.0,41.9,41.8,41.4,39.4,38.2,37.0,34.0,33.2,32.6,32.5,30.8,27.7,26.9,26.0,23.8,23.5,23.2,21.8,21.5,20.7,18.6,17.0,15.8,11.6.HRMS(ESI)m/z:[M+H]+607.4459,calculated.forC38H59N2O4607.4469.
实施例11 H-07的制备
将吡嗪酸(0.27mmol,制备为实施例2),EDCI(0.35mmol)和DMAP(0.027mmol)溶解到干燥的二氯甲烷(20mL)中。将化合物常春藤皂苷元醇(140mg,0.27mmol)溶解在二氯甲烷(20mL)中。将该溶液在20分钟内滴入到吡嗪酸溶液中,室温下搅拌12小时。然后将反应混合物用二氯甲烷(20mL)稀释,饱和NaCl水溶液洗涤,经无水硫酸钠干燥,并通过柱色谱法纯化,得到白色粉末,即H-07。Yield:20%(after chromatograph with DCM/MeOH,1%-2%)as a white powder,m.p.:154.7℃.1H NMR(400MHz,CDCl3)δ9.29(d,J=9.6Hz,1H,-N=C-H),8.80-8.70(m,2H,2×-N=C-H),5.30(s,1H,H-12),3.62(t,J=7.5Hz,1H,H-3),2.88(m,1H,H-18),0.98(s,3H,-CH3),0.91(d,J=10.4Hz,9H,3×-CH3),0.77(s,3H,-CH3).13C NMR(100MHz,CDCl3)δ178.3,163.9,148.0,146.2,144.7,144.3,143.4,122.4,77.4,71.9,66.2,61.6,49.6,48.0,47.1,45.9,42.3,41.9,41.7,39.5,38.3,37.0,34.0,33.2,32.6,30.8,27.7,26.4,26.1,25.8,23.7,23.5,23.1,18.8,17.2,15.7,12.3.HRMS(ESI)m/z:[M+H]+623.4045,calculated.for C37H55N2O6623.4055.
实施例12 H-08的制备
将6-甲基吡嗪酸(0.27mmol,制备为实施例2),EDCI(0.35mmol)和DMAP(0.027mmol)溶解到干燥的二氯甲烷(20mL)中。将化合物常春藤皂苷元醇(140mg,0.27mmol,制备为实施例3)溶解在二氯甲烷(20mL)中。将该溶液在20分钟内滴入到6-甲基吡嗪酸溶液中,室温下搅拌12小时。然后将反应混合物用二氯甲烷(20mL)稀释,饱和NaCl水溶液洗涤,经无水硫酸钠干燥,并通过柱色谱法纯化,得到白色粉末,即H-08。Yield:35%(after chromatograph with DCM/MeOH,1%-2%)as a white powder,m.p.:122.9℃.1HNMR(400MHz,CDCl3)δ9.06(d,J=21.2Hz,1H,-N=C-H),8.63(d,J=5.4Hz,1H,-N=C-H),5.31(s,1H,H-12),4.25-3.99(m,2H),2.87(m,1H,H-18),2.67(d,J=9.0Hz,3H,-CH3),1.11(s,3H,-CH3),0.92(m,12H,4×-CH3),0.77(s,3H,-CH3).13C NMR(100MHz,CDCl3)δ178.3,164.2,154.4,148.1144.2,143.0,142.2,122.4,74.1,72.0,66.2,61.6,49.7,48.0,47.1,45.9,42.3,41.9,41.7,39.4,38.3,37.0,33.9,33.2,32.6,32.7,30.8,27.7,26.3,26.1,25.9,23.5,23.1,21.9,18.8,17.2,15.7,12.3.HRMS(ESI)m/z:[M+H]+637.4219,calculated.for C38H57N2O6637.4211.
