CN102503951A - 一类藤黄属衍生物、其制备方法和医药用途 - Google Patents
一类藤黄属衍生物、其制备方法和医药用途 Download PDFInfo
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- CN102503951A CN102503951A CN2011103478863A CN201110347886A CN102503951A CN 102503951 A CN102503951 A CN 102503951A CN 2011103478863 A CN2011103478863 A CN 2011103478863A CN 201110347886 A CN201110347886 A CN 201110347886A CN 102503951 A CN102503951 A CN 102503951A
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- methyl
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- xanthene
- ene
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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衍生物(I)及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,分子量比藤黄酸小,通过杂原子及亲水性基团引入或进一步成盐,改善了胃肠道吸收性,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衍生物及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:
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.)有文献报道了藤黄酸结构简化物II,虽然保留了一定的抗肿瘤活性,但不具备良好的成药性特征,此外该类化合物的合成方法限制了其结构修饰空间。(Organic & Biomolecular Chemistry 5(2007)494-500;Bioorganic& Medicinal Chemistry 16(2008)4233-4241;专利WO 2008057604A2.)
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,首次对桥环区域进行了结构修饰,合成了一类藤黄属衍生物。本发明的化合物具有与藤黄酸相当的抗肿瘤活性,且分子整体成药性明显优于天然产物藤黄酸及其简化物II,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代表卤素、羟基、-NRaRb、硝酸酯基、硫氰基、C1~C6烷氧基、C2~C6不饱和烯氧基、C1~C6烷基酰氧基或C6~C8芳基酰氧基;或代表由卤素、甲氧基、硝基、羟基或-NRaRb取代的C6~C8芳基酰氧基;
上述-NRaRb中Ra、Rb各自独立代表氢、C1~C6烷基、C1~C6羟烷基、C1~C6烷酰基;或Ra、Rb连接形成含有1~2个N或O原子的5~6员杂环;
n代表1~3;
R2代表氢、羟基、C1~C6烷氧基、C1~C6烷基酰氧基或C1~C6烷基磺酰氧基;
R3、R5各自独立代表氢、C1~C8烷基或C2~C8不饱和烯基;
R4代表氢或羟基;
或R4与R3连接成5~6员含氧杂环;或R4与R5连接成5~6员含氧杂环。
Ra、Rb优选各自独立代表氢、甲基、乙基、丙基、异丙基、正丁基、羟乙基或羟丙基;或者Ra、Rb连接形成四氢吡咯基、咪唑基、哌啶基、4-氧代哌啶基、吗啡啉基、哌嗪基、N-甲基哌嗪基、N-苯基哌嗪基或N-苄基哌嗪基。
R2优选代表氢、羟基、甲氧基、乙酰基或甲磺酰基。
R3、R4、R5优选同时代表氢。
R3、R5优选各自独立代表氢或异戊烯基,R4代表羟基。
R4与R3优选连接成六员吡喃环,或R4与R5连接成六员吡喃环。
本发明部分化合物的代号及化学结构如下:
本发明还公开了通式I化合物的制备方法:
其中R1、R2、R3、R4、R5、n的定义同权利要求1,R2a代表氢、羟基,R4a代表氢、(2-甲基丁-3-炔-2-基)氧基,R4b代表氢、(2-甲基丁-3-炔-2-基)氧基、(2-甲基丁-3-烯-2-基)氧基,R4a、R4b也可与R3或R5连接成5~6员含氧杂环,X代表溴、氯、碘。
将化合物III与3-氯-3-甲基-丁-1-炔反应得化合物IV,反应温度优选20℃~60℃,反应时间优选2~8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、乙酸乙酯等。反应中还应加入无机碱或有机碱,如氢氧化钠、氢氧化钾、碳酸钾、碳酸钠、三乙胺等,并加入氯化亚铜、碘化亚铜或碘化钾为催化剂。
化合物IV经过常压催化氢化得到化合物V,反应温度优选20℃~60℃,反应时间优选0.5~4小时,反应溶剂可选乙酸乙酯、四氢呋喃、乙腈、乙醇等。催化剂可选5%钯碳、10%钯碳、5%钯-硫酸钡、10%钯-硫酸钡等。
化合物V可通过与二卤代烯反应得到化合物VI,反应温度优选20℃~80℃,反应时间优选2~4小时,反应溶剂可选DMF、乙腈、丙酮、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,如氢氧化钠、氢氧化钾、碳酸钾、碳酸钠、三乙胺、对二甲氨基吡啶等。
化合物VI再与R1H反应脱除HX得到化合物VII,反应温度优选20℃~80℃,反应时间优选0.5~4小时,反应溶剂可选DMF、乙腈、丙酮、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,如氢氧化钠、氢氧化钾、碳酸钾、碳酸钠、三乙胺、对二甲氨基吡啶等。
当化合物VII中的R2代表羟基时,其可以通过与卤代烷、烷酰氯、烷基磺酰氯反应将R2转变为烷氧基、烷基酰氧基、烷基磺酰氧基,反应温度为20℃~80℃,反应时间优选2~10小时,反应溶剂可选DMF、乙腈、丙酮、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,如氢氧化钠、氢氧化钾、碳酸钾、碳酸钠、三乙胺、对二甲氨基吡啶等。
化合物VII加热发生Claisen/Diels-Alder级联重排反应得到通式I化合物,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。
当通式I化合物中含有权利要求1定义的-NRaRb基团时,将通式I化合物溶于适当溶剂中,室温下通入盐酸气,立即有固体析出,抽滤,得到滤饼即为通式I化合物的盐酸盐,溶剂可选择四氢呋喃、乙醚、二氯甲烷、三氯甲烷、丙酮、甲醇、乙醇、乙酸乙酯、乙腈等。
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。
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,活性优于已报道的藤黄酸简化物II;分子量比藤黄酸小,通过杂原子及亲水性基团引入或进一步成盐,改善了胃肠道吸收性;本发明化合物的成药性明显优于藤黄酸及化合物II,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48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
由表1可见,本发明的化合物具有较强的抗肿瘤细胞增殖的活性,其活性与天然产物藤黄酸相当,优于化合物II。
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PAMPAExplorerTM说明书执行。①建立Excel表格:建立化合物信息表格,并导入PAMPAExplorerTM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 SinkBuffer)及200μL GIT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PAMPAExplorerTM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2。
表2本发明部分化合物的膜透过率
由表2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已经报道的化合物II。
具体实施方式
实施例1
3,3a,4,5-四氢-1,11-二(3-甲基丁-2-烯-1-基)-4-溴甲基-8,10-二羟基-1,5-亚甲基桥-1H,7H-呋喃[3,4-d]并呫吨-7,13-二酮(CPUYZ001)
(1)1,5-二羟基-3,6-双[(2-甲基丁-3-炔-2-基)氧基]-9H-呫吨-9-酮的制备
将1,3,5,6-四羟基-9H-呫吨-9-酮(5.2g,20mmol)溶于丙酮(100mL)中,加入碳酸钾(8.28g,60mmol)、碘化钾(9.96g,60mmol)、碘化亚酮(382mg,2mmol)及3-氯-3-甲基丁-1-炔(6.7mL,60mmol),升温至60℃反应1h。过滤,滤液浓缩,残留物柱层析(石油醚∶乙酸乙酯=8∶1),得黄色固体1.19g,收率15.2%,m.p.149~150℃。1H NMR(300MHz,CDCl3):δ1.75(s,6H,2×-CH 3 ),1.79(s,6H,2×-CH 3 ),2.71(d,2H,2×-C≡CH),5.84(s,1H,Ar-OH),6.66(d,J=2.4Hz,1H,Ar-H),6.91(d,J=2.4Hz,1H,Ar-H),7.54(d,J=9.0Hz,1H,Ar-H),7.76(d,J=9.0Hz,1H,Ar-H),12.84(s,1H,Ar-OH);EI-MS(m/z)392[M]+。
(2)1,5-二羟基-3,6-双[(2-甲基丁-3-烯-2-基)氧基]-9H-呫吨-9-酮的制备
将1,5-二羟基-3,6-双[(2-甲基丁-3-炔-2-基)氧基]-9H-呫吨-9-酮(2.0g,5.1mmol)溶于乙醇(20mL)中,加入10%钯-硫酸钡(50mg)室温常压氢化反应。TLC检测反应,原料点会逐渐消失,开始形成第一个产物,继续反应第一个产物点会逐渐消失,形成第二个产物。待第一个产物点消失后将反应液过滤,滤液浓缩,残留物柱层析(石油醚∶乙酸乙酯=8∶1),得黄色固体1.83g,收率90.6%,m.p.125~127℃。1H NMR(300MHz,CDCl3):δ1.56(s,6H,2×CH3),1.58(s,6H,2×CH3),5.28(m,4H,2×CH=CH 2 ),6.16(m,2H,2×CH=CH2),6.42(d,J=2.2Hz,1H,Ar-H),6.60(d,J=2.2Hz,1H,Ar-H),7.11(d,J=8.9Hz,1H,Ar-H),7.65(d,J=8.9Hz,1H,Ar-H),12.82(s,1H,OH);ESI-MS(m/z)396[M]+;Anal.(C23H24O6)C,H Calc:69.68,6.10,found:69.28,6.08。
(3)(E)-1-羟基-5-((4-溴丁-2-烯-1-基)氧基)-3,6-双[(2-甲基丁-3-烯-2-基)氧基]-9H-呫吨-9-酮的制备
将1,5-二羟基-3,6-双[(2-甲基丁-3-烯-2-基)氧基]-9H-呫吨-9-酮(100mg,0.253mmol)溶于丙酮中,依次加入碳酸钾(39mg,0.278mmol)、(E)-1,4-二溴丁-2-烯(60mg,0.278mmol),升温至50℃反应。TLC检测待原料消失后将反应液过滤,滤液浓缩,残留物柱层析(石油醚∶乙酸乙酯=8∶1),得黄色油状物102mg,收率76.5%。1H NMR(300MHz,CDCl3):δ1.49(s,6H,2×-CH 3 ),1.51(s,6H,2×-CH 3 ),3.90(d,2H,-CH 2 -),4.60(d,2H,-CH 2 -),5.15(m,2H,-CH=CH 2 ),5.22(m,2H,-CH=CH 2 ),6.02(m,2H,2×-CH=CH2),6.10(m,2H,-CH=CH-),6.37(d,J=2.7Hz,1H,Ar-H),6.50(d,J=2.7Hz,1H,Ar-H),7.04(d,J=9.0Hz,1H,Ar-H),7.76(d,J=9.0Hz,1H,Ar-H),12.73(s,1H,Ar-OH);EI-MS(m/z):528[M]+。
(4)标题化合物的制备
将(E)-1-羟基-5-((4-溴丁-2-烯-1-基)氧基)-3,6-双[(2-甲基丁-3-烯-2-基)氧基]-9H-呫吨-9-酮(100mg,0.19mmol)溶于DMF(3mL),在氮气保护下升温至120℃反应2h。减压蒸除溶剂,残留物柱层析,得黄色固体42mg,收率42%,m.p.163~164℃。IR(KBr,cm-1):2961,2922,2855,1740,1638,1595,1431,1271,1178,1135,1030,828;1HNMR(300MHz,CDCl3):δ1.10~1.81(m,12H),2.35~2.65(m,4H),3.15(m,2H),3.28(d,2H),3.65(m,1H),3.86(m,1H),4.29(m,1H),4.47(m,1H),5.08(m,1H),6.02(s,1H),6.40(s,1H),7.07(d,J=6.9Hz,1H),12.32(s,1H,OH);EI-MS(m/z)528[M]+,500,483,419;ESI-HRMS(m/z)calcd for C27H29BrO6[M+H]+,529.1148,Found,529.1200.
