CN112939910B - 珊塔玛内酯衍生物及其药物组合物和其制备方法与应用 - Google Patents
珊塔玛内酯衍生物及其药物组合物和其制备方法与应用 Download PDFInfo
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Abstract
本发明提供结构式(I)所示21个珊塔玛内酯衍生物1‑21及其药物组合物和其制备方法与应用,涉及药物制备技术领域。化合物1‑21对人肝星状细胞(HSC‑LX2)具有明显的细胞毒活性,能够与可药用载体或赋型剂组成药物组合物,能够用于制备抗肝纤维化药物。
Description
技术领域
本发明属于药物技术领域,具体涉及到珊塔玛内酯衍生物(1-21),以其为有效成分的药物组合物,其制备方法以及该类衍生物及其药物组合物在制备抗肝纤维化的药物或保健食品中的应用。
背景技术:
肝纤维化是各种慢性肝病向肝硬化发展过程中的必经阶段,其病因包括病毒性肝炎、酒精过度摄入、化学毒物或药物、寄生虫感染、遗传和代谢疾病等。当人体的肝细胞发生损伤时,会触发机体的一系列修复反应,具体表现为肌成纤维细胞激活和再生、细胞外基质大量产生和沉积,该进程如若得不到抑制或逆转则可能加速肝硬化的发展过程,严重影响人体的生存质量。目前以单一控制病因或中药治疗对抗肝纤维化的发生,而并无确切的化学药物进入临床使用。
肝星状细胞(hepatic stellate cells,HSCs)是肌成纤维细胞的主要来源。正常肝脏中, HSC增殖较慢,其通过调节细胞外基质的合成和降解而维持其动态平衡。当肝脏受到外界致病因子的持续刺激时,一系列复杂机制被启动,最终结果导致HSC由静息型转化为激活型,并分泌TGF-β、PDGF等各种促纤维因子,产生大量无序堆积的细胞外基质(extracellular matrix,ECM),促进纤维化的发生和发展。因而,HSC是抗肝纤维化治疗的一个潜在靶点,当前许多抗肝纤维化在研药物通过抑制HSC的增殖及纤维形成能力、促进HSC的凋亡等途径以期达到治疗目的。本研究旨在基于人肝星状细胞(hepatic stellatecells line LX2,HSC-LX2)筛选模型,从天然产物中寻找新的抗肝纤维化活性成分。
迄今,现有技术中没有本发明涉及的珊塔玛内酯衍生物的报道,没有其作为药物组合物的报道,也没有其及其药物组合物在抑制HSC-LX2和治疗肝纤维化方面的报道。
发明内容:
本发明的目的在于提供一类新的具有药用价值的珊塔玛内酯衍生物(1-21)及具有抑制HSC-LX2增殖有效量的珊塔玛内酯衍生物及药用载体或赋形剂所形成的药物组合物,其制备方法,该衍生物及其药物组合物在制备抑制HSC-LX2增殖的药物,治疗肝纤维化及在保健食品中的应用。
为了实现本发明的上述目的,本发明提供了如下的技术方案:
结构式(I)所示的珊塔玛内酯衍生物(1-21)
药物组合物,其中含有治疗有效量的珊塔玛内酯衍生物(1-21)中的任何一种和药用可授载体。
制备先珊塔玛内酯衍生物1-21的方法,以化合物珊塔玛内酯为反应原料,合成珊塔玛内酯衍生物1-21。
制备含珊塔玛内酯衍生物(1-21)有效成分的药物组合物的方法,以化合物珊塔玛内酯为反应原料,合成珊塔玛内酯衍生物(1-21),分别加入可药用载体或赋形剂。
珊塔玛内酯衍生物(1-21)在制备抗肝纤维化药物,治疗或改善肝纤维化药物或保健食品中的应用。
药物组合物在制备抗肝纤维化药物,治疗或改善抗肝纤维化药物或保健食品中的应用。
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。
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(静注、肌注)和口服两种形式给药。
附图说明
图1为本发明珊塔玛内酯衍生物(化合物1-21)的结构示意图。
具体实施方式
为了更好的理解本发明的实质,下面将用本发明的试验例来说明本发明珊塔玛内酯衍生物的合成方法和药理作用结果,但并不以此来限定本发明。
