CN113912482B - 愈创木烷型倍半萜类化合物及其制备和应用 - Google Patents
愈创木烷型倍半萜类化合物及其制备和应用 Download PDFInfo
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- C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
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Abstract
本发明属于医药技术领域,涉及愈创木烷型倍半萜类化合物及其制备和应用。尤其涉及植物瑞香狼毒中的新愈创木烷型类化合物及其制备方法和这类化合物在神经细胞保护方面的应用。本发明所述的化合物通过乙醇提取、乙酸乙酯萃取、经硅胶柱色谱、HP‑20柱和ODS开放柱色谱、经硅胶柱色谱、制备高效液相分离得到。本发明的化合物及其含有该化合物的组合物具有神经保护作用,可以用于制备神经保护药物。
Description
技术领域:
本发明属于医药技术领域,涉及愈创木烷型倍半萜类化合物及其制备和应用。尤其涉及植物瑞香狼毒中的新愈创木烷型类化合物及其制备方法和这类化合物在神经细胞保护方面的应用。
背景技术:
瑞香狼毒(Stellera chamaejasme L.)是瑞香科(Thymelaeaceae)狼毒属植物,主要分布于我国西北、东北、河北、内蒙古及尼泊尔等地。瑞香狼毒始载于《神农本草经》,为中药狼毒之正品,主要药用部位为根,传统中医认为瑞香狼毒性味辛、苦、平,归肺、脾、肝经,有毒,功能泻水逐饮,破积杀虫,主治水肿腹胀、痰食虫积、心腹疼痛、疥癣、癥瘕积聚等。瑞香狼毒的研究表明其含有多种化学成分,包含瑞香烷型二萜、倍半萜、黄酮、木脂素和香豆素等化合物。该植物被报道具有多种药理活性,如抗肿瘤、抗HIV、抗菌、杀虫、抗惊厥和免疫调节等作用。
氧化应激(oxidative stress,OS):指机体内活性氧产生过多,导致氧化和抗氧化系统失衡,引起细胞或组织氧化损伤的一种病理状态。活性氧(reactive oxygen species,ROS)造成DNA、蛋白质和脂质等氧化损伤,破坏细胞结构和功能的完整性,引起细胞凋亡或坏死,与多种疾病发生相关。
国内外研究氧化应激的模型大体分为动物模型和体外细胞培养模型两种,其中应用最广泛的体外细胞培养模型是H2O2氧化损伤模型。H2O2作为活性氧类物质之一,不仅极易透过细胞膜,与细胞内铁离子反应生成高活性自由基,而且易于获得,性质稳定,已成为国内外研究各类细胞氧化损伤的重要工具。
神经退行性疾病(Neurodegenerative diseases)与氧化应激:神经退行性疾病是由于大脑和脊髓的神经元丧失而引起的一类不可逆转的神经系统疾病,特征表现为发作迟缓和选择性神经元的功能障碍。氧化应激在神经退行性疾病病理改变过程中具有重要的作用,ROS会造成神经元的死亡,促进疾病的发展。
发明内容:
本发明提供四种从瑞香科(Thymelaeaceae)狼毒属(Stellera Linn.)植物瑞香狼毒(Stellera chamaejasme L.)中提取分离得到的新愈创木烷型倍半萜类化合物或其药学上可接受的盐:
本发明的化合物的制备包括如下步骤:
(1)取干燥的瑞香狼毒根以乙醇回流提取,合并提取液浓缩得浸膏,浸膏采用乙酸乙酯萃取并将所得馏分经硅胶柱色谱,以二氯甲烷-甲醇系统1:0-0:1v/v进行等度梯度洗脱,共收集到6个馏分(Fr.A-F)。
(2)馏分Fr.A经HP-20柱和ODS开放柱色谱,分别以甲醇-水系统10:90-90:10v/v进行梯度洗脱,得四个组分Fr.A1-A4。
(3)Fr.A3经硅胶柱色谱以石油醚-二氯甲烷系统50:1-1:1v/v在TLC分析的基础上得到四个亚组分Fr.A3a-Fr.A3d。
(4)在制备性反相高效液相色谱上使用甲醇-水(75:25-85:15v/v)的流动相来分离Fr.A3b得到了化合物1和化合物2;
在制备性反相高效液相色谱上使用乙腈-水(45:55-60:40v/v)的流动相来分离Fr.A3c得到了化合物3和化合物4。
所述步骤(1)中,乙醇为70%-80%工业乙醇,所述提取为回流提取,提取2-3次,每次2-4小时。
