CN101613356B - 喹唑啉类四环衍生物及制备方法和在制药中的应用 - Google Patents
喹唑啉类四环衍生物及制备方法和在制药中的应用 Download PDFInfo
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Abstract
本发明涉及一种通式为I的一类喹唑啉类四环衍生物,或其药学上可以接收的盐,及其在制备治疗肿瘤药物中的应用,其中,R1、R2及R3是氢、卤素、硝基、氨基、原子数为1-6的饱和的烷基、原子数为1-6的饱和的烷氨基或原子数为1-6的饱和的烷氧基,或在原子数为1-6的饱和的烷基、烷氨基、烷氧基末端有烷氨基取代的基团。Y是取代芳香环或者含有1-3个杂原子的5-7元杂环。本发明能够明显抑制肿瘤细胞的增值,与阳性药Gefitinib和Erlotinib活性相当,甚至超过阳性对照。
Description
技术领域
本发明涉及喹唑啉类四环衍生物及制备方法和在制药中的应用,属于药物制备的技术领域。
背景技术
近50年来,抗肿瘤药物的研究与开发取得了很大进展,据报道,全球有超过200万个样品曾用动物体内模型进行筛选,使用细胞培养或其他检测方法进行筛选的样品更是难以计数。按照来源抗肿瘤药物大致可以分为化学合成药物、植物来源药物、微生物来源药物和生物技术药物。自然界植物资源丰富,是研制新药的主要来源。目前,临床应用的抗肿瘤药物中,来源于植物的约占1/3,包括了植物原形成分和它们的衍生物,其中生物碱及其衍生物占据了重要的部分,如长春花碱类生物碱长春碱、长春新碱、长春地辛和长春瑞滨;喜树生物碱包括喜树碱、羟基喜树碱、伊诺替康、拓扑替康及9-氨基喜树碱;紫杉醇及其同类物;其他生物碱类还有三尖杉酯碱、秋水仙碱等。长春碱类与紫杉醇作用于微管系统促进微管蛋白解聚或聚合,喜树碱类作用于拓扑异构酶,而三尖杉酯碱主要是抑制蛋白质与DNA的合成。植物成分化学结构与作用机制的多样性表明,从植物来源的药物是寻找作用与各种靶点的活性物质有巨大潜力,因而,对于新生物碱的发现和结构修饰也成为抗肿瘤药物研究的热点之一。
迄今为止,已经从植物、动物及微生物中分离及鉴定的6000多个生物碱中,将近150种天然生物碱的结构中具有喹唑啉或喹唑啉酮结构单元,喹唑啉酮类生物碱具有广泛的生物活性,如Febrifugine(一种从亚洲植物Dichroa febrifuga提取分离,具有治疗疟疾作用,)被中医用于治疗疟疾;Methaqualone有镇静催眠作用;bronchodilating有治疗低血压、驱虫、抗过敏的作用,在印度被用于治疗风寒咳嗽、支气管炎、风湿病、肺结核及哮喘等疾病;而rutaecarpine、(-)vasicinone及luotonin类有抗肿瘤作用更是引起了药物化学家们的广泛兴趣。对于喹唑啉类生物碱的抗肿瘤研究比较多的是luotoninA,它对鼠类白血病细胞P-388的IC50=1.8mg/mL,对人DNA拓扑异构酶I的IC505.7-12.6mmol/mL。喹唑啉类生物碱的其他作用还有抗真菌、抗炎以及抗高血压等,这刺激人们制备更多的喹唑啉酮类衍生物,并对它们的活性进行研究,而这也正是药物化学家和药理学家研究的领域之一。
发明内容
技术问题:本发明的目的是提供一种能够起到靶向治疗肿瘤作用的喹唑啉类四环衍生物。
本发明的另一目的提供一种上述喹唑啉类四环衍生物的用途。此类喹唑啉类四环衍生物能够靶向抑制癌细胞,起到治疗肿瘤作用,特别是治疗胰腺癌和前列腺癌。
本发明还有一个目的在于提供一种喹唑啉类四环衍生物的制备方法。
技术方案:本发明的目的是通过以下技术措施实现的:
一种喹唑啉类四环衍生物,该喹唑啉类四环衍生物为具有下述结构通式I的化合物:
其中,
Y是下面两类结构之一:
其一,芳香苯环,该芳香苯环基团上含有或不含有一个或多个下列取代基:羟基、卤素、腈基、硝基、苯基、原子数为1-6的饱和烷基取代的苯基、原子数为1-6的饱和烷基、原子数为1-6的饱和烷氧基、原子数为1-6的饱和烷氨基、原子数为1-6的饱和烷硫基或氨基;
