CN116444443A - 一种苯甲酰-喹唑啉酮衍生物及其制备方法与应用 - Google Patents
一种苯甲酰-喹唑啉酮衍生物及其制备方法与应用 Download PDFInfo
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- A61P35/00—Antineoplastic agents
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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Abstract
本发明公开了一种苯甲酰‑喹唑啉酮衍生物及其制备方法以及在制备抗癌药物中的应用,其使用苯甲酰‑喹唑啉酮结构稳定分子的顺式构型,可以有效克服CA‑4分子结构不稳定的缺点。本发明制备的苯甲酰‑喹唑啉酮衍生物对全部五种癌细胞表现出优异的抗增殖活性,绝大多数化合物IC50在亚微摩尔级别以下,并且大多数化合物对微管蛋白有较强的抑制作用。
Description
技术领域
本发明涉及药物化学领域,特别涉及一种苯甲酰-喹唑啉酮衍生物及其制备方法与应用。
背景技术
癌症是人类身体健康的致命杀手,世界卫生组织(WHO)最新发布的全球癌症报告显示,2020年全球共有1929万新发癌症病例,以及996万癌症死亡病例,预计到2040年,全球新发癌症病例数将超过2700万。因此,寻找安全有效的抗癌药物是一项紧迫的任务。
微管是由微管蛋白构成的中空管状结构。现已发现的微管蛋白包括α、β、γ、δ、ε、ζ、η七种。其中,α微管蛋白与β微管蛋白是组成微管的主要亚单位,其分子量约为55Kd。微管几乎存在于除红细胞外的全部真核细胞内,是细胞骨架的重要组成部分,可以参与细胞内的物质运输及信号传递。此外,微管在有丝分裂中发挥重要作用,当细胞从有丝分裂间期进入分裂期时,胞质微管可以转化为纺锤体微管,牵引染色体向细胞两极运动,完成一次有丝分裂。而有丝分裂结束后,纺锤体微管又可重新解离为游离的胞质微管。这种微管的动态平衡是有丝分裂过程的必须条件。因此微管蛋白抑制剂可以抑制微管的动态平衡过程以阻止癌细胞的有丝分裂,抑制癌细胞增殖,并最终诱导癌细胞凋亡从而达到抗肿瘤的目的。目前,一些微管蛋白抑制剂,如紫杉醇、长春新碱等,已作为一线抗肿瘤药物在临床应用,但其来源稀少,结构复杂。Combretastatin A-4(CA-4)是由Pettit课题组1982年在风车子属植物南非柳树Combretum caffrum中分离得到的一种顺式二苯乙烯类化合物,属于目前化学结构最简单的微管蛋白抑制剂,其在体外抑制多种人源肿瘤细胞增殖的IC50可以达到纳摩尔级别;但其有明显的缺点,如水溶性差,顺式结构极易异构化为无活性的反式结构等。为了增加水溶性,OXIGEN公司开发了CA-4的磷酸二钠盐CA-4P,利用其作为前药,进入体内可以重新水解为CA-4而发挥药效,目前完成了Ⅲ期临床试验,已作为治疗甲状腺未分化癌的孤儿药被FDA和欧洲药品管理局批准上市。但CA-4P仍未解决分子结构易发生顺反异构导致活性大大降低的问题。因此,寻找结构稳定、抗肿瘤活性好的新型化合物分子,是抗肿瘤药物研究的重要方向之一。
发明内容
本发明的目的在于克服现有技术中存在的缺点,提供一种结构稳定的苯甲酰-喹唑啉酮衍生物。
本发明的另一目的在于提供一种上述苯甲酰-喹唑啉酮衍生物的制备方法。
本发明的再一目的在于提供一种上述苯甲酰-喹唑啉酮衍生物在制备抗癌药物中的应用。
本发明的目的通过下述技术方案实现:
一种苯甲酰-喹唑啉酮衍生物,其结构式如式I所示:
其中:
R1、R2为各自独立的H、OCH3;
R3、R4、R5、R6为各自独立的H、卤素、烷基、OH、NO2、NH2或OPO3Na2;
限制条件为:R1、R2不同时为OCH3。
所述烷基优选CH3、C2H5或C3H7。
所述苯甲酰-喹唑啉酮衍生物的制备方法,包括下述步骤:
(1)中间体1的制备:将原料(结构式II)滴加到HNO3中,反应完毕后,萃取、干燥,得到中间体1;
(2)中间体2的制备:将SOCl2滴加到中间体1中,搅拌,反应完毕后减压旋干,得到中间体2;
(3)中间体3的制备:将NH3溶液滴加到中间体2中,搅拌,反应完毕后减压旋干,得到中间体3;
(4)中间体4的制备:将中间体3加入到Na2S2O4中,升温反应,反应完毕后萃取,干燥,纯化,得到中间体4;
