CN110452252A - 二氢青蒿素含缩氨脲/缩氨硫脲酚类衍生物、合成方法及应用 - Google Patents
二氢青蒿素含缩氨脲/缩氨硫脲酚类衍生物、合成方法及应用 Download PDFInfo
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Abstract
本发明公开了一种二氢青蒿素含缩氨脲/缩氨硫脲酚类衍生物，或其消旋体、立体异构体、互变异构体、氮氧化物以及其药学上可接受的盐具有以下通式：
Description
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缩氨脲/缩氨硫脲酚类衍生物、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。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，对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的旧分子或新分子的新活性探索。至今，众多DHA新型衍生物被合成出来，部分青蒿素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。研究还发现，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。
N,N＇-二取代脲类衍生物是众多天然产物或合成化合物中的一种重要组成成分，目前已运用于染料、杀虫剂、药物合成、农业化学等领域。脲类化合物具有广泛的生物活性，主要作为活性片段出现在大量药物或活性分子中，如苯巴比妥、苯妥英、卡马西平等。硫脲衍生物是医药化学中一类重要化合物，具有抗艾滋病、抗结核病、抗心律不齐、抑菌等生物活性。硫脲衍生物也是一类重要的有机合成中间体，可以合成多种杂环类化合物。
氨基脲作为有机合成原料，主要用于制备热敏记录纸上的光色染料，也用于医药、农药等有机合成的中间体，用于生产呋喃西林、呋喃妥因、肾上腺色腙、氢化泼尼松、氢化可的松等药物。硫代氨基脲是重要的农药原料，用于生产非选择性除草剂、杀虫剂、灭鼠剂和植物生长时间调节剂等。在医药领域，硫代氨基脲主要用于合成抗结核药氨硫脲、磺胺药物以及2-取代肼基-4-取代基噻唑类抗菌素等。
虽有文献报道了DHA取代缩氨(硫)脲衍生物，但是均为复杂结构；本发明将氨基脲或硫代氨基脲以简单形式引入DHA中，合成分子量不大、结构不复杂的DHA缩氨脲/缩氨硫脲衍生物TM9。
人类致力于更多、更有效的治疗疾病的新药，本发明提供了一类基于二氢青蒿素的与含缩氨脲/缩氨硫脲酚类反应得到的衍生物及其合成、应用，为新药制备及推广、疾病治疗起到了推动作用，可以应用到更为广泛的领域。
发明内容
本发明提供一种二氢青蒿素含缩氨脲/缩氨硫脲酚类衍生物、合成方法及应用。
本发明提供了一种二氢青蒿素与含缩氨脲/缩氨硫脲酚类反应生成的衍生物，或其消旋体、立体异构体、互变异构体、氮氧化物以及其药学上可接受的盐，所述二氢青蒿素含缩氨脲/缩氨硫脲酚类衍生物用TM9表示，结构式如下所示：
其中，n＝1，2，3或4，R1为H、卤素、羟基、氨基、氰基、硝基、烷基、烷氧基或烷胺基，R2为H、烷基或芳基，X为O或S，m＝0，1，2，3或4。
较佳地，n＝2或3，R1为H或-OCH3，R2为H、-CH3或-CH2CH3，X为O或S，m＝0或2。
本发明还提供了所述二氢青蒿素含缩氨脲/缩氨硫脲酚类衍生物的合成方法，其特征在于，TM9的合成按以下反应方程式进行，包括以下步骤：
加入原料TM4、EtOH、氨基脲或氨基硫脲B，搅拌，反应1～12h，反应结束后，进行后处理，得到所述二氢青蒿素含缩氨脲/缩氨硫脲酚类衍生物，即TM9。
较佳地，原料TM4和氨基脲或硫代氨基脲的物质的量比为(0.6～1.6):(2～4)，反应温度为3～20℃。
较佳地，所述反应温度为6～16℃。
较佳地，TM4的合成按以下反应方程式进行，包括以下步骤：
加入含羰基的取代苯酚、IM1、K2CO3和溶剂二甲基甲酰胺,加热、搅拌溶解，反应1～12h，反应结束后，进行后处理，得到所述二氢青蒿素与含羰基酚的偶联物，即TM4。
较佳地，原料IM1和原料含羰基的取代苯酚的物质的量比为(1～2):(1～2.5)，反应温度为40～85℃。
本发明所述的二氢青蒿素含缩氨脲/缩氨硫脲酚类衍生物或其消旋体、立体异构体、互变异构体、氮氧化物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药物中的应用。
较佳地，所述衍生物结构式中的n＝2、R1为H、R2为-CH3、X为S、m＝0(TM9-38)，n＝3、R1为-OCH3、R2为H、X为S、m＝0(TM9-25)，n＝2、R1为H、R2为-CH3、X为S、m＝2(TM9-40)，n＝2、R1为-OCH3、R2为H、X为S、m＝0(TM9-29)，n＝3、R1为H、R2为CH3、X为S、m＝0(TM9-32)时在抗结核药物中的应用。
较佳地，所述衍生物结构式中的n＝3、R1为H、R2为H、X为S、m＝0(TM9-23)，n＝2、R1为H、R2为H、X为S、m＝0(TM9-27,TM9-28)，n＝2、R1为-OCH3、R2为H、X为S、m＝0(TM9-29,TM9-30)，n＝3、R1为H、R2为-CH3、X为S、m＝2(TM9-35)，n＝2、R1为H、R2为-CH3、X为S、m＝2(TM9-40)时在抗糖尿病药物中的应用；
所述衍生物结构式中的n＝3、R1为H、R2为H、X为O、m＝0(TM9-2,TM9-3)，n＝3、R1为-OCH3、R2为H、X为O、m＝0(TM9-4)，n＝2、R1为H、R2为H、X为O、m＝0(TM9-7)，n＝2、R1为-OCH3、R2为H、X为O、m＝0(TM9-9)，n＝3、R1为H、R2为-CH3、X为O、m＝0(TM9-13)，n＝3、R1为H、R2为-CH3、X为O、m＝2(TM9-15)，n＝3、R1为H、R2为H、X为S、m＝0(TM9-23)，n＝3、R1为-OCH3、R2为H、X为S、m＝0(TM9-25)，n＝2、R1为H、R2为H、X为S、m＝0(TM9-28)，n＝2、R1为-OCH3、R2为H、X为S、m＝0(TM9-30)，n＝3、R1为H、R2为-CH3、X为S、m＝0(TM9-33)，n＝2、R1为H、R2为-CH3、X为S、m＝0(TM9-36)在降脂药物中的应用。
所述衍生物结构式中的n＝3、R1为H、R2为H、X为O、m＝0(TM9-2,TM9-3)，n＝2、R1为H、R2为H、X为O、m＝0(TM9-6)，n＝2、R1为H、R2为-CH2CH3、X为O、m＝0(TM9-19)，n＝2、R1为H、R2为-CH3、X为O、m＝2(TM9-20)时在抑制白细胞介素-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含缩氨脲/缩氨硫脲酚类衍生物，该类衍生物通过合适的连接结构将二氢青蒿素与含羰基酚类连接、随后与氨基脲/氨基硫脲反应获得，合成方法简单，合成收率较高；经过生物活性实验测试，发现本发明的衍生物具有抗结核、抗糖尿病、降血脂及抑制白细胞介素-17等多种生物活性，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、二氢青蒿素含缩氨脲/缩氨硫脲酚类衍生物的制备
(1)中间体IM1的制备方法如下：
加入二氢青蒿素、乙醚以及溴代醇，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(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)TM4的制备方法如下：
其中，n＝1，2，3或4，R1为H、卤素、羟基、氨基、氰基、硝基、烷基、烷氧基或烷胺基，R2为H、烷基或芳基，X为O或S，m＝0，1，2，3或4。
进一步地，n＝2或3，R1为H或-OCH3，R2为H、-CH3或-CH2CH3，X为O或S，m＝0或2。
在100mL圆底烧瓶中依次加入含羰基取代苯酚12mmol、DMF 15mL、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EA15mL，分液，水层用EA 10mL萃取，合并有机相，5mL 2NNaOH洗两次，20mL水洗两次。无水MgSO4干燥，抽滤，减压旋蒸除去EA，多数得到浅黄色粘液，柱层析得纯品TM4。
(3)TM9的制备方法如下：
其中，n＝1，2，3或4，R1为H、卤素、羟基、氨基、氰基、硝基、烷基、烷氧基或烷胺基，R2为H、烷基或芳基，X为O或S，m＝0，1，2，3或4。
