CN111303178A - Ovatodiolide衍生物及其盐，制备方法及其在制备抗癌药物中的用途 - Google Patents

Ovatodiolide衍生物及其盐，制备方法及其在制备抗癌药物中的用途 Download PDF

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CN111303178A
CN111303178A CN201811511738.9A CN201811511738A CN111303178A CN 111303178 A CN111303178 A CN 111303178A CN 201811511738 A CN201811511738 A CN 201811511738A CN 111303178 A CN111303178 A CN 111303178A
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陈悦
向俊鸿
王良
丁亚辉
李家鑫
赵秀赫
陈宁
王蒙蒙
王正辉
李洪波
齐杰
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Nankai University
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Abstract

本发明提供了式(I)所示的Ovatodiolide衍生物及其盐，制备方法及其在制备抗癌药物中的用途。

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Ovatodiolide衍生物及其盐，制备方法及其在制备抗癌药物 中的用途
技术领域
本本发明提供了一种Ovatodiolide衍生物及其盐，并涉及Ovatodiolide 衍生物及其盐的制备方法，及其在制备治疗癌症药物中的用途，本发明属于药物技术领域。
背景技术
二萜内酯化合物Ovatodiolide是从防风草中提取的化合物。防风草作为传统中药，被用于祛风解表，解毒除湿，强壮筋骨，治感冒身热等。近期研究表明，Ovatodiolide可在体外抑制肝癌，肾癌，口腔癌，鼻咽癌，结肠癌细胞，胰腺癌等癌细胞的生长，同时其可选择性抑制包括造血干细胞，乳腺癌干细胞等干细胞的生长。但Ovatodiolide水溶性差，不利于药物被机体吸收，进入体内易被代谢分解，生物利用度差。对于此类化合物的修饰及其成盐处理，可能有利于增强其成药性。本发明在已有发现的基础上，合成了 Ovatodiolide衍生物，其药物组合物，及其在制备药物中的用途，特别是在制备治疗癌症的药物中的用途。
目前未见关于式(Ⅰ)化合物，其药物组合物，及其制备方法，及在制备药物中的用途，特别是在制备治疗癌症的药物中的用途的报道。
发明内容
本发明提供了式(I)化合物，其药物组合物及其制备方法和用途，特别是式(I)化合物用于治疗癌症的用途。
为了实现本发明的上述目的，本发明提供如下的技术方案：
一种如式(I)所示的Ovatodiolide衍生物及其盐，
Figure BDA0001900959190000021
式(I)中R1为碳原子，氧原子；R2为碳原子，氧原子；R3为氢原子，羟基；R4和R5可以相同或不同，分别为氢、烷基、环烷基、羟基取代烷基、烯基、炔基、芳基、烷基芳基、芳基烷基、芳基烯基、芳基炔基、杂环基、三氟甲基、多氟取代烷基、腈基、腈基甲基、酰基、氨基甲酰基、磺酰基、磺酰胺基或芳氧烷基；R4、R5和N原子形成环状结构，环优选为3–9元环，环状结构上可以被一个或多个取代基取代，包括氢、烷基、环烷基、烯基、炔基、芳基、烷基芳基、芳基烷基、芳基烯基、芳基炔基或杂环基；
其与无机酸或有机酸形成的在药学上可接受的盐，包括与R6Z形成的季铵盐，包括氢氟酸、盐酸、氢溴酸、氢碘酸、硫酸、磷酸、硝酸、亚磷酸、亚硫酸、碳酸、硼酸、磷钼酸、亚硒酸、甲基磺酸、取代甲基磺酸、苯基磺酸、取代苯基磺酸、富马酸、柠檬酸、马来酸、酒石酸、草酸、D-苹果酸、 L-苹果酸、DL-苹果酸、L-乳酸、D-乳酸、DL-乳酸、甲酸、取代甲酸、乙酸、丙酸、丁酸、戊酸、油酸、月桂酸、对甲基苯磺酸、1-萘磺酸、2-萘磺酸、酞酸、丙二酸、丁二酸、乙醇酸、硫醇酸、甘氨酸、肌氨酸、磺酸、烟酸、甲基吡啶酸、异烟酸、二氯乙酸、苯甲酸、取代苯甲酸；R6为烃基、环烷基、羟基取代烷基、烯基、炔基、芳基、杂环基、芳基取代烷基、芳基烯基、芳基炔基、氰基取代甲基、烷氧基取代烷基或芳氧取代烷基；Z为氟、氯、溴、碘、对甲基磺酸基、甲基磺酸基、苯基磺酸基、取代苯基磺酸基、三氟甲基磺酸基。
一种制备式(I)所示Ovatodiolide衍生物及其盐的方法，其特征在于以式(II)所示的化合物为原料，与(III)所示的化合物反应得式(I) 所示的化合物；
Figure BDA0001900959190000031
一种如式(I)所示的Ovatodiolide衍生物及其盐，在制备治疗癌症或治疗癌症的辅助药物中的用途，其中癌症为白血病、乳腺癌、前列腺癌、鼻咽癌、大肠癌、肺癌、肝癌、食道癌、胃癌、肠道癌、肾癌、口腔癌、何杰金淋巴癌、胰腺癌、直肠结肠癌、子宫颈癌、非何杰金淋巴癌、神经胶质瘤、黑瘤、膀胱癌、卵巢癌、甲状腺癌或卡波西肉瘤。
一种用于治疗癌症的药物组合物，其中含有有效量的式(I)Ovatodiolide 衍生物及其盐在药学上可接受的载体或与其他抗癌药物的组合物。
本发明化合物用作药物时，可以直接使用，或者以药物组合物的形式使用。该药物组合物含有0.1–99％，优选为0.5–90％的本发明化合物，其余为药物学上可接受的，对人和动物无毒和惰性的可药用载体和/或赋形剂或与其他抗癌药物联合用药。本发明的组合物可以制备成注射液、片剂和胶囊等。
所述的药用载体或赋形剂是一种或多种固体、半固体和液体稀释剂、填料以及药物制品辅剂。将本发明的药物组合物以单位体重服用量的形式使用。本发明的药物可经注射和口服两种形式给药，注射如静脉注射和肌肉注射，口服的剂型可以是片剂和胶囊剂。
附图说明
图1.化合物2-6的合成
图2.化合物7-12的合成
图3.化合物13-18的合成
图4.化合物19-23的合成
图5.化合物24-28的合成
图6.化合物29-34的合成
具体实施方式
为了理解本发明，下面以实施例进一步说明本发明，但不意于限制本发明的保护范围。
实施例1：Ovatodiolide衍生物及其盐的合成
具体合成路线见图1，图2，图3，图4，图5，图6，具体步骤如下：
0℃条件下，将Et2Zn(1.0M in hexane，1.52mmol，1.52ml)溶于无水DCM(3.0ml)中，然后将CH2I2(260.9ul，3.04mmol)缓慢滴加到体系中，然后搅拌30min，将化合物1(250mg，0.76mmol，1.0 eq)的DCM溶液(3.0mL)缓慢滴加到体系中。室温下搅拌过夜，向体系中加入饱和NH4Cl(5.0ml)，分离有机相。将水相用CH2Cl2(3×5 mL)萃取，并将合并的有机相用饱和NaCl(5mL)洗涤。有机相无水Na2SO4干燥，过滤并在减压下浓缩，然后通过柱色谱法(80％ EtOAc/hexane)纯化，得化合物2(162mg，65％，dr＝85:15白色固体)。1H NMR(400MHz,CDCl3)δ6.99(s,1H),6.21(s,1H),5.61(s,1H), 5.32–5.03(m,2H),4.78(d,J＝10.2Hz,1H),2.94(dd,J＝14.6,3.2Hz, 1H),2.67(t,J＝9.5Hz,1H),2.60–2.42(m,1H),2.29(ddd,J＝19.0,18.5, 7.7Hz,2H),2.18–2.07(m,1H),1.98(dt,J＝14.4,4.2Hz,1H),1.66(s, 3H),1.64–1.52(m,2H),1.34–1.25(m,1H),1.04(s,3H),0.68–0.54(m, 1H),0.32(dd,J＝8.2,4.3Hz,1H),0.14–0.03(m,1H),-0.02(t,J＝4.6 Hz,1H)；13C NMR(101MHz,CDCl3)δ173.2,170.3,146.6,139.5,135.0, 132.1,128.4,122.6,79.2,78.0,43.8,39.8,37.1,32.2,26.1,25.6,21.3,19.9, 19.8,17.0,16.9；MS-ESI(m/z):calcd.for C21H26O4Na[M+Na]+:365.1729, found 365.1728.
