CN118206507A - 一种含硒化合物及其制备方法与用途 - Google Patents
一种含硒化合物及其制备方法与用途 Download PDFInfo
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- CN118206507A CN118206507A CN202410319432.2A CN202410319432A CN118206507A CN 118206507 A CN118206507 A CN 118206507A CN 202410319432 A CN202410319432 A CN 202410319432A CN 118206507 A CN118206507 A CN 118206507A
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- pharmaceutically acceptable
- selenium
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- cancer
- acid
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6527—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and oxygen atoms as the only ring hetero atoms
- C07F9/6533—Six-membered rings
Landscapes
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- Health & Medical Sciences (AREA)
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- General Chemical & Material Sciences (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biochemistry (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及一种含硒化合物及其制备方法与用途，所述含硒化合物的结构式如式I所示，本发明所提供的含硒化合物或其药用盐具有良好的微管蛋白抑制活性和优秀的抗肿瘤活性，为抗肿瘤药物的进一步开发提供了研究基础。
Description
技术领域
本发明属于医药技术领域，具体地说，本发明涉及一种含硒化合物及其制备方法与抗肿瘤、抑制微管蛋白的用途。
背景技术
微管是细胞骨架的主要组成部分，在维持细胞形态、细胞分裂、信号转导等过程中起着重要作用，因此，微管蛋白是一个非常有前景的新型化疗药物的靶标。多种微管抑制剂已被用于一线治疗肿瘤，如紫杉醇用于治疗卵巢癌、乳腺癌、肺癌、大肠癌及黑色素瘤等，长春新碱用于治疗急性白血病、恶性淋巴瘤、生殖细胞肿瘤、小细胞肺癌及乳腺癌等，微管是肿瘤化疗中最成功的靶点之一。
尽管微管抑制剂在临床上广泛用于癌症治疗，但是耐药性肿瘤的出现限制了微管抑制剂在临床上的应用。瘤细胞中P-糖蛋白(P-glycoprotein)的高表达是耐药的重要原因之一。紫杉醇和长春新碱都是P-糖蛋白的底物，P-糖蛋白外排这些药物，降低药物在胞内的浓度，进而降低药物的抗肿瘤活性。临床常用微管抑制剂还存在其它技术缺陷，例如神经毒性、水溶性差以及难于合成纯化等。
IMB5046是本所研究发现的具有优秀抗肿瘤活性的微管蛋白抑制剂。研究发现，IMB5046靶向作用于秋水仙碱口袋，对A-431,HT-1080，HT29以及A549等肿瘤细胞均具有优秀的抑制活性(IC50＝0.037-0.426μM)。值得一提的是，IMB5046对秋水仙碱，长春新碱，以及紫杉醇耐药的肿瘤细胞KBV200和MCF7/ADR均具有优秀的抑制活性(Resistance index＝1.1-1.4)。另外，体内活性研究表明，IMB5046可显著抑制肿瘤的生长，15mg/kg的IMB5046通过腹腔给药，给药后第24天的抑瘤率达65.6％。(Scitific Reports,2016,6,31472)，本研究以IMB5046为先导化合物，设计合成了一系列含硒的IMB5046衍生物，部分化合物体外具有更为优秀的抗肿瘤活性，有望成为潜在的抗肿瘤药物。
发明内容
本发明的目的之一是提供一组含硒化合物或其药用盐。
本发明的又一目是提供所述含硒化合物的合成方法。
本发明的再一目是提供含有所述含硒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含硒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制备治疗或预防肿瘤相关疾病和抑制微管蛋白抑制药物方面的应用。
