CN110343033B - 厚朴酚系列衍生物及其制备方法和用途 - Google Patents

厚朴酚系列衍生物及其制备方法和用途 Download PDF

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CN110343033B
CN110343033B CN201810283433.0A CN201810283433A CN110343033B CN 110343033 B CN110343033 B CN 110343033B CN 201810283433 A CN201810283433 A CN 201810283433A CN 110343033 B CN110343033 B CN 110343033B
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magnolol
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diallyl
biphenyl
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陈俐娟
魏于全
叶昊宇
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Sichuan University
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Abstract

本发明属于药物化学技术领域，具体涉及厚朴酚系列衍生物及其制备方法和用途。本发明的厚朴酚系列衍生物主要为厚朴酚的5位的取代衍生物，厚朴酚系列衍生物结构式如式Ⅰ。本发明还提供了该厚朴酚系列衍生物的制备方法和用途。本发明提供的厚朴酚系列衍生物通过细胞毒性试验证明了该类化合物具有很好的抗肿瘤活性，在制备治疗癌症的药物中具有广阔的应用前景。
Figure DDA0001615288530000011

Description

厚朴酚系列衍生物及其制备方法和用途
技术领域
本发明属于化学医药领域，具体涉及厚朴酚系列衍生物及其制备方法和用途。
背景技术
厚朴酚(Honokiol)具有多种药理活性，随着Honokiol脂质体已获批进入1期临床试验，其抗肿瘤活性更是值得关注。然而，Honokiol的生物利用度低，其口服抗肿瘤活性受到限制，目前多数报道的体内抗肿瘤活性均以静脉给药，为了获得活性高，生物利用度较好的抗肿瘤化合物，我们对厚朴酚进行改性，期望能够找到高效低毒、可口服的抗肿瘤化合物。
我们从中药厚朴分离了一些化合物，并测定其抗肿瘤活性，其中化合物D在人肝癌细胞系HepG2和人肺癌细胞系H1795上IC50值分别为15.85μM和16.60μM，优于Honokiol的33.88μM和30.20μM，约为Honokiol的两倍。化合物D为天然产物，以其结构为基础将更有希望合成生物利用度高的抗肿瘤活性化合物。
受此启发，我们将模拟化合物D的骨架结构来设计Magnolol系列化合物。经过试验，依据化合物D为先导化合物，保留化合物D结构中的Magnolol结构，然后在一个酚羟基的邻位引入基团，制备得到了Magnolol系列化合物，并且对这些化合物进行体内外抗增殖活性测试，以期望能获得高效低毒、可口服的抗肿瘤化合物。
Figure BDA0001615288510000011
发明内容
本发明提供了一种厚朴酚系列衍生物，其结构式如式Ⅰ所示：
Figure BDA0001615288510000012
其中，R为-OH、卤素、-COOH、-CN、-CF3、-NO2、C1～C8烷基、C3～C8环烷基、
Figure BDA0001615288510000013
或取代的5～10元饱和或不饱和杂环，所述的杂原子为N、O、S，杂原子个数为1～3个；所述取代5～10元饱和或不饱和杂环的取代基为-H、-OH、C1～C8烷基、酮基、
Figure BDA0001615288510000014
Figure BDA0001615288510000021
羟基取代的C1～C8烷基、-NH2、
Figure BDA0001615288510000022
C1～C8醚基、苯基、苄基或C2～C8烯基；a＝0～4；
R1、R2独立的为-H、C1～C8烷基或5～10元饱和杂环，所述的杂原子为N、O、S，杂原子个数为1～3个；
R3为-H、C1～C8烷基、C1～C8烷氧基或C2～C8烯基；
R4为-H、C1～C8烷基、C1～C8烷氧基、C3～C8环烷基或
Figure BDA0001615288510000023
R5、R6独立的为-H或C1～C8烷基。
作为本发明的优选技术方案，上述厚朴酚系列衍生物中，R为-OH、卤素、-COOH、-CN、-CF3、-NO2、C1～C8烷基、C3～C8环烷基、
Figure BDA0001615288510000024
或取代的5～6元饱和杂环，所述的杂原子为N、O、S，杂原子个数为1～3个；所述取代5～6元饱和杂环的取代基为-H、-OH、C1～C8烷基、
Figure BDA0001615288510000025
羟基取代的C1～C8烷基、-NH2、
Figure BDA0001615288510000026
C1～C8醚基、苯基、苄基或C2～C8烯基；a＝0～4；
R1、R2独立的为-H、C1～C8烷基或5～10元饱和杂环，所述的杂原子为N、O、S，杂原子个数为1～3个；
R3为-H、C1～C8烷基、C1～C8烷氧基或C2～C8烯基；
R4为-H、C1～C8烷基、C1～C8烷氧基、C3～C8环烷基或
Figure BDA0001615288510000027
R5、R6独立的为-H或C1～C8烷基。
优选的，R为-OH、卤素、-COOH、-CN、-CF3、-NO2、C1～C8烷基、C3～C8环烷基、
Figure BDA0001615288510000028
或取代的5～6元饱和杂环，所述的杂原子为N，杂原子个数为1～2个；所述取代5～6元饱和杂环的取代基为-H、-OH、C1～C8烷基、
Figure BDA0001615288510000029
羟基取代的C1～C8烷基、-NH2、
Figure BDA00016152885100000210
C1～C8醚基、苯基、苄基或C2～C8烯基；a＝0～4；
R1、R2独立的为-H、C1～C8烷基或5～10元饱和杂环，所述的杂原子为N、O、S，杂原子个数为1～3个；
R3为-H、C1～C8烷基、C1～C8烷氧基或C2～C8烯基；
R4为-H、C1～C8烷基、C1～C8烷氧基、C3～C8环烷基或
Figure BDA0001615288510000031
R5、R6独立的为-H或C1～C8烷基。
进一步优选的，R为-OH、卤素、-COOH、-CN、-CF3、-NO2、C1～C8烷基、C3～C8环烷基、
Figure BDA0001615288510000032
Figure BDA0001615288510000033
R7～R12独立的为-H、-OH、C1～C8烷基、
Figure BDA0001615288510000034
Figure BDA0001615288510000035
羟基取代的C1～C8烷基、-NH2、
Figure BDA0001615288510000036
C1～C8醚基、苯基、苄基或C2～C8烯基；a＝0～4；
R1、R2独立的为-H、C1～C8烷基或5～10元饱和杂环，所述的杂原子为N、O、S，杂原子个数为1～3个；
R3为-H、C1～C8烷基、C1～C8烷氧基或C2～C8烯基；
R4为-H、C1～C8烷基、C1～C8烷氧基、C3～C8环烷基或
Figure BDA0001615288510000037
R5、R6独立的为-H或C1～C8烷基。
再进一步的，R为-OH、卤素、-COOH、-CN、-CF3、-NO2、C1～C6烷基、C3～C6环烷基、
Figure BDA0001615288510000038
Figure BDA0001615288510000039
R7～R12独立的为-H、-OH、C1～C6烷基、
Figure BDA00016152885100000310
羟基取代的C1～C6烷基、-NH2、
Figure BDA00016152885100000311
C1～C6醚基、苯基、苄基或C2～C6烯基；a＝0～3；
R1、R2独立的为-H、C1～C6烷基或5～6元饱和杂环，所述的杂原子为N、O、S，杂原子个数为1～2个；
R3为-H、C1～C6烷基、C1～C6烷氧基或C2～C6烯基；
R4为-H、C1～C6烷基、C1～C6烷氧基、C3～C6环烷基或
Figure BDA0001615288510000041
R5、R6独立的为-H或C1～C6烷基。
更进一步优选的，R为-OH、卤素、-COOH、-CN、-CF3、-NO2、C1～C4烷基、C3～C6环烷基、
Figure BDA0001615288510000042
Figure BDA0001615288510000043
R7～R12独立的为-H、-OH、C1～C4烷基、
Figure BDA0001615288510000044
Figure BDA0001615288510000045
羟基取代的C1～C4烷基、-NH2、
Figure BDA0001615288510000046
C1～C4醚基、苯基、苄基或C2～C4烯基；a＝0～2；
R1、R2独立的为-H、C1～C4烷基或5～6元饱和杂环，所述的杂原子为N、O、S，杂原子个数为1～2个；
R3为-H、C1～C4烷基、C1～C4烷氧基或C2～C4烯基；
R4为-H、C1～C4烷基、C1～C4烷氧基、C3～C6环烷基或
Figure BDA0001615288510000047
R5、R6独立的为-H或C1～C4烷基。
最优选的，R为-OH、-F、Cl、-Br、
Figure BDA0001615288510000048
Figure BDA0001615288510000049
R7～R12独立的为-H、-OH、C1～C4烷基
Figure BDA00016152885100000410
Figure BDA00016152885100000411
羟基取代的C1～C4烷基、
Figure BDA00016152885100000412
苯基、苄基或C2～C4烯基；a＝0或1；
R1、R2独立的为-H、C1～C4烷基或
Figure BDA00016152885100000413
R3为-H、C1～C4烷基、C1～C4烷氧基或C2～C4烯基；
R4为-H、C1～C4烷基、C1～C4烷氧基、环丙基或
Figure BDA0001615288510000051
R5、R6独立的为-H或C1～C4烷基。
作为本发明的优选技术方案，上述厚朴酚系列衍生物，当R为
Figure BDA0001615288510000052
时，结构式如式Ⅱ所示：
Figure BDA0001615288510000053
其中，R7为-H、-OH、C1～C8烷基、
Figure BDA0001615288510000054
羟基取代的C1～C8烷基、-NH2、
Figure BDA0001615288510000055
C1～C8醚基、苯基、苄基或C2～C8烯基；a＝0～4；
R3为-H、C1～C8烷基、C1～C8烷氧基或C2～C8烯基；R4为-H、C1～C8烷基、C1～C8烷氧基、C3～C8环烷基或
Figure BDA0001615288510000056
R5、R6独立的为-H或C1～C8烷基。
优选的，上述厚朴酚系列衍生物，R7为-H、-OH、C1～C6烷基、
Figure BDA0001615288510000057
Figure BDA0001615288510000058
羟基取代的C1～C6烷基、-NH2、
Figure BDA0001615288510000059
