CN103570738B - 新型青蒿素衍生物及其制法和应用 - Google Patents
新型青蒿素衍生物及其制法和应用 Download PDFInfo
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- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
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- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
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Abstract
本发明涉及新型青蒿素衍生物及其制法和应用。具体地,本发明公开了一类结构如式I所示的青蒿素衍生物或其药学上可接受的盐,或其对映异构体、非对映异构体或外消旋体,其中X、Y、Z、n、k、P如本文中定义。本发明还公开了所述化合物的制法及其应用,所述化合物对治疗肿瘤有优异的效果。
Description
技术领域
本发明属于化学医药领域。具体地,涉及新型青蒿素衍生物及其制法和应用。
背景技术
青蒿,属菊科,又名黄花蒿(ArtemisiaanauaL)是一年生草本植物。青蒿素是我国药学工作者于20世纪70年代初从中药青蒿中提取的倍半萜内酯类抗疟药物,并在此结构基础上又相继合成、半合成出一系列具有抗疟活性的衍生物,如双氢青蒿素、青蒿琥酯、蒿甲醚、双氢蒿甲醚、蒿乙醚等。
以下是本领域几种已知的青蒿素和青蒿素衍生物的化学式:
青蒿素及其衍生物的抗疟活性已得到世界公认,具有起效快、药效高、毒副作用低等优点。除广泛应用于抗疟治疗外,青蒿素类药物还具有其它多种药理作用,如抗血吸虫作用,抗心律失常、平喘,抗内毒素,抗变态反应、红斑狼疮、免疫抑制等作用。
随着对青蒿素及其衍生物活性研究的不断深入,揭示了该类化合物还具有一定的抗肿瘤作用,对多种肿瘤细胞的生长具有抑制作用。例如,Efferth等(EfferthT,OlbrichA,BauerR.,人肿瘤细胞系对抗疟疾药物青蒿琥酯、蒿乙醚、和蒿甲醚响应的mRNA表达模式(mRNAexpressionprofilesfortheresponseofhumantumorcelllinestotheantimalarialdrugsartesunate,arteether,andartemether)生物化学药学(BiochemPharmacol.)2002Aug15;64:617-23),研究了青蒿琥酯、蒿乙醚及蒿甲醚对55种肿瘤细胞的细胞毒作用,结果显示三种化合物对55种肿瘤细胞的增殖均有抑制作用,青蒿琥酯作用最为显著,平均半抑制浓度IC50是12.3μM,对包括白血病、结肠癌、黑色素瘤、前列腺癌、肝癌、卵巢癌、乳腺癌、宫颈癌、人低分化鳞状上皮鼻炎癌等在内的多种肿瘤细胞有选择性杀伤作用,青蒿琥酯对白血病细胞和直肠癌细胞有明显的细胞毒作用,其半抑制浓度(IC50)分别为1.11±0.56和2.13±0.74μM。
该文献还分析了青蒿琥酯、蒿乙醚及蒿甲醚作用前后464个药物活性相关基因(包括耐药基因,DNA损伤修复基因,凋亡调节基因,增殖相关基因,原癌基因,抑癌基因及细胞因子)的表达谱,发现208个基因与上述三种青蒿素类药物抗肿瘤活性相关,主要涉及增殖相关基因、癌基因及抑癌基因,如过氧化氢酶、谷胱氨酸合成酶、硫氧还蛋白过氧化物酶以及硫氧还蛋白还原酶等。
目前,现有技术主要是对双氢青蒿素、青蒿琥酯、蒿乙醚、和蒿甲醚的研究,本领域技术人员有必要研发一类结构新颖、抗肿瘤效果的优异的青蒿素衍生物。
发明内容
本发明的目的是提供一种具有抗肿瘤效果的青蒿素衍生物及其制法。
本发明另一目的是提供所述青蒿素衍生物在抑制肿瘤方面的应用。
在本发明第一方面中,提供了结构如式I所示的青蒿素衍生物或其药学上可接受的盐,或其对映异构体、非对映异构体或外消旋体,
其中,X为-O-、-S-、-NH-或-CH2-;Y为-CO-或-CH2-;Z为-CH2-、-O-、-CO-、-CH2CO-、-CH2NH-、-CH2O-、-COCH2-、-NHCH2-、-OCH2-、或-NH-;n为0~5的整数;k为0或1;
P为选自下组的基团(moiety):
其中,R、R4各自独立地为苯环上任意位置取代的选自下组的基团:氢、卤素、C1-C12直链或支链的烷基、C2-C12直链或支链的不饱和烃基、C3-C12环烃基、氰基、硝基、氨基或被C1-C4烷基所取代的胺基、羟基、羟甲基、三氟甲基、三氟甲氧基、羧基、巯基苯基、取代的苯基、萘基、联苯基、或者取代或未取代的饱和或者不饱和的C3-C12杂环基,其中所述取代基选自:卤素、三氟甲基、乙炔基、羟基、氨基、C1-C4羟烷基、羧基或C1-C4胺烷基或醛基;
q、t各自独立地为1~4的整数;
R7为苯环上一个或两个任意位置取代的选自下组的基团:氢、卤素、C1-C12直链或支链的烷基、C2-C12直链或支链的不饱和烃基、C3-C12环烃基、乙炔基、氰基、硝基、氨基、羟基、羟甲基、三氟甲基、三氟甲氧基、羧基、巯基苯基、取代的苯基、萘基、联苯基、或者取代或未取代的饱和或者不饱和的C3-C12杂环基,苄醇基、取代的苄醇基、N,N-二甲基,N,N-二乙基,其中所述取代基选自:卤素、三氟甲基、乙炔基、羟基、氨基、C1-C4羟烷基、羧基或C1-C4胺烷基或醛基;
R8、R9各自独立地为其中,
W为氢、氧、NH、卤素、C1-C12直链或支链的烷基或亚烷基、C2-C12直链或支链的不饱和烃基或亚烃基(优选乙炔基)、C3-C12环烃基或亚环烃基、氰基、硝基、氨基、羟基、C1-C4羟烷基、三氟甲基、三氟甲氧基、羧基、巯基苯基、取代的苯基、萘基、联苯基、或者取代或未取代的饱和或者不饱和的C3-C12杂环基或亚杂环基、N,N-二甲基,N,N-二乙基,其中所述取代基选自下组:卤素、三氟甲基、乙炔基、羟基、氨基、C1-C4羟烷基、羧基或C1-C4胺烷基或醛基;
D为羰基、C1-C12直链或支链的烷基或亚烷基、C2-C12直链或支链的不饱和烃基或亚烃基、取代或未取代的饱和或者不饱和的C3-C12杂环基或亚杂环基,其中所述取代基选自下组:卤素、三氟甲基、乙炔基、羟基、氨基、C1-C4羟烷基、羧基或C1-C4胺烷基或醛基;
E为C1-C12直链或支链的烷基或亚烷基、C2-C12直链或支链的不饱和烃基或亚烃基、取代或未取代的饱和或者不饱和的C3-C12杂环基或亚杂环基,其中所述取代基选自下组:卤素、三氟甲基、乙炔基、羟基、氨基、C1-C4羟烷基、羧基或C1-C4胺烷基或醛基;
j、r各自独立地为0~5的整数;
A为选自下组的连接基团:
B为选自下组的连接基团:
m为0或1。
在另一优选例中,所述的P通过-(A)m-或-(B)m-进行连接。
在另一优选例中,R、R4各自独立地为苯环上任意位置取代的选自下组的基团:氢、卤素、氰基、硝基、氨基或被C1-C4烷基所取代的胺基、羟基、羟甲基、三氟甲基、三氟甲氧基、羧基、巯基苯基、取代的苯基、萘基或联苯基。
在另一优选例中,R、R4各自独立地为苯环上任意位置取代的选自下组的基团:氢或被C1-C4烷基所取代的胺基。
在另一优选例中,q或t各自独立地为1或4。
在另一优选例中,R7为苯环上一个或两个任意位置取代的氢或卤素。
在另一优选例中,R8、R9各自独立地为其中,W为氧或NH;
D为羰基、C1-C6直链或支链的烷基或亚烷基、C2-C6直链或支链的不饱和烃基或亚烃基、取代或未取代的饱和或者不饱和的C3-C6杂环基或亚杂环基(优选含1-3个选自氧、氮或硫的杂原子的C3-C6杂环基或亚杂环基);
E为C1-C6直链或支链的烷基或亚烷基、C2-C6直链或支链的不饱和烃基或亚烃基、取代或未取代的饱和或者不饱和的C3-C6杂环基或亚杂环基(优选含1-3个选自氧、氮或硫的杂原子的C3-C6杂环基或亚杂环基);
j、r各自独立地为0~5的整数。
在另一优选例中,D为羰基、C1-C4直链的烷基或亚烷基、未取代的饱和的C3-C6杂环基(优选含1个选自氧、氮或硫的杂原子的C3-C6杂环基)。
在另一优选例中,E为C1-C4直链的亚烷基或C2-C4直链的不饱和亚烃基(如-CH2CH=CH-)。
在另一优选例中,j、r各自独立地为0或1。
在另一优选例中,X为-O-、-NH-或-CH2-。
在另一优选例中,X为-O-、-NH-或-CH2-;且Z为-O-、-CO-、-NH-或-CH2-。
在另一优选例中,X为-O-、-NH-或-CH2-;Z为-O-、-CO-、-NH-或-CH2-;且n为0或1。
在另一优选例中,X为-O-、-NH-或-CH2-;Z为-O-、-CO-、-NH-或-CH2-;n为0或1;且m为0或1。
在另一优选例中,为选自下组的化合物:
在本发明第二方面中,提供了本发明第一方面所述的青蒿素衍生物的制备方法,包括方法:将RaNH或RaNH2和RbCOOH进行酸碱缩合反应、或将RaCOOH和RbNH或RbNH2进行酸碱缩合反应、或将RaOH和RbCOOH进行成酯反应,从而形成式I化合物;
其中,RaNH或RaNH2、RaCOOH、RaOH为选自下组的化合物:
RbNH或RbNH2、RbCOOH为选自下组的化合物:
其中,R、q、R4、t的定义同本发明第一方面所述;
R2、R3与相邻的N共同构成:哌嗪、4-羟C1-C4烷基哌啶、4-羟C1-C4烷基哌嗪;
R5、R6各自独立地为选自下组的基团:
所述为3-7元的环烷基或杂环烷基、或5-10元的芳环或芳杂环。
在另一优选例中,所述杂环烷基或芳杂环含有1~2个选自氧、氮、硫的杂原子。
在另一优选例中,所述为苯基、奈环、或吡啶。
在本发明第三方面中,提供了本发明第一方面所述的青蒿素衍生物或其药学上可接受的盐的用途,用于制备治疗肿瘤、抑制肿瘤或肿瘤细胞生长的药物。
在另一优选例中,所述的青蒿素衍生物为式I化合物,且式I中,X为-O-或-CH2-;Y为-CO-或-CH2-;Z为-O-、-CH2-、-CO-或-CH2CO-;n为0~2的整数;k为0或1;
P为选自下组的基团:
其中,B为m为0或1;或
其中,A为 m为0或1;
且用于制备治疗前列腺癌、抑制前列腺癌或其细胞生长的药物。
在另一优选例中,所述青蒿素衍生物选自下组:
在另一优选例中,所述的青蒿素衍生物为式I化合物,且式I中,X为-O-或-CH2-;Y为-CO-或-CH2-;Z为-O-、-CH2-、-CO-或-CH2CO-;n为0~2的整数;k为0或1;
P为选自下组的基团:
其中,A为m为0或1;或
其中,B为m为0或1;或
其中,A为m为0或1,R为氢,q为1;或
其中,m为0,R为氢,q为1;或
其中,A为m为0或1;或
其中,A为m为0或1;或
其中,R4为二乙基取代的氨基,t为1,B为 m为0或1;
且用于制备治疗肝癌、抑制肝癌或其细胞生长的药物。
在另一优选例中,所述青蒿素衍生物选自下组:
在另一优选例中,所述的青蒿素衍生物为式I化合物,且式I中,X为-O-或-CH2-;
Y为-CO-或-CH2-;Z为-O-、-CH2-、-CO-或-CH2CO-;n为0~2的整数;k为0或1;
P为选自下组的基团:
其中,B为m为0或1;或
其中,A为m为0或1;
其中,A为m为0或1,R为氢,q为1;或
其中,m为0,R为氢,q为1;或
其中,A为m为0或1;或
其中,A为m为0或1;或
其中,m为0;或
其中,m为0;或
其中,m为0;或
其中,m为0,R4为二乙基取代的氨基,t为1;或
其中,B为m为0或1,R4为二乙基取代的氨基,t为1;或其中,B为 m为0或1,R4为二乙基取代的氨基,t为1;
且用于制备治疗卵巢癌、抑制卵巢癌或其细胞生长的药物。
在另一优选例中,所述青蒿素衍生物选自下组:
在另一优选例中,所述肿瘤包括肝癌、卵巢癌、前列腺癌、神经胶质瘤、胃肠间质瘤、乳腺癌、淋巴瘤、白血病、肺癌、或结肠癌。
在本发明第四方面中,提供了一种药物组合物,包括:(a)0.0001-99.99wt%的本发明第一方面所述的青蒿素衍生物或其药学上可接受的盐;和(b)药学上可接受的载体。
在另一优选例中,所述药物组合物还包含选自下组的抗肿瘤药物:卡铂、吉西他滨、青蒿素、二氢青蒿素、青蒿琥酯。
在本发明第五方面中,提供了一种治疗方法,对需要的对象施用本发明第一方面所述的青蒿素衍生物或其药学上可接受的盐或本发明第四方面所述的药物组合物。
在另一优选例中,所述治疗方法用于治疗肿瘤、抑制肿瘤或肿瘤细胞生长。
在本发明第五方面中,提供了一种本发明第一方面所述的青蒿素衍生物或其药学上可接受的盐的用途,用于制备抑制肿瘤或肿瘤细胞转移、抑制肿瘤细胞增殖、诱导肿瘤细胞凋亡和/或诱导肿瘤细胞周期阻滞的药物;
用于制备抑制PDGFAA、PDGFBB、PDGFRα和/或PDGFRβ表达的药物;
用于制备抑制肿瘤细胞诱导巨噬细胞或肿瘤相关巨噬细胞的迁移的药物和/或抑制诱导微环境中巨噬细胞凋亡的药物;
用于制备抑制IL-6、RANTES、MIP-1α和/或MIP-1β表达的药物;和/或
