CN112457284B - 寡聚木脂素类化合物及其制备方法和其药物组合物与用途 - Google Patents

寡聚木脂素类化合物及其制备方法和其药物组合物与用途 Download PDF

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CN112457284B
CN112457284B CN201910849217.2A CN201910849217A CN112457284B CN 112457284 B CN112457284 B CN 112457284B CN 201910849217 A CN201910849217 A CN 201910849217A CN 112457284 B CN112457284 B CN 112457284B
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张东明
叶菲
李川
田金英
李创军
马洁
张晓琳
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Abstract

本发明公开了寡聚木脂素类化合物及其制备方法和其药物组合物与用途，具体而言，本发明公开了从凹叶厚朴中发现的14个新寡聚木脂素类化合物(1‑14)，这类化合物通过植物化学的制备方法，含有新寡聚木脂素的药物组合物及它们在制备PTP1B抑制剂，预防和/或治疗糖尿病药物，预防和/或治疗高血脂药物中的应用。

Description

寡聚木脂素类化合物及其制备方法和其药物组合物与用途
技术领域
本发明属于医药领域，具体地涉及到凹叶厚朴中提取分离的新寡聚木脂素化合物以及制备方法和在制备预防和/或治疗以PTP1B为靶点的糖尿病以及高血脂疾病药物中的用途。
背景技术
凹叶厚朴(Magnolia offinalis Rehd.et Wils.var.biloba)是木兰科木兰属植物，分布于安徽、四川、福建、江西、湖北和湖南等省，凹叶厚朴的干燥树皮作为中药厚朴应用于临床，具有燥湿消痰，下气除满的功效，主治湿滞伤中，脘痞吐泻，食积气滞，腹胀便秘，痰饮喘咳。
糖尿病是以高血糖为特征的一类代谢性疾病，糖尿病发展到后期对人体多个组织器官具有严重的功能损伤，据权威资料统计截止到2013年，全球有3.82亿人患有糖尿病，预计到2035年，这一数字将上升至5.92亿，糖尿病的预防和治疗刻不容缓。糖尿病分为胰岛素依赖性糖尿病(Ⅰ型糖尿病)和非胰岛素依赖型糖尿病又称为成人发病型糖尿病(Ⅱ型糖尿病)，多在35-40岁之后发病。其中II型糖尿病大约占全世界糖尿病患者的90％左右，其特点是高血糖症、血脂异常以及代谢靶组织的胰岛素抵抗。1999年《science》杂志报道了研究人员发现敲除蛋白酪氨酸磷酸酶1B(PTP1B)基因的小鼠能够健康存活，同时发现其表现出胰岛素敏感性的提高和能量代谢的影响，而且在高脂饮食的诱导下小鼠不发展为II型糖尿病。后续的研究发现PTP1B抑制剂在动物体内在调节胰岛素敏感性和能量代谢的过程中均起着重要作用。目前，通过重组的大肠杆菌细胞中分离纯化得到了人的PTP1B催化结构域，PTP1B可以作为药物治疗II型糖尿病和高血脂的一个理想靶点，以PTP1B为靶点的抑制剂的研究成为近二十年来的研究热点，尽管PTP1B抑制剂研究已经取得很大进展，各类PTP1B抑制剂相继被报道，但尚未开发出已上市的PTP1B抑制剂，由此可以看到以PTP1B为靶点的预防或治疗糖尿病以及高血脂的新药开发仍然具有巨大潜力。
从传统中药凹叶厚朴中分离纯化得到的化学结构明确、具有显著PTP1B抑制活性的化合物1-14作为预防和治疗糖尿病和高血脂有极好的临床开发前景。
发明内容
发明人首次发现凹叶厚朴的树皮提取物具有PTP1B抑制活性，从凹叶厚朴提取物中提取分离得到14个新的寡聚木脂素类化合物，体外药理模型评价其具有治疗II型糖尿病和高血脂的作用。
本发明解决的技术问题在于提供了14个新的寡聚木脂素类化合物。
本发明解决的另一技术问题在于提供了14个新的寡聚木脂素的制备方法。
本发明解决的又一技术问题在于提供一种药物组合物，其中14个寡聚木脂素或其药学上可接受的盐具有明显的PTP1B抑制活性，可用于治疗II型糖尿病以及高血脂。
具体讲：本发明涉及的化合物1-14的结构式如下所示
Figure BDA0002196335390000021
本发明提供的14个新的寡聚木脂素的制备方法，具体如下
干燥的凹叶厚朴树皮重量为25kg，粉碎后用95％乙醇回流提取3次，每次2h。得到凹叶厚朴树皮95％乙醇总提取物，经减压回收溶剂后得到浸膏约2700g，此浸膏经过3L温水分散后进行二氯甲烷和乙酸乙酯萃取，每部分萃取三次，其中二氯甲烷萃取部位1810g，乙酸乙酯萃取部位150g，其中二氯甲烷萃取部位进行多次的柱层析(正反向硅胶、凝胶柱色谱)，最后通过HPLC进行纯化，得到14个新的寡聚木脂素。
本发明另一方面还涉及以本发明化合物作为活性成分的药物组合物。该药物组合物可以根据本领域公知的方法制备。可通过将本发明化合物与一种或多种药学上可接受的固体或液体赋形剂和或辅剂结合，制成适于人或动物使用的任何剂型。本发明化合物在其药物组合物中的含量通常为0.1-95重量％。
本发明化合物或含有它的药物组合物可以单位剂量形式给药，给药途径可为肠道或非肠道，如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔黏膜、眼、肺和呼吸道、皮肤、阴道、直肠等。
给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等；固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等；半固体剂型可以是软膏剂、凝胶剂、糊剂等。
本发明化合物可以制成普通制剂、缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
为了将本发明化合物制成片剂，可以广泛应用本领域公知的各种赋形剂，包括稀释剂、粘合剂、润湿剂、崩解剂、润滑剂、助流剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露糖、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等；湿润剂可以是水、乙醇、异丙醇等；粘合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等；崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等；润滑剂和助流剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。
还可以将片剂进一步制成包衣片，例如糖包衣片、薄膜包衣片、肠溶包衣片、或双层片和多层片。
为了将给药单元制成胶囊剂，可以将有效成分本发明化合物与稀释剂、助流剂混合，将混合物直接置于硬胶囊或软胶囊中。也可将有效成分本发明化合物先与稀释剂、粘合剂、崩解剂制成颗粒或微丸，再置于硬胶囊或软胶囊中。用于制备本发明化合物片剂的各种稀释剂、粘合剂、润湿剂、崩解剂、助流剂品种也可用于制备本发明化合物的胶囊剂。