核磁共振谱(1H and 13C)在400MHz核磁共振谱仪(Bruker,Bremerhaven,Germany)上测定,以TMS(四甲基硅烷)为内标。HRMS在LC/MS-IT-TOF质谱仪(Shimadzu,Kyoto,Japan)上测定。所有的化合物通过硅胶柱层析进行纯化(200-300目,青岛美高集团有限公司)。所有的反应试剂和溶剂均购自于正规厂商。
实施例1
本发明珊塔玛内酯衍生物的制备:
一.单酯化珊塔玛内酯(化合物1-18)的合成:
室温下,将相应的酸(0.16mmol)溶于1mL二氯甲烷并加入到10mL圆底烧瓶中,依次加入28μL 1-(3-二甲氨基丙基)-3-乙基碳二亚胺(EDCI,0.16mmol),1mg对二甲氨基吡啶(DMAP,0.02mmol),20mg珊塔玛内酯(0.08mmol)。反应2h后加入5%HCl水溶液猝灭反应,二氯甲烷(3mL)萃取三次,合并有机相,无水硫酸钠干燥,减压浓缩除去溶剂后经硅胶柱层析,用丙酮-石油醚(10:90,v/v)洗脱。
1-O-辛酰基珊塔玛内酯(化合物1)结构数据:
分子式:C23H35O4
分子量:374.52
性状:无色液体
收率:84%
HRESIMS(+)m/z:实验值375.2532([M+H]+),计算值375.2530
1H-NMR和13C-NMR数据:1H NMR(400MHz,CDCl3)δ6.07(d,J=3.2Hz,1H),5.39 (d,J=3.2Hz,1H),5.34(brs,1H),4.88(dd,J=9.9,6.7Hz,1H),3.91(t,J=10.9Hz,1H), 2.52-2.42(m,3H),2.29(t,J=7.5Hz,2H),2.05-1.95(m,2H),1.83-1.77(m,4H),1.64-1.58 (m,2H),1.34-1.24(m,10H),0.96(s,3H),0.87(t,J=6.6Hz,3H).13C NMR(100MHz, CDCl3)δ173.5,138.9,133.4,121.1,117.1,81.3,76.6,51.1,51.0,39.9,34.7,34.2,31.8,29.6,29.2,29.0,25.2,23.4,22.7,21.2,14.2,12.5.
1-O-琥珀酰基珊塔玛内酯(化合物2)结构数据:
分子式:C19H26O4
分子量:348.40
性状:白色蓬松固体
收率:63%
HRESIMS(+)m/z:实验值349.1645([M+H]+),计算值349.1646
1H-NMR和13C-NMR数据:1H NMR(400MHz,CD3OD)δ6.00(d,J=3.2Hz,1H),5.49 (d,J=3.2Hz,1H),5.38(brs,1H),4.93-4.89(m,1H),4.03(t,J=11.0Hz,1H),2.64-2.53(m,7H),2.50-2.40(m,1H),2.10-1.99(m,2H),1.90-1.82(m,4H),1.71-1.61(m,1H),1.38-1.29(m, 1H),1.01(s,3H).13C NMR(100MHz,CD3OD)δ175.9,173.6,172.5,140.7,134.8,121.9,117.2,82.9,78.5,52.0,41.0,35.2,30.4,30.3,29.8,23.5,22.0,12.6.
1-O-环戊酰基珊塔玛内酯(化合物3)结构数据:
分子式:C21H28O4
分子量:344.45
性状:无色液体
收率:80%
HRESIMS(+)m/z:实验值345.2056([M+H]+),计算值345.2060
1H-NMR和13C-NMR数据:1H NMR(400MHz,CDCl3)δ6.07(d,J=3.2Hz,1H),5.39 (d,J=3.2Hz,1H),5.34(brs,1H),4.87(dd,J=9.8,6.8Hz,1H),3.92(t,J=11.0Hz,1H), 2.77-2.69(m,1H),2.54-2.40(m,3H),2.03-1.67(m,12H),1.63-1.54(m,3H),1.35-1.27(m, 1H),0.97(s,3H).13C NMR(100MHz,CDCl3)δ176.3,139.0,133.4,121.1,117.1,81.3,76.5,51.1,51.0,44.3,40.0,34.2,30.3,23.0,29.6,26.0,25.8,23.4,21.2,12.5.
