CN104496970A - 3,4-二(3-吲哚)-2,5-二酮-3-吡咯啉亚胺类化合物及其制备方法和在抗癌药物中的应用 - Google Patents
3,4-二(3-吲哚)-2,5-二酮-3-吡咯啉亚胺类化合物及其制备方法和在抗癌药物中的应用 Download PDFInfo
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Abstract
本发明公开了一种3,4-二(3-吲哚)-2,5-二酮-3-吡咯啉亚胺类化合物及其制备方法和在抗癌药物中的应用。本发明的技术方案要点为:3,4-二(3-吲哚)-2,5-二酮-3-吡咯啉亚胺类化合物,是以醛类化合物R-CHO和1-氨基-3,4-二(3-吲哚)-3-吡咯啉-2,5-二酮 为原料制备而成的,其结构通式如下:
Description
技术领域
本发明属于具有抗癌活性的新化合物合成技术领域,具体涉及一种3,4-二(3-吲哚)-2,5-二酮-3-吡咯啉亚胺类化合物及其制备方法和在抗癌药物中的应用。
背景技术
双吲哚马来酰亚胺化合物是一类生物活性优良的生物碱,因与吲哚咔唑类生物碱生物合成上的相关性,因此也通常被归于吲哚咔唑化合物[1]。双吲哚马来酰亚胺自身即具有一定的PKC抑制活性(IC50 O.55μM±0.17 μM),其作用机制主要有两种:研究较多的是通过与PKC的ATP位点竞争性结合而直接抑制PKC活性[2]),另外一种机制是诱导细胞程序性死亡[3]。该类化合物的研究兴趣集中在PKC抑制剂的开发上,对肿瘤治疗、糖尿病、早老性痴呆以及心血管疾病的活性报道较多[4]。
Davis P D.课题组基于其对系列化合物的研究认为,酰亚胺环上上的双羰基被还原则活性降低[5]。对吲哚N上修饰以烷基或适当长度的烷基链则会增强其PKC活性及选择性[6]。
对双吲哚马来酰亚胺的修饰近年来取得了丰硕的研究成果,多个双吲哚马来酰亚胺类化合物已作为靶向抗肿瘤药物进入临床研究。其中, Ruboxistaurin是一种对PKC-β具有高选择性的双吲哚马来酰亚胺化合物,结构中由N-N’桥环接连双吲哚[8]。该化合物在美国已完成III期临床研究,研究结果表明口服Ruboxistaurin可通过改善糖尿病患者肾脏结构异常,减少蛋白尿,从而抑制患者肾组织中转化生长因子的过度表达。
发明人课题组也一直致力于研究具有抗肿瘤活性的吲哚咔唑类药物先导化合物,因此对吲哚咔唑母核的结构进行了多样化的修饰,并研究了其初步的抗肿瘤活性。
[1] Venkataraman H, Cha J K. A formal synthesis of forskolin: An electrocyclization approach[J]. J. Org. Chem., 1989, 54: 2505-2506.
[2] Bharti N, Husain K, Gonzalez Garza M T, et al. Synthesis and in vitro antiprotozoal activity of 5-nitrothiophene-2-carboxaldehyde thiosemicarbazone derivatives[J]. Bioorg. Med. Chem. Lett., 2002, 12: 3475–3478.
[3] Duffy K J, Shaw A N, Delorme E, et al. Identification of a pharmacophore for thrombopoietic activity of small, non-peptidyl molecules. 1. Discovery and optimization of salicylaldehyde thiosemicarbazone thrombopoietin mimics[J]. J. Med. Chem., 2002, 45: 3573-3575.
[4] Yogeeswari P, Sriram D, Kumar S S, et al. Anticonvulsant and neurotoxicity evaluation of some 6-chlorobenzothiazolyl-2-thiosemicarbazones[J]. Eur. J. Med. Chem., 2002, 37: 231-236.
[5] Greenbaum D C, Mackey Z, Hansell E, et al. Synthesis and structure-activity relationships of parasiticidal thiosemicarbazone cysteine protease inhibitors against plasmodium falciparum, trypanosoma brucei, and tTrypanosoma cruzi[J]. J. Med. Chem., 2004, 47: 3212-3219.
[6] Pandeya S N, Sriram D, Nath G, et al. Synthesis, antibacterial, antifungal and anti-HIV activities of Schiff and Mannich bases derived from isatin derivatives and N-[4-(49-chlorophenyl)thiazol-2-yl] thiosemicarbazide[J]. Eur. J. Pharm. Sci., 1999, 9: 25–31.
[7] Balkenhohl F, Lansky A, Zechel C, et al. Combinatorial synthesis of small organic molecules[J]. Angew. Chem. Int.. Ed. Engl., 1996, 35: 2288-2337。
发明内容
本发明的目的是提供了一种具有抗癌活性的3,4-二(3-吲哚)-2,5-二酮-3-吡咯啉亚胺类化合物及其制备方法,是利用活性片段拼接的原理合成了一类新化合物,并对其生物活性进行分析,该类新化合物具有抗癌活性,能够用于制备抗癌药物。
为实现上述目的,本发明采用如下技术方案:3,4-二(3-吲哚)-2,5-二酮-3-吡咯啉亚胺类化合物,其特征在于是以醛类化合物R-CHO和1-氨基-3,4-二(3-吲哚)-3-吡咯啉-2,5-二酮为原料制备而成的,其结构通式如下:,其中R为以下所列结构中的一种:
。
本发明所述的3,4-二(3-吲哚)-2,5-二酮-3-吡咯啉亚胺类化合物的制备方法,其特征在于具体合成步骤为:在反应容器中先加入1-氨基-3,4-二(3-吲哚)-3-吡咯啉-2,5-二酮和无水乙醇,然后加入醛类化合物和乙酸,于回流条件下反应,TLC跟踪,反应结束后,晾至室温,加水生成大量沉淀,抽滤,水洗,再用体积比为1:1的氯仿和正已烷清洗,柱层析分离得到红色固体3,4-二(3-吲哚)-2,5-二酮-3-吡咯啉亚胺类化合物,其中1-氨基-3,4-二(3-吲哚)-3-吡咯啉-2,5-二酮与醛类化合物的摩尔比为1:2,具体反应方程式为:
,
其中醛类化合物为以下所列结构中的一种:
。
进一步优选,所述的1-氨基-3,4-二(3-吲哚)-3-吡咯啉-2,5-二酮是由以下方法制备而成的:
(1)2,3-二氯马来酐的合成
在反应容器中加入马来酐,冰浴条件下加入二氯亚砜,磁力搅拌均匀,用恒压滴液漏斗滴加吡啶,滴加完毕后,冰浴条件下继续搅拌反应,然后撤去冰浴,油浴加热回流,减压蒸去残留的二氯亚砜,得到黄色蜡状固体,用甲苯进行浸取,抽滤,得黄色滤液,反复数次至固体泛白为止,合并滤液,减压蒸去溶剂后得到粗产品2,3-二氯马来酐;
(2)2,3-二氯-N-甲基马来酰亚胺的合成
向反应容器中加入2,3-二氯马来酐、甲胺盐酸盐和冰乙酸,回流条件下磁力搅拌反应,TLC跟踪检测至反应完全,溶液暗褐色,降至室温后加水,以乙酸乙酯萃取,依次用饱和碳酸氢钠溶液和饱和食盐水清洗,减压蒸去溶剂,得褐色粗品,柱层析分离得到白色片状固体2,3-二氯-N-甲基马来酰亚胺;
(3)2,3-二(3-吲哚)-N-甲基马来酰亚胺的合成