实施例2
3,3a,4,5-四氢-1,11-二(3-甲基丁-2-烯-1-基)-4-碘甲基-8,10-二羟基-1,5-亚甲基桥-1H,7H-呋喃[3,4-d]并呫吨-7,13-二酮(CPUYZ002)
(1)(E)-1-羟基-5-((4-碘丁-2-烯-1-基)氧基)-3,6-双[(2-甲基丁-3-烯-2-基)氧基]-9H-呫吨-9-酮的制备
将(E)-1-羟基-5-((4-溴丁-2-烯-1-基)氧基)-3,6-双[(2-甲基丁-3-烯-2-基)氧基]-9H-呫吨-9-酮(200mg,0.378mmol)溶于丙酮(10mL),加入碘化钠(114mg,0.756mmol),室温反应。TLC检测待原料消失后将反应液过滤,滤液浓缩,残留物柱层析(石油醚∶乙酸乙酯=8∶1),得黄色油状物191mg,收率87.2%。1HNMR(300MHz,CDCl3):δ1.51(s,12H,CH3×4),3.79(d,2H,CH2),4.56(d,2H,CH2),5.05~5.35(m,4H,CH=CH 2×2),5.95~6.15(m,4H,CH=CH2×2,CH=CH×2),6.36(d,J=2.1Hz,1H,ArH),6.49(d,J=2.1Hz,1H,ArH),7.02(d,J=9Hz,1H,ArH),7.75(d,J=9Hz,1H,ArH),12.73(s,1H,OH);EI-MS(m/z)576[M]+。
(2)标题化合物的制备
将(E)-1-羟基-5-((4-碘丁-2-烯-1-基)氧基)-3,6-双[(2-甲基丁-3-烯-2-基)氧基]-9H-呫吨-9-酮(100mg,0.17mmol)溶于DMF(3mL),在氮气保护下升温至120℃反应2h。减压蒸除溶剂,残留物柱层析,得黄色油状物36mg,收率36%。IR(KBr,cm-1):2956,2923,2853,1739,1638,1596,1430,1271,1177,1134,825;1H NMR(300MHz,CDCl3):δ1.10~1.81(m,12H),2.35~2.65(m,4H),2.81~3.05(m,2H),3.27(d,2H),3.65(m,1H),3.86(m,1H),4.29(m,1H),4.45(m,1H),5.13(m,1H),5.99(s,1H),6.64(s,1H),7.08(d,J=6.9Hz,1H),12.34(s,1H);EI-MS(m/z)576[M]+,501,480,448,421;ESI-HRMS(m/z)calcd for C27H29IO6[M+H]+,577.1009,Found,577.1081。
实施例3
3,3a,4,5-四氢-1,11-二(3-甲基丁-2-烯-1-基)-4-硫氰基甲基-8,10-二羟基-1,5-亚甲基桥-1H,7H-呋喃[3,4-d]并呫吨-7,13-二酮(CPUYZ003)
按实施例2方法制备,用硫氰化钾代替碘化钠,用95%乙醇代替丙酮作溶剂,得黄色油状物60mg,两步收率30.4%。IR(KBr,cm-1):2968,2908,2155,1739,1638,1595,1431,1371,1223,1134,826;1H NMR(300MHz,CDCl3):δ1.10~1.81(m,12H),2.35~2.75(m,4H),2.90(m,1H),3.25(m,2H),3.65(d,2H),3.92(m,1H),4.29(m,1H),4.47(m,1H),5.18(m,1H),6.02(s,1H),7.07(d,J=6.9Hz,1H),12.30(s,1H);EI-MS(m/z)507[M]+,479,448,396
ESI-HRMS(m/z)calcd for C28H29NO6S[M+H]+,508.1716,Found,508.1768。
实施例4
3,3a,4,5-四氢-1,11-二(3-甲基丁-2-烯-1-基)-4-羟甲基-8,10-二羟基-1,5-亚甲基桥-1H,7H-呋喃[3,4-d]并呫吨-7,13-二酮(CPUYZ004)
按实施例2方法制备,用氢氧化钾代替碘化钾,用丙酮/水(1∶1)代替丙酮作溶剂,得黄色油状物57mg,两步收率32.4%。IR(KBr,cm-1):2966,1738,1634,1596,1448,1323,1225,1153,1063,653;1H NMR(300MHz,CDCl3):δ1.10~1.81(m,12H),2.35~2.65(m,4H),3.28(m,3H),3.63(m,2H),3.81(m,1H),4.35(m,1H),4.42(m,1H),5.17(m,1H),5.95(s,1H),7.08(d,J=6.9Hz,1H),12.72(s,1H,OH);EI-MS(m/z)466[M]+,451,438,407;ESI-HRMS(m/z)calcd forC27H30O7[M+H]+,467.1992,Found,467.2046。
实施例5
3,3a,4,5-四氢-1,11-二(3-甲基丁-2-烯-1-基)-4-氨甲基-8,10-二羟基-1,5-亚甲基桥-1H,7H-呋喃[3,4-d]并呫吨-7,13-二酮(CPUYZ005)
按实施例2方法制备,用氨水代替碘化钾,用DMF代替丙酮作溶剂,得黄色油状物57mg,两步收率12.5%。IR(KBr,cm-1):3403,3347,2960,2922,2854,1738,1637,1597,1444,1315,1092,1023,783,728;1HNMR(300MHz,DMSO):δ1.10~1.81(m,12H),2.15~2.55(m,6H),3.15(m,2H),3.36(m,1H),3.87(m,1H),4.35(m,2H),5.16(m,1H),6.01(s,1H),7.09(d,J=6.9Hz,1H),10.94(br,2H,NH2),12.56(s,1H,OH);EI-MS(m/z)466[M]+,452,437,409;ESI-HRMS(m/z)calcd for C27H31NO6[M+H]+,466.2151,Found,466.2234.
实施例6
3,3a,4,5-四氢-1,11-二(3-甲基丁-2-烯-1-基)-4-二乙氨基甲基-8,10-二羟基-1,5-亚甲基桥-1H,7H-呋喃[3,4-d]并呫吨-7,13-二酮(CPUYZ006)
(1)(E)-1-羟基-5-((4-二乙基氨基丁-2-烯-1-基)氧基)-3,6-双[(2-甲基丁-3-烯-2-基)氧基]-9H-呫吨-9-酮的制备
将(E)-1-羟基-5-((4-溴丁-2-烯-1-基)氧基)-3,6-双[(2-甲基丁-3-烯-2-基)氧基]-9H-呫吨-9-酮(200mg,0.378mmol)溶于DMF(5mL)中,加入碳酸钾(78mg,0.567mmol)、二乙胺(42mg,0.567mmol),升温至40℃反应。TLC检测待原料消失后将反应液倒入水(20mL)中,用乙酸乙酯(15mL×3)萃取,合并有机层,浓缩,残留物柱层析(石油醚∶乙酸乙酯=1∶1,1%三乙胺),得黄色油状物182mg,收率92.3%。1HNMR(300MHz,CDCl3):δ0.75(m,6H,CH3×2),1.48(s,12H,CH3×4),2.13(m,4H,CH2×2),2.85(d,2H,CH2),4.65(d,2H,CH2),5.12~5.38(m,4H,CH=CH 2×2),5.50~5.90(m,2H,CH=CH),6.15(m,2H,CH=CH2×2),6.29(d,J=2.1Hz,1H,ArH),6.51(d,J=2.1Hz,1H,ArH),7.01(d,J=9Hz,1H,ArH),7.68(d,J=9Hz,1H,ArH),12.71(s,1H,OH);EI-MS(m/z)521[M]+,506,478,424,260。
(2)标题化合物的制备
将(E)-1-羟基-5-((4-二乙基氨基丁-2-烯-1-基)氧基)-3,6-双[(2-甲基丁-3-烯-2-基)氧基]-9H-呫吨-9-酮(100mg,0.192mmol)溶于DMF(3mL)中,在氮气保护下升温至120℃反应2h。减压蒸除溶剂,残留物柱层析,得黄色固体38mg,收率38%,m.p.120~121℃。IR(KBr,cm-1):3286,2958,1735,1644,1590,1316,1275,1261,1092,764,750;1H NMR(300MHz,CDCl3):δ0.96(m,6H),1.08(s,3H),1.37(s,3H,),1.74(s,3H),1.81(s,3H),2.15~2.30(m,4H),2.49(m,4H),2.60(m,2H),3.32(d,J=6.6Hz,2H),3.65(d,J=6.6Hz,1H),3.87(d,J=7.8Hz,1H),4.39(m,1H),4.51(dd,J1=8.1Hz,J2=3.6Hz,1H),5.20(m,1H),6.00(s,1H),7.15(d,J=6.6Hz,1H),12.49(s,1H,OH);EI-MS(m/z)521[M]+;ESI-HRMS(m/z)calcd for C31H39NO6[M+H]+,522.2856,Found,522.2865。
实施例7
3,3a,4,5-四氢-1,11-二(3-甲基丁-2-烯-1-基)-4-二正丁氨基甲基-8,10-二羟基-1,5-亚甲基桥-1H,7H-呋喃[3,4-d]并呫吨-7,13-二酮(CPUYZ007)
