CN110590803B - 二氢青蒿素含羰基酚偶联物及其还原产物、合成方法及应用 - Google Patents

二氢青蒿素含羰基酚偶联物及其还原产物、合成方法及应用 Download PDF

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CN110590803B
CN110590803B CN201910804350.6A CN201910804350A CN110590803B CN 110590803 B CN110590803 B CN 110590803B CN 201910804350 A CN201910804350 A CN 201910804350A CN 110590803 B CN110590803 B CN 110590803B
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杨大成
范莉
周福委
潘建芳
唐雪梅
刘建
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Abstract

本发明公开了一种二氢青蒿素含羰基酚偶联物及其还原产物，或其消旋体、立体异构体、互变异构体以及其药学上可接受的盐分别具有以下通式：
Figure DDA0002183201650000011
n＝2或3，m＝0或2，R1为H或‑OCH3，R2为H或烷基。本发明还公开了所述二氢青蒿素衍生物的合成方法，以及所述衍生物在抗结核、抗糖尿病、降脂和抑制白细胞介素‑17药物中的应用。

Description

二氢青蒿素含羰基酚偶联物及其还原产物、合成方法及应用
技术领域
本发明涉及化学医药技术领域，具体涉及一种二氢青蒿素含羰基酚偶联物及其还原产物、合成方法及应用。
背景技术
青蒿素是从植物青蒿中发现的萜类化合物，是一种白色针状结晶，同时它也是某些高效低毒新型药物的先导化合物。二氢青蒿素(DHA)是青蒿素的第一代衍生物，不仅结构独特，而且显示了比青蒿素更为优良的药学性质，是重要的临床抗疟药物。基于DHA的特殊结构和优异活性，DHA的研究持续不断，目前主要集中在DHA新型衍生物的设计合成、DHA旧分子的新活性探索或新分子的活性研究。至今，大量DHA新型衍生物被合成出来，部分DHA衍生物已用于抗乳腺癌、结直肠癌、非小细胞肺癌等的临床试验中；还发现某些DHA衍生物在抗病毒、抗菌增敏、抗艾滋病毒、抗巨细胞病毒及抗结核等疾病时表现出非常好的活性，显示了多靶点分子的潜质，值得进一步研究开发。
含羰基酚类化合物如水杨醛、香草醛、覆盆子酮等都是重要的化工原料及医药中间体。这类化合物有的可以直接作为香精或食品添加剂,有的作为重要的活性片段存在于药物分子之中。该类分子本身分子量小、结构简单，酚羟基及羰基是其重要的衍生化位点；含羰基酚类化合物活性广泛，毒性小。
水杨醛是一种香料,也是用途极广的有机合成中间体。在药物合成中常用于合成水杨酰肼、苯溴马隆和醋胺苯恶酮等。香草醛常用作化妆品的香精和定香剂,也是食品香料和调味剂；香草醛具有镇静作用，能对抗戊四氮引起的惊厥,抑制由戊四氮诱发的癫痫样脑癫，可用于治疗各种癫痫病,尤其对癫痫小发作效果较好，还适用于治疗多动症、眩晕等；在制药工业，香草醛用于生产降压药甲基多巴、儿茶酚类药物多巴，以及白内停、敌菌净等。间羟基苯甲醛主要用作医药、染料、杀菌剂、照相乳化剂等精细化学品的中间体。间羟基苯乙酮主要用于有机合成,是药物苯肾上腺素的中间体。覆盆子酮用于调制食品香料,主要用以配制树莓、葡萄、草莓等型香精,具有增香增甜作用,也可用于化妆品及皂用香精中。
醇类化合物较醛酮水溶性更强；将醛酮还原为醇后,原来的羰基变为羟基,氧由氢键受体变为氢键给体，是药物设计中的一种重要变换。在医药领域,醇也作为重要的活性片段出现在大量的药物中,2012年全球销售额Top 200的药物就有超过20种含有醇羟基,如分别用于治疗高血压、高胆固醇、心绞痛的瑞舒伐他汀、依泽替米贝、雷诺嗪等等。
通过对现有二氢青蒿素衍生物的文献查阅，我们发现二氢青蒿素与含羰基酚的偶联物以及该偶联物的还原产物还未见报道。本发明提供了一类基于二氢青蒿素与含羰基酚偶联物以及该偶联物的还原产物及其合成方法与应用，该类分子显示了一些独特的生物活性，可为新药研制、疾病治疗起到推动作用，可以应用到更为广泛的领域，尤其是药物开发领域。
发明内容
本发明提供一种二氢青蒿素与含羰基酚偶联物及其还原产物、合成方法及应用。
本发明提供了一种二氢青蒿素含羰基酚偶联物，或其消旋体、立体异构体、互变异构体以及其药学上可接受的盐，所述偶联物的化学结构式如下，用TM4表示：
Figure GDA0002256421180000021
其中，n＝2或3，m＝0或2，R1为H或-OCH3，R2为H或烷基。
本发明还提供了一种二氢青蒿素含羰基酚偶联物的合成方法，按以下反应方程式进行，包括以下步骤：
Figure GDA0002256421180000022
其中，n＝2或3，m＝0或2，R1为H或-OCH3，R2为H或烷基；
加入原料含羰基取代苯酚、IM1、K2CO3和溶剂二甲基甲酰胺，加热、搅拌溶解，反应2～12.5h，反应结束后，进行后处理，得到所述二氢青蒿素与含羰基酚偶联物，即 TM4。
优选的，原料IM1和原料酚的物质的量比为1～2：1～2.5，反应温度为40～85℃。
本发明还提供了一种二氢青蒿素含羰基酚偶联物的还原产物，利用上述偶联物TM4 经还原得到，二氢青蒿素含羰基酚偶联物的还原产物，或其消旋体、立体异构体、互变异构体以及其药学上可接受的盐，用TM7表示：
Figure GDA0002256421180000031
其中，n＝2或3，m＝0或2，R1为H或-OCH3，R2为H或烷基。
优选的，R1为H或-OCH3，R2为H、-CH3和-CH2CH3中的任意一个。
本发明还提供了该还原产物的制备方法，如下所示：
Figure GDA0002256421180000032
其中，n＝2或3，m＝0或2，R1为H或-OCH3，R2为H或烷基；
加入反应物TM4、甲醇和NaBH4进行反应，反应结束进行后处理即得还原产物 TM7。
优选的，TM4和NaBH4的物质的量之比为0.7～1:1.8～3，反应温度为15～30℃。
本发明还提供了二氢青蒿素含羰基酚偶联物及其还原产物的应用，所述的二氢青蒿素与含羰基酚偶联物及其还原产物或其消旋体、立体异构体、互变异构体以及其药学上可接受的盐在抗结核、抗糖尿病、降脂和抑制白细胞介素-17药物的应用。
所述的二氢青蒿素含羰基酚偶联物及其还原产物的应用，当
n＝3，m＝0,R1为H，R2为-CH3(用TM4-8表示)在抗结核药物中的应用；
n＝3，m＝0,R1为H，R2为-CH3(用TM4-8表示)在抑制白细胞介素-17药物中的应用。
所述的二氢青蒿素含羰基酚偶联物及其还原产物的应用，当
n＝2、m＝0、R1为-OCH3、R2为H(用TM7-13表示)，n＝2、m＝0、R1为H、R2为 -CH3(用TM7-17表示)，n＝2、m＝0、R1为H、R2为-CH2CH3(用TM7-18表示)，n＝2、 m＝2、R1为H、R2为-CH3(用TM7-19表示)在抗结核药物中的应用；
n＝3、m＝0、R1为-OCH3、R2为H(用TM7-3表示)，n＝3、m＝0、R1为H、R2为-CH3 (用TM7-7表示)，n＝3、m＝0、R1为H、R2为-CH2CH3(用TM7-8表示)在抗糖尿病药物中的应用；
n＝3、m＝2、R1为H、R2为-CH3(用TM7-9表示)，n＝2、m＝2、R1为H、R2为-CH3 (用TM7-19表示)在降脂药物中的应用；
n＝3、m＝0、R1为H、R2为H(用TM7-2表示)，n＝3、m＝0、R1为-OCH3、R2为 H(用TM7-3表示)，n＝3、m＝0、R1为H、R2为-CH2CH3(用TM7-8表示)，n＝2、 m＝0、R1为H、R2为H(用TM7-12表示)，n＝2、m＝0、R1为H、R2为-CH3(用TM7-17 表示)，n＝2、m＝2、R1为H、R2为-CH3(用TM7-19表示)在抑制白细胞介素-17药物中的应用。
与现有技术相比，本发明的有益效果是：本发明提供了二氢青蒿素与含羰基酚偶联物，该类衍生物通过合适的连接结构将二氢青蒿素及酚类相互连接而制备，合成方法简单，合成收率较高；本发明还提供了二氢青蒿素与含羰基酚偶联物的还原产物，还原方法简便，收率很高(95-98％)。二氢青蒿素与含羰基酚偶联物、该偶联物的还原产物均经过生物活性实验测试，发现本发明的两种衍生物具有抗结核、抗糖尿病、降血脂以及抑制白细胞介素-17活性，具有很好的应用前景。
具体实施方式
下面对本发明的具体实施方式进行详细描述，但应当理解本发明的保护范围并不受具体实施方式的限制。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动的前提下所获得的所有其他实施例，都属于本发明保护的范围。
