CN104447786B - 一类藤黄属三氮唑衍生物、其制备方法和医药用途 - Google Patents
一类藤黄属三氮唑衍生物、其制备方法和医药用途 Download PDFInfo
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- CN104447786B CN104447786B CN201410783393.8A CN201410783393A CN104447786B CN 104447786 B CN104447786 B CN 104447786B CN 201410783393 A CN201410783393 A CN 201410783393A CN 104447786 B CN104447786 B CN 104447786B
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/10—Spiro-condensed systems
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Abstract
本发明涉及药物化学领域，具体涉及一类藤黄属三氮唑衍生物(I)、其制备方法和在制药中的应用，其中R1、R2、n的定义同说明书。该衍生物是藤黄属天然产物藤黄酸的结构类似物，具有抗肿瘤作用，可用于制备抗肿瘤药物。
Description
技术领域
本发明涉及药物化学领域，具体涉及一类藤黄属三氮唑衍生物、其制备方法和在制药中的应用。该衍生物是藤黄属天然产物藤黄酸的结构类似物，具有抗肿瘤作用，可用于制备抗肿瘤药物。
背景技术
天然产物藤黄酸是从藤黄属植物树干划裂后分泌的胶状树脂中提取获得，是藤黄树脂中重要的抗肿瘤有效成分。研究表明：藤黄酸在有效剂量范围内能选择性地抑制移植瘤的生长，其抗肿瘤作用与一般的化疗药物有所区别，其能选择性杀死多种肿瘤细胞、而对于正常的造血系统和免疫功能无明显影响。藤黄酸能够调控多种凋亡基因的表达从而诱导肿瘤细胞凋亡，还能通过抑制血管内皮生长因子受体信号转导通路抑制肿瘤新生血管的生成。藤黄酸可作为一种有效的针对多种肿瘤系的细胞凋亡诱导剂及肿瘤新生血管抑制剂。藤黄酸的结构如下所示：
藤黄酸结构复杂，全合成难度极大，目前来源于天然植物的提取分离，但其自然界含量低，限制了工业生产。藤黄酸结构中环系复杂、官能团繁多，结构修饰具有一定局限性，而且藤黄酸分子本身具有较大的分子量，结构修饰会使得分子量进一步加大，可能导致成药性不理想。藤黄酸相关构效关系研究表明，藤黄酸中虚线方框所示的平面环区域及桥环区域组成了其抗肿瘤活性的必需骨架。(Organic & Biomolecular Chemistry 7(2009)4886-4894；European Journal of Medicinal Chemistry 46(2011)1280-1290.)在对藤黄酸进行结构改造研究过程中，我们发现了藤黄酸结构简化物2，相比于藤黄酸，其结构简单，可以通过化学合成获得，并且化合物2的体外抗肿瘤活性与藤黄酸相当(Journal of Medicinal Chemistry 56(2013)276-292；专利WO2011120303A1.)。然而，化合物2缺乏成药性所必要的水溶性:一方面，其 结构中的亲水性酚羟基与羰基形成了分子内氢键，这是导致低水溶性的原因之一；另一方面，结构中缺乏亲水性氮原子。化合物2的低水溶性是导致其体内活性较差的重要影响因素。
发明内容
本发明通过对藤黄酸的结构剖析，在保留天然产物藤黄酸分子抗肿瘤作用的关键药效骨架基础上，以藤黄酸简化物2为先导化合物，对其酚羟基进行结构修饰，破坏对水溶性不利的分子内氢键作用，同时采用“点击化学”策略，采用温和反应体系引入三氮唑杂环及含氮取代基侧链，合成了一类含有三氮唑杂环的藤黄属衍生物，提高了水溶性。与此同时，分子的细胞膜通过性也得到了提高。本发明分子整体成药性明显优于天然产物藤黄酸及其简化物2。本发明化合物具有良好的体内外抗肿瘤活性，特别是体内抗肿瘤活性明显优于先导物2，有望开发成抗肿瘤药物。
本发明的化合物结构通式如下：
其中R1、R2各自独立地代表氢、C1～C6烷基、C2～C4羟烷基、或C2～C4烷酰基；或R1、R2连接形成含有N或O原子的5～7员杂环；
n＝1～6。
R1、R2优选各自独立地代表氢、甲基、乙基或丙基。
R1、R2还优选连接形成四氢吡咯基、咪唑基、哌啶基、哌嗪基、高哌嗪基、吗啡啉基或N-甲基哌嗪基。
本发明还公开了通式I化合物的制备方法，包括以下步骤：
其中，R1、R2、n的定义同前。
化合物2与烯丙基溴反应得化合物3，反应温度优选20℃～60℃，反应时间优选6～24小 时，反应溶剂可选丙酮、乙腈、DMF、四氢呋喃、二氯甲烷、三氯甲烷等。反应中还应加入无机碱或有机碱，如碳酸钾、碳酸钠、氢氧化钠、氢氧化钾、三乙胺、吡啶等。
化合物3与含有氨基取代的叠氮化合物反应得通式I化合物，反应温度优选20℃～60℃，反应时间优选6～24小时，反应溶剂可选自DMF、四氢呋喃、乙腈、乙醇、甲醇、叔丁醇其中的一种与水形成的体积比为1:1的混合溶剂。反应体系中还应加入铜催化剂如硫酸铜、氯化铜、溴化铜、氯化亚铜、碘化亚铜等，以及抗氧化试剂抗坏血酸钠。
本发明还公开了通式I化合物的另一种制备方法，首先，以三步反应制备得到化合物2；然后，采用上述合成方法，从化合物2经过两步反应合成得到化合物I。
其中，R1、R2、n的定义同前。
化合物4可通过与叔丁氧羰基甲基丁烯醇反应得到化合物5，反应温度优选-5℃～20℃，反应时间优选1～12小时，反应溶剂可选DMF、四氢呋喃、乙腈、丙酮、二氯甲烷、三氯甲烷等。所采用的钯催化剂优选自Pd(OAc)2、PdCl2、Pd(PPh3)4、Pd(PPh3)2Cl2以及膦配体如PPh3。
化合物5加热发生Claisen/Diels-Alder级联重排反应得到化合物6，反应温度优选100℃～180℃，反应时间优选1～4小时，反应溶剂优选DMF、甲醇、水、甲苯、二苯醚以及DMF-水、甲醇-水混合溶剂。
化合物6在弱碱性或弱酸性条件下通过水解反应得到化合物2，反应温度优选-10℃～60℃，反应时间优选1～12小时，反应溶剂可选自DMF、四氢呋喃、乙腈、乙醇、甲醇、叔丁醇其中的一种与水形成的体积比为1:1的混合溶剂。反应中还应加入碱，如碳酸钾、碳酸钠、三乙胺等，或者反应体系中加入酸，如稀盐酸、醋酸、氢溴酸、稀硫酸等。
通式I化合物可以采用常见的分离方法进行纯化，如重结晶、柱层析等。
本发明也包括通式I化合物的水合物、立体异构体、溶剂化物和药学上可接受的盐等。
通式I化合物药学上可接受的盐可以通过将化合物I溶于一定溶剂如乙醇、乙酸乙酯、甲醇、叔丁醇、四氢呋喃、二氯甲烷等，加入相应的有机酸如盐酸、马来酸、酒石酸、枸橼酸等制备得到。