所述步骤(1)中所述的瑞香狼毒为瑞香科(Thymelaeaceae)狼毒属(StelleraLinn.)植物瑞香狼毒(Stellera chamaejasme L.)。
所得化合物经过系统结构鉴定结果如下:
利用高分辨质谱,一维NMR、二维NMR及计算ECD技术对化合物1-4的结构鉴定。
Stelleraterpenoid A(1):无色簇状针晶(甲醇),10%香草醛硫酸显橘色,HRESIMS给出准分子离子峰[M+Na]+峰m/z 257.1525(calcd for C15H22O2Na,257.1512),确定该化合物的分子量为234,分子式为C15H22O2,计算不饱和度为5。
1H-NMR(400MHz,CDCl3)谱中,4.73(1H,br s,H-12a),4.77(1H,br s,H-12b)为末端双键两个氢信号,δH 2.71(1H,d,J=18.8Hz,H-6β),2.48(1H,dd,J=18.8,11.6Hz,H-6α),2.58(1H,d,J=18.2Hz,H-2β),2.42(1H,d,J=18.2,H-2α)推测为两组磁不等同亚甲基的质子信号,δH1.73(3H,s,H-13),1.63(3H,s,H-15),0.74(3H,d,J=7.1Hz,H-14)为三个甲基氢质子信号。13C-NMR(100MHz,CDCl3)显示出15个碳信号,其中,低场区有5个碳信号,δC 205.5(C-3),138.6(C-4),171.8(C-5)为α,β不饱和酮的碳信号,δC 151.0(C-11),109.1(C-12)推测为一组末端双键的碳信号;δC 83.0(C-1)为连氧季碳的信号。通过HSQC数据将全部碳氢直接相关信号进行了全归属。
HMBC谱中,H-2(δH 2.58)与C-4(δC 138.6),C-5(δC 171.8)有相关,H3-15(δH 1.63)与C-3(δC 205.5),C-4(δC 138.6),C-5(δC 171.8)有相关,推测结构中有一个片段A;H-6(δH2.48)与C-1(δC 83.0),C-8(δC 30.1),C-11(δC 151.0)有相关,H-9(δH 1.51)与C-7(δC42.9)有相关,H2-12(δH4.73,4.67)与C-7(δC 42.9),C-13(δC 20.4)有相关,H3-13(δH 1.73)与C-7(δC 42.9)有相关,H3-14(δH 0.74)与C-1(δC 83.0),C-9(δC 30.8),C-10(δC 42.9)有相关,推测有一个片段B。H-6(δH 2.48)与C-4(δC 138.6)的相关峰以及H-2(δH 2.58)与C-10(δC 40.0)的相关峰的存在,表明片段A和B是通过C-1-C-5骈和起来的。由于化合物1的C-1化学位移值比较大(δC 83.0),推测该位置连有一个羟基。根据以上相关信息建立了化合物1的平面结构。
NOESY谱中,由于没有有效的相关信号,所以,通过计算NMR数据来确定其相对构型。四种可能的立体异构体(1R*,7R*,10R*)-1a,(1R*,7R*,10R*)-1b,(1R*,7R*,10S*)-1c和(1S*,7R*,10S*)-1d在mPW1PW91/6-311+G(d,p)的水平下进行量子化学计算,并用线性相关分析、MAE分析和DP4+分析来确定其可能的相对构型。四种立体异构体的线性回归方程对应的R2分别为0.9965,0.9981,0.9986和0.997,MAE值分别为6.18,5.84,5.29和5.57ppm,同时,DP4+统计分析给出19c的可能性为100%,表明化合物1的相对构型应为1R*,7R*,10S*。
化合物1的绝对构型是通过计算ECD与实测ECD进行比较确定的。1的实测值与1R,7R,10S-1的计算值表现出较好的拟合性,因此,化合物1的绝对构型为1R,7R,10S。X-单晶衍射的结果对此进行了验证,证明化合物化合物1的绝对构型确实为1R,7R,10S。
综上所述,最终确定了该化合物结构,为Stelleraterpenoid A(1)。
化合物1的1H(400MHz)与13C(100MHz)NMR数据(CDCl3)
