CN113698385B - 2,2-二取代吲哚啉-3-酮生物碱、其制备方法及其应用 - Google Patents

2,2-二取代吲哚啉-3-酮生物碱、其制备方法及其应用 Download PDF

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CN113698385B
CN113698385B CN202111146916.4A CN202111146916A CN113698385B CN 113698385 B CN113698385 B CN 113698385B CN 202111146916 A CN202111146916 A CN 202111146916A CN 113698385 B CN113698385 B CN 113698385B
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谢智宇
许志红
张占涛
方万航
吴增龙
傅一帆
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Abstract

本发明公开了一种2,2‑二取代吲哚啉‑3‑酮生物碱、制备方法及其应用，属于药物化学领域。所述2,2‑二取代吲哚啉‑3‑酮生物碱结构通式如（1）所示，R1为氢原子、卤素原子、1‑4个碳的烷基、1‑4四个碳的烷氧基，其位置是在苯环4位至7位单取代；R2为1‑4个碳的烷基或酯基、硅氧基、卤素取代的烷基、苯基、各种取代的苯基、呋喃基、噻吩基或吡啶基；R3可以是氢、卤素、1‑4个碳的烷基、1‑4四个碳的烷氧基、1‑4四个碳的烷氧羰基、三氟甲基、苯基，其位置是喹啉环的5‑8位单取代。该类化合物在抗菌方面具有很好的活性，以其为有效成分可以用于制备治疗细菌感染药物。

Description

2,2-二取代吲哚啉-3-酮生物碱、其制备方法及其应用
技术领域
本发明涉及一种2,2-二取代吲哚啉-3-酮生物碱、其绿色合成制备以及其在抗细菌感染药物制备中的用途，属于药物化学领域。
背景技术
细菌感染是常见的临床疾病，近一二十年来，由于抗生物的过量使用和错误使用导致耐药现象频出并快速传播，特别是多重耐药菌的出现已成为临床抗感染治疗失败的重要原因。随着对粘菌素、达托霉素和碳青霉烯等最新类型的抗菌剂产生耐药菌株的出现，目前，在临床上只能采取多种抗生素联合用药的方式对耐药菌感染进行治疗，但用药剂量和用药数也逐渐增长，因此，开发低毒、高选择性、作用机制新颖的抗细菌感染药物具有重要意义。
含吲哚结构的天然产物碱具有结构类型丰富、药理活性广泛等优点，成为新药研发中先导化合物的重要来源。而存在于多种植物及海洋真菌中的2,2-二取代吲哚啉-3-酮类生物碱拥有抗感染、抗寄生虫、抗肿瘤、抗HIV等多种生物活性而受到药物化学家的广泛关注。[Williams,R.M.；Stocking,E.M.；Sanz-Cervera,J.F.Biosynthesis of PrenylatedAlkaloids Derived from Tryptophan.In Topics in Current Chemistry:Vol.209,Biosynthesis-Terpenes and Alkaloids；Leeper,F.,Vederas,J.C.,Eds.；Springer-Verlag:New York,2000；pp 97-173；A.Asai,S.Nagamura,E.Kobajashi,K.Gomi andH.Saito,Bioorg.Med.Chem.Lett.,1996,6,1215–1220；Deka,B.；Deb,M.L.；Thakuria,R.；Baruah,P.K.Catal.Commun.2018,106,68；Wu,W.；Xiao,M.；Wang,J.；Li,Y.；Xie,Z.Org.Lett.2012,14,1624；Ding,X.；Dong,C.-L.；Guan,Z.；He,Y.-H.Angew.Chem.,Int.Ed.2019,58,118；CN110229152A]目前，制备2,2-二取代吲哚啉-3-酮衍生物的传统方法主要有氧化2,3-二取代吲哚重排反应[E.Schendera,S.Lerch,T.Von Drathen,L.N.Unkel and M.Brasholz,Eur.J.Org.Chem.,2017,3134–3138]、环化反应[W.Fu andQ.Song,Org.Lett.,2018,20,393–396]、以及对吲哚啉-3-酮亲核加成[Li,J.S.；Liu,Y.J.；Zhang,G.W.；Ma,J.A.Org.Lett.2017,19,6364-6367]。近年来，对吲哚底物进行氧化去芳构化-亲核加成成为构建此类结构的新策略，然而，目前已报道的新策略有如下不足：要用到有毒的氮-氧化物及其盐、昂贵的光催化剂或具有危险性的过氧化物作为氧化剂，同时其亲核试剂也都是传统的负电子芳烃、酮、醛或者相对昂贵的硼化合物，使其工业化应用受到限制。[Z.Deng,X.Peng,P.Huang,L.Jiang,D.Ye andL.Liu,Org.Biomol.Chem.,2017,15,442–448；H.Huang,J.Cai,X.Ji,F.Xiao,Y.Chen and G.Deng,Angew.Chem.,Int.Ed.,2016,55,307–311；X.Jiang,B.Zhu,K.Lin,G.Wang,W.Su and C.Yu,Org.Biomol.Chem.,2019,17,2199–2203；X.Ding,C.Dong,Z.Guan and Y.He,Angew.Chem.,Int.Ed.,2019,58,118–124]目前还需研发新的2,2-二取代吲哚啉-3-酮类化合物，才能满足市场需求。
发明内容
针对目前技术现状，本发明目的在于提供一种抗细菌感染活性好新化合物——2,2-二取代吲哚啉-3-酮类生物碱。