(5)苯甲酰-喹唑啉酮衍生物的制备:将含不同取代基的苯乙酮和I2加入到二甲基亚砜中,升温搅拌,加入中间体4,继续反应,反应完毕后淬灭反应,萃取,干燥,纯化,得到苯甲酰-喹唑啉酮衍生物。
所述步骤(1)中,是在冰浴下将1摩尔份的原料(结构式II)缓慢滴加到1~3摩尔份的HNO3中,反应完毕后加水、二氯甲烷萃取,有机相干燥,得到中间体1。
所述步骤(2)中,是将1~3摩尔份的SOCl2缓慢滴加到1摩尔份中间体1的二氯甲烷溶液中,25~80℃搅拌,反应完毕后减压旋干,得到中间体2。
所述步骤(3)中,是在室温下将1~2摩尔份的NH3的二氧六环溶液滴加到1摩尔份的中间体2中,搅拌,反应完毕后减压旋干,得到中间体3。
所述步骤(4)中,是在0~25℃下,将1摩尔份的中间体3加入到丙酮中,缓慢加入5~10摩尔份的Na2S2O4,升温至50~70℃继续反应,反应完毕后用水和乙酸乙酯萃取,有机相干燥,过柱纯化,得到中间体4。
所述步骤(5)中,是在0~25℃下,将1~2摩尔份的含不同取代基的苯乙酮及2~4摩尔份的I2加入到二甲基亚砜(DMSO)中,80~120℃搅拌0.5h~1h后缓慢加入1摩尔份的中间体4,80~120℃继续反应,反应完毕后加入饱和硫代硫酸钠溶液淬灭反应,用乙酸乙酯萃取,有机相干燥,过柱纯化,得到苯甲酰-喹唑啉酮衍生物。
上述苯甲酰-喹唑啉酮衍生物的合成路线如下所示:
所述苯甲酰-喹唑啉酮衍生物在制备抗癌药物中的应用,是以苯甲酰-喹唑啉酮衍生物为活性成分,可以有效地治疗肺癌、宫颈癌、卵巢癌、乳腺癌、肝癌或结肠癌等恶性肿瘤。
所述苯甲酰-喹唑啉酮衍生物是以药用的溶剂化物的形式使用,所述溶剂化物优选水合物。
本发明还提供一种用于治疗恶性肿瘤的药物组合物,其中含有治疗有效量的所述苯甲酰-喹唑啉酮衍生物和药学上可接受的辅助剂;还可以包含表皮生长因子受体激酶抑制剂、DNA烷化剂、组蛋白去乙酰化酶抑制剂或硫氧还蛋白还原酶抑制剂。所述药物组合物可以制成注射剂、片剂、胶囊剂、丸剂、悬浮剂或乳剂的形式使用;其给药途径可为口服、经皮、静脉或肌肉注射。
本发明的原理是:本发明将苯甲酰基与苯并喹唑啉酮结合到同一分子中,以羰基取代CA-4结构中间的双键连接桥,分子结构无法发生构型翻转,稳定分子的顺式构型,可以有效克服CA-4分子结构不稳定的缺点。
本发明与现有技术相比具有如下优点和效果:
(1)本发明提供的苯甲酰-喹唑啉酮衍生物是一种新型的抗肿瘤化合物,结构稳定。
(2)本发明对多种肿瘤细胞有显著的抑制作用。
(3)本发明化合物对微管蛋白聚集有较强的抑制作用。
具体实施方式
下面结合实施例对本发明做进一步详细的描述,但本发明的实施方式不限于此。
实施例1
2-(3-羟基-4-甲氧基苯甲酰基)-5,6,7-三甲氧基喹唑啉-4(3H)-酮
其制备步骤如下:
(1)2,3,4-三甲氧基-6-硝基苯甲酸的制备
0℃下将2,3,4-三甲氧基苯甲酸(212mg,1mmol)加入到65%HNO3(2.5mL)中,搅拌30分钟后加入大量冰水;然后加入二氯甲烷萃取,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,减压除去溶剂得粗产物,柱层析分离(石油醚:乙酸乙酯,3:1)得到产物2,3,4-三甲氧基-6-硝基苯甲酸,产率:79%。1H NMR(600MHz,Chloroform-d)δ7.54(s,1H),4.09–3.90(m,9H).
(2)2,3,4-三甲氧基-6-硝基苯甲酰氯的制备
将2,3,4-三甲氧基-6-硝基苯甲酸(257mg,1mmol)溶于二氯甲烷(5mL)中,加入氯化亚砜(143mg,1.2mmol);50℃搅拌1小时后,减压除去溶剂得到产物2,3,4-三甲氧基-6-硝基苯甲酰氯粗产物,直接用于下一步反应。
(3)2,3,4-三甲氧基-6-硝基苯甲酰胺的制备
将氨的1,4-二氧六环溶液(0.4mol/L,3mL)缓慢滴加到上一步反应制备得到的2,3,4-三甲氧基-6-硝基苯甲酰氯中,常温搅拌3小时后加入饱和碳酸氢钠溶液淬灭反应,乙酸乙酯萃取;合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,减压除去溶剂得粗产物,柱层析分离(石油醚:乙酸乙酯,1:1)得到2,3,4-三甲氧基-6-硝基苯甲酰胺。二步反应产率:60%。1H NMR(600MHz,Chloroform-d)δ7.47(s,1H),3.97(d,J=14.8Hz,9H).
