CN116120297A - 1,3-双环氧丙基-5-取代环状三聚脲类化合物及其作为铁死亡诱导剂的用途 - Google Patents
1,3-双环氧丙基-5-取代环状三聚脲类化合物及其作为铁死亡诱导剂的用途 Download PDFInfo
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- CN116120297A CN116120297A CN202310040324.7A CN202310040324A CN116120297A CN 116120297 A CN116120297 A CN 116120297A CN 202310040324 A CN202310040324 A CN 202310040324A CN 116120297 A CN116120297 A CN 116120297A
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- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
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Abstract
本发明涉及一类含有1,3‑双环氧丙基‑5‑取代环状三聚脲结构的小分子，结构如式I所示，该类化合物具有诱导异常增生细胞发生铁死亡，和/或增加这类细胞对其它细胞毒性药物治疗、放射治疗等的敏感性的作用。为治疗过渡性增生疾病例如恶性肿瘤、血管内皮异常增生所致心血管疾病提供了方向。
式I。
Description
技术领域
本发明属于医药技术领域，具体地说，本发明涉及一类含有1,3-双环氧丙基-5-取代环状三聚脲结构的小分子，所述小分子在肿瘤细胞及血管平滑肌细胞等增殖能力强的细胞内充当铁死亡诱导剂；以及它们用作治疗恶性肿瘤、血管内皮异常增生所致心血管疾病及其它疾病的治疗药物的用途。
背景技术
铁死亡是一种新型铁依赖的细胞程序性死亡(RCD)方式，以铁及过氧化脂质积累为特征。已发现包括弥漫性大B细胞淋巴瘤(DLBCL)、肾细胞癌(RCC)、胰腺癌、乳腺癌、非小细胞肺癌(NSCLC)和黑色素瘤在内的许多癌症对铁死亡敏感。另有研究表明，铁死亡也广泛参与心血管系统疾病的病理过程，特别是对于防止急性心梗PCI术后发生支架部位血管内皮过度增生，造成血管再堵有重要作用。现阶段的各种铁死亡诱导剂有诱导活性不高、成药性不好等问题，亟需一种高活性的新型铁死亡诱导剂，协助治疗临床过度增生性疾病。
发明内容
本发明的目的之一是提供一组1,3-双环氧丙基-5-取代环状三聚脲类化合物或其药用盐。
本发明的再一目是提供含有1,3-双环氧丙基-5-取代环状三聚脲类化合物或其药用盐的组合物。
本发明的另一目是提供以所述1,3-双环氧丙基-5-取代环状三聚脲类化合物或其药用盐作为活性成分的药物组合物或药物制剂，以及该药物组合物在用于治疗异常增生性疾病(如恶性肿瘤、血管内皮异常增生类疾病等)及其它潜在治疗应用。
术语定义
在本文中用于本发明描述中的术语仅是为了描述具体实施方案而不作为对本发明的限制。本文所用命名和在本文所述的有机化学、药物化学、生物学中的实验室操作是本领域熟知的和常用的。除非另外提及，本文所用的全部技术和科学术语与本领域所属技术领域的一般技术人员通常所理解的具有相同的含义。
如在本发明实施方案和所附权利要求的描述中所用，单数形式的“一”、“一种”、“该”、“其”是指该冠词的单数和复数，除非上下文另外明确提及。例如，一种化合物包括一种或多于一种化合物。
如本文所用，“和/或”是指和包括一或多个相关的所列项目的任意和所有可能的组合。
如本文所用，术语“疾病”是指身体状态或一些器官的任意改变，中断或干扰其功能的实施和/或引起症状。
如本文所用，术语“异常增生细胞”是指机体在各种致病因素作用下,细胞异常增殖而形成的局部形态，小鼠血管平滑肌细胞、人食管癌细胞、乳腺癌细胞、肾癌细胞、黑色素瘤细胞、胰腺癌细胞胶质瘤细胞、结直肠癌细胞、淋巴瘤细胞、非小细胞肺癌细胞。
如本文所用，术语“治疗”目的是减轻或消除所针对的疾病状态或病症。如果受试者按照本文所述方法接受了治疗量的化合物或其药学上可接受的盐、异构体、多晶型物、溶剂合物、同位素标记的化合物、代谢物或前药，或其药物组合物，该受试者一种或多种指征和症状表现出可观察到的和/或可检测出的降低或改善，则受试者被成功地“治疗”了。还应当理解，所述的疾病状态或病症的治疗的不仅包括完全地治疗，还包括未达到完全地治疗，但实现了一些生物学或医学相关的结果。
如本文所用，术语“受试者”可以指患者或者其它接受本发明组合物以治疗、预防、减轻和/或缓解本发明所述疾病或病症的动物，在本发明中尤其指人类和哺乳动物。
技术主题一
本发明提供了具有如式I所示结构的含硒化合物或其药用盐：
其中，Y代表O或NH；
L代表—(CH2)2—或
R1代表H或C1-C5烷基；
R2代表
R3为单取代或两个及以上的多取代，独立的选自H、卤素、叠氮基、氰基、甲磺基、C1-C5烷基、C2-C5烯基、C2-C5炔基、C1-C5烷氧基、C1-C5烷巯基、1-3卤素取代的C1-C5烷氧基、3-8元环烷基、含有1-3个选自N、O、S的5-6元杂环基、C1-C5烷基取代的含有1-3个选自N、O、S的5-6元杂环基、芳基、苄基、5-6元杂芳基。
在本发明的一些优选实施方案中，所述C1-C5烷基选自—CH3、—CH2CH3、—CH(CH3)2、—(CH2)2CH3、—(CH2)3CH3、—(CH2)4CH3、—CH(CH3)CH2CH3、—C(CH3)3、—CH(CH3)(CH2)2CH3、—CH2CH(CH2)2CH3、—CH2C(CH2)3；
在本发明的一些优选实施方案中，C1-C5烷氧基选自—OCH3、—OCH2CH3、—OCH(CH3)2、—O(CH2)2CH3、—O(CH2)3CH3、—O(CH2)4CH3、—OCH(CH3)CH2CH3、—OC(CH3)3、—OCH(CH3)(CH2)2CH3、—OCH2CH(CH2)2CH3、—OCH2C(CH2)3；
在本发明的一些优选实施方案中，所述C2-C5烯基选自乙烯基、异丙烯基、正丙烯基、正丁烯基、异丁烯基、仲丁烯基、正戊烯基、异戊烯基；
在本发明的一些优选实施方案中，所述C2-C5炔基选自乙炔基、丙炔基、丁炔基、戊炔基；
在本发明的一些优选实施方案中，C1-C5烷巯基选自—SCH3、—SCH2CH3、—SCH(CH3)2、—S(CH2)2CH3、—S(CH2)3CH3、—S(CH2)4CH3、—SCH(CH3)CH2CH3、—SC(CH3)3、—SCH(CH3)(CH2)2CH3、—SCH2CH(CH2)2CH3、—SCH2C(CH2)3；
在本发明的一些优选实施方案中，所述含有1-3个选自N、O、S的5-6元杂环基选自哌嗪基、吗啉基、哌啶、四氢吡咯基；
在本发明的一些优选实施方案中，所述5-6元杂芳基选自吡咯基、噻吩基、呋喃基、吡啶、咪唑基。
在本发明的一些优选实施方案中，所述R2选自如下结构：
在本发明的一些优选实施方案中，所述式I所示结构的1,3-双环氧丙基-5-取代环状三聚脲类化合物选自如下：
如本文所用，“卤代”或“卤素”可以是氟、氯、溴或碘，且优选为F、Cl、Br。
如本文所用，“药用盐”是指保留目标化合物的所需生物活性并表现出最小的不希望的毒理学效应的盐。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与本发明化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱包括无机碱及有机碱制备的盐，所述的无机碱的盐包括铝盐、铵盐、钙盐、铜盐、铁盐、亚铁盐、锂盐、镁盐、锰盐、亚锰盐、钾盐、钠盐、锌盐等。所述的有机无毒碱的盐，包括伯胺、仲胺和叔胺的盐，包括取取代胺和环状胺。例如：N,N'－二苄基乙二胺、二乙胺、2一二乙基氨基乙醇、2一二甲基氨基乙醇、氨基乙醇、乙醇胺、乙二胺、N一乙基吗啉、N一乙基哌啶、葡萄糖胺、氨基葡萄糖、组氨酸、羟钴胺、异丙基胺、赖氨酸、甲基葡萄糖胺、吗啉、哌嗪、哌啶、呱咤、多胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺等。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例盐酸、氢溴酸、氢碘酸、硫酸、磷酸或硝酸等；有机酸例如甲酸、乙酸、乙酰乙酸、丙酮酸、三氟乙酸、丙酸、丁酸、己酸、庚酸、十一酸、月桂酸、苯甲酸、水杨酸、2-(4-羟基苯甲酰基)-苯甲酸、樟脑酸、肉桂酸、环戊烷丙酸、二葡萄糖酸、3-羟基-2-萘甲酸、烟酸、巴莫酸、果胶酯酸、3-苯基丙酸、苦味酸、特戊酸、2-羟基乙磺酸、衣康酸、胺基磺酸、三氟甲磺酸、十二烷基硫酸、乙磺酸、苯磺酸、对-甲苯磺酸、甲磺酸、2-萘磺酸、萘二磺酸、樟脑磺酸、柠檬酸、酒石酸、硬脂酸、乳酸、草酸、丙二酸、琥珀酸、苹果酸、己二酸、海藻酸、马来酸、富马酸、D-葡萄糖酸、扁桃酸、抗坏血酸、葡庚糖酸、甘油磷酸、天冬胺酸、磺基水杨酸等包括钠、钾、镁、锂、铝、钙、锌、N,N’-二苄基乙二胺、氯代普鲁卡因、胆碱、二乙醇胺、乙二胺、N-甲基葡糖胺和普鲁卡因等形成的盐。