实施例13 H-09的制备
将5-甲基吡嗪酸(0.27mmol,制备为实施例2),EDCI(0.35mmol)和DMAP(0.027mmol)溶解到干燥的二氯甲烷(20mL)中。将化合物常春藤皂苷元醇(140mg,0.27mmol,制备为实施例3)溶解在二氯甲烷(20mL)中。将该溶液在20分钟内滴入到5-甲基吡嗪酸溶液中,室温下搅拌12小时。然后将反应混合物用二氯甲烷(20mL)稀释,饱和NaCl水溶液洗涤,经无水硫酸钠干燥,并通过柱色谱法纯化,得到白色粉末,即H-09。Yield:55%(after chromatograph with DCM/MeOH,1%-2%)as a white powder,m.p.:192.6℃.1HNMR(400MHz,CDCl3)δ9.17(s,1H,-N=C-H),8.59(s,1H,-N=C-H),5.22(s,1H,H-12),4.68-4.59(m,2H,H-31),4.46-4.31(m,2H,H-32),3.70(d,J=10.3Hz,1H,H-23a),3.61(t,J=7.8Hz,1H,H-3),3.40(d,J=10.3Hz,1H,H-23b),2.84(m,1H,H-18),2.67(s,3H,-CH3),1.08(s,3H),0.87(s,12H,4×-CH3),0.65(s,3H,-CH3).13C NMR(100MHz,CDCl3)δ177.6,163.9,158.1,145.5,144.6,143.6,140.5,122.6,77.0,72.2,63.6,62.0,49.9,47.7,46.9,45.9,41.9,41.8,41.3,39.4,38.2,37.0,33.9,33.2,32.5,32.5,30.8,27.7,26.9,26.0,23.7,23.4,23.0,22.1,18.6,17.0,15.7,11.5.HRMS(ESI)m/z:[M+H]+637.4208,calculated.forC38H57N2O6637.4211.
实施例14 H-10的制备
将3-甲基吡嗪酸(0.27mmol,制备为实施例2),EDCI(0.35mmol)和DMAP(0.027mmol)溶解到干燥的二氯甲烷(20mL)中。将化合物常春藤皂苷元醇(140mg,0.27mmol,制备为实施例3)溶解在二氯甲烷(20mL)中。将该溶液在20分钟内滴入到3-甲基吡嗪酸溶液中,室温下搅拌12小时。然后将反应混合物用二氯甲烷(20mL)稀释,饱和NaCl水溶液洗涤,经无水硫酸钠干燥,并通过柱色谱法纯化,得到白色粉末,即H-10。Yield:35%(after chromatograph with DCM/MeOH,1%-2%)as a white powder,m.p:146.8℃.1HNMR(400MHz,CDCl3)δ8.62(s,1H,-N=C-H),8.48(s,1H,-N=C-H),5.31(s,1H,H-12),4.59(d,J=10.8Hz,1H,H-23a),4.04(d,J=10.8Hz,1H,H-23b),3.67-3.58(m,1H,H-3),2.87(s,4H,H-18,-CH3),1.13(s,3H,-CH3),0.94(m,12H,4×-CH3),0.77(s,3H,-CH3).13C NMR(100MHz,CDCl3)δ178.3,165.0,155.7,146.5,144.2,142.5,141.7,122.4,74.8,73.7,66.2,61.6,50.0,47.9,47.1,45.9,42.1,42.0,41.7,39.4,38.2,37.0,34.0,33.2,32.6,32.6,30.8,27.8,26.3,25.9,23.7,23.5,23.3,23.2,19.0,17.2,15.6,12.36.HRMS(ESI)m/z:[M+H]+637.4222,calculated.for C38H57N2O6637.4211.
实施例15 H-11的制备
将5,6-二甲基吡嗪酸(0.27mmol,制备为实施例2),EDCI(0.35mmol)和DMAP(0.027mmol)溶解到干燥的二氯甲烷(20mL)中。将化合物常春藤皂苷元醇(140mg,0.27mmol,制备为实施例3)溶解在二氯甲烷(20mL)中。将该溶液在20分钟内滴入到5,6-甲基吡嗪酸溶液中,室温下搅拌12小时。然后将反应混合物用二氯甲烷(20mL)稀释,饱和NaCl水溶液洗涤,经无水硫酸钠干燥,并通过柱色谱法纯化,得到白色粉末,即H-11。Yield:25%(after chromatograph with DCM/MeOH,1%-2%)as a white powder,m.p.:146.2℃.1HNMR(400MHz,CDCl3)δ8.41(d,J=60.1Hz,1H,-N=C-H),5.31(s,1H,H-12),4.59(d,J=10.5Hz,1H,H-23a),4.00(d,J=10.7Hz,1H,H-23b),2.83(m,4H,H-18,-CH3),2.58(d,J=6.8Hz,3H,-CH3),1.13(s,3H,-CH3),0.97-0.90(m,12H,4×-CH3),0.76(s,3H,-CH3).13C NMR(100MHz,CDCl3)δ178.3,165.2,154.8,151.0,146.5,144.2,141.5,122.4,75.0,73.8,66.2,61.6,50.2,47.8,47.1,45.9,42.1,42.0,41.6,39.4,38.2,37.0,33.9,33.2,32.6,30.8,27.8,26.2,25.9,23.7,23.5,23.2,22.7,22.0,21.2,19.0,17.2,15.6,12.4.HRMS(ESI)m/z:[M+H]+651.4375,calculated.for C39H59N2O6651.4368.
