CN116239578A - 哌嗪二酮环类化合物及其合成方法和在制备抗肿瘤药物中的应用 - Google Patents
哌嗪二酮环类化合物及其合成方法和在制备抗肿瘤药物中的应用 Download PDFInfo
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- CN116239578A CN116239578A CN202211570567.3A CN202211570567A CN116239578A CN 116239578 A CN116239578 A CN 116239578A CN 202211570567 A CN202211570567 A CN 202211570567A CN 116239578 A CN116239578 A CN 116239578A
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- Prior art keywords
- compound
- piperazine
- methylene
- dione
- mmol
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- -1 Piperazine dione ring compound Chemical class 0.000 title claims abstract description 75
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 239000002246 antineoplastic agent Substances 0.000 title claims abstract description 10
- 229940041181 antineoplastic drug Drugs 0.000 title claims abstract description 9
- 238000001308 synthesis method Methods 0.000 title abstract description 7
- 125000003172 aldehyde group Chemical group 0.000 claims abstract description 16
- OCPZVUYZNSCXFZ-UHFFFAOYSA-N 1-acetylpiperazine-2,3-dione Chemical class CC(=O)N1CCNC(=O)C1=O OCPZVUYZNSCXFZ-UHFFFAOYSA-N 0.000 claims abstract description 7
- 206010009944 Colon cancer Diseases 0.000 claims abstract description 6
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims abstract description 6
- 208000029742 colonic neoplasm Diseases 0.000 claims abstract description 6
- 201000005202 lung cancer Diseases 0.000 claims abstract description 6
- 208000020816 lung neoplasm Diseases 0.000 claims abstract description 6
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims abstract description 5
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims abstract description 5
- 201000002528 pancreatic cancer Diseases 0.000 claims abstract description 5
- 208000008443 pancreatic carcinoma Diseases 0.000 claims abstract description 5
- SBNOTUDDIXOFSN-UHFFFAOYSA-N 1h-indole-2-carbaldehyde Chemical compound C1=CC=C2NC(C=O)=CC2=C1 SBNOTUDDIXOFSN-UHFFFAOYSA-N 0.000 claims abstract description 4
- 150000001413 amino acids Chemical class 0.000 claims abstract description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 47
- 238000003786 synthesis reaction Methods 0.000 claims description 47
- 150000001875 compounds Chemical class 0.000 claims description 46
- JMHLCUCEUQCHLL-YHYXMXQVSA-N (3z)-1-acetyl-3-[(5-tert-butyl-1h-imidazol-4-yl)methylidene]piperazine-2,5-dione Chemical group O=C1N(C(=O)C)CC(=O)N\C1=C/C1=C(C(C)(C)C)NC=N1 JMHLCUCEUQCHLL-YHYXMXQVSA-N 0.000 claims description 27
- 238000000034 method Methods 0.000 claims description 24
- 125000001424 substituent group Chemical group 0.000 claims description 14
- 125000001041 indolyl group Chemical group 0.000 claims description 12
- SPLTWZBWXIJQME-UHFFFAOYSA-N 3-(1,3-dioxolan-2-yl)aniline Chemical compound NC1=CC=CC(C2OCCO2)=C1 SPLTWZBWXIJQME-UHFFFAOYSA-N 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- ZETIVVHRRQLWFW-UHFFFAOYSA-N 3-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=CC(C=O)=C1 ZETIVVHRRQLWFW-UHFFFAOYSA-N 0.000 claims description 7
- 206010028980 Neoplasm Diseases 0.000 claims description 6
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 6
- 125000004076 pyridyl group Chemical group 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
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- 125000006727 (C1-C6) alkenyl group Chemical group 0.000 claims description 4
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- 238000006482 condensation reaction Methods 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
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- JIDDDPVQQUHACU-YFKPBYRVSA-N (2s)-pyrrolidine-2-carbaldehyde Chemical group O=C[C@@H]1CCCN1 JIDDDPVQQUHACU-YFKPBYRVSA-N 0.000 claims description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
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- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
- 229940079593 drug Drugs 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- JTHRRMFZHSDGNJ-UHFFFAOYSA-N piperazine-2,3-dione Chemical class O=C1NCCNC1=O JTHRRMFZHSDGNJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000002994 raw material Substances 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 44
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 32
- VIJWXJBKKGQCNO-UHFFFAOYSA-N 3-methylidenepiperazine-2,5-dione Chemical compound C=C1NC(=O)CNC1=O VIJWXJBKKGQCNO-UHFFFAOYSA-N 0.000 description 29