室温条件下，将1(1.2g，3.6mmol，1.0eq)溶于DCM(37mL) 中，然后将m-CPBA(1.1g，5.4mmol，85％，1.5eq)加入到体系中。室温下搅拌1h，将混合物倒入饱和Na2S2O3溶液(10mL)中，分离有机相。将水相用CH2Cl2(3×20mL)萃取，并将合并的有机相用饱和NaHCO3(2×20mL)洗涤，饱和NaCl(15mL)洗涤。有机相无水Na2SO4干燥，过滤并在减压下浓缩，然后通过柱色谱法(80％ EtOAc/hexane)纯化，得化合物3(1.0g，91％，白色固体)。[α]26 D＝ -23.3(c＝1.0,CHCl3)；IR(neat)2926,2855,1754,1661,1435,1389, 1329,1266,1237,1206,1116,971,944,797,760cm-1；1H NMR(400 MHz,CDCl3)δ7.10(s,1H),6.26(d,J＝1.6Hz,1H),5.65(d,J＝1.3Hz, 1H),5.21(d,J＝10.5Hz,1H),5.18(d,J＝1.2Hz,1H),4.81(dd,J＝10.2,1.9Hz,1H),2.96(dd,J＝14.7,3.3Hz,1H),2.59(d,J＝4.7Hz,1H),2.57 (d,J＝3.4Hz,1H),2.48–2.42(m,1H),2.42–2.34(m,1H),2.31(dd,J ＝10.6,3.7Hz,1H),2.29–2.26(m,1H),2.13(ddd,J＝14.3,5.3,2.8Hz, 1H),1.71(s,3H),1.70–1.63(m,2H),1.58–1.45(m,1H),1.29(s,3H), 1.21–1.09(m,1H)；13C NMR(101MHz,CDCl3)δ172.9,169.8,147.8, 139.1,134.1,132.5,128.5,123.4,79.4,77.8,60.7,58.6,44.0,39.9,35.6, 31.6,25.1,23.4,19.9,16.4；MS-ESI(m/z):calcd.for C20H24O5Na [M+Na]+:367.1521,found 367.1520.
室温条件下，将化合物3(10.0g,30.5mmol,1.0equiv)溶于二氯甲烷(300mL)，然后将m-CPBA(24.7g,121.8mmol,85％,4.0eq)加入到体系中，室温条件下继续搅拌2天，体系析出大量白色固体，过滤，滤液用饱和Na2S2O3(100mL)淬灭反应，体系用DCM(3x 150mL) 萃取，合并有机相，饱和NaCl(30mL)洗涤，无水Na2SO4干燥，过滤并在减压下浓缩，然后通过柱色谱法(100％EtOAc/hexane),得化合物4(8.0g,73％,白色固体)。[α]22 D＝-22.5(c＝0.52,CHCl3)；IR(neat) 2930,1754,1643,1435,1390,1326,1263,1201,1117,1082,1040,986,957,838,639cm-1；1H NMR(400MHz,CDCl3)δ7.34(s,1H),6.29(s, 1H),5.79(s,1H),5.17(s,1H),3.87(d,J＝9.3Hz,1H),2.84(d,J＝9.3 Hz,1H),2.57(dd,J＝12.7,7.3Hz,3H),2.48(dt,J＝8.2,4.3Hz,2H), 2.17–1.90(m,4H),1.62–1.35(m,3H),1.34(s,3H),1.32(s,3H)；13C NMR(101MHz,CDCl3)δ173.02,169.35,148.56,137.60,133.71,124.49, 81.58,78.74,77.48,77.16,76.84,61.97,60.17,58.59,55.99,41.65,41.05, 33.01,29.83,25.96,21.87,19.77,17.29；HRMS-ESI(m/z):calcd.for C20H24O6Na[M+Na]+:383.1471,found383.1470.
室温条件下，将化合物1(100mg,0.304mmol,1.0eq)溶于无水 DCM(2.0mL)，然后将SeO2(18.9mg,0.17mmol,0.56eq)和t-BuOOH (0.104ml,1.03mmol,3.4eq)加入到体系中，室温条件下继续搅拌过夜，向体系中加入饱和Na2S2O4溶液和饱和NaHCO3溶液(5ml:5ml)，搅拌10min，体系用DCM(3x 15mL)萃取，有机相饱和NaCl(5ml)洗涤，无水Na2SO4干燥，减压真空浓缩，柱层析(50％EtOAc/Hexane), 得化合物5(70mg,70％,白色固体)。[α]22 D＝-23.1(c＝0.2,CHCl3)；1H NMR(400MHz,CDCl3)δ7.01(s,1H),6.25(d,J＝1.8Hz,1H),5.63 (d,J＝1.6Hz,1H),5.09(d,J＝9.6Hz,3H),4.88(dd,J＝10.3,1.2Hz, 1H),4.04(dd,J＝11.2,4.0Hz,1H),3.02–2.90(m,1H),2.88(d,J＝3.7 Hz,1H),2.62–2.52(m,1H),2.51–2.40(m,1H),2.27(dd,J＝14.4,3.6 Hz,2H),2.22–2.13(m,1H),1.89(td,J＝13.3,4.0Hz,1H),1.80(s,1H), 1.72(d,J＝1.2Hz,4H),1.64(s,3H)；13C NMR(101MHz,CDCl3)δ172.9, 170.1,147.8,138.9,137.2,134.2,131.3,129.2,128.0,123.7,78.9,78.5, 75.8,42.1,41.0,40.3,25.0,23.3,19.4,10.3.HRMS-ESI(m/z):calcd.for C20H24O5Na[M+Na]+:367.1521,found 367.1520.
