CN113896620B - 补骨脂酚衍生物、其药学上可接受的盐及其制备方法和应用 - Google Patents

补骨脂酚衍生物、其药学上可接受的盐及其制备方法和应用 Download PDF

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CN113896620B
CN113896620B CN202011152645.9A CN202011152645A CN113896620B CN 113896620 B CN113896620 B CN 113896620B CN 202011152645 A CN202011152645 A CN 202011152645A CN 113896620 B CN113896620 B CN 113896620B
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bakuchiol
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CN113896620A (zh
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林水木
刘寿平
栗宏霞
江鸿
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Jiangxi Shi Mei Pharmaceutical Ltd By Share Ltd
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Priority to CN202011152645.9A priority Critical patent/CN113896620B/zh
Priority to PCT/CN2020/125481 priority patent/WO2022088091A1/zh
Priority to US18/033,414 priority patent/US11912650B2/en
Priority to KR1020237015909A priority patent/KR102630858B1/ko
Priority to JP2023527021A priority patent/JP7469567B2/ja
Priority to EP20959253.4A priority patent/EP4219437A4/en
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    • C07C43/225—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing halogen
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Abstract

本发明涉及补骨脂酚衍生物、其药学上可接受的盐及其制备方法和应用，其中补骨脂酚衍生物具有式(I)所示结构：
Figure DDA0002741636020000011
上述基于补骨脂酚的一系列两亲性抗菌化合物，具有较优的抗菌活性，且在实验室模拟的耐药性研究中能够克服细菌耐药性的产生。

Description

补骨脂酚衍生物、其药学上可接受的盐及其制备方法和应用
技术领域
本发明涉及药物化学技术领域，特别涉及补骨脂酚衍生物、其药学上可接受的盐及其制备方法和应用。
背景技术
目前，传染病已成为导致全球人类死亡的主要原因，而多重耐药细菌是感染致死的最常见原因之一。细菌对抗生素的耐药性伴随着发病率和死亡率的急剧上升，以及昂贵的治疗费用，对全球公共卫生系统构成严重威胁。世界卫生组织和许多国家已经认识到，抗生素的耐药性问题会严重妨碍传染病的控制和危害人类健康。然而，由于抗菌药物的用药周期短和易产生耐药性等原因，大多数制药公司大大减少了对抗菌药物研发的投资，在过去的二十年中，获批准的新型抗菌药物的数量急剧减少，尤其是那些基于新型分子实体的抗菌药物。因此，迫切需要开发高效低毒且能有效克服耐药性产生的新型抗菌药物。
发明内容
基于此，有必要提供一种补骨脂酚衍生物及其药学上可接受的盐及其制备方法和应用。
一种补骨脂酚衍生物及其药学上可接受的盐，所述补骨脂酚衍生物具有式(I)所示结构：
Figure BDA0002741634000000011
其中，n为1-16的整数；
R选自卤素基、-CONR1R2、-COOR3、-NR4R5、
Figure BDA0002741634000000012
R1和R2各自独立地选自：-H、
Figure BDA0002741634000000013
R12和R13各自独立地选自：-H、
Figure BDA0002741634000000014
R22和R23各自独立地选自：-H、
Figure BDA0002741634000000015
R32和R33各自独立地选自：-H、
Figure BDA0002741634000000021
R42和R43各自独立地选自：-H、
Figure BDA0002741634000000022
R52和R53各自独立地选自：-H、
Figure BDA0002741634000000023
R62和R63各自独立地选自：-H或
Figure BDA0002741634000000024
其中，R14、R24、R34、R44、R54、R64和R74各自独立选自：-H、胍基、-NR4R5、-SR4、5-20元含氮杂芳基、
Figure BDA0002741634000000025
R15-R17、R25-R27、R35-R37、R45-R47、R55-R57、R65-R67各自独立地选自：-H或C1-6烷基；
R18、R28、R38、R48、R58、R68各自独立地选自：-H、C1-6烷基或卤素；
n1、n2、n3、n4、n5、n6和n7各自独立地为0、1、2、3、4、5、6、7、8、9或10；
R77选自：-H或C1-6烷基；
R3选自：-H或C1-4烷基；
R4和R5各自独立地选自：-H、C1-16烷基、COOR8、-Fmoc、Ra取代C1-16烷基，或R4、R5可和与R4、R5相连的N一起形成5-20元杂环、5-20元杂芳环、Rb取代5-20元杂环、或Rb取代5-20元杂芳环；
Ra选自：5-10元芳基、5-10元杂芳基、-NRa1Ra2或-SRa3；
Rb选自：C1-10烷基、-(CH2)pNRb1Rb2或-SRb3；p为0、1、2、3、4、5、6、7、8、9或10；
Ra1、Ra2、Rb1和Rb2各自独立地为：-H、C1-10烷基、或Rc取代C1-10烷基；或Ra1和Ra2可和与Ra1和Ra2相连的N原子一起形成5-10元杂环或5-10元杂芳环；或Rb1和Rb2可和与Rb1和Rb2相连的N原子一起形成5-10元杂环或5-10元杂芳环；
Ra3和Rb3各自独立地为C1-10烷基；
Rc选自：-NRc1Rc2、胍基或5-6元含氮杂芳基；Rc1和Rc2各自独立地为：-H、C1-4烷基；或Rc1和Rc2可和与Rc1和Rc2相连的N原子一起形成5-10元杂环或5-10元杂芳环；
R6为C1-4烷基；R7选自：-H或C1-4烷基；R8为-H、C1-6烷基或
Figure BDA0002741634000000026
Y-为阴离子。
上述补骨脂酚衍生物及其药学上可接受的盐的制备方法，当R为卤素，所述制备方法包括以下步骤：
Figure BDA0002741634000000031
将式(I-1)所示化合物和
Figure BDA0002741634000000032
进行反应，制得R为卤素的式(I-1)所示化合物；
当R为NR4R5、
Figure BDA0002741634000000033
所述制备方法包括以下步骤：
Figure BDA0002741634000000034
将式(I-1)所示化合物和
Figure BDA0002741634000000035
进行反应，制得R为Br的中间体；
将R为Br的中间体与HNR4R5反应，制得R为NR4R5的式(I)所示化合物；
将R为NR4R5的式(I)所示化合物与卤代烷基反应，制得R为
Figure BDA0002741634000000036
的式(I)所示化合物；
将R为NH2的式(I)所示化合物与
Figure BDA0002741634000000037
反应，制得R为
Figure BDA0002741634000000038
的式(I)所示化合物；
当R选自CONR1R2、-COOR3时，所述制备方法包括以下步骤：
Figure BDA0002741634000000039
将式(I-1)所示化合物和溴烷基酸烷基酯进行缩合反应，制得R为-COOR3的式(I)所示化合物；
进行水解，制得式(I-2)所示化合物；
将式(I-2)所示化合物与
Figure BDA00027416340000000310
进行缩合反应，制得R为CONR1R2的式(I)所示化合物。
一种药物组合物，包括上述补骨脂酚衍生物及其药学上可接受的盐中至少一种，及药学上可接受的辅料。
上述补骨脂酚衍生物及其药学上可接受的盐、或上述药物组合物在制备抗菌药物中的应用。
上述补骨脂酚衍生物及其药学上可接受的盐、或上述药物组合物在制备治疗或预防细菌感染所导致的疾病的药物中的应用。
上述补骨脂酚衍生物及其药学上可接受的盐、或上述药物组合物在制备治疗或预防传染性疾病中的应用。
一种治疗或预防细菌感染的方法，包括施加有效量的上述补骨脂酚衍生物及其药学上可接受的盐、或上述药物组合物。
本发明设计合成了基于补骨脂酚的一系列两亲性抗菌化合物，具有较优的抗菌活性，具体地：上述补骨脂酚衍生物及其药学上可接受的盐对革兰氏阳性菌(包括耐甲氧西林金黄色葡萄球菌)和革兰氏阴性菌均表现出优异的抗菌活性，具有良好的水溶性，对哺乳动物细胞表现出较低的细胞毒性和溶血活性，具备较高的膜选择性和较好的成药性，且在实验室模拟的耐药性研究中能够克服细菌耐药性的产生。
附图说明
图1为化合物60和诺氟沙星对金黄色葡萄球菌ATCC29213的耐药性研究曲线图；
图2为化合物60在金黄色葡萄球菌ATCC29213导致的小鼠角膜感染模型中的体内抗菌功效研究柱状图。
具体实施方式
为了便于理解本发明，下面将对本发明进行更全面的描述，并给出了本发明的较佳实施例。但是，本发明可以以许多不同的形式来实现，并不限于本文所描述的实施例。相反地，提供这些实施例的目的是使对本发明的公开内容的理解更加透彻全面。
除非另有定义，本文所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。本文中在本发明的说明书中所使用的术语只是为了描述具体的实施例的目的，不是旨在于限制本发明。本文所使用的术语“和/或”包括一个或多个相关的所列项目的任意的和所有的组合。
术语解释
定义和通用术语
除非有相反陈述，否则下列用在说明书和权利要求书中的术语具有下述含义。
本发明中术语“任选地被一个或多个取代基取代”是指被一个或多个取代基取代，或者未取代。具体地，“任选”或“任选地”意味着随后所描述地事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生地场合。例如，“C1-16烷基任选被一个或多个羟基取代”意味着羟基可以但不必须存在，该说明包括C1-16烷基被羟基取代的情形和C1-16烷基不被羟基取代的情形。
本发明中，“可与···形成环”表述该情况可以发生也可以不发生，例如：Ra1和Ra2可和与Ra1和Ra2相连的N原子一起形成5-10元杂环，表述Ra1和Ra2可和与Ra1和Ra2相连的N原子一起形成5-10元杂环，也可以不形成5-10元杂环；
“烷基”是指饱和脂肪族烃基，包括直链和支链基团。C1-16烷基是指含有1至16个碳原子的烷基。本发明中的烷基非限定性实施例包括：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基。C1-C4烷基是指含有1至4个碳原子的烷基。在一实施例中，C1-C4烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基。烷基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上被取代。
术语“烷氧基”是指具有-O-烷基的基团，即如上所定义的烷基经由氧原子连接至母核结构。包含该术语的短语，合适的实例包括但不限于：甲氧基(-O-CH3或-OMe)、乙氧基(-O-CH2CH3或-OEt)和叔丁氧基(-O-C(CH3)3或-OtBu)。
“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其中一个或多个环原子选自氮、氧或S(O)m(其中m是整数0至2)的杂原子，优选氮或氧杂原子；但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。5-20元杂环基是指环包含5至20个环原子，其中至少有一个为杂原子；优选杂环基环包含5至6个环原子，其中1～2个是杂原子。在一实施例中，杂环基为二氢呋喃基、四氢呋喃基、吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基或高哌嗪基等。
“芳基”是指在芳香环化合物的基础上除去一个氢原子衍生的芳族烃基，可以为单环芳基、或稠环芳基、或多环芳基，对于多环的环种，至少一个是芳族环系。例如，5-20元芳基是指具有5至20个环原子的的芳基，且芳基上任选进一步被取代。本发明中“芳基”合适的实例包括但不限于：苯、联苯、萘、蒽、菲、二萘嵌苯、三亚苯及其衍生物。可以理解地，多个芳基也可以被短的非芳族单元间断(例如<10％的非H原子，比如C、N或O原子)，具体如苊、芴，或者9,9-二芳基芴、三芳胺、二芳基醚体系也应该包含在芳基的定义中。
“杂芳基”是指在芳基的基础上至少一个碳原子被非碳原子所替代，非碳原子可以为N原子、O原子、S原子等。例如，“5-20元杂芳基，是指具有5至20个环原子的杂芳基，且杂芳基任选进一步被取代。本发明中“杂芳基”合适的实例包括但不限于：呋喃、苯并呋喃、噻吩、苯并噻吩、吡咯、吡唑、三唑、咪唑、噁唑、噁二唑、噻唑、四唑、吲哚、咔唑、吡咯并咪唑、吡咯并吡咯、噻吩并吡咯、噻吩并噻吩、呋喃并吡咯、呋喃并呋喃、噻吩并呋喃、苯并异噁唑、苯并异噻唑、苯并咪唑、吡啶、吡嗪、哒嗪、嘧啶、三嗪、喹啉、异喹啉、邻二氮萘、喹喔啉、菲啶、伯啶、喹唑啉和喹唑啉酮。
“氨基”是指氨的衍生物，具有式-N(X)2的结构特征，其中每个“X”独立地是H、取代的或未被取代的烷基、取代的或未被取代的环烷基、取代的或未被取代的杂环基等。氨基的非限制性类型包括-NH2、-N(烷基)2、-NH(烷基)、-N(环烷基)2、-NH(环烷基)、-N(杂环基)2、-NH(杂环基)、-N(芳基)2、-NH(芳基)、-N(烷基)(芳基)、-N(烷基)(杂环基)、-N(环烷基)(杂环基)、-N(芳基)(杂芳基)、-N(烷基)(杂芳基)等。
“卤素”或“卤基”是指F、Cl、Br或I。
胍基是指
Figure BDA0002741634000000051
本发明中，当未指出手性碳原子的构型时，应理解为包括本领域可接受的任意构型；
本发明的化合物可以以非溶剂化形式和含有药学上可接受的溶剂(如水、乙醇等)的溶剂化形式存在，即包括溶剂化和非溶剂化形式。
本发明中，被波浪
Figure BDA0002741634000000054
打断的单键代表连接位置，例如：
Figure BDA0002741634000000052
表示丙烷2位的碳为连接位点，
Figure BDA0002741634000000053
表示N为连接位点。本发明中，*表述连接位点；
本发明中，某可取代位点可被一个或多个取代基取代，且当该可取代位点存在多个取代基时，多个取代基可以彼此相同或不同。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分。例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
组合物中所含有的赋形剂，可以为一种或多种缓冲剂、稳定剂、抗粘剂、表面活性剂、润湿剂、润滑剂、乳化剂、粘合剂、悬浮剂、崩解剂、填充剂、吸附剂、涂料(肠的或缓释的)防腐剂、抗氧化剂，不透明的剂、助流剂、加工助剂、着色剂、甜味剂、芳香剂、调味剂和其它已知的添加剂。
“可药用的盐”即“医药上可接受的盐”，是指医药上可接受的化合物的有机或无机盐。
当化合物是酸性或包括足够酸性生物电子等排体时，适当的“可药用的盐”指从医药上可接受的包括无机碱和有机碱的无毒碱中制备的盐。该盐衍生自含有铝、铵、钙、铜、铁、铁、锂、镁、锰盐、锰、钾、钠、辛等的无机碱。特定的实施方式包括铵、钙、镁、钾和钠盐。盐衍生自医药上可接受的有机无毒碱，该有机无毒碱包括一级、二级和三级胺的盐、包括自然存在的取代胺的取代胺、环胺和碱性离子交换树脂，如精氨酸、甜菜碱、咖啡因、胆碱、N，N.sup.1-二苄基乙二胺、乙二胺、2-二乙氨基乙醇、2-二甲基氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基六氢吡啶、还原葡糖胺、氨基葡萄糖、组氨酸、海巴明、异丙胺、赖氨酸、葡甲胺、吗啉、哌嗪、哌啶、聚胺树脂、普鲁卡因、嘌呤、可可碱、三乙基胺、三甲胺、三丙胺、氨丁三醇等等。
