CN101108846B - 4-芳香氨基喹唑啉衍生物及制备方法和在制药中的应用 - Google Patents
4-芳香氨基喹唑啉衍生物及制备方法和在制药中的应用 Download PDFInfo
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技术领域
本发明属于化学药物领域,涉及一种酪氨酸激酶抑制剂,即4-芳香氨基喹唑啉类化合物及其在制药中的应用。
背景技术
哺乳动物细胞具有相似的分子调节机制,在整个细胞周期内调节细胞的增值、分化和死亡等过程。其中蛋白质磷酸化是跨膜或细胞内信号转导的主要作用机制,具有调控细胞循环的功能,而磷酸化又受到蛋白激酶和蛋白磷酸酶的控制。蛋白激酶催化ATP末端的磷酰基向特定的氨基酸残基转移,从而改变蛋白结构,并最终影响其在体内的结合和催化活性。
1980年,Hunter等首次发现并鉴定一种RNA肿瘤病毒(RSV)感染的细胞转化基因产物是酪氨酸激酶(Tyrosine Kinases TKs)。TK是一组酶系,催化ATP的γ磷酸基转移到许多重要的蛋白质酪氨酸残基上使酚羟基磷酸化。从其结构方面来说,酪氨酸激酶可以被认为是一种与细胞膜有关的变构酶。很多肿瘤类型具有紊乱的生长因子酪氨酸激酶,从而导致不适当的有丝分裂信号。蛋白酪氨酸激酶(PTKs)在正常细胞的信号转导机制,以及它的下调在很多疾病尤其是肿瘤中起到关键作用,抑制改变了活性的酪氨酸激酶或恢复磷酸化平衡可以作为一种新的治疗手段。因而蛋白酪氨酸激酶成为寻找治疗肿瘤及其他许多疾病的有吸引力的药物作用靶点。
对于肿瘤的发生发展机理的不断研究表明,许多肿瘤中可见不同酪氨酸激酶受体的过度表达或过度激活。如上皮细胞肿瘤中常见表皮生长因子受体(EGFR)家族的过度表达,胶质瘤中常见血小板衍生生长因子受体(PDGFR)家族的过度表达等。这些受体或生长因子的过度表达导致受体的过度激活,导致其下游信号途径的激活,最终导致细胞的转化、增殖和抵抗细胞凋亡、促进细胞生存,因而与肿瘤的发生、发展密切相关。当抗信号转导药物以一个或多个细胞信号转导环节(病变环节)为作用靶点就可以影响这些异常信号的转导,从而影响肿瘤细胞的生命周期,最终达到治疗肿瘤的目的。各种肿瘤过度表达的蛋白酪氨酸激酶类型包括:表皮生长因子受体、血管内皮生长因子、血小板衍生生长因子等,它们已经成为发现选择性蛋白酪氨酸激酶抑制剂的主要靶点。目前已经上市及各临床期蛋白激酶抑制剂很多都是靶向作用于这些蛋白酪氨酸激酶。
一直以来,酪氨酸激酶区域ATP位点被认为是较难控制的靶点,因为有许多以ATP为底物的蛋白激酶以及其他酶都有可能受到影响,这将增加设计特异性抑制剂的难度。直到发现并设计出许多特异性小分子抑制剂后,这种观念才得到改变,使人们进入了小分子抑制剂与酪氨酸激酶ATP位点结合的研究新时代。虽然激酶中ATP位点是高度同源的,但是在ATP位点的一些区域还是存在微小差异,通过对ATP位点的研究,可以设计出特异性抑制剂。许多EGFR酪氨酸激酶小分子抑制剂被证明具有抗肿瘤活性,并具有较好的选择性,而这些靶向性的抑制剂的最大特点是,只选择性干扰引起癌变的异常环节,而对正常细胞不起作用,不会导致严重的全身性毒副作用。虽然正常细胞与肿瘤细胞都表达大量的蛋白激酶,这些激酶在不同的生物学过程如生长、代谢、分化和凋亡中起着重要作用。但相对于正常细胞,不同的肿瘤细胞常过度表达一种或多种激酶,因而,只需阻断或修饰这些过度表达的蛋白激酶活性,就可以达到治疗肿瘤的目的。作用于酪氨酸激酶的小分子抑制剂按照它们的化学结构,可以将它们分为:4-苯胺基喹唑啉类化合物、3-腈基喹啉类化合物、吡啶并嘧啶及嘧啶并嘧啶类、三环喹唑啉及嘧啶类化合物、苯甲酰胺和苯甲脒类、5,7-二氮吲哚酮类化合物、吡咯三嗪类化合物、吡咯并嘧啶类化合物等。