按实施例6方法制备,以二正丁胺替代二乙胺,得黄色固体40mg,收率40%,m.p.130~131℃。IR(KBr,cm-1):3422,2962,2920,1738,1644,1634,1587,1414,1101,798,751;1HNMR(300MHz,CDCl3):δ0.89(m,6H),1.09(s,3H),1.29(m,8H),1.37(s,3H,C20-H),1.71(s,3H),1.79(s,3H),2.15~2.27(m,4H),2.36(m,4H),2.60(m,2H),3.29(m,2H),3.65(d,J=6.9Hz,1H),3.86(d,J=7.8Hz,1H),4.38(m,1H),4.51(dd,J1=7.8Hz,J2=3.6Hz,1H),5.18(m,1H),5.98(s,1H),7.12(d,J=6.9Hz,1H),12.49(s,1H,OH);EI-MS(m/z)577[M]+;ESI-HRMS(m/z)calcd forC35H47NO6[M+H]+,578.3482,Found,578.3493。
实施例8
3,3a,4,5-四氢-1,11-二(3-甲基丁-2-烯-1-基)-4-((二(2-羟基乙基)氨基)甲基)-8,10-二羟基-1,5-亚甲基桥-1H,7H-呋喃[3,4-d]并呫吨-7,13-二酮(CPUYZ008)
按实施例6方法制备,以二乙醇胺替代二乙胺,得黄色固体38mg,收率38%,m.p.128~130℃。IR(KBr,cm-1):3357,2962,2926,1732,1642,1593,1431,1272,1071,1036,764,750;1HNMR(300MHz,CDCl3):δ1.07~1.78(m,12H),2.18~2.40(m,4H),2.55~2.73(m,2H),3.11(m,4H),3.28(m,2H),3.54~3.62(m,5H),3.74(m,1H),3.93(m,1H),4.36(m,1H),4.50(m,1H),5.17(m,1H),6.15(s,1H),7.15(d,J=6.9Hz,1H),12.42(s,1H,OH);EI-MS(m/z)553[M]+ESI-HRMS(m/z)calcd for C31H39NO8[M+H]+,554.2754,Found,554.2768。
实施例9
3,3a,4,5-四氢-1,11-二(3-甲基丁-2-烯-1-基)-4-(四氢吡咯-1-基甲基)-8,10-二羟基-1,5-亚甲基桥-1H,7H-呋喃[3,4-d]并呫吨-7,13-二酮(CPUYZ009)
按实施例6方法制备,以吡咯烷替代二乙胺,得黄色固体42mg,收率42%,m.p.137~138℃。IR(KBr,cm-1):3440,2973,2785,1741,1644,1633,1598,1455,1316,1169,1151,1098,1063,803;1H NMR(300MHz,CDCl3):δ1.05(s,3H),1.34(s,3H),1.71(s,3H),1.77(s,3H),1.83(m,4H),2.15~2.42(m,4H),2.48~2.68(m,6H),3.07(d,J=7.5Hz,2H),3.54(dd,J1=6.9Hz,J2=2.1Hz,1H),3.86(d,J=7.8Hz,1H),4.35(m,1H),4.52(dd,J1=7.8Hz,J2=3.6Hz,1H),5.13(m,1H),5.69(s,1H),7.13(d,J=6.9Hz,1H),12.46(s,1H);EI-MS(m/z)519[M]+;ESI-HRMS(m/z)calcd for C31H37NO6[M+H]+,520.2699,Found,520.2706。
实施例10
3,3a,4,5-四氢-1,11-二(3-甲基丁-2-烯-1-基)-4-(哌啶-1-基甲基)-8,10-二羟基-1,5-亚甲基桥-1H,7H-呋喃[3,4-d]并呫吨-7,13-二酮(CPUYZ010)
按实施例6方法制备,以哌啶替代二乙胺,得黄色固体40mg,收率40%,m.p.176~178℃。IR(KBr,cm-1):3451,2935,1651,1599,1456,1276,1261,1057,764,750;1H NMR(300MHz,CDCl3):δ1.11(s,3H),1.35(s,3H),1.44(m,2H),1.57(m,4H),1.72(s,3H),1.79(s,3H),2.12~2.30(m,4H),2.37(m,4H),2.57(m,2H),3.25(d,J=6.9Hz,2H),3.57(dd,J1=6.9Hz,J2=2.7Hz,1H),3.85(d,J=8.1Hz,1H),4.36(m,1H),4.51(dd,J1=7.8Hz,J2=3.6Hz,1H),5.18(m,1H),5.81(s,1H),7.14(d,J=6.9Hz,1H),12.48(s,1H,OH);EI-MS(m/z)533[M]+;ESI-HRMS(m/z)calcd for C32H39NO6[M+H]+,534.2856,Found,534.2875.
实施例11
3,3a,4,5-四氢-1,11-二(3-甲基丁-2-烯-1-基)-4-[(4-苯基哌嗪-1-基)甲基]-8,10-二羟基-1,5-亚甲基桥-1H,7H-呋喃[3,4-d]并呫吨-7,13-二酮(CPUYZ011)
按实施例6方法制备,以苯基哌嗪替代二乙胺,得黄色固体43mg,收率43%,m.p.189~190℃。IR(KBr,cm-1):3428,2963,2906,1740,1644,1584,1415,1260,1095,1025,799,698;1HNMR(300MHz,CDCl3):δ1.08(s,3H),1.64(s,3H),1.71(s,3H),2.21(m,2H),2.31(m,2H),2.55~2.71(m,6H),3.17(m,4H),3.30(m,2H),3.66(dd,J=6.9,3.0Hz,1H),3.88(m,1H),4.37(m,1H),4.55(m,1H),5.17(m,1H),5.97(s,1H),6.84~6.94(m,3H),7.15(d,J=6.6Hz,1H),7.26(m,2H),7.37(d,J=6.9Hz,1H),12.50(s,1H,OH);EI-MS(m/z)610[M]+;ESI-HRMS(m/z)calcd for C37H42N2O6[M+H]+,611.3121,Found,611.3120。
实施例12
3,3a,4,5-四氢-1,11-二(3-甲基丁-2-烯-1-基)-4-乙酰氧基甲基-8,10-二羟基-1,5-亚甲基桥-1H,7H-呋喃[3,4-d]并呫吨-7,13-二酮(CPUYZ012)
按实施例6方法制备,以乙酸替代二乙胺,得黄色固体38mg,收率38%,m.p.138~140℃。IR(KBr,cm-1):3268,2968,2920,1741,1644,1593,1269,1260,1042,801,749;1H NMR(300MHz,CDCl3):δ1.08(s,3H),1.34(s,3H),1.74(s,3H),1.81(s,3H),2.19(s,3H),2.20(m,2H),2.42(m,1H),2.52(m,1H),2.58(m,1H),3.32(m,2H),3.64(dd,J=6.9,3.0Hz,1H),3.77(m,1H),3.95(m,2H),4.37(m,1H),4.53(dd,J=8.4,3.6Hz,,1H),5.17(m,1H),6.06(s,1H),6.74(s,1H,OH),7.14(d,J=6.9Hz,1H),12.43(s,1H,OH);EI-MS(m/z)508[M]+;ESI-HRMS(m/z)calcdfor C29H32O8[M-H]+,507.2019,Found,507.2016。
实施例13
3,3a,4,5-四氢-1,11-二(3-甲基丁-2-烯-1-基)-4-((2-羟乙基)氧基甲基)-8,10-二羟基-1,5-亚甲基桥-1H,7H-呋喃[3,4-d]并呫吨-7,13-二酮(CPUYZ013)
按实施例6方法制备,以乙二醇代替二乙胺,得黄色固体36mg,收率36%,m.p.102~104℃。IR(KBr,cm-1):2957,2923,2080,1881,1813,1741,1636,1596,1431,1121,782,728,706;1HNMR(300MHz,CDCl3):δ1.10~1.81(m,12H),2.35~2.65(m,4H),3.20(m,4H),3.43(m,2H),3.63(m,3H),3.85(m,1H),4.31(m,1H),4.45(m,1H),5.13(m,1H),5.98(s,1H),7.07(d,J=6.9Hz,1H),12.39(s,1H,OH);EI-MS(m/z)510[M]+,482,437,407;ESI-HRMS(m/z)calcd forC29H34O8[M+H]+,511.2254,Found,511.2300。
实施例14
3,3a,4,5-四氢-1,11-二(3-甲基丁-2-烯-1-基)-4-异丙氧基甲基-8,10-二羟基-1,5-亚甲基桥-1H,7H-呋喃[3,4-d]并呫吨-7,13-二酮(CPUYZ014)
按实施例6方法制备,以异丙醇代替二乙胺,得黄色固体40mg,收率40%,m.p.187~188℃。IR(KBr,cm-1):3441,3345,2971,2918,1738,1637,1430,1373,1223,1079,1060,818;1H NMR(300MHz,CDCl3):δ1.02(s,3H),1.04(s,3H),1.10~1.81(m,12H),2.35~2.65(m,4H),2.81~3.05(m,2H),3.27(m,2H),3.45(m,1H),3.65(m,1H),3.86(m,1H),4.29(m,1H),4.45(m,1H),5.14(t,1H),5.99(s,1H),6.77(s,1H),7.06(d,J=6.9Hz,1H),12.42(s,1H);EI-MS(m/z)508[M]+;ESI-HRMS(m/z)calcd for C30H36O7[M+H]+,509.2461,Found,509.2508.