室温条件下，将化合物2(1.5g,4.38mmol,1.0equiv)溶于二氯甲烷(30mL)，然后将m-CPBA(1.78g,8.76mmol,85％,2.0eq)加入到体系中，室温条件下继续搅拌2天，体系析出大量白色固体，过滤，滤液用饱和Na2S2O3(30mL)淬灭反应，体系用DCM(3x 50mL)萃取，合并有机相，饱和NaCl(20mL)洗涤，无水Na2SO4干燥，过滤并在减压下浓缩，然后通过柱色谱法(60％EtOAc/hexane),得化合物6(1.2g,70％,白色固体)。[α]18 D＝-15.9(c＝1.0,CHCl3)；1HNMR (400MHz,CDCl3)δ7.22(s,1H),6.26(s,1H),5.77(s,1H),5.14(d,J＝ 1.5Hz,1H),3.85(d,J＝9.4Hz,1H),2.85(d,J＝9.5Hz,1H),2.79–2.62 (m,1H),2.61–2.39(m,3H),2.06(dd,J＝15.4,3.4Hz,1H),1.99–1.87 (m,2H),1.78(dd,J＝9.1,5.1Hz,1H),1.71–1.41(m,3H),1.32(s,3H), 1.08(s,3H),0.66–0.50(m,1H),0.42–0.27(m,1H),0.08–-0.05(m, 1H)；13CNMR(101MHz,CDCl3)δ173.0,169.7,147.3,138.5,134.6, 123.8,81.0,78.6,61.2,56.5,41.6,40.5,36.7,32.2,25.8,25.3,21.6,19.9, 18.9,16.9,16.8；HRMS-ESI(m/z):calcd.for C21H26O5Na[M+Na]+: 381.1678,found 381.1677.
室温条件下，将化合物1(1.0g,3.04mmol,1.0eq)溶于无水THF (15.0mL)，然后将二甲胺溶液(2.0M in THF,7.1ml,15.2mmol,5.0 eq)加入到体系中，室温条件下继续搅拌4h，体系直接浓缩，柱层析 (50％Hexane/EtOAc),得化合物7(0.5g,53％,白色固体)。1HNMR (400MHz,CDCl3)δ6.98(d,J＝1.2Hz,1H),5.35(d,J＝10.7Hz,1H), 5.11(s,1H),4.85(dd,J＝6.8,5.3Hz,1H),4.80(d,J＝10.6Hz,1H),2.99 (dd,J＝16.4,8.4Hz,1H),2.94–2.77(m,2H),2.53(d,J＝1.9Hz,2H), 2.51(s,1H),2.46–2.32(m,2H),2.23(s,6H),2.19–1.88(m,5H),1.75 (d,J＝1.4Hz,3H),1.58(s,3H),1.21–1.10(m,1H)；13C NMR(101MHz,CDCl3)δ178.1,173.1,147.0,136.0,134.9,131.4,127.6,124.4,78.8,78.4, 55.0,45.2,40.4,40.3,39.7,36.4,25.2,23.8,23.4,19.5,14.8；HRMS-ESI (m/z):calcd.for C22H32O4N[M+H]+:374.2331,found 374.2330.
室温条件下，将化合物1(1.0g,3.04mmol,1.0eq)溶于无水THF (15.0mL)，然后将吗啉(15.2ml,15.2mmol,5.0eq)加入到体系中，室温条件下继续搅拌4h，体系直接浓缩，柱层析(50％Hexane/EtOAc), 得化合物8(1.01g,80％,白色固体)。[α]18 D＝-33.1(c＝0.32,CHCl3)；1H NMR(400MHz,CDCl3)δ6.99(s,1H),5.32(dd,J＝27.1,9.2Hz,1H), 5.12(s,1H),4.92–4.76(m,2H),3.83–3.61(m,4H),3.20–3.02(m,1H), 3.00–2.74(m,2H),2.71–2.46(m,5H),2.46–2.19(m,5H),2.19–1.84 (m,4H),1.76(s,3H),1.68(s,3H),1.23–1.12(m,1H)；13CNMR(101 MHz,CDCl3)δ178.0,173.3,146.9,135.8,134.9,131.0,127.5,124.5,78.9,78.5,67.2,54.0,40.2,38.6,36.2,25.0,23.8,23.2,19.5,15.3.HRMS-ESI (m/z):calcd.for C24H34O5N[M+H]+:416.2437,found 416.2435.
室温条件下，将化合物1(1.0g,3.04mmol,1.0eq)溶于无水THF (15.0mL)，然后将N-甲基哌嗪(1.69ml,15.2mmol,5.0eq)加入到体系中，室温条件下继续搅拌4h，体系直接浓缩，柱层析(1.2％ MeOH/DCM-2.5％MeOH/DCM),得化合物9(1.1g,89％,白色固体)。 [α]23 D＝-44.3(c＝0.56,CHCl3)；IR(neat)2929,2874,2842,2798,1753, 1666,1450,1091,980,960,883,861cm-1；1H NMR(400MHz,CDCl3)δ 6.98(s,1H),5.35(d,J＝10.7Hz,1H),5.11(s,1H),4.84(dd,J＝17.8,8.8 Hz,2H),3.07(s,1H),2.90(dd,J＝14.3,3.5Hz,1H),2.85–2.75(m,1H), 2.63(dd,J＝12.6,5.0Hz,2H),2.59–2.47(m,4H),2.47–2.36(m,4H), 2.29(s,3H),2.27–2.18(m,3H),δ2.17–2.07(m,2H),2.07–1.87(m, 3H),1.75(s,3H),1.65(s,3H),1.22–1.10(m,1H)；13C NMR(101MHz, CDCl3)δ178.1,173.2,146.9,135.9,134.9,131.0,127.6,124.4,78.9,78.4, 55.3,53.6,46.2,40.3,40.2,38.9,36.2,25.1,23.7,23.2,19.5,15.5；HRMS- ESI(m/z):calcd.for C25H37O4N2[M+H]+:429.2753,found 429.2750.
室温条件下，将化合物3(300mg,0.87mmol,1.0eq)溶于无水 THF(10ml)，然后将N-甲基哌嗪(0.48ml,4.36mmol,5.0eq)加入到体系中，室温条件下继续搅拌过夜,体系直接浓缩，然后通过柱色谱法(2％MeOH/DCM)，得化合物10(309mg,80％，白色固体)。1H NMR(400MHz,CDCl3)δ7.07(s,1H),5.39(d,J＝10.7Hz,1H),5.18(s,1H), 4.78(d,J＝10.7Hz,1H),3.23–3.08(m,1H),2.94(dd,J＝14.6,3.3Hz, 1H),2.89–2.42(m,8H),2.40–2.30(m,2H),2.29(s,3H),2.25(dd,J＝ 10.2,4.5Hz,3H),2.19–2.11(m,1H),2.10–1.70(m,4H),1.68(s,3H), 1.33(s,3H),1.30–1.15(m,2H),1.03(td,J＝13.9,1.9Hz,1H).13C NMR(101MHz,CDCl3)δ177.1,173.0,147.4,134.0,131.3,126.9,79.2,78.4, 61.3,58.8,55.2,53.3,45.9,41.4,39.6,38.9,35.6,24.9,23.3,22.7,19.7, 16.1；HRMS-ESI(m/z):calcd.for C25H37O5N2[M+H]+:445.2702,found 445.2699.