1～C6醚基、苯基、苄基或C2～C6烯基；a＝0～3；
R3为-H、C1～C6烷基、C1～C6烷氧基或C2～C6烯基；R4为-H、C1～C6烷基、C1～C6烷氧基、C3～C6环烷基或
Figure BDA00016152885100000510
R5、R6独立的为-H或C1～C6烷基。
更进一步优选的，R7为-H、-OH、C1～C4烷基、
Figure BDA00016152885100000511
羟基取代的C1～C4烷基、-NH2、
Figure BDA00016152885100000512
C1～C4醚基、苯基、苄基或C2～C4烯基；a＝0～2；
R3为-H、C1～C4烷基、C1～C4烷氧基或C2～C4烯基；R4为-H、C1～C4烷基、C1～C4烷氧基、C3～C6环烷基或
Figure BDA0001615288510000061
R5、R6独立的为-H或C1～C4烷基。
最优选的，R7为-H、-OH、C1～C4烷基、
Figure BDA0001615288510000062
羟基取代的C1～C4烷基、-NH2、
Figure BDA0001615288510000063
苯基、苄基或C2～C4烯基；a＝0或1；R3为-H、C1～C4烷基、C1～C4烷氧基或C2～C4烯基；R4为-H、C1～C4烷基、C1～C4烷氧基、环丙基或
Figure BDA0001615288510000064
R5、R6独立的为-H或C1～C4烷基。
作为本发明的优选技术方案，上述厚朴酚系列衍生物，当R为
Figure BDA0001615288510000065
时，结构式如式Ⅲ所示：
Figure BDA0001615288510000066
其中，R8～R10独立的为-H、-OH、C1～C8烷基、
Figure BDA0001615288510000067
羟基取代的C1～C8烷基、-NH2、
Figure BDA0001615288510000068
C1～C8醚基、苯基、苄基或C2～C8烯基；a＝0～4；
R3为-H、C1～C8烷基、C1～C8烷氧基或C2～C8烯基；R4为-H、C1～C8烷基、C1～C8烷氧基、C3～C8环烷基或
Figure BDA0001615288510000069
R5、R6独立的为-H或C1～C8烷基。
优选的，上述厚朴酚系列衍生物，R8～R10独立的为-H、-OH、C1～C6烷基、
Figure BDA00016152885100000610
Figure BDA00016152885100000611
羟基取代的C1～C6烷基、-NH2、
Figure BDA00016152885100000612
C1～C6醚基、苯基、苄基或C2～C6烯基；a＝0～3；
R3为-H、C1～C6烷基、C1～C6烷氧基或C2～C6烯基；R4为-H、C1～C6烷基、C1～C6烷氧基、C3～C6环烷基或
Figure BDA0001615288510000071
R5、R6独立的为-H或C1～C6烷基。
更进一步优选的，R8～R10独立的为-H、-OH、C1～C4烷基、
Figure BDA0001615288510000072
Figure BDA0001615288510000073
羟基取代的C1～C4烷基、-NH2、
Figure BDA0001615288510000074
C1～C4醚基、苯基、苄基或C2～C4烯基；a＝0～2；
R3为-H、C1～C4烷基、C1～C4烷氧基或C2～C4烯基；R4为-H、C1～C4烷基、C1～C4烷氧基、C3～C6环烷基或
Figure BDA0001615288510000075
R5、R6独立的为-H或C1～C4烷基。
最优选的，R8～R10独立的为-H、-OH、C1～C4烷基、
Figure BDA0001615288510000076
Figure BDA0001615288510000077
羟基取代的C1～C4烷基、-NH2、
Figure BDA0001615288510000078
苯基、苄基或C2～C4烯基；a＝0或1；R3为-H、C1～C4烷基、C1～C4烷氧基或C2～C4烯基；R4为-H、C1～C4烷基、C1～C4烷氧基、环丙基或
Figure BDA0001615288510000079
R5、R6独立的为-H或C1～C4烷基。
本发明厚朴酚系列衍生物，其结构式为：
Figure BDA00016152885100000710
Figure BDA0001615288510000081
本发明还提供了上述厚朴酚系列衍生物的制备方法，其合成路线如下：合成路线一：
Figure BDA0001615288510000091
a、厚朴酚(原料1)、氢氧化钠、37％甲醛水溶液溶于乙醇中，室温下搅拌反应24h，得到中间体3；优选厚朴酚：氢氧化钠：37％甲醛水溶液＝1mmol：1mmol：0.61ml；
b、中间体3与二氯亚砜溶于二氯甲烷中，冰浴条件下搅拌反应24小时，得到中间体4；优选中间体3：二氯亚砜＝1mmol：1mmol；
c、中间体4、R-H(例如：取代的饱和六元环或五元环化合物)、碳酸铯，再加入催化量的碘化钾，溶于乙腈中，加热到80℃，搅拌反应24h，得到本发明厚朴酚系列衍生物；优选中间体4：取代饱和六元环或五元环化合物：碳酸铯＝0.32mmol：0.38mmol：0.43mmol；
其中，R为-OH、卤素、-COOH、-CN、-CF3、-NO2、C1～C8烷基、C3～C8环烷基、
Figure BDA0001615288510000092
或取代的5～10元饱和或不饱和杂环，所述的杂原子为N、O、S，杂原子个数为1～3个；所述取代5～10元饱和或不饱和杂环的取代基为-H、-OH、C1～C8烷基、酮基、
Figure BDA0001615288510000093
Figure BDA0001615288510000094
羟基取代的C1～C8烷基、-NH2、
Figure BDA0001615288510000095
C1～C8醚基、苯基、苄基或C2～C8烯基；a＝0～4；
R1、R2独立的为-H、C1～C8烷基或5～10元饱和杂环，所述的杂原子为N、O、S，杂原子个数为1～3个；
R3为-H、C1～C8烷基、C1～C8烷氧基或C2～C8烯基；
R4为-H、C1～C8烷基、C1～C8烷氧基、C3～C8环烷基或
Figure BDA0001615288510000096
R5、R6独立的为-H或C1～C8烷基。
合成路线二：
Figure BDA0001615288510000101
a、厚朴酚(原料1)、R-H(例如：取代的饱和六元环或五元环化合物)、37％甲醛水溶液溶于乙醇中，加热回流4～5h，得到本发明厚朴酚系列衍生物；优选厚朴酚：取代五元环或六元环化合物：37％甲醛水溶液＝1mmol：1mmol：1mmol；
其中，R为-OH、卤素、-COOH、-CN、-CF3、-NO2、C1～C8烷基、C3～C8环烷基、
Figure BDA0001615288510000102
或取代的5～10元饱和或不饱和杂环，所述的杂原子为N、O、S，杂原子个数为1～3个；所述取代5～10元饱和或不饱和杂环的取代基为-H、-OH、C1～C8烷基、酮基、
Figure BDA0001615288510000103
Figure BDA0001615288510000104
羟基取代的C1～C8烷基、-NH2、
Figure BDA0001615288510000105
C1～C8醚基、苯基、苄基或C2～C8烯基；a＝0～4；
R1、R2独立的为-H、C1～C8烷基或5～10元饱和杂环，所述的杂原子为N、O、S，杂原子个数为1～3个；
R3为-H、C1～C8烷基、C1～C8烷氧基或C2～C8烯基；
R4为-H、C1～C8烷基、C1～C8烷氧基、C3～C8环烷基或
Figure BDA0001615288510000107
R5、R6独立的为-H或C1～C8烷基。
合成路线三：
Figure BDA0001615288510000106
a、化合物5a，5h，5w，5y或5aa和三氟乙酸在冰浴条件下搅拌反应2～3h；优选化合物5a，5h，5w，5y或5aa：三氟乙酸＝1mmol：2mmol。
合成路线四：
Figure BDA0001615288510000111
a、7a或7b、三乙胺、丙烯酰氯溶解于二氯甲烷中，室温条件下搅拌反应2～3小时；优选7a或7b：三乙胺：丙烯酰氯＝0.66mmol：1.98mmol：0.66mmol。
本发明还提供了上述厚朴酚系列衍生物包括其互变异构体、立体异构体及其所有比例的混合物，还包括其同位素取代的化合物。
本发明还提供了上述厚朴酚系列衍生物药学上可接受的盐。
本发明所用的术语“药学上可接受的”是指在在合理的医学判断范围，能适于用来与人类和其他哺乳动物的组织接触，而没有不当毒性、刺激、过敏反应等，其在对受者给药时能直接或间接地提供本发明的化合物或化合物的前药。
本发明还提供了上述厚朴酚系列衍生物药学上可接受的水合物。术语“水合物”表示进一步通过非共价分子间作用力结合化学计量或非化学计量的水的化合物。
本发明还提供了上述厚朴酚系列衍生物药学上可接受的多晶型物。术语“多晶型物”表示化合物或其复合物的固体结晶形式，其可以通过物理方法，例如X.射线粉末衍射图或红外光谱进行表征。
本发明还提供了上述厚朴酚系列衍生物药学上可接受的药物组合物，这种药物组合物是由式I、Ⅱ、Ⅲ所示的厚朴酚系列衍生物或其盐或水合物添加药学上可以接受的辅助性成分制备而成的。
上述药物组合物可以为液体形式或固体形式。其中，所述的液体形式可以为水溶液形式。所述的固体形式可以为粉末、颗粒、片剂或冻干粉形式。该药物组合物还含有注射用水、盐水溶液、葡萄糖水溶液、注射/输注用盐水、注射/输注用葡萄糖、格林氏溶液或含有乳酸盐的格林氏溶液。
本发明还提供了上述式I、Ⅱ、Ⅲ所示的厚朴酚系列衍生物及其盐、水合物或药物组合物在制备抗肿瘤药物中的用途。
本发明还提供了上述式I、Ⅱ、Ⅲ所示的厚朴酚系列衍生物及其盐、水合物或药物组合物在制备口服或静脉注射制剂中的用途。所述的口服或静脉注射制剂至少包含一种式I、Ⅱ、Ⅲ所示的厚朴酚系列衍生物及其盐、水合物或药物组合物以及任意的赋形剂和/或佐剂。
本发明方法通过MTT法、细胞凋亡试验和抗肿瘤试验证明了本发明的厚朴酚系列衍生物具有优良的抗肿瘤活性，特别是化合物7b肿瘤抑制率是厚朴酚的3倍以上，为本领域抗肿瘤药物提供了一种更好的选择。
附图说明
图1化合物5n、7a和7b诱导细胞凋亡作用；其中A图：5n、7a、7b处理24小时后，H1975细胞凋亡的代表性流式细胞直方图；B图：5n、7a、7b处理24小时后，在双参数直方图不同区域中的细胞百分比。
图2化合物5n和7b对C26肿瘤模型的体内抗瘤活性。
具体实施方式
实施例1 5,5'-二烯丙基-3-(羟甲基)-[1,1'-联苯]-2,2'-二醇
Figure BDA0001615288510000121
将厚朴酚(266.13mg，1mmol)溶解于乙醇中，向其中加入氢氧化钠(40mg，1mmol)，37％甲醛水溶液(0.61ml)，室温下搅拌反应24小时，反应完全后加入饱和碳酸氢钠水溶液调节pH为6，然后用乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，旋干过柱(石油醚-乙酸乙酯＝3/1)即得到中间体3，呈淡黄色粉末状固体168mg，产率56.7％。
1H NMR(400MHz,DMSO)δ9.68(s,1H),7.92(s,1H),7.10(d,J＝2.1Hz,1H),6.99(dd,J＝8.2,2.2Hz,1H),6.95(d,J＝2.1Hz,1H),6.86(d,J＝8.0Hz,2H),6.10–5.87(m,2H),5.19(s,1H),5.12–4.98(m,4H),4.57(s,2H),3.33–3.27(m,4H).MS(ES),m/z:319.1[M+H]+.