实施例1、二氢青蒿素与含羰基酚偶联物及其还原产物的制备
(1)中间体IM1的制备方法如下：
Figure GDA0002256421180000051
加入二氢青蒿素(DHA)、乙醚(Et2O)以及溴代醇，在冰浴冷却下加入三氟化硼- 乙醚(BF3·Et2O)，搅拌下反应5～20h，反应完成后，加入饱和NaHCO3终止反应，静置分层，水层用乙酸乙酯(EtOAc或EA)萃取，合并有机相，饱和食盐水洗涤，无水MgSO4干燥，抽滤，滤液减压旋蒸除去溶剂得粗品，粗品用石油醚-EA混合溶剂重结晶即得中间体IM1。
(2)DHA与含羰基酚偶联物，在此申请中我们用TM4表示，其制备方法如下：
Figure GDA0002256421180000052
在100mL圆底烧瓶中依次加入含羰基取代苯酚12mmol、二甲基甲酰胺(DMF)15 mL、K2CO3(25mmol)和IM1(10mmol)，40～85℃水浴搅拌反应，TLC监测反应进程。反应完全后，加入水20mL和EA 15mL，分液，水层用EA 10mL萃取，合并有机相， 5mL 2NNaOH洗(5mL×2)，20mL水洗(20mL×2)。无水MgSO4干燥，抽滤，减压旋蒸除去EA，多数得到浅黄色粘液，柱层析得固体纯品TM4。
(3)TM4的还原产物TM7的制备方法如下：
Figure GDA0002256421180000053
在100mL圆底烧瓶中依次加入TM4(0.8mmol)、甲醇3mL，冰浴搅拌，缓慢加入 NaBH4(3mmol)，撤除冰浴，环境温度下搅拌。TLC监测反应进程。反应完全后，加入水20mL和EA15mL，1NHCl调节pH至7左右，继续搅拌5min，分液，水层用EA 10mL萃取，合并有机相，水洗(2×20mL)。无水Na2SO4干燥，抽滤，减压旋蒸除去EA，多数得到浅黄色粘液纯品，少数反应需柱层析。
实施例2、二氢青蒿素与含羰基酚偶联物TM4(TM4-1～TM4-19)的制备
依照实施例1所述的制备方法，当R1为H或-OCH3，R2为H、-CH3和-CH2CH3，m 为0或2中的任意一个，制备出TM4-1～TM4-19一系列产物，各自的反应条件、产量、产物得率、产物熔点如表1所示。
其中，
Figure GDA0002256421180000061
在此处可以用
Figure GDA0002256421180000062
结构式代替。
表1 TM4系列化合物合成实验结果
Figure GDA0002256421180000063
实施例3、TM4的还原产物TM7(TM7-1～TM7-19)的制备
依照实施例1所述的制备方法当R1为H或-OCH3，R2为H、-CH3和-CH2CH3中的任意一个，制备出TM4-1～TM4-19一系列产物，各自的反应条件、产量、产物得率、产物熔点如表2所示：
表2 TM7合成实验结果
Figure GDA0002256421180000071
Figure GDA0002256421180000081
实施例4、TM4-1～TM4-19和TM7-1～TM7-19的测试与表征
对实施例2和实施例3得到的TM4-1～TM4-19和TM7-1～TM7-19系列产物进行了1HNMR(AV-300)、13C NMR(AV-75)和HR MS(Varian 7.0T)测试和表征，数据如下所示：
Figure GDA0002256421180000082
TM4-12-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-i] isochromen-10-yl)oxy)propoxy)benzaldehyde 12-(3-(2-甲酰基苯氧基)丙基)二氢青蒿素
1H NMR(300MHz,CDCl3)δ:10.53(1H,s),7.86(1H,d,J＝6.6Hz),7.57-7.52(1H,m),7.07-6.98(2H,m), 5.30(1H,s),4.84(1H,d,J＝2.7Hz),4.22-4.10(3H,m),3.62-3.54(1H,m),2.67-2.61(1H,m),2.39-2.29(1H,m), 2.20-1.13(12H,m),1.42(3H,s),0.90(3H,d,J＝7.5Hz),0.85(3H,d,J＝6.0Hz).13C NMR(75MHz,CDCl3)δ: 189.51,161.27,135.85,128.37,125.01,120.75,112.33,104.11,101.90,87.71,80.99,65.26,64.04,52.45,44.33,37.32,36.39,34.55,30.92,29.16,26.16,24.62,24.60,20.35,13.04.HR MS calcd forC25H34O7[M+Na]+ 469.2202,found 469.2202.
TM4-23-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-i] isochromen-10-yl)oxy)propoxy)benzaldehyde 12-(3-(3-甲酰基苯氧基)丙基)二氢青蒿素
1H NMR(300MHz,CDCl3)δ:9.98(1H,s),7.46-7.42(2H,m),7.39(1H,s,H-20),7.21-7.17(1H,m), 5.28(1H,s),4.82(1H,d,J＝3.0Hz),4.17-4.10(3H,m),3.56-3.49(1H,m),2.64-2.59(1H,m),2.38-2.28(1H,m), 2.12-1.11(12H,m),1.44(3H,s),0.88(3H,d,J＝7.5Hz),0.81(3H,d,J＝4.5Hz).13C NMR(75MHz,CDCl3)δ: 192.11,159.60,137.83,130.09,123.49,121.97,112.61,104.04,101.85,87.73,81.00,64.85,63.97,52.40,44.32,37.17,36.38,34.48,30.88,29.05,26.21,24.57,24.55,20.35,13.04.
TM4-34-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-i] isochromen-10-yl)oxy)propoxy)benzaldehyde 12-(3-(4-甲酰基苯氧基)丙基)二氢青蒿素
1H NMR(300MHz,CDCl3)δ:9.89(1H,s),7.84(2H,d,J＝8.7Hz),7.02(2H,d,J＝8.4Hz),5.28(1H,s), 4.82(1H,d,J＝3.0Hz),4.17-4.09(3H,m),3.56-3.49(1H,m),2.65-2.60(1H,m),2.39-2.28(1H,m),2.13- 1.11(12H,m),1,44(3H,s),0.88(3H,d,J＝7.2Hz),0.84-0.81(3H,m).13C NMR(75MHz,CDCl3)δ:190.85, 164.14,132.08,129.99,114.79,104.14,101.94,87.81,81.03,65.08,63.98,52.43,44.34,37.24,36.42,34.56, 30.91,29.00,26.26,24.65,24.58,20.42,13.08.
TM4-4 3-Methoxy-4-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-3H-3,12-epoxy[1,2] dioxepino[4,3-i]isochromen-10-yl)oxy)propoxy)benzaldehyde 12-(3-(2-甲氧基-4-甲酰基苯氧基)丙基)二氢青蒿素
1H NMR(300MHz,CDCl3)δ:9.85(1H,s),7.44-7.42(2H,m),6.97(1H,d,J＝8.1Hz),5.27(1H,s), 4.82(1H,d,J＝3.3Hz),4.22-4.12(3H,m),3.94(3H,s),3.56-3.49(1H,m),2.64-2.59(1H,m),2.39-2.29(1H,m), 2.16-1.11(12H,m),1.43(3H,s),0.88(3H,d,J＝7.5Hz),0.84-0.81(3H,m).13C NMR(75MHz,CDCl3)δ: 190.99,154.12,149.99,130.12,126.81,111.32,109.07,104.08,101.93,87.84,81.05,65.90,63.97,56.08,52.44,44.38,37.26,36.47,34.58,30.91,28.97,26.30,24.72,24.58,20.46,13.09.HR MS calcdfor C26H36O8[M+Na]+ 499.2308,found 499.2310.
