CN113384567B - 一类续随子烷型大环二萜化合物的制备方法和应用 - Google Patents

一类续随子烷型大环二萜化合物的制备方法和应用 Download PDF

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CN113384567B
CN113384567B CN202110647740.4A CN202110647740A CN113384567B CN 113384567 B CN113384567 B CN 113384567B CN 202110647740 A CN202110647740 A CN 202110647740A CN 113384567 B CN113384567 B CN 113384567B
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macrocyclic diterpenoid
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CN113384567A (zh
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毕惠嫦
尹胜
刘培庆
黄冬
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Guangzhou Zhongda Nansha Technology Innovation Industrial Park Co Ltd
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Abstract

本发明公开了一类续随子烷型大环二萜化合物的制备方法和应用。本发明首次将续随子烷型大环二萜类化合物用于制备抗胆汁淤积药物中。通过细胞实验结果显示，本发明中的随子烷型大环二萜化合物有较好的孕烷X受体激动活性、抗胆汁淤积活性，有望开发为新型的孕烷X受体激动剂和抗胆汁淤积药物。

Description

一类续随子烷型大环二萜化合物的制备方法和应用
技术领域
本发明涉及医药领域，具体涉及一类续随子烷型大环二萜化合物的制备方法和应用。
背景技术
胆汁淤积是胆汁分泌及排泄障碍不断进展最终导致系列肝胆疾病的一个重要病理过程。长期胆汁淤积通常会引起系列的肝胆疾病，如原发性胆汁性肝硬化、原发性硬化性胆管炎等，最终发展为肝纤维化甚至肝硬化，严重威胁人类生命健康。据统计，约有60％的上述肝胆疾病患者均伴随着胆汁淤积的病症。目前经FDA批准上市的抗胆汁淤积药物仅有2个，在一定程度上能改善患者症状，但也存在甲状腺功能异常、心律失常等严重不良反应。因此，研发高效低毒的新型抗胆汁淤积药物具有迫切的社会需求。孕烷X受体(PXR)激动剂可调控胆汁酸代谢稳态，是目前治疗胆汁淤积药物研发中的热点。
续随子(学名：Euphorbia lathylris L)，又称千金子，为大戟科、大戟属下的一种二年生草本。续随子的种子、茎、叶及茎中白色乳汁均可入药、有逐水消肿、破症杀虫、导泻、镇静、镇痛、抗炎、抗菌、抗肿瘤等作用。同时具有一定的毒性。
现有技术中公开的专利申请文件及文献中，续随子二萜烷型化合物的应用集中在肿瘤治疗领域。
发明内容
本发明的目的在于提供一类新型的续随子烷型大环二萜化合物的制备方法和应用。
前期研究中发明人从中药续随子中发现了一系列结构新颖的续随子烷型大环二萜(5/11/3碳环系骨架)，该类化合物在细胞水平显示出良好的PXR激动活性，可显著上调PXR下游调控胆汁酸代谢与转运相关的基因水平。
本发明所采取的技术方案是：
本发明的第一个方面，提供：
续随子烷型大环二萜化合物及其衍生物在制备抗胆汁淤积组合物中的应用，所述续随子烷型大环二萜化合物具有5/11/3碳环系骨架，其结构式如下：
Figure GDA0003658387080000021
所述衍生物选自药学上可接受的盐、立体异构体、溶剂化物、配合物、酯化物、酰胺化物。
药学上可接受的盐无特殊要求，一般而言，通过成盐，可以改善化合物的溶解度、吸收情况。在一些实例中，所述药学上可接受的盐选自化合物的酸或碱加成盐。
在一些实例中，所述酸选自由乙酸、2,2-二氯乙酸、已二酸、藻酸、抗坏血酸、L-天冬氨酸、苯磺酸、苯甲酸、4-乙酰氨基苯甲酸、丁酸、(+)樟脑酸、樟脑-磺酸、(+)-(1S)-樟脑-10-磺酸、癸酸、己酸、辛酸、肉桂酸、柠檬酸、环拉酸、十二烷基硫酸、乙烷-1,2-二磺酸、乙烷磺酸、2-羟乙基磺酸、甲酸、富马酸、半乳糖酸、龙胆酸、葡庚糖酸、D-葡萄糖酸、葡萄糖醛酸、谷氨酸、α-酮戊二酸、乙醇酸、马尿酸、氢溴酸、盐酸、氢碘酸、羟乙磺酸、(+)-L-乳酸、(±)-DL-乳酸、乳糖酸、马来酸、苹果酸、(-)-L-苹果酸、丙二酸、(±)-DL-扁桃酸、甲基磺酸、萘-2-磺酸、萘-1,5-二磺酸、1-羟基-2-萘酸、烟酸、硝酸、油酸、乳清酸、草酸、棕榈酸、帕莫酸、磷酸、丙酸、L-焦谷氨酸、水杨酸、4-氨基-水杨酸、癸二酸、硬脂酸、丁二酸、硫酸、单宁酸、(+)-L-酒石酸、硫氰酸、p-甲苯磺酸、十一碳烯酸和戊酸，以及酰化氨基酸组成的组；所述碱为碱金属、碱土金属的氢氧化物。
本发明的第二个方面，提供：
续随子烷型大环二萜化合物及其衍生物在制备非治疗用孕烷X受体激动剂中的应用，所述续随子烷型大环二萜化合物具有5/11/3碳环系骨架，其结构式如下：
Figure GDA0003658387080000031
所述衍生物选自药学上可接受的盐、立体异构体、溶剂化物、配合物、酯化物、酰胺化物。
药学上可接受的盐无特殊要求，一般而言，通过成盐，可以改善化合物的溶解度、吸收情况。在一些实例中，所述药学上可接受的盐选自化合物的酸或碱加成盐。
在一些实例中，所述酸选自由乙酸、2,2-二氯乙酸、已二酸、藻酸、抗坏血酸、L-天冬氨酸、苯磺酸、苯甲酸、4-乙酰氨基苯甲酸、丁酸、(+)樟脑酸、樟脑-磺酸、(+)-(1S)-樟脑-10-磺酸、癸酸、己酸、辛酸、肉桂酸、柠檬酸、环拉酸、十二烷基硫酸、乙烷-1,2-二磺酸、乙烷磺酸、2-羟乙基磺酸、甲酸、富马酸、半乳糖酸、龙胆酸、葡庚糖酸、D-葡萄糖酸、葡萄糖醛酸、谷氨酸、α-酮戊二酸、乙醇酸、马尿酸、氢溴酸、盐酸、氢碘酸、羟乙磺酸、(+)-L-乳酸、(±)-DL-乳酸、乳糖酸、马来酸、苹果酸、(-)-L-苹果酸、丙二酸、(±)-DL-扁桃酸、甲基磺酸、萘-2-磺酸、萘-1,5-二磺酸、1-羟基-2-萘酸、烟酸、硝酸、油酸、乳清酸、草酸、棕榈酸、帕莫酸、磷酸、丙酸、L-焦谷氨酸、水杨酸、4-氨基-水杨酸、癸二酸、硬脂酸、丁二酸、硫酸、单宁酸、(+)-L-酒石酸、硫氰酸、p-甲苯磺酸、十一碳烯酸和戊酸，以及酰化氨基酸组成的组；所述碱为碱金属、碱土金属的氢氧化物。
本发明的第三个方面，提供：
续随子烷型大环二萜化合物及其衍生物，所述续随子烷型大环二萜化合物具有5/11/3碳环系骨架，其结构式如下：
Figure GDA0003658387080000041