实施例15
3,3a,4,5-四氢-1,11-二(3-甲基丁-2-烯-1-基)-4-烯丙氧基甲基-8,10-二羟基-1,5-亚甲基桥-1H,7H-呋喃[3,4-d]并呫吨-7,13-二酮(CPUYZ015)
按实施例6方法制备,以烯丙醇代替二乙胺,得黄色油状物37mg,收率37%。IR(KBr,cm-1):2967,2912,2856,1739,1637,1596,1430,1341,1130,1089,783,731;1H NMR(300MHz,CDCl3:δ1.10~1.81(m,12H),2.35~2.75(m,3H),3.18(m,2H),.30(m,2H),3.66(m,1H),3.85(m,4H),4.29(m,1H),4.47(m,1H),5.12(m,3H),5.82(m,1H),5.98(s,1H),7.19(d,J=6.9Hz,1H),12.41(s,1H,OH);EI-MS(m/z)506[M]+,478,461,437,407;ESI-HRMS(m/z)calcd forC30H34O7[M+H]+,507.2305,Found,507.2355。
实施例16
3,3a,4,5-四氢-1,11-二(3-甲基丁-2-烯-1-基)-4-二乙氨基甲基-10-羟基-8-乙酰氧基-1,5-亚甲基桥-1H,7H-呋喃[3,4-d]并呫吨-7,13-二酮(CPUYZ0016)
将(E)-1-羟基-5-((4-二乙基氨基丁-2-烯-1-基)氧基)-3,6-双[(2-甲基丁-3-烯-2-基)氧基]-9H-呫吨-9-酮(100mg,0.192mmol)溶于二氯甲烷(5mL)中,加入DMAP(35mg,0.288mmol)及乙酸酐(30mg,0.288mmol),室温反应。TLC检测待原料消失后将反应液倒入饱和氯化铵溶液(15mL)中,二氯甲烷(10mL×3)萃取,合并有机层,无水硫酸钠干燥,浓缩,将残留物溶于DMF(3mL)中,在氮气保护下升温至120℃反应2h。减压蒸除溶剂,残留物柱层析,得黄色固体74mg,收率68.5%。1H NMR(300MHz,CDCl3):δ0.97(m,6H),1.09(s,3H),1.37(s,3H,),1.74(s,3H),1.81(s,3H),2.14~2.30(m,4H),2.50(m,4H),2.60(m,2H),3.33(d,J=6.6Hz,2H),2.35(s,3H),3.65(d,J=6.6Hz,1H),3.87(d,J=7.8Hz,1H),4.38(m,1H),4.52(dd,J1=8.1Hz,J2=3.6Hz,1H),5.20(m,1H),6.22(s,1H),6.39(brs,1H),7.33(d,J=6.9Hz,1H);EI-MS(m/z)563[M]+;ESI-HRMS(m/z)calcd for C33H41NO7[M+H]+,564.2956Found,564.2965.
实施例17
3,3a,4,5-四氢-1,11-二(3-甲基丁-2-烯-1-基)-4-苯酰氧基甲基-8,10-二羟基-1,5-亚甲基桥-1H,7H-呋喃[3,4-d]并呫吨-7,13-二酮(CPUYZ017)
按实施例6方法制备,以苯甲酸替代二乙胺,得黄色固体36mg,收率36%,m.p.92~93℃。IR(KBr,cm-1):3469,2970,2907,1718,1637,1595,1431,1320,1272,1178,1103,817,712;1HNMR(300MHz,CDCl3):δ1.09~1.82(m,12H),2.57~2.68(m,4H),3.27(m,2H),3.68(m,1H),3.99(m,2H),4.15(m,1H),4.32(m,1H),4.49(m,1H),5.13(m,1H),5.99(s,1H),6.24(s,1H),7.15(d,J=6.9Hz,1H),7.93~7.40(m,5H),12.36(s,1H,OH);EI-MS(m/z)570[M]+,542,437,407;ESI-HRMS(m/z)calcd for C34H34O8[M-H]+,569.2175,Found,569.2178.
实施例18
3,3a,4,5-四氢-1,11-二(3-甲基丁-2-烯-1-基)-4-对甲氧基苯酰氧基甲基-8,10-二羟基-1,5-亚甲基桥-1H,7H-呋喃[3,4-d]并呫吨-7,13-二酮(CPUYZ018)
按实施例6方法制备,以对甲氧基苯甲酸替代二乙胺,得黄色油状物41mg,收率41%。IR(KBr,cm-1):2975,1741,1714,1637,1600,1510,1429,1260,1170,1101,769;1H NMR(300MHz,CDCl3):δ1.09~1.82(m,12H),2.57~2.68(m,4H),3.35(m,2H),3.74(m,1H),3.90(s,3H,OCH3),3.99(m,1H),4.06(m,2H),4.17(m,1H),4.56(m,1H),5.20(m,1H),6.07(s,1H),6.94(d,J=9Hz,2H),7.24(d,J=6.9Hz,1H),8.03(d,J=9Hz,2H),12.44(s,1H,OH);EI-MS(m/z)600[M]+,572,437,407;ESI-HRMS(m/z)calcd for C35H36NO9[M+H]+,601.2359,Found,601.2408。
实施例19
3,3a,4,5-四氢-1,11-二(3-甲基丁-2-烯-1-基)-4-对氯苯酰氧基甲基-8,10-二羟基-1,5-亚甲基桥-1H,7H-呋喃[3,4-d]并呫吨-7,13-二酮(CPUYZ019)
按实施例6方法制备,以对甲氯苯甲酸替代二乙胺,得黄色油状物42mg,收率42%。IR(KBr,cm-1):2962,2921,2389,2299,1740,1722,1639,1596,1428,1269,1092,1043,1014,781,759;1H NMR(300MHz,CDCl3):δ1.10~1.81(m,12H),2.57~2.68(m,4H),3.35(m,2H),3.77(m,1H),3.95(d,1H),4.11(m,2H),4.32(m,1H),4.57(m,1H),5.20(m,1H),6.08(s,1H),7.18(d,J=6.9Hz,1H),7.42(d,J=8.4Hz,2H),7.93(d,J=8.4Hz,2H),12.43(s,1H,OH);EI-MS(m/z)604[M]+,576,479,437,407;ESI-HRMS(m/z)calcd for C34H34ClO8[M+H]+,605.1864,Found,605.1900
实施例20
3,3a,4,5-四氢-1,11-二(3-甲基丁-2-烯-1-基)-4-对二甲氨基苯酰氧基甲基-8,10-二羟基-1,5-亚甲基桥-1H,7H-呋喃[3,4-d]并呫吨-7,13-二酮(CPUYZ020)
按实施例6方法制备,以对二甲氨基苯甲酸替代二乙胺,得黄色油状物35mg,收率35%。IR(KBr,cm-1):2970,1740,1705,1634,1602,1448,1370,1322,1276,1181,1098,1059;1H NMR(300MHz,CDCl3):δ1.09~1.82(m,12H),2.57~2.68(m,4H),2.89(s,3H),2.97(s,3H),3.36(m,2H),3.72(m,1H),3.98(m,2H),4.15(m,1H),4.50(m,1H),4.54(m,1H),5.24(m,1H),6.02(s,1H),6.63(d,J=9Hz,2H),7.19(d,J=6.9Hz,1H),7.81(d,J=9Hz,2H),12.79(s,1H,OH);EI-MS(m/z)613[M]+;ESI-HRMS(m/z)calcd for C36H40NO8[M+H]+,614.2676,Found,614.2726。
实施例21
3,3a,4,5-四氢-1,11-二(3-甲基丁-2-烯-1-基)-4-苄羰氧基甲基-8,10-二羟基-1,5-亚甲基桥-1H,7H-呋喃[3,4-d]并呫吨-7,13-二酮(CPUYZ021)
按实施例6方法制备,以苯乙酸替代二乙胺,得黄色油状物36mg,收率36%。IR(KBr,cm-1):2970,1740,1639,1589,1437,1372,1159,1129,1069,827,703;1H NMR(300MHz,CDCl3):δ1.09~1.82(m,12H),2.11~2.64(m,4H),2.68(m,2H),3.31(m,2H),3.49(m,1H),3.80(m,3H),4.15(m,1H),4.46(m,1H),5.21(m,1H),6.09(s,1H),7.05(d,J=6.9Hz,1H),7.15~7.35(m,5H),12.41(s,1H,OH);EI-MS(m/z)584[M]+;ESI-HRMS(m/z)calcd for C35H36O8[M-H]+,583.2332,Found,583.2329。
实施例22
3,3a,4,5-四氢-1,9-二(3-甲基丁-2-烯-1-基)-4-羟甲基-8,10-二羟基-1,5-亚甲基桥-1H,7H-呋喃[3,4-d]并呫吨-7,13-二酮(CPUYZ022)
按实施例6方法制备,得另一异构体为标题化合物,黄色油状物44mg,收率30.7%。IR(KBr,cm-1):2965,1733,1631,1593,1445,1328,1221,1154,1069,653;1H NMR(300MHz,CDCl3):δ1.10~1.81(m,12H),2.35~2.65(m,4H),3.28(m,3H),3.63(m,2H),3.81(m,1H),4.35(m,1H),4.42(m,1H),5.17(m,1H),δ5.95(s,1H),7.08(d,J=6.9Hz,1H),12.72(s,1H,OH);EI-MS(m/z)466[M]+,451,438,407;ESI-HRMS(m/z)calcd for C27H30O7[M+H]+,467.1992,Found,467.2046。
实施例23
3,3a,4,5-四氢-1,9-二(3-甲基丁-2-烯-1-基)-4-乙酰氧基甲基-8,10-二羟基-1,5-亚甲基桥-1H,7H-呋喃[3,4-d]并呫吨-7,13-二酮(CPUYZ023)
按实施例12方法制备,得另一异构体为标题化合物,黄色固体26mg,收率26%,m.p.182~184℃。IR(KBr,cm-1):3351,2961,2908,1735,1646,1633,1596,1451,1322,1057,813,760;1HNMR(300MHz,CDCl3):δ1.08(s,3H),1.56(s,3H),1.77(s,3H),1.82(s,3H),2.08(s,3H),2.18(m,2H),2.40(m,1H),2.55(m,1H),2.64(m,1H),3.37(m,2H),3.62(dd,J=6.9,3.0Hz,1H),3.77(m,1H),3.94(m,2H),4.40(m,1H),4.52(dd,J=7.8,3.3Hz,,1H),5.22(m,1H),6.00(s,1H),6.38(s,1H,OH),7.15(d,J=6.9Hz,1H),12.78(s,1H,OH);EI-MS(m/z)508[M]+;ESI-HRMS(m/z)calcd for C29H32O8[M-H]+,507.2019,Found,507.2016。