为将本发明化合物制成注射剂，可以用水、乙醇、异丙醇、丙二醇或它们的混合物作溶剂并加入适量本领域常用的增溶剂、助溶剂、pH调节剂、渗透压调节剂。增溶剂或助溶剂可以是泊洛沙姆、卵磷脂、羟丙基-β-环糊精等。pH调节剂可以是磷酸盐、醋酸盐、盐酸、氢氧化钠等；渗透压调节剂可以是氯化钠、甘露醇、葡萄糖、磷酸盐、醋酸盐等。如制备冻干粉针剂，还可加入甘露醇、葡萄糖等作为支撑剂。
此外，如需要，也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其它添加剂。
为达到用药目的，增强治疗效果，本发明的药物或药物组合物可用任何公知的给药方法给药。
本发明化合物药物组合物的给药剂量依照所要预防或治疗疾病的性质和严重程度，患者或动物的个体情况，给药途径和剂型等可以有大范围的变化。一般来讲，本发明化合物的每天的合适剂量范围为0.001-150mg/kg体重，优选0.1-100mg/kg体重，更优选为1-60mg/kg体重，最优选为2-30mg/kg体重。上述剂量可以一个剂量单位或分成几个剂量单位给药，这取决于医生的临床经验以及包括运用其它治疗手段的给药方案。
本发明的化合物或组合物可单独服用，或与其他治疗药物或对症药物合并使用。当本发明的化合物与其它治疗药物存在协同作用时，应根据实际情况调整它的剂量。
有益技术效果：本发明公开中药凹叶厚朴中新寡聚木脂素1-14的提取制备方法，并鉴定了新化合物1-14的化学结构，糖尿病和高血脂症相关的药理模型的活性评价发现化合物1-14具有显著PTP1B抑制活性，表明化合物1-14具有极高的预防及治疗糖尿病和高血脂症新药的开发价值。
附图说明
图1、凹叶厚朴树皮提取流程图
图2、凹叶厚朴树皮二氯甲烷萃取物分离流程图
具体实施方式
实施例及药理活性实验进一步说明本发明但并不意味着对本发明的任何限制1、化合物1-14的制备(见附图)
干燥的凹叶厚朴茎皮、枝皮和根皮重量为25kg，粉碎后用95％乙醇回流提取3次，每次2h。95％乙醇总提取物60℃减压浓缩后得到浸膏约2700g，此浸膏经过3L温水约40℃分散后进行二氯甲烷和乙酸乙酯萃取，每部分萃取三次，其中二氯甲烷萃取部位1810g。
二氯甲烷萃取部位1810g进一步进行硅胶柱色谱石油醚/乙酸乙酯(10:1—1:4梯度洗脱，每个梯度洗脱4个柱体积)分离，其中10：1的洗脱部位得到组分850.2g，该部位经甲醇(3.5L)形成混悬状态，与石油醚进行萃取，得到甲醇层500.9g,经过硅胶柱色谱石油醚-丙酮梯度洗脱(40:1—2:1梯度洗脱，每个梯度洗脱4个柱体积)进行梯度洗脱，洗脱28个柱体积后，每4个柱体积合并一个组分得到7个洗脱组分(记作Fr.1～Fr.7)。
Fr.4～Fr.6合并后过滤结晶得到母液约86g，记作Fr.1-1，经过硅胶柱色谱石油醚-丙酮梯度洗脱(100:1—1：4)进行梯度洗脱，洗脱36个柱体积后，每4个柱体积合并为一个组分得到9个洗脱组分，记作Fr.1-1-1～Fr.1-1-9。Fr.1-1-4-4-1(14.9g)进行中亚柱色谱(70％MeOH/H2O-95％MeOH/H2O,梯度洗脱6个小时)约500ml收集一份，得到30个流分(记作Fr.1-1-4-1Fr.1-1-4-30)。Fr.1-1-4-20-Fr.1-1-4-22合并经过高效液相色谱(80％MeCN–H2O等度洗脱)制备得到样品1和样品2，样品1经过手性柱色谱(30％2-propanol/hexanes等度洗脱)分离得到化合物11(8.6 1.8mg)和12(7.1 1.6mg)，样品2经过手性柱色谱(35％2-propanol/hexanes等度洗脱)分离得到化合物13(1.8mg)和14(1.6mg)Fr.1-1-4-18-Fr.1-1-4-19经过HPLC(72％MeCN–H2O等度洗脱)制备得到样品3和样品4，样品3经过手性柱色谱(30％2-propanol/hexanes等度洗脱)分离得到化合物7(1.2mg)和8(1.6mg)，样品4经过手性柱色谱(10％2-propanol/hexanes等度洗脱)分离得到化合物9(2.1mg)和10(2.4mg)，Fr.1-1-4-21经过HPLC(76％MeCN–H2O等度洗脱)制备得到样品5(8.5mg)，样品5经过手性柱色谱(50％2-propanol/hexanes等度洗脱)分离得到化合物5(3.5mg)和6(2.9mg),Fr.1-1-4-26经HPLC(78％MeCN–H2O等度洗脱)制备得到样品5(18.6mg)，样品6经过手性柱色谱(30％2-propanol/hexanes等度洗脱)分离得到化合物3(5.0mg)和4(6.2mg)。Fr.1-1--3经过MPLC色谱(70％MeOH/H2O-93％MeOH/H2O，梯度洗脱8小时)每400ml收集为1个组分，得到50个组分(Fr.1-1-3-1-Fr.1-1-3-50),Fr.1-1-3-1-30经HPLC(75％MeCN–H2O)制备得到样品7(12.6mg)，样品7经过手性柱色谱(30％2-propanol/hexanes等度洗脱)分离得到化合物1(4.3mg)和2(3.8mg)。
化合物1-14的理化、波谱数据如下：
化合物1的理化、波谱数据如下：
无色油状；
Figure BDA0002196335390000051
(-)-HRESI-MS m/z 825.3432[M-H]-,(calcd.for C54H49O8,825.3433)。1H NMR data(DMSO-d6,600MHz),δH:6.17(1H,s,H-2),6.52,(1H,s,H-6),4.94(1H,brs,H-7),4.45(1H,m,H-8),2.56(1H,dd,J＝4.8,16.8Hz,H-9a),2.45(1H,brt,J＝4.2Hz,H-9b),8.57,(1H,s,OH-4′),6.29(1H,s,H-6′),3.01(1H,brs,H-7′),5.80(1H,m,H-8′),4.99(2H,m,H-9′),7.02(1H,d,8.4,H-2″,6″),6.70(1H,d,J＝8.4Hz,H-3″,5″),3.27(1H,brs,H-7″),5.99,(1H,m,H-8″),4.99(1H,m,H-9″),7.00(1H,brs,H-2″′),6.82(1H,d,J＝7.2Hz,H-5″′),6.99(1H,brd,J＝8.4Hz,H-6″′),3.26(1H,brs,H-7″′),5.99(1H,m,H-8″′),4.99(2H,m,H-9″′),6.76(1H,brs,H-2″″),6.76(1H,d,J＝9.0,H-5″″),6.80(1H,brd,J＝7.8Hz,H-6″″),3.29(2H,brs,H-7″″),5.99(1H,m,H-8″″),4.99(2H,m,H-9″″),7.02(2H,d,J＝7.8,H-2″″′,6″″′),6.65(2H,d,J＝7.8,H-3″″′,5″″′),3.27(2H,brs,H-7″″′),5.99(1H,m,H-8″″′),4.99(2H,m,H-9″″′).