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“肿瘤”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肿块，包括良性肿瘤、恶性肿瘤和交界肿瘤。包括但不局限于乳腺癌、卵巢癌、结直肠癌、黑色素瘤、非小细胞肺癌、小细胞肺癌、胃肠道间质瘤、宫颈癌、胰腺癌、前列腺癌、胃癌、慢性髓样白细胞过多症、肝癌、淋巴瘤、腹膜癌和软组织肉瘤。
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，X代表CH2、O或S；
n1,n2分别独立的选在0、1或2；
Y代表O或NH；
R1代表NO2、C1-C5烷基、1-3卤代的C1-C5烷基、F、Cl或Br；
R2代表C1-C5烷基或1-3卤代的C1-C5烷基；
R3代表H、OH、SH、R4；
R4为磷酸酯基和氨基酸酯基。
作为本发明的一些优选实施方案，所述C1-C5烷基选自CH3、CH2CH3、CH(CH3)2、(CH2)2CH3、(CH2)3CH3、(CH2)4CH3、CH(CH3)CH2CH3、CH2CH(CH3)2、C(CH3)3、CH(CH3)(CH2)2CH3、CH2CH(CH2)2CH3、CH2C(CH2)3；
1-3卤代为1-3个任选自F、Cl或Br的取代基，当取代基为2或3个时，其可以相同或不同。
作为本发明的一些优选实施方案，所述R1选自NO2、CF3、F；
所述R2选自CH3、CH2CH3、CH(CH3)2、CHF2、CH2F、CF3；
所述R3选自H、OH、
作为本发明的一些优选实施方案，所述药用盐选自钠盐、钾盐、钙盐、盐酸盐、磷酸盐或硫酸盐。
在本发明的一些优选实施方案中，所述式I所示的含硒化合物或其药用盐选自如下：
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，单独或组合使用的术语“烷基”是指直链或支链的烷基。术语“Cm-n烷基”(m及n各自为整数)是指含有m至n个碳原子的直链或支链烷基。本发明中单独或组合使用的术语“C1-5烷基”是指含有1至5个碳原子的直链或支链烷基。表示性实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、特戊基。
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。
技术主题二
本发明还提供了式I所示含硒化合物的合成方法，虽然本发明化合物可通过如下的方法制得，然而该方法的条件，例如反应物、溶剂、酸、碱、所用化合物的量、反应温度、反应时间等不限于以下的描述。还可以任选将本说明书中描述的或本领域技术人员已知的各种合成方法的组合来方便地制得本发明的化合物，本发明所属领域的技术人员可以容易地进行上述组合。
路线1
路线2
路线3
X，n1,n2,Y,R1,R2如前所述。
技术主题三
本发明提供一种药物组合物，其包含式I所示的含硒化合物或其药用盐，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抗肿瘤药物中的应用。
在一些实施方案中，所述肿瘤包括结直肠癌、乳腺癌、胃癌、肺癌前列腺癌、胰腺癌、肝癌、卵巢癌、黑色素瘤、脑癌、转移性骨病、A型淋巴瘤、胃肠癌、白血病。
发明的有益效果
本发明研制开发的化合物经验证对微管蛋白具有良好的抑制性，具有优秀的抗肿瘤活性，有望成为潜在的抗肿瘤药物。
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。
本实施例部分化合物通过如下路线合成：
a)NaNO2,KSeCN,0℃-rt；b)KOH,MeOH,rt；c)NaBH4,R2I,EtOH:H2O＝1:1,rt；d)LiOH,MeOH:H2O＝3:1；e)LiAlH4,THF,Ar；f)1)EDCI,DMAP,DCM,2)Pd(Ph3P)4,K2CO3,Methanol,Ar,rt.
路线2
g)NH4Cl,HOAt,EDCI,DMF,rt；h)LiAlH4,THF,Ar；i)1)EDCI,DMAP,DCM,2)Pd(Ph3P)4,K2CO3,Methanol,Ar,rt.
实施例1化合物I-1
a)0℃下搅拌的1-1(3g，19.8mmol)的10％HCl(25mL)溶液中加入亚硝酸钠(1.6g，23.2mmol)，并将反应混合物保持在5℃以下。反应完成后，加入饱和乙酸钠以将pH调节至6.0。然后，滴加硒氰酸钾(4.2g，29.2mml)在水(1mL)中的溶液。将反应混合物在室温下搅拌3小时。乙酸乙酯(3X50ml)萃取，合并有机相，饱和食盐水冲洗，无水硫酸钠干燥，浓缩后柱层析(PE/EA＝10:1)得1-2的黄色固体粗品4.7g；