进一步地，n＝2或3，R1为H或-OCH3，R2为H、-CH3或-CH2CH3，X为O或S，m＝0或2。
在100mL圆底烧瓶中依次加入TM40.6～1.6mmol、EtOH 3mL、氨基脲或硫代氨基脲B2～4mmol，环境温度(6～16℃)搅拌反应，TLC监测反应进程。反应完全后，加入水20mL和EA15mL，分液，水层用EA 10mL萃取，合并有机相，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，干燥得纯品TM9，但少数反应需简单柱层析后才能得纯品TM9。
实施例2、二氢青蒿素含缩氨脲/缩氨硫脲酚类衍生物TM9-1～TM9-40的制备
依照实施例1所述的制备方法当n＝2或3，R1为H或-OCH3，R2为H、-CH3或-CH2CH3，X为O或S，m＝0或2，制备出TM9-1～TM9-40一系列产物，各自的反应条件、产量、产物得率、产物熔点如表1所示：
表1 TM9系列化合物合成实验结果
实施例3、TM9-1～TM9-40的测试与表征
对实施例2制备的TM9-1～TM9-40系列产物进行了1H NMR(AV-300)、13C NMR(AV-75)和HR MS(Varian 7.0T)测试和表征，数据如下所示：
TM9-1(E)-2-(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)benzylidene)hydrazinecarboxamide
1H NMR(300MHz,DMSO)δ:10.21(1H,s),8.23(1H,s,NH),7.99(1H,d,J＝7.8Hz),7.29(1H,t,J＝7.2Hz),7.01(1H,d,J＝8.4Hz),6.92(1H,t,J＝7.2Hz),6.42(2H,s,NH2),5.11(1H,s),4.72(1H,d,J＝2.7Hz),4.12-4.00(3H,m),3.46-3.42(1H,m),2.39-2.35(1H,m),2.14-0.95(13H,m),1.25(3H,s),0.80(3H,d,J＝7.2Hz),0.72-0.65(3H,m).13C NMR(75MHz,DMSO)δ:156.80,156.42,134.73,130.18,125.42,123.09,120.56,112.09,103.25,100.49,86.85,80.38,64.38,62.82,51.94,43.77,36.21,36.04,34.00,30.57,28.48,25.56,24.06,20.30,12.81.HR MS calcd for C26H37N3O7[M+Na]+526.2529,found526.2532.
TM9-2(E)-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)benzylidene)hydrazinecarboxamide
1H NMR(300 MHz,DMSO)δ:10.26(1H,s),7.79(1H,s,NH),7.31-7.25(2H,m),7.19(1H,d,J＝7.5 Hz),6.90(1H,d,J＝7.5 Hz),6.51(2H,s,NH2),5.13(1H,s),4.75-4.65(1H,m),4.07-3.95(3H,m),3.42-3.37(1H,m),2.44-2.30(1H,m),2.16-2.08(1H,m),1.99-1.02(12H,m),1.28(3H,s),0.82(3H,d,J＝7.2 Hz),0.73-0.65(3H,m).13C NMR(75 MHz,DMSO)δ:158.95,156.78,139.10,136.34,129.60,119.70,115.47,111.07,103.27,100.43,86.78,80.41,64.19,62.90,51.91,43.77,36.24,36.03,33.98,30.52,28.46,25.65,24.09,20.21,12.80.HR MS calcd for C26H37N3O7[M+Na]+526.2529,found 526.2531.
TM9-3(E)-2-(4-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepin o[4,3-i]isochromen-10-yl)oxy)propoxy)benzylidene)hydrazinecarboxamide
1H NMR(300 MHz,DMSO)δ:10.11(1H,s),7.77(1H,s,NH),7.64(2H,d,J＝8.4 Hz),6.92(2H,d,J＝8.7Hz),6.43(2H,s,NH2),5.16(1H,s),4.70(1H,d,J＝3.0 Hz),4.08-3.90(3H,m),3.49-3.40(1H,m),2.40-2.35(1 H,m),2.17-2.08(1H,m),1.99-1.04(12H,m),1.28(3H,s),0.82(3H,d,J＝7.2 Hz),0.72-0.66(3H,m).13C NMR(75MHz,DMSO)δ:159.43,156.89,139.14,128.07,127.59,114.36,103.30,100.49,86.82,80.43,64.31,63.00,51.90,43.76,36.28,36.01,34.01,30.51,28.44,25.67,24.19,24.02,20.25,12.80.HR MScalcd for C26H37N3O7[M+Na]+526.2529,found 526.2532.
TM9-4(E)-2-(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)benzylidene)hydrazinecarboxamide
1H NMR(300 MHz,DMSO)δ:10.11(1H,s),7.74(1H,s,NH),7.42(1H,s),7.04(1H,d,J＝7.2 Hz),6.91(1H,d,J＝8.1 Hz),6.51(2H,s,NH2),5.14(1H,s),4.69(1H,d,J＝3.3Hz),4.08-3.92(3H,m),3.82(3H,s),3.38-3.27(1H,m),2.39-2.34(1H,m),2.17-2.08(1H,m),1.99-1.01(12H,m),1.28(3H,s),0.82(3H,d,J＝7.5 Hz),0.73-0.66(3H,m).13C NMR(75MHz,DMSO)δ:156.92,149.25,139.44,127.79,120.71,112.00,108.15,103.21,100.43,86.84,80.44,64.84,62.95,55.61,51.90,43.79,36.29,36.07,34.01,30.50,28.55,25.69,24.20,24.00,20.27,12.80.HR MS calcd for C27H39N3O8[M+Na]+556.2635,found556.2632.
TM9-5(E)-2-(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)benzylidene)hydrazinecarboxamide
1H NMR(300 MHz,DMSO)δ:10.11(1H,s),7.73(1H,s,NH),7.41(1H,s),7.05(1H,d,J＝8.4 Hz),6.93(1H,d,J＝8.1 Hz),6.50(2H,s,NH2),5.05(1H,s),4.69(1H,d,J＝3.0Hz),4.08-3.99(3H,m),3.78(3H,s),3.53-3.40(1H,m),2.39-2.34(1H,m),2.15-2.06(1H,m),1.99-1.02(12H,m),1.27(3H,s),0.81(3H,d,J＝7.5 Hz),0.67(3H,d,J＝4.8 Hz).13CNMR(75 MHz,DMSO)δ:156.91,150.09,148.50,139.45,127.64,120.89,111.16,108.82,103.12,100.32,86.79,80.41,64.71,62.71,55.55,51.89,43.77,36.13,36.06,33.93,30.50,28.51,25.67,24.13,24.09,20.24,12.79.HR MS calcd for C27H39N3O8[M+Na]+556.2635,found 556.2632.