1-O-苯甲酰基珊塔玛内酯(化合物4)结构数据:
分子式:C22H24O4
分子量:352.43
性状:白色蓬松固体
收率:66%
HRESIMS(+)m/z:实验值353.1742([M+H]+),计算值353.1747
1H-NMR和13C-NMR数据:1H NMR(400MHz,CDCl3)δ8.03(d,J=7.2Hz,2H),7.57 (t,J=7.5Hz,1H),7.45(t,J=7.5Hz,2H),6.08(d,J=3.2Hz,1H),5.40(d,J=3.2Hz,2H), 5.15(dd,J=9.8,6.8Hz,1H),3.96(t,J=11.0Hz,1H),2.64-2.49(m,3H),2.23-2.11(m,1H),2.07-1.97(m,1H),1.95-1.89(m,1H),1.88(s,3H),1.69-1.58(m,1H),1.44-1.36(m,1H),1.11 (s,3H).13C NMR(100MHz,CDCl3)δ138.9,133.5,133.2,130.4,129.7,128.6,121.1,117.1, 81.3,77.5,51.1,51.0,40.2,34.4,29.7,23.4,21.2,12.8.
1-O-烟酰基珊塔玛内酯(化合物5)结构数据:
分子式:C24H21O4F5
分子量:353.42
性状:白色蓬松固体
收率:74%
HRESIMS(+)m/z:实验值354.1682([M+H]+),计算值353.1700
1H-NMR和13C-NMR数据:1H NMR(400MHz,CDCl3)δ9.22(s,1H),8.79(dd,J=4.9,1.8Hz,1H),8.30(d,J=8.0Hz,1H),7.42(dd,J=8.0,4.9Hz,1H),6.08(d,J=3.2Hz,1H),5.41(d,J=3.3Hz,2H),5.18(dd,J=9.9,6.8Hz,1H),3.96(t,J=10.9Hz,1H),2.64-2.50(m, 3H),2.23-2.14(m,1H),2.06-2.00(m,1H),1.91-1.87(m,4H),1.70-1.60(m,1H),1.44-1.36(m, 1H),1.11(s,3H).13C NMR(100MHz,CDCl3)δ170.7,164.8,153.6,150.9,138.8,137.3, 133.7,126.4,123.6,120.8,117.3,81.1,78.2,51.1,51.0,40.2,34.4,29.6,23.4,21.1,12.8.
1-O-噻吩酰基珊塔玛内酯(化合物6)结构数据:
分子式:C20H22O4S
分子量:358.45
性状:白色蓬松固体
收率:87%
HRESIMS(+)m/z:实验值359.1297([M+H]+),计算值359.1312
1H-NMR和13C-NMR数据:1H NMR(400MHz,CDCl3)δ7.80(dd,J=3.8,1.3Hz,1H), 7.57(dd,J=5.0,1.3Hz,1H),7.11(dd,J=5.0,3.8Hz,1H),6.08(d,J=3.2Hz,1H),5.39(t,J=4.2Hz,2H),5.08(dd,J=9.8,6.9Hz,1H),3.95(t,J=10.9Hz,1H),2.64-2.47(m,3H),2.21-2.12(m,1H),2.06-2.00(m,1H),1.93-1.87(m,1H),1.86(s,3H),1.68-1.58(m,1H),1.43-1.35(m,1H),1.07(s,3H).13C NMR(100MHz,CDCl3)δ170.7,161.8,138.9,133.9,133.5,133.5,132.6,128.0,121.0,117.1,81.2,77.8,51.1,51.0,40.2,34.4,29.6,23.4,21.2, 12.6.
1-O-(3’-三氟甲基苯基)珊塔玛内酯(化合物7)结构数据:
分子式:C23H23O4F3
分子量:420.43
性状:无色液体
收率:60%
HRESIMS(+)m/z:实验值359.1297([M+H]+),计算值359.1312
1H-NMR和13C-NMR数据:1H NMR(400MHz,CDCl3)δ8.27(s,1H),8.22(d,J=7.8 Hz,1H),7.83(d,J=7.8Hz,1H),7.61(t,J=7.8Hz,1H),6.09(d,J=3.2Hz,1H),5.41(d,J=3.2Hz,2H),5.19(dd,J=9.8,6.8Hz,1H),3.97(t,J=11.0Hz,1H),2.65-2.50(m,3H),2.25-2.13(m,1H),2.09-2.01(m,1H),1.94-1.85(m,4H),1.72-1.60(m,2H),1.45-1.37(m,1H), 1.12(s,3H).13C NMR(100MHz,CDCl3)δ170.7,164.8,138.8,133.7,132.9,131.3,129.8, 129.3,126.6,120.9,117.2,81.1,78.2,51.1,51.0,40.2,34.4,29.6,23.4,21.2,12.8.