技术主题三
本发明提供一种药物组合物，其包含式I所示的1,3-双环氧丙基-5-取代环状三聚脲类化合物或其药用盐，以及药学上可以接受的载体或赋形剂。
如本文所用，“药物组合物”其中含有治疗有效量的所述式I多取代苯并杂环类化合物其药用盐，以及一种或多种药学上可接受的载体，制备成片剂、胶囊、颗粒剂、散剂、混悬剂、乳剂、粉剂、溶液、凝胶剂、糖浆剂、丸剂、酊剂、酒剂、煎膏剂、锭剂、合剂、栓剂、注射剂、吸入剂或喷雾剂等形式。该药物组合物优选含有重量比为0.1％-99.5％的本发明的多取代苯并杂环类化合物或其药用盐作为活性成分，更优选含有重量比为0.5％-99.5％的活性成分。
如本文所用，“药学上可接受的载体或赋形剂”包括：稀释剂、填充剂、粘合剂、崩解剂、润滑剂、助流剂、粒化剂、包衣剂、润湿剂、溶剂、共溶剂、助悬剂、乳化剂、增甜剂、调味剂、掩味剂、着色剂、防结块剂、保湿剂、螯合剂、增塑剂、增粘剂、抗氧化剂、防腐剂、稳定剂、表面活性剂和缓冲剂，本领域技术人员将理解，某些药学上可接受的赋形剂可以以多于一种功能和以替代性功能来使用，取决于所述赋形剂在制剂中存在多少和在制剂中存在何种其它成分。例如：当用于口服时，可以制成口服制剂，如片剂、胶囊剂、颗粒剂和丸剂等，包含填充剂(例如糖类衍生物如乳糖、蔗糖、葡萄糖、甘露糖醇和山梨糖醇；淀粉衍生物如玉米淀粉、土豆淀粉、糊精和羧甲基淀粉；纤维素衍生物如结晶纤维素、羟丙基纤维素、羧甲基纤维素、羧甲基纤维素钙、羧甲基纤维素钠；阿拉伯胶；右旋糖酐；硅酸盐衍生物如偏硅酸镁铝；磷酸盐衍生物如磷酸钙；碳酸盐衍生物如碳酸钙；硫酸盐衍生物如硫酸钙等)、粘合剂(例如明胶、聚乙烯吡咯烃酮和聚乙二醇)、崩解剂(例如纤维素衍生物如羧甲基纤维素钠、聚乙烯吡咯烃酮)、润滑剂(例如滑石、硬脂酸钙、硬脂酸镁、鲸蜡、硼酸、苯甲酸钠、亮氨酸)、稳定剂(对羟基苯甲酸甲酯、对羟基苯甲酸丙酯等)、矫味剂(例如常用的甜味剂、酸味剂和香料等)。当用于肠胃外时，可以制成注射剂，包括注射用无菌粉末与注射用溶剂，所用载体或赋形剂包含无菌水、林格氏液和等渗氯化钠溶液，也可根据药物的性质加入适宜的附加剂例如抗氧化剂、缓冲剂和抑菌剂。当用于直肠给药时，所述药物可以制成栓剂等。用于经肺给药时，所述药物可以制成吸入剂或喷雾剂等。有许多本领域技术人员可用的资源，这些资源描述了药学上可接受的赋形剂且其可用于选择合适的药学上可接受的赋形剂，例如《雷明登药学大全》、《中国药学年鉴》、《药剂学》等书籍。
本发明可以通过本领域已知的任何合适的方法来施用，例如，口服、静脉内、腹膜内、肌肉内、局部、透皮、经眼、经鼻、吸入、皮下、肌内、口含、舌下、直肠给予等方式，可以以1μg～2000mg/kg受试者体重的任何量施用如上所述的化合物，例如以1μg～1000mg/kg体重/天，50μg～1000mg/kg体重/天，100μg～1000mg/kg体重/天，1～500mg/kg体重/天，2～200mg/kg体重/天，5～100mg/kg体重/天量施用如上所述的化合物。在本发明的一些的实施方案中，可以以每日4次、每日3次、每日2次、每日1次、每两日1次、每周1次或其他间隔的方式施用如上所述的化合物，任选地酌情每周或每月重复如上所述的给药方案。在本发明中，所述化合物的给药剂量可根据患者或受试者的病情轻重、年龄、体重、性别、给药方式及疗程等因素进行调整。
本发明化合物可以单独使用，经也可以和另一种或多种其它活性成分联合用于治疗、预防、抑制或者改善疾病或者病状，其中药物的联合使用比任何一种药物的单独使用更为安全或者更为有效。这种其它药物可以以对此通常使用的途径和量与本发明的化合物同时或者依次给药。当本发明的化合物与一种或者多种其它药物同时使用时，在单位剂型中含有该其它药物和本发明的化合物的药物组合物是优选的，特别是与药学可接受的载体联合。然而，联合治疗还可以包括在不同重叠日程中给予本发明的化合物和一种或者多种其它药物的治疗。还可以预期，当与一种或者多种其它活性成分联合使用时，本发明化合物和其它活性成分可以以比各自单独使用时更低的剂量使用。因此，除了本发明的化合物外，本发明药物组合物还包括含有一种或者多种其它活性成分的那些组合物。
技术主题四
本发明还提供了式I所示含硒化合物或其药用盐在制备抑制微管蛋白活性药物中的应用。
进一步的，还提供了式I所示含硒化合物或其药用盐在制备诱导异常增生细胞发生铁死亡的药物中的应用。
在一些实施方案中，所述异常增生细胞包括小鼠血管平滑肌细胞、人食管癌细胞、乳腺癌细胞、肾癌细胞、黑色素瘤细胞、胰腺癌细胞、胶质瘤细胞、结直肠癌细胞、淋巴瘤细胞、非小细胞肺癌细胞。
在一些实施方案中，提供了式I所示含硒化合物或其药用盐在制备治疗恶性肿瘤、血管内皮异常增生所致心血管疾病及其它过渡性增生疾病的治疗药物中的应用。
发明的有益效果
本发明所提供的1,3-双环氧丙基-5-取代环状三聚脲类化合物，经验证，具有诱导异常增生细胞发生铁死亡，和/或增加这类细胞对其它细胞毒性药物治疗、放射治疗等的敏感性的作用。为治疗过渡性增生疾病例如恶性肿瘤、血管内皮异常增生所致心血管疾病提供了方向。
附图说明
为了更清楚地说明本发明具体实施方式或现有技术中的技术方案，下面将对具体实施方式描述中所需要使用的附图作简单地介绍。
图1为本发明的化合物BY1对体外培养的小鼠平滑肌细胞的ROS诱导作用对比图，该图明确显示经BY1刺激的小鼠平滑肌细胞相较未刺激细胞具有更高水平的ROS，说明本发明的化合物BY1具有ROS诱导能力。
具体实施方式
以下结合结合具体实施例阐述本发明，这些实施例不旨在限制本发明的范围，而是为本领域技术人员制备和使用本发明化合物、组合物和方法提供指导。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。
本申请中描述的化合物的化学名称通常从ChemDraw Ultra(ChambridgeSoft)和生成/或通常遵循IUPAC命名法的原理。
本实施例部分的通用路线如下：
路线1
由商业可得的化合物1(2,4,6-三烯丙氧基-1,3,5-三嗪)在二价铜催化下发生克莱森重排反应制备中间体2(1,3-二烯丙基-1,3,5-三嗪-2,4,6-三酮)，再与1,2-二溴乙烷在碳酸钾存在下发生取代反应，生成中间体3(1,3-二烯丙基-5-(2-溴乙基)-1,3,5-三嗪-2,4,6-三酮)，中间体3在丙酮-水混合溶剂中与叠氮钠反应，制备中间体4(1,3-二烯丙基-5-(2-叠氮乙基)-1,3,5-三嗪-2,4,6-三酮)；与此同时由商业可得的3-丁炔-1-醇与商业可得的系列羧酸，以氯化亚砜为酰化剂合成系列酯6；系列酯6分别与上述中间体4在二价铜-抗坏血酸钠催化下发生“点击反应”合成系列中间体7，最后以OXONE为氧化剂将系列中间体7氧化为系列环氧化合物8，即目标化合物，取代基如表1所示。
表1取代基结构
路线二
由商业可得的Boc-溴乙胺与中间体2在碳酸钾存在下发生取代反应，再用三氟乙酸脱除Boc保护基，生成中间体9(1,3-二烯丙基-5-(2-氨基乙基)-1,3,5-三嗪-2,4,6-三酮)；随后与商业可得的系列羧酸，以氯化亚砜为酰化剂合成系列酰胺10，中间体10在以OXONE作为氧化剂的条件下发生氧化反应构建环氧化合物11，即目标化合物，取代基如表2所示。
实施例1制备1,3-二烯丙基-1,3,5-三嗪-2,4,6-三酮(中间体2)
向装有磁力搅拌的500mL单口茄形瓶中依次加入2,4,6-三烯丙氧基-1,3,5-三嗪(50g，200mmol)、二水合氯化铜(1.54g)、乙酸(12.01g)，200mL甲苯为反应溶剂。反应体系呈蓝色澄清，氮气保护下100℃搅拌反应8h。冷却，大量蓝色沉淀析出，减压过滤，使用6mol/L盐酸洗涤滤饼，烘干得到白色固体(36.74g，88.3％)。1H NMR(600MHz,DMSO-d6):δ11.76(s,1H),5.81(dddd,J＝15.8,8.8,6.1,4.4Hz,2H),5.14(dd,J＝29.7,13.9Hz,4H),4.29(d,J＝5.1Hz,4H).13C NMR(151MHz,DMSO-d6):δ149.87,148.89,132.67,117.01,43.77。ESI-MS(m/z):208.0[M-H]-。
实施例2制备1,3-二烯丙基-5-(2-溴乙基)-1,3,5-三嗪-2,4,6-三酮(中间体3)
向装有磁力搅拌的500mL单口茄形瓶中依次加入1,3-二烯丙基-1,3,5-三嗪-2,4,6-三酮(10g，47.8mmol)，1,2-二溴乙烷(17.9g，95.6mmol)，碳酸钾(19.82g，143.4mmol)，150mL DMF为反应溶剂。氮气保护下50℃搅拌反应9h，TLC监测反应完成。真空蒸去溶剂，100ml乙酸乙酯复溶，用水洗涤100ml*3，合并有机相并用无水硫酸钠干燥，浓缩，柱层析纯化，得浅黄色油状液体(14.04g，92.3％)。1H NMR(600MHz,Chloroform-d)δ5.86(ddt,J＝16.4,10.2,6.0Hz,1H),5.30(dt,J＝17.2,1.3Hz,1H),5.24(dd,J＝10.3,1.4Hz,1H),4.49(dt,J＝6.0,1.3Hz,2H),4.30(t,J＝6.8Hz,1H),3.57(t,J＝6.8Hz,1H)；13C NMR(151MHz,Chloroform-d)δ148.49,148.24,130.71,119.15,45.05,43.51,27.31。ESI-MS(m/z):316.2[M+H]+。