TM9-6(E)-2-(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)benzylidene)hydrazinecarboxamide
1H NMR(300 MHz,DMSO)δ:10.17(1H,s),8.21(1H,s,NH),7.99(1H,d,J＝7.5 Hz),7.30(1H,t,J＝7.2Hz),7.06(1H,d,J＝8.4 Hz),6.94(1H,t,J＝7.5 Hz),6.45(2H,s,NH2),5.27(1H,s),4.80(1H,d,J＝3.0 Hz),4.22-3.99(3H,m),3.72-3.68(1H,m),2.42-2.37(1H,m),2.21-2.11(1H,m),1.99-1.03(10H,m),1.29(3H,s),0.83(3H,d,J＝6.0 Hz),0.80(3H,d,J＝7.5 Hz).13C NMR(75 MHz,DMSO)δ:156.81,156.43,134.84,130.27,125.59,123.09,120.61,112.71,103.39,101.36,87.02,80.54,67.75,66.19,52.05,43.90,36.59,36.04,34.07,30.51,25.66,24.26,23.96,20.12,12.73.
TM9-7(E)-2-(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)benzylidene)hydrazinecarboxamide
1H NMR(300 MHz,DMSO)δ:10.28(1H,s),7.78(1H,s,NH),7.34-7.25(2H,m),7.20(1H,d,J＝7.2 Hz),6.90(1H,d,J＝7.5 Hz),6.54(2H,s,NH2),5.35(1H,s),4.82-4.70(1H,m),4.21-3.97(3H,m),3.70-3.67(1H,m),2,43-2.33(1H,m),2.21-2.13(1H,m),1.99-1.09(10H,m),1.29(3H,s),0.86-0.80(6H,m).13C NMR(75 MHz,DMSO)δ:158.87,156.81,139.02,136.31,129.66,119.74,115.80,111.25,103.35,100.70,86.96,80.53,67.13,65.81,52.05,43.88,36.71,36.04,34.12,30.52,25.68,24.35,23.96,20.15,12.78.
TM9-8(E)-2-(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)benzylidene)hydrazinecarboxamide
1H NMR(300 MHz,DMSO)δ:10.12,7.77(1H,s,NH),7.65(2H,d,J＝8.4 Hz),6.94(2H,d,J＝8.4 Hz),6.44(2H,s,NH2),5.36(1H,s),4.78(1H,d,J＝2.7Hz),4.18-3.97,3.71-3.67(1H,m),2.43-2.38(1H,m),2.23-2.13(1H,m),2.02-1.07(10,m),1.29(3H,s),0.87-0.82(6H,m).13C NMR(75 MHz,DMSO)δ:159.35,156.89,139.10,128.06,127.58,114.63,103.35,100.73,86.95,80.51,67.19,65.76,52.03,43.85,36.73,36.03,34.12,30.50,25.66,24.36,23.94,20.16,12.76.
TM9-9(E)-2-(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)benzylidene)hydrazinecarboxamide
1H NMR(300 MHz,DMSO)δ:10.13(1H,s),7.75(1H,s,NH),7.44(1H,s),7.05(1H,d,J＝8.4 Hz),6.96(1H,d,J＝8.1 Hz),6.53(2H,s,NH2),5.39(1H,s),4.77(1H,d,J＝3.0Hz,),4.15-3.98(3H,m),3.81(3H,s),3.70-3.66(1H,m),2.42-2.37(1H,m),2.23-2.13(1H,m),2.02-1.07(10H,m),1.29(3H,s),0.87(3H,d,J＝6.0 Hz),0.83(3H,d,J＝7.2 Hz).13CNMR(75 MHz,DMSO)δ:156.91,149.38,149.15,139.38,127.87,120.77,112.67,108.53,103.27,100.66,86.98,80.56,67.72,65.57,55.75,52.08,43.95,36.47,36.06,34.22,30.50,25.66,24.34,23.90,20.17,12.72.
TM9-10(E)-2-(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)benzylidene)hydrazinecarboxamide
1H NMR(300 MHz,DMSO)δ:10.13(1H,s),7.73(1H,s,NH),7.44(1H,s),7.07(1H,d,J＝8.4 Hz),6.94(1H,d,J＝8.4 Hz),6.53(2H,s,NH2),5.40(1H,s),4.78(1H,d,J＝3.0Hz),4.21-3.99(3H,m),3.77(3H,s),3.71-3.67(1H,m),2.42-2.37(1H,m),2.22-2.13(1H,m),2.02-1.07(10H,m),1.29(3H,s),0.87(3H,d,J＝6.0 Hz),0.81(3H,d,J＝7.2 Hz).13CNMR(75 MHz,DMSO)δ:156.97,150.11,148.38,139.37,127.68,120.96,111.49,109.35,103.31,100.61,87.00,80.60,67.67,65.70,55.69,52.11,43.99,36.52,36.09,34.25,30.54,25.69,24.35,23.95,20.17,12.74.
TM9-11(E)-2-(1-(2-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepi no[4,3-i]isochromen-10-yl)oxy)propoxy)phenyl)ethylidene)hydrazinecarboxamide
1H NMR(300 MHz,DMSO)δ:9.21(1H,s,NH),7.39(1H,dd,J＝1.2 Hz and 7.5 Hz),7.30(1H,t,J＝7.5Hz),7.01(1H,d,J＝8.1 Hz),6.92(1H,t,J＝7.5 Hz),6.31(2H,s,NH2),5.15(1H,s),4.69(1H,d,J＝3.0 Hz),4.10-3.86(3H,m),3.45-3.36(1H,m),2.40-2.35(1H,m),2.15-1.15(13H,m),2.14(3H,s),1.26(3H,s),0.82(3H,d,J＝7.2 Hz),0.74(3H,d,J＝5.1 Hz).13C NMR(151 MHz,DMSO)δ:157.28,156.39,145.85,129.62,129.37,129.03,120.25,111.85,103.25,100.53,86.83,80.37,64.40,63.21,51.96,43.77,36.38,35.96,34.03,30.51,28.68,25.57,24.11,24.04,21.05,20.17,12.75.HR MS calcd forC27H39N3O7[M+Na]+540.2684,found540.2684.
TM9-12(E)-2-(1-(3-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepi no[4,3-i]isochromen-10-yl)oxy)propoxy)phenyl)ethylidene)hydrazinecarboxamide
1H NMR(300 MHz,DMSO)δ:9.36(1H,s,NH),7.46(1H,d,J＝7.8 Hz),7.30-7.24(2H,m),6.91(1H,d,J＝7.8 Hz),6.49(2H,s,NH2),5.13(1H,s),4.70(1H,d,J＝3.3 Hz),4.13-3.95(3H,m),3.41-3.37(1H,m),2.40-2.35(1H,m),2.17(3H,s),2.12-2.06(1H,m),1.99-1.00(12H,m),1.28(3H,s),0.82(3H,d,J＝7.2 Hz),0.69-0.58(3H,m).13C NMR(151MHz,DMSO)δ:158.66,157.31,143.87,139.79,129.17,118.49,114.10,111.97,103.24,100.43,86.78,80.38,64.17,62.88,51.89,43.77,36.20,36.03,33.98,30.50,28.44,25.64,24.04,24.01,20.16,13.44,12.75.HR MS calcd for C27H39N3O7[M+Na]+540.2684,found 540.2687.
TM9-13(E)-2-(1-(4-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepi no[4,3-i]isochromen-10-yl)oxy)propoxy)phenyl)ethylidene)hydrazinecarboxamide
1H NMR(300 MHz,DMSO)δ:9.21(1H,s,NH),7.77(2H,d,J＝8.4 Hz),6.89(2H,d,J＝8.7 Hz),6.44(2H,s,NH2),5.16(1H,s),4.70(1H,d,J＝2.4 Hz),4.06-3.90(3H,m),3.42-3.37(1H,m),2.46-2.37(1H,m),2.14-1.04(13H,m),2.14(3H,s),1.28(3H,s),0.82(3H,d,J＝7.2 Hz),0.72-0.63(3H,m).13C NMR(151 MHz,DMSO)δ:158.99,157.38,143.82,130.87,127.32,113.82,103.25,100.48,86.79,80.39,64.23,63.03,51.91,43.75,36.23,36.00,33.99,30.47,28.45,25.62,24.12,23.97,20.09,13.16,12.74.HR MS calcd forC27H39N3O7[M+Na]+540.2684,found 540.2688.