室温条件下，将化合物3(300mg,0.87mmol,1.0equiv)溶于无水 THF(10ml)，然后将吗啉(0.38ml,4.36mmol,5.0eq)加入到体系中，室温条件下继续搅拌过夜,体系直接浓缩，然后通过柱色谱法(1％ MeOH/DCM)，得化合物11(311mg,83％，白色固体)。1H NMR(400MHz,CDCl3)δ7.08(d,J＝1.2Hz,1H),5.41(d,J＝10.7Hz,1H),5.19(s, 1H),4.81(d,J＝10.7Hz,1H),3.95–3.54(m,4H),3.26–3.08(m,1H), 2.96(dd,J＝14.6,3.1Hz,1H),2.77–2.60(m,3H),2.59–2.46(m,3H), 2.37–2.30(m,2H),2.30–2.22(m,2H),2.22–2.14(m,1H),1.99–1.75 (m,3H),1.70(d,J＝1.3Hz,3H),1.36(s,3H),1.33–1.22(m,2H),1.11– 1.00(m,1H).13C NMR(101MHz,CDCl3)δ177.1,173.0,147.4,134.1, 131.3,127.0,79.24,78.5,67.2,61.4,58.9,53.8,41.5,39.6,38.6,35.6,24.9, 23.3,22.8,19.7,16.1；HRMS-ESI(m/z):calcd.for C24H34O6N[M+H]+: 432.2386,found 432.2396.
室温条件下，将化合物4(7.47g,20.7mmol,1.0equiv)溶于无水 THF(100ml)，然后将N-甲基哌嗪(11.5ml,103.6mmol,5.0eq)加入到体系中，室温条件下继续搅拌过夜,体系直接浓缩，然后通过柱色谱法(5％MeOH/DCM-6.7％MeOH/DCM)，得化合物12(5.0g,52％,白色固体)。
[α]22 D＝-64.8(c＝0.53,CHCl3)；IR(neat)3084,2979,2937,1761,1740, 1640,1461,1288,1167,1072,1038,1012,996,903cm-1；1H NMR(400 MHz,CDCl3)δ7.20(s,1H),5.14(s,1H),3.80(d,J＝10.0Hz,1H),3.12 (ddd,J＝12.4,7.2,5.5Hz,1H),3.02(d,J＝9.9Hz,1H),2.71–2.51(m, 6H),2.50–2.31(m,6H),2.28(s,3H),2.12(dd,J＝15.4,3.0Hz,1H),2.00 (t,J＝12.7Hz,4H),1.79–1.53(m,1H),1.34(s,3H),1.12(d,J＝7.9Hz, 3H),1.12–1.01(m,1H),0.45(t,J＝13.8Hz,1H),0.28(s,2H)；13C NMR (101MHz,CDCl3)δ177.2,172.9,147.3,134.7,81.8,78.4,77.5,77.2,76.8, 59.1,57.0,55.5,54.3,46.2,41.8,39.7,37.0,36.6,25.6,25.4,23.3,22.1, 20.0,18.8,16.9,16.6；HRMS-ESI(m/z):calcd.for C25H37O6N2[M+H]+: 461.2652,found 461.2650.
室温条件下，将化合物4(50mg,0.138mmol,1.0equiv)溶于无水 THF(10ml)，然后将吗啉(60.4ul,0.70mmol,5.0eq)加入到体系中，室温条件下继续搅拌过夜,体系直接浓缩，然后通过柱色谱法(2％ MeOH/DCM)，得化合物13(40mg,60％，白色固体)。[α]18 D＝-61.2(c＝1.0,CHCl3)；1H NMR(400MHz,DMSO)δ7.95(s,1H),5.75(s,1H), 5.31(s,1H),4.00(d,J＝9.9Hz,1H),3.63(s,3H),3.24–3.11(m,1H), 2.99(d,J＝9.9Hz,1H),2.68(s,2H),2.61–2.51(m,4H),2.46–2.12(m, 5H),1.94(dd,J＝21.8,10.5Hz,2H),1.80(dd,J＝36.4,14.5Hz,3H),1.34 (s,6H),1.13(t,J＝12.5Hz,1H),0.91(t,J＝13.7Hz,1H)；13C NMR(101MHz,DMSO)δ176.9,173.5,150.2,132.0,81.3,79.3,66.8,61.6,58.9, 58.7,57.8,54.4,41.2,38.9,36.7,35.4,24.5,22.6,22.2,19.4,15.9.HRMS- ESI(m/z):calcd.for C24H34O7N[M+H]+:448.2335,found 448.2333.
室温条件下，将化合物5(816mg,2.37mmol,1.0equiv)溶于无水THF(5ml)，然后将N-甲基哌嗪(1.3ml,11.85mmol,5.0eq)加入到体系中，室温条件下继续搅拌3h,体系直接浓缩，然后通过柱色谱法(5％MeOH/DCM)，得化合物14(650mg,75％，白色固体)。[α] 18 D＝-54.5(c＝0.48,CHCl3)；1H NMR(400MHz,CDCl3)δ7.02(s,1H), 5.62(s,1H),5.33(d,J＝10.4Hz,1H),5.12(s,1H),4.65(d,J＝10.5Hz, 1H),4.14(s,1H),3.24–3.07(m,1H),2.86(dd,J＝14.1,4.2Hz,2H),2.73 (t,J＝12.5Hz,2H),2.68–2.52(m,5H),2.51–2.40(m,2H),2.31(s,3H), 2.28(dd,J＝14.3,2.8Hz,2H),2.24–2.13(m,2H),2.11–1.98(m,2H), 1.87–1.62(m,2H),1.60(s,3H),1.55(s,3H)；13C NMR(101MHz,CDCl3) δ177.3,173.8,147.7,136.8,135.9,130.9,128.1,125.2,83.5,78.3,73.2, 54.4,53.1,46.0,40.9,38.6,37.7,32.4,27.6,24.4,19.2,13.7；HRMS-ESI (m/z):calcd.for C25H37O5N2[M+H]+:445.2702,found 445.2701.
室温条件下，将化合物6(114mg,0.32mmol,1.0eq)溶于无水 THF(1.0mL)，然后将N-甲基哌嗪(352ul,3.17mmol,10.0eq)加入到体系中，室温条件下继续搅拌5h,体系直接浓缩,然后通过柱色谱法(3％MeOH/DCM)，得化合物15(71mg,65％，白色固体)。[α]22 D＝-78.7(c＝0.1,CHCl3)；1H NMR(400MHz,CDCl3)δ7.20(s,1H),5.14 (s,1H),3.80(d,J＝10.0Hz,1H),3.20–3.07(m,1H),3.02(d,J＝9.9Hz, 1H),2.86–2.51(m,6H),2.50–2.32(m,6H),2.28(s,3H),2.12(dd,J＝ 15.4,3.0Hz,2H),2.00(t,J＝12.7Hz,4H),1.66(dd,J＝8.4,5.7Hz,1H), 1.34(s,3H),1.13(s,3H),1.07(td,J＝13.2,4.3Hz,1H),0.45(t,J＝13.8 Hz,1H),0.28(s,2H),-0.01(s,1H)；13C NMR(101MHz,CDCl3)δ177.2, 172.9,147.3,134.7,81.8,78.4,59.1,56.9,55.5,54.3,46.2,41.8,39.7,37.0, 36.6,25.6,25.4,23.3,22.1,20.0,18.8,16.9,16.6；HRMS-ESI(m/z):calcd. for C26H39O5N2[M+H]+:459.2859,found459.2858.