其二,芳香杂环,该芳香杂环含有1-3个杂原子的5-7元杂环;该芳香苯环基团上含有或不含有一个或多个下列取代基:羟基、卤素、腈基、硝基、苯基、原子数为1-6的饱和烷基取代的苯基、原子数为1-6的饱和烷基、原子数为1-6的饱和烷氧基、原子数为1-6的饱和烷氨基、原子数为1-6的饱和烷硫基或氨基。其中杂原子为N、O或S;
R1、R2及R3是氢、卤素、硝基、氨基、原子数为1-6的饱和的烷基、原子数为1-6的饱和的烷氨基、原子数为1-6的饱和的烷氧基、原子数为1-6的饱和的卤代烷基、原子数为1-6的饱和的卤代烷氨基、原子数为1-6的饱和的卤代烷氧基、原子数为1-9烷氨基取代的原子数为1-6的饱和烷基、原子数为1-9的烷氨基取代的原子数为1-6的饱和烷氨基或原子数为1-9烷氨基取代的原子数为1-6饱和的烷氧基;或其药学上可以接受的盐。
本发明的喹唑啉类四环衍生物的一种优选为:
Y是取代苯环,最优Y是卤素取代的苯环;
R1是甲氧基;
R2是原子数为2-8的链状或环状烷氨基取代的原子数为3-5的烷氧基;
R3是氢、卤素、硝基、氨基;
本发明的喹唑啉类四环衍生物的另一种优选为:
Y是取代的含一个杂原子N、O或S的5-7元杂环,最优Y是噻吩杂环;
R1是甲氧基;
R2是原子数为2-8的链状或环状烷氨基取代的原子数为3-5的烷氧基;
R3是氢、卤素、硝基、氨基;
化合物或其药学上可以接受的盐选自:
3-甲氧基-2-(3-吗啉丙氧基)-喹唑啉[3,4-a]噻吩[3,2-d]并嘧啶-8-酮
3-甲氧基-2-(3-(4-甲基哌嗪-1-基)丙氧基)-喹唑啉[3,4-a]噻吩[3,2-d]并嘧啶-8-酮
3-甲氧基-2-(3-(吡咯啶-1-基)丙氧基)-喹唑啉[3,4-a]噻吩[3,2-d]并嘧啶-8-酮
3-甲氧基-2-(3-(哌啶-1-基)丙氧基)-喹唑啉[3,4-a]噻吩[3,2-d]并嘧啶-8-酮
3-甲氧基-2-(3-(二乙氨基)丙氧基)-喹唑啉[3,4-a]噻吩[3,2-d]并嘧啶-8-酮
3-甲氧基-2-(3-(4-甲基哌啶-1-基)丙氧基)-喹唑啉[3,4-a]噻吩[3,2-d]并嘧啶-8-酮
3-甲氧基-2-(3-(2-甲基哌啶-1-基)丙氧基)-喹唑啉[3,4-a]噻吩[3,2-d]并嘧啶-8-酮
2-甲氧基-3-(3-吗啉丙氧基)-喹唑啉[3,4-a]噻吩[3,2-d]并嘧啶-8-酮
2-甲氧基-3-(3-(4-甲基哌嗪-1-基)丙氧基)-喹唑啉[3,4-a]噻吩[3,2-d]并嘧啶-8-酮
2-甲氧基-3-(3-(吡咯啶-1-基)丙氧基)-喹唑啉[3,4-a]噻吩[3,2-d]并嘧啶-8-酮
2-甲氧基-3-(3-(哌啶-1-基)丙氧基)-喹唑啉[3,4-a]噻吩[3,2-d]并嘧啶-8-酮
2-甲氧基-3-(3-(二乙氨基)丙氧基)-喹唑啉[3,4-a]噻吩[3,2-d]并嘧啶-8-酮
2-甲氧基-3-(3-(4-甲基哌啶-1-基)丙氧基)-喹唑啉[3,4-a]噻吩[3,2-d]并嘧啶-8-酮
2-甲氧基-32-(3-(2-甲基哌啶-1-基)丙氧基)-喹唑啉[3,4-a]噻吩[3,2-d]并嘧啶-8-酮
3-甲氧基-2-(3-吗啉丙氧基)-10-溴-8H-喹唑啉[4,3-b]并喹唑啉-8-酮
3-甲氧基-2-(3-(4-甲基哌嗪-1-基)丙氧基)-10-溴-8H-喹唑啉[4,3-b]并喹唑啉-8-酮
3-甲氧基-2-(3-(哌啶-1-基)丙氧基)-10-溴-8H-喹唑啉[4,3-b]并喹唑啉-8-酮
3-甲氧基-2-(3-(二乙基氨基)丙氧基)-10-溴-8H-喹唑啉[4,3-b]并喹唑啉-8-酮
3-甲氧基-2-(3-(4-甲基哌啶-1-基)丙氧基)-10-溴-8H-喹唑啉[4,3-b]并喹唑啉-8-酮
2,3-二甲氧基乙氧基-10-溴-8H-喹唑啉[4,3-b]并喹唑啉-8-酮;
本发明所涉及的喹唑啉类四环衍生物的制备方法为:该衍生物以取代苯甲酸甲酯或乙酯为起始原料,按照下面反应式,经卤代烃烃基化、硝酸硝化、铁粉还原、醋酸甲脒关环、氯化亚砜氯代、胺解及关环得到目标化合物:
有益效果:
生物活性研究
以不同浓度本发明药物作用于人源性MiaPaCa2和DU145肿瘤细胞株72h后,MTT法检测药物对细胞增殖的影响。
试验材料
