CN115160257A - 一种姜黄素衍生物的合成制备方法 - Google Patents

一种姜黄素衍生物的合成制备方法 Download PDF

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CN115160257A
CN115160257A CN202111584532.0A CN202111584532A CN115160257A CN 115160257 A CN115160257 A CN 115160257A CN 202111584532 A CN202111584532 A CN 202111584532A CN 115160257 A CN115160257 A CN 115160257A
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徐学军
杨玉坡
段超群
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Henan Radiomedical Science And Technology Co ltd
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Abstract

本发明提供一类姜黄素衍生物的制备方法以及在生物学领域的应用，实验结果显示本发明所提供的姜黄素类化合物与人体内癌症相关的生物靶点(STAT3、NF‑kB和TNF‑Alpha等)密切相关，并对肿瘤相关的细胞信号传导通路(Jak‑STAT3、PI3K‑ALT等)有较强的抑制作用，肿瘤细胞增殖实验(CCK‑8)显示本发明所涉及的化合物能显著抑制非小细胞肺癌PC9细胞株以及耐药株的生长和增殖，进一步深入研究将对此类化合物在肿瘤临床治疗以及其他生物学方面的应用具有重要的意义。

Description

一种姜黄素衍生物的合成制备方法
技术领域
本发明属于肿瘤原药研发技术领域，具体涉及一种姜黄素类化合物及其生物学可接受的盐，其制备方法和应用。
背景技术
如何在药物研发方面做到“双创”(疾病相关的首次用于临床治疗的新靶点和全新化合物)是考验我们中国医药研发实力的试金石。寻求新的靶点和有潜力的药物先导化合物，在特定的肿瘤治疗领域有所突破，是医药研发科研人员的当务之急。STAT3-JAK信号传导通路对肿瘤细胞的生长有正向调控的作用，近十年来，STAT3蛋白作为治疗癌症的生物学靶点备受青睐，截止2017年，美国FDA批准在临床测试的STAT3信号传导通路抑制类抗癌药物先导化合物有30余种(Johnson D E，et al.，Nature Reviews Clinical Oncology，2018，15(4)：234)。基于STAT3信号传导的抗癌靶向药物有靶点新和抗癌谱宽等特点，近期的临床测试结果显示了此类药物在未来肿瘤临床治疗方面具有巨大的开发潜力和广阔的市场空间。本发明正基于此，探索新的能够用于制备基于STAT3 信号传导的抗癌靶向药物的化合物。
发明内容
本发明提供一类姜黄素衍生物的制备方法以及在生物学领域的应用，实验结果显示本发明所提供的姜黄素类化合物与人体内癌症相关的生物靶点(STAT3、NF-kB和TNF-Alpha等) 密切相关，并对肿瘤相关的细胞信号传导通路(Jak-STAT3、PI3K-ALT等)有较强的抑制作用，肿瘤细胞增殖实验(CCK-8)显示本发明所涉及的化合物能显著抑制非小细胞肺癌PC9细胞株以及耐药株的生长和增殖，进一步深入研究将对此类化合物在肿瘤临床治疗以及其他生物学方面的应用具有重要的意义。
本发明采用如下技术方案
一种姜黄素类化合物，其特征在于，结构式如通式I和II所示：
Figure RE-GSB0000199202140000021
其中，
X为-CH2-或-CO-；
p＝0、1、2、3、4、...10；
Y为-CH2-；
m＝1、2、3、4、...10；
L＝C或N；
Z＝C或N；
E＝C或N；
D＝C或N；