目前为止,已有近10种酪氨酸激酶抑制剂上市,主要包括单克隆抗体和小分子靶向抑制剂,它们在肿瘤治疗中起到的作用令人鼓舞。其中研究的比较多成果相对突出的小分子抑制剂,其中最具有代表性的是具有4-苯胺基喹唑啉结构的化合物,如Gefitinib、Erlotinib、Lapatinib等。这些药物的上市以及临床取得的成果,进一步证明了以特定靶点尤其是酪氨酸激酶为靶点进行抗肿瘤药物的研发是21世纪最有可能获得突破性进展的抗肿瘤药物领域,具有十分广阔的前景。
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4-芳香氨基喹唑啉衍生物。
本发明的另一目的提供一种上述4-芳香氨基喹唑啉衍生物,以一个或数个上述4-芳香氨基喹唑啉衍生物作为原料,制备临床可以使用的药物,用于治疗治疗肿瘤,特别是治疗非小细胞肺癌、肝癌及胃癌。
本发明还有一个目的在于提供一种4-芳香氨基喹唑啉衍生物的制备方法。
技术方案:本发明的目的是通过以下技术措施实现的:
本发明的4-芳香氨基喹唑啉衍生物为具有下述结构通式I的化合物或下述化合物与药学上可以接受的酸所成的盐:
其中,
Ar是下面两类结构之一:
其一,芳香杂环,该芳香杂环为C5-8酯基取代的、含有一个或多个杂原子的芳香杂环基团,该杂环基团上含有一个或多个下列取代基:羟基、卤素、腈基、硝基、苯基、C1-6烷基取代的苯基、C1-6烷基、C1-6烷氧基、C1-6烷氨基、C1-6烷硫基或氨基,其中杂原子为N、O或S;
其二,苯并芳香杂环,该苯并芳香杂环为C5-8的酯基取代的、含有一或多个杂原子的苯并芳香杂环基团,该苯并芳香杂环基团上含有一个或多个下列取代基:羟基、卤素、腈基、硝基、苯基、C1-6烷基取代的苯基、C1-6烷基、C1-6烷氧基、C1-6烷氨基、C1-6烷硫基或氨基,其中杂原子为N、O或S;
R1、R2是氢、卤素、硝基、氨基、C1-6的烷基、C1-6的烷氨基、C1-6的烷氧基、C1-6的卤代烷基、C1-6的卤代烷氨基、C1-6的卤代烷氧基、C1-9的烷氨基取代的C1-6的烷基、C1-9的烷氨基取代的C1-6的烷氨基或C1-9的烷氨基取代的C1-6的烷氧基;
X是N、O、S。
第一种情况:
Ar是C5-8的酯基取代的含一个杂原子N、O或S的芳香杂环基团;
R1是甲氧基;
R2是C2-8的链状或环状烷氨基取代的C3-5的烷氧基;
X是N。
第二种情况:
Ar是C5-8的酯基取代的吡咯环;
R1是甲氧基;
R2是具有链状或环状支链的C2-8的叔胺基取代的C3的烷氧基;
X是N。
第三种情况:
Ar是C5-8的酯基取代的含一个杂原子N、O或S的苯并芳香杂环基团;
X是N;
R1是甲氧基;
R2是C2-8的链状或环状烷氨基取代的C3-5的烷氧基。
第四种情况:
Ar是C5-8的酯基取代的苯并噻酚;
X是N;
R1是甲氧基;
R2是具有链状或环状支链的C2-8的叔胺基取代的C3的烷氧基。
在所述的化合物或这些化合物与药学上可以接受的酸所成的盐中,这些化合物选自下面所列特定化合物中的一个或多个:
3-(7-甲氧基-6-(3-(4-甲基哌嗪-1-基)丙氧基)喹唑啉-4-氨基)-1H-吡咯-2-甲酸乙酯,
3-(7-甲氧基-6-(3-吡咯丙氧基)喹唑啉-4-氨基)-1H-吡咯-2-甲酸乙酯,
3-(7-甲氧基-6-(3-哌啶丙氧基)喹唑啉-4-氨基)-1H-吡咯-2-甲酸乙酯,
3-(7-甲氧基-6-(3-(二乙胺基)丙氧基)喹唑啉-4-氨基)-1H-吡咯-2-甲酸乙酯,
3-(7-甲氧基-6-(3-(4-甲基哌啶-1-基)丙氧基)喹唑啉-4-氨基)-1H-吡咯-2-甲酸乙酯,
3-(6-甲氧基-7-(3-吗啉丙氧基)喹唑啉-4-氨基)-1H-吡咯-2-甲酸乙酯,
3-(6-甲氧基-7-(3-(4-甲基哌嗪-1-基)丙氧基)喹唑啉-4-氨基)-1H-吡咯-2-甲酸乙酯,
