CN104098506A - 一类苯并[c]咔唑酰胺化合物的制备方法及用途 - Google Patents
一类苯并[c]咔唑酰胺化合物的制备方法及用途 Download PDFInfo
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- CN104098506A CN104098506A CN201410336258.9A CN201410336258A CN104098506A CN 104098506 A CN104098506 A CN 104098506A CN 201410336258 A CN201410336258 A CN 201410336258A CN 104098506 A CN104098506 A CN 104098506A
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- carbazole
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
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Abstract
苯并[c]咔唑-5-甲酰胺类化合物是一类潜在的新颖抗肿瘤药物，类似结构已经被证实对某些肿瘤有较好的抑制作用。但目前报道的合成类似化合物的方法都存在反应路线长，总收率低等缺点。本发明利用苯炔作合成砌块，成功地实现了高效，短步骤合成苯并[c]咔唑母体核的方法，为该类药物的高效筛选提供了可能。本发明介绍了合成一类通式(I)所示的苯并[c]咔唑-5-甲酰胺类化合物，并介绍了以其作为抗肿瘤药物的活性及用途。
Description
技术领域
本发明涉及一类苯并[c]咔唑-5-甲酰胺化合物、其制备方法以及作为抗肿瘤药物的用途。
背景技术
当今社会，癌症频发，恶性肿瘤已严重影响人类健康、威胁人类生命。DNA拓扑异构酶是细胞内重要的核酶，主要通过催化作用改变DNA的拓扑结构。真核细胞的拓扑异构酶主要分为拓扑异构酶I和拓扑异构酶II，在细胞DNA复制、转录和有丝分裂等重要的生命过程中，拓扑异构酶II都发挥重要的作用。基于对拓扑异构酶II在细胞中关键作用的认识，对该类化合物的研究一直是抗肿瘤药物研发的热点之一。目前已上市的拓扑异构酶II抑制剂有依托泊苷、替尼泊苷、多柔比星、伊达比星、表柔比星和米托蒽醌等，随着科学技术的发展，也出现了许多新型的拓扑异构酶II抑制剂，如TAS-103、PNU-159548等。但药物的毒副作用也很明显。依托泊苷的一些常见毒性包括骨髓抑制、恶心、呕吐、脱发，最严重的副作用是导致急性髓细胞性白血病的产生，且在依托泊苷(或替尼泊苷)注射液的使用中，往往会引起低血压和高过敏性。阿霉素类抗生素静脉滴注过程中如果发生外渗则会引起严重的局部组织坏死等。因此，临床上迫切需要更加安全、有效的拓扑异构酶抑制性抗肿瘤药物。
咔唑生物碱是一类具有抗癌、抗病毒和抗菌活性的化合物。该类化合物由于在细胞周期进程控制和特定酶抑制等方面的显著作用已得到了科学家们的密切关注。咔唑系列化合物作为拓扑异构酶抑制剂及抗癌药物方面的构效关系已得到了广泛的研究。本发明人设计合成了一类苯并[c]咔唑-5-甲酰胺化合物，具备一定的抗肿瘤药效。
发明内容
本发明的目的是提供一种新型苯并[c]咔唑-5-酰胺类化合物，其具有通式(I)所示的结构。
其中，
R1为下列任意一种取代基：氢、卤素、硝基、氨基、磺酰基、羧基、烷基及芳基等。所述卤素为氟、氯、溴或者碘；
n为1或者大于1；
R2为氢、芳基或烷基、或羟基取代的烷基、或与和它们相连的原子一起形成吡咯烷、哌啶、哌嗪或吗啉等杂环；
R3为氢，烷基或芳基。
本发明的另一目的是提供该类化合物的合成方法。
本发明的再一目的是提供这类化合物在制备抗肿瘤(包括良性肿瘤和癌症，例如肺癌和结肠癌)等疾病的药物中的用途。
本发明的又一目的是提供一种药物组合，其含有治疗有效量的一种或多种通式(I)所示的苯并[c]咔唑-5-甲酰胺类化合物以及药学上可接受的辅料。
本发明的优势：本药物毒性小，溶解度好，且比类似结构的抗肿瘤药物的活性高。