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- UNRCMCRRFYFGFX-TYPNBTCFSA-N plinabulin Chemical compound N1C=NC(\C=C/2C(NC(=C\C=3C=CC=CC=3)/C(=O)N\2)=O)=C1C(C)(C)C UNRCMCRRFYFGFX-TYPNBTCFSA-N 0.000 description 13
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
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Abstract
本发明公开了哌嗪二酮环类化合物及其合成方法和在制备抗肿瘤药物中的应用。所述哌嗪二酮环类化合物的结构如通式Ⅰ或者通式Ⅱ所示，其结构新颖，具有很好的溶解度，且制备方法简单，利用乙酰基哌嗪二酮衍生物与吲哚醛、含醛基中间体、或者氨基酸缩合，即可得到哌嗪二酮环类化合物。经实验证明，所述哌嗪二酮类化合物具有抑制肺癌、结肠癌、胰腺癌生长的作用，且能够破坏肿瘤细胞的微管结构，因此具有很好的应用前景。
Description
技术领域
本发明属于药物化学技术领域，具体涉及哌嗪二酮环类化合物及其合成方法和在制备抗肿瘤药物中的应用。
背景技术
肿瘤目前已经成为危害人类生命健康的主要原因之一。据世界卫生组织国际癌症研究机构统计，2020年全球新发癌症病例1929万例，其中肺癌和结肠癌的死亡率位于首列。化疗药目前仍是治疗癌症的主流方法。传统化疗药如紫杉醇、长春碱等，易产生耐药性，且毒副作用较大，所以开发出新的理化性质优良的化疗药物十分关键。
普那布林(plinabulin)，是从海洋焦曲霉菌中分离得到的天然产物Phenylahistin的基础上进行结构改造得到的一种微管蛋白抑制剂。目前普那布林联合多西他赛治疗非小细胞肺癌和化疗导致的中性粒细胞减少症(CIN)三期临床研究取得较好数据。但由于普那布林溶解性较差，临床上需要与增溶剂联合注射，长久使用可能会产生意想不到的安全性问题或影响病人的生活质量。为提高生物活性及改善溶解性，对其进行结构改造具有重要意义。
发明内容
本发明的目的在于提供哌嗪二酮环类化合物及其合成方法和在制备抗肿瘤药物中的应用。本发明通过对左侧苯环进行结构改造，得到结构新颖、具有良好溶解度和明显抗肿瘤作用的新型化合物。
为实现上述发明目的，本发明采用以下技术方案予以实现：
本发明提供了哌嗪二酮环类化合物，其具有如通式Ⅰ或者通式Ⅱ所示结构：
其中，R1为吲哚基或具有1-6个取代基的吲哚基；
R2为氢、C1-C6烷基或环烷基、C1-C6烯基、氨基、氨甲基、苯基、具有1-5个取代基的苯基、吲哚基、具有1-6个取代基的吲哚基、吡啶基、具有1-5个取代基的吡啶基、吡咯基、具有1-5个取代基的吡咯基、苯甲酰基、具有1-8个取代基的苯甲酰基或者人体氨基酸基团；
所述取代基包括C1-C6烷基、C1-C6烯基、卤素、羟基、硝基、氨基、羧基、酰胺基、酯基、苯甲酰基、甲氧基、巯基、氰基、芳基烷烃、杂环芳基烷烃中的至少一种。
进一步的，所述哌嗪二酮环类化合物具有如通式Ⅰ或者通式Ⅱ所示结构：
其中，R1为吲哚基；
R2为氢、C1-C4烷基、C3-C6环烷基、苯基、苯甲基、具有卤素取代的苯甲基、对甲氧苯基、二甲基苯基、吡啶基、吲哚基、苯甲酰基、吡咯基、氨甲基、缬氨酸基、脯氨酸基。
进一步的，所述哌嗪二酮类化合物具体为：化合物1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26，其结构式分别如下：
进一步的，所述哌嗪二酮类化合物在乙醇、丙二醇、甘油、聚乙二醇-200中具有良好的溶解度。
本发明还提供了所述的哌嗪二酮环类化合物的合成方法，其特征在于：包括如下步骤：
先将乙酰基哌嗪二酮衍生物与吲哚醛、或者含醛基中间体发生缩合反应，得到化合物1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22；
或者将乙酰基哌嗪二酮衍生物与间硝基苯甲醛发生缩合反应，得到的产物与人体氨基酸反应，得到化合物23、24、25、26；
所述含醛基中间体具有如通式Ⅲ所示的结构：
其中，R2为苯基、吡啶基、甲基、乙基、异丙基、叔丁基、环丙基、环丁基、环戊基、环己基、苯甲基、对甲氧基、2,4-二甲基苯基、2-甲基-5-氟苯基、吲哚基、苯甲酰苯基。
进一步的，所述乙酰基哌嗪二酮衍生物为(Z)-1-乙酰基-3-((5-叔丁基-1H-咪唑-4-基)亚甲基)哌嗪-2,5-二酮。
进一步的，所述含醛基中间体的合成方法为：以间硝基苯甲醛为起始原料，将醛基保护后再将硝基还原为氨基，得到中间体3-(1,3-二氧戊环-2-基)苯胺，再与酰氯或羧酸进行缩合，将环氧基还原，得到含醛基中间体。
本发明还提供了所述的哌嗪二酮类化合物在制备抗肿瘤药物中的应用。
进一步的，所述肿瘤为肺癌、胰腺癌、结肠癌。
进一步的，所述药物中含有哌嗪二酮类化合物2、3、4、6、7、24和25中的至少一种。
本发明还提供了所述的哌嗪二酮类化合物在制备微管蛋白抑制剂中的应用。
与现有相比，本发明具有的优点和有益效果是：
本发明基于(Z)-1-乙酰基-3-((5-叔丁基-1H-咪唑-4-基)亚甲基)哌嗪-2,5-二酮，通过对其左侧苯环进行结构改造，得到结构新颖的哌嗪二酮环类化合物。这些化合物具有很好的溶解度，且能够明显抑制肿瘤细胞的生长，尤其是化合物2、3、4对肿瘤细胞的抑制活性优于现有的药物普那布林，并且溶解度也优于普那布林，因此，这些化合物非常适合用于制备抗肿瘤药物。另外，实验证明，哌嗪二酮环类化合物是通过破坏肿瘤细胞的微管结构达到抑制肿瘤细胞生长作用的，因此，其也可以作为一种新的微管蛋白抑制剂，进而具有很好的应用前景。
附图说明
图1为化合物对肿瘤细胞微管结构破坏作用。
具体实施方式
以下结合具体实施例对本发明的技术方案做进一步详细的说明。下述实施例中，如无特殊说明，所使用的实验方法均为常规方法，所用材料、试剂等均可从生物或化学试剂公司购买。
实施例1：系列一化合物的合成
系列一目标化合物的通式为：
1、系列一目标化合物(3Z,6Z)-3-[(5-叔丁基-1H-咪唑-4-基)亚甲基]-6-(2-吲哚)亚甲基-2,5-哌嗪二酮的合成(化合物1)
制备方法为：称取(Z)-1-乙酰基-3-((5-叔丁基-1H-咪唑-4-基)亚甲基)哌嗪-2,5-二酮(290mg，1mmol)，吲哚-2-甲醛(145mg，1mmol)，碳酸铯(489mg，1.5mmol)，DMF(5mL)于干燥的25mL单口瓶中，置换氮气保护，于50℃避光反应18小时。薄层色谱法检测反应完毕，将反应液滴加到20ml冷水中，有黄色固体析出，抽滤得滤饼，滤饼经柱层析纯化后得棕色固体191mg，即为所述化合物1，收率为51％。
1H NMR(400MHz,DMSO-d6)δ12.24(s,2H),11.41(s,1H),9.75(s,1H),7.79(s,1H),7.50(s,1H),7.31(s,1H),7.16–6.52(m,5H),1.31(s,9H).
13C NMR(101MHz,DMSO)δ157.96,156.63,141.01,137.46,134.85,131.89,131.23,128.89,125.31,124.14,123.28,120.98,120.14,111.69,105.76,105.47,32.40,31.10.
HRMS(ESI)m/z:[M+H]+Calcd for C21H21N5O2:376.1768,Found:376.1764
2、系列一目标化合物(3Z,6Z)-3-[(5-叔丁基-1H-咪唑-4-基)亚甲基]-6-(3-吲哚)亚甲基-2,5-哌嗪二酮的合成(化合物2)
制备方法为：称取(Z)-1-乙酰基-3-((5-叔丁基-1H-咪唑-4-基)亚甲基)哌嗪-2,5-二酮(145mg，0.5mmol)，吲哚-3-甲醛(72.5mg，0.5mmol)，碳酸铯(244.5mg，0.75mmol)，DMF(3mL)于干燥的25mL单口瓶中，置换氮气保护，于50℃避光反应18小时。薄层色谱法检测反应完毕，将反应液滴加到20ml冷水中，有黄色固体析出，抽滤得滤饼，滤饼经柱层析纯化后得棕色固体39mg，即为所述化合物2，收率为21％。
1H NMR(400MHz,DMSO-d6)δ12.27(s,1H),11.37(s,1H),7.87(s,1H),7.47–
7.39(m,2H),7.25(d,J＝7.3Hz,1H),7.17(t,J＝7.7Hz,1H),7.07(s,1H),6.86(s,1H),6.47(s,1H),1.38(s,9H).
13C NMR(101MHz,DMSO)δ157.62,156.87,140.88,136.57,134.92,131.24,127.14,126.73,124.93,124.32,121.73,119.96,113.14,112.47,105.49,100.31,32.43,31.14.
HRMS(ESI)m/z:[M+H]+Calcd for C21H21N5O2:376.1768,Found:376.1764
3、系列一目标化合物(3Z,6Z)-3-[(5-叔丁基-1H-咪唑-4-基)亚甲基]-6-(4-吲哚)亚甲基-2,5-哌嗪二酮的合成(化合物3)
制备方法为：称取(Z)-1-乙酰基-3-((5-叔丁基-1H-咪唑-4-基)亚甲基)哌嗪-2,5-二酮(145mg，0.5mmol)，吲哚-4-甲醛(72.5mg，0.5mmol)，碳酸铯(244.5mg，0.75mmol)，DMF(3mL)于干燥的25mL单口瓶中，置换氮气保护，于50℃避光反应18小时。薄层色谱法检测反应完毕，将反应液滴加到20ml冷水中，有黄色固体析出，抽滤得滤饼，滤饼经柱层析纯化后得棕色固体26mg，即为所述化合物2，收率为14％。
1H NMR(400MHz,DMSO-d6)δ12.34(s,1H),12.18(s,1H),11.25(s,1H),9.87(s,1H),7.86(s,1H),7.79(s,1H),7.45–7.36(m,2H),7.25(d,J＝8.5Hz,1H),6.85(d,J＝
17.3Hz,2H),6.48(s,1H),1.38(s,9H).
13C NMR(101MHz,DMSO-D6)δ157.63,156.91,140.85,136.61,134.92,131.29,127.20,126.75,124.94,124.39,121.80,120.03,113.24,112.54,105.52,100.38,32.46,31.18.