3-(6-甲氧基-7-(3-吡咯丙氧基)喹唑啉-4-氨基)-1H-吡咯-2-甲酸乙酯,
3-(6-甲氧基-7-(3-哌啶丙氧基)喹唑啉-4-氨基)-1H-吡咯-2-甲酸乙酯,
3-(6-甲氧基-7-(3-(二乙胺基)丙氧基)喹唑啉-4-氨基)-1H-吡咯-2-甲酸乙酯,
5-(6-(3-(4-甲基哌嗪-1-基)丙氧基)-7-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯
5-(6-(3-吡咯丙氧基)-7-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯,
5-(6-(3-哌啶丙氧基)-7-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯,
5-(6-(3-(二乙胺基)丙氧基)-7-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯,
5-(6-(3-(4-甲基哌啶-1-基)丙氧基)-7-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯,
5-(6-(3-(2-甲基哌啶-1-基)丙氧基)-7-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯,
5-(6-(3-(二甲胺基)丙氧基)-7-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯
5-(7-(3-(4-甲基哌嗪-1-基)丙氧基)-6-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯,
5-(7-(3-(二乙胺基)丙氧基)-6-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯,
5-(7-(3-(2-甲基哌啶-1-基)丙氧基)-6-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯,
5-(7-(3-(二甲胺基)丙氧基)-6-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯。
药学上可接受的盐是所述特定化合物与盐酸、氢溴酸、硫酸、硝酸、磷酸、琥珀酸、马来酸、富马酸、醋酸、枸橼酸、酒石酸、苯甲酸、苯磺酸或萘磺酸形成的盐。
所述的化合物或它们与药学上可以接受的酸所成的盐为原料,制备成临床上可使用的用于治疗肺癌、胃癌及肝癌、肿瘤的药物。
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1或2,经卤代烃烃基化、硝酸硝化、铁粉还原、醋酸甲脒关环、氯化亚砜氯代及两步选择性胺解得到目标化合物:
在本发明所述的化合物中,
“C1-6的烷基”这个词汇在这里如果没有另外说明是指碳原子数为1-6的饱和烷基,它可以是直链的、成环的(包括单环或多环)或者是有侧链的烷基,包括但不局限于甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基等。
“C1-6的烷氧基”这个词汇在这里如果没有另外说明是指碳原子数为1-6的饱和烷氧基,它可以是直链的、成环的(包括单环或多环)或者是有侧链的烷基,包括但不局限于甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、叔丁氧基、戊氧基等。
“C1-6的烷氨基”这个词汇在这里如果没有另外说明是指碳原子数为1-6的饱和烷氨基,它可以是直链的、成环的(包括单环或多环)或者是有侧链的烷基,包括但不局限于甲氨基、乙氨基、丙氨基、异丙氨基、丁氨基、异丁氨基、叔丁氨基、戊氨基等。