A选自：
Figure RE-GSB0000199202140000022
等，其中n＝0，1、2、3、4；
Figure RE-GSB0000199202140000023
其中，
X为-CH2-或-CO-；
p＝0、1、2、3、4、...10；
Y为-CH2-；
m＝1、2、3、4、...10；
Z＝C、O或N；
D＝C、O或N；
E＝C、O或N；
A选自：
Figure RE-GSB0000199202140000031
等，其中n＝0、1、2、3、4；
所述的姜黄素类化合物，其特征在于，具体为如下结构的化合物：
Figure RE-GSB0000199202140000032
所述的姜黄素类化合物与乙酸、二氢乙酸、苯甲酸、柠檬酸、山梨酸、丙酸、草酸、富马酸、马来酸、盐酸、苹果酸、磷酸、亚硫酸、硫酸、香草酸、酒石酸、抗坏血酸、硼酸、乳酸和乙二胺四乙酸中的至少一种形成的生物学可接受的盐。
所述的姜黄素类化合物的制备方法，其特征在于，包括以下步骤：
(1)将摩尔比为1∶1.1的
Figure RE-GSB0000199202140000033
与
Figure RE-GSB0000199202140000034
溶解于有机溶剂中，并加入碳酸钾，TLC检测反应结束后，后处理得到
Figure RE-GSB0000199202140000035
(2)将摩尔比为1∶6的
Figure RE-GSB0000199202140000041
与
Figure RE-GSB0000199202140000042
溶解于有机溶剂中，并加入吡啶，TLC检测反应结束后，后处理得到
Figure RE-GSB0000199202140000043
所述的姜黄素类化合物的制备方法，其特征在于，所述
Figure RE-GSB0000199202140000044
通过以下方法制备得到：将摩尔比为1∶1.1的
Figure RE-GSB0000199202140000045
与
Figure RE-GSB0000199202140000046
溶解于有机溶剂中，并加入碳酸钾，TLC检测反应结束后，后处理得到
Figure RE-GSB0000199202140000047
所述的姜黄素类化合物的制备方法，其特征在于，所述
Figure RE-GSB0000199202140000048
通过以下方法制备得到：将摩尔比为1∶1.5的
Figure RE-GSB0000199202140000051
与
Figure RE-GSB0000199202140000052
溶解于有机溶剂中，并加入醋酸铜，三乙胺， TLC检测反应结束后，后处理得到
Figure RE-GSB0000199202140000053
本发明所用的术语“卤素”是指氟、氯、溴或碘，优选的卤素基团为氟、氯或溴。
根据上述式I姜黄素类化合物的结构差异，本发明同时提供了两种制备方法，如下：
结构式如1a至1f所示的姜黄素类化合物可以由流程1所示路线合成，原料一步两步亲核取代反应即可得到目标化合物。
流程1
Figure RE-GSB0000199202140000054
1a：X＝-CH2-，Y＝-(CH2)2-，
Figure RE-GSB0000199202140000055
L＝C，E＝C，Z＝C，D＝C
1b：X＝-CH2-，Y＝-(CH2)2-，
Figure RE-GSB0000199202140000056
L＝C，E＝C，Z＝C，D＝C
1c：X＝-CH2-，Y＝-(CH2)2-，
Figure RE-GSB0000199202140000057
L＝C，E＝C，Z＝C，D＝C
1d：X＝-CH2-，Y＝-(CH2)2-，
Figure RE-GSB0000199202140000058
L＝N，E＝C，Z＝C，D＝C
1e：X＝-CH2-，Y＝-CH2-，
Figure RE-GSB0000199202140000059
L＝N，E＝C，Z＝N，D＝C
1f：X＝-CH2-，Y＝-(CH2)2-，