当化合物是碱性的或包括足够碱性生物电子等排体时，盐可以从医药上可接受的无毒酸中制备，包括无机和有机酸。这样的酸包括乙酸、苯磺酸、苯甲酸、樟脑磺酸、柠檬酸、乙磺酸、富马酸、葡萄糖酸、氢溴酸、盐酸、羟乙磺酸、乳酸、马来酸、苹果酸、苦杏仁酸，甲基磺酸、粘液酸、硝酸、双羟萘酸、泛酸、磷酸、硫酸、琥珀酸、酒石酸、对甲苯磺酸等等。特定的实施方式包括柠檬酸、氢溴酸、盐酸、磷酸、硫酸、马来酸、酒石酸。其它示例性的盐包括但不限于硫酸盐、柠檬酸盐、乙酸盐、草酸盐、氯化物、溴化物、碘化物、硝酸盐，硫酸盐，磷酸盐、酸性磷酸盐、异烟酸、乳酸、水杨酸盐、酸性柠檬酸盐、酒石酸盐、油酸盐、鞣酸盐、泛酸盐、酒石酸氢盐、抗坏血酸盐、琥珀酸盐、富马酸盐、马来酸盐、龙胆酸盐、葡萄糖酸盐，葡萄糖醛酸盐、糖酸盐、甲酸盐、苯甲酸盐、谷氨酸盐、甲基磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐和双羟萘酸盐(例如，1，1'-亚甲基-双-(2-羟基-3-萘甲酸盐))。
另外，包含化合物的药物制剂可以为片剂、胶囊剂、口服液体剂、丸剂、颗粒剂、散剂、软膏剂、贴剂、栓剂、口含片、滴眼剂、眼膏剂、眼膏剂、滴耳剂、喷剂、气雾剂、吸入剂、注射剂等。
术语“治疗有效量”是指有效化合物或药物试剂的用量，改善、治愈或治疗疾病或病症的一种或多种症状的必要的最小量。
另外，本发明所述的化合物和药物组合物可单独给药，也可以与其他药剂联合施用。对于与一种以上的活性剂的联合治疗，当该活性剂在分开的剂量制剂中时，该活性剂可以分开施用或联合施用。另外，一种药剂的施用可在另一种药剂施用之前、同时或之后进行。当与其他药剂联合施用时，第二药剂的“有效量”将视所用药物的类型而定。
本发明的化合物或药物组合物也可以包含在试剂盒中。
需要说明的是，本发明未注明具体来源的试剂，为市场购买的常规试剂。
详细说明
本发明一实施方式提供了一种补骨脂酚衍生物及其药学上可接受的盐，具有式(I)所示结构：
Figure BDA0002741634000000061
进一步地，具有式(I')所示结构：
Figure BDA0002741634000000062
其中，n为1-16的整数；在一实施例中，n为1、2、3、4、5、6、7、8、9、10、11或12；
R选自卤素、CONR1R2、-COOR3、NR4R5、
Figure BDA0002741634000000063
R1和R2各自独立地选自：-H、
Figure BDA0002741634000000064
R12和R13各自独立地选自：-H、
Figure BDA0002741634000000071
R22和R23各自独立地选自：-H、
Figure BDA0002741634000000072
R32和R33各自独立地选自：-H、
Figure BDA0002741634000000073
R42和R43各自独立地选自：-H、
Figure BDA0002741634000000074
R52和R53各自独立地选自：-H、
Figure BDA0002741634000000075
R62和R63各自独立地选自：-H或
Figure BDA0002741634000000076
其中，R14、R24、R34、R44、R54、R64和R74各自独立选自：-H、胍基、-NR4R5、-SR4、5-20元含氮杂芳基、
Figure BDA0002741634000000077
R15-R17、R25-R27、R35-R37、R45-R47、R55-R57、R65-R67各自独立地选自：-H或C1-6烷基；
R18、R28、R38、R48、R58、R68各自独立地选自：-H、C1-6烷基或卤素；
n1、n2、n3、n4、n5、n6和n7各自独立地为0、1、2、3、4、5、6、7、8、9或10；
R77选自：-H或C1-6烷基；
R3选自：-H或C1-4烷基；
R4和R5各自独立地选自：-H、C1-16烷基、COOR8、-Fmoc、Ra取代C1-16烷基，或R4、R5可和与R4、R5相连的N一起形成5-20元杂环、5-20元杂芳环、Rb取代5-20元杂环、或Rb取代5-20元杂芳环；
Ra选自：5-10元芳基、5-10元杂芳基、-NRa1Ra2或-SRa3；
Rb选自：C1-10烷基、-(CH2)pNRb1Rb2或-SRb3；p为0、1、2、3、4、5、6、7、8、9或10；
Ra1、Ra2、Rb1和Rb2各自独立地为：-H、C1-10烷基、或Rc取代C1-10烷基；或Ra1和Ra2可和与Ra1和Ra2相连的N原子一起形成5-10元杂环或5-10元杂芳环；或Rb1和Rb2可和与Rb1和Rb2相连的N原子一起形成5-10元杂环或5-10元杂芳环；
Ra3和Rb3各自独立地为C1-10烷基；
Rc选自：-NRc1Rc2、胍基或5-6元含氮杂芳基；Rc1和Rc2各自独立地为：-H、C1-4烷基；或Rc1和Rc2可和与Rc1和Rc2相连的N原子一起形成5-10元杂环或5-10元杂芳环；
R6为C1-4烷基；R7选自：-H或C1-4烷基；R8为-H、C1-6烷基或
Figure BDA0002741634000000081
Y-为阴离子；更进一步地，Y-为卤素阴离子，更进一步地，Y-为碘离子；
本发明以补骨脂酚(Bakuchiol)为起始原料，制备一系列两亲性的阳离子型补骨脂酚类化合物。补骨脂酚含有苯环和异戊烯基脂质链组成的疏水骨架，对革兰氏阳性菌具备良好的抗菌活性。通过在补骨脂酚分子骨架中引入不同的阳离子基团，可以合成一系列阳离子型的两亲性补骨脂酚类化合物作为小分子抗菌肽模拟物。补骨脂酚衍生物中引入的阳离子基团可以通过静电相互作用增强补骨脂酚衍生物与带负电荷的细菌细胞膜之间的相互作用，而其疏水部分可以通过疏水相互作用插入到细菌细胞膜的磷脂双层中，从而破坏细菌细胞膜的完整性，导致细胞内容物的泄漏，并最终导致细菌死亡。通过对补骨脂酚衍生物进行系统的结构优化，获得了一系列高效低毒，具备膜靶向或多靶向且能克服细菌耐药性产生的新型抗菌药物。
进一步地，R3选自：H、甲基、乙基或异丙基；
进一步地，R4和R5各自独立地选自：H、C1-12烷基、COOR8、-Fmoc、Ra取代C1-12烷基，且R4、R5可和与R4、R5相连的N一起形成5-15元杂环、5-10元杂芳环、Rb取代5-15元杂环、Rb取代5-15元杂芳环；进一步地，R4和R5各自独立地选自：H、C1-10烷基、COOR8、-Fmoc、Ra取代C1-10烷基，且R4、R5可和与R4、R5相连的N一起形成5-15元杂环、5-10元杂芳环、Rb取代5-15元杂环、Rb取代5-15元杂芳环；
进一步地，所述杂环基选自以下结构基团：
Figure BDA0002741634000000082
q1、q2、q3和q4各自独立地选自：1、2、3或4；
更进一步地，所述杂环基选自:
Figure BDA0002741634000000083
进一步地，Ra选自吡啶、嘧啶、三嗪、-NRa1Ra2或-SRa3；更进一步地，Ra选自吡啶、-NRa1Ra2或-SRa3；
进一步地，Ra1、Ra2各自独立地为H、C1-4烷基、NRc1Rc2取代C1-4烷基；进一步地，Ra3为C1-4烷基；进一步地，Rc1和Rc2各自独立地为H或C1-4烷基；进一步地，Rb选自H、C1-6烷基、-(CH2)pNRb1Rb2；p为0、1、2、3、4、5或6；更进一步地，Rb1和Rb2各自独立地为H或C1-4烷基。
进一步地，R选自以下基团：
Figure BDA0002741634000000091
其中，m1和m2各自独立地为1、2、3、4、5、6、7或8。
进一步地，R1和R2不同时为H；更进一步地，R1和R2中有一个为H，一个为
Figure BDA0002741634000000092
Figure BDA0002741634000000093
在一实施例中，R12和R13均为H；在一实施例中，R12和R13中有一个为H，一个选自
Figure BDA0002741634000000094
在一实施例中，R22和R23均为H；在一实施例中，R22和R23中有一个为H，一个选自
Figure BDA0002741634000000095
Figure BDA0002741634000000096
在一实施例中，R32和R33均为H；在一实施例中，R32和R33中有一个为H，一个选自
Figure BDA0002741634000000101
在一实施例中，R42和R43均为H；在一实施例中，R42和R43中有一个为H，一个选自
Figure BDA0002741634000000102
Figure BDA0002741634000000103
在一实施例中，R52和R53均为H；在一实施例中，R52和R53中有一个为H，一个选自
Figure BDA0002741634000000104
进一步地，R14、R24、R34、R44、R54、R64和R74各自独立选自：H、胍基、-NR4R5、-SR4、5-10元含氮杂芳基、
Figure BDA0002741634000000105
进一步地，R14、R24、R34、R44、R54、R64和R74各自独立选自H、胍基、-NR4R5、-SR4、5元含氮杂芳基、
Figure BDA0002741634000000106
进一步，R14、R24、R34、R44、R54、R64和R74各自独立选自H、胍基、-NR4R5、-N(CH3)2、-SCH3、
Figure BDA0002741634000000107
进一步地，R4和R5各自独立选自H或C1-4烷基；更进一步地，R4和R5各自独立选自H、甲基、乙基、丙基、异丙基或丁基；
进一步地，上述补骨脂酚衍生物选自以下通式的化合物：
Figure BDA0002741634000000108
X为NR12R13、OR15或
Figure BDA0002741634000000109
进一步地，上述补骨脂酚衍生物选自以下通式的化合物：
Figure BDA0002741634000000111
进一步地，上述通式(II)或式(II')中，X为OR15，且R14选自：H、胍基、-NH2、-SCH3、
Figure BDA0002741634000000112
Figure BDA0002741634000000113
进一步地，上述通式(II)或式(II')中，X为NR12R13，R14、R24、R34、R44、R54、R64和R74中至少有一个为胍基。
进一步地，上述通式(II)或式(II')中，X为NR12R13，R12和R13中有一个为H，一个选自
Figure BDA0002741634000000114
Figure BDA0002741634000000115
R22和R23中一个为H，一个选自
Figure BDA0002741634000000116
R32和R33中一个为H，一个选自
Figure BDA0002741634000000117
R42和R43中一个为H，一个选自
Figure BDA0002741634000000118
Figure BDA0002741634000000119
R62和R63中一个为H，一个选自
Figure BDA00027416340000001110
在一实施例中，上述通式(II)或式(II')中，X为
Figure BDA00027416340000001111
在一实施例中，上述通式(II)或式(II')中，X为NR12R13，R12和R13中有一个为H，一个选自
Figure BDA00027416340000001112
在一实施例中，上述通式(II)或式(II')中，X为NR12R13，R12和R13中有一个为H，一个选自
Figure BDA00027416340000001113
R22和R23中有一个为H，一个选自
Figure BDA0002741634000000121
在一实施例中，上述通式(II)或式(II')中，X为NR12R13，R12和R13中有一个为H，一个选自
Figure BDA0002741634000000122
R22和R23中有一个为H，一个选自
Figure BDA0002741634000000123
R32和R23中有一个为H，一个选自
Figure BDA0002741634000000124
进一步地，上述补骨脂酚衍生物选自以下通式的化合物：
Figure BDA0002741634000000125
其中，X2为NR22R23、OR25或
Figure BDA0002741634000000126
X3为NR32R33、OR35或
Figure BDA0002741634000000127
X4为NR42R43、OR45或
Figure BDA0002741634000000131
X5为NR52R53、OR55或
Figure BDA0002741634000000132
X6为NR62R63、OR65或
Figure BDA0002741634000000133
进一步地，上述补骨脂酚衍生物选自以下通式的化合物：
Figure BDA0002741634000000134
进一步地，上述补骨脂酚衍生物选自以下化合物：
Figure BDA0002741634000000135
Figure BDA0002741634000000141
Figure BDA0002741634000000151
Figure BDA0002741634000000161
Figure BDA0002741634000000171
本发明一实施方式还提供了上述补骨脂酚衍生物的制备方法，
(1)R为卤素；上述制备方法包括以下步骤：
Figure BDA0002741634000000172
S101：将式(I-1)所示化合物和
Figure BDA0002741634000000173
进行反应，制得R为卤素的式(I-1)所示化合物；
(2)R为NR4R5、
Figure BDA0002741634000000174
所述制备方法包括以下步骤：
Figure BDA0002741634000000175
S201:将式(I-1)所示化合物和
Figure BDA0002741634000000176
进行反应，制得R为Br的式(I)所示化合物；
S202：将R为Br的式(I)所示化合物与HNR4R5反应，制得R为NR4R5的式(I)所示化合物；
S203：将R为NR4R5的式(I)所示化合物与卤代烷基反应，制得R为
Figure BDA0002741634000000177
的式(I)所示化合物；
S204：将R为NH2的式(I)所示化合物与
Figure BDA0002741634000000178
反应，制得R为
Figure BDA0002741634000000179
的式(I)所示化合物；
(3)R选自CONR1R2、-COOR3时，制备方法包括以下步骤
Figure BDA00027416340000001710
S301：将式(I-1)所示化合物和溴烷基酸烷基酯进行缩合反应，制得R为-COOR3的式(I)所示化合物；
进一步地，溴烷基酸烷基酯为溴乙烷基C1-6烷基酯；
S302：将式(I-2)所示化合物与
Figure BDA0002741634000000181
进行缩合反应，制得式(II)所示化合物；
S303：将式(II-1)所示化合物进行水解反应，制得式(II-2)所示化合物；
Figure BDA0002741634000000182
S304:将式(II-2)所示化合物与
Figure BDA0002741634000000183
进行缩合反应，制得式(III)所示化合物；
Figure BDA0002741634000000184
S305:任选地，依此循环，将含酯基的化合物进行水解，然后与相应的胺进行缩合反应，制得式(IV)、(V)、(VI)、(VII)所示化合物；各通式的结构及定义如上所述，在此不再进行赘述。
可理解的，酯基水解步骤同S303，缩合反应步骤同S304，不同在于，反应底物不同，例如以X2为OR35的式(III)所示化合物为底物，进行水解反应，得到羧酸，再采用该羧酸基化合物为底物与相应的进行缩合反应即可；各水解和缩合的反应条件无特别限定，可以采用现有的水解和缩合反应条件，应理解为均在本发明的保护范围内。
本发明一实施方式还提供了一种药物组合物，包括上述的补骨脂酚衍生物及其药学上可接受的盐，及药学上可接受的辅料。
本发明一实施方式提供了上述补骨脂酚衍生物及其药学上可接受的盐、或上述药物组合物在制备抗菌药物中的应用。
本发明一实施方式提供了上述补骨脂酚衍生物及其药学上可接受的盐、或上述药物组合物在制备治疗或预防细菌感染所导致的疾病的药物中的应用。
本发明一实施方式提供了一种治疗或预防细菌感染的方法，包括施加有效量的上述补骨脂酚衍生物及其药学上可接受的盐、或上述药物组合物。
下面列举具体实施例来对本发明进行说明。
化合物1的制备
将补骨脂酚(162mg,0.632mmol)溶于丙酮(10mL)中，然后加入碳酸钾(436.6mg，3.16mmol)和1,3-二溴丙烷(480.8μL，4.74mmol)，将混合物回流搅拌6小时。反应完成后，将反应混合物用乙酸乙酯稀释并用水萃取两次。将有机相在减压条件下浓缩。粗产物通过硅胶色谱法(石油醚/乙酸乙酯，8：1，v/v)纯化，得到化合物1为无色透明油状物(190.2mg，80％)。1H NMR(400MHz,CDCl3)δ7.29(d,J＝8.7Hz,2H),6.84(d,J＝8.7Hz,2H),6.27(d,J＝16.3Hz,1H),6.07(d,J＝16.2Hz,1H),5.89(dd,J＝17.4,10.8Hz,1H),5.15–5.08(m,1H),5.06–4.99(m,2H),4.10(t,J＝5.8Hz,2H),3.60(t,J＝6.5Hz,2H),2.36–2.25(m,2H),2.00–1.91(m,2H),1.68(s,3H),1.59(s,3H),1.52–1.47(m,2H),1.20(s,3H).13C NMR(100MHz,CDCl3)δ157.91,146.05,136.06,131.38,131.07,127.27(2×CH),126.57,124.89,114.64(2×CH),111.96,65.45,42.62,41.38,32.48,30.11,25.79,23.44,23.32,17.73.HRMS(ESI+):calculated for C21H29BrO[M+H]+377.1480,found 377.1475.