室温条件下，将化合物7(100mg,0.26mmol,1.0eq)溶于无水 THF(5mL)，然后将富马酸(30.6mg,0.26mmol,1.0eq)加入到体系中，室温条件下继续搅拌5h,体系直接浓缩得化合物16(130mg,100％, 白色固体)。[α]22 D＝+25.2°(c＝0.14,MeOH)；1H NMR(400MHz,DMSO)δ7.46(s,1H),6.60(s,2H),5.38–5.10(m,2H),4.87(d,J＝10.8 Hz,2H),3.18–2.90(m,1H),2.74–2.53(m,3H),2.45–2.27(m,4H), 2.21(s,6H),2.14–2.00(m,3H),1.90–1.74(m,2H),1.72(s,3H),1.50 (s,3H),1.06(t,J＝13.2Hz,1H)；13C NMR(101MHz,DMSO)δ177.2,173.0,166.2,149.2,134.6,134.1,132.4,132.2,126.3,124.6,78.8,77.8, 54.5,44.6,39.6,39.4,38.8,35.5,24.3,23.1,22.8,18.8,14.5.
室温条件下，将化合物8(50mg,0.12mmol,1.0eq)溶于无水THF (0.6mL)，然后将富马酸(13.3mg,0.12mmol,1.0eq)加入到体系中，室温条件下继续搅拌5h,体系直接浓缩得化合物17(63mg,100％, 白色固体)。1H NMR(400MHz,DMSO)δ7.47(s,1H),6.63(s,2H), 5.29(d,J＝10.7Hz,1H),5.22(d,J＝1.4Hz,1H),4.89(d,J＝10.6Hz, 2H),3.68–3.50(m,4H),3.47–3.23(m,2H),3.18–3.07(m,1H),2.69 (dd,J＝14.1,3.5Hz,1H),2.66–2.56(m,1H),2.47–2.29(m,5H),2.29 –2.18(m,2H),2.12(dd,J＝16.5,8.6Hz,3H),1.88–1.75(m,2H),1.73 (s,3H),1.61(s,3H),1.12–1.00(m,1H)；13C NMR(101MHz,DMSO)δ 177.3,173.2,166.0,149.1,134.7,134.0,132.5,131.6,126.4,124.6,79.0, 77.9,66.3,53.3,37.7,35.5,24.2,23.1,22.6,18.8,14.9.
室温条件下，将化合物9(1.0g,2.3mmol,1.0eq)溶于无水THF (25mL)，然后将富马酸(270.8mg,2.3mmol,1.0eq)加入到体系中，室温条件下继续搅拌5h,体系直接浓缩得化合物18(1.27g,100％,白色固体)。[α]23 D＝-16.3(c＝0.15,MeOH)；IR(neat)2922,2851,1750cm-1；1H NMR(400MHz,DMSO)δ7.47(d,J＝0.9Hz,1H),6.55(s,2H), 5.76(s,1H),5.29(d,J＝10.7Hz,1H),5.22(d,J＝1.4Hz,1H),4.88(d,J ＝10.6Hz,2H),3.16–3.03(m,1H),2.69(dd,J＝14.2,3.4Hz,2H),2.66 –2.52(m,5H),2.47(s,1H),2.44–2.34(m,4H),2.33(s,3H),2.32–2.24 (m,1H),2.19–1.97(m,4H),1.88–1.74(m,2H),1.73(d,J＝0.7Hz,3H), 1.59(s,3H),1.14–0.96(m,1H)；13C NMR(101MHz,DMSO)δ177.2, 173.2,167.1,149.1,134.7,134.6,132.5,131.7,126.4,124.6,79.0,77.9, 54.9,54.1,52.8,44.7,38.1,35.5,24.2,23.1,22.6,18.8,15.0.
室温条件下，将化合物10(30mg,0.067mmol,1.0eq)溶于无水 THF(2mL)，然后将富马酸(7.8mg,0.067mmol,1.0eq)加入到体系中，室温条件下继续搅拌5h,体系直接浓缩得化合物19(38mg,100％, 白色固体)。1H NMR(400MHz,DMSO)δ7.65(s,1H),6.58(s,2H), 5.31(d,J＝11.4Hz,2H),4.92(d,J＝10.6Hz,1H),3.75–3.37(m,2H), 3.11(d,J＝4.5Hz,2H),2.86–2.60(m,7H),2.42(s,3H),2.38–2.20(m, 4H),2.12–1.85(m,4H),1.84–1.71(m,4H),1.68(s,3H),1.27(s,3H), 1.10(dt,J＝26.7,13.4Hz,2H)；13C NMR(101MHz,DMSO)δ176.6,173.3,166.7,149.2,134.4,132.2,132.1,125.7,79.5,77.9,60.6,58.4,53.9, 52.6,44.1,41.1,38.6,38.3,35.1,24.6,22.2,22.1,19.0,15.7.
室温条件下，将化合物11(30mg,0.069mmol,1.0eq)溶于无水 THF(2mL)，然后将富马酸(7.8mg,0.069mmol,1.0eq)加入到体系中，室温条件下继续搅拌5h，体系直接浓缩得化合物20(38mg,100％, 白色固体)。1H NMR(400MHz,DMSO)δ7.65(s,1H),6.63(s,2H), 5.31(d,J＝10.4Hz,2H),4.93(d,J＝10.6Hz,1H),3.60(s,4H),3.12(d, J＝5.2Hz,1H),2.75(dd,J＝14.4,2.7Hz,1H),2.69–2.54(m,2H),2.49 –2.38(m,3H),2.37–2.17(m,5H),2.09–1.85(m,3H),1.86–1.70(m, 3H),1.68(s,3H),1.30(s,3H),1.28–0.99(m,3H).13C NMR(101MHz, DMSO)δ176.7,173.2,166.0,149.2,134.0,132.1,132.1,125.7,79.5,78.1,66.3,60.6,58.4,53.3,41.2,38.6,37.9,35.2,24.5,22.3,22.1,19.0,15.5.
室温条件下，将化合物12(3.0g,6.5mmol,1.0eq)溶于无水THF (30ml)，然后将富马酸(1.4g,12.3mmol,1.9eq)加入到体系中，室温条件下继续搅拌3h，体系析出白色固体，过滤，滤饼用THF(3x 15mL)洗涤，无水Et2O(3x 10mL)洗涤，收集滤饼得化合物21(3.3 g,89％,白色固体)。[α]22 D＝-39.5(c＝0.5,MeOH)；IR(neat)2956, 2929,2835,1751,1703,1458,1390,1145,1103,981,645cm-1；1H NMR (400MHz,DMSO)δ7.95(s,1H),6.57(s,2H),5.32(s,1H),3.99(d,J＝ 9.7Hz,1H),3.18(s,1H),2.99(d,J＝9.9Hz,1H),2.80–2.45(m,9H), 2.46–2.18(m,8H),2.04–1.60(m,6H),1.33(s,3H),1.31(s,3H),1.13 (t,J＝11.2Hz,1H),0.90(t,J＝13.4Hz,1H)；13C NMR(101MHz,DMSO) δ176.2,173.1,167.2,149.8,134.6,131.5,80.7,78.9,61.1,58.4,58.2,57.3, 53.7,53.2,43.8,40.7,38.7,36.2,34.9,24.2,22.1,21.8,18.9,15.5.