TM4-5 4-Methoxy-3-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-3H-3,12-epoxy[1,2] dioxepino[4,3-i]isochromen-10-yl)oxy)propoxy)benzaldehyde 12-(3-(2-甲氧基-5-甲酰基苯氧基)丙基)二氢青蒿素
1H NMR(300MHz,CDCl3)δ:9.84(1H,s),7.45(1H,d,J＝8.1Hz),7.40(1H,s),6.98(1H,d,J＝8.4Hz), 5.26(1H,s),4.82(1H,d,J＝3.3Hz),4.19-4.12(3H,m),3.96(3H,s),3.56-3.50(1H,m),2.63-2.58(1H,m), 2.39-2.29(1H,m),2.16-1.10(12H,m),1.43(3H,s),0.87(3H,d,J＝7.5Hz),0.84-0.81(3H,m).13C NMR(75 MHz,CDCl3)δ:190.87,154.96,149.18,130.12,126.84,110.58,110.11,104.01,101.92,87.84,81.09,65.72, 64.06,56.25,52.49,44.43,37.23,36.51,34.52,30.94,29.09,26.30,24.70,24.60,20.42,13.07.HR MS calcd for C26H36O8[M+Na]+499.2308,found 499.2310.
TM4-6 1-(2-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino [4,3-i]isochromen-10-yl)oxy)propoxy)phenyl)ethanone 12-(3-(2-乙酰基苯氧基)丙基)二氢青蒿素
1H NMR(300MHz,CDCl3)δ:7.77(1H,d,J＝6.3Hz),7.44,(1H,t,J＝6.9Hz),7.02-6.94(2H,m),5.30(1H, s),4.82(1H,d,J＝3.0Hz),4.20-4.07(3H,m),3.61-3.54(1H,m),2.65-2.61(4H,m),2.38-2.28(1H,m), 2.16-1.13(12H,m),1.42(3H,s),0.90(3H,d,J＝7.5Hz),0.86(3H,d,J＝6.0Hz).13C NMR(75MHz,CDCl3)δ: 199.60,158.36,133.73,130.65,128.16,120.63,112.15,104.13,101.93,87.75,81.02,65.30,64.32,52.46,44.32,37.35,36.40,34.56,32.21,30.92,29.30,26.18,24.62,24.61,20.39,13.08.HR MS calcdfor C26H36O7[M+Na]+ 483.2359,found 483.2361.
Figure GDA0002256421180000101
TM4-7 1-(3-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino [4,3-i]isochromen-10-yl)oxy)propoxy)phenyl)ethanone 12-(3-(3-乙酰基苯氧基)丙基)二氢青蒿素
1H NMR(300MHz,CDCl3)δ:7.54(1H,d,J＝7.5Hz),7.49(1H,s),7.37(1H,t,J＝7.8Hz),7.12(1H,d,J ＝6.6Hz),5.27(1H,s),4.82(1H,d,J＝3.0Hz),4.21-4.09(3H,m),3.55-3.48(1H,m),2.63-2.60(4H,m), 2.38-2.28(1H,m),2.09-1.13(12H,m),1.44(3H,s),0.88(3H,d,J＝7.2Hz),0.84-0.80(3H,m).13C NMR(75 MHz,CDCl3)δ:197.89,159.24,138.44,129.61,121.06,119.89,113.16,104.03,101.83,87.74,81.02,64.73, 63.93,52.40,44.34,37.12,36.40,34.48,30.89,29.06,26.76,26.23,24.55,24.42,20.37,13.05.HR MS calcd for C26H36O7[M+Na]+483.2359,found 483.2361.
TM4-8 1-(4-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino [4,3-i]isochromen-10-yl)oxy)propoxy)phenyl)ethanone 12-(3-(4-乙酰基苯氧基)丙基)二氢青蒿素
1H NMR(300MHz,CDCl3)δ:7.94(2H,d,J＝8.7Hz),6.94(2H,d,J＝8.7Hz),5.28(1H,s5),4.82(1H,d,J ＝3.3Hz),4.16-4.09(3H,m),3.55-3.48(1H,m),2.64-2.59(1H,m),2.56(3H,s),2.39-2.28(1H,m),2.12-1.11(12H, m),1.44(3H,s),0.88(3H,d,J＝7.5Hz),0.83-0.81(3H,m).13C NMR(75MHz,CDCl3)δ:196.77,163.01, 130.67,130.32,114.15,104.11,101.91,87.80,81.04,64.88,63.99,52.44,44.35,37.19,36.43,34.55,30.91, 29.02,26.41,26.25,24.63,24.55,20.37,13.07.HR MS calcd for C26H36O7[M+Na]+483.2359,found 483.2356. TM4-9 1-(4-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino [4,3-i]isochromen-10-yl)oxy)propoxy)phenyl)propan-1-one 12-(3-(4-丙酰基苯氧基)丙基)二氢青蒿素
1H NMR(300MHz,CDCl3)δ:7.95(2H,d,J＝9.0Hz),6.93(2H,d,J＝8.7Hz),5.29(1H,s),4.81(1H,d,J ＝3.3Hz),4.16-4.10(3H,m),3.55-3.48(1H,m),2.95(2H,q,J＝7.2Hz),2.64-2.59(1H,m),2.39-2.28(1H,m), 2.12-1.11(12H,m),1.44(3H,s),1.22(3H,t,J＝7.2Hz),0.88(3H,d,J＝7.2Hz),0.80(3H,d,J＝4.8Hz).13C NMR(75MHz,CDCl3)δ:199.48,162.83,130.30,130.03,114.15,104.13,101.94,87.82,81.06,64.87,64.04, 52.47,44.38,37.21,36.45,34.58,31.46,30.93,29.06,26.27,24.65,24.57,20.38,13.09,8.54.HR MS calcd for C27H38O7[M+Na]+497.2515,found 497.2518.
TM4-10 4-(4-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino [4,3-i]isochromen-10-yl)oxy)propoxy)phenyl)butan-2-one 12-(3-(4-(3-羰基丁基)苯氧基)丙基)二氢青蒿素
1H NMR(300MHz,CDCl3)δ:7.08(2H,d,J＝8.4Hz),6.81(2H,d,J＝8.4Hz),5.32(1H,s),4.81(1H,d,J ＝3.3Hz),4.13-4.00(3H,m),3.57-3.47(1H,m),2.83(2H,d,J＝7.2Hz),2.73(2H,d,J＝7.4Hz),2.64-2.59(1H, m),2.40-2.29(1H,m),2.14(3H,s),2.09-0.95(12H,m),1.44(3H,s),1.44(3H,s),0.88(3H,d,J＝7.5Hz),0.84(3H, d,J＝6.0Hz).13C NMR(75MHz,CDCl3)δ:208.32,157.43,133.04,129.27,114.48,104.11,101.92,87.86, 81.15,64.63,64.36,52.54,45.55,44.45,37.19,36.50,34.63,30.98,30.22,29.35,28.96,26.30,24.67,24.56, 20.47,13.12.
TM4-11 2-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino [4,3-i]isochromen-10-yl)oxy)ethoxy)benzaldehyde12-(2-(2-甲酰基苯氧基)乙基)二氢青蒿素
1H NMR(300MHz,CDCl3)δ:10.52(1H,s),7.84(1H,d,J＝7.5Hz),7.57-7.52(1H,m),7.07-6.99(2H,m,), 5.42(1H,s),4.89(1H,d,J＝3.3Hz),4.30-4.23(3H,m),3.85-3.81(1H,m),2.68-2.63(1H,m),2.41-2.31(1H,m), 2.06-1.21(10H,m),1.44(3H,s),0.93(3H,d,J＝5.4Hz),0.90(3H,d,J＝7.5Hz).13C NMR(75MHz,CDCl3)δ: 189.58,161.31,135.97,128.32,125.07,120.99,112.77,104.23,102.43,87.98,81.09,67.96,66.57,52.52,44.37, 37.51,36.42,34.51,30.88,26.22,24.69,24.51,20.37,13.02.HR MS calcd forC24H32O7[M+Na]+455.2046, found 455.2048.