本发明中所提到的化合物总体制备方法为:
以取代苯甲酸甲酯或乙酯为起始原料,经卤代烃烃基化、硝酸硝化、铁粉还原、醋酸甲脒关环、氯化亚砜氯代及两步选择性胺解得到目标化合物,具体合成路线见反应式1及反应式2。
反应式1
反应式2
生物活性研究
以不同浓度本发明药物作用于人源性HepG2、A549、MGC-803肿瘤细胞株48h后,MTT法检测药物对细胞增殖的影响,ELISA法测定酪氨酸激酶活性。
试验材料
细胞株:人源性肝癌细胞株HepG2;人源性非小细胞性肺腺癌细胞株A549;人源性胃黏液腺癌细胞株MGC-803,均由中国药科大学郭青龙教授惠赠。
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:DMEM培养基(Gibco BRL);小牛血清(HyClone);胰蛋白酶(Amresco);噻唑蓝(MTT,Sigma);酪氨酸激酶(TK)活性分析ELISA测试盒(Chemicon);其他试剂均为国产分析纯。细胞培养板为Costar公司产品。恒温CO2孵箱购自Heraeus公司;酶标仪购自Tecan公司。
方法
1)肿瘤细胞株培养HepG2、A549及MGC-803细胞株生长于含10%小牛血清及双抗(青霉素100U·ml-1、链霉素100μg·ml-1)的DMEM培养基中,37℃,5%CO2恒温箱中培养,取对数生长期细胞进行实验。
2)细胞活力测定对数生长期细胞,0.25%胰蛋白酶消化成单细胞悬液后均匀接种于96孔培养板中常规培养,待细胞生长至单层后弃原培养液,分别加入含各受试及阳性药物的无血清DMEM 37℃作用48h。各孔加入MTT(5mg·ml-1)继续孵育4h后弃上清,加入DMSO分析纯振摇10min,酶标仪490nm波长处测定吸光度OD值。根据下列公式计算各浓度药物对三种肿瘤细胞株的抑制率:抑制率=(1-给药组OD值/对照组OD值)×100%。
3)TK活性分析对数生长期A549细胞株以冰冷D-Hank’s洗涤后,加入裂解液冰上裂解10min,收集细胞4℃ 12000g离心10min抽提TK细胞粗提物。选取A549细胞株MTT初筛有效化合物(10uM)分别与TK细胞粗提物37℃作用20min,加入分析液及底物肽30℃孵育45min后EDTA终止反应。取各组反应体系50μl至酶标孔37℃作用30min,洗涤后封闭30min,PY20-HRP抗体室温孵育1h,摇床振摇。洗涤后四甲基联苯胺(TMB)作用15min,酶标仪450nm波长处测定吸光度。细胞TK总活性=对照组吸光度/试药组吸光度X100%。
结果:
1、新化合物对各肿瘤细胞株细胞增殖的影响
每种新化合物对肿瘤细胞的抑制率以10uM为例,与阳性药物进行效应比较,结果以百分比示(表1~表4)。与阳性药物比较,GI-2~GI-6、GII-2~GII-5、BI-2~BI-8、BII-2、BII-5、BII-7、BII-8能够显著抑制肿瘤细胞增殖,其中BI-2~BI-8抑制效应显著强于同浓度阳性药物,抑制率最高达90%。
表1GI系列化合物(%,n=2)
表2GII系列化合物对肿瘤细胞的抑制率(%,n=2)
表3BI系列化合物对肿瘤细胞的抑制率(%,n=2)
表4BII系列化合物对肿瘤细胞的抑制率(%,n=2)
2初筛有效新化合物对TK活性影响
细胞TK粗提物分别给予21种初筛有效新化合物(10uM)作用20min,ELISA法测定新化合物对细胞TK总活性的影响,结果如表5所示:20个化合物中GI-5、GI-6、GII-4、GII-5、BI-8、BII-5、BII-7可明显抑制TK活性,与对照组比较有显著统计学差异(P<0.05)。