实施例3制备1,3-二烯丙基-5-(2-叠氮乙基)-1,3,5-三嗪-2,4,6-三酮(中间体4)
将中间体3(13.88g,44mmol)溶于200ml丙酮和75ml水，加入NaN3(4.55g,70mmol)，60℃搅拌回流24小时。在真空中除去丙酮，用乙酸乙酯萃取3*80ml。合并有机相，用无水硫酸钠干燥，浓缩得黄色油4(10.44g,85.3％)；1H NMR(600MHz,DMSO-d6)δ5.83(ddt,J＝17.2,10.4,5.2Hz,2H),5.23–5.10(m,4H),4.36(dt,J＝5.2,1.7Hz,4H),3.98(t,J＝6.0Hz,2H),3.52(t,J＝6.0Hz,2H)；ESI-MS(m/z):279.3[M+H]+。
实施例4制备2'-(1-(2-(3,5-二环氧丙基-2,4,6-三氧-1,3,5-三嗪-1-基)乙基)-1H-1,2,3-三唑-4-基)-2-(4-苯基苯-1-基)乙酸乙酯(8s/BY1)
向装有磁力搅拌的250mL单口茄形瓶中依次加入苯基乙酸(1eq)，吡啶(0.1eq)，氯化亚砜(1.2eq)，适量二氯甲烷为反应溶剂，加热至40℃搅拌反应约12h，向反应体系中加入3-丁炔-1-醇(1eq)，滴加三乙胺(2.4eq)，继续40℃搅拌约12h，真空下蒸去溶剂，加水、二氯甲烷震荡，分离水相，水相以二氯甲烷萃取50ml*3，合并有机相，无水硫酸钠干燥，浓缩，柱层析纯化，得到中间体4-苯基-苯乙酸-3-丁炔-1-醇酯(6s)。
向装有磁力搅拌的单口茄形瓶中依次加入4-苯基-苯乙酸-3-丁炔-1-醇酯6s(1eq)，中间体4(1eq)，硫酸铜(0.1eq)，DIPEA(2eq)，L-抗坏血酸钠(0.2eq)，适量DMF为溶剂。氮气保护下45℃搅拌反应约24h。真空下除去溶剂，加水、乙酸乙酯充分震荡，分液，水相以乙酸乙酯萃取(适量×3)，合并有机相，浓缩，柱层析纯化，得到中间体2'-(1-(2-(3,5-二烯丙基-2,4,6-三氧-1,3,5-三嗪-1-基)乙基)-1H-1,2,3-三唑-4-基)-2-(4-联苯基)乙酸乙酯(7s)。
在室温下向中间体7S(2mmol 1eq)的40ml丙酮溶液中加入40ml 0.4mM Na2EDTA水溶液。加入NaHCO3(6.4g)和OXONE(30.4g)。薄层色谱监测反应完成后，滤除白色沉淀，真空下蒸去丙酮。剩下的水用3*40ml乙酸乙酯萃取。合并有机相，用无水硫酸钠干燥。用制备型高效液相色谱法提纯，得到淡黄色油状液体(0.2g，16.1％)。1H NMR(400MHz,Chloroform-d)δ7.65–7.54(m,5H),7.48–7.41(m,2H),7.36(d,J＝8.1Hz,3H),4.45(t,J＝5.8Hz,2H),4.34(t,J＝6.3Hz,2H),4.15(t,J＝5.8Hz,2H),4.08(ddd,J＝14.0,5.3,2.2Hz,2H),3.94(dd,J＝14.1,4.7Hz,2H),3.68(s,2H),3.18(p,J＝4.5Hz,2H),3.04(t,J＝6.4Hz,2H),2.81(t,J＝4.3Hz,2H),2.63(dt,J＝4.9,2.5Hz,2H)。13C NMR(151MHz,Chloroform-d)δ171.21,148.60,148.49,144.53,140.39,139.88,133.26,129.95,128.91,127.50,126.89,122.32,63.63,48.52,46.99,46.32,46.26,44.63,44.55,42.25,41.13,25.42。HRMS(ESI):597.2030[M+Na]+。
实施例5 2'-(1-(2-(3,5-二环氧丙基-2,4,6-三氧-1,3,5-三嗪-1-基)乙基)-1H-1,2,3-三唑-4-基)-2-(3-氟-4-苯基苯-1-基)丙酸乙酯(8p/BY7)
应用路线1，制备方法同实施例4，得到淡黄色油状液体(0.2g，11.5％)。1H NMR(400MHz,CDCl3)δ7.55(dd,J＝6.9,1.5Hz,2H,benzene-H),7.49–7.34(m,4H,benzene-H),7.18–7.09(m,2H,benzene-H),7.07(s,1H,Triazole-H),4.48(dd,J＝6.5,5.0Hz,2H,Triazole-N-CH2),4.40–4.26(m,2H,O-CH2),4.20(t,J＝5.7Hz,2H,N-CH2),4.08(ddd,J＝14.0,5.3,2.4Hz,2H,N-CH2),3.93(ddd,J＝14.1,4.9,1.3Hz,2H,N-CH2),3.74(dq,J＝14.7,7.1Hz,1H,CH3-CH),3.22–3.13(m,2H,2O-CH),3.01(t,J＝6.4Hz,2H,Triazole-CH2),2.81(t,J＝4.4Hz,2H,O-CH2),2.64(dt,J＝5.0,2.6Hz,2H,O-CH2),1.53(d,J＝7.2Hz,3H,CH3)。13C NMR(151MHz,Chloroform-d)δ159.73(d,J＝248.4Hz),142.07(d,J＝7.6Hz),130.89(d,J＝3.9Hz),128.96(d,J＝3.1Hz),127.80(d,J＝13.4Hz),123.86(d,J＝3.4Hz),115.55(d,J＝23.6Hz)。HRMS(ESI):629.2109[M+Na]+。
实施例6 2'-(1-(2-(3,5-二环氧丙基-2,4,6-三氧-1,3,5-三嗪-1-基)乙基)-1H-1,2,3-三唑-4-基)-2-(3-苯甲酰基苯-1-基)丙酸乙酯(8t/BY8)
应用路线1，制备方法同实施例4，得到淡黄色油状液体(0.3g，15.5％)。1H NMR(400MHz,Chloroform-d)δ7.83–7.73(m,3H),7.71–7.57(m,2H),7.49(tt,J＝15.9,7.8Hz,4H),4.58(t,J＝5.7Hz,2H),4.31(tdd,J＝16.9,11.1,6.1Hz,4H),4.13–4.02(m,2H),3.93(dd,J＝14.1,4.9Hz,2H),3.82(q,J＝7.2Hz,1H),3.17(p,J＝4.5Hz,2H),2.97(t,J＝5.9Hz,2H),2.80(t,J＝4.4Hz,2H),2.63(dt,J＝5.0,2.5Hz,2H),1.54(d,J＝7.2Hz,3H)；13C NMR(151MHz,Chloroform-d)δ196.65,173.73,148.67,148.56,144.44,141.04,138.06,137.26,132.78,131.53,130.11,129.22,128.96,128.64,128.43,122.41,63.74,48.53,47.13,46.31,46.26,45.35,44.59,44.51,42.49,25.39,18.10。HRMS(ESI):639.2203[M+Na]+。
实施例7制备2'-(1-(2-(3,5-二环氧丙基-2,4,6-三氧-1,3,5-三嗪-1-基)乙基)-1H-1,2,3-三唑-4-基)-2-(4-氟苯基)乙酸乙酯(8d/BY9)
应用路线1，制备方法同实施例4，得到淡黄色油状液体(0.2g，18.5％)。1H NMR(600MHz,Chloroform-d)δ7.24(dd,J＝8.4,5.4Hz,2H),7.14(s,1H),7.02(t,J＝8.6Hz,2H),4.58(t,J＝5.8Hz,2H),4.33(t,J＝6.6Hz,2H),4.31(t,J＝6.0Hz,3H),4.11(dd,J＝5.3,3.6Hz,1H),4.08(dd,J＝5.3,3.5Hz,1H),3.97(dd,J＝5.0,2.0Hz,1H),3.94(dd,J＝4.9,2.0Hz,1H),3.60(s,2H),3.19(dt,J＝7.9,4.6Hz,2H),3.02(t,J＝6.5Hz,2H),2.81(t,J＝4.2Hz,2H),2.64(td,J＝4.5,2.5Hz,2H)；13C NMR(151MHz,Chloroform-d)δ171.16,161.99(d,J＝245.4Hz),148.62,148.56,144.48,130.99(d,J＝7.8Hz),129.84(d,J＝3.2Hz),122.20,115.43(d,J＝21.5Hz),63.60,48.52,47.11,46.31,46.26,44.62,44.54,42.37,40.50,25.39。HRMS(ESI):517.1842[M+H]+。
