CN114890882B - 柏木醇衍生物、其制备方法及其应用 - Google Patents
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Abstract
本发明涉及合成药物技术领域，具体而言，涉及柏木醇衍生物、其制备方法及其应用。柏木醇衍生物为以下结构式：
Description
本案为分案申请，母案的申请日为2020年12月14日，申请号为CN202011475888.6，名称为“柏木醇衍生物、其制备方法及其应用”。
技术领域
本发明涉及合成药物技术领域，具体而言，涉及柏木醇衍生物、其制备方法及其应用。
背景技术
柏木醇(cedrol)又称柏木脑，是一种倍半萜醇，它具有愉快而持久的柏木香气，广泛用于木香、辛香和东方型香精中，也大量用作消毒剂、卫生用品的增香剂和香精的定香剂，它也是合成其他香料的中间体。研究表明，柏木醇对大肠杆菌、金黄色葡萄球菌、枯草芽孢杆菌、伤寒沙门氏菌等细菌均有较明显的抑制作用。柏木醇的药理活性有抗痉挛,镇痛、抗炎、抗癌、抗病毒和抗自由基氧化作用等。另外,柏木醇能呈剂量依赖关系加速皮肤成纤维细胞的生长,并且能增加胶原I型蛋白和弹性蛋白的产生。此外,健康人吸入柏木醇能增加副交感神经兴奋,并且降低交感神经兴奋,对心血管系统产生作用,能降低血压。柏木醇也具有抗白蚁能力。
流行性感冒(流感)是一种由流感病毒引起的急性呼吸道传染疾病，主要通过空气飞沫传播，具有爆发突然、蔓延迅速、传播面广的特点。20世纪曾爆发过3次世界范围内的流感大流行，造成了上千万人的死亡。即便到了今天，流感依旧威胁着人类的生命健康，据世界卫生组织(WHO)估算，每年全世界季节性流感导致300万～500万例重症病例，29万～65万例死亡病例。流感病毒包括人流感病毒和动物流感病毒，人流感病毒分为甲(A)、乙(B)、丙(C)3型，是流行性感冒的病原体，其中甲型流感病毒容易发生抗原性变异，并多次引发世界性流感大流行。目前对于流感的预防和治疗主要采用接种疫苗预防和开发抗病毒药物防治并重的应对手段。尽管接种疫苗可以预防同型流感病毒的感染，但需要在流感感染发生前就要开始生产。精确地预测即将传入的流感毒株仍是一个严峻的挑战，并且由于流感病毒存在抗原转变和漂移，流感疫苗每年都要重新生成，这些都给疫苗的生产带来了很大的困难。
鉴于流感的巨大威胁，针对流感的抗病毒药物研发成为一直以来的研究热点，神经氨酸酶抑制剂奥司他韦、帕拉米韦等基于结构的药物设计取得了巨大成功。然而，随着流感病毒的变异，已有的抗流感药物面临严峻的耐药形势，因此，开发新型的抗病毒药物迫在眉睫。
鉴于此，特提出本发明。
发明内容
本发明的目的在于提供柏木醇衍生物、其制备方法及其应用。本发明实施例提供一系列新的柏木醇衍生物，其对病毒、特别是流感病毒有良好的拮抗作用，继而扩大了柏木醇及其衍生物的应用范围，且扩大了柏木醇类衍生物的种类。
本发明是这样实现的：
第一方面，本发明提供一种柏木醇衍生物，其为以下结构式：
第二方面，本发明提供一种前述实施方式所述的柏木醇衍生物的制备方法，包括利用柏木醇为原料进行化学反应合成得到柏木醇衍生物。
第三方面，本发明提供一种前述实施方式所述的柏木醇衍生物在制备抗病毒药物中的应用。
本发明具有以下有益效果：本发明实施例提供的柏木醇衍生物对于病毒有良好的治疗作用，特别是流感病毒，继而该柏木醇衍生物可以用于制备治疗病毒引起的疾病，扩大了柏木醇衍生物的应用范围，也扩大了柏木醇衍生物的种类。
具体实施方式
为使本发明实施例的目的、技术方案和优点更加清楚，下面将对本发明实施例中的技术方案进行清楚、完整地描述。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市售购买获得的常规产品。