实施例16 H-12的制备
将川芎嗪酸(0.27mmol,制备为实施例2),EDCI(0.35mmol)和DMAP(0.027mmol)溶解到干燥的二氯甲烷(20mL)中。将化合物常春藤皂苷元醇(140mg,0.27mmol,制备为实施例3)溶解在二氯甲烷(20mL)中。将该溶液在20分钟内滴入到川芎嗪酸溶液中,室温下搅拌12小时。然后将反应混合物用二氯甲烷(20mL)稀释,饱和NaCl水溶液洗涤,经无水硫酸钠干燥,并通过柱色谱法纯化,得到白色粉末,即H-12。Yield:90%(after chromatograph withDCM/MeOH,1%-2%)as a white powder,m.p.:150.6℃.1H NMR(400MHz,CDCl3)δ5.31(s,1H,H-12),4.60(d,J=10.7Hz,1H,H-23a),3.94(d,J=10.7Hz,1H,H-23b),3.66-3.59(m,1H,H-3),2.87(m,1H,H-18),2.79(s,3H,-CH3),2.57(m,9H,3×-CH3),1.13(s,3H,-CH3),0.99-0.89(m,15H,5×-CH3),0.77(s,3H,-CH3).13C NMR(100MHz,CDCl3)δ178.3,165.3,155.4,152.2,149.6,144.2,138.1,122.4,75.4,74.6,66.2,61.6,50.7,47.8,47.1,45.9,42.0,42.0,41.6,39.4,38.2,36.98,34.0,33.20,32.60,30.8,29.8,27.8,26.2,26.0,23.8,23.5,23.2,22.7,22.4,22.3,21.8,19.1,17.2,15.5,12.5.HRMS(ESI)m/z:[M+H]+665.4531,calculated.for C40H61N2O6665.4524.
实施例17 H-13的制备
将吡嗪酸(248mg,约2mmol,制备为实施例2),4-氯-1-丁醇(2.4mmol),EDCI(2.4mmol)和DMAP(0.2mmol)加入到干燥的二氯甲烷(20mL)中,室温下搅拌12小时,然后用二氯甲烷(20mL)稀释,饱和NaCl水溶液洗涤,经无水硫酸钠干燥,并通过柱色谱法纯化,得到油状液体。将常春藤皂苷元(236mg,0.5mmol,制备为实施例3),K2CO3(207mg,1.5mmol)和油状液体加入到DMF(20mL)中,并将混合物在85℃下搅拌4小时。然后用乙酸乙酯(20mL)稀释,饱和NaCl水溶液洗涤,经无水硫酸钠干燥,浓缩并通过柱色谱法纯化,得到白色粉末,即H-13。Yield:30%(after chromatograph with DCM/MeOH,1%-2%)as a white powder,m.p.:127℃.1H NMR(400MHz,CDCl3)δ9.31(s,1H,-N=C-H),8.77(s,1H,-N=C-H),8.74(s,1H,-N=C-H),5.27(s,1H,H-12),4.48(t,J=6.3Hz,2H,H-34),4.08(t,J=5.7Hz,2H,H-31),3.72(d,J=10.3Hz,1H,H-23a),3.62(t,J=7.5Hz,1H,H-3),3.42(d,J=10.1Hz,1H,H-23b),2.86(m,1H,H-18),1.12(s,3H,-CH3),0.93-0.88(m,12H,4×-CH3),0.71(s,3H,-CH3).13C NMR(100MHz,CDCl3)δ177.8,164.0,147.8,146.4,144.6,143.9,143.6,122.5,77.0,72.3,66.0,63.7,49.9,47.7,46.9,46.0,41.9,41.9,41.5,39.5,38.2,37.0,34.0,33.2,32.7,32.6,30.8,27.8,26.9,26.0,25.7,25.4,23.8,23,23.1,18.6,17.2,15.8,11.5.HRMS(ESI)m/z:[M+H]+651.4375,calculated.for C39H59N2O6651.4368.