所述衍生物选自药学上可接受的盐、立体异构体、溶剂化物、配合物、酯化物、酰胺化物。
药学上可接受的盐无特殊要求，一般而言，通过成盐，可以改善化合物的溶解度、吸收情况。在一些实例中，所述药学上可接受的盐选自化合物的酸或碱加成盐。
在一些实例中，所述酸选自由乙酸、2,2-二氯乙酸、已二酸、藻酸、抗坏血酸、L-天冬氨酸、苯磺酸、苯甲酸、4-乙酰氨基苯甲酸、丁酸、(+)樟脑酸、樟脑-磺酸、(+)-(1S)-樟脑-10-磺酸、癸酸、己酸、辛酸、肉桂酸、柠檬酸、环拉酸、十二烷基硫酸、乙烷-1,2-二磺酸、乙烷磺酸、2-羟乙基磺酸、甲酸、富马酸、半乳糖酸、龙胆酸、葡庚糖酸、D-葡萄糖酸、葡萄糖醛酸、谷氨酸、α-酮戊二酸、乙醇酸、马尿酸、氢溴酸、盐酸、氢碘酸、羟乙磺酸、(+)-L-乳酸、(±)-DL-乳酸、乳糖酸、马来酸、苹果酸、(-)-L-苹果酸、丙二酸、(±)-DL-扁桃酸、甲基磺酸、萘-2-磺酸、萘-1,5-二磺酸、1-羟基-2-萘酸、烟酸、硝酸、油酸、乳清酸、草酸、棕榈酸、帕莫酸、磷酸、丙酸、L-焦谷氨酸、水杨酸、4-氨基-水杨酸、癸二酸、硬脂酸、丁二酸、硫酸、单宁酸、(+)-L-酒石酸、硫氰酸、p-甲苯磺酸、十一碳烯酸和戊酸，以及酰化氨基酸组成的组；所述碱为碱金属、碱土金属的氢氧化物。
本发明的第四个方面，提供：
一种用于治疗胆汁淤积的组合物，所述组合物的活性成分选自本发明第三个方面所述续随子烷型大环二萜化合物及其衍生物中的至少一种。
在一些实例中，所述组合物还包括药学上可接受的载体。
本发明的第五个方面，提供：
本发明第三个方面所述续随子烷型大环二萜化合物及其衍生物的制备方法，包括：
S1)将续随子粉碎，95％乙醇水溶液浸渍、超声处理，过滤，减压浓缩，干燥，得到续随子醇粗提物；
S2)将续随子粗提物分散在水中，随后用乙酸乙酯萃取获得有机相组分；
S3)将有机相组分浓缩，通过正相硅胶柱层析、凝胶柱层析、ODS柱层析或高效液相色谱中的至少一种分离，得到续随子烷型大环二萜化合物1至化合物16；
S4)根据需要使用化合物1至化合物16为原料，进行水解反应、酰化反应和氧化还原反应中的至少一种，得到化合物17至化合物34。
本发明的有益效果是：
本发明的一些实例，首次从传统中药续随子中分离制备得到一批新型的续随子烷型大环二萜化合物。
本发明一些实例的，续随子烷型大环二萜及其衍生物在细胞水平显示出良好的PXR激动活性，可显著上调PXR下游调控胆汁酸代谢与转运相关的基因水平，并能明显改善石胆酸模型小鼠的肝损伤程度。其中活性最强的化合物8对PXR的激动倍数达6倍，远强于阳性药物利福平，具有进一步开发的潜力，有望获得新型抗胆汁淤积先导化合物。
附图说明
图1和图2分别为化合物8的核磁共振氢谱、碳谱和DEPT135谱图。
图3和图4分别为化合物26的核磁共振氢谱、碳谱和DEPT135谱图。
图5和图6分别为化合物30的核磁共振氢谱、碳谱和DEPT135谱图。
图7和图8分别为续随子烷型大环二萜及其衍生物抗胆汁淤积活性评价结果。
具体实施方式
本发明得到了项目名称为“炎症相关性重大疾病创新药物研发及关键技术”(编号2017BT01Y093)的资助。
下面结合实施例对本发明作进一步详细描述，但本发明的实施方式不限于此。
下列实施例中所涉及物料均可从商业渠道获得。
设备及试剂：
熔点在X-4熔点仪进行测量。旋光度由Perkin-Elmer 341旋光仪测得。通过压片法在Bruker Tensor 37红外分光光度计中确定红外光谱。在Bruker AM-400/500光谱仪上测量了25℃下的NMR(核磁共振)谱。HRESIMS(高分辨电喷雾电离质谱)在Finnigan-LCQ Deca仪器上测量。采用岛津LC-20AT液相色谱、SPD-M20A型PDA检测器、YMC-pack-ODS-A柱(250×10mm,S-5μm,12nm)联用，组合成半制备型HPLC分离系统。硅胶(300-400目，青岛海阳化工有限公司)，反相C18(Rp-C18)硅胶(12nm，S-50μm、YMC有限公司)、Sephadex LH-20凝胶(阿默森生物科学公司)和MCI凝胶(CHP20P，75-150μm，三菱化学工业有限公司)进行柱层析(CC)。所有溶剂均为分析纯(广州化学试剂有限公司)。通过岛津LC-20AT系列液相色谱系统和Inertsil ODS-SP柱(4.6mm×150mm,5μm or 4.6mm×100mm,5μm)测定样品的纯度。样品用90:10乙腈/水混合洗脱剂以3mL/min的流速洗脱。所有生物评价化合物的纯度大于95％。
续随子的种子于2018年1月采集自中国安徽。样本(登记号：QJZ201812)已存放在中山大学药学院。
实施例1：化合物1至5的制备
Figure GDA0003658387080000071
用95％乙醇(75L×3)浸泡续随子种子(8kg)，得到817.2g粗浸膏。将浸膏分散于水(3L)中，依次用石油醚、乙酸乙酯和正丁醇分别进行萃取。将乙酸乙酯部分提取物(352.8g)用D101大孔吸附树脂进行梯度洗脱(MeOH/H2O，6:4→10:0)分离，分为三部分(Fr.I-III)。其中Fr.II部分(215.6g)经过正相硅胶柱层析分离(PE/EtOAc,50:1→1:1)分为四部分(Fr.IIA-IID)。Fr.IIC段(2.9g)通过反相C18硅胶柱层析色谱(MeOH/H2O,6:4→10:0)分离为五部分(Fr.IIC1-IIC5)，其中Fr.IIC1部分(132.2mg)通过正相硅胶柱层析(CH2Cl2/MeOH,100:1→0:1)梯度洗脱分离和半制备型手性分离HPLC(MeCN/H2O,75/25,3mL/min)纯化得到化合物3(34mg,tR 13.0min)。Fr.IIC2段(1.435g)通过Sephadex LH-20凝胶柱(MeOH)，再通过正相硅胶柱层析(PE/EtOAc,10:1→0:1)分离得到三段(Fr.IIC2a-IIC2c)。Fr.IIC2b段(367.8mg)通过反相C18硅胶柱层析(MeOH/H2O,7:3→10:0)分离后再通过半制备型手性HPLC(MeCN/H2O,70/30,3mL/min)纯化得到化合物4(31.2mg,tR 15.6min)和5(18.0mg,tR14.6min)。Fr.IIC2b1段通过正相硅胶柱层析色谱(PE/EtOAc,15:1→0:1)分离，再通过Sephadex LH-20凝胶柱(EtOH)纯化得到化合物2(90.8mg)和1(24.6mg)。化合物1-5的1Hand 13C NMR数据总结见下表。
化合物1.无色油状物；[α]25 D+109.1(c 3.0,MeCN)；UV(MeCN)λmax(logε)273(3.97)nm,232(4.18)nm；IRνmax 3460,2928,1722,1659,1453,1370,1272,1113,1004,714cm-1；HRESIMS m/z 517.2193[M+Na]+(计算得C29H34O7Na+,517.2197).
