CN107629052B - 一种吡咯并[3,4b]喹啉-9-胺类化合物及其制备方法和应用 - Google Patents

一种吡咯并[3,4b]喹啉-9-胺类化合物及其制备方法和应用 Download PDF

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CN107629052B
CN107629052B CN201710903891.5A CN201710903891A CN107629052B CN 107629052 B CN107629052 B CN 107629052B CN 201710903891 A CN201710903891 A CN 201710903891A CN 107629052 B CN107629052 B CN 107629052B
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CN107629052A (zh
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陈海军
叶金祥
吕婷婷
吴国林
高瑜
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Fuzhou University
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Abstract

本发明公开了一种吡咯[3,4b]喹啉‑9‑胺类化合物其制备方法,所述的吡咯[3,4b]喹啉‑9‑胺类化合物具有如下结构式中的一种:

Description

一种吡咯并[3,4b]喹啉-9-胺类化合物及其制备方法和应用
技术领域
本发明属于药物化学领域,具体涉及一种吡咯[3,4b]喹啉-9-胺类化合物及其制备方法。
背景技术
吡咯[3,4b]喹啉骨架化合物是一种天然存在的生物活性化合物,它具有广泛的生物活性,如抗肿瘤活性,抗病毒活性,抗菌活性等。目前,大家主要关注其抗癌活性的研究,作为一种高效抗癌药物,对治疗多种恶性肿瘤具有显著疗效,经常将吡咯[3,4b]喹啉骨架化合物当作新的抗肿瘤药物的先导化合物。本发明从结构水平对母核7号位进行改造,通过简单的方法合成一类具有抗癌活性的吡咯[3,4b]喹啉-9-胺类化合物,这类反应具有条件温和,能耗低,反应速度快且污染小等诸多优点。
本发明是通过Michael加成反应,光催化氧化,酸催化环合等多步反应得到吡咯[3,4b]喹啉-9-胺类化合物衍生物,制备方法简单,反应条件温和,能耗低,种类多,收率高,产品纯度高,实用性强。此外,本发明合成的吡咯[3,4b]喹啉-9-胺类化合物是一类小分子化合物,相对分子质量在500左右,且具有一定的体外抗癌活性,说明本发明得到的小分子化合物有望用于制备相关的癌症治疗药物。
发明内容
本发明的目的在于提供一种吡咯[3,4b]喹啉-9-胺类化合物及其制备方法,所得化合物能够抑制A539细胞的生长,具有一定的药理活性,且制备方法简单,实验条件温和,不要求高温高压、强酸强碱等苛刻条件,且反应收率高。
为实现上述目的,本发明采用如下技术方案:
一种吡咯[3,4b]喹啉-9-胺类化合物,其结构式为:
该化合物的制备方法包括以下步骤:
1)以色胺、N,N-二甲基乙酰乙酰胺、衣康酸酐和1,4-二恶烷为原料,制得中间体1:
2)以中间体1、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐、NN-二异丙基乙胺、1-羟基苯并三唑和叔丁胺为原料,制得中间体2:
3)以中间体2和Ru(bpy)3Cl2·6H2O为原料,制得中间体3:
4)以中间体3、苯胺和三氟乙酸为原料,制得
进一步具体的,步骤3)具体为:将88 mg中间体2溶于乙腈中,加入8 mg Ru(bpy)3Cl2·6H2O,将反应体系在O2条件下室温搅拌8小时;然后将反应体系用乙酸乙酯稀释,并用蒸馏水萃取2次,合并有机相,用饱和盐水洗涤2次,用无水硫酸钠干燥,过滤,滤液减压浓缩得到粗产物,粗产物经硅胶色谱柱纯化得到中间体3,纯化所用的洗脱剂为CH2Cl2和MeOH 按体积比 30:1混合的洗脱剂。
