CN104188982B - 闭花木酮Cleistanone的O-(吗啉基)乙基衍生物在制备抗缺氧药物中的应用 - Google Patents
闭花木酮Cleistanone的O-(吗啉基)乙基衍生物在制备抗缺氧药物中的应用 Download PDFInfo
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Abstract
本发明涉及有机合成和药物化学领域，具体涉及闭花木酮Cleistanone的O‑(吗啉基)乙基衍生物、制备方法及其在制备抗缺氧药物上的用途。本发明合成了一个新的闭花木酮Cleistanone的O‑(吗啉基)乙基衍生物，并公开了其制备方法。药理学实验表明，本发明的闭花木酮Cleistanone的O‑(吗啉基)乙基衍生物具有抗缺氧的作用，具有开发抗缺氧药物的价值。
Description
技术领域
本发明涉及有机合成和药物化学领域，具体涉及闭花木酮Cleistanone的O-(吗啉基)乙基衍生物、制备方法及其用途。
背景技术
氧是人类及许多生物赖以生存的重要条件。低氧(Hypoxia)是指机体生命活动所需的氧不能得到充足的供给。氧和低氧是生命活动最重要的关键因素，是生命科学基本理论的重要课题。低氧的形成可分为三类：第一类是外界环境氧含量降低，使正常生理活动过程不能摄取足够氧，如高原和航空缺氧；第二类是指因疾病等导致外界正常氧量不能充分到达机体内，造成心、脑和呼吸系统等的缺氧；第三类是机体活动所需氧消耗量，超过了生理动员能力，造成相对氧供给不足，常见于剧烈运动和超限量劳动。长期低氧是危害人体健康的重要隐患，严重者可危及生命。因此，低氧造成心、脑和呼吸系统等损伤已成为21世纪医学界急待解决的主要问题之一。
从天然产物中寻找化合物或先导化合物并进行结构修饰获得其衍生物，从而得到高效低毒的潜在药物具有重要价值。
目前对于心衰的治疗，临床上没有特效药物，大部分药物在缓解心衰症状的同时具有不可避免的毒副作用，从天然产物中寻找化合物或先导化合物并进行结构修饰获得其衍生物，从而得到高效低毒的潜在药物具有重要价值。
本发明涉及的化合物闭花木酮Cleistanone是一个2011年发表(Van Trinh ThiThanh et al.,2011.Cleistanone:A Triterpenoid from Cleistanthus indochinensiswith a New Carbon Skeleton.Volume2011,Issue22,pages4108–4111,August2011)的化合物，我们对化合物闭花木酮Cleistanone进行了结构修饰，获得了一个新的闭花木酮Cleistanone的O-(吗啉基)乙基衍生物，并对其抗缺氧活性进行了评价，其具有抗缺氧活性。
发明内容
本发明公开了一个闭花木酮Cleistanone的O-(吗啉基)乙基衍生物，其结构为：
本发明闭花木酮Cleistanone的O-(吗啉基)乙基衍生物(III)可通过下面方法制备：
(1)闭花木酮Cleistanone(I)与1,2-二溴乙烷反应得到闭花木酮Cleistanone的O-溴乙基衍生物(II)；
(2)闭花木酮Cleistanone的O-溴乙基衍生物(II)与吗啉发生取代反应制得闭花木酮Cleistanone的O-(吗啉基)乙基衍生物(III)。
进一步的闭花木酮Cleistanone的O-(吗啉基)乙基衍生物(III)的制备方法为：
(1)将440mg化合物闭花木酮Cleistanone(I)溶于10mL苯，向溶液中加入0.04g的四丁基溴化铵，3.760g的1,2-二溴乙烷和6mL的50％氢氧化钠溶液；混合物在25摄氏度搅拌24h；24h之后将反应液倒入冰水中，立即用二氯甲烷萃取两次，合并有机相溶液；然后对有机相溶液依次用水和饱和食盐水洗涤3次，再用无水硫酸钠干燥，最后减压浓缩去除溶剂得到产物粗品；产物粗品用硅胶柱层析纯化，流动相为：石油醚/丙酮＝100:1，v/v，收集黄色集中洗脱带即得到闭花木酮Cleistanone的O-溴乙基衍生物(II)的黄色固体。
(2)将273mg的闭花木酮Cleistanone的O-溴乙基衍生物(II)溶于20mL乙腈当中，向其中加入345mg的无水碳酸钾，84mg的碘化钾和1742mg的吗啉，混合物加热回流8h；反应结束后将反应液倒入30mL冰水中，用等量二氯甲烷萃取三次，合并有机相；依次用水和饱和食盐水洗涤合并之后的有机相，再用无水硫酸钠干燥，减压浓缩去除溶剂得到产物粗品；产物粗品用硅胶柱层析纯化，流动相为：石油醚/丙酮＝100:0.5，v/v，收集黄色集中洗脱带即得到闭花木酮Cleistanone的O-(吗啉基)乙基衍生物(III)的黄色固体185.3mg。
本发明公开的化合物可以制成药学上可接受的盐或药学上可接受的载体。
