CN107445963B - 一种喹喔啉类衍生物及其制备方法和应用 - Google Patents
一种喹喔啉类衍生物及其制备方法和应用 Download PDFInfo
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- 125000001567 quinoxalinyl group Chemical class N1=C(C=NC2=CC=CC=C12)* 0.000 title 1
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 claims abstract description 22
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 15
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 15
- 150000003252 quinoxalines Chemical class 0.000 claims abstract description 14
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- 150000001875 compounds Chemical class 0.000 claims description 35
- 238000006243 chemical reaction Methods 0.000 claims description 14
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- -1 formula (Ia) Chemical class 0.000 claims description 8
- 239000002994 raw material Substances 0.000 claims description 5
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- ANUAIBBBDSEVKN-UHFFFAOYSA-N benzene-1,2,4,5-tetramine Chemical compound NC1=CC(N)=C(N)C=C1N ANUAIBBBDSEVKN-UHFFFAOYSA-N 0.000 claims description 4
- 239000012362 glacial acetic acid Substances 0.000 claims description 4
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
- C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
- C07D241/40—Benzopyrazines
- C07D241/42—Benzopyrazines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种喹喔啉类衍生物,所述喹喔啉类衍生物的结构式如式(Ι)或式(Ⅱ)所示,本发明同时公开了该喹喔啉类衍生物的制备方法及其在制备抗肿瘤药物中的应用。本发明所提供的喹喔啉衍生物可以与新靶点—细胞内的波形蛋白vimentin相互作用,抑制肿瘤细胞增殖和迁移,可以应用于新型抗肿瘤药物的开发。同时对正常细胞毒性小,在制备抗癌药物的应用中安全性高,且所述喹唑啉衍生物对多种肿瘤细胞均有较强的抑制作用,在制备抗癌药物上具有很高的医学价值和广阔的市场前景。
Description
技术领域
本发明涉及药物和化工技术领域,更具体地,涉及一种喹喔啉类衍生物及其制备方法和应用。
背景技术
癌症是威胁人类健康和生命安全的主要疾病之一。据统计,全世界每年新增癌症患者达600万人左右。抗癌药物的研究与开发一直是化学家和药物学家关注的热点,寻找高效、高选择性、毒副作用小的抗癌药物是药物研究开发的重要方向之一。
波形蛋白(vimentin)与微管蛋白一样是维持细胞正常形态和功能的重要骨架蛋白,多个研究表明波形蛋白在癌细胞中普遍高表达,对于恶性癌细胞的生长、迁移起着重要作用。因此波形蛋白有可能与微管蛋白一样成为抗癌靶点,多项研究也开发了相关的microRNA、多肽、以及化合物,这些都具有抗肿瘤作用。目前报道的直接作用于vimentin蛋白的小分子只有三个,因而急需更多的能够与vimentin蛋白结合的化合物应用于抗癌药物中。
发明内容
本发明的目的在于针对现有技术的不足,提供一种喹喔啉类衍生物。