步骤4)具体为:将94 mg中间体3溶于二甲基亚砜中,加入38 mg苯胺和46 mg三氟乙酸,反应体系在65℃下搅拌30小时,然后将反应体系用乙酸乙酯稀释,并用蒸馏水萃取2次,合并有机相,用饱和盐水洗涤2次,用无水硫酸钠干燥,过滤,滤液减压浓缩得到粗产物,粗产物经硅胶色谱柱纯化得到,纯化所用的洗脱剂为CH2Cl2和MeOH 按体积比 30:1混合的洗脱剂。
一种吡咯[3,4b]喹啉-9-胺类化合物,其结构式为:
该化合物的制备方法包括以下步骤:
1)以中间体1、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐、NN-二异丙基乙胺和苯胺为原料,制得中间体5:
2)以中间体5和Ru(bpy)3Cl2·6H2O为原料,制得中间体6:
3)以中间体6、苯胺和三氟乙酸为原料,制得
一种如上所述的吡咯[3,4b]喹啉-9-胺类化合物(两种结构)对A539细胞的生长有一定的抑制活性,可用于制备抗肺癌药物。
本发明的显著优点在于:
(1)本发明的合成方法简单,通过常用试剂简单反应即可得到目标产物,实验条件温和,不要求高温高压、强酸强碱等苛刻条件,反应时间短且收率一般可达到70%以上;
(2)所设计合成的吡咯[3,4b]喹啉-9-胺类化合物的分子量适中,一般在500左右,且生物实验证实该类化合物具有一定得抗癌活性,因此所得的目标产物具有用于制备抗癌药物的前景。
具体实施方式
实施例1
的制备方法,具体步骤为:
(1)2 –((1S,3R,12bS)-1-(二甲基氨基甲)-12b甲基-4-氧-1,2,3,4,6,7,12,12b-
八氢吲哚[2,3-a]喹嗪-3-基)乙酸(中间体1的制备)
将160 mg色胺溶于5 mL氯仿中,加入129 mg N,N-二甲基乙酰乙酰胺和500 mg 4Å分子筛,将反应体系在50℃下加热24小时,等反应体系温度降至室温,过滤去除分子筛,将滤液真空浓缩得到粗产物;在粗产物中加入112 mg衣康酸酐和3 mL 1,4-二恶烷。将反应混合物在40℃下加热7小时,然后滴加0.39 mL 4 M 盐酸/1,4-二氧六环溶液。在相同温度下继续反应3小时。然后将反应混合物用20 mL 乙酸乙酯稀释,并用蒸馏水萃取2次。将有机相合并,用饱和食盐水盐水洗涤2次,用无水硫酸钠干燥,过滤,滤液减压浓缩的到粗产物。将粗产物通过硅胶色谱纯化,得到产物280 mg。洗脱剂为CH2Cl2/MeOH = 20:1(体积比);反应收率为73%;产物室温下为白色固体,熔点115.3-115.6℃。1H NMR (400 MHz,CDCl3). 1HNMR (400 MHz,DMSO-d 6) δ 12.07 (s,1H),10.30 (s,1H),7.38 (t,J = 7.4 Hz,2H),7.05(t,J = 7.7 Hz,1H),6.96 (t,J = 7.7 Hz,1H),4.79 (d,J = 11.2 Hz,1H), 3.56-3.48(m,1H),3.00-2.90 (m,2H),2.87 (s,3H),2.65 (s,3H),2.65-2.58 (m,2H), 2.57 (d,J =5.0 Hz,1H),2.45 (d,J = 7.3 Hz,1H),2.31- 2.22 (m,1H),1.72 (s,3H),1.58 (d,J =5.5 Hz,1H). 13C NMR (101 MHz,DMSO-d 6)δ 173.90,172.00,171.08,137.92,136.55,126.55,121.61,119.10,118.26,112.14,108.73,59.88,44.05,37.78,37.58,37.30,36.06,34.93,26.96,23.13,21.28.HRMS (ESI): calcd for C21H25N3O4 [M + H]+ m/z384.1918 found 384.1928.