表5各系列新化合物对细胞TK活性的影响(%,n=3)
*P<0.05,与对照组比较有显著抑制效应
-:MTT初筛无显著生物抑制效应药物,未行TK活性测定
3同时具有生物学抑瘤效应且可抑制TK活性化合物小结
分别在MTT生物学效应筛选及TK活性测定中显示抑制效应的新化合物总结见表6。
表6具有抑制TK活性及抑制肿瘤细胞(A549)增殖作用的新化合物
附图说明
图1为GI系列化合物对肿瘤细胞的抑瘤率(%)示意图。
图2为GII系列化合物对肿瘤细胞的抑瘤率(%)示意图。
图3为GI系列化合物对细胞TK总活性的影响示意图。
图4为GII系列化合物对细胞TK总活性的影响示意图。
图3,图4中,*,P<0.05,与对照组比较。
具体实施方式:
制备I:3-(6-(3-氯丙氧基)-7-甲氧基喹唑啉-4-氨基)-1H-吡咯-2-甲酸乙酯(GI-Cl)
3-(3-氯丙氧基)-4-甲氧基苯甲酸甲酯(1)
将3-羟基-4-甲氧基苯甲酸甲酯(84.6g,0.46mol)和1-溴-3-氯丙烷(101.6g,0.65mol)溶于DMF(500ml),加入碳酸钾(138.1g,1.0mol),于70℃反应4小时,反应液冷却至室温后,连续搅拌下将其缓慢倒入冰水中(3L),过滤收集析出的固体,以冷水洗涤,得到的类白色固体以乙酸乙酯(200ml)重结晶,得113.9克白色粉末,收率95%。mp:111-113℃;1H-NMRδ:2.02-2.22(tt,2H,-CH2CH2CH2-),3.65(t,2H,-CH2Cl),3.79(s,3H,-OCH3),3.88(s,3H,-OCH3),4.10(t,2H,-CH2O),6.84(d,1H,HAr),7.49(s,1H,HAr),7.71(d,1H,HAr)。
5-(3-氯丙氧基)-4-甲氧基-2-硝基苯甲酸甲酯(2)
3-(3-氯丙氧基)-4-甲氧基苯甲酸甲酯(1,93.0g,0.36mol)溶于冰醋酸(300ml)和醋酐(100ml),冰水浴冷却控温在0-5℃,硝酸(84.5ml,66-68%)缓慢滴加到反应液中,滴加结束后反应液室温搅拌6小时后,将反应液缓慢倒入冰水(3L)中,乙酸乙酯(4×200ml)萃取,饱和碳酸钠溶液(2×200ml)及盐水(2×100ml)洗涤,无水硫酸钠干燥,减压浓缩除去乙酸乙酯,得到本色油状物,冰箱放置过夜后固化,乙酸乙酯-石油醚重结晶,得浅黄色结晶97.1克,收率89%,mp:54-56℃;1H-NMRδ:2.03-2.24(tt,2H,-CH2CH2CH2-),3.66(t,2H,-CH2Cl),3.78(s,3H,-OCH3),3.89(s,3H,-OCH3),4.12(t,2H,-CH2O),7.82(s,1H,HAr),8.01(d,1H,HAr)。
5-(3-氯丙氧基)-4-甲氧基-2-氨基苯甲酸甲酯(3)
铁粉(50g,0.89mol),加入到冰醋酸(500ml)中,于50℃搅拌15分钟,控温50℃,氮气保护下,将5-(3-氯丙氧基)-4-甲氧基-2-硝基苯甲酸甲酯(2,90.0g,0.30mol)甲醇(300ml)溶液滴加其中,滴加结束后继续搅拌30分钟,过滤除去铁粉,滤液缓慢倒入水(4L)中,乙酸乙酯(4×200ml)萃取,饱和碳酸钠溶液(2×200ml)及盐水(2×100ml)洗涤,无水硫酸钠干燥,减压浓缩除去乙酸乙酯,得棕色固体,乙酸乙酯-石油醚重结晶,得浅黄色结晶63.1克,收率77%,mp:96-98℃;1H-NMRδ:1.98-2.20(tt,2H,-CH2CH2CH2-),3.62(t,2H,-CH2Cl),3.76(s,3H,-OCH3),3.85(s,3H,-OCH3),4.07(t,2H,-CH2O),5.10-5.35(b,2H,-NH2),6.09(d,1H,HAr),7.21(s,1H,HAr).