化合物2的制备
以补骨脂酚(162mg,0.632mmol)，碳酸钾(436.6mg,3.16mmol)和1,4-二溴丁烷(565.3μL,4.74mmol)为起始原料，根据合成化合物1的方法，制备得到化合物2，为黄色油状物(207.6mg,84％)。1H NMR(400MHz,CDCl3)δ7.28(d,J＝8.7Hz,2H),6.82(d,J＝8.7Hz,2H),6.26(d,J＝16.3Hz,1H),6.06(d,J＝16.2Hz,1H),5.88(dd,J＝17.4,10.8Hz,1H),5.15–5.08(m,1H),5.06–4.98(m,2H),3.99(t,J＝6.1Hz,2H),3.49(t,J＝6.6Hz,2H),2.11–2.03(m,2H),1.99–1.91(m,4H),1.68(s,3H),1.58(s,3H),1.52–1.47(m,2H),1.20(s,3H).13CNMR(100MHz,CDCl3)δ158.09,146.06,135.94,131.37,130.87,127.25(2×CH),126.59,124.90,114.56(2×CH),111.94,66.94,42.62,41.38,33.56,29.55,27.99,25.78,23.44,23.31,17.72.HRMS(ESI+):calculated for C22H31BrO[M+H]+391.1637found 391.1632.
化合物3的制备
以补骨脂酚(48,2mg,0.301mmol)，碳酸钾(129.9mg,0.94mmol)和1,8-二溴辛烷(259μL,1.41mmol)为起始原料，根据合成化合物1的方法，制备得到化合物3，为白色油状物(40.5mg,48％)。1H NMR(400MHz,CDCl3)δ7.28(d,J＝8.8Hz,2H),6.83(d,J＝8.7Hz,2H),6.26(d,J＝16.3Hz,1H),6.06(d,J＝16.2Hz,1H),5.89(dd,J＝17.4,10.8Hz,1H),5.11(t,J＝7.1Hz,1H),5.06–4.98(m,2H),3.95(t,J＝6.5Hz,2H),3.41(t,J＝6.8Hz,2H),2.00–1.91(m,2H),1.90–1.73(m,4H),1.68(s,3H),1.59(s,3H),1.52–1.42(m,6H),1.38–1.34(m,4H),1.20(s,3H).13C NMR(100MHz,CDCl3)δ158.34,146.10,135.73,131.39,130.59,127.21(2×CH),126.65,124.90,114.58(2×CH),111.93,68.02,42.62,41.39,34.13,32.87,29.32,29.28,28.78,28.19,26.04,25.81,23.44,23.32,17.74.HRMS(ESI+):calculated forC26H39BrO[M+H]+447.2263,found 447.2258.
化合物4的制备
以补骨脂酚(49.5mg,0.193mmol)，碳酸钾(133.4mg,0.965mmol)和1,10-二溴癸烷(325μL,1.45mmol)为起始原料，根据合成化合物1的方法，制备得到化合物4，为黄色油状物(46.9mg,52％)。1H NMR(400MHz,CDCl3)δ7.27(d,J＝8.6Hz,2H),6.82(d,J＝8.8Hz,2H),6.25(d,J＝16.3Hz,1H),6.05(d,J＝16.2Hz,1H),5.87(dd,J＝17.4,10.8Hz,1H),5.13–5.07(m,1H),5.04–4.97(m,2H),3.93(t,J＝6.6Hz,2H),3.40(t,J＝6.9Hz,2H),1.99–1.89(m,2H),1.89–1.70(m,4H),1.67(s,3H),1.57(s,3H),1.52–1.39(m,6H),1.37–1.29(m,8H),1.19(s,3H).13C NMR(100MHz,CDCl3)δ158.37,146.10,135.71,131.39,130.56,127.21(2×CH),126.66,124.91,114.58(2×CH),111.93,68.08,42.62,41.39,34.18,32.91,29.54,29.45,29.43,29.35,28.84,28.25,26.11,25.81,23.44,23.32,17.75.HRMS(ESI+):calculated for C28H43BrO[M+H]+475.2576,found 475.3253.
化合物5的制备
将化合物2(35mg,0.089mmol)溶于无水DMF(4mL)溶液中，然后加入二甲胺(1mL)，将混合物在50℃下搅拌24小时。反应完成后，将反应混合物用乙酸乙酯稀释并用水萃取两次。将有机相在减压条件下浓缩。粗产物通过RP-HPLC纯化，得到化合物5为黄色油状物(23mg，74％)。1H NMR(400MHz,CDCl3)δ7.27(d,J＝9.9Hz,2H),6.82(d,J＝8.7Hz,2H),6.26(d,J＝16.3Hz,1H),6.05(d,J＝16.2Hz,1H),5.88(dd,J＝17.4,10.8Hz,1H),5.14–5.07(m,1H),5.05–4.98(m,2H),3.97(t,J＝6.4Hz,2H),2.36–2.30(m,2H),2.23(s,6H),1.99–1.92(m,2H),1.85–1.76(m,4H),1.67(s,3H),1.58(s,3H),1.52–1.47(m,2H),1.19(s,3H).13CNMR(100MHz,CDCl3)δ158.30,146.10,135.76,131.36,130.65,127.20(2×CH),126.65,124.91,114.61,111.91,100.00,67.83,59.47,45.50(2×CH3),42.60,41.39,27.25,25.78,24.29,23.45,23.31,17.72.HRMS(ESI+):calculated for C24H37NO[M+H]+356.2953,found 356.2947.
化合物6的制备
以化合物2(35mg,0.089mmol)和二乙胺(1mL)为起始原料，根据合成化合物5的方法，制备得到化合物6，为黄色油状物(22.3mg,66％).1H NMR(400MHz,CDCl3)δ7.27(d,J＝9.9Hz,2H),6.82(d,J＝8.7Hz,2H),6.26(d,J＝16.3Hz,1H),6.05(d,J＝16.2Hz,1H),5.88(dd,J＝17.4,10.8Hz,1H),5.14–5.08(m,1H),5.05–4.97(m,2H),3.97(t,J＝6.4Hz,2H),2.61–2.46(m,6H),2.00–1.92(m,2H),1.82–1.74(m,4H),1.67(s,3H),1.58(s,3H),1.52–1.46(m,2H),1.19(s,3H),1.03(t,J＝7.2Hz,6H).13C NMR(100MHz,CDCl3)δ158.27,146.09,135.79,131.36,130.68,127.21(2×CH),126.64,124.90,114.60(2×CH),111.91,67.85,52.48,46.85(2×CH2),42.60,41.39,27.40,25.78(2×CH2),23.45,23.31,17.72,11.46(2×CH3).HRMS(ESI+):calculated for C26H41NO[M+H]+384.3266,found 384.3260.
化合物7的制备
以化合物2(62.1mg,0.159mmol)，和二丁胺(1mL)为起始原料，根据合成化合物9的方法，制备得到化合物7，为黄色油状物(59.1mg,88％)。1H NMR(400MHz,CDCl3)δ7.28(d,J＝8.7Hz,2H),6.83(d,J＝8.7Hz,2H),6.26(d,J＝16.3Hz,1H),6.05(d,J＝16.2Hz,1H),5.88(dd,J＝17.4,10.8Hz,1H),5.14–5.07(m,1H),5.06–4.97(m,2H),3.96(t,J＝6.5Hz,2H),2.51–2.44(m,2H),2.43–2.37(m,4H),1.99–1.91(m,2H),1.83–1.69(m,4H),1.67(s,3H),1.58(s,3H),1.52–1.46(m,2H),1.45–1.37(m,4H),1.35–1.28(m,4H),1.19(s,3H),0.91(t,J＝7.3Hz,6H).13C NMR(100MHz,)δ158.31,146.10,135.76,131.36,130.64,127.20(2×CH),126.66,124.91,114.61(2×CH),111.91,67.93,53.81(2×CH2),53.76,42.60,41.39,29.79,29.03,27.36,25.78(2×CH2),23.45,23.31,20.82(2×CH2),17.72,14.16(2×CH3).HRMS(ESI+):calculated for C30H49NO[M+H]+440.3892,found 440.3892.
化合物8的制备
以化合物1(49mg,0.130mmol)，和二甲胺(1mL)为起始原料，根据合成化合物5的方法，制备得到化合物8，粗产物通过硅胶色谱法(乙酸乙酯/乙醇，1：1，v/v)纯化，为黄色油状物(38.6mg,87％).1H NMR(400MHz,CDCl3)δ7.25(d,J＝8.7Hz,2H),6.81(d,J＝8.6Hz,2H),6.23(d,J＝16.2Hz,1H),6.03(d,J＝16.2Hz,1H),5.86(dd,J＝17.4,10.8Hz,1H),5.08(t,J＝6.6Hz,1H),5.05–4.95(m,2H),3.98(t,J＝6.4Hz,2H),2.47–2.41(m,2H),2.24(s,6H),1.98–1.89(m,4H),1.65(s,3H),1.56(s,3H),1.50–1.43(m,2H),1.17(s,3H).13C NMR(100MHz,CDCl3)δ158.24,146.09,135.80,131.36,130.71,127.21(2×CH),126.64,124.91,114.60(2×CH),111.91,66.32,56.49,45.53(2×CH3),42.60,41.39,27.57,25.78,23.44,23.31,17.72.HRMS(ESI+):calculated for C23H35NO[M+H]+342.2797,found342.2791.
化合物9的制备
以化合物1(59.6mg,0.158mmol)，和二乙胺(1mL)为起始原料，根据合成化合物5的方法，制备得到化合物9，为黄色油状物(48.9mg,91％)。1H NMR(400MHz,CDCl3)δ7.28(d,J＝8.7Hz,2H),6.83(d,J＝8.7Hz,2H),6.26(d,J＝16.3Hz,1H),6.06(d,J＝16.2Hz,1H),5.88(dd,J＝17.4,10.8Hz,1H),5.15–5.08(m,1H),5.06–4.97(m,2H),4.00(t,J＝6.3Hz,2H),2.64–2.51(m,6H),2.00–1.88(m,4H),1.67(s,3H),1.58(s,3H),1.52–1.46(m,2H),1.20(s,3H),1.04(t,J＝7.1Hz,6H).13C NMR(100MHz,CDCl3)δ158.33,146.10,135.74,131.35,130.63,127.19(2×CH),126.67,124.91,114.61(2×CH),111.91,66.49,49.46,47.09(2×CH2),42.60,41.39,27.06,25.78,23.45,23.32,17.72,11.84(2×CH3).HRMS(ESI+):calculated for C25H39NO[M+H]+370.3110,found 370.3103.
化合物10的制备
以化合物1(59.5mg,0.158mmol)，和二丁胺(1mL)为起始原料，根据合成化合物5的方法，制备得到化合物10，为无色透明油状物(56mg,86％)。1H NMR(400MHz,CDCl3)δ7.28(d,J＝8.7Hz,2H),6.83(d,J＝8.7Hz,2H),6.26(d,J＝16.3Hz,1H),6.06(d,J＝16.2Hz,1H),5.89(dd,J＝17.4,10.8Hz,1H),5.15–5.08(m,1H),5.06–4.98(m,2H),4.00(t,J＝6.4Hz,2H),2.61–2.54(m,2H),2.44–2.38(m,4H),1.97–1.87(m,4H),1.68(s,3H),1.59(s,3H),1.52–1.46(m,2H),1.44–1.38(m,4H),1.33–1.28(m,4H),1.20(s,3H),0.90(t,J＝7.3Hz,6H).13C NMR(100MHz,CDCl3)δ158.36,146.11,135.70,131.35,130.59,127.18(2×CH),126.69,124.92,114.61(2×CH),111.90,66.45,54.06(2×CH2),50.63,42.60,41.40,29.38,27.17,25.78(2×CH2),23.46,23.32,20.81(2×CH2),17.72,14.18(2×CH3).HRMS(ESI+):calculated for C29H47NO[M+H]+426.3736,found 426.3728.
化合物11的制备
以化合物3(40.5mg,0.091mmol)，和二乙胺(1mL)为起始原料，根据合成化合物5的方法，制备得到化合物11，为黄色油状物(32.3mg,81％)。1H NMR(400MHz,CD3OD)δ7.27(d,J＝8.7Hz,2H),6.82(d,J＝8.7Hz,2H),6.26(d,J＝16.3Hz,1H),6.07(d,J＝16.3Hz,1H),5.90(dd,J＝17.4,10.8Hz,1H),5.15–5.08(m,1H),5.05–4.98(m,2H),3.95(t,J＝6.4Hz,2H),2.89(q,J＝7.3Hz,4H),2.81–2.75(m,2H),2.00–1.92(m,2H),1.81–1.72(m,2H),1.66(s,3H),1.62–1.55(m,5H),1.51–1.45(m,4H),1.42–1.34(m,6H),1.20–1.15(m,9H).13C NMR(100MHz,CD3OD)δ159.78,147.33,136.40,131.99,131.82,128.15(2×CH),128.01,125.94,115.50(2×CH),112.28,68.86,53.35,47.95(2×CH2),43.54,42.57,30.36(2×CH2),30.30,28.09,27.07,25.90(2×CH2),24.36,23.86,17.69,10.06(2×CH3).HRMS(ESI+):calculated for C30H49NO[M+H]+440.3892,found 440.3875.
化合物12的制备
以化合物4(46.9mg,0.099mmol)，和二乙胺(1mL)为起始原料，根据合成化合物5的方法，制备得到化合物12，为橙色油状物(34.8mg,76％)。1H NMR(400MHz,CD3OD)δ7.26(d,J＝8.7Hz,2H),6.82(d,J＝8.7Hz,2H),6.26(d,J＝16.3Hz,1H),6.07(d,J＝16.3Hz,1H),5.90(dd,J＝17.4,10.8Hz,1H),5.15–5.08(m,1H),5.06–4.97(m,2H),3.94(t,J＝6.4Hz,2H),3.18(q,J＝7.3Hz,4H),3.11–3.02(m,2H),2.02–1.91(m,2H),1.82–1.60(m,7H),1.57(s,3H),1.52–1.42(m,4H),1.42–1.33(m,10H),1.29(t,J＝7.3Hz,6H),1.19(s,3H).13C NMR(100MHz,CD3OD)δ159.78,147.31,136.39,131.98,131.79,128.15(2×CH),128.00,125.94,115.49(2×CH),112.29,68.91,52.95,48.15(2×CH2),43.54,42.56,30.55,30.44(2×CH2),30.41,30.20,27.64,27.15,25.92,24.91,24.35,23.85,17.70,9.08(2×CH3).HRMS(ESI+):calculated for C32H53NO[M+H]+468.4205,found 468.4199.