实施例8制备2'-(1-(2-(3,5-二环氧丙基-2,4,6-三氧-1,3,5-三嗪-1-基)乙基)-1H-1,2,3-三唑-4-基)-2-(4-氯苯基)乙酸乙酯(8e/BY10)
应用路线1，制备方法同实施例4，得到淡黄色油状液体(0.3g，19.1％)。1H NMR(600MHz,Chloroform-d)δ7.31(d,J＝8.4Hz,2H),7.21(d,J＝8.4Hz,2H),7.07(s,1H),4.57(dd,J＝6.5,5.0Hz,2H),4.33(t,J＝6.5Hz,2H),4.30(dd,J＝6.5,5.0Hz,2H),4.11(dd,J＝5.3,3.5Hz,1H),4.08(dd,J＝5.3,3.5Hz,1H),3.96(dd,J＝4.9,2.0Hz,1H),3.94(dd,J＝4.9,2.0Hz,1H),3.60(s,2H),3.19(dtdd,J＝5.7,4.4,2.7,1.7Hz,2H),3.02(t,J＝6.4Hz,2H),2.81(ddd,J＝5.0,3.9,1.2Hz,2H),2.64(ddd,J＝4.9,4.1,2.5Hz,2H)；13C NMR(151MHz,Chloroform-d)δ170.82,148.62,148.56,144.45,133.03,132.62,130.86,128.73,122.22,63.67,48.53,47.12,46.31,46.26,44.62,44.53,42.38,40.72,25.37。HRMS(ESI):533.1537[M+H]+。
实施例9制备2'-(1-(2-(3,5-二环氧丙基-2,4,6-三氧-1,3,5-三嗪-1-基)乙基)-1H-1,2,3-三唑-4-基)-2-(4-溴苯基)乙酸乙酯(8b/BY11)
应用路线1，制备方法同实施例4，得到淡黄色油状液体(0.3g，18.6％)。1H NMR(600MHz,Chloroform-d)δ7.47(d,J＝8.4Hz,2H),7.16(d,J＝8.3Hz,2H),7.05(s,1H),4.57(t,2H),4.33(t,J＝6.4Hz,2H),4.30(t,J＝5.7Hz,2H),4.11(dd,J＝5.3,3.5Hz,1H),4.08(dd,J＝5.3,3.5Hz,1H),3.97(dd,J＝4.9,2.0Hz,1H),3.94(dd,J＝4.9,2.0Hz,1H),3.59(s,2H),3.19(dddt,J＝5.6,4.3,3.1,1.6Hz,2H),3.02(t,J＝6.4Hz,2H),2.83–2.79(m,2H),2.64(td,J＝4.4,2.5Hz,2H)；13C NMR(151MHz,Chloroform-d)δ170.70,148.62,148.56,144.45,133.14,131.70,131.25,122.23,121.10,63.70,48.53,47.14,46.32,46.26,44.62,44.53,42.40,40.81,25.37。HRMS(ESI):577.1034[M+H]+。
实施例10制备2'-(1-(2-(3,5-二环氧丙基-2,4,6-三氧-1,3,5-三嗪-1-基)乙基)-1H-1,2,3-三唑-4-基)-2-(4-三氟甲基苯基)乙酸乙酯(8f/BY12)
应用路线1，制备方法同实施例4，得到淡黄色油状液体(0.4g，25.3％)。1H NMR(600MHz,Chloroform-d)δ7.56(d,J＝7.9Hz,2H),7.37(d,J＝7.9Hz,2H),7.23(d,J＝4.5Hz,1H),4.55(q,J＝6.5,6.1Hz,3H),4.32(q,J＝6.2Hz,2H),4.30–4.23(m,2H),4.09–3.90(m,4H),3.67(d,J＝2.3Hz,2H),3.15(dtd,J＝6.4,4.9,3.2Hz,2H),3.00(td,J＝6.6,2.0Hz,2H),2.80–2.75(m,2H),2.60(qd,J＝4.6,2.7Hz,2H)。HRMS(ESI):567.1803[M+H]+。
实施例11制备2'-(1-(2-(3,5-二环氧丙基-2,4,6-三氧-1,3,5-三嗪-1-基)乙基)-1H-1,2,3-三唑-4-基)-2-(4-甲磺酰基苯基)乙酸乙酯(8c/BY13)
应用路线1，制备方法同实施例4，得到淡黄色油状液体(0.4g，25.3％)。1H NMR(600MHz,Chloroform-d)δ7.91(d,J＝8.2Hz,2H),7.48(d,J＝8.2Hz,2H),7.12(s,1H),4.57(dq,J＝5.8,3.7,2.2Hz,2H),4.36(t,J＝6.3Hz,2H),4.29(t,J＝5.9Hz,2H),4.11(dd,J＝5.3,3.4Hz,1H),4.09(dd,J＝5.3,3.4Hz,1H),3.98(dd,J＝4.9,2.0Hz,1H),3.95(dd,J＝4.9,1.9Hz,1H),3.73(s,2H),3.23–3.17(m,2H),3.05(s,3H),3.03(t,J＝6.4Hz,2H),2.84–2.78(m,2H),2.68–2.63(m,2H)；13C NMR(151MHz,Chloroform-d)δ170.07,148.60,140.33,139.52,130.52,127.68,122.17,63.96,48.56,47.11,46.31,46.25,44.64,44.56,44.46,42.38,41.17,25.33。HRMS(ESI):577.1703[M+H]+。
实施例12制备2'-(1-(2-(3,5-二环氧丙基-2,4,6-三氧-1,3,5-三嗪-1-基)乙基)-1H-1,2,3-三唑-4-基)-2-苯基乙酸乙酯(8a/BY14)
应用路线1，制备方法同实施例4，得到淡黄色油状液体(0.2g，15.4％)。1H NMR(600MHz,Chloroform-d)δ7.34(t,J＝7.3Hz,2H),7.31–7.27(m,3H),7.01(s,1H),4.54(t,J＝5.8Hz,2H),4.32(t,J＝6.4Hz,2H),4.29(t,J＝5.8Hz,2H),4.11(dd,J＝5.3,3.4Hz,1H),4.08(dd,J＝5.3,3.4Hz,1H),3.96(dd,J＝4.9,2.0Hz,1H),3.94(dd,J＝4.9,2.0Hz,1H),3.64(s,2H),3.22–3.16(m,2H),3.02(t,J＝6.4Hz,2H),2.84–2.78(m,2H),2.64(td,J＝4.6,2.6Hz,2H)；13C NMR(151MHz,Chloroform-d)δ171.25,148.62,148.55,144.51,134.20,129.46,128.61,127.08,122.31,63.53,48.52,47.07,46.32,46.27,44.62,44.54,42.38,41.48,25.40。HRMS(ESI):499.1940[M+H]+。
实施例13制备2'-(1-(2-(3,5-二环氧丙基-2,4,6-三氧-1,3,5-三嗪-1-基)乙基)-1H-1,2,3-三唑-4-基)-2-(4-碘苯基)乙酸乙酯(8i/BY15)
应用路线1，制备方法同实施例4，得到淡黄色油状液体(0.3g，21.2％)。1H NMR(500MHz,Chloroform-d)δ7.62–7.56(m,2H),7.52(s,1H),7.17(dt,J＝7.6,1.0Hz,2H),4.47(dt,J＝11.9,7.0Hz,1H),4.39(dt,J＝11.9,6.8Hz,1H),4.32(dt,J＝12.2,6.8Hz,2H),4.21(dt,J＝12.4,7.1Hz,1H),4.14(dt,J＝12.3,7.1Hz,1H),4.04(dd,J＝11.9,6.9Hz,2H),3.97(p,J＝6.8Hz,2H),3.84(dd,J＝11.9,6.7Hz,2H),3.66(dd,J＝12.4,6.8Hz,2H),3.57(q,J＝1.2Hz,2H),3.39(dd,J＝12.3,6.9Hz,2H),3.13(dt,J＝12.5,7.1Hz,1H),3.00(dt,J＝12.5,7.1Hz,1H)。HRMS(ESI):625.0907[M+H]+。
实施例14制备2'-(1-(2-(3,5-二环氧丙基-2,4,6-三氧-1,3,5-三嗪-1-基)乙基)-1H-1,2,3-三唑-4-基)-2-(4-甲氧苯基)乙酸乙酯(8j/BY16)