TM9-14(E)-2-(1-(4-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepi no[4,3-i]isochromen-10-yl)oxy)propoxy)phenyl)propylidene)hydrazinecarboxamide
1H NMR(300 MHz,DMSO)δ:9.36(1H,s,NH),7.77(2H,d,J＝8.1 Hz),6.90(2H,d,J＝8.1 Hz),6.44(2H,s,NH2),5.17(1H,s),4.76-4.64(1H,m),4.06-3.93(3H,m),3.42-3.39(1H,m),2.76-2.62(2H,m),2.44-2.30(1H,m),2.17-2.09(1H,m),1.99-1.07(12H,m),1.28(3H,s),1.76(3H,t,J＝6.9 Hz)0.83(3H,d,J＝7.2 Hz),0.72-0.62(3H,m).13C NMR(151MHz,DMSO)δ:158.92,157.33,147.89,129.61,127.33,113.94,103.25,100.47,86.79,80.39,64.21,63.02,51.91,43.75,36.26,36.00,34.00,30.48,28.45,25.62,24.13,23.97,20.75,20.12,12.74,10.56.
TM9-15(E)-2-(4-(4-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepi no[4,3-i]isochromen-10-yl)oxy)propoxy)phenyl)butan-2-ylidene)hydrazinecarboxamide
1H NMR(300 MHz,DMSO)δ:8.91(1H,s,NH),7.13(2H,d,J＝8.1 Hz),6.81(2H,d,J＝8.1 Hz),6.17(2H,s,NH2),5.20(1H,s),4.70(1H,d,J＝2.1 Hz),4.06-3.90(3H,m),3.42-3.38(1H,m),2.75-2.63(2H,m),2.45-2.40(3H,m),2.18-2.09(1H,m),1.99-1.04(12H,m),1.79(3H,s),1.28(3H,s),0.82(3H,d,J＝6.9 Hz),0.78-0.70(3H,m).13C NMR(151MHz,DMSO)δ:157.38,156.74,148.59,133.47,129.13,114.03,103.25,100.49,86.81,80.41,64.08,63.22,51.95,43.78,40.01,36.29,36.02,34.03,31.00,30.49,28.62,25.63,24.15,23.97,20.16,14.08,12.75.HR MS calcd for C29H43N3O7[M+Na]+568.2999,found 568.2996.
TM9-16(E)-2-(1-(2-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepi no[4,3-i]isochromen-10-yl)oxy)ethoxy)phenyl)ethylidene)hydrazinecarboxamide
1H NMR(300 MHz,DMSO)δ:9.24(1H,s,NH),7.37-7.29(2H,m),7.05(1H,d,J＝8.1Hz),6.93(1H,t,J＝7.5 Hz),6.30(2H,s,NH2),5.33(1H,s),4.76(1H,d,J＝3.0 Hz),4.19-3.98(3H,m),3.71-3.66(1H,m),2.43-2.38(1H,m),2.21-2.09(1H,m),2.14(3H,s),2.02-1.06(10H,m),1.30(3H,s),0.87(3H,d,J＝6.0 Hz),0.82(3H,d,J＝7.2 Hz).13C NMR(151MHz,DMSO)δ:157.23,156.38,146.04,129.65,129.55,129.20,120.30,112.17,103.34,101.09,86.97,80.48,67.39,66.39,52.07,43.85,36.61,36.03,34.04,30.45,25.63,24.22,23.91,20.17,17.35,12.69.
TM9-17(E)-2-(1-(3-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepi no[4,3-i]isochromen-10-yl)oxy)ethoxy)phenyl)ethylidene)hydrazinecarboxamide
1H NMR(300MHz,DMSO)δ:9.34(1H,s,NH),7.38(1H,d,J＝7.8Hz),7.33(1H,s),7.27(1H,t,J＝8.1Hz),6.92(1H,dd,J＝1.5Hz and 7.8Hz),6.50(2H,s,NH2),5.35(1H,s),4.77(1H,d,J＝3.3Hz),4.21-3.97(3H,m),3.70-3.67(1H,m),2.42-2.37(1H,m),2.21-2.13(1H,m),2.16(3H,s),1.99-1.11(10H,m),1.30(3H,s),0.83-0.81(6H,m).13C NMR(151MHz,DMSO)δ:158.56,157.52,143.78,139.81,129.19,118.56,114.63,112.01,103.30,100.67,86.92,80.48,67.13,65.77,52.03,43.86,36.68,36.01,34.10,30.48,25.63,24.28,23.91,20.09,13.46,12.72.
TM9-18(E)-2-(1-(4-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepi no[4,3-i]isochromen-10-yl)oxy)ethoxy)phenyl)ethylidene)hydrazinecarboxamide
1H NMR(300MHz,DMSO)δ:9.22(1H,s,NH),7.78(2H,d,J＝8.7Hz),6.91(2H,d,J＝8.7H),6.46(2H,s,NH2),5.36(1H,s),4.78(1H,d,J＝3.0Hz),4.17-3.97(3H,m),3.72-3.68(1H,m),2.41-2.38(1H,m),2.23-2.14(1H,m),2.14(3H,s),2.02-1.07(10H,m),1.29(3H,s),0.86-0.82(6H,m).13C NMR(151MHz,DMSO)δ:158.91,157.40,143.83,130.90,127.34,114.09,103.30,100.73,86.93,80.47,67.13,65.75,52.02,43.83,36.68,36.01,34.09,30.47,25.63,24.32,23.89,20.11,13.20,12.71.
TM9-19(E)-2-(1-(4-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepi no[4,3-i]isochromen-10-yl)oxy)ethoxy)phenyl)propylidene)hydrazinecarboxamide
1H NMR(300MHz,DMSO)δ:9.36(1H,s,NH),7.77(2H,d,J＝8.7Hz),6.91(2H,d,J＝8.4Hz,),6.44(2H,s,NH2),5.35(1H,s),4.78(1H,d,J＝3.0Hz),4.18-3.97(3H,m),3.71-3.68(1H,m),2.70(2H,q,J＝7.2Hz),2.41-2.39(1H,m),2.22-2.13(1H,m),2.01-1.07(10H,m),1.29(3H,s),0.98(3H,t,J＝7.2Hz),0.86-0.82(6H,m).13C NMR(151MHz,DMSO)δ:158.86,157.36,148.00,130.08,127.38,114.23,103.30,100.72,86.93,80.48,67.12,65.73,52.03,43.84,36.69,36.02,32.47,30.48,25.63,24.32,23.90,21.05,20.12,12.72,10.55.25个C
TM9-20(E)-2-(4-(4-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepi no[4,3-i]isochromen-10-yl)oxy)ethoxy)phenyl)butan-2-ylidene)hydrazinecarboxamide
1H NMR(300MHz,DMSO)δ:8.90(1H,s,NH),7.13(2H,d,J＝8.4Hz),6.83(2H,d,J＝8.4Hz),6.17(2H,s,NH2),5.36(1H,s),4.77(1H,d,J＝3.0Hz),4.09-3.94(3H,m),3.69-3.62(1H,m),2.75-2.70(2H,m),2.45-2.39(3H,m),2.23-2.13(1H,m),2.09-1.07(10H,m),1.79(3H,s),1.29(3H,s),0.87(3H,d,J＝6.0Hz),0.83(3H,d,J＝7.2 Hz).13C NMR(75 MHz,DMSO)δ:157.47,156.73,148.60,133.65,129.22,114.34,103.35,100.71,86.96,80.53,67.05,65.75,52.07,43.90,40.13,36.73,36.06,34.16,31.04,30.53,25.67,24.37,23.96,20.19,14.13,12.78.