HRMS(ESI)m/z:[M+H]+Calcd for C21H21N5O2:376.1768,Found:376.1764
4、系列一目标化合物(3Z,6Z)-3-[(5-叔丁基-1H-咪唑-4-基)亚甲基]-6-(5-吲哚)亚甲基-2,5-哌嗪二酮的合成(化合物4)
制备方法为：称取(Z)-1-乙酰基-3-((5-叔丁基-1H-咪唑-4-基)亚甲基)哌嗪-2,5-二酮(145mg，0.5mmol)，吲哚-5-甲醛(72.5mg，0.5mmol)，碳酸铯(244.5mg，0.75mmol)，DMF(3mL)于干燥的25mL单口瓶中，置换氮气保护，于50℃避光反应18小时。薄层色谱法检测反应完毕，将反应液滴加到20ml冷水中，有黄色固体析出，抽滤得滤饼，滤饼经柱层析纯化后得棕色固体109mg，即为所述化合物4，收率为58％。
1H NMR(400MHz,DMSO-d6)δ12.48(s,1H),12.11(s,1H),11.28(s,1H),9.89(s,1H),7.94(s,1H),7.81(s,1H),7.45(d,J＝8.4Hz,1H),7.42–7.39(m,1H),7.29–7.24(m,1H),6.91(s,1H),6.84(s,1H),6.50(s,1H),1.39(s,9H).
13C NMR(101MHz,DMSO)δ157.88,157.37,140.47,136.19,134.71,128.40,126.85,124.54,124.36,123.40,121.89,117.25,112.33,104.68,104.65,102.25,32.36,31.04.
HRMS(ESI)m/z:[M+H]+Calcd for C21H21N5O2:376.1768,Found:376.1764
5、系列一目标化合物(3Z,6Z)-3-[(5-叔丁基-1H-咪唑-4-基)亚甲基]-6-(6-吲哚)亚甲基-2,5-哌嗪二酮的合成(化合物5)
制备方法为：称取(Z)-1-乙酰基-3-((5-叔丁基-1H-咪唑-4-基)亚甲基)哌嗪-2,5-二酮(145mg，0.5mmol)，吲哚-6-甲醛(72.5mg，0.5mmol)，碳酸铯(244.5mg，0.75mmol)，DMF(3mL)于干燥的25mL单口瓶中，置换氮气保护，于50℃避光反应18小时。薄层色谱法检测反应完毕，将反应液滴加到20ml冷水中，有黄色固体析出，抽滤得滤饼，滤饼经柱层析纯化后得棕色固体109mg即为所述化合物5，收率为58％。
1H NMR(400MHz,DMSO-d6)δ12.29(s,1H),12.16(s,1H),11.20(s,1H),9.94(s,1H),7.85(s,1H),7.66–7.44(m,2H),7.37(s,1H),7.07(s,1H),6.81(d,J＝16.0Hz,2H),6.39(s,1H),1.33(s,9H).
13C NMR(101MHz,DMSO-D6)δ157.91,156.95,140.77,134.90,134.42,131.34,128.86,127.71,126.27,124.67,121.91,121.18,119.74,117.69,111.02,105.36,102.27,32.45,31.19.
HRMS(ESI)m/z:[M+H]+Calcd for C21H21N5O2:376.1768,Found:376.1764
6、系列一目标化合物(3Z,6Z)-3-[(5-叔丁基-1H-咪唑-4-基)亚甲基]-6-(7-吲哚)亚甲基-2,5-哌嗪二酮的合成(化合物6)
制备方法为：称取(Z)-1-乙酰基-3-((5-叔丁基-1H-咪唑-4-基)亚甲基)哌嗪-2,5-二酮(145mg，0.5mmol)，吲哚-6-甲醛(72.5mg，0.5mmol)，碳酸铯(244.5mg，0.75mmol)，DMF(3mL)于干燥的25mL单口瓶中，置换氮气保护，于50℃避光反应18小时。薄层色谱法检测反应完毕，将反应液滴加到20ml冷水中，有黄色固体析出，抽滤得滤饼，滤饼经柱层析纯化后得棕色固体109mg即为所述化合物5，收率为58％。
1H NMR(400MHz,DMSO-d6)δ12.26(d,J＝8.0Hz,2H),11.19(s,1H),9.58(s,1H),7.80(s,1H),7.50(s,1H),7.24(d,J＝12.0Hz,2H),7.02(s,2H),6.80(s,1H),6.43(s,1H),1.33(s,9H).
13C NMR(101MHz,DMSO-D6)δ157.91,156.95,140.77,134.90,134.42,131.34,128.86,127.71,126.27,124.67,121.91,121.18,119.74,117.69,111.02,105.36,102.27,32.45,31.19.
HRMS(ESI)m/z:[M+H]+Calcd for C21H21N5O2:376.1768,Found:376.1764
表1：系列一目标化合物的结构式和化学名称
实施例2：系列二化合物的合成
系列二目标化合物具有如下通式：
含醛基中间体具有如下通式：
具体合成路线为：
以间硝基苯甲醛为起始原料，将醛基保护后再将硝基还原为氨基，得到中间体3-(1,3-二氧戊环-2-基)苯胺。
3-(1,3-二氧戊环-2-基)苯胺与相应的酰氯或羧酸进行缩合，将环氧基还原得到相应的含醛基中间体。
含醛基中间体与(Z)-1-乙酰基-3-((5-叔丁基-1H-咪唑-4-基)亚甲基)哌嗪-2,5-二酮进行缩合得到系列二部分目标化合物。
(Z)-1-乙酰基-3-((5-叔丁基-1H-咪唑-4-基)亚甲基)哌嗪-2,5-二酮与间硝基苯甲醛进行缩合得到中间体(3Z,6Z)-3-[(5-叔丁基-1H-咪唑-4-基)亚甲基]-6-(邻硝基苯亚甲基)-2,5-哌嗪二酮，经过还原得到(3Z,6Z)-3-[(5-叔丁基-1H-咪唑-4-基)亚甲基]-6-(邻氨基苯亚甲基)-2,5-哌嗪二酮。
(3Z,6Z)-3-[(5-叔丁基-1H-咪唑-4-基)亚甲基]-6-(邻氨基苯亚甲基)-2,5-哌嗪二酮与相应的氨基酸反应得到系列二部分目标化合物。
一、已知中间体的合成
1、已知中间体2-(3-硝基-苯基)-1,3-二氧戊环的合成
称取邻硝基苯甲醛(25.70g，170mmol)，乙二醇(21.10g，340mmol)，对甲苯磺酸(100mg，0.58mmol)加入到甲苯(150mL)中，115℃回流反应20小时。冷却到室温，用饱和碳酸氢钠和饱和食盐水溶液分别洗涤三次，无水硫酸钠干燥，用(石油醚：乙酸乙酯＝7：1)过柱，减压蒸干后得白色固体产物28.89g，收率为95％。
2、已知中间体3-(1,3-二氧戊环-2-基)苯胺的合成
称取2-(3-硝基-苯基)-1,3-二氧戊环(28.88g，148mmol)，钯碳(2.89g，10％)加入到甲醇(200mL)中，于室温下在氢气环境中反应过夜。过滤、减压蒸干后得到黄色油状液体，石油醚：乙酸乙酯＝3：1过柱得黄色油状液体23.70g，收率为97％。
3、已知中间体N-(3-甲酰苯基)-苯甲酰胺的合成
将3-(1,3-二氧戊环-2-基)苯胺(300mg，1.68mmol)，三乙胺(350μL，2.52mmol)加入到二氯甲烷(10mL)中，0℃下搅拌过程中加入苯甲酰氯(233.58mg，1.68mmol)，搅拌30min后置于室温继续反应2h，分别用4N的盐酸水溶液、饱和氯化钠水溶液洗涤两次，无水硫酸钠干燥有机相，减压蒸干。将减压蒸干后的固体加入到二氧六环和3N HCl(1.5:1)的混合溶液中，于50℃下反应90min，反应完毕，乙酸乙酯提取，柱层析纯化得白色固体279mg，收率为74％。
4、已知中间体N-(3-甲酰苯基)-吡啶酰胺的合成
将吡啶甲酸(369.3mg，3mmol)、EDCI(690.1，2.4mmol)，HOBT(324.3mg，2.4mmol)，DIPEA(0.52mL，3mmol)加入到二氯甲烷中，搅拌30min后加入3-氨基苯甲醛乙二醇缩醛(495mg，3mmol)，反应17小时后，用2N HCl溶液和饱和碳酸氢钠溶液分别洗涤三次，无水硫酸钠干燥有机层后减压蒸干。将减压蒸干后的固体加入到二氧六环和3N HCl(1.5:1)的混合溶液中，于50℃下反应90min，反应完毕，乙酸乙酯提取，柱层析纯化得白色固体282mg，收率为41％。
其余含醛基中间体合成方式均可参考制备方法3和4。
二、系列二目标化合物的制备
1、系列二目标化合物(3Z,6Z)-3-[(5-叔丁基-1H-咪唑-4-基)亚甲基]-6-(N-(3-苯基)-苯甲酰胺)亚甲基-2,5-哌嗪二酮的合成(化合物7)
参考化合物1的合成方法，以(Z)-1-乙酰基-3-((5-叔丁基-1H-咪唑-4-基)亚甲基)哌嗪-2,5-二酮(145.2mg，0.5mmol)，N-(3-甲酰苯基)-苯甲酰胺(112.5mg，0.5mmol)为原料，得淡黄色固体96mg，产率为42％。
1H NMR(400MHz,DMSO-d6)δ12.29(s,1H),10.35(s,1H),7.97(d,J＝6.7Hz,2H),7.90(s,1H),7.86(s,1H),7.82(d,J＝7.6Hz,1H),7.59(d,J＝6.3Hz,1H),7.55(d,J＝6.9Hz,2H),7.41(t,J＝7.5Hz,1H),7.24(d,J＝7.0Hz,1H),6.88(s,1H),6.74(s,1H),1.38(s,9H).