应用路线1，制备方法同实施例4，得到淡黄色油状液体(0.08g，8.2％)。1H NMR(500MHz,Chloroform-d)δ7.52(s,1H),7.19(dt,J＝7.5,1.1Hz,2H),6.89–6.83(m,2H),4.47(dt,J＝12.3,7.1Hz,1H),4.39(dt,J＝12.3,7.0Hz,1H),4.36–4.29(m,1H),4.31–4.24(m,1H),4.21(dt,J＝12.4,7.1Hz,1H),4.13(dt,J＝12.5,7.1Hz,1H),4.02(dd,J＝11.9,6.8Hz,2H),3.96(p,J＝6.7Hz,2H),3.85(dd,J＝11.9,6.6Hz,2H),3.78(s,2H),3.66(dd,J＝12.4,6.8Hz,2H),3.57(dt,J＝2.0,1.1Hz,2H),3.39(dd,J＝12.4,6.8Hz,2H),3.12(dt,J＝12.3,7.1Hz,1H),2.99(dt,J＝12.5,7.1Hz,1H)。HRMS(ESI):529.2045[M+H]+。
实施例15制备2'-(1-(2-(3,5-二环氧丙基-2,4,6-三氧-1,3,5-三嗪-1-基)乙基)-1H-1,2,3-三唑-4-基)-2-(3,4-二甲氧苯基)乙酸乙酯(8m/BY17)
应用路线1，制备方法同实施例4，得到淡黄色油状液体(0.15g，20.4％)。1H NMR(500MHz,Chloroform-d)δ7.52(s,1H),6.90–6.79(m,3H),4.47(dt,J＝12.3,7.1Hz,1H),4.39(dt,J＝12.3,7.0Hz,1H),4.30(ddt,J＝12.5,11.4,7.0Hz,2H),4.20(dt,J＝12.3,7.0Hz,1H),4.13(dt,J＝12.3,7.0Hz,1H),4.06–3.92(m,4H),3.88–3.81(m,8H),3.66(dd,J＝12.4,6.8Hz,2H),3.61(q,J＝1.0Hz,2H),3.39(dd,J＝12.4,6.8Hz,2H),3.13(dt,J＝12.5,7.1Hz,1H),3.00(dt,J＝12.5,7.1Hz,1H)。HRMS(ESI):559.2154[M+H]+。
实施例16制备2'-(1-(2-(3,5-二环氧丙基-2,4,6-三氧-1,3,5-三嗪-1-基)乙基)-1H-1,2,3-三唑-4-基)-2-(3,4-亚甲二氧苯基)乙酸乙酯(8l/BY18)
应用路线1，制备方法同实施例4，得到淡黄色油状液体(0.19g，26.2％)。1H NMR(600MHz,Chloroform-d)δ7.25–7.18(m,5H),6.95(s,1H),4.54(t,J＝5.7Hz,2H),4.29(dt,J＝15.3,6.0Hz,4H),4.09(ddd,J＝14.1,5.3,3.5Hz,2H),3.95(ddd,J＝14.1,4.9,1.9Hz,2H),3.59(s,2H),3.18(dq,J＝8.0,4.7,4.3Hz,2H),3.01(t,J＝6.3Hz,2H),2.81(t,J＝4.5Hz,2H),2.64(td,J＝4.6,3.1Hz,2H),2.48(s,3H)。HRMS(ESI):543.1841[M+H]+。
实施例17制备2'-(1-(2-(3,5-二环氧丙基-2,4,6-三氧-1,3,5-三嗪-1-基)乙基)-1H-1,2,3-三唑-4-基)-2-(4-甲硫基苯基)乙酸乙酯(8o/BY19)
应用路线1，制备方法同实施例4，得到淡黄色油状液体(0.17g，23.8％)。1H NMR(500MHz,Chloroform-d)δ7.52(s,1H),7.32(dt,J＝7.5,1.0Hz,2H),7.20–7.14(m,2H),4.47(dt,J＝12.3,7.1Hz,1H),4.43–4.33(m,1H),4.35–4.25(m,2H),4.21(dt,J＝12.4,7.0Hz,1H),4.13(dt,J＝12.3,7.1Hz,1H),4.02(dd,J＝11.9,6.8Hz,2H),3.96(p,J＝6.7Hz,2H),3.85(dd,J＝11.9,6.6Hz,2H),3.66(dd,J＝12.4,6.8Hz,2H),3.57(dt,J＝2.0,1.1Hz,2H),3.39(dd,J＝12.4,6.8Hz,2H),3.13(dt,J＝12.5,7.1Hz,1H),3.00(dt,J＝12.5,7.1Hz,1H),2.50(s,2H)。HRMS(ESI):545.1820[M+H]+。
实施例18制备2'-(1-(2-(3,5-二环氧丙基-2,4,6-三氧-1,3,5-三嗪-1-基)乙基)-1H-1,2,3-三唑-4-基)-2-(4-正戊基苯基)乙酸乙酯(8g/BY20)
应用路线1，制备方法同实施例4，得到淡黄色油状液体(0.25g，36.4％)。1H NMR(500MHz,Chloroform-d)δ7.52(s,1H),7.24(dt,J＝7.4,1.0Hz,2H),6.95(dt,J＝7.6,1.0Hz,2H),4.47(dt,J＝12.3,7.1Hz,1H),4.43–4.33(m,1H),4.35–4.25(m,2H),4.21(dt,J＝12.5,7.1Hz,1H),4.13(dt,J＝12.2,7.0Hz,1H),4.06–3.94(m,4H),3.92–3.79(m,2H),3.70–3.62(m,2H),3.57(dt,J＝3.1,0.9Hz,2H),3.43–3.34(m,2H),3.13(dt,J＝12.5,7.1Hz,1H),3.00(dt,J＝12.5,7.1Hz,1H),2.70–2.56(m,2H),1.66–1.50(m,2H),1.46–1.26(m,4H),0.94–0.84(m,3H)。HRMS(ESI):569.2723[M+H]+。
实施例19制备2'-(1-(2-(3,5-二环氧丙基-2,4,6-三氧-1,3,5-三嗪-1-基)乙基)-1H-1,2,3-三唑-4-基)-2-(4-叔丁基苯基)乙酸乙酯(8h/BY21)
应用路线1，制备方法同实施例4，得到淡黄色油状液体(0.20g，30.1％)。1H NMR(600MHz,Chloroform-d)δ7.37–7.34(m,2H),7.25(s,1H),7.22–7.19(m,2H),4.59(dd,J＝6.5,4.9Hz,2H),4.32(dt,J＝11.0,5.9Hz,4H),4.10(ddd,J＝14.1,5.3,3.5Hz,2H),3.95(ddd,J＝14.1,4.9,2.0Hz,2H),3.60(s,2H),3.19(tddd,J＝5.0,3.7,2.3,1.1Hz,2H),3.04(t,J＝6.6Hz,2H),2.81(ddd,J＝5.0,3.9,1.2Hz,2H),2.64(ddd,J＝4.9,4.1,2.5Hz,2H),1.32(s,9H)。HRMS(ESI):555.2564[M+H]+。
实施例20制备2'-(1-(2-(3,5-二环氧丙基-2,4,6-三氧-1,3,5-三嗪-1-基)乙基)-1H-1,2,3-三唑-4-基)-2-(4-异丁基苯基)丙酸乙酯(8q/BY22)
应用路线1，制备方法同实施例4，得到淡黄色油状液体(0.09g，36.1％)。1H NMR(500MHz,Chloroform-d)δ7.52(s,1H),7.27–7.21(m,2H),7.10(dt,J＝7.5,1.1Hz,2H),4.47(dt,J＝12.3,7.1Hz,1H),4.39(dt,J＝12.3,7.0Hz,1H),4.34–4.23(m,3H),4.13(dt,J＝12.3,7.0Hz,1H),4.06–3.94(m,4H),3.91–3.80(m,2H),3.75(qt,J＝6.8,1.1Hz,1H),3.70–3.61(m,2H),3.43–3.34(m,2H),3.13(dt,J＝12.3,7.1Hz,1H),3.00(dt,J＝12.5,7.1Hz,1H),2.47(qdt,J＝12.3,7.0,0.9Hz,2H),1.84(dp,J＝13.7,6.9Hz,1H),1.53(d,J＝6.8Hz,3H),0.90(d,J＝6.8Hz,3H),0.85(d,J＝6.8Hz,3H)。HRMS(ESI):569.2724[M+H]+。
实施例21制备2'-(1-(2-(3,5-二环氧丙基-2,4,6-三氧-1,3,5-三嗪-1-基)乙基)-1H-1,2,3-三唑-4-基)(2S)-2-(6-甲氧基萘-2-基)丙酸乙酯(8r/BY23)
应用路线1，制备方法同实施例4，得到淡黄色油状液体(0.08g，32.4％)。1H NMR(600MHz,Chloroform-d)δ7.77–7.67(m,3H),7.41(dd,J＝8.5,1.8Hz,1H),7.19–7.14(m,2H),6.30(s,1H),4.37–4.30(m,1H),4.20(ddd,J＝11.3,6.5,5.0Hz,1H),4.06(dddd,J＝14.0,5.2,3.4,1.6Hz,2H),3.93(s,3H),3.92–3.90(m,3H),3.89–3.84(m,4H),3.19–3.12(m,2H),2.94(t,J＝6.0Hz,2H),2.79(t,J＝4.4Hz,2H),2.61(dt,J＝5.0,3.0Hz,2H),2.01(s,3H)。HRMS(ESI):593.2361[M+H]+。