1-O-肉桂酰基珊塔玛内酯(化合物8)结构数据:
分子式:C24H26O4
分子量:378.47
性状:白色蓬松固体
收率:73%
HRESIMS(+)m/z:实验值379.1888([M+H]+),计算值379.1904
1H-NMR和13C-NMR数据:1H NMR(400MHz,CDCl3)δδ7.68(d,J=16.0Hz,1H), 7.55-7.52(m,3.0Hz,2H),7.45-7.36(m,3H),6.44(d,J=16.0Hz,1H),6.08(d,J=3.2Hz, 1H),5.41(d,J=3.2Hz,1H),5.39(brs,1H),5.05(dd,J=9.9,6.7Hz,1H),3.95(t,J=11.0 Hz,1H),2.57-2.47(m,3H),2.15-2.00(m,2H),1.90-1.87(m,4H),1.68-1.58(m,1H), 1.41-1.33(m,1H),1.05(s,3H).13C NMR(100MHz,CDCl3)δ170.8,166.7,145.2,138.9, 134.4,133.5,130.6,129.1,128.2,121.1,118.2,117.1,81.3,76.9,51.1,51.0,40.1,34.3,29.7,23.5,21.2,12.6.
1-O-((E)-4’-吡啶丙烯酰基)珊塔玛内酯(化合物9)结构数据:
分子式:C23H25O4N
分子量:379.46
性状:白色蓬松固体
收率:43%
HRESIMS(+)m/z:实验值380.1840([M+H]+),计算值380.1856
1H-NMR和13C-NMR数据:1H NMR(400MHz,CDCl3)δ8.66(d,J=5.1Hz,2H),7.59 (d,J=16.0Hz,1H),7.38(d,J=5.6Hz,2H),6.59(d,J=16.0Hz,1H),6.08(d,J=3.2Hz, 1H),5.41(d,J=3.2Hz,1H),5.38(brs,1H),5.06(dd,J=9.9,6.7Hz,1H),3.94(t,J=11.0 Hz,1H),2.58-2.47(m,3H),2.15-2.01(m,2H),1.90-1.83(m,4H),1.69-1.58(m,1H), 1.40-1.33(m,1H),1.04(s,3H).13C NMR(100MHz,CDCl3)δ171.0,166.0,151.0,142.5, 142.1,139.2,133.9,123.3,122.3,121.2,117.5,81.5,77.9,51.4,51.3,40.4,34.6,29.9,23.7,21.5,12.9.
1-O-(2’-三氟甲基肉桂酰基)珊塔玛内酯(化合物10)结构数据:
分子式:C25H25O4F3
分子量:446.47
性状:无色液体
收率:43%
HRESIMS(+)m/z:实验值447.1777([M+H]+),计算值447.1778
1H-NMR和13C-NMR数据:1H NMR(400MHz,CDCl3)δ8.07(d,J=15.8Hz,1H),7.72 (t,J=7.2Hz,2H),7.57(t,J=7.6Hz,1H),7.49(t,J=7.6Hz,1H),6.40(d,J=15.8Hz,1H),6.08(d,J=3.2Hz,1H),5.41(d,J=3.2Hz,1H),5.39(brs,1H),5.03(dd,J=9.8,6.8Hz,1H), 3.95(t,J=11.0Hz,1H),2.59-2.47(m,3H),2.17-2.00(m,2H),1.90-1.86(m,4H),1.69- 1.59(m,1H),1.41-1.33(m,1H),1.04(s,3H).13C NMR(100MHz,CDCl3)δ170.7,165.7,140.5,138.9,133.5,132.3,129.9,127.9,126.3,122.4,121.0,117.1,81.2,77.4,51.1,51.0,40.1, 34.3,29.6,23.4,21.2,12.5.
1-O-(3’-三氟甲基肉桂酰基)珊塔玛内酯(化合物11)结构数据:
分子式:C25H25O4F3
分子量:446.47
性状:无色液体
收率:74%
HRESIMS(+)m/z:实验值447.1767([M+H]+),计算值447.1778
1H-NMR和13C-NMR数据:1H NMR(400MHz,CDCl3)δ7.78(s,1H),7.73-7.66(m, 2H),7.64(d,J=7.8Hz,1H),7.53(t,J=7.8Hz,1H),6.50(d,J=16.0Hz,1H),6.08(d,J=3.1Hz,1H),5.41(d,J=3.1Hz,1H),5.39(brs,1H),5.06(dd,J=9.9,6.8Hz,1H),3.95(t,J= 10.9Hz,1H),2.58-2.47(m,3H),2.17-2.00(m,2H),1.93-1.83(m,4H),1.69-1.59(m,1H), 1.41-1.34(m,1H),1.05(s,3H).13C NMR(100MHz,CDCl3)δ170.7,166.1,143.3,138.9,135.2,133.6,131.3,129.6,126.9,124.7,121.0,120.2,117.1,81.2,77.3,51.1,51.0,40.1,34.3, 29.6,23.4,21.2,12.6.