Figure RE-GSB00001992021400000510
L＝N，E＝N，Z＝C，D＝C
对于X，Y，A，L，E，Z和D的具体基团包括上述1a，1b，1c，1d，1e，1f对应的基团但不限于这些基团/化合物，还可以是其他的本领域技术人员容易理解想到采用该流程1进行合成的化合物。对于权利要求书中的限定的合成工艺/流程的情况应作同样的理解，不应被视为限定，更不能限定为具体的化合物。
结构式如1g至1i所示的姜黄素类化合物可以由流程2所示路线合成，原料一步两步亲核取代反应即可得到目标化合物。
流程2
Figure RE-GSB0000199202140000061
1g：X＝-CH2-，Y＝-(CH2)2-，
Figure RE-GSB0000199202140000062
Z＝O，D＝C，E＝C
1h：X＝-CH2-，Y＝-(CH2)2-，
Figure RE-GSB0000199202140000063
Z＝O，D＝N，E＝C
1i：X＝-CH2-，Y＝-(CH2)2-，
Figure RE-GSB0000199202140000064
Z＝N，D＝C，E＝C
对于X，Y，A，E，Z和D的具体基团包括上述1g，1h，1i对应的基团但不限于这些基团/化合物，还可以是其他的本领域技术人员容易理解想到采用该流程2进行合成的化合物。包对于权利要求书中的限定的合成工艺/流程的情况应作同样的理解，不应被视为限定，更不能限定为具体的化合物。
结构式如2a至2f所示的姜黄素类化合物可以由流程3所示路线合成，原料经过一步酯化反应即可得到目标化合物。
流程3
Figure RE-GSB0000199202140000065
2a：X＝-CO-，Y＝-(CH2)2-，
Figure RE-GSB0000199202140000066
L＝C，E＝C，Z＝C，D＝C
2b：X＝-CO-，Y＝-(CH2)2-，
Figure RE-GSB0000199202140000067
L＝C，E＝C，Z＝C，D＝C
2c：X＝-CO-，Y＝-(CH2)2-，
Figure RE-GSB0000199202140000071
L＝C，E＝C，Z＝C，D＝C
2d：X＝-CO-，Y＝-(CH2)2-，
Figure RE-GSB0000199202140000072
L＝N，E＝C，Z＝C，D＝C
2e：X＝-CO-，Y＝-CH2-，
Figure RE-GSB0000199202140000073
L＝N，E＝C，Z＝N，D＝C
2f：X＝-CO-，Y＝-(CH2)2-，
Figure RE-GSB0000199202140000074
L＝N，E＝N，Z＝C，D＝C
对于X，Y，A，L，E，Z和D的具体基团包括上述2a～2f对应的基团但不限于这些基团/化合物，还可以是其他的本领域技术人员容易理解想到采用该流程3进行合成的化合物。包对于权利要求书中的限定的合成工艺/流程的情况应作同样的理解，不应被视为限定，更不能限定为具体的化合物。
结构式如3a至3c所示的姜黄素类化合物可以由流程5所示路线合成，原料经过一步酯化反应即可得到目标化合物。
流程4
Figure RE-GSB0000199202140000075
3a：Y＝-(CH2)2-，
Figure RE-GSB0000199202140000076
3b：Y＝-(CH2)2-，
Figure RE-GSB0000199202140000077
3c：Y＝-(CH2)2-，
Figure RE-GSB0000199202140000078
对于Y，m和A的具体基团包括上述3a～3c对应的基团但不限于这些基团/化合物，还可以是其他的本领域技术人员容易理解想到采用该流程4进行合成的化合物。包对于权利要求书中的限定的合成工艺/流程的情况应作同样的理解，不应被视为限定，更不能限定为具体的化合物。
本发明的目的是寻找具有高STAT3抑制作用且具有较低毒性的新化合物。