TM9-21(E)-2-(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)benzylidene)hydrazinecarbothioamide
1H NMR(300 MHz,DMSO)δ:11.48(1H,s),8.50(1H,s,NH2),8.11-8.09(2H,m),7.85(1H,s,NH2),7.33(1H,t,J＝7.2 Hz),7.02(1H,d,J＝8.1 Hz),6.93(1H,t,J＝7.5 Hz),5.06(1H,s),4.72(1H,d,J＝3.0 Hz),4.12-4.02(3H,m),3.46-3.43(1H,m),2.37-2.35(1H,m),2.07-1.08(13H,m),1.27(3H,s),0.80(3H,d,J＝7.2 Hz),0.65(3H,d,J＝6.0 Hz).13CNMR(75 MHz,DMSO)δ:177.52,157.13,138.02,131.09,125.88,122.45,120.56,112.08,103.22,100.40,86.77,80.33,64.24,62.43,51.92,43.73,36.09,36.07,33.97,30.57,28.32,25.64,24.04,20.33,12.81.HR MS calcd for C26H37N3O6S[M+Na]+542.2301,found542.2304.
TM9-22(E)-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)benzylidene)hydrazinecarbothioamide
1H NMR(300 MHz,DMSO)δ:11.44(1H,s),8.25(1H,s,NH2),8.05(1H,s,NH2),8.00(1H,s,NH),7.43(1H,s),7.33-7.24(2H,m),6.94(1H,d,J＝7.8 Hz),5.12(1H,s),4.70(1H,d,J＝2.7 Hz),4.69-3.93(3H,m),3.42-3.36(1H,m),2.37-2.36(1H,m),2.16-2.06(1H,m),1.99-1.01(12H,m),1.28(3H,s),0.82(3H,d,J＝7.2 Hz),0.71-0.62(3H,m).13C NMR(75MHz,CDCl3)δ:177.93,159.00,142.16,135.72,129.69,120.67,116.49,111.41,103.26,100.43,86.77,80.41,64.26,62.85,51.90,43.75,36.25,36.03,33.96,30.52,28.46,25.66,24.10,20.23,12.81.HR MS calcd for C26H37N3O6S[M+Na]+542.2301,found542.2399.
TM9-23(E)-2-(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)benzylidene)hydrazinecarbothioamide
1H NMR(300 MHz,DMSO)δ:11.31(1H,s),8.12(1H,s,NH2),7.99(1H,s,NH),7.92(1H,s,NH2),7.73(2H,d,J＝8.7 Hz),6.94(2H,d,J＝8.7 Hz),5.16(1H,s),4.70(1H,d,J＝3.0 Hz),4.07-3.90(3H,m),3.42-3.37(1H,m),2.39-2.37(1H,m),2.17-2.09(1H,m),1.99-1.04(12H,m),1.28(3H,s),0.82(3H,d,J＝7.2 Hz),0.73-0.64(3H,m).13C NMR(75 MHz,DMSO)δ:177.57,160.09,142.18,128.95,126.89,114.44,103.30,100.48,86.81,80.41,64.38,62.96,51.88,43.75,36.28,36.02,33.99,30.50,28.40,25.66,24.19,24.01,20.26,12.79.HR MS calcd for C26H37N3O6S[M+Na]+542.2301,found 542.2302.
TM9-24(E)-2-(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)benzylidene)hydrazinecarbothioamide
1H NMR(300 MHz,DMSO)δ:8.17(1H,s,NH2),8.01(1H,s,NH2),7.96(1H,s,NH),7.52(1H,s),7.10(1H,d,J＝7.8 Hz),6.93(1H,d,J＝8.1 Hz),5.13(1H,s),4.75-4.62(1H,m),4.06-3.97(3H,m),3.83(3H,s),3.61-3.42(1H,m),2.43-2.29(m,1H),2.18-2.09(m,1H),1.99-1.02(12H,m),1.28(3H,s),0.82(3H,d,J＝6.6 Hz),0.73-0.65(3H,m).13C NMR(75MHz,DMSO)δ:177.48,149.98,149.31,142.57,127.04,122.06,111.89,108.39,103.20,100.42,86.83,80.42,64.85,62.89,55.70,51.88,43.77,36.28,36.07,34.00,30.50,28.48,25.70,24.20,23.98,20.28,12.80.HR MS calcd for C27H39N3O7S[M+Na]+572.2406,found 572.2409.
TM9-25(E)-2-(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)benzylidene)hydrazinecarbothioamide
1H NMR(300 MHz,DMSO)δ:11.30(1H,s),8.16(1H,s,NH2),8.01(1H,s,NH2),7.95(1H,s,NH),7.52(1H,s,),7.20-7.04(1H,m),7.02-6.89(1H,m),5.03(1H,s),4.75-4.60(1H,m),4.24-3.95(3H,m),3.79(3H,s),3.56-3.48(1H,m),2.44-2.28(m,1H),2.10-0.99(13H,m),1.27(3H,s),0.90-0.75(3H,m),0.74-0.56(3H,m).13C NMR(75 MHz,DMSO)δ:177.46,150.82,148.60,142.58,126.92,122.30,111.09,108.99,103.13,100.29,86.78,80.42,64.74,62.58,55.61,51.88,43.76,36.10,36.08,33.93,30.52,28.46,25.70,24.13,20.31,12.83.HR MS calcd for C27H39N3O7S[M+Na]+572.2406,found 572.2408.
TM9-26(E)-2-(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)benzylidene)hydrazinecarbothioamide
1H NMR(300 MHz,DMSO)δ:11.42(1H,s),8.45(1H,s,NH),8.14-8.08(2H,m),7.92(1H,s,NH2),7.34(1H,t,J＝7.2 Hz),7.07(1H,d,J＝8.1 Hz),6.94(1H,t,J＝7.5 Hz),5.29(1H,s),4.86-4.78(1H,m),4.22-4.01(3H,m),3.79-3.67(1H,m),2.45-2.33(1H,m),2.20-2.11(1H,m),2.02-1.12(10,m),1.30(3H,s),0.83(3H,d,J＝4.5 Hz),0.77(3H,d,J＝6.9 Hz).13C NMR(75 MHz,DMSO)δ:177.76,157.25,138.05,131.18,126.08,122.49,120.62,112.81,103.38,101.46,87.02,80.54,68.05,66.31,52.06,43.88,36.56,36.05,34.07,30.50,25.69,24.25,23.90,20.13,12.72.
TM9-27(E)-2-(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)benzylidene)hydrazinecarbothioamide
1H NMR(300 MHz,DMSO)δ:11.46(1H,s),8.26(1H,s,NH2),8.07(1H,s,NH2),8.00(1H,s,NH),7.45(1H,s),7.33-7.24(2H,m),6.95(1H,d,J＝7.8 Hz),5.34(1H,s),4.77(1H,d,J＝3.0 Hz),4.33-4.13(2H,m),4.06-3.97(1H,m),3.71-3.67(1H,m),2.42-2.37(1H,m),2.22-2.10(1H,m),2.01-1.02(10,m),1.29(3H,s),0.85(3H,d,J＝6.0 Hz),0.81(3H,d,J＝7.5 Hz).13C NMR(75 MHz,DMSO)δ:177.95,158.91,142.05,135.66,129.72,120.66,116.75,111.62,103.33,100.71,86.94,80.51,67.17,65.84,52.04,43.86,36.70,36.03,34.12,30.49,25.67,24.33,23.95,20.14,12.75.
TM9-28(E)-2-(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)benzylidene)hydrazinecarbothioamide
1H NMR(300 MHz,DMSO)δ:11.33(1H,s),8.13(1H,s,NH2),7.99(1H,s,NH),7.93(1H,s,NH2),7.73(2H,d,J＝8.4 Hz),6.96(2H,d,J＝8.4 Hz),5.35(1H,s),4.78(1H,d,J＝2.7Hz),4.28-4.10(2H,m),4.06-3.97(1H,m),3.71-3.68(1H,m),2.41-2.39(1H,m),2.22-2.13(1H,m),2.02-1.10(10,m),1.29(3H,s),0.87-0.81(6H,m).13C NMR(75 MHz,DMSO)δ:177.59,160.02,142.15,128.96,126.88,114.7123,103.36,100.72,86.95,80.51,67.24,65.73,52.02,43.84,36.74,36.04,34.12,30.50,25.67,24.37,23.94,20.18,12.77.