(4)6-氨基-2,3,4-三甲氧基苯甲酰胺的制备
将连二亚硫酸钠(870mg,5mmol)分批加入到中间体2,3,4-三甲氧基-6-硝基苯甲酰胺(256mg,1mmol)的丙酮(10mL)溶液中;50℃搅拌反应3h后,加入饱和碳酸氢钠溶液淬灭,乙酸乙酯萃取;合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,减压除去溶剂得粗产物,柱层析分离(石油醚:乙酸乙酯,1:1)得到6-氨基-2,3,4-三甲氧基苯甲酰胺。产率:67%。1H NMR(600MHz,Chloroform-d)δ5.98(s,1H),3.92(s,3H),3.84(s,3H),3.77(s,3H).
(5)2-(3-羟基-4-甲氧基苯甲酰基)-5,6,7-三甲氧基喹唑啉-4(3H)-酮的制备
将3-羟基-4-甲氧基苯乙酮(199mg,1.2mmol)溶于1mL DMSO中,搅拌下分批加入I2(508mg,2mmol),110℃搅拌30min后分批加入6-氨基-2,3,4-三甲氧基苯甲酰胺(226mg,1mmol)。110℃继续搅拌反应12h,反应结束后加饱和硫代硫酸钠溶液淬灭,乙酸乙酯萃取三次;合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,减压除去溶剂得粗产物,柱层析分离(石油醚:乙酸乙酯,2:1),得到2-(3-羟基-4-甲氧基苯甲酰基)-5,6,7-三甲氧基喹唑啉-4(3H)-酮。产率:82%。1H NMR(600MHz,Chloroform-d)δ9.95(s,1H),8.22–8.15(m,2H),7.18(s,1H),7.00(d,J=8.4Hz,1H),4.06–4.00(m,9H),3.99(s,3H).13C NMR(151MHz,CDCl3)δ184.54,161.63,156.06,154.84,153.58,147.75,145.12,141.87,131.91,126.41,117.35,114.55,111.32,104.31,60.78,60.76,56.48,56.18.HRMS(ESI)(m/z)[M+H]+calcd forC19H18N2O7,387.1187;found,387.1183.Purity:99.4%(by HPLC).
实施例2
5,6,7-三甲氧基-2-(4-甲氧基苯甲酰基)喹唑啉-4(3H)-酮,结构式如下所示:
5,6,7-三甲氧基-2-(4-甲氧基苯甲酰基)喹唑啉-4(3H)-酮的制备
将4-甲氧基苯乙酮(180mg,1.2mmol)溶于1mL DMSO中,搅拌下分批加入I2(508mg,2mmol),110℃搅拌30min后分批加入6-氨基-2,3,4-三甲氧基苯甲酰胺(226mg,1mmol)。110℃继续搅拌反应12h,反应结束后加饱和硫代硫酸钠溶液淬灭,乙酸乙酯萃取三次;合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,减压除去溶剂得粗产物,柱层析分离(石油醚:乙酸乙酯,2:1),得到5,6,7-三甲氧基-2-(4-甲氧基苯甲酰基)喹唑啉-4(3H)-酮。产率:85%。1H NMR(600MHz,Chloroform-d)δ9.91(s,1H),8.63–8.54(m,2H),7.15(s,1H),7.06–6.98(m,2H),4.02(d,J=1.2Hz,6H),3.99(s,3H),3.93(s,3H).13C NMR(151MHz,CDCl3)δ183.25,164.72,158.68,158.54,153.36,146.34,146.13,143.83,134.38,126.90,113.85,111.61,106.74,62.34,61.56,56.38,55.62.HRMS(ESI)(m/z)[M+H]+calcd for C19H18N2O6,371.1238;found,371.1234.Purity:98.4%(by HPLC).
实施例3
5,6,7-三甲氧基-2-(4-甲氧基-3-甲基苯甲酰基)喹唑啉-4(3H)-酮,结构式如下所示:
5,6,7-三甲氧基-2-(4-甲氧基-3-甲基苯甲酰基)喹唑啉-4(3H)-酮的制备
将4-甲氧基-3-甲基苯乙酮(197mg,1.2mmol)溶于1mL DMSO中,搅拌下分批加入I2(508mg,2mmol),110℃搅拌30min后分批加入6-氨基-2,3,4-三甲氧基苯甲酰胺(226mg,1mmol)。110℃继续搅拌反应12h,反应结束后加饱和硫代硫酸钠溶液淬灭,乙酸乙酯萃取三次;合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,减压除去溶剂得粗产物,柱层析分离(石油醚:乙酸乙酯,3:1),得到5,6,7-三甲氧基-2-(4-甲氧基-3-甲基苯甲酰基)喹唑啉-4(3H)-酮。产率:83%。1H NMR(600MHz,Chloroform-d)δ9.88(s,1H),8.56(dd,J=8.7,2.3Hz,1H),8.24(dd,J=2.1,1.0Hz,1H),7.15(s,1H),6.95(d,J=8.7Hz,1H),4.02(d,J=3.8Hz,6H),3.99(s,3H),3.95(s,3H),2.30(s,3H).13C NMR(151MHz,CDCl3)δ183.61,163.13,158.65,158.56,153.35,146.47,146.20,143.77,133.91,132.78,127.14,126.37,111.59,109.22,106.73,62.33,61.56,56.36,55.68,16.34.HRMS(ESI)(m/z)[M+H]+calcdfor C20H20N2O6,385.1394;found,385.1392.Purity:97.5%(by HPLC).