本发明还涉及所述姜黄素类化合物、其药学上可接受的盐、所述衍生物的溶剂化合物、或者所述盐的溶剂化合物在制备用于治疗或辅助治疗和/或预防哺乳动物的肿瘤的药物中的用途，主要是由STAT3介导的肿瘤或由STAT3驱动的肿瘤细胞增殖和迁移药物中的用途，也可以是与STAT3细胞信号传导相关疾病的药物，具体地，所述哺乳动物为人类。
本发明一个方面涉及上述的具有式I结构的新型姜黄素类化合物、其药学上可接受的盐、所述衍生物的溶剂合物、或者所述盐的溶剂合物制备用于治疗和/或预防哺乳动物中与STAT3 细胞信号传导相关疾病的药物中的用途。具体地，所述哺乳动物为人类。
根据本发明，完全可以预期本发明化合物可用于治疗STAT3信号传导异常活跃或蛋白高表达而引起的肿瘤。STAT3相关的肿瘤包括肺癌、乳腺癌、结直肠癌、白血病、头颈癌以及前列腺癌等其他所有癌症。
具体实施方式
为了使本发明的技术目的、技术方案和有益效果更加清楚，下面结合附图和具体实施例对本发明的技术方案作出进一步的说明。
在本发明合成式I和式II化合物的方法中，反应所用的各种原材料是本领域技术人员根据已有知识可以制备得到的，或者是可以通过文献公知的方法制得的，或者是可以通过商业购得的。以上反应方案中所用的中间体、原材料、试剂、反应条件等均可以根据本领域技术人员已有知识做适当改变的。
在本发明中，除非另外说明，其中：(i)温度以摄氏度(℃)表示，操作在室温环境下进行；更具体地，所述室温是指20-30℃；(ii)有机溶剂用常用干燥方法干燥，溶剂的蒸发使用旋转蒸发仪减压蒸发，浴温不高于50℃；展开剂和洗脱剂均为体积比；(iii)反应过程用薄层色谱(TLC)跟踪；(iv)终产物具有满意的质子核磁共振(1H-NMR)。
实施例1：化合物1a-1f的合成
参照流程1
Figure RE-GSB0000199202140000081
1a：X＝-CH2-，Y＝-(CH2)2-，
Figure RE-GSB0000199202140000082
L＝C，E＝C，Z＝C，D＝C
1b：X＝-CH2-，Y＝-(CH2)2-，
Figure RE-GSB0000199202140000083
L＝C，E＝C，Z＝C，D＝C
1c：X＝-CH2-，Y＝-(CH2)2-，
Figure RE-GSB0000199202140000091
L＝C，E＝C，Z＝C，D＝C
1d：X＝-CH2-，Y＝-(CH2)2-，
Figure RE-GSB0000199202140000092
L＝N，E＝C，Z＝C，D＝C
1e：X＝-CH2-，Y＝-CH2-，
Figure RE-GSB0000199202140000093
L＝N，E＝C，Z＝N，D＝C
1f：X＝-CH2-，Y＝-(CH2)2-，
Figure RE-GSB0000199202140000094
L＝N，E＝N，Z＝C，D＝C
具体合成方法，以化合物1a为例，结构式如下：
Figure RE-GSB0000199202140000095
化合物1a名称为(1E，6E)-1-(4-羟基-3-甲氧基苯基)-7-(3-甲氧基-4-(4-(2-(哌啶-1-基)乙氧基) 苄氧基)苯基)-1，6-庚二烯-3，5-二酮，其合成路线如下所示：
Figure RE-GSB0000199202140000096
步骤1.(1E，6E)-1-(4-羟基-3-甲氧基苯基)-7-(3-甲氧基-4-(4-(2-(哌啶-1-基)乙氧基)苄氧基) 苯基)-1，6-庚二烯-3，5-二酮(1a)
将姜黄素(1)(300mg，0.814mmol，1.0eq)，1-(2-(4-(氯甲基)苯氧基)乙基)哌啶(227mg， 0.896mmol，1.1eq)和碳酸钾(225mg，1.63mmol，2.0eq)溶于N，N-二甲基甲酰胺(10mL)， 25℃反应36小时。TLC(二氯甲烷∶甲醇＝10∶1，Rf/化合物1＝0.85，Rf/化合物1a＝0.30)显示原料反应完毕。将反应液用50毫升乙酸乙酯稀释，并依次用水(50mL)，食盐水(50mL*3) 洗涤，有机相用无水硫酸钠干燥，然后旋干得到粗品。粗产物用柱层析纯化(二氯甲烷∶甲醇，＝80∶1～20∶1)得到52mg(1E，6E)-1-(4-羟基-3-甲氧基苯基)-7-(3-甲氧基-4-(4-(2-(哌啶-1-基)乙氧基)苄氧基)苯基)-1，6-庚二烯-3，5-二酮(1a)，棕红色固体，产率10.9％。