实施例2 5,5'-二烯丙基-3-(氯甲基)-[1,1'-联苯]-2,2'-二醇
Figure BDA0001615288510000122
将中间体3(148mg，0.5mmol)溶解于二氯甲烷中，在冰浴条件下同样滴液漏斗向其中滴加二氯亚砜(118.96mg，1mmol)，反应完成后，用饱和碳酸氢钠溶液洗涤，收集有机层，无水硫酸钠干燥，旋干，即得到中间体4，淡黄色油状液体123mg，产率78％。MS(ES),m/z:314.8[M+H]+.
实施例3N-叔丁氧羰基-4-((5,5'-二烯丙基-2,2'-二羟基-[1,1'-联苯]-3-基)甲基)哌嗪(5a)
Figure BDA0001615288510000123
将100mg(0.32mmol)5,5'-二烯丙基-3-(氯甲基)-[1,1'-联苯]-2,2'-二醇(中间体4)、71mg(0.38mmol)Boc-哌嗪，140.44mg(0.43mmol)碳酸铯，催化量碘化钾加入到10ml圆底烧瓶中，加入乙腈做溶解，加热到80℃，反应过夜，反应完全后，将反应液冷却至室温，然后倒入水中，用乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，旋干，过柱(二氯甲烷-甲醇＝20/1)，即得到淡棕黄色粉末状固体104mg，产率69.8％。
1H NMR(400MHz,DMSO)δ6.97–6.89(m,3H),6.84(d,J＝1.9Hz,1H),6.80(d,J＝8.0Hz,1H),6.01–5.85(m,2H),5.12–4.97(m,4H),3.71(s,2H),3.43–3.33(m,4H),3.27(d,J＝6.8Hz,4H),2.49(dd,J＝11.4,9.7Hz,4H),1.39(s,9H).MS(ES),m/z:465.2[M+H]+.HPLC纯度:98.0％
实施例4 5,5'-二烯丙基-3-(吗啉代甲基)-[1,1'-联苯]-2,2'-二醇(5b)
Figure BDA0001615288510000131
将100mg(0.32mmol)5,5'-二烯丙基-3-(氯甲基)-[1,1'-联苯]-2,2'-二醇(中间体4)、33mg(0.38mmol)吗啉，140.44mg(0.43mmol)碳酸铯，催化量碘化钾加入到10ml圆底烧瓶中，加入乙腈做溶解，加热到80℃，反应过夜，反应完全后，将反应液冷却至室温，然后倒入水中，用乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，旋干，过柱(二氯甲烷-甲醇＝20/1)，即得到白色粉末状固体59mg，产率50.2％。
1H NMR(400MHz,CDCl3)δ7.18–7.07(m,3H),7.12(d,J＝8.8Hz,1H),6.89(s,1H),6.06–5.88(m,2H),5.15–5.02(m,4H),3.84(s,2H),3.77(s,4H),3.39(d,J＝6.6Hz,2H),3.34(d,J＝6.7Hz,2H),2.69(s,4H).MS(ES),m/z:366.1[M+H]+.HPLC纯度:98.1％
实施例5 5,5'-二烯丙基-3-(((四氢-2H-吡喃-4-基)氨基)甲基)-[1,1'-联苯]-2,2'-二醇(5c)
Figure BDA0001615288510000132
将100mg(0.32mmol)5,5'-二烯丙基-3-(氯甲基)-[1,1'-联苯]-2,2'-二醇(中间体4)、38mg(0.38mmol)4-氨基四氢吡喃，140.44mg(0.43mmol)碳酸铯，催化量碘化钾加入到10ml圆底烧瓶中，加入乙腈做溶解，加热到80℃，反应过夜，反应完全后，将反应液冷却至室温，然后倒入水中，用乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，旋干，过柱(二氯甲烷-甲醇＝20/1)，即得到黄色粉末状固体48mg，产率39.5％。
1H NMR(400MHz,CDCl3)δ7.17–7.06(m,3H),6.98(d,J＝8.1Hz,1H),6.82(s,1H),6.03–5.90(m,2H),5.17–4.99(m,4H),4.10(s,2H),3.96(d,J＝10.3Hz,2H),3.36(dd,J＝19.2,7.2Hz,6H),2.84–2.72(m,1H),1.90(d,J＝12.4Hz,2H),1.53–1.37(m,2H).MS(ES),m/z:380.5[M+H]+.HPLC纯度:98.4％
实施例6 5,5'-二烯丙基-3-((4-异丙基哌嗪-1-基)甲基)-[1,1'-联苯]-2,2'-二醇(5d)
Figure BDA0001615288510000133
将100mg(0.32mmol)5,5'-二烯丙基-3-(氯甲基)-[1,1'-联苯]-2,2'-二醇(中间体4)、49mg(0.38mmol)1-异丙基哌嗪，140.44mg(0.43mmol)碳酸铯，催化量碘化钾加入到10ml圆底烧瓶中，加入乙腈做溶解，加热到80℃，反应过夜，反应完全后，将反应液冷却至室温，然后倒入水中，用乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，旋干，过柱(二氯甲烷-甲醇＝20/1)，即得到棕黄色油状液体53mg，产率40.7％。
1H NMR(400MHz,CDCl3)δ7.15–7.08(m,3H),6.99(d,J＝8.1Hz,1H),6.85(d,J＝1.8Hz,1H),6.06–5.90(m,2H),5.13–5.02(m,4H),3.82(s,2H),3.39(d,J＝6.7Hz,2H),3.34(d,J＝6.7Hz,2H),2.80(s,8H),2.17(s,1H),1.09(s,6H).MS(ES),m/z:407.1[M+H]+.HPLC纯度:98.2％
实施例7 5,5'-二烯丙基-3-((八氢喹啉-1(2H)-基)甲基)-[1,1'-联苯]-2,2'-二醇(5e)
Figure BDA0001615288510000141
将100mg(0.32mmol)5,5'-二烯丙基-3-(氯甲基)-[1,1'-联苯]-2,2'-二醇53mg(中间体4)、(0.38mmol)十氢喹啉，140.44mg(0.43mmol)碳酸铯，催化量碘化钾加入到10ml圆底烧瓶中，加入乙腈做溶解，加热到80℃，反应过夜，反应完全后，将反应液冷却至室温，然后倒入水中，用乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，旋干，过柱(二氯甲烷-甲醇＝20/1)，即得到红棕色粉末状固体57mg，产率42.9％。
1H NMR(400MHz,CDCl3)δ7.14(d,J＝2.1Hz,1H),7.08(s,2H),6.99(d,J＝8.2Hz,1H),6.81(s,1H),6.06–5.89(m,2H),5.12–5.01(m,4H),4.51(d,J＝14.5Hz,1H),4.12(q,J＝7.1Hz,1H),3.75(s,2H),3.38(d,J＝6.7Hz,2H),3.33(d,J＝6.7Hz,2H),3.18(d,J＝10.3Hz,1H),2.24(d,J＝21.3Hz,2H),2.04(s,1H),1.84(d,J＝2.8Hz,1H),1.68(d,J＝10.8Hz,5H),1.41(d,J＝12.7Hz,1H),1.26(t,J＝7.1Hz,2H),1.25(dd,J＝12.1,4.9Hz,4H),1.17–0.98(m,2H).MS(ES),m/z:418.1[M+H]+.HPLC纯度:98.6％
实施例8 5,5'-二烯丙基-3-(硫代吗啉代甲基)-[1,1'-联苯]-2,2'-二醇(5f)
Figure BDA0001615288510000142
将100mg(0.32mmol)5,5'-二烯丙基-3-(氯甲基)-[1,1'-联苯]-2,2'-二醇(中间体4)、39mg(0.38mmol)硫代吗啉，140.44mg(0.43mmol)碳酸铯，催化量碘化钾加入到10ml圆底烧瓶中，加入乙腈做溶解，加热到80℃，反应过夜，反应完全后，将反应液冷却至室温，然后倒入水中，用乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，旋干，过柱(二氯甲烷-甲醇＝20/1)，即得到米黄色粉末状固体50mg，产率41.1％。
1H NMR(400MHz,CDCl3)δ7.13–7.09(m,3H),6.99(d,J＝8.4Hz,1H),6.85(d,J＝2.0Hz,1H),6.05–5.88(m,2H),5.14–5.02(m,4H),3.80(s,2H),3.38(d,J＝6.7Hz,2H),3.34(d,J＝6.7Hz,2H),2.90(s,4H),2.72(s,4H).MS(ES),m/z:382.2[M+H]+.HPLC纯度:98.1％
实施例9 5,5'-二烯丙基-3-(吡咯烷-1-基甲基)-[1,1'-联苯]-2,2'-二醇(5g)
Figure BDA0001615288510000143
将100mg(0.32mmol)5,5′-二烯丙基-3-(氯甲基)-[1,1′-联苯]-2,2′-二醇(中间体4)、27mg(0.38mmol)四氢吡咯，140.44mg(0.43mmol)碳酸铯，催化量碘化钾加入到10ml圆底烧瓶中，加入乙腈做溶解，加热到80℃，反应过夜，反应完全后，将反应液冷却至室温，然后倒入水中，用乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，旋干，过柱(二氯甲烷-甲醇＝20/1)，即得到棕红色粉末状固体53mg，产率47.3％。
1H NMR(400MHz,CDCl3)δ7.18–7.05(m,3H),6.98(d,J＝8.2Hz,1H),6.83(d,J＝2.0Hz,1H),6.05–5.90(m,2H),5.15–4.99(m,4H),3.95(s,2H),3.37(d,J＝6.8Hz,2H),3.34(d,J＝6.7Hz,2H),2.77(s,4H),2.00–1.73(m,4H).MS(ES),m/z:350.2[M+H]+.HPLC纯度:98.9％
实施例10 1-((5,5'-二烯丙基-2,2'-二羟基-[1,1'-联苯]-3-基)甲基)-3-Boc-氨基-哌啶(5h)
Figure BDA0001615288510000151