细胞株:人源性胰腺癌细胞株MiaPaCa2和前列腺癌细胞株DU145。
药物:阳性药物吉非替尼(Gefitinib,Gefi)、埃罗替尼(Erlotinib,Erlo)为自己合成,药物经过结构确证。
试剂与仪器:WST-8(Sigma);电子耦合试剂1-Methoxy PMS(Sigma);胰酶,CO2培养箱、无菌操作台、酶标仪和离心机等,移液枪、移液管、离心管和96孔板等。
方法
1)细胞活力测定取细胞悬液接种于96孔板上,100μl/孔(含肿瘤细胞5000个/孔)。将培养板转入恒温CO2培养箱中,在37℃,5%CO2及饱和湿度条件下培养24小时。50μl/孔,培养72小时,每组设3个平行孔,并重复实验。化合物作用72小时后,去掉细胞生长培养液,将WST-8加入96孔板中,10μL/孔,置于培养箱中在37℃孵育1.5小时,酶标仪在450nm波长处检测每孔的吸光度(650nm波长处校正)。求出T/C=50%时的药物浓度(IC50)。抑制率高于50%的化合物,用GraphPad Prism 5.0软件计算IC50值。
A-IC50<10μM
B-10<IC50<100μM
C-IC50>100μM
Cytotoxicity to different cell lines(IC50,μM)
具体实施方式:
化合物1-5的合成方法见文献(WO2004024703;Bioorg.Med.Chem.Lett.,2006,16,4102;CNl733738;Molecules,2006,11,286)。
制备I:3-甲氧基-2-(3-氯丙氧基)-10-溴-8H-喹唑啉[4,3-b]并喹唑啉-8-酮
6-(3-氯丙氧基)-4-氯-7-甲氧基喹唑啉(8.2g,29mmol)溶于冰醋酸(50mL),加入2-氨基-5-溴苯甲酸(21.9g,102mmol),反应液加热回流反应24小时,冷却后,在搅拌下将反应液缓慢倒入400mL水中,过滤收集得到的黄色粉末,甲醇重结晶,得6.7g,收率53%,mp:218-220℃。
制备II:3-甲氧基-2-(3-氯丙氧基)-喹唑啉[3,4-a]噻吩[3,2-d]并嘧啶-8-酮
4-氯-6-(3-氯丙氧基)-7-甲氧基喹唑啉(10.1g,35mmol),异丙醇200mL,3-氨基-2-噻吩甲酸甲酯(6.7g,43mmol),三乙氨10mL,回流反2小时,冷却后冰箱中放置过夜,过滤,异丙醇洗涤,乙醇重结晶,得黄色粉末12.1g,收率92%。mp:202-204℃;1H-NMR(CDCl3)δ:2.43(t,2H),3.86(t,2H),3.96(s,3H),4.02(s,3H),4.41(t,2H),7.26(d,1H),7.32(s,1H),7.53(d,1H),8.62(d,1H),8.72(s,1H),10.94(b,1H)。
实施例1:3-甲氧基-2-(3-吗啉丙氧基)-10-溴-8H-喹唑啉[4,3-b]并喹唑啉-8-酮(LI-1)
3-甲氧基-2-(3-氯丙氧基)-8H-喹唑啉[4,3-b]并喹唑啉-8-酮(0.8g,1.8mmol),溶于DMF(10mL),加入0.1g碘化钾,吗啉(2mL),碳酸钾2.0g,于60℃反应30分钟,将反应液冷却后倒入水中,氯仿萃取,饱和碳酸钠溶液和水洗涤,无水硫酸钠干燥,200~300目硅胶柱层析,得黄色粉末0.67g,收率74%。mp:208-211℃;1H-NMR(CDCl3)δ:2.16(t,2H),2.54(t,4H),2.64(t,2H),3.76(t,4H),4.02(s,3H),4.34(t,2H),7.24(s,1H),7.67(d,1H),7.89(dd,1H),8.10(s,1H),8.50(d,1H),9.37(s,1H);IR(cm-1):3454,2951,2816,1700,1627,1574,1559,1540,1501,1448,1395,1272,1214,1115,1032,987,870,748,628;M/z:501.1,([M+H]+,100%).Elem.Anal.Calcd:C,55.32;H,4.64;N,11.22;Found C,54.87;H,4.39;N,11.28.