实施例22制备2'-(1-(2-(3,5-二环氧丙基-2,4,6-三氧-1,3,5-三嗪-1-基)乙基)-1H-1,2,3-三唑-4-基)-2-苯丙酸乙酯(8n/BY24)
应用路线1，制备方法同实施例4，得到淡黄色油状液体(0.06g，26.6％)。1H NMR(500MHz,Chloroform-d)δ7.52(s,1H),7.34–7.28(m,4H),7.28–7.20(m,1H),4.47(dt,J＝12.3,7.0Hz,1H),4.38(dt,J＝12.3,7.0Hz,1H),4.35–4.25(m,3H),4.13(dt,J＝12.3,7.1Hz,1H),4.02(dd,J＝11.9,6.8Hz,2H),3.96(p,J＝6.7Hz,2H),3.85(dd,J＝11.9,6.6Hz,2H),3.79–3.71(m,1H),3.66(dd,J＝12.4,6.8Hz,2H),3.39(dd,J＝12.4,6.8Hz,2H),3.12(dt,J＝12.3,7.1Hz,1H),2.99(dt,J＝12.5,7.1Hz,1H),1.52(d,J＝6.8Hz,3H)。HRMS(ESI):513.2099[M+H]+。
实施例23制备2'-(1-(2-(3,5-二环氧丙基-2,4,6-三氧-1,3,5-三嗪-1-基)乙基)-1H-1,2,3-三唑-4-基)-2-(4-苯氧基苯)乙酸乙酯(8k/BY25)
应用路线1，制备方法同实施例4，得到淡黄色油状液体(0.06g，25.4％)。1H NMR(500MHz,Chloroform-d)δ7.52(s,1H),7.39–7.32(m,2H),7.15(dt,J＝7.5,1.0Hz,2H),7.09(tt,J＝7.5,1.5Hz,1H),7.04–6.97(m,4H),4.47(dt,J＝12.3,7.1Hz,1H),4.39(dt,J＝12.3,7.0Hz,1H),4.30(ddt,J＝20.7,12.3,7.1Hz,2H),4.21(dt,J＝12.3,7.1Hz,1H),4.13(dt,J＝12.2,7.1Hz,1H),4.06–3.94(m,4H),3.91–3.78(m,2H),3.70–3.60(m,2H),3.59(dt,J＝5.5,0.9Hz,2H),3.43–3.34(m,2H),3.13(dt,J＝12.5,7.1Hz,1H),3.00(dt,J＝12.5,7.1Hz,1H)。HRMS(ESI):591.2201[M+H]+。
实施例24制备2'-(1-(2-(3,5-二环氧丙基-2,4,6-三氧-1,3,5-三嗪-1-基)乙基)-1H-1,2,3-三唑-4-基)-2-(1-(4-氯苯甲酰基)-5-甲氧基-2-甲基1H吲哚-3-基)乙酸乙酯(8u/BY27)
应用路线1，制备方法同实施例4，得到无色油状物(0.08g，29.9％)。1H NMR(500MHz,Chloroform-d)δ7.73–7.67(m,2H),7.54–7.48(m,3H),7.05(d,J＝1.5Hz,1H),6.99(d,J＝7.5Hz,1H),6.75(dd,J＝7.5,1.5Hz,1H),4.52–4.43(m,1H),4.45–4.34(m,2H),4.33(dt,J＝12.1,6.8Hz,1H),4.26–4.11(m,2H),4.07–3.98(m,4H),3.89–3.82(m,2H),3.80(d,J＝9.5Hz,5H),3.71–3.61(m,2H),3.44–3.34(m,2H),3.13(dt,J＝12.5,7.1Hz,1H),3.00(dt,J＝12.5,7.1Hz,1H),2.35(s,2H)。HRMS(ESI):720.2185[M+H]+。
实施例25制备2'-(1-(2-(3,5-二环氧丙基-2,4,6-三氧-1,3,5-三嗪-1-基)乙基)-1H-1,2,3-三唑-4-基)-2-(1,8-二乙基-1,3,4,9-四氢吡喃并[3,4-b]吲哚-1-基)乙酸乙酯(8w/BY28)
应用路线1，制备方法同实施例4，得到无色油状物(0.09g，25.4％)。1H NMR(500MHz,Chloroform-d)δ9.69(s,1H),7.52(s,1H),7.46(dd,J＝7.5,1.5Hz,1H),7.17(t,J＝7.5Hz,1H),7.02(dd,J＝7.5,1.5Hz,1H),4.52–4.39(m,2H),4.42–4.34(m,1H),4.37–4.24(m,2H),4.14(dt,J＝12.3,7.1Hz,1H),4.07–3.95(m,5H),3.94(dt,J＝12.4,7.1Hz,1H),3.89–3.79(m,2H),3.70–3.61(m,2H),3.43–3.36(m,2H),3.30(d,J＝12.3Hz,1H),3.20–3.09(m,2H),2.96(dt,J＝12.3,7.1Hz,1H),2.91–2.78(m,2H),2.67–2.50(m,2H),2.32(dq,J＝12.5,8.0Hz,1H),2.21(dq,J＝12.5,8.0Hz,1H),1.24(t,J＝8.0Hz,3H),1.04(t,J＝8.0Hz,3H)。HRMS(ESI):650.2934[M+H]+。
实施例26制备2'-(1-(2-(3,5-二环氧丙基-2,4,6-三氧-1,3,5-三嗪-1-基)乙基)-1H-1,2,3-三唑-4-基)-2-(5-氟-2-甲基-1-(4-甲磺酰基苯基甲叉基)1H茚-3-基)乙酸乙酯(8v/BY29)
应用路线1，制备方法同实施例4，得到无色油状物(0.11g，28.2％)。1H NMR(500MHz,Chloroform-d)δ7.67–7.60(m,4H),7.52(s,1H),7.51(dd,J＝7.6,5.0Hz,1H),7.35(dd,J＝8.2,1.5Hz,1H),7.02(td,J＝7.8,1.5Hz,1H),6.67(s,1H),4.47(dt,J＝11.5,6.9Hz,1H),4.43–4.28(m,4H),4.21–4.11(m,1H),4.07–3.98(m,4H),3.89–3.79(m,2H),3.71(d,J＝12.3Hz,1H),3.70–3.61(m,3H),3.44–3.34(m,2H),3.13(dt,J＝12.5,7.1Hz,1H),3.00(dt,J＝12.5,7.1Hz,1H),2.75(s,2H),2.29(s,2H)。HRMS(ESI):719.2301[M+H]+。
实施例27制备2'-(1-(2-(3,5-二环氧丙基-2,4,6-三氧-1,3,5-三嗪-1-基)乙基)-1H-1,2,3-三唑-4-基)-2-(4-(哌啶-1-基)苯基)乙酸乙酯(8z/BY31)
应用路线1，制备方法同实施例4，得到无色油状物(0.21g，31.5％)。1H NMR(500MHz,Chloroform-d)δ7.52(s,1H),7.22(dt,J＝7.5,1.1Hz,2H),6.90–6.84(m,2H),4.47(dt,J＝12.3,7.1Hz,1H),4.30(dddt,J＝57.0,34.2,12.5,7.1Hz,4H),4.13(dt,J＝12.2,7.1Hz,1H),4.06–3.94(m,4H),3.92–3.80(m,2H),3.70–3.61(m,2H),3.57(q,J＝1.0Hz,2H),3.43–3.34(m,6H),3.13(dt,J＝12.5,7.1Hz,1H),3.00(dt,J＝12.5,7.1Hz,1H),1.73–1.57(m,7H)。HRMS(ESI):582.2675[M+H]+。
实施例28制备2'-(1-(2-(3,5-二环氧丙基-2,4,6-三氧-1,3,5-三嗪-1-基)乙基)-1H-1,2,3-三唑-4-基)-2-(4-(哌嗪-1-基)苯基)乙酸乙酯(8x/BY32)
应用路线1，制备方法同实施例4，得到无色油状物(0.15g，19.5％)。1H NMR(500MHz,Chloroform-d)δ7.52(s,1H),7.20(dt,J＝7.5,1.0Hz,2H),6.98–6.92(m,2H),4.47(dt,J＝12.3,7.1Hz,1H),4.30(dddt,J＝57.0,34.2,12.5,7.1Hz,4H),4.13(dt,J＝12.2,7.1Hz,1H),4.06–3.94(m,4H),3.91–3.80(m,2H),3.70–3.61(m,2H),3.57(q,J＝1.0Hz,2H),3.43–3.34(m,6H),3.17–3.08(m,2H),3.08(dd,J＝7.1,5.1Hz,3H),3.00(dt,J＝12.5,7.1Hz,1H),1.93(p,J＝5.1Hz,1H)。HRMS(ESI):583.2629[M+H]+。
实施例29制备2'-(1-(2-(3,5-二环氧丙基-2,4,6-三氧-1,3,5-三嗪-1-基)乙基)-1H-1,2,3-三唑-4-基)-2-(4-(4-甲基哌嗪-1-基)苯基)乙酸乙酯(8y/BY33)