药效学实验表明，本发明的闭花木酮Cleistanone的O-(吗啉基)乙基衍生物(III)具有较好的抗缺氧作用。本发明的药学上可接受的盐与其化合物具有同样的药效。
以下通过实施例对本发明作进一步详细的说明，但本发明的保护范围不受具体实施例的任何限制，而是由权利要求加以限定。
具体实施方式
实施例1 化合物闭花木酮Cleistanone的制备
化合物闭花木酮Cleistanone(I)的制备方法参照Van Trinh Thi Thanh等人发表的文献(Van Trinh Thi Thanh et al.,2011.Cleistanone:A Triterpenoid fromCleistanthus indochinensis with a New Carbon Skeleton.Volume2011,Issue22,pages4108–4111,August2011)的方法。
实施例2 闭花木酮Cleistanone的O-溴乙基衍生物(II)的合成
将化合物I(440mg，1.00mmol)溶于10mL苯，向溶液中加入四丁基溴化铵(TBAB)(0.04g)，1,2-二溴乙烷(3.760g，20.00mmol)和6mL的50％氢氧化钠溶液。混合物在25摄氏度搅拌24h。24h之后将反应液倒入冰水中，立即用二氯甲烷萃取两次，合并有机相溶液。然后对有机相溶液依次用水和饱和食盐水洗涤3次，再用无水硫酸钠干燥，最后减压浓缩去除溶剂得到产物粗品。产物粗品用硅胶柱层析纯化(流动相为：石油醚/丙酮＝100:1，v/v)，收集黄色集中洗脱带即得到化合物II的黄色固体(344mg，63％)。
1H NMR(500MHz,DMSO-d6)δ5.04(s,1H),4.82(s,1H),3.94(d,J＝26.5Hz,1H),3.87(d,J＝26.5Hz,2H),3.57(s,2H),2.40(d,J＝14.0Hz,1H),2.39(d,J＝14.0Hz,1H),2.27(s,1H),2.21(s,1H),2.15(s,1H),1.82(s,1H),1.62(s,2H),1.57(d,J＝3.3Hz,1H),1.54(d,J＝3.3Hz,1H),1.50(d,J＝1.2Hz,1H),1.47(d,J＝1.2Hz,1H),1.39(d,J＝15.3Hz,2H),1.34(d,J＝15.3Hz,1H),1.26(dd,J＝32.6,13.7Hz,4H),1.13(d,J＝18.0Hz,2H),1.05(s,6H),0.98(s,1H),0.88(s,12H),0.78(s,3H),0.74(s,1H)。
13C NMR(125MHz,DMSO-d6)δ216.59(s),154.50(s),105.23(s),74.63(s),69.85(s),59.71(s),52.55(s),51.21(s),47.92(s),44.10(s),42.25(s),41.73(s),40.64(s),40.16(s),38.88(s),38.65(s),37.21(s),36.23(s),33.34(d,J＝1.1Hz),32.96(s),29.91(s),27.18(s),26.03(s),24.23(s),23.96(s),20.77(s),18.48(s),17.98(s),16.93(s)。
HRMS(ESI)m/z[M+H]+calcd for C32H52BrO2:547.3151；found547.3159.
实施例3 闭花木酮Cleistanone的O-(吗啉基)乙基衍生物(III)的合成
将化合物II(273mg，0.5mmol)溶于20mL乙腈当中，向其中加入无水碳酸钾(345mg，2.5mmol)，碘化钾(84mg，0.5mmol)和吗啉(1742mg，20mmol)，混合物加热回流8h。反应结束后将反应液倒入30mL冰水中，用等量二氯甲烷萃取三次，合并有机相。依次用水和饱和食盐水洗涤合并之后的有机相，再用无水硫酸钠干燥，减压浓缩去除溶剂得到产物粗品。产物粗品用硅胶柱层析纯化(流动相为：石油醚/丙酮＝100:0.5，v/v)，收集黄色集中洗脱带即得到Cleistanone的O-(吗啉基)乙基衍生物的黄色固体(185.3mg,67％)。
1H NMR(500MHz,DMSO-d6)δ5.11(s,1H),4.81(s,1H),4.39(s,1H),3.51(d,J＝17.7Hz,6H),2.59(s,2H),2.47(s,4H),2.32(t,J＝36.5Hz,2H),2.24(s,1H),2.20(s,1H),2.11(s,1H),1.79(d,J＝90.0Hz,3H),1.59(d,J＝7.0Hz,2H),1.40(d,J＝4.2Hz,2H),1.35(d,J＝14.5Hz,3H),1.30–1.16(m,4H),1.11(d,J＝6.5Hz,2H),1.02(s,6H),0.82(d,J＝8.5Hz,13H),0.73(s,3H),0.65(s,1H).