实施例2:3-甲氧基-2-(3-(4-甲基哌嗪-1-基)丙氧基)-10-溴-8H-喹唑啉[4,3-b]并喹唑啉-8-酮(LI-2)
参照化合物(LI-1)的制备方法,得黄色粉末0.49g,收率62%。mp:195-196℃;1H-NMR(CDCl3)δ:2.16(t,2H),2.35(s,3H),2.58-2.68(m,10H),4.02(s,3H),4.33(t,2H),7.24(s,1H),7.67(d,1H),7.89(d,1H),8.10(s,1H),8.50(s,1H),9.37(s,1H);13C-NMR(CDCl3)δ:26.54,45.17,45.78,52.89,54.93,55.00,56.36,67.78,106.64,109.21,114.60,119.02,119.36,129.13,129.86,136.28,138.80,139.41,144.65,147.01,150.06,155.07,158.29;IR(cm-1):3438,2938,2793,1708,1626,1574,1561,1541,1501,1464,1449,1393,1273,1213,1149,1037,990,787,706;M/z:512.1([M+H]+,100%).Elem.Anal.Calcd:C,56.26;H,5.11;N,13.67;Found C,55.87;H,5.18;N,12.97.
实施例3:3-甲氧基-2-(3-(哌啶-1-基)丙氧基)-10-溴-8H-喹唑啉[4,3-b]并喹唑啉-8-酮(LI-4)
参照化合物(LI-1)的制备方法,得浅黄色粉末0.53g,收率65%。mp:209-211℃;1H-NMR(CDCl3)δ:1.47(m,2H),1.59-1.64(m,4H),2.16(p,2H),2.46(m,4H),2.58(t,2H),4.02(s,3H),4.32(t,2H),7.24(s,1H),7.70(d,1H),7.90(d,1H),8.10(s,1H),8.50(s,1H),9.37(s,1H);13C-NMR(CDCl3)δ:24.49,26.04,26.67,54.71,55.81,56.34,68.12,106.61,109.17,114.61,118.98,119.34,129.15,129.84,136.22,138.78,139.33,144.65,147.02,150.14,155.07,158.31;IR(cm-1):3452,3068,2929,2762,1703,1627,1578,1542,1498,1471,1446,1394,1268,1214,1123,1033,948,866,789,703;M/z:497.1([M+H]+,65%).Elem.Anal.Calcd:C,57.95;H,5.07;N,11.26;Found C,58.02;H,4.92;N,11.29.
实施例4:3-甲氧基-2-(3-(二乙基氨基)丙氧基)-10-溴-8H-喹唑啉[4,3-b]并喹唑啉-8-酮(LI-5)
参照化合物(LI-1)的制备方法,得黄色粉末0.58g,收率59%。mp:℃;1H-NMR(CDCl3)δ:1.03(t,6H),2.09(t,2H),2.43(t,4H),2.69(t,2H),4.00(s,3H),4.38(t,2H),7.26(s,1H),7.81(d,1H),7.99(d,1H),8.14(s,1H),8.62(s,1H),9.01(s,1H);13C-NMR(CDCl3)δ:24.23,26.76,27.12,55.69,55.98,56.56,69.34,106.68,109.46,115.09,118.35,119.93,129.88,130.86,136.86,138.28,139.01,145.15,147.45,150.78,156.17,159.11;IR:IR(cm-1):3302,3109,2989,2712,1705,1624,,1507,1469,1456,1424,1244,1214,1120,1008,877,786,652;M/z:485.1([M+H]+,100%).Elem.Anal.Calcd:C,56.91;H,5.19;N,11.54;Found:C,56.23;H,4.92;N,11.01;
实施例5:3-甲氧基-2-(3-(4-甲基哌啶-1-基)丙氧基)-10-溴-8H-喹唑啉[4,3-b]并喹唑啉-8-酮(LI-6)
参照化合物(LI-1)的制备方法,得黄色粉末0.61g,收率71%。mp:180-182℃;1H-NMR(CDCl3)δ:0.93(d,3H),1.26-1.35(m,3H),1.65(d,2H),2.00(t,2H),2.18(t,2H),2.60(t,2H),2.96(d,2H),4.02(s,3H),4.31(t,2H),13C-NMR(CDCl3)δ:21.85,26.80,30.85,34.39,54.13,55.49,56.35,68.10,106.58,109.17,114.59,118.99,119.33,129.16,129.83,136.22,138.78,139.33,144.63,147.01,150.12,155.06,158.29;IR(cm-1):3453,2947,1704,1626,1578,1542,1499,1446,1393,1268,1214,1147,1033,944,870,827,784,702;M/z:512.1([M+H]+,55%).Elem.Anal.Calcd:C,58.71;H,5.32;N,10.96;Found C,58.52;H,5.11;N,11.01.