本发明的另一个目的在于提供上述喹喔啉类衍生物的制备方法。
本发明的再一个目的在于提供上述喹喔啉类衍生物在制备抗癌药物中的应用。
本发明通过以下技术方案实现上述目的:
本发明提供一种喹喔啉类衍生物,所述喹喔啉类衍生物的结构式如式(Ι)或式(Ⅱ)所示,
其中,R表示卤素、脂肪胺、芳香胺或芳香胺盐;X表示O或N原子;n代表0~5中任意一个整数。
优选地,R表示卤素、环状脂肪胺、芳香胺或芳香胺盐。
优选地,R表示氯、溴、五元环或六元环状脂肪胺、五元环或六元环状芳香胺或芳香胺盐。
更优选地,五元环或六元环状芳香胺盐为溴盐。
优选地,R表示氯、溴、哌啶基、吡咯基、甲基哌嗪基、二乙胺基或溴吡啶盐。
最优选地,R表示氯、溴、哌啶基、甲基哌嗪基或溴吡啶盐。
进一步地,X表示O原子。
本发明同时提供所述的喹喔啉类衍生物的制备方法,包括如下步骤:
S1.将原料1(4,4'-二羟基苯偶酰)或2(4,4'-二氨基苯偶酰)与二溴烷烃反应,得到化合物3
S2.将化合物3与1,2,4,5-苯四胺四盐酸盐或3,3,-二氨基联苯胺在冰醋酸中发生缩合反应,得到化合物4或5
S3.将化合物4或5发生取代反应或成盐反应,得到结构式如(Ι)或(Ⅱ)所示的双喹喔啉衍生物。
更具体地,本发明制备方法步骤如下:
本发明同时保护所述的双喹喔啉衍生物在制备抗肿瘤药物中的应用。
优选地,所述双喹喔啉衍生物应用于结合细胞骨架蛋白波形蛋白。
其中,本发明中化合物Ia、Ib、Ic和Ⅱ系列化合物与波形蛋白有较强的结合作用,可以作为靶向波形蛋白抗肿瘤药物进一步研发。由于目前能够与vimentin相互结合的化合物较少,本发明能够扩充上述领域的开发,从而研究新型靶点的药物。
优选地,是在制备抗人肝癌、宫颈癌、乳腺癌、肺腺癌或淋巴癌药物中的应用。
进一步地,所述药物包括药学上可接受的盐或辅料。药物的剂型包括片剂、丸剂、胶囊、注射剂、悬浮剂或乳剂等。
与现有技术相比,本发明具有以下优点及有益效果:
1.本发明所提供的喹喔啉衍生物可以与新靶点—细胞内的波形蛋白vimentin相互作用,抑制肿瘤细胞增殖和迁移,可以应用于抗肿瘤药物研发。
2.本发明的所提供的喹喔啉衍生物对正常细胞毒性小,在制备抗癌药物的应用中安全性高。
3.本发明的所提供的喹唑啉衍生物对多种肿瘤细胞均有较强的抑制作用,在制备抗癌药物上具有很高的医学价值和广阔的市场前景。
附图说明
图1为本发明提供的化合物与波形蛋白vimentin的SPR结合实验结果。
图2为化合物Ιa对正常细胞的增殖的影响。
图3为化合物Ιa对宫颈癌移植瘤的抑制作用。
具体实施方式
以下通过具体的实施例和附图进一步说明本发明的技术方案。除非特别说明,本发明采用的试剂、方法和设备为本技术领域常规试剂、方法和设备。
实施例1:化合物3a的合成
1000mL圆底烧瓶中加入(19.6g,81.1mmol)化合物1,加500mL干燥丙酮溶解后加(33.6g,243mmol)无水碳酸钾,及(70.1g,324mmol)1,4-二溴丁烷,升温至80℃反应,TLC监测反应。6小时后,取样点板(PE/EA=2:1)可以看出,原料基本反应完全,停反应,过滤除去碳酸钾,浓缩拌样过柱得到12.4g白色固体3a。
产率30%;1H NMR(400MHz,CDCl3)δ7.93(d,J=8.8Hz,4H),6.95(d,J=8.8Hz,4H),4.08(t,J=6.0Hz,4H),3.49(t,J=6.4Hz,4H),2.11–2.04(m,4H),2.01–1.95(m,4H);13CNMR(100MHz,CDCl3)δ193.5,164.2,132.4,126.3,114.7,67.3,33.2,29.3,27.7.
实施例2:化合物3b的合成
方法同实施例1,所不同的是用1,2-二溴乙烷替代1,4-二溴丁烷,得白色固体3b。
产率46%;1H NMR(400MHz,CDCl3)δ7.98(d,J=8.8Hz,4H),6.94(d,J=8.8Hz,4H),4.33(t,J=6.0Hz,4H),3.79(t,J=6.4Hz,4H);13C NMR(100MHz,CDCl3)δ195.2,165.8,130.5,124.6,114.9,68.3,29.0.
实施例3:化合物3c的合成
方法同实施例1,所不同的是用1,3-二溴丙烷替代1,4-二溴丁烷,得白色固体3c。
产率52%;1H NMR(400MHz,CDCl3)δ7.93(d,J=8.8Hz,4H),6.95(d,J=8.8Hz,4H),4.08(t,J=6.0Hz,4H),3.49(t,J=6.4Hz,4H),2.20–2.08(m,4H);13C NMR(100MHz,CDCl3)δ194.2,165.1,131.6,126.3,114.9,67.3,32.7,29.3.