实施例18 H-14的制备
将6-甲基吡嗪酸(248mg,约2mmol,制备为实施例2),4-氯-1-丁醇(2.4mmol),EDCI(2.4mmol)和DMAP(0.2mmol)加入到干燥的二氯甲烷(20mL)中,室温下搅拌12小时,然后用二氯甲烷(20mL)稀释,饱和NaCl水溶液洗涤,经无水硫酸钠干燥,并通过柱色谱法纯化,得到油状液体。将常春藤皂苷元(236mg,0.5mmol),K2CO3(207mg,1.5mmol)和油状液体加入到DMF(20mL)中,并将混合物在85℃下搅拌4小时。然后用乙酸乙酯(20mL)稀释,饱和NaCl水溶液洗涤,经无水硫酸钠干燥,浓缩并通过柱色谱法纯化,得到白色粉末,即H-14。Yield:35%(after chromatograph with DCM/MeOH,1%-2%)as a white powder,m.p.:128℃.1HNMR(400MHz,CDCl3)δ9.09(s,1H,-N=C-H),8.63(s,1H,-N=C-H),5.27(s,1H,H-12),4.47(t,J=6.3Hz,2H,H-34),4.08(t,J=5.8Hz,2H,H-31),3.71(d,J=10.2Hz,1H,H-23a),3.62(t,J=7.5Hz,1H,H-3),3.42(d,J=10.2Hz,1H,H-23b),2.86(m,1H,H-18),2.68(s,3H,-CH3),1.11(s,3H,-CH3),0.92-0.87(m,12H,4×-CH3),0.71(s,3H,-CH3).13C NMR(100MHz,CDCl3)δ177.8,164.3,154.4,147.8,143.9,143.2,142.6,122.5,77.0,72.3,65.8,63.7,49.9,47.7,46.9,46.0,41.9,41.9,41.5,39.5,38.2,37.0,34.0,33.2,32.7,32.6,30.8,27.8,26.9,26.0,25.7,25.4,23.8,23.5,23.1,21.9,18.6,17.2,15.8,11.5.HRMS(ESI)m/z:[M+H]+665.4527,calculated.for C40H61N2O6665.4524.
实施例19 H-15的制备
将5-甲基吡嗪酸(248mg,约2mmol,制备为实施例2),4-氯-1-丁醇(2.4mmol),EDCI(2.4mmol)和DMAP(0.2mmol)加入到干燥的二氯甲烷(20mL)中,室温下搅拌12小时,然后用二氯甲烷(20mL)稀释,饱和NaCl水溶液洗涤,经无水硫酸钠干燥,并通过柱色谱法纯化,得到油状液体。将常春藤皂苷元(236mg,0.5mmol,制备为实施例3),K2CO3(207mg,1.5mmol)和油状液体加入到DMF(20mL)中,并将混合物在85℃下搅拌4小时。然后用乙酸乙酯(20mL)稀释,饱和NaCl水溶液洗涤,经无水硫酸钠干燥,浓缩并通过柱色谱法纯化,得到白色粉末,即H-15。Yield:26%(after chromatograph with DCM/MeOH,1%-2%)as a white powder,m.p.:166.1℃.1H NMR(400MHz,CDCl3)δ9.17(s,1H,-N=C-H),8.58(s,1H,-N=C-H),5.27(s,1H,H-12),4.46(t,J=6.4Hz,2H,H-34),4.08(t,J=5.9Hz,2H,H-31),3.71(d,J=10.2Hz,1H,H-23a),3.62(t,J=7.5Hz,1H,H-3),3.42(d,J=10.2Hz,1H,H-23b),2.85(m,1H,H-18),2.67(s,3H,-CH3),1.11(s,3H,-CH3),0.92-0.88(m,12H,4×-CH3),0.71(s,3H,-CH3).13C NMR(100MHz,CDCl3)δ177.8,164.3,158.0,145.5,144.5,143.9,140.8,122.5,77.0,72.3,65.7,63.7,49.9,47.7,46.9,46.0,41.9,41.9,41.5,39.5,38.2,37.0,34.0,33.2,32.7,32.6,30.8,27.8,26.9,26.0,25.7,25.4,23.8,23.5,23.1,22.1,18.6,17.2,15.8,11.5.HRMS(ESI)m/z:[M+H]+665.4538,calculated.for C40H61N2O6665.4524.