室温条件下，将化合物12(20.0mg,0.043mmol,1.0eq)溶于无水 THF(1.0ml)，然后将二氯乙酸(5.3mg,0.043mmol,1.0eq)加入到体系中，室温条件下继续搅拌3h，体系直接浓缩得化合物22(25.3mg, 100％,白色固体)。[α]18 D＝-29.9(c＝0.35,MeOH)；1H NMR(400MHz, DMSO)δ7.97(s,1H),6.14(s,1H),5.75(s,1H),5.47–5.03(m,1H),4.01 (d,J＝10.0Hz,2H),3.84–3.74(m,2H),3.31–3.17(m,2H),3.02(d,J ＝10.0Hz,2H),2.79(s,3H),2.66–2.52(m,3H),2.48–2.39(m,1H), 2.36–2.17(m,3H),2.03–1.76(m,5H),1.74–1.62(m,2H),1.33(s,3H), 1.29(s,3H),1.18–1.00(m,1H),1.00–0.84(m,1H)；13C NMR(101 MHz,DMSO)δ176.10,173.31,165.53,150.03,131.48,106.98,80.64, 79.03,70.12,66.61,61.14,58.46,58.19,57.30,53.09,52.72,40.64,38.75, 36.21,34.79,28.89,24.23,23.57,22.09,21.85,18.87,15.47.
室温条件下，将化合物12(20.0mg,0.043mmol,1.0eq)溶于无水 THF(1.0ml)，然后将L-苹果酸(5.5mg,0.043mmol,1.0eq)加入到体系中，室温条件下继续搅拌3h，体系直接浓缩得化合物23(25.3mg, 100％,白色固体)。[α]18 D＝-40.0(c＝0.27,MeOH)；1H NMR(400MHz,DMSO)δ7.96(s,1H),5.75(s,1H),5.46–4.90(m,1H),4.07(t,J ＝6.5Hz,1H),4.00(d,J＝10.0Hz,1H),3.80(ddd,J＝14.8,9.8,6.3Hz, 1H),3.26–3.11(m,1H),3.00(d,J＝10.0Hz,1H),2.73(s,3H),2.63– 2.51(m,5H),2.45(s,3H),2.43–2.21(m,6H),2.01–1.67(m,7H),1.33 (s,3H),1.31(s,3H),1.20–1.03(m,1H),0.99–0.81(m,1H)；13C NMR (101MHz,DMSO)δ176.34,175.63,173.17,172.01,149.89,131.53, 107.01,80.75,78.94,66.63,66.55,61.13,58.49,58.20,57.38,54.20,53.28, 44.35,40.68,40.46,38.68,36.20,34.89,28.90,24.17,23.58,22.11,21.78, 18.90,15.54.
室温条件下，将化合物13(15.0mg,0.033mmol,1.0eq)溶于无水 THF(2.0ml)，然后将富马酸(3.9mg,0.033mmol,1.0eq)加入到体系中，室温条件下继续搅拌3h，体系直接浓缩得化合物24(19mg,100％, 白色固体)。[α]18 D＝-62.1(c＝0.165,MeOH:CHCl3＝1:1)；1H NMR(400 MHz,DMSO)δ7.95(s,1H),6.63(s,2H),5.38(d,J＝5.9Hz,1H),5.32 (s,1H),4.01(d,J＝9.9Hz,1H),3.64(s,3H),3.27–3.14(m,1H),3.00(d, J＝9.9Hz,1H),2.69(s,2H),2.63–2.52(m,4H),2.47–2.23(m,5H), 2.04–1.90(m,2H),1.88–1.77(m,3H),1.35(s,6H),1.20–1.07(m,1H), 0.91(t,J＝13.8Hz,1H)；13C NMR(101MHz,DMSO)δ176.4,173.1, 166.0,149.8,134.0,131.6,80.9,78.9,66.4,61.1,58.5,58.2,57.4,54.0, 40.7,38.4,36.2,34.9,24.1,22.2,21.8,18.9,15.4.
室温条件下，将化合物13(15.0mg,0.033mmol,1.0eq)溶于无水 THF(2.0ml)，然后将二氯乙酸(4.2mg,0.033mmol,1.0eq)加入到体系中，室温条件下继续搅拌3h，体系直接浓缩得化合物25(19mg, 100％,白色固体)。[α]19 D＝-25.4(c＝0.24,MeOH)；1H NMR(400MHz,DMSO)δ7.94(s,1H),6.61(s,1H),5.37(d,J＝5.9Hz,1H),5.31(s,1H), 4.01(d,J＝9.9Hz,1H),3.65(s,3H),3.27–3.16(m,1H),3.01(d,J＝9.9 Hz,1H),2.74(s,2H),2.65–2.51(m,4H),2.37(m,5H),2.03–1.89(m, 2H),1.90–1.77(m,3H),1.33(s,6H),1.19–1.02(m,1H),0.91(t,J＝ 13.9Hz,1H)；13C NMR(101MHz,DMSO)δ176.7,173.6,166.2,150.3, 132.0,81.3,79.4,66.6,66.6,61.5,58.9,58.7,57.8,54.2,41.1,38.8,36.8, 35.4,24.5,22.6,22.2,19.3,15.9.
室温条件下，将化合物13(15.0mg,0.033mmol,1.0eq)溶于无水 THF(2.0ml)，然后将L-苹果酸(4.5mg,0.033mmol,1.0eq)加入到体系中，室温条件下继续搅拌3h，体系直接浓缩得化合物26(19mg, 100％,白色固体)。1H NMR(400MHz,DMSO)δ7.96(s,1H),5.76(s,1H),5.32(s,1H),4.25(dd,J＝7.7,4.9Hz,1H),4.01(d,J＝10.0Hz,1H), 3.73–3.49(m,5H),3.38(dd,J＝9.6,4.7Hz,3H),3.26–3.14(m,1H), 3.00(d,J＝10.0Hz,1H),2.66–2.53(m,3H),2.48–2.17(m,7H),2.05– 1.68(m,5H),1.34(s,6H),1.21–1.05(m,1H),0.93(d,J＝13.5Hz,1H)；13C NMR(101MHz,DMSO)δ176.5,174.7,173.1,171.9,149.8,131.6, 80.9,78.9,67.0,66.4,61.2,58.5,58.2,57.4,55.0,53.9,40.7,38.4,36.2, 34.9,24.1,22.2,21.8,18.9,15.4.