1H NMR data(DMSO-d6,150MHz),δC:129.5(C-1),110.6(C-2),143.4(C-3),137.6(C-4),147.4(C-5),110.2(C-6),77.5(C-7),74.6(C-8),25(C-9),128.3(C-1′),115.6(C-2′),143.4(C-3′),136.3(C-4′),141.4(C-5′),114.2(C-6′),36(C-7′),136.9(C-8′),115.2(C-9′),133.3(C-1″),129.8(C-2″),116.4(C-3″),156.6(C-4″),116.4(C-5″),129.8(C-6″),39(C-7″),138.3(C-8″),116(C-9″),133.4(C-1″′),132.4(C-2″′),128.4(C-3″′),153.3(C-4″′),118.3(C-5″′),129.5(C-6″′),39.1(C-7″′),138.3(C-8″′),115.6(C-9″′),130.2(C-1″″),131.8(C-2″″),125.5(C-3″″),153(C-4″″),116.1(C-5″″),128.6(C-6″″),39.2(C-7″″),138.3(C-8″″),115.6(C-9″″),133.3(C-1″″′),129.7(C-2″″′),116.5(C-3″″′),156.6(C-4″″′),116.5(C-5″″′),129.7(C-6″″′),39.2(C-7″″′),138.4(C-8″″′),116.0(C-9″″′).
化合物2的理化、波谱数据如下：
无色油状，
Figure BDA0002196335390000061
(-)-HRESI-MS m/z 825.3432[M-H]-,(calcd.for C54H49O8,825.3433)。1H NMR data(DMSO-d6,600MHz),δH:6.17(1H,s,H-2),6.52,(1H,s,H-6),4.94(1H,brs,H-7),4.45(1H,m,H-8),2.56(1H,dd,J＝4.8,16.8Hz,H-9a),2.45(1H,brt,J＝4.2Hz,H-9b),8.57,(1H,s,OH-4′),6.29(1H,s,H-6′),3.01(1H,brs,H-7′),5.80(1H,m,H-8′),4.99(2H,m,H-9′),7.02(1H,d,8.4,H-2″,6″),6.70(1H,d,J＝8.4Hz,H-3″,5″),3.27(1H,brs,H-7″),5.99,(1H,m,H-8″),4.99(1H,m,H-9″),7.00(1H,brs,H-2″′),6.82(1H,d,J＝7.2Hz,H-5″′),6.99(1H,brd,J＝8.4Hz,H-6″′),3.26(1H,brs,H-7″′),5.99(1H,m,H-8″′),4.99(2H,m,H-9″′),6.76(1H,brs,H-2″″),6.76(1H,d,J＝9.0,H-5″″),6.80(1H,brd,J＝7.8Hz,H-6″″),3.29(2H,brs,H-7″″),5.99(1H,m,H-8″″),4.99(2H,m,H-9″″),7.02(2H,d,J＝7.8,H-2″″′,6″″′),6.65(2H,d,J＝7.8,H-3″″′,5″″′),3.27(2H,brs,H-7″″′),5.99(1H,m,H-8″″′),4.99(2H,m,H-9″″′).
1H NMR data(DMSO-d6,150MHz),δC:129.5(C-1),110.6(C-2),143.4(C-3),137.6(C-4),147.4(C-5),110.2(C-6),77.5(C-7),74.6(C-8),25(C-9),128.3(C-1′),115.6(C-2′),143.4(C-3′),136.3(C-4′),141.4(C-5′),114.2(C-6′),36(C-7′),136.9(C-8′),115.2(C-9′),133.3(C-1″),129.8(C-2″),116.4(C-3″),156.6(C-4″),116.4(C-5″),129.8(C-6″),39(C-7″),138.3(C-8″),116(C-9″),133.4(C-1″′),132.4(C-2″′),128.4(C-3″′),153.3(C-4″′),118.3(C-5″′),129.5(C-6″′),39.1(C-7″′),138.3(C-8″′),115.6(C-9″′),130.2(C-1″″),131.8(C-2″″),125.5(C-3″″),153(C-4″″),116.1(C-5″″),128.6(C-6″″),39.2(C-7″″),138.3(C-8″″),115.6(C-9″″),133.3(C-1″″′),129.7(C-2″″′),116.5(C-3″″′),156.6(C-4″″′),116.5(C-5″″′),129.7(C-6″″′),39.2(C-7″″′),138.4(C-8″″′),116.0(C-9″″′).
化合物3的理化、波谱数据如下：
无色油状；
Figure BDA0002196335390000071
(+)-HRESI-MS m/z 811.3618[M+H]+,(calcd.for C54H51O7,811.3629)。1H NMR data(DMSO-d6,600MHz),δH:6.49(1H,brs,H-2),6.64,(1H,brs,H-6),4.67,(1H,d,J＝9.6Hz,H-7),3.98(1H,brt,J＝9.0Hz,H-8a),3.95(1H,brt,J＝10.2Hz,H-8b),3.66(1H,d,J＝10.2Hz H-9),7.09(1H,brs,H-2),6.31(1H,d,J＝6.4Hz,H-5),6.88(1H,brd,J＝7.8Hz,H-6′),3.35(1H,d,J＝4.8Hz,H-7′),5.88(1H,m,H-8′),5.12(2H,m,H-9′),7.03(1H,brs,H-2″),6.94(1H,brd,J＝8.4Hz,H-5″),7.13(1H,brd,J＝8.4Hz,H-5″),3.35(1H,brd,J＝4.8Hz,H-7″),5.81,(1H,m,H-8″),5.04(1H,m,H-9″),6.82(1H,brs,H-2″′),6.63(1H,d,J＝9.0Hz,H-5″′),7.00(1H,brd,J＝8.4Hz,H-6″′),3.28(1H,brd,J＝7.8Hz,H-7″′),5.99(1H,m,H-8″′),5.02(2H,m,H-9″′),6.95(1H,brs,H-2″″),6.82(1H,d,J＝7.2,H-5″″),7.02(1H,brd,J＝8.4Hz,H-6″″),3.20(2H,d,J＝7.2Hz,H-7″″),5.99(1H,m,H-8″″),4.99(2H,m,H-9″″),7.09(2H,d,J＝7.8,H-2″″′,6″″′),6.77(2H,d,J＝7.8,H-3″″′,5″″′),3.19(2H,d,J＝7.2Hz,H-7″″′),6.01(1H,m,H-8″″′),4.99(2H,d,J＝8.0Hz,H-9″″′),13C NMR data(DMSO-d6,150MHz),δC:129.1(C-1),111.6(C-2),143.6(C-3),138.4(C-4),147.7(C-5),110.6(C-6),85.7(C-7),87.9(C-8),67.6(C-9),136.1(C-1′),129.1(C-2′),131.8(C-3′),156.4(C-4′),122.8(C-5′),129.7(C-6′),39.1(C-7′),138.2(C-8′),116.3(C-9′),136.2(C-1″),129.5(C-2″),131.8(C-3″),156.5(C-4″),122.8(C-5″),129.6(C-6″),39.1(C-7″),138.2(C-8″),116.3(C-9″),129.2(C-1″′),131.6(C-2″′),128.3(C-3″′),154.6(C-4″′),111.4(C-5″′),128.2(C-6″′),39.4(C-7″′),138.3(C-8″′),115.7(C-9″′),133.6(C-1″″),129.8(C-2″″),116.9(C-3″″),156.7(C-4″″),116.9(C-5″″),129.8(C-6″″),39.2(C-7″″),138.3(C-8″″),115.8(C-9″″),131.8(C-1″″′),131.5(C-2″″′),125.6(C-3″″′),153.4(C-4″″′),116.0(C-5″″′),128.2(C-6″″′),39.3(C-7″″′),138.5(C-8″″′),116.0(C-9″″′).