将100mg(0.32mmol)5,5'-二烯丙基-3-(氯甲基)-[1,1'-联苯]-2,2'-二醇(中间体4)、76mg(0.38mmol)3-Boc氨基哌啶，140.44mg(0.43mmol)碳酸铯，催化量碘化钾加入到10ml圆底烧瓶中，加入乙腈做溶解，加热到80℃，反应过夜，反应完全后，将反应液冷却至室温，然后倒入水中，用乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，旋干，过柱(二氯甲烷-甲醇＝20/1)，即得到棕黄色粉末状固体85mg，产率55.6％。
1H NMR(400MHz,CDCl3)δ7.10(dd,J＝6.3,3.9Hz,3H),7.00(d,J＝8.0Hz,1H),6.83(s,1H),6.06–5.89(m,2H),5.15–5.01(m,4H),4.65(s,1H),3.81(s,1H),3.74(s,2H),3.38(d,J＝6.7Hz,2H),3.33(d,J＝6.7Hz,2H),3.15–2.09(m,4H),2.10–1.52(m,4H),1.39(s,9H).MS(ES),m/z:479.4[M+H]+.HPLC纯度:98.1％
实施例11 1-(4-((5,5'-二烯丙基-2,2'-二羟基-[1,1'-联苯]-3-基)甲基)-4-乙酰基哌嗪(5i)
Figure BDA0001615288510000152
将100mg(0.32mmol)5,5'-二烯丙基-3-(氯甲基)-[1,1'-联苯]-2,2'-二醇(中间体4)、49mg(0.38mmol)1-乙酰哌嗪，140.44mg(0.43mmol)碳酸铯，催化量碘化钾加入到10ml圆底烧瓶中，加入乙腈做溶解，加热到80℃，反应过夜，反应完全后，将反应液冷却至室温，然后倒入水中，用乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，旋干，过柱(二氯甲烷-甲醇＝20/1)，即得到淡黄色粉末状固体92mg，产率71.0％。
1H NMR(400MHz,CDCl3)δ7.12(s,3H),6.99(d,J＝8.1Hz,1H),6.87(s,1H),6.07–5.88(m,2H),5.18–5.00(m,4H),3.82(s,2H),3.51(s,4H),3.37(dd,J＝16.0,6.3Hz,4H),2.62(s,4H),2.09(s,3H).MS(ES),m/z:407.2[M+H]+.HPLC纯度:98.7％
实施例12 5,5'-二烯丙基-3-((3-甲基哌啶-1-基)甲基)-[1,1'-联苯]-2,2'-二醇(5j)
Figure BDA0001615288510000161
将100mg(0.32mmol)5,5'-二烯丙基-3-(氯甲基)-[1,1'-联苯]-2,2'-二醇(中间体4)、38mg(0.38mmol)3-甲基哌啶，140.44mg(0.43mmol)碳酸铯，催化量碘化钾加入到10ml圆底烧瓶中，加入乙腈做溶解，加热到80℃，反应过夜，反应完全后，将反应液冷却至室温，然后倒入水中，用乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，旋干，过柱(二氯甲烷-甲醇＝20/1)，即得到黄褐色油状液体62mg，产率51.4％。
1H NMR(400MHz,CDCl3)δ8.65(s,2H),7.15(d,J＝2.1Hz,1H),7.10(dd,J＝7.9,2.1Hz,2H),6.98(d,J＝8.2Hz,1H),6.82(d,J＝1.8Hz,1H),6.06–5.89(m,2H),5.15–5.00(m,4H),3.78(d,J＝4.2Hz,2H),3.38(d,J＝6.7Hz,2H),3.34(d,J＝6.7Hz,2H),2.98(s,2H),2.11(s,1H),1.91–1.69(m,4H),1.68–1.53(m,1H),1.05–0.92(m,1H),0.88(d,J＝6.1Hz,3H).MS(ES),m/z:478.1[M+H]+.HPLC纯度:98.2％
实施例13 5,5'-二烯丙基-3-(哌啶-1-基甲基)-[1,1'-联苯]-2,2'-二醇(5k)
Figure BDA0001615288510000162
将100mg(0.32mmol)5,5'-二烯丙基-3-(氯甲基)-[1,1'-联苯]-2,2'-二醇32mg(中间体4)、(0.38mmol)六氢吡啶，140.44mg(0.43mmol)碳酸铯，催化量碘化钾加入到10ml圆底烧瓶中，加入乙腈做溶解，加热到80℃，反应过夜，反应完全后，将反应液冷却至室温，然后倒入水中，用乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，旋干，过柱(二氯甲烷-甲醇＝20/1)，即得到米黄色粉末状固体74mg，产率63.3％。
1H NMR(400MHz,DMSO)δ6.97(d,J＝2.2Hz,1H),6.96–6.91(m,2H),6.80(d,J＝2.1Hz,1H),6.76(d,J＝8.1Hz,1H),6.02–5.84(m,2H),5.11–4.96(m,4H),3.79(s,2H),3.27(t,J＝6.7Hz,4H),2.55(d,J＝30.0Hz,4H),1.62–1.37(m,6H).MS(ES),m/z:364.0[M+H]+.HPLC纯度:98.1％
实施例14 5,5'-二烯丙基-3-((4-甲基哌嗪-1-基)甲基)-[1,1'-联苯]-2,2'-二醇(5l)
Figure BDA0001615288510000163
将100mg(0.32mmol)5,5'-二烯丙基-3-(氯甲基)-[1,1'-联苯]-2,2'-二醇(中间体4)、38mg(0.38mmol)N-甲基哌嗪，140.44mg(0.43mmol)碳酸铯，催化量碘化钾加入到10ml圆底烧瓶中，加入乙腈做溶解，加热到80℃，反应过夜，反应完全后，将反应液冷却至室温，然后倒入水中，用乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，旋干，过柱(二氯甲烷-甲醇＝20/1)，即得到棕黄色粉末状固体70mg，产率57.6％。
1H NMR(400MHz,CDCl3)δ7.15–7.08(m,3H),6.99(d,J＝8.0Hz,1H),6.85(d,J＝1.8Hz,1H),6.05–5.90(m,2H),5.17–4.95(m,4H),3.82(s,2H),3.39(d,J＝6.7Hz,2H),3.34(d,J＝6.7Hz,2H),2.70(s,8H),2.34(s,3H).MS(ES),m/z:379.46[M+H]+.HPLC纯度:98.2％
实施例15(1-((5,5'-二烯丙基-2,2'-二羟基-[1,1'-联苯])-4-环丙甲酰基哌嗪(5m)
Figure BDA0001615288510000171
将100mg(0.32mmol)5,5'-二烯丙基-3-(氯甲基)-[1,1'-联苯]-2,2'-二醇(中间体4)、59mg(0.38mmol)1-环丙甲酰基哌嗪，140.44mg(0.43mmol)碳酸铯，催化量碘化钾加入到10ml圆底烧瓶中，加入乙腈做溶解，加热到80℃，反应过夜，反应完全后，将反应液冷却至室温，然后倒入水中，用乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，旋干，过柱(二氯甲烷-甲醇＝20/1)，即得到米白色粉末状固体98mg，产率70.9％。
1H NMR(400MHz,CDCl3)δ7.16–7.10(m,3H),7.02(d,J＝8.8Hz,1H),6.91(s,1H),6.06–5.90(m,2H),5.15–5.02(m,4H),3.89(s,2H),3.39(d,J＝6.7Hz,2H),3.35(d,J＝6.7Hz,2H),2.71(s,8H),1.71–1.63(m,1H),1.02–0.94(m,2H),0.81–0.71(m,2H).MS(ES),m/z:433.3[M+H]+.HPLC纯度:98.5％
实施例16 5,5'-二烯丙基-3-((4-甲基哌嗪-1-基)甲基)-[1,1'-联苯]-2,2'-二醇(5n)
Figure BDA0001615288510000172
将100mg(0.32mmol)5,5'-二烯丙基-3-(氯甲基)-[1,1'-联苯]-2,2'-二醇(中间体4)、55mg(0.38mmol)1-(2-甲氧基乙基)哌嗪，140.44mg(0.43mmol)碳酸铯，催化量碘化钾加入到10ml圆底烧瓶中，加入乙腈做溶解，加热到80℃，反应过夜，反应完全后，将反应液冷却至室温，然后倒入水中，用乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，旋干，过柱(二氯甲烷-甲醇＝20/1)，即得到黄色油状液体93mg，产率68.9％。
1H NMR(400MHz,CDCl3)δ7.14–7.07(m,3H),6.98(d,J＝8.1Hz,1H),6.84(d,J＝2.0Hz,1H),6.07–5.87(m,2H),5.18–4.98(m,4H),4.12(q,J＝7.1Hz,2H),3.80(s,2H),3.50(t,J＝5.4Hz,2H),3.36(dd,J＝16.3,5.0Hz,4H),3.34(s,3H),2.66(s,8H),2.60(t,J＝5.4Hz,2H).MS(ES),m/z:423.1[M+H]+.HPLC纯度:98.4％
实施例17(1-((5,5'-二烯丙基-2,2'-二羟基-[1,1'-联苯])-4-环丙甲酰基哌嗪(5o)
Figure BDA0001615288510000181
将100mg(0.32mmol)5,5'-二烯丙基-3-(氯甲基)-[1,1'-联苯]-2,2'-二醇(中间体4)、43mg(0.38mmol)1-甲醛哌嗪，140.44mg(0.43mmol)碳酸铯，催化量碘化钾加入到10ml圆底烧瓶中，加入乙腈做溶解，加热到80℃，反应过夜，反应完全后，将反应液冷却至室温，然后倒入水中，用乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，旋干，过柱(二氯甲烷-甲醇＝20/1)，即得到黄色粉末状固体87mg，产率69.4％。
1H NMR(400MHz,CDCl3)δ8.01(s,1H),7.11(d,J＝7.1Hz,3H),6.98(d,J＝8.7Hz,1H),6.86(d,J＝1.3Hz,1H),6.05–5.87(m,2H),5.15–5.01(m,4H),3.81(s,2H),3.72–3.40(m,4H),3.38(d,J＝6.7Hz,2H),3.34(d,J＝6.6Hz,2H),2.61(s,4H).MS(ES),m/z:415.0[M+Na]+.HPLC纯度:98.1％
