CN106380400A - 一种萜品烯醇类化合物及其制备方法和应用 - Google Patents

一种萜品烯醇类化合物及其制备方法和应用 Download PDF

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CN106380400A
CN106380400A CN201610079970.4A CN201610079970A CN106380400A CN 106380400 A CN106380400 A CN 106380400A CN 201610079970 A CN201610079970 A CN 201610079970A CN 106380400 A CN106380400 A CN 106380400A
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terpinene
alcohol compound
terpinenol
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CN106380400B (zh
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朱婉萍
胡永洲
刘霞
孔繁智
王昱霁
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Zhejiang Traditional Chinese Medicine Research Institute
Zhejiang Academy of Traditional Chinese Medicine
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Abstract

本发明公开了一种萜品烯醇类化合物及其制备方法和应用，该萜品烯醇类化合物的结构如式(Ⅰ)或(Ⅱ)所示，式(Ⅰ)中，R独立地选自C12～C16烷基、-NR1R2、-SR3或-OR4；R1、R2、R3和R4独立地选自C1～C6烷基或-NO2，所述的C1～C6烷基可被OH取代；或者所述的R1、R2与连接它们的N共同形成五元环或者六元环，所述的五元环或者六元环可以含有一个O或者C＝O。活性测试结果表明，该萜品烯醇类化合物具有较好的抗哮喘作用、抗炎作用和抗肺动脉高压作用，具有重要的药学意义。