1H NMR(DMSO-d6，400MHz)δ：9.68(brs，1H)，7.59，7.55(dd，J＝4.0Hz，J＝4.0Hz，2H)， 7.39-7.33(m，4H)，7.26-7.24(m，1H)，6.97(d，J＝12Hz，2H)，6.85-6.75(m，3H)，5.76(s，1H)， 5.07(s，2H)，4.13(m，2H)，3.84(s，3H)，3.83(s，3H)，3.40(m，4H)，2.70(m，2H)，1.55(m，4H)，1.40 (m，2H)
化合物1b～1f的合成方法参照实施例1，区别之处在于：化合物1b～1f的合成过程中，在步骤1中，分别用1-(2-(4-(氯甲基)苯氧基)乙基)吗啡啉，2-(4-(氯甲基)苯氧基)-N，N-二乙基胺， 1-(2-((6-(氯甲基)吡啶-3-基)氧代)乙基)环己亚胺，2-(氯甲基)-5-(1-四氢吡咯甲氧基)嘧啶， 2-(6-(氯甲基)哒嗪-3-氧代)-N，N-二甲基乙基胺代替1-(2-(4-(氯甲基)苯氧基)乙基)哌啶。此处对于其详细的制备过程不再赘述。
实施例2：化合物1g-1i的合成
参照流程2
Figure RE-GSB0000199202140000101
1g：X＝-CH2-，Y＝-(CH2)2-，
Figure RE-GSB0000199202140000102
Z＝O，D＝C，E＝C
1h：X＝-CH2-，Y＝-(CH2)2-，
Figure RE-GSB0000199202140000103
Z＝O，D＝N，E＝C
1i：X＝-CH2-，Y＝-(CH2)2-，
Figure RE-GSB0000199202140000104
Z＝N，D＝C，E＝C
具体合成方法，以化合物1g为例，结构式如下：
Figure RE-GSB0000199202140000105
化合物1g名称为(1E，6E)-1-(4-(5-(2--环己亚胺基)呋喃)-3-甲氧基苯基)-7-(4-羟基-3-甲氧基苯基)-1，6-庚二烯-3，5-二酮，其合成路线如下所示：
Figure RE-GSB0000199202140000106
步骤1.(1E，6E)-1-(4-(5-(2--环己亚胺基)呋喃)-3-甲氧基苯基)-7-(4-羟基-3-甲氧基苯基) -1，6-庚二烯-3，5-二酮(1g)
将姜黄素(1)(300mg，0.814mmol，1.0eq)，1-(2-(5-(氯甲基)呋喃氧基)乙基)环己亚胺(231 mg，0.896mmol，1.1eq)和碳酸钾(225mg，1.63mmol，2.0eq)溶于N，N-二甲基甲酰胺(10 mL)，25℃反应36小时。TLC(二氯甲烷∶甲醇＝10∶1，Rf/化合物1＝0.85，Rf/化合物1a＝0.30) 显示原料反应完毕。将反应液用50毫升乙酸乙酯稀释，并依次用水(50mL)，食盐水(50mL*3) 洗涤，有机相用无水硫酸钠干燥，然后旋干得到粗品。粗产物用柱层析纯化(二氯甲烷∶甲醇＝80∶1～20∶1)得到60mg(1E，6E)-1-(4-(5-(2--环己亚胺基)呋喃)-3-甲氧基苯基)-7-(4-羟基-3-甲氧基苯基)-1，6-庚二烯-3，5-二酮(1g)，棕红色固体，产率12.5％。
1H NMR(DMSO-d6，400MHz)δ：9.68(brs，1H)，7.59，7.55(dd，J＝4.0Hz，J＝4.0Hz，2H)， 7.39-7.33(m，3H)，6.97(d，J＝12Hz，2H)，6.85-6.75(m，3H)，5.76(s，1H)，5.07(s，2H)，4.13(m， 2H)，3.84(s，3H)，3.83(s，3H)，3.40(m，4H)，2.70(m，2H)，1.55(m，4H)，1.40(m，4H)