b)将KOH(2.1g，37.4mmol)加入到1-2(4.7g，19.6mmol)的甲醇(45ml)溶液中。将混合物搅拌1小时，滤出所得橙黄色沉淀，用甲醇洗涤，并在真空下干燥，得到1-3的黄色固体1.14g；
c)向1-3(1.14g，2.7mmol)的乙醇/水(1∶1，8ml)溶液中分批加入NaBH4(200mg，5.3mmol)，并将混合物搅拌20分钟。加入碘甲烷(376mg，2.7mmol)并将反应在室温下搅拌1小时。反应完成后，加入水，并将混合物用乙酸乙酯萃取三次。用饱和食盐水洗涤有机相，并用无水硫酸钠干燥。蒸发溶剂得到粗产物，将其通过硅胶柱(PE/EA＝10∶1)纯化，得到1-4的白色固体1.08g；
d)将1-4溶于MeOH/H2O(3:1,40ml)中，加入LiOH(338mg，3mmol)，45℃下反应，反应完全后浓缩，调PH＝3。乙酸乙酯(3X30ml)萃取，合并有机相，饱和食盐水冲洗，无水硫酸钠干燥，浓缩后柱层析(DCM:MeOH＝80:1)得1-5的白色固体976mg；
e)在N2气氛下，将LiAlH4(514m g，13.5mmol)在0℃下加入到1-5(976mg，4.5mmol)的无水THF溶液(20ml)中。在0℃下搅拌20分钟后，在室温下搅拌4小时，用THF(40ml)稀释反应物并加入水(4mL)。然后将混合物在硅藻土上过滤，用乙酸乙酯(4×30ml)洗涤并在减压下浓缩,将其通过硅胶柱(PE/EA＝3∶1)纯化得1-6的黄色油状物520mg；
f)1-6(100mg，0.5mmol)在10毫升DCM中的溶液中加入2-吗啉-5-硝基苯甲酸(187mg,0.7mmol)、EDCI(474mg，2.5mmol)和催化量的DMAP。将混合物搅拌4小时，并用DCM(3X25ml)。然后用盐水洗涤合并的有机层，用无水硫酸钠干燥，真空浓缩，得到粗产物，用进行柱层析(PE/EA-3:1)纯化，得到目标化合物化合物I-1(132mg，产率60％)；
1H NMR(500MHz,CDCl3)δ8.61(d,J＝2.6Hz,1H),8.22(dd,J＝9.2,2.5Hz,1H),7.42(d,J＝8.0Hz,4H),6.96(d,J＝9.2Hz,1H),5.31(s,2H),3.76(t,J＝4.5Hz,4H),3.16(t,J＝4.6Hz,4H),2.37(s,3H)；
13C NMR(151MHz,CDCl3)δ165.95,156.20,139.90,133.20,133.04,130.44,129.64,128.55,128.12,120.88,117.53,67.12,66.46,51.86,7.26；
APCI(m/z):437.1[M+H]+。
实施例2化合物I-2
制备方法同化合物I-1，使用2-吗啉-5-氟苯甲酸为原料可制得油状化合物I-2；
1H NMR(500MHz,CDCl3)δ7.46-7.40(m,3H),7.34(d,J＝7.9Hz,2H),7.13(td,J＝8.3,7.9,2.8Hz,1H),7.03(dd,J＝9.0,4.7Hz,1H),5.28(s,2H),3.77-3.71(m,4H),3.03-2.89(m,4H),2.36(s,3H)；
13C NMR(151MHz,CDCl3)δ166.21(d,J＝2.3Hz),158.74,157.13,148.86(d,J＝2.7Hz),133.67,132.65,130.53,129.46,128.76(d,J＝7.2Hz),126.81(d,J＝7.0Hz),121.14(d,J＝7.7Hz),119.49(d,J＝22.0Hz),117.94(d,J＝23.9Hz),67.14,66.73,53.42,7.34；
APCI(m/z):410.1[M+H]+。
实施例3化合物I-3
制备方法同化合物I-1，使用2-吗啉-5-(三氟甲基)苯甲酸为原料可制得化合物I-3；
1H NMR(500MHz,CDCl3)δ7.98(s,1H),7.63(d,J＝8.6Hz,1H),7.43(d,J＝8.0Hz,2H),7.35(d,J＝8.0Hz,2H),7.04(d,J＝8.6Hz,1H),5.30(s,2H),3.73(t,J＝4.6Hz,4H),3.04(t,J＝4.6Hz,4H),2.36(s,3H)；
13C NMR(151MHz,CDCl3)δ166.21(d,J＝2.3Hz),158.74,157.13,148.86(d,J＝2.7Hz),133.67,132.65,130.53,129.46,128.76(d,J＝7.2Hz),126.81(d,J＝7.0Hz),121.14(d,J＝7.7Hz),119.49(d,J＝22.0Hz),117.94(d,J＝23.9Hz),67.14,66.73,53.42,7.34；
APCI(m/z):460.1[M+H]。
实施例4化合物I-4