化合物4的理化、波谱数据如下：
无色油状；
Figure BDA0002196335390000072
(+)-HRESI-MS m/z 811.3618[M+H]+,(calcd.for C54H51O7,811.3629)。1H NMR data(DMSO-d6,600MHz),δH:6.49(1H,brs,H-2),6.64,(1H,brs,H-6),4.67,(1H,d,J＝9.6Hz,H-7),3.98(1H,brt,J＝9.0Hz,H-8a),3.95(1H,brt,J＝10.2Hz,H-8b),3.66(1H,d,J＝10.2Hz H-9),7.09(1H,brs,H-2),6.31(1H,d,J＝6.4Hz,H-5),6.88(1H,brd,J＝7.8Hz,H-6′),3.35(1H,d,J＝4.8Hz,H-7′),5.88(1H,m,H-8′),5.12(2H,m,H-9′),7.03(1H,brs,H-2″),6.94(1H,brd,J＝8.4Hz,H-5″),7.13(1H,brd,J＝8.4Hz,H-5″),3.35(1H,brd,J＝4.8Hz,H-7″),5.81,(1H,m,H-8″),5.04(1H,m,H-9″),6.82(1H,brs,H-2″′),6.63(1H,d,J＝9.0Hz,H-5″′),7.00(1H,brd,J＝8.4Hz,H-6″′),3.28(1H,brd,J＝7.8Hz,H-7″′),5.99(1H,m,H-8″′),5.02(2H,m,H-9″′),6.95(1H,brs,H-2″″),6.82(1H,d,J＝7.2,H-5″″),7.02(1H,brd,J＝8.4Hz,H-6″″),3.20(2H,d,J＝7.2Hz,H-7″″),5.99(1H,m,H-8″″),4.99(2H,m,H-9″″),7.09(2H,d,J＝7.8,H-2″″′,6″″′),6.77(2H,d,J＝7.8,H-3″″′,5″″′),3.19(2H,d,J＝7.2Hz,H-7″″′),6.01(1H,m,H-8″″′),4.99(2H,d,J＝8.0Hz,H-9″″′),13C NMR data(DMSO-d6,150MHz),δC:129.1(C-1),111.6(C-2),143.6(C-3),138.4(C-4),147.7(C-5),110.6(C-6),85.7(C-7),87.9(C-8),67.6(C-9),136.1(C-1′),129.1(C-2′),131.8(C-3′),156.4(C-4′),122.8(C-5′),129.7(C-6′),39.1(C-7′),138.2(C-8′),116.3(C-9′),136.2(C-1″),129.5(C-2″),131.8(C-3″),156.5(C-4″),122.8(C-5″),129.6(C-6″),39.1(C-7″),138.2(C-8″),116.3(C-9″),129.2(C-1″′),131.6(C-2″′),128.3(C-3″′),154.6(C-4″′),111.4(C-5″′),128.2(C-6″′),39.4(C-7″′),138.3(C-8″′),115.7(C-9″′),133.6(C-1″″),129.8(C-2″″),116.9(C-3″″),156.7(C-4″″),116.9(C-5″″),129.8(C-6″″),39.2(C-7″″),138.3(C-8″″),115.8(C-9″″),131.8(C-1″″′),131.5(C-2″″′),125.6(C-3″″′),153.4(C-4″″′),116.0(C-5″″′),128.2(C-6″″′),39.3(C-7″″′),138.5(C-8″″′),116.0(C-9″″′).
化合物5的理化、波谱数据如下：
无色油状；
Figure BDA0002196335390000081
(-)-HRESI-MS m/z 1089.4588[M-H]-,(calcd.for C72H65O10,1089.4583)。1H NMR data(DMSO-d6,600MHz),δH:6.29(1H,brs,H-2),6.59,(1H,brs,H-6),4.76,(1H,d,J＝7.8Hz,H-7),4.28(1H,brt,J＝2.4,6.6Hz,H-8),4.53(1H,brd,J＝4.2Hz,H-9a),4.00(1H,brt,J＝3.6Hz H-9b),6.75(1H,brs,H-2′),6.46(1H，brs,H-6′),6.34(1H,d,J＝15.6Hz,H-7′),6.13(1H,m,H-8′),4.53(2H,m,H-9′),6.94(1H,brs,H-2″),6.77(1H,d,J＝8.4Hz,H-5″),6.95(1H,brd,J＝6.0Hz,H-6″),3.28(1H,brs,H-7″),5.99,(1H,m,H-8″),4.98(2H,m,H-9″),6.68(1H,brs,H-2″′),6.72(1H,d,J＝8.4Hz,H-5″′),6.76(1H,brd,J＝8.4Hz,H-6″′),3.17(1H,brd,J＝6.6Hz,H-7″′),5.99(1H,m,H-8″′),5.02(2H,m,H-9″′),6.95(1H,brs,H-2″″,H-6″″),6.67(1H,d,J＝8.4,H-3″″,5″″),3.23(2H,d,J＝6.6Hz,H-7″″),5.99(1H,m,H-8″″),4.99(2H,m,H-9″″),6.84(1H,brs,H-2″″′),6.94(1H,brs,,H-5″″′),7.03(1H,brd,J＝8.4Hz,H-6″″′),3.28(1H,brs,H-7″″′),5.99,(1H,m,H-8″″′),4.99(2H,m,H-9″″′),6.95(1H,brs,H-2″″″),6.73(1H,d,J＝9.6Hz,H-5″″″),6.83(1H,brd,J＝9.6Hz,H-6″″″),3.02(1H,brd,J＝3.0Hz,H-7″″″),5.99,(1H,m,H-8″″″),4.99(2H,m,H-9″″″),7.06(2H,brs,H-2″″″′,6″″″′),6.80(2H,d,J＝8.4,H-3″″″′,5″″″′),3.28(2H,d,J＝7.2Hz,H-7″″″′),5.99(1H,m,H-8″″″′),4.99(2H,m,H-9″″″′),13C NMR data(DMSO-d6,150MHz),δC:126.9(C-1),111.9(C-2),143.7(C-3),138.4(C-4),147.6(C-5),110.0(C-6),75.2(C-7),76.2(C-8),67.2(C-9),129.7(C-1′),111.3(C-2′),144.1(C-3′),135.6(C-4′),145.0(C-5′),112.7(C-6′),130.5(C-7′),124.8(C-8′),68.5(C-9′),131.2(C-1″),131.8(C-2″),128.1(C-3″),154.2(C-4″),115.7(C-5″),129.8(C-6″),39.1(C-7″),138.3(C-8″),115.6(C-9″),131.8(C-1″′),129.7(C-2″′),131.7(C-3″′),153.1(C-4″′),115.9(C-5″′),128.5(C-6″′),39.1(C-7″′),138.3(C-8″′),115.6(C-9″′),131.7(C-1″″),131.8(C-2″″),128.1(C-3″″),154.7(C-4″″),113.4(C-5″″),131.8(C-6″″),39.1(C-7″″),138.2(C-8″″),115.5(C-9″″),131.7(C-1″″′),131.7(C-2″″′),125.8(C-3″″′),153.4(C-4″″′),115.9(C-5″″′),128.4(C-6″″′),39.1(C-7″″′),138.6(C-8″″′),115.6(C-9″″′),133.7(C-1″″″),130(C-2″″″),116.7(C-3″″″),156.8(C-4″″″),116.7(C-5″″″),130(C-6″″″),39.2(C-7″″″),138.1(C-8″″″),116(C-9″″″),134.6(C-1″″″′),130.1(C-2″″″′),117.8(C-3″″″′),155.7(C-4″″″′),117.8(C-5″″″′),130.1(C-6″″″′),39.1(C-7″″″′),139.4(C-8″″″′),115.8(C-9″″″′).