实施例18 4-((5,5'-二烯丙基-2,2'-二羟基-[1,1'-联苯]-3-基)甲基)-N,N-二甲基哌嗪-1-甲酰胺(5p)
Figure BDA0001615288510000182
将100mg(0.32mmol)5,5'-二烯丙基-3-(氯甲基)-[1,1'-联苯]-2,2'-二醇(中间体4)、60mg(0.38mmol)N,N-二甲基哌嗪-1-甲酰胺，140.44mg(0.43mmol)碳酸铯，催化量碘化钾加入到10ml圆底烧瓶中，加入乙腈做溶解，加热到80℃，反应过夜，反应完全后，将反应液冷却至室温，然后倒入水中，用乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，旋干，过柱(二氯甲烷-甲醇＝20/1)，即得到黄色粉末状固体98mg，产率70.5％。
1H NMR(400MHz,CDCl3)δ8.25(s,2H),7.14–7.08(m,3H),6.98(d,J＝8.1Hz,1H),6.84(d,J＝1.8Hz,1H),6.05–5.89(m,2H),5.14–5.01(m,4H),3.79(s,2H),3.38(d,J＝6.7Hz,2H),3.34(d,J＝6.7Hz,2H),3.31–3.18(m,4H),2.81(s,6H),2.75–2.50(m,4H).MS(ES),m/z:436.1[M+H]+.HPLC纯度:98.7％
实施例19 1-((5,5'-二烯丙基-2,2'-二羟基-[1,1'-联苯]-3-基)甲基)-4-乙基哌嗪-2,3-二酮(5q)
Figure BDA0001615288510000183
将100mg(0.32mmol)5,5'-二烯丙基-3-(氯甲基)-[1,1'-联苯]-2,2'-二醇(中间体4)、54mg(0.38mmol)N-乙基-2,3-二酮哌嗪，140.44mg(0.43mmol)碳酸铯，催化量碘化钾加入到10ml圆底烧瓶中，加入乙腈做溶解，加热到80℃，反应过夜，反应完全后，将反应液冷却至室温，然后倒入水中，用乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，旋干，过柱(二氯甲烷-甲醇＝20/1)，即得到黄色粉末状固体42mg，产率31.1％。
1H NMR(400MHz,CDCl3)δ7.19–6.91(m,5H),6.02–5.86(m,2H),5.15–4.99(m,4H),4.57(s,2H),3.66(s,2H),3.49(s,2H),3.35(t,J＝7.2Hz,4H),1.60(s,2H),1.14(t,J＝6.7Hz,3H).MS(ES),m/z:443.0[M+Na]+.HPLC纯度:98.3％
实施例20 1-((5,5'-二烯丙基-2,2'-二羟基-[1,1'-联苯]-3-基)甲基)-4-乙基哌嗪-2,3-二酮(5r)
Figure BDA0001615288510000191
将100mg(0.32mmol)5,5'-二烯丙基-3-(氯甲基)-[1,1'-联苯]-2,2'-二醇(中间体4)、67mg(0.38mmol)1-苄基哌嗪，140.44mg(0.43mmol)碳酸铯，催化量碘化钾加入到10ml圆底烧瓶中，加入乙腈做溶解，加热到80℃，反应过夜，反应完全后，将反应液冷却至室温，然后倒入水中，用乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，旋干，过柱(二氯甲烷-甲醇＝20/1)，即得到米白色粉末状固体78mg，产率53.9％。
1H NMR(400MHz,CDCl3)δ7.33–7.29(m,4H),7.27(dd,J＝5.1,3.5Hz,1H),7.11(d,J＝8.9Hz,3H),6.99(d,J＝8.0Hz,1H),6.84(d,J＝1.9Hz,1H),6.06–5.88(m,2H),5.14–5.01(m,4H),3.81(s,2H),3.54(s,2H),3.38(d,J＝6.8Hz,4H),3.33(d,J＝6.8Hz,4H),2.48(s,8H).MS(ES),m/z:455.2[M+H]+.HPLC纯度:98.3％
实施例21 1-((5,5'-二烯丙基-2,2'-二羟基-[1,1'-联苯]-3-基)甲基)-4-乙基哌嗪-2,3-二酮(5s)
Figure BDA0001615288510000192
将100mg(0.32mmol)5,5'-二烯丙基-3-(氯甲基)-[1,1'-联苯]-2,2'-二醇(中间体4)、62mg(0.38mmol)N-苯基哌嗪，140.44mg(0.43mmol)碳酸铯，催化量碘化钾加入到10ml圆底烧瓶中，加入乙腈做溶解，加热到80℃，反应过夜，反应完全后，将反应液冷却至室温，然后倒入水中，用乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，旋干，过柱(二氯甲烷-甲醇＝20/1)，即得到米黄色粉末状固体79mg，产率55.8％。
1H NMR(400MHz,CDCl3)δ7.31–7.26(m,2H),7.15–7.09(m,3H),6.99(d,J＝8.1Hz,1H),6.93–6.87(m,4H),6.06–5.91(m,2H),5.14–5.02(m,4H),3.87(s,2H),3.39(d,J＝6.7Hz,2H),3.36(d,J＝6.7Hz,2H),3.24(s,4H),2..65(s,4H).MS(ES),m/z:441.2[M+H]+.HPLC纯度:98.1％
实施例22 5,5'-二烯丙基-3-((4-烯丙基哌嗪-1-基)甲基)-[1,1'-联苯]-2,2'-二醇(5t)
Figure BDA0001615288510000201
将100mg(0.32mmol)5,5'-二烯丙基-3-(氯甲基)-[1,1'-联苯]-2,2'-二醇(中间体4)、48mg(0.38mmol)1-烯丙基哌嗪，140.44mg(0.43mmol)碳酸铯，催化量碘化钾加入到10ml圆底烧瓶中，加入乙腈做溶解，加热到80℃，反应过夜，反应完全后，将反应液冷却至室温，然后倒入水中，用乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，旋干，过柱(二氯甲烷-甲醇＝20/1)，即得到浅棕黄色油状液体90mg，产率69.8％。
1H NMR(400MHz,CDCl3)δ7.14–7.08(m,3H),6.99(d,J＝8.1Hz,1H),6.85(d,J＝1.7Hz,1H),6.06–5.89(m,2H),5.89–5.77(m,1H),5.23–5.14(m,2H),5.13–5.02(m,4H),3.81(s,2H),3.38(d,J＝6.7Hz,2H),3.34(d,J＝6.7Hz,2H),3.02(d,J＝6.6Hz,2H),2.42(s,8H).MS(ES),m/z:405.0[M+H]+.HPLC纯度:98.3％
实施例23 1-((5,5'-二烯丙基-2,2'-二羟基-[1,1'-联苯]-3-基)甲基)哌啶-4-甲酸乙酯(5u)
Figure BDA0001615288510000202
将100mg(0.32mmol)5,5'-二烯丙基-3-(氯甲基)-[1,1'-联苯]-2,2'-二醇(中间体4)、60mg(0.38mmol)4-哌啶甲酸乙酯，140.44mg(0.43mmol)碳酸铯，催化量碘化钾加入到10ml圆底烧瓶中，加入乙腈做溶解，加热到80℃，反应过夜，反应完全后，将反应液冷却至室温，然后倒入水中，用乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，旋干，过柱(二氯甲烷-甲醇＝20/1)，即得到米黄色粉末状固体80mg，产率57.2％。
1H NMR(400MHz,CDCl3)δ7.14–7.08(m,3H),6.99(d,J＝8.1Hz,1H),6.84(s,1H),6.06–5.89(m,2H),5.13–5.01(m,4H),4.14(q,J＝4.0Hz,2H),3.80(s,2H),3.38(d,J＝6.7Hz,2H),3.34(d,J＝6.7Hz,2H),3.10(s,2H),2.50–2.12(m,3H),1.98(d,J＝11.4Hz,2H),1.86(s,2H),1.26(t,J＝4.0Hz,3H).MS(ES),m/z:436.1[M+H]+.HPLC纯度:98.1％
实施例24 4-((5,5'-二烯丙基-2,2'-二羟基-[1,1'-联苯]-3-基)甲基)哌嗪-1-甲酸乙酯(5v)
Figure BDA0001615288510000203
将100mg(0.32mmol)5,5'-二烯丙基-3-(氯甲基)-[1,1'-联苯]-2,2'-二醇(中间体4)、60mg(0.38mmol)N-哌嗪甲酸乙酯，140.44mg(0.43mmol)碳酸铯，催化量碘化钾加入到10ml圆底烧瓶中，加入乙腈做溶解，加热到80℃，反应过夜，反应完全后，将反应液冷却至室温，然后倒入水中，用乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，旋干，过柱(二氯甲烷-甲醇＝20/1)，即得到浅棕黄色油状液体76mg，产率54.6％。
1H NMR(400MHz,CDCl3)δ7.15–7.09(m,3H),7.05–7.00(m,1H),6.91(s,1H),6.05–5.88(m,2H),5.14–5.02(m,4H),4.14(q,J＝7.1Hz,2H),3.88(s,2H),3.50(s,4H),3.39(d,J＝6.4Hz,4H),3.34(d,J＝6.4Hz,4H),2.68(s,4H),1.25(t,J＝7.2Hz,4H).MS(ES),m/z:437.3[M+H]+.MS(ES),m/z:479.1[M+H]+.HPLC纯度:98.1％
实施例25((1-((5,5'-二烯丙基-2,2'-二羟基-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)氨基甲酸叔丁酯(5w)
Figure BDA0001615288510000211
将100mg(0.32mmol)5,5'-二烯丙基-3-(氯甲基)-[1,1'-联苯]-2,2'-二醇(中间体4)、81mg(0.38mmol)4-Boc氨甲基哌啶，140.44mg(0.43mmol)碳酸铯，催化量碘化钾加入到10ml圆底烧瓶中，加入乙腈做溶解，加热到80℃，反应过夜，反应完全后，将反应液冷却至室温，然后倒入水中，用乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，旋干，过柱(二氯甲烷-甲醇＝20/1)，即得到红棕色晶体110mg，产率69.8％。