化合物2.无色油状物；[α]25 D-25.0(c 3.0,MeCN)；UV(MeCN)λmax(logε)274(4.15)nm,232(4.17)nm；IRνmax 3446,2926,1717,1606,1452,1268,1108,1057,714cm-1；HRESIMSm/z439.2487[M+Na]+(计算得C27H34O5Na+,439.2479).
化合物3.无色油状物；[α]25 D+55.3(c 3.0,MeCN)；UV(MeCN)λmax(logε)233(4.53)nm；272(4.31),IRνmax 2931,1722,1629,1453,1369,1275,1236,1112,1024,943,712cm-1；HRESIMS m/z 559.2306[M+Na]+(计算得C31H36O8Na+,559.2302).
化合物4.无色油状物；[α]25 D+202.7(c 3.0,MeCN)；UV(MeCN)λmax(logε)275(4.38)nm；IR νmax 2926,1738,1630,1450,1369,1273,1228,1114,906,769cm-1；HRESIMS m/z571.2659[M+Na]+(计算得C33H40O7Na+,571.2666).
化合物5.无色油状物；[α]25 D-46.7(c 3.0,MeCN)；UV(MeCN)λmax(logε)275(4.26)nm；IR νmax 3478,2929,1739,1623,1455,1375,1245,1154,1021cm-1；HRESIMS m/z499.2271[M+Na]+(计算得C26H36O8Na+,499.2302).
Figure GDA0003658387080000081
Figure GDA0003658387080000091
Figure GDA0003658387080000092
Figure GDA0003658387080000101
a 400MHz核磁测定.
b 500MHz核磁测定。
实施例2：化合物8的制备
Figure GDA0003658387080000102
实施例1中的Fr.IIC2段(1.435g)通过Sephadex LH-20凝胶柱(MeOH)，再通过正相硅胶柱层析(PE/EtOAc,10:1→0:1)分离得到三段(Fr.IIC2a-IIC2c)。Fr.IIC2a(207.2mg)通过正相硅胶柱层析(PE/EtOAc,15:1→0:1)分离后再通过半制备型手性分离的HPLC(MeCN/H2O,70/30,3mL/min)得到化合物8(67.3mg,tR 8.9min)。
图1和图2分别为化合物8的核磁共振氢谱、碳谱和DEPT135谱图。其波谱数据与已知化合物Euphorbia Factor L9一致。
实施例3：化合物17的制备
Figure GDA0003658387080000103
将化合物15(30mg,0.047mmol)溶于2mL甲醇中，加入1％的氢氧化钠，常温下反应1小时。用5mL水将反应液淬灭后，用乙酸乙酯(5mL×3)萃取。将有机层浓缩旋干，通过硅胶柱层析CC(PE/EtOAc,10:1)纯化，得到化合物17(15.3mg)。
其波谱数据文献报道一致，因此确定其结构。
实施例4：化合物20的制备
Figure GDA0003658387080000111
将化合物17(20mg,0.057mmol)溶于新蒸馏的吡啶(2mL)中，加入过量的呋喃甲酰氯。反应体系在室温下搅拌2小时。然后用2mL水淬灭。反应混合液真空旋蒸挥干溶剂后，通过半制备高效液相色谱(MeCN/H2O＝75:25,3mL/min)纯化。得到化合物20(11.8mg,tR10.2min)。
结构确证：
无色油状；[α]25 D-53.3(c 0.3,MeCN)；UV(MeCN)λmax(logε)253(3.94)nm；IR(KBr)νmax3419,2925,1718,1672,1614,1471,1393,1298,1178,1115,1073,1010,925,763cm-1；1HNMR(CDCl3,400MHz)δH 5.81(1H,d,J＝9.3Hz,H-12),5.32(1H,s,H-17a),5.18(1H,s,H-17b),5.00(1H,d,J＝8.2Hz,H-7),4.39(1H,brs,H-3),4.23(1H,brs,H-5),2.74(1H,dd,J＝14.7,10.2Hz,H-1a),2.51(1H,brs,H-4),2.30(1H,m,H-2),2.05(3H,s,H-20),2.04(1H,m,H-8a),1.76(1H,dd,J＝14.7,9.8Hz,H-1b),1.39(1H,d,J＝9.3Hz,H-11),1.27(1H,m,H-8b),1.25(1H,m,H-9),1.16(3H,d,J＝6.3Hz,H-16),1.15(3H,s,H-19),1.12(3H,s,H-18),for 7-O-2-furoyl:7.62(1H,m),7.28(1H,m),6.56(1H,m)；13C NMR(CDCl3,100MHz)δC207.9(C-14),148.1(C-6),139.4(C-13),137.0(C-12),108.5(C-17),87.9(C-15),76.3(C-3),75.3(C-7),69.5(C-5),52.3(C-4),45.9(C-1),38.1(C-2),31.0(C-9),30.6(C-8),28.3(C-18),25.5(C-11),23.5(C-10),15.3(C-19),14.0(C-16and20),for 7-O-2-furoyl:158.4,146.7,144.3,118.3,112.0；HRESIMS m/z 467.2048[M+Na]+(calcd for C25H32O7Na+,467.2040).