a)0℃下搅拌的2-1(200mg，1mmol)的10％HCl(5mL)溶液中加入亚硝酸钠(81mg，1.2mmol)，并将反应混合物保持在5℃以下。反应完成后，加入饱和乙酸钠以将pH调节至6.0。然后，滴加硒氰酸钾(210mg，1.5mmol)在水(0.5mL)中的溶液。将反应混合物在室温下搅拌3小时。乙酸乙酯(3X25mL)萃取，合并有机相，饱和食盐水冲洗，无水硫酸钠干燥，浓缩后柱层析(PE/EA＝5：1)得2-2的黄色固体粗品65mg；
b)将KOH(23mg，0.4mmol)加入到2-2(60mg，0.2mmol)的甲醇(5mL)溶液中。将混合物搅拌1小时，滤出所得橙黄色沉淀，用甲醇洗涤，并在真空下干燥，得2-3的橙黄色固体90mg；
c)向2-3(361mg，0.67mol)的乙醇/水(1∶1，8mL)溶液中分批加入NaBH4(50mg，1.3mmol)，并将混合物搅拌20分钟。加入碘甲烷(95mg，0.67mmol)并将反应在室温下搅拌1小时。反应完成后，加入水，并将混合物用乙酸乙酯萃取三次。用盐水洗涤有机相，并用无水硫酸钠干燥。蒸发溶剂得到粗产物，将其通过硅胶柱(PE/EA＝10∶1)纯化，得到2-4的白色固体435mg；
d)将2-4(620mg,2.2mol)溶于MeOH/H2O(3：1,12mL)中，加入LiOH(124mg，6.9mmol)，45℃下反应，浓缩，调pH＝3。EA(3X25mL)萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩后柱层析(DCM：MeOH＝80：1)得2-5的淡黄色固体416mg；
e)在氩气下，将LiAlH4(172mg，4.5mmol)在0℃下加入到2-5(410mg，1.5mmol)的无水THF溶液(8mL)中。在0℃下搅拌20分钟后，在室温下搅拌4小时，用THF(16mL)稀释反应物并加入水(4mL)。然后将混合物在硅藻土上过滤，用乙酸乙酯(4×30mL)洗涤并在减压下浓缩,将其通过硅胶柱(PE/EA＝3∶1)纯化得2-6的黄色油状物293mg；
f)2-6(266mg，1mmol)在10毫升DCM中的溶液中加入2-吗啉-5-硝基苯甲酸(521mg,2mmol)、EDCI(992mg，5.1mmol)和催化量的DMAP。将混合物搅拌4小时，并用DCM(3X40mL)萃取，然后用饱和食盐水洗涤合并的有机层，用无水硫酸钠干燥，真空浓缩，得到粗产物，进行柱层析(PE/EA＝3∶1)纯化，得到合成酯的黄色油状物310mg
将酯(310mg，0.6mmol)溶解在甲醇(8mL)中，并在氮气氛下加入Pd(PPh 3)4(50mg，0.04mmol)。将淡黄色溶液搅拌5分钟，并加入K2CO3(261mg，1.8mmol)。3小时后原料完全消耗，蒸发甲醇，将粗产物通过硅胶柱(PE/EA＝2∶1)纯化得到目标化合物化合物I-4(128mg，产率45％)；
1H NMR(500MHz,CDCl3)δ8.64(d,J＝2.6Hz,1H),8.23(dd,J＝9.2,2.8Hz,1H),7.59(d,J＝7.8Hz,1H),7.08(s,1H),6.97(d,J＝9.2Hz,1H),6.92(d,J＝7.8Hz,1H),6.54(s,1H),5.30(s,2H),3.77(t,J＝4.6Hz,4H),3.19(t,J＝4.6Hz,4H),2.19(s,3H)；
13C NMR(151MHz,CDCl3)δ165.86,156.61,156.32,139.98,138.76,137.04,128.65,128.21,120.99,120.80,117.62,117.26,114.46,66.79,66.48,51.95,9.90；
ES-ESI(m/z):451.1[M-H]-。
实施例5化合物I-5
制备方法同化合物I-4，使用2-吗啉-5-氟苯甲酸为原料可制得油状化合物I-5；
1H NMR(500MHz,CDCl3)δ7.63(d,J＝7.8Hz,1H),7.50(dd,J＝8.9,3.2Hz,1H),7.19(td,J＝8.3,7.6,3.1Hz,1H),7.15-7.05(m,2H),6.95(dd,J＝7.8,1.9Hz,1H),6.58(s,1H),5.32(s,2H),3.78(t,J＝4.6Hz,4H),3.00(t,J＝4.6Hz,4H),2.23(s,3H)；
13C NMR(151MHz,CDCl3)δ166.14(d,J＝2.5Hz),158.79,157.18,156.58,148.99(d,J＝2.7Hz),139.25,136.98,126.79(d,J＝7.2Hz),121.24(d,J＝7.7Hz),120.83,119.58(d,J＝22.0Hz),117.97(d,J＝24.3Hz),116.95,114.28,67.14,66.40,53.48,9.92；
MS-ESI(m/z):424.0[M-H]-。