本发明所述的化合物可以添加药学上可接受的载体制成常见的药用制剂，如片剂、胶囊、粉剂、糖浆、液剂、悬浮剂、针剂，可以加入香料、甜味剂、液体或固体填料或稀释剂等常用药用辅料。
本发明所述的化合物在临床上的给药方式可以采用口服、注射等方式。
本发明的化合物临床所用剂量为0.01mg～1000mg/天，也可根据病情的轻重或剂型的不同偏离此范围。
本发明的优点在于：无需采用分离自天然产物的藤黄酸作为原料加以修饰，可以直接通过合成得到；结构新颖且比藤黄酸简单，其抗肿瘤活性与藤黄酸相当；通过杂原子及亲水性基团引入或进一步成盐，水溶性、透膜性等成药性，明显好于藤黄酸及先导物2；本发明化合物具有良好的体内抗肿瘤活性，明显优于先导化合物2，有望开发成为抗肿瘤药物。
以下是本发明部分化合物的药理学试验结果：
实验方法：采用经典的MTT染色法(Cancer Research 47(1987)936-942)，培养时间为72小时。用酶标仪，在波长570nm条件下测定光密度值(OD)。以溶剂对照处理的肿瘤细胞为对照组，用下面公式计算药物对肿瘤细胞的抑制率，用SigmaPlot软件计算IC50，结果见表1。
表1本发明部分化合物抑制肿瘤细胞增殖活性IC50 a
aHepG2：人肝癌细胞；A549：人肺癌细胞；U2OS：人骨肉瘤细胞
由表1可见，本发明的化合物具有较强的体外抗肿瘤细胞增殖的活性，其活性与天然产物藤黄酸及化合物2相当，部分化合物活性好于藤黄酸及化合物2。
以下是本发明部分化合物的水溶性实验结果：
实验方法：采用pION公司基于经典的Avdeef-Bucher电位滴定法的Gemini测定仪测得，具体操作严格按照Gemini测定仪的说明书进行。实验数据由Gemini pD软件采集，结果采用Gemini pS软件进行拟合优化，结果见表2。
表2本发明部分化合物的水溶性
由表2可见，本发明的化合物的水溶性好于先导物化合物2，且远远好于藤黄酸。此外，本发明的化合物以盐酸盐形成存在时，水溶性大幅度提升。
以下是本发明部分化合物的膜透过率试验结果：
实验方法：(一)试药配制：精密称取待测化合物，加入适量辅料无水乙醇溶液，配置成浓度10mmol/L，超声至完全溶解，并涡旋1分钟使分布均匀，置于4℃保存。(二)系统溶液配制：将50mL系统溶液储备液用超纯水稀释至2L，混匀后用NaOH调节pH至7.4，并通过0.22μm滤膜过滤，置于4℃保存。(三)测定方法：严格按照pION提供的PAMPA ExplorerTM说明书执行。①建立Excel表格：建立化合物信息表格，并导入PAMPA ExplorerTM软件，设置pH和3分平行样品数；②制备空白板和参比板：空白板，移液枪移取150μL系统溶液至UV Plate各孔，盖上板盖待测；参比板，取系统溶液至Deep Well Plate孔，每孔2mL，分布加入各试药溶液4μL，混匀后各移取150μL至UV Plate孔，盖上板盖待测；③建立转运模型：去除STIRWELLTM PAMPA sandwith，从Deep Well Plate中移取200μL含药系统溶液于Donor Plate中，加盖。向Acceptor Plate各孔的膜上依次加入5μL ASB缓冲液(Acceptor Sink Buffer)及200μLGIT脂溶液(GIT lipid solution)。将Donor和Acceptor组装好后，置于37℃50rpm振荡器中，半小时后取出，每板各孔取150μL至UV Plate待测；④测定：分别将空 白孔、参比板，以及Donor和Acceptor的UV Plate，放入酶标仪中按照软件提示进行扫描测定，波长范围200～500nm；(四)数据处理：按PAMPA ExplorerTM自带软件进行数据分析，自动生成得到Pe值，去除异常值后，具体透过率结果见表3。
表3本发明部分化合物的膜透过率
由表3可见，本发明的化合物具有良好的膜通透性，提示其具有良好的胃肠道吸收特性，且明显好于天然产物藤黄酸和化合物2。
表4本发明部分化合物静脉给药对Heps肝癌移植瘤的生长抑制作用
a隔天给药，共给药4次；
由表4可见，本发明的化合物在较低的剂量组下，其抑瘤率要高于化合物2，具有良好的体内抗肿瘤作用。这也说明水溶性、透膜性等成药性的改善，可以提高体内抗肿瘤作用，
具体实施方式
实施例1
8-(1-(2-(二甲氨基)乙基)-1H-1,2,3-三氮唑-4-基)甲氧基-3,3-二甲基-1-(3-甲基丁-2-烯-1-基)-3,3a,4,5-四氢-1,5-甲基桥-1H,7H-呋喃[3,4-d]并呫吨-7,13-二酮(I-1)
(1)将1-羟基-5,6-双(2-甲基丁-3-烯-2-基氧基)-9H-呫吨-9-酮(化合物2)(30g,0.105mol)溶于无水四氢呋喃(400mL)中，冰浴冷却至10℃，加入叔丁氧羰基甲基丁烯醇(195g,1.05mol)，氮气保护下加入四三苯基膦钯(1.2g,1.05mmol)，于10℃反应10h。通入空气猝灭反应，硅胶助滤。减压蒸馏浓缩滤液，得化合物3，为黄色油状物。1H NMR(300MHz,CDCl3):δ1.56(s,6H),1.57(s,6H),2.48(s,3H),5.04(d,J＝10.8Hz,1H),5.17-5.24(m,3H),5.11-6.32(m,2H),6.97(d,J＝8.4Hz,1H),7.08(d,J＝9.0Hz,1H),7.41(d,J＝8.4Hz,1H),7.63(t,J＝8.4Hz,1H),7.82(d,J＝9.0Hz,1H)；EI-MS m/z:422[M]+(5),286(12),244(100),69(93).将上述所得化合物3溶于DMF(200mL)中，N2保护，于120℃下反应4h。将反应液冷至室温，加入饱和食盐水(500mL)，有固体析出，抽滤，滤饼(石油醚：乙酸乙酯＝1:1)重结晶，得白色固体，为化合物4(29.9g，两步收率90％)。m.p.167-169℃；1H NMR(300MHz,CDCl3):δ1.09(s,3H),1.24-1.30(m,4H),1.44(s,3H),1.72(s,3H),2.30-2.32(m,1H),2.35(s,3H),2.43-2.46(m,1H),2.63(d,J＝7.8Hz,2H),3.46-3.49(m,1H),4.34-4.48(m,1H),6.72(d,J＝7.8Hz,1H),6.99(d,J＝8.4Hz,1H),7.33(d,J＝6.9Hz,1H),7.50(t,J＝8.1Hz,1H)；IR(KBr,cm-1):2976,2893,1773,1739,1673,1613,1467,1261,1196,1052,741；HRMS(ESI)calcd.for C25H26O6[M+Na]+445.1627,found 445.1627.