本发明实施例提供一种柏木醇衍生物，其为其为以下结构式：
本发明实施例还提供一种上述柏木醇衍生物在制备抗病毒药物中的应用，特别地，该病毒为流感病毒。
需要说明的是：本发明实施例采用的1H-和13C-NMR由Bruker AVANCE III-600、DRX-500或AM-400测定，内标为TMS，其中1H NMR在400MHz，500MHz和600MHz下测定，13C NMR在100MHz，125MHz和150MHz下测定；质谱HREI-MS和EI-MS由Finnigan-MAT 90质谱仪测定；HRESI-MS和ESI-MS由API QSTAR Pulsar i质谱仪测定；旋转蒸发仪：Buchi R-200、R-201；DLSB5110型低温反应冷却液循环泵，IKA RCT basic(安全控制型)加热磁力搅拌器。
柱色谱材料：柱层析用硅胶(80-100目和200-300目)与预制GF254 TLC板均为青岛海洋化工厂生产；Sephadex LH-20为瑞典Amersham Biosciences公司产品；ChromatorexC-18(40-75μm)为日本Fuji Silysia化学公司产品。HPLC：Agilent 1100，Zorbax SB-C18column，5μm，4.6mm×150mm；Prep-HPLC：Agilent 1200，Zorbox SB-C18 column，5μm，9.4mm×150mm。显色方法为荧光灯下波长254、365nm处观察荧光，I2蒸气显色，10％硫酸香草醛处理后加热显色。
其它试剂来自于Sigma Aldrich,J&K百灵威，北京伊诺凯公司或安耐吉试剂公司，均为商品化的分析纯或化学纯试剂，本发明实验部分所采用的无水试剂(如无水THF、DCM、Toluene、DMF等)均按无水溶剂标准处理程序制备。
以下结合实施例对本发明的特征和性能作进一步的详细描述。
实施例1
本实施例提供一种柏木醇衍生物(编号为化合物2)，名为：(3R,3aS,7S,8aS)-3,6,8,8-四甲基-2,3,4,7,8,8a-六氢-1H-3a,7-雪松烷，其结构式如下所示：
本实施例提供该柏木醇衍生物的制备方法：在反应容器中加入0.1mmol柏木醇(编号为化合物1)，对甲苯磺酸0.1mmol，然后加入2mL乙腈，50℃反应0.5小时后，反应结束后，反应溶液加入水或饱和盐溶液洗涤淬灭反应，然后用有机溶剂萃取，干燥，减压蒸馏浓缩除去溶剂，粗产品经柱色谱分离，即得目标产物，产率96％。
化合物2的表征数据如下：Colorless oil,96％,1H NMR(600MHz,CDCl3)δ5.23-5.22(m,1H),2.19-2.15(m,1H),1.86-1.57(m,11H),1.40-1.34(m,3H),1.02(s,3H),0.95(s,3H),0.85(d,3H,J＝7.3Hz)；13C NMR(150MHz,CDCl3)δ140.59,119.21,58.92,54.80,53.85,48.17,41.45,40.65,38.81,36.06,27.67,25.61,24.79,15.45。
实施例2
本实施例提供一种柏木醇衍生物(编号为化合物3)，名为：(3R,3aR,6S,7S,8aS)-3,6,8,8-四甲基八氢-1H-3a,7-雪松烷-5-醇，其结构式如下：
本实施例提供该柏木醇衍生物的制备方法：在反应容器中加入实施例1制备得到的0.1mmol化合物2溶于2mLTHF中，加入0.5mmol BH3.DMS反应4h后，然后加入1eq.的NaOH和H2O2，反应3小时后，反应结束后，反应溶液加入水或饱和盐溶液洗涤淬灭反应，然后用有机溶剂萃取，干燥，减压蒸馏浓缩除去溶剂，粗产品经重结晶，即得目标产物，产率81％。