TM9-29(E)-2-(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)benzylidene)hydrazinecarbothioamide
1H NMR(300 MHz,DMSO)δ:11.33(1H,s),8.18(1H,s,NH2),8.03(1H,s,NH2),7.96(1H,s,NH),7.53(1H,s),7.12(1H,d,J＝8.1 Hz),6.98(1H,d,J＝8.1 Hz),5.38(1H,s),4.85-4.69(1H,m),4.17-3.99(3H,m),3.82(3H,s),3.70-3.67(1H,m),2.46-2.33(m,1H),2.22-2.14(m,1H),1.99-1.10(10H,m),1.29(3H,s),0.87(3H,d,J＝5.7 Hz),0.83(3H,d,J＝7.2 Hz).13C NMR(75 MHz,DMSO)δ:177.52,149.86,149.38,142.47,127.08,122.11,112.44,108.67,103.29,100.61,86.98,80.57,67.17,65.52,55.84,52.07,43.94,36.47,36.06,34.22,30.51,25.67,24.35,23.91,20.18,12.74.
TM9-30(E)-2-(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)benzylidene)hydrazinecarbothioamide
1H NMR(300 MHz,DMSO)δ:11.33(1H,s),8.18(1H,s,NH2),8.02(1H,s,NH2),7.95(1H,s,NH),7.54(1H,s),7.13(1H,d,J＝7.5 Hz),6.96(1H,d,J＝8.4 Hz),5.39(1H,s),4.77(1H,d,J＝3.0 Hz),4.23-3.99(3H,m),3.78(3H,s),3.71-3.67(1H,m),2.42-2.37(m,1H),2.22-2.09(m,1H),2.02-1.06(10H,m),1.29(3H,s),0.87(3H,d,J＝6.0 Hz),0.81(3H,d,J＝7.2 Hz).13C NMR(75 MHz,DMSO)δ:177.56,150.80,148.43,142.41,126.92,122.19,111.45,109.65,103.24,100.60,86.96,80.54,67.67,65.70,55.70,52.07,43.94,36.48,36.05,34.21,30.48,25.64,24.30,23.90,20.11,12.67.
TM9-31(E)-2-(1-(2-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepi no[4,3-i]isochromen-10-yl)oxy)propoxy)phenyl)ethylidene)hydrazinecarbothioamide
1H NMR(300 MHz,DMSO)δ:10.12(1H,s,NH),8.26(1H,s,NH2),7.60(1H,s,NH2),7.49(1H,d,J＝7.2Hz),7.31(1H,t,J＝7.5 Hz),7.03(1H,d,J＝8.1 Hz),6.93(1H,t,J＝7.2 Hz),5.12(1H,),4.69(1H,d,J＝2.4 Hz),4.08-3.90(3H,m),3.65-3.52(1H,m),2.43-2.35(1H,m),2.27(3H,s),2.23-1.031.99-1.03(13H,m),1.28(3H,s),0.82(3H,d,J＝6.9Hz),0.76-0.68(3H,m).13C NMR(75 MHz,DMSO)δ:178.83,156.64,149.81,130.24,129.64,128.29,120.30,111.87,103.30,100.44,86.81,80.36,64.35,62.98,51.94,43.76,36.32,35.95,34.04,30.52,28.55,25.64,24.13,24.06,20.26,18.11,12.81.HR MS calcd forC27H39N3O6S[M+Na]+556.2457,found556.2409.
TM9-32(E)-2-(1-(3-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepi no[4,3-i]isochromen-10-yl)oxy)propoxy)phenyl)ethylidene)hydrazinecarbothioamide
1H NMR(300MHz,DMSO)δ:10.23(1H,s,NH),8.32(1H,s,NH2),7.88(1H,s,NH2),7.48(1H,d,J＝7.5Hz),7.40(1H,s),7.29(1H,t,J＝7.8Hz),6.95(1H,d,J＝7.8Hz),5.13(1H,s),4.72-4.65(1H,m),4.10-3.94(3H,m),3.41-3.38(1H,m),2.43-2.32(1H,m),2.28(3H,s),2.15-0.99(13H,m),1.28(3H,s),0.82(3H,d,J＝7.2Hz),0.71-0.66(3H,m).13C NMR(151MHz,DMSO)δ:178.91,158.66,147.68,139.13,129.24,119.12,114.95,112.50,103.24,100.41,86.75,80.37,67.02,64.24,51.87,43.74,36.21,36.00,33.97,30.48,28.42,25.63,24.03,24.01,20.18,14.14,12.75.HR MS calcd for C27H39N3O6S[M+Na]+556.2457,found 556.2410.27个C
TM9-33(E)-2-(1-(4-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepi no[4,3-i]isochromen-10-yl)oxy)propoxy)phenyl)ethylidene)hydrazinecarbothioamide
1H NMR(300MHz,DMSO)δ:10.14(1H,s,NH),8.23(1H,s,NH2),7.89(3H,d,J＝8.7Hz),6.90(2H,d,J＝8.7Hz),5.15(1H,s),4.70(1H,d,J＝3.0Hz),4.07-3.91(3H,m),3.41-3.35(1H,m),2.40-2.35(1H,m),2.25(3H,s),2.17-2.09(1H,m),1.99-1.03(12H,m),1.22(3H,s),0.82(3H,d,J＝7.2Hz),0.69-0.63(3H,m).13C NMR(151MHz,DMSO)δ:178.62,159.61,147.68,130.10,128.11,113.86,103.25,100.47,86.78,80.37,64.28,63.00,51.88,43.74,36.23,35.99,33.98,30.46,28.40,25.63,24.12,23.96,20.10,13.78,12.74.HR MS calcd for C27H39N3O6S[M+Na]+556.2457,found 556.2410.
TM9-34(E)-2-(1-(4-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepi no[4,3-i]isochromen-10-yl)oxy)propoxy)phenyl)propylidene)hydrazinecarbothioamide
1H NMR(300MHz,DMSO)δ:10.25(1H,s,NH),8.24(1H,s,NH2),7.88(3H,d,J＝8.4Hz),6.91(2H,d,J＝8.7Hz),5.16(1H,s),4.70(1H,d,J＝3.0Hz),4.06-3.91(3H,m),3.42-3.36(1H,m),2.84(2H,q,J＝6.9Hz),2.40-2.37(1H,m),2.17-2.09(1H,m),1.99-1.07(12H,m),1.28(3H,s),1.01(3H,t,J＝7.5Hz),0.82(3H,d,J＝7.2Hz),0.71-0.64(3H,m).13CNMR(151MHz,DMSO)δ:178.64,159.56,151.56,128.81,128.18,114.00,103.26,100.47,86.80,80.39,64.27,62.99,51.90,43.75,36.27,36.00,33.99,30.48,28.41,25.63,24.13,23.98,20.14,19.08,12.75,11.08.HR MS calcd for C28H41N3O6S[M+Na]+570.2614,found 570.2615.