本发明所涉及的苯并[c]咔唑-5-甲酰胺类化合物的制备方法通过下列步骤实施：
所述通式I化合物的制备方法包括如下步骤：其中，R为烷基链。
a、化合物1室温下在四氢呋喃中经LiAlH4还原，得到化合物2；
b、化合物2在乙酸作用下，经IBX氧化得到化合物3；
c、化合物3在乙醇中与膦叶立德发生Wittig反应得到化合物4；
d、化合物4在DMAP催化下，用(Boc)2O保护吲哚得化合物5；
e、化合物5在CsF和Cs2CO3作用下与苯炔反应得咔唑产物6和副产物7；
f、化合物6经三氟乙酸脱保护得7；
g、合并化合物7，经氢氧化钠水溶液水解，再经酸化得8；
h、化合物8在N,N-二甲基甲酰胺催化下与草酰氯反应生成酰氯，再经胺化到目标化合物I。
其中，下面举例了一些结构上有代表性的该类化合物：
具体实施方式
下面结合实施例对本发明作进一步阐释，但这些实施例绝不是对本发明的任何限制。所有实施例中，熔点用WRS-1B型数字熔点仪测定，温度计未经校正；1H NMR由BrucherAM-400型核磁共振仪记录，化学位移以δ(ppm)表示；分离用硅胶为400目。
制备实施例
化合物2的制备：
氮气保护下向100mL两口瓶中加入LiAlH4(2.6g,66mmol)和30mL四氢呋喃溶液，并置于冰浴中，将化合物1(5.0g,26mmol)溶于20mL四氢呋喃后，氮气保护下缓慢滴加至反应瓶中。滴加完毕后，撤去冰浴，室温搅拌过夜。反应结束后，缓慢将反应液加入100mL冰水中，用乙酸乙酯萃取(50mL×3)，无水硫酸钠干燥。减压蒸去溶剂得粗产物2(3.9g)。
化合物3的制备：
依次将粗产物2(1.9g,13mmol)、70mL乙腈、IBX(4.4g,16mmol)和醋酸(0.9mL,16mmol)加入至100mL单口瓶中，室温搅拌过夜。反应结束后，用砂芯滤除固体，滤液浓缩后经柱层析(石油醚：乙酸乙酯比例为5:1)得白色固体3(1.5g，产率81％)。
化合物4的制备：
在100mL单口瓶中，向化合物3(1.5g，10mmol)的乙醇溶液(60mL)中加入叶立德(4.0g，11mmol)，室温搅拌2小时。反应结束后，减压旋去溶剂，柱层析(石油醚：乙酸乙酯比例为10:1)得到白色固体4(2.2g，产率71％)。
化合物5的制备：
将化合物4(1.6g，7.3mmol)、三乙胺(2.0g，22mmol)、DMAP(0.2g，1.4mmol)溶于25mL二氯甲烷中，冰浴下向其中滴加(Boc)2O的二氯甲烷(10mL)溶液。滴加完毕后，撤去冰浴，室温搅拌0.5小时。反应结束后，加入10mL水淬灭反应，用二氯甲烷萃取三次，无水硫酸钠干燥，滤除干燥剂后减压浓缩，柱层析(石油醚：乙酸乙酯比例为10:1)得到淡黄色固体4(2.3g，产率97％)。
化合物6和化合物7的制备：
在封管反应器中依次加入化合物5(315mg,1.0mmol)、CsF(456mg,3.0mmol)、Cs2CO3(358mg,1.1mmol)，抽真空充氧气，然后再注入溶剂(MeCN和toluene依次为2mL和8mL) 及苯炔前体(447mg,1.5mmol)，100℃搅拌反应48小时。反应结束后滤除固体，浓缩后柱层析(石油醚：乙酸乙酯比例为10:1)，得淡黄色固体6(323mg，产率83％)和另一黄色固体7(37mg，产率12％)。
反应瓶中加入上述黄色固体6(323mg，0.8mmol)和5mL二氯甲烷，冰浴下缓慢滴加三氟乙酸(946mg，8.3mmol)，滴加完毕后室温搅拌1小时。反应结束后，加入饱和NaHCO3溶液淬灭反应，并用二氯甲烷萃取(20mL×3)，合并有机相，无水硫酸钠干燥，过滤浓缩，得粗产物7(240mg)，未经分离直接进行下一步反应。
化合物8的制备：
将粗产物7(240mg，0.8mmol)溶于3mL乙醇中，加入3N的NaOH溶液2mL，加热回流2小时。待原料反应完全后用稀盐酸中和反应液至pH约为5，并用二氯甲烷萃取三次，有机相用无水硫酸钠干燥，滤去干燥剂，浓缩得固体粗产物8(210mg)，未经分离直接进行下一步反应。
化合物Ia的合成：