实施例4
5,6,7-三甲氧基-2-(3,4,5-三甲氧基苯甲酰基)喹唑啉-4(3H)-酮,结构式如下所示:
5,6,7-三甲氧基-2-(3,4,5-三甲氧基苯甲酰基)喹唑啉-4(3H)-酮的制备
将3,4,5-三甲氧基苯乙酮(252mg,1.2mmol)溶于1mL DMSO中,搅拌下分批加入I2(508mg,2mmol),110℃搅拌30min后分批加入6-氨基-2,3,4-三甲氧基苯甲酰胺(226mg,1mmol)。110℃继续搅拌反应12h,反应结束后加饱和硫代硫酸钠溶液淬灭,乙酸乙酯萃取三次;合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,减压除去溶剂得粗产物,柱层析分离(石油醚:乙酸乙酯,3:1),得到5,6,7-三甲氧基-2-(3,4,5-三甲氧基苯甲酰基)喹唑啉-4(3H)-酮。产率:78%。1H NMR(600MHz,Chloroform-d)δ9.88(s,1H),7.85(s,2H),7.10(s,1H),4.03(s,3H),4.00(d,J=5.2Hz,9H),3.96(s,6H).13C NMR(151MHz,CDCl3)δ183.80,158.79,158.45,153.45,152.77,146.12,145.95,144.10,144.03,128.70,111.67,109.56,106.56,62.37,61.58,61.09,56.38,56.33.HRMS(ESI)(m/z)[M+H]+calcd for C21H22N2O8,431.1449;found,431.1448.Purity:97.5%(by HPLC).
实施例5
2-(3-溴-4-甲氧基苯甲酰基)-5,6,7-三甲氧基喹唑啉-4(3H)-酮,结构式如下所示:
2-(3-溴-4-甲氧基苯甲酰基)-5,6,7-三甲氧基喹唑啉-4(3H)-酮的制备
将3-溴-4-甲氧基苯乙酮(274mg,1.2mmol)溶于1mL DMSO中,搅拌下分批加入I2(508mg,2mmol),110℃搅拌30min后分批加入6-氨基-2,3,4-三甲氧基苯甲酰胺(226mg,1mmol)。110℃继续搅拌反应12h,反应结束后加饱和硫代硫酸钠溶液淬灭,乙酸乙酯萃取三次;合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,减压除去溶剂得粗产物,柱层析分离(石油醚:乙酸乙酯,3:1),得到2-(3-溴-4-甲氧基苯甲酰基)-5,6,7-三甲氧基喹唑啉-4(3H)-酮。产率:81%。1H NMR(600MHz,Chloroform-d)δ9.95(s,1H),8.80(d,J=2.1Hz,1H),8.62(dd,J=8.7,2.1Hz,1H),7.15(s,1H),7.03(d,J=8.8Hz,1H),4.04–4.01(m,9H),3.99(s,3H).13C NMR(151MHz,CDCl3)δ182.28,160.73,158.76,158.44,153.40,145.97,144.04,137.10,133.47,127.87,111.81,111.68,111.03,106.81,62.35,61.56,56.63,56.40.HRMS(ESI)(m/z)[M+H]+calcd for C19H17BrN2O6,449.0343;found,449.0339.Purity:98.4%(byHPLC).
实施例6
2-(3,4-二甲氧基苯甲酰基)-5,6,7-三甲氧基喹唑啉-4(3H)-酮,结构式如下所示:
2-(3,4-二甲氧基苯甲酰基)-5,6,7-三甲氧基喹唑啉-4(3H)-酮的制备
将3,4-二甲氧基苯乙酮(216mg,1.2mmol)溶于1mL DMSO中,搅拌下分批加入I2(508mg,2mmol),110℃搅拌30min后分批加入6-氨基-2,3,4-三甲氧基苯甲酰胺(226mg,1mmol)。110℃继续搅拌反应12h,反应结束后加饱和硫代硫酸钠溶液淬灭,乙酸乙酯萃取三次;合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,减压除去溶剂得粗产物,柱层析分离(石油醚:乙酸乙酯,3:1),得到2-(3,4-二甲氧基苯甲酰基)-5,6,7-三甲氧基喹唑啉-4(3H)-酮。产率:78%。1H NMR(600MHz,Chloroform-d)δ9.91(s,1H),8.50(dd,J=8.5,2.0Hz,1H),7.93(d,J=2.0Hz,1H),7.14(s,1H),7.00(d,J=8.6Hz,1H),4.03(s,3H),4.01(d,J=2.6Hz,6H),3.99(d,J=3.3Hz,6H).13C NMR(151MHz,CDCl3)δ183.14,158.73,158.51,154.77,153.41,149.01,146.38,146.11,143.88,127.91,126.94,113.26,111.63,110.14,106.67,62.34,61.56,56.34,56.22,56.11.HRMS(ESI)(m/z)[M+H]+calcd forC20H20N2O7,401.1343;found,401.1341.Purity:96.9%(by HPLC).
