CN114057626B - 一种吲哚-2,3-二酮的衍生物和制备方法、抑制recql4特异性表达的抗肝癌药物 - Google Patents
一种吲哚-2,3-二酮的衍生物和制备方法、抑制recql4特异性表达的抗肝癌药物 Download PDFInfo
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Abstract
Description
技术领域
本发明属于有机化合物技术领域,具体涉及一种吲哚-2,3-二酮的衍生物和制备方法、抑制RECQL4特异性表达的抗肝癌药物。
背景技术
肝细胞癌(Hepatocellular carcinoma,HCC)是一种原发性肝部恶性肿瘤。研究显示,HCC的发病原因较为复杂,患病人数和死亡人数也在逐年增加,除了种族和遗传背景外,全世界HCC发生的主要原因各不相同,肝炎病毒,脂肪肝,自身免疫性肝病以及真菌代谢产物黄曲霉毒素B1的摄入、DNA发生损伤等均可能导致HCC发生。但是基因组的不稳定性是癌症发生的主要特征,而RECQ解旋酶是DNA解旋酶成员中的一员,在维持基因稳定性方面发挥重要作用。RECQ解旋酶家族包括RECQ1、WRN、BLM、RECQL4和RECQ五种蛋白。RECQL4异常低表达与癌症易感性和早衰有关,RECQL4上调与癌症发生和转移有关。体外实验表明RECQL4可以与BLM发挥协同作用,增加细胞周期的S期的解旋酶活性,增加核基因组稳定性。RECQL4可以调节染色体发挥正常功能,提高线粒体的稳定性,使人体基因维持正常状态。研究表明,RECQL4参与了DNA末端剪切,这是DNA损伤修复的关键,敲除RecQL4能够显著降低DNA损伤程度。
因此,在RECQL4表达水平上调的HCC患者中,沉默或抑制RECQL4的功能,抑制肿瘤细胞的增殖,促进其凋亡也可能是一种新的抗癌治疗方法,对RECQL4蛋白表达进行靶向控制可能发挥治疗肝癌的作用。目前尚没有以RECQL4作为靶点筛选抗肝癌细胞增殖的抑制剂的研究。
发明内容
有鉴于此,本发明提供了一种吲哚-2,3-二酮的衍生物和制备方法、抑制RECQL4特异性表达的抗肝癌药物,所述吲哚-2,3-二酮的衍生物能够抑制以RECQL4作为靶点的肝癌细胞的增殖。
为了解决上述技术问题,本发明提供了一种吲哚-2,3-二酮的衍生物,具有式I的结构式:
R2为-H、羟基、甲氧基或-Cl;
R3为-H、烷基、-O(CH2)3CH3、苯基、取代苯基或卤素;
R4为-H或甲氧基;
R5、R2、R3和R4不同时为-H。
优选的,所述烷基包括甲基、丙基、丁基、戊基或已基。
优选的,所述卤素包括-Cl或-Br。
优选的,所述吲哚-2,3-二酮的衍生物具有式1~46所示的结构式:
本发明提供了上述技术方案所述吲哚-2,3-二酮的衍生物的制备方法,包括以下步骤:
将反应物1、反应物2、极性有机溶剂和碱试剂混合,进行加成反应,得到所述吲哚-2,3-二酮的衍生物;
R5、R2、R3和R4不同时为-H。
优选的,所述反应物1和反应物2的摩尔比为1:1~2;所述反应物1和碱试剂的摩尔比为1:2.8~3.2。
优选的,所述加成反应的温度为室温,时间为2~4h。
优选的,所述混合包括以下步骤:
将反应物1、极性有机溶剂和碱试剂进行第一混合,得到第一混合液;
向所述第一混合液加入反应物2。
本发明提供了一种抑制RECQL4特异性表达的抗肝癌药物,所述药物的活性组分包括吲哚-2,3-二酮的衍生物;
所述吲哚-2,3-二酮的衍生物为上述技术方案所述吲哚-2,3-二酮的衍生物或上述技术方案所述制备方法制备得到的吲哚-2,3-二酮的衍生物。
本发明提供了一种吲哚-2,3-二酮的衍生物,具有式Ⅰ的结构式:
具体实施方式
本发明提供了一种吲哚-2,3-二酮的衍生物,具有式Ⅰ的结构式:
R2为-H、羟基、甲氧基或-Cl;
R3为-H、烷基、-O(CH2)3CH3、苯基、取代苯基或卤素;
R4为-H或甲氧基;
R5、R2、R3和R4不同时为-H。
在本发明中,所述R2为-H、羟基、甲氧基或-Cl,优选为-H、羟基或-Cl。
在本发明中,所述R3为-H、烷基、-O(CH2)3CH3、苯基、取代苯基或卤素,优选为烷基、取代苯基或卤素;所述烷基优选包括甲基、丙基、丁基、戊基或已基,更优选为丙基或丁基;所述取代苯基优选包括苯氧基或更优选为/>所述卤素优选包括-Cl或-Br,更优选为-Cl。
在本发明中,所述R4为-H或甲氧基,优选为-H。
在本发明中,所述吲哚-2,3-二酮的衍生物的结构式优选为式1~46所示:
本发明还提供了上述技术方案所述吲哚-2,3-二酮的衍生物的制备方法,包括以下步骤:
将反应物1、反应物2、极性有机溶剂(以下称为第一极性有机溶剂)和碱试剂混合,进行加成反应,得到所述吲哚-2,3-二酮的衍生物;
R5、R2、R3和R4不同时为-H。
在本发明中,所述第一极性有机溶剂优选为低碳醇、四氢呋喃、二甲基亚砜和N,N二甲基甲酰胺中的一种或多种,更优选为了甲醇、乙醇、四氢呋喃、二甲基亚砜和N,N二甲基甲酰胺中的一种或多种,最优选为甲醇。
在本发明中,所述碱试剂优选为二乙胺、三乙胺、1,8-二氮杂二环[5.4.0]十一碳-7-烯(DBU)、叔丁醇钾、吡啶和无机碱性物质中的一种或多种,更优选为二乙胺、三乙胺、DBU、叔丁醇钾、吡啶、氢氧化钠、碳酸钠、碳酸钾和碳酸氢钠中的一种或多种,最优选为二乙胺或三乙胺。
在本发明中,所述反应物1和反应物2的摩尔比优选为1:1~2,更优选为1:1.3~1.7,最优选为1:1.5;所述反应物1和碱试剂的摩尔比优选为1:2.8~3.2,更优选为1:3。本发明对所述第一极性有机溶剂的用量无特殊限定,只要能够将反应物1和反应物2分散均匀即可。
将吲哚-2,3-二酮、反应物1-1、碳酸钾和N,N-二甲基甲酰胺混合,进行取代反应,得到所述反应物1。
在本发明中,所述反应物1-1优选包括氯化苄、氯乙酰氯和吗啉中的一种或多种,更优选为氯化苄,在本发明中,当所述反应物1-1优选包括氯化苄和氯乙酰氯时,所述氯化苄和氯乙酰氯的摩尔比优选为1:4~5。在本发明中,所述吲哚-2,3-二酮和反应物1-1的摩尔比优选为1:1~1.2,更优选为1∶1.1;所述吲哚-2,3-二酮和碳酸钾的摩尔比优选为1:1.2~1.4,更优选为1:1.3。本发明对所述N,N-二甲基甲酰胺的用量无特殊限定只要能够充分溶解吲哚-2,3-二酮、反应物1-1和碳酸钾即可。
在本发明中,所述混合优选包括以下步骤:
向N,N-二甲基甲酰胺中依次加入碳酸钾、吲哚-2,3-二酮和反应物1-1。
在本发明中,所述取代反应的温度优选为118~122℃,更优选为120℃;所述取代反应的时间优选为28~65min,更优选为30~60min。
在本发明中,所述取代反应后优选还包括:将冰水混合物与取代反应后体系混合,过滤后将滤渣进行干燥,得到所述反应物1。
在本发明中,所述冰水混合物和取代反应后体系的体积比优选为23~27:1,更优选为25~26:1。本发明将冰水混合物和取代反应后体系混合的目的是将取代反应后的产物析出,本发明对所述混合无特殊限定,只要能够使取代反应产物析出即可。本发明对所述过滤无特殊要求,采用本领域常规的过滤方式即可。在本发明中,所述干燥的温度优选为75~85℃,更优选为78~80℃;所述干燥的时间优选为2.5~4.5h,更优选为3~4h。在本发明中,所述反应物1为橙色固体。
在本发明中,当R1为R5为甲基时,所述反应物1为/>所述反应物1的制备方法优选参照当反应物1为/>时的制备方法进行,不同之处在于,将反应物1-1替换为反应物1-2。在本发明中,所述反应物1-2优选包括对甲基氯化苄、氯乙酰氯和苯乙酰氯中的一种或多种,更优选为对甲基氯化苄。
在本发明中,当R1为时,所述反应物1为/>所述反应物1的制备方法优选参照当反应物1为/>的制备方法进行,不同之处在于,将所述反应物1-1替换为反应物1-3。在本发明中,所述反应物1-3优选包括2-溴乙基苯、2-溴乙基-4-溴苯醚、4-硝基苯乙基溴、N-(2-溴乙基)琥珀酰亚胺、3-(2-溴乙基)吲哚和1-(2-溴乙基)吡咯中的一种或多种,更优选为2-溴乙基苯。
将吲哚-2,3-二酮、吗啉、甲醛溶液和第二极性有机溶剂混合,进行取代反应,得到所述反应物1。