TM9-35(E)-2-(4-(4-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepi no[4,3-i]isochromen-10-yl)oxy)propoxy)phenyl)butan-2-ylidene)hydrazinecarbothioamide
1H NMR(300 MHz,DMSO)δ:9.96(1H,s,NH),8.06(1H,s,NH2),7.45(1H,s,NH2),7.132H,d,J＝7.2Hz),6.812H,d,J＝6.9 Hz),5.20(1H,s),4.75-4.65(1H,m),3.98-3.90(3H,m),3.46-3,38(1H,m),2.75-2.65(2H,m),2.50-2.38(3H,m),2.18-1.07(13H,m),1.91(3H,s),1.28(3H,s),0.82(3H,d,J＝6.0 Hz),0.78-0.71(3H,m).13C NMR(75 MHz,DMSO)δ:178.49,156.78,153.64,133.33,129.19,114.03,103.29,100.48,86.83,80.44,64.06,63.19,51.95,43.79,40.07,36.30,36.04,34.05,30.75,30.52,28.61,25.67,24.19,24.01,20.23,16.75,12.81.HR MS calcd for C29H43N3O6S[M+Na]+584.2770,found584.2773.
TM9-36(E)-2-(1-(2-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepi no[4,3-i]isochromen-10-yl)oxy)ethoxy)phenyl)ethylidene)hydrazinecarbothioamide
1H NMR(300 MHz,DMSO)δ:10.11(1H,s,NH),8.21(1H,s,NH2),7.64(1H,s,NH2),7.44(1H,d,J＝7.5Hz),7.35(1H,t,J＝7.5 Hz),7.07(1H,d,J＝8.1 Hz),6.94(1H,d,J＝7.5 Hz),5.33(1H,s),4.76(1H,d,J＝2.7Hz),4.21-3.98(3H,m),3.69-3.58(1H,m),2.44-2.34(1H,m),2.26(3H,s),2.20-1.09(11H,m),1.31(3H,s),0.87-0.81(6H,m).13C NMR(151MHz,DMSO)δ:178.91,156.63,150.15,130.24,129.80,128.51,120.33,112.30,103.37,101.03,86.97,80.47,67.49,66.30,52.06,43.84,36.64,36.02,34.06,30.45,25.64,24.26,23.91,20.18,17.90,12.71.
TM9-37(E)-2-(1-(3-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepi no[4,3-i]isochromen-10-yl)oxy)ethoxy)phenyl)ethylidene)hydrazinecarbothioamide
1H NMR(300 MHz,DMSO)δ:10.23(1H,s,NH),8.33(1H,s,NH2),7.94(1H,s,NH2),7.48-7.43(2H,m),7.29(1H,t,J＝8.1 Hz),6.96(1H,dd,J＝1.5 Hz and 8.1 Hz),5.35(1H,s),4.78(1H,d,J＝3.3 Hz),4.23-3.97(3H,m),3.71(1H,m),2.42-2.34(1H,m),2.28(3H,s),2.22-2.09(1H,m),2.01-1.09(10H,m),1.29(3H,s),0.85-0.81(6H,m).13C NMR(151MHz,DMSO)δ:178.92,158.58,147.66,139.16,129.25,119.21,115.53,112.47,103.30,100.68,86.91,80.47,67.18,65.78,52.03,43.85,36.69,36.01,34.10,30.47,25.63,24.28,23.91,20.10,14.18,12.71.
TM9-38(E)-2-(1-(4-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepi no[4,3-i]isochromen-10-yl)oxy)ethoxy)phenyl)ethylidene)hydrazinecarbothioamide
1HNMR(300MHz,DMSO)δ:10.14(1H,s,NH),8.23(1H,s,NH2),7.89(3H,d,J＝8.1Hz),6.92(2H,d,J＝8.4Hz),5.35(1H,s),4.84-4.73(1H,m),4.19-3.97(3H,m),3.72-3.68(1H,m),2.46-2.34(1H,m),2.26(3H,s),2.18-2.09(1H,m),2.02-1.15(10H,m),1.29(3H,s),0.86-0.82(6H,m).13C NMR(151MHz,DMSO)δ:178.64,159.54,147.71,130.13,128.13,114.12,103.30,100.72,86.93,80.46,67.17,65.72,52.01,43.82,36.69,36.01,34.09,30.46,25.62,24.32,23.89,20.11,13.82,12.70.
TM9-39(E)-2-(1-(4-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepi no[4,3-i]isochromen-10-yl)oxy)ethoxy)phenyl)propylidene)hydrazinecarbothioamide
1HNMR(300MHz,DMSO)δ:10.25(1H,s,NH),8.23(1H,s,NH2),7.87(3H,d,J＝8.4Hz),6.92(2H,d,J＝8.7Hz),5.35(1H,s),4.78(1H,d,J＝3.0Hz),4.19-3.97(3H,m),3.72-3.68(1H,m),2.91-2.76(2H,m),2.42-2.39(1H,m),2.22-2.13(1H,m),2.09-1.15(10H,m),1.29(3H,s),1.00(3H,t,J＝7.2Hz),0.86-0.82(6H,m).13C NMR(151MHz,DMSO)δ:178.66,159.48,151.63,128.82,128.22,114.27,103.30,100.72,86.92,80.47,67.15,65.69,52.02,43.83,36.69,36.01,34.09,30.47,25.63,24.32,23.90,20.76,20.12,12.71,11.05.
TM9-40(E)-2-(4-(4-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepi no[4,3-i]isochromen-10-yl)oxy)ethoxy)phenyl)butan-2-ylidene)hydrazinecarbothioamide
1H NMR(300MHz,DMSO)δ:9.96(1H,s,NH),8.06(1H,s,NH2),7.45(1H,s,NH2),7.13(2H,d,J＝8.1Hz),6.83(2H,d,J＝8.1Hz),5.37(1H,s),4.80-4.71(1H,m),4.09-3.94(3H,m),3.69-3.60(1H,m),2.79-2.66(2H,m),2.48-2.39(3H,m),2.22-2.13(1H,m),2.02-1.03(10H,m),1.91(3H,s),1.31(3H,s),0.87(3H,d,J＝6.0Hz),0.83(3H,d,J＝7.5Hz).13C NMR(75MHz,DMSO)δ:178.50,156.73,153.62,133.46,129.21,114.34,103.33,100.70,86.94,80.52,67.05,65.74,52.05,43.88,40.08,36.72,36.05,34.14,30.74,30.51,25.66,24.36,23.95,20.18,16.75,12.77.