实施例7
2-(3-氟-4-甲氧基苯甲酰基)-5,6,7-三甲氧基喹唑啉-4(3H)-酮,结构式如下所示:
2-(3-氟-4-甲氧基苯甲酰基)-5,6,7-三甲氧基喹唑啉-4(3H)-酮的制备
将3-氟-4-甲氧基苯乙酮(202mg,1.2mmol)溶于1mL DMSO中,搅拌下分批加入I2(508mg,2mmol),110℃搅拌30min后分批加入6-氨基-2,3,4-三甲氧基苯甲酰胺(226mg,1mmol)。110℃继续搅拌反应12h,反应结束后加饱和硫代硫酸钠溶液淬灭,乙酸乙酯萃取三次;合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,减压除去溶剂得粗产物,柱层析分离(石油醚:乙酸乙酯,2:1),得到2-(3-氟-4-甲氧基苯甲酰基)-5,6,7-三甲氧基喹唑啉-4(3H)-酮。产率:79%。1H NMR(600MHz,Chloroform-d)δ9.94(s,1H),8.54–8.36(m,2H),7.16(d,J=1.0Hz,1H),7.10(t,J=8.3Hz,1H),4.04(d,J=1.0Hz,3H),4.02(t,J=1.4Hz,6H),3.99(d,J=1.1Hz,3H).13C NMR(151MHz,CDCl3)δ182.30,158.77,158.43,153.40,153.19,151.51,146.01,145.97,144.03,129.70,126.89,119.59,112.38,111.68,106.81,62.35,61.56,56.43,56.40.HRMS(ESI)(m/z)[M+H]+calcd for C19H17FN2O6,389.1143;found,389.1141.Purity:97.2%(by HPLC).
实施例8
2-(3-碘-4-甲氧基苯甲酰基)-5,6,7-三甲氧基喹唑啉-4(3H)-酮,结构式如下所示:
2-(3-碘-4-甲氧基苯甲酰基)-5,6,7-三甲氧基喹唑啉-4(3H)-酮的制备
将3-碘-4-甲氧基苯乙酮(331mg,1.2mmol)溶于1mL DMSO中,搅拌下分批加入I2(508mg,2mmol),110℃搅拌30min后分批加入6-氨基-2,3,4-三甲氧基苯甲酰胺(226mg,1mmol)。110℃继续搅拌反应12h,反应结束后加饱和硫代硫酸钠溶液淬灭,乙酸乙酯萃取三次;合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,减压除去溶剂得粗产物,柱层析分离(石油醚:乙酸乙酯,2:1),得到2-(3-碘-4-甲氧基苯甲酰基)-5,6,7-三甲氧基喹唑啉-4(3H)-酮。产率:74%。1H NMR(600MHz,Chloroform-d)δ9.96(s,1H),8.98(d,J=2.1Hz,1H),8.66(dd,J=8.7,2.1Hz,1H),7.15(s,1H),6.95(d,J=8.7Hz,1H),4.05–4.00(m,9H),3.99(s,3H).13C NMR(151MHz,CDCl3)δ182.12,162.82,158.76,158.45,153.40,145.95,144.03,143.31,134.49,128.48,111.65,109.93,106.79,85.71,62.36,61.56,56.77,56.39.HRMS(ESI)(m/z)[M+H]+calcd for C19H17IN2O6,497.0204;found,497.0201.Purity:97.5%(byHPLC).
实施例9
2-苯甲酰基-5,6,7-三甲氧基喹唑啉-4(3H)-酮,结构式如下所示:
2-苯甲酰基-5,6,7-三甲氧基喹唑啉-4(3H)-酮的制备
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将苯乙酮(144mg,1.2mmol)溶于1mL DMSO中,搅拌下分批加入I2(508mg,2mmol),110℃搅拌30min后分批加入6-氨基-2,3,4-三甲氧基苯甲酰胺(226mg,1mmol)。110℃继续搅拌反应12h,反应结束后加饱和硫代硫酸钠溶液淬灭,乙酸乙酯萃取三次;合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,减压除去溶剂得粗产物,柱层析分离(石油醚:乙酸乙酯,5:1),得到2-苯甲酰基-5,6,7-三甲氧基喹唑啉-4(3H)-酮。产率:74%。1H NMR(600MHz,Chloroform-d)δ9.88(s,1H),8.46(dd,J=8.0,1.4Hz,2H),7.69(t,J=7.4Hz,1H),7.56(t,J=7.7Hz,2H),7.16(s,1H),4.02(d,J=5.0Hz,6H),4.00(s,3H).13C NMR(151MHz,CDCl3)δ185.48,158.73,158.44,153.40,146.04,145.80,144.05,134.22,134.07,131.68,128.41,111.72,106.93,62.35,61.56,56.39.HRMS(ESI)(m/z)[M+H]+calcd for C18H16IN2O5,341.1132;found,341.1130.Purity:96.7%(by HPLC).