(2)将化合物4(10g)溶于甲醇：水(v:v＝2:1)的混合溶剂(200mL)中，加入碳酸钠(3.5g)，室温搅拌反应10h。抽滤，滤液中加入饱和食盐水溶液(200mL)，乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，浓缩得化合物2，为黄色固体(8.4g，收率93％)。若用10％稀盐酸(20mL)代替碳酸钾，其他同上，也可得化合物2(8.6，收率94％)。m.p.130-132℃；1H NMR(300MHz,CDCl3):δ0.95(s,3H),1.18-1.25(m,4H),1.30(s,3H),1.61(s,3H),2.26(dd,J1＝13.5Hz,J2＝4.5Hz,1H),2.37(d,J＝9.6,1H),2.54(d,J＝7.8Hz,2H),3.44(dd,J1＝6.9Hz,J2＝4.5Hz,1H),4.34-4.37(m,1H),6.43(dd,J1＝8.1Hz,J2＝0.9Hz,1H),6.45(dd,J1＝8.1Hz,J2＝0.9Hz,1H),7.32(t,J＝8.1Hz,1H),7.41(d,J＝9.6Hz,1H),12.00(s,1H)；IR(KBr,cm-1):3442,2969,2934,17340,1648,1599,1462,1379,1235,1142,1057,883,798,764,699；EI-MS m/z:380[M]+,352；HRMS(ESI):calcd.for C23H24O5[M+H]+381.1697,found 381.1715.(5)将化合物3(0.6g,1.4mmol)溶于t-BuOH/H2O的混合溶液(v:v＝1:1,20mL)中，依次加入侧链叠氮化物N,N-二甲氨基叠氮乙烷(2.2mmol)、抗坏血酸钠(0.4mmol)、五水硫酸铜(0.01 mmol)，N2保护，室温反应24h。向反应液中加40ml水，CH2Cl2萃取(15mL×4)，合并有机层，无水NaSO4干燥，抽滤，减压浓缩滤液，得产品为浅黄色固体I-1(0.70g,92％)。m.p.156-158℃；1H NMR(300MHz,CDCl3):δ1.01(s,3H),1.18-1.24(m,4H),1.31(s,3H),1.63(s,3H),2.22-2.27(m,7H),2.33(d,J＝9.5Hz,1H),2.54(d,J＝7.8Hz,2H),2.73(t,J＝6.5Hz,2H),4.37-4.46(m,1H),4.31-4.42(m,3H),5.26(s,2H),6.61-6.69(m,2H),7.20-7.23(m,1H),7.35(t,J＝8.3Hz,1H),7.95(s,1H)；13C NMR(75MHz,CDCl3):δ16.5,25.0,25.1,28.5,29.8,30.4,44.9,46.2,48.0,58.2,63.4,76.1,76.5,76.9,82.9,83.9,89.5,105.7,110.6,118.1,123.0,131.9,134.2,135.7,136.0,143.6,159.1,160.7,175.1,202.7；IR(KBr,cm-1):3197,3109,2996,1737,1667,1603,1474,1460,1401,1258,1111,1066,846,791,669；HRMS(ESI):calcd.for C30H37N4O5[M+H]+533.2758,found 533.2774.
实施例2
8-(1-(3-(二甲氨基)丙基)-1H-1,2,3-三氮唑-4-基)甲氧基-3,3-二甲基-1-(3-甲基丁-2-烯-1-基)-3,3a,4,5-四氢-1,5-甲基桥-1H,7H-呋喃[3,4-d]并呫吨-7,13-二酮(I-2)
将化合物3(0.6g,1.4mmol)溶于t-BuOH/H2O的混合溶液(v:v＝1:1,20mL)中，依次加入侧链叠氮化物N,N-二甲氨基叠氮丙烷(0.28g，2.2mmol)、抗坏血酸钠(0.4mmol)、五水硫酸铜(0.01mmol)，N2保护，室温反应24h。向反应液中加40ml水，CH2Cl2萃取(15mL×4)，合并有机层，无水NaSO4干燥，抽滤，减压浓缩滤液，得产品为浅黄色固体I-2(0.71g,93％)。m.p.133-136℃；1H NMR(300MHz,CDCl3):δ1.08(s,3H),1.25-1.29(m,4H),1.37(s,3H),1.69(s,3H),2.15-2.25(m,2H),2.28-2.41(m,8H),2.48-2.53(m,2H),2.61(d,J＝7.7Hz,2H,C11-H),3.43-3.47(m,1H),4.45-4.49(m,3H),5.31(s,2H),6.71(t,J＝7.8Hz,2H),7.26-7.29(m,1H),7.43(t,J＝8.3Hz,1H),7.98(s,1H)；IR(KBr,cm-1):3196,3106,2996,1737,1669,1603,1475,1401,1258,1111,1066,846,791,669；HRMS(ESI):calcd.for C31H39N4O5[M+H]+547.2915,found 547.2916.