实施例4、TM9目标分子抗结核活性测试
美国礼来制药(Eli Lilly and Company)公司对实施例2制备出的TM9-1～TM9-40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2所示。
表2 TM9系列目标分子对结核分枝杆菌H37Rv的抑制率(抗结核)
表3 部分TM9目标分子对HELA Cytotox的抑制率
抗结核活性筛选结果显示(见表2、表3)，在20μM样品测试浓度下，40个化合物中有18个目标分子活性超过60％，其中有16个超过80％，对结核分支杆菌表现出较强的抑制作用；发现X为硫原子(缩氨硫脲)的活性普遍高于X为氧原子(缩氨脲)，同一类型结构中对位间位者的活性强于邻位者；更重要的是，二氢青蒿素和缩氨脲/缩氨硫脲酚类两者本身均无抗结核活性，但二氢青蒿素与某些缩氨脲/缩氨硫脲酚类的偶联物(目标化合物)却具有中等或很强的生物活性。这是首次发现DHA的某些缩氨脲/缩氨硫脲酚类衍生物具有抗结核活性。值得注意的是，TM9-38,TM9-25,TM9-40,TM9-29,TM9-32毒性很低，值得进一步开发。
实施例5、TM9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：
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 andnon-linear regression拟合方程拟合算出。实验结果如表4、表5所示：
表4 TM9目标化合物的GLP-1百分激动活性
表5 部分TM9目标化合物GLP-1激动活性的EC50值
由目标分子的胰高血糖素样肽-1活性测试结果显示(见表4、表5)，在20μM样品测试浓度下，40个化合物中有11个目标分子活性超过30％，其中有7个超过60％，活性最好为TM9-25，达到了70.5％，生物活性较佳；其中，X为硫原子(缩氨硫脲)的活性普遍高于X为氧原子(缩氨脲)；TM9-35和TM9-40的EC50值均低于1μM。更重要的是，二氢青蒿素和缩氨脲/缩氨硫脲酚类两者本身均无GLP-1这方面的活性，但二氢青蒿素与某些缩氨脲/缩氨硫脲酚类的偶联物(目标化合物)却具有中等或很强的生物活性。这是首次发现DHA的某些缩氨脲/缩氨硫脲酚类衍生物具有GLP-1的生物活性，可以开发为抗糖尿病药物。
实施例6、TM9降血脂活性研究
蛋白转化酶枯草溶菌素9(Proprotein convertase subtilisin/kexin type 9，PCSK9)是2003年发现的一个脂质代谢调节蛋白，属于前蛋白转化酶(proproteinconvertase，PC)家族,由信号肽、前结构域、催化结构域和羧基末端结构域组成，在肝脏、小肠和肾脏中表达量较多，皮肤、神经系统中少量表达。大量研究发现，PCSK9能介导低密度脂蛋白受体(low density lipoprotein receptor,LDLR)降解，调节血浆低密度脂蛋白胆固醇(low density lipoprotein cholesterol,LDL-C)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，目前PCSK9作为一个新的治疗靶点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部分TM9进行PCSK9抑制活性测试，在5μM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7。
表6 部分TM9目标化合物的PCSK9(Eff-1)的抑制活性结果
表7 部分TM9目标化合物PCSK抑制活性的IC50值
由表6发现，当样品浓度为5μM时，40个分子中，31个分子的Basal_PCSK9 HepG2抑制活性超过70％，24个分子的抑制活性高于80％，且这些分子中38个分子的细胞毒性低于15％。从表7发现，对Basal_PCSK9 HepG2细胞，40个分子中有20个分子的IC50值低于4.8μM，13个分子的IC50值低于3.0μM，其中TM9-2和TM9-31的IC50值低至0.730μM和0.867μM；结构分析发现，含硫脲结构单元的分子的活性强于含脲结构单元的分子；此外，这些分子的细胞毒性很低，毒性最低者其IC50>50μM，具有优秀的应用潜力。本发明首次发现DHA与氨基脲/氨基硫脲酚类反应生成的衍生物具有降血脂活性。
实施例7、TM9目标分子的白细胞介素-17(IL-17)活性测试
TM9的化合物的白细胞介素-17(IL-17)活性委托美国礼来公司Open InnovationDrug Discovery(OIDD)program进行测试。结果见表8
表8 TM9目标化合物的IL-17活性结果
表8活性结果显示：TM9系列的目标分子在10μM的样品浓度下对IL-17有中等偏上的抑制作用，所有分子的IL-17分泌抑制活性超过50％，细胞毒性很低(<25％)，而且X为氧原子的毒性低于X为硫原子，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，其IL-17和IL-5分泌抑制活性有高有低，低者IC50<0.5μM；测试过的分子，对antiCD3/antiCD28/IL23_PBMC的细胞毒性很低(EC50>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0.04034μM。有5个目标化合物经过两轮活性，说明有进一步研究的价值和应用的潜力。本发明首次发现DHA与含羧基酚/酯基酚/酰胺基酚偶联物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 (10)
1.二氢青蒿素含缩氨脲/缩氨硫脲酚类衍生物，或其消旋体、立体异构体、互变异构体、氮氧化物以及其药学上可接受的盐，其特征在于，所述二氢青蒿素含缩氨脲/缩氨硫脲酚类衍生物用TM9表示，结构式如下所示：
其中，n＝1，2，3或4，R1为H、卤素、羟基、氨基、氰基、硝基、烷基、烷氧基或烷胺基，R2为H、烷基或芳基，X为O或S，m＝0，1，2，3或4。
2.如权利要求1所述的二氢青蒿素含缩氨脲/缩氨硫脲酚类衍生物，其特征在于，n＝2或3，R1为H或-OCH3，R2为H、-CH3或-CH2CH3，X为O或S，m＝0或2。
3.如权利要求1或2所述的二氢青蒿素含缩氨脲/缩氨硫脲酚类衍生物的合成方法，其特征在于，TM9的合成按以下反应方程式进行，包括以下步骤：
加入原料TM4、EtOH、氨基脲或氨基硫脲B，搅拌，反应1～12h，反应结束后，进行后处理，得到所述二氢青蒿素含缩氨脲/缩氨硫脲酚类衍生物，即TM9。
4.如权利要求3所述的二氢青蒿素含缩氨脲/缩氨硫脲酚类衍生物的合成方法，其特征在于，原料TM4和氨基脲或硫代氨基脲的物质的量比为0.6～1.6:2～4，反应温度为3～20℃。
5.如权利要求4所述的二氢青蒿素含缩氨脲/缩氨硫脲酚类衍生物的合成方法，其特征在于，所述反应温度为6～16℃。
6.如权利要求3所述的二氢青蒿素含缩氨脲/缩氨硫脲酚类衍生物的合成方法，其特征在于，TM4的合成按以下反应方程式进行，包括以下步骤：
加入含羰基的取代苯酚、IM1、K2CO3和溶剂二甲基甲酰胺，加热、搅拌溶解，反应1～12h，反应结束后，进行后处理，得到所述二氢青蒿素与含羰基酚的偶联物，即TM4。
7.如权利要求6所述的合成方法，其特征在于，原料IM1和原料含羰基的取代苯酚的物质的量比为1～2:1～2.5，反应温度为40～85℃。
8.二氢青蒿素含缩氨脲/缩氨硫脲酚类衍生物的应用，其特征在于，权利要求1或2所述的二氢青蒿素含缩氨脲/缩氨硫脲酚类衍生物或其消旋体、立体异构体、互变异构体、氮氧化物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药物中的应用。
9.如权利要求8所述的二氢青蒿素含缩氨脲/缩氨硫脲酚类衍生物的应用，其特征在于，所述衍生物结构式中的n＝2、R1为H、R2为-CH3、X为S、m＝0，n＝3、R1为-OCH3、R2为H、X为S、m＝0，n＝2、R1为H、R2为-CH3、X为S、m＝2，n＝2、R1为-OCH3、R2为H、X为S、m＝0，n＝3、R1为H、R2为CH3、X为S、m＝0时在抗结核药物中的应用。
10.如权利要求8所述的二氢青蒿素含缩氨脲/缩氨硫脲酚类衍生物的应用，其特征在于，所述衍生物结构式中的n＝3、R1为H、R2为H、X为S、m＝0，n＝2、R1为H、R2为H、X为S、m＝0，n＝2、R1为-OCH3、R2为H、X为S、m＝0，n＝3、R1为H、R2为-CH3、X为S、m＝2，n＝2、R1为H、R2为-CH3、X为S、m＝0时在抗糖尿病药物中的应用；
所述衍生物结构式中的n＝3、R1为H、R2为H、X为O、m＝0，n＝3、R1为-OCH3、R2为H、X为O、m＝0，n＝2、R1为H、R2为H、X为O、m＝0，n＝2、R1为-OCH3、R2为H、X为O、m＝0，n＝3、R1为H、R2为-CH3、X为O、m＝0，n＝3、R1为H、R2为-CH3、X为O、m＝2，n＝3、R1为H、R2为H、X为S、m＝0，n＝3、R1为-OCH3、R2为H、X为S、m＝0，n＝2、R1为H、R2为H、X为S、m＝0，n＝2、R1为-OCH3、R2为H、X为S、m＝0，n＝3、R1为H、R2为-CH3、X为S、m＝0，n＝2、R1为H、R2为-CH3、X为S、m＝0时在降脂药物中的应用；
所述衍生物结构式中的n＝3、R1为H、R2为H、X为O、m＝0，n＝2、R1为H、R2为H、X为O、m＝0，n＝2、R1为H、R2为-CH2CH3、X为O、m＝0，n＝2、R1为H、R2为-CH3、X为O、m＝2时在抑制白细胞介素-17药物中的应用。
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