TM4-12 3-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino [4,3-i]isochromen-10-yl)oxy)ethoxy)benzaldehyde12-(2-(3-甲酰基苯氧基)乙基)二氢青蒿素
1H NMR(300MHz,CDCl3)δ:9.98(1H,s),7.47-7.40(3H,m),7.20-7.16(1H,m),5.47(1H,s),4.90(1H,d,J ＝3.0Hz),4.20-4.15(3H,m),3.85-3.76(1H,m),2.67-2.62(1H,m),2.43-2.32(1H,m),2.07-1.18(10H,m,1.45(3H, s),0.93,0.90(3H,d,J＝7.2Hz).13C NMR(75MHz,CDCl3)δ:192.11,159.48,137.80,130.13,123.69,122.02, 112.89,104.13,102.21,87.92,81.11,67.62,66.42,52.52,44.39,37.48,36.42,34.60,30.88,26.21,24.72,24.44, 20.36,12.98.
Figure GDA0002256421180000111
Figure GDA0002256421180000121
TM4-13 3-Methoxy-4-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-3H-3,12-epoxy[1,2] dioxepino[4,3-i]isochromen-10-yl)oxy)ethoxy)benzaldehyde12-(2-(2-甲氧基-4-甲酰基苯氧基)乙基)二氢青蒿素
1H NMR(300MHz,CDCl3)δ:9.86(1H,s),7.45-7.41(2H,m),7.01(1H,d,J＝8.1Hz),5.49(1H,s), 4.90(1H,d,J＝3.0Hz),4.32-4.22(3H,m),3.91(3H,s),3.87-3.82(1H,m),2.67-2.62(1H,m),2.43-2.32(1H,m), 2.06-1.17(10H,m),1.44(3H,s),0.93(3H,d,J＝5.7Hz),0.89(3H,d,J＝7.5Hz).13C NMR(75MHz,CDCl3)δ: 190.86,153.90,149.88,130.05,126.58,111.68,109.20,103.96,102.02,87.83,81.03,68.09,66.03,55.90,52.42,44.34,37.17,36.34,34.60,30.77,26.11,24.65,24.31,20.30,12.82.HR MS calcd forC25H34O8[M+Na]+ 485.2151,found 485.2151.
TM4-14 4-Methoxy-3-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-3H-3,12-epoxy[1,2] dioxepino[4,3-i]isochromen-10-yl)oxy)ethoxy)benzaldehyde12-(2-(2-甲氧基-5-甲酰基苯氧基)乙基)二氢青蒿素
1H NMR(300MHz,CDCl3)δ:9.85(1H,s),7.48-7.44(2H,m),6.98(1H,d,J＝8.1Hz),5.50(1H,s), 4.90(1H,d,J＝3.0Hz),4.26-4.19(3H,m),3.94(3H,s),3.84-3.80(1H,m),2.66-2.61(1H,m),2.43-2.32(1H,m), 2.06-1.17(10H,m),1.44(3H,s),0.94(3H,d,J＝6.0Hz),0.88(3H,d,J＝7.2Hz).13C NMR(75MHz,CDCl3)δ: 190.91,155.02,149.02,130.00,126.91,110.87,110.74,104.07,102.20,87.95,81.19,68.18,66.39,56.17,52.56,44.48,37.32,36.47,34.70,30.90,26.24,24.76,24.45,20.40,12.91.
TM4-15 1-(2-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino [4,3-i]isochromen-10-yl)oxy)ethoxy)phenyl)ethanone 12-(2-(2-乙酰基苯氧基)乙基)二氢青蒿素
1H NMR(300MHz,CDCl3)δ:7.76(1H,d,J＝6.3Hz),7.46(1H,t,J＝7.2Hz),7.04-6.95(2H,m),5.41(1H, s),4.88(1H,d,J＝3.3Hz),4.27-4.22(3H,m),3.88-3.80(1H,m),2.69-2.65(4H),2.43-2.32(1H,m), 2.06-1.18(10H,m),1.45(3H,s),0.94(3H,d,J＝5.7Hz),0.90(3H,d,J＝7.5Hz).13C NMR(75MHz,CDCl3)δ: 199.78,158.26,133.75,130.57,128.37,120.86,112.37,104.25,102.56,88.01,81.09,67.79,67.01,52.51,44.34,37.47,36.43,34.53,32.22,30.87,26.23,24.72,24.51,20.40,13.06.HR MS calcd forC25H34O7[M+Na]+ 469.2202,found 469.2202.
TM4-16 1-(3-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino [4,3-i]isochromen-10-yl)oxy)ethoxy)phenyl)ethanone 12-(2-(3-乙酰基苯氧基)乙基)二氢青蒿素
1H NMR(300MHz,CDCl3)δ:7.56(1H,d,J＝7.5Hz),7.51(1H,s),7.39(1H,t,J＝7.8Hz),7.13(1H,d,J＝ 6.3Hz),5.50(1H,s),4.92(1H,d,J＝3.3Hz),4.20-4.15(3H,m),3.86-3.78(1H,m),2.68-2.65(1H,m),2.62(3H, s),2.44-2.34(1H,m),2.08-1.19(10H,m),1.47(3H,s),0.95(3H,d,J＝5.7Hz),0.92(3H,d,J＝7.5Hz).13C NMR (75MHz,CDCl3)δ:197.97,159.18,138.52,129.68,121.31,120.17,113.26,104.17,102.22,87.97,81.18,67.61,66.46,52.59,44.46,37.53,36.47,34.66,30.93,26.81,26.26,24.77,24.48,20.42,13.03.
TM4-17 1-(4-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino [4,3-i]isochromen-10-yl)oxy)ethoxy)phenyl)ethanone 12-(2-(4-乙酰基苯氧基)乙基)二氢青蒿素
1H NMR(300MHz,CDCl3)δ:7.94(2H,d,J＝8.7Hz),6.94(2H,d,J＝8.7Hz),5.46(1H,s),4.90(1H,d,J ＝3.0Hz),4.23-4.16(3H,m),3.85-3.77(1H,m),2.67-2.62(1H,m),2.43-2.32(1H,m),2.07-1.21(10H,m), 1.45(3H,s),0.97-0.89(6H,m).13C NMR(75MHz,CDCl3)δ:196.83,162.85,130.66,130.43,114.28,104.17, 102.24,87.96,81.13,67.56,66.35,52.55,44.41,37.51,36.44,34.63,30.89,26.44,26.24,24.76,24.45,20.40, 13.00.
TM4-18 1-(4-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino [4,3-i]isochromen-10-yl)oxy)ethoxy)phenyl)propan-1-one 12-(2-(4-丙酰基苯氧基)乙基)二氢青蒿素
1HNMR(300MHz,CDCl3)δ:7.96(2H,d,J＝8.7Hz),6.95(2H,d,J＝8.7Hz),5.48(1H,s),4.92(1H,d,J ＝3.3Hz),4.24-4.16(3H,m),3.87-3.78(1H,m),2.98(2H,q,J＝7.2Hz),2.69-2.64(1H,m),2.45-2.34(1H,m), 2.08-1.21(10H,m),1.47(3H,s),1.24(3H,d,J＝7.2Hz),0.95-0.90(6H,m).13C NMR(75MHz,CDCl3)δ: 199.52,162.66,130.27,130.10,114.26,104.16,102.23,87.95,81.13,67.52,66.36,52.55,44.41,37.50,36.44, 34.62,31.47,30.89,26.23,24.75,24.45,20.39,13.00,8.50.
TM4-19 4-(4-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino [4,3-i]isochromen-10-yl)oxy)ethoxy)phenyl)butan-2-one12-(2-(4-(3-羰基丁基)苯氧基)乙基)二氢青蒿素
1H NMR(300MHz,CDCl3)δ:7.09(2H,d,J＝8.4Hz),6.81(2H,d,J＝8.4Hz),5.48(1H,s),4.90(1H,d,J ＝3.3Hz),4.18-4.05(3H,m),3.80-3.74(1H,m),2.84(2H,t,J＝7.2Hz),2.73(2H,t,J＝7.2Hz),2.66-2.61(1H, m),2.43-2.32(1H,m),2.14(3H,s),2.06-1.17(10H,m),1.45(3H,s),0.93(3H,d,J＝6.3Hz),0.90(3H,d,J＝7.5 Hz).13C NMR(75MHz,CDCl3)δ:208.24,157.29,133.20,129.26,114.69,104.11,102.14,87.94,81.19,67.41,66.53,52.58,45.48,44.48,37.44,36.46,34.67,30.93,30.18,28.91,26.25,24.75,24.44,20.42,13.03.HR MS calcd for C27H38O7[M+Na]+497.2515,found 497.2515.