1-O-(4’-三氟甲基肉桂酰基)珊塔玛内酯(化合物12)结构数据:
分子式:C25H25O4F3
分子量:446.47
性状:无色液体
收率:67%
HRESIMS(+)m/z:实验值447.1769([M+H]+),计算值447.1778
1H-NMR和13C-NMR数据:1H NMR(400MHz,CDCl3)δ7.69(d,J=16.0Hz,1H),7.66 -7.62(m,4H),6.51(d,J=16.0Hz,1H),6.08(d,J=3.2Hz,1H),5.41(d,J=3.2Hz,1H), 5.39(brs,1H),5.06(dd,J=9.9,6.7Hz,1H),3.95(t,J=10.9Hz,1H),2.61-2.46(m,3H), 2.18-2.01(m,2H),1.90-1.84(m,4H),1.68-1.59(m,1H),1.42-1.34(m,1H),1.05(s, 3H).13C NMR(101MHz,CDCl3)δ170.7,166.1,143.3,138.9,137.8,133.6,131.8,128.3, 126.0,122.6,121.0,120.8,117.2,81.2,77.3,51.1,51.0,40.1,34.3,29.6,23.4,21.2,12.6.
1-O-(4’-氟桂酰基)珊塔玛内酯(化合物13)结构数据:
分子式:C25H25O4F
分子量:396.46
性状:白色蓬松固体
收率:82%
HRESIMS(+)m/z:实验值397.1795([M+H]+),计算值397.1810
1H-NMR和13C-NMR数据:1H NMR(400MHz,CDCl3)δ7.64(d,J=16.0Hz,1H),7.52 (dd,J=8.5,5.4Hz,2H),7.08(t,J=8.5Hz,2H),6.36(d,J=16.0Hz,1H),6.08(d,J=3.2Hz,1H),5.40(d,J=3.2Hz,1H),5.38(brs,1H),5.05(dd,J=9.9,6.7Hz,1H),3.95(t,J=10.9Hz,1H),2.55-2.48(m,3H),2.14-2.00(m,2H),1.90-1.84(m,4H),1.69-1.57(m,1H), 1.41-1.33(m,1H),1.04(s,3H).13C NMR(100MHz,CDCl3)δ170.8,166.7,145.2,138.9, 134.4,133.5,130.6,129.1,128.2,121.1,118.2,117.1,81.3,76.9,51.1,51.0,40.1,34.3,29.7,23.5,21.2,12.6.
1-O-(2’,3’,4’,5’,6’-五氟肉桂酰基)珊塔玛内酯(化合物14)结构数据:
分子式:C25H21O4F5
分子量:468.42
性状:白色蓬松固体
收率:83%
HRESIMS(+)m/z:实验值469.1422([M+H]+),计算值469.1433
1H-NMR和13C-NMR数据:1H NMR(400MHz,CDCl3)δ7.64(d,J=16.4Hz,1H),6.73 (d,J=16.4Hz,1H),6.08(d,J=3.1Hz,1H),5.41(d,J=3.1Hz,1H),5.38(brs,1H),5.06(dd, J=9.9,6.8Hz,1H),3.94(t,J=11.0Hz,1H),2.57-2.48(m,3H),2.16-2.01(m,2H),1.87(s,3H),1.86-1.83(m,1H),1.67-1.61(m,1H),1.40-1.34(m,1H),1.04(s,3H).13C NMR(100MHz,CDCl3)δ170.7,165.7,138.8,133.6,128.7,126.3,120.9,117.2,109.9,81.2,77.8,51.1, 51.0,40.1,34.3,29.6,23.4,21.2,12.6.
1-O-(4’–醛基肉桂酰基)珊塔玛内酯(化合物15)结构数据:
分子式:C25H26O5
分子量:406.48
性状:白色蓬松固体
收率:81%
HRESIMS(+)m/z:实验值407.1840([M+H]+),计算值407.1853
1H-NMR和13C-NMR数据:1H NMR(400MHz,CDCl3)δ10.03(s,1H),7.90(d,J=8.0 Hz,2H),7.75-7.66(m,3H),6.55(d,J=16.0Hz,1H),6.08(d,J=3.2Hz,1H),5.40(d,J=3.2Hz,1H),5.38(brs,1H),5.06(dd,J=9.9,6.7Hz,1H),3.95(t,J=10.9Hz,1H),2.59-2.47(m,3H),2.17-2.00(m,2H),1.90-1.84(m,4H),1.67-1.60(m,1H),1.41-1.37(m,1H),1.05(s,3H).13C NMR(100MHz,CDCl3)δ191.6,170.8,166.1,143.5,140.2,139.0,137.5,133.7,130.4,128.8,121.5,121.1,117.3,81.3,77.5,51.2,51.1,40.2,34.4,29.7,23.5,21.3, 12.7.