实施例4:化合物4a的合成
50mL圆底烧瓶中加1,2,4,5-苯四胺四盐酸盐(1.50g,5.30mmol),加20mL冰醋酸以及醋酸钠(17.4g,21.2mmol),室温下搅拌半小时,化合物3a(5.41g,10.6mmol)先溶于50mL冰醋酸再慢慢滴加到上面溶液中,滴加完成后,120℃反应,TLC监测反应。12小时后,取样点板(PE/CH2Cl2=1:1)发现,原料无剩余反应后,停止反应,降温,用饱和NaHCO3溶液调节pH至8左右,用二氯甲烷萃取三次,合并有机层,经无水Na2SO4干燥后旋干,过柱,得到1.6g黄色固体4a。
产率:28%;1H NMR(400MHz,CDCl3)δ8.88(s,2H),7.59(d,J=8.8Hz,8H),6.90(d,J=8.8Hz,8H),4.05(t,J=6.0Hz,8H),3.51(t,J=6.6Hz,8H),2.13–2.06(m,8H),2.01–1.96(m,8H).13C NMR(100MHz,CDCl3)δ159.9,154.5,140.3,131.5,114.3,100.0,67.0,33.5,29.5,27.9.
实施例5:化合物4b的合成
方法同实施例4,所不同的是用3b替代3a,得到黄色固体4b。
产率:32%;1H NMR(400MHz,CDCl3)δ8.72(s,2H),7.43(d,J=8.8Hz,8H),6.77(d,J=8.8Hz,8H),4.08(t,J=6.0Hz,8H),3.55(t,J=6.6Hz,8H);13C NMR(100MHz,CDCl3)δ159.4,155.2,135.5,129.6,117.3,102.1,68.5,29.9.
实施例6:化合物4c的合成
方法同实施例4,所不同的是用3c替代3a,得黄色固体4c。
产率:38%;1H NMR(400MHz,DMSO)δ8.82(s,2H),7.48(d,J=8.8Hz,8H),6.76(d,J=8.8Hz,8H),4.06(t,J=6.0Hz,8H),3.50(t,J=6.4Hz,8H),2.23–2.11(m,8H);13C NMR(100MHz,CDCl3)δ159.3,155.1,135.1,129.1,118.1,104.8,67.0,32.1,29.2.
实施例7:化合物5a的合成
方法同实施例4,所不同的是用3,3,-二氨基联苯胺替代1,2,4,5-苯四胺四盐酸盐,得到黄色固体5a。
产率:41%;1H NMR(400MHz,DMSO)δ8.59(s,2H),8.42(d,J=8.8Hz,2H),8.23(J=8.8Hz,,2H),7.51(d,J=8.4Hz,8H),6.97(dd,J=8.8,2.8Hz,8H),4.06(t,J=6.0Hz,8H),3.52(t,J=6.6Hz,8H),1.98–1.87(m,8H),1.82–1.73(m,8H);13C NMR(100MHz,DMSO)δ159.4,153.2,142.1,141.0,128.8,125.5,114.9,67.7,30.3,28.9,28.0.
实施例8:化合物5b的合成
方法同实施例7,所不同的是用3b替代3a,得到黄色固体5b。
产率:37%;1H NMR(400MHz,DMSO)δ8.55(s,2H),8.40(d,J=8.8Hz,2H),8.25(J=8.8Hz,,8H),7.53(d,J=8.4Hz,8H),6.96(dd,J=8.6,3.0Hz,8H),4.02(t,J=6.2Hz,8H),3.54(t,J=6.4Hz,8H);13C NMR(100MHz,DMSO)δ159.2,155.2,141.1,140.8,127.8,125.3,114.1,68.0,29.3.
实施例8:化合物5c的合成
方法同实施例7,所不同的是用3c替代3a,得到黄色固体5c。
产率:40%;1H NMR(400MHz,DMSO)δ8.55(s,2H),8.44(d,J=8.4Hz,2H),8.20(J=8.4Hz,,8H),7.50(d,J=8.8Hz,8H),6.95(dd,J=8.6,2.6Hz,8H),4.08(t,J=6.2Hz,8H),3.50(t,J=6.6Hz,8H),2.19–2.06(m,8H);13C NMR(100MHz,DMSO)δ159.2,155.2,142.7,141.1,128.5,125.0,114.6,67.8,32.3,29.1.