在本发明中,所述甲醛溶液的质量浓度优选为35~37%,更优选为36%。在本发明中,所述甲醛溶液的体积优选占总反应体系的1/10。在本发明中,所述吲哚-2,3-二酮和吗啉的摩尔比优选为1:0.8~1.2,更优选为1:1。在本发明中,所述第二极性有机溶剂优选为四氢呋喃或甲醇。在本发明中,所述混合优选包括以下步骤:依次将吲哚-2,3-二酮、甲醛溶液、吗啉加入第二极性有机溶剂中。在本发明中,所述取代反应优选在搅拌的条件下进行,所述搅拌优选为磁力搅拌。在本发明中,所述取代反应的温度优选为室温,所述室温优选为20~30℃,更优选为23~25℃。在本发明中,所述取代反应的时间优选为1.8~2.2h,更优选为2h。
在本发明中,所述取代反应后优选还包括:将取代反应后体系依次进行过滤和烘干,得到所述反应物1。本发明对所述过滤无特殊要求,采用本领域常规的方式即可,在本发明的实施例中,所述过滤优选为抽滤。本发明在过滤过程中优选进行水洗。在本发明中,所述烘干的温度优选为55~65℃,更优选为60℃;时间优选为2~3.5h,更优选为2.5~3h。在本发明中,所述反应物1为橙色固体。
本发明对所述反应物2的来源无特殊限定,采用本领域常规市售产品即可。
在本发明中,将反应物1、反应物2、第一极性有机溶剂和碱试剂的混合优选包括以下步骤:
将反应物1、第一极性有机溶剂和碱试剂进行第一混合,得到第一混合液;
向所述第一混合液中加入反应物2。
本发明将反应物1、第一极性有机溶剂和碱试剂进行第一混合,得到第一混合液。本发明对所述第一混合无特殊限定,只要能够混合均匀即可。
得到第一混合液后,本发明向所述第一混合液中加入反应物2。
在本发明中,所述碱试剂作为催化剂促进反应的进行。
在本发明中,所述加成反应的温度优选为室温,所述室温优选为20~30℃,更优选为23~25℃;所述加成反应的时间优选为2.5~4.5h,更优选为2~4h。
在本发明中,所述加成反应后优选进行后处理,所述后处理优选包括以下步骤:
利用水将加成反应后的体系进行淬灭;
淬灭后进行萃取,收集有机相;
将所述有机相依次进行干燥、旋蒸和色谱分离,得到所述吲哚-2,3-二酮的衍生物。
本发明对所述淬灭无特殊要求采用本领域常规的方式即可。
在本发明中,所述萃取用萃取液优选为二氯甲烷。
在本发明中,所述干燥优选为将所述有机相和硫酸钠混合,以除去有机相中的水。在本发明中,所述干燥后优选进行过滤,收集滤液。本发明对所述过滤无特殊限定,采用本领域常规的方式即可。
在本发明中,所述旋蒸的温度优选为50~60℃,更优选为53~56℃。本发明对所述旋蒸的时间无特殊限定,只要能够将溶剂除去即可。
在本发明中,所述色谱分离用色谱柱优选为硅胶柱;所述色谱分离用洗脱剂优选为石油醚和乙酸乙酯的混合物,所述石油醚和乙酸乙酯的体积比优选为4~6:1,更优选为5:1。
在本发明中,当反应物1为反应物2为/>时,所述后处理优选为:直接将加成反应后体系进行过滤和干燥。本发明对所述过滤无特殊限定,采用本领域常规的方式即可。将过滤得到的固体进行干燥,所述干燥优选为烘干,所述烘干的温度优选为55~65℃,更优选为60℃;时间优选为2.0~3.5h,更优选为2.5~3h。
在本发明中,所述加成反应的反应方程式如式c所示:
本发明还提供了一种抑制RECQL4表达的药物,所述药物的活性组分包括吲哚-2,3-二酮的衍生物;
所述吲哚-2,3-二酮的衍生物为上述技术方案所述吲哚-2,3-二酮的衍生物或上述技术方案所述制备方法制备得到的吲哚-2,3-二酮的衍生物。
本发明提供的药物对肝癌细胞株SNU398增殖具有较高的抑制作用,且对RECQL4高表达的肝癌细胞有较好的选择性。
为了进一步说明本发明,下面结合实施例对本发明提供的技术方案进行详细地描述,但不能将它们理解为对本发明保护范围的限定。
实施例1
向20mLN,N-二甲基甲酰胺中依次加入6.5mmol碳酸钾、5.0mmol吲哚-2,3-二酮和5.5mmol氯化苄,120℃进行取代反应30min,将反应后的溶液转移置500mL冰水混合物中,过滤后于80℃烘干4h,得到1270mg(反应物1),所述反应物1为橙色固体,收率为87%;
将0.85mmol所述反应物1和2.55mmol二乙胺(催化剂)分散于20mL甲醇中,得到第一混合液;
将1.02mmol邻羟基苯乙酮加入至所述第一混合液中,在25℃进行加成反应4h;加水淬灭后利用二氯甲烷进行萃取,收集有机相;将有机相和硫酸钠混合除水后进行过滤;将过滤得到的滤液56℃旋蒸,将旋蒸得到的固体进行色谱分离,得到色谱分离用色谱柱为硅胶柱,色谱分离用洗脱剂为体积比为5∶1的石油醚和乙酸乙酯的混合物。
实施例2
按照实施例1的方法制备吲哚-2,3-二酮的衍生物,不同之处在于,将邻羟基苯乙酮替换为邻甲氧基苯乙酮。
实施例3
按照实施例1的方法制备吲哚-2,3-二酮的衍生物,不同之处在于,将邻羟基苯乙酮替换为对甲基苯乙酮。
实施例4
按照实施例1的方法制备吲哚-2,3-二酮的衍生物,不同之处在于,将邻羟基苯乙酮替换为对丙基苯乙酮。
实施例5
按照实施例1的方法制备吲哚-2,3-二酮的衍生物,不同之处在于,将邻羟基苯乙酮替换为对丁基苯乙酮。
实施例6
按照实施例1的方法制备吲哚-2,3-二酮的衍生物,不同之处在于,将邻羟基苯乙酮替换为对戊基苯乙酮。
实施例7
按照实施例1的方法制备吲哚-2,3-二酮的衍生物,不同之处在于,将邻羟基苯乙酮替换为对己基苯乙酮。
实施例8
按照实施例1的方法制备吲哚-2,3-二酮的衍生物,不同之处在于,将邻羟基苯乙酮替换为对丁氧基苯乙酮。
实施例9
按照实施例1的方法制备吲哚-2,3-二酮的衍生物,不同之处在于,将邻羟基苯乙酮替换为对苯甲氧基苯乙酮。
实施例10
按照实施例1的方法制备吲哚-2,3-二酮的衍生物,不同之处在于,将邻羟基苯乙酮替换为对氯苯乙酮。
实施例11
按照实施例1的方法制备吲哚-2,3-二酮的衍生物,不同之处在于,将邻羟基苯乙酮替换为对苯基苯乙酮。
实施例12
按照实施例1的方法制备吲哚-2,3-二酮的衍生物,不同之处在于,将邻羟基苯乙酮替换为4-溴-2-羟基苯乙酮。
实施例13
按照实施例1的方法制备吲哚-2,3-二酮的衍生物,不同之处在于,将邻羟基苯乙酮替换为2,4-二氯苯乙酮。
实施例14
实施例15
按照实施例14的方法制备吲哚-2,3-二酮的衍生物,不同之处在于,将邻羟基苯乙酮替换为邻甲氧基苯乙酮。
实施例16
按照实施例14的方法制备吲哚-2,3-二酮的衍生物,不同之处在于,将邻羟基苯乙酮替换为对甲基苯乙酮。
实施例17
按照实施例14的方法制备吲哚-2,3-二酮的衍生物,不同之处在于,将邻羟基苯乙酮替换为对丙基苯乙酮。
实施例18
按照实施例14的方法制备吲哚-2,3-二酮的衍生物,不同之处在于,将邻羟基苯乙酮替换为对丁基苯乙酮。
实施例19
按照实施例14的方法制备吲哚-2,3-二酮的衍生物,不同之处在于,将邻羟基苯乙酮替换为对戊基苯乙酮。
实施例20
按照实施例14的方法制备吲哚-2,3-二酮的衍生物,不同之处在于,将邻羟基苯乙酮替换为对己基苯乙酮。
实施例21
按照实施例14的方法制备吲哚-2,3-二酮的衍生物,不同之处在于,将邻羟基苯乙酮替换为对丁氧基苯乙酮。
实施例22
按照实施例14的方法制备吲哚-2,3-二酮的衍生物,不同之处在于,将邻羟基苯乙酮替换为对苯氧基苯乙酮。
实施例23
按照实施例14的方法制备吲哚-2,3-二酮的衍生物,不同之处在于,将邻羟基苯乙酮替换为对苯甲氧基苯乙酮。
实施例24
按照实施例14的方法制备吲哚-2,3-二酮的衍生物,不同之处在于,将邻羟基苯乙酮替换为对氯苯乙酮。
实施例25
按照实施例14的方法制备吲哚-2,3-二酮的衍生物,不同之处在于,将邻羟基苯乙酮替换为对苯基苯乙酮。
实施例26
按照实施例14的方法制备吲哚-2,3-二酮的衍生物,不同之处在于,将邻羟基苯乙酮替换为4-溴-2-羟基苯乙酮。
实施例27
按照实施例14的方法制备吲哚-2,3-二酮的衍生物,不同之处在于,将邻羟基苯乙酮替换为2,4-二氯苯乙酮。
实施例28
按照实施例14的方法制备吲哚-2,3-二酮的衍生物,不同之处在于,将邻羟基苯乙酮替换为苯乙酮。
实施例29
按照实施例1的方法制备吲哚-2,3-二酮的衍生物,不同之处在于,将氯化苄替换为2-溴乙基苯,取代反应时间有30min调整为60min。
实施例30
按照实施例29的方法制备吲哚-2,3-二酮的衍生物,不同之处在于,将邻羟基苯乙酮替换为邻甲氧基苯乙酮。
实施例31
按照实施例29的方法制备吲哚-2,3-二酮的衍生物,不同之处在于,将邻羟基苯乙酮替换为对甲基苯乙酮。
实施例32