称取8(78mg，0.3mmol)溶于5mL干燥的THF中，加一滴DMF，冰浴至0℃，加草酰氯0.5mL，升至室温搅拌30分钟后，减压蒸去溶剂，得淡黄色固体(84mg)。将其溶于THF中，滴加(66mg，0.8mmol)N,N-二甲基乙二胺，常温搅拌2小时后，减压蒸去溶剂，倒入冰水中，析出固体，过滤，干燥得化合物Ia。
Ia白色固体(85mg，产率：85％)。m.p.209.0-210.0℃。
1H NMR(400MHz,CDCl3):δ10.33(s,1H),8.60(d,J＝8.4Hz,1H),8.36(d,J＝8.0Hz,1H),8.25(d,J＝8.4Hz,1H),7.67(s,1H),7.56(t,J＝7.6Hz,1H),7.40(d,J＝8.0Hz,1H),7.35-7.23(m,3H),6.24(s,1H),3.41-3.36(m,2H),2.42(t,J＝6.0Hz,2H),2.10(s,6H)；13C NMR(100MHz,CDCl3):δ170.5,139.2,135.5,132.6,130.0,126.9,126.3,125.5,124.7,123.4,123.3,123.1,122.0, 120.0,116.5,112.7,111.6,57.6,44.7,37.1；IR(neat):3247,2944,2858,2824,2779,1638,1528,1466,1360,1250,909,749cm-1；HRMS(EI)calcd for C21H21N3O(M+):331.1685,found331.1680.
目标化合物Ib的制备方法：
除了用77mg的N,N-二甲基丙二胺代替66mg的N,N-二甲基乙二胺外，以与化合物Ia相同的制备方法制备化合物Ib。
Ib白色固体。m.p.186.2-187.2℃。
1H NMR(400MHz,DMSO-d6):δ11.94(s,1H),8.83(d,J＝8.0Hz,1H),8.70-8.67(m,1H),8.61(d,J＝8.4Hz,1H),8.32(d,J＝8.0Hz,1H),7.82(s,1H),7.76-7.68(m,2H),7.52-7.44(m,2H),7.36-7.31(m,1H),3.43-3.38(m,2H),2.37-2.33(m,2H),2.18(s,6H),1.79-1.72(m,2H)；13CNMR(100MHz,DMSO-d6):δ169.0,139.2,135.9,134.0,129.6,127.0,126.8,125.4,124.5,123.3,123.0,122.6,121.9,119.8,114.9,112.7,111.8,56.9,45.3,37.6,27.2；IR(neat):3399,3253,2913,1610,1358,1261,1103,881,764,749cm-1；HRMS calcd for C22H24N3O[M+H]+:346.1919,found346.1919.
目标化合物Ic的制备方法：
除了用96mg的N-(2-氨基乙基)哌啶代替66mg的N,N-二甲基乙二胺外，制备方法同Ia。
Ic白色固体。m.p.206.0-207.8℃。
1H NMR(400MHz,DMSO-d6):δ11.94(s,1H),8.83(d,J＝7.6Hz,1H),8.61(d,J＝7.2Hz,1H),8.54(s,1H),8.42(d,J＝7.6Hz,1H),7.81(s,1H),7.74-7.67(m,2H),7.49-7.46(m,2H),7.36-7.33(m,1H),3.50-3.49(m,2H),2.54-2.44(m,6H),1.55(s,4H),1.42(s,2H)；13C NMR(100MHz,DMSO-d6):δ168.9,139.2,136.0,134.2,129.5,127.1,127.0,125.4,124.5,123.1,122.9,122.6,121.9,119.8,114.8,112.6,111.8,57.7,54.1,36.8,25.7,24.1；IR(neat):3270,2927,2854,1670,1458,1275,1261,1091,764,750cm-1；HRMS calcd for C24H26N3O[M+H]+:372.2076,found372.2074.