实施例24
3,3a,4,5-四氢-1,9-二(3-甲基丁-2-烯-1-基)-4-((二(2-羟基乙基)氨基)甲基)-8,10-二羟基-1,5-亚甲基桥-1H,7H-呋喃[3,4-d]并呫吨-7,13-二酮(CPUYZ024)
按实施例8方法制备,得另一异构体为标题化合物,黄色固体328mg,收率28%,m.p.168~170℃。IR(KBr,cm-1):3381,2962,2920,1732,1644,1633,1593,1452,1060,765,748;1H NMR(300MHz,CDCl3):δ1.07~1.78(m,12H),2.17~2.44(m,4H),2.53~2.68(m,2H),3.09(m,4H),3.32(m,2H),3.57~3.66(m,5H),3.74(m,1H),3.89(m,1H),4.40(m,1H),4.48(m,1H),5.21(m,1H),6.03(s,1H),7.15(d,J=6.9Hz,1H),12.77(s,1H,OH);EI-MS(m/z)553[M]+;ESI-HRMS(m/z)calcd for C31H39NO8[M+H]+,554.2754,Found,554.2764。
实施例25
3,3a,4,5-四氢-1,9-二(3-甲基丁-2-烯-1-基)-4-二乙氨基甲基-8,10-二羟基-1,5-亚甲基桥-1H,7H-呋喃[3,4-d]并呫吨-7,13-二酮(CPUYZ025)
按实施例6方法制备,得另一异构体为标题化合物,黄色固体38mg,收率38%,m.p.122~123℃。IR(KBr,cm-1):3327,2962,2920,1741,1643,1633,1599,1455,1319,1063,815,748;1HNMR(300MHz,CDCl3):δ0.96(m,6H),1.12(s,3H),1.37(s,3H),1.76(s,3H),1.82(s,3H),2.14~2.28(m,4H),2.48(m,4H),2.64(m,2H),3.36(d,J=6.9Hz,2H),3.64(d,J=6.6Hz,1H),3.83(d,J=7.8Hz,1H),4.46(m,2H),5.24(m,1H),5.98(s,1H),7.15(d,J=6.9Hz,1H,),12.84(s,1H,OH);EI-MS(m/z)521[M]+;ESI-HRMS(m/z)calcd for C31H39NO6[M+H]+,522.2856,Found,522.2865。
实施例26
3,3a,4,5-四氢-1,9-二(3-甲基丁-2-烯-1-基)-4-(吡咯烷-1-基甲基)-8,10-二羟基-1,5-亚甲基桥-1H,7H-呋喃[3,4-d]并呫吨-7,13-二酮(CPUYZ026)
按实施例9方法制备,得另一异构体为标题化合物,黄色固体27mg,收率27%,m.p.162~163℃。IR(KBr,cm-1):3347,2971,2920,1736,1645,1633,1594,1459,1327,1061,819,746;1HNMR(300MHz,CDCl3):δ1.13(s,3H),1.37(s,3H),1.72(s,3H),1.79(m,7H),2.18~2.36(m,4H),2.55(m,6H),3.07(d,J=6.9Hz,2H),3.58(dd,J1=6.9Hz,J2=3.0Hz,1H),3.81(d,J=8.1Hz,1H),4.39(m,2H),5.22(m,1H),5.86(s,1H),7.12(d,J=6.9Hz,1H),12.77(s,1HOH);EI-MS(m/z)519[M]+;ESI-HRMS(m/z)calcd for C31H37NO6[M+H]+,520.2699,Found,520.2709。
实施例27
3,3a,4,5-四氢-1,9-二(3-甲基丁-2-烯-1-基)-4-(哌啶-1-基甲基)-8,10-二羟基-1,5-亚甲基桥-1H,7H-呋喃[3,4-d]并呫吨-7,13-二酮(CPUYZ027)
按实施例10方法制备,得另一异构体为标题化合物,黄色固体22mg,收率22%,m.p.200~202℃。IR(KBr,cm-1):3368,2935,1736,1645,1633,1596,1454,1320,1061,817;1H NMR(300MHz,CDCl3):δ1.10(s,3H),1.37(s,3H),1.41(m,2H),1.53(m,4H),1.75(s,3H),1.81(s,3H),2.08(m,2H),2.26(m,2H),2.37(m,4H),2.61(m,2H),3.35(d,J=6.9Hz,2H),3.60(dd,J1=6.9Hz,J2=3.3Hz,1H),3.81(d,J=7.8Hz,1H),4.42(m,2H),5.24(m,1H),5.95(s,1H),7.13(d,J=6.9Hz,1H),12.82(s,1H,OH);EI-MS(m/z)533[M]+;ESI-HRMS(m/z)calcd for C32H39NO6[M+H]+,534.2856,Found,534.2864。
实施例28
3,3a,4,5-四氢-11,11-二甲基-1-(3-甲基丁-2-烯-1-基)-4-(吗啉-1-基甲基)-8-羟基-1,5-亚甲基桥-1H,7H,11H-呋喃[3,4-g]吡喃[3,2-b]并呫吨-7,15-二酮(CPUYZ028)
(1)1,5-二羟基-6-[(2-甲基丁-3-烯-2-基)氧基]-3-[(2-甲基丁-3-炔-2-基)氧基]-9H-呫吨-9-酮的制备
将1,5-二羟基-3,6-双[(2-甲基丁-3-炔-2-基)氧基]-9H-呫吨-9-酮(实施例1中步骤(1)方法制备得到)(2.0g,5.1mmol)溶于乙醇(20mL)中,加入10%钯-硫酸钡(50mg)室温常压氢化。TLC检测待原料消失后,第一个产物形成时停止反应,将反应液过滤,滤液浓缩,残留物柱层析(石油醚∶乙酸乙酯=8∶1),得黄色油状物1.76g,收率88.3%。1H NMR(300MHz,CDCl3):δ1.58(s,6H),1.73(s,6H),2.62(s,1H),5.24(d,J=9.0Hz,1H),5.30(d,J=8.4Hz,1H),6.00(s,1H),6.16(m,1H),6.36(d,J=2.1Hz,1H),6.89(d,J=2.1Hz,1H),7.12(d,J=9.0Hz,1H),7.65(d,J=9.0Hz,1H),12.85(s,1H);EI-MS(m/z)394[M]+。
(2)(E)-1-羟基-5-((4-溴丁-2-烯-1-基)氧基)-6-[(2-甲基丁-3-烯-2-基)氧基]-3-[(2-甲基丁-3-炔-2-基)氧基]-9H-呫吨-9-酮的制备
将1,5-二羟基-6-[(2-甲基丁-3-烯-2-基)氧基]-3-[(2-甲基丁-3-炔-2-基)氧基]-9H-呫吨-9-酮(100mg,0.254mmol)溶于丙酮中,依次加入碳酸钾(39mg,0.278mmol)、(E)-1,4-二溴丁-2-烯替代烯丙基溴(60mg,0.278mmol),升温至50℃反应。TLC检测待原料消失后将反应液过滤,滤液浓缩,残留物柱层析(石油醚∶乙酸乙酯=8∶1),得黄色油状物101mg,收率75.6%。
1H NMR(300MHz,CDCl3):δ1.58(s,6H),1.75(s,6H),2.73(s,1H),3.96(m,2H),4.67(m,2H),5.23(m,2H),6.14(m,3H),6.98(d,J=2.1Hz,1H),6.83(d,J=2.1Hz,1H),7.12(d,J=9.0Hz,1H),7.84(d,J=9.0Hz,1H),12.83(s,1H);EI-MS(m/z)528[M]+,526
(3)(E)-1-羟基-5-((4-吗啉基丁-2-烯-1-基)氧基)-6-[(2-甲基丁-3-烯-2-基)氧基]-3-[(2-甲基丁-3-炔-2-基)氧基]-9H-呫吨-9-酮的制备
将(E)-1-羟基-5-((4-溴丁-2-烯-1-基)氧基)-6-[(2-甲基丁-3-烯-2-基)氧基]-3-[(2-甲基丁-3-炔-2-基)氧基]-9H-呫吨-9-酮(100mg)溶于DMF(5mL)中,加入碳酸钾(78mg,0.567mmol)、吗啉(49mg,0.567mmol),升温至40℃反应。TLC检测待原料消失后将反应液倒入水(20mL)中,用乙酸乙酯(15mL×3)萃取,合并有机层,浓缩,得黄色油状物100mg,收率98.6%。
(4)将上述所得残留物溶于DMF(3mL),在氮气保护下升温至120℃反应2h。减压蒸除溶剂,残留物柱层析,得黄色固体27mg,收率27%,m.p.177~178℃。IR(KBr,cm-1):3445,2961,2920,1738,1651,1633,1598,1455,1316,1260,1118,1025,801,745;1HNMR(300MHz,CDCl3):δ1.17(s,3H),1.39(s,3H),1.45(s,6H),2.16(m,2H),2.26(m,2H),2.40(m,4H),2.64(m,2H),3.66(m,5H),3.81(d,J=8.1Hz,1H),4.47~4.51(m,2H),5.52(d,J=9.9Hz,1H),5.96(s,1H),6.63(d,J=9.9Hz,1H),7.14(d,J=6.9Hz,1H),12.72(s,1H,OH);EI-MS(m/z)433[M]+;ESI-HRMS(m/z)calcd for C31H35NO7[M+H]+,434.2492,Found,434.2503。
实施例29
3,3a,4,5-四氢-11,11-二甲基-1-(3-甲基丁-2-烯-1-基)-4-正丁基氨基甲基-8-羟基-1,5-亚甲基桥-1H,7H,11H-呋喃[3,4-g]吡喃[3,2-b]并呫吨-7,15-二酮(CPUYZ029)
按实施例28方法制备,以正二丁胺代替吗啉,得黄色固体27mg,收率27%,m.p.200~202℃。IR(KBr,cm-1):3421,2962,2932,1741,1691,1644,1599,1457,1095,1022,799,731;1H NMR(300MHz,CDCl3):δ0.89(m,6H),1.17(s,3H),1.31(m,8H),1.39(s,3H,C20-H),1.44(s,6H),2.17(m,4H),2.34(m,4H),2.62(m,2H),3.65(d,J=6.6Hz,1H),3.83(d,J=8.1Hz,1H),4.47(m,2H),5.52(d,J=10.2Hz,1H),5.96(s,1H),6.63(d,J=10.2Hz,1H),7.13(d,J=6.9Hz,1H),12.77(s,1H,OH);EI-MS(m/z)575[M]+;ESI-HRMS(m/z)calcd for C33H45NO6[M+H]+,576.3325,Found,576.3336.
