CN105503709B - 3,5-双(芳基亚甲基)-1-取代-4-哌啶酮系列化合物及其在制备抗食管癌药物的应用 - Google Patents

3,5-双(芳基亚甲基)-1-取代-4-哌啶酮系列化合物及其在制备抗食管癌药物的应用 Download PDF

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CN105503709B
CN105503709B CN201510909949.8A CN201510909949A CN105503709B CN 105503709 B CN105503709 B CN 105503709B CN 201510909949 A CN201510909949 A CN 201510909949A CN 105503709 B CN105503709 B CN 105503709B
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宋森川
陈智勇
梁慧
陈江韩
朱国勋
周杰
易洲
潘文龙
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Institute Of Testing And Analysis Guangdong Academy Of Sciences Guangzhou Analysis And Testing Center China
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
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Abstract

本发明公开了式I所示的3,5‑双(芳基亚甲基)‑1‑取代‑4‑哌啶酮系列化合物：其中，R选自C1‑C10烷基、C1‑C10烷氧基、C1‑C10酯、C1‑C10酯对应的酰胺；R1、R2和R3分别选自氟、氯、溴、烷基、烷氧基。本发明所涉及的3,5‑双(芳基亚甲基)‑1‑取代‑4‑哌啶酮系列化合物制备简单，显示出优良的抗食管癌活性，符合新药研发的卫生标准要求。