按照实施例29的方法制备吲哚-2,3-二酮的衍生物,不同之处在于,将邻羟基苯乙酮替换为对丙基苯乙酮。
实施例33
按照实施例29的方法制备吲哚-2,3-二酮的衍生物,不同之处在于,将邻羟基苯乙酮替换为对丁基苯乙酮。
实施例34
按照实施例29的方法制备吲哚-2,3-二酮的衍生物,不同之处在于,将邻羟基苯乙酮替换为对戊基苯乙酮。
实施例35
按照实施例29的方法制备吲哚-2,3-二酮的衍生物,不同之处在于,将邻羟基苯乙酮替换为对己基苯乙酮。
实施例36
按照实施例29的方法制备吲哚-2,3-二酮的衍生物,不同之处在于,将邻羟基苯乙酮替换对丁氧基苯乙酮。
实施例37
按照实施例29的方法制备吲哚-2,3-二酮的衍生物,不同之处在于,将邻羟基苯乙酮替换为对苯氧基苯乙酮。
实施例38
按照实施例29的方法制备吲哚-2,3-二酮的衍生物,不同之处在于,将邻羟基苯乙酮替换为对苯甲氧基苯乙酮。
实施例39
按照实施例29的方法制备吲哚-2,3-二酮的衍生物,不同之处在于,将邻羟基苯乙酮替换为对氯苯乙酮。
实施例40
按照实施例29的方法制备吲哚-2,3-二酮的衍生物,不同之处在于,将邻羟基苯乙酮替换为对苯基苯乙酮。
实施例41
按照实施例29的方法制备吲哚-2,3-二酮的衍生物,不同之处在于,将邻羟基苯乙酮替换为4-溴-2-羟基苯乙酮。
实施例42
按照实施例29的方法制备吲哚-2,3-二酮的衍生物,不同之处在于,将邻羟基苯乙酮替换为2,4-二氯苯乙酮。
实施例43
按照实施例29的方法制备吲哚-2,3-二酮的衍生物,不同之处在于,将邻羟基苯乙酮替换为苯乙酮。
实施例44
按照实施例29的方法制备吲哚-2,3-二酮的衍生物,不同之处在于,将邻羟基苯乙酮替换为2-羟基-5甲氧基苯乙酮。
实施例45
按照实施例1的方法制备吲哚-2,3-二酮的衍生物,不同之处在于,反应物1按照以下步骤进行制备:
依次将5mmol吲哚-2,3-二酮、2mL浓度为37%的甲醛溶液、5mmol吗啉加入到20mL四氢呋喃中,在磁力搅拌下25℃取代反应2h;对取代反应后体系进行抽滤(水洗),将抽滤得到的固体60℃烘干3h,得到766mg(反应物1),所述反应物1为橙色固体,收率为63%。
实施例46
按照实施例45的方法制备吲哚-2,3-二酮的衍生物,不同之处在于,将邻羟基苯乙酮替换为2-羟基-5-甲氧基苯乙酮;后处理为:将加成反应后产物进行抽滤后60℃烘干。
为了便于清楚了解实施例1~46制备得到的吲哚-2,3-二酮的衍生物的结构将实施例1~46制备得到的吲哚-2,3-二酮的衍生物中的R1、R2、R3、R4和R5的基团列于表1中。
表1实施例1~46制备得到的吲哚-2,3-二酮的衍生物中R1、R2、R3、R4和R5的基团
将实施例1~46制备得到的产物进行核磁共振氢谱(1HNMR)检测、核磁共振碳谱(13CNMR)和高分辨质谱(电喷雾电离,HRMS(ESI+))检测结果如下。
实施例1检测结果:1H NMR(DMSO-d6)δ11.50–11.06(s,1H),7.89–7.75(dd,J=8.3,1.7Hz,1H),7.52–7.41(m,3H),7.38–7.31(t,J=7.6,6.6,1.4Hz,3H),7.30–7.25(m,1H),7.21–7.14(m,J=7.7,1.3Hz,1H),6.99–6.88(m,3H),6.85–6.72(d,J=7.6Hz,1H),6.37–6.12(s,1H),5.00–4.81(d,2H),4.27–4.13(d,J=17.8Hz,1H),3.84–3.71(d,J=17.8Hz,1H).
13C NMR(DMSO-d6)δ201.55,177.21,160.54,143.85,136.92,136.55,131.50,131.13,129.48,128.86,127.85,127.73,123.84,122.47,121.25,119.74,118.05,109.43,73.19,48.07,43.20.
HRMS(ESI+):化学式:C23H19NO;[M+H]+:374.1348,实测值:374.1388。
实施例2检测结果:1H NMR(DMSO-d6)δ7.56–7.51(m,J=8.7,7.2,1.9Hz,1H),7.51–7.41(d,2H),7.43–7.31(m,3H),7.32–7.28(m,2H),7.22–7.12(m,2H),7.02–6.87(m,J=12.0,7.5,0.9Hz,2H),6.82–6.70(d,J=7.8Hz,1H),6.31–6.04(s,1H),5.03–4.75(s,2H),4.09–4.00(d,J=18.0Hz,1H),4.01–3.83(s,3H),3.82–3.70(d,J=17.9Hz,1H).
13C NMR(DMSO-d6)δ197.97,177.36,159.01,143.95,136.96,134.75,131.62,129.86,129.34,128.93,127.72,127.68,127.13,123.65,122.38,120.89,113.00,109.32,73.19,56.34,51.63,43.16.
HRMS(ESI+):化学式:C24H21NO;[M+H]+:388.1504,实测值:388.1546。
实施例3检测结果:1HNMR(DMSO-d6)δ7.78–7.68(d,J=8.2Hz,2H),7.44–7.37(d,J=7.1Hz,2H),7.33–7.24(t,J=7.4Hz,3H),7.26–7.18(t,J=7.6Hz,3H),7.16–6.99(t,J=7.7Hz,1H),6.89–6.80(t,J=7.5Hz,1H),6.73–6.62(d,J=7.8Hz,1H),6.28–6.13(s,1H),5.10–4.48(s,2H),4.17–3.56(dd,J=187.4,17.6Hz,2H),2.45–1.97(s,3H).
13C NMR(DMSO-d6)δ196.44,177.39,144.44,143.96,136.93,134.05,131.63,129.75,129.42,128.93,128.57,127.72,127.69,123.80,122.42,109.39,73.27,46.29,43.22,21.63.
HRMS(ESI+):化学式:C24H21NO3;[M+H]+:372.1555,实测值:372.1596。
实施例4检测结果:1HNMR(DMSO-d6)δ7.89–7.78(d,J=7.9Hz,2H),7.51–7.43(d,J=7.3Hz,2H),7.41–7.23(m,6H),7.20–7.09(t,J=7.7Hz,1H),6.95–6.89(t,J=7.5Hz,1H),6.82–6.66(d,J=7.8Hz,1H),6.38–6.14(s,1H),5.08–4.72(s,2H),4.39–3.63(dd,J=187.6,17.6Hz,2H),2.69–2.55(t,J=7.5Hz,2H),1.64–1.55(q,J=7.4Hz,2H),0.93–0.83(t,J=7.3Hz,3H).
13C NMR(DMSO-d6)δ196.49,177.37,148.88,143.95,136.93,134.30,131.63,129.41,129.17,128.93,128.58,127.72,127.68,123.80,122.40,109.38,73.25,46.29,43.21,37.57,24.18,14.02.
HRMS(ESI+):化学式:C26H25NO3;[M+H]+:400.1068,实测值:400.1011。
实施例5检测结果:1HNMR(DMSO-d6)δ7.89–7.72(d,J=8.2Hz,2H),7.51–7.43(d,J=7.2Hz,2H),7.38–7.32(m,4H),7.32–7.26(m,2H),7.20–7.11(t,J=8.4Hz,1H),6.96–6.87(t,J=7.0Hz,1H),6.78–6.71(d,J=7.6Hz,1H),6.30–6.22(s,1H),4.98–4.84(s,2H),4.19–3.68(dd,J=185.8,17.4Hz,2H),2.68–2.57(t,J=7.6Hz,2H),1.59–1.50(m,2H),1.28–1.25(m,J=6.4Hz,2H),0.91–0.86(t,J=7.3Hz,3H).