室温条件下，将化合物14(500mg,1.12mmol,1.0eq)溶于无水 THF(5.0ml)，然后将富马酸(130.5mg,1.12mmol,1.0eq)加入到体系中，室温条件下继续搅拌3h，体系直接浓缩得化合物27(630mg, 100％,白色固体)。[α]19 D＝-40.7(c＝0.33,MeOH)；1H NMR(400MHz,DMSO)δ7.50(s,1H),6.57(s,2H),5.76(s,1H),5.44–5.14(m,2H),5.13 –4.78(m,2H),3.95(d,J＝10.5Hz,1H),3.15(d,J＝13.5Hz,1H),3.05 –2.50(m,9H),2.47–2.25(m,8H),2.24–2.07(m,1H),1.91(s,1H),1.70 (d,J＝13.3Hz,4H),1.54(d,J＝20.8Hz,4H),1.19(t,J＝12.7Hz,1H)；13C NMR(101MHz,DMSO)δ177.0,173.2,166.9,149.3,138.6,134.5, 132.4,131.7,126.4,124.7,79.0,78.6,74.6,55.0,53.8,52.7,44.2,40.0, 37.9,31.3,24.1,22.7,21.2,18.9,10.3.
室温条件下，将化合物15(67mg,0.145mmol,1.0eq)溶于无水 THF(1.5ml)，然后将富马酸(16.8mg,0.145mmol,1.0eq)加入到体系中，室温条件下继续搅拌3h，体系直接浓缩得化合物28(83mg, 100％,白色固体)。[α]19 D＝-50.3(c＝0.4,MeOH)；13C NMR(101MHz,DMSO)δ176.6,173.2,166.3,149.7,134.2,132.1,81.0,78.7,67.0,58.3, 57.3,54.2,53.3,44.4,40.9,36.2,35.8,25.1,25.1,24.6,22.7,21.5,19.0, 18.3,16.4,16.1.
室温条件下，将化合物9(50mg,0.117mmol,1.0eq)溶于无水THF (2.0ml)，然后将柠檬酸(22mg,0.11mmol,1.0eq)加入到体系中，室温条件下继续搅拌3h，体系直接浓缩得化合物29(72mg,100％,白色固体)。[α]18 D＝-15.8(c＝0.35,MeOH)；1H NMR(400MHz,DMSO) δ7.50(s,1H),5.76(s,1H),5.30(d,J＝10.7Hz,1H),5.24(s,1H),4.90 (d,J＝10.6Hz,2H),3.17(s,2H),3.08–2.61(m,11H),2.59–2.48(m, 6H),2.49–2.23(m,5H),2.21–1.99(m,3H),1.83–1.74(m,2H),1.73 (s,3H),1.58(s,3H),1.06(t,J＝13.1Hz,1H)；13C NMR(101MHz,DMSO)δ177.49,176.79,173.87,171.85,149.74,135.20,132.96,132.13, 126.83,125.07,79.50,78.28,72.11,54.01,52.72,44.32,43.76,40.27, 38.58,35.93,24.59,23.68,23.02,19.26,15.45.
室温条件下，将化合物10(30mg,0.067mmol,1.0eq)溶于无水 THF(2.0ml)，然后将柠檬酸(12.2mg,0.067mmol,1.0eq)加入到体系中，室温条件下继续搅拌3h，体系直接浓缩得化合物30(42mg, 100％,白色固体)。1H NMR(400MHz,DMSO)δ7.66(s,1H),5.76(s, 2H),5.31(d,J＝11.6Hz,2H),4.93(d,J＝10.7Hz,1H),3.29–3.08(m, 2H),3.05–2.70(m,6H),2.61(dd,J＝21.9,12.0Hz,8H),2.54(s,1H), 2.45(dd,J＝12.6,4.9Hz,2H),2.38–2.20(m,3H),2.09–1.89(m,3H), 1.74(dd,J＝12.8,7.8Hz,1H),1.68(s,3H),1.26(s,3H),1.19–1.01(m, 2H)；13C NMR(101MHz,DMSO)δ176.5,176.1,173.4,171.4,149.3, 132.2,132.0,125.61,79.6,77.9,71.7,60.6,58.4,55.0,53.7,52.4,43.7, 43.5,41.1,38.6,38.3,35.1,24.6,22.2,22.1,19.0,15.6.
室温条件下，将化合物11(30mg,0.069mmol,1.0eq)溶于无水 THF(2.0ml)，然后将柠檬酸(12.7mg,0.069mmol,1.0eq)加入到体系中，室温条件下继续搅拌3h，体系直接浓缩得化合物31(43mg, 100％,白色固体)。1H NMR(400MHz,DMSO)δ7.54(d,J＝86.5Hz, 1H),5.93–5.27(m,2H),5.39–5.10(m,2H),4.95(t,J＝18.7Hz,1H), 3.60(s,4H),3.48–2.95(m,2H),2.75(d,J＝15.3Hz,3H),2.60(dd,J＝ 42.6,11.4Hz,4H),2.46–2.14(m,7H),2.09–1.85(m,3H),1.84–1.72 (m,3H),1.68(s,3H),1.30(s,3H),1.28–0.89(m,3H)；13C NMR(101MHz,DMSO)δ176.7,174.7,173.3,171.3,149.2,132.2,132.1,125.7, 79.5,78.1,72.4,66.3,60.6,58.39,54.9,53.3,42.8,41.2,38.6,37.9,35.2, 24.5,22.3,22.1,19.0,15.6.
室温条件下，将化合物12(50mg,0.107mmol,1.0eq)溶于无水 THF(2.0ml)，然后将柠檬酸(20mg,0.107mmol,1.0eq)加入到体系中，室温条件下继续搅拌3h，体系直接浓缩得化合物32(70mg,100％, 白色固体)。[α]18 D＝-55.9(c＝0.185,MeOH:CHCl3＝1:1)；1H NMR(400 MHz,DMSO)δ7.98(s,1H),5.34(s,1H),4.02(d,J＝10.0Hz,1H),3.28 –3.18(m,1H),3.17(s,3H),3.01(d,J＝10.0Hz,2H),2.82–2.59(m, 10H),2.55–2.39(m,6H),2.39–2.16(m,3H),2.08–1.62(m,5H),1.34 (s,3H),1.30(s,3H),1.22–1.05(m,1H),0.92(t,J＝13.6Hz,1H)；13C NMR(101MHz,DMSO)δ176.30,176.26,173.31,171.41,150.01, 131.53,80.72,79.04,71.69,61.17,58.51,58.21,57.39,53.76,52.98,48.64, 43.86,43.43,40.67,38.75,36.22,34.86,24.23,22.12,21.84,18.90,15.53.
室温条件下，将化合物13(50mg,0.112mmol,1.0eq)溶于无水 THF(2.0ml)，然后将柠檬酸(21mg,0.112mmol,1.0eq)加入到体系中，室温条件下继续搅拌3h，体系直接浓缩得化合物33(71mg,100％, 白色固体)。
[α]18 D＝-27.3(c＝0.4,MeOH)；1H NMR(400MHz,DMSO)δ7.96(s, 1H),5.76(s,1H),5.32(s,1H),4.01(d,J＝10.0Hz,1H),3.75–3.48(m, 5H),3.38(dd,J＝9.5,4.6Hz,2H),3.27–3.12(m,2H),3.00(d,J＝10.0 Hz,1H),2.70(dd,J＝41.7,15.4Hz,6H),2.61–2.52(m,3H),2.35(ddd, J＝36.5,16.4,7.9Hz,5H),2.06–1.68(m,5H),1.34(s,6H),1.21–1.03 (m,1H),0.91(t,J＝13.5Hz,1H)；13C NMR(101MHz,DMSO)δ176.47, 174.66,173.11,171.34,149.83,131.56,80.88,78.93,72.44,66.38,61.17, 58.53,58.23,57.41,54.96,53.95,42.77,40.70,38.41,36.23,34.95,24.10, 22.19,21.80,18.93,15.44.