Stelleraterpenoid B(2):黄色油状物(氯仿),10%香草醛硫酸显橘色,HRESIMS给出准分子离子峰[M+Na]+峰m/z 257.1513(calcd for C15H22O2Na,257.1512),确定该化合物的分子量为234,分子式为C15H22O2,计算不饱和度为5。
1H-NMR(600MHz,CDCl3)谱中,4.79(br s,H-12a),4.71(m,H-12b)为末端双键两个氢信号,δH 2.58(1H,d,J=18.1Hz,H-2β),2.44(1H,d,J=18.1,H-2α)推测为一组磁不等同亚甲基的质子信号,δH 1.78(3H,s,H-13),1.73(3H,s,H-15),1.09(3H,d,J=6.9Hz,H-14)为三个甲基氢质子信号。13C-NMR(150MHz,CDCl3)显示出15个碳信号,其中,低场区有5个碳信号,δC 205.7(C-3),137.3(C-4),173.8(C-5)为α,β不饱和酮的碳信号,δC 149.7(C-11),109.5(C-12)推测为一组末端双键的碳信号;δC 79.7(C-1)为连氧季碳的信号。通过HSQC数据将全部碳氢直接相关信号进行了全归属。
HMBC谱中,H-2(δH 2.58)与C-4(δC 137.3),C-5(δC 173.8)有相关,H3-15(δH 1.73)与C-3(δC 205.5),C-5(δC 171.8)有相关,推测结构中有如图所示的片段A;H-6(δH 2.39)与C-1(δC 79.7),C-8(δC 30.9),C-11(δC 149.7)有相关,H-9(δH 1.39)与C-7(δC 41.7),C-1(δC 79.7)有相关,H2-12(δH 4.79,4.75)与C-7(δC 41.7),C-13(δC 20.7)有相关,H3-13(δH1.78)与C-7(δC 41.7)有相关,H3-14(δH 1.09)与C-1(δC 79.7),C-9(δC 27.4),C-10(δC45.9)有相关,推测有如图所示的片段B。H-6(δH 2.39)与C-4(δC 137.3)的相关峰以及H-2(δH 2.58)与C-10(δC 45.9)的相关峰的存在,表明片段A和B是通过C-1-C-5骈和起来的。由于化合物2的C-1化学位移值比较大(δC 79.7),推测该位置连有一个羟基。通过上述信息,得到化合物2的平面结构。实验证明化合物2与化合物1有相同的平面结构。
化合物2的NOESY谱图同样无法提供有价值的信息,故而通过计算核磁的方法来确定化合物2的相对构型。由于2与化合物1具有相同的平面结构,四种可能的立体异构体1a-1d在mPW1PW91/6-311+G(d,p)的水平下进行量子化学计算。实测和计算的核磁数据的分析结果表明,化合物2的相对构型为1S*,7R*,10S*。
化合物2的绝对构型是通过实测ECD与计算ECD的比较来确定的。化合物2的实测ECD与1S,7R,10S-2的拟合度比较好。因此,化合物2的绝对构型进一步确定为1S,7R,10S。
综上所述,最终确定了该化合物结构,为Stelleraterpenoid B(2)。
化合物2的1H(600MHz)与13C(150MHz)NMR数据(CDCl3)
Stelleraterpenoid D(3):淡黄色油状物(氯仿),10%香草醛硫酸显橘色,HRESIMS给出准分子离子峰[M+Na]+峰m/z 271.1304(calcd for C15H20O3Na,271.1305),确定该化合物的分子量为234,分子式为C15H20O3,计算不饱和度为5。
1H-NMR(600MHz,CDCl3)谱中,δH 6.21(1H,s,H-2)推测为一个烯键质子信号,δH4.72(1H,m,H-12a),4.71(1H,t,J=1.2Hz,H-12b)推测为一组末端双键的两个氢信号,δH3.06(1H,dd,J=14.3,9.9Hz,H-6α),2.48(1H,d,J=14.3,H-6β)推测为一组磁不等同CH2的偕偶质子信号,δH 2.25(3H,s,H-14),1.77(3H,s,H-13),1.75(3H,s,H-15)推测为三个甲基氢质子信号。13C-NMR(150MHz,CDCl3)显示出15个碳信号,其中,低场区有7个碳信号,δC150.7(C-11),109.3(C-12)推测为一组末端双键的碳信号,因此,结构中存在一个羰基片段,结合碳谱中化学位移值最大的信号峰为δC 163.7(C-3),因此推测结构中应该存在一个酯羰基片段;δC 73.8(C-10)为连氧季碳的信号。通过HSQC数据将全部碳氢直接相关信号进行了全归属。