(2)TM7-1～TM7-19
Figure GDA0002256421180000131
TM7-1(2-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3 -i]isochromen-10-yl)oxy)propoxy)phenyl)methanol12-(3-(2-羟甲基)苯氧基)丙基)二氢青蒿素
1H NMR(300MHz,CDCl3)δ:7.39(1H,d,J＝7.2Hz),7.23(1H,t,J＝7.8Hz)6.95(1H,t,J＝7.5Hz),6.85(1H, d,J＝8.1Hz),5.11(1H,s),4.86-4.61(3H,m),4.2-4.05(3H,m),3.52-3.45(1H,m),2.63-2.58(1H,m), 2.34-2.25(1H,m),2.15-1.94(4H,m),1.74-1.57(3H,m),1.46-1.35(1H,m),1.42(3H,s),1.28-1.08(4H,m), 0.88(3H,d,J＝7.5Hz),0.77(3H,d,J＝6.0Hz).13C NMR(75MHz,CDCl3)δ:156.35,129.71,128.76,128.61, 120.77,110.84,104.31,101.71,87.73,81.06,64.36,63.57,60.80,52.29,44.30,36.83,36.36,34.48,30.90, 28.99,26.18,24.64,24.50,20.45,13.05.HR MS calcd for C25H36O7[M+Na]+471.2359,found 471.2361. TM7-2(3-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino
[4,3-i]isochromen-10-yl)oxy)propoxy)phenyl)methanol 12-(3-(3-羟甲基)苯氧基)丙基)二氢青蒿素
1H NMR(300MHz,CDCl3)δ:7.28-7.23(1H,m),6.94-6.81(3H,m),5.25(1H,s),4.81(1H,d,J＝2.7Hz), 4.67(2H,s),4.16-4.03(3H,m),3.53-3.47(1H,m),2.63-2.60(1H,m),2.39-2.28(1H,m),2.07-1.65(8H,m,), 1.44(3H,s),1.35-1.14(4H,m),0.88(3H,d,J＝7.2Hz)0.83(3H,d,J＝4.5Hz).13C NMR(75MHz,CDCl3)δ: 159.43,142.77,129.65,119.16,113.56,113.09,104.19,101.93,87.84,81.14,65.24,64.69,64.25,52.47,44.42, 37.12,36.46,34.60,30.94,29.30,26.25,24.63,24.58,20.44,13.11.HR MS calcd for C25H36O7[M+Na]+ 471.2359,found 471.2356.
TM7-3(4-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3 -i]isochromen-10-yl)oxy)propoxy)phenyl)methanol12-(3-(4-羟甲基)苯氧基)丙基)二氢青蒿素
1H NMR(300MHz,CDCl3)δ:7.38(2H,d,J＝8.7Hz),6.89(2H,d,J＝8.4Hz),5.32(1H,s),4.81(1H,d, J＝3.3Hz),4.62(2H,s),4.14-4.03(3H,m),3.55-3.47(1H,m),2.64-2.59(1H,m),2.39-2.29(1H,m),2.09-1.99(3H, m),1.84-1.68(4H,m),1.5-1.35(5H,m),1.32-1.12(3H,m),0.88(3H,d,J＝7.5Hz),0.83(3H,d,J＝5.7Hz).13C NMR(75MHz,CDCl3)δ:158.62,133.19,128.67,114.48,104.14,101.91,87.84,81.14,65.03,64.65,64.30,52.49,44.41,37.17,36.46,34.59,30.95,29.27,26.26,24.65,24.54,20.44,13.10.HR MScalcd for C25H36O7 [M+Na]+471.2359,found 471.2361.
Figure GDA0002256421180000141
TM7-4(3-Methoxy-4-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-3H-3,12-epoxy[1,2]di- oxepino[4,3-i]isochromen-10-yl)oxy)propoxy)phenyl)methanol 12-(3-(2-甲氧基-4-羟甲基)苯氧基)丙基)二氢青蒿素
1H NMR(300MHz,CDCl3)δ:6.93(1H,s),6.88-6.82(2H,m),5.32(1H,s),4.8(1H,d,J＝3.0Hz),4.62(2H, s),4.13-4.09(3H,m),3.88(3H,s),3.56-3.47(1H,m),2.62-2.60(1H,m),2.40-2.30(1H,m),2.13-1.99(3H), 1.86-1.69(4H,m),1.52-1.38(2H,m),1.44(3H,s),1.25-1.15(3H),0.89-0.86(6H,m).13C NMR(75MHz,CDCl3) δ:149.57,147.98,133.80,119.32,112.61,110.70,104.09,101.94,87.87,81.15,65.90,65.33,64.46,55.93,52.51,44.43,37.26,36.49,34.61,30.95,29.34,26.28,24.71,24.55,20.45,13.11.HR MScalcd for C26H38O8 [M+Na]+501.2464,found 501.2467.
TM7-5(4-Methoxy-3-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-3H-3,12-epoxy[1,2]di- oxepino[4,3-i]isochromen-10-yl)oxy)propoxy)phenyl)methanol 12-(3-(2-甲氧基-5-羟甲基)苯氧基)丙基)二氢青蒿素
1H NMR(300MHz,CDCl3)δ:6.93-6.83(3H,m),5.29(1H,s),4.81(1H,d,J＝3.0Hz),4.61(2H,s), 4.16-4.06(3H,m),3.86(3H,s),3.57-3.50(1H,m),2.63-2.58(1H,m),2.40-2.29(1H,m),2.13-1.12(12H,m), 1.44(3H,s),0.89-0.85(6H,m).13C NMR(75MHz,CDCl3)δ:149.06,148.62,133.64,119.67,112.19,111.48, 104.11,101.96,87.87,81.15,65.96,65.27,64.51,56.04,52.52,44.44,37.21,36.50,34.63,30.95,29.43,26.27, 24.69,24.58,20.47,13.10.HR MS calcd for C26H38O8[M+Na]+501.2464,found 501.2467.
TM7-6 1-(2-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino [4,3-i]isochromen-10-yl)oxy)propoxy)phenyl)ethanol 12-(3-(2-(1-羟基)乙基)苯氧基)丙基)二氢青蒿素
1H NMR(300MHz,CDCl3)δ:7.35(1H,d,J＝7.2Hz),7.22(1H,t,J＝8.1Hz),6.96(1H,t,J＝7.5Hz), 6.87(1H,d,J＝7.2Hz),5.27(1H,s),5.15(1H,q,J＝6.3Hz),4.81(1H,d,J＝3.3Hz),4.15-4.08(3H,m), 3.58-3.47(1H,m),2.64-2.59(1H,m),2.39-2.28(1H,m),2.14-1.12(12H,m),1.53(3H,d,J＝6.6Hz),1.42(3H,s), 0.89(3H,d,J＝7.5Hz),0.85(3H,d,J＝6.0Hz).13C NMR(75MHz,CDCl3)δ:155.95,133.54,128.34,126.22, 120.86,111.09,104.14,101.92,87.78,81.09,66.17,64.63,64.21,52.47,44.37,37.27,36.45,34.58,30.95, 29.40,26.25,24.64,22.59,20.42,13.11.HR MS calcd for C26H38O7[M+Na]+485.2515,found 485.2513.
Figure GDA0002256421180000151
TM7-7 1-(3-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino [4,3-i]isochromen-10-yl)oxy)propoxy)phenyl)ethanol 12-(3-(3-(1-羟基)乙基)苯氧基)丙基)二氢青蒿素
1H NMR(300MHz,CDCl3)δ:7.27-7.22(1H,m),6.99-6.90(2H,m),6.80(1H,d,J＝8.7Hz),5.29(1H,s), 4.87(1H,q,J＝6.6Hz),4.81(1H,d,J＝3.0)4.19-3.99(3H,m),3.55-3.45(1H,m),2.68-2.53(1H,m),2.38-2.29(1H, m),2.09-1.59(8H,m),1.49(3H,d,J＝6.6Hz),1.44(3H,s),1.39-1.12(4H,m),0.88(3H,d,J＝7.5Hz),0.84(3H,d, J＝7.5Hz).13CNMR(75MHz,CDCl3)δ:159.48,147.94,129.56,117.72,113.02,111.83,104.22,101.94,87.83, 81.14,70.33,64.75,64.23,52.45,44.43,37.09,36.44,34.59,30.93,29.33,26.25,25.30,24.66,24.58,20.42, 13.11.HR MS calcd for C26H38O7[M+Na]+485.2515,found 485.2513.