6-(3-氯丙氧基)-7-甲氧基喹唑啉-4(3H)-酮(4)
5-(3-氯丙氧基)-4-甲氧基-2-氨基苯甲酸甲酯(3,98.2g,0.36mol)溶于乙醇(800ml),加入醋酸甲脒(52.6g,0.51mol),回流反应6小时,反应液冷却至室温后冰箱中静置过夜,过滤收集析出的固体,冷乙醇洗涤,烘干,得白色结晶性固体88.7克,收率92%,mp:218-219℃;1H-NMRδ:2.10-2.31(tt,2H,-CH2CH2CH2-),3.72(t,2H,-CH2Cl),3.83(s,3H,-OCH3),4.02(t,2H,-CH2O),6.98(d,1H,HAr),7.89(s,1H,HAr),8.02(d,1H,HAr),9.03-9.42(b,1H,-NH-).
6-(3-氯丙氧基)-4-氯-7-甲氧基喹唑啉(5)
6-(3-氯丙氧基)-7-甲氧基喹唑啉-4(3H)-酮(4,102g,0.38mol)加入到氯化亚砜(500ml)中,缓慢滴加DMF(20ml),回流反应4小时,蒸除过量氯化亚砜后,以氯仿(500ml)溶解得到的黄色固体,饱和碳酸钠溶液(2×200ml)及水(2×100ml)洗涤,无水硫酸钠干燥,减压浓缩除去氯仿,得类白色固体,乙酸乙酯重结晶得白色粉末93.5克,收率86%,mp:150-152℃;1H-NMRδ:2.43(tt,2H,-CH2CH2CH2-),3.85(t,2H,-CH2Cl),4.09(s,3H,-OCH3),4.39(t,2H,-OCH2),7.43(s,1H,HAr),7.47(s,1H,HAr),8.91(s,1H,HAr).
3-(6-(3-氯丙氧基)-7-甲氧基喹唑啉-4-氨基)-1H-吡咯-2-甲酸乙酯(GI-Cl)
4-氯-6-(3-氯丙氧基)-7-甲氧基喹唑啉(3,15.0g,52mmol),异丙醇(300ml),3-氨基-2-吡咯甲酸乙酯盐酸盐(2,12.1g,64mmol),回流反应4小时,冷却后冰箱中放置过夜,过滤,异丙醇洗涤,乙醇重结晶,得浅黄色粉末19.1克,收率91%。mp:239-240℃;1H-NMR(CDCl3)δ:1.43(t,3H),2.41(tt,2H),3.85(t,2H),4.02(s,3H),3.37(t,2H),4.16-4.46(m,2H),7.24(s,1H),7.29(s,1H),7.46(d,1H),8.58(b,1H),8.72(d,1H),10.18(b,1H);M/z:405.1([M+H]+,100%).