室温条件下，将化合物14(50mg,0.117mmol,1.0eq)溶于无水 THF(2.0ml)，然后将柠檬酸(22mg,0.11mmol,1.0eq)加入到体系中，室温条件下继续搅拌3h，体系直接浓缩得化合物34(72mg,100％, 白色固体)。
[α]18 D＝-34.6(c＝0.32,MeOH)；1H NMR(400MHz,DMSO)δ7.51(s, 1H),5.76(s,2H),5.40–5.19(m,2H),5.08–4.94(m,1H),4.92(d,J＝ 10.8Hz,1H),3.96(dd,J＝11.1,3.7Hz,1H),3.28–3.07(m,2H),3.08– 2.62(m,11H),2.60–2.27(m,10H),2.26–2.09(m,1H),1.91(s,1H), 1.71(s,3H),1.69–1.58(m,1H),1.56(s,3H),1.18(td,J＝12.8,3.6Hz, 1H)；13C NMR(101MHz,DMSO)δ176.87,176.21,173.38,171.39, 149.49,138.56,132.35,131.69,126.36,124.71,79.09,78.58,74.52,71.73, 54.96,53.51,52.34,43.80,43.29,40.08,37.91,31.26,24.01,22.75,18.84, 10.20.
实施例2：Ovatodiolide衍生物及其盐对人恶性脑胶质母细胞瘤细胞系U87，人胰腺癌细胞系Panc-1，人肝癌细胞系HepG2和人肝癌细胞系SMMC7721的抑制作用
将待测试细胞配成2×105/mL细胞悬液，加入96孔板圆底细胞培养板内，分别加入待测化合物，每一测试浓度3孔，置37℃、5％CO2饱和湿度条件下培养72小时，用MTT法在酶联检测仪570nm波长测得吸光度(A) 值，计算出本发明化合物对测试癌细胞的抑制作用。
如表1所示，所测试化合物对测试的癌细胞系显示出较强的抗癌活性。表1.Ovatodiolide衍生物及其盐对各种癌细胞的抑制活性(IC50，μM)
Figure BDA0001900959190000201
Figure BDA0001900959190000211
实施例3：Ovatodiolide衍生物在肝微粒体中的代谢实验
向冰冷的50mM Tris-柠檬酸缓冲液(pH＝7.4)加入适量人肝微粒体蛋白、化合物1、4、18、21、MgCl2，整个孵育体积为50μl，包括0.2mg/ml 肝微粒体、5mM MgCl2、1μM化合物1、4、18、21，孵育体系甲醇比例小于1％。37℃水浴预孵育3min后，加入1μl 50mM NADPH启动反应，继续孵育0、0.25、0.5、1h后，另设未加NADPH的对照组，相同条件下孵育1h，向孵育体系加入1ml含1ng/ml盐酸丁螺环酮的甲醇溶液终止反应，涡旋混匀2min，12000rpm离心5min，进样2μl检测化合物1、4、 18、21剩余量，各样本平行3份。
如表2所示，Ovatodiolide修饰的化合物的肝微粒体代谢实验显示，稳定性显著提高。
表2.化合物1、4、18、21的肝微粒体稳定性实验
肝微粒体代谢数据(n＝3)
Figure BDA0001900959190000221
肝微粒体代谢数据(n＝3)
Figure BDA0001900959190000222
肝微粒体代谢数据(n＝3)
Figure BDA0001900959190000223
注：“+”表示加入，“-”表示未加入。
肝微粒体代谢数据(n＝3)
Figure BDA0001900959190000224
注“+”表示加入，“-”表示未加入。

Claims (4)

1.一种如式(I)所示的Ovatodiolide衍生物及其盐，
Figure FDA0001900959180000011
式(I)中R1为碳原子，氧原子；R2为碳原子，氧原子；R3为氢原子，羟基；R4和R5可以相同或不同，分别为氢、烷基、环烷基、羟基取代烷基、烯基、炔基、芳基、烷基芳基、芳基烷基、芳基烯基、芳基炔基、杂环基、三氟甲基、多氟取代烷基、腈基、腈基甲基、酰基、氨基甲酰基、磺酰基、磺酰胺基或芳氧烷基；R4、R5和N原子形成环状结构，环优选为3–9元环，环状结构上可以被一个或多个取代基取代，包括氢、烷基、环烷基、烯基、炔基、芳基、烷基芳基、芳基烷基、芳基烯基、芳基炔基或杂环基；
其与无机酸或有机酸形成的在药学上可接受的盐，包括与R6Z形成的季铵盐，包括氢氟酸、盐酸、氢溴酸、氢碘酸、硫酸、磷酸、硝酸、亚磷酸、亚硫酸、碳酸、硼酸、磷钼酸、亚硒酸、甲基磺酸、取代甲基磺酸、苯基磺酸、取代苯基磺酸、富马酸、柠檬酸、马来酸、酒石酸、草酸、D-苹果酸、L-苹果酸、DL-苹果酸、L-乳酸、D-乳酸、DL-乳酸、甲酸、取代甲酸、乙酸、丙酸、丁酸、戊酸、油酸、月桂酸、对甲基苯磺酸、1-萘磺酸、2-萘磺酸、酞酸、丙二酸、丁二酸、乙醇酸、硫醇酸、甘氨酸、肌氨酸、磺酸、烟酸、甲基吡啶酸、异烟酸、二氯乙酸、苯甲酸、取代苯甲酸；R6为烃基、环烷基、羟基取代烷基、烯基、炔基、芳基、杂环基、芳基取代烷基、芳基烯基、芳基炔基、氰基取代甲基、烷氧基取代烷基或芳氧取代烷基；Z为氟、氯、溴、碘、对甲基磺酸基、甲基磺酸基、苯基磺酸基、取代苯基磺酸基、三氟甲基磺酸基。
2.一种制备式(I)所示Ovatodiolide衍生物及其盐的方法，其特征在于以式(II)所示的化合物为原料，与(III)所示的化合物反应得式(I)所示的化合物；
Figure FDA0001900959180000021
3.一种如式(I)所示的Ovatodiolide衍生物及其盐，在制备治疗癌症或治疗癌症的辅助药物中的用途，其中癌症为白血病、乳腺癌、前列腺癌、鼻咽癌、大肠癌、肺癌、肝癌、食道癌、胃癌、肠道癌、肾癌、口腔癌、何杰金淋巴癌、胰腺癌、直肠结肠癌、子宫颈癌、非何杰金淋巴癌、神经胶质瘤、黑瘤、膀胱癌、卵巢癌、甲状腺癌或卡波西肉瘤。
4.一种用于治疗癌症的药物组合物，其中含有有效量的式(I)Ovatodiolide衍生物及其盐在药学上可接受的载体或与其他抗癌药物的组合物。
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