用于制备PDGF抑制剂的增敏剂。
在本发明第六方面中,提供了一种药物组合物,含有:活性成分a:如本发明第一方面所述的青蒿素衍生物或其药学上可接受的盐;以及活性成分b:抗癌药物。
在另一优选例中,所述抗癌药物为PDGF抑制剂。
在另一优选例中,所述PDGF抑制剂包括舒尼替尼(sunitinib)、伊马替尼(Imatinib)、AG13736(Axitinib)、马赛替尼(Masitinib)、帕唑帕尼(Pazopanib)、(索拉菲尼)Sorafenib、阿法替尼(Nintedanib)、西地尼布(Cediranib)等。
在另一优选例中,所述药物组合物还含有药学上可接受的载体。
在另一优选例中,所述药物组合物中,活性成分(a)与活性成分(b)的含量比为1:0.1-1:10;优选1:0.5-1:5或1:0.1-1:1。
在本发明第七方面中,提供了一种癌症治疗方法,
所述方法包括步骤:给癌症患者施用本发明第一方面所述的青蒿素衍生物或其药学上可接受的盐、本发明第四方面或第六方面所述的药物组合物;或
所述方法包括步骤:
给癌症患者分别施用:(i)本发明第一方面所述的青蒿素衍生物或其药学上可接受的盐、本发明第四方面或第六方面所述的药物组合物;和(ii)抗癌药物。
在另一优选例中,所述抗癌药物为PDGF抑制剂。
在另一优选例中,所述PDGF抑制剂包括:舒尼替尼(sunitinib)、伊马替尼(Imatinib)、AG13736(Axitinib)、马赛替尼(Masitinib)、帕唑帕尼(Pazopanib)、(索拉菲尼)Sorafenib、阿法替尼(Nintedanib)、西地尼布(Cediranib)等。
在另一优选例中,本发明第一方面所述的青蒿素衍生物或其药学上可接受的盐与抗癌药物)的施用量之比为1:0.1-1:10;优选1:0.5-1:5或1:0.1-1:1。
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显示了AR7和DHA的在多种肿瘤类型中的抗癌效果比较;其中,A图显示了AR7和DHA体外抑制卵巢癌细胞的生长;B图显示了AR7和DHA体外抑制肝癌细胞的生长;C图显示了AR7和DHA体外抑制神经胶质瘤细胞的生长;D图显示了AR7和DHA体外抑制胃肠间质瘤的原代细胞的生长。
图2显示了AR7和DHA对淋巴瘤细胞的生长抑制作用。
图3显示了AR7体内抑制体内显著抑制卵巢癌和肝癌肿瘤的生长;其中,A图和B图显示了AR7体内抑制卵巢癌的生长;C图显示了AR7体内抑制肝癌肿瘤的生长。
图4显示了AR7和DHA在A2780和OVCAR-3卵巢癌裸鼠异体移植瘤模型中的体内抗肿瘤活性;其中,A1图、B1图、C1图显示了在A2780卵巢癌裸鼠异体移植瘤模型中的体内抗肿瘤活性;A2图、B2图、C2图显示了在OVCAR-3卵巢癌裸鼠异体移植瘤模型中的体内抗肿瘤活性。
图5显示了AR7和DHA对肿瘤迁移的抑制作用。
图6显示了AR7对A2780和OVCAR-3细胞增殖的抑制作用和凋亡的诱导作用。
图7显示了AR7对微环境中巨噬细胞的作用。
图8显示了AR7对肿瘤细胞与肿瘤微环境相互作用的干扰和阻滞作用。
图9显示了AR7对临床抗肿瘤药物的增敏作用。
具体实施方式
本发明人通过长期而深入的研究,意外地发现一类结构新颖的青蒿素衍生物,所述青蒿素衍生物具有更加优异的抑制肿瘤或肿瘤细胞生长的效果。在此基础上,发明人完成了本发明。
本发明所用“卤素”是指氟、氯、溴和碘。
本发明所用“C1-C12直链或支链的烷基”是指含有1-12个碳原子的直链或含支链的烷基,如甲基、乙基、丙基、丁基、戊基、己基等等。
本发明所用“C2-C12直链或支链的不饱和烃基”是指含2-12个碳原子的直链或含支链的烯基或炔基,如乙烯、丙烯、丁烯、乙炔、丙炔、丁炔等等。
本发明所用“C3-C12环烃基”是指含有3-12个碳原子的环烷基,环烯基或环炔基,例如环丙基、环丁基、环丁烯基、环戊烯基等等。
本发明所用“取代或未取代的饱和或者不饱和的C3-C12杂环基”是指含3-12个碳原子,含一个或多个(如2个)氧、氮、硫等杂原子的饱和或不饱和的杂环基,且所述杂环基可以是被取代或未取代的,其中所述取代基选自下组:卤素、三氟甲基、乙炔基、羟基、氨基、C1-C4羟烷基(如羟甲基、羟乙基、羟丙基、羟丁基)、羧基、C1-C4胺烷基(如胺甲基(NH2CH2-)、胺乙基、胺丙基、胺丁基)或醛基等。
本发明所用“羟C1-C4烷基”是指被羟基取代的C1-C4烷基,例如羟甲基、羟乙基、羟丙基、羟丁基等。
本发明所用“4-羟C1-C4烷基哌啶”是指哌啶4位被羟C1-C4烷基取代。
本发明所用“0~5的整数”是指0、1、2、3、4或5。
本发明所用“1~4的整数”是指1、2、3或4。
活性成分
如本文所用,术语“本发明化合物”指式I所示的化合物。该术语还包括及式I化合物的各种晶型形式、药学上可接受的盐、水合物或溶剂合物。
本发明化合物可能具有不对称中心、手性轴和手性平面,并且可以以对映异构体、非对映异构体、外消旋体、或其混合物的形式存在。
本发明提供了式I化合物的药学上可接受的盐,例如包括:(i)式I化合物与无机酸或有机酸反应形成常规的无毒盐。例如,常规的无毒盐可通过式I化合物与无机酸或有机酸反应制得,所述无机酸包括盐酸、氢溴酸、硫酸、硝酸、胺基磺酸和磷酸等,以及所述有机酸包括柠檬酸、酒石酸、乳酸、丙酮酸、乙酸、苯磺酸、对甲苯磺酸、甲磺酸、萘磺酸、乙磺酸、萘二磺酸、马来酸、苹果酸、丙二酸、富马酸、琥珀酸、丙酸、草酸、三氟乙酸、硬酯酸、扑酸、羟基马来酸、苯乙酸、苯甲酸、水杨酸、谷氨酸、抗坏血酸、对胺基苯磺酸、2-乙酰氧基苯甲酸和羟乙磺酸等;或者通式(I)化合物与丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、天冬氨酸或谷氨酸形成酯后再与无机碱形成的钠盐、钾盐、钙盐、铝盐或铵盐;(ii)式I化合物与有机碱形成的甲胺盐、乙胺盐或乙醇胺盐;(iii)式I化合物与赖氨酸、精氨酸、鸟氨酸形成酯后,再与盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸形成的对应的无机酸盐或与甲酸、乙酸、苦味酸、甲磺酸和乙磺酸形成的对应的有机酸盐。
式I化合物的制备
下面更具体地描述本发明式I化合物的制备方法,但这些具体方法不对本发明构成任何限制。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便的制得,这样的组合可由本发明所属领域的技术人员容易地进行。
本发明所用“室温”是指15-30℃,优选18-25℃。本发明所用“过夜”通常是指为12-16小时,
本发明提供了一种优选的式I化合物的制备方法,包括步骤:将含羟基的中间体RaOH、含氨基或胺基的中间体RaNH或RaNH2或含羧基的中间体RaCOOH,分别和相应地含氨基或胺基的中间体RbNH或RbNH2、或含羧基的中间体RbCOOH溶于CH2Cl2中,在EDCI和DMAP的存在下,于一定温度(如室温或18-30℃)下,搅拌一段时间(优选1-48小时;较佳地为5-40小时;更佳地为20-30小时;最佳地为24小时),得到式I化合物。
其中,相应的反应分别为:(1)将RaNH或RaNH2和RbCOOH进行酸碱缩合反应,从而形成酰胺类式I化合物;(2)将RaCOOH和RbNH或RbNH2进行酸碱缩合反应,从而形成酰胺类式I化合物;(3)将RaOH和RbCOOH进行成酯反应,从而形成酯类式I化合物。
中间体及其制备
本发明所用中间体化合物可以是市售可得的,也可以是按本领域普通技术人员所熟知的方法制得,例如优选(但不限于)按如下方法进行制备,且以下条件并不对本发明所用的中间体的制备构成任何限制。
(一)、含羧基的中间体RaCOOH可以为任何具有羧基的化合物或优选自下组的化合物:
所述含羧基的中间体RaCOOH的制备方法可优选(但不限于)按如下方法进行,包括:
方法(1):化合物3的制备
a.将二氢青蒿素(化合物1)和环丁酸酐(化合物2)溶于惰性溶剂(如CH2Cl2)中,加入咪唑,于一定温度(如室温)下,搅拌一段时间(如1-5h或3h),从而得到化合物3。
方法(2):化合物8的制备
b.将二氢青蒿素(化合物1)溶于惰性溶剂(如CH2Cl2)中,加入碱(如吡啶),冷却(如到约0℃)后,滴加苯甲酰氯,反应一段时间(如18h),得到化合物5。
c.将丙烯基三甲基硅烷溶于惰性溶剂(如1,2-二氯乙烷)中,加入ZnCl2,于一定温度(如约0℃)下,惰性气体(如氮气等)保护下,滴加化合物5的惰性溶剂(如1,2-二氯乙烷)溶液,于一定温度(如约0℃)继续反应一段时间(如1h),转至室温搅拌一段时间(如3h),从而得到化合物6。
d.将化合物6溶于惰性溶剂(如二氧六环和水的混合溶剂)中,加入氧化试剂(如OsO4(催化量)/NaIO4)以及2,6-二甲基吡啶,于一定温度(如室温)反应一段时间(如24h),从而得到化合物7。
e.将化合物7溶于惰性溶剂(如叔丁醇和水的混合溶剂)中,加入2-甲基1-丁烯,NaH2PO4,NaClO2,于一定温度(如室温)下,反应一段时间(如2h),得到化合物8。
方法(3):化合物12的制备
f.将化合物6溶于惰性溶剂(如乙醚)中,冷却(如到约-20℃)后,加入BH3SMe2的惰性溶剂(如四氢呋喃)溶液,反应一段时间(如1-30小时;较佳地为5-20小时),加入少量Na2CO3溶液,pH值调到碱性(如大于7),搅拌一段时间(如10min)后,加入30%的H2O2,搅拌一段时间(如1h)后,升温(如至室温)后,搅拌一段时间(如1h),得到化合物9。
g.将化合物9溶于惰性溶剂(如CH2Cl2)中,加入碱(如三乙胺),在一定温度(如约0℃)下,加入TsCl,升温(如至室温)后,反应一段时间(如20h),得到化合物10。
h.将化合物10溶于惰性溶剂(如四氢呋喃)中,加入相应的仲胺(例如,),于一定温度(如80℃)下,反应一段时间(如5h),得到化合物11。
i.将化合物11溶于惰性溶剂(如四氢呋喃)中,加入NaOH的水溶液,反应一段时间(如3h),得到化合物12。
方法(4):化合物16的制备
j.将化合物7溶于惰性溶剂(如甲醇)中,加入还原剂(如NaBH4),反应一段时间(如3h),得到化合物13。
k.将化合物13溶于惰性溶剂(如CH2Cl2)中,加入碱(如三乙胺),在一定温度(如0℃)下,加入甲基磺酰氯(MsCl),升温(如至室温)后,反应一段时间(如20h),得到化合物14。
h.步骤同方法(3)的步骤h,不同点在于用化合物14代替化合物10。
i.步骤同方法(3)的步骤i,不同点在于用化合物15代替化合物11。
方法(5):化合物21的制备
l.将二氢青蒿素(化合物1)溶于惰性溶剂(如CH2Cl2)中,加入叠氮化试剂(如NaN3),在一定温度(如约0℃)下,滴加三甲基氯硅烷(TMSCl),滴加完毕后,加入催化量的NaI,升温(如至室温)后,反应一段时间(如30h),得到化合物17。
m.将化合物17溶于惰性溶剂(如四氢呋喃)中,加入三苯基磷(Ph3P)和少量水,惰性气体(如氮气等)保护,在一点温度(如约80℃)下,反应一段时间(如10h),得到化合物18。
n.将化合物18溶于惰性溶剂(如无水CH2Cl2)中,加入碱(如三乙胺),在一定温度(如约0℃)下,滴加氯乙酰氯的溶液(如CH2Cl2溶液),反应一段时间(如2h),得到化合物19。
h.步骤同方法(3)的步骤h,不同点在于用化合物19代替化合物10。
i.步骤同方法(3)的步骤i,不同点在于用化合物20代替化合物11。
方法(6):化合物22的制备
a.步骤同方法(1)的步骤a,不同点在于用化合物18代替化合物1。
(二)、含氨基或胺基的中间体RaNH或RaNH2,或含羟基的中间体RaOH可以为任何具有氨基、胺基、或羟基的化合物,或优选自下组的化合物:
含氨基或胺基的中间体RaNH或RaNH2,或含羟基的中间体RaOH的制备方法可优选(但不限于)按如下方法进行,包括:
方法(1):化合物23和化合物24的制备
或
h.制备方法同中间体及其制备(一)中方法(3)的步骤h,不同点在于用化合物19代替化合物10,和相应的仲胺(如哌嗪,或N-羟乙基哌嗪)反应。
方法(2):化合物25-28、化合物46-1、或化合物46的制备
2.1化合物25-28、化合物46-1
h.制法同中间体及其制备(一)中方法(3)的步骤h,不同点在于相应的仲胺分别为哌嗪,N-羟乙基哌嗪,4-羟甲基哌啶和4-羟乙基哌啶反应。
2.2化合物46
将带保护基团(如叔丁氧羰基,即Boc)的化合物(如化合物46-1)于惰性溶剂中,在酸(如三氟乙酸)的存在下,进行脱去保护基反应,从而得到化合物46。
方法(3):化合物29或化合物30的制备
o.将化合物10或化合物14溶于惰性溶剂(如EtOH)中,加入氨水,于一定温度(如室温)下,反应一段时间(如1-10天,优选5天),从而得到化合物29或化合物30.