本发明的另一目的在于提供2,2-二取代吲哚啉-3-酮类生物碱的绿色制备方法。
本发明的又目的在于提2,2-二取代吲哚啉-3-酮类生物碱及其盐形式在制备抗细菌感染药物中的应用。
本发明的目的通过以下技术方案实现：
所述2,2-二取代吲哚啉-3-酮类生物碱具有如通式(1)所示结构：
Figure BDA0003285786260000021
其中，R1为氢原子、卤素原子、1-4个碳的烷基、1-4四个碳的烷氧基，其位置是在苯环4位至7位单取代；R2为1-4个碳的烷基或酯基、硅氧基、卤素取代的烷基、苯基、取代的苯基、呋喃基、噻吩基或吡啶基；R3是氢、卤素、1-4个碳的烷基、1-4四个碳的烷氧基、1-4四个碳的烷氧羰基、三氟甲基、苯基，其位置是喹啉环的5-8位单取代。
本发明较佳选择：R1为氢原子，氟，氯，溴，碘，甲基，乙基或甲氧基，乙氧基，其位置是苯环4位至7位单取代；
R2为甲基，乙基或饱和脂肪酸酯基，苯基，被氟、氯、溴、碘、硝基、三氟甲基、甲氧基，乙氧基、甲基、乙基取代的苯基，呋喃基。
R3为氢，氟，氯，溴，碘，甲氧基，乙氧基，甲基，乙基，三氟甲基，苯基，其位置是喹啉环的5-8位单取代。
本发明优选2,2-二取代吲哚啉-3-酮类生物碱为如下化合物：
2-苯基-2-(2-喹啉基甲基)吲哚啉-3-酮；
3-甲基-2-苯基-2-(2-喹啉基甲基)吲哚啉-3-酮；
5-甲基-2-苯基-2-(2-喹啉基甲基)吲哚啉-3-酮；
5-甲氧基-2-苯基-2-(2-喹啉基甲基)吲哚啉-3-酮；
6-甲基-2-苯基-2-(2-喹啉基甲基)吲哚啉-3-酮；
7-甲基-2-苯基-2-(2-喹啉基甲基)吲哚啉-3-酮；
7-氯-2-苯基-2-(2-喹啉基甲基)吲哚啉-3-酮；
4-氟-2-苯基-2-(2-喹啉基甲基)吲哚啉-3-酮；
5-氟-2-苯基-2-(2-喹啉基甲基)吲哚啉-3-酮；
2-甲基-2-(2-喹啉基甲基)吲哚啉-3-酮；
2-乙基-2-(2-喹啉基甲基)吲哚啉-3-酮；
5-(3-氧代-2-(2-喹啉基甲基)吲哚啉-2-基)戊酸乙酯；
2-(2-(5-氯喹啉基)-甲基)-2-苯基吲哚啉-3-酮；
2-(2-(6-溴喹啉基)-甲基)-2-苯基吲哚啉-3-酮；
2-(2-(6-氯喹啉基)-甲基)-2-苯基吲哚啉-3-酮；
2-(2-(6-氟喹啉基)-甲基)-2-苯基吲哚啉-3-酮；
2-(2-(6-碘喹啉基)-甲基)-2-苯基吲哚啉-3-酮；
2-(2-(6-甲基喹啉基)-甲基)-2-苯基吲哚啉-3-酮；
2-(2-(6-甲氧基喹啉基)-甲基)-2-苯基吲哚啉-3-酮；
2-(2-(6-三氟甲基喹啉基)-甲基)-2-苯基吲哚啉-3-酮；
2-(2-(6-苯基喹啉基)-甲基)-2-苯基吲哚啉-3-酮；
2-(2-(7-氟喹啉基)-甲基)-2-苯基吲哚啉-3-酮；
2-(2-(8-甲氧基喹啉基)-甲基)-2-苯基吲哚啉-3-酮；
2-(3-氯苯基)-2-(2-喹啉基甲基)吲哚啉-3-酮；
2-(4-甲基苯基)-2-(2-喹啉基甲基)吲哚啉-3-酮；
2-(4-甲氧基苯基)-2-(2-喹啉基甲基)吲哚啉-3-酮；
2-(4-氯苯基)-2-(2-喹啉基甲基)吲哚啉-3-酮；
2-(4-三氟甲基苯基)-2-(2-喹啉基甲基)吲哚啉-3-酮；
2-(4-硝基苯基)-2-(2-喹啉基甲基)吲哚啉-3-酮；
2-(4-溴苯基)-2-(2-喹啉基甲基)吲哚啉-3-酮；
2-(2-喹啉基甲基)-2-(2-噻吩基)吲哚啉-3-酮。
Figure BDA0003285786260000041
Figure BDA0003285786260000051
通式(1)化合物的制备方法如下：
Figure BDA0003285786260000052
将化合物II吲哚衍生物置于含有磁子的干燥反应器中，相继加入无水乙酸乙酯、氯化亚铜、2-甲基喹啉III、特戊酸，置换反应瓶中的空气，并在氧气条件下置于油浴锅中搅拌反应，反应结束后，直接减压蒸馏除去溶剂，残渣进行柱层析纯化得纯品产物。
本发明优点：提供了一种利用金属盐、酸共催化氧化2-取代吲哚和2-甲基喹啉去芳构化-亲核加成串联反应的绿色制备方法，该制备方法具有官能团兼容性好、底物范围广、条件温和、操作简便、环境友好等优势，适合工业化应用；同时发现本发明化合物在抗菌方面具有很好的活性，以其为有效成分可以用于制备治疗细菌感染药物。
具体实施方式
为对本发明进行更好地说明，举实施例如下：
实施例1
2-苯基-2-(2-喹啉基甲基)吲哚啉-3-酮的制备：
将2-苯基吲哚(38.6mg，0.2mmol)置于含有磁子的10ml干燥圆底烧瓶中，相继加入无水乙酸乙酯(4ml)、氯化亚铜(2.0mg,0.02mmol)、2-甲基喹啉III(57.3mg,0.4mmol)、特戊酸(2.2mg,0.02mmol)，用带有高纯氧气球的三通置换反应瓶中的空气，并在氧气条件下置于，50℃的油浴锅中，搅拌反应至原料消失，直接减压蒸馏除去溶剂，残渣直接进行柱层析纯化得纯品产物1。1H NMR(400MHz,CDCl3)δ8.04(d,J＝8.3Hz,1H),7.90(d,J＝8.4Hz,1H),7.70(t,J＝7.7Hz,4H),7.59(d,J＝7.7Hz,1H),7.47(td,J＝8.2,1.1Hz,2H),7.23(t,J＝7.4Hz,2H),7.19–7.06(m,3H),7.03(d,J＝8.3Hz,1H),6.80(t,J＝7.4Hz,1H),3.85(d,J＝14.1Hz,1H),3.47(d,J＝14.1Hz,1H)；13C NMR(101MHz,CDCl3)δ202.18,160.95,158.01,147.66,138.89,137.57,136.53,129.75,129.03,128.47,127.81,127.52,127.01,126.40,126.39,125.52,123.15,119.94,119.22,113.25,71.71,46.19。
实施例2
3-甲基-2-苯基-2-(2-喹啉基甲基)吲哚啉-3-酮的制备：