a溴乙烷格氏试剂的制备,N2保护下,向反应容器中加入镁条和无水乙醚,并滴加溴乙烷,微热引发反应后剧烈搅拌,滴加溴乙烷使溶剂保持微沸状态,滴加完毕补加无水乙醚,回流使反应充分,得烟灰色溴乙烷格氏试剂,
b吲哚格氏试剂的制备及2,3-二(3-吲哚)-N-甲基马来酰亚胺的制备
先向反应容器中加入四氢呋喃、吲哚和溴乙烷格氏试剂的甲苯溶液,溶液变黑色,40 ℃反应,然后加入2,3-二氯-N-甲基马来酰亚胺的甲苯溶液,滴加完毕,溶液棕黑色,回流条件下反应完全,降至室温,加入饱和NH4Cl溶液猝灭反应,用乙酸乙酯萃取,合并有机相,减压蒸去溶剂,柱层析分离得到红色固体2,3-二(3-吲哚)-N-甲基马来酰亚胺;
(4)2,3-二(3-吲哚)马来酸酐的的合成
在反应容器中加入双吲哚马来酰亚胺和质量浓度为10%的 KOH溶液 ,回流条件下磁力搅拌反应,TLC监测至反应完全,降至室温,用2 mol/L的盐酸猝灭反应,出现红色沉淀,至溶液中性,室温下搅拌,乙酸乙酯萃取,依次以饱和碳酸氢钠溶液和饱和食盐水清洗,无水硫酸镁干燥,过滤,减压蒸去溶剂,得到红色固体2,3-二(3-吲哚)马来酸酐;
(5)1-氨基-3,4-二(3-吲哚)-3-吡咯啉-2,5-二酮的合成
在反应容器中加入双吲哚马来酸酐和四氢呋喃,滴加水合肼,溶液由浑浊变清,加热至回流条件下反应,TLC监测至反应完全,减压蒸去溶剂,用乙酸乙酯萃取,以饱和食盐水洗,以无水硫酸镁干燥,过滤,减压蒸去溶剂,柱层析分离得到红色固体1-氨基-3,4-二(3-吲哚)-3-吡咯啉-2,5-二酮。
本发明所述的抗癌药物组合物,其特征在于包括3,4-二(3-吲哚)-2,5-二酮-3-吡咯啉亚胺类化合物或/和其药学上可接受的盐以及药学上可接受的载体。
本发明的制备方法原料价廉易得,操作简单,制备的3,4-二(3-吲哚)-2,5-二酮-3-吡咯啉亚胺类化合物具有较好的生物活性,在制备抗癌药物化合物中具有较好的应用前景。
具体实施方式
以下通过实施例对本发明的上述内容做进一步详细说明,但不应该将此理解为本发明上述主题的范围仅限于以下的实施例,凡基于本发明上述内容实现的技术均属于本发明的范围。
实施例
(1)2,3-二氯马来酐的合成
反应路线:
反应步骤:
在干燥的250 mL 圆底烧瓶中,加入9.8 g (0.1 mol )马来酐,冰浴条件下,加入二氯亚砜100 mL(1.38 mol),磁力搅拌均匀,用恒压滴液漏斗滴加吡啶16.6 mL(0.2 mol),1 h滴加完毕。滴加完毕后,冰浴条件下继续搅拌1 h。撤去冰浴,油浴加热到75 ℃, 回流40 min。减压蒸去残留的二氯亚砜,得到黄色蜡状固体。用甲苯进行浸取,抽滤,得黄色滤液,反复数次至固体泛白为止。合并滤液,减压蒸去溶剂后得到粗产品10.9 g,收率65.9%。
(2)2,3-二氯-N-甲基马来酰亚胺的合成。
反应路线:
反应步骤:
向250 mL圆底烧瓶中加入2,3-二氯马来酐10.9 g(65.9 mmol) 和甲胺盐酸盐4.42 g(65.9 mmol),加入冰乙酸100 mL,回流条件下磁力搅拌6 h,TLC跟踪检测至反应完全。溶液暗褐色,降至室温后,加水100 mL,以乙酸乙酯萃取,依次用饱和碳酸氢钠溶液和饱和食盐水清洗,减压蒸去溶剂,得褐色粗品,柱层析分离(石油醚:乙酸乙酯=9:1,硅胶200-300目)得到白色片状固体7.3 g,收率62%。
(3)2,3-二(3-吲哚)-N-甲基马来酰亚胺的合成
反应路线:
反应步骤:
a溴乙烷格氏试剂的制备
N2保护下,向250 mL三颈瓶中加入镁条1.5 g(61.6 mmol),加入无水乙醚10 mL,滴加溴乙烷4.56 mL(61.6 mmol),微热使引发后,剧烈搅拌,缓慢滴加溴乙烷,使溶剂保持微沸状态。滴加完毕,补加无水乙醚10 mL,40 ℃下回流约1 h使反应充分,得烟灰色溴乙烷格氏试剂。
b吲哚格氏试剂的制备及2,3-二(3-吲哚)-N-甲基马来酰亚胺的制备
先向反应瓶中加入THF(10 mL),加入40 mL吲哚和7.2 g(61.6 mmol) 溴乙烷格氏试剂的甲苯溶液,溶液变黑色,40 ℃下反应约1 h。加入40 mL 2,3-二氯-N-甲基马来酰亚胺5 g(28 mmol)的甲苯溶液,约40 min 滴加完毕,溶液红黑色。回流条件下反应约6 h反应完全。降至室温后,加入80mL饱和NH4Cl溶液猝灭反应,用乙酸乙酯萃取(5×50 mL),合并有机相,减压蒸去溶剂,柱层析分离(石油醚:乙酸乙酯=3:1,硅胶200-300目)得到红色固体5.26 g, 收率55.1%
(4)2,3-二(3-吲哚)马来酸酐的的合成。
反应路线:
反应步骤:
在25 mL圆底烧瓶中加入双吲哚马来酰亚胺500 mg(1.46 mmol),加入质量浓度为10%的KOH溶液10 mL,回流条件下磁力搅拌约3 h, TLC监测至反应完全。降至室温后,以2 M盐酸猝灭反应,出现大量红色沉淀,至溶液中性,室温下搅拌1 h,用乙酸乙酯萃取(4×20 mL),以饱和碳酸氢钠溶液(3×30 mL)和饱和食盐水(3×30 mL)清洗,以无水硫酸镁干燥,过滤。减压蒸去溶剂,得到红色固体478 mg(100%)。
(5)1-氨基-3,4-二(3-吲哚)-3-吡咯啉-2,5-二酮的合成。
反应路线:
反应步骤:
在25 mL圆底烧瓶中加入双吲哚马来酸酐478 mg(1.46 mmol),加入THF(20 mL),滴加水合肼500 mg(10 mmol),溶液由浑浊变清澈,反应放热,回流条件下反应。TLC监测,20 min反应完全。减压蒸去溶剂,用乙酸乙酯萃取,以饱和食盐水清洗(5×50 mL),以无水硫酸镁干燥,过滤,减压蒸去溶剂,柱层析分离(石油醚:乙酸乙酯=1:2 )得到红色固体397.5 mg,收率 80%。
(6)3,4-二(3-吲哚)-2,5-二酮-3-吡咯啉亚胺类化合物的合成
反应路线:
其中R-CHO为以下所列结构:
反应步骤:
在25 mL圆底烧瓶中加入85.5 mg(0.25 mmol) 1-氨基-3,4-二(3-吲哚)-3-吡咯啉-2,5-二酮和无水乙醇5 mL,然后加入醛类化合物(0.5 mmol)和乙酸0.01 mL(0.002 mmol),回流条件下反应,TLC跟踪。反应结束后,冷至室温,加入约10 mL水, 生成大量沉淀,抽滤,水洗,体积比为1:1的氯仿和正已烷清洗,柱层析分离(石油醚:乙酸乙酯=1:1)得到红色固体,收率78%-95%,原料不同,对应的产物如下。
活性研究:
此系列化合物在国家新药筛选中心进行了初步活性研究,初步的抗肿瘤活性测试表明,20 μg /mL 的3,4-二(3-吲哚)-2,5-二酮-3-吡咯啉亚胺类化合物对细胞周期分裂蛋白25B(CDC 25B)有很好的抑制作用。
1、
(E)-1-(benzylideneamino)-3,4-di(1H-indol-3-yl)-1H-pyrrole-2,5-dione
1H NMR (400 MHz, DMSO-d 6 ) δ 11.75 (s, 2H), 9.29 (s, 1H), 7.94 – 7.86 (m, 2H), 7.83 (d, J = 2.5 Hz, 2H), 7.57 – 7.50 (m, 3H), 7.40 (d, J = 8.1 Hz, 2H), 7.01 (t, J = 7.5 Hz, 2H), 6.87 (d, J = 8.0 Hz, 2H), 6.67 (t, J = 7.5 Hz, 2H).13C NMR (100 MHz, DMSO-d 6 ) δ 168.48 (s), 157.55 (s), 136.21 (s), 131.61 (s), 129.85 (s), 129.20 (s), 127.95 (s), 126.29 (s), 125.48 (s), 122.05 (s), 121.16 (s), 119.76 (s), 112.08 (s), 105.53 (s). HRMS (ESI), m/z calcd. for C27H18N4O2 ([M+Na]+) 453.1322, found: 453.1326,对CDC 25B的抑制率为99.37±0.77%。
2、