实施例5：化合物23的制备
Figure GDA0003658387080000112
将化合物15(30.0mg,0.047mmol)溶于甲醇(2mL)中，加入硼氢化钠(3.5mg,0.093mmol)。室温下搅拌15min，然后用过量的冰醋酸淬灭。反应混合液真空旋蒸挥干溶剂后，通过半制备高效液相色谱(MeCN/H2O＝85:15,3mL/min)纯化得到化合物23(13.0mg,tR15.5min)。
结构确证：
无色油状；[α]25 D+60.00(c 0.3,MeCN)；UV(MeCN)λmax(logε)232(4.32)nm；IR(KBr)νmax3489,2925,1718,1452,1373,1276,1241,1110,1026,916,713cm-1；1H NMR(CDCl3,400MHz)δH 5.84(1H,dd,J＝3.2,3.2Hz,H-3),5.80(1H,brs,H-5),5.65(1H,d,J＝10.0Hz,H-12),5.47(1H,s,H-14),5.14(1H,d,J＝8.2Hz,H-7),5.10(1H,s,H-17a),4.92(1H,s,H-17b),2.54(1H,dd,J＝14.3,9.8Hz,H-1a),2.46(1H,d,J＝3.2Hz,H-4),2.41(1H,m,H-2),2.05(1H,m,H-8α),1.98(1H,dd,J＝14.3,9.2Hz,H-1b),1.93(3H,s,H-20),1.62(1H,m,H-8β),1.37(1H,t,J＝10.0Hz,H-11),1.18(1H,m,H-9；3H,s,H-19),1.09(3H,s,H-18),1.05(3H,d,J＝6.7Hz,H-16),for 3-OBz:δH8.10(2H,m),7.47(2H,m),7.59(1H,m)；5-OAc:δH1.46(3H,s)；7-OBz:δH 8.10(2H,m),7.44(2H,m),7.55(1H,m)；14-OAc:δH 2.14(3H,s)；13CNMR(CDCl3,100MHz)δC 146.1(C-6),132.1(C-13),123.8(C-12),107.3(C-17),82.1(C-15),78.8(C-14),76.8(C-3),75.1(C-7),69.8(C-5),49.8(C-4),48.0(C-1),36.1(C-2),30.2(C-8),29.9(C-9),28.6(C-18),24.9(C-11),22.3(C-10),16.6(C-20),15.1(C-19),14.7(C-16),for 3-OBz:165.3,133.1,130.0,129.7×2,128.5×2；5-OAc:δC 170.1,20.5；7-OBz:δC 166.1,132.9,130.8,129.6×2,128.4×2；14-OAc:δC 169.8,20.9；HRESIMS m/z667.2888[M+Na]+(calcd for C38H44O9Na+,667.2878).
实施例6：化合物24和25的制备
Figure GDA0003658387080000121
将化合物15(80.0mg,0.125mmol)溶于二氯甲烷(2mL)中，加入m-CPBA(24.1mg,0.150mmol)，在60℃下反应1小时，随后加入过量的饱和碳酸氢钠溶液并反应10分钟。反应体系用水淬灭并用乙酸乙酯萃取。萃取液真空旋干溶剂后，通过硅胶柱色谱(PE:EtOAc＝15:1)和半制备高效液相色谱(MeCN/H2O＝80:20,3mL/min)纯化得到化合物24(22.4mg,tR11.7min)和化合物25(27.6mg,tR 14.1min)。
结构确证：
化合物24：白色粉末；[α]25 D+76.33(c 0.3,MeCN)；UV(MeCN)λmax(logε)233(4.46)nm；IR(KBr)νmax 2922,1718,1458,1375,1276,1239,1113,714cm-1；1H NMR(CDCl3,400MHz)δH5.98(1H,m,H-3),5.40(1H,s,H-5),5.30(1H,d,J＝8.2Hz,H-7),3.50(1H,brs,H-4),3.12(1H,d,J＝9.8Hz,H-12),3.02(1H,d,J＝4.5Hz,H-17a),2.96(1H,dd,J＝15.4,8.6Hz,H-1α),2.66(1H,m,H-2),2.64(1H,d,J＝4.5Hz,H-17b),2.48(1H,dd,J＝15.4,11.3Hz,H-1β),2.19(1H,m,H-8α),1.85(3H,s,H-20),1.82(1H,m,H-8β),1.30(3H,s,H-19),1.13(3H,s,H-18),1.12(1H,m,H-9),1.10(3H,d,J＝6.6Hz,H-16),0.46(1H,t,J＝9.8Hz,H-11),for 3-OBz:δH 8.04(2H,d,J＝7.5Hz),7.58(1H,t,J＝7.5Hz),7.44(2H,t,J＝7.5Hz)；5-OAc:δH1.33(3H,s)；7-OBz:δH 8.08(2H,d,J＝7.5Hz),7.63(1H,t,J＝7.5Hz),7.49(2H,t,J＝7.5Hz)；15-OAc:δH 2.08(3H,s)；13C NMR(CDCl3,100MHz)δC 201.3(C-14),92.3(C-15),76.2(C-3),72.9(C-7),65.5(C-5),62.7(C-13),62.5(C-12),60.4(C-6),50.4(C-4),46.8(C-17),44.4(C-1),37.9(C-2),28.4(C-18),26.8(C-9),25.3(C-8),22.8(C-11),21.5(C-10),15.0(C-19and 20),13.9(C-16),for 3-OBz:165.5,133.4,130.1,129.5×2,128.4×2；5-OAc:δC 168.7,19.7；7-OBz:δC 166.7,133.8,129.9×2,128.8,128.6×2；15-OAc:δC169.7,21.1；HRESIMS m/z 697.2608[M+Na]+(calcd for C38H42O11Na+,697.2619).
化合物25：白色粉末；[α]25 D+61.33(c 0.3,MeCN)；UV(MeCN)λmax(logε)232(4.30)nm；IR(KBr)νmax 2926,1718,1453,1371,1275,1111,1068,1026,714cm-1；1H NMR(CDCl3,500MHz)δH 5.84(1H,brs,H-3),5.79(1H,brs,H-5),5.44(1H,t,J＝5.2Hz,H-7),5.34(1H,s,H-17a),5.10(1H,s,H-17b),3.25(1H,brs,H-4),3.15(1H,d,J＝9.5Hz,H-12),2.90(1H,dd,J＝15.2,9.0Hz,H-1α),2.49(1H,m,H-2),2.29(1H,dd,J＝15.2,11.9Hz,H-1β),2.22(1H,m,H-8α),2.01(1H,m,H-8β),1.69(3H,s,H-20),1.27(3H,s,H-19),1.14(3H,s,H-18),1.13(1H,m,H-9),1.02(3H,d,J＝6.5Hz,H-16),0.49(1H,d,J＝9.5Hz,H-11),for 3-OBzand 7-OBz:δH 8.09(2H,d,J＝7.3Hz),8.06(2H,d,J＝7.3Hz),7.58(2H,t,J＝7.3Hz),7.45(4H,m)；5-OAc:δH 1.31(3H,s)；15-OAc:δH2.13(3H,s)；13C NMR(CDCl3,125MHz)δC 204.0(C-14),142.8(C-6),113.2(C-17),91.2(C-15),77.0(C-3and C-7),67.8(C-5),63.8(C-13),61.8(C-12),52.4(C-4),46.4(C-1),37.1(C-2),28.6(C-8),28.4(C-18),27.3(C-9),22.6(C-11),20.5(C-10),15.5(C-19),14.9(C-20),14.1(C-16),for 3-OBz and 7-OBz:166.1,165.5,133.4,133.1,130.3×2,129.7×2,129.6×2,128.5×2,128.3×2；5-OAc:δC168.9,20.3；15-OAc:δC 169.8,21.2；HRESIMS m/z 681.2668[M+Na]+(calcd forC38H42O10Na+,681.2670).