化合物6的理化、波谱数据如下：
无色油状；
Figure BDA0002196335390000091
(-)-HRESI-MS m/z 1089.4588[M-H]-,(calcd.for C72H65O10,1089.4583)。1H NMR data(DMSO-d6,600MHz),δH:6.29(1H,brs,H-2),6.59,(1H,brs,H-6),4.76,(1H,d,J＝7.8Hz,H-7),4.28(1H,brt,J＝2.4,6.6Hz,H-8),4.53(1H,brd,J＝4.2Hz,H-9a),4.00(1H,brt,J＝3.6Hz H-9b),6.75(1H,brs,H-2′),6.46(1H，brs,H-6′),6.34(1H,d,J＝15.6Hz,H-7′),6.13(1H,m,H-8′),4.53(2H,m,H-9′),6.94(1H,brs,H-2″),6.77(1H,d,J＝8.4Hz,H-5″),6.95(1H,brd,J＝6.0Hz,H-6″),3.28(1H,brs,H-7″),5.99,(1H,m,H-8″),4.98(2H,m,H-9″),6.68(1H,brs,H-2″′),6.72(1H,d,J＝8.4Hz,H-5″′),6.76(1H,brd,J＝8.4Hz,H-6″′),3.17(1H,brd,J＝6.6Hz,H-7″′),5.99(1H,m,H-8″′),5.02(2H,m,H-9″′),6.95(1H,brs,H-2″″,H-6″″),6.67(1H,d,J＝8.4,H-3″″,5″″),3.23(2H,d,J＝6.6Hz,H-7″″),5.99(1H,m,H-8″″),4.99(2H,m,H-9″″),6.84(1H,brs,H-2″″′),6.94(1H,brs,,H-5″″′),7.03(1H,brd,J＝8.4Hz,H-6″″′),3.28(1H,brs,H-7″″′),5.99,(1H,m,H-8″″′),4.99(2H,m,H-9″″′),6.95(1H,brs,H-2″″″),6.73(1H,d,J＝9.6Hz,H-5″″″),6.83(1H,brd,J＝9.6Hz,H-6″″″),3.02(1H,brd,J＝3.0Hz,H-7″″″),5.99,(1H,m,H-8″″″),4.99(2H,m,H-9″″″),7.06(2H,brs,H-2″″″′,6″″″′),6.80(2H,d,J＝8.4,H-3″″″′,5″″″′),3.28(2H,d,J＝7.2Hz,H-7″″″′),5.99(1H,m,H-8″″″′),4.99(2H,m,H-9″″″′),13C NMR data(DMSO-d6,150MHz),δC:126.9(C-1),111.9(C-2),143.7(C-3),138.4(C-4),147.6(C-5),110.0(C-6),75.2(C-7),76.2(C-8),67.2(C-9),129.7(C-1′),111.3(C-2′),144.1(C-3′),135.6(C-4′),145.0(C-5′),112.7(C-6′),130.5(C-7′),124.8(C-8′),68.5(C-9′),131.2(C-1″),131.8(C-2″),128.1(C-3″),154.2(C-4″),115.7(C-5″),129.8(C-6″),39.1(C-7″),138.3(C-8″),115.6(C-9″),131.8(C-1″′),129.7(C-2″′),131.7(C-3″′),153.1(C-4″′),115.9(C-5″′),128.5(C-6″′),39.1(C-7″′),138.3(C-8″′),115.6(C-9″′),131.7(C-1″″),131.8(C-2″″),128.1(C-3″″),154.7(C-4″″),113.4(C-5″″),131.8(C-6″″),39.1(C-7″″),138.2(C-8″″),115.5(C-9″″),131.7(C-1″″′),131.7(C-2″″′),125.8(C-3″″′),153.4(C-4″″′),115.9(C-5″″′),128.4(C-6″″′),39.1(C-7″″′),138.6(C-8″″′),115.6(C-9″″′),133.7(C-1″″″),130(C-2″″″),116.7(C-3″″″),156.8(C-4″″″),116.7(C-5″″″),130(C-6″″″),39.2(C-7″″″),138.1(C-8″″″),116(C-9″″″),134.6(C-1″″″′),130.1(C-2″″″′),117.8(C-3″″″′),155.7(C-4″″″′),117.8(C-5″″″′),130.1(C-6″″″′),39.1(C-7″″″′),139.4(C-8″″″′),115.8(C-9″″″′).
化合物7的理化、波谱数据如下：
无色油状,
Figure BDA0002196335390000101
1H NMR data(DMSO-d6,600MHz)and 13C NMRdata(DMSO-d6,150MHz)；(+)-HRESI-MS m/z 881.3640[M+Na]+,(calcd.for C55H54O9Na,881.3660)。1H NMR data(DMSO-d6,600MHz),δH:6.05(1H,d，J＝1.8Hz,H-2),6.47,(1H,d,J＝1.8Hz,H-6),4.30,(2H,d,J＝4.8Hz,H-7),3.30(1H,m,H-8),3.99(1H,m,H-9a),4.02(1H,m,H-9b),2.96(3H,s,H-10),6.21(1H,s,H-2′),8.06(1H,s,OH-5′),2.51(1H,m,H-7′a),2.57(1H,m,H-7′b),5.76(1H,m,H-8′),5.00(2H,m,H-9′),6.85(1H,brs,H-2″),6.37(1H,d,J＝9.0Hz,H-5″),6.87(1H,brd,J＝2.4Hz,H-6″),3.22(1H,d,J＝4.8Hz,H-7″),5.87,(1H,m,H-8″),5.02(2H,m,H-9″),6.57(1H,d,J＝1.8Hz,H-2″′),6.72(1H,d,J＝8.4Hz,H-5″′),6.82(1H,dd,J＝1.8,8.4Hz,H-6″′),3.10(1H,d,J＝4.8Hz,H-7″′),5.81(1H,m,H-8″′),4.94(2H,m,H-9″′),6.86(1H,d,J＝7.8Hz,H-2″″,H-6″″),6.60(1H,d,J＝7.8,H-3″″,5″″),3.22(2H,d,J＝6.0Hz,H-7″″),5.85(1H,m,H-8″″),5.01(2H,m,H-9″″),7.04(1H,d,J＝8.4Hz,H-2″″′,H-6″″),6.52(1H,d,J＝8.4,H-3″″′,5″″′),3.27(2H,d,J＝6.0Hz,H-7″″′),5.91(1H,m,H-8″″′),5.03(2H,m,H-9″″′).13C NMR data(DMSO-d6,150MHz),δC:131.1(C-1),111.2(C-2),143.1(C-3),136.5(C-4),147(C-5),110.4(C-6),83.3(C-7),46.2(C-8),69.9(C-9),56.4(C-10),130.1(C-1′),112.6(C-2′),144.9(C-3′),136.7(C-4′),141.2(C-5′),121.7(C-6′),36.7(C-7′),138.0(C-8′),115.7(C-9′),129.4(C-1″),131.7(C-2″),127.9(C-3″),154.5(C-4″),112.3(C-5″),131.9(C-6″),39.2(C-7″),138.5(C-8″),115.7(C-9″),129.7(C-1″′),131.7(C-2″′),125.6(C-3″′),152.8(C-4″′),115.9(C-5″′),128.6(C-6″′),39.2(C-7″′),138.7(C-8″′),115.6(C-9″′),132.3(C-1″″),129.4(C-2″″),115.5(C-3″″),156.2(C-4″″),115.5(C-5″″),129.4(C-6″″),39.1(C-7″″),138.5(C-8″″),115.8(C-9″″),133.5(C-1″″′),129.8(C-2″″′),116.8(C-3″″′),156.3(C-4″″′),116.8(C-5″″′),129.8(C-6″″′),39.1(C-7″″′),138.4(C-8″″′),115.9(C-9″″′).