应用路线1，制备方法同实施例4，得到无色油状物(0.19g，20.9％)。1H NMR(500MHz,Chloroform-d)δ7.20(dt,J＝7.5,1.0Hz,1H),6.91–6.85(m,1H),4.52–4.09(m,3H),4.06–3.94(m,2H),3.90–3.80(m,1H),3.70–3.61(m,1H),3.57(q,J＝1.0Hz,1H),3.43–3.34(m,1H),3.27–3.08(m,2H),3.00(dt,J＝12.5,7.1Hz,0H),2.72–2.56(m,2H),2.27(s,1H)。HRMS(ESI):597.2780[M+H]+。
实施例30制备2'-(1-(2-(3,5-二环氧丙基-2,4,6-三氧-1,3,5-三嗪-1-基)乙基)-1H-1,2,3-三唑-4-基)-2-(4-(吗啉-1-基)苯基)乙酸乙酯(8aa/BY34)
应用路线1，制备方法同实施例4，得到无色油状物(0.22g，21.7％)。1H NMR(500MHz,Chloroform-d)δ7.52(s,1H),7.20(dt,J＝7.5,1.1Hz,2H),6.97–6.91(m,2H),4.47(dt,J＝12.3,7.1Hz,1H),4.30(dddt,J＝57.0,34.2,12.4,7.1Hz,4H),4.13(dt,J＝12.3,7.1Hz,1H),4.06–3.94(m,4H),3.91–3.80(m,2H),3.78(t,J＝7.1Hz,4H),3.70–3.61(m,2H),3.57(q,J＝1.0Hz,2H),3.43–3.34(m,2H),3.23(dt,J＝15.9,7.1Hz,4H),3.13(dt,J＝12.5,7.1Hz,1H),3.00(dt,J＝12.5,7.1Hz,1H)。HRMS(ESI):584.2466[M+H]+。
实施例31制备中间体9(1,3-二烯丙基-5-(2-氨基乙基)-1,3,5-三嗪-2,4,6-三酮)
将Boc-溴乙胺(11.90g,57.0mmol)、中间体2(12.45g,55.8mmol)和无水碳酸钾(9.81g,71.1mmol)加入到装有200ml DMF的烧瓶中。氮气保护下搅拌并加热至65℃，反应8h。反应完成后，将DMF在真空中蒸去，加入蒸馏水100ml溶解无机盐。用3*100ml乙酸乙酯萃取有机物，合并有机相，依次用100ml 10％ NaOH、100ml饱和氯化钠溶液洗涤，无水硫酸钠干燥，浓缩至20ml，加入100ml石油醚并搅拌至固体析出，过滤得到白色粉末。再将粉末溶于50ml二氯甲烷，滴加10ml三氟乙酸，室温搅拌24小时，真空除去溶剂和剩余酸性物，得到淡黄色油状中间体9(12.14g 61.7％)。1H NMR(600MHz,DMSO-d6)δ7.84(s,3H),5.88–5.76(m,2H),5.20(dd,J＝56.1,13.8Hz,4H),4.36(d,J＝5.2Hz,4H),4.07–3.98(m,2H),3.05(p,J＝5.6Hz,2H)。ESI-MS(m/z):253.1[M+H]+。
实施例32制备2-([1,1’联苯]-4-基)-N-(2-(3 5-二环氧丙基-2 4 6-三酮-1 35-三嗪-1-基)乙基)乙酰胺(11s/BY3)
按照路线2，向装有磁力搅拌的250mL单口茄形瓶中依次加入羧酸(1eq)，吡啶(0.1eq)，氯化亚砜(1.2eq)，加入适量二氯甲烷为反应溶剂，加热至45℃并搅拌反应约12h，向反应体系中加入中间体9(1eq)，滴加三乙胺(2.4eq)，继续在45℃下搅拌约12h，真空下蒸去溶剂，加适量水、二氯甲烷充分震荡，分离水相并用二氯甲烷萃取3次，合并有机相，无水硫酸钠干燥，浓缩，柱层析纯化，得到中间体2-([1,1’联苯]-4-基)-N-(2-(3 5-二烯丙基-24 6-三酮-1 3 5-三嗪-1-基)乙基)乙酰胺(10S)，为淡黄色油状液体(3.32g,74.5％)。1HNMR(600MHz,Chloroform-d)δ7.58(dd,J＝7.8,4.8Hz,4H),7.45(t,J＝7.6Hz,2H),7.36(t,J＝7.4Hz,1H),7.31(d,J＝7.9Hz,2H),5.85(ddt,J＝16.5,11.1,5.9Hz,2H),5.81(s,1H),5.34–5.21(m,4H),4.45(d,J＝5.9Hz,4H),4.04(t,J＝6.6,4.0Hz,2H),3.55(t,2H),3.53(s,2H)。ESI-HRMS(m/z):469.1759[M+Na]+。
在室温下向中间体10S(2mmol 1eq)的40ml丙酮溶液，加入40ml 0.4mM Na2EDTA水溶液。加入NaHCO3(6.4g)和OXONE(30.4g)。薄层色谱监测反应完成后，过滤除去白色无机盐，真空下蒸去丙酮。剩下的水用3*40ml乙酸乙酯萃取。合并有机相，用无水硫酸钠干燥，浓缩，用制备型高效液相色谱法提纯，得到化合物2-([1,1’联苯]-4-基)-N-(2-(3 5-二环氧丙基-2 4 6-三酮-1 3 5-三嗪-1-基)乙基)乙酰胺(11S)，为淡黄色油状液体(95mg,9.9％)。1H NMR(400MHz,Chloroform-d)δ7.59(dt,J＝8.2,2.5Hz,5H),7.45(t,J＝7.5Hz,2H),7.37(dd,J＝7.1,1.7Hz,1H),7.32(dd,J＝7.8,5.8Hz,2H),5.82(s,1H),4.10(ddd,J＝14.1,5.4,3.2Hz,2H),4.07–4.03(m,2H),4.00(ddd,J＝14.1,4.6,1.9Hz,2H),3.55(d,J＝5.6Hz,4H),3.23(p,J＝4.3Hz,2H),2.80(t,J＝4.4Hz,2H),2.67(dd,J＝4.8,2.4Hz,2H)；13C NMR(151MHz,Chloroform-d)δ170.81,148.18,147.85,139.44,139.23,132.56,129.01,127.85,126.62,126.45,125.95,47.66,45.22,45.15,43.55,43.45,42.15,41.92,37.28。HRMS(ESI):479.1933。
实施例33制备2-(4-异丁基苯基)-N-(2-(3 5-二环氧丙基-2 4 6-三酮-1 3 5-三嗪-1-基)乙基)丙酰胺(11q/BY6)
应用通用方法E，得到淡黄色油状液体(340mg,38.1％)。1H NMR(400MHz,Chloroform-d)δ7.16(d,J＝8.1Hz,2H),7.10(d,J＝8.0Hz,2H),5.73(d,J＝6.5Hz,1H),4.12(dtd,J＝14.1,6.2,5.7,2.3Hz,2H),4.06–4.00(m,2H),4.00–3.92(m,2H),3.51(p,J＝5.1Hz,2H),3.45(t,J＝7.2Hz,1H),3.23(td,J＝7.0,5.7,3.2Hz,2H),2.82(t,J＝4.5Hz,2H),2.72–2.66(m,2H),2.45(d,J＝7.2Hz,2H),1.85(hept,J＝6.8Hz,1H),1.45(d,J＝7.2Hz,3H),0.90(d,J＝6.6Hz,7H)；13C NMR(151MHz,Chloroform-d)δ175.26,149.16,148.86,140.77,138.21,129.61,127.42,48.64,46.67,46.38,46.36,46.33,46.30,45.02,44.62,44.55,44.47,42.85,38.21,30.17,22.40,18.52。HRMS(ESI):495.2226。
实施例34制备2-(3-氟-4-苯基苯-1-基)-N-(2-(3 5-二烯丙基-2 4 6-三酮-1 35-三嗪-1-基)乙基)丙酰胺(11p/BY4)
应用通用方法E，得到淡黄色油状液体(355mg,33.0％)。1H NMR(400MHz,Chloroform-d)δ7.54(d,J＝7.6Hz,2H),7.48–7.36(m,5H),7.12(dd,J＝14.4,9.8Hz,2H),5.88(s,1H),4.15–4.05(m,4H),3.98(dt,J＝14.4,3.4Hz,2H),3.60–3.49(m,3H),3.23(s,2H),2.81(t,J＝4.5Hz,2H),2.69–2.64(m,2H),1.50(d,J＝7.2Hz,3H)；13C NMR(151MHz,Chloroform-d)δ174.27,159.75(d,J＝248.8Hz),149.22,148.81,142.42(d,J＝7.5Hz),135.30,131.03(d,J＝3.9Hz),128.89(d,J＝2.9Hz),128.52,127.91(d,J＝13.3Hz),127.78,123.74(d,J＝3.3Hz),115.41(d,J＝23.5Hz),48.64(d,J＝2.6Hz),46.54,46.28(d,J＝3.3Hz),46.22(d,J＝4.9Hz),45.02–44.04(m),42.77,38.54,18.50(d,J＝2.3Hz)。HRMS(ESI):533.1790。