化合物1h～1i的合成方法参照实施例2，区别之处在于：化合物1h～1i的合成过程中，在步骤1中，分别用2-(氯甲基)-5-(2-哌啶乙氧基)噁唑，1-(2-(5-(氯甲基)吡咯氧基)乙基)哌啶。此处对于其详细的制备过程不再赘述。
实施例3：化合物2a-2f的合成
参照流程3
Figure RE-GSB0000199202140000111
2a：X＝-CO-，Y＝-(CH2)2-，
Figure RE-GSB0000199202140000112
L＝C，E＝C，Z＝C，D＝C
2b：X＝-CO-，Y＝-(CH2)2-，
Figure RE-GSB0000199202140000113
L＝C，E＝C，Z＝C，D＝C
2c：X＝-CO-，Y＝-(CH2)2-，
Figure RE-GSB0000199202140000114
L＝C，E＝C，Z＝C，D＝C
2d：X＝-CO-，Y＝-(CH2)2-，
Figure RE-GSB0000199202140000115
L＝N，E＝C，Z＝C，D＝C
2e：X＝-CO-，Y＝-CH2-，
Figure RE-GSB0000199202140000116
L＝N，E＝C，Z＝N，D＝C
2f：X＝-CO-，Y＝-(CH2)2-，
Figure RE-GSB0000199202140000121
L＝N，E＝N，Z＝C，D＝C
具体合成方法，以化合物2a为例，结构式如下：
Figure RE-GSB0000199202140000122
化合物2a的名称为4-((1E，6E)-7-(4-羟基-3-甲氧基苯基)-3，5-二氧代-1，6-庚二烯-1-基)-2-甲氧基苯基-4-(2-(哌啶-1-基)乙氧基)苯酯，其合成路线如下：
Figure RE-GSB0000199202140000123
步骤1.4-((1E，6E)-7-(4-羟基-3-甲氧基苯基)-3，5-二氧代-1，6-庚二烯-1-基)-2-甲氧基苯基 -4-(2-(哌啶-1-基)乙氧基)苯酯(2a)
将姜黄素(1)(300mg，0.814mmol，1.0eq)，4-(2-哌啶乙氧基)苯甲酰氯(4)(1.31g，4.89mmol， 6.0eq)和吡啶(386mg，4.89mmol，6.0eq)溶于50mL无水二氯甲烷，0℃反应5小时。TLC(二氯甲烷∶甲醇＝10∶1，Rf/化合物3＝0.85，Rf/化合物2a＝0.30)显示原料反应完毕，并有新点产生。将反应液缓慢倒入100mL水中，用二氯甲烷萃取(100mL*3)，合并有机相，用无水硫酸钠干燥，然后减压浓缩旋干得到粗品。粗产品用柱层析纯化(二氯甲烷∶甲醇＝80∶1～20∶1) 得到48mg 4-((1E，6E)-7-(4-羟基-3-甲氧基苯基)-3，5-二氧代-1，6-庚二烯-1-基)-2-甲氧基苯基 -4-(2-(哌啶-1-基)乙氧基)苯酯(2a)，黄色固体，产率10.1％。
1H NMR(DMSO-d6，400MHz)δ：9.90(brs，1H)，9.72(brs，1H)，8.11(d，J＝8.0Hz，2H)，7.62-7.56(m，3H)，7.35-7.18(m，5H)，7.01(d，J＝12Hz，1H)，6.85-6.82(m，2H)，6.15(s，1H)，4.49 (m，2H)，4.02(s，3H)，4.01(s，3H)，3.51(m，4H)，3.01(m，2H)，1.96-1.91(m，4H)，1.75(m，2H)
化合物2b～2f的合成方法参照实施例2，区别之处在于：化合物2b～2f的合成过程中，在步骤1中，分别用4-(2-吗啉乙氧基)苯甲酰氯，4-(2-二乙胺基乙氧基)苯甲酰氯，5-(2-(环己亚胺基)乙氧基)吡啶甲酰氯，5-(1-四氢吡咯甲氧基)嘧啶-2-甲酰氯，6-(2-(二甲胺基)乙氧基)哒嗪 -3-甲酰氯代替4-(2-哌啶乙氧基)苯甲酰氯。此处对于其详细的制备过程不再赘述。
实施例4：化合物3a-3c的合成
参照流程4
Figure RE-GSB0000199202140000131