实施例7：化合物26的制备
Figure GDA0003658387080000131
将化合物15(80.0mg,0.125mmol)溶于乙酸乙酯(2mL)中，在氢气氛围下，加入10％Pd/C，50℃搅拌反应24小时。随后将反应混合液过滤并旋干，通过硅胶柱色谱(PE:EtOAc＝30:1)和半制备高效液相色谱(MeCN/H2O＝80:20,3mL/min)得到化合物26(18.6mg,tR15.3min)。
结构确证：
无色晶体；mp 146.7-147.9℃；[α]25 D+49.67(c 0.3,MeCN)；UV(MeCN)λmax(logε)232(4.29)nm；IR(KBr)νmax 2924,1720,1455,1370,1275,1231,1111,712cm-1；1H NMR(CDCl3,400MHz)δH 5.64(1H,dd,J＝3.2,3.2Hz,H-3),5.39(1H,d,J＝11.0Hz,H-5),5.14(1H,d,J＝6.1Hz,H-7),3.41(1H,dd,J＝11.0,3.2Hz,H-4),3.25(1H,m,H-13),2.61(1H,dd,J＝14.1,6.8Hz,H-1α),2.40(1H,m,H-2),2.13(1H,dd,J＝14.1,14.1Hz,H-1β),1.81(1H,brd,J＝15.0Hz,H-8α),1.69(1H,m,H-6),1.62(1H,m H-12α),1.43(1H,m,H-12β),1.36(1H,m,H-8β),1.27(6H,d,J＝7.0Hz,H-17and 20),1.04(3H,s,H-18),0.99(1H,m,H-11),0.92(1H,m,H-9),0.90(3H,d,J＝6.6Hz,H-16),0.78(3H,s,H-19),for 3-OBz and 7-OBz:δH7.99(2H,d,J＝7.5Hz),7.91(2H,d,J＝7.5Hz),7.53(2H,m),7.41(4H,m)；5-OAc:δH 1.40(3H,s)；15-OAc:δH 2.30(3H,s)；13C NMR(CDCl3,100MHz)δC 217.2(C-14),93.6(C-15),78.2(C-3),72.8(C-7),71.7(C-5),56.3(C-4),48.7(C-1),39.3(C-6),38.4(C-2),38.0(C-13),30.1(C-8),29.0(C-12),28.7(C-18),25.6(C-10),20.0(C-20),19.4(C-11),16.4(C-10),15.2(C-19),13.3(C-11),12.6(C-17),for 3-OBz and 7-OBz:165.9,165.5,133.0,132.9,130.7,130.3,129.4×2,129.3×2,128.4×2,128.3×2；5-OAc:δC 170.3,20.5；15-OAc:δC170.0,22.1；HRESIMS m/z 669.3028[M+Na]+(calcd for C38H46O9Na+,669.3034).
图3和图4分别为化合物26的核磁共振氢谱、碳谱和DEPT135谱图。
实施例8：化合物28的制备
Figure GDA0003658387080000141
将化合物27(25.0mg,0.075mmol)溶于二氯甲烷(2mL)中，加入戴斯-马丁试剂(31.7mg,0.075mmol)，室温搅拌3小时后，将反应混合液过滤旋干，通过快速柱色谱(PE:EtOAc＝15:1)纯化得到化合物28(17.3mg)。
结构确证：
无色晶体；[α]25 D+146.00(c 0.3,MeCN)；UV(MeCN)λmax(logε)248(4.21)nm；IR(KBr)νmax 3452,2926,1642,1453,1379,1260,1230,1150,1113,1057,1000,904,861cm-1；1HNMR(CDCl3,400MHz)δH 7.02(1H,dd,J＝11.6,1.0Hz,H-12),5.80(1H,s,H-17a),5.61(1H,s,H-17b),4.24(1H,dd,J＝2.9,2.9Hz,H-3),3.35(1H,dd,J＝13.5,8.5Hz,H-1a；1H,d,J＝2.9Hz,H-4),2.97(1H,dd,J＝13.7,5.7Hz,H-7a),1.99(2H,m,H-7b and 8a),1.90(1H,m,H-2),1.74(3H,d,J＝1.0Hz,H-20),1.63(1H,dd,J＝13.5,11.7Hz,H-1b),1.55(1H,m,H-8b),1.39(1H,dd,J＝11.6,8.2Hz,H-11),1.14(3H,s,H-18),1.11(3H,d,J＝6.7Hz,H-16),1.09(1H,m,H-9),1.01(3H,s,H-19),for 3-OH:δH 4.63(1H,brs)；13C NMR(CDCl3,100MHz)δC203.9(C-5),197.2(C-14),151.1(C-12),149.9(C-6),133.3(C-13),127.3(C-17),90.7(C-15),79.4(C-3),56.1(C-4),47.1(C-1),38.8(C-2),35.3(C-9),32.7(C-7),29.0(C-11and18),25.4(C-10),22.0(C-8),16.1(C-19),13.3(C-16),12.6(C-20)；HRESIMS m/z355.1861[M+Na]+(calcd for C20H28O4Na+,355.1880).
实施例9：化合物29和30的制备
Figure GDA0003658387080000151
将化合物14(80.0mg,0.153mmol)溶于乙酸乙酯(2mL)中，在氢气氛围下，加入10％Pd/C，50℃搅拌反应24小时。得到的反应混合物用快速柱色谱(PE:EtOAc＝35:1)和半制备高效液相色谱(MeCN/H2O＝80:20,3mL/min)纯化得到化合物29(19.2mg,tR 15.3min)和化合物30(16.8mg,tR 15.9min)。
结构确证
化合物29：白色晶体；[α]25 D-21.67(c 0.3,MeCN)；UV(MeCN)λmax(logε)232(4.32)nm；IR(KBr)νmax 2924,1742,1719,1453,1370,1272,1231,1111,1025,735,710cm-1；1H NMR(CDCl3,400MHz)δH 5.82(1H,d,J＝9.5Hz,H-5),5.76(1H,dd,J＝4.4,4.4Hz,H-3),5.41(1H,s,H-17a),5.15(1H,s,H-17b),3.31(1H,dd,J＝11.7,7.2Hz,H-13),3.17(1H,dd,J＝9.5,4.4Hz,H-4),2.84(1H,dd,J＝11.8,4.8Hz,H-1α),2.35(1H,m,H-7β),2.10(1H,m,H-2),2.07(1H,m,H-1β),1.88(2H,m,H-7αand 8α),1.76(1H,m,H-12α),1.27(1H,m H-12β),1.02(3H,d,J＝6.7Hz,H-20；1H,m,H-8β),0.99(3H,s,H-18),0.93(3H,d,J＝6.2Hz,H-16),0.83(3H,s,H-19),0.50(1H,m,H-11),0.34(1H,m,H-9)；for 3-OBz:δH 8.03(2H,m),7.56(1H,t,J＝7.5Hz),7.44(2H,t,J＝7.5Hz)；5-OAc:δH 1.81(3H,s)；15-OAc:δH 2.18(3H,s)；13C NMR(CDCl3,100MHz)δC 211.8(C-14),147.2(C-6),117.7(C-17),92.1(C-15),78.3(C-3),73.6(C-5),50.6(C-4),43.9(C-1),38.4(C-13),37.3(C-2),30.4(C-7),28.8(C-18),28.5(C-12),28.4(C-9),22.6(C-8),21.8(C-11),18.8(C-20),17.3(C-10),15.2(C-19),13.2(C-16),for 3-OBz:165.9,133.0,130.0,129.5×2,128.4×2；5-OAc:δC 169.2,20.9；15-OAc:δC 169.7,21.7；HRESIMS m/z 547.2653[M+Na]+(calcd for C31H40O7Na+,547.2666).