参照实施例1的方法。11H NMR(400MHz,CDCl3)δ8.05(dd,J＝11.9,6.8Hz,2H),7.90(d,J＝8.4Hz,1H),7.70(dd,J＝7.4,5.5Hz,5H),7.49(q,J＝7.7Hz,2H),7.31(dd,J＝8.0,6.4Hz,2H),7.23(t,J＝7.5Hz,2H),7.15(t,J＝7.3Hz,1H),7.09(d,J＝8.4Hz,2H),6.85(d,J＝8.2Hz,1H),6.54(d,J＝7.2Hz,1H),3.85(d,J＝14.1Hz,1H),3.46(d,J＝14.1Hz,1H),2.55(s,3H)；13C NMR(101MHz,CDCl3)δ202.65,161.46,158.14,147.55,140.77,139.17,137.02,136.53,129.76,128.96,128.43,127.79,127.43,126.97,126.40,125.93,123.17,122.22,120.64,110.42,71.50,46.23,18.45。
实施例3
5-甲基-2-苯基-2-(2-喹啉基甲基)吲哚啉-3-酮的制备：
参照实施例1的方法。1H NMR(400MHz,CDCl3)δ8.03(d,J＝8.5Hz,1H),7.87(d,J＝8.4Hz,1H),7.72–7.62(m,4H),7.47(d,J＝7.5Hz,1H),7.35(s,1H),7.28–7.18(m,3H),7.14(t,J＝7.2Hz,1H),7.07(d,J＝8.4Hz,1H),7.00–6.88(m,2H),3.81(d,J＝14.0Hz,1H),3.47(d,J＝14.0Hz,1H),2.25(s,3H)；13C NMR(101MHz,CDCl3)δ202.27,159.44,157.98,147.53,139.12,139.07,136.56,129.75,128.88,128.65,128.42,127.79,127.45,126.98,126.38,125.91,124.69,123.15,120.00,113.17,72.01,46.26,20.70。
实施例4
5-甲氧基-2-苯基-2-(2-喹啉基甲基)吲哚啉-3-酮的制备：
参照实施例1的方法。1H NMR(400MHz,CDCl3)δ8.03(d,J＝8.4Hz,1H),7.89(d,J＝8.4Hz,1H),7.80–7.66(m,4H),7.48(t,J＝7.1Hz,1H),7.23(t,J＝7.5Hz,2H),7.19–7.11(m,2H),7.07(d,J＝8.4Hz,1H),7.00(t,J＝5.9Hz,2H),6.84(s,1H),3.82(d,J＝13.9Hz,1H),3.76(s,3H),3.47(d,J＝13.9Hz,1H)；13C NMR(101MHz,CDCl3)δ202.58,157.97,156.90,153.76,147.69,139.11,136.51,129.76,129.06,128.45,128.33,127.83,127.50,127.02,126.49,126.39,123.17,120.23,114.97,105.12,72.64,56.01,46.50。
实施例5
6-甲基-2-苯基-2-(2-喹啉基甲基)吲哚啉-3-酮的制备：
参照实施例1的方法。1H NMR(400MHz,CDCl3)δ8.04(d,J＝8.4Hz,1H),7.90(d,J＝8.4Hz,1H),7.78–7.63(m,4H),7.52–7.44(m,2H),7.22(dd,J＝10.2,4.7Hz,2H),7.14(t,J＝7.3Hz,1H),7.11–7.00(m,2H),6.85(s,1H),6.63(d,J＝7.9Hz,1H),3.85(d,J＝14.1Hz,1H),3.45(d,J＝14.1Hz,1H),2.37(s,3H)；13C NMR(101MHz,CDCl3)δ201.42,161.43,158.16,149.22,147.58,139.03,136.54,129.74,129.02,128.43,127.82,127.43,127.00,126.37,125.25,124.59,123.21,121.10,117.62,113.28,71.90,46.13,22.70。
实施例6
7-甲基-2-苯基-2-(2-喹啉基甲基)吲哚啉-3-酮的制备：
参照实施例1的方法。1H NMR(400MHz,CDCl3)δ8.15–7.95(m,2H),7.90(d,J＝8.4Hz,1H),7.72(dt,J＝10.5,4.5Hz,4H),7.56–7.41(m,2H),7.30(d,J＝8.5Hz,1H),7.25(dd,J＝10.0,4.7Hz,2H),7.21–7.15(m,1H),7.09(d,J＝8.5Hz,1H),3.81(d,J＝13.8Hz,1H),3.47(d,J＝13.8Hz,1H),2.39(s,3H)；13C NMR(101MHz,CDCl3)δ201.95,160.83,158.72,146.56,138.76,138.48,137.64,136.55,135.25,130.71,129.66,128.53,127.61,126.31,125.53,123.81,122.23,119.91,119.33,113.16,71.57,46.33,27.34。
实施例7
7-氯-2-苯基-2-(2-喹啉基甲基)吲哚啉-3-酮的制备：
参照实施例1的方法。1H NMR(400MHz,CDCl3)δ8.01(d,J＝8.4Hz,1H),7.92(d,J＝8.4Hz,1H),7.77–7.67(m,2H),7.66–7.60(m,2H),7.56–7.45(m,2H),7.39(dd,J＝8.7,2.2Hz,1H),7.22(t,J＝7.4Hz,3H),7.16(d,J＝7.2Hz,1H),7.08(d,J＝8.4Hz,1H),6.98(d,J＝8.7Hz,1H),3.82(d,J＝14.2Hz,1H),3.46(d,J＝14.2Hz,1H)；13C NMR(101MHz,CDCl3)δ200.86,158.96,157.46,147.31,138.13,137.30,136.60,129.71,128.68,128.37,127.67,127.52,126.81,126.32,126.06,124.52,124.19,122.90,120.70,114.24,72.35,45.76。