实施例10
5,6,7-三甲氧基-2-(2-甲基苯甲酰基)喹唑啉-4(3H)-酮,结构式如下所示:
5,6,7-三甲氧基-2-(2-甲基苯甲酰基)喹唑啉-4(3H)-酮
将2-甲基苯乙酮(144mg,1.2mmol)溶于1mL DMSO中,搅拌下分批加入I2(508mg,2mmol),110℃搅拌30min后分批加入6-氨基-2,3,4-三甲氧基苯甲酰胺(226mg,1mmol)。110℃继续搅拌反应12h,反应结束后加饱和硫代硫酸钠溶液淬灭,乙酸乙酯萃取三次;合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,减压除去溶剂得粗产物,柱层析分离(石油醚:乙酸乙酯,5:1),得到5,6,7-三甲氧基-2-(2-甲基苯甲酰基)喹唑啉-4(3H)-酮。产率:76%。1HNMR(600MHz,Chloroform-d)δ9.91(s,1H),7.68(dd,J=7.2,2.0Hz,1H),7.51(td,J=7.5,2.0Hz,1H),7.44–7.36(m,2H),7.04(s,1H),3.90(s,3H),3.85(d,J=7.0Hz,6H),2.34(d,J=0.9Hz,3H).13C NMR(151MHz,CDCl3)δ186.74,161.63,156.06,154.84,147.75,144.83,141.87,138.56,136.79,131.30,130.73,130.19,126.48,114.55,104.31,60.78,60.76,56.48,19.06.Purity:97.7%(by HPLC).
实施例11
2-苯甲酰基-6,7,8-三甲氧基喹唑啉-4(3H)-酮,结构式如下所示:
其制备步骤如下:
(1)3,4,5-三甲氧基-6-硝基苯甲酸的制备
0℃下将3,4,5-三甲氧基苯甲酸(212mg,1mmol)加入到65%HNO3(2.5mL)中,搅拌30分钟后加入大量冰水;然后加入二氯甲烷萃取,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,减压除去溶剂得粗产物,柱层析分离(石油醚:乙酸乙酯,3:1)得到产物2,3,4-三甲氧基-6-硝基苯甲酸,产率:67%。1H NMR(600MHz,Chloroform-d)δ7.68(s,1H),3.89(d,J=5.9Hz,6H),3.84(s,3H).
(2)3,4,5-三甲氧基-6-硝基苯甲酰氯的制备
将3,4,5-三甲氧基-6-硝基苯甲酸(257mg,1mmol)溶于二氯甲烷(5mL)中,加入氯化亚砜(143mg,1.2mmol);50℃搅拌1小时后,减压除去溶剂得到产物3,4,5-三甲氧基-6-硝基苯甲酰氯粗产物,直接用于下一步反应。
(3)3,4,5-三甲氧基-6-硝基苯甲酰胺的制备
将氨的1,4-二氧六环溶液(0.4mol/L,3mL)缓慢滴加到上一步反应制备得到的3,4,5-三甲氧基-6-硝基苯甲酰氯中,常温搅拌3小时后加入饱和碳酸氢钠溶液淬灭反应,乙酸乙酯萃取;合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,减压除去溶剂得粗产物,柱层析分离(石油醚:乙酸乙酯,1:1)得到3,4,5-三甲氧基-6-硝基苯甲酰胺。二步反应产率:56%。1H NMR(600MHz,Chloroform-d)δ7.68(s,1H),3.92–3.82(m,9H).
(4)6-氨基-3,4,5-三甲氧基苯甲酰胺的制备
将连二亚硫酸钠(870mg,5mmol)分批加入到中间体3,4,5-三甲氧基-6-硝基苯甲酰胺(256mg,1mmol)的丙酮(10mL)溶液中;50℃搅拌反应3h后,加入饱和碳酸氢钠溶液淬灭,乙酸乙酯萃取;合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,减压除去溶剂得粗产物,柱层析分离(石油醚:乙酸乙酯,1:1)得到6-氨基-3,4,5-三甲氧基苯甲酰胺。产率:71%。1H NMR(600MHz,Chloroform-d)δ7.52(s,1H),3.90(s,3H),3.84(d,J=1.8Hz,6H).