HMBC谱中,H2-2(δH 6.21)与C-5(δC 115.8)有相关,H3-15(δH 2.25)与C-4(δC157.2),C-5(δC 115.8)有相关,结合C-3(δC 163.7)/C-4(δC 157.2)的化学位移值,推测结构中一个片段A;H2-6(δH 3.06,2.48)与C-1(δC 163.6),C-8(δC 29.9),C-11(δC 150.2)有相关,H-9(δH 2.24)与C-1(δC163.6),C-7(δC 47.2)有相关,H2-12(δH 4.72,4.71)与C-7(δC47.2),C-11(δC 150.2),C-13(δC 21.0)有相关,H3-13(δH 1.77)与C-7(δC 47.2)有相关,H3-14(δH 1.33)与C-1(δC 163.6),C-9(δC 40.1),C-10(δC 73.8)有相关,结合C-10(δC 73.8)的化学位移值,推测有一个片段B。H2-6(δH 3.06,2.48)与C-4(δC 157.2)的相关峰以及H-2(δH6.21)与C-10(δC 73.8)的相关峰的存在,表明片段A和B是通过C-1-C-5骈和起来的。根据以上相关信息建立了化合物3的平面结构。
由于NOESY谱中缺乏有效的相关信号,因此,采用计算核磁的方法来确定其相对构型。两种可能的立体异构体(7R*,10R*)-3a,(7R*,10S*)-3b在mPW1PW91/6-311+G(d,p)的水平下进行量子化学计算。两种立体异构体的线性回归方程对应的R2分别为0.9965和0.998,MAE值分别为5.93和5.30ppm,同时,DP4+统计分析给出3b的可能性为100%,表明化合物3的相对构型应为7R*,10S*。
化合物3的绝对构型是通过计算ECD的方法确定的。实测ECD的谱图与计算得到的谱图相似性很高,因而可以确定化合物3的绝对构型为7R,10S。
综上所述,最终确定了该化合物结构,为Stelleraterpenoid D(3)。
化合物3的1H(600MHz)与13C(150MHz)NMR数据(CDCl3)
Stelleraterpenoid K(4):黄色油状物(二氯甲烷),10%香草醛显蓝色。 HRESIMS给出准分子离子峰[M+Na]+峰m/z(calcd for C15H20O4Na,273.1461),结合1H-NMR,13C-NMR推测其分子式为C15H20O4,计算不饱和度为5。
1H-NMR(600MHz,CDCl3)中,δH 3.81(1H,d,J=11.7Hz,H-12a),3.74(1H,d,J=11.7Hz,H-12b)推测为含氧亚甲基上两个磁不等同的氢信号,δH 2.77(1H,d,J=19.4Hz,H-6β),2.24(1H,d,J=19.4Hz,H-6α)推测为一组亚甲基上两个磁不等同的氢信号,δH 1.53(3H,s,H-14),δH1.17(3H,d,J=6.8Hz,H-15),δH 0.95(3H,s,H-13)推测为三个甲基氢信号。13C-NMR(150MHz,CDCl3,Table 2-12)显示15个碳信号,低场区显示出δC 205.3(C-2),174.9(C-5),145.4(C-1)的一组α,β-不饱和羰基的碳信号,δC 218.9(C-8)推测为一个酮羰基的碳信号,δC 82.3(C-7),64.3(C-12)为两个连氧碳信号,在高场区δC 18.7(C-15),13.2(C-14),11.5(C-13)为三个甲基的碳信号。通过HSQC谱将全部碳氢直接相关信号进行了全归属。