实施例3
8-(1-(二甲胺甲基)-1H-1,2,3-三氮唑-4-基)甲氧基-3,3-二甲基-1-(3-甲基丁-2-烯-1-基)-3,3a,4,5-四氢-1,5-甲基桥-1H,7H-呋喃[3,4-d]并呫吨-7,13-二酮(I-3)
将化合物3(0.6g,1.4mmol)溶于t-BuOH/H2O的混合溶液(v:v＝1:1,2mL)中，依次加入侧链叠氮化物N,N-二甲氨基叠氮甲烷(0.22g,2.2mmol)、抗坏血酸钠(0.4mmol)、五水硫酸铜(0.01mmol)，N2保护，室温反应过夜。向反应液中加20mL水，CH2Cl2萃取(15mL×4)，合并有机层，无水NaSO4干燥，抽滤，减压浓缩滤液，得产品为浅黄色固体I-3(0.70g,93％)。m.p.146-148℃；1H NMR(300MHz,CDCl3):δ1.01(s,3H),1.18-1.24(m,4H),1.32(s,3H),1.65(s,3H),2.22-2.27(m,7H),2.33(d,J＝9.5Hz,1H),2.54(d,J＝7.8Hz,2H),,4.37-4.46(m,1H),4.49(s,1H),4.52(s,2H),5.26(s,2H),6.62-6.71(m,2H),7.21-7.24(m,1H),7.35(t,J＝8.3Hz,1H),7.95(s,1H)；HRMS(ESI):calcd.for C29H35N4O5[M+H]+519.2602found 519.2606.
实施例4
8-(1-(6-(甲氨基)己基)-1H-1,2,3-三氮唑-4-基)甲氧基-3,3-二甲基-1-(3-甲基丁-2-烯-1-基)-3,3a,4,5-四氢-1,5-甲基桥-1H,7H-呋喃[3,4-d]并呫吨-7,13-二酮(I-4)
将化合物3(0.6g,1.4mmol)溶于t-BuOH/H2O的混合溶液(v:v＝1:1,20mL)中，依次加入侧链叠氮化物N-甲氨基叠氮己烷(0.34g，2.2mmol)、碘化亚铜(1.89mg，0.01mmol)，N2保护，室温反应24h。向反应液中加40ml水，CH2Cl2萃取(15mL×4)，合并有机层，无水NaSO4干燥，抽滤，减压浓缩滤液，得产品为浅黄色固体I-4(0.75g,93％)。m.p.162-164℃；1H NMR(300MHz,CDCl3):δ1.08(s,3H),1.25-1.27(m,4H),1.37(s,3H),1.29-1.38(m,6H),1.69(s,3H),1.74(m,2H),2.0(m,1H),2.28-2.41(m,2H),2.61(d,J＝7.7Hz,2H),3.26(m,3H),3.43-3.47(m,1H),4.46(m,2H),5.31(s,2H),6.71(t,J＝7.8Hz,2H),7.26-7.29(m,1H),7.43(t,J＝8.3Hz,1H),7.98(s,1H)；HRMS(ESI):calcd.for C33H43N4O5[M+H]+575.3228,found 575.3234；
实施例5
8-(1-(2-(N-甲基-N-乙基氨基)乙基)-1H-1,2,3-三氮唑-4-基)甲氧基-3,3-二甲基-1-(3-甲基丁-2-烯-1-基)-3,3a,4,5-四氢-1,5-甲基桥-1H,7H-呋喃[3,4-d]并呫吨-7,13-二酮(I-5)
将化合物3(0.6g,1.4mmol)溶于t-BuOH/H2O的混合溶液(v:v＝1:1,20mL)中，依次加入侧链叠氮化物N-甲基-N-乙基氨基叠氮乙烷(0.28g，2.2mmol)、碘化亚铜(0.01mmol)，N2保护，室温反应24h。向反应液中加40ml水，CH2Cl2萃取(15mL×4)，合并有机层，无水NaSO4干燥，抽滤，减压浓缩滤液，得产品为浅黄色固体I-5(0.69g,91％)。m.p.156-158℃；1H NMR(300MHz,CDCl3):δ1.02(s,6H),1.18-1.28(m,4H),1.31(s,3H),1.63(s,3H),2.22-2.27(m,4H),2.33(d,J＝9.5Hz,1H),2.46(m,2H),2.56(d,J＝7.8Hz,2H),2.75(t,J＝6.5Hz,2H),4.39-4.46(m,1H),4.33-4.42(m,3H),5.26(s,2H),6.61-6.69(m,2H),7.20-7.23(m,1H),7.35(t,J＝8.3Hz,1H),7.95(s,1H)HRMS(ESI):calcd.for C31H39N4O5[M+H]+547.2915,found 547.2916.
实施例6
8-(1-(2-(N-正丁基氨基)乙基)-1H-1,2,3-三氮唑-4-基)甲氧基-3,3-二甲基-1-(3-甲基丁-2-烯-1-
基)-3,3a,4,5-四氢-1,5-甲基桥-1H,7H-呋喃[3,4-d]并呫吨-7,13-二酮(I-6)
将化合物3(0.6g,1.4mmol)溶于t-BuOH/H2O的混合溶液(v:v＝1:1,20mL)中，依次加入侧链叠氮化物N-正丁基氨基叠氮乙烷(0.31g，2.2mmol)、氯化亚铜(0.01mmol)，N2保护，室温反应24h。向反应液中加40ml水，CH2Cl2萃取(15mL×4)，合并有机层，无水NaSO4干燥，抽滤，减压浓缩滤液，得产品为浅黄色固体I-6(0.71g,91％)。m.p.162-164℃；1H NMR(300MHz,CDCl3):δ0.90(m,3H),1.03(s,3H),1.18-1.26(m,4H),1.30(s,3H),1.32-1.38(m,4H),1.63(s,3H),2.22-2.27(m,1H),2.33(d,J＝9.5Hz,1H),2.52(d,J＝7.8Hz,2H),2.55(m,2H),2.74(t,J＝6.5Hz,2H),4.37-4.46(m,1H),4.42(m,3H),5.26(s,2H),6.61-6.69(m,2H),7.20-7.23(m,1H),7.35(t,J＝8.3Hz,1H),7.95(s,1H)HRMS(ESI):calcd.for C32H41N4O5[M+H]+560.3671,found 560.3675.