实施例20 H-16的制备
将3-甲基吡嗪酸(248mg,约2mmol,制备为实施例2),4-氯-1-丁醇(2.4mmol),EDCI(2.4mmol)和DMAP(0.2mmol)加入到干燥的二氯甲烷(20mL)中,室温下搅拌12小时,然后用二氯甲烷(20mL)稀释,饱和NaCl水溶液洗涤,经无水硫酸钠干燥,并通过柱色谱法纯化,得到油状液体。将常春藤皂苷元(236mg,0.5mmol),K2CO3(207mg,1.5mmol)和油状液体加入到DMF(20mL)中,并将混合物在85℃下搅拌4小时。然后用乙酸乙酯(20mL)稀释,饱和NaCl水溶液洗涤,经无水硫酸钠干燥,浓缩并通过柱色谱法纯化,得到白色粉末,即H-16。Yield:31%(after chromatograph with DCM/MeOH,1%-2%)as a white powder,m.p.:145.2℃.1HNMR(400MHz,CDCl3)δ8.61(s,1H,-N=C-H),8.52(s,1H,-N=C-H),5.29(s,1H,H-12),4.44(t,J=6.5Hz,2H,H-34),4.07(t,J=6.0Hz,2H,H-31),3.71(d,J=10.1Hz,1H,H-23a),3.62(t,J=7.6Hz,1H,H-3),3.42(d,J=10.2Hz,1H,H-23b),2.84(s,3H,-CH3),1.11(s,3H,-CH3),0.92-0.87(m,12H,4×-CH3),0.71(s,3H,-CH3).13C NMR(100MHz,CDCl3)δ177.8,165.4,155.3,146.0,143.9,143.3,141.6,122.5,77.0,72.3,65.8,63.7,49.9,47.71,46.9,46.0,41.9,41.9,41.5,39.5,38.2,37.0,34.0,33.2,32.7,32.6,30.8,27.8,26.9,26.0,25.7,25.4,23.8,23.5,23.4,23.1,18.6,17.2,15.8,11.5.HRMS(ESI)m/z:[M+H]+665.4542,calculated.for C40H61N2O6665.4524.
实施例21 H-17的制备
将5,6-二甲基吡嗪酸(248mg,约2mmol,制备为实施例2),4-氯-1-丁醇(2.4mmol),EDCI(2.4mmol)和DMAP(0.2mmol)加入到干燥的二氯甲烷(20mL)中,室温下搅拌12小时,然后用二氯甲烷(20mL)稀释,饱和NaCl水溶液洗涤,经无水硫酸钠干燥,并通过柱色谱法纯化,得到油状液体。将常春藤皂苷元(236mg,0.5mmol),K2CO3(207mg,1.5mmol)和油状液体加入到DMF(20mL)中,并将混合物在85℃下搅拌4小时。然后用乙酸乙酯(20mL)稀释,饱和NaCl水溶液洗涤,经无水硫酸钠干燥,浓缩并通过柱色谱法纯化,得到白色粉末,即H-17。Yield:27%(after chromatograph with DCM/MeOH,1%-2%)as a white powder,m.p.:134.7℃.1H NMR(400MHz,CDCl3)δ8.43(d,J=32.0Hz,1H,-N=C-H),5.27(s,1H,H-12),4.43(d,J=6.2Hz,2H,H-34),4.07(d,J=3.0Hz,2H,H-34),3.72(d,J=10.1Hz,1H,H-23a),3.62(t,J=7.6Hz,1H,H-3),3.42(d,J=10.2Hz,1H,H-23b),2.88-2.59(m,7H,H-18,2×-CH3),1.11(s,3H,-CH3),0.93-0.87(m,12H,4×-CH3),0.71(s,3H,-CH3).13C NMR(100MHz,CDCl3)δ177.8,155.9,154.5,145.8,143.9,142.8,141.4,122.5,77.0,72.3,65.6,63.8,49.9,47.7,46.9,46.0,41.9,41.9,41.5,39.5,38.2,37.0,34.0,33.2,32.6,30.8,27.8,26.9,26.0,25.7,25.4,23.8,23.5,23.1,22.6,21.9,21.3,18.6,17.2,15.8,11.5.HRMS(ESI)m/z:[M+H]+679.4682,calculated.for C41H63N2O6679.4681.