实施例6化合物I-6
制备方法同化合物I-4，使用2-吗啉-5-(三氟甲基)苯甲酸为原料可制得化合物I-6；
1H NMR(500MHz,CDCl3)δ8.01(s,1H),7.64(d,J＝6.3Hz,1H),7.59(d,J＝8.0Hz,1H),7.09(s,1H),7.06(d,J＝8.7Hz,1H),6.92(d,J＝6.2Hz,1H),6.54(s,1H),5.30(s,2H),3.75(t,J＝4.6Hz,4H),3.07(t,J＝4.6Hz,4H),2.18(s,3H)；
13C NMR(151MHz,CDCl3)δ166.53,156.59,154.76,139.07,136.99,129.74(d,J＝3.5Hz),129.28(d,J＝3.8Hz),123.04,120.90,118.59,117.07,114.38,66.75,66.51,52.41,9.91；
MS-ESI(m/z):474.1[M-H]-。
实施例7化合物I-7
制备方法同化合物I-4，使用2-硫代吗啉-5-氟苯甲酸为原料可制得化合物I-7；
1H NMR(600MHz,CDCl3)δ7.59(d,J＝7.9Hz,1H),7.40(dd,J＝8.8,3.1Hz,1H),7.13(ddd,J＝8.9,7.6,3.1Hz,1H),7.09-7.05(m,2H),6.91(dd,J＝7.8,1.9Hz,1H),6.54(s,1H),5.28(s,2H),3.21-3.18(m,4H),2.71-2.65(m,4H),2.19(s,3H)；
13C NMR(151MHz,CDCl3)δ166.00,158.88,157.26,156.45,149.83(d,J＝2.8Hz),139.16,136.87,122.60(d,J＝7.9Hz),120.67,119.27,119.12,117.41,117.25,116.79,114.09,66.27,55.61,28.03,9.81；
MS-ESI(m/z):440.0[M-H]-。
实施例8化合物I-8
制备路线与化合物1-4类似，使用2-吗啉-5-氟苯甲酸为原料，用碘乙烷替代碘甲烷可制得黄色固体化合物I-8；
1H NMR(600MHz,CDCl3)δ7.57(d,J＝7.8Hz,1H),7.47(dd,J＝8.9,3.1Hz,1H),7.15(ddd,J＝9.0,7.5,3.1Hz,1H),7.10(d,J＝1.8Hz,1H),7.05(dd,J＝9.0,4.7Hz,1H),6.91(dd,J＝7.8,1.9Hz,1H),6.65(s,1H),5.29(s,2H),3.74(d,J＝4.6Hz,4H),2.96(t,J＝4.6Hz,4H),2.72(q,J＝7.4Hz,2H),1.36(t,J＝7.5Hz,3H)；13C NMR(151MHz,CDCl3)δ166.01(d,J＝2.4Hz),158.64,157.02(d,J＝2.2Hz),148.87(d,J＝2.7Hz),139.34,137.85,126.59(d,J＝6.8Hz),121.09(d,J＝7.7Hz),120.40,119.53,119.39,117.95,117.79,115.12,113.94,67.01,66.29,53.34,23.43,15.73；
MS-ESI(m/z):438.0[M-H]-。
实施例9化合物I-9
制备方法同化合物1-8，使用2-碘代丙烷为原料可制得油状化合物I-9；
1H NMR(600MHz,CDCl3)δ7.54(d,J＝7.8Hz,1H),7.48(dd,J＝8.9,3.1Hz,1H),7.15(td,J＝8.4,7.8,3.1Hz,1H),7.11(s,1H),7.05(dd,J＝8.9,4.7Hz,1H),6.90(d,J＝8.1Hz,1H),6.73(d,J＝0.8Hz,1H),5.29(s,2H),3.74(d,J＝4.6Hz,4H),3.26(p,J＝7.0Hz,1H),2.96(d,J＝4.6Hz,4H),1.37(d,J＝6.8Hz,6H)；
13C NMR(151MHz,CDCl3)δ166.01(d,J＝2.3Hz),158.63,157.28,157.02,148.88(d,J＝2.5Hz),139.51,138.44,126.57(d,J＝6.8Hz),121.08(d,J＝7.7Hz),120.20,119.54,119.40,117.98,117.82,113.82,67.01,66.30,53.34,35.78,24.26；
MS-ESI(m/z):452.0[M-H]-。
实施例10化合物I-10