Description

3,5-双(芳基亚甲基)-1-取代-4-哌啶酮系列化合物及其在制 备抗食管癌药物的应用
技术领域：
本发明涉及具有抗癌活性的化合物及其应用领域，具体涉及一种3,5-双(芳基亚甲基)-1-取代-4-哌啶酮系列化合物及其在制备抗食管癌药物的应用。
背景技术：
癌症是人类死亡的主要“杀手”之一，征服癌症是人类的共同愿望。过去30年，中国癌症死亡率增加了80％，每年因此去世的有180万人，占全球癌症死亡人数的1/4，且发病呈年轻化趋势。2010年2月3日世界卫生组织2号警告说，如果人们不认真采取措施预防癌症，到2030年全球每年的癌症死亡人数将可能在现有基础上翻番，达1700万。
癌症的主要治疗手段是手术、放疗和化学药物治疗。随着新型化学抗癌药物的不断面世，其疗效不断提高，抗癌药物在癌症治疗方面占据越来越重要的地位。目前临床应用的抗癌药物毒副作用均较大，再加上精神上的折磨，治疗过程中给癌症患者带来巨大的痛苦。开发高效、低毒的抗癌药物既是征服癌症必不可缺的工作，也是拯救病人、帮助病人家属的人道主义精神体现。
黄素是天然存在的物质，抗癌活性较高、抗癌谱较广，且毒副作用很低。研究结果表明，连续三代喂饲姜黄素，未对大鼠表现出任何致畸性或致癌性；用较大剂量给大鼠连续口服80天，对大鼠的进食量和生长发育均无影响，病理学检查证实体内各器官未见损伤性改变；人每日口服1200mg/kg也是安全的。有不少这方面的研究报道，如Ashok Khar(Immunomodulatory and therapeutic activity of curcumin,InternationalImmunopharmacology,2011,331)；Sahdeo Prasad(Regulation of survival,proliferation,invasion,angiogenesis,and metastasis of tumor cells throughmodulation of inflammatory pathways by nutraceuticals,Cancer MetastasisReview,2010,29:405)；Veerapol Kukongviriyapan(Redox modulation and human bileduct cancer inhibition by curcumin,Biochemical Pharmacology,2010,1658),BharatB.Aggarwal(Bisdemethylcurcumin and structurally related hispolon analogues ofcurcumin exhibit enhanced prooxidant,anti-proliferative and anti-inflammatoryactivities in vitro,Biochemical Pharmacology,2010,1658),Xianzhang Bu(Synthesis and identification of new 4-arylidene curcumin analogues aspotential anticancer agents targeting nuclear factor-KB signaling pathway,J.Med.Chem.2010,53,8260),Shijun Zhang(“Clicked”bivalent ligands containingcurcumin and cholesterol as multifunctional Aβ-oligomeriza-tion inhibitors:design,synthesis,and biological characterization,J.Med.Chem.2010,53,6198)；宋森川等，(新型3,5-双(芳香基次甲基)-1-甲基哌啶-4-酮类化合物，其合成方法及其作为抗癌药物的用途，申请号：201410128589.3)。
发明内容：
本发明的目的是提供一种3,5-双(芳基亚甲基)-1-取代-4-哌啶酮系列化合物，及其在制备抗食管癌药物中的应用。
本发明是通过以下技术方案予以实现的：
式I所示的3,5-双(芳基亚甲基)-1-取代-4-哌啶酮系列化合物：
其中，R选自C1-C10烷基、C1-C10烷氧基、C1-C10酯、C1-C10酯对应的酰胺；R1、R2和R3分别选自氟、氯、溴、烷基、烷氧基。
式I所涉及的3,5-双(芳基亚甲基)-1-取代-4-哌啶酮系列化合物的制备按照文献报道方法完成[Martina Bazzaro,Ravi K.Anchoori,Mohana Krishna R.Mudiam,OlgaIssaenko,Srinivas Kumar,Balasubramanyam Karanam,Zhenhua Lin,Rachel IsakssonVogel,Riccardo Gavioli,Federica Destro,Valeria Ferretti,Richard B.S.Roden,andSaeed R.Khan.α,β-Unsaturated carbonyl system of chalcone-based derivatives isresponsible for broad Inhibition of proteasomal activity and preferentialkilling of human papilloma Virus(HPV)positive cervical cancer cells,J.Med.Chem.2011,54,449–456；Babasaheb Yadav,Sebastien Taurin,RhondaJ.Rosengren,Marc Schumacher,Marc Diederich,Tiffany J.Somers-Edgar,LesleyLarsen.Synthesis and cytotoxic potential of heterocyclic cyclohexanoneanalogues of curcumin.Bioorg.Med.Chem.2010,18.6701–6707]。
所述式I所示的3,5-双(芳基亚甲基)-1-取代-4-哌啶酮系列化合物的部分典型化合物如表1所示：
表1
式I所示的3,5-双(芳基亚甲基)-1-取代-4-哌啶酮系列化合物作为制备抗食管癌药物的应用。
本发明还保护3,5-双(芳基亚甲基)-1-取代-4-哌啶酮系列化合物及其药学上可接受的盐组合成的药学上可接受的药物组合物或制剂在制备抗食管癌药物的应用。一种药物组合物，包含至少一种式I所示的3,5-双(芳基亚甲基)-1-取代-4-哌啶酮系列化合物作为活性成分，单独或结合一种或几种药学上可接受的、惰性的、无毒的赋形剂或载体。
本发明所涉及的3,5-双(芳基亚甲基)-1-取代-4-哌啶酮系列化合物，制备简单，显示出优良的抗食管癌活性，符合新药研发的卫生标准要求。
具体实施方式：
以下是对本发明的进一步说明，而不是对本发明的限制。
本发明对3,5-双(芳基亚甲基)-1-取代-4-哌啶酮系列化合物进行抗食管癌活性试验。
式I所示的3,5-双(芳基亚甲基)-1-取代-4-哌啶酮系列化合物的部分典型化合物如表2所示：
表2
本发明所述3,5-双(芳基亚甲基)-1-取代-4-哌啶酮系列化合物的可实现结构不限于表2所示的结构，可以是与该结构具有抗食管癌癌活性的异构体、取代物或衍生物。
实施例1 3,5-双(芳基亚甲基)-1-取代-4-哌啶酮系列化合物1-18的制备
3,5-双(芳基亚甲基)-1-取代-4-哌啶酮系列化合物1-18的制备按照文献报道方法完成[Martina Bazzaro,Ravi K.Anchoori,Mohana Krishna R.Mudiam,Olga Issaenko,Srinivas Kumar,Balasubramanyam Karanam,Zhenhua Lin,Rachel Isaksson Vogel,Riccardo Gavioli,Federica Destro,Valeria Ferretti,Richard B.S.Roden,and SaeedR.Khan.α,β-Unsaturated carbonyl system of chalcone-based derivatives isresponsible for broad Inhibition of proteasomal activity and preferentialkilling of human papilloma Virus(HPV)positive cervical cancer cells,J.Med.Chem.2011,54,449–456；Babasaheb Yadav,Sebastien Taurin,RhondaJ.Rosengren,Marc Schumacher,Marc Diederich,Tiffany J.Somers-Edgar,LesleyLarsen.Synthesis and cytotoxic potential of heterocyclic cyclohexanoneanalogues of curcumin.Bioorg.Med.Chem.2010,18.6701–6707]。
实施例2 3,5-双(芳基亚甲基)-1-取代-4-哌啶酮系列化合物1-18抗食管癌活性试验
3,5-双(芳基亚甲基)-1-取代-4-哌啶酮系列化合物1-18抗食管癌活性试验操作过程
细胞培养：肿瘤细胞株按常规方法培养传代，均培养于RPMI 1640，补充10％热灭活胎牛血清，2μmol/L谷氨酰胺，105U/L青霉素，100mg/L·860链霉素，37℃、5％CO2培养箱中饱和湿度下培养，取对数生长期细胞用于实验。
使用的肿瘤细胞株有：人食管鳞癌细胞SLMT-1，HKESC-1，HKESC-2和Esophageal由香港大学生命科学学院提供。
MTT法比色实验：取对数生长期细胞，调整细胞浓度为1×105个/mL接种于96孔培养板，100μL/孔，培养24h后，加入不同浓度的样品；同时设阴性对照组、阳性对照组(姜黄素)，空白对照组(即只加培养液，不加细胞以调零)，每组均设4复孔。共同培养48h后，每孔加入20μL MTT(5mg/mL PBS液，pH 7.2)，再培养4h，弃上清液，每孔加入150μL DMSO，振荡10min，应用酶标仪于570nm处测吸光度值(A)。
数据处理：把MTT法测得的吸光度值，用SPSS 11.0软件进行统计学分析，计算出样品相对姜黄素为参考的IC50值。3,5-双(芳基亚甲基)-1-取代-4-哌啶酮系列化合物1-18的IC50值见表3-4。其中表3为3,5-双(芳基亚甲基)-1-取代-4-哌啶酮系列化合物1-8抗SLMT-1、HKESC-1、HKESC-2细胞的活性的试验结果对照表；表4为3,5-双(芳基亚甲基)-1-取代-4-哌啶酮系列化合物9-18抗Esophageal细胞的活性实验结果对照表。
表3
由表3得出：化合物1-8对所测试的3种人食管鳞癌细胞SLMT-1、HKESC-1和HKESC-2与姜黄素本身相比，均表现出很高的抗癌活性，尤其是化合物2、6和7，其抗癌活性最高。所以这类化合物作为新型抗人食管癌药物，具有明显的潜在开发价值。
表4
表4的测试结果表明，化合物9-18对所测试的人食管癌细胞，除化合物10和12之外，其余化合物均比姜黄素本身的抗癌活性高，这些化合物作为新型抗人食管癌药物，具有明显的潜在开发价值。
实施例3 3,5-双(芳基亚甲基)-1-取代-4-哌啶酮系列化合物1-18急性毒性试验
按照新药研发药物活性评价标准，采用小鼠进行急性毒性试验。采用注射方式用药，每周2次，在剂量为12.5mg/kg和25mg/kg时，对小鼠的急性毒性进行了试验，3,5-双(芳基亚甲基)-1-取代-4-哌啶酮系列化合物1-18的急性毒性试验结果列于表5，如表5所示。
表5
表5的试验结果表明，在12.5mg/kg和25mg/kg的剂量下没有测试出其毒性。姜黄素和所合成出的3,5-双(芳基亚甲基)-1-取代-4-哌啶酮系列化合物1-18，毒性非常低，上述剂量对小鼠显示不出急毒性。所以该类化合物具有明显优势，即由于该类化合物毒性非常低，可以通过增加服用量来进一步提高药物的抗癌活性。
上列详细说明是针对本发明可行实施例的具体说明，该实施例并非用以限制本发明的专利范围，凡未脱离本发明所为的等效实施或变更，均应包含于本案的专利保护范围中。