实施例30
3,3a,4,5-四氢-11,11-二甲基-1-(3-甲基丁-2-烯-1-基)-4-二异丙基氨基甲基-8-羟基-1,5-亚甲基桥-1H,7H,11H-呋喃[3,4-g]吡喃[3,2-b]并呫吨-7,15-二酮(CPUYZ030)
按实施例28方法制备,以二异丙胺代替吗啉,得黄色固体28mg,收率28%,m.p.185~186℃。IR(KBr,cm-1):3445,2968,2920,1738,1651,1645,1593,1455,1391,1313,1261,1096,1021,801;1H NMR(300MHz,CDCl3):δ0.85(s,3H),0.88(s,3H),0.90(s,3H),0.92(s,3H),1.16(s,3H),1.38(s,3H),1.56(s,6H),2.22~2.30(m,4H),2.62(m,2H),2.94(m,2H),3.65(m,1H),3.81(d,J=7.8Hz,1H),4.42~4.50(m,2H),5.52(d,J=10.2Hz,1H),5.96(s,1H),6.63(d,J=9.9Hz,1H),7.16(d,J=6.9Hz,1H),12.80(s,1H,OH);EI-MS(m/z)447[M]+;ESI-HRMS(m/z)calcdfor C31H41NO6[M+H]+,548.3012,Found,548.3023。
实施例31
3,3a,4,5-四氢-11,11-二甲基-1-(3-甲基丁-2-烯-1-基)-4-(吗啉-1-基甲基)-8-羟基-1,5-亚甲基桥-1H,7H,11H-呋喃[3,4-g]吡喃[2,3-b]并呫吨-7,15-二酮(CPUYZ031)
按实施例28方法制备,得另一异构体为标题化合物,黄色固体35mg,收率36%,m.p.164~166℃。IR(KBr,cm-1):3286,2956,2903,1735,1644,1590,1275,1261,1116,1036,801,750;1HNMR(300MHz,CDCl3):δ1.17(s,3H),1.39(s,3H),1.46(s,6H),2.14(m,2H),2.26(m,2H),2.38(m,4H),2.63(m,2H),3.66(m,5H),3.86(d,J=8.4Hz,1H),4.42(m,1H),4.49(dd,J1=7.8Hz,J2=3.9Hz,1H),5.53(d,J=9.9Hz,1H),5.96(s,1H),6.63(d,J=9.9Hz,1H),7.14(d,J=6.9Hz,1H),12.57(s,1H,OH);EI-MS(m/z)533[M]+;ESI-HRMS(m/z)calcd for C31H35NO7[M+H]+,534.2492,Found,534.2498。
实施例32
3,3a,4,5-四氢-11,11-二甲基-1-(3-甲基丁-2-烯-1-基)-4-二正丁氨基甲基-8-羟基-1,5-亚甲基桥-1H,7H,11H-呋喃[3,4-g]吡喃[2,3-b]并呫吨-7,15-二酮(CPUYZ032)
按实施例31方法制备,以正二丁胺代替吗啉,得黄色固体36mg,收率36%,m.p.169~170℃。IR(KBr,cm-1):3421,2963,2927,1738,1649,1644,1584,1416,1261,1090,1013,801,765;1HNMR(300MHz,CDCl3):δ0.89(m,6H),1.17(s,3H),1.31(m,8H),1.39(s,3H),1.44(s,6H),2.18(m,4H),2.35(m,4H),2.62(m,2H),3.67(d,J=6.6Hz,1H),3.88(d,J=7.8Hz,1H),4.42(d,J=6.9Hz,1H),4.50(dd,J=7.5,3.3Hz,1H),5.54(d,J=9.9Hz,1H),6.02(s,1H),6.56(d,J=9.9Hz,1H),7.14(d,J=6.9Hz,1H);12.61(s,1H);EI-MS(m/z)575[M]+;ESI-HRMS(m/z)calcd for C33H45NO6[M+H]+,576.3325,Found,576.3336。
实施例33
3,3a,4,5-四氢-11,11-二甲基-1-(3-甲基丁-2-烯-1-基)-4-烯丙氧基甲基-8-羟基-1,5-亚甲基桥-1H,7H,11H-呋喃[3,4-g]吡喃[2,3-b]并呫吨-7,15-二酮(CPUYZ033)
按实施例31方法制备,以烯丙醇代替吗啉,得黄色油状物35mg,收率35%。IR(KBr,cm-1):2968,2913,2856,1739,1638,1597,1430,1131,1090,783,732;1H NMR(300MHz,CDCl3):δ1.10~1.71(m,12H),2.35~2.65(m,4H),3.15(m,1H),3.65(m,2H),3.87(m,3H),4.34(m,1H),4.45(m,1H),5.12(m,2H),5.47(d,J=9.9Hz,1H),5.75(m,1H),5.95(s,1H),6.47(d,J=9.9Hz,1H),7.08(d,J=6.9Hz,1H),12.50(s,1H,OH);EI-MS(m/z)504[M]+,491,461,405;ESI-HRMS(m/z)calcd for C30H32O7[M+H]+,505.2148,Found,505.2221。
实施例34
3,3a,4,5-四氢-11,11-二甲基-1-(3-甲基丁-2-烯-1-基)-4-硝酸酯基甲基-8-羟基-1,5-亚甲基桥-1H,7H,11H-呋喃[3,4-g]吡喃[2,3-b]并呫吨-7,15-二酮(CPUYZ034)
按实施例31方法制备,以硝酸银溶液代替吗啉,得黄色油状物33mg,收率33%。IR(KBr,cm-1):3548,1637,1462,1384,1218,1172,1041,799,732;1H NMR(300MHz,CDCl3):δ1.10~1.81(m,12H),2.35~2.65(m,4H),3.69(m,1H),3.97(m,1H),4.21(d,2H),4.30(m,1H),4.47(m,1H),5.51(d,J=9.9Hz,1H),5.95(s,1H),6.47(d,J=9.9Hz,1H),7.19(d,J=6.9Hz,1H),12.37(s,1H,OH);EI-MS(m/z)509[M]+,464,449,421,405;ESI-HRMS(m/z)calcd for C34H33NO10[M+H]+,616.2106,Found,616.2162。
实施例35
3,3a,4,5-四氢-11,11-二甲基-1-(3-甲基丁-2-烯-1-基)-4-苯酰氧基甲基-8-羟基-1,5-亚甲基桥-1H,7H,11H-呋喃[3,4-g]吡喃[2,3-b]并呫吨-7,15-二酮(CPUYZ035)
按实施例34方法制备,以苯甲酸代替吗啉,得黄色油状物37mg,收率37%。IR(KBr,cm-1):2970,1740,1639,1589,1437,1372,1159,1129,1069,827,703;1H NMR(300MHz,CDCl3):δ1.09~1.82(m,12H),2.12~2.64(m,4H),3.44(m,1H),3.81(m,3H),4.25(m,1H),4.55(m,1H),5.45(d,J=9.9Hz,1H),5.95(s,1H),6.55(d,J=9.9Hz,1H),7.10(d,J=6.9Hz,1H),7.19(m,5H,Ph-H),12.61(s,1H,OH);EI-MS(m/z)568[M]+;ESI-HRMS(m/z)calcd for C34H32O8[M+H]+,569.2170,Found,569.2182。
实施例36
3,3a,4,5-四氢-1-(3-甲基丁-2-烯-1-基)-4-(二甲氨基甲基)-8-羟基-1,5-亚甲基桥-1H,7H-呋喃[3,4-d]并呫吨-7,13-二酮(CPUYZ036)
(1)1-羟基-6-(2-甲基-3-丁炔-2-氧基)-9H-呫吨-9-酮的制备
将1,5,6-三羟基-9H-呫吨-9-酮(4.88g,20mmol)溶于乙腈(100mL)中,加入碳酸钾(8.28g,60mmol)、碘化钾(9.96g,60mmol)、碘化亚酮(382mg,2mmol)及3-氯-3-甲基丁-1-炔(6.7mL,60mmol),升温至50℃反应。TLC检测待原料消失后将反应液过滤,滤液浓缩,残留物柱层析(石油醚∶乙酸乙酯=8∶1),得黄色固体2.18g,收率35.2%,m.p.142~144℃。1H NMR(300MHz,CDCl3):δ1.60(s,6H,2×-CH 3 ),2.72(s,1H,-C≡CH),5.85(s,1H,Ar-OH),6.80(d,1H,J=8.1Hz,Ar-H),7.03(d,1H,J=8.1Hz,Ar-H),7.59(m,2H,2×Ar-H),7.80(d,1H,J=9Hz,Ar-H),12.72(s,1H,Ar-OH);EI-MS(m/z)310[M]+,244,187。
(2)1-羟基-6-(2-甲基-3-丁烯-2-氧基)-9H-呫吨-9-酮的制备
将1-羟基-6-(2-甲基-3-丁炔-2-氧基)-9H-呫吨-9-酮的制备(2.0g,6.45mmol)溶于乙醇(20mL)中,加入10%钯-硫酸钡(50mg)常压氢化,室温反应。TLC检测待原料消失后将反应液过滤,滤液浓缩,残留物柱层析(石油醚∶乙酸乙酯=8∶1),得黄色固体1.85g,收率91.9%,m.p.150~152℃。1H NMR(300MHz,CDCl3):δ1.61(s,6H,2×-CH 3 ),5.31(m,2H,CH=CH 2 ),5.88(s,1H,Ar-OH),6.22(m,1H,CH=CH2),6.79(d,1H,J=9Hz,Ar-H),7.03(d,1H,J=9Hz,Ar-H),7.17(d,1H,J=9Hz,Ar-H),7.58(t,1H,Ar-H),7.71(d,1H,J=9Hz,Ar-H),12.76(s,1H,Ar-OH);EI-MS(m/z)312[M]+,246。
(3)(E)-1-羟基-5-(4-溴-2-丁烯氧基)-6-(2-甲基-3-丁烯-2-氧基)-9H-呫吨-9-酮的制备将1-羟基-6-[(2-甲基丁-3-烯-2-基)氧基]-9H-呫吨-9-酮(100mg,0.32mmol)溶于丙酮(10mL)中,依次加入碳酸钾(49mg,0.35mmol)、(E)-1,4-二溴丁-2-烯(74mg,0.35mmol),升温至50℃反应。TLC检测待原料消失后将反应液过滤,滤液浓缩,残留物柱层析(石油醚∶乙酸乙酯=8∶1),得黄色固体129mg,收率90.2%,m.p.:56~58℃。1HNMR(300MHz,CDCl3):δ1.40(s,6H,2×-CH 3 ),3.96(d,2H,-CH 2 -),4.70(d,2H,-CH 2 -),5.25(m,2H,-CH=CH 2 ),6.14(m,3H,3×-CH=CH-),6.79(d,1H,J=8.1Hz,Ar-H),6.99(d,1H,J=8.1Hz,Ar-H),7.15(d,1H,J=9Hz,Ar-H),7.57(t,1H,Ar-H)),7.88(d,1H,J=9Hz,Ar-H),12.71(s,1H,-OH);EI-MS(m/z)446[M]+。