化合物3的表征数据如下：White salt,81％,m.p.143-145℃.1H NMR(600MHz,CDCl3)δ3.79-3.78(m,1H),1.99-1.95(m,1H),1.85-1.83(m,1H),1.75-1.71(m,3H),1.62-1.48(m,5H),1.40-1.24(m,3H),1.20-1.18(m,2H),1.16(d,3H,J＝7.4Hz),1.13(s,3H),0.94(s,3H),0.85(d,3H,J＝6.8Hz)；13C NMR(150MHz,CDCl3)δ72.16,57.28,54.11,53.92,45.87,45.27,42.99,42.83,40.73,35.70,27.85,26.87,24.72,16.83,14.55。
实施例3
本实施例提供一种柏木醇衍生物(编号为化合物4)，名为：(3R,3aR,6S,7S,8aS)-5-(二氟甲氧基)-3,6,8,8-四甲基八氢-1H-3a,7-雪松烷，其结构式如下：
本实施例提供该柏木醇衍生物的制备方法：在反应容器中加入0.1mmol实施例2提供的化合物3溶于2mL二氯甲烷：水(1:1)中，加入3.8mmol TMSCF2Br和7.6mmol KHF2，室温条件下反应2h，反应结束后，反应溶液加入水或饱和盐溶液洗涤淬灭反应，然后用有机溶剂萃取，干燥，减压蒸馏浓缩除去溶剂，粗产品经柱色谱分离，即得目标产物，产率72％左右。
化合物4的表征数据如下：White salt,72％,m.p.135-136℃.1H NMR(600MHz,CDCl3)δ6.39-6.13(m,1H),4.26-4.21(m,1H),1.99-1.96(m,1H),1.85-1.82(m,1H),1.75-1.70(m,2H),1.68-1.66(m,2H),1.62-1.57(m,2H),1.52-1.49(m,2H),1.22-1.18(m,2H),1.15(d,3H,J＝6.9Hz),1.12(s,3H),0.94(s,3H),0.85(d,3H,J＝6.9Hz)；13C NMR(150MHz,CDCl3)δ117.11,115.40,113.69,72.14,57.28,54.11,53.92,45.88,45.26,42.99,42.83,40.73,35.70,27.85,26.87,24.72,16.83,14.55。
实施例4
本实施例提供一种柏木醇衍生物(编号为化合物5)，名为：(3R,3aR,6S,7S,8aS)-3,6,8,8-四甲基六氢-1H-3a,7-雪松烷-5(4H)-酮，其结构式如下：
本实施例提供该柏木醇衍生物的制备方法：在反应容器中加入0.1mmol化合物3溶于2mL二氯甲烷中，加入0.11mmol PCC，室温条件下反应3h，反应结束后，减压蒸馏浓缩除去溶剂，粗产品经柱色谱分离，即得目标产物，产率84％左右。
化合物5的表征数据如下：Colorless oil,84％,1H NMR(600MHz,CDCl3)δ2.67-2.65(m,1H),2.35(d,1H,J＝1.6.2Hz),2.22-2.18(m,1H),1.89-1.83(m,3H),1.73-1.66(m,2H),1.63-1.56(m,2H),1.44-1.27(m,2H),1.12(d,3H,J＝7.5Hz),0.97(s,3H),0.95(s,3H),0.83(d,3H,J＝6.9Hz)；13C NMR(150MHz,CDCl3)δ215.92,57.46,54.63,54.17,48.75,45.89,41.73,40.57,36.55,35.74,25.96,25.87,24.72,17.18,14.34.HR-EI-MS(positive)m/z 221.18999[M+H]+(calcd for C15H25O 221.18272)。