实施例9:化合物Ιa的合成
50mL圆底烧瓶中加4a(1.09g,1mmol),加20mL干燥的THF溶解,再加DIPEA(0.78g,6mmol),碘化钾(0.66g,4mmol)以及哌啶(0.43g,5mmol),加热回流反应,TLC监测反应。18小时后取样点板(CH2Cl2/CH3OH=10:1)可以看到,原料和中间体基本上都转化为产物,反应后,乙酸乙酯萃取,水洗,干燥,浓缩,拌样过柱,得到黄棕色固体Ιa。
产率:36%;1H NMR(400MHz,CDCl3)δ8.89(s,2H),7.60(d,J=8.8Hz,8H),6.91(d,J=8.8Hz,8H),4.05(t,J=6.4Hz,8H),2.50–2.37(m,24H),1.89–1.81(m,8H),1.77–1.69(m,8H),1.67–1.61(m,16H),1.52–1.44(m,8H);13C NMR(100MHz,CDCl3)δ160.2,154.5,140.2,131.5,131.4,127.9,114.4,67.9,59.0,54.6,27.4,25.8,24.4,23.4.
实施例10:化合物Ιb的合成
方法同实施例9,所不同的是用甲基哌嗪替代哌啶,用4b代替4a得到黄棕色固体Ιb。
产率:42%;1H NMR(400MHz,CDCl3)δ8.90(s,2H),7.90(d,J=8.8Hz,8H),6.93(d,J=8.8Hz,8H),4.17(t,J=6.0Hz,8H),2.84(t,J=6.0Hz,8H),2.75–2.38(m,32H),2.32(s,12H);13C NMR(100MHz,CDCl3)δ163.2,155.5,135.2,129.5,128.4,126.9,114.8,66.5,56.8,55.3,53.8,46.6.
实施例11:化合物Ιc的合成
方法同实施例9,所不同的是用吡啶替代哌啶,得到棕色固体Ιc。
产率:52%;1H NMR(400MHz,DMSO)δ9.28(d,J=5.6Hz,8H),8.74(d,J=4.4Hz,2H),8.67(t,J=7.6Hz,4H),8.23(t,J=6.6Hz,8H),7.55(d,J=8.0Hz,8H),6.99(d,J=8.0Hz,8H),4.79(t,J=6.6Hz,8H),4.09(s,8H),2.13(d,J=6.4Hz,8H),1.79(s,8H);13CNMR(100MHz,DMSO)δ159.9,154.8,146.1,145.3,140.0,131.8 131.5,128.6,114.6,67.5,60.8,28.2,25.7.
实施例12:化合物Ⅱa的合成
方法同实施例9,所不同的是用5a替代4a,得到黄棕色固体Ⅱa。
产率:25%;1H NMR(400MHz,DMSO)δ8.58(s,2H),8.40(d,J=8.8Hz,2H),8.20(J=8.8Hz,,2H),7.52(d,J=8.8Hz,8H),6.93(dd,J=8.4,2.4Hz,8H),4.06(t,J=6.0Hz,8H),2.57–2.32(m,24H),1.84–1.75(m,8H),1.73–1.65(m,8H),1.63(dt,J=11.4,5.8Hz,16H),1.55–1.43(m,8H);13C NMR(100MHz,DMSO)δ159.5,155.2,141.1,140.9,128.6,125.5,114.9,68.5,58.6,54.8,27.5,26.2,24.7,23.8.
实施例13:化合物Ⅱb的合成
方法同实施例12,所不同的是用甲基哌嗪替代哌啶,得到黄棕色固体Ⅱb。
产率:42%;1H NMR(400MHz,DMSO)δ8.59(s,2H),8.43(d,J=8.8Hz,2H),8.22(J=8.8Hz,,2H),δ7.91(d,J=8.8Hz,8H),6.92(d,J=8.8Hz,8H),4.16(t,J=6.0Hz,8H),2.81(t,J=6.0Hz,8H),2.75–2.30(m,32H),2.28(s,12H);13C NMR(100MHz,DMSO)δ159.8,154.9,141.6,140.5,129.0.6,125.7,114.7,66.3,56.8,55.2,53.8,46.0.