(E)-3,4-di(1H-indol-3-yl)-1-((2-methylbenzylidene)amino)-1H-pyrrole-2,5-dione 1H NMR (400 MHz, DMSO-d 6 ) δ 11.79 (s, 2H), 9.24 (s, 1H), 7.82 (s, 2H), 7.73 – 7.65 (m, 2H), 7.43 – 7.35 (m, 4H), 7.00 (t, J = 7.5 Hz, 2H), 6.85 (d, J = 8.0 Hz, 2H), 6.67 (t, J = 7.6 Hz, 2H), 2.40 (s, 3H).13C NMR (100 MHz, DMSO-d 6 ) δ168.36 (s), 157.53 (s), 138.41 (s), 136.12 (s), 133.81 (s), 132.18 (s), 129.77 (s), 129.00 (s), 128.02 (s), 126.17 (s), 125.37 (s), 125.34 (s), 121.92 (s), 121.10 (s), 119.64 (s), 111.98 (s), 105.42 (s), 20.97 (s). HRMS (ESI), m/z calcd. for C28H20N4O2 ([M+Na]+) 467.1478, found: 467.1478,对CDC 25B的抑制率为95.04±0.58%。
3、
(E)-3,4-di(1H-indol-3-yl)-1-((3-methylbenzylidene)amino)-1H-pyrrole-2,5-dione 1H NMR (400 MHz, DMSO-d 6 ) δ 11.79 (s, 2H), 9.24 (s, 1H), 7.83 (s, 2H), 7.73 – 7.64 (m, 2H), 7.43 – 7.34 (m, 4H), 7.01 (t, J = 7.6 Hz, 2H), 6.85 (d, J = 8.0 Hz, 2H), 6.67 (t, J = 7.5 Hz, 2H), 2.40 (s, 3H).13C NMR (101 MHz, DMSO-d 6 ) δ168.38 (s), 157.49 (s), 138.42 (s), 136.13 (s), 133.83 (s), 132.20 (s), 129.79 (s), 129.01 (s), 128.03 (s), 126.17 (s), 125.39 (s), 125.35 (s), 121.93 (s), 121.12 (s), 119.66 (s), 112.00 (s), 105.44 (s),20.98 (s). HRMS (ESI), m/z calcd. for C28H20N4O2 ([M+Na]+) 467.1478, found: 467.1462,对CDC 25B的抑制率为94.74±1.48%。
4、
(E)-3,4-di(1H-indol-3-yl)-1-((4-methylbenzylidene)amino)-1H-pyrrole-2,5-dione 86% 1H NMR (400 MHz, DMSO-d 6 ) δ 11.77 (s, 2H), 9.22 (s, 1H), 7.89 – 7.71 (m, 4H), 7.37 (dd, J = 22.2, 8.1 Hz, 4H), 7.00 (dd, J = 11.2, 4.0 Hz, 2H), 6.86 (d, J = 8.0 Hz, 2H), 6.67 (t, J = 7.3 Hz, 2H), 2.39 (s, 3H).13C NMR (100 MHz, DMSO-d 6 ) δ 168.26 (s), 136.02 (s), 131.07 (s), 129.60 (d, J = 6.5 Hz), 127.74 (s), 126.05 (s), 125.27 (s), 121.75 (s), 121.00 (s), 119.49 (s), 111.84 (s), 105.33 (s), 21.12 (s). HRMS (ESI), m/z calcd. for C28H20N4O2 ([M+Na]+) 467.1478, found: 467.1479,对CDC 25B的抑制率为95.90±1.60%。
5、
(E)-1-((2-chlorobenzylidene)amino)-3,4-di(1H-indol-3-yl)-1H-pyrrole-2,5-dione 1H NMR (400 MHz, DMSO-d 6 ) δ 11.80 (s, 2H), 9.78 (s, 1H), 8.13 (d, J = 7.5 Hz, 1H), 7.85 (d, J = 2.4 Hz, 2H), 7.62 (d, J = 7.7 Hz, 1H), 7.55 (dd, J = 18.9, 7.3 Hz, 2H), 7.40 (d, J = 8.1 Hz, 2H), 7.00 (t, J = 7.5 Hz, 2H), 6.84 (d, J = 8.0 Hz, 2H), 6.66 (t, J = 7.6 Hz, 2H). HRMS (ESI), m/z calcd. for C27H17ClN4O2 ([M+Na]+) 487.0932, found: 487.0929,对CDC 25B的抑制率为94.79±1.26%。
6、
(E)-1-((3-chlorobenzylidene)amino)-3,4-di(1H-indol-3-yl)-1H-pyrrole-2,5-dione 1H NMR (400 MHz, DMSO-d 6 ) δ 11.77 (s, 2H), 9.36 (s, 1H), 7.94 (s, 1H), 7.83 (d, J = 10.4 Hz, 3H), 7.58 (d, J = 13.0 Hz, 2H), 7.40 (d, J = 8.1 Hz, 2H), 7.01 (t, J = 7.4 Hz, 2H), 6.86 (d, J = 7.9 Hz, 2H), 6.68 (d, J = 7.9 Hz, 2H). HRMS (ESI), m/z calcd. for C27H17ClN4O2 ([M+Na]+) 487.0932, found: 487.0931,对CDC 25B的抑制率为90.87±1.00%。
7、
(E)-1-((4-chlorobenzylidene)amino)-3,4-di(1H-indol-3-yl)-1H-pyrrole-2,5-dione 1H NMR (400 MHz, DMSO-d 6 ) δ 11.78 (s, 2H), 9.33 (s, 1H), 7.91 (d, J = 8.6 Hz, 2H), 7.83 (s, 2H), 7.60 (d, J = 8.5 Hz, 2H), 7.41 (d, J = 8.1 Hz, 2H), 7.01 (dd, J = 11.2, 4.0 Hz, 2H), 6.87 (d, J = 8.0 Hz, 2H), 6.67 (dd, J = 11.2, 4.0 Hz, 2H).13C NMR (100 MHz, DMSO-d 6 )δ168.17 (s), 155.14 (s), 136.04 (s), 135.81 (s), 132.82 (s), 129.72 (s), 129.34 (s), 129.11 (s), 126.13 (s), 125.27 (s), 121.80 (s), 121.04 (s), 119.53 (s), 111.88 (s), 105.30 (s). HRMS (ESI), m/z calcd. for C27H17ClN4O2 ([M+Na]+) 487.0932, found: 487.0926,对CDC 25B的抑制率为92.47±1.02%。
8、