13C NMR(101MHz,DMSO-d6)δ166.17,158.02,156.75,141.01,140.00,135.42,134.96,134.04,132.21,131.23,128.99,128.20,127.38,125.21,124.21,121.07,31.18.
HRMS(ESI)m/z:[M+H]+Calcd for C26H25N5O3:456.2030,Found:456.2030
2、(3Z,6Z)-3-[(5-叔丁基-1H-咪唑-4-基)亚甲基]-6-(N-(3-苯基)-乙酰胺)亚甲基-2,5-哌嗪二酮的合成(化合物8)
参考化合物1的合成方法，以(Z)-1-乙酰基-3-((5-叔丁基-1H-咪唑-4-基)亚甲基)哌嗪-2,5-二酮(145.2mg，0.5mmol)，N-(3-苯甲酰基)-乙酰胺(81.5mg，0.5mmol)为原料，得淡黄色固体92mg，产率为47％。
1H NMR(400MHz,DMSO-d6)δ12.27(s,1H),10.09(s,1H),7.84(s,1H),7.67(s,1H),7.59(d,J＝8.0Hz,1H),7.32(t,J＝7.9Hz,1H),7.18(d,J＝7.6Hz,1H),6.86(s,1H),6.67(s,1H),2.06(s,3H),1.38(s,9H).
13C NMR(101MHz,DMSO-d6)δ169.02,158.20,156.91,140.95,140.09,134.96,134.27,131.26,129.62,127.86,124.49,124.33,119.86,119.20,114.09,105.59,32.47,31.19,24.56.
HRMS(ESI)m/z:[M+H]+Calcd for C21H23N5O3:94.1874,Found:394.1872
3、(3Z,6Z)-3-[(5-叔丁基-1H-咪唑-4-基)亚甲基]-6-(N-(3-苯基)-丙酰胺)亚甲基-2,5-哌嗪二酮的合成(化合物9)
参考化合物1的合成方法，以(Z)-1-乙酰基-3-((5-叔丁基-1H-咪唑-4-基)亚甲基)哌嗪-2,5-二酮(145.2mg，0.5mmol)，N-(3-苯甲酰基)-丙酰胺(88.5mg，0.5mmol)为原料，得淡黄色固体79mg，产率为39％。
1H NMR(400MHz,DMSO-d6)δ12.27(s,2H),9.99(d,J＝6.0Hz,2H),7.85(s,1H),7.68(s,1H),7.61(d,J＝8.2Hz,1H),7.33(t,J＝7.9Hz,1H),7.16(d,J＝7.7Hz,1H),6.86(s,1H),6.68(s,1H),2.34(q,J＝7.5Hz,2H),1.38(d,J＝1.2Hz,9H),1.09(td,J＝7.5,1.2Hz,3H).
13C NMR(101MHz,DMSO-d6)δ172.57,157.90,156.67,140.92,140.11,134.90,133.99,131.13,129.58,124.32,124.13,119.70,119.20,114.20,105.67,32.40,31.11,29.99,10.10.
HRMS(ESI)m/z:[M+H]+Calcd for C22H25N5O3:408.2030,Found:408.2025
4、(3Z,6Z)-3-[(5-叔丁基-1H-咪唑-4-基)亚甲基]-6-(N-(3-苯基)-异丁酰胺)亚甲基-2,5-哌嗪二酮的合成(化合物10)
参考化合物1的合成方法，以(Z)-1-乙酰基-3-((5-叔丁基-1H-咪唑-4-基)亚甲基)哌嗪-2,5-二酮(145.2mg，0.5mmol)，N-(3-苯甲酰基)-异丁酰胺(95.5mg，0.5mmol)为原料，得淡黄色固体84mg，产率为40％。
1H NMR(400MHz,DMSO-d6)δ12.37(s,1H),12.23(s,1H),9.92(s,1H),9.88(s,1H),7.82(s,1H),7.66(d,J＝2.3Hz,1H),7.60(d,J＝8.3Hz,1H),7.30(t,J＝7.9Hz,1H),7.12(d,J＝7.7Hz,1H),6.83(s,1H),6.65(s,1H),1.35(s,9H),1.07(d,J＝6.8Hz,6H).
13C NMR(101MHz,DMSO-d6)δ175.89,157.98,156.75,140.98,140.26,134.97,129.65,127.30,124.47,124.22,119.84,119.37,114.33,105.74,35.50,32.48,31.19,20.05.
HRMS(ESI)m/z:[M+H]+Calcd for C23H27N5O3:422.2187,Found:422.2182
5、(3Z,6Z)-3-[(5-叔丁基-1H-咪唑-4-基)亚甲基]-6-(N-(3-苯基)-三甲基乙酰胺)亚甲基-2,5-哌嗪二酮的合成(化合物11)
参考化合物1的合成方法，以(Z)-1-乙酰基-3-((5-叔丁基-1H-咪唑-4-基)亚甲基)哌嗪-2,5-二酮(145.2mg，0.5mmol)，N-(3-苯甲酰基)-三甲基乙酰胺(102.5mg，0.5mmol)为原料，得淡黄色固体115mg，产率为53％。
1H NMR(400MHz,DMSO-d6)δ12.37(s,1H),12.26(s,1H),9.87(s,1H),9.27(s,1H),7.86(s,1H),7.75(d,J＝1.9Hz,1H),7.67(dd,J＝8.3,2.1Hz,1H),7.33(t,J＝7.9Hz,1H),7.16(d,J＝7.7Hz,1H),6.87(s,1H),6.70(s,1H),1.38(s,9H),1.24(s,9H).
13C NMR(101MHz,DMSO-d6)δ172.36,157.69,156.46,140.71,139.90,134.69,133.78,130.92,129.37,124.11,123.92,119.49,118.99,113.99,105.46,32.19,30.90,29.78,9.89.