(三)、片段P可以是具有氨基或胺基的化合物,可以相应地和上述两类化合物进行反应,从而形成相应的酰胺类化合物或酯类化合物,优选化合物及其制备,如下(但不限于):
方法(1):化合物32或化合物47的制备
p.将化合物31或化合物47-1溶于惰性溶剂(如甲醇)中,加入氯化亚砜(SOCl2),回流,反应一段时间(如12h),得到化合物32或化合物47;
其中,R、q的定义同上文所述。
方法(2):化合物33或化合物48的制备
q.将化合物31或化合物47-1溶于惰性溶剂(如二氧六环)中,加入碱(如三乙胺),二碳酸二叔丁酯,于一定温度(如室温)下,搅拌一段时间(如3h),得到化合物33或化合物48,其中,R或q的定义同方法(1)中所述。
方法(3):化合物36的制备
r.将化合物34溶于惰性溶剂(如四氢呋喃)中,加入碱(如三乙胺eq),冷却(如到约0℃),惰性气体(如氮气等)保护,滴加氯乙酰氯(2.0eq),反应一段时间(如2h),得到化合物35。
s.将化合物35溶于惰性溶剂(如四氢呋喃)中,加入相应的仲胺(NR2R3,如哌嗪、4-羟甲基哌啶和4-羟乙基哌啶),于一定温度(如80℃),反应一段时间(如5h),得到化合物36。
方法(4):化合物38的制备
t.将化合物37溶于惰性溶剂(如CH2Cl2)中,加入相应的酸酐(即),于一定温度(如40℃)下,搅拌一段时间(如1-20小时,或5-15小时),得到化合物38。
其中,所述相应的酸酐,可选自:邻苯二甲酸酐、5-7元环酸酐,5-7元杂环酸酐。当所述相应的酸酐为邻苯二甲酸酐时,得到化合物38-1。
方法(5):化合物41的制备
u.将氰基乙酸甲酯溶于惰性溶剂(如乙醇)中,加入相应的胺(NR5H),回流一段时间(如1-20小时或8-16小时),得到化合物40;
v.将化合物40和相应的取代的邻醛基苯酚()溶于惰性溶剂(如乙醇)中,回流一段时间(如1-20小时或8-16小时),得到化合物41;
z.将化合物41溶于惰性溶剂(如EtOH和AcOH的混合溶剂)中,加入4-羟基苄胺,回流一段时间(如1-20小时或8-16小时),得到化合物54。
上述各式中,R4、t的定义同上文所述,R5定义同片段B的定义。
方法(6):化合物45的制备
w.将化合物42和丙二酸二乙酯溶于惰性溶剂(如甲醇)中,回流一段时间(如1-20小时或8-16小时),得到化合物43。
x.将化合物43溶于惰性溶剂(如四氢呋喃)中,加入碱(如NaOH等),于一定温度(如室温)下,搅拌一段时间(如2h),得到化合物44。
y.将化合物44溶于惰性溶剂(如CH2Cl2)中,加入相应的胺(NHR6),EDCI,DMAP,于一定温度(如室温)下,搅拌一段时间(如5h),得到化合物45。
其中,R4或t定义同上,所述R6的定义同片段B的定义。
药物组合物和施用方法
由于本发明化合物具有优异抗肿瘤活性,因此本发明化合物及其药学上可接受的无机或有机盐,以及含有本发明化合物为主要活性成分的药物组合物可用于治疗肿瘤。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药学上可接受的盐及药学上可以接受的赋形剂或载体。其中“安全有效量”指的是:化合物的量足以明显改善病情,而不至于产生严重的副作用。通常,药物组合物含有1-2000mg本发明化合物/剂,更佳地,含有10-200mg本发明化合物/剂。较佳地,所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是:一种或多种相容性固体或液体填料或凝胶物质,它们适合于人使用,而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和,而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或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)、和局部给药,优选注射给药。
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或生物药物(如本发明所述的活性成分b)联合给药。
本发明所述的活性成分b为抗癌药物,主要包括PDGF抑制剂。本发明所述PDGF抑制剂可为任意一种可抑制PDGF活性或抑制PDGF受体或因子表达的物质。例如,所述抑制PDGF活性的物质包括(但不限于):PDGF抗体,或舒尼替尼(sunitinib)、伊马替尼(Imatinib)、AG13736(Axitinib)、马赛替尼(Masitinib)、帕唑帕尼(Pazopanib)、(索拉菲尼)Sorafenib、阿法替尼(Nintedanib)、西地尼布(Cediranib)、Cediranib、Motesanib、Linifinib等药物。
使用药物组合物时,是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人),其中施用时剂量为药学上认为的有效给药剂量,对于60kg体重的人而言,日给药剂量通常为1~2000mg,优选20~500mg。当然,具体剂量还应考虑给药途径、病人健康状况等因素,这些都是熟练医师技能范围之内的。
本发明主要优点在于:
1.提供了一类结构新颖、抗肿瘤效果优异的青蒿素衍生物。
2.提供了一种用于抗肿瘤的药物组合物,包含本发明所述的青蒿素衍生物以及药学上可接受的载体或赋形剂。
下面结合具体实施,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,例如Sambrook等人,分子克隆:实验室手册(NewYork:ColdSpringHarborLaboratoryPress,1989)中所述的条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按重量计算。本发明所用原料若非特别说明,均市售可得或按照常规方法制得。
中间体制备实施例
1.含羧基的中间体RaCOOH
1.1化合物3的制备
a.将化合物1(1.0eq)和化合物2(1.6eq)溶于CH2Cl2中,加入咪唑(1.2eq),室温搅拌3h,得到化合物3。
1.2化合物8的制备
b.将二氢青蒿素(1.0eq)溶于CH2Cl2中,加入吡啶(6.0eq),冷却到0℃后,滴加苯甲酰氯(化合物2,1.5eq),反应18h,得到化合物5。
c.将丙烯基三甲基硅烷(5.0eq)溶于1,2-二氯乙烷中,加入ZnCl2(1.2eq),在0℃下,N2保护下,滴加化合物5(1.0eq)的1,2-二氯乙烷溶液,在0℃继续反应1h,转至室温搅拌3h,得到化合物6。
d.将化合物6(1.0eq)溶于二氧六环和水的混合溶剂中,加入OsO4(催化量)/NaIO4(1.1eq),2,6-二甲基吡啶(2.0eq),室温反应24h,得到化合物7。
e.将化合物7(1.0eq)溶于叔丁醇和水的混合溶剂中,加入2-甲基1-丁烯(1.2eq),NaH2PO4(2.0eq),NaClO2(1.2eq),室温反应2h,得到化合物8。
1.3化合物12的制备
f.将化合物6(1.0eq)溶于乙醚中,冷却到-20℃,加入BH3SMe2的四氢呋喃溶液(1.2eq),反应过夜,加入少量Na2CO3溶液,pH值调到碱性(>7),搅拌10min后,加入30%的H2O2,搅拌1h后,转至室温搅拌1h,得到化合物9。
g.将化合物9(1.0eq)溶于CH2Cl2中,加入三乙胺(5.0eq),在0℃下,加入TsCl(2.0eq),转至室温反应20h,得到化合物10。
h.将化合物10(1eq)溶于四氢呋喃中,加入(5.0eq),80℃,5h,得到化合物11。
i.将化合物11(1.0eq)溶于四氢呋喃中,加入2M的NaOH的水溶液(1.5eq),反应3h,得到化合物12。
1.4化合物16的制备
j.将化合物7(1.0eq)溶于甲醇中,加入NaBH4(1.2eq),反应3h,得到化合物13。
k.将化合物13(1.0eq)溶于CH2Cl2中,加入三乙胺(5.0eq),在0℃下,加入MsCl(1.5eq),转室温反应20h,得到化合物14。
h.制法同3的步骤h,不同点在于用化合物14代替化合物10。
i.制法同3的步骤i,不同点在于用化合物15代替化合物11。
1.5化合物21的制备
l.将二氢青蒿素(化合物1,1.0eq)溶于CH2Cl2中,加入NaN3(3.0eq),在0℃下,滴加TMSCl(1.5eq),滴加完毕后,加入催化量的NaI,转至室温反应30h,得到化合物17。
m.将化合物17(1.0eq)溶于四氢呋喃中,加入Ph3P(5.0eq)和少量水,N2保护,在80℃下,反应10h,得到化合物18。
n.将化合物18溶于无水CH2Cl2中,加入三乙胺,在0℃下,滴加氯乙酰氯(1.5eq)的CH2Cl2溶液,反应2h,得到化合物19。
h.制法同3的步骤h,不同点在于用化合物19代替化合物10。
i.制法同3的步骤i,不同点在于用化合物20代替化合物11。
1.6.化合物22的制备
a.制法同1的步骤a,不同点在于用化合物18代替化合物1。
2.含氨基或胺基的中间体RaNH或RaNH2
2.1式29化合物和式30化合物的制备
o.将化合物10或化合物14溶于EtOH中,加入氨水,室温反应5天,从而得到化合物29或化合物30。
3.具有氨基或胺基的片段P
3.1.化合物47的制备
p.将化合物47-1(1eq)溶于甲醇中,加入氯化亚砜(SOCl2)(4.0eq),回流,反应12h,得到化合物47
3.2.化合物48的制备
q.将化合物47-1(1eq)溶于二氧六环中,加入三乙胺(2.0eq),Boc2O(1.0eq),室温搅拌3h,得到化合物48。
3.3.化合物38-1的制备
t.将化合物37(1.0eq)溶于CH2Cl2中,加入邻苯二甲酸酐(1.0eq),40℃搅拌过夜,得到化合物38-1。
3.4.化合物BB10的制备
3.4.1化合物57:
aaa.将巴豆酸溶于CCl4中,加入少量(PhCO)2O和1.2eq的NBS,升温至80℃,反应12h后,过滤,浓缩滤液,用正己烷重结晶,得到化合物56。
bbb.将化合物56溶于SOCl2中,室温搅拌12h后,旋干SOCl2,得到化合物57。
3.4.2化合物BB10:
aa.将10g化合物BB1,醋酸甲脒8g(1.3eq)置于100ml茄形瓶中,混合均匀,微波炉中反应4min(60%功率)。冷却后,加入30ml水,洗涤固体,过滤得10g化合物BB2,收率95%。
bb.将10g化合物BB2冰浴下缓慢加入浓硫酸和发烟硝酸(20ml:20ml)混酸中,加完升温至90℃,反应约1小时。将反应液倒入300ml冰水中,析出固体,过滤,收集固体得化合物BB3的粗品12g。
cc.将10g化合物BB3置于40ml乙腈中,依次加入三氯氧磷8.3g,三乙胺5.4g,然后加热至80℃反应至TLC监测反应完全后。
dd.将7.8g3-氯4-氟苯胺的二氧六环(50ml)溶液滴加入反应液中,析出固体,TLC监测反应完全后,加入40ml水,用KOH溶液调节pH至微碱性,过滤,得到黄色固体化合物BB5粗品。将固体置于锥形瓶中,加入适量四氢呋喃,超声洗涤固体,过滤得13g化合物BB5。
ee.将10g化合物BB5溶于40mlDMF中,加入苯亚磺酸钠6.1g,加完升温至90℃反应2小时,TLC监测反应完全后,将反应液冷却后搅拌下倒入150ml水中,过滤,收集固体,干燥,得11.5g化合物BB6。
ff.将10g化合物BB6分散于60mlDMF中,冰浴下缓慢加入NaH1.8g(2eq),加完转室温搅拌3h,tlc监测反应完全后,倒入200ml水中,过滤,干燥,得7.6g化合物BB7。
gg.将7.6g化合物BB7溶于35mlDMF中,加入2.5gRaney镍,1.8g氯化铵,氢化反应过夜。反应完全后,滤去不溶物,搅拌下将滤液倒入350ml水中,析出固体,过滤,收集固体,得6.4g化合物BB8。
hh.将2g化合物BB8用于四氢呋喃中,冷却到0℃,滴加化合物57的四氢呋喃溶液(1.5eq),然后转至室温搅拌2h后,加入水,用乙酸乙酯萃取,干燥得到化合物BB9粗品。
ii.将200mg化合物BB9溶于5mLDMF中,加入10eq的哌嗪,室温搅拌过夜,得到化合物BB10。
3.5.化合物GG9的制备
3.5.1化合物59:
ccc.将5g化合物58溶于20mLDMF中,加入10eq的1-Boc-哌嗪,100℃反应12h,得到化合物59。
3.5.2化合物GG9:
aa.将20g化合物GG1,醋酸甲脒17g(1.3eq)置于100ml茄形瓶中,混合均匀,微波炉中反应4min(60%功率)。冷却后,加入30ml水,洗涤固体,过滤得20g化合物GG2。
gg.将20g化合物GG2溶于100mL甲磺酸中,加入MgSO4搅拌,得到15g化合物GG3。
kk.将15g化合物GG3置于40ml吡啶中,加入醋酐(1.5eq),室温搅拌过夜,反应完全后,倒入水中,析出固体,过滤得到化合物GG4。
cc.将10g化合物GG4置于40ml乙腈中,依次加入三氯氧磷8.3g,三乙胺5.4g,然后加热至80℃反应,TLC监测反应完全后;
dd.将7.8g3-氯4-氟苯胺的二氧六环(50ml)溶液滴加入反应液中,析出固体,TLC监测反应完全后,加入40ml水,用KOH溶液调节pH至微碱性,过滤,水洗,得到黄色固体化合物GG6粗品。将固体置于锥形瓶中,加入适量四氢呋喃,超声洗涤固体,过滤得13g化合物GG6。
ll.将10g化合物GG6溶于200ml四氢呋喃中,30mL水,1.5eq的NaOH,室温搅拌4h,TLC监测反应完全后,用盐酸调节pH值为4,将反应液,倒入500ml水中,过滤,收集固体,干燥,得78g化合物GG。
mm.将5g化合物GG7分散于50mlDMF中,加入K2CO3(2.0eq),化合物59(1.2eq),80℃反应3h,tlc监测反应完全后,倒入400ml水中,过滤,干燥,得5.5g化合物GG8。
nn.将2g化合物GG8分散于50mlCH2Cl2中,加入3mLTFA室温反应3h,TLC监测反应完全后,旋干反应液,得到化合物GG9。
实施例1:化合物AR1
将化合物3(1.0eq)和二(2-二氯乙基)胺盐酸盐(1.3eq)溶于CH2Cl2中,加入EDCI(1.2eq)和DMAP(1.2eq),室温搅拌24h,得到化合物AR1。1HNMR(400MHz,CDCl3)δ0.83-0.86(m,3H),0.94-0.95(m,4H),1.13-1.70(m,13H),2.33-2.36(m,1H),2.53-2.61(m,4H),3.48(brs,4H),3.64(brs,4H),5.02(s,1H),6.06(s,1H);ESI-MSm/z508[M+H]+.
实施例2:化合物AR2
制法同实施例1,不同点在于,用化合物12代替化合物3。1HNMR(400MHz,CDCl3)δ0.82-0.85(m,3H),0.94-0.95(m,4H),1.13-1.75(m,17H),2.31-2.39(m,8H),2.41-2.44(m,2H),3.29(s,2H),3.46-3.49(m,4H),3.56-3.59(m,5H),5.02(s,1H);ESI-MSm/z576[M+H]+.
实施例3:化合物AR3
制法同实施例1,不同点在于,用化合物9代替化合物3,用4-二(2-二氯乙基)胺基苯丁酸代替二(2-二氯乙基)胺盐酸盐。1HNMR(400MHz,CDCl3)δ0.83-0.86(m,3H),0.94-0.95(m,4H),1.24-1.30(m,3H),1.39-1.45(m,5H),1.54-1.68(m,4H),1.74-1.81(m,1H),1.86-2.05(m,5H),2.27-2.35(m,3H),2.52-2.57(m,2H),2.62-2.67(m,1H),3.59-3.63(m,4H),3.67-3.71(m,4H),4.08-4.13(m,2H),4.15-4.20(m,1H),5.28(s,1H),6.62(d,J=8.8Hz,2H),7.06(d,J=8.8Hz,2H);ESI-MSm/z612[M+H]+.
实施例4:化合物AR4
制法同实施例1,不同点在于,用化合物25代替化合物3,用4-二(2-二氯乙基)胺基苯丁酸代替二(2-二氯乙基)胺盐酸盐。1HNMR(400MHz,CDCl3)δ0.82(d,J=7.2Hz,3H),0.91-0.95(m,4H),1.18-1.33(m,4H),1.34-1.48(m,5H),1.49-1.65(m,4H),1.68-1.77(m,2H),1.85-1.92(m,4H),1.97-2.02(m,1H),2.25-2.33(m,3H),2.53-2.62(m,8H),3.56-3.61(m,6H),3.66-3.75(m,5H),4.12-4.16(m,1H),5.27(s,1H),6.58(d,J=8.4Hz,2H),7.06(d,J=8.4Hz,2H);13CNMR(100MHz,CDCl3)δ12.8,20.1,23.5,24.6,24.7,26.1,26.7,26.8,30.2,32.2,34.0,34.3,36.4,37.3,40.1,52.1,52.3,52.6,53.4,57.7,74.8,81.0,89.1,103.0,112.0,129.6,130.5,144.2,171.1;ESI-MSm/z680[M+H]+.
实施例5:化合物AR5
制法同实施例1,不同点在于,用化合物29代替化合物3,用4-二(2-二氯乙基)胺基苯丁酸代替二(2-二氯乙基)胺盐酸盐。1HNMR(400MHz,CDCl3)δ0.83-0.86(m,3H),0.94-0.95(m,4H),1.24-1.30(m,3H),1.39-1.45(m,5H),1.54-1.68(m,4H),1.74-1.81(m,1H),1.86-2.05(m,5H),2.27-2.35(m,3H),2.52-2.57(m,2H),2.62-2.67(m,1H),3.59-3.63(m,4H),3.67-3.71(m,4H),4.08-4.13(m,2H),4.15-4.20(m,1H),5.28(s,1H),6.60-6.63(m,2H),7.05-7.07(m,2H);ESI-MSm/z611[M+H]+.