化合物13的制备
以化合物2(69.3mg,0.177mmol)和氨水(3mL)为起始原料，根据合成化合物24的方法，制备得到化合物13，为黄色泡沫状(44.8mg,77％)。1H NMR(400MHz,CD3OD)δ7.28(d,J＝8.7Hz,2H),6.88–6.83(m,2H),6.26(d,J＝16.3Hz,1H),6.08(d,J＝16.3Hz,1H),5.90(dd,J＝17.5,10.8Hz,1H),5.14–5.09(m,1H),5.05–4.99(m,2H),4.03(t,J＝5.3Hz,2H),3.13–3.06(m,2H),2.00–1.84(m,6H),1.66(s,3H),1.57(s,3H),1.50–1.45(m,2H),1.19(s,3H).13C NMR(100MHz,CD3OD)δ159.44,147.28,136.63,132.14,131.98,128.18(2×CH),127.92,125.93,115.51(2×CH),112.29,68.17,43.54,42.54,40.52,27.29,25.89,25.69,24.35,23.86,17.68.HRMS(ESI+):calculated for C22H33NO[M+H]+328.2640,found328.2632.
化合物14的制备
以化合物2(38.9mg,0.099mmol)和乙胺(1mL)为起始原料，根据合成化合物5的方法，制备得到化合物14，为黄色油状(30.1mg,85％)。1H NMR(400MHz,CD3OD)δ7.28(d,J＝8.7Hz,2H),6.85(d,J＝8.7Hz,2H),6.26(d,J＝16.3Hz,1H),6.08(d,J＝16.3Hz,1H),5.90(dd,J＝17.5,10.8Hz,1H),5.12(t,J＝7.2Hz,1H),5.05–4.97(m,2H),4.02(t,J＝5.3Hz,2H),3.11–2.98(m,4H),2.00–1.92(m,2H),1.91–1.81(m,4H),1.66(s,3H),1.57(s,3H),1.51–1.44(m,2H),1.31(t,J＝7.3Hz,3H),1.19(s,3H).13C NMR(100MHz,CD3OD)δ159.44,147.31,136.69,132.20,132.00,128.21(2×CH),127.93,125.95,115.54(2×CH),112.31,68.12,48.22,43.94,43.56,42.56,27.38,25.90,24.44,24.36,23.87,17.69,11.56.HRMS(ESI+):calculated for C24H37NO[M+H]+356.2953,found 356.2949.
化合物15的制备
以化合物2(43mg,0.11mmol)和正丁胺(1mL)为起始原料，根据合成化合物5的方法，制备得到化合物15，为黄色油状物(35.5mg,84％)。1H NMR(400MHz,CD3OD)δ7.28(d,J＝7.3Hz,2H),6.85(d,J＝8.4Hz,2H),6.26(d,J＝15.8Hz,1H),6.12–6.03(m,1H),5.96–5.84(m,1H),5.11(t,J＝7.8Hz,1H),5.05–4.98(m,2H),4.06–3.99(m,2H),3.08–3.00(m,2H),3.00–2.93(m,2H),2.00–1.91(m,2H),1.90–1.80(m,4H),1.70–1.61(m,5H),1.57(s,3H),1.50–1.37(m,4H),1.20–1.17(m,3H),1.01–0.95(m,3H).13C NMR(100MHz,CD3OD)δ159.41,147.28,136.67,132.16,132.00,128.19(2×CH),127.90,125.92,115.54(2×CH),112.30,68.14,48.74(2×CH2),43.53,42.53,29.44,27.41,25.89,24.48,24.33,23.85,20.84,17.68,13.92.HRMS(ESI+):calculated for C26H41NO[M+H]+384.3266,found 384.3261.
化合物16的制备
以化合物2(65.8mg,0.168mmol)和正己胺(1mL)为起始原料，根据合成化合物5的方法，制备得到化合物16，为黄色油状物(46.7mg,68％)。1H NMR(400MHz,CDCl3)δ7.24(d,J＝8.1Hz,2H),6.76(d,J＝8.7Hz,2H),6.23(d,J＝16.3Hz,1H),6.03(d,J＝16.2Hz,1H),5.86(dd,J＝17.4,10.8Hz,1H),5.13–5.06(m,1H),5.04–4.96(m,2H),3.89(t,J＝5.9Hz,2H),2.98–2.80(m,4H),1.98–1.86(m,4H),1.82–1.65(m,7H),1.56(s,3H),1.50–1.44(m,2H),1.31–1.21(m,6H),1.17(s,3H),0.84(t,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3)δ168.26,157.88,146.03,135.96,131.36,130.96,127.25,126.56,124.88,114.54(2×CH),111.95,67.04,47.65,47.28,42.60,41.37,31.28,26.58,26.51,25.99,25.78,23.41,23.30,23.10,22.50,17.71,14.00.HRMS(ESI+):calculated for C28H45NO[M+H]+412.3579,found 412.3573.
化合物17的制备
以化合物2(34.7mg,0.089mmol)和正辛胺(1mL)为起始原料，根据合成化合物5的方法，制备得到化合物17，为黄色油状物(28.4mg,72％)。1H NMR(400MHz,CD3OD)δ7.25(d,J＝8.8Hz,2H),6.82(d,J＝8.8Hz,2H),6.24(d,J＝16.3Hz,1H),6.05(d,J＝16.3Hz,1H),5.88(dd,J＝17.4,10.8Hz,1H),5.12–5.06(m,1H),5.04–4.95(m,2H),4.07–3.92(m,2H),3.08–2.76(m,4H),1.99–1.78(m,6H),1.63(s,5H),1.55(s,3H),1.48–1.42(m,2H),1.36–1.26(m,10H),1.17(s,3H),0.88(t,J＝6.9Hz,3H).13C NMR(100MHz,CD3OD)δ159.44,147.30,136.67,132.18,131.99,128.20,127.93,125.94,115.54(2×CH),112.29,101.33,68.17,48.55,48.54,43.55,42.55,32.90,30.24,30.20,30.19,27.68,27.45,25.88,24.35,23.87,23.68,23.67,17.67,14.41.HRMS(ESI+):calculated for C30H49NO[M+H]+440.3892,found 440.3886.
化合物18的制备
以化合物2(66.7mg,0.170mmol)和正癸胺(1mL)为起始原料，根据合成化合物5的方法，制备得到化合物18，为黄色油状(64.8mg,81％)。1H NMR(400MHz,CDCl3)δ7.26–7.23(m,2H),6.77(d,J＝8.8Hz,2H),6.24(d,J＝16.2Hz,1H),6.04(d,J＝16.2Hz,1H),5.87(dd,J＝17.4,10.7Hz,1H),5.13–5.07(m,1H),5.04–4.97(m,2H),3.90(t,J＝5.9Hz,2H),2.99–2.90(m,2H),2.89–2.81(m,2H),1.99–1.85(m,4H),1.84–1.60(m,7H),1.57(s,3H),1.51–1.45(m,2H),1.29–1.18(m,17H),0.86(t,J＝6.9Hz,3H).13C NMR(100MHz,CDCl3)δ167.98,157.87,146.01,135.97,131.35,130.96,127.25,126.56,124.88,114.54(2×CH),111.95,67.04,47.68,47.32,42.60,41.36,31.95,29.56,29.52,29.35,29.18,26.87,26.57,26.05,25.78,23.41,23.30,23.11,22.74,17.71,14.19.HRMS(ESI+):calculated forC32H53NO[M+H]+468.4205,found 468.4197.
化合物19的制备
以化合物2(47.3mg,0.121mmol)和硫代吗啉(1mL)为起始原料，根据合成化合物8的方法，制备得到化合物19，为黄色油状物(39.5mg,81％)。1H NMR(400MHz,CDCl3)δ7.28(d,J＝8.7Hz,2H),6.82(d,J＝8.7Hz,2H),6.26(d,J＝16.3Hz,1H),6.06(d,J＝16.2Hz,1H),5.88(dd,J＝17.4,10.8Hz,1H),5.15–5.07(m,1H),5.06–4.96(m,2H),3.96(t,J＝6.3Hz,2H),2.75–2.61(m,8H),2.46–2.38(m,2H),2.00–1.91(m,2H),1.81–1.73(m,2H),1.70–1.62(m,5H),1.58(s,3H),1.52–1.45(m,2H),1.20(s,3H).13C NMR(100MHz,CDCl3)δ158.24,146.08,135.82,131.36,130.70,127.22(2×CH),126.63,124.90,114.58(2×CH),111.93,67.77,58.99,55.08(2×CH2),42.61,41.39,28.07(2×CH2),27.31,25.79,23.45,23.32,23.13,17.73.HRMS(ESI+):calculated for C26H39NOS[M+H]+414.2831,found 414.2822.
化合物20的制备
以化合物2(47.3mg,0.121mmol)和四氢吡咯(1mL)为起始原料，根据合成化合物5的方法，制备得到化合物20，为无色透明油状物(40.5mg,88％)。1H NMR(400MHz,CDCl3)δ7.27(d,J＝8.7Hz,2H),6.84(d,J＝8.7Hz,2H),6.26(d,J＝16.3Hz,1H),6.07(d,J＝16.3Hz,1H),5.90(dd,J＝17.4,10.8Hz,1H),5.15–5.07(m,1H),5.05–4.97(m,2H),4.00(t,J＝5.6Hz,2H),2.88(dt,J＝15.1,6.7Hz,6H),1.99–1.88(m,6H),1.83–1.76(m,4H),1.66(s,3H),1.57(s,3H),1.50–1.44(m,2H),1.19(s,3H).13C NMR(100MHz,CDCl3)δ159.55,147.30,136.57,132.04,131.97,128.18(2×CH),127.96,125.95,115.55(2×CH),112.30,68.38,56.69,54.98(2×CH2),43.54,42.55,28.00,25.90,25.32,24.35,24.06(2×CH2),23.88,17.70.HRMS(ESI+):calculated for C26H39NO[M+H]+382.3110,found 382.3101.
化合物21的制备
以化合物2(66.3mg,0.169mmol)和1-甲基哌嗪(1mL)为起始原料，根据合成化合物5的方法，制备得到化合物21，为棕色油状物(48.7mg,71％)。1H NMR(400MHz,CDCl3)δ7.28–7.25(m,2H),6.79(d,J＝8.7Hz,2H),6.24(d,J＝16.3Hz,1H),6.04(d,J＝16.2Hz,1H),5.86(dd,J＝17.4,10.8Hz,1H),5.12–5.05(m,1H),5.03–4.96(m,2H),3.94(t,J＝6.1Hz,2H),2.88–2.45(m,10H),2.43(s,3H),1.98–1.88(m,2H),1.82–1.67(m,4H),1.65(s,3H),1.56(s,3H),1.50–1.44(m,2H),1.17(s,3H).13C NMR(100MHz,CDCl3)δ167.96,158.13,146.05,135.88,131.37,130.76,127.23,126.58,124.88,114.55(2×CH),111.94,67.53,57.50,53.62(2×CH2),51.37(2×CH2),44.64,42.61,41.37,27.14,25.79,23.42,23.30,22.91,17.72.HRMS(ESI+):calculated for C27H42N2O[M+H]+411.3375,found 411.3365.
化合物22的制备
以化合物2(66.3mg,0.169mmol)和二甲基吡啶胺(1mL)为起始原料，根据合成化合物5的方法，制备得到化合物22，为棕色凝胶(71.4mg,83％)。1H NMR(400MHz,CDCl3)δ8.53–8.48(m,2H),7.65–7.58(m,2H),7.51(d,J＝7.8Hz,2H),7.26–7.22(m,2H),7.15–7.08(m,2H),6.75(d,J＝8.7Hz,2H),6.24(d,J＝16.3Hz,1H),6.04(d,J＝16.2Hz,1H),5.87(dd,J＝17.4,10.8Hz,1H),5.13–5.06(m,1H),5.04–4.96(m,2H),3.85(t,J＝6.2Hz,2H),3.81(s,4H),2.59(t,J＝6.9Hz,2H),1.99–1.89(m,2H),1.80–1.62(m,7H),1.56(s,3H),1.51–1.44(m,2H),1.18(s,3H).13C NMR(100MHz,CDCl3)δ159.94,158.24(2×C),149.02(2×CH),146.08,136.51(2×CH),135.75,131.36,130.61,127.18(2×CH),126.65,124.90,123.01(2×CH),122.02(2×CH),114.58(2×CH),111.93,67.74,60.50(2×CH2),53.96,42.61,41.38,27.04,25.79,23.70,23.44,23.31,17.73.HRMS((ESI+):calculated for C34H43N3O[M+H]+510.3484,found 510.3478.
化合物23的制备
以化合物2(67.6mg,0.173mmol)和1-(3-二甲氨基丙基)哌嗪(1mL)为起始原料，根据合成化合物5的方法，制备得到化合物23，为棕色凝胶(68.4mg,83％)。1H NMR(400MHz,CDCl3)δ7.27–7.23(m,2H),6.79(d,J＝8.5Hz,2H),6.23(d,J＝16.2Hz,1H),6.03(d,J＝16.2Hz,1H),5.85(dd,J＝17.4,10.8Hz,1H),5.11–5.05(m,1H),5.03–4.94(m,2H),3.93(t,J＝6.1Hz,2H),2.63–2.39(m,20H),1.97–1.88(m,2H),1.82–1.73(m,4H),1.69–1.62(m,5H),1.55(s,3H),1.49–1.42(m,2H),1.17(s,3H).13C NMR(100MHz,CDCl3)δ168.54,158.19,146.06,135.80,131.36,130.68,127.21,126.61,124.88,114.56(2×CH),111.92,67.67,57.96,56.62,55.66,52.62(2×CH2),43.90(2×CH3),42.60,41.37,27.28,25.78,23.43,23.30,23.16,23.07,17.72.HRMS(ESI+):calculated for C31H51N3O[M+H]+482.4110,found482.4101.
化合物24的制备
以化合物2(63.6mg,0.163mmol)和N,N'-二甲基-1,3-丙二胺(203μL,1.62mmol)为起始原料，根据合成化合物5的方法，制备得到化合物24，为黄色油状物(56.5mg,87％)。1HNMR(400MHz,CD3OD)δ7.27(dd,J＝8.7,1.9Hz,2H),6.84(d,J＝8.8Hz,2H),6.26(d,J＝16.3Hz,1H),6.07(d,J＝16.3Hz,1H),5.90(dd,J＝17.4,10.8Hz,1H),5.15–5.09(m,1H),5.06–4.98(m,2H),4.03–3.95(m,2H),3.37–3.31(m,2H),2.98–2.84(m,2H),2.60–2.36(m,5H),2.33–2.24(m,3H),2.00–1.92(m,2H),1.85–1.67(m,6H),1.66(s,3H),1.57(s,3H),1.51–1.45(m,2H),1.19(s,3H).13C NMR(100MHz,CDCl3)δ157.84,145.92,136.05,131.38,130.90,127.30(2×CH),126.43,124.83,114.54(2×CH),112.03,67.10,55.01,47.70,45.12,43.16,42.98,42.60,41.31,26.45,25.82(2×CH2),23.29,23.17,21.76,17.75.HRMS((ESI+):calculated for C27H44N2O[M+H]+413.3532,found 413.3523.
化合物25的制备
以化合物2(47mg,0.12mmol)和2-(甲硫基)乙胺(55.8μL,0.600mmol)为起始原料，根据合成化合物24的方法，制备得到化合物25，为黄色油状物(23.2mg,60％)。1H NMR(400MHz,CDCl3)δ7.27(d,J＝8.8Hz,2H),6.82(d,J＝8.8Hz,2H),6.25(d,J＝16.3Hz,1H),6.05(d,J＝16.2Hz,1H),5.88(dd,J＝17.4,10.8Hz,1H),5.13–5.07(m,1H),5.05–4.98(m,2H),3.96(t,J＝6.3Hz,2H),2.85(t,J＝6.5Hz,2H),2.73–2.61(m,4H),2.23(s,3H),2.10–2.10(m,2H),1.98–1.91(m,2H),1.86–1.77(m,2H),1.73–1.69(m,1H),1.67(s,3H),1.57(s,3H),1.51–1.46(m,2H),1.19(s,3H).13C NMR(100MHz,CDCl3)δ158.20,146.07,135.81,131.38,130.70,127.22(2×CH),126.62,124.89,114.58(2×CH),111.93,67.75,49.10,47.65,42.61,41.38,34.12,27.11,26.51,25.79,23.43,23.31,17.73,15.36.HRMS(ESI+):calculated for C25H39NOS[M+H]+402.2831,found 402.2822.