TM7-8 1-(4-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino [4,3-i]isochromen-10-yl)oxy)propoxy)phenyl)ethanol 12-(3-(4-(1-羟基)乙基)苯氧基)丙基)二氢青蒿素
1H NMR(300MHz,CDCl3)δ:7.29(2H,d,J＝8.4Hz),6.88(2H,d,J＝8.4Hz)5.34(1H,s),4.89-4.85(1H,m), 4.81(1H,d,J＝3Hz),4.13-4.02(3H,m),3.56-3.47(1H,m),2.63-2.61(1H,m),2.40-2.29(1H,m),2.09-1.99(3H,m, 1.85-1.63(5H,m),1.48(3H,d,J＝6.3Hz),1.44(3H,s),1.38-1.04(4H,m),0.89(3H,d,J＝7.5Hz),0.85(3H,d,J＝ 6.0Hz).13CNMR(75MHz,CDCl3)δ:158.43,138.04,126.74,114.42,104.16,101.96,87.89,81.17,70.06, 64.71,64.42,52.55,44.46,37.29,36.50,34.64,30.99,29.37,26.31,25.12,24.69,24.58,20.50,13.14.HR MS calcd for C26H38O7[M+Na]+485.2515,found 485.2514.
TM7-9 1-(4-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino [4,3-i]isochromen-10-yl)oxy)propoxy)phenyl)propan-1-ol 12-(3-(4-(1-羟基)丙基)苯氧基)丙基)二氢青蒿素
1H NMR(300MHz,CDCl3)δ:7.25(2H,d,J＝8.4Hz),6.87(2H,d,J＝8.4Hz),5.35(1H,s),4.81(1H,d, J＝3.0Hz),4.54(1H,t,J＝6.6Hz),4.10-4.02(3H,m),3.56-3.47(1H,m),2.64-2.59(1H,m),2.40-2.30(1H,m), 2.09-2.00(3H,m),1.87-1.64(6H,m),1.55-1.39(5H,m),1.26-1.08(3H,m),0.96-0.86(9H,m).13C NMR(75 MHz,CDCl3)δ:158.42,136.85,127.25,114.33,104.15,101.97,87.89,81.16,75.72,64.72,64.50,52.55,44.45, 37.31,36.48,34.64,31.88,30.97,29.41,26.29,24.69,24.57,20.47,13.13,10.38.HR MS calcdfor C27H40O7 [M+Na]+499.2672,found 499.2675.
TM7-10 4-(4-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino [4,3-i]isochromen-10-yl)oxy)propoxy)phenyl)butan-2-ol 12-(3-(4-(3-羟基)丁基)苯氧基)丙基)二氢青蒿素
1H NMR(300MHz,CDCl3)δ:7.10(2H,d,J＝8.1Hz),6.82(2H,d,J＝8.1Hz),5.33(1H,s),4.81(1H,d, J＝2.7Hz),4.13-4.00(3H,m),3.85-3.79(1H,m),3.55-3.48(1H,m),2.72-2.55(3H,m),2.39-2.29(1H,m), 2.08-1.52(11H,m),1.44(3H,s),1.33-1.12(3H,m),1.30(3H,d,J＝6.3Hz),0.88(3H,d,J＝7.5Hz),0.84(3H,d, J＝6.0Hz).13C NMR(75MHz,CDCl3)δ:157.24,134.13,129.33,114.43,104.14,101.94,87.89,81.19,67.62, 64.65,64.41,52.57,44.48,41.17,37.21,36.52,34.65,31.33,31.00,29.39,26.32,24.68,24.58,23.75,20.49, 13.14.HR MS calcd for C28H42O7[M+Na]+513.2828,found 513.2827.
TM7-11(2-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino [4,3-i]isochromen-10-yl)oxy)ethoxy)phenyl)methanol 12-(2-(2-羟甲基)苯氧基)乙基)二氢青蒿素
1H NMR(300MHz,CDCl3)δ:7.29-7.25(2H),6.95(1H,t,J＝7.5Hz),6.89(1H,d,J＝8.1Hz),5.43(1H,s), 4.90(1H,d,J＝3.3Hz),4.68(2H,d,J＝3.6Hz),4.24-3.79(4H,m),2.67-2.64(1H,m),2.42-2.32(1H,m), 2.06-1.53(6H,m),1.45(3H,s),1.28-1.19(4H,m),0.93-0.91(6H,m).13C NMR(75MHz,CDCl3)δ:156.80, 129.61,128.99,128.94,121.02,111.32,104.30,102.40,88.04,81.17,67.45,67.03,62.19,52.55,44.40,37.44, 36.46,34.61,30.91,26.22,24.76,24.54,20.43,12.99.HR MS calcd for C24H34O7[M+Na]+457.2202,found 457.2201.
TM7-12(3-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino [4,3-i]isochromen-10-yl)oxy)ethoxy)phenyl)methanol 12-(2-(3-羟甲基)苯氧基)乙基)二氢青蒿素
1H NMR(300MHz,CDCl3)δ:7.31-7.22(1H,m),6.95-6.80(3H,m),5.46(1H,s),4.89(1H,d,J＝2.7Hz), 4.67(2H,s),4.17-3.76(4H,m),2.70-2.61(1H,m),2.42-2.32(1H,m),2.07-1.71(5H,m8),1.59-1.45(5H), 1.28-1.21(3H),0.96(3H,d,J＝7.8Hz),0.91(3H,d,J＝8.1Hz).13C NMR(75MHz,CDCl3)δ:159.17,142.73, 129.65,119.31,114.07,112.98,104.22,102.20,87.97,81.24,67.37,66.53,65.20,52.57,44.48,37.47,36.47, 34.67,30.95,26.23,24.77,24.47,20.42,13.05.
Figure GDA0002256421180000171
TM7-13(3-Methoxy-4-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-3H-3,12-epoxy[1,2] dioxepino[4,3-i]isochromen-10-yl)oxy)ethoxy)phenyl)methanol 12-(2-(2-甲氧基4-羟甲基)苯氧基)乙基) 二氢青蒿素
1H NMR(300MHz,CDCl3)δ:6.93-6.87(3H,m),5.49(1H,s),4.88(1H,d,J＝3.0Hz),4.63(2H,s), 4.21-4.16(3H,m),3.86(3H,s),3.82-3.75(1H,m),2.66-2.61(1H,m),2.42-2.32(1H,m),2.05-1.46(7H,m), 1.44(3H,s),1.33-1.19(3H,m),0.93(3H,d,J＝6.0Hz),0.90(3H,d,J＝7.8Hz).13C NMR(75MHz,CDCl3)δ: 149.86,147.96,134.17,119.39,113.65,111.11,104.12,102.18,87.99,81.27,68.44,66.59,65.28,55.96,52.61, 44.54,37.31,36.51,34.76,30.95,26.25,24.77,24.46,20.46,12.99.
TM7-14(4-Methoxy-3-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-3H-3,12-epoxy[1,2] dioxepino[4,3-i]isochromen-10-yl)oxy)ethoxy)phenyl)methanol 12-(2-(2-甲氧基5-羟甲基)苯氧基)乙基)二氢青蒿素
1H NMR(300MHz,CDCl3)δ:6.97(1H,s),6.91(1H,d,J＝8.4Hz),6.84(1H,d,J＝8.1Hz),5.42(1H,s), 4.87(1H,d,J＝3.3Hz),4.60(2H,s),4.22-4.13(3H,m),3.84(3-H,s),3.81-3.77(1H,m),2.65-2.60(1H,m), 2.42-2.31(1H,m),2.05-1.66(5H,m),1.58-1.51(1H,m),1.46-1.40(1H,m),1.43(3H,s),1.25-1.16(3H,m), 0.94-0.89(6H,m).13C NMR(75MHz,CDCl3)δ:149.28,148.42,133.70,120.01,112.99,111.77,104.19, 102.22,87.96,81.27,68.20,66.50,65.27,56.08,52.58,44.54,37.27,36.49,34.76,30.96,26.23,24.76,24.46, 20.44,13.01.