g)将2-5(50mg，0.18mmol)、氯化铵(20mg，0.37mmol)、1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐(70mg，0.36mmol)、1-羟基-7-氮杂苯并三唑(50mg，0.37mmol)和二异丙基乙胺(0.121mL，0.73mmol)在DMF(4mL)中的溶液在室温下搅拌1h，反应完成后蒸发溶剂，并用DCM(3X40mL)萃取，然后用盐水洗涤合并的有机层，用无水硫酸钠干燥，过滤，真空浓缩，得到粗产物，进行柱层析(PE/EA＝2：1)纯化，得到3-8的60mg；
h)在氩气下，将LiAlH4(25mg，0.65mmol)在0℃下加入到3-8(60mg，0.22mmol)的无水THF溶液(5mL)中。在0℃下搅拌20分钟后，回流下搅拌4小时，反应完全后，0℃下冷却，用THF(5mL)稀释反应物并加入水(1mL)。然后将混合物在硅藻土上过滤，用乙酸乙酯(3×20mL)洗涤并在减压下浓缩,将其通过硅胶柱(DCM/MEOH＝20：1)纯化得3-9的黄色油状物30mg；
i)将3-9(335mg，1.3mmol)的DCM溶液(15mL)中加入2-吗啉-5-硝基苯甲酸(656mg,2.6mmol)、EDCI(1.2g，6.2mmol)和催化量的DMAP。将混合物搅拌4小时，并用DCM(3X50mL)萃取，然后用盐水洗涤合并有机层，用无水硫酸钠干燥，真空浓缩，得到粗产物，进行柱层析(PE/EA＝3∶1)纯化，得到黄色油状物N-(3-烯丙基氧基-4-甲基硒基)苄基-2-吗啉-5-硝基苯甲酰胺435mg
N-(3-烯丙基氧基-4-甲基硒基)苄基-2-吗啉-5-硝基苯甲酰胺(435mg,0.88mmol)溶解在甲醇(10mL)中，并在氩气下加入Pd(PPh 3)4(72mg，0.06mmol)。将淡黄色溶液搅拌5分钟，并加入K2CO3(367mg，2.65mmol)。3小时后原料完全消耗，蒸发甲醇，将粗产物通过硅胶柱(PE/EA＝2∶1)纯化得到目标化合物化合物I-10(199mg，产率50％)；
1H NMR(500MHz,CDCl3)δ8.85(s,1H),8.62(s,1H),8.26(d,J＝9.0Hz,1H),7.57(d,J＝7.8Hz,1H),7.18(d,J＝9.0Hz,1H),7.01(s,1H),6.86(d,J＝8.0Hz,1H),6.63(s,1H),4.60(d,J＝5.8Hz,2H),3.58(t,J＝4.5Hz,4H),3.04(t,J＝4.6Hz,4H),2.17(s,3H)；
13C NMR(151MHz,CDCl3)δ164.90,156.86,155.60,143.73,141.30,137.23,128.45,127.59,127.10,120.86,119.67,116.58,114.14,66.54,53.02,43.74,9.91；
MS-ESI(m/z):450.0[M-H]-。
实施例11化合物I-11
制备方法同化合物I-10，使用5-氟-2-吗啉苯甲酸为原料可制得白色固体化合物I-11。1HNMR(500MHz,CDCl3)δ8.84(d,J＝2.7Hz,1H),8.62(s,1H),8.26(d,J＝9.0Hz,1H),7.57(d,J＝7.8Hz,1H),7.18(d,J＝9.0Hz,1H),7.01(s,1H),6.86(d,J＝8.0Hz,1H),6.63(s,1H),4.60(d,J＝5.8Hz,2H),3.58(t,J＝4.5Hz,4H),3.04(t,J＝4.6Hz,4H),2.17(s,3H)；
13C NMR(151MHz,CDCl3)δ164.72,161.11,159.49,156.83,146.89,142.00,137.29,123.06(d,J＝7.9Hz),120.90,119.01(d,J＝22.4Hz),118.52(d,J＝24.4Hz),116.23,114.16,66.99,53.82,43.67,10.03；
MS-ESI(m/z):423.1[M-H]-。
实施例12化合物I-12
a)室温下，向化合物1-5(700mg，3.2mmol)的DMF溶液(15mL)中加入EDCI(1.2g，6.2mmol)、HOAT(882mg，6.4mmol)、DIEA(2.2mL，12.4mmol)和氯化铵(347mg，6.5mmol)，室温下反应过夜。加入水(100mL)，乙酸乙酯(30mL)萃取三次，饱和食盐水水洗一次合并的有机层，无水Na2SO4干燥，过滤，减压浓缩，直接投下一步。
b)氩气保护，0℃下向化合物4-8(921mg，4.2mmol)的无水THF(30mL)溶液中加入氢化铝锂(487mg，12.8mmol)，0℃搅拌10分钟，随后转移到室温下反应10分钟，最后在回流温度下反应2小时。反应液冷却到室温，0℃下滴加水(1mL)，滴加10％NaOH(1mL)，滴加水(2mL)，室温下搅拌15分钟，硅藻土过滤，乙酸乙酯(25mL)萃取三次，饱和食盐水水洗一次合并的有机层，无水Na2SO4干燥，过滤，减压浓缩，残留物柱层析(二氯甲烷/甲醇：氨水＝10：1：0.05)纯化得化合物4-9。