实施例6:2,3-二甲氧基乙氧基-10-溴-8H-喹唑啉[4,3-b]并喹唑啉-8-酮(LIII-1)
6,7-二甲氧基乙氧基-4-氯喹唑啉(0.9g,2.8mmol),溶于冰醋酸(10mL),2-氨基-5-溴苯甲酸(2.1g,10mmol),回流反应20小时,反应液冷却后倒入水中,过滤收集析出黄色沉淀,水洗涤,得到黄色粉末,干燥后200-300目硅胶柱层析,得黄色粉末0.82g,收率62%。mp>280℃;1H-NMR(DMSO-D6)δ:3.60(s,3H),3.62(s,3H),3.97-4.04(m,4H),4.43(t,2H),4.51(t,2H),7.36(d,1H),7.83(d,1H),8.02(dd,1H),8.30(s,1H),8.63(d,1H),9.49(s,1H);13C-NMR(DMSO-D6)δ:105.28,106.16,110.32,117.69,118.67,129.23,129.99,135.35,137.62,139.12,144.54,146.96,153.32,154.89,159.54;IR:3443,2929,2888,2811,1704,1620,1595,1573,1504,1470,1280,1215,1123,1057,1036,879,787;M/z:474.3([M+H]+,100%).Elem.Anal.Calcd:C,53.18;H,4.25;N,8.86;Found C,53.05;H,4.06;N,8.92.
实施例7:3-甲氧基-2-(3-吗啉丙氧基)-喹唑啉[3,4-a]噻吩[3,2-d]并嘧啶-8-酮KI-1
3-甲氧基-2-(3-氯丙氧基)-喹唑啉[3,4-a]噻吩[3,2-d]并嘧啶-8-酮(0.75g,2mmol),吗啉2mL,碳酸钾(1.0g,7mmol),碘化钾少量,DMF(10mL),100℃反应30分钟,减压除去过量吗啉,残留物以50mL氯仿溶解,水洗涤(3×20mL),200~300目硅胶柱层析,乙酸乙酯:三乙胺洗脱,得白色粉末0.48g,收率78%。mp:226-228℃;1H-NMR(CDCl3)δ:2.15(t,2H),2.52(t,4H),2.62(t,2H),3.76(t,4H),4.04(s,3H),4.35(t,2H),7.31(s,1H),7.46(d,1H),7.98(d,1H),8.18(d,1H),9.53(b,1H);13C-NMR(CDCl3)δ:26.21,53.81,55.42,56.39,67.00,67.68,106.15,108.92,114.85,117.33,125.36,136.09,137.08,139.77,146.47,150.05,154.88,154.95,157.63;IR:787,854,1013,1113,1227,1290,1497,1610,1699,2820,2932,3413,3439;IR(cm-1):3480,3067,2939,2868,2820,1700,1681,1606,1540,1492,1456,1390,1288,1232,1218,1116,1011,944,902,784,653;M/z:427.0,([M+H]+,100%).Elem.Anal.Calcd:C,59.14;H,5.20;N,13.14.Found C,58.34;H,5.07;N,12.43.
实施例8:3-甲氧基-2-(3-(4-甲基哌嗪-1-基)丙氧基)-喹唑啉[3,4-a]噻吩[3,2-d]并嘧啶-8-酮KI-2
参照化合物(KI-1)的制备方法,得白色粉末0.62g,收率68%。mp:202-204℃;1H-NMR(CDCl3)δ:2.12-2.17(m,2H),2.30(s,3H),2.49-2.58(b,8H),2.62(t,3H),4.03(s,3H),4.33(t,2H),7.82(d,1H),7.45(d,1H),7.98(d,1H),8.15(s,1H),9.52(s,1H);13C-NMR(CDCl3)δ:26.61,46.04,53.29,55.00,55.22,56.31,67.85,106.19,108.88,114.77,117.25,125.34,135.96,136.87,139.71,146.41,150.08,154.78,154.97,157.59;IR(em-1):3487,2932,1701,1623,1541,1495,1452,1389,1289,1221,1150,1111,1011,966,848,788,653;M/z:440.1,([M+H]+,100%).Elem.Anal.Calcd:C,60.12;H,5.73;N,15.93.Found C,60.20;H,5.87;N,16.20.
实施例9:3-甲氧基-2-(3-(吡咯啶-1-基)丙氧基)-喹唑啉[3,4-a]噻吩[3,2-d]并嘧啶-8-酮KI-3
参照化合物(KI-1)的制备方法,得黄色粉末0.45g,收率54%。mp:187-188℃;1H-NMR(CDCl3)δ:1.75-1.80(m,4H),2.09(p,2H),2.51-2.56(m,4H),2.66(t,3H),3.88(s,3H),4.22(t,2H),6.27(s,1H),6.56(s,1H),7.30(d,1H),7.38(s,1H),7.79(d,1H),;13C-NMR(CDCl3)δ:23.53,23.98,28.56,52.97,55.21,57.07,62.05,103.34,108.21,113.87,117.98,126.65,136.76,137.47,140.42,145.87,151.28,155.58,156.03,158.76;IR(cm-1):3347,3265,2892,1704,1624,1554,1485,1455,1213,1180,1150,,1008,966,754;M/z:411.2,([M+H]+,100%).Elem.Anal.Calcd:C,61.44;H,5.40;N,13.65;Found:C,60.72;H,5.80;N,12.98.