Description

一种萜品烯醇类化合物及其制备方法和应用
技术领域
本发明属于生物医药领域，具体涉及一种萜品烯醇类化合物及其制备方法和应用。
背景技术
艾叶油为菊科植物艾(Artemisia argyi)的干叶或鲜叶中所含的挥发油，能直接松弛气管平滑肌，对抗原、乙酰胆碱和组胺诱发的气管平滑肌痉挛和哮喘均有保护作用。还具有抗过敏作用，可抑制致敏肺组织释放过敏的慢反应物质(SRS-A)，并能拮抗SRS-A和5-羟色胺的作用。亦具有一定的祛痰、镇咳作用。对心脏无兴奋作用，主要用于支气管哮喘和哮喘型慢性支气管炎。
α-萜品烯醇是从艾叶油中提取的一种平喘有效成分，化学名称为：α,α,4-三甲基--3-环己烯-1-甲醇。卞如濂等人报道了α-萜品烯醇的药理作用(“新平喘药—α-萜品烯醇的药理作用”，《中国药理学通报》，1987年第3卷第6期，323页～328页)，发现α-萜品烯醇在豚鼠整体和离体实验中具有气道松弛作用，能升高气管平滑肌内cAMP含量，还有抗过敏、镇咳和祛痰作用,并且毒性低，为一安全有效的新平喘药。α-萜品烯醇不同于β受体激动剂，对豚鼠离体心房具有抑制作用。
公开号为CN 103922927 A的中国专利申请公开了一种α-萜品烯醇衍生物及其制备方法和应用，该α-萜品烯醇衍生物的结构如下：
其中，R选自C1～C5烷基，通过对α-萜品烯醇的衍生化，使得平喘活性有了一定程度的增强，然而平喘活性仍然不够好。
发明内容
本发明提供了一种萜品烯醇类化合物及其制备方法和应用，该萜品烯醇类化合物具有更好的抗哮喘活性，同时还具有一定的抗炎活性。
一种抗哮喘化合物，结构如式(Ⅰ)或(Ⅱ)所示：
式(Ⅰ)中，R独立地选自C12～C16烷基、-NR1R2、-SR3或-OR4；
R1、R2、R3和R4独立地选自C1～C6烷基或-NO2，所述的C1～C6烷基可被OH取代；
或者所述的R1、R2与连接它们的N共同形成五元环或者六元环，所述的五元环或者六元环可以含有一个O或者C＝O。
经过活性测试表明，本发明的萜品烯醇类化合物可以有效舒张支气管平滑肌、减少炎症细胞，同时有效地缓解肺动脉高压。
作为优选，所述的R为-NR1R2，此时，所述的萜品烯醇类化合物可以与酸形成药学上可接受的盐，更容易被水溶解，便于制药应用。
作为优选，所述的R为C12H25、C16H33或以下基团中的一种：
其中，表示连接位置。
采用这些基团时，化合物活性较好，并且更容易获得。
本发明还提供了一种所述的萜品烯醇类化合物的制备方法。
当萜品烯醇类化合物为式(Ⅰ)所示的化合物，且R为C12～C16烷基时，该制备方法包括以下步骤：
在吡啶的作用下，将α-萜品烯醇与烷酰氯在二氯甲烷中进行反应，反应完成后得到所述的萜品烯醇类化合物；
所述的烷酰氯为C14～C16烷酰氯。
当萜品烯醇类化合物为式(Ⅰ)所示的化合物，且R为-NR1R2、-SR3或-OR4时，该制备方法包括以下步骤：
(1)在吡啶的作用下，α-萜品烯醇与溴乙酰溴在二氯甲烷中发生酯化反应，得到酯化中间体；
(2)在无机碱的作用下，步骤(1)得到的酯化中间体与亲核试剂在乙腈中发生取代反应，得到所述的萜品烯醇类化合物；
所述的亲核试剂为HNR1R2、HSR3或HOR4。
当萜品烯醇类化合物为式(Ⅱ)所示的化合物，该制备方法包括以下步骤：
在Pd/C和氢气氛围下，α-萜品烯醇在甲醇中进行加氢反应，得到所述的萜品烯醇类化合物。
本发明还提供了一种所述的萜品烯醇类化合物在制药领域中的应用。
作为优选，所述的萜品烯醇类化合物用于制备抗哮喘药物；
所述的抗哮喘药物用于舒张支气管。
试验结果表明，所述的萜品烯醇类化合物还可以有效地减少炎症细胞的数量，作为另外的优选，所述的萜品烯醇类化合物用于制备抗炎药物。
作为另外的优选，所述的萜品烯醇类化合物用于制备治疗或者缓解肺动脉高压的药物。
同现有技术相比，本发明的有益效果体现在：
(1)本发明通过对萜品烯醇类化合物的进行衍生化，有效地提高了这类化合物的抗哮喘作用和抗肺动脉高压作用；
(2)本发明的萜品烯醇类化合物可以减少炎症细胞，具有较好的抗炎活性。
具体实施方式
实施例1
精密称取原料α-萜品烯醇(4mmol)溶于10ml二氯甲烷中，加入吡啶(6mmol)，冰浴下滴加十四烷酰氯(6mmol)，室温反应8小时得终产物2a(3.74mmol,产率93.5％)。产物结构如下：
实施例2
精密称取原料α-萜品烯醇(4mmol)溶于10ml二氯甲烷中，加入吡啶(6mmol)，冰浴下滴加十八烷酰氯(6mmol)，室温反应8小时得终产物2b(3.86mmol,产率96.5％)。
实施例3～12
(1)称取原料α-萜品烯醇1.85g(10mmol)置于50ml圆底烧瓶内，加入30ml二氯甲烷，吡啶1.91ml(20mmol),冰浴下加入溴乙酰溴2.09ml(20mmol)，室温反应7小时得中间体3(5.9mmol,产率48.2％)。
反应式如下：
(2)将中间体3(274mg,1mmol)溶于10mL乙腈中，室温下加入无水碳酸钾(276.4mg,2mmol)和中间体4(2mmol)，得到产物5，中间体4的结构和收率见表1。
表1 实施例3～12的底物与结果
实施例13
将α-萜品烯醇(400mg)加入到10mL甲醇中，加入Pd/C(40mg)，氢气环境下搅拌8h。分离得到无色油状物6(38mg,93.5％)，反应式如下：
部分化合物的结构表征数据如下：
化合物A：
1H NMR(500MHz,CDCl3)：δ5.37(s,1H),2.25–2.16(m,2H),2.07–1.90(m,4H),1.89–1.76(m,2H),1.64(s,3H),1.61–1.52(m,2H),1.43(s,3H),1.41(s,3H),1.25(s,21H),0.91–0.82(m,3H).
化合物B
1H NMR(500MHz,CDCl3)：δ5.36(dd,J＝8.3,6.9Hz,1H),2.20(t,J＝7.5Hz,2H),2.08–1.91(m,4H),1.88–1.75(m,2H),1.64(s,3H),1.58–1.53(m,2H),1.44(s,3H),1.41(s,3H),1.34–1.19(m,29H),0.88(t,J＝7.0Hz,3H).
化合物C
1HNMR(500MHz,CDCl3)：δ5.38(d,J＝2.0Hz,1H),3.62–3.58(m,2H),3.24(s,2H),2.73–2.69(m,2H),2.44(s,3H),2.13–1.93(m,4H),1.89–1.76(m,2H),1.66(s,3H),1.49(s,3H),1.46(s,3H),1.32(tt,J＝10.4,5.3Hz,1H).