实施例6:化合物AR6
制法同实施例1,不同点在于,用化合物23代替化合物3,用4-二(2-二氯乙基)胺基苯丁酸代替二(2-二氯乙基)胺盐酸盐。1HNMR(400MHz,CDCl3)δ0.82-0.85(m,3H),0.94-0.95(m,4H),1.13-1.76(m,15H),2.32-2.40(m,3H),2.49-2.52(m,4H),2.60-2.63(m,2H),3.25(s,2H),3.41-3.45(m,4H),3.60-3.65(m,8H),5.28(s,1H),5.68(d,J=10.0Hz,1H),6.70-6.72(m,2H),7.09-7.12(m,2H);ESI-MSm/z695[M+H]+.
实施例7:化合物AR7
制法同实施例1,不同点在于,用化合物32(R为H时)代替二(2-二氯乙基)胺盐酸盐。1HNMR(400MHz,CDCl3)δ0.83(d,J=6.8Hz,3H),0.94(d,J=6.0Hz,3H),0.98-1.05(m,1H),1.22-1.52(m,8H),1.58-1.64(m,1H),1.68-1.79(m,2H),1.84-1.91(m,1H),1.99-2.04(m,1H),2.32-2.58(m,4H),2.63-2.71(m,1H),2.76-2.84(m,1H),3.59-3.63(m,4H),3.67-3.72(m,4H),3.73(s,3H),4.80-4.82(m,1H),5.43(s,1H),5.76(d,J=10.0Hz,1H),6.00(d,J=8.0Hz,1H),6.60(d,J=8.4Hz,2H),6.97(d,J=8.8Hz,2H);13CNMR(100MHz,CDCl3)δ12.0,20.2,21.9,24.5,25.9,29.2,30.4,31.7,34.0,36.1,36.6,37.2,40.2,45.1,51.4,52.3,52.4,53.2,53.5,80.0,91.4,92.1,104.4,112.2,130.6,144.8,170.6,171.4,172.0;ESI-MSm/z685[M+H]+.
实施例8:化合物AR8
制法同实施例1,不同点在于,用化合物22代替化合物3,用化合物32(R为H时)代替二(2-二氯乙基)胺盐酸盐。1HNMR(400MHz,CDCl3)δ0.82(d,J=6.5Hz,3H),0.93(d,J=6.2Hz,3H),0.97-1.05(m,1H),1.23-1.55(m,8H),1.58-1.64(m,1H),1.67-1.79(m,2H),1.82-1.91(m,1H),1.99-2.04(m,1H),2.31-2.58(m,4H),2.61-2.71(m,1H),2.76-2.82(m,1H),3.59-3.62(m,4H),3.67-3.73(m,4H),3.75(s,3H),4.81-4.84(m,1H),5.45(s,1H),5.75(d,J=10.0Hz,1H),6.02(d,J=8.0Hz,1H),6.61(d,J=8.5Hz,2H),6.94(d,J=8.5Hz,2H);ESI-MSm/z684[M+H]+.
实施例9:化合物AR9
制法同实施例1,不同点在于,用化合物12代替化合物3,用化合物32(R为H时)代替二(2-二氯乙基)胺盐酸盐。1HNMR(400MHz,CDCl3)δ0.81-0.86(m,3H),0.89-0.93(m,4H),1.20-1.32(m,3H),1.38-1.42(m,4H),1.44-1.64(m,4H),1.74-2.01(m,5H),2.23-2.48(m,11H),2.88-3.03(m,4H),3.57-3.60(m,4H),3.63-3.72(m,6H),4.08-4.12(m,1H),4.77-4.79(m,1H),5.21(s,1H),6.56(d,J=8.8Hz,1H),6.96(d,J=8.4Hz,2H),7.50(d,J=8.4Hz,2H);ESI-MSm/z753[M+H]+.
实施例10:化合物AR10
制法同实施例1,不同点在于,用化合物21代替化合物3,用化合物32(R为H时)代替二(2-二氯乙基)胺盐酸盐。1HNMR(400MHz,CDCl3)δ0.81-0.85(m,3H),0.90-0.93(m,4H),1.12-1.81(m,13H),2.33-2.39(m,9H),2.90-3.26(m,6H),3.57-3.65(m,8H),3.68(s,3H),4.52-4.55(m,1H),5.27(s,1H),5.69(d,J=9.6Hz,1H),6.70(d,J=8.2Hz,2H),7.40(d,J=8.2Hz,2H);ESI-MSm/z768[M+H]+.
实施例11:化合物AR11
制法同实施例1,不同点在于,用化合物16代替化合物3,用化合物32(R为H时)代替二(2-二氯乙基)胺盐酸盐。1HNMR(400MHz,CDCl3)δ0.82-0.85(m,3H),0.92-0.94(m,4H),1.10-1.78(m,16H),2.30-2.45(m,10H),2.91-3.29(m,4H),3.60-3.65(m,8H),3.70(s,3H),4.51-4.54(m,1H),5.21(s,1H),6.69(d,J=8.4Hz,2H),7.10(d,J=8.2Hz,2H);ESI-MSm/z739[M+H]+.
实施例12:化合物AR12
制法同实施例1,不同点在于,用化合物8代替化合物3,用化合物32(R为H时)代替二(2-二氯乙基)胺盐酸盐。1HNMR(400MHz,CDCl3)δ0.82-0.84(m,3H),0.91-0.94(m,4H),1.11-1.79(m,14H),2.19-2.45(m,2H),2.98-3.23(m,2H),3.60-3.65(m,8H),3.71(s,3H),3.80-3.81(m,1H),4.52-4.55(m,1H),5.27(s,1H),7.09(d,J=8.6Hz,2H),7.36(d,J=8.8Hz,2H);ESI-MSm/z627[M+H]+.
实施例13:化合物AR13
制法同实施例1,不同点在于,用化合物9代替化合物3,用化合物33(R为H时)代替二(2-二氯乙基)胺盐酸盐。1HNMR(400MHz,CDCl3)δ0.83(d,J=7.2Hz,3H),0.89-0.96(m,4H),1.21-1.32(m,3H),1.39-1.42(m,12H),1.43-1.51(m,2H),1.55-1.66(m,3H),1.68-1.78(m,2H),1.87-2.04(m,3H),2.26-2.34(m,1H),2.56-2.64(m,1H),2.92-3.03(m,2H),3.57-3.61(m,4H),3.66-3.70(m,4H),4.10-4.24(m,3H),4.47-4.52(m,1H),4.96(d,J=8.0Hz,1H),5.28(s,1H),6.60(d,J=8.4Hz,2H),6.97(d,J=8.4Hz,2H);13CNMR(100MHz,CDCl3)δ12.7,20.0,24.6,24.8,25.8,26.0,26.2,28.2,30.2,34.2,36.4,37.0,37.3,40.2,44.0,52.0,53.4,54.3,64.9,73.8,79.6,81.0,89.2,102.9,112.0,124.9,130.5,144.7,155.0,171.9;ESI-MSm/z713[M+H]+.
实施例14:化合物AR14
制法同实施例1,不同点在于,用化合物9代替化合物3,用化合物31(R为H时)代替二(2-二氯乙基)胺盐酸盐。1HNMR(400MHz,CDCl3)δ0.82-0.84(m,3H),0.89-0.96(m,4H),1.21-1.32(m,3H),1.40-1.42(m,3H),1.43-1.51(m,2H),1.55-1.66(m,3H),1.68-1.78(m,2H),1.87-2.04(m,3H),2.26-2.34(m,1H),2.56-2.64(m,1H),2.92-3.03(m,2H),3.57-3.61(m,4H),3.66-3.70(m,4H),4.10-4.24(m,3H),4.47-4.52(m,1H),4.96(d,J=8.2Hz,1H),5.28(s,1H),6.60(d,J=8.2Hz,2H),6.97(d,J=8.3Hz,2H);ESI-MSm/z613[M+H]+.
实施例15:化合物AR15
制法同实施例1,不同点在于,用化合物29代替化合物3,用化合物33(R为H时)代替二(2-二氯乙基)胺盐酸盐。1HNMR(400MHz,CDCl3)δ0.81-0.83(m,3H),0.87-0.95(m,4H),1.21-1.32(m,3H),1.40-1.42(m,12H),1.43-1.51(m,2H),1.55-1.66(m,3H),1.68-1.78(m,2H),1.87-2.04(m,3H),2.26-2.34(m,1H),2.56-2.64(m,1H),2.92-3.03(m,2H),3.57-3.61(m,4H),3.66-3.70(m,4H),4.10-4.24(m,3H),4.47-4.52(m,1H),4.96(d,J=8.3Hz,1H),5.28(s,1H),6.60(d,J=8.4Hz,2H),6.97(d,J=8.8Hz,2H);ESI-MSm/z712[M+H]+.
实施例16:化合物AR16
按实施例15的制法,制得化合物AR15;然后经三氟乙酸脱BOC保护基得到化合物AR16。1HNMR(400MHz,CDCl3)δ0.82-0.85(m,3H),0.89-0.96(m,4H),1.21-1.32(m,3H),1.40-1.42(m,3H),1.43-1.51(m,2H),1.55-1.66(m,3H),1.68-1.78(m,2H),1.87-2.04(m,3H),2.26-2.34(m,1H),2.56-2.64(m,1H),2.92-3.03(m,2H),3.57-3.61(m,4H),3.66-3.70(m,4H),4.10-4.24(m,3H),4.47-4.52(m,1H),4.96(d,J=8.4Hz,1H),5.23(s,1H),6.60(d,J=8.4Hz,2H),6.97(d,J=8.4Hz,2H);ESI-MSm/z612[M+H]+.
实施例17:化合物AR17
制法同实施例1,不同点在于,用化合物28代替化合物3,用化合物33(R为H时)代替二(2-二氯乙基)胺盐酸盐。1HNMR(400MHz,CDCl3)δ0.82-0.85(m,3H),0.90-0.95(m,4H),1.12-1.81(m,34H),2.40-2.50(m,6H),2.96-3.20(m,2H),3.61-3.64(m,8H),4.06-4.10(m,2H),4.67-4.69(m,1H),5.24(s,1H),6.92(d,J=8.2Hz,2H),7.10(d,J=8.1Hz,2H);ESI-MSm/z824[M+H]+.
实施例18:化合物AR18
按实施例17的制法,制得化合物AR17;然后经三氟乙酸脱BOC保护基得到化合物AR18。1HNMR(400MHz,CDCl3)δ0.82-0.84(m,3H),0.91-0.95(m,4H),1.11-1.81(m,25H),2.40-2.50(m,6H),2.96-3.21(m,2H),3.62-3.64(m,8H),4.06-4.11(m,2H),4.67-4.69(m,1H),5.25(s,1H),6.93(d,J=8.4Hz,2H),7.13(d,J=8.2Hz,2H);ESI-MSm/z724[M+H]+.
实施例19:化合物AR19
制法同实施例1,不同点在于,用化合物46代替化合物3,用化合物33(R为H时)代替二(2-二氯乙基)胺盐酸盐。1HNMR(400MHz,CDCl3)δ0.82-0.85(m,3H),0.90-0.95(m,4H),1.12-1.82(m,33H),2.40-2.50(m,6H),2.97-3.21(m,2H),3.61-3.63(m,8H),4.04-4.10(m,2H),4.68-4.69(m,1H),5.23(s,1H),6.92(d,J=8.1Hz,2H),7.10(d,J=8.4Hz,2H);ESI-MSm/z824[M+H]+.
实施例20:化合物AR20
按实施例19的制法,制得化合物AR19;然后经三氟乙酸脱BOC保护基得到化合物AR20。1HNMR(400MHz,CDCl3)δ0.81-0.84(m,3H),0.91-0.94(m,4H),1.13-1.81(m,24H),2.40-2.50(m,6H),2.96-3.22(m,2H),3.62-3.64(m,8H),4.06-4.11(m,2H),4.67-4.68(m,1H),5.29(s,1H),6.94(d,J=8.2Hz,2H),7.15(d,J=8.1Hz,2H);ESI-MSm/z724[M+H]+.
实施例21:化合物AR21
制法同实施例1,不同点在于,用化合物23代替化合物3,用化合物33(R为H时)代替二(2-二氯乙基)胺盐酸盐。1HNMR(400MHz,CDCl3)δ0.83-0.86(m,3H),0.92-0.95(m,4H),1.13-1.79(m,13H),2.37-2.39(m,1H),2.49-2.51(m,4H),3.19-3.45(m,8H),3.61-3.67(m,8H),4.91-4.93(m,1H),5.23(s,1H),5.70(d,J=8.2Hz,1H),7.02(d,J=8.1Hz,2H),7.12(d,J=8.2Hz,2H);ESI-MSm/z796[M+H]+.
实施例22:化合物AR22
按实施例21的制法,制得化合物AR21;然后经三氟乙酸脱BOC保护基得到化合物AR22。1HNMR(400MHz,CDCl3)δ0.81-0.84(m,3H),0.92-0.95(m,4H),1.12-1.77(m,4H),2.37-2.39(m,1H),2.49-2.51(m,4H),3.19-3.44(m,8H),3.61-3.66(m,8H),4.91-4.92(m,1H),5.24(s,1H),5.70(d,J=8.1Hz,1H),7.02(d,J=8.2Hz,2H),7.11(d,J=8.1Hz,2H);ESI-MSm/z696[M+H]+.
实施例23:化合物AR23
制法同实施例1,不同点在于,用化合物47代替二(2-二氯乙基)胺盐酸盐。1HNMR(400MHz,CDCl3)δ0.82(d,J=6.8Hz,3H),0.95(d,J=6.0Hz,3H),0.98-1.05(m,1H),1.22-1.52(m,8H),1.58-1.64(m,1H),1.68-1.79(m,2H),1.84-1.91(m,1H),1.99-2.04(m,1H),2.32-2.58(m,4H),2.63-2.71(m,1H),2.76-2.84(m,1H),3.59-3.63(m,4H),3.67-3.72(m,4H),3.73(s,3H),4.80-4.82(m,1H),5.43(s,1H),5.76(d,J=10.0Hz,1H),6.00(d,J=8.0Hz,1H),7.44(s,1H),7.90(s,1H),8.06(s,1H);ESI-MSm/z744[M+H]+.
实施例24:化合物AR24
制法同实施例1,不同点在于,用化合物8代替化合物3,用化合物47代替二(2-二氯乙基)胺盐酸盐。1HNMR(400MHz,CDCl3)δ0.82-0.84(m,3H),0.91-0.94(m,4H),1.11-1.79(m,14H),2.19-2.45(m,2H),2.98-3.23(m,2H),3.60-3.65(m,8H),3.71(s,3H),3.80-3.81(m,1H),4.52-4.55(m,1H),5.27(s,1H),7.46(s,1H),7.92(s,1H),8.10(s,1H);ESI-MSm/z686[M+H]+.
实施例25:化合物AR25
制法同实施例1,不同点在于,用化合物12代替化合物3,用化合物47代替二(2-二氯乙基)胺盐酸盐。1HNMR(400MHz,CDCl3)δ0.81-0.86(m,3H),0.89-0.93(m,4H),1.20-1.32(m,3H),1.38-1.42(m,4H),1.44-1.64(m,4H),1.74-2.01(m,5H),2.23-2.48(m,11H),2.88-3.03(m,4H),3.57-3.60(m,4H),3.63-3.72(m,6H),4.08-4.12(m,1H),4.77-4.79(m,1H),5.21(s,1H),6.56(d,J=8.8Hz,1H),7.50(s,1H),7.93(s,1H),8.12(s,1H);ESI-MSm/z812[M+H]+.