13C NMR(125MHz,DMSO-d6)δ216.37(s),154.55(s),105.98(s),73.28(s),69.13(s),66.17(s),58.23(s),54.02(s),53.01(s),52.77(s),51.83(s),48.12(s),46.23(s),42.97(s),41.13(s),40.99(s),39.93(s),38.92(s),38.67(s),37.13(s),36.59(s),33.21(s),32.13(s),29.41(s),27.38(s),26.01(s),24.33(s),23.12(s),20.13(s),19.13(s),17.25(s),16.16(s).
HRMS(ESI):m/z[M+H]+calcd for C36H60NO3:554.4573；found:554.4579。
实施例4 Cleistanone的O-(吗啉基)乙基衍生物抗缺氧活性
(一)小鼠特异性心肌缺氧实验
1、方法：
30只昆明小鼠，体重(20±2)g。随机分为3组，灌胃给药。前2组给予0.3％羧甲基纤维素钠(CMC-Na)溶液，后1组给予Cleistanone的O-(吗啉基)乙基衍生物0.015g·Kg-1，50min后，除第1组外，均腹腔注射异丙肾上腺素(ISO)15mg·Kg-1，15min后，将小鼠放入常压缺氧装置中，记录小鼠死亡时间及耗氧量。
2、结果：
异丙肾上腺素可通过兴奋心脏β受体，使心肌耗氧量增加。本实验显示，与溶媒对照组相比，Cleistanone的O-(吗啉基)乙基衍生物0.015g·Kg-1能显著对抗异丙肾上腺素(ISO)导致的心肌耗氧量增加(P<0.01)，同时延长小鼠缺氧密闭状态下的存活时间(P<0.01)，结果见表1。
表1 Cleistanone的O-(吗啉基)乙基衍生物对异丙肾上腺素致特异性缺氧小鼠的影响(n＝10)
注：1)P<0.01，与异丙肾上腺素组比较。
(二)小鼠常压窒息性缺氧实验
1、方法：
20只昆明小鼠，体重(20±2)g。随机分为2组，灌胃给药。第1组给予0.3％羧甲基纤维素钠(CMC-Na)溶液，第2组给予含Cleistanone的O-(吗啉基)乙基衍生物的CMC-Na溶液，浓度为0.015g·Kg-1。给药50min后，置于广口瓶中并盖紧瓶塞(瓶内放置5g钠石灰)。以呼吸停止为标志，记录小鼠存活时间。
2、结果：
与溶媒对照组相比，Cleistanone的O-(吗啉基)乙基衍生物的0.015g·Kg-1使小鼠在常压密闭条件下的存活时间延长了41.52％，差异具有显著性(P<0.01)。
(三)小鼠减压缺氧实验
1、方法：
20只昆明小鼠，体重(20±2)g。随机分为2组，灌胃给药。给药组给予Cleistanone的O-(吗啉基)乙基衍生物，浓度为0.015g·Kg-1，对照组给予0.3％CMC-Na溶液，灌胃体积均为2ml·Kg-1。50min后，给药组和对照组各取5只，放入减压装置中，在26.7Kpa(相当于海拔约10000m)时停止减压，保持此压力15分钟不变，15分钟停止减压，缓缓放入空气，取出动物，记录各组死亡及存活数目，重复操作至实验完成。
2、结果：
Cleistanone的O-(吗啉基)乙基衍生物0.015g·Kg-1使小鼠在减压缺氧条件下的存活率由对照组的40％提高至60％，差异具有显著性(P<0.05)。
结论：Cleistanone的O-(吗啉基)乙基衍生物可显著提高异丙肾上腺素致特异性缺氧的存活时间，窒息性缺氧和急性减压缺氧小鼠的存活率，提供了Cleistanone的O-(吗啉基)乙基衍生物在制备抗缺氧药物中的用途。
实施例5 本发明所涉及Cleistanone的O-(吗啉基)乙基衍生物片剂的制备
取20克Cleistanone的O-(吗啉基)乙基衍生物或者其药学上可接受的盐当中的一种，加入制备片剂的常规辅料180克，混匀，常规压片机制成1000片。
实施例6 本发明所涉及Cleistanone的O-(吗啉基)乙基衍生物胶囊的制备
取20克Cleistanone的O-(吗啉基)乙基衍生物或者其药学上可接受的盐当中的一种，加入制备胶囊剂的常规辅料如淀粉180克，混匀，装胶囊制成1000粒。
Claims (3)
1.一种具有式III所示结构的闭花木酮Cleistanone的O-(吗啉基)乙基衍生物及其药学上可接受的盐在制备抗缺氧药物中的应用，其特征在于：所述缺氧为异丙肾上腺素致特异性缺氧，
2.一种具有式III所示结构的闭花木酮Cleistanone的O-(吗啉基)乙基衍生物及其药学上可接受的盐在制备抗缺氧药物中的应用，其特征在于：所述缺氧为常压窒息性缺氧，
3.一种具有式III所示结构的闭花木酮Cleistanone的O-(吗啉基)乙基衍生物及其药学上可接受的盐在制备抗缺氧药物中的应用，其特征在于：所述缺氧为减压缺氧，
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