实施例7
8-(1-(2-(N-异丙基氨基)乙基)-1H-1,2,3-三氮唑-4-基)甲氧基-3,3-二甲基-1-(3-甲基丁-2-烯-1- 基)-3,3a,4,5-四氢-1,5-甲基桥-1H,7H-呋喃[3,4-d]并呫吨-7,13-二酮(I-7)
将化合物3(0.6g,1.4mmol)溶于t-BuOH/H2O的混合溶液(v:v＝1:1,2mL)中，依次加入侧链叠氮化物N-异丙基氨基叠氮乙烷(0.28g,2.2mmol)、抗坏血酸钠(0.4mmol)、溴化铜(0.01mmol)，N2保护，室温反应过夜。向反应液中加20mL水，CH2Cl2萃取(15mL×4)，合并有机层，无水NaSO4干燥，抽滤，减压浓缩滤液，得产品为浅黄色固体I-7(0.69g,91％)。m.p.152-154℃；1H NMR(300MHz,CDCl3):δ1.05(s,3H),1.09(m,6H),1.20-1.21(m,4H),1.31(s,3H),1.64(s,3H),2.0(m,1H),2.22-2.27(m,1H),2.33(d,J＝9.5Hz,1H),2.54(d,J＝7.8Hz,2H),2.73(t,J＝6.5Hz,2H),2.97(m,1H),4.37-4.46(m,1H),4.42(m,3H),5.26(s,2H),6.61-6.69(m,2H),7.20-7.23(m,1H),7.35(t,J＝8.3Hz,1H),7.95(s,1H).HRMS(ESI):calcd.for C31H39N4O5[M+H]+547.2915,found 547.2915.
实施例8
8-(1-(2-(N-羟乙基氨基)乙基)-1H-1,2,3-三氮唑-4-基)甲氧基-3,3-二甲基-1-(3-甲基丁-2-烯-1-基)-3,3a,4,5-四氢-1,5-甲基桥-1H,7H-呋喃[3,4-d]并呫吨-7,13-二酮(I-8)
将化合物3(0.6g,1.4mmol)溶于t-BuOH/H2O的混合溶液(v:v＝1:1,2mL)中，依次加入侧链叠氮化物N-羟乙基氨基叠氮乙烷(0.29g,2.2mmol)、抗坏血酸钠(0.4mmol)、氯化铜(0.01mmol)，N2保护，室温反应过夜。向反应液中加20mL水，CH2Cl2萃取(15mL×4)，合并有机层，无水NaSO4干燥，抽滤，减压浓缩滤液，得产品为浅黄色固体I-8(0.69g,90％)。m.p.155-157℃；1H NMR(300MHz,CDCl3):δ1.02(s,3H),1.18-1.26(m,4H),1.31(s,3H),1.63(s,3H),2.22-2.27(m,1H),2.1(m,1H),2.33(d,J＝9.5Hz,1H),2.54(d,J＝7.8Hz,2H),2.73(t,J＝6.5Hz,2H),2.76(m,2H),3.74(m,2H),3.91(m,1H),4.37-4.46(m,1H),4.31-4.42(m,3H),5.26(s,2H),6.61-6.69(m,2H),7.20-7.23(m,1H),7.35(t,J＝8.3Hz,1H),7.95(s,1H).HRMS(ESI):calcd.for C30H37N4O6[M+H]+579.2708,found 579.2711.
实施例9
8-(1-(2-(N-(3-羟基-2-丁基)氨基)乙基)-1H-1,2,3-三氮唑-4-基)甲氧基-3,3-二甲基-1-(3-甲基丁-2-烯-1-基)-3,3a,4,5-四氢-1,5-甲基桥-1H,7H-呋喃[3,4-d]并呫吨-7,13-二酮(I-9)
将化合物3(0.6g,1.4mmol)溶于t-BuOH/H2O的混合溶液(v:v＝1:1,2mL)中，依次加入侧链叠氮化物N-(3-羟基-2-丁基)氨基叠氮乙烷(0.35g,2.2mmol)、抗坏血酸钠(0.4mmol)、五水硫酸铜(0.01mmol)，N2保护，室温反应过夜。向反应液中加20mL水，CH2Cl2萃取(15mL×4)，合并有机层，无水NaSO4干燥，抽滤，减压浓缩滤液，得产品为浅黄色固体I-9(0.73g,91％)。m.p.162-164℃；1H NMR(300MHz,CDCl3):δ1.04(s,3H),1.19-1.26(m,4H),1.12-1.18(m,6H),1.31(s,3H),1.63(s,3H),2.0(m,1H),2.22-2.27(m,1H),2.33(d,J＝9.5Hz,1H),2.55(d,J＝7.8Hz,2H),2.73(t,J＝6.5Hz,2H),2.87(m,1H),3.56(m,1H),3.62(m,1H)4.37-4.46(m,1H),4.31-4.42(m,3H),5.26(s,2H),6.61-6.69(m,2H),7.20-7.23(m,1H),7.35(t,J＝8.3Hz,1H),7.95(s,1H).HRMS(ESI):calcd.for C32H41N4O6[M+H]+577.3021,found 577.3023.