实施例8
4-氟-2-苯基-2-(2-喹啉基甲基)吲哚啉-3-酮的制备：
参照实施例1的方法。1H NMR(400MHz,CDCl3)δ8.03(d,J＝8.4Hz,1H),7.93(d,J＝8.4Hz,1H),7.74–7.64(m,3H),7.50(d,J＝7.9Hz,1H),7.45–7.31(m,2H),7.27–7.05(m,4H),6.79(d,J＝8.2Hz,1H),6.43–6.30(m,1H),3.86(d,J＝14.3Hz,1H),3.49(d,J＝14.3Hz,1H)；13C NMR(101MHz,CDCl3)δ198.28,161.72,161.66,161.52,158.91,157.78,139.22,139.12,138.31,136.78,129.88,128.91,128.54,127.87,127.73,127.02,126.50,126.29,123.17,108.77,108.73,108.51,105.03,104.84,72.12,45.91。
实施例9
5-氟-2-苯基-2-(2-喹啉基甲基)吲哚啉-3-酮的制备：
参照实施例1的方法。1H NMR(400MHz,CDCl3)δ8.02(d,J＝8.6Hz,1H),7.91(d,J＝8.4Hz,1H),7.81–7.59(m,4H),7.54–7.44(m,1H),7.27–7.12(m,5H),7.11–6.91(m,3H),3.81(d,J＝14.0Hz,1H),3.47(d,J＝14.0Hz,1H)；13C NMR(101MHz,CDCl3)δ202.07,202.04,158.00,157.71,157.63,155.61,147.61,138.60,136.65,129.84,128.96,128.54,127.85,127.68,127.01,126.47,126.37,125.80,125.55,123.11,120.44,120.36,114.52,114.45,110.15,109.93,72.84,46.34。
实施例10
2-甲基-2-(2-喹啉基甲基)吲哚啉-3-酮的制备：
参照实施例1的方法。1H NMR(400MHz,CDCl3)δ8.18(d,J＝8.4Hz,1H),8.11(d,J＝8.4Hz,1H),7.88–7.69(m,2H),7.55(dd,J＝14.7,7.5Hz,2H),7.42–7.29(m,2H),6.88(d,J＝8.3Hz,1H),6.70(t,J＝7.4Hz,1H),6.61(s,1H),3.41(d,J＝13.6Hz,1H),3.23(d,J＝13.7Hz,1H),1.93(dt,J＝14.6,7.3Hz,1H),1.67(dd,J＝13.8,7.3Hz,1H),0.76(t,J＝7.4Hz,3H)；13C NMR(101MHz,CDCl3)δ203.64,160.30,156.43,136.69,136.20,129.41,126.65,126.59,125.84,125.75,123.23,122.10,120.05,117.32,111.77,69.84,42.85,28.36,6.77。
实施例11
2-乙基-2-(2-喹啉基甲基)吲哚啉-3-酮的制备：
参照实施例1的方法。1H NMR(400MHz,CDCl3)δ8.18(d,J＝8.4Hz,1H),8.11(d,J＝8.4Hz,1H),7.88–7.69(m,2H),7.55(dd,J＝14.7,7.5Hz,2H),7.42–7.29(m,2H),6.88(d,J＝8.3Hz,1H),6.70(t,J＝7.4Hz,1H),6.61(s,1H),3.41(d,J＝13.6Hz,1H),3.23(d,J＝13.7Hz,1H),1.93(dt,J＝14.6,7.3Hz,1H),1.67(dd,J＝13.8,7.3Hz,1H),0.76(t,J＝7.4Hz,3H)；13C NMR(101MHz,CDCl3)δ203.64,160.30,156.43,136.69,136.20,129.41,126.65,126.59,125.84,125.75,123.23,122.10,120.05,117.32,111.77,69.84,42.85,28.36,6.77。
实施例12
5-(3-氧代-2-(2-喹啉基甲基)吲哚啉-2-基)戊酸乙酯的制备：
参照实施例1的方法。1H NMR(400MHz,CDCl3)δ8.19–8.09(m,2H),7.81–7.73(m,2H),7.55(t,J＝8.9Hz,2H),7.34(dd,J＝19.1,7.9Hz,2H),6.88(d,J＝8.3Hz,1H),6.70(dd,J＝17.1,9.7Hz,2H),4.04(q,J＝7.1Hz,2H),3.35(d,J＝13.5Hz,1H),3.18(d,J＝13.8Hz,1H),2.16(td,J＝7.5,4.5Hz,3H),1.91(td,J＝12.6,4.7Hz,1H),1.72–1.39(m,4H),1.18(t,J＝7.1Hz,3H)；13C NMR(101MHz,CDCl3)δ204.51,173.71,161.36,157.25,137.54,137.22,130.97,127.91,127.87,127.21,127.10,124.50,123.36,122.90,120.96,118.63,113.01,70.59,60.36,44.06,36.29,34.28,25.29,23.12,14.37.