化合物8的理化、波谱数据如下：
无色油状,
Figure BDA0002196335390000102
1H NMR data(DMSO-d6,600MHz)and13C NMRdata(DMSO-d6,150MHz)；(+)-HRESI-MS m/z 881.3640[M+Na]+,(calcd.for C55H54O9Na,881.3660)。1H NMR data(DMSO-d6,600MHz),δH:6.05(1H,d，J＝1.8Hz,H-2),6.47,(1H,d,J＝1.8Hz,H-6),4.30,(2H,d,J＝4.8Hz,H-7),3.30(1H,m,H-8),3.99(1H,m,H-9a),4.02(1H,m,H-9b),2.96(3H,s,H-10),6.21(1H,s,H-2′),8.06(1H,s,OH-5′),2.51(1H,m,H-7′a),2.57(1H,m,H-7′b),5.76(1H,m,H-8′),5.00(2H,m,H-9′),6.85(1H,brs,H-2″),6.37(1H,d,J＝9.0Hz,H-5″),6.87(1H,brd,J＝2.4Hz,H-6″),3.22(1H,d,J＝4.8Hz,H-7″),5.87,(1H,m,H-8″),5.02(2H,m,H-9″),6.57(1H,d,J＝1.8Hz,H-2″′),6.72(1H,d,J＝8.4Hz,H-5″′),6.82(1H,dd,J＝1.8,8.4Hz,H-6″′),3.10(1H,d,J＝4.8Hz,H-7″′),5.81(1H,m,H-8″′),4.94(2H,m,H-9″′),6.86(1H,d,J＝7.8Hz,H-2″″,H-6″″),6.60(1H,d,J＝7.8,H-3″″,5″″),3.22(2H,d,J＝6.0Hz,H-7″″),5.85(1H,m,H-8″″),5.01(2H,m,H-9″″),7.04(1H,d,J＝8.4Hz,H-2″″′,H-6″″),6.52(1H,d,J＝8.4,H-3″″′,5″″′),3.27(2H,d,J＝6.0Hz,H-7″″′),5.91(1H,m,H-8″″′),5.03(2H,m,H-9″″′).13C NMR data(DMSO-d6,150MHz),δC:131.1(C-1),111.2(C-2),143.1(C-3),136.5(C-4),147(C-5),110.4(C-6),83.3(C-7),46.2(C-8),69.9(C-9),56.4(C-10),130.1(C-1′),112.6(C-2′),144.9(C-3′),136.7(C-4′),141.2(C-5′),121.7(C-6′),36.7(C-7′),138.0(C-8′),115.7(C-9′),129.4(C-1″),131.7(C-2″),127.9(C-3″),154.5(C-4″),112.3(C-5″),131.9(C-6″),39.2(C-7″),138.5(C-8″),115.7(C-9″),129.7(C-1″′),131.7(C-2″′),125.6(C-3″′),152.8(C-4″′),115.9(C-5″′),128.6(C-6″′),39.2(C-7″′),138.7(C-8″′),115.6(C-9″′),132.3(C-1″″),129.4(C-2″″),115.5(C-3″″),156.2(C-4″″),115.5(C-5″″),129.4(C-6″″),39.1(C-7″″),138.5(C-8″″),115.8(C-9″″),133.5(C-1″″′),129.8(C-2″″′),116.8(C-3″″′),156.3(C-4″″′),116.8(C-5″″′),129.8(C-6″″′),39.1(C-7″″′),138.4(C-8″″′),115.9(C-9″″′).
化合物9的理化、波谱数据如下：
无色油状,
Figure BDA0002196335390000111
(+)-HRESI-MS m/z 895.3802[M+Na]+,(calcd.for C56H56O9Na,895.3816)。1H NMR data(DMSO-d6,600MHz),δH:6.05(1H,d，J＝1.8Hz,H-2),6.48,(1H,d,J＝1.8Hz,H-6),4.42,(2H,d,J＝10.2Hz,H-7),3.34(1H，m，H-8),4.00(1H，dd,J＝9.0,18.6Hz，H-9a),4.27(1H,dd,J＝4.8,9.6Hz,H-9b),3.10(2H,m,H-10),0.94(3H,t,J＝7.2Hz,H-11),6.22(1H,s,H-2′),2.54(1H,m,H-7′),5.21(1H,m,H-8′),4.64(2H,m,H-9′),6.88(1H,brs,H-2″),6.41(1H,d,J＝8.4Hz,H-5″),6.88(1H,brd,J＝1.8,8.4Hz,H-6″),3.23(1H,d,J＝6.6Hz,H-7″),5.91,(1H,m,H-8″),5.03(2H,m,H-9″),6.58(1H,d,J＝2.4Hz,H-2″′),6.71(1H,d,J＝8.4Hz,H-5″′),6.83(1H,brd,J＝8.4Hz,H-6″′),3.11(1H,d,J＝5.4Hz,H-7″′),5.83(1H,m,H-8″′),4.94(2H,m,H-9″′),6.87(1H,d,brs,H-2″″),6.71(1H,d,J＝8.4Hz,H-5″′),6.83(1H,brd,J＝8.4Hz,H-6″′),3.11(1H,d,J＝5.4Hz,H-7″′),5.83(1H,m,H-8″′),4.94(2H,m,H-9″′),7.04(1H,d,J＝8.4Hz,H-2″″′,H-6″″′),6.52(1H,d,J＝8.4,H-3″″′,5″″′),3.27(2H,d,J＝6.6Hz,H-7″″′),5.90(1H,m,H-8″″′),5.00(2H,m,H-9″″′).13C NMR data(DMSO-d6,150MHz),δC:131.9(C-1),111.1(C-2),143.2(C-3),136.5(C-4),146.8(C-5),111.0(C-6),80.8(C-7),46.3(C-8),70.0(C-9),63.5(C-10),15.4(C-11),130.2(C-1′),112.7(C-2′),144.9(C-3′),136.7(C-4′),141.2(C-5′),121.8(C-6′),36.7(C-7′),138.0(C-8′),115.6(C-9′),129.4(C-1″),131.0(C-2″),128.1(C-3″),154.6(C-4″),112.5(C-5″),129.4(C-6″),39.2(C-7″),138.5(C-8″),115.4(C-9″),129.7(C-1″′),131.6(C-2″′),125.7(C-3″′),152.9(C-4″′),116.0(C-5″′),128.1(C-6″′),39.2(C-7″′),138.4(C-8″′),115.9(C-9″′),132.4(C-1″″),129.8(C-2″″),115.5(C-3″″),156.4(C-4″″),115.5(C-5″″),129.4(C-6″″),39.1(C-7″″),138.4(C-8″″),115.5(C-9″″),133.5(C-1″″′),129.8(C-2″″′),116.8(C-3″″′),156.3(C-4″″′),116.8(C-5″″′),129.8(C-6″″′),39.1(C-7″″′),138.4(C-8″″′),115.9(C-9″″′).