1H NMR(400MHz,CDCl3)δ7.15–7.08(m,3H),7.00(d,J＝8.1Hz,1H),6.85(d,J＝1.7Hz,1H),6.05–5.89(m,2H),5.13–5.00(m,4H),4.61(s,1H),3.82(s,2H),3.38(d,J＝6.8Hz,2H),3.34(d,J＝6.8Hz,2H),3.11(d,J＝8.9Hz,2H),2.99(d,J＝5.9Hz,2H),2.23(s,2H),1.77(d,J＝12.8Hz,2H),1.43(s,9H),1.39–1.18(m,3H).MS(ES),m/z:493.2[M+H]+.HPLC纯度:98.7％
实施例26 5,5'-二烯丙基-3-((3,4-二氢喹啉-1(2H)-基)甲基)-[1,1'-联苯]-2,2'-二醇(5x)
Figure BDA0001615288510000212
将100mg(0.32mmol)5,5'-二烯丙基-3-(氯甲基)-[1,1'-联苯]-2,2'-二醇(中间体4)、51mg(0.38mmol)1,2,3,4-四氢喹啉，140.44mg(0.43mmol)碳酸铯，催化量碘化钾加入到10ml圆底烧瓶中，加入乙腈做溶解，加热到80℃，反应过夜，反应完全后，将反应液冷却至室温，然后倒入水中，用乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，旋干，过柱(二氯甲烷-甲醇＝20/1)，即得到米黄色粉末状固体69mg，产率52.4％。
1H NMR(400MHz,CDCl3)δ7.19–7.12(m,4H),7.12–7.06(m,2H),7.01(d,J＝6.8Hz,1H),6.96(d,J＝8.2Hz,1H),6.91(d,J＝1.9Hz,1H),6.05–5.92(m,2H),5.15–5.01(m,4H),4.00(s,2H),3.85(s,2H),3.37(d,J＝5.6Hz,4H),2.97(s,4H).MS(ES),m/z:412.1[M+H]+.HPLC纯度:98.6％
实施例27(1-((5,5'-二烯丙基-2,2'-二羟基-[1,1'-联苯]-3-基)甲基)哌啶-4-基)氨基甲酸酯(5y)
Figure BDA0001615288510000221
将100mg(0.32mmol)5,5'-二烯丙基-3-(氯甲基)-[1,1'-联苯]-2,2'-二醇(中间体4)、76mg(0.38mmol)4-Boc氨基哌啶，140.44mg(0.43mmol)碳酸铯，催化量碘化钾加入到10ml圆底烧瓶中，加入乙腈做溶解，加热到80℃，反应过夜，反应完全后，将反应液冷却至室温，然后倒入水中，用乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，旋干，过柱(二氯甲烷-甲醇＝20/1)，即得到白色粉末状固体105mg，产率68.3％。
1H NMR(400MHz,CDCl3)δ9.22(s,1H),7.17–7.07(m,3H),6.99(d,J＝8.1Hz,1H),6.82(s,1H),6.07–5.87(m,2H),5.17–4.97(m,4H),4.49(s,1H),3.77(s,2H),3.54(s,1H),3.37(d,J＝6.4Hz,2H),3.33(d,J＝6.4Hz,2H),3.02(s,2H),2.28(s,2H),2.10–1.90(m,3H),1.43(s,9H).MS(ES),m/z:479.1[M+H]+.
实施例28 5,5'-二烯丙基-3-((4-丁基哌嗪-1-基)甲基)-[1,1'-联苯]-2,2'-二醇(5z)
Figure BDA0001615288510000222
将100mg(0.32mmol)5,5'-二烯丙基-3-(氯甲基)-[1,1'-联苯]-2,2'-二醇(中间体4)、54mg(0.38mmol)1-丁基哌嗪，140.44mg(0.43mmol)碳酸铯，催化量碘化钾加入到10ml圆底烧瓶中，加入乙腈做溶解，加热到80℃，反应过夜，反应完全后，将反应液冷却至室温，然后倒入水中，用乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，旋干，过柱(二氯甲烷-甲醇＝20/1)，即得到棕黄色油状液体65mg，产率48.6％。
1H NMR(400MHz,CDCl3)δ7.20–7.07(m,3H),6.99(d,J＝8.1Hz,1H),6.85(d,J＝1.8Hz,1H),6.06–5.89(m,2H),5.13–5.02(m,4H),3.80(s,2H),3.39(d,J＝6.7Hz,2H),3.34(d,J＝6.7Hz,2H),2.72(s,8H),2.35(t,J＝7.6Hz,2H),1.52–1.40(m,2H),1.37–1.28(m,2H),0.91(t,J＝7.3Hz,3H).MS(ES),m/z:421.1[M+H]+.HPLC纯度:98.7％
实施例29(1-((5,5'-二烯丙基-2,2'-二羟基-[1,1'-联苯]-3-基)甲基)吡咯烷-3-基)氨基甲酸酯(5aa)
Figure BDA0001615288510000223
将100mg(0.32mmol)5,5'-二烯丙基-3-(氯甲基)-[1,1'-联苯]-2,2'-二醇(中间体4)、71mg(0.38mmol)3-(Boc-氨基)吡咯烷，140.44mg(0.43mmol)碳酸铯，催化量碘化钾加入到10ml圆底烧瓶中，加入乙腈做溶解，加热到80℃，反应过夜，反应完全后，将反应液冷却至室温，然后倒入水中，用乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，旋干，过柱(二氯甲烷-甲醇＝20/1)，即得到红棕色粉末状固体84mg，产率56.7％。
1H NMR(400MHz,CDCl3)δ7.10(d,J＝8.5Hz,3H),6.99(d,J＝8.0Hz,1H),6.84(d,J＝1.6Hz,1H),6.05–5.90(m,2H),5.14–5.02(m,4H),4.67(s,1H),4.21(s,1H),3.90(q,J＝13.9Hz,2H),3.38(d,J＝6.7Hz,2H),3.34(d,J＝6.7Hz,2H),3.02–2.71(m,3H),2.54(s,1H),2.32(s,1H),1.73–1.59(m,1H),1.42(s,9H).MS(ES),m/z:465.4[M+H]+.HPLC纯度:98.4％
实施例30(R)-5,5'-二烯丙基-3-((3-羟基吡咯烷-1-基)甲基)-[1,1'-联苯]-2,2'-二醇(6a)
Figure BDA0001615288510000231
将266.33mg厚朴酚(1mmol)和87mg(1mmol)(R)-3-吡咯烷醇用乙醇溶解，再加入37％甲醛水溶液(75μL，1mmol)，加热回流，点板监测反应的进行，待反应完全后，直接将溶剂旋掉，拌样过柱(石油醚-乙酸乙酯＝5/1)，即可得到米黄色粉末状固体219mg，产率59.9％。
1H NMR(400MHz,CDCl3)δ7.16–7.07(m,3H),6.97(d,J＝8.2Hz,1H),6.84(s,1H),6.05–5.92(m,2H),5.14–5.01(m,4H),4.46(s,1H),3.96(s,2H),3.38(d,J＝6.7Hz,2H),3.34(d,J＝6.7Hz,2H),3.08–2.64(m,4H),2.26–2.10(m,1H),1.86(m,1H).MS(ES),m/z:366.0[M+H]+.HPLC纯度:98.5％
实施例31 5,5'-二烯丙基-3-((4-(2-(2-羟基乙氧基)乙基)哌嗪-1-基)甲基)-[1,1'-联苯]-2,2'-二醇(6b)
Figure BDA0001615288510000232
将266.33mg厚朴酚(1mmol)和174mg(1mmol)2-[2-(1-哌嗪基)乙氧基]乙醇用乙醇溶解，再加入37％甲醛水溶液(75μL，1mmol)，加热回流，点板监测反应的进行，待反应完全后，直接将溶剂旋掉，拌样过柱(石油醚-乙酸乙酯＝5/1)，即得到棕黄色油状液体222mg，产率49.1％。
1H NMR(400MHz,CDCl3)δ7.11(dt,J＝10.2,2.8Hz,3H),6.98(d,J＝8.1Hz,1H),6.84(d,J＝1.6Hz,1H),6.06–5.88(m,2H),5.14–5.01(m,4H),3.81(s,2H),3.72–3.57(m,6H),3.38(d,J＝6.8Hz,2H),3.34(d,J＝6.8Hz,2H),2.51(m,10H).MS(ES),m/z:453.2[M+H]+.HPLC纯度:98.4％
实施例32 5,5'-二烯丙基-3-((3-(羟甲基)哌啶-1-基)甲基)-[1,1'-联苯]-2,2'-二醇(6c)
Figure BDA0001615288510000241
将266.33mg厚朴酚(1mmol)和115mg(1mmol)3-羟甲基哌啶用乙醇溶解，再加入37％甲醛水溶液(75μL，1mmol)，加热回流，点板监测反应的进行，待反应完全后，直接将溶剂旋掉，拌样过柱(石油醚-乙酸乙酯＝5/1)，即得到黄色粉末状固体276mg，产率70.1％。
1H NMR(400MHz,CDCl3)δ7.14(d,J＝1.9Hz,1H),7.10(s,1H),7.08(d,J＝2.1Hz,1H),6.98(d,J＝8.2Hz,1H),6.83(s,1H),6.05–5.90(m,2H),5.15–5.00(m,4H),3.80(s,2H),3.55(m,1H),3.47(s,1H),3.38(d,J＝6.7Hz,2H),3.34(d,J＝6.7Hz,2H),3.10(s,2H),2.28(s,1H),1.94–1.54(m,5H),1.11(s,1H).MS(ES),m/z:394.0[M+H]+.HPLC纯度:98.5％
实施例33 5,5'-二烯丙基-3-((4-(2-羟乙基)哌嗪-1-基)甲基)-[1,1'-联苯]-2,2'-二醇(6d)
Figure BDA0001615288510000242
将266.33mg厚朴酚(1mmol)和130mg(1mmol)1-(2-羟乙基)哌嗪用乙醇溶解，再加入37％甲醛水溶液(75μL，1mmol)，加热回流，点板监测反应的进行，待反应完全后，直接将溶剂旋掉，拌样过柱(石油醚-乙酸乙酯＝5/1)，即得到黄色粉末状固体277mg，产率67.7％。