制备II:5-(6-(3-氯丙氧基)-7-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯(BI-Cl)
4-氯-6-(3-氯丙氧基)-7-甲氧基喹唑啉(3,14.9g,52mmol),异丙醇(300ml),5-氨基苯[b]并噻吩-2-甲酸乙酯(16.1g,73mmol),回流反应4小时,冷却后冰箱中放置过夜,过滤,异丙醇洗涤,乙醇重结晶,得类白色粉末22.8克,收率93%,mp:>270℃。
制备III:3-(7-(3-氯丙氧基)-6-甲氧基喹唑啉-4-氨基)-1H-吡咯-2-甲酸乙酯(GII-Cl)
4-(3-氯丙氧基)-3-甲氧基苯甲酸甲酯(6)
将4-羟基-3-甲氧基苯甲酸甲酯(95.6g,0.53mol)和1-溴-3-氯丙烷(140g,0.90mol)溶于DMF(200ml),加入碳酸钾(200g,1.45mol),于70℃反应4小时,反应液冷却至室温后,连续搅拌下将其缓慢倒入冰水中(4L),过滤收集析出的固体,以冷水洗涤,得到的类白色固体以乙酸乙酯(200ml)重结晶,得白色粉末121克,收率88%,mp:98-100℃。
4-(3-氯丙氧基)-5-甲氧基-2-硝基苯甲酸甲酯(7)
4-(3-氯丙氧基)-3-甲氧基苯甲酸甲酯(6,120g,0.47mol)溶于冰醋酸(400ml)和醋酐(100ml),冰水浴冷却控温在0-5℃,硝酸(90ml,65-68%)缓慢滴加到反应液中,滴加结束后反应液室温搅拌6小时后,将反应液缓慢倒入冰水(4L)中,乙酸乙酯(4×300ml)萃取,饱和碳酸钠溶液(3×200ml)及盐水(2×100ml)洗涤,无水硫酸钠干燥,减压浓缩除去乙酸乙酯,得到本色油状物,冰箱放置过夜后固化,乙酸乙酯-石油醚重结晶,得浅黄色结晶126克,收率89%,mp:66-68℃。
4-(3-氯丙氧基)-5-甲氧基-2-氨基苯甲酸甲酯(8)
铁粉(50g,0.89mol),加入到冰醋酸(500ml)中,于50℃搅拌15分钟,控温50℃,氮气保护下,将4-(3-氯丙氧基)-5-甲氧基-2-硝基苯甲酸甲酯(7,90.0g,0.30mol)的甲醇(300ml)溶液滴加于其中,滴加结束后继续搅拌30分钟,过滤除去铁粉,滤液缓慢倒入水(4L)中,乙酸乙酯(4×300ml)萃取,饱和碳酸钠溶液(2×200ml)及盐水(2×100ml)洗涤,无水硫酸钠干燥,减压浓缩除去乙酸乙酯,得浅黄色固体,乙酸乙酯-石油醚重结晶,得类白色结晶63.1克,收率77%,mp:96-98℃。
7-(3-氯丙氧基)-6-甲氧基喹唑啉-4(3H)-酮(9)
4-(3-氯丙氧基)-5-甲氧基-2-氨基苯甲酸甲酯(8,98.2g,0.36mol)溶于乙醇(800ml),加入醋酸甲脒(78.9g,0.76mol),回流反应6小时,反应液冷却至室温后冰箱中静置过夜,过滤收集析出的固体,冷乙醇洗涤,烘干,得白色结晶性固体88.7克,收率92%,mp:218-219℃。
7-(3-氯丙氧基)-4-氯-6-甲氧基喹唑啉(10)
7-(3-氯丙氧基)-6-甲氧基喹唑啉-4(3H)-酮(9,102g,0.38mol)加入到氯化亚砜(500ml)中,缓慢滴加DMF(20ml),回流反应4小时,蒸除过量氯化亚砜后,以氯仿(500ml)溶解得到的黄色固体,饱和碳酸钠溶液(2×200ml)及水(2×100ml)洗涤,无水硫酸钠干燥,减压浓缩除去氯仿,得类白色固体,乙酸乙酯重结晶得白色粉末93.5克,收率86%,mp:150-152℃;1H-NMR(CDCl3)δ:2.40(p,2H,-CH2CH2CH2-),3.81(t,2H,-CH2Cl),4.05(s,3H,-OCH3),4.37(t,2H,-OCH2),7.38(s,1H,HAr),7.407(s,1H,HAr),8.87(s,1H,HAr).