化合物30：无色油状；[α]25 D+51.33(c 0.3,MeCN)；UV(MeCN)λmax(logε)273(4.54),232(4.47)nm；IR(KBr)νmax 2926,1738,1652,1621,1453,1368,1271,1233,1114,1028,712cm-1；1HNMR(CDCl3,400MHz)δH 6.76(1H,d,J＝11.5Hz,H-12),6.02(1H,d,J＝7.7Hz,H-5),5.69(1H,dd,J＝3.4,3.4Hz,H-3),3.47(1H,dd,J＝13.9,7.7Hz,H-1α),2.28(1H,dd,J＝7.7,3.4Hz,H-4),2.26(1H,m,H-2),1.87(3H,br.s,H-20),1.82(1H,m,H-8α),1.75(1H,m,H-8β),1.62(1H,m,H-6),1.61(1H,m,H-1β),1.49(1H,dd,J＝11.5,8.3Hz,H-11),1.21(3H,s,H-19),1.19(3H,s,H-18；2H,m,H-7α和H-7β),1.11(1H,ddd,J＝11.5,8.3,4.1Hz,H-9),0.92(3H,d,J＝6.7Hz,H-16),0.81(3H,d,J＝6.7Hz,H-17),for 3-OBz:δH 7.99(2H,m),7.57(1H,t,J＝7.5Hz),7.43(2H,t,J＝7.5Hz)；5-OAc:δH 1.65(3H,s)；15-OAc:δH 2.22(3H,s)；13C NMR(CDCl3,100MHz)δC 196.8(C-14),146.1(C-12),133.9(C-13),92.0(C-15),80.8(C-3),66.4(C-5),54.7(C-4),48.0(C-1),38.5(C-2),36.6(C-9),35.8(C-6),32.8(C-7),29.2(C-18),29.1(C-11),25.4(C-10),20.1(C-8),16.8(C-19),14.8(C-17),14.0(C-16),12.6(C-20),for 3-OBz:166.0,133.1,130.1,129.5×2,128.5×2；5-OAc:δC 170.2,20.5；15-OAc:δC 169.8,21.7；HRESIMS m/z 547.2622[M+Na]+(calcd for C31H40O7Na+,547.2666).
图5和图6分别为化合物30的核磁共振氢谱、碳谱和DEPT135谱图。
实施例10：化合物32、33和34的制备
Figure GDA0003658387080000161
将化合物14(150.0mg,0.287mmol)溶于甲醇(2mL)溶液中，加入硼氢化钠(13.0mg,0.344mmol)，常温下搅拌15分钟。然后加入10％盐酸，在60℃的条件下反应30min，随后将反应混合液真空旋干。将得到的反应混合物用快速柱色谱(PE:EtOAc＝40:1)和半制备高效液相色谱(MeCN/H2O＝75:25,3mL/min)纯化得到化合物32(21.2mg,tR 15.9min)、化合物33(13.8mg,tR 15.4min)和化合物34(15.8mg,tR 13.6min)。
结构确证：
化合物32：白色晶体；[α]25 D+43.67(c 0.3,MeCN)；UV(MeCN)λmax(logε)232(4.26)nm；IR(KBr)νmax 3476,2926,1718,1452,1371,1275,1114,1026,900,712cm-1；1H NMR(CDCl3,400MHz)δH 6.24(1H,d,J＝16.2Hz,H-12),5.85(1H,d,J＝7.0Hz,H-5),5.71(1H,dd,J＝4.5,4.5Hz,H-3),5.59(1H,dd,J＝16.2,7.8Hz,H-11),5.48(1H,s,H-14),5.04(1H,s,H-17a),4.96(1H,s,H-17b),4.76(1H,s,H-18a),4.75(1H,s,H-18b),3.20(1H,dd,J＝7.0,4.5Hz,H-4),2.66(1H,ddd,J＝12.0,7.8,3.0Hz,H-9),2.34(1H,m,H-7α),2.08(2H,m,H-1α和H-1β),2.07(1H,m,H-2),1.97(1H,m,H-8α),1.95(1H,m,H-7β),1.83(3H,s,H-20),1.75(1H,m,H-8β),1.72(3H,s,H-19),0.94(3H,d,J＝5.5Hz,H-16),for 3-OBz:δH 8.06(2H,m),7.57(1H,t,J＝7.5Hz),7.45(2H,t,J＝7.5Hz)；5-OAc:δH 1.77(3H,s)；15-OH:2.40(1H,brs)；13C NMR(CDCl3,100MHz)δC 147.6(C-10),147.2(C-6),134.6(C-13),134.4(C-11),133.9(C-14),129.7(C-12),113.5(C-17),110.2(C-18),80.0(C-15),78.9(C-3),73.6(C-5),52.5(C-9),51.8(C-1),49.4(C-4),35.6(C-2),30.2(C-7),29.5(C-8),23.8(C-20),20.9(C-19),13.7(C-16),for 3-OBz:165.8,133.0,130.1,129.6×2,128.4×2；5-OAc:δC169.7,21.0；HRESIMS m/z 487.2445[M+Na]+(calcd for C29H36O5Na+,487.2455).