(2)(1S, 3R, 12bS)-3-(2-(叔丁基氨基)-2-氧乙基)-NN, 12b三甲基-4-氧1,2,3,4,6,7,12,12B八氢吲哚[2,3-a]喹嗪-1-甲酰胺 (中间体2的制备)
将153 mg中间体1溶解在3 mL THF/CHCl3 = 1:1(体积比)溶液里,依次加入115mg 1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐,180 mg N,N-二异丙基乙胺,81 mg 1-羟基苯并三唑和88 mg 叔丁胺,反应体系物在室温下搅拌8小时,将粗反应体系用乙酸乙酯稀释,用蒸馏水萃取两次,用饱和食盐水洗涤2次,用无水硫酸钠干燥,过滤,滤液减压浓缩得到粗产物。将粗产物通过硅胶色谱柱纯化得到175mg产物,洗脱剂为CH2Cl2/MeOH = 30:1(体积比)。反应收率为97%;产物室温下为黄色油状物。1H NMR (400 MHz,CDCl3)δ 8.84 (s,1H),7.49 (d,J = 7.7 Hz,1H),7.31 (d,J = 8.0 Hz,1H),7.16 (t,J = 7.5 Hz,1H),7.09(t,J = 7.4 Hz,1H),6.15 (s,1H),5.17-5.05 (m,1H), 3.25- 3.14 (m,1H),2.95 (s,3H),2.93 (s,1H),2.88 (s,3H), 2.85 (d,J = 7.8 Hz,1H),2.81 (d,J = 6.0 Hz,1H),2.76 (d,J = 4.3 Hz,1H),2.74-2.66 (m,1H),2.50-2.37 (m,2H),2.19-2.11 (m, 1H),1.96 (s,3H),1.28 (s,9H). 13C NMR (101 MHz, CDCl3) δ 173.81,170.84,170.77,136.55,135.86,126.08,122.06,119.43,118.31,111.31, 108.78,59.81,0.92,46.19,41.14,37.68,37.35,36.81,36.19,28.77,25.84,21.98,21.41.HRMS (ESI): calcd forC25H34N4O3 [M + H]+ m/z 439.2704 found 439.2716.
(3)(6a,7S,9R)-9-(2-(叔丁基氨基)-2-氧乙基)-NN,6a-二甲基-6,10,14-三氧-5,6,6a,7,8,9,10,12,13,14-十氢苯并[e]吡啶并[1,2-a][1,4] -7-甲酰胺 (中间体3的制备)
将88 mg 中间体2溶液5 mL 乙腈中,加入8 mg Ru(bpy)3Cl2·6H2O,将反应体系在O2条件下室温搅拌8小时。然后将反应体系用乙酸乙酯稀释,并用蒸馏水萃取2次。合并有机相,用饱和盐水洗涤2次,用无水硫酸钠干燥,过滤,滤液减压浓缩得到粗产物。将粗产物通过硅胶色谱柱纯化得到87 mg产物,洗脱剂为CH2Cl2/MeOH = 30:1(体积比)。反应收率为89%;产物室温下为黄色油状物。1H NMR (400 MHz,CDCl3) δ 10.73 (s,1H) ,7.56 (d,J =7.6 Hz,1H) ,7.51 (t,J = 7.6 Hz,1H) ,7.37 (t,J = 7.5 Hz,1H) ,7.15 (d,J = 7.7Hz,1H) ,6.14 (s, 1H) ,4.50 (t,J = 12.1 Hz,1H) ,3.88-3.77 (m,1H) ,3.19 (d,J =6.0 Hz,1H) ,3.15 (s,3H), 3.08-2.98 (m,2H) ,2.91 (s,3H) ,2.88 (s,1H) ,2.80 (t,J = 11.5 Hz,1H) ,2.37-2.28 (m,1H),2.20-2.13 (m,1H),2.08-2.01 (m,1H),1.39 (s,3H),1.20 (s,9H). 13C NMR (101 MHz, CDCl3) δ 204.62,174.50,172.04,170.87,170.46,140.27,136.67,132.28,128.73,127.91, 127.85,67.05,51.85,43.88,40.69,39.69,38.83,37.60,36.21,34.79,28.67,27.54,19.23. HRMS (ESI): calcd forC25H34N4O5 [M + H]+ m/z 471.2602 found 471.2614.