实施例35制备2-(3-氟-4-苯基苯-1-基)-N-(2-(3 5-二烯丙基-2 4 6-三酮-1 35-三嗪-1-基)乙基)丙酰胺(11t/BY5)
应用通用方法E，得到淡黄色油状液体(398mg,39.3％)。1H NMR(400MHz,Chloroform-d)δ7.83–7.77(m,2H),7.74–7.68(m,1H),7.68–7.41(m,7H),5.89(s,1H),4.14–4.03(m,4H),4.01–3.93(m,2H),3.63–3.46(m,3H),3.21(s,2H),2.80(t,J＝4.4Hz,2H),2.67(dd,J＝4.9,2.5Hz,2H),1.51(d,J＝7.2Hz,3H)；13CNMR(151MHz,Chloroform-d)δ195.49,173.32,148.22,148.20,147.81,140.59,137.04,136.34,131.61,130.65,129.06,128.18,128.13,127.68,127.35,47.62,47.60,45.84,45.29,45.23,43.61,43.53,43.43,41.75,37.57,17.58。HRMS(ESI):543.1863。
实施例36体外培养的小鼠血管平滑肌细胞ROS诱导活性检测
使用BY1对体外培养的小鼠血管平滑肌细胞ROS诱导活性进行检测，结果如图1所示。
具体方法如下：
首先将化合物BY1溶于二甲亚砜中并配制30mmol/L(60μmol/L)的工作液；
实验组：向含5mL培养基的T25培养瓶培养的小鼠血管平滑肌细胞中加入5μL上述工作液，使BY1在培养液中的浓度为30μmol/L(60μmol/L)，将培养瓶置于培养箱中孵育24小时，弃去培养基，用5mL PBS洗涤细胞，弃去PBS，按ROS试剂盒说明书要求加入适量ROS-FITC检测试剂并孵育30min；
对照组：对照组(CON)为没有接受任何刺激的同培养时间的上述细胞，用实验组相同条件加入检测试剂；
将实验组细胞与对照组细胞同时弃去含ROS-FITC试剂的培养基，按照5mL/瓶加入PBS洗涤细胞，弃去PBS，按照1mL/瓶加入胰酶消化细胞1.5分钟，再按照1mL/瓶加入含血清的培养基终止消化，收集细胞悬液，以1000r/min离心，弃去上清，加入2mL PBS重悬细胞，使用流式细胞仪检测并计算ROS诱导率，其它化合物ROS诱导率实验计算结果见表5。
实施例37KYSE410细胞、Mia PaCa-2细胞、小鼠血管平滑肌细胞(VSMCs)
本发明使用从中国科学院获得的KYSE410、Mia PaCa-2、VSMCs细胞系，在37℃、5％二氧化碳培养箱中培养，培养基采用含10％胎牛血清(FBS)的RPMI1640或含血清的DMEM培养基。
CCK8法测定细胞抑制率
将T25培养瓶内培养的上述细胞弃去培养基，按1mL/瓶加入PBS洗涤细胞，弃去PBS，再按照1mL/瓶加入胰酶消化1.5分钟，后按1mL/瓶加入含血清的培养基终止消化，按照10000个/孔的细胞密度将细胞悬液接种于96孔板，将接种细胞的96孔板置于培养箱中培养24小时。将本发明中的化合物溶于二甲亚砜中并配制成10mmol/L的溶液，分别将每个化合物按照合适的浓度梯度加入上述含细胞的96孔板中(本发明提供通用浓度梯度：10μmol/L、25μmol/L、50μmol/L、75μmol/L、100μmol/L、125μmol/L、150μmol/L、175μmol/L、200μmol/L、250μmol/L、300μmol/L)，再置于培养箱中孵育24小时；弃去含化合物的培养基，按100μL/孔加入PBS洗涤细胞，弃去PBS，按100μL/孔加入10％ CCK8试剂并置于培养箱中孵育2小时，使用酶标仪在450nm波长下读取吸光度并计算化合物IC50值，结果见表3、表4和表5。
表3 KYSE410细胞IC50结果
| 化合物 | IC50(μM)KYSE410细胞 |
| BY-1 | 24.3 |
| BY-7 | 49.8 |
| BY-9 | 65.4 |
| BY-15 | 50.9 |
| BY-17 | 41.3 |
| BY-18 | 48.9 |
| BY-19 | 93.4 |
| BY-21 | 59.9 |
| BY-23 | 70.4 |
| BY-24 | 58.6 |
表4 MIA PaCa-2细胞IC50结果
| 化合物 | IC50(μM)MIA PaCa-2细胞 |
| BY-1 | 77.22 |
| BY-3 | 65.88 |
| BY-4 | 99.64 |
| BY-5 | 125.31 |
| BY-6 | 87.60 |
| BY-7 | 54.55 |
| BY-9 | 109.62 |
| BY-15 | 186.90 |
| BY-16 | 157.20 |
| BY-19 | 219.60 |
| BY-21 | 158.7 |
| BY-23 | 111.65 |
| BY-24 | 109.27 |
| BY-25 | 56.32 |
| BY-26 | 158.96 |
| BY-27 | 89.65 |
| BY-28 | 88.31 |
| BY-29 | 101.19 |
| BY-30 | ＞200 |
| BY-33 | 121.45 |
| BY-34 | 69.50 |
表5 VSMCs细胞IC50及ROS诱导率结果
最后应说明的是：以上实施例仅用以说明本发明的技术方案，而非对其限制；尽管参照前述实施例对本发明进行了详细的说明，本领域的普通技术人员应当理解：其依然可以对前述实施例所记载的技术方案进行修改，或者对其中部分技术特征进行等同替换；而这些修改或者替换，并不使相应技术方案的本质脱离本发明实施例技术方案的精神和范围。
Claims (8)
1.式I所示结构的1,3-双环氧丙基-5-取代环状三聚脲类化合物或其药用盐：
其中，Y代表O或NH；
X代表—(CH2)2—或
R1代表H或C1-C5烷基；
R2代表
R3为单取代或两个及以上的多取代，独立的选自H、卤素、叠氮基、氰基、甲磺基、C1-C5烷基、C2-C5烯基、C2-C5炔基、C1-C5烷氧基、C1-C5烷巯基、1-3卤素取代的C1-C5烷氧基、3-8元环烷基、含有1-3个选自N、O、S的5-6元杂环基、C1-C5烷基取代的含有1-3个选自N、O、S的5-6元杂环基、芳基、苄基、5-6元杂芳基。
2.根据权利要求1所述的式I所示结构的1,3-双环氧丙基-5-取代环状三聚脲类化合物或其药用盐，其特征在于：
所述C1-C5烷基选自—CH3、—CH2CH3、—CH(CH3)2、—(CH2)2CH3、—(CH2)3CH3、—(CH2)4CH3、—CH(CH3)CH2CH3、—C(CH3)3、—CH(CH3)(CH2)2CH3、—CH2CH(CH2)2CH3、—CH2C(CH2)3；
所述C1-C5烷氧基选自—OCH3、—OCH2CH3、—OCH(CH3)2、—O(CH2)2CH3、—O(CH2)3CH3、—O(CH2)4CH3、—OCH(CH3)CH2CH3、—OC(CH3)3、—OCH(CH3)(CH2)2CH3、—OCH2CH(CH2)2CH3、—OCH2C(CH2)3；
所述C2-C5烯基选自乙烯基、异丙烯基、正丙烯基、正丁烯基、异丁烯基、仲丁烯基、正戊烯基、异戊烯基；
所述C2-C5炔基选自乙炔基、丙炔基、丁炔基、戊炔基；
所述C1-C5烷巯基选自—SCH3、—SCH2CH3、—SCH(CH3)2、—S(CH2)2CH3、—S(CH2)3CH3、—S(CH2)4CH3、—SCH(CH3)CH2CH3、—SC(CH3)3、—SCH(CH3)(CH2)2CH3、—SCH2CH(CH2)2CH3、—SCH2C(CH2)3；
所述含有1-3个选自N、O、S的5-6元杂环基选自哌嗪基、吗啉基、哌啶、四氢吡咯基；
所述5-6元杂芳基选自吡咯基、噻吩基、呋喃基、吡啶、咪唑基。
3.根据权利要求1所述的式I所示结构的1,3-双环氧丙基-5-取代环状三聚脲类化合物或其药用盐，其特征在于，所述R2选自如下结构：
4.所述的式I所示结构的1,3-双环氧丙基-5-取代环状三聚脲类化合物或其药用盐，其特征在于，选自如下：
5.药物组合物，其包含权利要求1-4任一项所述的式I所示结构的1,3-双环氧丙基-5-取代环状三聚脲类化合物或其药用盐，以及任选地，一种或多种药学上可接受的载体或赋形剂。
6.根据权利要求1-4任一项所述的式I所示结构的1,3-双环氧丙基-5-取代环状三聚脲类化合物或其药用盐在制备诱导异常增生细胞发生铁死亡的药物中的应用。
7.根据权利要求6所述的应用，其特征在于，异常增生细胞包括小鼠血管平滑肌细胞、人食管癌细胞、乳腺癌细胞、肾癌细胞、黑色素瘤细胞、胰腺癌细胞、胶质瘤细胞、结直肠癌细胞、淋巴瘤细胞、非小细胞肺癌细胞。
8.根据权利要求6所述应用，其特征在于，在制备治疗恶性肿瘤、血管内皮异常增生所致心血管疾病药物中的应用。
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