HRMS(ESI)m/z:[M+H]+Calcd for C24H29N5O3:436.2343,Found:436.2340
6、(3Z,6Z)-3-[(5-叔丁基-1H-咪唑-4-基)亚甲基]-6-(N-(3-苯基)-环丙基乙酰胺)亚甲基-2,5-哌嗪二酮的合成(化合物12)
参考化合物1的合成方法，以(Z)-1-乙酰基-3-((5-叔丁基-1H-咪唑-4-基)亚甲基)哌嗪-2,5-二酮(145.2mg，0.5mmol)，N-(3-苯甲酰基)-环丙基基乙酰胺(94.5mg，0.5mmol)为原料，得淡黄色固体70mg，产率为33％。
1H NMR(400MHz,DMSO-d6)δ12.35(s,1H),12.26(s,1H),10.27(s,1H),9.94(s,1H),7.86(s,1H),7.67(d,J＝1.9Hz,1H),7.62–7.56(m,1H),7.33(t,J＝7.9Hz,1H),7.15(d,J＝7.7Hz,1H),6.86(s,1H),6.68(s,1H),1.38(s,9H),0.88–0.72(m,4H).
13C NMR(101MHz,DMSO-d6)δ172.27,157.97,156.74,140.94,140.13,134.95,134.10,131.23,129.67,127.32,124.45,119.78,119.26,114.29,105.69,32.47,31.18,15.13.
HRMS(ESI)m/z:[M+H]+Calcd for C23H25N5O3:420.2030,Found:420.2026.
7、(3Z,6Z)-3-[(5-叔丁基-1H-咪唑-4-基)亚甲基]-6-(N-(3-苯基)-环丁基乙酰胺)亚甲基-2,5-哌嗪二酮的合成(化合物13)
参考化合物1的合成方法，以(Z)-1-乙酰基-3-((5-叔丁基-1H-咪唑-4-基)亚甲基)哌嗪-2,5-二酮(145.2mg，0.5mmol)，N-(3-苯甲酰基)-环丁基基乙酰胺(101.5mg，0.5mmol)为原料，得淡黄色固体80mg，产率为37％。
1H NMR(400MHz,DMSO-d6)δ12.34(d,J＝2.6Hz,1H),12.26(s,1H),10.27(s,1H),9.94(s,1H),7.86(s,1H),7.67(s,1H),7.59(d,J＝8.0Hz,1H),7.33(t,J＝7.9Hz,1H),7.15(d,J＝7.8Hz,1H),6.86(s,1H),6.68(s,1H),2.50(p,J＝1.9Hz,3H),1.38(s,9H),0.81(s,4H).
13C NMR(101MHz,DMSO-d6)δ173.66,158.01,141.07,140.28,135.00,133.99,131.15,129.61,124.14,119.93,105.88,32.54,31.23,25.12,18.27.
HRMS(ESI)m/z:[M+H]+Calcd for C24H27N5O3:434.2187,Found:434.2184.
8、(3Z,6Z)-3-[(5-叔丁基-1H-咪唑-4-基)亚甲基]-6-(N-(3-苯基)-环戊基乙酰胺)亚甲基-2,5-哌嗪二酮的合成(化合物14)
参考化合物1的合成方法，以(Z)-1-乙酰基-3-((5-叔丁基-1H-咪唑-4-基)亚甲基)哌嗪-2,5-二酮(145.2mg，0.5mmol)，N-(3-苯甲酰基)-环戊基基乙酰胺(108.5mg，0.5mmol)为原料，得淡黄色固体98mg，产率为44％。
1H NMR(400MHz,DMSO-d6)δ12.25(d,J＝32.9Hz,2H),9.86(d,J＝25.0Hz,2H),7.79(s,1H),7.61(d,J＝26.5Hz,2H),7.28(s,1H),7.10(s,1H),6.81(s,1H),6.64(s,1H),2.73(s,1H),1.80(s,2H),1.63(s,4H),1.50(s,2H),1.32(s,9H).
13C NMR(101MHz,DMSO-d6)δ175.06,157.99,156.75,140.97,140.28,134.94,134.07,131.25,129.65,127.30,124.44,124.22,119.81,119.37,114.34,105.78,45.88,32.46,31.18,30.64,26.24.
HRMS(ESI)m/z:[M+H]+Calcd for C25H29N5O3:448.2343,Found:448.2340.
9、(3Z,6Z)-3-[(5-叔丁基-1H-咪唑-4-基)亚甲基]-6-(N-(3-苯基)-环己基乙酰胺)亚甲基-2,5-哌嗪二酮的合成(化合物15)
参考化合物1的合成方法，以(Z)-1-乙酰基-3-((5-叔丁基-1H-咪唑-4-基)亚甲基)哌嗪-2,5-二酮(145.2mg，0.5mmol)，N-(3-苯甲酰基)-环己基基乙酰胺(115.5mg，0.5mmol)为原料，得淡黄色固体118mg，产率为51％。
1H NMR(400MHz,DMSO-d6)δ12.33(s,1H),12.24(s,1H),9.87(s,2H),7.84(s,1H),7.66(s,1H),7.61(s,1H),7.28(s,1H),7.13(s,1H),6.84(s,1H),6.66(s,1H),2.48(s,2H),2.31(s,1H),1.76(s,5H),1.61(s,1H),1.36(s,9H).
13C NMR(101MHz,DMSO-d6)δ174.95,157.96,156.74,140.95,140.30,134.95,134.06,131.23,129.63,127.30,124.42,124.24,119.75,119.30,114.33,105.71,45.45,32.47,31.18,29.68,25.94,25.78.
HRMS(ESI)m/z:[M+H]+Calcd for C25H29N5O3:462.2500,Found:462.2496.
10、(3Z,6Z)-3-[(5-叔丁基-1H-咪唑-4-基)亚甲基]-6-(N-(3-苯基)-苯乙酰胺)亚甲基-2,5-哌嗪二酮的合成(化合物16)
参考化合物1的合成方法，以(Z)-1-乙酰基-3-((5-叔丁基-1H-咪唑-4-基)亚甲基)哌嗪-2,5-二酮(145.2mg，0.5mmol)，N-(3-苯甲酰基)-苯乙酰胺(119.5mg，0.5mmol)为原料，得淡黄色固体91mg，产率为39％。
1H NMR(400MHz,DMSO-d6)δ12.36(s,1H),12.28(s,1H),10.29(s,1H),9.93(s,1H),7.85(s,1H),7.69(s,1H),7.63(d,J＝8.3Hz,1H),7.33(d,J＝7.8Hz,5H),7.24(q,J＝5.5,4.4Hz,1H),7.17(d,J＝7.8Hz,1H),6.87(s,1H),6.70(s,1H),3.66(s,2H),1.38(s,9H).
13C NMR(101MHz,DMSO-d6)δ169.79,158.00,156.74,140.98,140.03,136.45,134.93,134.17,131.24,129.69,128.86,127.39,127.11,124.75,124.23,119.89,119.36,114.23,105.78,43.90,32.46,31.17.
HRMS(ESI)m/z:[M+H]+Calcd for C27H27N5O3:470.2187,Found:470.2181.
11、(3Z,6Z)-3-[(5-叔丁基-1H-咪唑-4-基)亚甲基]-6-(N-(3-苯基)-对甲氧基苯甲酰胺)亚甲基-2,5-哌嗪二酮的合成(化合物17)
参考化合物1的合成方法，以(Z)-1-乙酰基-3-((5-叔丁基-1H-咪唑-4-基)亚甲基)哌嗪-2,5-二酮(145.2mg，0.5mmol)，N-(3-苯甲酰基)-对甲氧基苯甲酰胺(127.5mg，0.5mmol)为原料，得淡黄色固体85mg，产率为35％。
1H NMR(400MHz,DMSO-d6)δ12.23(s,1H),12.16(s,1H),10.04(s,1H),9.75(s,1H),7.84(d,J＝8.5Hz,2H),7.76(s,1H),7.72(s,1H),7.69–7.64(m,1H),7.25(t,J＝7.9Hz,1H),7.08(d,J＝7.7Hz,1H),6.93(d,J＝8.5Hz,2H),6.75(s,1H),6.61(s,1H),3.69(s,3H),1.24(s,9H).