1H NMR(400MHz,CDCl3)δ7.11(m,3H),6.98(d,J＝8.1Hz,1H),6.85(d,J＝1.7Hz,1H),6.06–5.89(m,2H),5.15–5.01(m,4H),3.81(s,2H),3.65–3.57(m,2H),3.38(d,J＝6.7Hz,2H),3.34(d,J＝6.7Hz,2H),3.16–2.19(m,10H).MS(ES),m/z:409.1[M+H]+.HPLC纯度:98.3％
实施例34 5,5'-二烯丙基-3-((4-(2-羟乙基)哌嗪-1-基)甲基)-[1,1'-联苯]-2,2'-二醇(6e)
Figure BDA0001615288510000243
将266.33mg厚朴酚(1mmol)和144mg(1mmol)1-哌嗪基丙醇用乙醇溶解，再加入37％甲醛水溶液(75μL，1mmol)，加热回流，点板监测反应的进行，待反应完全后，直接将溶剂旋掉，拌样过柱(石油醚-乙酸乙酯＝5/1)，即得到棕黄色油状液体273mg，产率64.7％。
1H NMR(400MHz,CDCl3)δ7.15–7.08(m,3H),6.98(d,J＝8.0Hz,1H),6.85(d,J＝1.9Hz,1H),6.06–5.89(m,2H),5.15–4.99(m,4H),3.80(s,2H),3.79(d,J＝5.5Hz,2H),3.38(d,J＝6.8Hz,2H),3.34(d,J＝6.8Hz,2H),3.23–2.16(m,10H),1.76–1.68(dt,J＝11.0,5.5Hz,2H).MS(ES),m/z:423.2[M+H]+.HPLC纯度:98.4％
实施例35 5,5'-二烯丙基-3-((3-氨基哌啶-1-基)甲基)-[1,1'-联苯]-2,2'-二醇(7a)
Figure BDA0001615288510000251
将化合物239mg1-((5,5'-二烯丙基-2,2'-二羟基-[1,1'-联苯]-3-基)甲基)-3-Boc-氨基-哌啶(0.5mmol)(5h)溶解于二氯甲烷中，在冰浴条件下滴加三氟乙酸，待反应完全后，旋掉多余的二氯甲烷和三氟乙酸，向残渣中加入饱和碳酸氢钠溶液，再用乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，旋干过柱(二氯甲烷-甲醇＝20/1)，即可得到米白色粉末状固体172mg，产率91.0％。
1H NMR(400MHz,DMSO)δ6.97(s,1H),6.92(s,1H),6.89(d,J＝8.1Hz,1H),6.82(s,1H),6.70(d,J＝8.1Hz,1H),6.01–5.86(m,2H),5.10–4.96(m,4H),3.72(d,J＝13.6Hz,1H),3.63(d,J＝13.6Hz,1H),3.26(d,J＝6.4Hz,4H),2.92–2.65(m,3H),2.21–1.95(m,2H),1.80–1.62(m,2H),1.52–1.35(m,1H),1.31–1.02(m,3H).MS(ES),m/z:479.1[M+H]+.HPLC纯度:98.3％
实施例36 5,5'-二烯丙基-3-((4-氨基哌啶-1-基)甲基)-[1,1'-联苯]-2,2'-二醇(7b)
Figure BDA0001615288510000252
将化合物239mg1-((5,5'-二烯丙基-2,2'-二羟基-[1,1'-联苯]-3-基)甲基)-4-Boc-氨基-哌啶(0.5mmol)(5y)溶解于二氯甲烷中，在冰浴条件下滴加三氟乙酸，待反应完全后，旋掉多余的二氯甲烷和三氟乙酸，向残渣中加入饱和碳酸氢钠溶液，再用乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，旋干过柱(二氯甲烷-甲醇＝20/1)，即可得到黄色粉末状固体174mg，产率92.1％。
1H NMR(400MHz,DMSO-d6)δ8.20(s,2H),7.16(s,1H),7.10–6.98(m,3H),6.91(d,J＝8.2Hz,1H),6.02–5.88(m,2H),5.16–4.98(m,4H),4.22(t,J＝6.5Hz,2H),3.39(s,3H),3.31(d,J＝7.1Hz,4H),3.01(s,2H),2.06(d,J＝12.1Hz,2H),1.80(s,2H),1.69–1.58(m,1H),1.43–1.32(m,1H).MS(ES),m/z:379.1[M+H]+.HPLC纯度:98.1％
实施例37 5,5'-二烯丙基-3-((4-(氨基甲基)哌啶-1-基)甲基)-[1,1'-联苯]-2,2'-二醇(7c)
Figure BDA0001615288510000253
将化合物246mg((1-((5,5'-二烯丙基-2,2'-二羟基-[1,1'-联苯]-3-基)甲基)哌啶-4-基)甲基)氨基甲酸叔丁酯(0.5mmol)(5w)溶解于二氯甲烷中，在冰浴条件下滴加三氟乙酸，待反应完全后，旋掉多余的二氯甲烷和三氟乙酸，向残渣中加入饱和碳酸氢钠溶液，再用乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，旋干过柱(二氯甲烷-甲醇＝20/1)，即可得到棕褐色粉末状固体178mg，产率90.8％。
1H NMR(400MHz,DMSO)δ10.66(s,1H),10.18(s,1H),8.38(s,2H),7.38(S,1H),7.07(S,1H),7.04–6.96(m,3H),6.05–5.89(m,2H),5.15–4.95(m,4H),4.30(d,J＝3.4Hz,2H),3.40(d,J＝11.3Hz,2H),3.33(d,J＝6.8Hz,2H),3.30(d,J＝6.8Hz,2H),3.05–2.89(m,2H),2.70(d,J＝22.5Hz,2H),1.98–1.85(m,3H),1.66–1.53(m,2H).MS(ES),m/z:393.1[M+H]+.HPLC纯度:98.2％
实施例38 5,5'-二烯丙基-3-(哌嗪-1-基甲基)-[1,1'-联苯]-2,2'-二醇(7d)
Figure BDA0001615288510000261
将化合物232mgN-叔丁氧羰基-4-((5,5'-二烯丙基-2,2'-二羟基-[1,1'-联苯]-3-基)甲基)哌嗪(0.5mmol)(5a)溶解于二氯甲烷中，在冰浴条件下滴加三氟乙酸，待反应完全后，旋掉多余的二氯甲烷和三氟乙酸，向残渣中加入饱和碳酸氢钠溶液，再用乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，旋干过柱(二氯甲烷-甲醇＝20/1)，即可得到米黄色粉末状固体166mg，产率91.3％。
1H NMR(400MHz,CDCl3)δ7.11(dd,J＝6.1,4.0Hz,3H),6.99(d,J＝7.9Hz,1H),6.85(d,J＝1.5Hz,1H),6.06–5.88(m,2H),5.14–5.02(m,4H),3.81(s,2H),3.39(d,J＝6.6Hz,2H),3.34(d,J＝6.7Hz,2H),2.95(s,4H),2.69(s,4H),1.25(s,1H).MS(ES),m/z:365.1[M+H]+.HPLC纯度:98.1％
实施例39 N-(1-((5,5'-二烯丙基-2,2'-二羟基-[1,1'-联苯]-3-基)甲基)哌啶-4-基)丙烯酰胺(9a)
Figure BDA0001615288510000262
将250mg 5,5'-二烯丙基-3-((4-氨基哌啶-1-基)甲基)-[1,1'-联苯]-2,2'-二醇(7b)(0.66mmol)以及275μL三乙胺(1.98mmol)溶解于二氯甲烷中，室温条件下滴加54μL丙烯酰氯(0.66mmol)，点板监测反应，待反应完成后，旋掉多余的二氯甲烷和丙烯酰氯即得黄色粉末状固体87mg，产率30.5％。
1H NMR(400MHz,CDCl3)δ7.52(s,2H),7.14(d,J＝1.7Hz,1H),7.10(dt,J＝4.9,2.6Hz,2H),6.97(d,J＝8.2Hz,1H),6.83(s,1H),6.26(d,J＝16.9Hz,1H),6.10–5.89(m,3H),5.81(d,J＝7.6Hz,1H),5.62(d,J＝10.3Hz,1H),5.15–5.00(m,4H),4.00–3.87(m,1H),3.79(s,2H),3.38(d,J＝6.6Hz,2H),3.33(d,J＝6.7Hz,2H),3.03(s,2H),2.31(t,J＝18.0Hz,2H),2.01(d,J＝13.2Hz,2H),1.57–1.39(m,2H).MS(ES),m/z:433.2[M+H]+.HPLC纯度:98.7％
实施例40 N-(1-((5,5'-二烯丙基-2,2'-二羟基-[1,1'-联苯]-3-基)甲基)哌啶-3-基)丙烯酰胺(9b)
Figure BDA0001615288510000271
将250mg 5,5'-二烯丙基-3-((3-氨基哌啶-1-基)甲基)-[1,1'-联苯]-2,2'-二醇(7a)(0.66mmol)以及275μL三乙胺(1.98mmol)溶解于二氯甲烷中，室温条件下滴加54μL丙烯酰氯(0.66mmol)，点板监测反应，待反应完成后，旋掉多余的二氯甲烷和丙烯酰氯即得黄色粉末状固体82mg，产率28.7％。
1H NMR(400MHz,CDCl3)δ12.80(d,J＝7.7Hz,1H),11.75–11.64(m,3H),11.58(d,J＝1.6Hz,1H),11.58(d,J＝8.4Hz,1H),10.95(dd,J＝17.1,10.1Hz,1H),10.81(dd,J＝17.1,2.2Hz,1H),10.75–10.63(m,2H),10.31(dd,J＝10.0,2.2Hz,1H),9.80(dd,J＝26.1,13.5Hz,4H),8.56(s,1H),8.48(s,2H),8.03(t,J＝5.7Hz,4H),7.65(d,J＝8.1Hz,1H),7.50(d,J＝10.1Hz,1H),6.97–6.78(m,2H),6.59–6.45(m,2H),6.31–6.17(m,1H),6.08–5.98(m,1H).MS(ES),m/z:433.2[M+H]+.HPLC纯度:98.6％
生物学实验：
(1)MTT法检测肿瘤细胞增殖活性