c)室温下，向化合物4-9(100mg，0.5mmol)的二氯甲烷(10mL)溶液中加入3c(250mg，1mmol)、EDCI(497mg，2.5mmol)和催化量的DMAP，室温下搅拌过夜。用二氯甲烷(25mL)萃取三次，饱和食盐水水洗一次合并的有机层，无水Na2SO4干燥，过滤，减压浓缩，残留物进行柱层析(PE/EA＝2：1)纯化得到化合物I-12，黄色油状(130mg，收率60％)。
1H NMR(600MHz,CDCl3)δ8.85(d,J＝2.8Hz,1H),8.56(s,1H),8.25(dd,J＝8.9,2.8Hz,1H),7.42(d,J＝8.2Hz,2H),7.28(d,J＝7.9Hz,2H),7.17(d,J＝8.9Hz,1H),4.61(d,J＝5.8Hz,2H),3.61-3.55(m,4H),3.04-3.01(m,4H),2.35(s,3H)；
13C NMR(151MHz,CDCl3)δ164.89,155.53,143.66,135.88,131.96,130.99,129.15,127.56,127.06,119.56,66.55,52.95,43.72,7.48；
MS-ESI(m/z):434.0[M-H]-。
实施例13化合物I-13
制备方法同化合物I-12，使用5-氟-2-吗啉苯甲酸为原料可制得油状化合物I-13；1H NMR(600MHz,CDCl3)δ10.38(s,1H),7.97(dd,J＝9.7,3.2Hz,1H),7.42(d,J＝8.2Hz,2H),7.28(d,J＝8.2Hz,2H),7.21(dd,J＝8.8,4.8Hz,1H),7.14(ddd,J＝8.8,7.2,3.2Hz,1H),4.60(d,J＝5.5Hz,2H),3.51(s,4H),2.87(t,J＝4.6Hz,4H),2.35(s,3H)；
13C NMR(151MHz,CDCl3)δ164.55,160.95,159.32,146.71(d,J＝3.2Hz),136.39,131.42,130.93,129.00,128.42,122.86,122.81,118.90,118.76,118.45,118.28,66.88,53.65,43.46,7.45；
MS-ESI(m/z):409.1[M+H]+。
实施例14化合物I-14
0℃下，向化合物1-11(382mg，0.9mmol)的乙腈(10mL)溶液中加入DIEA(314μl，1.8mmol),随后滴加三氯氧磷(164μl，1.8mmol)，0℃下反应15min后转移至室温，室温下反应5小时。0℃下加入碳酸氢钠(302mg，3.6mmol)溶液淬灭反应液，0℃下搅拌8小时。乙酸乙酯(20mL)萃取两次，将水层调pH为酸性，乙酸乙酯(20mL)萃取两次，无水Na2SO4干燥，过滤，滤液浓缩，柱层析(二氯甲烷：甲醇：乙酸＝1：2：0.05)纯化得无色油状物。将油状物(118mg，0.23mmol)溶于甲醇(8mL)加入NaOH(18mg，0.46mmol)，室温下搅拌30min，反应液浓缩固化后无水乙醚冲洗，得化合物I-14，白色固体(100mg，收率80％)。
1H NMR(500MHz,D2O)δ7.46-7.32(m,2H),7.28-7.15(m,3H),7.01(d,J＝8.0Hz,1H),4.46(s,2H),3.46(t,J＝4.6Hz,4H),2.79(t,J＝4.7Hz,4H),2.19(s,3H)；
13C NMR(126MHz,D2O)δ171.06,168.33,159.88,157.96,152.11,146.80,136.10,128.41,123.14,122.57,118.88,118.66,116.34,116.15,66.57,52.51,43.26,4.28；
MS-ESI(m/z):549.0[M+H]+。
实施例15化合物I-15
j)室温下，向化合物I-11(200mg，0.47mmol)的二氯甲烷溶液(10mL)中加入EDCI(453mg，2.36mmol)、DMAP(34mg，0.28mmol)和化合物19(204mg，0.94mmol)，室温下反应三小时。二氯甲烷(20mL)萃取三次，饱和食盐水洗有机层，无水Na2SO4干燥，过滤，浓缩，柱层析(二氯甲烷/甲醇＝100：1)，得到无色油状化合物3-11。
k)室温下，向化合物3-11(150mg，0.24mmol)的二氯甲烷的溶液(8mL)中加入4MHCl的乙醚溶液(2mL)，室温下搅拌4小时，过滤，二氯甲烷冲洗滤饼，干燥得白色固体I-15。
(100mg，收率70％)