(4)标题化合物的制备
将(E)-1-羟基-5-(4-溴-2-丁烯氧基)-6-(2-甲基-3-丁烯-2-氧基)-9H-呫吨-9-酮(100mg,0.22mmol)溶于DMF(5mL)中,依次加入碳酸钾(34mg,0.24mmol)、二甲胺水溶液(0.24mmol),升温至50℃反应。TLC检测待原料消失后将反应液倒入水(20mL)中,用乙酸乙酯(15mL×3)萃取,合并有机层,浓缩得黄色油状物,将其溶于DMF(3mL),在氮气保护下升温至120℃反应2h。减压蒸除溶剂,残留物柱层析,得黄色固体43mg,收率46.7%,m.p.170~173℃。IR(cm-1,KBr):3451,2973,2896,1738,1640,1590,1461,1375,1260,1228,1045,1028,801,764,750;1H NMR(300MHz,CDCl3):δ1.02(s,3H),1.35(s,3H),2.19~2.33(m,8H),2.57~2.65(m,2H),3.65~3.66(m,1H),3.87(d,J=7.2Hz,1H),4.38~4.40(m,1H),4.54(dd,J1=3.6Hz,J2=7.5Hz,1H),6.49(d,J=7.8Hz,1H),6.54(d,J=8.4Hz,1H),7.23(d,J=6.9Hz,1H),7.39(t,J=8.4Hz,1H),12.10(s,1H,OH);EI-MS(m/z)409[M]+;HRMS(ESI):calcd.for C24H27NO5[M+H]+410.1962,found 410.1963。
实施例37
3,3a,4,5-四氢-1-(3-甲基丁-2-烯-1-基)-4-(二甲氨基甲基)-8-甲氧基-1,5-亚甲基桥-1H,7H-呋喃[3,4-d]并呫吨-7,13-二酮(CPUYZ037)
将3,3a,4,5-四氢-1-(3-甲基丁-2-烯-1-基)-4-(二甲氨基甲基)-8-羟基-1,5-亚甲基桥-1H,7H-呋喃[3,4-d]并呫吨-7,13-二酮(CPUYZ036)(30mg,0.073mmol)溶于二氯甲烷(2mL)中,加入碳酸钾(20mg,0.15mmol)、碘甲烷(16mg,0.11mmol),室温反应。TLC检测待原料消失后将反应液过滤,滤液浓缩,残留物柱层析,得类白色油状物28mg,收率90.8%。1H NMR(300MHz,CDCl3):δ1.02(s,3H),1.35(s,3H),2.19~2.33(m,8H),2.58~2.68(m,2H),3.46(s,3H),3.52(m,1H),3.92(d,J=8.1Hz,1H),4.42(m,1H),4.52(m,1H),7.01~7.08(m,2H),7.23(m,1H),7.52(m,1H);HRMS(ESI):calcd.for C25H29NO5[M+H]+424.2188,found 424.2194。
实施例38
3,3a,4,5-四氢-1-(3-甲基丁-2-烯-1-基)-4-(二甲氨基甲基)-8-甲磺酰氧基-1,5-亚甲基桥-1H,7H-呋喃[3,4-d]并呫吨-7,13-二酮(CPUYZ038)
将3,3a,4,5-四氢-1-(3-甲基丁-2-烯-1-基)-4-(二甲氨基甲基)-8-羟基-1,5-亚甲基桥-1H,7H-呋喃[3,4-d]并呫吨-7,13-二酮(CPUYZ036)(30mg,0.073mmol)溶于二氯甲烷(2mL)中,加入DMAP(18mg,0.15mmol)、甲磺酰氯(14mg,0.11mmol),室温反应。TLC检测待原料消失后,向反应液中加入二氯甲烷(10mL),饱和氯化铵(5mL×3)洗涤,有机层用无水硫酸钠干燥,浓缩,残留物柱层析,得类白色油状物33mg,收率92.4%。1H NMR(300MHz,CDCl3):δ1.08(s,3H),1.45(s,3H),2.19~2.33(m,8H),2.39(s,3H),2.57~2.66(m,2H),3.51(m,1H),3.88(d,J=8.4Hz,1H),4.42(m,1H),4.51(m,1H),6.71(d,J=7.8Hz,1H),6.97(d,J=8.1Hz,1H),7.20(d,J=6.9Hz,1H),7.49(m,1H);HRMS(ESI):calcd.for C25H29NO7S[M+H]+488.1737,found 488.1743。
实施例39
3,3a,4,5-四氢-1-(3-甲基丁-2-烯-1-基)-4-((2,4-二氧代吡咯烷-1基)甲基)-8-羟基-1,5-亚甲基桥-1H,7H-呋喃[3,4-d]并呫吨-7,13-二酮(CPUYZ039)
按实施例36中步骤(4)方法制备,用2,4-二吡咯烷酮代替二甲胺,得黄色固体43mg,收率43.2%,m.p.220~222℃。IR(cm-1,KBr):3451,2973,2914,1738,1705,1646,1602,1458,1375,1349,1222,1172,803;1H NMR(300MHz,CDCl3):δ1.02(s,3H),1.35(s,3H),2.29(m,1H),2.37(m,1H),2,57~2.65(m,2H),2.71~2.76(m,4H),3.37~3.42(m,3H),3.92(d,J=7.8Hz,1H),4.35~4.37(m,1H),4.51(dd,J1=3.6Hz,J2=7.8Hz,1H,6.49(d,J=8.4Hz,1H),6.56(d,J=8.4Hz,1H),7.33(d,J=6.6Hz,1H),7.40(t,J=8.4Hz,1H),12.09(s,1H,OH);EI-MS(m/z)463[M]+;HRMS(ESI):calcd.for C26H25NO7[M+Na]+486.1523,found 486.1516。
实施例40
3,3a,4,5-四氢-1-(3-甲基丁-2-烯-1-基)-4-((4-氧代哌啶-1基)甲基)-8-羟基-1,5-亚甲基桥-1H,7H-呋喃[3,4-d]并呫吨-7,13-二酮(CPUYZ040)
按实施例36中步骤(4)方法制备,用4-哌啶酮代替二甲胺,得黄色固体51mg,收率48.7%,m.p.181~184℃。IR(cm-1,KBr):3404,2973,2920,1741,1641,1593,1458,1375,1225,1060,1033,807,754;1H NMR(300MHz,CDCl3):δ1.03(s,3H),1.36(s,3H),2.17~2.44(m,6H),2.58~2.71(m,8H),3.72~3.74(m,1H),3.86(d,J=7.8Hz,1H),4.37~4.40(m,1H),4.56(dd,J1=3.9Hz,J2=7.8Hz,1H),6.51(d,J=8.4Hz,1H),6.56(d,J=8.4Hz,1H),7.25(d,J=6.9Hz,1H),7.41(t,J=8.4Hz,1H),12.08(s,1H,OH);EI-MS(m/z)463[M]+;HRMS(ESI):calcd.forC27H29NO6[M+H]+464.2068,found 464.2069。
实施例41
3,3a,4,5-四氢-1-(3-甲基丁-2-烯-1-基)-4-(N-甲基哌嗪-1基甲基)-8-羟基-1,5-亚甲基桥-1H,7H-呋喃[3,4-d]并呫吨-7,13-二酮(CPUYZ041)
按实施例36中步骤(4)方法制备,用N-甲基哌嗪代替二甲胺,得黄色固体55mg,收率53.2%,m.p.145~147℃。IR(cm-1,KBr):3457,2932,2796,1740,1644,1600,1462,1375,1230,1160,1101,1060,1028,801,739;1HNMR(300MHz,CDCl3):δ1.02(s,3H),1.35(s,3H),2.10~2.27(m,6H),2.35(s,3H,C22-H),2.51~2.57(m,6H),2.62~2.70(m,2H),3.65~3.68(m,1H),3.84(d,J=7.8Hz,1H),4.38~4.39(m,1H),4.53(dd,J1=3.3Hz,J2=8.1Hz,1H),6.49(d,J=8.4Hz,1H),6.55(d,J=8.4Hz,1H),7.22(d,J=6.9Hz,1H),7.41(t,J=8.4Hz,1H),12.10(s,1H,OH);EI-MS(m/z)464[M]+;HRMS(ESI):calcd.for C27H32N2O5[M+H]+465.2384,found 465.2380.
实施例42
3,3a,4,5-四氢-1-(3-甲基丁-2-烯-1-基)-4-((3-(二甲氨基))丙基)-8-羟基-1,5-亚甲基桥-1H,7H-呋喃[3,4-d]并呫吨-7,13-二酮(CPUYZ047)
按实施例36方法制备,用(E)-1,6-二溴丁-2-烯代替(E)-1,4-二溴丁-2-烯,得黄色油状物39mg,收率39.6%。
实施例43
3,3a,4,5-四氢-1-(3-甲基丁-2-烯-1-基)-4-(甲氧基甲基)-8-羟基-1,5-亚甲基桥-1H,7H-呋喃[3,4-d]并呫吨-7,13-二酮(CPUYZ043)
按实施例36中步骤(4)方法制备,用甲醇钠代替二甲胺,得黄色油状物46mg,收率51.2%。IR(cm-1,KBr):3451,2991,2891,1742,1643,1601,1462,1376,1230,1109,1031,803,7471H NMR(300MHz,CDCl3):δ1.02(s,3H),1.35(s,3H),2.17~2.24(m,1H),2.37(m,1H),2.57~2.66(m,2H),3.09~3.20(m,2H),3.30(s,3H),3.68~3.70(m,1H),3.89~3.91(m,1H),4.37~4.39(m,1H),4.51~4.55(m,1H),6.49(d,J=8.3Hz,1H),6.55(d,J=8.3Hz,1H),7.22(d,J=6.8Hz,1H),7.39(t,J=8.3Hz),12.10(s,1H,OH);EI-MS(m/z)396[M]+;HRMS(ESI):calcd.for C23H24O6[M+Na]+419.1465,found 419.1468.