13C NMR(101MHz,DMSO-d6)δ165.53,162.50,158.02,156.76,141.01,140.18,134.92,133.97,131.25,130.15,129.57,127.31,124.96,124.20,121.01,120.53,114.17,105.84,55.95,32.46,31.17.
HRMS(ESI)m/z:[M+H]+Calcd for C27H27N5O4:486.2136,Found:486.2129.
12、(3Z,6Z)-3-[(5-叔丁基-1H-咪唑-4-基)亚甲基]-6-(N-(3-苯基)-2，4-二甲基苯甲酰胺)亚甲基-2,5-哌嗪二酮的合成(化合物18)
参考化合物1的合成方法，以(Z)-1-乙酰基-3-((5-叔丁基-1H-咪唑-4-基)亚甲基)哌嗪-2,5-二酮(145.2mg，0.5mmol)，N-(3-苯甲酰基)-2,4-二甲基苯甲酰胺(126.5mg，0.5mmol)为原料，得淡黄色固体104mg，产率为43％。
1H NMR(400MHz,DMSO-d6)δ12.32(s,1H),12.25(s,1H),10.25(s,1H),9.85(s,1H),7.81(d,J＝20.8Hz,3H),7.36(s,2H),7.20(s,1H),7.10(s,2H),6.84(s,1H),6.69(s,1H),2.34(s,3H),2.29(s,3H),1.35(s,9H).
13C NMR(101MHz,DMSO-d6)δ168.48,157.96,156.74,140.97,140.21,139.90,136.02,134.97,134.74,134.10,131.60,131.24,127.37,126.50,124.22,120.28,114.21,32.47,31.24,31.11,21.40.
HRMS(ESI)m/z:[M+H]+Calcd for C27H27N5O3:484.2343,Found:484.2339.
13、(3Z,6Z)-3-[(5-叔丁基-1H-咪唑-4-基)亚甲基]-6-(N-(3-苯基)-2-吡啶甲酰胺)亚甲基-2,5-哌嗪二酮的合成(化合物19)
参考化合物1的合成方法，以(Z)-1-乙酰基-3-((5-叔丁基-1H-咪唑-4-基)亚甲基)哌嗪-2,5-二酮(145.2mg，0.5mmol)，N-(3-苯甲酰基)-吡啶甲酰胺(113mg，0.5mmol)为原料，得淡黄色固体55mg，产率为24％。
1H NMR(400MHz,DMSO-d6)δ12.33(s,1H),12.27(s,1H),10.70(s,1H),9.97(s,1H),8.75(s,1H),8.16(d,J＝7.8Hz,1H),8.06(t,J＝7.1Hz,1H),8.00(d,J＝8.2Hz,1H),7.94(s,1H),7.84(s,1H),7.70–7.64(m,1H),7.39(t,J＝7.9Hz,1H),7.21(d,J＝7.6Hz,1H),6.86(s,1H),6.73(s,1H),1.36(s,9H).
13C NMR(101MHz,DMSO-d6)δ162.97,158.12,156.75,150.26,149.09,148.91,140.99,139.04,134.95,133.99,131.25,127.55,127.33,124.21,121.02,114.03,105.87,32.48,31.26,31.13.
HRMS(ESI)m/z:[M+H]+Calcd for C25H24N6O3:457.1983,Found:457.1976.
14、(3Z,6Z)-3-[(5-叔丁基-1H-咪唑-4-基)亚甲基]-6-(N-(3-苯基)-2-甲基-5-氟-苯甲酰胺)亚甲基-2,5-哌嗪二酮的合成(化合物20)
参考化合物1的合成方法，以(Z)-1-乙酰基-3-((5-叔丁基-1H-咪唑-4-基)亚甲基)哌嗪-2,5-二酮(145.2mg，0.5mmol)，N-(3-苯甲酰基)-2-甲基-5-氟苯甲酰胺(128.5mg，0.5mmol)为原料，得淡黄色固体131mg，产率为54％。
1H NMR(400MHz,DMSO-d6)δ12.03(s,1H),11.94(s,1H),10.09(s,1H),9.52(s,1H),7.47(s,1H),7.45–7.38(m,2H),7.06(t,J＝7.9Hz,1H),7.03–6.92(m,2H),6.89(d,J＝8.0Hz,2H),6.52(s,1H),6.37(s,1H),2.00(s,3H),1.02(s,9H).
13C NMR(101MHz,DMSO-d6)δ167.20,158.08,156.80,141.29,139.72,134.89,134.08,133.09,133.01,131.97,131.14,129.84,127.31,125.26,123.99,120.51,120.08,114.65,114.42,114.28,106.09,32.40,31.10,19.01.
HRMS(ESI)m/z:[M+H]+Calcd for C27H26FN5O3:488.2092,Found:488.2085.
15、(3Z,6Z)-3-[(5-叔丁基-1H-咪唑-4-基)亚甲基]-6-(N-(3-醛基苯基)-2-吲哚甲酰胺)亚甲基-2,5-哌嗪二酮的合成(化合物21)
参考化合物1的合成方法，以(Z)-1-乙酰基-3-((5-叔丁基-1H-咪唑-4-基)亚甲基)哌嗪-2,5-二酮(145.2mg，0.5mmol)，N-(3-苯甲酰基)-1H-吲哚-2-甲酰胺(132mg，0.5mmol)为原料，得淡黄色固体54mg，产率为22％。
1H NMR(400MHz,DMSO-d6)δ12.30(s,1H),11.81(s,1H),10.31(s,1H),7.93(s,1H),7.85(d,J＝19.3Hz,2H),7.69(d,J＝7.9Hz,1H),7.52–7.37(m,3H),7.23(t,J＝8.0Hz,2H),7.07(t,J＝7.4Hz,1H),6.89(s,1H),6.76(s,1H),1.39(s,9H).
13C NMR(101MHz,DMSO-d6)δ160.34,140.97,139.80,137.42,134.96,131.96,131.25,129.68,127.56,125.07,124.39,124.25,120.87,120.49,120.30,114.26,112.96,105.76,104.50,32.48,31.18.
HRMS(ESI)m/z:[M+H]+Calcd for C28H26N6O3:495.2139,Found:495.2132
16、(3Z,6Z)-3-[(5-叔丁基-1H-咪唑-4-基)亚甲基]-6-(N-(3-醛基苯基)烟酰胺)亚甲基-2,5-哌嗪二酮的合成(化合物22)
参考化合物1的合成方法，以(Z)-1-乙酰基-3-((5-叔丁基-1H-咪唑-4-基)亚甲基)哌嗪-2,5-二酮(145.2mg，0.5mmol)，N-(3-苯甲酰基)烟酰胺(164.5mg，0.5mmol)为原料，得淡黄色固体60mg，产率为26％。
1H NMR(400MHz,DMSO-d6)δ12.43(s,1H),12.29(s,1H),10.56(s,1H),9.12(s,1H),8.76(s,1H),8.32(s,1H),7.87(d,J＝13.4Hz,2H),7.80(d,J＝7.6Hz,1H),7.58(s,1H),7.41(t,J＝7.6Hz,1H),7.26(d,J＝7.2Hz,1H),6.87(s,1H),6.74(s,1H),1.38(s,9H).
13C NMR(101MHz,DMSO-d6)δ164.67,158.05,152.72,149.21,141.04,139.66,136.04,134.96,134.13,131.22,129.69,127.45,125.50,124.10,121.10,114.13,32.47,31.17.
HRMS(ESI)m/z:[M+H]+Calcd for C25H24N6O3:457.1983,Found:457.1976.