在HMBC谱图中,H2-3(δH 2.64,2.04)与C-2(δC 205.3)有相关,H-4(δH 2.65)与C-2(δC205.3)有相关,H3-15(δH 1.17)与C-3(δC 45.3),C-4(δC 34.4),C-5(δC 174.9)有相关,得到一个片段A;H2-6(δH 2.77,2.24)与C-1(δC 145.4),C-8(δC218.9)有相关,H2-9(δH2.62,2.35)与C-1(δC145.4)有相关H3-14(δH 1.53)与C-1(δC 145.4),C-9(δC 51.4),C-10(δC 41.6)有相关,可以得到片段B;H3-13(δH 0.95)与C-11(δC 49.8),C-12(δC 64.3)有相关,并且考虑到C-12的化学位移值,推测有片段C。H2-6(δH 1.94,1.54)与C-1(δC 145.4)的相关峰,表明片段A和B是通过C-1-C-5骈和起来的;H2-6(δH 1.94,1.54)/H2-9(δH 2.62,2.35)/H3-14(δH 1.53)与C-11(δC 49.8)有相关,H3-13(δH 0.95)与C-7(δC 82.3),C-10(δC41.6)推测片段C通过C-11与片段B中的C-7/C-10相连形成了一个桥环结构。此外,考虑到C-7(δC 82.3)的化学位移值,推测该位置连有一个羟基。根据以上相关信息建立了化合物4的平面结构,如图所示,化合物4为一个愈创木烷型倍半萜类化合物。
化合物的相对构型通过NOESY光谱进行确定,H-15(δH 1.17)与和H-13(δH 0.95)均与H-6β(δH 2.77)有相关,因此确定该化合物的相对构型为4S*,7R*,10S*,11R*。
化合物4的绝对构型同样是通过计算ECD的方法确定的。该化合物的实测ECD曲线与4S,7R,10S,11R-4的计算值具有高度的相似性,因此,该化合物4的绝对构型为4S,7R,10S,11R。
综上所述,最终确定了该化合物结构,为Stelleraterpenoid K(4)。
化合物4的1H(600MHz)与13C(150MHz)NMR数据(CDCl3)
对发明所述四个新的愈创木烷型倍半萜类化合物对H2O2诱导的人神经母细胞瘤SH-SY5Y损伤的神经保护作用进行了考察,体外细胞试验结果表明所述化合物对H2O2诱导的人SH-SY5Y细胞氧化损伤均具有保护作用。化合物1与2的作用更显著。故本发明所述的新的愈创木烷型倍半萜类化合物具有治疗神经退行性疾病的医药新用途。
本发明的优点在于,所述化合物均为新化合物,结构新颖,且均为立体构型确定的光学纯化合物,同时其神经细胞保护活性强,具有进一步开发的价值。
附图说明:
图1化合物1的UV谱;
图2化合物1的HR-ESIMS谱;
图3化合物1的CD谱;
图4化合物1的1H-NMR谱(400MHz,CDCl3);
图5化合物1的13C-NMR谱(100MHz,CDCl3);
图6化合物1的HSQC谱(600MHz,CDCl3);
图7化合物1的HMBC谱(600MHz,CDCl3);
图8化合物2的UV谱;
图9化合物2的HR-ESIMS谱;
图10化合物2的CD谱;
图11化合物2的1H-NMR谱(600MHz,DMSO);
图12化合物2的13C-NMR谱(150MHz,DMSO);
图13化合物2的HSQC谱(600MHz,DMSO);
图14化合物2的HMBC谱(600MHz,DMSO);
图15化合物3的UV谱;
图16化合物3的HR-ESIMS谱;
图17化合物3的CD谱;
图18化合物3的1H-NMR谱(600MHz,CDCl3);
图19化合物3的13C-NMR谱(150MHz,CDCl3);
图20化合物3的H-H COSY谱(600MHz,CDCl3);
图21化合物3的HSQC谱(600MHz,CDCl3);
图22化合物3的HMBC谱(600MHz,CDCl3);
图23化合物4的UV谱;
图24化合物4的HR-ESIMS谱;
图25化合物4的CD谱;
图26化合物4的1H-NMR谱(600MHz,CDCl3);
图27化合物4的13C-NMR谱(150MHz,CDCl3);
图28化合物4的H-H COSY谱(600MHz,CDCl3);
图29化合物4的HSQC谱(600MHz,CDCl3);
图30化合物4的HMBC谱(600MHz,CDCl3);
图31化合物4的NOESY谱(600MHz,CDCl3);
具体实施方式:
下面所列实施例有助于本领域技术人员更好地理解本发明,但不以任何方式限制本发明。
实施例1:化合物1-4的制备。