3a：Y＝-(CH2)2-，
Figure RE-GSB0000199202140000132
3b：Y＝-(CH2)2-，
Figure RE-GSB0000199202140000133
3c：Y＝-(CH2)2-，
Figure RE-GSB0000199202140000134
具体合成方法，以化合物3a为例，结构式如下：
Figure RE-GSB0000199202140000135
化合物3a名称为(1E，6E)-1-(4-(5-(2--环己亚胺基)呋喃)-3-甲氧基苯基)-7-(4-羟基-3-甲氧基苯基)-1，6-庚二烯-3，5-二酮，其合成路线如下所示：
Figure RE-GSB0000199202140000136
步骤1.(1E，6E)-1-(4-羟基-3-甲氧基苯基)-7-(3-甲氧基-4-(4-(2-哌啶乙氧基)苯氧基)苯基)-1，6-庚二烯-3，5-二酮(3a)
将姜黄素(1)(300mg，0.814mmol，1.0eq)，4-(2-哌啶乙氧基)苯硼酸(304mg，1.22mmol， 1.5eq)，醋酸铜(148mg，0.814mmol，1.0eq)和三乙胺(412mg，4.07mmol，5.0eq)溶于二氯甲烷(10mL)，25℃反应18小时。TLC(二氯甲烷∶甲醇＝10∶1，Rf/化合物1＝0.85，Rf/化合物1a ＝0.30)显示原料反应完毕。将反应液旋干得到粗品。粗产物用柱层析纯化(二氯甲烷∶甲醇＝ 80∶1～20∶1)得到55mg(1E，6E)-1-(4-羟基-3-甲氧基苯基)-7-(3-甲氧基-4-(4-(2-哌啶乙氧基)苯氧基)苯基)-1，6-庚二烯-3，5-二酮(3a)，棕红色固体，产率11.8％。
1H NMR(DMSO-d6，400MHz)δ：9.68(brs，1H)，7.59，7.55(dd，J＝4.0Hz，J＝4.0Hz，2H)，7.39-7.33(m，4H)，7.26-7.24(m，1H)，6.97(d，J＝12Hz，2H)，6.85-6.75(m，3H)，5.76(s，1H)，4.13 (m，2H)，3.84(s，3H)，3.83(s，3H)，3.40(m，4H)，2.70(m，2H)，1.55(m，4H)，1.40(m，2H)
化合物4b～4c的合成方法参照实施例5，区别之处在于：化合物3b～3c的合成过程中，在步骤1中，分别用4-(2-吗啡啉乙氧基)苯硼酸，4-(2-环己亚胺乙氧基)苯硼酸。此处对于其详细的制备过程不再赘述。
附图说明：
图1是结构通式，图2是化合物1a的核磁，图3是化合物2a的核磁。

Claims (10)

1.一种姜黄素类化合物，其特征在于，结构式如通式I所示：
Figure FSA0000261624870000011
其中，
X为-CH2-或-CO-；
p＝0、1、2、3、4、...10；
Y为-CH2-；
m＝1、2、3、4、...10；
L＝C或N；
Z＝C或N；
E＝C或N；
D＝C或N；
A选自：
Figure FSA0000261624870000012
等，其中n＝0，1、2、3、4；
Figure FSA0000261624870000013
其中，
X为-CH2-或-CO-；
p＝0、1、2、3、4、...10；
Y为-CH2-；
m＝1、2、3、4、...10；
Z＝C、O或N；
D＝C、O或N；
E＝C、O或N；
A选自：
Figure FSA0000261624870000021
等，其中n＝0、1、2、3、4。
2.根据权利要求1所述的姜黄素类化合物，其特征在于，具体为如下结构的化合物：
Figure FSA0000261624870000022
3.权利要求1或2所述的姜黄素类化合物与乙酸、二氢乙酸、苯甲酸、柠檬酸、山梨酸、丙酸、草酸、富马酸、马来酸、盐酸、苹果酸、磷酸、亚硫酸、硫酸、香草酸、酒石酸、抗坏血酸、硼酸、乳酸和乙二胺四乙酸中的至少一种形成的生物学可接受的盐。
4.权利要求1或2所述的姜黄素类化合物的制备方法，其特征在于，包括以下步骤：