实施例22 H-18的制备
将川芎嗪酸(248mg,约2mmol,制备为实施例2),4-氯-1-丁醇(2.4mmol),EDCI(2.4mmol)和DMAP(0.2mmol)加入到干燥的二氯甲烷(20mL)中,室温下搅拌12小时,然后用二氯甲烷(20mL)稀释,饱和NaCl水溶液洗涤,经无水硫酸钠干燥,并通过柱色谱法纯化,得到油状液体。将常春藤皂苷元(236mg,0.5mmol),K2CO3(207mg,1.5mmol)和油状液体加入到DMF(20mL)中,并将混合物在85℃下搅拌4小时。然后用乙酸乙酯(20mL)稀释,饱和NaCl水溶液洗涤,经无水硫酸钠干燥,浓缩并通过柱色谱法纯化,得到白色粉末,即H-18。Yield:90.4%(after chromatograph with DCM/MeOH,1%-2%)as a white powder,m.p.:110.1℃.1H NMR(400MHz,CDCl3)δ5.27(s,1H,H-12),4.42(t,J=6.3Hz,2H,H-34),4.08(t,J=5.7Hz,2H,H-31),3.72(d,J=10.3Hz,1H,H-23a),3.62(t,J=7.5Hz,1H,H-3),3.42(d,J=10.2Hz,1H,H-23b),2.86(m,1H,H-18),2.74(s,3H,-CH3),2.57(s,6H,2×-CH3),1.12(s,3H,-CH3),0.92-0.87(m,12H,4×-CH3),0.71(s,3H,-CH3).13C NMR(100MHz,CDCl3)δ177.8,166.1,154.5,151.1,149.5,143.9,139.8,122.5,77.0,72.3,65.5,63.8,49.9,47.70,46.8,46.0,41.9,41.8,41.5,39.4,38.2,37.0,34.0,33.2,32.6,32.6,30.8,27.8,26.9,26.0,25.7,25.5,23.7,23.5,23.1,22.7,22.3,21.7,18.6,17.2,15.8,11.5.HRMS(ESI)m/z:[M+H]+693.4849,calculated.for C42H65N2O6693.4837.
实施例23 H-19的制备
将吡嗪酸(约0.27mmol,制备为实施例2),EDCI(0.35mmol)和DMAP(0.027mmol)溶解到干燥的二氯甲烷(20mL)中,然后将氯代常春藤皂苷元(152mg,0.27mmol,制备为实施例4)溶解在二氯甲烷(20ml)中。20分钟内将其滴入吡嗪酸溶液中,室温下搅拌12小时。然后用二氯甲烷(20mL)稀释,饱和NaCl水溶液洗涤,经无水硫酸钠干燥,浓缩并通过柱色谱法纯化,得到白色粉末,即H-19。Yield:31%(after chromatograph with DCM/MeOH,1%-2%)as a white powder,m.p.:117.1℃.1H NMR(400MHz,CDCl3)δ9.28(d,J=9.3Hz,1H,-N=C-H),8.85-8.59(m,2H,2×-N=C-H),5.28(s,1H,H-12),2.86(m,1H,H-18),1.09(s,3H,-CH3),1.02-0.83(m,12H,4×-CH3),0.75(s,3H,-CH3).13C NMR(100MHz,CDCl3)δ177.8,163.9,148.0,146.4,146.2,144.7,143.9,122.4,74.0,71.9,63.5,49.6,48.0,46.9,45.9,44.6,42.3,41.8,41.5,39.5,38.3,37.0,34.0,33.2,32.6,30.8,29.5,27.7,26.4,26.2,26.1,25.8,23.7,23.5,23.1,18.8,17.2,15.7,12.3.HRMS(ESI)m/z:[M+H]+669.4045,calculated.for C39H58ClN2O5669.4029.
实施例24 H-20的制备
将6-甲基吡嗪酸(约0.27mmol,制备为实施例2),EDCI(0.35mmol)和DMAP(0.027mmol)溶解到干燥的二氯甲烷(20mL)中,然后将氯代常春藤皂苷元(152mg,0.27mmol,制备为实施例4)溶解在二氯甲烷(20ml)中。20分钟内将其滴入6-甲基吡嗪酸溶液中,室温下搅拌12小时。然后用二氯甲烷(20mL)稀释,饱和NaCl水溶液洗涤,经无水硫酸钠干燥,浓缩并通过柱色谱法纯化,得到白色粉末,即H-20。Yield:35%(afterchromatograph with DCM/MeOH,1%-2%)as a white powder,m.p.:126.9℃.1H NMR(400MHz,CDCl3)δ9.07(s,1H,-N=C-H),8.63(s,1H,-N=C-H),5.27(s,1H,H-12),2.84(m,1H,H-18),2.64(s,3H,-CH3),1.09(s,3H,-CH3),0.96(s,3H,-CH3),0.89(m,9H,3×-CH3),0.74(s,3H,-CH3).13C NMR(100MHz,CDCl3)δ177.7,164.6,154.4,148.0,143.8,142.9,142.2,122.4,74.0,71.8,63.4,49.6,47.9,46.8,45.9,44.6,42.2,41.8,41.5,39.4,38.3,36.9,34.0,33.2,32.7,32.6,30.8,29.5,27.7,26.3,26.2,25.8,23.7,23.5,23.1,21.8,18.8,17.2,15.6,12.3.HRMS(ESI)m/z:[M+H]+683.4185,calculated.forC40H60ClN2O5683.4185.