实施例26:化合物AR26
制法同实施例1,不同点在于,用化合物21代替化合物3,用化合物47代替二(2-二氯乙基)胺盐酸盐。1HNMR(400MHz,CDCl3)δ0.81-0.85(m,3H),0.90-0.93(m,4H),1.12-1.81(m,13H),2.33-2.39(m,9H),2.90-3.26(m,6H),3.57-3.65(m,8H),3.68(s,3H),4.52-4.55(m,1H),5.27(s,1H),5.69(d,J=9.6Hz,1H),7.40(s,1H),7.92(s,1H),8.12(s,1H);ESI-MSm/z827[M+H]+.
实施例27:化合物AR27
制法同实施例1,不同点在于,用化合物25代替化合物3,用化合物48代替二(2-二氯乙基)胺盐酸盐。1HNMR(400MHz,CDCl3)δ0.83-0.86(m,3H),0.91-0.94(m,4H),1.10-1.81(m,26H),2.41-2.53(m,6H),2.61-2.64(m,4H),3.19-3.50(m,6H),3.56-3.59(m,8H),3.66(s,2H),4.90-4.92(m,1H),5.13(s,1H),7.41(s,1H),7.91(s,1H),8.02(s,1H);ESI-MSm/z840[M+H]+.
实施例28:化合物AR28
按实施例27的制法,制得化合物AR27;然后经三氟乙酸脱BOC保护基得到化合物AR28。1HNMR(400MHz,CDCl3)δ0.83-0.86(m,3H),0.91-0.94(m,4H),1.10-1.81(m,15H),2.41-2.53(m,6H),2.61-2.64(m,4H),3.19-3.50(m,6H),3.56-3.59(m,8H),3.66(s,2H),4.90-4.92(m,1H),5.13(s,1H),7.41(s,1H),7.91(s,1H),8.02(s,1H);ESI-MSm/z740[M+H]+.
实施例29:化合物AR29
制法同实施例1,不同点在于,用化合物9代替化合物3,用化合物48代替二(2-二氯乙基)胺盐酸盐。1HNMR(400MHz,CDCl3)δ0.83(d,J=7.2Hz,3H),0.89-0.96(m,4H),1.21-1.32(m,3H),1.39-1.42(m,12H),1.43-1.51(m,2H),1.55-1.66(m,3H),1.68-1.78(m,2H),1.87-2.04(m,3H),2.26-2.34(m,1H),2.56-2.64(m,1H),2.92-3.03(m,2H),3.57-3.61(m,4H),3.66-3.70(m,4H),4.10-4.24(m,3H),4.47-4.52(m,1H),4.96(d,J=8.0Hz,1H),5.28(s,1H),7.43(s,1H),7.94(s,1H),8.11(s,1H);ESI-MSm/z772[M+H]+.
实施例30:化合物AR30
按实施例29的制法,制得化合物AR29;然后经三氟乙酸脱BOC保护基得到化合物AR30。1HNMR(400MHz,CDCl3)δ0.83(d,J=7.2Hz,3H),0.89-0.96(m,4H),1.21-1.32(m,3H),1.39-1.42(m,3H),1.43-1.51(m,2H),1.55-1.66(m,3H),1.68-1.78(m,2H),1.87-2.04(m,3H),2.26-2.34(m,1H),2.56-2.64(m,1H),2.92-3.03(m,2H),3.57-3.61(m,4H),3.66-3.70(m,4H),4.10-4.24(m,3H),4.47-4.52(m,1H),4.96(d,J=8.0Hz,1H),5.28(s,1H),7.43(s,1H),7.94(s,1H),8.11(s,1H);ESI-MSm/z672[M+H]+.
实施例31:化合物AR31
制法同实施例1,不同点在于,用化合物29代替化合物3,用化合物48代替二(2-二氯乙基)胺盐酸盐。1HNMR(400MHz,CDCl3)δ0.83(d,J=7.2Hz,3H),0.89-0.96(m,4H),1.21-1.32(m,3H),1.39-1.42(m,12H),1.43-1.51(m,2H),1.55-1.66(m,3H),1.68-1.78(m,2H),1.87-2.04(m,3H),2.26-2.34(m,1H),2.56-2.64(m,1H),2.92-3.03(m,2H),3.57-3.61(m,4H),3.66-3.70(m,4H),4.10-4.24(m,3H),4.47-4.52(m,1H),4.96(d,J=8.0Hz,1H),5.28(s,1H),7.43(s,1H),7.94(s,1H),8.11(s,1H);ESI-MSm/z771[M+H]+.
实施例32:化合物AR32
按实施例31的制法,制得化合物AR31;然后经三氟乙酸脱BOC保护基得到化合物AR32。1HNMR(400MHz,CDCl3)δ0.83(d,J=7.2Hz,3H),0.89-0.96(m,4H),1.21-1.32(m,3H),1.39-1.42(m,3H),1.43-1.51(m,2H),1.55-1.66(m,3H),1.68-1.78(m,2H),1.87-2.04(m,3H),2.26-2.34(m,1H),2.56-2.64(m,1H),2.92-3.03(m,2H),3.57-3.61(m,4H),3.66-3.70(m,4H),4.10-4.24(m,3H),4.47-4.52(m,1H),4.96(d,J=8.0Hz,1H),5.28(s,1H),7.43(s,1H),7.94(s,1H),8.11(s,1H);ESI-MSm/z671[M+H]+.
实施例33:化合物AR33
制法同实施例1,不同点在于,用化合物23代替化合物3,用化合物48代替二(2-二氯乙基)胺盐酸盐。1HNMR(400MHz,CDCl3)δ0.83-0.86(m,3H),0.92-0.95(m,4H),1.13-1.79(m,13H),2.37-2.39(m,1H),2.49-2.51(m,4H),3.19-3.45(m,8H),3.61-3.67(m,8H),4.91-4.93(m,1H),5.23(s,1H),5.70(d,J=8.2Hz,1H),7.43(s,1H),7.94(s,1H),8.03(s,1H);ESI-MSm/z855[M+H]+.
实施例34:化合物AR34
按实施例33的制法,制得化合物AR33;然后经三氟乙酸脱BOC保护基得到化合物AR34。1HNMR(400MHz,CDCl3)δ0.83-0.86(m,3H),0.92-0.95(m,4H),1.13-1.79(m,4H),2.37-2.39(m,1H),2.49-2.51(m,4H),3.19-3.45(m,8H),3.61-3.67(m,8H),4.91-4.93(m,1H),5.23(s,1H),5.70(d,J=8.2Hz,1H),7.43(s,1H),7.94(s,1H),8.03(s,1H);ESI-MSm/z755[M+H]+.
实施例35:化合物AR35
制法同实施例1,不同点在于,用化合物36(NR3R2为哌嗪)代替二(2-二氯乙基)胺盐酸盐。1HNMR(400MHz,CDCl3)δ0.83-0.85(m,3H),0.92-0.95(m,4H),0.98-1.05(m,1H),1.23-1.38(m,3H),1.39-1.41(m,3H),1.42-1.49(m,1H),1.58-1.64(m,1H),1.68-1.78(m,2H),1.85-1.91(m,1H),1.98-2.03(m,1H),2.29-2.38(m,1H),2.49-2.71(m,7H),2.72-2.83(m,2H),3.25(s,2H),3.62-3.73(m,4H),5.41(s,1H),5.75(d,J=10.0Hz,1H),7.95-8.00(m,2H),8.04-8.06(m,1H),9.50(s,1H);13CNMR(100MHz,CDCl3)δ12.0,20.1,21.9,24.4,25.9,27.3,29.4,31.8,33.9,36.1,37.2,41.5,45.1,51.4,53.1,53.3,61.7,80.1,91.4,92.0,104.4,117.9,118.0,122.0,127.1,141.6,143.0,168.5,169.7,171.6;ESI-MSm/z699[M+H]+.
实施例36:化合物AR36
制法同实施例1,不同点在于,用化合物12代替化合物3,用化合物34代替二(2-二氯乙基)胺盐酸盐。1HNMR(400MHz,CDCl3)δ0.83-0.85(m,3H),0.91-0.94(m,4H),1.13-1.85(m,18H),2.30-2.40(m,8H),2.41-2.45(m,2H),3.34(s,2H),3.54-3.60(m,1H),5.15(s,1H),7.82(s,1H),8.17(s,1H),8.38(s,1H);ESI-MSm/z641[M+H]+.
实施例37:化合物AR37
制法同实施例1,不同点在于,用化合物36(NR3R2为4-羟甲基哌啶)代替二(2-二氯乙基)胺盐酸盐。1HNMR(400MHz,CDCl3)δ0.81(m,J=6.8Hz,3H),0.92(d,J=5.6Hz,3H),0.95-1.00(m,1H),1.21-1.25(m,3H),1.35-1.40(m,4H),1.41-1.45(m,1H),1.55-1.61(m,1H),1.63-1.78(m,5H),1.83-1.88(m,1H),1.96-2.02(m,1H),2.28-2.36(m,3H),2.50-2.55(m,1H),2.63-2.68(m,2H),2.72-2.75(m,2H),2.90-2.96(m,2H),3.17(s,2H),3.97-4.07(m,2H),5.29(s,1H),5.71(d,J=10.0Hz,1H),7.95(d,J=8.8Hz,1H),8.00(s,1H),8.08(s,1H),9.71(s,1H);13CNMR(100MHz,CDCl3)δ12.0,20.1,21.8,24.4,25.8,24.4,25.8,28.8,29.1,31.6,33.9,34.5,36.0,37.2,45.0,51.4,53.7,62.0,68.2,80.0,91.4,92.1,104.4,117.9,117.9,121.8,127.0,141.8,142.8,171.2,171.9;ESI-MSm/z728[M+H]+.
实施例38:化合物AR38
制法同实施例1,不同点在于,用化合物36(NR3R2为4-羟乙基哌啶)代替二(2-二氯乙基)胺盐酸盐。1HNMR(400MHz,CDCl3)δ0.81(d,J=7.2Hz,3H),0.92-1.02(m,4H),1.21-1.27(m,2H),1.29-1.35(m,3H),1.36(s,3H),1.38-1.45(m,2H),1.57-1.60(m,3H),1.61-1.77(m,4H),1.81-1.89(m,1H),2.00-2.01(m,1H),2.25-2.33(m,3H),2.59-2.64(m,3H),2.68-2.71(m,2H),2.85-2.88(m,2H),3.13(s,2H),4.11-4.14(m,2H),5.38(s,1H),5.73(d,J=9.6Hz,1H),7.93-8.00(m,3H),9.69(s,1H);13CNMR(100MHz,CDCl3)δ11.9,20.5,21.8,24.4,25.8,28.7,29.0,31.6,31.8,32.1,33.9,34.7,36.0,37.1,45.0,51.3,54.1,62.1,62.3,80.0,91.4,92.0,104.3,117.7,117.8,121.7,127.0,141.8,142.6,169.6,171.0,172.0;ESI-MSm/z742[M+H]+.
实施例39:化合物AR39
制法同实施例1,不同点在于,用化合物37代替二(2-二氯乙基)胺盐酸盐。1HNMR(400MHz,CDCl3)δ0.78-0.86(m,6H),0.92(d,J=5.6Hz,3H),0.94-1.01(m,1H),1.21-1.34(m,3H),1.37(s,3H),1.39-1.44(m,1H),1.55-1.62(m,1H),1.66-1.74(m,2H),1.82-1.89(m,2H),1.95-2.02(m,2H),2.13-2.21(m,1H),2.29-2.40(m,3H),2.49-2.58(m,3H),2.60-2.63(m,1H),2.65-2.67(m,1H),2.71-2.81(m,1H),5.44(s,1H),5.75(d,J=9.6Hz,1H),7.13(d,J=8.4Hz,2H),7.53(d,J=7.6Hz,2H),8.35(s,1H),8.70(d,J=8.4Hz,1H);13CNMR(100MHz,CDCl3)δ8.9,11.9,20.120.2,21.8,24.4,25.9,29.1,31.3,32.6,36.0,37.0,45.0,50.4,51.3,80.1,91.4,92.3,104.4,120.0,126.5,133.9,134.0,137.5,170.1,171.9,173.1,175.7;ESI-MSm/z599[M+H]+.
实施例41:化合物AR41
制法同实施例1,不同点在于,用化合物25代替化合物3,用化合物38-1代替二(2-二氯乙基)胺盐酸盐。1HNMR(400MHz,CDCl3)δ0.78-0.86(m,6H),0.90-0.95(m,4H),1.20-1.47(m,9H),1.53-1.64(m,3H),1.73-1.76(m,2H),1.85-1.90(m,2H),1.98-2.02(m,2H),2.17-2.41(m,11H),2.54-2.63(m,2H),3.18-3.20(m,2H),4.01-4.08(m,1H),5.26(s,1H),7.18-7.25(m,3H),7.45-7.48(m,2H),7.61(d,J=8.4Hz,2H),7.82-7.84(m,1H),8.52(s,1H),9.19(s,1H);13CNMR(100MHz,CDCl3)δ9.0,13.0,20.1,24.6,24.8,26.1,29.2,32.8,36.5,37.4,42.0,44.3,47.4,50.5,52.2,52.4,57.7,58.8,75.3,81.1,88.8,103.1,120.3,123.8,126.1,129.4,131.0,133.4,137.5,165.6,167.0,169.9,172.4,175.2;ESI-MSm/z757[M+Na]+.
实施例42:化合物AR42
制法同实施例1,不同点在于,用去氧氟尿苷代替二(2-二氯乙基)胺盐酸盐。1HNMR(400MHz,CDCl3)δ0.79-0.83(m,6H),0.89-0.93(m,6H),0.95-1.01(m,2H),1.20-1.50(m,18H),1.55-1.61(m,2H),1.67-1.75(m,4H),1.83-1.88(m,2H),1.96-2.00(m,2H),2.29-2.37(m,2H),2.45-2.54(m,2H),2.56-2.78(m,8H),4.18-4.21(m,1H),5.01-5.04(m,1H),5.37-5.39(m,1H),5.41(s,1H),5.46(s,1H),5.66(d,J=9.6Hz,1H),5.72(d,J=10.0Hz,1H),5.76(d,J=4.8Hz,1H),7.31(d,J=6.0Hz,1H);13CNMR(100MHz,CDCl3)δ11.9,18.5,20.0,21.7,21.8,24.4,25.7,25.7,28.3,28.4,28.7,28.8,29.5,31.5,31.6,33.9,36.0,37.0,45.0,51.3,72.6,74.0,78.1,79.9,80.9,91.2,91.3,92.1,92.2,104.3,104.4,139.3,141.6,148.5,156.7,157.0,170.7,171.0,171.1;ESI-MSm/z978[M+H]+.
实施例43:化合物AR43
制法同实施例1,不同点在于,用卡培他滨代替二(2-二氯乙基)胺盐酸盐。1HNMR(400MHz,CDCl3)δ0.78-0.80(m,6H),0.83-0.86(m,3H),0.90-0.97(m,8H),1.18-1.23(m,3H),1.24-1.31(m,7H),1.36-1.38(m,7H),1.39-1.43(m,4H),1.55-1.58(m,2H),1.61-1.74(m,6H),1.82-1.85(m,2H),1.95-1.96(m,1H),1.98-1.99(m,2H),2.28-2.34(m,2H),2.47-2.50(m,2H),2.61-2.71(m,8H),4.05-4.12(m,3H),4.18-4.21(m,1H),4.98-5.00(m,1H),5.38(s,2H),5.41-5.43(m,1H),5.65-5.66(m,1H),5.69-5.73(m,2H),7.38(d,J=5.2Hz,1H);13CNMR(100MHz,CDCl3)δ11.8,13.7,14.0,18.2,20.0,20.8,21.7,22.1,24.3,25.7,27.7,28.0,28.2,28.7,31.5,33.8,35.9,37.0,44.9,51.3,60.1,66.3,72.8,74.0,77.8,79.8,90.2,91.2,92.0,92.1,104.2,153.2,153.4,170.6,170.8,171.0;ESI-MSm/z1094[M+H]+.