目标化合物Id的制备方法：
除了用98mg的N-(2-氨基乙基)吗啉代替66mg的N,N-二甲基乙二胺外，以与化合物Ia相同的制备方法制备化合物Id。
Id白色固体。m.p.213.3-214.8℃。
1H NMR(400MHz,DMSO-d6):δ11.94(s,1H),8.83(d,J＝8.4Hz,1H),8.63-8.56(m,2H),8.42(d,J＝8.4Hz,1H),7.82(s,1H),7.76-7.68(m,2H),7.53-7.44(m,2H),7.36-7.31(m,1H), 3.64(t,J＝8.0Hz,4H),3.54-3.49(m,2H),2.59-2.55(m,2H),2.49(s,4H)；13C NMR(100MHz,DMSO-d6):δ169.0,139.2,136.0,134.1,129.5,127.1,127.0,125.4,124.5,123.2,123.0,122.6,121.9,119.8,114.9,112.6,111.8,66.3,57.4,53.3,36.3；IR(neat):3254,2923,2852,1635,1523,1457,1359,1287,1114,748cm-1；HRMS calcd for C23H24N3O2[M+H]+:374.1869,found374.1866.
目标化合物Ie的制备方法：
除了用5-氯吲哚-2-甲酸乙酯代替吲哚-2-甲酸乙酯外，以与化合物Ia相同的制备方法制备化合物Ie。
Ie白色固体。m.p.189.8-191.2℃。
1H NMR(400MHz,DMSO-d6):δ12.11(s,1H),8.81(d,J＝6.8Hz,1H),8.66-8.60(m,2H),8.34(d,J＝8.8Hz,1H),7.82-7.70(m,3H),7.52-7.47(m,2H),3.48(s,2H),2.51(s,2H),2.25(s,6H)；13C NMR(100MHz,DMSO-d6):δ168.8,137.6,136.8,134.9,129.3,127.4,126.9,125.4,124.4,124.3,123.5,123.4,123.2,121.0,114.2,113.3,112.6,58.2,45.3,37.4；IR(neat):3411,3241,2918,1612,1458,1352,1285,1010,1055,748cm-1；HRMS calcd for C21H21ClN3O[M+H]+:366.1373,found366.1379.
目标化合物If的制备方法：
除了用5-溴吲哚-2-甲酸乙酯代替吲哚-2-甲酸乙酯外，以与化合物Ia相同的制备方法制备化合物If。
If白色固体。m.p.283℃分解。
1H NMR(400MHz,CD3OD):δ8.58(d,J＝8.0Hz,1H),8.54(s,1H),8.26(d,J＝8.4Hz,1H),7.88(s,1H),7.65(t,J＝8.0Hz,1H),7.44-7.38(m,3H),3.77(t,J＝6.0Hz,2H),3.34(t,J＝6.0Hz,2H),2.90(s,6H)；13C NMR(100MHz,DMSO-d6):δ168.9,137.9,136.6,134.7,129.3,127.4,127.0,126.9,125.4,124.2,123.9,123.4,123.3,114.1,113.8,112.7,112.1,57.9,44.9,37.0；IR(neat):3234,2925,2857,1638,1527,1474,1350,1287,1049,800,750cm-1；HRMS calcd for C21H21BrN3O[M+H]+:410.0868,found410.0862.