实施例44
3,3a,4,5-四氢-1-(3-甲基丁-2-烯-1-基)-4-(乙酰氧基甲基)-8-羟基-1,5-亚甲基桥-1H,7H-呋喃[3,4-d]并呫吨-7,13-二酮(CPUYZ044)
按实施例36中步骤(4)方法制备,用乙酸钠代替二甲胺,得黄色固体54mg,收率48.6%,m.p.176~178℃。IR(cm-1,KBr):3463,2962,2903,1741,1644,1602,1462,1374,1228,1042,803,768,749;1H NMR(300MHz,CDCl3):δ1.02(s,3H),1.35(s,3H),2.07(s,3H),2.25(m,1H),2.41~2.43(m,1H),2.63~2.66(m,2H),3.65~3.68(m,1H),3.76~3.83(m,1H),3.91~3.97(m,2H),4.36~4.38(m,1H),4.52~4.57(m,1H),6.49(d,J=8.3Hz,1H),6.56(d,J=8.3Hz,1H),7.23(d,J=6.8Hz,1H),7.40(t,1H,J=8.3Hz),12.04(s,1H,OH);EI-MS(m/z)424[M]+;HRMS(ESI):calcd.for C24H24O7[M+Na]+447.1414,found 447.1405。
实施例45
3,3a,4,5-四氢-1-(3-甲基丁-2-烯-1-基)-4-(二正丁氨基甲基)-8-羟基-1,5-亚甲基桥-1H,7H-呋喃[3,4-d]并呫吨-7,13-二酮(CPUYZ045)
按实施例36中步骤(4)方法制备,用正丁胺代替二甲胺,得黄色固体51mg,收率47.6%,m.p.96~98℃。IR(cm-1,KBr):3457,2956,2926,2869,1738,1644,1372,1275,1260,1057,1030,804,749;1H NMR(300MHz,CDCl3):δ0.89(m,6H),1.03(s,3H),1.24~1.35(m,11H),2.12~2.41(m,8H),2.57~2.65(m,2H),3.68~3.71(m,1H),3.85(d,J=7.8Hz,1H),4.37~4.42(m,1H),4.52(dd,J1=3.6Hz,J2=7.8Hz,1H),6.49(d,J=8.4Hz,1H),6.54(d,J=8.4Hz,1H),7.21(d,J=6.9Hz,1H),7.38(t,J=8.4Hz,1H),12.14(s,1H,-OH);EI-MS(m/z)493[M]+;HRMS(ESI):calcd.for C20H39NO5[M+H]+494.2901,found 494.2900.
实施例46
3,3a,4,5-四氢-1-(3-甲基丁-2-烯-1-基)-4-(N-甲基哌嗪-1基甲基)-1,5-亚甲基桥-1H,7H-呋喃[3,4-d]并呫吨-7,13-二酮(CPUYZ046)
(1)4-羟基-3-(2-甲基-3-丁炔-2-氧基)-9H-呫吨-9-酮的制备
按实施例36中步骤(1)及步骤(2)方法制备,用3,4二羟基-9H-呫吨-9-酮代替1,5,6-三羟基-9H-呫吨-9-酮作为起始原料,得黄色油状物1.80g,两步收率27.1%。1HNMR(300MHz,CDCl3):δ1.60(s,6H,2×-CH 3 ),5.29(t,2H,J=15.9Hz,CH=CH 2 ),5.89(s,1H,Ar-OH),6.18(dd,1H,J=18.0,10.8Hz,CH=CH2),7.15(d,1H,J=9.0Hz,Ar-H),7.40(t,1H,J=6.9Hz,Ar-H),7.61(m,1H,Ar-H),7.70(t,1H,J=1.8Hz,Ar-H),7.72(d,1H,J=1.5Hz,Ar-H),8.34(m,1H,Ar-H);EI-MS(m/z)296[M]+,253,241。
(2)标题化合物的制备
将4-羟基-3-(2-甲基-3-丁烯-2-氧基)-9H-呫吨-9-酮(100mg,0.23mmol)溶于丙酮(10mL)中,依次加入碳酸钾(25mg,0.25mmol)、(E)-1,4-二溴丁-2-烯(53mg,0.25mmol),升温至50℃反应。TLC检测待原料消失后将反应液过滤,滤液浓缩,残留物柱层析(石油醚∶乙酸乙酯=8∶1),得黄色油状物135mg。用DMF(3mL)将其溶解,在氮气保护下升温至120℃反应2h。减压蒸除溶剂,残留物柱层析,得黄色固体72mg,两步收率46%,m.p.154~156℃。IR(cm-1,KBr):2976,2902,1737,1642,1600,1461,1380,1275,1229,1086,1031,749;1HNMR(300MHz,CDCl3):δ0.93(s,3H),1.25(m,1H),1.28(s,3H),2.01~2.20(m,3H),2.27(s,3H),2.40(m,8H),2.61~2.65(m,2H),3.62(m,1H),3.84(d,J=7.8Hz,1H),4.39(m,1H),4.54(dd,J1=3.3Hz,J2=7.5Hz,1H),7.01~7.08(m,2H),7.16(d,J=7.5Hz,1H),7.95(d,J=8.1Hz).;EI-MS(m/z)448[M]+;HRMS(ESI):calcd.for C27H31N2O4[M+H]+449.2435,found 449.2435。
Claims (9)
1.通式(I)的化合物或其药学上可接受的盐:
其中R1代表卤素、羟基、-NRaRb、硝酸酯基、硫氰基、C1~C6烷氧基、C2~C6不饱和烯氧基、C1~C6烷基酰氧基或C6~C8芳基酰氧基;或代表由卤素、甲氧基、硝基、羟基或-NRaRb取代的C6~C8芳基酰氧基;
上述-NRaRb中Ra、Rb各自独立代表氢、C1~C6烷基、C1~C6羟烷基或C1~C6烷酰基;或Ra、Rb连接形成含有1~2个N或O原子的5~6员杂环;
n代表1~3;
R2代表氢、羟基、C1~C6烷氧基、C1~C6烷基酰氧基或C1~C6烷基磺酰氧基;
R3、R5各自独立代表氢、C1~C8烷基或C2~C8不饱和烯基;
R4代表氢或羟基;
或R4与R3连接成5~6员含氧杂环;或R4与R5连接成5~6员含氧杂环。
2.权利要求1的化合物或其药学上可接受的盐,其中R1代表-NRaRb,n代表1~3,Ra、Rb各自独立代表氢、甲基、乙基、丙基、异丙基、正丁基、羟乙基或羟丙基;或者Ra、Rb连接形成四氢吡咯基、咪唑基、哌啶基、4-氧代哌啶基、吗啡啉基、哌嗪基、N-甲基哌嗪基、N-苯基哌嗪基或N-苄基哌嗪基。
3.权利要求1的化合物或其药学上可接受的盐,其中R2代表氢、羟基、甲氧基、乙酰基或甲磺酰基。
4.权利要求1的化合物或其药学上可接受的盐,其中R3、R4、R5同时代表氢。
5.权利要求1的化合物或其药学上可接受的盐,其中R3、R5各自独立代表氢或异戊烯基,R4代表羟基。
6.权利要求1的化合物或其药学上可接受的盐,其中R4与R3连接成六员吡喃环,或R4与R5连接成六员吡喃环。
8.一种药物组合物,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。
9.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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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103613602A (zh) * | 2013-12-10 | 2014-03-05 | 南开大学 | 藤黄酸衍生物及其制备方法和应用 |
CN104447786A (zh) * | 2014-12-17 | 2015-03-25 | 中国药科大学 | 一类藤黄属三氮唑衍生物、其制备方法和医药用途 |
CN105541858A (zh) * | 2015-12-09 | 2016-05-04 | 上海中医药大学 | Xanthone类化合物及其制备方法、组合物和用途 |
CN111517938A (zh) * | 2020-04-27 | 2020-08-11 | 华东师范大学 | 七元桥环类衍生物的合成及其制备方法 |
CN113880857A (zh) * | 2021-11-11 | 2022-01-04 | 山东大学 | 多异戊烯基取代的笼状氧杂蒽酮类化合物及其制备方法和应用 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000044216A2 (en) * | 1999-02-01 | 2000-08-03 | Cytovia Inc | Gambogic acid, analogs and derivatives as activators of caspases and inducers of apoptosis |
CN1309125A (zh) * | 2001-01-17 | 2001-08-22 | 中国药科大学 | 具抗癌活性的藤黄酸类化合物的复合物及其制备方法 |
WO2004002428A2 (en) * | 2002-07-01 | 2004-01-08 | Cytovia, Inc. | Derivatives of gambogic acid and induce apoptosis |
CN102212067A (zh) * | 2010-04-02 | 2011-10-12 | 中国药科大学 | 藤黄属衍生物、其制备方法和医药用途 |
-
2011
- 2011-11-07 CN CN201110347886.3A patent/CN102503951B/zh not_active Expired - Fee Related
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000044216A2 (en) * | 1999-02-01 | 2000-08-03 | Cytovia Inc | Gambogic acid, analogs and derivatives as activators of caspases and inducers of apoptosis |
CN1309125A (zh) * | 2001-01-17 | 2001-08-22 | 中国药科大学 | 具抗癌活性的藤黄酸类化合物的复合物及其制备方法 |
WO2004002428A2 (en) * | 2002-07-01 | 2004-01-08 | Cytovia, Inc. | Derivatives of gambogic acid and induce apoptosis |
CN102212067A (zh) * | 2010-04-02 | 2011-10-12 | 中国药科大学 | 藤黄属衍生物、其制备方法和医药用途 |
Non-Patent Citations (3)
Title |
---|
LI NIAN GUANG,等: "Structure-activity Relationship of Gambogic Acid", 《CHINESE JOURNAL OF NATURAL MEDICINES》 * |
冯锋,等: "藤黄酸及其类似物抗肿瘤的定量构效关系", 《中国药科大学学报》 * |
王进欣,等: "藤黄酸氧化类似物的合成及抗肿瘤活性的二维定量构效关系", 《高等学校化学学报》 * |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103613602A (zh) * | 2013-12-10 | 2014-03-05 | 南开大学 | 藤黄酸衍生物及其制备方法和应用 |
CN103613602B (zh) * | 2013-12-10 | 2016-06-01 | 南开大学 | 藤黄酸衍生物及其制备方法和应用 |
CN104447786A (zh) * | 2014-12-17 | 2015-03-25 | 中国药科大学 | 一类藤黄属三氮唑衍生物、其制备方法和医药用途 |
CN104447786B (zh) * | 2014-12-17 | 2016-08-24 | 中国药科大学 | 一类藤黄属三氮唑衍生物、其制备方法和医药用途 |
CN105541858A (zh) * | 2015-12-09 | 2016-05-04 | 上海中医药大学 | Xanthone类化合物及其制备方法、组合物和用途 |
CN105541858B (zh) * | 2015-12-09 | 2018-02-02 | 上海中医药大学 | Xanthone类化合物及其制备方法、组合物和用途 |
CN111517938A (zh) * | 2020-04-27 | 2020-08-11 | 华东师范大学 | 七元桥环类衍生物的合成及其制备方法 |
CN113880857A (zh) * | 2021-11-11 | 2022-01-04 | 山东大学 | 多异戊烯基取代的笼状氧杂蒽酮类化合物及其制备方法和应用 |
CN113880857B (zh) * | 2021-11-11 | 2023-03-10 | 山东大学 | 多异戊烯基取代的笼状氧杂蒽酮类化合物及其制备方法和应用 |
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