13C NMR(DMSO-d6)δ196.46,177.36,149.09,143.95,136.93,134.29,131.64,129.40,129.11,128.92,128.59,127.72,127.67,123.80,122.39,109.37,73.26,46.30,43.22,35.21,33.16,22.15,14.20.
HRMS(ESI+):化学式:C27H27NO3;[M+H]+:414.2024,实测值:414.2070。
实施例6检测结果:1H NMR(DMSO-d6)δ7.96–7.68(m,2H),7.55–7.43(m,2H),7.41–7.31(m,4H),7.31–7.24(m,2H),7.19–7.12(m,1H),6.95–6.87(m,1H),6.81–6.70(d,J=7.8Hz,1H),6.35–6.21(m,1H),5.02–4.80(s,2H),4.23–4.08(d,J=17.6Hz,1H),3.78–3.64(d,J=17.2Hz,1H),2.71–2.54(t,J=7.6Hz,2H),1.63–1.50(m,2H),1.31–1.22(m,4H),0.89–0.76(t,J=7.0Hz,3H).
13C NMR(DMSO-d6)δ196.46,177.37,149.11,143.97,136.93,134.30,131.65,129.40,129.10,128.92,128.60,127.72,127.67,123.80,122.39,109.37,73.28,46.32,43.24,35.50,31.26,30.68,22.39,14.35.
HRMS(ESI+):化学式:C28H29NO3;[M+H]+:428.2288,实测值:428.2227。
实施例7检测结果:1H NMR(DMSO-d6)δ7.95–7.70(d,J=8.2Hz,2H),7.53–7.42(m,2H),7.41–7.28(m,5H),7.29–7.18(m,1H),7.18–7.09(td,J=7.8,1.3Hz,1H),6.99–6.85(m,1H),6.85–6.68(d,J=7.8Hz,1H),6.41–6.08(s,1H),5.10–4.72(s,2H),4.27–4.04(d,J=17.6Hz,1H),3.79–3.63(d,J=17.6Hz,1H),2.77–2.55(t,J=7.6Hz,2H),1.61–1.47(t,J=7.3Hz,2H),1.28–1.22(m,6H),0.97–0.73(q,J=5.0,3.3Hz,3H).
13C NMR(DMSO-d6)δ196.46,177.36,149.11,143.95,136.94,134.29,131.64,129.40,129.10,128.92,128.59,127.72,127.67,123.81,122.38,109.37,73.26,46.30,43.22,35.53,31.52,30.97,28.71,22.50,14.41.
HRMS(ESI+):化学式:C29H31NO3;[M+H]+:442.2337,实测值:442.2382。
实施例8检测结果:1HNMR(DMSO-d6)δ8.15–7.51(d,J=8.7Hz,2H),7.67–7.39(d,J=7.6Hz,2H),7.45–7.30(m,J=7.6,3.9Hz,3H),7.31–7.23(m,1H),7.19–7.08(m,1H),7.11–6.94(d,J=8.6Hz,2H),6.95–6.80(t,J=7.5Hz,1H),6.80–6.65(d,J=7.8Hz,1H),5.04–4.57(s,2H),4.20–4.10(d,J=17.4Hz,1H),4.11–3.89(t,J=6.5Hz,2H),3.72–3.60(d,J=17.4Hz,1H),1.84–1.54(q,J=7.5,7.1Hz,2H),1.49–1.36(q,J=7.5Hz,2H),1.03–0.79(t,J=7.3Hz,3H).
13C NMR(DMSO-d6)δ195.18,177.42,163.29,143.97,136.95,131.72,130.82,129.36,128.92,127.72,127.66,123.78,122.36,114.77,109.35,73.32,68.06,46.04,43.22,31.01,19.13,14.13.
HRMS(ESI+):化学式:C27H27NO4;[M+H]+:430.2074,实测值:430.2017。
实施例9检测结果:1H NMR(DMSO-d6)δ7.87–7.75(d,J=8.9Hz,2H),7.45–7.36(t,J=6.2Hz,4H),7.38–7.29(t,J=7.2Hz,2H),7.33–7.23(t,4H),7.26–7.16(d,J=7.3Hz,1H),7.13–7.04(t,J=7.1Hz,1H),7.05–7.00(d,J=8.9Hz,2H),6.91–6.78(m,1H),6.74–6.61(d,J=7.8Hz,1H),6.27–6.09(s,1H),5.22–5.02(s,2H),4.89–4.62(s,2H),4.13–3.46(dd,J=190.6,17.5Hz,2H).
13C NMR(DMSO-d6)δ195.24,177.40,162.87,143.94,136.93,136.88,130.81,129.63,129.38,128.98,128.92,128.51,128.27,127.71,127.66,123.77,122.38,115.16,109.36,73.29,69.96,46.04,43.19.
HRMS(ESI+):化学式:C30H25NO4;[M+H]+:464.1817,实测值:464.1861。
实施例10检测结果:1H NMR(DMSO-d6)δ8.05–7.79(m,2H),7.64–7.53(m,2H),7.53–7.42(m,2H),7.41–7.32(m,3H),7.33–7.23(m,1H),7.23–7.06(m,1H),7.01–6.85(m,1H),6.83–6.71(d,J=7.7Hz,1H),6.41–6.27(s,1H),5.00–4.82(s,2H),4.27–4.10(d,J=17.6Hz,1H),3.79–3.63(d,J=17.6Hz,1H).
13C NMR(DMSO-d6)δ196.07,177.25,143.87,138.96,136.88,135.13,131.45,130.43,129.50,129.32,128.94,127.72,123.92,122.47,109.44,73.25,46.38,43.22.
HRMS(ESI+):化学式:C23H18ClNO3;[M+H]+:392.1048,实测值:392.1049。
实施例11检测结果:1H NMR(DMSO-d6)δ8.24–7.87(d,J=8.1Hz,2H),7.88–7.77(d,J=8.0Hz,2H),7.79–7.64(d,J=7.6Hz,2H),7.59–7.46(m,4H),7.47–7.42(d,J=7.2Hz,1H),7.42–7.32(q,J=7.6Hz,3H),7.32–7.24(t,J=7.3Hz,1H),7.23–7.13(t,J=7.7Hz,1H),7.05–6.88(t,J=7.5Hz,1H),6.85–6.65(d,J=7.8Hz,1H),6.50–6.12(s,1H),5.14–4.72(s,2H),4.42–4.13(d,J=17.6Hz,1H),3.89–3.66(d,J=17.6Hz,1H).
13C NMR(DMSO-d6)δ196.55,177.36,145.27,143.94,139.22,136.93,135.26,131.58,129.60,129.47,129.23,128.95,127.74,127.48,127.38,123.86,122.46,109.42,73.29,46.41,43.21.
HRMS(ESI+):化学式:C29H23NO3;[M+H]+:434.1711,实测值:434.1753。
实施例12检测结果:1H NMR(DMSO-d6)δ11.60–11.53(s,1H),7.71–7.66(d,J=8.5Hz,1H),7.54–7.49(d,J=7.1Hz,2H),7.43–7.38(m,3H),7.36–7.30(m,1H),7.26–7.19(m,2H),7.18–7.13(m,1H),7.02–6.96(m,1H),6.88–6.79(d,J=7.8Hz,1H),6.42–6.34(s,1H),5.02–4.91(m,2H),4.27–4.18(d,J=18.0Hz,1H),3.86–3.78(d,J=17.9Hz,1H).
13C NMR(DMSO-d6)δ199.75,177.19,160.52,143.82,136.90,132.61,131.44,129.48,129.11,128.89,127.80,127.73,123.81,122.85,122.48,121.46,120.59,109.43,73.15,49.09,43.16.
HRMS(ESI+):化学式:C23H18BrNO4;[M+H]+:452.0419,实测值:452.0490。
实施例13检测结果:1H NMR(DMSO-d6)δ7.65–7.55(d,J=2.1Hz,1H),7.57–7.48(d,J=8.4Hz,1H),7.45–7.40(dd,J=8.4,2.0Hz,1H),7.41–7.34(d,J=7.1Hz,2H),7.34–7.30(d,J=7.4,1.3Hz,1H),7.30–7.21(m,2H),7.22–7.16(m,1H),7.14–7.01(t,J=7.7,1.3Hz,1H),6.94–6.81(m,1H),6.78–6.57(d,J=7.8Hz,1H),6.47–6.14(s,1H),4.99–4.62(s,2H),4.04–3.84(d,J=17.0Hz,1H),3.68–3.51(d,J=17.0Hz,1H).
13C NMR(DMSO-d6)δ198.13,176.89,143.64,136.97,136.78,136.75,131.66,131.40,130.88,130.54,129.70,128.93,128.03,127.76,124.20,122.62,109.56,73.33,50.00,43.24.
HRMS(ESI+):化学式:C23H17Cl2NO3;[M+H]+:426.0685,实测值:426.0659。
实施例14检测结果:1HNMR(DMSO-d6)δ13.13–10.13(s,1H),7.90–7.77(m,1H),7.61–7.50(m,1H),7.44–7.33(m,3H),7.26–7.15(m,3H),7.05–6.92(m,3H),6.87–6.79(d,J=7.7Hz,1H),6.42–6.27(s,1H),5.03–4.82(q,J=15.8Hz,2H),4.31–4.21(d,J=17.9Hz,1H),3.91–3.78(d,J=17.8Hz,1H),2.40–2.22(s,3H).