(1)将摩尔比为1∶1.1的
Figure FSA0000261624870000023
与
Figure FSA0000261624870000024
溶解于有机溶剂中，并加入碳酸钾，TLC检测反应结束后，后处理得到
Figure FSA0000261624870000025
(2)将摩尔比为1∶6的
Figure FSA0000261624870000031
与
Figure FSA0000261624870000032
溶解于有机溶剂中，并加入吡啶，TLC检测反应结束后，后处理得到
Figure FSA0000261624870000033
5.根据权利要求4所述的姜黄素类化合物的制备方法，其特征在于，所述
Figure FSA0000261624870000034
通过以下方法制备得到：将摩尔比为1∶1.1的
Figure FSA0000261624870000035
与
Figure FSA0000261624870000036
溶解于有机溶剂中，并加入碳酸钾，TLC检测反应结束后，后处理得到
Figure FSA0000261624870000037
6.根据权利要求4所述的姜黄素类化合物的制备方法，其特征在于，所述
Figure FSA0000261624870000038
通过以下方法制备得到：将摩尔比为1∶1.5的
Figure FSA0000261624870000041
与
Figure FSA0000261624870000042
溶解于有机溶剂中，并加入醋酸铜，三乙胺，TLC检测反应结束后，后处理得到
Figure FSA0000261624870000043
7.权利要求3所述的姜黄素类化合物和生物学可接受的盐，其特征在于，通过以下方法制备：将所述姜黄素类化合物溶于4M的HCl/MeOH溶液中，室温下反应，TLC检测反应结束后，后处理即得。
8.权利要求1至3任一项所述的姜黄素类化合物以及生物学可接受的盐作为STAT3抑制剂在物理、化学、生物学和医学等方面的用途。
9.权利要求1至3任一项所述的姜黄素类化合物及其生物学可接受的盐在制备用于治疗与STAT3细胞信号传导相关疾病如肺癌、乳腺癌、结直肠癌、白血病、头颈癌以及前列腺癌等的药物中的用途。
10.疾病的药物中的用途。
CN202111584532.0A 2021-12-17 2021-12-17 一种姜黄素衍生物的合成制备方法 Pending CN115160257A (zh)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103848747A (zh) * 2012-11-30 2014-06-11 沈阳药科大学 姜黄素类似物、其药用盐及其制备和应用
CN111253339A (zh) * 2019-12-16 2020-06-09 河南省锐达医药科技有限公司 一类新型姜黄素衍生物的合成制备方法以及在癌症治疗的应用
CN111349057A (zh) * 2020-02-27 2020-06-30 河南省锐达医药科技有限公司 一类新型姜黄素衍生物的合成制备方法以及在肿瘤治疗的应用

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103848747A (zh) * 2012-11-30 2014-06-11 沈阳药科大学 姜黄素类似物、其药用盐及其制备和应用
CN111253339A (zh) * 2019-12-16 2020-06-09 河南省锐达医药科技有限公司 一类新型姜黄素衍生物的合成制备方法以及在癌症治疗的应用
CN111349057A (zh) * 2020-02-27 2020-06-30 河南省锐达医药科技有限公司 一类新型姜黄素衍生物的合成制备方法以及在肿瘤治疗的应用

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Application publication date: 20221011