TM7-15 1-(2-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino [4,3-i]isochromen-10-yl)oxy)ethoxy)phenyl)ethanol 12-(2-(2-(1-羟基)乙基)苯氧基)乙基)二氢青蒿素
1H NMR(300MHz,CDCl3)δ:7.36-7.33(1H,m),7.27-7.21(1H,m),6.97(1H,t,J＝7.5Hz),6.89(1H,d, J＝8.4Hz),5.45(1H,s)5.09(1H,q,J＝6.3Hz),4.89(1H,m),4.26-4.11(3H,m),3.85-3.76(1H,m),2.67-2.66(1H, m),2.42-2.33(1H,m),2.06-1.19(10H,m),1.51(3H,q,J＝3.3Hz),1.45(3H,s),0.94-0.91(6H,m).13C NMR(75 MHz,CDCl3)δ:155.77,133.97,128.35,126.44,121.10,111.33,104.26,102.47,88.02,81.16,67.30,67.01,66.47,52.50,44.38,37.43,36.46,34.58,30.90,26.23,24.75,24.55,23.15,20.43,13.01.
TM7-16 1-(3-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino [4,3-i]isochromen-10-yl)oxy)ethoxy)phenyl)ethanol 12-(2-(3-(1-羟基)乙基)苯氧基)乙基)二氢青蒿素
1H NMR(300MHz,CDCl3)δ:7.28-7.23(1H,m),6.98-6.94(2H,m),6.81(1H,d,J＝7.5Hz),5.46(1H,s), 4.90-4.84(2H,m),4.19-3.76(4H,m),2.66-2.61(1H,m),2.43-2.32(1H,m),2.06-1.55(7H,m),1.49(3H,d,J＝6.3 Hz),1.45(3H,s),1.28-1.19(3H,m),0.97-0.86(6H,m).13C NMR(75MHz,CDCl3)δ:159.15,147.74,129.62, 117.95,113.67,111.66,104.22,102.25,87.99,81.26,70.37,67.41,66.49,52.60,44.52,37.50,36.50,34.71,30.98,26.27,25.26,24.79,24.50,20.46,13.08.
TM7-17 1-(4-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino [4,3-i]isochromen-10-yl)oxy)ethoxy)phenyl)ethanol 12-(2-(4-(1-羟基)乙基)苯氧基)乙基)二氢青蒿素
1H NMR(300MHz,CDCl3)δ:7.30(2H,d,J＝8.7Hz),6.88(2H,d,J＝8.7Hz),5.48(1H,s),4.90-4.83(2H, m),4.18-4.11(3H,m),3.81-3.76(1H,m),2.66-2.61(1H,m),2.43-2.32(1H,m),2.06-1.54(6H,m),1.48(3H,d, J＝6.6Hz),1.45(3H,s),1.35-1.19(4H,m),0.94(3H,d,J＝6.3Hz),0.91(3H,d,J＝7.5Hz).13C NMR(75MHz, CDCl3)δ:158.34,138.26,126.76,114.64,104.19,102.19,88.00,81.24,70.03,67.48,66.50,52.63,44.51,37.51,36.50,34.71,30.97,26.28,25.15,24.79,24.49,20.46,13.06.
TM7-18 1-(4-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino [4,3-i]isochromen-10-yl)oxy)ethoxy)phenyl)propan-1-ol 12-(2-(4-(1-羟基)丙基)苯氧基)乙基)二氢青蒿素
1H NMR(300MHz,CDCl3)δ:7.26(2H,d,J＝8.4Hz),6.88(2H,d,J＝8.4Hz),5.48(1H,s),4.90(1H,d, J＝3.0Hz),4.55(1H,t,J＝6.6Hz,),4.20-4.10(3H,m),3.81-3.76(1H,m),2.66-2.61(1H,m),2.43-2.32(1H,m), 2.09-1.55(9H,m),1.45(3H,s),1.28-1.19(3H,m),0.95-0.88(9H,m).13C NMR(75MHz,CDCl3)δ:158.40, 137.05,127.31,114.63,104.21,102.23,88.03,81.26,75.75,67.49,66.55,52.68,44.57,37.54,36.54,34.75, 31.90,31.00,26.29,24.82,24.53,20.46,13.08,10.33.
TM7-19 4-(4-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino [4,3-i]isochromen-10-yl)oxy)ethoxy)phenyl)butan-2-ol12-(2-(4-(3-羟基)丁基)苯氧基)乙基)二氢青蒿素
1H NMR(300MHz,CDCl3)δ:7.12(2H,d,J＝7.8Hz),6.82(2H,d,J＝8.1Hz),5.48(1H,s),4.90(1H,m), 4.17-4.11(3H,m),3.85-3.77(2H,m),2.72-2.56(3H,m),2.42-2.32(1H,m),2.06-1.54(8H),1.45(3H,s), 1.25-1.22(7H,m),0.94-0.85(6H,m).13C NMR(75MHz,CDCl3)δ:157.17,134.34,129.36,114.70,104.19, 102.21,88.02,81.28,67.61,67.49,66.63,52.66,44.55,41.17,37.51,36.53,34.73,31.33,31.00,26.31,24.81, 24.51,23.75,20.48,13.08.
实施例5、TM4和TM7目标分子抗结核活性测试
美国礼来制药(Eli Lilly and Company)公司对TM4-1～TM4-19、TM7-1～TM7-19样品的抗结核活性进行了测试，首先测试单浓度样品对结核分枝杆菌的百分抑制率；其次筛选出高活性分子进行多浓度测试；最后对多种细胞进行测试。测试结果如表3所示。
表3 TM4和TM7系列目标分子对结核分枝杆菌H37Rv的抑制率
Figure GDA0002256421180000191
Figure GDA0002256421180000201
表3的抗结核活性筛选结果显示，在20μM样品测试浓度下，比DHA活性高的有 16个，其中TM4系列化合物中有4个目标分子活性超过40％，TM7系列化合物中有8 个目标分子活性超过40％，对结核分支杆菌表现出中等的抑制作用，本发明首次发现 DHA含羰基酚偶联物TM4及其还原产物TM7具有抗结核活性。
实施例6、TM4和TM7目标分子的胰高血糖素样肽-1(GLP-1)活性测试
目标分子的GLP-1活性是由美国礼来制药公司进行测试的。本研究测试的是目标分子的GLP-1分泌结果。实验操作如下：
实验之前，先把人源NCI-H716细胞的培养基换成分化培养基。实验当天，首先用含有BSA和DPP-IV抑制剂(终浓度分别为0.1％和1％)的HBSS缓冲液洗细胞2遍，然后用该缓冲液(含有终浓度分别为0.1％和1％的BSA和DPP-IV抑制剂的HBSS缓冲液)重悬细胞。接下来，把细胞按照10000个细胞/50μL/孔的密度接种到包被了多聚 D-赖氨酸的透明底黑色384孔板中。
待测化合物配制：待测化合物起始浓度为40μM，按照3倍梯度往下稀释。
化合物量效曲线确定：将上面配制好的化合物加到之前已经接种好细胞的384孔板孔中，然后在37℃培养2小时。在化合物刺激下，细胞分泌GLP-1到培养基中。细胞分泌的GLP-1用384孔板格式的Alpha LISA assay试剂盒来定量。信号采集用的是Perkin Elmer公司的全功能酶标仪Envision。采集到的信号再通过GLP-1标准曲线拟合计算出细胞合成的GLP-1多肽的量。
相对激动百分比的计算：以能激起细胞分泌最多GLP-1的化合物为标准，其余待测化合物的每个数据点得到的信号和标准化合物的最高信号(Maximum response)相除得出相对激动百分比。激动率(stimulation(％))和抑制率(inhibition(％))的计算公式如下所示：