(5)2-苯甲酰基-6,7,8-三甲氧基喹唑啉-4(3H)-酮的制备
将苯乙酮(144mg,1.2mmol)溶于1mL DMSO中,搅拌下分批加入I2(508mg,2mmol),110℃搅拌30min后分批加入6-氨基-3,4,5-三甲氧基苯甲酰胺(226mg,1mmol)。110℃继续搅拌反应12h,反应结束后加饱和硫代硫酸钠溶液淬灭,乙酸乙酯萃取三次;合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,减压除去溶剂得粗产物,柱层析分离(石油醚:乙酸乙酯,5:1),得到2-苯甲酰基-6,7,8-三甲氧基喹唑啉-4(3H)-酮。产率:75%。1H NMR(600MHz,Chloroform-d)δ9.88(s,1H),7.92–7.86(m,2H),7.67(s,1H),7.53(qd,J=4.3,1.5Hz,3H),3.90(d,J=4.0Hz,6H),3.84(s,3H).13C NMR(151MHz,CDCl3)δ186.70,160.70,150.27,146.39,144.69,142.78,135.89,132.42,131.57,130.92,128.66,124.94,110.34,61.50,60.30,56.32.HRMS(ESI)(m/z)[M+H]+calcd for C18H16IN2O5,341.1132;found,341.1130.Purity:97.8%(by HPLC).
实施例12
6,7,8-三甲氧基-2-(4-甲氧基苯甲酰基)喹唑啉-4(3H)-酮,结构式如下所示:
6,7,8-三甲氧基-2-(4-甲氧基苯甲酰基)喹唑啉-4(3H)-酮的制备
将4-甲氧基苯乙酮(180mg,1.2mmol)溶于1mL DMSO中,搅拌下分批加入I2(508mg,2mmol),110℃搅拌30min后分批加入6-氨基-2,3,4-三甲氧基苯甲酰胺(226mg,1mmol)。110℃继续搅拌反应12h,反应结束后加饱和硫代硫酸钠溶液淬灭,乙酸乙酯萃取三次;合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,减压除去溶剂得粗产物,柱层析分离(石油醚:乙酸乙酯,2:1),得到6,7,8-三甲氧基-2-(4-甲氧基苯甲酰基)喹唑啉-4(3H)-酮。产率:85%。1H NMR(600MHz,Chloroform-d)δ9.89(s,1H),δ7.84–7.78(m,2H),7.66(s,1H),7.12–7.06(m,2H),3.90(s,6H),3.82(d,J=20.0Hz,6H).13CNMR(151MHz,CDCl3)δ186.70,163.69,160.70,150.27,146.39,144.69,142.78,133.47,131.57,126.26,124.94,114.05,110.34,61.50,60.30,56.32,55.35.HRMS(ESI)(m/z)[M+H]+calcd for C19H18N2O6,371.1238;found,371.1234.Purity:98.8%(by HPLC).
测试例1:苯甲酰-喹唑啉酮衍生物抑制癌细胞增殖作用
本发明采用MTT法(MTT的中文名称为3-(4,5-二甲基噻唑-2)-2,5-二苯基四氮唑溴盐)来评价目标化合物对癌细胞的增殖抑制作用。取对数生长期的细胞胰酶消化,细胞计数后以5000个/孔接种于96孔板,每孔含100μL细胞悬液,置于细胞培养箱中培养24h。细胞培养24h后从培养箱中取出,吸走孔内的培养基,给药组加入含不同浓度药物的新鲜培养基,设置三个复孔,对照组加入等体积的空白培养基继续培养,空白组加入等体积的PBS。加药48h后,每孔加入20μL MTT溶液(5mg/mL)。细胞培养箱中继续培养4h后取出细胞板,吸走孔内培养基,每孔加入150μL DMSO溶解甲簪颗粒,轻度震荡后使用多功能酶标仪在参考波长450nm,检测波长570nm的条件下测定光密度值(OD值)。以溶剂组作为空白组,以空白培养基组作为对照组,以给予不同浓度药物组作为给药组。用下列公式求得药物不同浓度下对细胞增殖的抑制率。再根据得到的不同浓度下的抑制率用GraphPad Prism5软件求得半数抑制浓度(IC50)。实验结果重复三次,取平均值作为最终结果,如表1所示。
测试例2:苯甲酰-喹唑啉酮衍生物抑制微管蛋白聚集作用