实验例
病毒株：流感病毒株H1N1 PR8由本实验室扩增保存。
细胞模型：狗肾细胞系MDCK，本实验室传代保存。培养条件：DMEM+10％胎牛血清、37℃、5％CO2。
采用CellTiter-GloTM(Promega)试剂盒检测样品对细胞的毒性作用。
细胞毒性实验原理：CellTiter-Glo试剂盒通过对ATP进行定量测定来检测培养物中活细胞数目。有代谢活性细胞的呼吸作用和其他生命活动过程可以产生ATP，试剂盒中使用萤光素酶生成的稳定辉光型信号，发光过程中萤光素酶需要ATP的参与。向细胞培养基中加入CellTiter-Glo试剂测量发光值，光信号和体系中ATP量成正比，而ATP量和活细胞数呈正相关，因此光信号值可以反映活细胞的数目。
细胞毒性试验步骤：将MDCK细胞接种于96孔细胞培养板中，细胞贴壁后备用。化合物1-5分别用DMEM培养基从2倍最高检测浓度起连续3倍梯度稀释8个梯度。将化合物及适量培养基加入到细胞中，于37℃的CO2培养箱中培养。加药培养24h后，显微镜下观察药物引起的细胞病变效应(CPE)，加入CellTiter-Glo检测细胞存活率。药物对细胞的毒性以细胞的活性表示。
计算公式：细胞活性(％)＝药物组数值/细胞对照组平均值*100。
抗病毒活性实验原理：实验采用测定流感病毒蛋白表达水平来检测病毒的复制水平。流感病毒的结构蛋白的表达水平与病毒的复制成正比；实验采用高灵敏度的试剂检测流感病毒蛋白的表达，通过荧光强度的变化反应出来。
抗病毒活性检测步骤：MDCK细胞接种于96孔细胞培养板中，37℃培养过夜后备用。MDCK细胞中同时加入对应的化合物及H1N1病毒液。置于37℃细胞培养箱培养24h后，取培养液上清进行检测。
实验设空白对照孔(正常细胞)，病毒对照孔(病毒感染后未加药物)，阳性药物对照孔(感染后加利巴韦林)。
抑制率(％)＝100-(样品孔数值-空白对照数值)/(病毒对照数值-空白对照数值)*100。
检测结果如下表。
根据上述表格可以看出，本发明实施例提供的系列柏木醇衍生物具有良好的抗病毒效果，可以用于制备具有抗病毒的药物。
以上所述仅为本发明的优选实施例而已，并不用于限制本发明，对于本领域的技术人员来说，本发明可以有各种更改和变化。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (4)
1.一种柏木醇衍生物在制备抗病毒药物中的应用；其特征在于，所述病毒为流感病毒；
所述柏木醇衍生物的结构式如下：
2.根据权利要求1所述的应用，其特征在于，所述柏木醇衍生物的制备包括以下步骤：
在反应容器中加入0.1mmol柏木醇和对甲苯磺酸0.1mmol，然后加入2mL乙腈，50℃反应0.5小时后，反应结束后，反应溶液加入水或饱和盐溶液洗涤淬灭反应，然后用有机溶剂萃取，干燥，减压蒸馏浓缩除去溶剂，粗产品经柱色谱分离，得化合物2；
在反应容器中加入0.1mmol化合物2溶于2mLTHF中，加入0.5mmol BH3.DMS反应4h后，然后加入1eq.的NaOH和H2O2，反应3小时后，反应结束后，反应溶液加入水或饱和盐溶液洗涤淬灭反应，然后用有机溶剂萃取，干燥，减压蒸馏浓缩除去溶剂，粗产品经重结晶，得化合物3；
在反应容器中加入0.1mmol化合物3溶于2mL二氯甲烷中，加入0.11mmol PCC，室温条件下反应3h，反应结束后，减压蒸馏浓缩除去溶剂，粗产品经柱色谱分离，即得所述柏木醇衍生物。
3.根据权利要求1所述的应用，其特征在于，所述药物中所述柏木醇衍生物的质量含量为0.1-99％。
4.根据权利要求3所述的应用，其特征在于，所述药物中所述柏木醇衍生物的质量含量为0.5-90％。
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