1H NMR(500MHz,D2O)δ7.66(ddd,J＝9.4,6.2,3.8Hz,2H),7.54(d,J＝8.1Hz,1H),7.45(td,J＝8.9,8.4,3.0Hz,1H),7.36(d,J＝8.1Hz,1H),7.22(s,1H),4.57(s,2H),4.41(d,J＝4.2Hz,1H),3.82(t,J＝4.6Hz,4H),3.32(t,J＝4.6Hz,4H),2.63(tt,J＝11.2,5.7Hz,1H),2.32(s,3H),1.18(dd,J＝10.5,7.0Hz,6H)。
生物实施例1、IMB5046衍生物体外活性
细胞培养：人肺癌细胞NCI-H460及A549及SMMC-7721、人口腔鳞癌KB及其耐药细胞株KBV200用含10％胎牛血清的RPMI-1640培养基(Hyclone公司)培养于37℃、5％CO2培养箱中，培养KBV200细胞时添加200nM的长春新碱，实验前3天撤去药物。人乳腺癌细胞MCF7、其耐药细胞株MCF7/ADR及MDA-MB-231、用含10％胎牛血清的DMEM培养基(Hyclone公司)培养于37℃、5％CO2培养箱，培养MCF7/ADR时添加1μg/mL的阿霉素，实验前3天，撤去药物。
活性分析：取对数生长期的细胞按4000个/孔种96孔板，细胞贴壁过夜。加入不同待测药物，同时以IMB5046作为对照，设3个复孔。培养箱培养48小时，加入MTT(5mg/mL,20μL)，继续培养4小时。酶标仪上(Multiskan MK3 microplate reader,Thermo Labsystems,Franklin,MA)检测570nm的光吸收值计算IC50值，耐药指数＝IC50(耐药细胞)/IC50(敏感细胞)。
本研究以IMB5046为先导化合物，设计合成了一系列含硒的IMB5046衍生物。部分化合物体外具有优秀的抗肿瘤活性，其中化合物I-5(IC50＝46nM)和I-11(IC50＝76nM)具有优于先导物的细胞毒活性。筛选得到的I-5和I-11将进一步评价生物活性和水溶性。
表1IMB5046衍生物对NCI-H460细胞体外活性
表2化合物I-5和I-11对多种肿瘤细胞的细胞毒活性
表3化合物I-5和I-11对耐药细胞的细胞毒活性
生物实施例2
水溶性：称取样品6mg，将样品溶于1mL乙腈(HPLC)中，依次分别配置6mg/mL、0.6mg/mL、0.06mg/mL和0.006mg/mL的四个样品溶液。通过液相色谱在254nm下检测四个样品溶液，根据样品浓度和相应峰面积得到一条标准曲线。
再次称取样品6mg，在样品中加入1mL纯净水，超声24小时后通过液相色谱在254nm下检测样品溶液的峰面积。将样品水溶液的峰面积带入标准曲线，得到相应的水溶性。
化合物I-5、I-11、I-14和I-15的水溶性
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 (10)
1.式I所示结构的含硒化合物或其药用盐：
其中，X代表CH2、O或S；
n1,n2分别独立的选在0、1或2；
Y代表O或NH；
R1代表NO2、C1-C5烷基、1-3卤代的C1-C5烷基、F、Cl或Br；
R2代表C1-C5烷基或1-3卤代的C1-C5烷基；
R3代表H、OH、SH、R4；
R4为磷酸酯基和氨基酸酯基。
2.根据权利要求1所述的式I所示结构的含硒化合物或其药用盐，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、CH2CH(CH3)2、C(CH3)3、CH(CH3)(CH2)2CH3、CH2CH(CH2)2CH3、CH2C(CH2)3；
1-3卤代为1-3个任选自F、Cl或Br的取代基，当取代基为2或3个时，其可以相同或不同。
3.根据权利要求1所述的式I所示结构的含硒化合物或其药用盐，其特征在于，
所述R1选自NO2、CF3、F；
所述R2选自CH3、CH2CH3、CH(CH3)2、CHF2、CH2F、CF3；
所述R3选自H、OH、
4.根据权利要求1所述的式I所示结构的含硒化合物或其药用盐，其特征在于，所述药用盐选自钠盐、钾盐、钙盐、盐酸盐、磷酸盐或硫酸盐。
5.根据权利要求1所述的式I所示结构的含硒化合物或其药用盐，其特征在于，选自如下：
6.一种如权利要求1所述的化合物的制备方法，其特征在于，选自任一如下路线：路线1
路线2
路线3
X，n1,n2,Y,R1,R2如前所述。
7.药物组合物，其包含权利要求1-5任一项所述的式I所示结构的含硒化合物或其药用盐，以及任选地，一种或多种药学上可接受的载体或赋形剂。
8.根据权利要求1-5任一项所述的式I所示结构的含硒化合物或其药用盐在制备抑制微管蛋白的药物中的应用。
9.根据权利要求1-5任一项所述的式I所示结构的含硒化合物或其药用盐在制备抗肿瘤药物中的应用。
10.根据权利要求9所述应用，其特征在于，所述肿瘤包括结直肠癌、乳腺癌、胃癌、肺癌前列腺癌、胰腺癌、肝癌、卵巢癌、黑色素瘤、脑癌、转移性骨病、A型淋巴瘤、胃肠癌或白血病。
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