(4)(5bS,6S,8R)-8-(2-(叔丁基氨基)-2-氧乙基)-NN,5b三甲基-9-氧-12-(苯基氨基)-5b,6,7,8,9,11-六氢吲哚嗪[1,2-b]喹啉-6-甲酰胺 (化合物4的制备);
将94 mg 中间体3溶解在 1 mL 二甲基亚砜中,加入38 mg苯胺和46 mg三氟乙酸。反应体系在65℃下搅拌30小时。然后将反应体系用乙酸乙酯稀释,并用蒸馏水萃取2次。合并有机相,用饱和盐水洗涤2次,用无水硫酸钠干燥,过滤,滤液减压浓缩得到粗产物。将粗产物通过硅胶色谱柱纯化得到86 mg产物,洗脱剂为CH2Cl2/MeOH = 30:1(体积比)。反应收率为82%;产物室温下为淡黄色油状物。1H NMR (400 MHz,CDCl3) δ 8.04-7.87 (m,2H),7.66 (t,J = 7.5 Hz, 1H),7.48 (t,J = 7.5 Hz,1H),7.34 (t,J = 7.6 Hz,2H),7.14(t,J = 7.3 Hz,1H),7.01 (d,J = 7.7 Hz,2H),6.73 (s,1H),5.92 (s,1H),4.57 (d,J =16.7 Hz,1H),4.12 (d,J = 16.7 Hz,1H), 3.31-3.24 (m,1H),3.10 (s,3H),3.04-2.99(m,1H),2.82-2.73 (m,1H),2.70 (s,3H),2.64-2.58 (m,1H),2.41-2.34 (m,1H),1.88-1.83 (m,1H),1.70 (s,3H),1.21 (s,9H). 13C NMR (101 MHz,CDCl3) δ 172.11,170.75,170.53,166.29,149.28,142.01,140.64,129.86,129.43,129.34,125.52,124.22,121.62,121.49,120.84,111.07,67.61,50.85,47.75,41.96,40.91,40.11,38.11,36.26,35.70,29.68,28.70,28.34,22.14. HRMS (ESI): calcd for C31H37N5O3 [M + H]+ m/z 528.2969found 528.2983.
实施例2
的制备方法,具体步骤为:
(1)(1S,3R,12bS)-NN,12b三甲基-4-氧-3-(2-氧-2-(苯基氨基)乙基)-1,2,3,4,6,7,12,12b-八氢吲哚[2,3-a]喹嗪-1-甲酰胺 (中间体5的制备)
中间体5的制备按实施例1中步骤(2)的反应条件反应得到,反应收率为98%;该中间体5在常温下为白色固体,熔点为158.3-158.7℃。1H NMR (400 MHz,CDCl3) δ 8.79 (s,1H),8.67 (s,1H),7.48 (d,J = 8.1 Hz,3H),7.32 (d,J = 8.1 Hz,1H),7.28 (s,1H),7.24 (s,1H),7.18(t, J = 7.6 Hz,1H),7.11 (t,J = 7.5 Hz,1H),7.05 (t,J = 7.2 Hz,1H),5.17-5.06 (m,1H),3.34-3.26 (m,1H),3.13-3.05 (m,2H),2.95 (s,4H),2.85 (s,3H),2.83-2.75 (m,2H),2.75 -2.61 (m,2H),2.57-2.47 (m,1H),2.15 (d,J = 13.8 Hz,1H),1.98 (s,3H). 13C NMR (101 MHz,CDCl3) δ 173.75,171.17,169.89,138.21,136.26,135.80,128.92,126.02,124.05,122.15,119.60,119.50,118.34,111.26,108.92,59.96,46.23,41.26,37.75,37.67,36.54,36.16,26.43,21.81,21.23. HRMS (ESI): calcd forC27H30N4O3 [M + H]+ m/z 459.2391 found 459.2391.