Figure GDA0002256421180000202
其中，Max和Min的定义根据每个实验的最高信号和最低信号来定。IC50或EC50的计算是通过把计算出来的激动率或抑制率用standard 4parameter logistic and non-linear regression拟合方程拟合算出。实验结果如表4、表5所示。
表4 TM4和TM7目标化合物的GLP-1百分激动活性
Figure GDA0002256421180000211
Figure GDA0002256421180000221
表5部分TM7目标化合物GLP-1激动活性的EC50值
Figure GDA0002256421180000222
通过表4、表5可知，二氢青蒿素与含羰基酚偶联得到的TM4系列，GLP-1激动活性较差，但将TM4还原得到TM7，GLP-1激动活性有明显的改善。在第一轮活性测试中发现，当样品浓度为10μM时，有12个化合物的GLP-1激动活性强于DHA，3个化合物TM7-3、TM7-7、TM7-8的GLP-1激动活性，分别为35.9％、28.4％和37.8％，较其他化合物高好几倍。将TM7-3、TM7-7、TM7-8这三个目标分子进行EC50值测试，活性最高的仍为TM7-8，EC50值为6.27μM。接着TM7-8进行针对GLUTag的第二轮测试，激动活性达到了46.39％。本发明首次发现DHA含羰基酚偶联物TM4及其还原产物TM7具有抗糖尿病活性。
实施例7、TM4和TM7降血脂活性研究
前蛋白转化酶枯草溶菌素9(Proprotein convertase subtilisin/kexin type9，PCSK9)是 2003年发现的一个脂质代谢调节蛋白。大量研究发现，PCSK9能介导低密度脂蛋白受体降解，调节血浆低密度脂蛋白胆固醇水平。因此，抑制或降低PCSK9水平的治疗方法可有效治疗高胆固醇血症，已成为高胆固醇血症研究的热点。
美国礼来制药公司公司对TM4和TM7进行PCSK9抑制活性测试，在不同的样品浓度下，测定了目标分子的PCSK9抑制活性，活性结果见表6。
表6 TM4和TM7目标化合物的PCSK9的抑制活性结果
Figure GDA0002256421180000223
Figure GDA0002256421180000231
Figure GDA0002256421180000241
由表6可知，大部分目标化合物的Basal_PCSK9 HepG2 SP抑制活性较好。在第一轮活性筛选中，当样品浓度为2μM时，在测试的16个化合物中，PCSK9抑制活性比对照物DHA高的目标化合物有15个；当样品浓度为5μM时，在测试的22个化合物中， PCSK9抑制率活性超过40％的有8个，最高抑制率达到了67％；当样品浓度为20μM 时，在测试的16个化合物中，PCSK9抑制活性比对照物DHA(71.7％)好的目标化合物有9个，其中有8个抑制率超过91％，最高达97.9％。在细胞毒性cell health测试中，无论测试浓度为20μM、5μM还是2μM，除了TM4-1、TM4-7、TM4-11和TM4-16外， TM4和TM7系列的其它分子的细胞毒性都低于DHA，整体毒性很低。在第二轮、第三轮活性测试中，所测试的TM7-9和TM7-19的PCSK9 ELISARPH抑制活性都较好，当样品浓度为20μM时，TM7-9的PCSK9抑制率平均值达到了69.58％，TM7-19抑制率平均值达到了72％；TM7-19的PCSK9 ELISAHelaViability达到IC50>100μM，毒性非常低。
实施例8、TM4和TM7在白细胞介素-17(IL-17)家族细胞因子的活性研究
白细胞介素-17(IL-17)家族细胞因子被发现与炎症的发生有着密切的联系，是目前自身免疫类疾病治疗的热门靶点，通过促进释放前沿性细胞因子放大炎症反应。
IL-17是免疫反应中调控炎症发生的重要因素，其功能从细胞层面可以分为全身性和局部功能两方面。全身性反应方面，其对于中性粒细胞的募集、成熟和激活有非常重要的作用，研究发现缺乏IL17或者Th17会导致中性粒细胞缺陷以及对金黄色葡萄球菌和真菌等抵抗力减弱，另外还能促进肝合成急性期蛋白，造成机体稳态失衡；局部功能主要是IL17能够诱导间充质细胞分泌炎症因子。
IL-17失调与急性炎症反应相关，造成银屑病、类风湿性关节炎和多发性硬化症等疾病。主要病症银屑病是一种慢性免疫介导的皮肤疾病，全世界发病率约为2％～3％，以角质形成细胞过度增殖引起瘙痒、鳞屑、红色斑块为主要症状。斑块银屑病是最常见的类型，占银屑病患者的80％～90％。大约80％的银屑病患者是轻度至中度银屑病，20％属于中度至重度银屑病。约20～30％的银屑病患者可能发展成为银屑病性关节炎，因此对这些患者进行早期干预至关重要。
美国礼来制药公司公司对TM4和TM7进行IL-17靶点的抑制活性测试，在不同的样品浓度下，测定了目标分子的抑制活性，活性结果见表7。
表7 TM4和TM7目标化合物的IL-17的抑制活性结果
Figure GDA0002256421180000251
Figure GDA0002256421180000261
表7活性结果显示：TM4和TM7系列的目标分子在10μM的样品浓度下对IL-17 具备一定的抑制作用，绝大多数分子的IL-17分泌抑制活性超过50％，细胞毒性很低 (<20％)，且和IL-5分泌抑制活性存在差别，显示一定的选择性；测试过的分子(TM7-2 ～TM7-4,TM7-8,TM7-12,TM7-17,TM7-19)，其IL-17和IL-5分泌抑制活性存在差别(2倍甚至10倍以上)，活性有高有低，低者IC50<1μM(TM7-19)；测试过的分子，对antiCD3 /antiCD28/IL23_PBMC的细胞毒性很低(IC50>30μM)。对HEK-293细胞的第二轮测试中，两种测试结果都有差别，且IC50有高有低，最低者达到0.2379μM。总体来说，有 7个目标化合物经过两轮活性，说明这几个化合物的活性不错，有进一步研究的价值和应用的潜力。本发明首次发现DHA含羰基酚偶联物TM4及其还原产物TM7具有免疫病方面的生物活性。
本发明中涉及的未说明部分与现有技术相同或采用现有技术加以实施。
以上公开的仅为本发明的几个具体实施例，但是，本发明实施例并非局限于此，任何本领域的技术人员能思之的变化都应落入本发明的保护范围。

Claims (7)

1.二氢青蒿素含羰基酚偶联物，或其互变异构体以及其药学上可接受的盐，其特征在于，所述偶联物的化学结构式如下，TM4表示：
Figure FDA0003478439600000011
其中，n＝2或3，m＝0或2，R1为H或-OCH3，R2为H、CH3或CH2CH3。
2.如权利要求1所述的二氢青蒿素含羰基酚偶联物的合成方法，其特征在于，按以下反应方程式进行，包括以下步骤：
Figure FDA0003478439600000012
加入原料含羰基取代苯酚、IM1、K2CO3和溶剂二甲基甲酰胺，加热、搅拌溶解，反应2～12.5h，反应结束后，进行后处理，得到所述二氢青蒿素与含羰基酚偶联物，即TM4。
3.如权利要求2所述的二氢青蒿素含羰基酚偶联物的合成方法，其特征在于，原料IM1和原料酚的物质的量比为1～2∶1～2.5，反应温度为40～85℃。
4.二氢青蒿素含羰基酚偶联物的还原产物，其特征在于，所述还原产物的化学结构式如下，TM7表示：
Figure FDA0003478439600000013
其中，n＝2或3，m＝0或2，R1为H或-OCH3，R2为H、CH3或CH2CH3。
5.如权利要求4所述的还原产物的合成方法，其特征在于，所述还原产物由以下方法制得：
Figure FDA0003478439600000021
加入反应物TM4、甲醇和NaBH4进行反应，反应结束后，进行后处理，即得还原产物TM7。
6.如权利要求5所述的还原产物的合成方法，其特征在于，TM4和NaBH4的物质的量之比为0.7～1∶1.8～3，反应温度为15～30℃。
7.二氢青蒿素含羰基酚偶联物及其还原产物在制备药物的应用，其特征在于，
TM4-18表示的化合物在制备抗结核药物中的应用；
TM4-8表示的化合物在制备抑制白细胞介素-17药物中的应用；
TM7-13表示的化合物、TM7-17表示的化合物、TM7-18表示的化合物、TM7-19表示的化合物在制备抗结核药物中的应用；
TM7-3表示的化合物、TM7-7表示的化合物、TM7-8表示的化合物在制备抗糖尿病药物中的应用；
TM7-9表示的化合物、TM7-19表示的化合物在制备降脂药物中的应用；
TM7-2表示的化合物、TM7-3表示的化合物、TM7-8表示的化合物、TM7-12表示的化合物、TM7-17表示的化合物、TM7-19表示的化合物在制备抑制白细胞介素-17药物中的应用；
上述各化合物的结构式分别如下：
Figure FDA0003478439600000022
Figure FDA0003478439600000031
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