化合物26的制备
以化合物2(60.65mg,0.155mmol)和N,N,N'-三甲基-1,3-丙二胺(113.5μL,0.775mmol)为起始原料，根据合成化合物24的方法，制备得到化合物26，为黄色油状物(46.3mg,70％)。1H NMR(400MHz,CD3OD)δ7.29(d,J＝8.7Hz,2H),6.86(d,J＝8.8Hz,2H),6.26(d,J＝16.3Hz,1H),6.08(d,J＝16.3Hz,1H),5.90(dd,J＝17.4,10.8Hz,1H),5.15–5.09(m,1H),5.06–4.98(m,2H),4.03(t,J＝5.5Hz,2H),3.07–2.97(m,6H),2.73–2.69(m,9H),2.07–1.92(m,4H),1.90–1.81(m,4H),1.66(s,3H),1.57(s,3H),1.51–1.44(m,2H),1.19(s,3H).13C NMR(100MHz,CD3OD)δ159.47,147.29,136.65,132.13,131.99,128.20(2×CH),127.92,125.94,115.55(2×CH),112.30,68.20,57.45,43.87,43.81,43.55(3×CH3),42.54,40.78,27.58,25.89,24.35,23.84,22.92,21.62,17.69.HRMS(ESI+):calculatedfor C28H46N2O[M+H]+427.3688,found 427.3679.
化合物27的制备
以化合物2(67.1mg,0.171mmol)和N,N',N”-三甲基二丙撑三胺(208μL,1.03mmol)为起始原料，根据合成化合物5的方法，制备得到化合物27，为黄色油状物(58.3mg,72％)。1H NMR(400MHz,CD3OD)δ7.28(d,J＝8.7Hz,2H),6.85(d,J＝8.7Hz,2H),6.26(d,J＝16.3Hz,1H),6.08(d,J＝16.3Hz,1H),5.90(dd,J＝17.4,10.8Hz,1H),5.16–5.09(m,1H),5.06–4.98(m,2H),4.01(t,J＝5.2Hz,2H),3.38–3.31(m,2H),2.99–2.84(m,2H),2.82–2.61(m,5H),2.56–2.36(m,7H),2.34–2.23(m,3H),2.00–1.90(m,2H),1.85–1.72(m,8H),1.66(s,3H),1.57(s,3H),1.51–1.45(m,2H),1.19(s,3H).13C NMR(100MHz,CDCl3)δ157.79,145.96,136.06,131.41,130.97,127.29(2×CH),126.44,124.82,114.48(2×CH),112.00,66.92,55.61,54.00,53.58,53.38,47.60,42.61(2×CH3),41.32,40.89,39.50,33.14,26.52,25.81,23.32,23.28,22.09,20.99,17.73.HRMS(ESI+):calculated for C31H53N3O[M+H]+484.4267,found 484.4258.
化合物28的制备
以化合物2(56mg,0.143mmol)和N'-[3-(二甲氨基)丙基]-N,N-二甲基-1,3-丙二胺(159μL,0.715mmol)为起始原料，根据合成化合物24的方法，制备得到化合物28，为黄色凝胶(67.1mg,94％)。1H NMR(400MHz,CD3OD)δ7.32–7.27(m,2H),6.91–6.83(m,2H),6.27(d,J＝16.2Hz,1H),6.14–6.05(m,1H),5.90(dd,J＝17.5,10.8Hz,1H),5.16–5.08(m,1H),5.06–4.98(m,2H),4.12–3.98(m,2H),3.50–3.38(m,3H),3.21–2.97(m,9H),2.87–2.72(m,10H),2.24–1.73(m,10H),1.66(s,3H),1.57(s,3H),1.50–1.45(m,2H),1.19(s,3H).13C NMR(100MHz,CD3OD)δ159.57,159.37,147.28,136.63,131.99,128.21,127.90,127.88,125.92,115.56,115.54,112.30,68.53,67.96,51.59,51.37,51.32,43.55(2×CH3),43.41,43.40,43.35(2×CH3),42.53,27.13,25.89,25.87,24.34,23.83,20.73,17.68,17.66.HRMS(ESI+):calculated for C32H55N3O[M+H]+498.4423,found 498.4411.
化合物29的制备
以化合物2(50mg,0.128mmol)和三(2-氨基乙基)胺(96μL,0.639mmol)为起始原料，根据合成化合物24的方法，制备得到化合物29，为黄色凝胶(37.4mg,64％)。1H NMR(400MHz,CD3OD)δ7.28(d,J＝8.6Hz,2H),6.85(d,J＝8.7Hz,2H),6.26(d,J＝16.2Hz,1H),6.08(d,J＝16.2Hz,1H),5.90(dd,J＝17.5,10.7Hz,1H),5.12(t,J＝7.2Hz,1H),5.05–5.01(m,2H),4.02(t,J＝5.5Hz,2H),3.18–3.01(m,8H),2.87–2.72(m,6H),2.00–1.82(m,6H),1.66(s,3H),1.57(s,3H),1.51–1.44(m,2H),1.19(s,3H).13C NMR(100MHz,CD3OD)δ159.44,147.28,136.62,132.11,132.00,128.18(2×CH),127.91,125.92,115.53(2×CH),112.29,68.13,52.53(2×CH2),51.52,46.28,43.54(3×CH2),42.53,38.07,27.52,25.89,24.42,24.34,23.84,17.67.HRMS(ESI+):calculated for C28H48N4O[M+H]+457.3906,found457.3890.
化合物30的制备
以化合物2(36.7mg,0.094mmol)和1,4,8,11-四氮杂环十四烷(147μL,0.75mmol)为起始原料，根据合成化合物24的方法，制备得到化合物30，为黄色凝胶(29.8mg,62％)。1HNMR(400MHz,CD3OD)δ7.29(d,J＝8.7Hz,2H),6.87(d,J＝8.8Hz,2H),6.27(d,J＝16.3Hz,1H),6.09(d,J＝16.3Hz,1H),5.91(dd,J＝17.5,10.8Hz,1H),5.15–5.10(m,1H),5.05–4.99(m,2H),4.08–3.98(m,2H),3.58–3.35(m,2H),3.24–3.09(m,6H),2.99–2.50(m,10H),2.00–1.64(m,13H),1.57(s,3H),1.50–1.44(m,2H),1.20(s,3H).13C NMR(100MHz,)δ159.55,147.28,136.67,132.09,132.00,128.22(2×CH),127.89,125.92,115.56(2×CH),112.30,68.42,54.07,51.98,51.76,50.65,50.44,47.44(2×CH2),45.94,45.76,43.55,42.54,28.04,25.89,25.47,24.35,23.84,23.36,21.34,17.68.HRMS((ESI+):calculated forC32H54N4O[M+H]+511.4376,found 511.4367.
化合物31的制备
以化合物2(56mg,0.143mmol)和1,4,7,10,13-五氮杂环十五烷(176.3μL,0.715mmol)为起始原料，根据合成化合物24的方法，制备得到化合物31，为黄色凝胶(68.8mg,92％)。1H NMR(400MHz,CD3OD)δ7.26(dd,J＝8.5,3.4Hz,2H),6.84(dd,J＝8.7,5.0Hz,2H),6.24(d,J＝16.3Hz,1H),6.06(dd,J＝16.3,2.1Hz,1H),5.88(dd,J＝17.5,10.8Hz,1H),5.12–5.06(m,1H),5.03–4.95(m,2H),4.07–3.39(m,10H),3.15–2.60(m,14H),1.97–1.89(m,2H),1.80–1.60(m,7H),1.55(s,3H),1.48–1.42(m,2H),1.17(s,3H).13C NMR(100MHz,CD3OD)δ159.55,147.27,136.70,136.60,132.00,128.25,128.20,127.91,127.87,125.91,115.52,112.31,68.66,52.22,51.95,51.22,48.04,47.79,46.85,46.72,46.22,45.54,45.09,44.88,43.55,42.53,28.23,25.90,24.34,23.83,22.49,17.69.HRMS(ESI+):calculated for C32H55N5O[M+H]+526.4485,found 526.4476.
化合物32的制备
将化合物5(31.7mg,0.089mmol)溶于甲醇(8mL)中，然后加入碘甲烷(1mL)，将反应混合物在室温下搅拌过夜。反应完成后，将反应混合物用正丁醇稀释并用水萃取两次。将有机相在减压条件下浓缩。粗产物通过RP-HPLC纯化，得到化合物32，为黄色凝胶(31.6mg,72％)。1H NMR(400MHz,CD3OD)δ7.29(d,J＝8.7Hz,2H),6.87(d,J＝8.7Hz,2H),6.27(d,J＝16.3Hz,1H),6.08(d,J＝16.3Hz,1H),5.90(dd,J＝17.5,10.8Hz,1H),5.15–5.09(m,1H),5.06–4.97(m,2H),4.06(t,J＝5.9Hz,2H),3.46–3.38(m,2H),3.14(s,9H),2.04–1.82(m,6H),1.66(s,3H),1.57(s,3H),1.51–1.45(m,2H),1.19(s,3H).13C NMR(100MHz,CD3OD)δ159.38,147.29,136.72,132.23,131.99,128.21(2×CH),127.90,125.94,115.56(2×CH),112.30,67.93,67.54,53.54,53.50,53.46,43.55,42.54,27.17,25.88,24.35,23.84,21.10,17.67.HRMS(ESI+):calculated for C25H40INO[M-I]+370.3104,found 370.3105.
化合物33的制备
以化合物6(31.3mg,0.082mmol)和碘甲烷(1mL)为起始原料，根据合成化合物32的方法，制备得到化合物33，为黄色凝胶(34.7mg,83％)。1H NMR(400MHz,CD3OD)δ7.29(d,J＝8.7Hz,2H),6.88(d,J＝8.8Hz,2H),6.27(d,J＝16.3Hz,1H),6.09(d,J＝16.3Hz,1H),5.90(dd,J＝17.5,10.8Hz,1H),5.15–5.08(m,1H),5.06–4.98(m,2H),4.06(t,J＝5.7Hz,2H),3.41–3.31(m,6H),3.00(s,3H),1.99–1.83(m,6H),1.66(s,3H),1.57(s,3H),1.51–1.45(m,2H),1.36–1.31(m,6H),1.19(s,3H).13C NMR(100MHz,CD3OD)δ159.34,147.29,136.76,132.28,131.99,128.22(2×CH),127.89,125.94,115.56(2×CH),112.30,67.89,61.22,57.61,57.58,57.54,43.55,42.54,27.08,25.88,24.35,23.85,20.16,17.67,9.12,8.01.HRMS(ESI+):calculated for C27H44INO[M-I]+398.3417,found 398.3418.
化合物34的制备
以化合物7(34.5mg,0.078mmol)和碘甲烷(1mL)为起始原料，根据合成化合物32的方法，制备得到化合物34，为黄色油状物(37mg,81％)。1H NMR(400MHz,CD3OD)δ7.27(d,J＝8.8Hz,2H),6.85(d,J＝8.8Hz,2H),6.24(d,J＝16.3Hz,1H),6.06(d,J＝16.3Hz,1H),5.88(dd,J＝17.5,10.8Hz,1H),5.13–5.06(m,1H),5.03–4.95(m,2H),4.04(t,J＝5.7Hz,2H),3.36–3.30(m,2H),3.28–3.21(m,4H),3.00(s,3H),1.98–1.78(m,6H),1.73–1.61(m,7H),1.54(s,3H),1.49–1.34(m,6H),1.18–1.15(m,3H),0.97(t,J＝7.4Hz,6H).13C NMR(100MHz,CD3OD)δ159.30,147.28,136.76,132.29,131.98,128.24(2×CH),127.88,125.94,115.56(2×CH),112.30,67.71,62.71,62.68,62.65,62.07,43.55,42.54,26.96,25.89,25.12(2×CH2),24.35,23.86,20.74,20.72,20.14,17.68,13.93(2×CH3).HRMS(ESI+):calculatedfor C31H52INO[M-I]+454.4043,found 454.4043.
化合物35的制备
以13(45.6mg,0.139mmol)，1H-吡唑-1-甲脒盐酸盐(61.2mg,0.418mmol)和DIPEA(138μL,0.835mmol))为起始原料，根据合成化合物38的方法，制备得到化合物35，为黄色凝胶(30.6mg,55％)。1H NMR(400MHz,CD3OD)δ7.28(d,J＝8.6Hz,2H),6.85(d,J＝8.8Hz,2H),6.26(d,J＝16.3Hz,1H),6.07(d,J＝16.3Hz,1H),5.90(dd,J＝17.5,10.8Hz,1H),5.16–5.09(m,1H),5.05–4.98(m,2H),4.00(t,J＝5.9Hz,2H),3.25(t,J＝6.9Hz,2H),2.00–1.92(m,2H),1.88–1.74(m,4H),1.66(s,3H),1.57(s,3H),1.50–1.45(m,2H),1.19(s,3H).13CNMR(100MHz,CD3OD)δ159.54,158.70,147.28,136.55,132.03,131.97,128.15(2×CH),127.94,125.92,115.51(2×CH),112.28,68.36,43.53,42.53,42.17,27.46,26.76,25.88,24.33,23.84,17.67.HRMS(ESI+):calculated for C23H35N3O[M+H]+370.2858,found370.2849.
化合物36的制备
将补骨脂酚(93.5mg，0.357mmol)溶于丙酮(10mL)中，然后加入碳酸钾(123.5mg，0.893mmol)和溴代乙酸乙酯(81μL，0.081mmol)。将反应混合物回流搅拌3h。反应完成后，将所得混合物用乙酸乙酯稀释并用水萃取两次。将有机相在减压条件下浓缩。粗产物通过硅胶色谱法(石油醚/乙酸乙酯，6：1，v/v)纯化，得到化合物36为淡黄色油状(114.1mg，93％)。1H NMR(400MHz,CDCl3)δ7.29(d,J＝8.7Hz,2H),6.85(d,J＝8.8Hz,2H),6.26(d,J＝16.3Hz,1H),6.08(d,J＝16.3Hz,1H),5.88(dd,J＝17.4,10.7Hz,1H),5.14–5.07(m,1H),5.06–4.98(m,2H),4.61(s,2H),4.27(q,J＝7.1Hz,2H),1.99–1.91(m,2H),1.67(s,3H),1.58(s,3H),1.52–1.47(m,2H),1.30(t,J＝7.1Hz,3H),1.19(s,3H).13C NMR(100MHz,CDCl3)δ169.03,157.02,145.96,136.51,131.85,131.40,127.31(2×CH),126.43,124.86,114.80(2×CH),112.02,65.64,61.46,42.64,41.35,25.78,23.42,23.31,17.72,14.25.HRMS(ESI+):calculated for C22H30O3[M+H]+343.2273,found 343.2265.