目标化合物Ig的制备方法：
除了用碘甲烷代替(Boc)2O外，以与化合物Ia相同的制备方法制备化合物Ig。
Ig白色固体。m.p.160.1-160.8℃。
1H NMR(400MHz,CDCl3):δ8.66(d,J＝8.4Hz,1H),8.45(d,J＝8.0Hz,1H),8.36(d,J＝8.4Hz,1H),7.66-7.61(m,2H),7.49-7.39(m,3H),7.36-7.31(m,1H),6.88(s,1H),3.75(s,3H), 3.67-3.62(m,2H),2.57(t,J＝6.0Hz,2H),2.26(s,6H)；13C NMR(100MHz,CDCl3):δ170.1,140.2,136.6,133.2,130.0,126.9,126.4,125.3,124.6,123.3,123.3,122.7,122.2,119.8,116.0,110.2,109.1,57.8,45.5,37.4,29.0；IR(neat):3278,3046,2937,1636,1524,1474,1382,1336,1295,1089,746cm-1；HRMS calcd for C22H24N3O[M+H]+:346.1919,found346.1924.
实验实施例：
体外肿瘤细胞增殖生长抑制活性
1：收集对数期细胞，调整细胞悬液浓度，每孔加入100μL，铺板使待测细胞稠密度1000-10000孔，(边缘孔用无菌PBS填充)。
2：5％CO2，37℃孵育，24h至细胞单层铺满孔底(96孔平底板)，加入浓度梯度的药物。设6个梯度浓度(0,12.5,25,50,100,200μM)，每孔100μL，设4个平行孔。
3：5％CO2，37℃孵育48小时，倒置显微镜下观察。
用磺酰罗丹明B蛋白染色法(SRB法)检测了本发明化合物抑制肿瘤细胞增殖作用。在96孔板中按一定密度种下肿瘤细胞，待贴壁后，加入一定浓度待测化合物培养液作用72小时。小心吸弃含药培养基，用PBS洗2-3遍，每孔加入100μL MTT溶液(5mg/mL，即0.5％MTT，用培养基稀释10倍，即MTT占总培养液的10％)，继续培养4h。终止培养，小心吸去孔内培养液。每孔加入100μL二甲基亚砜，置摇床上低速振荡10min，使结晶物充分溶解。在全自动多功能酶标仪检测在492nm和630nm处测量各孔的吸光值，计算抑制率。
结果表明，受试化合物均具有不同程度的抑制人肺癌A549细胞和人结肠癌HCT-116细胞增殖生长活性(表1)；其中，化合物1a对人肺癌A549细胞和人结肠癌HCT-116细胞都有良好的抑制作用，其他类似结构的有一定的活性。结果见表1。
表1苯并[c]咔唑-5-酰胺类化合物
对人肺癌A549细胞和人结肠癌HCT-116细胞增殖生长的抑制活性。
Claims (6)
1.一类通式(I)所示的苯并[c]咔唑-5-甲酰胺化合物；
其中，
R1为下列任意一种取代基：氢、卤素、硝基、氨基、磺酰基、羧基、烷基及芳基等。所述卤素为氟、氯、溴或者碘；
n为1或者大于1；
R2为氢、芳基或烷基、或羟基取代的烷基、或与和它们相连的原子一起形成吡咯烷、哌啶、哌嗪或吗啉等杂环；
R3为氢，烷基或芳基。
2.根据权利要求1所述的苯并[c]咔唑-5-甲酰胺类化合物，下图举例了一些结构上有代表性的该类化合物：
3.一种苯并[c]咔唑-5-甲酰胺类化合物的制备方法，该方法主要通过下列步骤实施：
其中，R为烷基链。
a、化合物1在DMAP催化下，用(Boc)2O保护吲哚得化合物2；
b、化合物2在CsF和Cs2CO3作用下与苯炔反应得咔唑产物3；
c、化合物3经三氟乙酸脱保护，再于氢氧化钠水溶液中水解成4；
d、化合物4在N,N-二甲基甲酰胺催化下与草酰氯反应生成酰氯，再经酰胺化得目标化合物I。
4.权利要求1所述的苯并[c]咔唑-5-甲酰胺类化合物在制备治疗肿瘤疾病的药物中的用途。
5.根据权利要求4所述的用途，其特征在于，所述的肿瘤包括肺癌和结肠癌等。
6.一种药物组合物，其含有治疗有效量的一种或多种权利要求的苯并[c]咔唑-5-甲酰胺类化合物以及药学上可接受的辅料。
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