化合物33：白色晶体；[α]25 D+58.67(c 0.3,MeCN)；UV(MeCN)λmax(logε)232(4.30)nm；IR(KBr)νmax 3450,2926,1717,1453,1368,1275,1179,1114,1071,907,712cm-1；1H NMR(CDCl3,400MHz)δH 6.19(1H,d,J＝16.1Hz,H-12),5.84(1H,d,J＝6.2Hz,H-5),5.70(1H,dd,J＝4.0,4.0Hz,H-3),5.58(1H,dd,J＝16.1,8.6Hz,H-11),5.47(1H,s,H-14),4.93(1H,s,H-17a),4.89(1H,s,H-17b),3.19(1H,m,H-4),2.34(1H,m,H-7β),2.17(1H,m,H-9),2.12(1H,m,H-1α),2.07(1H,m,H-2),2.05(1H,m,H-1β),2.01(1H,m,H-8α),1.84(1H,m,H-7α),1.82(3H,s,H-20),1.50(1H,m,H-8β),1.12(3H,s H-19),1.11(3H,s H-18),0.94(3H,d,J＝5.7Hz,H-16),for 3-OBz:δH 8.06(2H,m),7.56(1H,t,J＝7.5Hz),7.44(2H,t,J＝7.5Hz)；5-OAc:δH 1.76(3H,s)；10-OMe:δH 3.19(3H,s)；15-OH:δH 2.53(1H,s)；13C NMR(CDCl3,100MHz)δC 147.1(C-6),134.2(C-13),133.3(C-11),133.0(C-14),130.7(C-12),112.7(C-17),80.3(C-15),78.9(C-3),76.3(C-10),73.2(C-5),54.0(C-9),51.8(C-1),49.0(C-4),35.6(C-2),30.6(C-7),24.8(C-8),24.5(C-20),23.5(C-18),21.9(C-19),13.9(C-16),for3-OBz:165.8,133.0,130.1,129.6×2,128.4×2；5-OAc:δC 169.7,21.0；10-OMe:δC 48.9；HRESIMS m/z 519.2710[M+Na]+(calcd for C30H40O6Na+,519.2717).
化合物34：白色晶体；[α]25 D+57.00(c 0.3,MeCN)；UV(MeCN)λmax(logε)232(4.27)nm；IR(KBr)νmax 3447,2965,1716,1452,1371,1277,1118,1026,908,713cm-1；1H NMR(CDCl3,400MHz)δH 6.23(1H,d,J＝16.1Hz,H-12),5.84(1H,d,J＝6.1Hz,H-5),5.71(1H,dd,J＝4.0,4.0Hz,H-3),5.61(1H,dd,J＝16.1,8.7Hz,H-11),5.47(1H,s,H-14),4.91(1H,s,H-17a),4.86(1H,s,H-17b),3.19(1H,m,H-4),2.34(1H,dd,J＝13.3,10.0Hz,H-7β),2.13(1H,m,H-1α),2.07(1H,m,H-2),2.03(1H,m,H-9；1H,m,H-1β；1H,m,H-8α),1.85(1H,m,H-7α),1.82(3H,s,H-20),1.55(1H,m,H-8β),1.19(6H,s,H-18and 19),0.93(3H,d,J＝5.8Hz,H-16),for 3-OBz:δH 8.05(2H,m),7.56(1H,t,J＝7.5Hz),7.44(2H,t,J＝7.5Hz)；5-OAc:δH1.76(3H,s)；15-OH:δH 2.55(1H,brs)；13C NMR(CDCl3,100MHz)δC 146.8(C-6),134.2(C-13),133.0(C-11and 14),131.8(C-12),112.6(C-17),80.3(C-15),78.9(C-3),72.9(C-5),72.2(C-10),56.9(C-9),51.9(C-1),48.9(C-4),35.5(C-2),30.8(C-7),28.1(C-18),26.9(C-19),25.2(C-8),24.7(C-20),13.9(C-16),for 3-OBz:165.8,133.0,130.0,129.6×2,128.4×2；5-OAc:δC 169.8,21.0；HRESIMS m/z 505.2568[M+Na]+(calcd for C29H38O6Na+,505.2561).
实施例11：双荧光素酶报告基因实验-考察化合物对hPXR的激动作用
HEK293T细胞用含10％FBS和青霉素(100U/mL)/链霉素(100μg/mL)的DMEM培养基进行培养，随后将对数生长期的细胞接种于96孔板中，密度为1.5×104个细胞/孔。对于PXR报告基因反式激活试验，每孔加入100ngpGL3-CYP3A4-XREM-Luc、50ng pSG5-hPXR和3ngpGL4.54-TK-Luc。
根据Lipofectamine 2000说明书进行转染程序。配制A液：25μL减血清培养基Opti-MEM中加入所需质粒，轻弹混匀，室温孵育5min。配制B液：25μL减血清培养基Opti-MEM中加入0.4μL Megatran 1.0转染试剂，轻弹混匀，室温孵育5min。混合A、B液体，轻弹混匀，室温孵育10min。弃去96孔板中50μL原培养基。沿壁加入50μL上述混合液，轻轻摇晃均匀。于标准条件下继续培养6h。
6小时后，每孔吸取50μL原培养体系，替换为50μL完全培养基配制的新体系。阳性对照组给予含有DMSO的完全培养基，利福平组给药RIF，化合物组给药相应化合物母液(DMSO配制)，使得每孔终浓度均为10μM。继续培养24h后，进行双荧光素酶报告基因活性检测。
使用4倍的PBS将5×PLB稀释至1×PLB细胞裂解缓冲液。将培养基从96孔板中吸出。每孔贴壁加入50μL PBS漂洗细胞1次，之后用10μL枪头吸尽孔板中残留的PBS。每孔加入20μL 1×PLB细胞裂解缓冲液，将孔板在常温条件下振荡20min使细胞裂解完全。
在避光条件下，吸取20μL细胞裂解液加入盛有等量萤光素酶测定试剂的流式管中摇晃均匀，立即放入超灵敏管式发光仪中检测荧火虫荧光素酶活性。
加入20μL Stop&Glo试剂，震荡10s，以猝灭萤火虫荧光素酶的发光，同时活化海肾荧光素酶，检测海肾荧光素酶信号值。相对荧光素酶强度＝荧火虫荧光素酶信号值/海肾荧光素酶信号值。