化合物38的制备
将化合物36(121.8mg，0.356mmol)溶于四氢呋喃(10mL)中，然后加入LiOH(34.1mg，1.42mmol)水溶液(5mL)。将反应混合物在室温下搅拌0.5小时。然后将所得混合物用乙酸酸化，用正丁醇和水萃取两次。合并的有机相在减压下浓缩，得到粗产物37。化合物37未经进一步纯化即直接用于下一步反应。将化合物37溶于无水DMF(8mL)中，然后加入HATU(405.6mg，1.07mmol)，H-Arg-OMe·2HCl(278.6mg，1.07mmol)，HOBt(144.1mg，1.07mmol)，EDC·HCl(204.5mg，1.07mmol)和DIPEA(470.1μL，2.84mmol)。将反应混合物在室温搅拌48小时。反应完成后，将反应混合物用正丁醇和水萃取两次。将有机相在减压条件下浓缩。所得粗产物通过RP-HPLC纯化，获得化合物38，为黄色胶状(122.4mg，71％)。1H NMR(400MHz,CDCl3)δ8.15(s,1H),7.59(d,J＝8.0Hz,1H),7.29(d,J＝8.7Hz,2H),7.07(br,3H),6.86(d,J＝8.7Hz,2H),6.24(d,J＝16.2Hz,1H),6.07(d,J＝16.2Hz,1H),5.86(dd,J＝17.5,10.7Hz,1H),5.09(t,J＝7.1Hz,1H),5.06–4.96(m,2H),4.64–4.42(m,3H),3.72(s,3H),3.20(d,J＝55.2Hz,2H),2.01–1.91(m,6H),1.66(s,3H),1.57(s,3H),1.51–1.45(m,2H),1.18(s,3H).13C NMR(100MHz,CD3OD)δ173.31,171.43,158.65,158.29,147.19,137.37,133.23,132.02,128.28(2×CH),127.71,125.90,115.96(2×CH),112.37,68.17,52.94,52.84,43.59,42.51,41.77,29.49,26.23,25.88,24.34,23.79,17.67.HRMS(ESI+):calculated for C27H40N4O4[M+H]+485.3128,found 485.3125.
化合物39的制备
以36(40.9mg,0.119mmol)，HATU(136mg,0.358mmol)，H-Arg-NH2·2HCl(93.9mg,0.358mmol)，HOBt(48.2mg,0.358mmol)，EDC·HCl(68.4mg,0.358mmol)和DIPEA(157.9μL,0.955mmol)为起始原料，根据合成化合物38的方法，制备得到化合物39，为黄色凝胶(30.6mg,55％)。1H NMR(400MHz,CD3OD)δ7.33(d,J＝8.7Hz,2H),6.94(d,J＝8.8Hz,2H),6.28(d,J＝16.3Hz,1H),6.12(d,J＝16.3Hz,1H),5.91(dd,J＝17.5,10.8Hz,1H),5.16–5.08(m,1H),5.06–4.98(m,2H),4.60–4.56(m,2H),4.52–4.48(m,1H),3.21–3.14(m,2H),1.99–1.72(m,4H),1.66(s,3H),1.63–1.55(m,5H),1.51–1.45(m,2H),1.20(s,3H).13C NMR(100MHz,CD3OD)δ171.14,158.63,158.20,147.19,137.43,133.29,132.03,128.33(2×CH),127.70,125.91,115.93,112.38,101.33,68.22,53.31,43.60,42.51,41.88,30.52,26.13,25.87,24.34,23.80,17.67.HRMS(ESI+):calculated for C26H39N5O3[M+H]+470.3131,found 470.3127.
化合物40的制备
以36(99.6mg,0.291mmol)，HATU(221.2mg,0.582mmol)，H-His-OMe·2HCl(140.8mg,0.582mmol)，HOBt(78.4mg,0.582mmol)，EDC·HCl(111.2mg,0.582mmol)和DIPEA(288μL,1.74mmol)为起始原料，根据合成化合物38的方法，制备得到化合物40，为黄色凝胶(87.4mg,64％)。1H NMR(400MHz,CD3OD)δ7.94(s,1H),7.31(d,J＝8.7Hz,2H),6.98–6.84(m,3H),6.28(d,J＝16.3Hz,1H),6.12(d,J＝16.3Hz,1H),5.91(dd,J＝17.5,10.8Hz,1H),5.15–5.08(m,1H),5.07–4.98(m,2H),4.83–4.79(m,1H),4.54–4.46(m,2H),3.72(s,3H),3.26–3.09(m,2H),2.00–1.92(m,2H),1.66(s,3H),1.57(s,3H),1.51–1.46(m,2H),1.20(s,3H).13C NMR(100MHz,CD3OD)δ171.02,169.03,156.31,145.80,136.84,134.51,132.11,131.46,130.82,127.41(2×CH),126.20,124.78,116.80,114.87(2×CH),112.14,67.23,52.96,51.77,42.66,41.28,28.11,25.83,23.28,23.24,17.76.HRMS((ESI+):calculatedfor C27H35N3O4[M+H]+466.2706,found 466.2698.
化合物41的制备
以36(50mg,0.146mmol)，HATU(111mg,0.292mmol)，H-Lys(Boc)-OMe·HCl(108.3mg,0.365mmol)，HOBt(39.3mg,0.292mmol)，EDC·HCl(55.8mg,0.292mmol)和DIPEA(144.8μL,0.876mmol)为起始原料，根据合成化合物38的方法，制备得到化合物41，为黄色凝胶(72.5mg,82％)。1H NMR(400MHz,CDCl3)δ7.30(d,J＝8.8Hz,2H),7.04(d,J＝8.3Hz,1H),6.87(d,J＝8.8Hz,2H),6.25(d,J＝16.3Hz,1H),6.08(d,J＝16.2Hz,1H),5.86(dd,J＝17.5,10.7Hz,1H),5.13–4.94(m,3H),4.72–4.60(m,1H),4.57–4.44(m,3H),3.73(s,3H),3.10–2.98(m,2H),1.96–1.71(m,4H),1.65(s,3H),1.56(s,3H),1.50–1.43(m,4H),1.41(s,9H),1.31–1.23(m,2H),1.18(s,3H).HRMS(ESI+):calculated for C32H48N2O6[M+Na]+579.3410,found 579.3398.
化合物42的制备
以36(48mg,0.14mmol)，HATU(133.9mg,0.352mmol)，H-Ala-OMe·HCl(59mg,0.423mmol)和DIPEA(186μL,1.13mmol)为起始原料，根据合成化合物44的方法，制备得到粗产物化合物42。反应完成后，将所得混合物用乙酸乙酯稀释并用水萃取两次。将有机相在减压条件下浓缩。粗产物通过硅胶色谱法(石油醚/乙酸乙酯，2：1，v/v)纯化，得到化合物42为无色透明凝胶(45.2mg,81％)。1H NMR(400MHz,CDCl3)δ7.32(d,J＝8.8Hz,2H),7.13(d,J＝7.6Hz,1H),6.88(d,J＝8.8Hz,2H),6.26(d,J＝16.3Hz,1H),6.09(d,J＝16.3Hz,1H),5.87(dd,J＝17.4,10.7Hz,1H),5.15–5.07(m,1H),5.06–4.96(m,2H),4.76–4.63(m,1H),4.49(s,2H),3.76(s,3H),1.99–1.90(m,2H),1.67(s,3H),1.58(s,3H),1.51–1.45(m,5H),1.19(s,3H).13C NMR(100MHz,CDCl3)δ173.07,167.93,156.28,145.85,136.84,132.22,131.47,127.47(2×CH),126.26,124.81,114.87(2×CH),112.12,67.41,52.71,47.70,42.68,41.32,25.82,23.33,23.30,18.48,17.75.HRMS(ESI+):calculated for C24H33NO4[M+H]+400.2488,found 400.2471.
化合物43的制备
以36(79.5mg,0.232mmol)，HATU(176.5mg,0.464mmol)，H-Lys(Fmoc)-OH·HCl(243.1mg,0.58mmol)和DIPEA(230μL,1.39mmol)为起始原料，根据合成化合物44的方法，制备得到化合物43，为无色透明凝胶(155.5mg,98％)。HRMS(ESI+):calculated forC42H50N2O6[M+H]+679.3747,found 679.3727.
化合物44的制备
以36(89.3mg，0.261mmol)，HATU(198.3mg，0.522mmol)，H-Arg-Arg-OMe·2HCl(217.7mg，0.522mmol)和DIPEA(174μL，1.04mmol)为起始原料，根据合成化合物38的方法，制备得到化合物44，为白色胶状固体(166mg,98％)。1H NMR(400MHz,CD3OD)δ7.33(d,J＝8.8Hz,2H),6.93(d,J＝8.8Hz,2H),6.28(d,J＝16.3Hz,1H),6.12(d,J＝16.3Hz,1H),5.91(dd,J＝17.5,10.8Hz,1H),5.15–5.09(m,1H),5.07–4.98(m,2H),4.58(s,2H),4.52–4.44(m,2H),3.73(s,3H),3.25–3.12(m,4H),2.01–1.86(m,4H),1.83–1.62(m,9H),1.57(s,3H),1.52–1.45(m,2H),1.20(s,3H).13C NMR(100MHz,CD3OD)δ173.80,173.51,171.21,158.69,158.24(2×C),147.19,137.46,133.28,132.05,128.33(2×CH),127.68,125.90,115.91(2×CH),112.39,68.08,53.94,53.17,52.90,43.60,42.51,41.93,41.78,30.28,29.49,26.17,26.08,25.87,24.34,23.79,17.67.HRMS(ESI+):calculated for C33H52N8O5[M+H]+641.4139,found 641.4130.
化合物45的制备
以36(54.7mg,0.160mmol)，HATU(121.7mg,0.32mmol)，H-Arg-Arg-Arg-OMe·2HCl(160.2mg,0.32mmol)和DIPEA(158.4μL,0.96mmol)为起始原料，根据合成化合物44的方法，制备得到化合物45，为白色凝胶(118.5mg,93％)。1H NMR(400MHz,CD3OD)δ7.33(d,J＝8.8Hz,2H),6.93(d,J＝8.8Hz,2H),6.28(d,J＝16.3Hz,1H),6.12(d,J＝16.3Hz,1H),5.91(dd,J＝17.5,10.8Hz,1H),5.15–5.09(m,1H),5.06–4.98(m,2H),4.59(s,2H),4.49–4.36(m,3H),3.72(s,3H),3.22–3.16(m,6H),1.98–1.63(m,17H),1.57(s,3H),1.52–1.45(m,2H),1.20(s,3H).13C NMR(100MHz,CD3OD)δ174.00,173.78,173.58,171.42,158.65,158.22(3×C),147.16,137.41,133.20,132.03,128.33,127.66,125.88,115.86(2×CH),112.40,101.32,68.02,54.23,54.12,53.30,52.87,43.59,42.49,41.90,41.85,41.80,30.11,30.06,29.41,26.21,26.15,26.11,25.88,24.33,23.75,17.67.HRMS(ESI+):calculatedfor C39H64N12O6[M+H]+797.5150,found 797.5121.
化合物46的制备
以36(48mg,0.14mmol)，HATU(160.7mg,0.423mmol)，H-Met-OMe·HCl(84.4mg,0.423mmol)和DIPEA(186μL,1.13mmol)为起始原料，根据合成化合物42的方法，制备得到化合物46，为无色透明凝胶(50.4mg,78％)。1H NMR(400MHz,CDCl3)δ7.30(d,J＝8.8Hz,2H),7.23(d,J＝8.2Hz,1H),6.86(d,J＝8.8Hz,2H),6.25(d,J＝16.3Hz,1H),6.08(d,J＝16.2Hz,1H),5.86(dd,J＝17.5,10.7Hz,1H),5.13–5.05(m,1H),5.04–4.97(m,2H),4.84–4.74(m,1H),4.50(s,2H),3.75(s,3H),2.53–2.43(m,2H),2.25–1.89(m,7H),1.66(s,3H),1.56(s,3H),1.51–1.45(m,2H),1.18(s,3H).13C NMR(100MHz,CDCl3)δ172.01,168.32,156.23,145.84,136.89,132.28,131.47,127.49(2×CH),126.23,124.80,114.83(2×CH),112.13,67.39,52.78,51.12,42.68,41.32,31.54,29.95,25.82,23.33,23.30,17.75,15.54.HRMS(ESI+):calculated for C26H37NO4S[M+H]+460.2522,found 460.2507.
化合物47的制备
将43(76mg，0.112mmol)溶于无水DMF(4mL)中，然后加入哌啶(1mL)，将反应混合物在室温下搅拌0.5h。反应完成后，将所得混合物用正丁醇稀释并用水萃取两次。将有机相在减压条件下浓缩。粗产物通过RP-HPLC纯化，得到化合物47为黄色凝胶(38.2mg,75％)。1HNMR(400MHz,CDCl3)δ7.32(dd,J＝19.6,8.5Hz,3H),6.86(d,J＝8.7Hz,2H),6.24(d,J＝16.2Hz,1H),6.08(d,J＝16.2Hz,1H),5.86(dd,J＝17.4,10.8Hz,1H),5.09(t,J＝7.1Hz,1H),5.06–4.97(m,2H),4.70–4.59(m,1H),4.57–4.40(m,2H),3.77–3.67(m,3H),2.88(s,2H),1.98–1.62(m,9H),1.57(s,3H),1.52–1.34(m,4H),1.18(s,3H).13C NMR(100MHz,CDCl3)δ172.28,168.63,156.25,145.82,136.86,132.22,131.46,127.46(2×CH),126.23,124.79,114.94(2×CH),112.13,67.32,52.76,51.48,42.67,41.30,39.19,31.97,27.08,25.83(2×CH2),23.29,22.46,17.76.HRMS(ESI+):calculated for C27H40N2O4[M+H]+457.3066,found 457.3050.
化合物49的制备
以38(43.2mg,0.092mmol)，HATU(69.9mg,0.184mmol)，H-Arg-NH2·2HCl(45.2mg,0.184mmol)，HOBt(24.8mg,0.184mmol)，EDC·HCl(35.2mg,0.184mmol)和DIPEA(91.9μL,0.551mmol)为起始原料，根据合成化合物38的方法，制备得到化合物49，为黄色凝胶(26.6mg,47％)。1H NMR(400MHz,CD3OD)δ7.33(d,J＝8.8Hz,2H),6.93(d,J＝8.8Hz,2H),6.28(d,J＝16.3Hz,1H),6.12(d,J＝16.3Hz,1H),5.91(dd,J＝17.5,10.8Hz,1H),5.15–5.09(m,1H),5.06–4.99(m,2H),4.58(s,2H),4.50–4.45(m,1H),4.42–4.36(m,1H),3.21–3.15(m,4H),2.01–1.74(m,6H),1.69–1.61(m,7H),1.57(s,3H),1.52–1.45(m,2H),1.20(s,3H).13C NMR(100MHz,CD3OD)δ176.28,173.66,171.35,158.70,158.25(2×C),147.18,137.44,133.25,132.04,128.33(2×CH),127.68,125.90,115.92(2×CH),112.39,68.11,54.06,53.89,43.60,42.51,41.88,41.86,30.36,30.10,26.23,26.03,25.87,24.34,23.80,17.67.HRMS(ESI+):calculated for C32H51N9O4[M+H]+626.4142,found 626.4135.
化合物50的制备
以38(93mg,0.192mmol)，HATU(218.9mg,0.576mmol)，H-His-OMe·2HCl(139.4mg,0.576mmol)，HOBt(77.6mg,0.576mmol)，EDC·HCl(110.1mg,0.576mmol)和DIPEA(190.3μL,1.15mmol)为起始原料，根据合成化合物49的方法，制备得到化合物50，为黄色凝胶(60.6mg,51％)。1H NMR(400MHz,CD3OD)δ7.72(s,1H),7.33(d,J＝8.8Hz,2H),6.93(d,J＝8.7Hz,3H),6.28(d,J＝16.3Hz,1H),6.12(d,J＝16.3Hz,1H),5.91(dd,J＝17.5,10.8Hz,1H),5.15–5.09(m,1H),5.06–4.99(m,2H),4.73–4.67(m,1H),4.56(s,2H),4.53–4.48(m,1H),3.71(s,3H),3.20–3.02(m,4H),2.01–1.70(m,4H),1.66(s,3H),1.63–1.56(m,5H),1.51–1.46(m,2H),1.20(s,3H).13C NMR(100MHz,CD3OD)δ173.51,172.65,171.12,168.75,158.60,158.20,158.17,147.16,137.36,135.88,133.19,133.01,132.04,128.33,127.66,125.88,118.33,115.88,112.40,68.06,53.68,53.02,43.60,42.49,41.83,38.88,30.22,28.99,26.02,25.90,24.33,23.73,17.68.HRMS(ESI+):calculated for C33H47N7O5[M+H]+622.3717,found 622.3692.