(E)-1-((2-bromobenzylidene)amino)-3,4-di(1H-indol-3-yl)-1H-pyrrole-2,5-dione 87.7% 1H NMR (400 MHz, DMSO-d 6 )δ 11.79 (s, 2H), 9.75 (s, 1H), 8.11 (dd, J = 7.8, 1.7 Hz, 1H), 7.86 (d, J = 2.5 Hz, 2H), 7.78 (d, J = 8.0 Hz, 1H), 7.55 (t, J = 7.6 Hz, 1H), 7.47 (t, J = 7.6 Hz, 1H), 7.40 (d, J = 8.2 Hz, 2H), 7.05 – 6.95 (m, 2H), 6.85 (d, J = 8.1 Hz, 2H), 6.67 (t, J = 7.5 Hz, 2H).13C NMR (100 MHz, DMSO-d 6 ) δ 168.21 (s), 153.02 (s), 136.01 (s), 133.31 (s), 132.81 (s), 129.77 (s), 128.26 (s), 127.23 (s), 126.17 (s), 125.29 (s), 124.46 (s), 121.76 (s), 120.99 (s), 119.51 (s), 111.84 (s), 105.25 (s), 99.49 (s). HRMS (ESI), m/z calcd. for C27H17BrN4O2 ([M+Na]+) 531.0427, found: 531.0421,对CDC 25B的抑制率为90.15±3.96%。
9、
(E)-1-((3-bromobenzylidene)amino)-3,4-di(1H-indol-3-yl)-1H-pyrrole-2,5-dione 1H NMR (400 MHz, DMSO-d 6 ) δ 11.80 (s, 2H), 9.34 (s, 1H), 8.08 (s, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.82 (d, J = 2.1 Hz, 2H), 7.74 (d, J = 8.0 Hz, 1H), 7.49 (t, J = 7.8 Hz, 1H), 7.40 (d, J = 8.1 Hz, 2H), 7.01 (t, J = 7.6 Hz, 2H), 6.85 (d, J = 8.0 Hz, 2H), 6.67 (t, J = 7.5 Hz, 2H).13C NMR (100 MHz, DMSO-d 6 ) δ 168.17 (s), 154.25 (s), 136.39 (s), 136.08 (s), 133.79 (s), 131.20 (s), 129.80 (s), 129.72 (s), 126.90 (s), 126.16 (s), 125.28 (s), 122.32 (s), 121.86 (s), 121.09 (s), 119.59 (s), 111.94 (s), 105.31 (s). HRMS (ESI), m/z calcd. for C27H17BrN4O2 ([M+Na]+) 531.0427, found: 531.0415,对CDC 25B的抑制率为85.22±0.99%。
10、
(E)-1-((4-bromobenzylidene)amino)-3,4-di(1H-indol-3-yl)-1H-pyrrole-2,5-dione 1H NMR (400 MHz, DMSO-d 6 ) δ 11.79 (s, 2H), 9.32 (s, 1H), 7.85 (s, 1H), 7.82 (s, 3H), 7.74 (d, J = 8.1 Hz, 2H), 7.40 (d, J = 8.1 Hz, 2H), 7.00 (t, J = 7.5 Hz, 2H), 6.85 (d, J = 8.2 Hz, 2H), 6.67 (t, J = 7.6 Hz, 2H).13C NMR (100 MHz, DMSO-d 6 ) δ168.24 (s), 155.33 (s), 136.09 (s), 133.21 (s), 132.12 (s), 129.80 (s), 129.61 (s), 126.17 (s), 125.32 (s), 124.80 (s), 121.89 (s), 121.09 (s), 119.62 (s), 111.97 (s), 105.35 (s). HRMS (ESI), m/z calcd. for C27H17BrN4O2 ([M+Na]+) 531.0427, found: 531.0422,对CDC 25B的抑制率为94.88±1.15%。
11、
(E)-1-((2-fluorobenzylidene)amino)-3,4-di(1H-indol-3-yl)-1H-pyrrole-2,5-dione 1H NMR (400 MHz, DMSO-d 6 ) δ 11.81 (s, 2H), 9.57 (s, 1H), 8.06 (t, J = 7.3 Hz, 1H), 7.85 (s, 2H), 7.65 – 7.52 (m, 1H), 7.38 (dd, J = 19.0, 7.5 Hz, 4H), 7.01 (t, J = 7.5 Hz, 2H), 6.86 (d, J = 8.0 Hz, 2H), 6.67 (t, J = 7.5 Hz, 2H), 3.39 (s, 2H).13C NMR (100 MHz, DMSO-d 6 ) δ 168.24 (s), 163.66 – 161.29 (m), 160.10 (s), 148.34 (s), 136.08 (s), 129.82 (s), 126.41 (s), 126.14 (s), 125.32 (s), 125.10 (s), 121.82 (s), 121.09 (s), 119.58 (s), 116.34 (s), 116.13 (s), 111.91 (s), 105.32 (s). HRMS (ESI), m/z calcd. for C27H17FN4O2 ([M+Na]+) 471.1228, found: 471.1227,对CDC 25B的抑制率为88.68±5.05%。
12、
(E)-1-((3-fluorobenzylidene)amino)-3,4-di(1H-indol-3-yl)-1H-pyrrole-2,5-dione 1H NMR (400 MHz, DMSO-d 6 ) δ 11.81 (d, J = 2.3 Hz, 2H), 9.37 (s, 1H), 7.83 (d, J = 2.8 Hz, 2H), 7.72 (dd, J = 16.3, 8.8 Hz, 2H), 7.59 (dd, J = 13.9, 7.9 Hz, 1H), 7.39 (dd, J = 14.5, 5.5 Hz, 3H), 7.01 (t, J = 7.6 Hz, 2H), 6.86 (d, J = 8.0 Hz, 2H), 6.68 (t, J = 7.4 Hz, 2H).13C NMR (100 MHz, DMSO-d 6 ) δ168.21 (s), 161.24 (s), 154.78 (s), 136.11 (s), 131.22 – 131.15 (m), 131.11 (s), 129.81 (s), 126.20 (s), 125.32 (s), 124.19 (s), 121.88 (s), 121.11 (s), 119.61 (s), 113.73 (s), 113.50 (s), 111.95 (s), 105.35 (s). HRMS (ESI), m/z calcd. for C27H17FN4O2 ([M+Na]+) 471.1228, found: 471.1229,对CDC 25B的抑制率为91.69±2.08%。
13、
(E)-1-((4-fluorobenzylidene)amino)-3,4-di(1H-indol-3-yl)-1H-pyrrole-2,5-dione 1H NMR (400 MHz, DMSO-d 6 )δ 11.79 (d, J = 2.2 Hz, 2H), 9.29 (s, 1H), 7.96 (dd, J = 8.6, 5.7 Hz, 2H), 7.82 (d, J = 2.7 Hz, 2H), 7.43 – 7.34 (m, 4H), 7.01 (t, J = 7.6 Hz, 2H), 6.86 (d, J = 8.1 Hz, 2H), 6.67 (t, J = 7.6 Hz, 2H).13C NMR (100 MHz, DMSO-d 6 ) δ168.25 (s), 155.85 (s), 136.07 (s), 130.11 (d, J = 8.8 Hz), 130.07 (s), 129.72 (s), 126.09 (s), 125.31 (s), 121.82 (s), 121.07 (s), 119.56 (s), 116.24 (s), 116.02 (s), 111.91 (s), 105.35 (s). HRMS (ESI), m/z calcd. for C27H17FN4O2 ([M+Na]+) 471.1228, found: 471.1230,对CDC 25B的抑制率为87.98±6.47%。