实施例10:3-甲氧基-2-(3-(哌啶-1-基)丙氧基)-喹唑啉[3,4-a]噻吩[3,2-d]并嘧啶-8-酮KI-4
参照化合物(KI-1)的制备方法,得白色粉末0.61g,收率81%。mp:203-204℃;1H-NMR(CDCl3)δ:1.47(d,2H),1.63(p,4H),2.16(t,2H),2.46(b,4H),2.58(t,2H),4.03(s,3H),4.32(t,2H),7.30(s,1H),7.46(d,1H),7.98(d,1H),8.16(s,1H),9.52(s,1H),;13C-NMR(CDCl3)δ:24.51,26.06,26.68,54.71,55.80,56.33,68.12,106.23,108.89,114.84,117.26,125.38,135.97,136.88,139.71,146.46,150.16,154.84,155.01,157.65;IR(cm-1):3452,3053,2939,2874,1697,1680,1605,1540,1494,1456,1390,1287,1217,1144,1108,1012,962,845,783,653;M/z:425.0,([M+H]+,100%).Elem.Anal.Calcd:C,61.44;H,5.40;N,13.65.Found C,61.16;H,6.14;N,13.59.
实施例11:3-甲氧基-2-(3-(二乙氨基)丙氧基)-喹唑啉[3,4-a]噻吩[3,2-d]并嘧啶-8-酮KI-5
参照化合物(KI-1)的制备方法,得白色粉末0.81g,收率84%。mp:159-160℃;1H-NMR(CDCl3)δ:1.06(t,6H),2.10(t,2H),2.59(t,4H),2.71(t,2H),4.03(s,3H),4.33(t,2H),7.32(s,1H),7.46(d,1H),7.98(d,1H),8.19(s,1H),9.53(s,1H);13C-NMR(CDCl3)δ:11.75,26.80,47.06,49.23,56.33,67.33,106.14,108.83,114.84,117.23,125.37,135.97,136.93,139.67,146.44,150.13,154.85,154.95,157.65;IR(cm-1):3466,3046,2953,1694,1617,1603,1542,1501,1491,1456,1392,1289,1221,1147,1100,1008,873,784,649;M/z:413.1,([M+H]+,100%).Elem.Anal.Calcd:C,61.14;H,5.86;N,13.58.Found C,61.15;H,5.84;N,13.59.
实施例12:3-甲氧基-2-(3-(4-甲基哌啶-1-基)丙氧基)-喹唑啉[3,4-a]噻吩[3,2-d]并嘧啶-8-酮KI-6
参照化合物(KI-1)的制备方法,得0.54g,收率64%。mp:201-203℃;1H-NMR(CDCl3)δ:0.93(d,2H),1.25-1.38(m,3H),1.65(d,2H),1.99(t,2H),2.16(p,2H),2.59(t,2H),2.95(d,2H),4.33(t,2H),7.31(s,1H),7.47(d,1H),7.98(d,1H),8.18(s,1H),9.53(s,1H);13C-NMR(CDCl3)δ:21.83,26.75,30.82,34.35,54.09,55.45,56.33,68.05,106.13,108.85,114.81,117.25,125.37,135.98,136.94,139.68,146.44,150.10,154.84,154.95,157.64;IR(cm-1):3459,3046,2924,1698,1673,1534,1494,1449,1385,1287,1230,1150,1107,1008,966,780;M/z:438.9,([M+H]+,100%).Elem.Anal.Calcd:C,62.99;H,5.98;N,12.78.Found C,62.90;H,5.92;N,12.91.
实施例13:3-甲氧基-2-(3-(2-甲基哌啶-1-基)丙氧基)-喹唑啉[3,4-a]噻吩[3,2-d]并嘧啶-8-酮KI-7
参照化合物(KI-1)的制备方法,得类白色粉末0.49g,收率58%。mp:173-174℃;1H-NMR(CDCl3)δ:1.10(d,2H),1.24-1.34(m,2H),1.54-1.70(m,4H),2.04-2.37(m,4H),2.60(m,1H),2.90-3.009(m,2H),4.03(d,2H),4.25-4.32(m,2H),7.28(s,1H),7.44(d,1H),7.97(d,1H),8.12(s,1H),9.50(s,1H);13C-NMR(CDCl3)δ:18.98,23.99,24.51.25.58,26.06,26.24,34.68,50.39,52.30,54.71,55.80,55.93,56.32,68.10,106.22,108.88,114.84,117.25,125.38,135.97,136.89,139.71,146.46,150.15,154.83,155.02,157.65;IR(cm-1):2925,1699,1605,1496,1456,1389,1288,1229,1217,1190,1145,1108,1008,962,841,784;M/z:439.1,([M+H]+,100%).Elem.Anal.Calcd:C,62.99;H,5.98;N,12.78.Found C,62.86;H,5.94;N,12.95.