1-O-(4’–乙酰氧基肉桂酰基)珊塔玛内酯(化合物16)结构数据:
分子式:C26H28O6
分子量:436.50
性状:白色蓬松固体
收率:71%
HRESIMS(+)m/z:实验值437.1950([M+H]+),计算值437.1959
1H-NMR和13C-NMR数据:1H NMR(400MHz,CDCl3)δ7.65(d,J=16.0Hz,1H),7.55 (d,J=8.7Hz,2H),7.13(d,J=8.7Hz,2H),6.38(d,J=16.0Hz,1H),6.08(d,J=3.2Hz,1H),5.40(d,J=3.2Hz,1H),5.39(brs,1H),5.04(dd,J=9.9,6.7Hz,1H),3.94(t,J=11.0Hz,1H),2.58-2.47(m,3H),2.31(s,3H),2.18-2.00(m,2H),1.92-1.82(m,4H),1.65-1.59(m,1H),1.41-1.33(m,1H),1.04(s,3H).13C NMR(100MHz,CDCl3)δ170.7,169.2,166.5, 152.3,144.0,139.0,133.5,129.4,122.3,121.1,118.4,117.1,81.3,77.0,51.1,51.0,40.1,34.3, 29.7,23.4,21.3,21.2,12.6.
1-O-(吡非尼酮基甲酰基)珊塔玛内酯(化合物17)结构数据:
分子式:C28H29O5N
分子量:459.54
性状:白色蓬松固体
收率:83%
HRESIMS(+)m/z:实验值460.2102([M+H]+),计算值460.2118
1H-NMR和13C-NMR数据:1H NMR(400MHz,CDCl3)δ8.14(d,J=8.0Hz,2H),7.48 (d,J=8.0Hz,2H),7.28(dd,J=9.4,2.6Hz,1H),7.09(s,1H),6.61(d,J=9.4Hz,1H),6.08 (d,J=3.2Hz,1H),5.40(t,J=3.3Hz,2H),5.17(dd,J=9.8,6.8Hz,1H),3.96(t,J=10.9Hz,1H),2.64-2.49(m,3H),2.22-2.01(m,6H),1.90-1.87(m,4H),1.69-1.60(m,1H),1.43-1.36(m,1H),1.11(s,3H).13C NMR(100MHz,CDCl3)δ170.7,165.2,161.6,143.1,138.8,134.5,133.6,130.8,130.2,126.9,121.8,120.9,117.2,115.6,81.2,77.8,51.1,51.0,40.2,34.4, 29.6,23.4,21.1,17.2,12.7.
琥珀酸羟尼酮酯-1-O-珊塔玛内酯(化合物18)结构数据:
分子式:C31H33O7N
分子量:531.61
性状:白色蓬松固体
收率:75%
HRESIMS(+)m/z:实验值532.2319([M+H]+),计算值532.2330
1H-NMR和13C-NMR数据:1H NMR(400MHz,CDCl3)δ7.39(d,J=8.8Hz,2H),7.27 (d,J=5.8Hz,1H),7.20(d,J=8.8Hz,2H),7.10(s,1H),6.60(d,J=9.3Hz,1H),6.07(d,J=3.2Hz,1H),5.41(d,J=3.2Hz,1H),5.35(brs,1H),4.96(dd,J=9.9,6.8Hz,1H),3.92(t,J= 10.9Hz,1H),2.98-2.86(m,2H),2.82-2.71(m,2H),2.53-2.42(m,3H),2.10(s,3H),2.05- 2.00(m,2H),1.89-1.81(m,4H),1.60-1.54(m,1H),1.35-1.29(m,1H),0.98(s,3H).13C NMR(100MHz,CDCl3)δ171.7,170.8,170.7,161.8,150.2,142.9,138.7,135.2,133.5,127.9, 122.5,121.6,120.9,117.2,115.2,81.2,77.5,51.1,51.0,39.9,34.2,29.5,29.4,29.3,23.4,21.1, 17.1,12.5..