实施例13
2-(2-(5-氯喹啉基)-甲基)-2-苯基吲哚啉-3-酮的制备：
参照实施例1的方法。1H NMR(400MHz,CDCl3)δ8.11(d,J＝8.3Hz,1H),8.02(d,J＝8.3Hz,1H),7.86–7.63(m,3H),7.58(dd,J＝15.0,7.7Hz,2H),7.47(t,J＝7.5Hz,1H),7.26–7.11(m,4H),7.07–6.93(m,2H),6.81(t,J＝7.3Hz,1H),3.81(d,J＝14.5Hz,1H),3.42(d,J＝14.4Hz,1H)；13C NMR(101MHz,CDCl3)δ201.78,160.79,158.01,148.41,142.96,138.57,137.66,130.68,129.40,128.60,127.68,127.38,126.28,125.62,125.25,124.25,123.03,119.78,119.34,113.10,71.49,45.80。
实施例14
2-(2-(6-溴喹啉基)-甲基)-2-苯基吲哚啉-3-酮的制备：
参照实施例1的方法。1H NMR(400MHz,CDCl3)δ7.81(dt,J＝23.8,10.8Hz,4H),7.62(dd,J＝29.6,7.5Hz,2H),7.47(t,J＝7.5Hz,1H),7.27–7.07(m,4H),7.02(d,J＝8.2Hz,1H),6.91(s,1H),6.81(t,J＝7.1Hz,1H),3.83(d,J＝14.1Hz,1H),3.46(d,J＝14.2Hz,1H)；13C NMR(101MHz,CDCl3)δ201.96,160.82,158.55,146.23,138.72,137.65,135.47,133.21,130.79,129.84,128.53,128.07,127.60,126.31,125.54,123.97,120.20,119.90,119.36,113.18,71.56,46.25。
实施例15
2-(2-(6-氯喹啉基)-甲基)-2-苯基吲哚啉-3-酮的制备：
参照实施例1的方法。1H NMR(400MHz,CDCl3)δ7.95(d,J＝9.0Hz,1H),7.80(d,J＝8.4Hz,1H),7.66(t,J＝5.3Hz,3H),7.63–7.54(m,2H),7.48–7.41(m,1H),7.22(t,J＝7.4Hz,2H),7.18–7.13(m,1H),7.10(d,J＝8.4Hz,1H),7.00(d,J＝8.3Hz,1H),6.92(s,1H),6.79(t,J＝7.2Hz,1H),3.82(d,J＝14.2Hz,1H),3.47(d,J＝14.2Hz,1H)；13CNMR(101MHz,CDCl3)δ201.96,160.83,158.35,145.98,138.77,137.64,135.58,132.13,130.70,130.60,128.53,127.61,127.55,126.47,126.31,125.52,123.98,119.90,119.32,113.14,71.60,46.24。
实施例16
2-(2-(6-氟喹啉基)-甲基)-2-苯基吲哚啉-3-酮的制备：
参照实施例1的方法。1H NMR(400MHz,CDCl3)δ8.12–7.96(m,1H),7.85(d,J＝8.4Hz,1H),7.67(d,J＝7.5Hz,2H),7.59(d,J＝7.6Hz,1H),7.48(d,J＝7.0Hz,2H),7.32(d,J＝8.7Hz,1H),7.23(t,J＝7.0Hz,2H),7.20–7.14(m,1H),7.10(d,J＝8.3Hz,1H),7.03(d,J＝8.2Hz,1H),6.95(s,1H),6.81(t,J＝7.2Hz,1H),3.84(d,J＝14.2Hz,1H),3.46(d,J＝14.2Hz,1H)；13C NMR(101MHz,CDCl3)δ202.05,161.61,160.86,159.15,157.35,144.75,138.77,137.61,135.88,135.83,131.51,131.42,128.51,127.58,126.34,125.54,123.85,120.08,119.93,119.83,119.33,113.20,110.90,110.69,71.63,46.08。
实施例17
2-(2-(6-碘喹啉基)-甲基)-2-苯基吲哚啉-3-酮的制备：
参照实施例1的方法。1H NMR(400MHz,CDCl3)δ8.09(d,J＝1.8Hz,1H),7.91(dd,J＝8.8,1.9Hz,1H),7.76(dd,J＝10.3,9.0Hz,2H),7.70–7.63(m,2H),7.58(d,J＝7.7Hz,1H),7.50–7.41(m,1H),7.23(dd,J＝10.1,4.7Hz,2H),7.16(dd,J＝8.4,6.0Hz,1H),7.09(d,J＝8.4Hz,1H),7.01(d,J＝8.3Hz,1H),6.94(s,1H),6.80(t,J＝7.3Hz,1H),3.82(d,J＝14.2Hz,1H),3.46(d,J＝14.2Hz,1H)；13C NMR(101MHz,CDCl3)δ201.96,160.82,158.68,146.52,138.72,138.47,137.66,136.54,135.27,130.68,128.65,128.53,127.61,126.29,125.52,123.81,119.85,119.31,113.14,91.74,71.56,46.30。
实施例18
2-(2-(6-甲基喹啉基)-甲基)-2-苯基吲哚啉-3-酮的制备的制备：