13C NMR(DMSO-d6)δ201.55,177.16,160.55,143.84,136.86,136.57,133.82,131.48,131.14,129.45,129.42,127.87,123.80,122.41,121.21,119.75,118.05,109.47,73.18,48.05,42.95,21.16.
HRMS(ESI+):化学式:C24H21NO4;[M+H]+:388.1504,实测值:388.1540。
实施例15检测结果:1H NMR(DMSO-d6)δ7.50–7.34(s,2H),7.34–7.25(d,J=11.8Hz,2H),7.23–7.03(d,J=7.7Hz,4H),7.00–6.88(m,2H),6.78–6.68(d,J=7.8Hz,1H),6.35–6.11(s,1H),4.98–4.69(s,2H),4.09–3.99(d,J=18.0Hz,1H),3.99–3.78(s,3H),3.79–3.66(d,J=18.0Hz,1H),2.39–2.10(s,3H).
13C NMR(DMSO-d6)δ197.92,177.31,159.02,143.96,136.78,134.76,133.87,131.61,129.87,129.48,129.30,127.75,127.09,123.61,122.32,120.89,112.99,109.37,73.17,56.33,51.63,42.91,21.16.
HRMS(ESI+):化学式:C25H23NO4;[M+H]+:402.1761,实测值:402,1703。
实施例16检测结果:1H NMR(DMSO-d6)δ7.97–7.59(m,2H),7.49–7.33(m,3H),7.33–7.24(d,J=8.0Hz,2H),7.22–7.09(m,3H),6.96–6.87(m,1H),6.81–6.70(d,J=7.7Hz,1H),6.34–6.17(s,1H),4.99–4.76(s,2H),4.23–4.07(d,J=17.6Hz,1H),3.74–3.58(d,J=17.5Hz,1H),2.44–2.32(s,3H),2.31–2.11(s,3H).
13C NMR(DMSO-d6)δ196.41,177.31,144.42,143.95,136.78,134.05,133.84,131.61,129.74,129.49,129.37,128.56,127.75,123.76,122.34,109.42,73.25,46.26,42.97,21.63,21.16.
HRMS(ESI+):化学式:C25H23NO3;[M+H]+:386.1711,实测值:386.1752。
实施例17检测结果:1H NMR(DMSO-d6)δ7.89–7.71(d,J=8.2Hz,2H),7.40–7.34(m,3H),7.35–7.28(d,J=8.1Hz,2H),7.22–7.12(d,J=8.1,7.0Hz,3H),6.95–6.88(t,J=7.6,0.9Hz,1H),6.80–6.71(d,J=7.7Hz,1H),6.31–6.18(s,1H),4.93–4.76(s,2H),4.24–4.12(d,J=17.6Hz,1H),3.76–3.64(d,J=17.6Hz,1H),2.67–2.55(t,J=7.5Hz,2H),2.33–2.17(s,3H),1.65–1.52(m,2H),0.92–0.85(t,J=7.3Hz,3H).
13C NMR(DMSO-d6)δ196.44,177.32,148.86,143.96,136.79,134.31,133.83,131.63,129.49,129.37,129.16,128.57,127.75,123.76,122.34,109.42,73.26,46.29,42.98,37.57,24.19,21.16,14.02.
HRMS(ESI+):化学式:C27H27NO3;[M+H]+:414.2024,实测值:414.2064。
实施例18检测结果:1H NMR(DMSO-d6)δ7.85–7.77(m,2H),7.37–7.29(m,5H),7.17–7.12(m,3H),6.93–6.88(m,1H),6.76–6.71(m,1H),6.26–6.22(s,1H),4.87–4.78(s,2H),4.19–4.10(d,J=17.6Hz,1H),3.73–3.64(d,J=17.5Hz,1H),2.67–2.59(t,J=7.6Hz,2H),2.31–2.24(s,3H),1.59–1.51(m,2H),1.30–1.25(m,2H),0.91–0.86(t,J=7.3Hz,3H).
13C NMR(DMSO-d6)δ196.43,177.29,149.07,143.95,136.78,134.31,133.84,131.62,129.48,129.36,129.10,128.59,127.75,123.77,122.33,109.40,73.26,46.28,42.98,35.21,33.16,22.15,21.16,14.20.
HRMS(ESI+):化学式:C28H29NO3;[M+H]+:428.2281,实测值:428.2229。
实施例19检测结果:1H NMR(DMSO-d6)δ8.09–7.55(d,J=8.3Hz,2H),7.44–7.33(m,3H),7.33–7.25(m,2H),7.20–7.06(m,3H),6.94–6.85(m,1H),6.79–6.69(d,J=7.9,0.7Hz,1H),6.35–6.18(s,1H),4.95–4.66(s,2H),4.24–4.08(d,J=17.6Hz,1H),3.78–3.62(d,J=17.5Hz,1H),2.77–2.57(t,J=7.6Hz,2H),2.34–2.10(s,3H),1.63–1.47(m,J=7.4Hz,2H),1.31–1.21(m,4H),0.92–0.75(t,J=7.0Hz,3H).
13C NMR(DMSO-d6)δ196.42,177.31,149.09,143.96,136.78,134.31,133.84,131.63,129.48,129.36,129.09,128.59,127.75,123.77,122.33,109.41,73.28,46.30,43.00,35.50,31.26,30.69,22.38,21.16,14.35。
HRMS(ESI+):化学式:C29H31NO3;[M+H]+:442.2337,实测值:442.2382
实施例20检测结果:1H NMR(DMSO-d6)δ7.89–7.69(d,J=8.3Hz,2H),7.45–7.33(m,3H),7.33–7.24(m,2H),7.19–7.09(m,3H),6.95–6.86(m,1H),6.78–6.70(d,J=7.8Hz,1H),6.30–6.21(s,1H),4.91–4.70(s,2H),4.20–4.06(d,J=17.6Hz,1H),3.75–3.64(d,J=17.5Hz,1H),2.68–2.57(t,J=7.6Hz,2H),2.34–2.21(s,3H),1.62–1.50(m,2H),1.28–1.22(m,6H),0.88–0.61(m,3H).
13C NMR(DMSO-d6)δ196.39,177.33,149.07,143.99,136.77,134.33,133.84,131.66,129.49,129.35,129.07,128.59,127.76,123.76,122.33,109.41,73.30,46.34,43.03,35.57,31.55,31.00,28.74,22.53,21.16,14.40.
HRMS(ESI+):化学式:C30H33NO3;[M+H]+:456.2594,实测值:456.2537。
实施例21检测结果:1HNMR(DMSO-d6)δ8.11–7.58(m,2H),7.45–7.23(m,3H),7.21–7.07(m,3H),7.06–6.95(m,2H),6.93–6.86(m,1H),6.76–6.67(m,1H),6.30–6.14(s,1H),4.95–4.68(s,2H),4.19–4.08(d,J=17.3Hz,1H),4.08–3.98(t,J=6.5Hz,2H),3.72–3.57(d,J=17.3Hz,1H),2.38–2.15(s,3H),1.78–1.59(m,2H),1.49–1.38(m,2H),0.98–0.83(t,J=7.4Hz,3H).
13C NMR(DMSO-d6)δ195.14,177.34,163.28,143.95,136.76,133.85,131.69,130.81,129.47,129.37,129.32,127.74,123.74,122.30,114.76,109.39,73.31,68.06,46.02,42.97,31.01,21.16,19.13,14.13.
HRMS(ESI+):化学式:C28H29NO4;[M+H]+:444.2130,实测值:444.2175。
实施例22检测结果:1H NMR(Chloroform-d)δ7.91–7.77(m,2H),7.42–7.38(m,1H),7.39–7.35(m,2H),7.26–7.23(s,2H),7.22–7.18(m,1H),7.18–7.12(m,1H),7.13–7.07(m,2H),7.08–7.02(d,J=1.1Hz,1H),7.05–7.00(t,J=1.1Hz,1H),7.02–6.93(m,1H),6.95–6.92(m,2H),6.75–6.68(m,1H),4.96–4.88(d,J=15.6Hz,1H),4.88–4.76(t,J=7.8Hz,2H),3.87–3.76(d,J=17.2Hz,1H),3.62–3.45(d,J=17.2Hz,1H),2.36–2.21(s,3H).
13C NMR(CDCl3)δ196.61,176.67,162.65,155.23,142.96,137.33,132.51,131.03,130.65,130.20,130.15,129.82,129.51,127.36,124.87,123.98,123.06,120.35,117.24,109.74,74.63,44.38,43.76,21.15.
HRMS(ESI+):化学式:C30H25NO4;[M+H]+:464.1817,实测值:464.1864。
实施例23检测结果:1H NMR(DMSO-d6)δ8.00–7.77(m,2H),7.51–7.42(m,2H),7.42–7.37(m,2H),7.37–7.29(m,4H),7.18–7.11(m,3H),7.11–7.05(m,2H),6.93–6.87(m,1H),6.76–6.70(d,J=7.8Hz,1H),6.26–6.15(s,1H),5.26–5.09(s,2H),4.92–4.78(s,2H),4.15–4.06(d,J=17.5Hz,1H),3.68–3.61(d,J=17.4Hz,1H),2.33–2.22(s,3H).
13C NMR(DMSO-d6)δ195.20,177.35,162.87,143.95,136.89,136.78,133.84,131.67,130.81,129.64,129.48,129.34,128.98,128.51,128.26,127.75,123.74,122.32,115.16,109.40,73.30,69.96,46.04,42.96,21.16.