化合物10的理化、波谱数据如下：
无色油状,
Figure BDA0002196335390000121
(+)-HRESI-MS m/z 895.3802[M+Na]+,(calcd.for C56H56O9Na,895.3816)。1H NMR data(DMSO-d6,600MHz),δH:6.05(1H,d，J＝1.8Hz,H-2),6.48,(1H,d,J＝1.8Hz,H-6),4.42,(2H,d,J＝10.2Hz,H-7),3.34(1H，m，H-8),4.00(1H，dd,J＝9.0,18.6Hz，H-9a),4.27(1H,dd,J＝4.8,9.6Hz,H-9b),3.10(2H,m,H-10),0.94(3H,t,J＝7.2Hz,H-11),6.22(1H,s,H-2′),2.54(1H,m,H-7′),5.21(1H,m,H-8′),4.64(2H,m,H-9′),6.88(1H,brs,H-2″),6.41(1H,d,J＝8.4Hz,H-5″),6.88(1H,brd,J＝1.8,8.4Hz,H-6″),3.23(1H,d,J＝6.6Hz,H-7″),5.91,(1H,m,H-8″),5.03(2H,m,H-9″),6.58(1H,d,J＝2.4Hz,H-2″′),6.71(1H,d,J＝8.4Hz,H-5″′),6.83(1H,brd,J＝8.4Hz,H-6″′),3.11(1H,d,J＝5.4Hz,H-7″′),5.83(1H,m,H-8″′),4.94(2H,m,H-9″′),6.87(1H,d,brs,H-2″″),6.71(1H,d,J＝8.4Hz,H-5″′),6.83(1H,brd,J＝8.4Hz,H-6″′),3.11(1H,d,J＝5.4Hz,H-7″′),5.83(1H,m,H-8″′),4.94(2H,m,H-9″′),7.04(1H,d,J＝8.4Hz,H-2″″′,H-6″″′),6.52(1H,d,J＝8.4,H-3″″′,5″″′),3.27(2H,d,J＝6.6Hz,H-7″″′),5.90(1H,m,H-8″″′),5.00(2H,m,H-9″″′).13C NMR data(DMSO-d6,150MHz),δC:131.9(C-1),111.1(C-2),143.2(C-3),136.5(C-4),146.8(C-5),111.0(C-6),80.8(C-7),46.3(C-8),70.0(C-9),63.5(C-10),15.4(C-11),130.2(C-1′),112.7(C-2′),144.9(C-3′),136.7(C-4′),141.2(C-5′),121.8(C-6′),36.7(C-7′),138.0(C-8′),115.6(C-9′),129.4(C-1″),131.0(C-2″),128.1(C-3″),154.6(C-4″),112.5(C-5″),129.4(C-6″),39.2(C-7″),138.5(C-8″),115.4(C-9″),129.7(C-1″′),131.6(C-2″′),125.7(C-3″′),152.9(C-4″′),116.0(C-5″′),128.1(C-6″′),39.2(C-7″′),138.4(C-8″′),115.9(C-9″′),132.4(C-1″″),129.8(C-2″″),115.5(C-3″″),156.4(C-4″″),115.5(C-5″″),129.4(C-6″″),39.1(C-7″″),138.4(C-8″″),115.5(C-9″″),133.5(C-1″″′),129.8(C-2″″′),116.8(C-3″″′),156.3(C-4″″′),116.8(C-5″″′),129.8(C-6″″′),39.1(C-7″″′),138.4(C-8″″′),115.9(C-9″″′).
化合物11的理化、波谱数据如下：
无色油状,
Figure BDA0002196335390000122
(+)-HRESI-MS m/z 613.2548[M+Na]+,(calcd.for C38H38O6Na,613.2560)。1H NMR data(DMSO-d6,600MHz),δH:6.42(1H,d，J＝1.8Hz,H-2),6.65,(1H,d,J＝1.8Hz,H-6),4.34,(1H,d,J＝4.8Hz,H-7),4.85(1H,m,H-8),2.68(1H,dd,J＝9.0,15.6Hz,H-9a),2.77(1H,dd,J＝9.0,15.6Hz,H-9b),3.34(2H,m,H-10),1.00(3H,t,J＝7.2Hz,H-11),6.86(1H,brs,H-2′),6.87(1H,brs,H-6′),3.24(1H,m,H-7′),5.84(1H,m,H-8′),5.04(2H,m,H-9′),6.98(1H,d,J＝1.8Hz,H-2″),6.76(1H,d,J＝7.8Hz,H-5″),6.88(1H,brd,J＝7.8Hz,H-6″),3.20(1H,d,J＝6.6Hz,H-7″),5.89,(1H,m,H-8″),4.99(2H,brd,J＝10.2Hz,H-9″),7.04(1H,d,J＝8.4Hz,H-2″′,H-6″′),6.69(1H,d,J＝8.4,H-3″′,5″′),3.27(2H,d,J＝6.6Hz,H-7″′),5.92(1H,m,H-8″′),5.03(2H,m,H-9″′).13CNMR data(DMSO-d6,150MHz),δC:129.3(C-1),111.1(C-2),143.6(C-3),137.3(C-4),147.2(C-5),112.1(C-6),81.5(C-7),86.5(C-8),29.8(C-9),64.2(C-10),15.6(C-11),123.7(C-1′),126.1(C-2′),148.8(C-3′),132.4(C-4′),143.6(C-5′),113.4(C-6′),36.8(C-7′),136.8(C-8′),115.8(C-9′),133.5(C-1″),129.8(C-2″),116.5(C-3″),156.1(C-4″),116.5(C-5″),129.8(C-6″),39.1(C-7″),138.3(C-8″),115.9(C-9″),133.5(C-1″′),129.8(C-2″′),116.5(C-3″′),156.1(C-4″′),116.5(C-5″′),129.8(C-6″′),39.1(C-7″′),138.3(C-8″′),115.9(C-9″′).