Claims (2)

1.3,5-双(芳基亚甲基)-1-取代-4-哌啶酮系列化合物作为制备抗食管癌药物的应用，所述的3,5-双(芳基亚甲基)-1-取代-4-哌啶酮系列化合物如下表所示：
2.权利要求1所述的3,5-双(芳基亚甲基)-1-取代-4-哌啶酮系列化合物及其药学上可接受的盐组合成的药学上可接受的药物组合物或制剂在制备抗食管癌药物的应用。
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102863376A (zh) * 2012-09-27 2013-01-09 上海师范大学 N-取代甲基-3,5-双取代苄叉基-4-哌啶酮及制备和应用
CN103601672A (zh) * 2013-11-04 2014-02-26 广东中烟工业有限责任公司 一种类姜黄素及其制备方法和应用
CN103626692A (zh) * 2013-11-12 2014-03-12 中国人民解放军第二军医大学 3,5-双芳基甲叉基哌啶酮衍生物及其在制备降糖降脂药物中的应用
CN103936667A (zh) * 2014-03-31 2014-07-23 中山大学 新型3,5-双（芳香基次甲基）-1-甲基哌啶-4-酮类化合物，其合成方法及其作为抗癌药物的用途

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102863376A (zh) * 2012-09-27 2013-01-09 上海师范大学 N-取代甲基-3,5-双取代苄叉基-4-哌啶酮及制备和应用
CN103601672A (zh) * 2013-11-04 2014-02-26 广东中烟工业有限责任公司 一种类姜黄素及其制备方法和应用
CN103626692A (zh) * 2013-11-12 2014-03-12 中国人民解放军第二军医大学 3,5-双芳基甲叉基哌啶酮衍生物及其在制备降糖降脂药物中的应用
CN103936667A (zh) * 2014-03-31 2014-07-23 中山大学 新型3,5-双（芳香基次甲基）-1-甲基哌啶-4-酮类化合物，其合成方法及其作为抗癌药物的用途

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Curcumin and synthetic analogs induce reactive oxygen species and decreases specificity protein (Sp) transcription factors by targeting microRNAs;Shruti U Gandhy et al;《BMC Cancer》;20121130;第12卷;564，第4页Figure 1
两个α，β-不饱和酮药物的合成及抗肿瘤活性研究;刘文帅 等;《分析测试学报》;20150825;第34卷(第8期);900-904，第901页图1

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