(2)(6aS,7S,9R)-NN,6a-二甲基-6,10,14-三氧-9-(2-氧-2-(苯基氨基)乙基)-5,6,6a, 7,8,9,10,12,13,14-十氢苯并[e]吡啶并[1,2-a][1,4] -7-甲酰胺(中间体6的制备)
中间体6按实施例1中步骤(3)的反应条件反应得到,反应收率为73%;中间体6在常温下为白色固体,熔点为173.4-174.5℃。1H NMR (400 MHz,DMSO-d 6) δ 10.30 (s,1H),10.21 (s,1H),7.67 (t,J = 7.6 Hz,1H),7.57 (d,J = 8.1 Hz,2H),7.54-7.46 (m,2H),7.29 (t,J = 7.9 Hz, 2H),7.23 (d,J = 7.7 Hz,1H),7.06 (t,J = 7.5 Hz,1H), 4.41-4.34 (m,1H),3.83-3.77 (m,1H), 3.16 (s,3H),2.98 (s,1H),2.94 (d,J = 8.8 Hz,1H),2.91-2.85 (m,2H),2.83 (s,3H), 2.81-2.74 (m,2H),2.38-2.29 (m,1H),1.95 (d,J =13.6 Hz,1H),1.40 (s,3H). 13C NMR (101 MHz,DMSO-d 6) δ 203.93,172.54,171.38,170.70,170.31,139.78,139.26,136.93,132.85, 129.14,128.92,128.86,128.25,123.98,119.93,66.91,44.28,38.64,37.78,36.37,36.08, 26.53,18.31.HRMS (ESI):calcd for C27H30N4O5 [M + H]+ m/z 491.2289 found 491.2301.
(3)(5bS, 6S, 8R)-NN,5b三甲基-9-氧-8-(2-氧-2-(苯基氨基)乙基)-12-(苯基氨基)-5b, 6,7,8,9,11-六氢吲哚嗪[1,2-b]喹啉-6-甲酰胺(化合物7的制备)
产物7按实施例1中(4)的反应条件反应得到目标产物7,反应收率为91%;化合物7在常温下为黄色油状物。1H NMR (400 MHz, CDCl3) δ 8.76 (s,1H), 7.98 (d,J = 8.3Hz,1H), 7.91 (d,J = 8.4 Hz,1H),7.65 (t,J = 7.6 Hz,1H),7.45 (d,J = 7.7 Hz,3H),7.31 (t,J = 7.5 Hz, 2H),7.20 (t,J = 7.3 Hz,2H),7.11 (t,J = 7.1 Hz,1H),7.00(d,J = 7.5 Hz,3H),4.58 (d,J = 16.6 Hz,1H),4.09 (d,J = 16.6 Hz,1H),3.43-3.28(m,1H),3.14 (s,1H),3.09 (s,3H),2.81 (t,J = 12.7 Hz,2H),2.73-2.67 (m,1H),2.64(s,3H),1.90-1.81 (m,1H),1.69 (s,3H). 13C NMR (101 MHz,CDCl3) δ 172.03,171.15,169.99,166.05,149.34,142.12,140.50,138.26,129.83, 129.52,129.36,128.78,125.58,124.32,123.83,121.77,121.46,120.75,119.74,110.71,67.77,47.88,42.29,39.68,38.23,36.32,35.59,28.81,22.15. HRMS (ESI): calcd for C33H35N5O3 [M + H]+ m/z 548.2656 found 548.2669.