17、已知化合物含硝基中间体(3Z,6Z)-3-[(5-叔丁基-1H-咪唑-4-基)亚甲基]-6-(邻硝基苯亚甲基)-2,5-哌嗪二酮的合成
参考化合物1的合成方法，以(Z)-1-乙酰基-3-((5-叔丁基-1H-咪唑-4-基)亚甲基)哌嗪-2,5-二酮(1452mg，5mmol)，间硝基苯甲醛(755mg，5mmol)为原料，得淡黄色固体1047mg，产率为55％。
1H NMR(400MHz,DMSO-d6)δ12.28(s,2H),10.58(s,1H),8.26(s,1H),8.08(s,1H),7.82(s,2H),7.61(s,1H),6.83(s,1H),6.76(s,1H),1.34(s,9H).
HRMS(ESI)m/z:[M+H]+Calcd for C19H19N5O4:382.1510,Found:382.1505.
18、已知化合物含氨基中间体(3Z,6Z)-3-[(5-叔丁基-1H-咪唑-4-基)亚甲基]-6-(邻氨基苯亚甲基)-2,5-哌嗪二酮
称取(3Z,6Z)-3-[(5-叔丁基-1H-咪唑-4-基)亚甲基]-6-(邻硝基苯亚甲基)-2,5-哌嗪二酮(800mg，2.1mmol)，锌粉(1176mg，21mmol)，加入到甲醇中，于0摄氏度下搅拌，搅拌过程中滴加4N HCl水溶液(5mL,42mmol)，后置室温反应7小时，薄层色谱法检测，反应完毕，过滤掉锌粉，减压蒸干得到淡黄色固体，乙酸乙酯打浆后得淡黄色固体560.2mg，产率为76％。
1H NMR(400MHz,DMSO-d6)δ12.26(d,J＝48.4Hz,2H),9.50(s,1H),7.82(s,1H),6.82(s,1H),6.68(s,1H),6.63–6.57(m,2H),6.51(d,J＝7.7Hz,1H),5.16(s,2H),1.35(s,9H).
HRMS(ESI)m/z:[M+H]+Calcd for C19H21N5O2:352.1768,Found:352.1764.
19、(3Z,6Z)-3-[(5-叔丁基-1H-咪唑-4-基)亚甲基]-6-(N-(3-苯基)-2-吡咯-甲酰胺)亚甲基-2,5-哌嗪二酮(化合物23)
(3Z,6Z)-3-[(5-叔丁基-1H-咪唑-4-基)亚甲基]-6-(N-(3-苯基)-(2-甲基-1-甲酸丙酯)四氢吡咯-甲酰胺)亚甲基-2,5-哌嗪二酮(化合物26)
将(3Z,6Z)-3-[(5-叔丁基-1H-咪唑-4-基)亚甲基]-6-(邻氨基苯亚甲基)-2,5-哌嗪二酮(150mg，0.43mmol)，N-Boc-L-脯氨酸(137.8mg，0.64mmol)加入到DMF中，随后加入BopCl(136.8mg，0.54mmol)，三乙胺(0.3mL,2.15mmol)，室温搅拌，5h后反应完毕，将反应物倒入水中，有大量固体析出，过滤并柱层析纯化后得淡黄色固体128mg，即化合物26，产率为54％。
将产物溶于HCl-MeOH溶于，置于室温搅拌，2h后停止反应，加碳酸氢钠调节pH至中性，二氯甲烷萃取，干燥有机相得淡黄色固体产物，即化合物23。
1H NMR(400MHz,DMSO-d6)δ11.37(s,1H),10.51(s,1H),10.33(s,1H),8.75(s,1H),7.82(s,1H),7.67(s,1H),7.41(s,1H),7.26(s,1H),6.74(s,1H),6.67(s,1H),4.47(s,1H),1.95(s,3H),1.37(s,9H).
13C NMR(101MHz,DMSO-D6)δ174.10,158.09,156.77,140.97,139.23,134.94,134.03,131.23,129.62,127.27,125.07,124.23,120.09,119.51,114.17,105.73,61.37,47.32,40.63,40.42,40.21,40.00,39.79,39.58,39.38,32.46,31.17,26.44.
HRMS(ESI)m/z:[M+H]+Calcd for C24H28N6O3:449.2296,Found:449.2292
20、(3Z,6Z)-3-[(5-叔丁基-1H-咪唑-4-基)亚甲基]-6-(N-(3-苯基)-2-(R)异丙基-3-氨基丙酰胺)亚甲基-2,5-哌嗪二酮(化合物24)
将(3Z,6Z)-3-[(5-叔丁基-1H-咪唑-4-基)亚甲基]-6-(邻氨基苯亚甲基)-2,5-哌嗪二酮(150mg，0.43mmol)，BOC-L-缬氨酸(139.1mg，0.64mmol)加入到DMF中，随后加入BopCl(136.8mg，0.54mmol)，三乙胺(0.3mL,2.15mmol)，室温搅拌，5h后反应完毕，将反应物倒入水中，有大量固体析出，过滤并柱层析纯化后得淡黄色固体93mg，产率为46％。
将产物溶于HCl-MeOH溶于，置于室温搅拌，2h后停止反应，加碳酸氢钠调节pH至中性，二氯甲烷萃取，干燥有机相得淡黄色固体产物，即化合物24。
1H NMR(400MHz,DMSO-d6)δ11.34(s,1H),11.10(s,1H),10.23(s,1H),8.60(s,1H),8.44(s,3H),7.75–7.59(m,2H),7.40–7.11(m,2H),6.65(d,J＝29.2Hz,2H),3.91(s,2H),2.20(s,1H),1.31(s,9H),1.17(s,1H),0.97(s,6H).
13C NMR(101MHz,DMSO-D6)δ157.19,139.97,138.87,134.33,133.90,129.63,127.02,125.12,120.20,119.62,115.14,103.11,58.20,32.10,30.28,18.78,18.21.
HRMS(ESI)m/z:[M+H]+Calcd for C25H32N6O3:465.2609,Found:465.2610.
22、(3Z,6Z)-3-[(5-叔丁基-1H-咪唑-4-基)亚甲基]-6-(N-(3-苯基)-氨基乙酰胺)亚甲基-2,5-哌嗪二酮(化合物25)
将(3Z,6Z)-3-[(5-叔丁基-1H-咪唑-4-基)亚甲基]-6-(邻氨基苯亚甲基)-2,5-哌嗪二酮(150mg，0.43mmol)，Boc-甘氨酸(112.1mg，0.64mmol)加入到DMF中，随后加入BopCl(136.8mg，0.54mmol)，三乙胺(0.3mL,2.15mmol)，室温搅拌，5h后反应完毕，将反应物倒入水中，有大量固体析出，过滤并柱层析纯化后得淡黄色固体108mg，产率为62％。
将产物溶于HCl-MeOH溶于，置于室温搅拌，2h后停止反应，加碳酸氢钠调节pH至中性，二氯甲烷萃取，干燥有机相得淡黄色固体产物即化合物25。
1H NMR(400MHz,DMF-d7)δ11.40(s,1H),11.00(s,1H),10.27(s,1H),8.65(s,1H),8.38(s,3H),7.73(s,1H),7.62(d,J＝7.6Hz,1H),7.39(t,J＝7.5Hz,1H),7.23(d,J＝7.2Hz,1H),6.73(s,1H),6.66(s,1H),3.82(s,2H),1.35(s,9H).
13C NMR(101MHz,DMSO-D6)δ165.44,157.63,140.18,139.18,134.57,134.15,129.90,127.26,125.26,120.10,119.54,115.57,115.33,41.48,32.33,30.51.
HRMS(ESI)m/z:[M+H]+Calcd for C21H24N6O3:409.1983,Found:409.1980.