实施例25 H-21的制备
将5-甲基吡嗪酸(约0.27mmol,制备为实施例2),EDCI(0.35mmol)和DMAP(0.027mmol)溶解到干燥的二氯甲烷(20mL)中,然后将氯代常春藤皂苷元(152mg,0.27mmol,制备为实施例4)溶解在二氯甲烷(20ml)中。20分钟内将其滴入5-甲基吡嗪酸溶液中,室温下搅拌12小时。然后用二氯甲烷(20mL)稀释,饱和NaCl水溶液洗涤,经无水硫酸钠干燥,浓缩并通过柱色谱法纯化,得到白色粉末,即H-21。Yield:40%(afterchromatograph with DCM/MeOH,1%-2%)as a white powder,m.p.:175.8℃.1H NMR(400MHz,CDCl3)δ9.17(s,1H,-N=C-H),8.56(s,1H,-N=C-H),5.29(s,1H,H-12),2.87(m,1H,H-18),2.66(d,J=5.3Hz,3H,-CH3),1.10(s,3H,-CH3),0.98(s,3H,-CH3),0.91(m,9H,3×-CH3),0.75(s,3H,-CH3).13C NMR(100MHz,CDCl3)δ177.8,164.3,158.2,145.2,144.6,143.9,140.5,122.5,74.1,71.8,63.5,49.7,48.0,46.9,46.0,44.6,42.3,41.8,41.5,39.5,38.3,37.0,34.0,33.3,32.7,32.6,30.8,29.5,27.7,27.1,26.3,25.9,23.7,23.5,23.1,22.1,18.8,17.2,15.7,12.3.HRMS(ESI)m/z:[M+H]+683.4183,calculated.forC40H60ClN2O5683.4185.
实施例26 H-22的制备
将3-甲基吡嗪酸(约0.27mmol,制备为实施例2),EDCI(0.35mmol)和DMAP(0.027mmol)溶解到干燥的二氯甲烷(20mL)中,然后将氯代常春藤皂苷元(152mg,0.27mmol,制备为实施例4)溶解在二氯甲烷(20ml)中。20分钟内将其滴入3-甲基吡嗪酸溶液中,室温下搅拌12小时。然后用二氯甲烷(20mL)稀释,饱和NaCl水溶液洗涤,经无水硫酸钠干燥,浓缩并通过柱色谱法纯化,得到白色粉末,即H-22。Yield:36%(afterchromatograph with DCM/MeOH,1%-2%)as a white powder,m.p.:106.1℃.1H NMR(400MHz,CDCl3)δ8.62(s,1H,-N=C-H),8.49(s,1H,-N=C-H),5.29(s,1H,H-12),3.65-3.59(m,1H,H-3),2.86(m,4H,H-18,-CH3),1.12(s,3H,-CH3),0.93(m,12H,3×-CH3),0.75(s,3H,-CH3).13C NMR(100MHz,CDCl3)δ177.8,165.0,155.7,146.4,143.9,142.5,141.7,122.5,74.9,73.7,63.5,50.1,47.9,46.9,46.0,44.6,42.1,41.9,41.5,39.5,38.2,37.0,34.0,33.3,32.6,32.6,30.8,29.5,27.8,26.3,26.3,25.9,23.7,23.5,23.3,23.1,19.0,17.2,15.6,12.4.HRMS(ESI)m/z:[M+H]+683.4175,calculated.for C40H60ClN2O5683.4185.