生物活性测试实施例:
化合物对Α539肿瘤细胞增殖和存活的抑制作用
材料:肺癌细胞株Α539
受试药物:5 μΜ、10 μΜ、20 μΜ、40 μΜ、80 μΜ的5个浓度的化合物;
细胞培养方法:取出液氮中冻存的Α539 细胞,在37℃的温水中解冻,将细胞悬液移入1.5 mL 离心管中,置于离心机中,1500 rpm 离心5 min,弃去上清液,加入1 mL RPMI1640 完全培养液,轻轻吹打均匀,将细胞悬液加入培养皿中,补加3 mL RPMI 1640 完全培养液,将培养皿置于5% CO2、37℃培养箱中培养。
细胞毒性实验:将Α539 细胞以8×103个细胞/孔的密度接种到96 孔培养板中,培养24 h 后,吸弃旧的培养基,并于每孔中加入200 µL含有不同浓度化合物4或化合物7的培养基,另设溶剂对照组和空白对照组,在培养箱中孵育72h后,吸弃孔中溶液,用PBS 洗涤3 遍,加入新鲜培养液90 μL,同时每孔加入10 μL MTT 溶液(5 mg/mL),继续在37 ℃、5%CO2(相对湿度90%)培养箱中培养4 h 后,终止培养,小心吸弃上清液,每孔加入150 μLDMSO,避光振荡10 min 使结晶物充分溶解;以酶标仪检测570 nm 处的吸收度(A),细胞毒性结果表明化合物可有效抑制肿瘤细胞增殖。并按下式计算细胞的存活率:细胞存活率 =(试验组A 值/ 空白对照组A 值)×100%。
表1. 各实施例所得化合物的活性参数
以上所述仅为本发明的较佳实施例,凡依本发明申请专利范围所做的均等变化与修饰,皆应属本发明的涵盖范围。

Claims (7)

1.一种吡咯[3,4b]喹啉-9-胺类化合物,其特征在于:其结构式为:
2.一种吡咯[3,4b]喹啉-9-胺类化合物,其特征在于:其结构式为:
3.一种制备如权利要求1所述的化合物的方法,其特征在于:包括以下步骤:
1)以色胺、N,N-二甲基乙酰乙酰胺、衣康酸酐和1,4-二噁烷为原料,制得中间体1:
2)以中间体1、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐、NN-二异丙基乙胺、1-羟基苯并三唑和叔丁胺为原料,制得中间体2:
3)以中间体2和Ru(bpy)3Cl2·6H2O、O2为原料,制得中间体3:
4)以中间体3、苯胺和三氟乙酸为原料,制得
4.根据权利要求3所述的制备化合物的方法,其特征在于:步骤3)具体为:将88 mg中间体2溶于乙腈中,加入8 mg Ru(bpy)3Cl2·6H2O,将反应体系在O2条件下室温搅拌8小时;然后将反应体系用乙酸乙酯稀释,并用蒸馏水萃取2次,合并有机相,用饱和盐水洗涤2次,用无水硫酸钠干燥,过滤,滤液减压浓缩得到粗产物,粗产物经硅胶色谱柱纯化得到中间体3,纯化所用的洗脱剂为CH2Cl2和MeOH 按体积比 30:1混合的溶剂。
5.根据权利要求3所述的制备化合物的方法,其特征在于:步骤4)具体为:将94 mg中间体3溶于二甲基亚砜中,加入38 mg苯胺和46 mg三氟乙酸,反应体系在65℃下搅拌30小时,然后将反应体系用乙酸乙酯稀释,并用蒸馏水萃取2次,合并有机相,用饱和盐水洗涤2次,用无水硫酸钠干燥,过滤,滤液减压浓缩得到粗产物,粗产物经硅胶色谱柱纯化得到,纯化所用的洗脱剂为CH2Cl2和MeOH 按体积比 30:1混合的溶剂。
6.一种制备如权利要求2所述的化合物的方法,其特征在于:包括以下步骤:
1)以中间体1、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐、NN-二异丙基乙胺和苯胺为原料,制得中间体5:
2)以中间体5和Ru(bpy)3Cl2·6H2O、O2为原料,制得中间体6:
3)以中间体6、苯胺和三氟乙酸为原料,制得
7.一种如权利要求1或2所述的吡咯[3,4b]喹啉-9-胺类化合物在制备抗肺癌药物中的应用。
CN201710903891.5A 2017-09-29 2017-09-29 一种吡咯并[3,4b]喹啉-9-胺类化合物及其制备方法和应用 Expired - Fee Related CN107629052B (zh)

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