化合物D
1HNMR(500MHz,CDCl3)：δ5.38(dd,J＝3.1,1.7Hz,1H),3.78(dd,J＝8.3,3.6Hz,4H),3.13(d,J＝1.3Hz,2H),2.64–2.56(m,4H),2.12–1.92(m,4H),1.89–1.76(m,2H),1.66(s,3H),1.48(s,3H),1.45(s,3H),1.36–1.26(m,1H).
化合物E
1H NMR(500MHz,CDCl3)：δ5.36(s,1H),3.75(s,2H),2.13–1.94(m,4H),1.92–1.76(m,2H),1.64(s,3H),1.45(s,3H),1.36(s,3H),1.33(qd,J＝12.3,5.6Hz,1H).
化合物F
1H NMR(500MHz,CDCl3)：5.38(dd,J＝2.9,1.5Hz,1H),3.23(s,2H),2.67(q,J＝7.3Hz,4H),2.10–1.93(m,4H),1.88–1.76(m,2H),1.65(s,3H),1.47(s,3H),1.44(s,3H),1.35–1.25(m,1H),1.08(td,J＝7.2,4.1Hz,6H).
化合物G
1H NMR(500MHz,CDCl3)：δ5.37–5.34(m,1H),3.75(t,J＝5.6Hz,2H),3.18(s,2H),2.81(t,J＝5.5Hz,2H),2.09–1.94(m,4H),1.86–1.76(m,2H),1.63(s,3H),1.45(s,3H),1.43(s,3H),1.35–1.25(m,1H)；
化合物H
1H NMR(500MHz,CDCl3)：δ5.33(t,J＝8.9Hz,1H),3.24(s,2H),2.87(t,J＝6.1Hz,4H),2.48(t,J＝6.1Hz,4H),2.09–1.89(m,4H),1.86–1.73(m,2H),1.63(s,3H),1.46(s,3H),1.43(s,3H),1.34–1.25(m,1H)；
化合物J
1H NMR(500MHz,CDCl3)：δ5.35(d,J＝2.1Hz,1H),3.73–3.66(m,1H),3.11(s,2H),2.81(td,J＝8.9,3.8Hz,2H),2.38–2.30(m,2H),2.10–1.88(m,4H),1.85–1.74(m,2H),1.68–1.58(m,6H),1.45(s,3H),1.42(s,3H),1.33–1.26(m,1H)；
化合物K
1H NMR(500MHz,CDCl3)：δ5.35(s,1H),3.81(s,1H),3.71(d,J＝11.0Hz,1H),3.60–3.46(m,1H),3.27–3.15(m,2H),2.85–2.77(m,1H),2.68(dd,J＝14.0,8.4Hz,1H),2.09–1.90(m,4H),1.86–1.75(m,2H),1.63(s,3H),1.45(s,3H),1.43(s,3H),1.33–1.25(m,1H)；
化合物L
1H NMR(500MHz,CDCl3)：δ5.42–5.33(m,1H),3.06(d,J＝1.2Hz,2H),2.55–2.43(m,4H),2.10–1.89(m,4H),1.86–1.71(m,2H),1.62(s,3H),1.59(dd,J＝11.3,5.7Hz,4H),1.43(d,J＝5.8Hz,3H),1.42–1.37(m,5H),1.27(ddd,J＝24.4,12.2,5.7Hz,1H)；
化合物M
1H NMR(500MHz,CDCl3)：δ5.33(s,1H),3.56–3.54(m,1H),3.11(s,2H),2.81(td,J＝8.9,3.8Hz,2H),2.38–2.30(m,2H),2.10–1.88(m,4H),1.85–1.74(m,2H),1.68–1.58(m,6H),1.45(s,3H),1.42(s,3H),1.33–1.26(m,1H)；
化合物N
1H NMR(500MHz,CDCl3)：δ1.75(ddd,J＝16.6,10.2,4.5Hz,4H),1.43–1.42(m,1H),1.29–1.17(m,2H),1.13(s,6H),1.07–0.96(m,2H),0.89(dd,J＝12.0,2.9Hz,1H),0.85(d,J＝6.5Hz,3H).
扩张支气管及抗炎作用试验：
方法：制作离体气管条置于气管离体试验装置中，调张力，平衡后加入氯化乙酰胆碱100μL诱导气管收缩，使气管张力升高，待张力升高到最高值且张力趋于平衡后给予相应的受试药拮抗收缩的气管，描记等长肌张力变化曲线，计算平滑肌舒张率。舒张率＝(造模后张力-给药后张力)/(造模后张力)*100％
建立大鼠哮喘模型，末次给药后钝性分离气管，进行支气管肺泡灌洗，收集支气管细胞灌洗液(BALF)，计数有核细胞总数。结果如表2所示。
表2
aCN 103922927 A中具体实施方式中的几个化合物，舒张率的计算公式有改进，同时，不同批次的测定结果有一定的误差，因此，舒张率数据有所差别。
表示取代位置，化合物N为产物结构。
**表示与a-萜品烯醇组比较，P＜0.01；*表示与a-萜品烯醇组比较P＜0.05
△△表示与空白组比较，P＜0.01；△表示与空白组比较，P＜0.05；
与模型组比较，#P＜0.05，##P＜0.01
各化合物组在不同剂量下都能扩大气管平滑肌的舒张率，且有抑制炎症的作用。可应用于哮喘，慢性阻塞性肺疾病及其他各种疾病的炎症治疗，如关节炎，类风湿性关节炎，支气管炎、过敏性鼻炎、过敏性皮炎等。
对野百合碱诱导大鼠肺动脉高压的影响
方法：制作大鼠肺动脉高压模型，正常对照组给予注射等体积生理盐水。造模后第2天给予药物干预，每日给予各个化合物200mg/Kg；正常对照组及模型组每日给予等体积生理盐水灌胃。于第30天，在麻醉状态下以右心导管法测定大鼠右心室收缩压，结果见表3。
表3 不同组别大鼠右心室收缩压(±s)
与模型组相比，△P＜0.05，△△P＜0.01；与a-萜品烯醇组比较，#P＜0.05，##P＜0.01
试验结果表明，各化合物对野百合碱诱导大鼠肺动脉高压有一定保护作用，能改善血流动力学指标，降低右心室收缩压，减轻右心室负荷，降低右心肥厚指数，缓解肺血管重塑。