实施例44:化合物AR44
制法同实施例1,不同点在于,用化合物53代替二(2-二氯乙基)胺盐酸盐。1HNMR(400MHz,CDCl3)δ0.78-0.82(m,3H),0.89-0.95(m,4H),1.20-1.28(m,2H),1.30-1.42(m,4H),1.54-1.60(m,1H),1.64-1.74(m,2H),1.82-1.85(m,1H),1.95-2.00(m,1H),2.27-2.38(m,5H),2.50-2.52(m,1H),2.76-2.94(m,4H),5.39-5.41(m,1H),5.75-5.79(m,1H),6.19-6.21(m,1H),7.03-7.07(m,2H),7.53-7.57(m,1H);ESI-MSm/z543[M+H]+
实施例45:化合物AR45
制法同实施例1,不同点在于用化合物54-1代替二(2-二氯乙基)胺盐酸盐。
1HNMR(400MHz,CDCl3)δ0.84(d,J=7.2Hz,3H),0.92-0.99(m,4H),1.17-1.21(m,7H),1.23-1.36(m,3H),1.41-1.42(m,4H),1.57-1.61(m,1H),1.66-1.75(m,2H),1.81-1.91(m,1H),1.98-2.02(m,1H),2.34-2.35(m,1H),2.52-2.60(m,1H),2.82-2.92(m,4H),3.36-3.41(m,4H),3.78(s,3H),4.49(d,J=5.2Hz,2H),4.65(s,2H),5.42(s,1H),5.79-5.86(m,1H),6.33-6.34(m,1H),6.44-6.47(m,1H),6.81-6.83(m,2H),6.93-6.95(m,2H),7.18-7.26(m,5H)8.30(s,1H);13CNMR(100MHz,CDCl3)δ11.9,12.4,20.0,21.8,24.4,25.8,28.9,29.0,31.6,33.9,36.0,37.1,43.1,44.6,45.0,49.0,51.3,55.1,79.9,91.3,92.1,96.1,104.3,107.5,108.0,113.8,114.1,121.1,128.1,129.1,130.4,130.5,138.2,139.9,148.9,151.0,151.3,156.0,158.6,163.3,170.7,170.8;EI-MSm/z852[M+H]+.
实施例46:化合物AR46
制法同实施例1,不同点在于,用化合物45(R6为乙醇胺、R4为二乙基胺基)代替二(2-二氯乙基)胺盐酸盐。1HNMR(400MHz,CDCl3)δ0.79-0.82(m,3H),0.87-0.96(m,4H),1.15-1.33(m,11H),1.36-1.37(m,4H),1.54-1.55(m,1H),1.64-1.70(m,2H),1.91-2.01(m,1H),1.95-1.96(m,1H),1.98-2.02(m,1H),2.25-2.35(m,1H),2.49-2.51(m,1H),2.65-2.72(m,1H),2.80-2.82(m,1H),2.82-2.90(m,1H),3.72-3.41(m,4H),3.55(s,2H),3.75-3.76(m,2H),5.37-5.38(m,1H),5.74-5.76(m,1H),6.35-6.42(m,1H),6.52-6.54(m,1H),7.28-7.31(m,1H),8.50-8.51(m,1H)9.50(s,1H);13CNMR(100MHz,CDCl3)δ11.9,12.3,20.0,21.8,24.4,25.7,33.9,36.0,37.1,42.7,44.8,44.9,45.0,51.3,79.9,80.0,91.3,91.3,92.0,96.2,96.3,104.3,107.8,109.9,111.0.,130.9,145.2,148.1,151.6,152.2,156.0,171.4,182.9;ESI-MSm/z692[M+Na]+;HRMS(EI)calcd.forC35H47N3O10Na[M+Na]+692.3159,found692.3154.
实施例47:化合物AR47
制法同实施例1,不同点在于,用化合物45(R6为哌嗪、R4为二乙基胺基)代替二(2-二氯乙基)胺盐酸盐。1HNMR(400MHz,CDCl3)δ0.83(d,J=7.2Hz,3H),0.91-1.00(m,4H),1.18-1.33(m,9H),1.36-1.40(m,4H),1.58-1.61(m,1H),1.67-1.76(m,2H),1.83-2.02(m,3H),2.25-2.40(m,2H),2.45-2.52(m,2H),2.54-2.72(m,3H),3.86-3.44(m,5H),3.58-3.76(m,5H),5.41(s,1H),5.74-5.77(m,1H),6.44-6.45(m,1H),6.57-6.60(m,1H),7.28-7.30(m,1H),7.86(s,1H);13CNMR(100MHz,CDCl3)δ11.9,12.3,14.0,20.1,21.9,24.5,25.9,27.6,29.6,31.7,34.0,36.1,37.1,51.4,80.0,91.4,92.0,96.8,104.4,107.6,109.4,115.4,129.9,151.8,157.3,159.1,162.5,165.2,165.3,169.7,171.7;ESI-MSm/z718[M+Na]+;HRMS(EI)calcd.forC37H49N3O10Na[M+Na]+718.3316,found718.3326.
实施例48:化合物AR48
制法同实施例1,不同点在于,用化合物45(R6为乙二胺、R4为二乙基胺基)代替二(2-二氯乙基)胺盐酸盐。1HNMR(400MHz,CDCl3)δ0.75(d,J=6.8Hz,3H),0.85-0.92(m,4H),1.14-1.30(m,8H),1.32-1.38(m,4H),1.49-1.52(m,1H),1.60-1.69(m,2H),1.77-1.80(m,1H),1.91-1.96(m,1H),2.22-2.26(m,1H),2.42-2.71(m,6H),3.35-3.40(m,6H),3.50-3.51(m,2H),5.33(s,1H),5.68(d,J=10.0Hz,1H),6.38(s,1H),6.56(d,J=8.8Hz,1H),6.97(s,1H),7.33(d,J=8.8Hz,1H),8.56(s,1H),8.94(s,1H);13CNMR(100MHz,CDCl3)δ11.8,12.2,20.0,21.7,24.3,25.6,29.4,29.5,30.5,31.5,33.8,35.9,36.9,38.9,40.3,44.8,51.2,53.3,79.8,91.1,91.8,96.2,104.1,108.0,109.4,109.8,131.0,147.9,152.4,157.4,162.3,164.1,171.5;ESI-MSm/z692[M+Na]+;HRMS(EI)calcd.forC35H47N3O10Na[M+Na]+692.3159,found692.3157.
实施例49:化合物AR49
制法同实施例1,不同点在于,用化合物45(R6为4-胺基哌啶、R4为二乙基胺基)代替二(2-二氯乙基)胺盐酸盐。1HNMR(400MHz,CDCl3)δ0.82(d,J=7.2Hz,3H),0.93-1.00(m,4H),1.18-1.26(m,8H),1.37-1.40(m,3H),1.47-1.61(m,4H),1.69-1.77(m,2H),1.85-2.03(m,5H),2.34-2.54(m,4H),2.68-2.79(m,2H),2.88-2.97(m,1H),3.10-3.20(m,1H),3.39-3.44(m,4H),3.59-3.63(m,1H),4.50-4.60(m,1H),5.41(s,1H),5.74(d,J=9.6Hz,1H),5.97(d,J=8.4Hz,1H),6.47(s,1H),6.58-6.61(m,1H),7.27(d,J=9.2Hz,1H),7.79(s,1H);13CNMR(100MHz,CDCl3)δ12.0,12.3,20.2,21.9,24.5,25.9,29.6,29.7,30.9,31.4,31.7,34.0,36.1,37.2,45.0,45.1,46.3,51.5,80.1,91.4,92.1,97.1,104.4,107.8,109.4,116.7,129.7,144.4,151.4,157.0,159.1,164.8,170.7,171.7;ESI-MSm/z732[M+Na]+;HRMS(EI)calcd.forC38H51N3O10Na[M+Na]+732.3472,found732.3472.
实施例50:化合物AR50
制法同实施例1,不同点在于,用化合物12代替化合物3,用化合物45(R6为乙二胺、R4为二乙基胺基)代替二(2-二氯乙基)胺盐酸盐。1HNMR(400MHz,CDCl3)δ0.80-0.86(m,3H),0.89-0.94(m,4H),1.19-1.26(m,8H),1.19-1.36(m,11H),1.36-1.41(m,5H),1.49-1.63(m,2H),1.72-1.77(m,2H),1.96-2.01(m,2H),2.42-2.49(m,2H),2.56-262(m,6H),2.99(s,2H),3.40-3.49(m,6H),3.56-3.58(m,2H),4.05-4.10(m,1H),5.25(s,1H),6.47(s,1H),6.62-6.65(m,1H),7.42(d,J=8.8Hz,1H),7.58(s,1H),8.65(s,1H),8.95(s,1H);13CNMR(100MHz,CDCl3)δ12.3,12.9,20.1,22.6,24.6,26.1,26.9,29.2,29.6,30.2,34.3,37.4,38.2,44.3,45.0,52.2,52.7,52.9,57.6,61.2,75.2,81.0,88.9,96.4,103.0,108.2,109.6,110.0,131.1,148.1,152.6,157.6,162.6,163.6,163.8,170.6;EI-MSm/z737[M]+;HRMS(EI)calcd.forC40H59N5O8[M]+737.4364,found737.4383.
实施例51:化合物AR51
制法同实施例1,不同点在于,用化合物45(R6为丁二胺、R4为二乙基胺基)代替二(2-二氯乙基)胺盐酸盐。1HNMR(400MHz,CDCl3)δ0.79-0.82(m,3H),0.89-0.93(m,4H),1.18-1.24(m,9H),1.36-1.37(m,3H),1.54-1.63(m,6H),1.65-1.71(m,2H),1.77-1.87(m,1H),1.95-2.00(m,1H),2.25-2.36(m,1H),2.46-2.51(m,3H),2.71-2.74(m,2H),3.24-3.27(m,2H),3.38-3.44(m,6H),5.39(s,1H),5.72(s,1H),5.74(d,J=10.0Hz,1H),6.44(s,1H),6.60-6.63(m,1H),7.38-7.41(m,1H),8.64(s,1H),8.81(s,1H);13CNMR(100MHz,CDCl3)δ11.9,12.3,20.1,21.8,25.8,26.4,27.1,29.7,31.6,33.9,36.1,33.9,36.1,37.1,39.0,39.1,45.0,45.1,51.4,80.0,91.3,92.0,96.4,104.3,108.2,109.9,110.0,131.0,147.9,152.4,157.4,162.6,163.2,171.2,171.7;ESI-MSm/z720[M+Na]+;HRMS(EI)calcd.forC37H51N3O10Na[M+Na]+720.3472,found720.3470.
实施例52:化合物AR52
制法同实施例1,不同点在于,用化合物25代替化合物3,用化合物44(R4为二乙基胺基)代替二(2-二氯乙基)胺盐酸盐。1HNMR(400MHz,CDCl3)δ0.86-0.88(d,J=7.6Hz,3H),0.96-0.99(m,4H),1.21-1.26(m,6H),1.29-1.33(m,3H),1.40-1.42(m,3H),1.45-1.46(m,1H),1.54-1.69(m,5H),1.78-1.82(m,2H),1.86-1.96(m,1H),2.00-2.07(m,1H),2.28-2.38(m,1H),2.43-2.48(m,4H),2.53(bs,2H),2.62-2.71(m,1H),3.41-3.47(m,6H),3.78(s,2H),4.10-4.18(m,1H),5.31(d,J=4.8Hz,1H),6.48(s,1H),6.59-6.62(m,1H),7.30-7.33(m,1H),7.83(s,1H);13CNMR(100MHz,CDCl3)δ12.3,12.9,20.1,24.6,24.7,26.0,26.7,30.1,34.3,36.4,37.3,42.0,44.2,44.8,47.2,52.2,53.1,57.8,75.3,81.0,88.8,96.8,103.0,107.5,109.1,116.3,129.6,144.5,151.4,157.0,158.9,164.6;EI-MSm/z637[M]+;HRMS(EI)calcd.forC36H51N3O7[M]+637.3727,found637.3727.
实施例53:化合物AR53
制法同实施例1,不同点在于,用化合物12代替化合物3,用化合物45(R6为哌嗪、R4为二乙基胺基)代替二(2-二氯乙基)胺盐酸盐。1HNMR(400MHz,CDCl3)δ0.79-0.83(m,3H),0.87-0.91(m,4H),1.00-1.25(m,11H),1.29-1.42(m,5H),1.52-1.61(m,4H),1.71-1.86(m,3H),1.95-1.99(m,1H),2.07-2.65(m,10H),3.15-3.18(m,2H),3.38-3.40(m,6H),3.58-3.72(m,6H),4.08(s,1H),5.24-5.26(m,1H),6.43(s,1H),6.55(d,J=9.2Hz,1H),7.28(d,J=7.6Hz,1H),7.84(d,J=9.2Hz,1H);13CNMR(100MHz,CDCl3)δ12.3,12.9,20.1,24.1,24.5,24.7,26.0,26.9,29.5,30.1,34.3,36.4,37.3,44.2,44.8,52.2,52.4,52.5,57.7,61.0,75.3,81.0,88.8,92.9,96.7,103.0,107.6,109.3,115.4,127.3,145.4,151.7,157.2,165.3,170.0,170.6;EI-MSm/z763[M]+;HRMS(EI)calcd.forC42H61N5O8[M]+763.4520,found763.4505.
实施例54:化合物AR54
制法同实施例1,不同点在于,用化合物BB10代替二(2-二氯乙基)胺盐酸盐。1HNMR(400MHz,CDCl3)δ0.83-0.87(m,3H),1.11-1.75(m,17H),2.10-2.38(m,3H),2.49-2.63(m,8H),3.00-3.05(m,2H),3.44(brs,4H),3.65-4.26(m,5H),5.02(s,1H),6.06(d,J=10.0Hz,1H),6.37-6.39(m,1H),6.74-6.79(m,2H),7.15-7.16(m,1H),7.28-7.29(m,1H),7.50(s,1H),8.11(s,1H),8.49(s,1H);ESI-MSm/z893[M+H]+.
实施例55:化合物AR55
制法同实施例1,不同点在于,用化合物12代替化合物3,用化合物BB10代替二(2-二氯乙基)胺盐酸盐。1HNMR(400MHz,CDCl3)δ0.81-0.95(m,6H),1.09-1.79(m,19H),2.10-2.53(m,16H),3.01-3.03(m,2H),3.30(s,2H),3.46(brs,4H),3.70-3.80(m,2H),3.95-4.25(m,3H),5.05(s,1H),6.37-6.39(m,1H),6.74-6.80(m,2H),7.17-7.18(m,1H),7.30-7.31(m,1H),7.56(s,1H),8.13(s,1H),8.47(s,1H);ESI-MSm/z961[M+H]+.