实施例14:2-甲氧基-3-(3-吗啉丙氧基)-喹唑啉[3,4-a]噻吩[3,2-d]并嘧啶-8-酮KII-1
参照化合物(KI-1)的制备方法,得白色粉末0.69g,收率71%。mp:215-217℃;1H-NMR(CDCl3)δ:2.13(t,2H),2.50(t,4H),2.58(t,2H),3.74(t,4H),4.10(s,3H),4.29(t,2H),7.35(s,1H),7.46(d,1H),7.98(d,1H),8.16(d,1H),9.52(s,1H);13C-NMR(CDCl3)δ:26.10,53.82,55.33,56.56,67.05,67.71,105.23,109.74,114.79,117.35,125.43,136.14,137.10,139.87,146.53,150.87,154.18,154.93,157.71;IR(cm-1):2939,1696,1609,1538,1551,1470,1392,1290,1231,1220,1117,1108,1050,1018,980,866,784,653;M/z:427.1,([M+H]+,100%).Elem.Anal.Calcd:C,59.14;H,5.20;N,13.14.Found C,59.05;H,5.18;N,13.23.
实施例15:2-甲氧基-3-(3-(4-甲基哌嗪-1-基)丙氧基)-喹唑啉[3,4-a]噻吩[3,2-d]并嘧啶-8-酮KII-2
参照化合物(KI-1)的制备方法,得白色粉末0.58g,收率65%。mp:199-201℃;1H-NMR(CDCl3)δ:2.13(q,2H),2.31(s,3H),2.50-2.60(m,10H),4.10(s,3H),4.27(t,2H),7.33(s,1H),7.45(d,1H),7.98(d,1H),8.14(s,1H),9.52(s,1H);13C-NMR(CDCl3)δ:26.39,46.03,53.21,54.78,55.18,56.46,67.80,105.13,109.67,114.65,117.23,125.34,136.00,136.96,139.79,146.45,150.81,154.16,154.84,157.63;IR(cm-1):3366,3082,2963,1664,1654,1573,1521,1449,1381,1264,1232,1208,1172,1037,855,777,646;M/z:440.0,([M+H]+,100%).Elem.Anal.Calcd:C,60.12;H,5.73;N,15.93.Found C,60.05;H,5.80;N,16.03.
实施例16:2-甲氧基-3-(3-(吡咯啶-1-基)丙氧基)-喹唑啉[3,4-a]噻吩[3,2-d]并嘧啶-8-酮KII-3
参照化合物(KI-1)的制备方法,得黄色粉末0.47g,收率51%。mp:172-173℃;1H-NMR(CDCl3)δ:1.82-1.93(m,4H),2.15(p,2H),2.56-2.65(m,4H),2.78(t,3H),3.98(s,3H),4.35(t,2H),6.46(s,1H),6.86(s,1H),7.42(d,1H),7.54(s,1H),7.86(d,1H),;13C-NMR(CDCl3)δ:23.34,24.08,29.06,53.97,55.46,57.77,63.45,101.24,108.61,113.21,117.45,127.85,137.24,137.47,141.42,146.87,152.28,155.18,156.89,159.36;IR(cm-1):3407,3315,2902,1702,1625,1565,1455,1421,1212,1100,1008,986,778;M/z:411.2,([M+H]+,100%).Elem.Anal.Calcd:C,61.44;H,5.40;N,13.65;Found:C,60.72;H,5.80;N,12.98.
实施例17:2-甲氧基-3-(3-(哌啶-1-基)丙氧基)-喹唑啉[3,4-a]噻吩[3,2-d]并嘧啶-8-酮KII-4
参照化合物(KI-1)的制备方法,得白色粉末0.61g,收率74%。mp:202-204℃;1H-NMR(CDCl3)δ:1.46(d,2H),1.60(d,4H),2.16(t,2H),2.44(b,4H),2.55(b,2H),4.10(s,3H),4.26(t,2H),7.33(s,1H),7.45(d,1H),7.97(d,1H),8.14(s,1H),9.52(s,1H),;13C-NMR(CDCl3)δ:24.48,26.03,26.49,54.67,55.61,56.49,68.08,105.22,109.77,114.65,117.25,125.38,135.99,136.92,139.87,146.52,150.91,154.29,154.87,157.69;IR(cm-1):3445,3077,2929,1695,1666,1613,1539,1500,1471,1385,1290,1232,1147,1107,1022,987,866,784,653;M/z:425.0,([M+H]+,100%).Elem.Anal.Calcd:C,61.44;H,5.40;N,13.65.Found C,62.02;H,5.57;N,13.30.