二.二酯化珊塔玛内酯(化合物19-21)的合成:
室温下,将相应二酸(0.08mmol)溶于1mL二氯甲烷并加入到10mL厚壁耐压管中,依次加入25μL N,N'-二异丙基碳二亚胺(DIC,0.16mmol),1mg对二甲氨基吡啶(DMAP,0.02mmol),40mg珊塔玛内酯(0.16mmol)。将耐压管密封加热至50℃反应24h后冷却至室温,加入5%HCl水溶液猝灭反应,二氯甲烷(3mL)萃取三次,合并有机相,无水硫酸钠干燥,减压浓缩除去溶剂后经硅胶柱层析,用丙酮-石油醚(10:90,v/v)洗脱。
琥珀酸-1-O-二珊塔玛内酯(化合物19)结构数据:
分子式:C34H44O8
分子量:578.70
性状:白色蓬松固体
收率:60%
HRESIMS(+)m/z:实验值601.2772([M+H]+),计算值601.2763
1H-NMR和13C-NMR数据:1HNMR(400MHz,CDCl3)δ6.08(d,J=3.1Hz,2H),5.40 (d,J=3.1Hz,2H),5.35(brs,2H),4.92(dd,J=9.9,6.8Hz,2H),3.92(t,J=10.9Hz,2H), 2.69-2.58(m,4H),2.53-2.41(m,6H),2.07-1.97(m,4H),1.88-1.80(m,8H),1.64-1.59(m,2H),1.34-1.26(m,2H),0.97(s,6H).13C NMR(100MHz,CDCl3)δ171.9,170.7,138.9,133.6,120.9,117.2,81.2,77.4,51.1,51.0,39.9,34.2,29.6,29.3,23.4,21.2,12.5.
戊二酸-1-O-二珊塔玛内酯(化合物20)结构数据:
分子式:C35H46O8
分子量:592.72
性状:白色蓬松固体
收率:40%
HRESIMS(+)m/z:实验值615.2929([M+H]+),计算值615.2928
1H-NMR和13C-NMR数据:1H NMR(400MHz,CDCl3)δ6.08(d,J=3.1Hz,2H),5.41 (d,J=3.1Hz,2H),5.36(brs,2H),4.91(dd,J=9.9,6.7Hz,2H),3.93(t,J=10.9Hz,2H), 2.55-2.42(m,6H),2.39(t,J=7.4Hz,4H),2.08-1.91(m,6H),1.85(s,6H),1.83-1.78(m,2H),1.69-1.57(m,2H),1.36-1.28(m,2H),0.98(s,6H).13C NMR(100MHz,CDCl3)δ172.4,170.6,138.8,133.5,120.9,117.1,81.1,77.0,51.0,50.9,39.8,34.2,33.6,29.5,23.4,21.1,20.4,12.5.
戊二酸-1-O-二珊塔玛内酯(化合物21)结构数据:
分子式:C38H42O8
分子量:626.75
性状:白色蓬松固体
收率:32%
HRESIMS(+)m/z:实验值627.2964([M+H]+),计算值627.2952
1H-NMR和13C-NMR数据:1H NMR(600MHz,CDCl3)δ8.11(s,4H),6.09(d,J=3.2 Hz,2H),5.41(d,J=3.1Hz,4H),5.17(dd,J=9.8,6.9Hz,2H),3.97(t,J=10.9Hz,2H), 2.65-2.60(m,2H),2.59-2.50(m,4H),2.22-2.14(m,2H),2.07-2.01(m,2H),1.91-1.85(m,8H),1.68-1.61(m,2H),1.44-1.38(m,2H),1.12(s,6H).13C NMR(150MHz,CDCl3)δ170.7,165.2,138.8,134.3,133.7,129.8,120.9,117.3,81.1,78.2,51.1,51.0,40.2,34.5,29.6,23.5,21.2, 12.8.