我们使用商品化的微管蛋白聚集测试试剂盒(cytoskeleton,cat.#BK011P)进行实验。实验前,首先根据试剂盒的说明书将固体微管蛋白用试剂盒中提供的缓冲液溶解并分装成10mg/mL/管的微管蛋白储备液,置于-80℃冰箱保存。然后,根据试剂盒的说明设置好荧光酶标仪参数。准备相应浓度的待测化合物溶液(DMSO终浓度为1%),冰上解冻试剂盒中的20μL GTP stock、1.5mL Buffe1、Tubulin glycerol buffer及1管微管蛋白储备液。实验时,按205μL Buffe1:4.4μL GTP stock:150μL Tubulin glycerol buffer:85μL微管蛋白储备液的比例混匀上述溶液,置于冰上备用。向96孔板中加入5μL不同浓度的化合物,空白对照组加入等量的空白溶剂,37℃预热1min后迅速加入上述混匀溶液55μL。在发射波长410nm、激发波长340nm、孵育温度37℃条件使用荧光酶标仪动态监测微管聚合过程,反应持续90min,每隔1min读数一次。读数完毕后,计算每个浓度对应的抑制率,结果表1所示,在20μM能抑制50%以上的微管蛋白聚合的化合物标记为“+”,在20μM不能抑制50%的微管蛋白聚合的化合物标记为“-”。
表1苯甲酰-喹唑啉酮衍生物抑制癌细胞增殖活性
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由表1可见,本发明制备的苯甲酰-喹唑啉酮衍生物对全部五种癌细胞表现出优异的抗增殖活性,绝大多数化合物IC50在亚微摩尔级别以下,并且大多数化合物对微管蛋白有较强的抑制作用。
Claims (10)
1.一种苯甲酰-喹唑啉酮衍生物,其特征在于:结构式如式I所示:
其中:
R1、R2为各自独立的H、OCH3;
R3、R4、R5、R6为各自独立的H、卤素、烷基、OH、NO2、NH2或OPO3Na2;
限制条件为:R1、R2不同时为OCH3。
2.根据权利要求1所述的苯甲酰-喹唑啉酮衍生物,其特征在于:所述烷基为CH3、C2H5或C3H7。
3.一种权利要求1或2所述的苯甲酰-喹唑啉酮衍生物的制备方法,其特征在于包括下述步骤:
(1)中间体1的制备:将原料(结构式II)滴加到HNO3中,反应完毕后,萃取、干燥,得到中间体1;
(2)中间体2的制备:将SOCl2滴加到中间体1中,搅拌,反应完毕后减压旋干,得到中间体2;
(3)中间体3的制备:将NH3溶液滴加到中间体2中,搅拌,反应完毕后减压旋干,得到中间体3;
(4)中间体4的制备:将中间体3加入到Na2S2O4中,升温反应,反应完毕后萃取,干燥,纯化,得到中间体4;
(5)苯甲酰-喹唑啉酮衍生物的制备:将含不同取代基的苯乙酮和I2加入到二甲基亚砜中,升温搅拌,加入中间体4,继续反应,反应完毕后淬灭反应,萃取,干燥,纯化,得到苯甲酰-喹唑啉酮衍生物;
原料及各中间体的结构式如下所示:
4.根据权利要求3所述的所述的苯甲酰-喹唑啉酮衍生物的制备方法,其特征在于:所述步骤(1)中,是在冰浴下将1摩尔份的原料(结构式II)缓慢滴加到1~3摩尔份的HNO3中,反应完毕后加水、二氯甲烷萃取,有机相干燥,得到中间体1;所述步骤(2)中,是将1~3摩尔份的SOCl2缓慢滴加到1摩尔份中间体1的二氯甲烷溶液中,25~80℃搅拌,反应完毕后减压旋干,得到中间体2。
5.根据权利要求3所述的所述的苯甲酰-喹唑啉酮衍生物的制备方法,其特征在于:所述步骤(3)中,是在室温下将1~2摩尔份的NH3的二氧六环溶液滴加到1摩尔份的中间体2中,搅拌,反应完毕后减压旋干,得到中间体3;所述步骤(4)中,是在0~25℃下,将1摩尔份的中间体3加入到丙酮中,缓慢加入5~10摩尔份的Na2S2O4,升温至50~70℃继续反应,反应完毕后用水和乙酸乙酯萃取,有机相干燥,过柱纯化,得到中间体4。
6.根据权利要求3所述的所述的苯甲酰-喹唑啉酮衍生物的制备方法,其特征在于:所述步骤(5)中,是在0~25℃下,将1~2摩尔份的含不同取代基的苯乙酮及2~4摩尔份的I2加入到二甲基亚砜中,80~120℃搅拌0.5h~1h后缓慢加入1摩尔份的中间体4,80~120℃继续反应,反应完毕后加入饱和硫代硫酸钠溶液淬灭反应,用乙酸乙酯萃取,有机相干燥,过柱纯化,得到苯甲酰-喹唑啉酮衍生物。
7.一种权利要求1或2所述的苯甲酰-喹唑啉酮衍生物在制备抗癌药物中的应用,其特征在于:是以苯甲酰-喹唑啉酮衍生物为活性成分,用于制备抗癌药物。
8.根据权利要求7所述的苯甲酰-喹唑啉酮衍生物在制备抗癌药物中的应用,其特征在于:所述苯甲酰-喹唑啉酮衍生物是以药用的溶剂化物的形式使用。
9.一种用于治疗恶性肿瘤的药物组合物,其特征在于:含有治疗有效量的所述权利要求1或2所述的苯甲酰-喹唑啉酮衍生物和药学上可接受的辅助剂。
10.根据权利要求9所述的用于治疗恶性肿瘤的药物组合物,其特征在于:还包含表皮生长因子受体激酶抑制剂、DNA烷化剂、组蛋白去乙酰化酶抑制剂或硫氧还蛋白还原酶抑制剂。
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