HRMS(ESI+):化学式:C31H27NO4;[M+H]+:478.3474,实测值:478.3437。
实施例24检测结果:1HNMR(Chloroform-d)δ7.92–7.46(m,2H),7.49–7.40(m,J=9.2,2.5Hz,2H),7.40–7.34(m,1H),7.24–7.18(m,2H),7.16–7.06(m,2H),7.02–6.97(t,J=7.6,1.0Hz,1H),6.87–6.59(d,J=7.9,0.8Hz,1H),5.07–4.72(m,2H),3.90–3.77(d,J=17.2Hz,1H),3.62–3.32(d,J=17.3,1.2Hz,1H),2.37–2.22(s,3H).
13C NMR(CDCl3)δ196.94,176.24,142.94,140.42,137.44,134.73,132.39,130.01,129.81,129.64,129.52,129.08,127.36,123.98,123.11,109.80,74.49,44.52,43.78,21.13.
HRMS(ESI+):化学式:C24H20ClNO3;[M+H]+:406.1202,实测值:406.1207。
实施例25检测结果:1H NMR(DMSO-d6)δ8.19–7.80(d,J=8.2Hz,2H),7.91–7.70(d,J=8.2Hz,2H),7.73–7.58(m,2H),7.57–7.39(t,J=7.5Hz,2H),7.39–7.19(m,4H),7.16–6.98(m,3H),6.90–6.81(t,J=7.5Hz,1H),6.75–6.62(d,J=7.8Hz,1H),6.36–6.04(s,1H),4.95–4.71(s,2H),4.25–4.12(d,J=17.6Hz,1H),3.74–3.64(d,J=17.5Hz,1H),2.37–2.01(s,3H).
13C NMR(DMSO-d6)δ196.49,177.29,145.26,143.94,139.23,136.81,135.30,133.82,131.57,129.59,129.50,129.43,129.22,128.94,127.76,127.47,127.36,123.82,122.39,109.46,73.30,46.41,43.00,21.16.
HRMS(ESI+):化学式:C30H25NO3;[M+H]+:448.1968,实测值:448.1915。
实施例26检测结果:1H NMR(DMSO-d6)δ11.92–11.23(s,1H),7.75–7.63(d,J=8.5Hz,1H),7.47–7.33(m,3H),7.26–7.24(s,1H),7.24–7.17(d,J=7.9Hz,3H),7.19–7.12(m,1H),7.00–6.97(t,J=7.2Hz,1H),6.88–6.78(d,J=7.8Hz,1H),6.43–6.27(s,1H),5.85–5.77(s,1H),5.03–4.82(m,2H),4.29–4.18(d,J=17.9Hz,1H),3.88–3.73(d,J=17.9Hz,1H),2.40–2.27(s,3H).
13C NMR(DMSO-d6)δ199.85,177.14,160.59,143.83,136.85,133.80,132.63,131.44,129.45,129.16,127.83,123.78,122.85,122.43,121.38,120.61,109.48,73.17,55.40,49.01,42.95,21.17.
HRMS(ESI+):化学式:C24H20BrNO4;[M+H]+:466.0655,实测值:466.0648。
实施例27检测结果:1H NMR(DMSO-d6)δ7.86–7.61(d,J=1.8Hz,1H),7.62–7.53(d,J=8.3Hz,1H),7.56–7.43(m,1H),7.44–7.36(m,1H),7.37–7.22(d,J=7.9Hz,2H),7.23–7.16(m,1H),7.16–7.11(d,J=7.8Hz,2H),6.99–6.90(m,1H),6.88–6.63(d,J=7.8Hz,1H),6.60–6.14(s,1H),4.99–4.63(s,2H),4.07–3.90(d,J=17.0Hz,1H),3.70–3.59(d,J=17.0Hz,1H),2.42–1.99(s,3H).
13C NMR(DMSO-d6)δ198.11,176.80,143.62,136.93,136.87,136.81,133.67,131.62,131.40,130.85,130.54,129.66,129.49,128.03,127.80,124.17,122.54,109.59,73.30,49.97,42.98,21.15.
HRMS(ESI+):化学式:C24H19ClNO3;[M+H]+:440.0812,实测值:440.0817。
实施例28检测结果:1H NMR(DMSO-d6)δ8.04–7.77(m,2H),7.67–7.57(m,1H),7.55–7.42(t,J=8.3,7.1Hz,2H),7.41–7.27(d,J=7.6,1.6Hz,3H),7.23–7.06(m,J=7.7,6.4,1.1Hz,3H),6.95–6.87(t,J=7.5,1.0Hz,1H),6.81–6.66(m,1H),6.57–6.06(s,1H),4.97–4.65(s,2H),4.25–4.08(d,J=17.6Hz,1H),3.80–3.64(d,J=17.6Hz,1H),2.37–2.13(s,3H).
13C NMR(DMSO-d6)δ196.96,177.26,143.95,136.80,136.49,133.99,133.83,131.57,129.49,129.40,129.22,128.44,127.76,123.81,122.36,109.43,73.25,46.39,42.99,21.16.
HRMS(ESI+):化学式:C24H21NO3;[M+H]+:372.1555,实测值:372.1598。
实施例29检测结果:1H NMR(DMSO-d6)δ11.53–10.96(d,J=1.1Hz,1H),7.85–7.69(m,1H),7.51–7.43(m,1H),7.43–7.28(m,5H),7.28–7.21(m,2H),7.07–6.99(d,J=7.6Hz,1H),6.98–6.81(m,3H),6.30–6.13(d,J=1.7Hz,1H),4.20–4.09(d,J=17.7Hz,1H),3.98–3.79(m,J=37.4,13.7,9.0,6.7Hz,2H),3.76–3.63(d,J=17.6,1.7Hz,1H),3.08–2.75(t,J=9.1,6.8,2.2Hz,2H).
13C NMR(DMSO-d6)δ201.47,176.90,160.48,143.82,139.11,136.50,131.43,131.13,129.61,129.34,128.93,126.86,123.90,122.27,121.28,119.71,118.03,109.03,73.08,48.25,41.31,33.27.
HRMS(ESI+):化学式:C24H21NO4;[M+H]+:388.1504,实测值:388.1539。
实施例30检测结果:1H NMR(DMSO-d6)δ7.56–7.44(m,1H),7.44–7.28(m,5H),7.28–7.20(m,3H),7.20–7.12(m,1H),7.04–6.98(d,J=7.7Hz,1H),6.98–6.88(m,2H),6.22–6.05(s,1H),4.00–3.95(d,J=17.8Hz,1H),3.95–3.90(s,3H),3.91–3.73(m,2H),3.72–3.61(d,J=17.8Hz,1H),3.02–2.74(t,J=8.0Hz,2H).
13C NMR(DMSO-d6)δ197.97,176.98,158.93,143.92,139.17,134.68,131.56,129.85,129.47,129.32,128.95,127.20,126.85,123.74,122.18,120.86,112.94,108.90,73.08,56.31,51.81,41.29,33.32.
HRMS(ESI+):化学式:C25H23NO4;[M+H]+:402.1761,实测值:402.1704。
实施例31检测结果:1H NMR(DMSO-d6)δ7.90–7.69(m,2H),7.46–7.34(m,5H),7.34–7.31(d,J=8.1Hz,2H),7.30–7.25(m,2H),7.10–7.03(d,J=7.7Hz,1H),7.00–6.91(t,J=7.5,0.9Hz,1H),6.27–6.12(s,1H),4.21–4.08(d,J=17.6Hz,1H),4.00–3.80(m,J=30.9,13.7,9.2,6.7Hz,2H),3.70–3.56(d,J=17.5Hz,1H),3.06–2.86(m,2H),2.46–2.14(s,3H).
13C NMR(DMSO-d6)δ196.38,177.02,144.37,143.91,139.15,134.07,131.58,129.73,129.55,129.33,128.96,128.55,126.86,123.88,122.21,108.96,73.15,46.48,41.31,33.34,21.62.
HRMS(ESI+):化学式:C25H23NO3;[M+H]+:386.1711,实测值:386.1753。
实施例32检测结果:1H NMR(DMSO-d6)δ8.07–7.58(d,J=8.3Hz,2H),7.57–7.33(m,4H),7.33–7.28(m,3H),7.27–7.21(m,2H),7.08–6.99(d,J=7.8Hz,1H),6.97–6.86(m,1H),6.28–6.07(s,1H),4.19–4.03(d,J=17.5Hz,1H),3.98–3.77(m,2H),3.71–3.56(d,J=17.5Hz,1H),3.10–2.80(m,2H),2.79–2.52(m,2H),1.68–1.47(m,2H),0.94–0.72(t,J=7.3Hz,3H).
13C NMR(DMSO-d6)δ196.40,177.03,148.79,143.92,139.17,134.39,131.60,129.54,129.31,129.12,128.95,128.56,126.84,123.89,122.20,108.94,73.19,46.53,41.35,37.57,33.36,24.17,13.99.
HRMS(ESI+):化学式:C27H27NO3;[M+H]+:414.2024,实测值:414.2070。
实施例33检测结果:1H NMR(DMSO-d6)δ7.87–7.74(m,2H),7.43–7.34(m,3H),7.34–7.28(m,4H),7.27–7.21(m,2H),7.05–6.99(d,J=7.8Hz,1H),6.97–6.88(m,1H),6.19–6.13(s,1H),4.14–4.03(d,J=17.4Hz,1H),3.94–3.79(m,2H),3.66–3.55(d,J=17.4Hz,1H),2.98–2.85(m,2H),2.68–2.57(t,J=7.6Hz,2H),1.58–1.49(m,2H),1.30–1.23(m,2H),0.91–0.85(t,J=7.3Hz,3H).