取干燥的瑞香狼毒根以70%工业乙醇回流提取两次,合并提取液浓缩得浸膏,浸膏采用乙酸乙酯萃取并将所得组分经硅胶柱色谱,以二氯甲烷-甲醇系统1:0-0:1v/v进行等度梯度洗脱,共收集到6个馏分(Fr.A-F);
馏分Fr.A经HP-20柱和ODS开放柱色谱,以分别以甲醇-水系统10:90-90:10v/v进行梯度洗脱,得四个组分Fr.A1-A4;
Fr.A3经硅胶柱色谱以石油醚-二氯甲烷系统50:1-1:1在TLC分析的基础上得到四个亚组分Fr.A3a-Fr.A3d;
在制备性反相高效液相色谱上使用甲醇-水(75:25-85:15v/v)的流动相来分离Fr.A3b得到了化合物1和化合物2;
在制备性反相高效液相色谱上使用乙腈-水(45:55-60:40v/v)的流动相来分离Fr.A3c得到了化合物3和化合物4。
实施例2:化合物1-4在体外对H2O2诱导的人SH-SY5Y神经细胞损伤保护作用的考察。
利用MTT实验,考察化合物对H2O2诱导的SH-SY5Y细胞损伤的保护作用。将细胞放置在96孔板中,以100μL培养液静置12h,使用不同浓度的化合物1-4(12.5,25,50μM)预处理SH-SY5Y神经细胞1h,并用H2O2(1mM)处理细胞36h。随后将培养液替换为含有0.5mg/mL MTT的磷酸盐缓冲溶液并在37℃下放置4h。除去上清液并加入DMSO(150mL/孔),以H2O2(1mM)单独处理的细胞为对照组,利用紫外分光光度计(Thermo Scientific Multiskan MK3,上海,中国)检测不同浓度处理的细胞在490nm波长下的吸光度。细胞的存活程度以存活百分比表示,并利用GraphPad Prism 6软件进行分析。结果显示,化合物1-4不同浓度下均表现出显著的保护作用。2在12.5μM浓度下作用最强,相较于阳性药的63.9±4.63%,其细胞存活率达到了73.4±3.88%。1、2在25μM浓度下作用最强,相较于阳性药的65.4±3.89%,其细胞存活率达到了70.9±2.17%和69.7±3.49%。4在50μM浓度下作用最强,相较于阳性药的70.9±4.23%,其细胞存活率达到了68.8±1.09%。
模型组相比于对照组的细胞存活百分比###P<0.001;实验组相比于模型组的细胞存活百分比**P<0.05,***P<0.001。
Claims (8)
1.如下结构所示的愈创木烷型倍半萜类化合物或其药学上可接受的盐:
。
2.一种制备权利要求1所述的化合物或其药学上可接受的盐的方法,其特征在于,包括如下步骤:
(1)取干燥的瑞香狼毒根以乙醇提取,合并提取液浓缩得浸膏,浸膏采用乙酸乙酯萃取并将所得馏分经硅胶柱色谱,以二氯甲烷-甲醇系统1:0-0:1进行等度梯度洗脱,共收集到6个馏分Fr.A-F;
(2)馏分Fr.A经HP-20柱和ODS开放柱色谱,分别以甲醇-水系统10:90-90:10 进行梯度洗脱,得四个组分Fr.A1-A4;
(3)Fr.A3经硅胶柱色谱以石油醚-二氯甲烷系统50:1-1:1在TLC分析的基础上得到四个亚组分Fr.A3a-Fr.A3d;
(4)在制备性反相高效液相色谱上使用甲醇-水为流动相来分离Fr.A3b得到了化合物1和化合物2。
3.如权利要求2所述的方法,其特征在于,步骤(1)所述的乙醇为70-80%工业乙醇,所述提取为回流提取,提取2-3次,每次2-4小时。
4.如权利要求2所述的方法,其特征在于,步骤(1)所述的瑞香狼毒为瑞香科(Thymelaeaceae)狼毒属(Stellera Linn.)植物瑞香狼毒(Stellera chamaejasme L.)的干燥根。
5.如权利要求2所述的方法,其特征在与,步骤(4)中所述的甲醇-水的体积比为75:25-85:15 v/v, 乙腈-水的体积比为45:55-60:40 v/v。
6.一种药物组合物,包含权利要求1所述的愈创木烷型倍半萜类化合物或其药学上可接受的盐和药学上可接受的载体或赋形剂。
7.权利要求1所述的愈创木烷型倍半萜类化合物或其药学上可接受的盐或权利要求6所述的药物组合物在制备神经保护药物中的应用。
8.权利要求1所述的愈创木烷型倍半萜类化合物或其药学上可接受的盐或权利要求6所述的药物组合物在制备保护SH-SY5Y神经细胞损伤药物中的应用。
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