实施例27 H-23的制备
将5,6-二甲基吡嗪酸(约0.27mmol,制备为实施例2),EDCI(0.35mmol)和DMAP(0.027mmol)溶解到干燥的二氯甲烷(20mL)中,然后将氯代常春藤皂苷元(152mg,0.27mmol,制备为实施例4)溶解在二氯甲烷(20ml)中。20分钟内将其滴入5,6-二甲基吡嗪酸溶液中,室温下搅拌12小时。然后用二氯甲烷(20mL)稀释,饱和NaCl水溶液洗涤,经无水硫酸钠干燥,浓缩并通过柱色谱法纯化,得到白色粉末,即H-23。Yield:36%(afterchromatograph with DCM/MeOH,1%-2%)as a white powder,m.p.:123.6℃.1H NMR(400MHz,CDCl3)δ8.42(d,J=59.1Hz,1H,-N=C-H),5.29(s,1H,H-12),2.83(d,J=8.1Hz,3H,-CH3),2.59(d,J=6.8Hz,3H,-CH3),1.12(s,3H,-CH3),0.99-0.89(m,12H,4×-CH3),0.75(s,3H,-CH3).13C NMR(100MHz,CDCl3)δ177.8,165.2,156.4,154.8,146.4,143.9,141.5,122.5,75.0,73.9,63.5,50.3,47.9,46.9,46.0,44.6,42.1,41.9,41.5,39.4,38.2,37.0,34.0,33.2,32.6,30.8,29.5,27.8,26.3,25.9,23.7,23.5,23.3,23.1,22.0,21.2,19.0,17.3,15.6,12.4,12.4.HRMS(ESI)m/z:[M+H]+697.4343,calculated.forC41H62ClN2O5697.4342.
实施例27 H-24的制备
将川芎嗪酸(约0.27mmol,制备为实施例2),EDCI(0.35mmol)和DMAP(0.027mmol)溶解到干燥的二氯甲烷(20mL)中,然后将氯代常春藤皂苷元(152mg,0.27mmol,制备为实施例4)溶解在二氯甲烷(20ml)中。20分钟内将其滴入川芎嗪酸溶液中,室温下搅拌12小时。然后用二氯甲烷(20mL)稀释,饱和NaCl水溶液洗涤,经无水硫酸钠干燥,浓缩并通过柱色谱法纯化,得到白色粉末,即H-24。Yield:90%(after chromatograph with DCM/MeOH,1%-2%)as a white powder,m.p.:168.1℃.1H NMR(400MHz,CDCl3)δ5.28(s,1H,H-12),2.86(m,1H,H-18),2.79(s,3H,-CH3),2.55(d,J=6.2Hz,6H,2×-CH3),0.99-0.86(m,15H,5×-CH3),0.75(s,3H,-CH3).13C NMR(100MHz,CDCl3)δ177.8,165.3,155.4,152.2,149.6,143.9,138.1,122.5,75.3,74.6,63.5,50.7,47.8,46.9,46.0,44.6,42.0,42.0,41.5,39.4,38.2,37.0,34.0,33.2,33.0,30.8,29.5,27.8,27.0,26.2,26.0,23.7,23.5,23.1,22.7,22.3,21.8,19.1,17.2,15.5,12.5.HRMS(ESI)m/z:[M+H]+711.4497,calculated.forC42H64C1N2O5711.4498.
实施例28
取实施例5~27任一制备的化合物10g,加入注射剂(包括冻干粉针剂和无菌分装干粉针剂)适当辅料,按注射剂(包括冻干粉针剂和无菌分装干粉针剂)工艺制备成抗肿瘤药注射剂。
实施例25
取实施例5~27任一制备的化合物10g,加入片剂(包括缓控释片、骨架片、包衣片、分散片等)适当辅料,按片剂(包括缓控释片、骨架片、包衣片、分散片等)工艺制备成抗肿瘤药片剂。
实施例26
取实施例5~27任一制备的化合物10g,加入胶囊剂适当辅料,按胶囊剂工艺制备成抗肿瘤药胶囊剂。
实施例27
取实施例5~27任一制备的化合物10g,加入乳剂(包括微乳、纳米乳等)适当辅料,按乳剂(包括微乳、纳米乳等)工艺制备成抗肿瘤药乳剂。
实施例28
取实施例5~27任一制备的化合物10g,加入颗粒剂适当辅料,按颗粒剂工艺制备成抗肿瘤药颗粒剂。
实施例29
取实施例5~27任一制备的化合物10g,加入缓释控释剂适当辅料,按缓释控释剂工艺制成抗肿瘤药缓释控释剂。
实施例30
取实施例5~27任一制备的化合物10g,加入口服液适当辅料,按口服液工艺制备成抗肿瘤药口服液。
实施例31
取实施例5~27任一制备的化合物10g,加入脂质体剂型适当辅料,按脂质体工艺制备成抗肿瘤药脂质体剂型。
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