13C NMR(DMSO-d6)δ196.39,177.00,149.01,143.90,139.16,134.34,131.58,129.52,129.31,129.07,128.94,128.57,126.84,123.89,122.18,108.93,73.17,46.50,41.32,35.20,33.34,33.16,22.15,14.19.
HRMS(ESI+):化学式:C28H29NO3;[M+H]+:428.2248,实测值:428.2227。
实施例34检测结果:1H NMR(DMSO-d6)δ7.96–7.45(m,2H),7.44–7.33(m,3H),7.34–7.26(m,4H),7.27–7.18(t,J=7.7,1.4Hz,2H),7.11–6.97(d,J=7.7Hz,1H),6.97–6.74(td,J=7.5,1.0Hz,1H),6.55–5.62(s,1H),4.28–3.97(d,J=17.5Hz,1H),4.03–3.66(m,J=29.9,13.7,9.1,6.7Hz,2H),3.71–3.45(d,J=17.4Hz,1H),3.23–2.71(m,J=9.3,6.8,2.6Hz,2H),2.86–2.53(t,J=7.6Hz,2H),1.68–1.42(t,J=7.4Hz,2H),1.29–1.21(m,J=10.1,7.0,1.4Hz,4H),0.98–0.66(t,J=7.0Hz,3H).
13C NMR(DMSO-d6)δ196.39,176.99,149.03,143.90,139.16,134.34,131.58,129.52,129.31,129.07,128.94,128.57,126.83,123.89,122.18,108.93,73.16,46.49,41.32,35.48,33.34,31.25,30.67,22.37,14.35.
HRMS(ESI+):化学式:C29H31NO3;[M+H]+:442.2337,实测值:442.2386。
实施例35检测结果:1H NMR(DMSO-d6)δ9.72–7.42(d,J=8.3Hz,2H),7.50–7.34(m,3H),7.34–7.26(m,4H),7.26–7.11(m,2H),7.10–6.95(d,J=7.8Hz,1H),7.01–6.83(t,J=7.5,0.9Hz,1H),6.56–5.59(s,1H),4.39–3.97(d,J=17.4Hz,1H),4.06–3.67(m,J=31.5,13.7,9.1,6.7Hz,2H),3.74–3.41(d,J=17.4Hz,1H),3.32–2.69(m,J=9.3,6.9,2.4Hz,2H),2.88–2.52(t,J=7.6Hz,2H),1.67–1.44(m,2H),1.26–1.19(s,J=5.7,3.7,2.8Hz,6H),0.98–0.62(t,J=3.3,2.7Hz,3H).
13C NMR(DMSO-d6)δ196.37,177.00,149.02,143.91,139.17,134.35,131.60,129.51,129.31,129.05,128.93,128.57,126.83,123.89,122.17,108.93,73.17,46.52,41.33,35.53,33.35,31.52,30.98,28.72,22.50,14.40.
HRMS(ESI+):化学式:C30H33NO3;[M+H]+:456.2594,实测值:456.2541。
实施例36检测结果:1H NMR(DMSO-d6)δ7.95–7.82(m,2H),7.46–7.35(m,5H),7.32–7.25(m,2H),7.10–7.00(m,3H),7.01–6.93(m,1H),6.25–6.08(s,1H),4.14–4.10(d,J=10.3Hz,1H),4.10–3.99(d,J=6.3Hz,2H),4.01–3.81(m,2H),3.68–3.59(d,J=17.3Hz,1H),3.08–2.75(m,2H),1.81–1.70(m,2H),1.52–1.43(m,2H),1.01–0.92(t,J=7.4Hz,3H).
13C NMR(DMSO-d6)δ195.11,177.06,163.25,143.93,139.18,131.67,130.79,129.49,129.43,129.31,128.94,126.83,123.86,122.16,114.72,108.91,73.24,68.05,46.25,41.33,33.36,31.01,19.13,14.11.
HRMS(ESI+):化学式:C28H29NO4;[M+H]+:444.2130,实测值:444.2175。
实施例37检测结果:1HNMR(Chloroform-d)δ7.87–7.77(m,2H),7.42–7.34(td,J=7.4,1.5Hz,3H),7.29–7.26(m,2H),7.25–7.24(d,J=4.5Hz,2H),7.24–7.17(m,3H),7.06–7.02(m,2H),7.02–6.97(m,1H),6.96–6.90(m,2H),6.84–6.79(d,J=7.8Hz,1H),4.82–4.63(m,1H),4.07–3.98(m,1H),3.90–3.82(m,1H),3.72–3.63(m,1H),3.42–3.32(m,1H),3.06–2.96(t,J=7.7Hz,2H).
13C NMR(CDCl3)δ196.75,176.27,162.65,155.21,142.83,138.21,131.03,130.62,130.27,130.15,129.83,128.98,128.63,126.69,124.88,124.25,122.93,120.34,117.22,108.79,74.48,44.31,41.44,33.39.
HRMS(ESI+):化学式:C30H25NO4;[M+H]+:464.1817,实测值:464.1863。
实施例38检测结果:1H NMR(DMSO-d6)δ8.05–7.57(d,J=8.8Hz,2H),7.41–7.32(m,3H),7.31–7.21(m,6H),7.20–7.10(t,J=8.4,6.8Hz,2H),7.07–6.97(m,2H),6.97–6.89(d,J=7.8Hz,1H),6.90–6.75(t,J=7.4Hz,1H),6.23–5.90(s,1H),5.25–4.88(s,2H),4.09–3.95(d,J=17.4Hz,1H),3.88–3.66(m,2H),3.54–3.46(d,J=17.4Hz,1H),3.04–2.67(t,J=9.1,6.8,2.1Hz,2H).
13C NMR(DMSO-d6)δ195.19,177.05,162.82,143.90,139.17,136.88,131.63,130.80,129.69,129.51,129.32,128.97,128.97,128.50,128.25,126.85,123.85,122.18,115.13,108.93,73.20,69.95,46.24,41.31,33.34.
HRMS(ESI+):化学式:C31H27NO4;[M+H]+:478.2074,实测值:478.2020。
实施例39检测结果:1H NMR(DMSO-d6)δ7.95–7.83(m,2H),7.59–7.52(m,2H),7.39–7.35(m,3H),7.35–7.29(m,2H),7.28–7.23(m,2H),7.08–7.01(d,J=7.8Hz,1H),6.97–6.83(m,1H),6.30–6.21(s,1H),4.18–4.08(d,J=17.5Hz,1H),3.95–3.79(m,2H),3.68–3.56(d,J=17.5Hz,1H),2.98–2.89(m,2H).
13C NMR(DMSO-d6)δ196.00,176.90,143.82,139.11,138.90,135.17,131.40,130.42,129.63,129.33,129.29,128.96,126.86,123.99,122.27,109.01,73.13,46.57,41.32,33.34.
HRMS(ESI+):化学式:C24H20ClNO3;[M+H]+:406.1202,实测值:406.1205。
实施例40检测结果:1H NMR(DMSO-d6)δ8.03–7.92(d,J=8.5Hz,2H),7.84–7.76(m,2H),7.76–7.67(m,2H),7.53–7.46(m,2H),7.46–7.41(m,1H),7.42–7.36(m,3H),7.38–7.29(t,J=7.5Hz,2H),7.30–7.21(m,2H),7.10–7.00(d,J=7.8Hz,1H),6.99–6.85(m,1H),6.34–6.05(s,1H),3.98–3.82(m,2H),3.73–3.64(d,J=17.4Hz,1H),3.13–2.87(m,J=9.3,6.9,2.3Hz,2H).
13C NMR(DMSO-d6)δ196.46,176.99,145.22,143.90,139.23,139.16,135.37,131.54,129.58,129.32,129.21,128.95,128.92,127.45,127.33,126.85,123.95,122.25,108.99,73.21,55.38,46.61,41.34,33.36.
HRMS(ESI+):化学式:C30H25NO3;[M+H]+:448.1968,实测值:448.1914。
实施例41检测结果:1H NMR(DMSO-d6)δ11.74–11.00(s,1H),7.56–7.48(d,J=8.5Hz,1H),7.32–7.23(m,5H),7.20–7.15(m,2H),7.12–7.08(d,J=1.9Hz,1H),7.03–6.99(d,J=8.5,1.9Hz,1H),6.98–6.93(d,J=7.8Hz,1H),6.91–6.84(t,J=7.5Hz,1H),6.20–6.08(s,1H),4.05–3.97(d,J=17.9Hz,1H),3.87–3.71(m,2H),3.63–3.56(d,J=17.8Hz,1H),2.91–2.80(t,J=9.3,6.8,2.6Hz,2H).
13C NMR(DMSO-d6)δ199.75,176.83,160.47,143.78,139.11,132.62,131.38,129.60,129.32,129.01,128.92,126.85,123.88,122.81,122.27,121.57,120.57,109.02,73.07,49.20,41.29,33.27.