实施例18:2-甲氧基-3-(3-(二乙氨基)丙氧基)-喹唑啉[3,4-a]噻吩[3,2-d]并嘧啶-8-酮KII-5
参照化合物(KI-1)的制备方法,得白色粉末0.59g,收率72%。mp:186-188℃;1H-NMR(CDCl3)δ:1.05(t,6H),2.08(t,2H),2.56(t,4H),2.68(t,2H),4.10(s,3H),4.26(t,2H),7.34(s,1H),7.46(d,1H),7.98(d,1H),8.16f(s,1H),9.53(s,1H);13C-NMR(CDCl3)δ:11.94,26.88,47.12,49.24,56.48,67.95,105.21,109.73,114.63,117.24,125.38,135.99,136.90,139.88,146.53,150.93,154.35,154.86,157.69;IR(cm-1):3473,3074,2964,1697,1616,1602,1540,1499,1471,1385,1288,1232,1221,1147,1100,1065,1008,873,788,649;M/z:413.2,([M+H]+,100%).Elem.Anal.Calcd:C,61.14;H,5.86;N,13.58.Found C,60.94;H,5.93;N,13.90.
实施例19:2-甲氧基-3-(3-(4-甲基哌啶-1-基)丙氧基)-喹唑啉[3,4-a]噻吩[3,2-d]并嘧啶-8-酮KII-6
参照化合物(KI-1)的制备方法,得白色粉末0.46g,收率68%。mp:160-162℃;1H-NMR(CDCl3)δ:0.92(d,3H),1.24-1.32(m,3H),1.63(dd,2H),1.92-2.00(m,3H),2.12(t,2H),2.54(t,2H),2.92(d,2H),4.09(s,3H),4.25(t,2H),7.33(s,1H),7.44(d,1H),7.97(d,1H),8.13(s,1H),9.52(s,1H);13C-NMR(CDCl3)δ:21.81,26.63,30.84,34,40,54.06,55.24,56.48,68.07,105.24,109.78,114.66,125.37,135.99,136.90,139.87,146.52,150,91,154.29,154.86,157.68;IR(cm-1):3459,2939,2064,1694,1616,1602,1538,1499,1385,1289,1221,1147,1108,1026,980,866,780;M/z:438.9,([M+H]+,100%).Elem.Anal.Calcd:C,62.99;H,5.98;N,12.78.Found C,62.16;H,5.99;N,12.95.
实施例20:2-甲氧基-32-(3-(2-甲基哌啶-1-基)丙氧基)-喹唑啉[3,4-a]噻吩[3,2-d]并嘧啶-8-酮KII-7
参照化合物(KI-1)的制备方法,得白色粉末0.41g,收率58%。mp:191-193℃;1H-NMR(CDCl3)δ:1.07(d,3H),1.25-1.30(m,3H),1.56-1.67(m,4H),2.03-2.32(m,4H),2.49-2.56(m,2H),2.92(m,2H),4.10(s,3H),4.20-4.28(m,2H),7.34(s,1H),7.46(d,1H),7.98(d,1H),8.16(s,1H),9.53(s,1H);13C-NMR(CDCl3)δ:18.91,23.93,25.61,26.06,26.22,34.66,50.21,52.21,55.98,56.48,68.08,105.25,109.75,114.68,117.26,125.38,136.02,136.92,139.88,146.55,150.94,154.31,154.88,157.70;IR(cm-1):3459,3077,2931,1696,1666,1612,1538,1499,1424,1389,1289,1231,1223,1150,1104,866,784,646;M/z:439.0,([M+H]+,100%).Elem.Anal.Calcd:C,62.99;H,5.98;N,12.78.Found C,62.40;H,5.90;N,12.895。
以下为实例化合物的抗肿瘤活性
A-IC50<10μM
B-10<IC50<100μM
C-IC50>100μM
Claims (2)
1.一种喹唑啉类四环衍生物,该喹唑啉类四环衍生物选自:
3-甲氧基-2-(3-吗啉丙氧基)-10-溴-8H-喹唑啉[4,3-b]并喹唑啉-8-酮
3-甲氧基-2-(3-(4-甲基哌嗪-1-基)丙氧基)-10-溴-8H-喹唑啉[4,3-b]并喹唑啉-8-酮
3-甲氧基-2-(3-(哌啶-1-基)丙氧基)-10-溴-8H-喹唑啉[4,3-b]并喹唑啉-8-酮
3-甲氧基-2-(3-(4-甲基哌啶-1-基)丙氧基)-10-溴-8H-喹唑啉[4,3-b]并喹唑啉-8-酮。
2.如权利要求1所述的喹唑啉类四环衍生物在制备治疗胰腺癌药物方面的应用。
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