实施例56:化合物AR56
制法同实施例1,不同点在于,用化合物8代替化合物3,用化合物BB10代替二(2-二氯乙基)胺盐酸盐。1HNMR(400MHz,CDCl3)δ0.81-0.96(m,6H),1.13-1.85(m,15H),2.15-2.57(m,8H),3.12(m,2H),3.60(brs,4H),3.71-3.90(m,3H),3.99-4.32(m,3H),5.03(s,1H),6.37-6.38(m,1H),6.79-6.82(m,2H),7.18-7.19(m,1H),7.31-7.32(m,1H),7.52(s,1H),8.15(s,1H),8.60(s,1H);ESI-MSm/z835[M+H]+.
实施例57:化合物AR57
制法同实施例1,不同点在于,用化合物GG90代替二(2-二氯乙基)胺盐酸盐。1HNMR(400MHz,CDCl3)δ0.82-0.95(m,6H),1.11-1.88(m,16H),2.31-2.71(m,11H),3.47(brs,4H),3.90(s,3H),4.10-4.12(m,2H),5.04(s,1H),6.08(m,J=10.1Hz,1H),6.78-6.79(m,1H),7.16-7.19(m,1H),7.26-7.29(m,2H),7.44(s,1H),8.51(s,1H);ESI-MSm/z812[M+H]+.
实施例58:化合物AR58
制法同实施例1,不同点在于,用化合物12代替化合物3,用化合物GG90代替二(2-二氯乙基)胺盐酸盐。1HNMR(400MHz,CDCl3)δ0.86-0.97(m,6H),1.08-1.95(m,21H),2.21-2.48(m,16H),3.30(s,2H),3.47(brs,4H),3.60-3.62(m,1H),3.89(s,3H),4.11-4.12(m,2H),5.10(s,1H),6.81-6.83(m,1H),7.17-7.19(m,1H),7.20-7.30(m,2H),7.44(s,1H),8.61(s,1H);ESI-MSm/z880[M+H]+.
实施例59:化合物AR59
制法同实施例1,不同点在于,用化合物8代替化合物3,用化合物GG90代替二(2-二氯乙基)胺盐酸盐。1HNMR(400MHz,CDCl3)δ0.81-0.93(m,6H),1.12-1.85(m,17H),2.12-2.61(m,8H),3.43(brs,4H),3.80-3.84(m,4H),4.04-4.05(m,3H),5.12(s,1H),6.81-6.82(m,1H),7.17-7.19(m,1H),7.21-7.30(m,2H),7.46(s,1H),8.62(s,1H);ESI-MSm/z754[M+H]+.
实施例60:式I所示的青蒿素衍生物体内外抗肿瘤活性评价
1.通用实验方法
1.1细胞生长抑制实验
细胞生长及增殖抑制试验通过CCK-8实验测定。
细胞以3×103个细胞每孔的密度铺种于96孔板中。12~18小时后,以一定浓度梯度(0、1、5、10、25、50μM)的青蒿素衍生物处理48小时之后,在96孔板每孔中加10μLCCK-8溶液进行药物处理后的细胞生长活性评价,实验最后通过酶标仪(SpectraMax190microplatereader;MolecularDevices,USA)测量450nm处的光吸收(OD值)(每实验浓度至少设置三个复孔,每次实验至少重复三次)。
1.2裸鼠异体移植瘤模型体内治疗实验
四到六周龄的雌性BALB/c(nu/nu)购自上海斯莱克实验动物有限公司(ShanghaiExperimentalAnimalCenter),并按规定饲养于SPF级动物房。
主要步骤如下:将收集的A2780,OVCAR-3或Hep3B细胞,重悬于无血清并含20%(v/v)Matrigel(BDBiosciences,Bedford,MA)的无血清培养基中。然后皮下注射等量细胞(~5×106cells/0.2ml)于小鼠的左侧腹股沟。每3天监测肿瘤的生长情况和小鼠的体重并同时测量检测肿瘤的大小。
等到肿瘤成长至可触摸大小(~70mg)时,将小鼠随机分成治疗组和对照组(每组5只老鼠)。AR7的给药剂量为5、10或25mg/kg体重,给药频率为每天给药(自第0天起),给药途径为皮下注射给药(阳性药物:如卡铂或吉西他滨给药剂量为120mg/kg体重)。对照组注射生理盐水。
2.青蒿素衍生物抗肿瘤活性筛选
2.1实验化合物和对照化合物对实体瘤细胞系和永生化的对照细胞的半数抑制率(IC50)的对比
实验化合物:挑选本发明中的24种青蒿素衍生物进行实验,化合物分别是化合物AR1、AR3、AR4、AR7、AR9、AR13、AR35、AR37~AR53。对照化合物:双氢青蒿素(DHA)、青蒿素(ARS)、美法仑、氨鲁米特和去氧氟尿苷。按照常规的方法,比较上述24种青蒿素衍生物和对照药物对以下四组细胞的细胞毒性。
表1实体瘤细胞系和永生化的对照细胞
比较结果如表2所示,化合物AR1、AR3、AR4、AR7、AR9、AR13、AR35、AR37~AR53对于肝癌和卵巢癌细胞生长都具有抑制效应,且均优于青蒿素的抑制效果。其中AR7是其中抗肿瘤效果最为明显的药物之一,尤其是对肝癌细胞和卵巢癌细胞的抑制活性显著高于双氢青蒿素(DHA)和美法仑(Melphalan)。与对照药物相比,其IC50降低大于10倍。
表2:AR1-59系列化合物对多种肿瘤细胞的半数抑制率(IC50)
注:B为美法仑(Melphalan);D为氨鲁米特(Aminoglutethimide);E为去氧氟尿苷(Doxifluridin),ARS(青蒿素),DHA(二氢青蒿素);wt表示野生型,nut表示突变,null表示缺失。
2.2AR7与DHA体外抗肿瘤效果比较
比较AR7与DHA分别在卵巢癌、肝癌、神经胶质瘤不同细胞系以及胃肠间质瘤病人肿瘤原代细胞(所述原代细胞是在临床新鲜的胃肠间质瘤(GIST)样本中,分离出的原代的肿瘤细胞)中的体外抗肿瘤效果,实验方法同上述步骤1.1中所述。
结果如图1D所示,结果表明AR7体外抗肿瘤效果优于DHA。图1中,
A图表明:AR7可以剂量依赖的抑制卵巢癌细胞A2780、OVCAR3、SK-OV3细胞活力;且与DHA相比,AR7表现出一定的抗癌优势,对卵巢正常上皮细胞IOSE144抑制效应不明显。
B图显示:AR7对肝癌细胞Hep3B及肝癌门静脉癌栓细胞PVTT2具有显著的抑制作用,其抑制效果较DHA更为显著。而对正常肝细胞7702则表现出一定的保护作用。
C图显示:在神经胶质瘤细胞株SHG-44、A172、U251中,AR7显著抑制肿瘤细胞的生长,抑制效果与DHA相比,表现出一定的优势。
D图显示:AR7对于原代的GIST细胞具有一定的抑制作用,其抗癌效果也显著高于DHA。
2.3AR7与DHA对血液系统肿瘤的抑制效果比较
比较AR7和DHA,对三种Burkitt’s淋巴瘤(Raji、BJAB、NAMALWA)的生长抑制作用,实验方法同上述步骤1.1中所述。
结果如图2显示,AR7和DHA对于三种淋巴瘤细胞系具有明显的抑制作用,并且AR7的抑制效果要高于DHA。
2.4AR7体内抗肿瘤活性
2.4.1建立A2780和OVCAR-3卵巢癌裸鼠异体移植瘤模型,来检测实验药物和阳性药物的抗肿瘤效果。并测试用药前后裸鼠体重的变化,以监测药物对动物的毒副作用,实验方法同上述步骤1.2中所述。
实验药物:AR7
阳性药物:卡铂(CBP)
阴性对照:生理盐水(Saline)
结果如图3的A图和B图所示,结果表明:AR7可以剂量依赖的抑制卵巢癌细胞A2780和OVCAR3在动物体内的生长,且抑制效果优于卡铂:相同的抑制率下,所用的剂量远少于卡铂。且在整个治疗过程中,动物的体重与对照组相比并没有明显的差异,提示AR7对小鼠无明显的毒副作用。
如图3的A图所示,AR7在剂量为5mg/kg,10mg/kg和25mg/kg情况下分别导致A2780异体移植肿瘤40.5%,58.4%和73.6%的生长抑制率(与给生理盐水的对照组相比)(P<0.05);
如图3的B图所示,AR7在剂量为5mg/kg,10mg/kg和25mg/kg情况下,分别导致OVCAR-3肿瘤模型49.7%,65.7%和82.6%的肿瘤生长抑制(P<0.05)。
其中,25mg/kgAR7对于肿瘤的抑制效果接近于与120mg/KgCBP治疗效果。
2.4.2建立Hep3B肝癌裸鼠异体移植瘤模型,来检测实验药物和阳性药物的抗肿瘤效果。并测试用药前后裸鼠体重的变化,以监测药物对动物的毒副作用,实验方法同上述步骤1.2中所述。
实验药物:AR7
阳性药物:吉西他滨(GEMZAR)
阴性对照:生理盐水(Saline)
如图3的C图所示,结果表明:AR7可以剂量依赖的抑制Hep3B肝癌,且抑制效果优于吉西他滨:相同的抑制率下,所用的剂量远少于卡铂。且在治疗过程中,小鼠的体重也未发现明显的变化。
其中,AR7在剂量为5mg/kg,10mg/kg和25mg/kg情况下分别导致Hep3B异体移植肿瘤23.8%,46.4%和56.7%的生长抑制率(与给生理盐水的对照组相比)(P<0.05)。用120mg/kg阳性药物吉西他滨治疗后,肿瘤的抑制率为66.7%。25mg/kgAR7对于肿瘤的抑制效果接近于与120mg/Kg吉西他滨的治疗效果。
2.4.3AR7与DHA体内抗肿瘤活性比较
建立A2780和OVCAR-3卵巢癌裸鼠异体移植瘤模型,检测AR7和DHA的体内抗肿瘤活性。并测量给药前后裸鼠体重的变化,以检测药物对动物的毒副作用。
实验方法:
与上述步骤1.2类似,不同点在于:
实验药物:AR7(25mg/kg)
阳性药物:DHA(25mg/kg)
CTRL:表示蓖麻油、乙醇和生理盐水溶剂(蓖麻油:乙醇:生理盐水=5:5:90,v/v/v)。
实验结果:
结果如图4的A1图、A2图所示:AR7具有比DHA更好地抑制肿瘤细胞A2780和OVCAR-3在动物体内生长的作用。对A2780卵巢癌裸鼠异体移植瘤模型,AR7能够抑制71%,而DHA只能抑制41%;对OVCAR-3裸鼠异体移植瘤模型,AR7能够抑制63%,而DHA只能抑制43%。
实验结束后,取出肿瘤块测量肿瘤的大小。结果如图4的B1图、B2图所示:AR7治疗组的肿瘤块重量有明显的减轻。在A2780卵巢癌裸鼠异体移植瘤模型AR7能减轻64.37%,而DHA只有40.15%。在OVCAR-3卵巢癌裸鼠异体移植瘤模型AR7能减轻57.61%,而DHA只有22.82%。
在整个治疗过程中,动物的体重与对照组相比没有明显的差异,表明AR7对小鼠无明显的毒副作用(如图4的C1图、C2图所示)。
2.4.4体内和体外AR7与DHA抑制肿瘤转移活性比较
一、体外实验
(a)进行体外transwell侵袭实验。
实验方法:
将A2780细胞给予10μM或25μMAR7或DHA孵育8个小时,对照组给予相同体积浓度的DMSO处理。然后撤去药物将处理后相同数目的细胞重悬于无血清1640培养基,种植在transwell上室,同时在下室中加入含有10%FBS的1640培养基作为趋化剂。8-12小时后擦去transwell未穿过细胞,并固定染色统计迁移到对侧的细胞数目。
实验结果:
如图5的A图所示:AR7能够显著抑制A2780的转移,在25μM下,AR7能抑制96%,而DHA只能抑制71.97%。
(b)细胞活力检测
在体外transwell侵袭实验的实验条件下,发明人检测了细胞的活力。
结果如图5的B图所示:药物对细胞的活力没有显著性影响。这表明药物对细胞转移的抑制是通过对细胞的运动能力的抑制作用,而不是通过药物对细胞的杀伤作用。
二、体内实验
建立卵巢癌的腹腔原位模型,以检测AR7对肿瘤细胞在体内播散和转移的影响。
实验方法:
四到六周龄的雌性BALB/C(nu/nu)购自上海斯莱克实验动物有限公司(ShanghaiExperimentalAnimalCenter),并按规定饲养于SPF级动物房。
将稳定表达荧光素酶的A2780细胞,重悬于无血清的RPMI1640培养基中,然后腹腔注射等量细胞(约为3×106细胞数/0.2ml)于小鼠的腹腔内部。利用IVISLumina生物荧光系统实时监测肿瘤的生长情况,并记录小鼠的体重。注射一定时间后,根据肿瘤的荧光强度将小鼠平均分成治疗组和对照组。
CTRL:表示蓖麻油、乙醇和生理盐水溶剂(蓖麻油:乙醇:生理盐水=5:5:90,v/v/v)。
治疗组:AR7(10μM和25μM)
对照组:DHA(25μM)
所有药物均通过腹腔给药。给药频率为每天给药,每周停歇两天。治疗过程中利用活体成像系统实时监测肿瘤的生长状况。
实验结果
结果如图5的C图和D图所示:随着时间的推移,对照组的A2780肿瘤在小鼠腹腔里播散,荧光素酶的活性越来越强,而AR7处理组能够导致99.4%的抑制,而DHA组只有65.1%的抑制。这些数据表明AR7具有比DHA更强的抑制肿瘤转移的能力。
在整个治疗过程中,动物的体重与对照组相比没有明显的差异,表明AR7对小鼠无明显的毒副作用(如图5的E图所示)。
2.4.5AR7抑制肿瘤细胞进程
体外实验表明AR7通过抑制卵巢癌细胞系A2780和OVCAR-3的增值,诱导细胞凋亡和诱导细胞周期阻滞以抑制肿瘤细胞的进程。
实验方法:AR7对细胞周期分布的影响采用PI染色及流式细胞仪分析DNA含量的方法进行测定。大体步骤为:卵巢癌A2780和OVCAR-3细胞经过不同浓度的AR7处理24小时后,离心收集细胞,然后加入预冷的70%乙醇(700μL无水乙醇和300μL的PBS)于4℃固定过夜。之后离心弃去固定液,经PBS清洗后加入100μL(100μg/mL)RNaseA于37℃孵育30分钟,然后加入500μL的PI染色液(50μg/mL)于黑暗中放置染色15分钟,然后用流式细胞仪(CellLabQuantaTMSCflowcytometer;BeckmanCoulter,USA)检测并分析细胞的DNA含量进而得到各个周期(G0-G1、S和G2/M期)的细胞的百分比。
实验结果:
(a)在10μM下,AR7能够显著抑制肿瘤细胞的增值,对A2780和OVCAR-3增值的抑制基本都可以达到80%以上。如图6的A1图和A2图所示。
(b)AR7能够诱导肿瘤细胞的凋亡,并呈现浓度依赖性的提高。在5μM、10μM的浓度处理下,在A2780和OVCAR-3分别诱导了405%、705%和318%、708.2%的凋亡。如图6的B1图和B2图所示。
(c)AR7能够诱导A2780和OVCAR-3细胞在S期的阻滞,而且具有浓度和时间依赖性。如图6的C1图、C2图、C3图、C4图所示。
2.4.6AR7抑制肿瘤微环境中的巨噬细胞