Claims (9)

1.一种萜品烯醇类化合物，其特征在于，结构如式(Ⅰ)或(Ⅱ)所示：
式(Ⅰ)中，R独立地选自C12～C16烷基、-NR1R2、-SR3或-OR4；
R1、R2、R3和R4独立地选自C1～C6烷基或-NO2，所述的C1～C6烷基可被OH取代；
或者所述的R1、R2与连接它们的N共同形成五元环或者六元环，所述的五元环或者六元环可以含有一个O或者C＝O。
2.根据权利要求1所述的萜品烯醇类化合物，其特征在于，所述的R为C12H25、C16H33或以下基团中的一种：
其中，表示连接位置。
3.一种如权利要求1所述的萜品烯醇类化合物的制备方法，其特征在于，包括以下步骤：
在吡啶的作用下，将α-萜品烯醇与烷酰氯在二氯甲烷中进行反应，反应完成后得到所述的萜品烯醇类化合物；
所述的烷酰氯为C14～C16烷酰氯，所述的R为C12～C16烷基。
4.一种如权利要求1所述的萜品烯醇类化合物的制备方法，其特征在于，包括以下步骤：
(1)在吡啶的作用下，α-萜品烯醇与溴乙酰溴在二氯甲烷中发生酯化反应，得到酯化中间体；
(2)在无机碱的作用下，步骤(1)得到的酯化中间体与亲核试剂在乙腈中发生取代反应，得到所述的萜品烯醇类化合物；
所述的亲核试剂为HNR1R2、HSR3或HOR4。
5.一种如权利要求1所述的萜品烯醇类化合物的制备方法，其特征在于，包括以下步骤：
在Pd/C和氢气氛围下，α-萜品烯醇在甲醇中进行加氢反应，得到所述的萜品烯醇类化合物；
所述的萜品烯醇类化合物为式(Ⅱ)所示的化合物。
6.一种如权利要求1或2所述的萜品烯醇类化合物在制药领域中的应用。
7.根据权利要求6所述的萜品烯醇类化合物在制药领域中的应用，其特征在于，所述的萜品烯醇类化合物用于制备抗哮喘药物；
所述的抗哮喘药物用于舒张支气管。
8.根据权利要求6所述的萜品烯醇类化合物在制药领域中的应用，其特征在于，所述的萜品烯醇类化合物用于制备抗炎药物。
9.根据权利要求6所述的萜品烯醇类化合物在制药领域中的应用，其特征在于，所述的萜品烯醇类化合物用于制备治疗或者缓解肺动脉高压的药物。
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