结果如图7所示，在HEK-293T细胞同时转染hPXR过表达质粒、含有PXRE片段的CYP3A4报告质粒以及内参质粒后，给予10μM人源激动剂RIF(阳性药)，能够上调报告基因相对荧光值2.9倍，具有显著性的诱导作用，表明该报告基因体系可以用来确定化合物对于hPXR是否存在转录激活作用。除了化合物22和27两个化合物外，结构修饰后的衍生物对hPXR均存在不同程度的激动作用。以下五个化合物对hPXR的激动作用较为突出，具有与RIF相似或更强的hPXR激动作用：其中化合物8对hPXR激动作用最强，hPXR激动作用达6.9倍；化合物30和26分别具有4.9、3.4倍激动作用；化合物7和阳性药RIF作用相当，具有2.8倍激动作用。随后对活性最好的化合物8、26和30进行了剂量依赖实验，结果显示都具有较好的剂量依赖性。
实施例12：化合物对hPXR下游靶基因的影响
进一步考察上述具有较强hPXR激动作用的化合物对hPXR下游靶基因的影响。实验方法如下
(1)RNA的提取
细胞给药24h后，取出孔板，移除旧培养基。每孔加入适量的PBS漂洗细胞2次，依照每10cm2底面积加入1mL Trizol试剂的比例加入Trizol。将培养孔板置于4℃环境中，摇床上摇晃，充分破碎细胞。10min后将其转移至1.5mL EP管中。按照Trizol体积的1/5加入三氯甲烷，涡旋仪上混匀15s。室温静置3min后，4℃12700rpm条件下离心15min。吸取400μL的上层液体于新的1.5mL EP管中，每管加入1/2Trizol体积的异丙醇，上下轻轻颠倒15次，室温条件下静置10min。
4℃下12700rpm离心10min，除尽上层液体，加入与Trizol等体积的75％乙醇(1％DEPC水配制)，上下轻轻颠倒，使RNA沉淀悬浮，7600g 4℃离心10min。除尽上清，在通风橱中挥干乙醇，20min后在每管中加入适量1％DEPC水，轻弹使沉淀溶解。使用微量紫外分光光度计Nanadrop 2000测定浓度。
(2)逆转录合成cDNA
以每体系1μg RNA绝对量进行基因组DNA的去除和逆转录为cDNA。反应体系如下：
去除基因组DNA反应体系
Figure GDA0003658387080000191
PCR反应条件：42℃，2min之后维持4℃。
逆转录反应体系
Figure GDA0003658387080000192
PCR仪中设置程序:37℃反应15min，85℃维持5s，后维持4℃。
将所有试剂以及样本提前放置于冰上融化。将逆转录所得样本cDNA使用无RNA酶水稀释5倍，轻弹混匀。根据待测基因及样本量和复孔数目计算出qPCR反应液各溶液组分的体积，并按表中所示提前配制好qPCR反应混合液。将配置好的qPCR体系放入ABI 7500仪器中，选择合适的基座。
qPCR反应混合液
Figure GDA0003658387080000201
提前开机预热qPCR仪器，选择SYBR@Green染料法和比较Ct法定量方法。扩增程序，导出样本、基因名称及对应的Ct值数据，以Gapdh或β-ACTIN基因的循环数为内参，采用相对Ct值法，得到给药组目的基因表达水平相对于对照组表达水平的变化倍数，并计算两组的统计学差异。
如图8所示，给予双能肝祖细胞系HepaRG人源激动剂RIF以及化合物8、26和30(10μM)后，能显著上调hPXR下游CYP3A4、CYP2B6、MDR1等靶基因的表达。其中，化合物8上调作用最强，能够显著上调hPXR下游Ⅰ相代谢酶CYP3A4(28.7倍)、CYP2B6(7.3倍)和转运体MDR1(2.1倍)的表达。
以上是对本发明所作的进一步详细说明，不可视为对本发明的具体实施的局限。对于本发明所属技术领域的普通技术人员来说，在不脱离本发明构思的简单推演或替换，都在本发明的保护范围之内。

Claims (8)

1.续随子烷型大环二萜化合物或其药学上可接受的盐作为唯一活性成分在制备抗胆汁淤积组合物中的应用，其特征在于：所述续随子烷型大环二萜化合物选自化合物7、化合物8、化合物18、化合物19、化合物20、化合物21、化合物26和化合物30中的一种：
Figure 136883DEST_PATH_IMAGE002
Figure 668007DEST_PATH_IMAGE004
。
2.根据权利要求1所述的应用，其特征在于：所述药学上可接受的盐选自化合物的酸或碱加成盐。
3.根据权利要求2所述的应用，其特征在于：所述酸选自乙酸、2,2-二氯乙酸、已二酸、藻酸、抗坏血酸、L-天冬氨酸、苯磺酸、苯甲酸、4-乙酰氨基苯甲酸、丁酸、（+）樟脑酸、樟脑-磺酸、癸酸、己酸、辛酸、肉桂酸、柠檬酸、环拉酸、十二烷基硫酸、乙烷-1,2-二磺酸、乙烷磺酸、2-羟乙基磺酸、甲酸、富马酸、半乳糖酸、龙胆酸、葡庚糖酸、D-葡萄糖酸、葡萄糖醛酸、谷氨酸、α-酮戊二酸、乙醇酸、马尿酸、氢溴酸、盐酸、氢碘酸、（+）-L-乳酸、（±）-DL-乳酸、乳糖酸、马来酸、苹果酸、丙二酸、（±）-DL-扁桃酸、甲基磺酸、萘-2-磺酸、萘-1,5-二磺酸、1-羟基-2-萘酸、烟酸、硝酸、油酸、乳清酸、草酸、棕榈酸、帕莫酸、磷酸、丙酸、L-焦谷氨酸、水杨酸、4-氨基-水杨酸、癸二酸、硬脂酸、丁二酸、硫酸、单宁酸、（+）-L-酒石酸、硫氰酸、p-甲苯磺酸、十一碳烯酸和戊酸，以及酰化氨基酸；所述碱为碱金属、碱土金属的氢氧化物。
4.续随子烷型大环二萜化合物或其药学上可接受的盐，所述续随子烷型大环二萜化合物的结构式如下：
Figure 916585DEST_PATH_IMAGE006
Figure 905270DEST_PATH_IMAGE008
。
5.根据权利要求4所述的续随子烷型大环二萜化合物或其药学上可接受的盐，其特征在于：所述药学上可接受的盐选自化合物的酸或碱加成盐。
6.根据权利要求5所述的续随子烷型大环二萜化合物或其药学上可接受的盐，其特征在于：所述酸选自乙酸、2,2-二氯乙酸、已二酸、藻酸、抗坏血酸、L-天冬氨酸、苯磺酸、苯甲酸、4-乙酰氨基苯甲酸、丁酸、（+）樟脑酸、樟脑-磺酸、癸酸、己酸、辛酸、肉桂酸、柠檬酸、环拉酸、十二烷基硫酸、乙烷-1,2-二磺酸、乙烷磺酸、2-羟乙基磺酸、甲酸、富马酸、半乳糖酸、龙胆酸、葡庚糖酸、D-葡萄糖酸、葡萄糖醛酸、谷氨酸、α-酮戊二酸、乙醇酸、马尿酸、氢溴酸、盐酸、氢碘酸、（+）-L-乳酸、（±）-DL-乳酸、乳糖酸、马来酸、苹果酸、丙二酸、（±）-DL-扁桃酸、甲基磺酸、萘-2-磺酸、萘-1,5-二磺酸、1-羟基-2-萘酸、烟酸、硝酸、油酸、乳清酸、草酸、棕榈酸、帕莫酸、磷酸、丙酸、L-焦谷氨酸、水杨酸、4-氨基-水杨酸、癸二酸、硬脂酸、丁二酸、硫酸、单宁酸、（+）-L-酒石酸、硫氰酸、p-甲苯磺酸、十一碳烯酸和戊酸，以及酰化氨基酸；所述碱为碱金属、碱土金属的氢氧化物。
7.一种用于治疗胆汁淤积的组合物，其特征在于：所述组合物的活性成分选自权利要求4～6任一项所述续随子烷型大环二萜化合物或其药学上可接受的盐中的至少一种。
8.根据权利要求7所述的组合物，其特征在于：所述组合物还包括药学上可接受的载体。
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