化合物65和51的制备
将化合物38(63.7mg,0.131mmol)溶于无水DMF(8mL)中，然后加入HATU(124.9mg,0.329mmol)，H-Lys(Fmoc)-OH·HCl(137.7mg,0.329mmol)，和DIPEA(130μL,0.789mmol)。根据合成化合物43的方法，制备得到化合物65。反应完成后，将反应混合物用正丁醇和水萃取两次。将有机相在减压条件下浓缩。化合物65未经进一步纯化即用于下一步反应。随后，将粗产物65溶于无水DMF(4mL)中，加入哌啶(1mL)，根据合成47的方法，制备得到51，为橙色凝胶(44.5mg,55％)。1H NMR(400MHz,CD3OD)δ7.33(d,J＝8.8Hz,2H),6.93(d,J＝8.8Hz,2H),6.28(d,J＝16.3Hz,1H),6.12(d,J＝16.3Hz,1H),5.91(dd,J＝17.5,10.8Hz,1H),5.14–5.09(m,1H),5.07–5.00(m,2H),4.58(s,2H),4.50–4.42(m,2H),3.72(s,3H),3.25–3.17(m,2H),2.92–2.82(m,2H),2.01–1.89(m,4H),1.78–1.62(m,9H),1.57(s,3H),1.52–1.45(m,4H),1.20(s,3H).13C NMR(100MHz,CD3OD)δ173.89,173.75,171.25,158.66,158.24(2×C),147.17,137.38,133.18,132.04,128.34(2×CH),127.66,125.88,115.87(2×CH),112.40,67.97,54.04,53.17,52.86,43.60,42.50,41.87,40.40,31.67,30.19,27.78,26.08,25.90,24.34,23.73,23.69,17.68.HRMS(ESI+):calculated for C33H52N6O5[M+H]+613.4077,found 613.4056.
化合物52的制备
以38(40mg,0.083mmol)，HATU(62.8mg,0.165mmol)，N,N-二乙基-1,3-丙二胺(78.1μL,0.495mmol)和DIPEA(68.2μL,0.413mmol)为起始原料，根据合成化合物38的方法，制备得到化合物52，为黄色凝胶(43.2mg,89％)。1H NMR(400MHz,CDCl3)δ7.29(d,J＝8.5Hz,2H),6.90(d,J＝8.4Hz,2H),6.25(d,J＝16.3Hz,1H),6.09(d,J＝16.3Hz,1H),5.87(dd,J＝17.5,10.8Hz,1H),5.08(t,J＝7.2Hz,1H),5.02–4.95(m,2H),4.56(s,2H),4.32–4.26(m,1H),3.28–3.26(m,2H),3.17–3.02(m,8H),1.97–1.69(m,6H),1.68–1.55(m,5H),1.54(s,3H),1.48–1.42(m,2H),1.23(t,J＝7.3Hz,6H),1.16(s,3H).13C NMR(100MHz,CDCl3)δ172.59(2×C),156.81,156.48,145.79,136.69,131.87,131.42,127.40,126.23,124.78,114.94,114.91,112.10,100.00,60.53,58.51,58.44,50.85(2×CH2),46.34,42.63(2×CH2),41.27,25.81(2×CH2),23.28,23.21,21.18,17.75,14.29,8.43(2×CH3).HRMS(ESI+):calculated for C33H54N6O3[M+H]+583.4336,found 583.4327.
化合物53的制备
以38(48mg,0.101mmol)，HATU(115.3mg,0.303mmol)，(S)-N-((3-(3-氟-4-哌嗪-1-基苯基)-2-氧代噁唑烷-5-基)甲基)-乙酰胺(85.0mg,0.253mmol)，HOBt(46.4mg,0.303mmol)，EDC·HCl(58.3mg,0.303mmol)和DIPEA(133.7μL,0.809mmol)为起始原料，根据合成化合物38的方法，制备得到化合物53，为黄色凝胶(32.4mg,41％)。1H NMR(400MHz,CD3OD)δ7.50(dd,J＝14.5,2.5Hz,1H),7.32(d,J＝8.7Hz,2H),7.17(d,J＝8.7Hz,1H),7.03(t,J＝9.1Hz,1H),6.94(d,J＝8.8Hz,2H),6.27(d,J＝16.3Hz,1H),6.11(d,J＝16.3Hz,1H),5.89(dd,J＝17.5,10.8Hz,1H),5.14–5.09(m,1H),5.05–4.97(m,3H),4.83–4.74(m,2H),4.61–4.56(m,2H),4.11(t,J＝9.0Hz,1H),3.92–3.75(m,3H),3.73–3.61(m,2H),3.55(d,J＝5.0Hz,2H),3.28–3.14(m,2H),3.10–2.93(m,4H),1.99–1.74(m,7H),1.67–1.60(m,5H),1.57(s,3H),1.50–1.45(m,2H),1.19(s,3H).13C NMR(100MHz,CD3OD)δ174.06,171.20,170.77,158.61,158.17,158.03,156.56,155.59,147.17,137.45,137.00,135.38,133.30,132.03,128.35,127.66,125.90,120.85,115.97,115.49,112.40,108.55,108.29,73.46,68.16,49.85,48.34(2×CH2),46.95,43.59(2×CH2),43.52,43.14,42.49,41.96,30.28,25.89(2×CH3),24.34,23.78,22.46,17.69.
化合物55的制备
以40(66.4mg,0.143mmol)，HATU(108.5mg,0.285mmol)，H-His-OMe·2HCl(86.3mg,0.357mmol)，HOBt(38.4mg,0.285mmol)，EDC·HCl(54.5mg,0.285mmol)和DIPEA(141.4μL,0.856mmol)为起始原料，根据合成化合物40的方法，制备得到化合物55，为黄色凝胶(41.2mg,48％)。1H NMR(400MHz,CD3OD)δ8.28(d,J＝9.4Hz,2H),8.11(d,J＝40.2Hz,2H),7.28(d,J＝8.8Hz,2H),7.07(d,J＝25.4Hz,2H),6.85(d,J＝8.7Hz,2H),6.17(dd,J＝64.9,16.3Hz,2H),5.88(dd,J＝17.5,10.8Hz,1H),5.12–4.94(m,4H),4.74–4.64(m,2H),4.55–4.41(m,2H),3.70(s,3H),3.19–3.06(m,2H),2.78(s,2H),1.98–1.89(m,2H),1.63(s,3H),1.54(s,3H),1.49–1.41(m,2H),1.17(s,3H).13C NMR(100MHz,CD3OD)δ172.47,172.35,171.08,158.18,147.18,137.45,135.76,135.63,133.24,132.74,132.03,132.00,128.31,127.68,125.90,118.32,118.16,115.90,115.87,112.38,97.37,68.14,53.66,53.09,43.60,42.50,38.88,29.25,28.52,25.87,24.34,23.78,17.67.HRMS(ESI+):calculatedfor C33H42N6O5[M+H]+603.3295,found 603.3278.
化合物66和56的制备
以40(89.9mg,0.193mmol)，HATU(220.1mg,0.597mmol)，H-Lys(Fmoc)-OH·HCl(242.7mg,0.597mmol)和DIPEA(255μL,1.54mmol)为起始原料，根据合成化合物51的方法，制备得到化合物56，为黄色凝胶(39.5mg,35％)。1H NMR(400MHz,CD3OD)δ7.82(s,1H),7.31(d,J＝8.7Hz,2H),6.98(s,1H),6.88(d,J＝8.8Hz,2H),6.28(d,J＝16.3Hz,1H),6.12(d,J＝16.3Hz,1H),5.91(dd,J＝17.5,10.8Hz,1H),5.15–5.09(m,1H),5.08–5.02(m,2H),4.70–4.63(m,1H),4.55–4.43(m,3H),3.74–3.69(m,3H),3.19–3.03(m,2H),2.91–2.83(m,2H),1.98–1.92(m,2H),1.77–1.55(m,10H),1.52–1.42(m,4H),1.20(s,3H).13C NMR(100MHz,CD3OD)δ173.64,173.24,171.21,158.21,147.17,137.35,136.19,133.14,132.04,128.31(2×CH),127.69,125.88,117.97,115.86(2×CH),112.40,101.32,67.99,54.49,53.11,52.86,43.60,42.50,40.41,31.79,29.93,27.77,25.90,24.34,23.74,23.57,17.69.HRMS((ESI+):calculated for C33H47N5O5[M+H]+594.3655,found 594.3637.
化合物58的制备
以44(74.7mg,0.119mmol)，HATU(135.9mg,0.358mmol)，H-Arg-NH2·2HCl(93.7mg,0.358mmol)，HOBt(47.6mg,0.358mmol)，EDC·HCl(68.5mg,0.358mmol)和DIPEA(157.6μL,0.953mmol)为起始原料，根据合成化合物38的方法，制备得到化合物58，为黄色凝胶(66.6mg,70％)。1H NMR(400MHz,CD3OD)δ7.33(d,J＝8.7Hz,2H),6.93(d,J＝8.7Hz,2H),6.28(d,J＝16.3Hz,1H),6.12(d,J＝16.3Hz,1H),5.91(dd,J＝17.4,10.8Hz,1H),5.12(t,J＝7.2Hz,1H),5.07–4.92(m,3H),4.59(s,2H),4.49–4.32(m,3H),3.22–3.15(m,6H),2.00–1.73(m,8H),1.66(s,9H),1.57(s,3H),1.51–1.46(m,2H),1.20(s,3H).13C NMR(100MHz,CD3OD)δ176.33,173.84,171.47,169.92,158.69,158.24(3×C),147.17,137.43,133.22,132.04,128.33,127.67,125.89,115.89(2×CH),112.40,101.33,68.08,54.48,54.25,53.93,43.60(3×CH2),42.50,41.84,30.42,30.07,29.87,26.24,26.14,25.88,24.34(2×CH2),23.77,17.68.HRMS(ESI+):calculated for C38H63N13O5[M+H]+782.5153,found 782.5142.
化合物59的制备
以44(38.9mg,0.061mmol)，HATU(69.3mg,0.182mmol)，(S)-N-((3-(3-氟-4-哌嗪-1-基苯基)-2-氧代噁唑烷-5-基)甲基)-乙酰胺(40.9mg,0.122mmol)，HOBt(27.9mg,0.182mmol)，EDC·HCl(35.7mg,0.182mmol)和DIPEA(80.3μL,0.486mmol)为起始原料，根据合成化合物38的方法，制备得到化合物59，为黄色凝胶(23.2mg,41％)。1H NMR(400MHz,CD3OD)δ7.51(d,J＝14.6Hz,1H),7.33(d,J＝8.6Hz,2H),7.18(d,J＝8.9Hz,1H),7.09–7.01(m,1H),6.93(d,J＝6.6Hz,2H),6.28(d,J＝16.4Hz,1H),6.13(d,J＝16.3Hz,1H),5.97–5.82(m,1H),5.16–5.09(m,1H),5.08–4.95(m,3H),4.79–4.46(m,3H),4.11(t,J＝9.2Hz,1H),3.88–3.50(m,6H),3.30–2.84(m,10H),2.05–1.72(m,8H),1.72–1.53(m,11H),1.51–1.43(m,2H),1.20(s,3H).13C NMR(100MHz,CD3OD)δ174.10,173.42,171.61,171.26,169.98,158.68,158.25,158.24,156.61,147.17(2×CH),137.43,137.04,134.99,133.22,132.05,128.34(2×CH),127.67,125.89(2×CH),115.89(2×CH),113.39,112.40,73.50,53.95,50.16,49.71,48.34(2×CH2),48.33(2×CH2),48.32,43.60,43.13,42.50,41.91,41.84,30.22,29.92,25.96,25.88(2×CH2),24.34,23.78,22.44,17.68.HRMS(ESI+):calculated for C48H69FN12O7[M+H]+945.5474,found 945.5457.
化合物60的制备
以44(52.6mg,0.084mmol)，HATU(63.8mg,0.168mmol)，H-Arg-Arg-OMe·2HCl(70.1mg,0.168mmol)和DIPEA(55.5μL,0.336mmol)为起始原料，根据合成化合物44的方法，制备得到化合物60，为白色泡沫状物(43.3mg,55％)。1H NMR(400MHz,CD3OD)δ7.32(d,J＝8.7Hz,2H),6.93(d,J＝8.7Hz,2H),6.28(d,J＝16.3Hz,1H),6.12(d,J＝16.3Hz,1H),5.91(dd,J＝17.5,10.8Hz,1H),5.12(t,J＝7.2Hz,1H),5.06–4.98(m,2H),4.60(s,2H),4.45–4.34(m,4H),3.72(s,3H),3.23–3.15(m,8H),1.99–1.86(m,6H),1.83–1.70(m,6H),1.69–1.61(m,9H),1.57(s,3H),1.51–1.46(m,2H),1.20(s,3H).13C NMR(100MHz,CD3OD)δ174.08,173.97,173.86,173.59,171.51,158.68(2×C),158.67(2×C),158.22,147.15,137.40,133.19,132.03,128.32(2×CH),127.65,125.88,115.87(2×CH),112.39,68.04,54.39,54.28,54.25,53.36,52.88,43.59(2×CH2),42.48,41.92,41.85,41.80,30.16,29.98,29.89,29.40,26.28,26.17,26.15,26.13,25.88,24.33,23.74,17.67.HRMS(ESI+):calculated for C45H76N16O7[M+2H]2+477.3120,found 477.3114.
化合物61的制备
以44(67.2mg,0.107mmol)，HATU(101.9mg,0.268mmol)，H-Arg-Arg-NH2·2HCl(107.8mg,0.268mmol)和DIPEA(141.8μL,0.858mmol)为起始原料，根据合成化合物60的方法，制备得到化合物61，为黄色凝胶(56.8mg,57％)。1H NMR(400MHz,CD3OD)δ7.33(d,J＝8.8Hz,2H),6.93(d,J＝8.8Hz,2H),6.28(d,J＝16.3Hz,1H),6.12(d,J＝16.3Hz,1H),5.91(dd,J＝17.5,10.8Hz,1H),5.15–5.09(m,1H),5.06–4.99(m,2H),4.60(s,2H),4.47–4.41(m,1H),4.38–4.31(m,3H),3.22–3.16(m,8H),2.00–1.85(m,6H),1.82–1.72(m,4H),1.70–1.62(m,11H),1.57(s,3H),1.51–1.46(m,2H),1.20(s,3H).13C NMR(100MHz,CD3OD)δ176.35,174.12,174.09,173.89,171.56,169.99,158.69(4×C),158.24,147.16,137.45,133.23,132.04,128.33(2×CH),127.66,125.89,115.88(2×CH),112.40,68.08,54.57,54.50,54.39,54.00,43.60(3×CH2),42.50,41.89,41.84,30.41,29.99,29.96,29.85,26.31,26.23,26.18,26.12,25.88,24.34,23.76,17.67.HRMS(ESI+):calculated forC44H75N17O6[M+2H]2+469.8122,found 469.8108.