表2：系列二目标化合物的化学式和化学名称
实施例3：化合物的相关检测
1、生物部分测试
1)细胞接种培养
选用结肠癌(HCT116)、肺癌(H460)、胰腺癌细胞(bxpc-3)三种肿瘤细胞。用含10％(v/v)胎牛血清(FBS)的培养液(EMEM、RMPI640、5A)配成单个细胞悬液，将处于对数生长期的细胞按5000～8000个/孔的密度接种于96孔板，每孔体积100μL，细胞提前24小时接种培养。
2)MTT法测定肿瘤细胞生长半抑制浓度(IC50)
化合物用DMSO溶解，保持DMSO在培养基中的终浓度为0.1％。每孔含化合物培养基的终体积为200μL，每种处理设置三个复孔，在37℃下培养48小时后，每孔加20μL MTT溶液(5mg/mL)，继续培养4小时使其反应充分进行，吸走培养基上清，每孔加100μL DMSO，完全溶解后用酶标仪在490nm波长下测定光吸收值。以plinabulin(普那布林)为阳性对照。细胞抑制率的计算方法为：细胞抑制率(％)＝(1-实验组OD值/空白组OD值)×100％。利用graphpad计算每个化合物的IC50值，每个实验重复三次。
化合物抑制肿瘤细胞增殖的IC50结果如表3所示。结果表明，化合物2、3、4、6、7、24、25这7种化合物对3种人肿瘤细胞增殖具有较强的生长抑制活性，其中化合物2、3、4的活性优于普那布林。
表3：化合物对肿瘤细胞株增殖抑制活性测定
3)免疫荧光法测试肿瘤细胞微管结构破坏作用
在超净台内将经过高压蒸汽灭菌的2cm×2cm盖玻片平铺在六孔板内，HCT116细胞以1.5×105细胞密度接种于6孔板中。孵育过夜，加入浓度为10nM的化合物继续培养24小时。在六孔板中将细胞爬片用PBS浸洗3次，每次3min；用4％的多聚甲醛固定爬片15min，PBS浸洗玻片3次，每次3min；0.5％ Triton X-100(PBS配制)室温作用20min；PBS浸洗玻片3次，每次3min，吸水纸吸干PBS，在玻片上滴加正常山羊血清，室温封闭30min；吸水纸吸掉封闭液，每张玻片滴加足够量的稀释好的一抗并放入湿盒，4℃孵育过夜。PBST浸洗爬片3次，每次3min，吸水纸吸干爬片上多余液体后滴加稀释好的荧光二抗，湿盒中20-37℃孵育1h，PBST浸洗切片3次，每次3min(从加荧光二抗起，后面所有操作步骤都在较暗处进行)。滴加DAPI避光孵育5min，对标本进行染核，PBST 5min×4次洗去多余的DAPI。用吸水纸吸干爬片上的液体，用含抗荧光淬灭剂的封片液封片，然后在荧光显微镜下观察采集图像；通过Image-pro Plus 6.0(Media Cybernetics,Inc.,美国)软件对微管的免疫荧光强度进行半定量分析，来比较化合物与对照药plinabulin对微管的抑制作用。
如图1所示，化合物2对微管破坏作用强于普那布林。
2、溶解度测试
向1.5ml EP管中加入100微升溶剂(乙醇、甘油、丙二醇、聚乙二醇-200)，不断向其中加入化合物3，涡旋溶解，直至固体不再溶解。
结果如表4所示，化合物3在以上四种注射用溶剂中溶解度均优于普那布林，约为普那布林的1.6倍，有助于生物利用度的提高。
表4：本发明在不同溶剂中的溶解度
综上所述，本发明分离得到的化合物可以在抗肿瘤药物中进行应用，所述的肿瘤为结肠癌、肺癌、胰腺癌，且化合物具有很好的溶解度。
以上实施例仅用以说明本发明的技术方案，而非对其进行限制；尽管参照前述实施例对本发明进行了详细的说明，对于本领域的普通技术人员来说，依然可以对前述实施例所记载的技术方案进行修改，或者对其中部分技术特征进行等同替换；而这些修改或替换，并不使相应技术方案的本质脱离本发明所要求保护的技术方案的精神和范围。
Claims (10)
1.哌嗪二酮环类化合物，其特征在于：其具有如通式Ⅰ或者通式Ⅱ所示结构：
其中，R1为吲哚基或具有1-6个取代基的吲哚基；
R2为氢、C1-C6烷基或环烷基、C1-C6烯基、氨基、氨甲基、苯基、具有1-5个取代基的苯基、吲哚基、具有1-6个取代基的吲哚基、吡啶基、具有1-5个取代基的吡啶基、吡咯基、具有1-5个取代基的吡咯基、苯甲酰基、具有1-8个取代基的苯甲酰基或者人体氨基酸基团；
所述取代基包括C1-C6烷基、C1-C6烯基、卤素、羟基、硝基、氨基、羧基、酰胺基、酯基、苯甲酰基、甲氧基、巯基、氰基、芳基烷烃、杂环芳基烷烃中的至少一种。
2.根据权利要求1所述的哌嗪二酮环类化合物，其特征在于：其具有如通式Ⅰ或者通式Ⅱ所示结构：
其中，R1为吲哚基；
R2为氢、C1-C4烷基、C3-C6环烷基、苯基、苯甲基、具有卤素取代的苯甲基、对甲氧苯基、二甲基苯基、吡啶基、吲哚基、苯甲酰基、吡咯基、氨甲基、缬氨酸基、脯氨酸基。
3.根据权利要求2所述的哌嗪二酮环类化合物，其特征在于：其具体为：化合物1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26，其结构式分别如下：
4.权利要求3所述的哌嗪二酮环类化合物的合成方法，其特征在于：包括如下步骤：
先将乙酰基哌嗪二酮衍生物与吲哚醛、或者含醛基中间体发生缩合反应，得到化合物1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22；
或者将乙酰基哌嗪二酮衍生物与间硝基苯甲醛发生缩合反应，得到的产物与人体氨基酸反应，得到化合物23、24、25、26；
所述含醛基中间体具有如通式Ⅲ所示的结构：
其中，R2为苯基、吡啶基、甲基、乙基、异丙基、叔丁基、环丙基、环丁基、环戊基、环己基、苯甲基、对甲氧基、2,4-二甲基苯基、2-甲基-5-氟苯基、吲哚基、苯甲酰苯基。
5.根据权利要求4所述的合成方法，其特征在于，所述乙酰基哌嗪二酮衍生物为(Z)-1-乙酰基-3-((5-叔丁基-1H-咪唑-4-基)亚甲基)哌嗪-2,5-二酮。
6.根据权利要求4所述的合成方法，其特征在于，所述含醛基中间体的合成方法为：以间硝基苯甲醛为起始原料，将醛基保护后再将硝基还原为氨基，得到中间体3-(1,3-二氧戊环-2-基)苯胺，再与酰氯或羧酸进行缩合，将环氧基还原，得到含醛基中间体。
7.权利要求1-3任一项所述的哌嗪二酮类化合物在制备抗肿瘤药物中的应用。
8.根据权利要求7所述的哌嗪二酮类化合物在制备抗肿瘤药物中的应用，其特征在于，所述肿瘤为肺癌、胰腺癌、结肠癌。
9.根据权利要求7所述的哌嗪二酮类化合物在制备抗肿瘤药物中的应用，其特征在于，所述药物中含有哌嗪二酮类化合物2、3、4、6、7、24和25中的至少一种。
10.权利要求1-3任一项所述的哌嗪二酮类化合物在制备微管蛋白抑制剂中的应用。
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| US20070078138A1 (en) * | 2002-08-02 | 2007-04-05 | Michael Palladino | Analogs of dehydrophenylahistins and their therapeutic use |
| US20180140600A1 (en) * | 2015-06-02 | 2018-05-24 | Marine Biomedical Research Institute Of Qingdao Co., Ltd. | Deuterated dehydrophenylahistin compounds and preparation method thereof and use thereof in preparation of anti-tumor drugs |
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| US20070078138A1 (en) * | 2002-08-02 | 2007-04-05 | Michael Palladino | Analogs of dehydrophenylahistins and their therapeutic use |
| US20180140600A1 (en) * | 2015-06-02 | 2018-05-24 | Marine Biomedical Research Institute Of Qingdao Co., Ltd. | Deuterated dehydrophenylahistin compounds and preparation method thereof and use thereof in preparation of anti-tumor drugs |
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