参照实施例1的方法。1H NMR(400MHz,CDCl3)δ7.93(d,J＝8.0Hz,1H),7.80(d,J＝7.6Hz,1H),7.67(d,J＝7.2Hz,2H),7.59(d,J＝7.4Hz,1H),7.55–7.42(m,3H),7.22(t,J＝7.0Hz,2H),7.15(d,J＝8.6Hz,2H),7.09–6.96(m,2H),6.80(t,J＝6.8Hz,1H),3.82(d,J＝14.0Hz,1H),3.43(d,J＝14.0Hz,1H),2.50(s,3H)；13C NMR(101MHz,CDCl3)δ202.29,160.96,157.01,146.27,138.86,137.54,136.22,135.84,132.00,128.71,128.42,127.46,127.00,126.64,126.40,125.50,123.15,119.94,119.20,113.31,71.74,46.08,21.69。
实施例19
2-(2-(6-甲氧基喹啉基)-甲基)-2-苯基吲哚啉-3-酮的制备：
参照实施例1的方法。1H NMR(400MHz,CDCl3)δ7.92(d,J＝9.0Hz,1H),7.78(d,J＝8.2Hz,1H),7.67(d,J＝7.6Hz,2H),7.58(d,J＝7.7Hz,1H),7.46(t,J＝7.6Hz,1H),7.34(d,J＝9.1Hz,1H),7.25–6.98(m,6H),6.96(s,1H),6.80(t,J＝7.4Hz,1H),3.88(d,J＝7.9Hz,3H),3.79(d,J＝14.1Hz,1H),3.42(d,J＝14.1Hz,1H)；13C NMR(101MHz,CDCl3)δ202.33,160.97,157.71,155.28,143.79,138.92,137.54,135.28,130.42,128.43,127.94,127.47,126.41,125.48,123.41,122.50,119.99,119.21,113.31,105.23,71.80,55.73,45.97。
实施例20
2-(2-(6-三氟甲基喹啉基)-甲基)-2-苯基吲哚啉-3-酮的制备：
参照实施例1的方法。1H NMR(400MHz,CDCl3)δ8.56(d,J＝8.8Hz,1H),8.49–8.38(m,2H),8.29(dd,J＝8.8,1.7Hz,1H),8.10(d,J＝7.5Hz,2H),8.03(d,J＝7.7Hz,1H),7.90(t,J＝7.6Hz,1H),7.69–7.57(m,4H),7.46(d,J＝8.2Hz,1H),7.34(s,1H),7.24(t,J＝7.4Hz,1H),4.32(d,J＝14.3Hz,1H),3.95(d,J＝14.2Hz,1H)；13C NMR(101MHz,CDCl3)δ201.82,160.79,160.56,148.53,145.68,138.65,137.71,137.24,130.22,128.58,127.68,126.27,125.91,125.84,125.80,125.56,125.51,125.48,124.59,124.35,123.70,122.80,119.83,119.39,113.11,71.52,46.36。
实施例21
2-(2-(6-苯基喹啉基)-甲基)-2-苯基吲哚啉-3-酮：
参照实施例1的方法。1H NMR(400MHz,CDCl3)δ8.10(d,J＝8.7Hz,1H),8.00–7.91(m,2H),7.89(d,J＝1.9Hz,1H),7.70(ddd,J＝9.1,8.4,7.7Hz,4H),7.61(d,J＝7.7Hz,1H),7.53–7.44(m,3H),7.41(t,J＝7.3Hz,1H),7.24(dd,J＝10.2,4.7Hz,2H),7.20–7.00(m,4H),6.82(t,J＝7.4Hz,1H),3.87(d,J＝14.1Hz,1H),3.48(d,J＝14.1Hz,1H)；13C NMR(101MHz,CDCl3)δ202.18,160.94,158.01,147.02,140.45,139.23,138.83,137.61,136.71,129.52,129.44,129.18,128.49,127.95,127.60,127.54,127.16,126.39,125.54,125.51,123.56,119.90,119.25,113.28,71.72,46.18。
实施例22
2-(2-(7-氟喹啉基)-甲基)-2-苯基吲哚啉-3-酮的制备：
参照实施例1的方法。1H NMR(400MHz,CDCl3)δ8.03(s,1H),7.88(d,J＝8.4Hz,1H),7.77–7.54(m,4H),7.53–7.35(m,2H),7.23(t,J＝7.3Hz,2H),7.15(t,J＝6.9Hz,1H),7.12–6.94(m,3H),6.82(t,J＝7.4Hz,1H),3.85(d,J＝14.3Hz,1H),3.44(d,J＝14.3Hz,1H)；13CNMR(101MHz,CDCl3)δ201.98,160.84,159.29,147.96,138.67,137.69,136.32,135.62,129.04,128.51,128.07,127.56,127.45,126.32,125.55,125.31,123.36,119.77,119.30,113.20,71.57,46.06。
实施例23
2-(2-(8-甲氧基喹啉基)-甲基)-2-苯基吲哚啉-3-酮的制备：
参照实施例1的方法。1H NMR(400MHz,CDCl3)δ7.86(d,J＝8.4Hz,1H),7.73–7.64(m,2H),7.62–7.51(m,2H),7.43(ddd,J＝19.4,12.1,4.5Hz,2H),7.29(s,1H),7.21(t,J＝7.5Hz,2H),7.17–6.99(m,4H),6.78(t,J＝7.4Hz,1H),4.14(s,3H),3.84(d,J＝14.0Hz,1H),3.50(d,J＝14.0Hz,1H)；13C NMR(101MHz,CDCl3)δ202.10,160.94,156.47,155.01,139.34,138.76,137.28,136.24,128.18,127.83,127.22,126.84,126.25,125.27,123.35,119.67,119.42,118.75,113.12,108.00,71.42,56.20,45.78。