将细胞收集计数后，按3000-4000个/孔铺板于96孔板中，待细胞贴壁后，通过加入不同浓度的化合物处理72h，对照孔加等体积二甲基亚砜。处理时间点到后，加入3-(4,5-二甲基噻唑-2)-2,5-二苯基四氮唑溴盐(MTT)孵育2-4h，待显微镜下观察MTT作用产生的蓝色沉淀明显后，弃含MTT的培养基，按每孔加入150μl二甲基亚砜充分溶解沉淀，570nm波长检测吸光值。按抑制率＝1-对照孔吸光值/实验孔吸光值计算各实验组抑制率。计算出各浓度化合物对细胞增殖活性的抑制率后，将化合物处理浓度换算成对数形式，与其对应的抑制率用Graphpad prism 5.0软件拟合剂量-响应曲线，并拟合IC50值。
本实施例所使用的人肺腺癌细胞(H1975)、人肺腺癌细胞(H441)、人非小细胞肺癌细胞(HCC827)、人肺腺癌细胞(SPC-A1)、人支气管肺泡腺癌细胞(H1650)、人肺癌细胞(A549)等所有细胞均购自美国American Type Culture Collection(ATCC)。
表1化合物5a-5aa，6a-6f，7a-7e，9a-9b在肿瘤细胞上的抑制率
Figure BDA0001615288510000272
Figure BDA0001615288510000281
注：“++”代表在10μM浓度下抑制率≥50％，“+”代表在20μM浓度下抑制率≥50％，“-”代表在20μM浓度下抑制率<50％。
表2厚朴酚系列衍生物的抗肿瘤增殖活性
Figure BDA0001615288510000282
Figure BDA0001615288510000291
从上表1、2可以看出，本发明厚朴酚系列衍生物具有较好的抗肿瘤活性。
(2)细胞凋亡的流式检测
按双染试剂盒说明书指导进行操作。5n、7a和7b按0、5、10、20μM浓度处理A1975细胞48h后，收集培养液，用不含乙二胺四乙酸的胰酶消化收集细胞，连同培养液一起2000rpm离心5min。磷酸缓冲盐溶液洗细胞2次后。加结合缓冲液重悬细胞，每组加3μl AnnexinV液染色，再加3μl PI液染色，避光放置，1h内完成上机检测，结果见图1。5n的细胞凋亡分别为16.49％(0μM)、28.93％(5μM)、31.29％(10μM)和76.20％(20μM)；7a的细胞凋亡分别为16.49％(0μM)、30.06％(5μM)、34.75％(10μM)和97.60％(20μM)；7b的细胞凋亡分别为16.49％(0μM)、32.98％(5μM)、42.9％(10μM)和95.9％(20μM)。这些结果证实化合物5n、7a和7b可诱导H1975细胞以浓度依赖性方式凋亡。
(3)动物皮下瘤模型上的抗瘤效果
4-5周龄的雌性Balb/c小鼠购买自北京华阜康生物科技股份有限公司。实验动物抵达后，饲养于四川大学生物治疗国家重点实验室华西动物房中。实验动物经过一周适应动物房环境后，对实验动物右侧肩部皮下进行肿瘤细胞接种。
接种量为：107个细胞/只。待实体肿瘤长起，定期通过用游标卡尺度量实体肿瘤较长一维，记为长度(Length,L)，和较短一维，记为宽度(Width,W)。按公式TV＝L×W2×0.52计算肿瘤体积TV。当大多数实验动物肿瘤体积达到100mm3左右时，对实验动物进行随机分组，每组6只。按照给药方案进行给药。
分组当天记为day 0，开始给药。从day 0起每两天测量肿瘤体积和实验动物体重一次。全程记录实验动物生存情况并统计动物体重下降参数BWL。
共给药10天，实验终止当天，颈椎脱臼法处死实验动物，剥离实体肿瘤，测量肿瘤重量，统计并按公式TGI＝(溶剂对照组平均肿瘤重量–实验组平均肿瘤重量)/溶剂对照组平均肿瘤重量计算抑瘤率TGI(Tumor Growth inhibition)并以标尺为参照，摆放照相。结果见图2。同时剥离实验动物内脏(心、肝、脾、肺、肾)，与照相后的肿瘤一起，存入4％多聚甲醛中。
表3实验分组表
实验组编号 对应化合物 剂量(mg/kg) 给药途径 给药频率 抑瘤率
1 空白组 生理盐水 p.o. 每天1次
2 和厚朴酚 100 p.o. 每天1次 16.69％
3 5n 100 p.o. 每天1次 4.14％
4 7a 100 p.o. 每天1次 --
5 7b 100 p.o. 每天1次 47.91％
从上表3可以看出，本发明的化合物7a具有一定的毒性导致老鼠死亡，7b能明显抑制体内外肿瘤的增殖，具有作为抗肿瘤小分子药物的活性。

Claims (16)

1.厚朴酚系列衍生物，其结构式如式Ⅰ所示：
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式Ⅰ
其中，R为
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、
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或
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；R7为
Figure 831108DEST_PATH_IMAGE005
、羟基取代的C1～C8烷基或C1～C8醚基；R8为-H，R9、R10独立的为-H、
Figure 16102DEST_PATH_IMAGE006
或-NH2；R9和R10不同时为-H；a=0；R3为C1～C8烷氧基。
2.根据权利要求1所述的厚朴酚系列衍生物，其特征在于：R为
Figure 975968DEST_PATH_IMAGE002
、
Figure 96370DEST_PATH_IMAGE003
或
Figure 220315DEST_PATH_IMAGE004
；R7为
Figure 881104DEST_PATH_IMAGE005
、羟基取代的C1～C6烷基或C1～C6醚基；R8为-H，R9、R10独立的为-H、
Figure 633159DEST_PATH_IMAGE006
或-NH2；R9和R10不同时为-H；a=0；R3为C1～C6烷氧基。
3.根据权利要求2所述的厚朴酚系列衍生物，其特征在于：R为
Figure 314676DEST_PATH_IMAGE002
、
Figure 847289DEST_PATH_IMAGE003
或
Figure 249451DEST_PATH_IMAGE004
；R7为
Figure 918330DEST_PATH_IMAGE005
、羟基取代的C1～C4烷基或C1～C4醚基；R8为-H，R9、R10独立的为-H、
Figure 255901DEST_PATH_IMAGE006
或-NH2；R9和R10不同时为-H；a=0；R3为C1～C4烷氧基。
4.根据权利要求3所述的厚朴酚系列衍生物，其特征在于：R为
Figure 479072DEST_PATH_IMAGE002
、
Figure 481663DEST_PATH_IMAGE003
或
Figure 332945DEST_PATH_IMAGE004
；R7为
Figure 28368DEST_PATH_IMAGE005
、羟基取代的C1～C4烷基或
Figure 207677DEST_PATH_IMAGE007
；R8为-H，R9、R10独立的为-H、
Figure 13959DEST_PATH_IMAGE006
或-NH2；R9和R10不同时为-H；a=0；R3为C1～C4烷氧基。
5.根据权利要求1所述的厚朴酚系列衍生物，其特征在于：当R为
Figure 998708DEST_PATH_IMAGE003
时，结构式如式Ⅱ所示：
Figure 537137DEST_PATH_IMAGE008
式Ⅱ
其中，R7为
Figure 531637DEST_PATH_IMAGE005
、羟基取代的C1～C8烷基或C1～C8醚基。
6.根据权利要求5所述的厚朴酚系列衍生物，其特征在于：R7为
Figure 938348DEST_PATH_IMAGE005
、羟基取代的C1～C6烷基或C1～C6醚基。
7.根据权利要求6所述的厚朴酚系列衍生物，其特征在于：R7为
Figure 701905DEST_PATH_IMAGE005
、羟基取代的C1～C4烷基或C1～C4醚基。
8.根据权利要求7所述的厚朴酚系列衍生物，其特征在于：R7为
Figure 676814DEST_PATH_IMAGE005
、羟基取代的C1～C4烷基或
Figure 971660DEST_PATH_IMAGE007
。
9.根据权利要求1所述的厚朴酚系列衍生物，其特征在于：当R为
Figure 119745DEST_PATH_IMAGE004
时，结构式如式Ⅲ所示：
Figure 675491DEST_PATH_IMAGE009
式Ⅲ
其中，R8为-H，R9、R10独立的为-H、
Figure 883618DEST_PATH_IMAGE006
或-NH2；R9和R10不同时为-H；a=0；R3为C1～C8烷氧基。
10.根据权利要求9所述的厚朴酚系列衍生物，其特征在于：R8为-H，R9、R10独立的为-H、
Figure 915028DEST_PATH_IMAGE006
或-NH2；R9和R10不同时为-H；a=0；R3为C1～C6烷氧基。
11.根据权利要求10所述的厚朴酚系列衍生物，其特征在于：R8为-H，R9、R10独立的为-H、
Figure 538908DEST_PATH_IMAGE006
或-NH2；R9和R10不同时为-H；a=0；R3为C1～C4烷氧基。
12.厚朴酚系列衍生物，其特征在于：其结构式为：
Figure 277057DEST_PATH_IMAGE010
、
Figure 203555DEST_PATH_IMAGE011
、
Figure 394365DEST_PATH_IMAGE012
、
Figure 821936DEST_PATH_IMAGE013
、
Figure 742487DEST_PATH_IMAGE014
、
Figure 292417DEST_PATH_IMAGE015
、
Figure 908206DEST_PATH_IMAGE016
或
Figure 936205DEST_PATH_IMAGE017
。
13.权利要求1～12任一项所述厚朴酚系列衍生物药学上可接受的盐或水合物。
14.药物组合物，由权利要求1～12任一项所述厚朴酚系列衍生物或权利要求13所述的盐或水合物添加药学上可接受的辅助性成分制备而成。
15.权利要求1～12任一项所述厚朴酚系列衍生物、权利要求13所述的盐或水合物或权利要求14所述的药物组合物在制备抗肿瘤药物中的用途。
16.权利要求1～12任一项所述厚朴酚系列衍生物、权利要求13所述的盐或水合物或权利要求14所述的药物组合物在制备口服或静脉注射制剂中的用途。
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