构建一个模型PMArTHP1,测试AR7对这个细胞模型的影响,进而模拟AR7对肿瘤微环境的影响。
PMArTHP1构建方法:
人单核细胞THP-1经200nM的PMA处理48小时后用20ng/mLIL-4继续刺激24小时,然后用RPIM1640完全培养基培养48小时,以此诱导的PMArTHP1细胞为M2型巨噬细胞。
通过用PMA/IL-4刺激THP1细胞,并检测了CD14、FE/80、CD206这几个常见的THP1成功分型为巨噬细胞的因子,表明实验模型的成功。
实验方法:分别对构建的PMArTHP1进行给药:
CTRL:表示DMSO
治疗组:AR7(1μM、5μM和10μM)
对照组:DHA(10μM)
实验结果:
(a)AR7对PMArTHP1细胞具有杀伤性,杀伤作用强与DHA。如图7的D图所示。
(b)AR7能够诱导PMArTHP1细胞的凋亡,在10μM下,能够增加1.5倍的凋亡比例,而DHA只有0.2倍的增加比例。如图7的E图所示。
(c)AR7能够抑制PMArTHP1的迁移,在10μM下,能够78%抑制PMArTHP1的迁移,而在该浓度下DHA只有36%的抑制。如图7的F图所示。
(d)AR7能够抑制PMArTHP1的侵袭,在10μM下,能够89.7%抑制PMArTHP1的转移,而在该浓度下DHA只有52.1%的抑制。如图7的G图所示。
(e)PDGF受体和因子都与细胞的生长和迁移有关,发明人检测了AR7是否通过降低PMArTHP1中PDGF受体和因子的表达,进而影响PMArTHP1的细胞活性和迁移能力。
实验表明AR7降低了PDGFRα(如图7的H图所示)和PDGFRβ(如图7的I图所示)的表达,以及PDGFAA(如图7的G图所示)和PDGFBB(如图7的K图所示)mRNA的表达。
可见,AR7能够针对肿瘤微环境中的巨噬细胞发挥作用,进而影响肿瘤的进程。
2.4.7AR7能够干扰和阻滞肿瘤细胞与肿瘤微环境的相互作用,进而抑制肿瘤的进展。
实验方法:将THP1或者PMArTHP1细胞重悬于无血清1640培养基,相同数目种植在transwell上室,同时在下室中加入AR7处理前后的A2780无血清的细胞上清作为趋化剂。一定时间后擦去transwell未穿过细胞,并固定染色统计迁移到对侧的细胞数目。
细胞因子表达谱的分泌通过Bio-Rad悬浮芯片细胞因子试剂盒检测(Bio-PlexMouseCytokineAssays,Bio-RadLaboratories,Inc)。将等量的不同处理的细胞无血清培养上清离心弃去细胞碎片,并根据试剂盒说明书要求检测相关细胞因子的表达。
实验结果:
(a)AR7能够抑制肿瘤细胞对微环境中THP1的招募作用,在25μM时达到了88.3%的抑制。该过程可以减少肿瘤细胞周围的单核细胞的数量,也会导致减少了肿瘤相关性巨噬细胞的数量。如图8的A图所示。
(b)AR7能够抑制肿瘤细胞对PMArTHP1的迁移诱导能力,能在25μM处理A2780后,能达到了对A2780诱导能力55.6%的抑制,而DHA在这个过程中只达到了27.2%的抑制。如图8的B图所示。
(c)AR7能够通过抑制PMArTHP-1,从而阻断其对肿瘤细胞的迁移或侵袭诱导作用。在25μM处理PMArTHP1后,能达到对PMArTHP1诱导能力94%的抑制,而DHA只有68%的抑制。如图8的C图所示。
(d)AR7能够抑制PMArTHP-1分泌IL-6,RANTES,MIP-1α,MIP-1β。如图8的E图所示。
2.4.8AR7的增敏作用
Sunitinib是临床上一种新型多靶向性的治疗药物,发明人检测了AR7对这种药物的增敏作用。
构建A2780和OVCAR-3卵巢癌裸鼠异体移植瘤模型。构建方法与1.2类似。将人卵巢癌细胞A2780和OVCAR-3分别接种于BALB/c裸鼠皮下,建立卵巢癌裸鼠异体移植瘤模型。待肿瘤长至一定大小,根据不同组别用药。每隔两天测量肿瘤大小,治疗3周后,停止用药,用药情况为:
A.对照组:灌胃0.2ml溶剂/天。
B.AR7组:腹腔注射AR710mg/kg/天,每星期5天。
Csunitinib组:灌胃sunitinib25mg/kg/天,每星期5天。
D.AR7联合sunitinib组:灌胃sunitinib25mg/kg/天,腹腔注射AR710mg/kg/天,每星期5天。每隔两天测量肿瘤大小,治疗3周后停止用药。
实验结果如图9的A1图和A2图所示,A2780和OVCAR-3卵巢癌裸鼠异体移植瘤在经sunitinib治疗后生长得到了抑制,单药抑制率分别为84%和60%,AR7联合sunitinib治疗后抑制率达到了92%和68%。
实验结果如图9的B1图和B2图所示,A2780和OVCAR-3卵巢癌裸鼠异体移植瘤经sunitinib治疗后肿瘤的重量减少了79.15%和52.06%,AR7联合sunitinib治疗后抑制率达到了86%和59%。
可见,AR7和sunitinib联用效果都高于单药的抑制率,二者变现出协调作用。
在整个治疗过程中,动物的体重与对照组相比没有明显的差异,表明AR7对小鼠无明显的毒副作用。如图9的C1图和C2图所示。
综上所述:
AR7可以通过作用与肿瘤细胞本身和肿瘤微环境从而抑制肿瘤发生发展的进程。AR7可以对sunitinib进行增敏作用。可见,AR7是一个具有成药性的化合物。
实施例61药物组合物
化合物AR1~AR59中任一化合物或其组合5~20g
淀粉140g
微晶纤维素60g
按常规方法,将上述物质混合均匀后,装入普通明胶胶囊,得到1000颗胶囊。
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 (16)
1.一种结构如式I所示的青蒿素衍生物或其药学上可接受的盐,
其中,X为-O-、-S-、-NH-或-CH2-;
Y为-CO-或-CH2-;
Z为-CH2-、-O-、-CO-、-CH2CO-、-CH2NH-、-CH2O-、-COCH2-、-NHCH2-、-OCH2-或-NH-;
n为0~5的整数;k为0或1;
P为选自下组的基团:
其中,R、R4各自独立地为位于苯环上任意位置的选自下组的取代基:氢、卤素、C1-C12直链或支链的烷基、C2-C12直链或支链的不饱和烃基、C3-C12环烃基、氰基、硝基、氨基或被C1-C4烷基所取代的胺基、羟基、羟甲基、三氟甲基、三氟甲氧基、羧基、巯基苯基、取代的苯基、萘基、联苯基、或者取代或未取代的饱和或者不饱和的C3-C12杂环基,其中所述取代基选自:卤素、三氟甲基、乙炔基、羟基、氨基、C1-C4羟烷基、羧基或C1-C4胺烷基或醛基;
q、t各自独立地为1~4的整数;
R7为位于苯环上任意位置的一个或两个选自下组的取代基团:氢、卤素、C1-C12直链或支链的烷基、C2-C12直链或支链的不饱和烃基、C3-C12环烃基、乙炔基、氰基、硝基、氨基、羟基、羟甲基、三氟甲基、三氟甲氧基、羧基、巯基苯基、取代的苯基、萘基、联苯基、或者取代或未取代的饱和或者不饱和的C3-C12杂环基,苄醇基、取代的苄醇基、N,N-二甲胺基,N,N-二乙胺基,其中所述取代基选自:卤素、三氟甲基、乙炔基、羟基、氨基、C1-C4羟烷基、羧基或C1-C4胺烷基或醛基;
R8、R9各自独立地为其中,
W为氢、氧、NH、卤素、C1-C12直链或支链的烷基或亚烷基、C2-C12直链或支链的不饱和烃基或亚烃基、C3-C12环烃基或亚环烃基、氰基、硝基、氨基、羟基、C1-C4羟烷基、三氟甲基、三氟甲氧基、羧基、巯基苯基、取代的苯基、萘基、联苯基、或者取代或未取代的饱和或者不饱和的C3-C12杂环基或亚杂环基、N,N-二甲胺基,N,N-二乙胺基,其中所述取代基选自下组:卤素、三氟甲基、乙炔基、羟基、氨基、C1-C4羟烷基、羧基或C1-C4胺烷基或醛基;
D为羰基、C1-C12直链或支链的烷基或亚烷基、C2-C12直链或支链的不饱和烃基或亚烃基、取代或未取代的饱和或者不饱和的C3-C12杂环基或亚杂环基,其中所述取代基选自下组:卤素、三氟甲基、乙炔基、羟基、氨基、C1-C4羟烷基、羧基或C1-C4胺烷基或醛基;
E为C1-C12直链或支链的烷基或亚烷基、C2-C12直链或支链的不饱和烃基或亚烃基、取代或未取代的饱和或者不饱和的C3-C12杂环基或亚杂环基,其中所述取代基选自下组:卤素、三氟甲基、乙炔基、羟基、氨基、C1-C4羟烷基、羧基或C1-C4胺烷基或醛基;
j、r各自独立地为0~5的整数;
A为选自下组的连接基团:
B为选自下组的连接基团:
m为0或1。
2.如权利要求1所述的青蒿素衍生物,其特征在于,R8、R9各自独立地为其中,W为氧或NH;
D为羰基、C1-C6直链或支链的烷基或亚烷基、C2-C6直链或支链的不饱和烃基或亚烃基、取代或未取代的饱和或者不饱和的C3-C6杂环基或亚杂环基;
E为C1-C6直链或支链的烷基或亚烷基、C2-C6直链或支链的不饱和烃基或亚烃基、取代或未取代的饱和或者不饱和的C3-C6杂环基或亚杂环基;
j、r各自独立地为0~5的整数。
3.如权利要求1所述的青蒿素衍生物,其特征在于,X为-O-、-NH-或-CH2-。
4.如权利要求1所述的青蒿素衍生物,其特征在于,X为-O-、-NH-或-CH2-;且Z为-O-、-CO-、-NH-或-CH2-。
5.如权利要求1所述的青蒿素衍生物,其特征在于,X为-O-、-NH-或-CH2-;Z为-O-、-CO-、-NH-或-CH2-;且n为0或1。
6.如权利要求1所述的青蒿素衍生物,其特征在于,X为-O-、-NH-或-CH2-;Z为-O-、-CO-、-NH-或-CH2-;n为0或1;且m为0或1。
7.如权利要求1所述的青蒿素衍生物,其特征在于,P为选自下组的基团:
8.如权利要求1所述的青蒿素衍生物,其特征在于,为选自下组的化合物:
9.一种权利要求1-8任一项所述的青蒿素衍生物的制备方法,其特征在于,包括方法:将RaNH或RaNH2和RbCOOH进行酸碱缩合反应、或将RaCOOH和RbNH或RbNH2进行酸碱缩合反应、或将RaOH和RbCOOH进行成酯反应,从而形成式I化合物;
其中,RaNH或RaNH2、RaCOOH、RaOH为选自下组的化合物:
RbNH或RbNH2、RbCOOH为选自下组的化合物:
其中,R、q、R4、t的定义同权利要求1中所述;
R2、R3与相邻的N共同构成:哌嗪、4-羟C1-C4烷基哌啶、4-羟C1-C4烷基哌嗪;
R5、R6各自独立地为选自下组的基团:
所述为3-7元的环烷基或杂环烷基、或5-10元的芳环或芳杂环。
10.一种权利要求1-8任一项所述的青蒿素衍生物或其药学上可接受的盐的用途,其特征在于,用于制备治疗肿瘤、抑制肿瘤或肿瘤细胞生长的药物。
11.如权利要求10所述的用途,其特征在于,所述的青蒿素衍生物为式I化合物,且式I中,X为-O-或-CH2-;
Y为-CO-或-CH2-;
Z为-O-、-CH2-、-CO-或-CH2CO-;
n为0~2的整数;k为0或1;
P为选自下组的基团:
其中,B为m为0或1;或
其中,A为m为0或1;
且用于制备治疗前列腺癌、抑制前列腺癌或其细胞生长的药物。
12.如权利要求10所述的用途,其特征在于,所述的青蒿素衍生物为式I化合物,且式I中,X为-O-或-CH2-;
Y为-CO-或-CH2-;
Z为-O-、-CH2-、-CO-或-CH2CO-;
n为0~2的整数;k为0或1;
P为选自下组的基团:
其中,A为m为0或1;或
其中,B为m为0或1;或
其中,A为m为0或1,R为氢,q为1;或
其中,m为0,R为氢,q为1;或
其中,A为m为0或1;或
其中,A为m为0或1;或
其中,R4为二乙基取代的氨基,t为1,B为 m为0或1;
且用于制备治疗肝癌、抑制肝癌或其细胞生长的药物。
13.如权利要求10所述的用途,其特征在于,所述的青蒿素衍生物为式I化合物,且式I中,X为-O-或-CH2-;
Y为-CO-或-CH2-;
Z为-O-、-CH2-、-CO-或-CH2CO-;
n为0~2的整数;k为0或1;
P为选自下组的基团:
其中,B为m为0或1;或
其中,A为m为0或1;
其中,A为m为0或1,R为氢,q为1;或
其中,m为0,R为氢,q为1;或
其中,A为m为0或1;或
其中,A为m为0或1;或
其中,m为0;或
其中,m为0;或
其中,m为0;或
其中,m为0,R4为二乙基取代的氨基,t为1;或
其中,B为m为0或1,R4为二乙基取代的氨基,t为1;或
其中,B为 m为0或1,R4为二乙基取代的氨基,t为1;
且用于制备治疗卵巢癌、抑制卵巢癌或其细胞生长的药物。
14.一种药物组合物,其特征在于,包括:(a)0.0001-99.99wt%的权利要求1-7任一项所述的青蒿素衍生物或其药学上可接受的盐;和(b)药学上可接受的载体。
15.一种权利要求1-8任一项所述的青蒿素衍生物或其药学上可接受的盐的用途,其特征在于,
用于制备抑制肿瘤或肿瘤细胞转移、抑制肿瘤细胞增殖、诱导肿瘤细胞凋亡和/或诱导肿瘤细胞周期阻滞的药物;
用于制备抑制PDGFAA、PDGFBB、PDGFRα和/或PDGFRβ表达的药物;
用于制备抑制肿瘤细胞诱导巨噬细胞或肿瘤相关巨噬细胞的迁移的药物和/或抑制诱导微环境中巨噬细胞凋亡的药物;
用于制备抑制IL-6、RANTES、MIP-1α和/或MIP-1β表达的药物;和/或
用于制备PDGF抑制剂的增敏剂。
16.一种药物组合物,其特征在于,含有:活性成分a:如权利要求1-8任一项所述的青蒿素衍生物或其药学上可接受的盐;以及活性成分b:抗癌药物。
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CN106188088B (zh) * | 2016-07-26 | 2019-03-01 | 沈阳药科大学 | 青蒿素-香豆素杂合分子及其制备方法和应用 |
CN118440096A (zh) | 2017-06-20 | 2024-08-06 | C4医药公司 | 用于蛋白降解的n/o-连接的降解决定子和降解决定子体 |
CN107485609A (zh) * | 2017-08-30 | 2017-12-19 | 上海交通大学医学院附属第九人民医院 | 双氢青蒿素在制备抑制肿瘤药物中的应用 |
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CN108484632B (zh) * | 2018-05-16 | 2021-09-10 | 中国科学院昆明植物研究所 | 青蒿素-苯胺基喹唑啉类衍生物及其制备方法和应用 |
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