HRMS(ESI+):化学式:C24H20BrNO4;[M+H]+:466.0655,实测值:466.0647。
实施例42检测结果:1H NMR(DMSO-d6)δ7.73–7.53(d,J=1.9Hz,1H),7.49–7.46(d,J=8.4Hz,1H),7.45–7.40(m,1H),7.33–7.25(m,4H),7.25–7.19(m,2H),7.18–7.15(m,1H),6.98–6.94(d,J=7.8Hz,1H),6.93–6.88(m,1H),6.23–6.19(s,1H),3.85–3.81(d,J=10.1Hz,1H),3.81–3.55(m,2H),3.54–3.46(d,J=16.7Hz,1H),2.87–2.78(m,2H).
13C NMR(DMSO-d6)δ198.10,176.47,143.55,139.02,136.90,131.58,131.39,130.74,130.49,129.82,129.31,128.94,128.00,126.87,124.32,122.41,109.15,73.23,50.15,41.31,33.31
HRMS(ESI+):化学式:C24H19Cl2NO3;[M+H]+:440.0812,实测值:440.0817。
实施例43检测结果:1H NMR(DMSO-d6)δ7.95–7.78(m,2H),7.66–7.59(m,1H),7.55–7.46(t,J=7.8Hz,2H),7.40–7.37(m,2H),7.37–7.28(m,3H),7.28–7.19(m,2H),7.09–7.01(d,J=7.7Hz,1H),6.99–6.89(m,1H),6.31–6.18(s,1H),4.21–4.09(d,J=17.6Hz,1H),3.98–3.78(m,2H),3.71–3.59(d,J=17.6Hz,1H),3.02–2.86(m,3H).
13C NMR(DMSO-d6)δ196.93,176.98,143.90,139.14,136.47,133.97,131.53,129.58,129.34,129.21,128.96,128.43,126.86,123.91,122.24,108.99,73.13,46.58,41.32,33.34.
HRMS(ESI+):化学式:C24H21NO3;[M+H]+:372.1555,实测值:372.1597。
实施例44检测结果:1HNMR(DMSO-d6)δ11.04–10.40(s,J=1.6Hz,1H),7.51–7.27(m,J=14.1,7.2Hz,5H),7.28–7.19(q,J=7.2Hz,2H),7.19–7.14(s,J=2.3Hz,1H),7.14–7.08(d,J=9.1,2.3Hz,1H),7.07–7.00(d,J=7.8Hz,1H),6.99–6.91(t,J=7.4Hz,1H),6.91–6.83(d,J=9.0,1.6Hz,1H),6.42–5.87(s,1H),4.31–4.07(d,J=17.7Hz,1H),4.02–3.79(m,J=14.2,7.4Hz,2H),3.78–3.47(d,1H),3.78–3.47(s,3H),3.05–2.80(t,J=8.0Hz,2H).
13C NMR(DMSO-d6)δ200.56,176.92,154.71,152.04,143.87,139.13,131.54,129.56,129.33,128.92,126.85,124.26,123.87,122.25,121.16,119.19,112.86,109.00,73.11,56.00,48.79,41.32,33.30.
HRMS(ESI+):化学式:C25H23NO5;[M+H]+:418.1610,实测值:418.1650。
实施例45检测结果:1H NMR(DMSO-d6)δ7.93–7.83(d,J=7.6Hz,2H),7.66–7.59(t,J=7.4Hz,1H),7.54–7.46(t,J=7.6Hz,2H),7.40–7.32(d,J=7.4Hz,1H),7.28–7.22(t,J=7.8Hz,1H),7.16–7.10(d,J=7.9Hz,1H),7.01–6.89(t,J=7.5Hz,1H),6.38–6.08(s,1H),4.67–4.28(s,2H),4.23–4.07(d,J=17.7Hz,1H),3.72–3.62(d,J=17.7Hz,1H),3.63–3.52(d,J=4.9Hz,4H),2.67–2.55(d,J=11.6,6.9,6.1Hz,4H).
13C NMR(DMSO-d6)δ201.48,178.11,160.52,144.66,136.50,131.15,131.09,129.47,123.64,122.44,121.27,119.70,118.04,110.25,73.12,66.57,61.93,51.02,48.25.
HRMS(ESI+):化学式:C21H22N2O5;[M+H]+:383.1662,实测值:383.1608。
实施例46检测结果:1HNMR(DMSO-d6)δ11.53–10.20(s,1H),7.40–7.31(d,J=7.3Hz,1H),7.30–7.22(t,J=7.8Hz,1H),7.21–7.05(m,3H),7.02–6.91(t,J=7.5Hz,1H),6.90–6.81(d,J=8.9Hz,1H),6.26–6.13(s,1H),4.51–4.33(s,2H),4.28–4.10(d,J=18.1Hz,1H),3.81–3.74(d,J=18.3Hz,1H),3.73–3.69(s,3H),3.62–3.49(d,J=4.6Hz,4H),2.72–2.55(s,J=6.8,5.8Hz,4H).
13C NMR(DMSO-d6)δ200.57,178.16,154.68,152.07,144.64,131.25,129.44,124.25,123.63,122.48,121.14,119.19,112.87,110.24,73.13,66.49,61.86,56.00,50.99,48.83.
HRMS(ESI+):化学式:C22H24N2O6,[M+H]+:413.1768,实测值:413.1708。
利用CCK-8试剂盒检测衍生物对细胞增殖能力影响
CCK-8试剂盒可以通过检测450nm波长处的吸光度,评估细胞的增殖活力。将SNU398和LO2细胞消化制成细胞悬液,用培养基稀释至密度约为5×103个/孔,每孔加入100μl细胞液,设置空白组和阴性对照组。分别称取1.0000mg左右衍生物置于0.5mL EP管中,用DMSO(二甲基亚砜)配制成5×10-2M的母液,-20℃储存。
使用培养基稀释46种化合物母液至终浓度100μmol/L。将96孔板原培养基吸弃,各100μL加入46种化合物稀释液,均设置三个平行复孔。细胞培养箱中培养48h。配置10%的CCK-8供试溶液,吸弃原药液后,每孔100μL加入96孔板,培养2h后,测量450nm波长处的OD值,计算细胞存活率(Cell Viability)和抑制率,其结果列于表2中。
表2实施例1~46制备得到的衍生物对细胞增殖活性影响的初筛结果
初筛结果:(1)实施例5、6、10、15、16、30、45和46的初筛结果,只要对LO2或者SNU398任何一种细胞的抑制率大于50%,进行精筛;(2)在初筛中,抑制率虽然小于50%,如果是因为化合物溶解度低造成的,进行精筛。例如实施例15制备的化合物,在100μmol/L浓度时溶解度很低,造成抑制率降低,当精筛时,随着浓度由100μmol/L稀释到0.16μmol/L时,化合物溶解,抑制率提高。在初筛结果的基础上,采用浓度梯度逐级稀释法,使化合物浓度在细胞基中的终浓度为100μmol/L、20μmol/L、4μmol/L、0.8μmol/L、0.16μmol/L进行细胞水平的精筛。根据所得数据进行数据分析,测定IC50值,衡量化合物对肿瘤细胞增殖的干预能力,干预能力越强,IC50值越低,得到的IC50值列于表3中。
表3衍生物对细胞增殖活性影响的复筛结果
结合表2和表3的结果可知,实施例1~46制备得到的衍生物对肝癌细胞株SNU398具有较高的抑制作用,且对RECQL4高表达的肝癌细胞有较好的选择性。其中实施例38制备得到的衍生物对SNU-398细胞的IC50为6.69±1.54μM,对LO2细胞的IC50是149.40±1.34μM,表现出较好的选择性。本发明实施例38制备得到的衍生物在吲哚-2,3-二酮1位N原子上连接(2-溴乙基)苯基团及在C3位上连接有对苯甲氧基苯乙酮的化合物,该结构有效增强了3-(2-(4-(苯氧基)苯基)-2-氧乙基)-3-羟基-1-苯乙基吲哚-2-酮对RECQL4高表达的SNU-398细胞的抑制作用,为进一步修饰得到对RECQL4高表达的肝癌细胞具有更高抑制活性的先导化合物提供参考。
尽管上述实施例对本发明做出了详尽的描述,但它仅仅是本发明一部分实施例,而不是全部实施例,人们还可以根据本实施例在不经创造性前提下获得其他实施例,这些实施例都属于本发明保护范围。
Claims (6)
3.根据权利要求2所述制备方法,其特征在于,所述反应物1和反应物2的摩尔比为1:1~2;所述反应物1和碱试剂的摩尔比为1:2.8~3.2。
4.根据权利要求2或3所述制备方法,其特征在于,所述加成反应的温度为室温,时间为2~4h。
5.根据权利要求2所述制备方法,其特征在于,所述混合包括以下步骤:
将反应物1、极性有机溶剂和碱试剂进行第一混合,得到第一混合液;
向所述第一混合液中加入反应物2。
6.一种抗肝癌药物,所述药物的活性组分包括吲哚-2,3-二酮的衍生物;所述吲哚-2,3-二酮的衍生物为权利要求1所述吲哚-2,3-二酮的衍生物或权利要求2~5任一项所述制备方法制备得到的吲哚-2,3-二酮的衍生物。
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KR20160065986A (ko) * | 2013-10-24 | 2016-06-09 | 조지타운 유니버시티 | 암 치료용 방법 및 조성물 |
US20190134056A1 (en) * | 2017-03-10 | 2019-05-09 | The Trustees Of The Stevens Institute Of Technolog | K-ras mutations and antagonists |
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