14、
(E)-3,4-di(1H-indol-3-yl)-1-((2-methoxybenzylidene)amino)-1H-pyrrole-2,5-dione 1H NMR (400 MHz, DMSO-d 6 )δ 11.78 (s, 2H), 9.59 (s, 1H), 8.02 – 7.97 (m, 1H), 7.85 (d, J = 2.6 Hz, 2H), 7.55 – 7.48 (m, 1H), 7.40 (d, J = 8.1 Hz, 2H), 7.17 (d, J = 8.4 Hz, 1H), 7.08 (t, J = 7.5 Hz, 1H), 7.00 (t, J = 7.5 Hz, 2H), 6.86 (d, J = 8.0 Hz, 2H), 6.67 (t, J = 7.5 Hz, 2H), 3.90 (s, 3H).13C NMR (100 MHz, DMSO-d 6 ) δ168.39 (s), 158.49 (s), 151.80 (s), 136.03 (s), 132.95 (s), 129.70 (s), 126.03 (s), 125.59 (s), 125.34 (s), 121.76 (s), 121.03 (s), 120.79 (s), 119.50 (s), 111.94 (d, J = 17.9 Hz), 105.36 (s), 55.81 (s). HRMS (ESI), m/z calcd. for C28H20N4O3 ([M+Na]+) 483.1428, found: 483.1428,对CDC 25B的抑制率为95.59±2.42%。
15、
(E)-3,4-di(1H-indol-3-yl)-1-((3-methoxybenzylidene)amino)-1H-pyrrole-2,5-dione.Mp 148-150oC;1H NMR (400 MHz, DMSO-d 6 ) δ 11.78 (s, 2H), 9.27 (s, 1H), 7.82 (d, J = 2.6 Hz, 2H), 7.42 (dd, J = 17.1, 7.0 Hz, 5H), 7.15 – 7.07 (m, 1H), 7.01 (t, J = 7.6 Hz, 2H), 6.87 (d, J = 8.0 Hz, 2H), 6.67 (t, J = 7.6 Hz, 2H), 3.83 (s, 3H). HRMS (ESI), m/z calcd. for C28H20N4O3 ([M+Na]+) 483.1428, found: 483.1426,对CDC 25B的抑制率为89.33±1.04%。
16、
(E)-3,4-di(1H-indol-3-yl)-1-((4-methoxybenzylidene)amino)-1H-pyrrole-2,5-dione.Mp 208-211 oC;1H NMR (400 MHz, DMSO-d 6 ) δ 11.77 (s, 2H), 9.14 (s, 1H), 7.83 (dd, J = 9.0, 5.8 Hz, 4H), 7.40 (d, J = 8.1 Hz, 2H), 7.09 (d, J = 8.3 Hz, 2H), 7.00 (t, J = 7.6 Hz, 2H), 6.85 (d, J = 8.1 Hz, 2H), 6.67 (t, J = 7.5 Hz, 2H), 3.84 (d, J = 1.2 Hz, 3H). HRMS (ESI), m/z calcd. for C28H20N4O3 ([M+Na]+) 483.1428, found: 483.1429,对CDC 25B的抑制率为96.94±0.01%。
17、
(E)-1-((2,4-dinitrobenzylidene)amino)-3,4-di(1H-indol-3-yl)-1H-pyrrole-2,5-dione 1H NMR (400 MHz, DMSO-d 6 ) δ11.82 (s, 2H), 9.98 (d, J = 5.4 Hz, 1H), 8.87 – 8.74 (m, 1H), 8.63 (d, J = 10.4 Hz, 1H), 8.39 (dd, J = 14.9, 8.5 Hz, 1H), 7.86 (s, 2H), 7.40 (d, J = 8.1 Hz, 2H), 7.00 (t, J = 7.6 Hz, 2H), 6.84 (d, J = 8.0 Hz, 2H), 6.66 (t, J = 7.5 Hz, 2H).HRMS (ESI), m/z calcd. for C27H16N6O6 ([M+Na]+) 543.1024, found: 543.1006,对CDC 25B的抑制率为93.70±0.24%。
18、
(E)-3,4-di(1H-indol-3-yl)-1-((3-nitrobenzylidene)amino)-1H-pyrrole-2,5-dione 1H NMR (400 MHz, DMSO-d 6 ) δ 11.81 (s, 2H), 9.55 (s, 1H), 8.72 (s, 1H), 8.34 (dd, J = 17.0, 8.0 Hz, 2H), 7.82 (t, J = 5.6 Hz, 3H), 7.41 (d, J = 8.1 Hz, 2H), 7.01 (t, J = 7.6 Hz, 2H), 6.86 (d, J = 8.1 Hz, 2H), 6.68 (t, J = 7.5 Hz, 2H).13C NMR (100 MHz, DMSO-d 6 ) δ 168.11 (s), 153.13 (s), 148.30 (s), 136.08 (s), 135.83 (s), 133.97 (s), 130.69 (s), 129.85 (s), 126.23 (s), 125.41 (s), 125.26 (s), 121.88 (s), 121.54 (s), 121.11 (s), 119.61 (s), 111.96 (s), 105.28 (s). HRMS (ESI), m/z calcd. for C27H17N5O4 ([M+Na]+) 498.1173, found: 498.1172,对CDC 25B的抑制率为91.89±1.31%。
19、
(E)-3,4-di(1H-indol-3-yl)-1-((4-nitrobenzylidene)amino)-1H-pyrrole-2,5-dione 1H NMR (400 MHz, DMSO-d 6 ) δ11.80 (s, 2H), 9.53 (s, 1H), 8.34 (d, J = 8.8 Hz, 2H), 8.12 (d, J = 8.8 Hz, 2H), 7.83 (d, J = 2.1 Hz, 2H), 7.41 (d, J = 8.1 Hz, 2H), 7.01 (t, J = 7.4 Hz, 2H), 6.86 (d, J = 8.0 Hz, 2H), 6.68 (t, J = 7.5 Hz, 2H). 13C NMR (100 MHz, DMSO-d 6 ) δ 168.04 (s), 152.51 (s), 140.17 (s), 136.07 (s), 129.83 (s), 128.62 (s), 126.30 (s), 125.25 (s), 124.11 (s), 121.85 (s), 121.09 (s), 119.59 (s), 111.92 (s), 105.27 (s). HRMS (ESI), m/z calcd. for C27H17N5O4 ([M+Na]+) 498.1173, found: 498.1173,对CDC 25B的抑制率为97.56±6.43%。