实施例10
8-(1-(2-(N-环丙基氨基)乙基)-1H-1,2,3-三氮唑-4-基)甲氧基-3,3-二甲基-1-(3-甲基丁-2-烯-1-基)-3,3a,4,5-四氢-1,5-甲基桥-1H,7H-呋喃[3,4-d]并呫吨-7,13-二酮(I-10)
将化合物3(0.6g,1.4mmol)溶于t-BuOH/H2O的混合溶液(v:v＝1:1,2mL)中，依次加入侧链叠氮化物N-环丙基氨基叠氮乙烷(0.27g,2.2mmol)、抗坏血酸钠(0.4mmol)、五水硫酸铜(0.01mmol)，N2保护，室温反应过夜。向反应液中加20mL水，CH2Cl2萃取(15mL×4)，合并有机层，无水NaSO4干燥，抽滤，减压浓缩滤液，得产品为浅黄色固体I-10(0.71g,93％)。m.p.147-149℃；1H NMR(300MHz,CDCl3):δ0.44(m,2H),0.65(m,2H),1.02(s,3H),1.18-1.26(m,4H),1.30(s,3H),1.35(m,1H),1.63(s,3H),2.0(m,1H),2.23-2.29(m,1H),2.34(d,J＝9.5Hz,1H),2.54(d,J＝7.8Hz,2H),2.73(t,J＝6.5Hz,2H),4.37-4.46(m,1H),4.31-4.42(m,3H),5.26(s,2H),6.61-6.69(m,2H),7.21-7.24(m,1H),7.36(t,J＝8.3Hz,1H),7.95(s,1H).HRMS(ESI):calcd.for C31H37N4O5[M+H]+545.2758,found 545.2764.
实施例11
8-(1-(2-(N-环己基氨基)乙基)-1H-1,2,3-三氮唑-4-基)甲氧基-3,3-二甲基-1-(3-甲基丁-2-烯-1-基)-3,3a,4,5-四氢-1,5-甲基桥-1H,7H-呋喃[3,4-d]并呫吨-7,13-二酮(I-11)
将化合物3(0.6g,1.4mmol)溶于t-BuOH/H2O的混合溶液(v:v＝1:1,2mL)中，依次加入侧链叠氮化物N-环己基氨基叠氮乙烷(0.37g,2.2mmol)、抗坏血酸钠(0.4mmol)、五水硫酸铜(0.01mmol)，N2保护，室温反应过夜。向反应液中加20mL水，CH2Cl2萃取(15mL×4)，合并有机层，无水NaSO4干燥，抽滤，减压浓缩滤液，得产品为浅黄色固体I-11(0.74g,90％)。m.p.151-153℃；1H NMR(300MHz,CDCl3):δ1.02(s,3H),1.18-1.26(m,8H),1.31(s,3H),1.35(m,2H),1.49(m,2H),1.59(m,2H),1.63(s,3H),2.22-2.27(m,1H),2.32(d,J＝9.5Hz,1H),2.52(d,J＝7.8Hz,2H),2.57(m,1H),2.74(t,J＝6.5Hz,2H),4.37-4.46(m,1H),4.31-4.42(m,3H),5.26(s,2H),6.61-6.69(m,2H),7.20-7.23(m,1H),7.32(t,J＝8.3Hz,1H),7.96(s,1H).HRMS(ESI):calcd.for C34H43N4O5[M+H]+587.3228,found 587.3231.
实施例12
8-(1-(2-(N-乙酰基氨基)乙基)-1H-1,2,3-三氮唑-4-基)甲氧基-3,3-二甲基-1-(3-甲基丁-2-烯-1-基)-3,3a,4,5-四氢-1,5-甲基桥-1H,7H-呋喃[3,4-d]并呫吨-7,13-二酮(I-12)
将化合物3(0.6g,1.4mmol)溶于t-BuOH/H2O的混合溶液(v:v＝1:1,2mL)中，依次加入侧链叠氮化物N-乙酰基氨基叠氮乙烷(0.22g,2.2mmol)、抗坏血酸钠(0.4mmol)、五水硫酸铜(0.01mmol)，N2保护，室温反应过夜。向反应液中加20mL水，CH2Cl2萃取(15mL×4)，合并有机层，无水NaSO4干燥，抽滤，减压浓缩滤液，得产品为浅黄色固体I-12(0.71g,93％)。m.p.136-138℃；1H NMR(300MHz,CDCl3):δ1.01(s,3H),1.18-1.24(m,4H),1.33(s,3H),1.65(s,3H),1.84(s,3H),2.22-2.27(m,1H),2.33(d,J＝9.5Hz,1H),2.54(d,J＝7.8Hz,2H),4.39-4.46(m,1H),4.49(s,1H,C12-H),4.52(s,2H),5.26(s,2H),6.62-6.71(m,2H),7.21-7.24(m,1H),7.36(t,J＝8.3Hz,1H),7.94(s,1H),8.03(s,1H)；HRMS(ESI):calcd.for C39H35N4O6 [M+H]+547.2551found 547.2552.
实施例13
8-(1-(2-(N-丁酰基氨基)乙基)-1H-1,2,3-三氮唑-4-基)甲氧基-3,3-二甲基-1-(3-甲基丁-2-烯-1-基)-3,3a,4,5-四氢-1,5-甲基桥-1H,7H-呋喃[3,4-d]并呫吨-7,13-二酮(I-13)
将化合物3(0.6g,1.4mmol)溶于t-BuOH/H2O的混合溶液(v:v＝1:1,2mL)中，依次加入侧链叠氮化物N-丁酰基氨基叠氮乙烷(0.34g,2.2mmol)、抗坏血酸钠(0.4mmol)、五水硫酸铜(0.01mmol)，N2保护，室温反应过夜。向反应液中加20mL水，CH2Cl2萃取(15mL×4)，合并有机层，无水NaSO4干燥，抽滤，减压浓缩滤液，得产品为浅黄色固体I-13(0.73g,91％)。1H NMR(300MHz,CDCl3):δ0.9(m,3H),1.04(s,3H),1.18-1.26(m,4H),1.31(m,5H),1.63(s,3H),2.22-2.27(m,1H),2.29(m,2H),2.35(d,J＝9.5Hz,1H),2.54(d,J＝7.8Hz,2H),2.73(t,J＝6.5Hz,2H),4.37-4.46(m,1H),4.31-4.42(m,3H),5.26(s,2H),6.61-6.69(m,2H),7.20-7.23(m,1H),7.35(t,J＝8.3Hz,1H),7.96(s,1H),8.03(s,1H)；HRMS(ESI):calcd.for C32H39N4O6[M+H]+575.2864found 575.2866.