化合物63的制备
以45(47mg,0.059mmol)，HATU(67.3mg,0.177mmol)，(S)-N-((3-(3-氟-4-哌嗪-1-基苯基)-2-氧代噁唑烷-5-基)甲基)-乙酰胺(49.6mg,0.147mmol)，HOBt(27.1mg,0.177mmol)，EDC·HCl(33.8mg,0.177mmol)和DIPEA(78μL,0.472mmol)为起始原料，根据合成化合物38的方法，制备得到化合物63，为黄色凝胶(18.5mg,28％)。1H NMR(400MHz,CD3OD)δ7.53–7.43(m,1H),7.30(d,J＝8.8Hz,2H),7.15(d,J＝8.2Hz,1H),7.03(t,J＝9.1Hz,1H),6.90(d,J＝8.7Hz,2H),6.25(d,J＝16.3Hz,1H),6.09(d,J＝16.3Hz,1H),5.88(dd,J＝17.5,10.8Hz,1H),5.09(t,J＝7.2Hz,1H),5.03–4.96(m,2H),4.82–4.70(m,2H),4.61–4.53(m,2H),4.47–4.34(m,2H),4.12–4.02(m,1H),3.84–3.64(m,4H),3.55–3.48(m,2H),3.25–3.12(m,6H),3.10–2.82(m,5H),1.97–1.57(m,20H),1.54(s,3H),1.49–1.42(m,2H),1.17(s,3H).13C NMR(100MHz,CD3OD)δ174.08,173.86,173.56,171.62,171.40,170.11,158.71,158.23,158.22,156.60,155.61,147.15,137.45,133.21,132.04,128.33,127.65,125.88,120.91,115.93,115.91,115.57,115.53,112.41,108.60,108.34,101.31,73.47,68.09,54.34,54.14,52.48,52.21,51.13,51.10,50.16(2×CH2),43.59(2×CH2),43.13,42.48,41.93,41.84,30.12,30.02,29.96,26.19,26.13,25.98,25.88,24.33,23.77,22.46,17.68.
化合物64的制备
以45(53.9mg,0.068mmol)，HATU(51.4mg,0.135mmol)，H-Arg-Arg-Arg-OMe·2HCl(67.7mg,0.135mmol)和DIPEA(67.1μL,0.407mmol)为起始原料，根据合成化合物60的方法，制备得到化合物64，为黄色凝胶(12.9mg,16％)。1H NMR(400MHz,CD3OD)δ7.30(d,J＝8.7Hz,2H),6.90(d,J＝8.7Hz,2H),6.26(d,J＝16.3Hz,1H),6.10(d,J＝16.3Hz,1H),5.88(dd,J＝17.5,10.8Hz,1H),5.13–5.06(m,1H),5.05–4.95(m,2H),4.58(s,2H),4.42–4.29(m,6H),3.69(s,3H),3.21–3.14(m,12H),1.96–1.82(m,8H),1.80–1.60(m,21H),1.55(s,3H),1.49–1.42(m,2H),1.17(s,3H).13C NMR(100MHz,CD3OD)δ174.26,174.14,173.97,173.60,173.01,171.69,170.23,158.67(6×C),158.22,147.14,137.39,133.16,132.05,128.35,128.33,127.64,125.87,115.84(2×CH),112.42,68.01,61.55(5×CH),53.40,52.89,43.60(5×CH2),42.48,41.88,41.80,30.17,30.00,29.88,29.68,29.38,26.29,26.18,25.90(4×CH2),24.33,23.71,20.88,17.68,14.47.HRMS(ESI+):calculated forC57H100N24O9[M+2H]2+633.4131,found 633.4116.
生物实验评估方法
抗菌活性测定。根据临床和实验室标准协会(CLSI)指南规定的肉汤稀释法测定所有化合物的抗菌活性。将细菌细胞接种到Mueller-Hinton琼脂(MHA)平板上培养过夜，并用PBS将细菌细胞浓度调整为大约1×106CFU/mL。将样品首先溶解在DMSO/H2O中制备浓度为1000μg/mL(DMSO的最终浓度≤2％)的储备液，然后用Mueller-Hinton Broth(MHB)将储备液稀释至初始浓度100μg/mL，并用MHB将样品溶液(100μL)于96孔板中进行两倍梯度稀释，以获得100μg/mL至0.78μg/mL的浓度。接着在96孔板的每个孔中加入细菌悬浮液(100μL)与测试样品溶液(100μL)混合。其中化合物38、44-45、58-61和63-64的测试体系中含0.05％吐温80。最后将96孔板在37℃下孵育24小时，测试其于0和24h在600nm处的吸光度，将MIC值定义为未见细菌生长发生的最低浓度。所有实验至少进行两次，并可实现生物学重复。
溶血活性测定。将兔红细胞以2500rpm离心3分钟，然后用PBS洗涤两次。随后用PBS重悬兔红细胞制备8％(v/v)的细胞悬浮液。首先将样品溶解在DMSO或PBS中(DMSO的终浓度≤0.5％)，然后用PBS稀释以制备两倍梯度稀释液(400μg/mL至3.125μg/mL)。将兔红细胞悬浮液(100μL)与样品的两倍梯度稀释液(100μL)混合加入无菌96孔板后于37℃下孵育1小时，然后以2500rpm离心5分钟。其中化合物38、44-45、58-61和63-64的测试体系中含0.05％吐温80。将上清液(100μL)转移至新的96孔板中，使用Biotek多功能酶标仪测定576nm处的吸光度，阳性对照组经2％Triton X-100溶液处理，阴性对照组用PBS或含0.5％DMSO处理。通过以下等式计算溶血活性：％溶血活性＝[(Abs样品–Abs阴性对照)/(Abs阳性对照–Abs阴性对照)]×100。所有实验至少进行两次，并可实现生物学重复。
对哺乳动物细胞的毒性测定。通过CCK-8法评估待测化合物对小鼠成纤维细胞NCTC clone 929，小鼠角膜细胞CM120和人肝癌细胞Hep-G2的细胞毒性。按CCK-8试剂盒(碧云天，中国)说明书所述的细胞量接种至96孔板，在5％CO2气氛下于37℃培养24h。然后向每孔加入特定浓度的待测样品，于37℃培养箱继续孵育24h。最后向每孔加入终浓度为10％的CCK-8溶液，并于培养箱继续孵育1.0h后用酶标仪测定溶液在450nm处的吸光度(OD450)。根据公式(2)计算可获得待测样品的细胞毒性：
Figure BDA0002741634000000321
A加样：具有细胞、CCK8溶液和待测样品溶液的孔的吸光度；
A空白：具有培养基和CCK8溶液而没有细胞的孔的吸光度；
A未加样：具有细胞、CCK8溶液而没有待测样品溶液的孔的吸光度。
耐药性发展倾向评估。通过上述MIC测定方法获得化合物60，诺氟沙星和加替沙星对金黄色葡萄球菌ATCC29213的初始MIC值。取出浓度为0.5×MIC的96孔板中的细菌细胞，以制备细菌悬液(约1×106CFU/mL)，用于下一次的MIC值测定。将样品在37℃下孵育24小时后，测量每种化合物的MIC值变化。该实验连续进行15天。
体内功效评估。动物体内抗菌功效评估实验已获得华南农业大学实验动物中心的批准，并按照中国卫生部的政策进行。细菌性角膜炎模型使用雌性C57BL6小鼠(6-8周，平均体重20g)。为了建立免疫抑制的小鼠模型，在感染前5天向小鼠腹膜内注射环磷酰胺(100mg/kg)3次。将接种在Mueller Hinton琼脂(MHA)平板上的细菌细胞(金黄色葡萄球菌ATCC 29213)用PBS悬浮，并将细菌细胞浓度调整为约5×107CFU/mL用于小鼠角膜感染。首先将小鼠麻醉，然后用无菌针头对小鼠左眼的角膜进行划痕，并将15μL细菌悬液滴到受损的角膜上。感染一天后将小鼠随机分为三组(每组5只)，每天分别局部使用3种化合物(0.5％60、5％葡萄糖溶液，5％万古霉素)四次，连续使用3天。最后将小鼠安乐死，收集小鼠角膜，并通过MHA平板计数法对活菌进行计数。使用SPSS 22.0软件计算P值，并认为P≤0.05具有统计显著性。
腹腔感染模型使用CD-1小鼠(6-8周，平均体重25g)，首先对小鼠腹腔注射金黄色葡萄球菌ATCC29213(OD600≈1.0)，将小鼠随机分为三组(每组5只)，感染1小时后使用58(5mg/kg)进行静脉注射给药治疗，间隔4小时再给药一次，同时用万古霉素(20mg/kg，IP)做阳性对照组和0.9％氯化钠注射液为空白对照组，治疗两天后，考察小鼠生存率。
实验结果
补骨脂酚衍生物的体外抗菌活性结果如表1和2所示。
其中化合物5、6、9、11-16、23-35、38、39、44、45、49、51-53和58-64对革兰氏阳性菌表现出非常优异的抗菌活性，最低抑菌浓度(MIC)为0.39-3.125μg/mL；化合物23、24、26-30、44、59和63呈现出广谱的抗菌活性，对革兰氏阴性菌也表现出非常优异的抗菌活性，MIC值为1.56-3.125μg/mL。
表1.补骨脂酚衍生物5-29的体外抗菌活性(μg/mL)
Figure BDA0002741634000000322
Figure BDA0002741634000000331
表2.补骨脂酚衍生物30-64的体外抗菌活性(μg/mL)
Figure BDA0002741634000000332
体外细胞毒性和溶血活性研究结果
活性化合物44和60在100μg/mL的浓度下对小鼠角膜细胞未显示出明显的细胞毒性，仍然保持大于90％的细胞存活率。活性化合物58和60在100μg/mL的浓度下对小鼠成纤维细胞NCTC clone 929未显示出明显的细胞毒性，仍然保持89.3±0.6％和93.7±0.7％的细胞存活率。
活性化合物45、53、58、60、61、64、63的溶血毒性非常低，HC50数值(裂解50％兔红细胞所需化合物的浓度)都大于400μg/mL。活性化合物28的溶血毒性也比较低，HC50数值为112.9±5.0μg/mL。以上结果表明这些补骨脂酚类化合物具备较高的安全性。
耐药性研究结果
克服细菌耐药性的产生已成为评估新型抗菌化合物的最重要指标之一。如图1所示，经过15天连续传代后，化合物60的MIC值未发生明显变化。而诺氟沙星则产生了明显的耐药性，经过15天连续传代后MIC值增加了16倍。这些结果表明，化合物60可有效克服细菌耐药性的产生。
体内抗菌活性评估结果
化合物58和60表现出优异的体外抗革兰氏阳性菌活性，非常低的溶血活性和细胞毒性。在金黄色葡萄球菌ATCC29213导致的小鼠细菌性角膜炎模型中，如图2所示，局部使用的0.5％化合物60和5％万古霉素使感染小鼠角膜中的细菌数量分别减少4.48log(p＜0.01)和4.16log(p＜0.01)。在金黄色葡萄球菌ATCC29213导致的小鼠细菌性腹腔炎模型中，经过两天的治疗后，阴性对照组5只小鼠全部死亡，而化合物58治疗组和万古霉素阳性对照组5只小鼠全部存活，存活率都为100％。化合物58和60都表现出优异的体内抗菌功效，可与万古霉素相互比拟。这些结果表明，化合物58和60能够治愈由金黄色葡萄球菌引起的细菌感染。
可以看出，化合物60在金黄色葡萄球菌ATCC29213导致的小鼠角膜感染模型(局部给药)中表现出优异的抗菌效果，58在小鼠体内表现出优异的药代动力学特性，且在小鼠腹腔感染模型(分别通过皮下，腹腔和静脉注射给药)中表现出优异的抗菌功效。这类基于新分子实体和新型抗菌机制的补骨脂酚衍生物能够有效对抗耐药性细菌感染，为当前抗生素耐药性危机的解决提供一种新方案。
以上所述实施例的各技术特征可以进行任意的组合，为使描述简洁，未对上述实施例中的各个技术特征所有可能的组合都进行描述，然而，只要这些技术特征的组合不存在矛盾，都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。

Claims (10)

1.一种补骨脂酚衍生物及其药学上可接受的盐，其特征在于，选自以下任一通式所示的化合物：
Figure 470855DEST_PATH_IMAGE001
；
X2为NR22R23或
Figure 318725DEST_PATH_IMAGE002
；X3为NR32R33、OR35或
Figure 837431DEST_PATH_IMAGE003
；X4 为OR45或
Figure 796160DEST_PATH_IMAGE004
；
其中，
R22和R23各自独立地选自：-H；
R32和R33各自独立地选自：-H；
其中，R14、R24、R34和R44各自独立选自：胍基、-NR4R5或5-20元含氮杂芳基；R4和R5各自独立地选自-H；
R26、R35、R36和R45和R46各自独立地选自：C1-6烷基；
R28、R38和R48各自独立地选自：-H或卤素；
n1、n2、n3和n4各自独立地为0、1、2、3或4；
n为1-10的整数。
2.根据权利要求1所述补骨脂酚衍生物及其药学上可接受的盐，其特征在于，选自以下任一通式所示的化合物：
Figure 451132DEST_PATH_IMAGE005
其中，
R14、R24、R34和R44各自独立选自：胍基、-NR4R5或5-20元含氮杂芳基；R4和R5各自独立地选自-H；
R26、R36和R46各自独立地选自：C1-6烷基；
R28、R38和R48各自独立地选自：-H或卤素；
n1、n2、n3和n4各自独立地为0、1、2、3或4；
n为1-10的整数。
3.根据权利要求1所述补骨脂酚衍生物及其药学上可接受的盐，其特征在于，选自以下任一通式所示的化合物：
Figure 469904DEST_PATH_IMAGE006
；
X3为OR35；X4为OR45；
其中，
R14、R24、R34和R44各自独立选自：胍基、-NR4R5或5-20元含氮杂芳基；R4和R5各自独立地选自-H；
R35和R45各自独立地选自：C1-6烷基；
n1、n2、n3和n4各自独立地为0、1、2、3或4；
n为1-10的整数。
4.根据权利要求1所述补骨脂酚衍生物及其药学上可接受的盐，其特征在于，选自以下任一通式所示的化合物：
Figure 351272DEST_PATH_IMAGE007
；
X2为NR22R23；X3为NR32R33；
其中，
R22和R23各自独立地选自：-H；
R32和R33各自独立地选自：-H；
R14、R24和R34各自独立选自：胍基、-NR4R5或5-20元含氮杂芳基；R4和R5各自独立地选自-H；
n1、n2、n3和n4各自独立地为0、1、2、3或4；
n为1-10的整数。
5.根据权利要求1所述的补骨脂酚衍生物及其药学上可接受的盐，其特征在于，R14、R24、R34和R44各自独立选自：胍基、-NR4R5、5元含氮杂芳基。
6.根据权利要求1所述的补骨脂酚衍生物及其药学上可接受的盐，其特征在于，选自以下通式所述的化合物：
Figure 238325DEST_PATH_IMAGE008
（
Figure 888750DEST_PATH_IMAGE009
'）；
X为NR12R13；
R12和R13中有一个为H，一个选自
Figure 812843DEST_PATH_IMAGE010
。
7.根据权利要求1所述补骨脂酚衍生物及其药学上可接受的盐，其特征在于，选自以下化合物：
Figure 819325DEST_PATH_IMAGE011
。
8.权利要求1-7中任一项所述的补骨脂酚衍生物及其药学上可接受的盐的制备方法，其特征在于，所述制备方法包括以下步骤：
Figure 119856DEST_PATH_IMAGE012
将式（
Figure 155945DEST_PATH_IMAGE009
-1）所示化合物进行水解反应，制得式（
Figure 375574DEST_PATH_IMAGE009
-2）所示化合物；
将式（
Figure 231535DEST_PATH_IMAGE009
-2）所示化合物与
Figure 335757DEST_PATH_IMAGE013
或
Figure 85407DEST_PATH_IMAGE014
进行缩合反应，制 得式（
Figure 351303DEST_PATH_IMAGE015
）所示化合物；
R15的定义同权利要求1所述R35。
9.一种药物组合物，其特征在于，包括权利要求1-7中任一项所述的补骨脂酚衍生物及其药学上可接受的盐中的至少一种，及药学上可接受的辅料。
10.权利要求1-7中任一项所述的补骨脂酚衍生物及其药学上可接受的盐、或权利要求9所述的药物组合物在制备抗菌药物中的应用。
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