20、
(E)-1-((2-hydroxybenzylidene)amino)-3,4-di(1H-indol-3-yl)-1H-pyrrole-2,5-dione 1H NMR (400 MHz, DMSO-d 6 ) δ 11.80 (s, 2H), 10.80 (s, 1H), 9.49 (s, 1H), 7.83 (d, J = 2.2 Hz, 2H), 7.77 (d, J = 7.8 Hz, 1H), 7.39 (t, J = 9.6 Hz, 3H), 6.99 (dt, J = 9.1, 6.5 Hz, 4H), 6.85 (d, J = 8.0 Hz, 2H), 6.66 (t, J = 7.6 Hz, 2H). 13C NMR (101 MHz, DMSO-d 6 ) δ 168.47 (s), 136.30 (s), 131.06 (s), 130.71 (s), 130.00 (s), 129.86 (s), 129.23 (s), 127.75 (s), 126.39 (s), 125.91 (s), 125.60 (s), 125.07 (s), 122.02 (s), 121.27 (s), 119.79 (s), 112.12 (s), 105.67 (s). HRMS (ESI), m/z calcd. for C27H18N4O3 ([M+Na]+) 469.1271, found: 469.1271,对CDC 25B的抑制率为93.73±0.25%。
21、
(E)-1-((4-(dimethylamino)benzylidene)amino)-3,4-di(1H-indol-3-yl)-1H-pyrrole-2,5-dione 1H NMR (400 MHz, DMSO-d 6 ) δ11.74 (s, 2H), 8.92 (s, 1H), 7.81 (s, 2H), 7.67 (t, J = 13.1 Hz, 2H), 7.39 (d, J = 8.1 Hz, 2H), 7.00 (t, J = 7.6 Hz, 2H), 6.83 (dd, J = 19.1, 8.3 Hz, 4H), 6.66 (t, J = 7.5 Hz, 2H), 3.19 – 2.87 (m, 6H). HRMS (ESI), m/z calcd. for C29H23N5O2 ([M+Na]+) 496.1744, found: 496.1740,对CDC 25B的抑制率为96.26±0.14%。
22、
(E)-1-(((1H-pyrrol-2-yl)methylene)amino)-3,4-di(1H-indol-3-yl)-1H-pyrrole-2,5-dione 1H NMR (400 MHz, DMSO-d 6 ) δ 11.76 (d, J = 2.0 Hz, 2H), 8.83 (s, 1H), 7.81 (d, J = 2.7 Hz, 2H), 7.40 (d, J = 8.1 Hz, 2H), 7.02 (dd, J = 19.8, 11.9 Hz, 3H), 6.84 (t, J = 11.1 Hz, 2H), 6.68 (dd, J = 18.3, 10.6 Hz, 3H), 6.24 (dd, J = 5.6, 2.3 Hz, 1H).13C NMR (100 MHz, DMSO-d 6 ) δ 168.64 (s), 152.24 (s), 136.24 (s), 129.76 (s), 126.61 (s), 126.08 (s), 125.52 (s), 124.37 (s), 121.95 (s), 121.21 (s), 119.69 (s), 116.43 (s), 112.06 (s), 110.05 (s), 105.63 (s). HRMS (ESI), m/z calcd. for C25H17N5O2 ([M+Na]+) 442.1274, found: 442.1273,对CDC 25B的抑制率为93.23±0.92%。
23、
(E)-3,4-di(1H-indol-3-yl)-1-((thiophen-2-ylmethylene)amino)-1H-pyrrole-2,5-dione 1H NMR (400 MHz, DMSO-d 6 ) δ 11.78 (s, 2H), 9.44 (s, 1H), 7.81 (t, J = 5.0 Hz, 3H), 7.71 (d, J = 3.2 Hz, 1H), 7.40 (d, J = 8.1 Hz, 2H), 7.26 – 7.20 (m, 1H), 7.01 (t, J = 7.5 Hz, 2H), 6.86 (d, J = 8.0 Hz, 2H), 6.67 (t, J = 7.5 Hz, 2H).13C NMR (100 MHz, DMSO-d 6 ) δ 168.77 (s), 152.49 (s), 136.37 (s), 129.89 (s), 126.74 (s), 126.20 (s), 125.65 (s), 124.51 (s), 122.09 (s), 121.34 (s), 119.83 (s), 116.58 (s), 112.19 (s), 110.19 (s), 105.76 (s). HRMS (ESI), m/z calcd. for C25H16N4O2S ([M+Na]+) 459.0886, found: 459.0884,对CDC 25B的抑制率为93.17±1.63%。
24、
(E)-3,4-di(1H-indol-3-yl)-1-((pyridin-2-ylmethylene)amino)-1H-pyrrole-2,5-dione 1H NMR (400 MHz, DMSO-d 6) δ 11.79 (s, 2H), 9.39 (s, 1H), 8.71 (d, J = 4.2 Hz, 1H), 8.10 (d, J = 7.9 Hz, 1H), 7.97 (t, J = 7.1 Hz, 1H), 7.84 (s, 2H), 7.55 – 7.49 (m, 1H), 7.40 (d, J = 8.1 Hz, 2H), 7.01 (t, J = 7.6 Hz, 2H), 6.85 (d, J = 8.0 Hz, 2H), 6.67 (t, J = 7.6 Hz, 2H) 13C NMR (100 MHz, DMSO-d 6)δ 168.20 (s), 155.14 (s), 152.92 (s), 149.89 (s), 137.22 (s), 136.11 (s), 129.84 (s), 126.36 (s), 125.42 (s), 125.35 (s), 121.90 (s), 121.09 (s), 119.63 (s), 111.96 (s), 105.34 (s)HRMS (ESI), m/z calcd. for C26H17N5O2 ([M+Na]+) 454.1274, found: 454.1283,对CDC 25B的抑制率为84.98±0.27%。
25、
(E)-3,4-di(1H-indol-3-yl)-1-((pyridin-3-ylmethylene)amino)-1H-pyrrole-2,5-dione 1H NMR (400 MHz, DMSO-d 6 ) δ11.80 (s, 2H), 9.43 (s, 1H), 9.02 (s, 1H), 8.71 (d, J = 4.6 Hz, 1H), 8.30 (d, J = 8.2 Hz, 1H), 7.83 (s, 2H), 7.59 – 7.54 (m, 1H), 7.40 (d, J = 8.1 Hz, 2H), 7.01 (t, J = 7.5 Hz, 2H), 6.86 (d, J = 8.0 Hz, 2H), 6.68 (t, J = 7.6 Hz, 2H). HRMS (ESI), m/z calcd. for C26H17N5O2 ([M]+) 432.1455, found: 432.1459,对CDC 25B的抑制率为86.70±1.80%。
26、