实施例14
8-(1-(2-(吡咯-1-基)乙基-1H-1,2,3-三氮唑-4-基)甲氧基-3,3-二甲基-1-(3-甲基丁-2-烯-1-基)-3,3a,4,5-四氢-1,5-甲基桥-1H,7H-呋喃[3,4-d]并呫吨-7,13-二酮(I-14)
将化合物3(0.6g,1.4mmol)溶于t-BuOH/H2O的混合溶液(v:v＝1:1,2mL)中，依次加入侧链叠氮化物2-(吡咯-1-基)烷基叠氮乙烷(0.31g,.2mmol)、抗坏血酸钠(0.4mmol)、五水硫酸铜(0.01mmol)，N2保护，室温反应过夜。向反应液中加20mL水，CH2Cl2萃取(15mL×4)，合并有机层，无水NaSO4干燥，抽滤，减压浓缩滤液，得产品为浅黄色固体I-14(0.71g,91％)。1H NMR(300MHz,CDCl3):δ1.08(s,3H),1.25-1.29(m,4H),1.37(s,3H),1.70(s,3H),1.78-1.81(m,4H),2.33(dd,J1＝8.8Hz,J2＝4.5Hz,1H),2.42(d,J＝9.6Hz,1H),2.60-2.62(m,6H),3.04
(t,J＝6.7Hz,2H),3.44-3.47(m,1H),4.49-4.56(m,3H),5.33(s,2H),6.68-6.76(m,2H),7.27-7.29(m,1H),7.42(t,J＝8.4Hz,1H),8.05(s,1H)；IR(KBr,cm-1):3196,3110,2996,1737,1668,1603,1474,1458,1400,1258,1110,1066,847,791,669；HRMS(ESI):calcd.for C32H39N4O5[M+H]+559.2915,found 559.2920.
实施例15
8-(1-(2-(咪唑-1-基)乙基-1H-1,2,3-三氮唑-4-基)甲氧基-3,3-二甲基-1-(3-甲基丁-2-烯-1-基)-3,3a,4,5-四氢-1,5-甲基桥-1H,7H-呋喃[3,4-d]并呫吨-7,13-二酮(I-15)
将化合物3(0.6g,1.4mmol)溶于t-BuOH/H2O的混合溶液(v:v＝1:1,2mL)中，依次加入侧链叠氮化物2-(咪唑-1-基)叠氮乙烷(0.30g,.2mmol)、抗坏血酸钠(0.4mmol)、五水硫酸铜(0.01mmol)，N2保护，室温反应过夜。向反应液中加20mL水，CH2Cl2萃取(15mL×4)，合并有机层，无水NaSO4干燥，抽滤，减压浓缩滤液，得产品为浅黄色固体I-15(0.71g,91％。m.p.137-139℃；1H NMR(300MHz,CDCl3):δ1.01(s,3H),1.18-1.24(m,4H),1.33(s,3H),1.65(s,3H),2.22-2.27(m,1H),2.33(d,J＝9.5Hz,1H),2.54(d,J＝7.8Hz,2H),4.39-4.46(m,1H),4.49(s,1H,C12-H),4.52(s,2H),5.26(s,2H,OCH2),6.62-6.71(m,2H),6.78(m,1H),7.21-7.24(m,2H,C8-H),7.36(t,J＝8.3Hz,1H),7.90(m,1H),7.94(s,1H)；HRMS(ESI):calcd.for C31H34N5O5[M+H]+556.2554found 556.2551.
实施例16
8-(1-(2-(哌嗪-1-基)乙基-1H-1,2,3-三氮唑-4-基)甲氧基-3,3-二甲基-1-(3-甲基丁-2-烯-1-基)-3,3a,4,5-四氢-1,5-甲基桥-1H,7H-呋喃[3,4-d]并呫吨-7,13-二酮(I-16)
将化合物3(0.6g,1.4mmol)溶于t-BuOH/H2O的混合溶液(v:v＝1:1,2mL)中，依次加入侧链叠氮化物2-(哌嗪-1-基)叠氮乙烷(034g,2.2mmol)、抗坏血酸钠(0.4mmol)、五水硫酸铜(0.01 mmol)，N2保护，室温反应过夜。向反应液中加20mL水，CH2Cl2萃取(15mL×4)，合并有机层，无水NaSO4干燥，抽滤，减压浓缩滤液，得产品为浅黄色固体I-16(0.74g,92％)。m.p.161-163℃；1H NMR(300MHz,CDCl3):δ1.01(s,3H),1.18-1.24(m,4H),1.33(s,3H),1.65(s,3H),1.91(m,1H),2.22-2.27(m,1H),2.33(d,J＝9.5Hz,1H),2.37(m,4H),2.54(d,J＝7.8Hz,2H),2.65(m,4H),4.41-4.46(m,1H),4.49(s,1H),4.52(s,2H),5.26(s,2H),6.61-6.71(m,2H),7.21-7.24(m,1H),7.36(t,J＝8.3Hz,1H),7.95(s,1H)；HRMS(ESI):calcd.for C32H40N2O5[M+H]+574.3018found 574.3020.
实施例17
8-(1-(2-(高哌嗪-1-基)乙基-1H-1,2,3-三氮唑-4-基)甲氧基-3,3-二甲基-1-(3-甲基丁-2-烯-1-基)-3,3a,4,5-四氢-1,5-甲基桥-1H,7H-呋喃[3,4-d]并呫吨-7,13-二酮(I-17)
将化合物3(0.6g,1.4mmol)溶于t-BuOH/H2O的混合溶液(v:v＝1:1,2mL)中，依次加入侧链叠氮化物2-(高哌嗪-1-基)叠氮乙烷(037g,2.2mmol)、抗坏血酸钠(0.4mmol)、五水硫酸铜(0.01mmol)，N2保护，室温反应过夜。向反应液中加20mL水，CH2Cl2萃取(15mL×4)，合并有机层，无水NaSO4干燥，抽滤，减压浓缩滤液，得产品为浅黄色固体I-17(0.74g,90％)。m.p.164-166℃；1H NMR(300MHz,CDCl3):δ1.01(s,3H),1.18-1.24(m,4H),1.33(s,3H,C19-H),1.51(m,2H),1.65(s,3H),2.01(m,1H),2.22-2.27(m,1H),2.33(d,J＝9.5Hz,1H),2.48-2.50(m,4H),2.56(d,J＝7.8Hz,2H),2.65(m,2H),4.39-4.46(m,1H),4.49(s,1H),4.52(s,2H),5.26(s,2H),6.62-6.71(m,2H),7.21-7.24(m,1H),7.36(t,J＝8.3Hz,1H),7.94(s,1H)；HRMS(ESI):calcd.for C33H42N5O5[M+H]+588.3175found 588.3178.