化合物12的理化、波谱数据如下：
无色油状,
Figure BDA0002196335390000131
(+)-HRESI-MS m/z 613.2548[M+Na]+,(calcd.for C38H38O6Na,613.2560)。1H NMR data(DMSO-d6,600MHz),δH:6.42(1H,d，J＝1.8Hz,H-2),6.65,(1H,d,J＝1.8Hz,H-6),4.34,(1H,d,J＝4.8Hz,H-7),4.85(1H,m,H-8),2.68(1H,dd,J＝9.0,15.6Hz,H-9a),2.77(1H,dd,J＝9.0,15.6Hz,H-9b),3.34(2H,m,H-10),1.00(3H,t,J＝7.2Hz,H-11),6.86(1H,brs,H-2′),6.87(1H,brs,H-6′),3.24(1H,m,H-7′),5.84(1H,m,H-8′),5.04(2H,m,H-9′),6.98(1H,d,J＝1.8Hz,H-2″),6.76(1H,d,J＝7.8Hz,H-5″),6.88(1H,brd,J＝7.8Hz,H-6″),3.20(1H,d,J＝6.6Hz,H-7″),5.89,(1H,m,H-8″),4.99(2H,brd,J＝10.2Hz,H-9″),7.04(1H,d,J＝8.4Hz,H-2″′,H-6″′),6.69(1H,d,J＝8.4,H-3″′,5″′),3.27(2H,d,J＝6.6Hz,H-7″′),5.92(1H,m,H-8″′),5.03(2H,m,H-9″′).13CNMR data(DMSO-d6,150MHz),δC:129.3(C-1),111.1(C-2),143.6(C-3),137.3(C-4),147.2(C-5),112.1(C-6),81.5(C-7),86.5(C-8),29.8(C-9),64.2(C-10),15.6(C-11),123.7(C-1′),126.1(C-2′),148.8(C-3′),132.4(C-4′),143.6(C-5′),113.4(C-6′),36.8(C-7′),136.8(C-8′),115.8(C-9′),133.5(C-1″),129.8(C-2″),116.5(C-3″),156.1(C-4″),116.5(C-5″),129.8(C-6″),39.1(C-7″),138.3(C-8″),115.9(C-9″),133.5(C-1″′),129.8(C-2″′),116.5(C-3″′),156.1(C-4″′),116.5(C-5″′),129.8(C-6″′),39.1(C-7″′),138.3(C-8″′),115.9(C-9″′).
化合物13的理化、波谱数据如下：
无色油状，
Figure BDA0002196335390000132
(+)-HRESI-MS m/z 629.2498[M+Na]+,(calcd.for C38H38O7Na,629.2520)。1H NMR data(DMSO-d6,600MHz),δH:6.45(1H,d，J＝1.8Hz,H-2),6.67,(1H,d,J＝1.8Hz,H-6),4.28,(1H,d,J＝7.2Hz,H-7),4.85(1H,m,H-8),2.68(1H,dd,J＝9.0,15.6Hz,H-9a),2.77(1H,dd,J＝9.0,15.6Hz,H-9b),3.34(2H,m,H-10),1.05(3H,t,J＝7.2Hz,H-11),6.15(1H,brs,H-2′),6.87(1H,brs,H-6′),3.02(1H,m,H-7′),5.73(1H,m,H-8′),4.88(2H,m,H-9′),7.06(1H,d,J＝8.4Hz,H-2″,H-6″),6.72(1H,d,J＝8.4,H-3″,5″),3.27(2H,d,J＝6.6Hz,H-7″),5.89(1H,m,H-8″),4.86(2H,brd,J＝10.2Hz,H-9″),7.08(1H,d,J＝8.4Hz,H-2″′,H-6″′),6.77(1H,d,J＝8.4,H-3″′,5″′),3.26(2H,d,J＝6.6Hz,H-7″′),5.89(1H,m,H-8″′),4.86(2H,brd,J＝10.2Hz,H-9″′).13C NMRdata(DMSO-d6,150MHz),δC:129.3(C-1),111.1(C-2),143.6(C-3),137.3(C-4),147.2(C-5),112.1(C-6),81.5(C-7),86.5(C-8),29.8(C-9),64.2(C-10),15.6(C-11),123.7(C-1′),126.1(C-2′),148.8(C-3′),132.4(C-4′),143.6(C-5′),113.4(C-6′),36.8(C-7′),136.8(C-8′),115.8(C-9′),133.5(C-1″),129.8(C-2″),116.5(C-3″),156.1(C-4″),116.5(C-5″),129.8(C-6″),39.1(C-7″),138.3(C-8″),115.9(C-9″),133.5(C-1″′),129.8(C-2″′),116.5(C-3″′),156.1(C-4″′),116.5(C-5″′),129.8(C-6″′),39.1(C-7″′),138.3(C-8″′),115.9(C-9″′).
化合物14的理化、波谱数据如下：
无色油状,
Figure BDA0002196335390000141
(+)-HRESI-MS m/z 629.2498[M+Na]+,(calcd.for C38H38O7Na,629.2520)。1H NMR data(DMSO-d6,600MHz),δH:6.45(1H,d，J＝1.8Hz,H-2),6.67,(1H,d,J＝1.8Hz,H-6),4.28,(1H,d,J＝7.2Hz,H-7),4.85(1H,m,H-8),2.68(1H,dd,J＝9.0,15.6Hz,H-9a),2.77(1H,dd,J＝9.0,15.6Hz,H-9b),3.34(2H,m,H-10),1.05(3H,t,J＝7.2Hz,H-11),6.15(1H,brs,H-2′),6.87(1H,brs,H-6′),3.02(1H,m,H-7′),5.73(1H,m,H-8′),4.88(2H,m,H-9′),7.06(1H,d,J＝8.4Hz,H-2″,H-6″),6.72(1H,d,J＝8.4,H-3″,5″),3.27(2H,d,J＝6.6Hz,H-7″),5.89(1H,m,H-8″),4.86(2H,brd,J＝10.2Hz,H-9″),7.08(1H,d,J＝8.4Hz,H-2″′,H-6″′),6.77(1H,d,J＝8.4,H-3″′,5″′),3.26(2H,d,J＝6.6Hz,H-7″′),5.89(1H,m,H-8″′),4.86(2H,brd,J＝10.2Hz,H-9″′).13C NMRdata(DMSO-d6,150MHz),δC:129.3(C-1),111.1(C-2),143.6(C-3),137.3(C-4),147.2(C-5),112.1(C-6),81.5(C-7),86.5(C-8),29.8(C-9),64.2(C-10),15.6(C-11),123.7(C-1′),126.1(C-2′),148.8(C-3′),132.4(C-4′),143.6(C-5′),113.4(C-6′),36.8(C-7′),136.8(C-8′),115.8(C-9′),133.5(C-1″),129.8(C-2″),116.5(C-3″),156.1(C-4″),116.5(C-5″),129.8(C-6″),39.1(C-7″),138.3(C-8″),115.9(C-9″),133.5(C-1″′),129.8(C-2″′),116.5(C-3″′),156.1(C-4″′),116.5(C-5″′),129.8(C-6″′),39.1(C-7″′),138.3(C-8″′),115.9(C-9″′).
药理实验
实验例1：利用BL21 E.Coli大肠杆菌制备基因重组的人PTP1B工程菌，并应用GST亲和层析纯化蛋白，得到PTP1B蛋白。以硝基磷酸盐为底物，进行PTP1B的酶学反应，体外观察药物对PTP1B蛋白活性的影响。
结果：测定了上述化合物在终浓度为10μM时对基因重组的人PTP1B的抑制率；结果如表1所示：
表1凹叶厚朴中化合物1-14对PTP1B酶抑制活性(10μM)
Figure BDA0002196335390000151
小结：新寡聚木脂素类化合物1-14对PTP1B具有较强的抑制活性。

Claims (5)

1.如式1-14所示的寡聚木脂素类化合物或其药学上可接受的盐
Figure FDA0002196335380000011
2.一种药物组合物，其特征在于，含有至少一个权利要求1所示的化合物或其药学上可接受的盐以及药效学上可接受的载体。
3.权利要求1的化合物或其药学上可接受的盐在制备PTP1B抑制剂中的应用。
4.权利要求1的化合物或其药学上可接受的盐在制备预防和/或治疗糖尿病药物中的应用。
5.权利要求1的化合物或其药学上可接受的盐在制备预防和/或治疗高血脂药物中的应用。
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