(E)-3,4-di(1H-indol-3-yl)-1-((quinolin-3-ylmethylene)amino)-1H-pyrrole-2,5-dione 1H NMR (400 MHz, DMSO-d 6 ) δ11.81 (s, 2H), 9.59 (s, 1H), 9.41 (s, 1H), 8.83 (s, 1H), 8.13 (dd, J = 15.6, 8.3 Hz, 2H), 7.85 (s, 2H), 7.72 (dd, J = 16.1, 8.7 Hz, 2H), 7.41 (d, J = 8.1 Hz, 2H), 7.02 (t, J = 7.5 Hz, 2H), 6.88 (d, J = 8.0 Hz, 2H), 6.69 (t, J = 7.6 Hz, 2H). 13C NMR (101 MHz, DMSO-d 6 ) δ 168.23 (s), 153.71 (s), 148.44 (s), 148.36 (s), 136.24 (s), 136.11 (s), 129.85 (s), 129.05 (s), 128.97 (s), 127.57 (s), 127.25 (s), 127.12 (s), 126.21 (s), 125.35 (d, J = 8.8 Hz), 121.89 (s), 121.14 (s), 119.63 (s), 111.97 (s), 105.33 (s). HRMS (ESI), m/z calcd. for C30H19N5O2 ([M]+) 482.1612, found: 482.1612,对CDC 25B的抑制率为88.19±0.13%。
27、
(E)-3,4-di(1H-indol-3-yl)-1-((quinolin-2-ylmethylene)amino)-1H-pyrrole-2,5-dione 1H NMR (400 MHz, DMSO-d 6 ) δ 11.82 (s, 2H), 9.58 (d, J = 3.5 Hz, 1H), 8.52 (d, J = 8.9 Hz, 1H), 8.23 (d, J = 8.6 Hz, 1H), 8.12 (d, J = 8.8 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.84 (d, J = 10.6 Hz, 3H), 7.70 (t, J = 7.4 Hz, 1H), 7.41 (d, J = 8.2 Hz, 2H), 7.01 (t, J = 7.6 Hz, 2H), 6.85 (d, J = 7.4 Hz, 2H), 6.68 (s, 2H).13C NMR (100 MHz, DMSO-d 6 ) δ168.27 (s), 154.56 (s), 153.58 (s), 147.55 (s), 137.28 (s), 136.21 (s), 130.47 (s), 130.00 (s), 129.27 (s), 128.40 (s), 128.22 (s), 128.00 (s), 126.55 (s), 125.43 (s), 122.04 (s), 121.20 (s), 119.77 (s), 117.37 (s), 112.08 (s), 105.42 (s). HRMS (ESI), m/z calcd. for C30H19N5O2 ([M]+) 482.1612, found: 482.1611,对CDC 25B的抑制率为87.29±2.83%。
28、
(E)-1-(((1H-indol-3-yl)methylene)amino)-3,4-di(1H-indol-3-yl)-1H-pyrrole-2,5-dione 1H NMR (400 MHz, DMSO-d 6 ) δ 11.84 (s, 1H), 11.75 (s, 2H), 9.19 (s, 1H), 8.28 (d, J = 7.4 Hz, 1H), 8.04 (d, J = 2.8 Hz, 1H), 7.82 (d, J = 2.7 Hz, 2H), 7.50 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 8.1 Hz, 2H), 7.23 (dt, J = 14.9, 7.1 Hz, 2H), 7.00 (t, J = 7.6 Hz, 2H), 6.87 (d, J = 8.0 Hz, 2H), 6.67 (t, J = 7.6 Hz, 2H). HRMS (ESI), m/z calcd. for C29H19N5O2 ([M]+) 470.1612, found: 470.1611,对CDC 25B的抑制率为92.80±2.52%。
29、
(E)-1-((anthracen-9-ylmethylene)amino)-3,4-di(1H-indol-3-yl)-1H-pyrrole-2,5-dione 1H NMR (400 MHz, DMSO-d 6 ) δ11.83 (s, 2H), 10.27 (s, 1H), 8.84 (s, 1H), 8.78 (d, J = 8.8 Hz, 2H), 8.22 (d, J = 8.3 Hz, 2H), 7.93 (d, J = 2.6 Hz, 2H), 7.73 – 7.67 (m, 2H), 7.66 – 7.60 (m, 2H), 7.42 (d, J = 8.1 Hz, 2H), 7.02 (t, J = 7.6 Hz, 2H), 6.91 (d, J = 8.0 Hz, 2H), 6.69 (t, J = 7.6 Hz, 2H).13C NMR (100 MHz, DMSO-d 6 ) δ168.09 (s), 157.87 (s), 155.52 (s), 136.05 (s), 132.74 (s), 129.74 (s), 128.69 (s), 126.07 (s), 125.29 (s), 121.81 (s), 121.06 (s), 119.55 (s), 118.99 (s), 116.59 (s), 111.89 (s), 105.34 (s). HRMS (ESI), m/z calcd. for C35H22N4O2 ([M]+) 531.1816, found: 531.1815,对CDC 25B的抑制率为92.14±0.97%。
30、
3,4-di(1H-indol-3-yl)-1-((E)-((E)-3-phenylallylidene)amino)-1H-pyrrole-2,5-dione 1H NMR (400 MHz, DMSO-d 6 ) δ 11.77 (s, 2H), 9.08 (d, J = 9.2 Hz, 1H), 7.82 (d, J = 2.7 Hz, 2H), 7.69 (d, J = 7.1 Hz, 2H), 7.38 (m, J = 36.7, 18.2, 11.5 Hz, 6H), 7.16 (dd, J = 16.0, 9.3 Hz, 1H), 7.00 (t, J = 7.6 Hz, 2H), 6.86 (d, J = 8.0 Hz, 2H), 6.67 (t, J = 7.2 Hz, 2H).13C NMR (100 MHz, DMSO-d 6 ) δ 168.26 (s), 158.87 (s), 142.75 (s), 136.04 (s), 135.50 (s), 129.68 (s), 128.90 (s), 127.54 (s), 125.77 (d, J = 59.3 Hz), 125.48 (s), 125.29 (s), 121.77 (s), 121.02 (s), 119.42 (d, J = 20.1 Hz), 119.32 (s), 111.87 (s), 105.32 (s). HRMS (ESI), m/z calcd. for C29H20N4O2 ([M+Na]+) 479.1478, found: 479.1472,对CDC 25B的抑制率为92.85±0.44%。
31、