实施例18
8-(1-(3-(哌啶-1-基)丙基-1H-1,2,3-三氮唑-4-基)甲氧基-3,3-二甲基-1-(3-甲基丁-2-烯-1-基)-3,3a,4,5-四氢-1,5-甲基桥-1H,7H-呋喃[3,4-d]并呫吨-7,13-二酮(I-18)
将化合物3(0.6g,1.4mmol)溶于t-BuOH/H2O的混合溶液(v:v＝1:1,2mL)中，依次加入侧链 叠氮化物3-(哌啶-1-基)叠氮丙烷(0.37g,2.2mmol)、抗坏血酸钠(0.4mmol)、五水硫酸铜(0.01mmol)，N2保护，室温反应过夜。向反应液中加20mL水，CH2Cl2萃取(15mL×4)，合并有机层，无水NaSO4干燥，抽滤，减压浓缩滤液，得产品为浅黄色固体I-18(0.74g,93％)。m.p.125-128℃；1H NMR(300MHz,CDCl3):δ1.07(s,3H),1.23-1.30(m,4H),1.36(s,3H),1.42-1.44(m,2H),1.57-1.61(m,4H),1.68(s,3H),2.10-2.15(m,2H),2.29-2.40(m,8H),2.60(d,J＝7.7Hz,2H),3.42-3.46(m,1H),4.42-4.49(m,3H),5.31(s,2H),6.67-6.73(m,2H),7.26-7.28(m,1H),7.41(t,J＝8.3Hz,1H),7.93(s,1H)；IR(KBr,cm-1):3200,3111,2996,1739,1668,1605,1478,1462,1401,1267,1116,1064,878,791,669；HRMS(ESI):calcd.for C34H43N4O5[M+H]+587.3228,found 587.3228.
实施例19
8-(1-(3-(4-甲基哌嗪-1-基)丙基-1H-1,2,3-三氮唑-4-基)甲氧基-3,3-二甲基-1-(3-甲基丁-2-烯-1-基)-3,3a,4,5-四氢-1,5-甲基桥-1H,7H-呋喃[3,4-d]并呫吨-7,13-二酮(I-19)
将化合物3(0.6g,1.4mmol)溶于t-BuOH/H2O的混合溶液(v:v＝1:1,2mL)中，依次加入侧链叠氮化物3-(4-甲基哌嗪-1-基)叠氮丙烷(040g,2.2mmol)、抗坏血酸钠(0.4mmol)、五水硫酸铜(0.01mmol)，N2保护，室温反应过夜。向反应液中加20mL水，CH2Cl2萃取(15mL×4)，合并有机层，无水NaSO4干燥，抽滤，减压浓缩滤液，得产品为浅黄色固体I-19(0.76g,90％)。m.p.126-129℃；1H NMR(300MHz,CDCl3):δ1.10(s,3H),1.24-1.33(m,4H),1.39(s,3H),1.71(s,3H),2.05-2.15(m,2H),2.31-2.48(m,15H),2.63(d,J＝7.5Hz,1H),3.45-3.49(m,1H),4.44-4.51(m,3H),5.34(s,2H),6.70-6.76(m,2H),7.28-7.31(m,1H),7.44(t,J＝8.3Hz,1H),7.96(s,1H)；IR(KBr,cm-1):3103,2973,1741,1683,1616,1605,1478,1462,1399,1262,1110,1013,878,792,695；HRMS(ESI):calcd.for C34H44N5O5[M+H]+602.3337found 602.3346.
实施例20
8-(1-(3-(吗啉-1-基)丙基-1H-1,2,3-三氮唑-4-基)甲氧基-3,3-二甲基-1-(3-甲基丁-2-烯-1-基)-3,3a,4,5-四氢-1,5-甲基桥-1H,7H-呋喃[3,4-d]并呫吨-7,13-二酮(I-20)
将化合物3(0.6g,1.4mmol)溶于t-BuOH/H2O的混合溶液(v:v＝1:1,2mL)中，依次加入侧链叠氮化物3-(吗啉-1-基)叠氮乙烷(0.37g,2.2mmol)、抗坏血酸钠(0.4mmol)、五水硫酸铜(0.01mmol)，N2保护，室温反应过夜。向反应液中加20mL水，CH2Cl2萃取(15mL×4)，合并有机层，无水NaSO4干燥，抽滤，减压浓缩滤液，得产品为浅黄色固体I-20(0.76g,92％)。m.p.143-145℃；1H NMR(300MHz,CDCl3):δ1.09(s,3H),1.26-1.30(m,4H),1.38(s,3H),1.71(s,3H),2.10-2.17(m,2H),2.30-2.44(m,8H),2.60(d,J＝7.7Hz,1H,C17-H),3.45-3.48(m,1H,C7-H),3.72(t,J＝4.7Hz,4H),4.46-4.53(m,3H),5.33(s,2H),6.72(t,J＝7.6Hz,2H),7.27-7.30(m,1H),7.44(t,J＝8.4Hz,1H),7.97(s,1H)；IR(KBr,cm-1):3201,3112,2963,1737,1668,1604,1477,1457,1400,1267,1115,1064,878,844,793,696；HRMS(ESI):calcd.for C33H41N4O6[M+H]+589.3021,found 589.3037。
Claims (7)
1.通式(I)所示的化合物或其药学上可接受的盐：
其中R1、R2各自独立地代表氢、C1～C6烷基、C2～C4羟烷基或C2～C4烷酰基；或R1、R2连接形成含有N原子的5～7员杂环；
n＝1～6。
2.权利要求1的化合物或其药学上可接受的盐，其中R1、R2各自独立地代表氢、甲基、乙基或丙基。
3.权利要求1的化合物或其药学上可接受的盐，其中R1、R2连接形成四氢吡咯基、咪唑基、哌啶基、哌嗪基、高哌嗪基、吗啡啉基或N-甲基哌嗪基。
4.权利要求1的化合物的制备方法，包括：
其中，R1、R2、n的定义同权利要求1。
5.权利要求1的化合物的制备方法，包括：
其中，R1、R2、n的定义同权利要求1。
6.一种药物组合物，其中含有权利要求1的化合物或其药学上可接受的盐及药学上可接受的载体。
7.权利要求1的化合物或其药学上可接受的盐用于制备治疗恶性肿瘤的药物的用途。
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