实施例14:化合物Ⅱc的合成
方法同实施例12,所不同的是用吡啶替代哌啶,得到黄色固体Ⅱc。
产率:31%;1H NMR(400MHz,DMSO)δ9.21(d,J=5.6Hz,8H),8.65(t,J=7.8Hz,4H),8.44(d,J=7.2Hz,2H),8.24–8.18(m,8H),7.51(d,J=7.6Hz,8H),6.97(dd,J=8.8,2.8Hz,8H),4.75(t,J=7.4Hz,8H),4.08(t,J=6.0Hz,8H),2.13(dt,J=14.8,7.4Hz,8H),1.82–1.73(m,8H);13C NMR(100MHz,DMSO)δ159.5,153.7,153.3,146.1,145.3,141.0,140.6,140.5,131.7,129.9,128.6,127.0,114.6,67.4,60.9,28.2,25.7.
实施例15:本发明所述喹喔啉衍生物与波形蛋白相互结合
将实施例1~14中化合物,采用表面等离子共振作用仪实施SPR实验,如图1所示,其中,横坐标为化合物,纵坐标为平衡常数。具体实验为将波形蛋白标记在SPR芯片上,然后用不同浓度化合物(10μM,5μM,2.5μM,1.25μM,0.625μM),依次流过SPR芯片,根据芯片响应值,采用动力学拟合模式,得到该拟合结果,化合物Ia平衡常数为微摩级别,表示该化合物可以与波形蛋白有较强的结合作用,可以作为靶向波形蛋白抗肿瘤药物进一步研发。化合物Ib,Ic,和Ⅱ系列化合物平衡常数为10-5,也具有较强的结合能力,化合物3,4,5系列检测不到结合。
实施例16:本发明所述喹喔啉衍生物对多种癌细胞的抑制作用
将实施例1~14中化合物,采用MTT法检测化合物对宫颈癌细胞Hela细胞株的抑制作用,如表1所示,体现了该类化合物对不同癌细胞均具有较好的细胞毒性。结果显示该类化合物中Ia,Ⅱa,Ⅱb,4a,4c,5a能够较强抑制各种肿瘤细胞的增殖,可以作为抗肿瘤化合物进行进一步研发。而Ib,3c对于淋巴瘤细胞具有较为特异性的毒性,可以作用特异性抗淋巴瘤活性化合物进行开发。
表1
实施例17:本发明所述喹喔啉衍生物对正常细胞毒性实验
选择以上实施例中的化合物Ιa,采用RTCA法检测对正常细胞的毒性作用,如图2所示,在对肿瘤细胞起抑制作用的5μM浓度下,对正常细胞的增殖作用没有明显影响,该实验结果表明,化合物Ιa是一个对肿瘤细胞起抑制作用而对正常细胞的副作用较小的化合物,可以作为抗肿瘤药物进行开发。
实施例18:本发明所述吡嗪并喹喔啉衍生物对抑制瘤的抑制作用
选择以上实施例中的化合物Ιa,先异种移植在免疫缺陷型小鼠体内建立宫颈癌模型,然后以藤黄酸为阳性药,每天腹腔注射给化合物Ιa5mg/Kg,连续给药21天,对小鼠进行解剖,称量瘤重,结果如图3所示,对比阳性药藤黄酸,化合物Ιa具有相当的肿瘤抑制作用,抑制率有46%。因此该化合物能够作为抗肿瘤先到化合物进行进一步开发。
Claims (4)
1.一种喹喔啉了衍生物,其特征在于,所述喹喔啉类衍生物的结构式如式(Ia)、式(Ib)、式(IIa)、式(IIb)、式(4a)、式(4c)或式(5a)所示,
2.一种权利要求1所述的喹喔啉类衍生物的制备方法,其特征在于,包括如下步骤:
S1.将原料4,4’-二羟基苯偶酰与二溴烷烃反应,得到化合物
S2.将化合物3与1,2,4,5-苯四胺四盐酸盐或3,4-二氨基联苯胺在冰醋酸中发生缩合反应,得到化合物4a、4c或5a,
S3.将化合物4a、4c或5a发生取代反应,得到如结构式式(Ia)、式(Ib)、式(IIa)或式(IIb)、所示的双喹喔啉衍生物。
3.权利要求1所述的双喹喔啉衍生物在制备抗肿瘤药物中的应用。
4.根据权利要求3所述的应用,其特征在于,所述药物包括医学上可接受的盐或辅料。
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