(E)-1-((cyclohexylmethylene)amino)-3,4-di(1H-indol-3-yl)-1H-pyrrole-2,5-dione 1H NMR (400 MHz, DMSO-d 6 ) δ 11.74 (d, J = 2.3 Hz, 2H), 8.38 (d, J = 5.4 Hz, 1H), 7.78 (d, J = 2.8 Hz, 2H), 7.39 (d, J = 8.1 Hz, 2H), 6.99 (dd, J = 11.1, 4.0 Hz, 2H), 6.82 (d, J = 8.1 Hz, 2H), 6.65 (dd, J = 11.1, 4.0 Hz, 2H), 3.34 (s, 7H), 2.00 (s, 1H), 1.81 (d, J = 33.1 Hz, 4H), 1.36 (t, J = 10.7 Hz, 4H), 1.18 (t, J = 7.1 Hz, 2H).13C NMR (100 MHz, DMSO-d 6 ) δ 168.75 (s), 168.38 (s), 136.42 (s), 129.95 (s), 126.25 (s), 125.73 (s), 122.14 (s), 121.37 (s), 119.88 (s), 112.24 (s), 105.76 (s), 41.52 (s), , 29.64 (s), 25.88 (s), 25.23 (s). HRMS (ESI), m/z calcd. for C27H24N4O2 ([M+Na]+) 459.1791, found: 459.1794,对CDC 25B的抑制率为97.42±0.46%。
32、
(E)-3,4-di(1H-indol-3-yl)-1-((3-phenylpropylidene)amino)-1H-pyrrole-2,5-dione 1H NMR (400 MHz, DMSO-d 6 ) δ 11.74 (d, J = 2.2 Hz, 2H), 8.55 (t, J = 5.2 Hz, 1H), 7.78 (d, J = 2.8 Hz, 2H), 7.38 (d, J = 8.1 Hz, 2H), 7.31 (dd, J = 8.6, 5.4 Hz, 4H), 7.21 (td, J = 5.8, 2.7 Hz, 1H), 7.03 – 6.95 (m, 2H), 6.81 (d, J = 7.9 Hz, 2H), 6.65 (t, J = 7.5 Hz, 2H), 2.93 (t, J = 7.7 Hz, 2H), 2.75 (dt, J = 12.3, 6.0 Hz, 2H).13C NMR (100 MHz, DMSO-d 6 ) δ 168.39 (s), 163.68 (s), 140.87 (s), 136.12 (s), 129.68 (s), 128.57 (s), 128.48 (s), 126.15 (s), 125.91 (s), 125.41 (s), 121.85 (s), 121.07 (s), 119.59 (s), 111.95 (s), 105.43 (s), 34.99 (s), 31.60 (s). HRMS (ESI), m/z calcd. for C29H22N4O2 ([M+Na]+) 481.1635, found: 481.1637,对CDC 25B的抑制率为95.68±0.46%。
33、
1H NMR (400 MHz, DMSO-d 6 ) δ11.76 (s, 2H), 8.89 (s, 1H), 7.82 (s, 2H), 7.39 (d, J = 8.2 Hz, 2H), 7.00 (t, J = 7.6 Hz, 2H), 6.85 (d, J = 8.1 Hz, 2H), 6.66 (t, J = 7.5 Hz, 2H), 4.80 (s, 2H), 4.57 (s, 2H), 4.31 (s, 5H). HRMS (ESI), m/z calcd. for C31H22FeN4O2 ([M+Na]+) 559.1031, found: 559.1032。
以上实施例仅为说明本发明的技术思想,不能以此限定本发明的保护范围,凡是按照本发明提出的技术思想,在技术方案基础上所做的任何改动,均落入本发明保护范围之内。
Claims (4)
1.3,4-二(3-吲哚)-2,5-二酮-3-吡咯啉亚胺类化合物,其特征在于是以醛类化合物R-CHO和1-氨基-3,4-二(3-吲哚)-3-吡咯啉-2,5-二酮 为原料制备而成的,其结构通式如下:,其中R为以下所列结构中的一种:
。
2.一种权利要求1所述的3,4-二(3-吲哚)-2,5-二酮-3-吡咯啉亚胺类化合物的制备方法,其特征在于具体合成步骤为:在反应容器中先加入1-氨基-3,4-二(3-吲哚)-3-吡咯啉-2,5-二酮和无水乙醇,然后加入醛类化合物和乙酸,于回流条件下反应,TLC跟踪,反应结束后,晾至室温,加水生成大量沉淀,抽滤,水洗,再用体积比为1:1的氯仿和正已烷清洗,柱层析分离得到红色固体3,4-二(3-吲哚)-2,5-二酮-3-吡咯啉亚胺类化合物,其中1-氨基-3,4-二(3-吲哚)-3-吡咯啉-2,5-二酮与醛类化合物的摩尔比为1:2,具体反应方程式为:
,
其中醛类化合物为以下所列结构中的一种:
。
3.根据权利要求2所述的3,4-二(3-吲哚)-2,5-二酮-3-吡咯啉亚胺类化合物的制备方法,其特征在于所述的1-氨基-3,4-二(3-吲哚)-3-吡咯啉-2,5-二酮是由以下方法制备而成的:
(1)2,3-二氯马来酐的合成
在反应容器中加入马来酐,冰浴下加入二氯亚砜,磁力搅拌均匀,用恒压滴液漏斗滴加吡啶,滴加完毕后,冰浴条件下继续搅拌反应,然后撤去冰浴,油浴下加热回流。减压蒸去残留的二氯亚砜,得到黄色蜡状固体,用甲苯进行浸取,抽滤,得黄色滤液,反复数次至固体泛白为止,合并滤液,减压蒸去溶剂后得到粗产品2,3-二氯马来酐;
(2)2,3-二氯-N-甲基马来酰亚胺的合成
向反应容器中加入2,3-二氯马来酐、甲胺盐酸盐和冰乙酸,回流条件下磁力搅拌反应,TLC跟踪检测至反应完全,溶液暗褐色,降至室温后加水,乙酸乙酯萃取,依次用饱和碳酸氢钠溶液和饱和食盐水洗涤,减压蒸去溶剂,得褐色粗品,柱层析分离得到白色片状固体2,3-二氯-N-甲基马来酰亚胺;
(3)2,3-二(3-吲哚)-N-甲基马来酰亚胺的合成
a溴乙烷格氏试剂的制备,N2保护下,向反应容器中加入镁条和无水乙醚,并滴加溴乙烷,微热引发反应后剧烈搅拌,滴加溴乙烷使溶剂保持微沸状态,滴加完毕补加无水乙醚,回流使反应充分,得烟灰色溴乙烷格氏试剂,
b吲哚格氏试剂的制备及2,3-二(3-吲哚)-N-甲基马来酰亚胺的制备
先向反应容器中加入四氢呋喃、吲哚和溴乙烷格氏试剂的甲苯溶液,溶液变黑色,40 ℃反应,然后加入2,3-二氯-N-甲基马来酰亚胺的甲苯溶液,滴加完毕,溶液棕黑色,回流条件下反应完全,降至室温,加入饱和NH4Cl溶液猝灭反应,用乙酸乙酯萃取,合并有机相,减压蒸去溶剂,柱层析分离得到红色固体2,3-二(3-吲哚)-N-甲基马来酰亚胺;
(4)2,3-二(3-吲哚)马来酸酐的的合成
向反应容器中加入双吲哚马来酰亚胺和质量浓度为10%的 KOH溶液 ,回流条件下磁力搅拌反应,TLC监测至反应完全,降至室温,用2 mol/L的盐酸猝灭反应,出现红色沉淀,调至溶液中性,用乙酸乙酯萃取,依次以饱和碳酸氢钠溶液和饱和食盐水清洗,以无水硫酸镁干燥,过滤,减压蒸去溶剂,得到红色固体2,3-二(3-吲哚)马来酸酐。
(5)1-氨基-3,4-二(3-吲哚)-3-吡咯啉-2,5-二酮的合成
在反应容器中加入双吲哚马来酸酐和四氢呋喃,滴加水合肼,溶液由浑浊变清澈,加热至回流条件下反应,TLC监测至反应完全,减压蒸去溶剂,用乙酸乙酯萃取,饱和食盐水洗,无水硫酸镁干燥,过滤,减压蒸去溶剂,柱层析分离得到红色固体1-氨基-3,4-二(3-吲哚)-3-吡咯啉-2,5-二酮。
4.一种抗癌药物组合物,其特征在于包括权利要求1所述的3,4-二(3-吲哚)-2,5-二酮-3-吡咯啉亚胺类化合物或/和其药学上可接受的盐以及药学上可接受的载体。
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CN106525782B (zh) * | 2016-10-10 | 2019-02-12 | 河南师范大学 | 3,4-二(3-吲哚)-3-吡咯啉-2,5-二酮-1-(2-羟基苯基)腙作为荧光探针在检测铜离子中的应用 |
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