实施例24
2-(3-氯苯基)-2-(2-喹啉基甲基)吲哚啉-3-酮的制备：
参照实施例1的方法。1H NMR(400MHz,CDCl3)δ8.04(d,J＝8.4Hz,1H),8.00–7.93(m,1H),7.75–7.65(m,3H),7.65–7.56(m,2H),7.55–7.46(m,2H),7.22(s,1H),7.20–7.03(m,4H),6.83(t,J＝7.3Hz,1H),3.81(d,J＝14.4Hz,1H),3.43(d,J＝14.4Hz,1H)；13C NMR(101MHz,CDCl3)δ201.54,160.91,157.57,147.61,141.05,137.83,136.82,134.40,129.93,129.71,129.00,127.86,127.71,127.03,126.70,126.55,125.59,124.77,123.06,119.68,119.56,113.47,71.29,45.91。
实施例25
2-(4-甲基苯基)-2-(2-喹啉基甲基)吲哚啉-3-酮的制备：
参照实施例1的方法。1H NMR(400MHz,CDCl3)δ8.04(d,J＝8.4Hz,1H),7.91(d,J＝8.4Hz,1H),7.69(dd,J＝12.8,4.5Hz,2H),7.57(dd,J＝7.6,5.9Hz,3H),7.53–7.39(m,2H),7.12(d,J＝8.5Hz,2H),7.02(dd,J＝15.5,8.2Hz,3H),6.78(t,J＝7.4Hz,1H),3.83(d,J＝14.1Hz,1H),3.48(d,J＝14.1Hz,1H),2.24(s,3H)；13C NMR(101MHz,CDCl3)δ202.35,160.92,158.04,147.55,137.50,137.15,136.56,135.81,129.73,129.23,128.91,127.79,126.98,126.35,126.22,125.47,123.20,119.82,119.03,113.11,71.62,45.96,21.13。
实施例26
2-(4-甲氧基苯基)-2-(2-喹啉基甲基)吲哚啉-3-酮的制备：
参照实施例1的方法。1H NMR(400MHz,CDCl3)δ8.04(d,J＝8.3Hz,1H),7.91(d,J＝8.4Hz,1H),7.70(ddd,J＝9.7,6.3,2.1Hz,2H),7.58(dd,J＝6.8,2.1Hz,3H),7.52–7.38(m,2H),7.09(d,J＝8.4Hz,2H),7.01(t,J＝11.4Hz,1H),6.88–6.66(m,3H),3.81(d,J＝14.1Hz,1H),3.71(s,3H),3.43(d,J＝14.1Hz,1H)；13C NMR(101MHz,CDCl3)δ202.55,160.90,159.07,158.15,147.65,137.53,136.55,130.85,129.75,129.02,127.82,127.54,126.99,126.37,125.52,123.24,119.95,119.17,113.88,113.26,71.31,55.36,46.10。
实施例27
2-(4-氯苯基)-2-(2-喹啉基甲基)吲哚啉-3-酮的制备：
参照实施例1的方法。1H NMR(400MHz,CDCl3)δ8.04(d,J＝8.4Hz,1H),7.93(d,J＝8.4Hz,1H),7.71(ddd,J＝9.7,6.5,2.3Hz,2H),7.67–7.56(m,3H),7.54–7.43(m,2H),7.25(s,1H),7.20–7.11(m,2H),7.07(dd,J＝8.3,5.6Hz,2H),6.83(t,J＝7.4Hz,1H),3.80(d,J＝14.3Hz,1H),3.42(d,J＝14.3Hz,1H)；13C NMR(101MHz,CDCl3)δ201.81,160.89,157.70,147.61,137.78,137.46,136.78,133.47,129.90,128.97,128.54,127.92,127.87,127.00,126.52,125.59,123.07,119.75,119.50,113.44,71.27,46.02。
实施例28
2-(4-三氟甲基苯基)-2-(2-喹啉基甲基)吲哚啉-3-酮的制备：
参照实施例1的方法。1H NMR(400MHz,CDCl3)δ8.05(d,J＝8.3Hz,1H),7.94(d,J＝8.4Hz,1H),7.85(d,J＝8.2Hz,2H),7.72(t,J＝7.8Hz,2H),7.61(d,J＝7.7Hz,1H),7.49(dt,J＝6.6,4.6Hz,4H),7.38(s,1H),7.09(dd,J＝17.2,8.3Hz,2H),6.83(t,J＝7.4Hz,1H),3.85(d,J＝14.4Hz,1H),3.51(d,J＝14.4Hz,1H)；13C NMR(101MHz,CDCl3)δ201.18,160.77,157.17,147.31,142.89,137.71,136.74,129.80,129.66,129.50,129.34,128.62,127.68,127.49,126.83,126.68,126.41,125.73,125.48,125.37,125.21,125.18,125.14,125.10,122.78,122.74,122.06,119.38,119.37,113.21,71.34,45.83。