实施例2:
珊塔玛内酯衍生物1-21对人肝星状细胞系HSC-LX2的细胞毒活性。
1.材料和方法
1.1材料
人肝星状细胞系(hepatic stellate cells line LX2,HSC-LX2)购自上海纪宁生物科技有限公司;RPMI-1640培养基和胎牛血清均购自Gibco BRL(NY,USA);MTT购自广州赛国生物科技有限公司。
1.2仪器
Flex Station 3台式多功能酶标仪(Bio-RAD 680,美国);分析天平(AG135,Metler Toledo,中国);恒温箱(DHP-9082,上海)。
1.3实验过程
采用MTT法测定样品对HSC-LX2细胞的毒活性。HSC-LX2细胞于含有10%胎牛血清的RPMI-1640培养基中培养。取对数期生长的细胞以1×104/孔的密度接种于96孔板中,24h后将其维持液替换为含不同浓度供试样品的培养基,同时设置只加维持液的细胞对照组,并以水飞蓟宾做阳性药物对照。培养48h后,弃掉培养液并加入100μL MTT 溶液(浓度为1mg/mL);置于37℃恒温箱孵育4h,弃掉MTT溶液并加入100μL DMSO 溶解甲躜晶体;最后,在490nm处用酶标仪检测每孔吸光度值。HSC-LX2细胞抑制率计算公式为抑制率(%)=[A(空白)–A(样品)]/A(空白)×100%。其半数抑制浓度(50% inhibitory concentration,IC50)利用Graphpad Prism 5软件计算。
2.结果
对所有衍生物评价了其体外的HSC-LX2细胞毒活性,其IC50值如表1所示。
表1.衍生物1-21的HSC-LX2细胞毒活性
a活性数据表示为平均值±SD(n=3);bSilybin为阳性对照
3.结论
实验结果显示衍生物1-21对肝星状细胞展现出较好的细胞毒活性,其IC50值在3.5到92.0μM之间,活性好于阳性Silybin(IC50151.1μM)。尤其,化合物11,14和19(IC50: 6.4±0.4,4.6±0.1,和3.5±0.1μM),活性是珊塔玛内酯(IC5017.5±0.4μM)的3-5倍。以上结果表明珊塔玛内酯衍生物物1-21可作为药物用于肝纤维化相关的疾病。
制剂实施例1-7:
在以下制剂实施例中,选择常规试剂,并按照现有常规方法进行制剂制备,本应用例仅体现本发明所述化合物1-21中的至少一种能够制备成不同的制剂,对具体试剂和操作不作具体限定:
1.将实施例1制备的化合物1-21中的至少一种,用DMSO溶解后,按常规方法加注射用水,精滤,灌封灭菌制成注射液,所述注射液的浓度为0.5-5mg/mL。
2.将实施例1制备的化合物1-21中的至少一种,用DMSO溶解后,将其溶于无菌注射用水中,搅拌使其溶解,用无菌抽滤漏斗过滤,再无菌精滤,分装于安瓿中,低温冷冻干燥后无菌熔封,得粉针剂。
3.将实施例1制备的化合物1-21中的至少一种,按其与赋形剂质量比为9:1的比例加入赋形剂,制成粉剂。
4.将实施例1制备的化合物1-21中的至少一种,按其与赋形剂质量比为5:1的比例加入赋形剂,制粒压片。
5.将实施例1制备的化合物1-21中的至少一种,按常规口服液制备方法制成口服液。
6.将实施例1制备的化合物1-21中的至少一种,按其与赋形剂质量比为5:1的比例加入赋形剂,制成胶囊。
7.将实施例1制备的化合物1-21中的至少一种,按其与赋形剂质量比为5:1的比例加入赋形剂,制成颗粒剂。
由以上实施例可知,本发明提供了一种珊塔玛内酯衍生物及其制备方法和应用,药物组合物及其应用。本发明提供的21种塔玛内酯衍生物,对人肝星状细胞HSC-LX2具有不同程度的细胞毒活性,能够与可药用载体或赋型剂组成药物组合物,能够用于制备抗肝纤维化药物。
以上所述仅是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以做出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。
Claims (10)
2.药物组合物,含有权利要求1所述的珊塔玛内酯衍生物3、7、11、14、19、20、21及可药用载体或赋形剂。
3.制备权利要求1结构式(I)所示的珊塔玛内酯衍生物3、7、11、14、19、20、21的方法,以化合物珊塔玛内酯为反应原料,合成珊塔玛内酯衍生物3、7、11、14、19、20、21。
4.制备权利要求2所述的药物组合物的方法,以化合物珊塔玛内酯为反应原料,合成珊塔玛内酯衍生物3、7、11、14、19、20、21,分别加入可药用载体或赋形剂。
5.权利要求1所述的珊塔玛内酯衍生物3、7、11、14、19、20、21在制备人肝星状细胞HSC-LX2抑制剂中的应用。
6.权利要求2所述的药物组合物在制备人肝星状细胞HSC-LX2抑制剂中的应用。
7.权利要求1所述的珊塔玛内酯衍生物3、7、11、14、19、20、21在制备治疗或改善肝纤维化的药物中的应用。
8.权利要求2所述的药物组合物在制备治疗或改善肝纤维化的药物中的应用。
9.权利要求1所述的珊塔玛内酯衍生物3、7、11、14、19、20、21在制备抗肝纤维化药物或保健食品中的应用。
10.权利要求2所述的药物组合物在制备抗肝纤维化药物或保健食品中的应用。
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