实施例29
2-(4-硝基苯基)-2-(2-喹啉基甲基)吲哚啉-3-酮的制备：
参照实施例1的方法。1H NMR(400MHz,CDCl3)δ8.31(d,J＝8.9Hz,1H),8.10–7.93(m,4H),7.92–7.82(m,2H),7.72(dd,J＝12.5,4.3Hz,2H),7.63(d,J＝7.8Hz,1H),7.58–7.45(m,3H),7.11(dd,J＝11.9,8.3Hz,2H),6.89(t,J＝7.4Hz,1H),3.88(d,J＝14.8Hz,1H),3.46(d,J＝14.8Hz,1H)；13C NMR(101MHz,CDCl3)δ200.72,160.90,157.14,146.48,138.17,130.15,127.93,127.57,127.32,127.02,126.75,125.73,124.55,123.53,122.80,121.53,119.95,119.44,113.63,112.04,71.66,46.04。
实施例30
2-(4-溴苯基)-2-(2-喹啉基甲基)吲哚啉-3-酮的制备：
参照实施例1的方法。1H NMR(400MHz,CDCl3)δ8.03(d,J＝8.4Hz,1H),7.94(d,J＝8.4Hz,1H),7.72(dd,J＝12.7,7.4Hz,2H),7.58(dd,J＝12.3,8.2Hz,3H),7.54–7.46(m,2H),7.33(d,J＝8.7Hz,2H),7.24(s,1H),7.07(t,J＝8.4Hz,2H),6.83(t,J＝7.4Hz,1H),3.79(d,J＝14.3Hz,1H),3.41(d,J＝14.4Hz,1H)；13C NMR(101MHz,CDCl3)δ201.75,160.90,157.69,147.63,138.01,137.81,136.82,131.50,129.92,128.99,128.30,127.89,127.02,126.54,125.61,123.08,121.74,119.74,119.52,113.45,71.33,45.95。
实施例31
2-(2-喹啉基甲基)-2-(2-噻吩基)吲哚啉-3-酮的制备：
参照实施例1的方法。1H NMR(400MHz,CDCl3)δ8.03(d,J＝8.4Hz,1H),7.93(d,J＝8.4Hz,1H),7.74–7.64(m,3H),7.50(d,J＝7.9Hz,1H),7.45–7.31(m,2H),7.27–7.05(m,4H),6.79(d,J＝8.2Hz,1H),6.43–6.30(m,1H),3.86(d,J＝14.3Hz,1H),3.49(d,J＝14.3Hz,1H)；13C NMR(101MHz,CDCl3)δ198.28,161.72,161.66,161.52,158.91,157.78,139.22,139.12,138.31,136.78,129.88,128.91,128.54,127.87,127.73,127.02,126.50,126.29,123.17,108.77,108.73,108.51,105.03,104.84,72.12,45.91。
通过药理实验说明本发明2,2-二取代吲哚啉-3-酮类生物碱对细菌细胞的生长抑制作用。
1.实验方法
在96孔板上用BHI肉汤将目标化合物二倍稀释后加入到等体积生长对数期的菌液中，目标化合物的浓度为1-64μg/mL，菌液细胞终浓度为1×106CFU/mL，孔溶液终体积为200μL。37℃厌氧环境中培育24h，酶标仪测定625nm下的OD值。同时设置培养基空白对照、细菌对照以及青霉素G钠阳性药对照。
MIC50(％)＝(OD样品–OD空白)/(OD参照–OD空白)×100
2.实验结果
表一.2,2-二取代吲哚啉-3-酮类生物碱对细菌生长抑制作用
Figure BDA0003285786260000171
Figure BDA0003285786260000181
通过对以上化合物的细菌细胞抑制活性评价结果可看出，大部分化合物均有一定的抑菌效果，化合物2、3、9、24、25、26、27具有明显的抑制效果，其中化合物9、24、25具有进一步开发研究价值。

Claims (4)

1.2,2-二取代吲哚啉-3-酮生物碱，其特征在于，具有如通式(1)所示结构：
Figure FDA0003924634750000011
其中：R1为氢原子，氟，氯，溴，碘，甲基，乙基或甲氧基，乙氧基，其位置是在苯环上4位至7位单取代；
R2为甲基，乙基或
Figure FDA0003924634750000012
苯基，被氟、氯、溴、碘、硝基、三氟甲基、甲氧基、乙氧基、甲基、乙基单取代的苯基，呋喃基；
R3为氢、氟、氯、溴、碘、甲氧基、乙氧基、甲基、乙基、三氟甲基或苯基，其位置是在喹啉环上5位至8位单取代。
2.根据权利要求1所述的2,2-二取代吲哚啉-3-酮生物碱，其特征在于，选如下化合物：
Figure FDA0003924634750000013
Figure FDA0003924634750000021
3.根据权利要求2所述的2,2-二取代吲哚啉-3-酮生物碱，其特征在于，选自化合物9、24或25。
4.制备权利要求1或2所述的2,2-二取代吲哚啉-3-酮生物碱的方法，其特征在于，将化合物(II)吲哚衍生物置于含有磁子的反应器中，相继加入无水乙酸乙酯、氯化亚铜、化合物(III)2-甲基喹啉衍生物、特戊酸，置换反应瓶中的空气，并在氧气环境下置于油浴锅中加热搅拌反应，反应结束后，直接减压蒸馏除去溶剂，残渣进行柱层析纯化得产物；
Figure FDA0003924634750000031
R1、R2、R3如权利要求1或2中所定义。
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