3-(7-(3-氯丙氧基)-6-甲氧基喹唑啉-4-氨基)-1H-吡咯-2-甲酸乙酯(GII-Cl)
4-氯-7-(3-氯丙氧基)-6-甲氧基喹唑啉(8,16.2g,56mmol),异丙醇(300ml),3-氨基-2-吡咯甲酸乙酯盐酸盐(14.0g,74mmol),回流反应4小时,冷却后冰箱中放置过夜,过滤,异丙醇洗涤,乙醇重结晶,得类白色粉末18.9克,收率84%。mp:244-246℃;1H-NMR(CDCl3)δ:1.42(t,3H),2.38(q,2H),3.80(t,2H),4.07(s,3H),4.33-4.47(m,4H),6.90(s,1H),7.20(s,1H),7.45(d,1H),8.54(b,1H),8.72(d,1H);M/z:405.1([M+H]+,100%).
制备IV:5-(6-(3-氯丙氧基)-7-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯(BII-Cl)
4-氯-7-(3-氯丙氧基)-6-甲氧基喹唑啉(8,15.2g,53mmol),异丙醇(300ml),5-氨基苯[b]并噻吩-2-甲酸乙酯(15.0g,68mmol),回流反应4小时,冷却后冰箱中放置过夜,过滤,异丙醇洗涤,乙醇重结晶,得类白色粉末21.5克,收率86%,mp:>270℃。
实施例1:3-(7-甲氧基-6-(3-吗啉丙氧基)喹唑啉-4-氨基)-1H-吡咯-2-甲酸乙酯(GI-1)
3-(6-(3-氯丙氧基)-7-甲氧基喹唑啉-4-氨基)-1H-吡咯-2-甲酸乙酯(GI-Cl,0.81g,2mmol),吗啉5ml,DMF(20ml),70℃反应30分钟,减压除去剩余吗啉,以60ml氯仿溶解残留物,20ml水洗涤2次,无水硫酸镁干燥,200-300目硅胶柱层析,乙酸乙酯∶三乙胺=20∶1洗脱,得白色粉末0.78克,收率86%。mp:181-183℃;1H-NMR(CDCl3)δ:1.39(t,3H),2.04-2.18(m,2H),2.51(t,4H),2.63(t,2H),3.74(t,4H),4.00(s,3H),4.29(t,2H),4.40(q,2H),6.90(t,1H),7.20(s,1H),7.24(s,1H),7.45(t,1H),8.71(s,1H),9.10(b,1H),9.95(b,1H);13C-NMR(CDCl3)δ:14.68,26.19,53.76,55.44,56.10,60.10,66.98,67.76,101.38,103.73,107.92,108.41,109.35,122.36,147.17,149.01,153.86,155.18,155.30,161.83;IR(cm-1):3417,3311,3147,2968,2847,2193,1657,1621,1559,1509,1464,1393,1318,1238,1208,1122,1072,1040,934,855,780;M/z:456.2([M+H]+,100%).Elem.Anal.Calcd:C,60.65;H,6.42;N,15.37.Found C,59.46;H,6.60;N,13.69.
实施例2:3-(7-甲氧基-6-(3-(4-甲基哌嗪-1-基)丙氧基)喹唑啉-4-氨基)-1H-吡咯-2-甲酸乙酯(GI-2)
具体实施方法参照实施例1,以N甲基哌嗪代替吗啉,得白色粉末0.65克,收率71%。mp:175-178℃;1H-NMR(CDCl3)δ:1.43(t,3H),1.58(m,2H),2.15(t,2H),2.34(s,3H),2.62-2.69(m,8H),4.01(s,3H),4.27(t,2H),4.41(q,2H),6.69(t,1H),7.10(s,1H),7.24(s,1H),7.47(d,1Hr),8.58(b,1H),8.71(d,1H),9.54(b,1H);13C-NMR(CDCl3)δ:14.73,26.53,46.01,53.21,55.02,55.20,56.11,60.11,67.89,101.33,103.73,107.95,108.42,109.36,122.35,147.20,149.03,153.87,155.18,155.29,161.78;IR(cm-1):2952,2936,2873,2776,1659,1624,1604,1585,1559,1513,1471,1437,1413,1398,1316,1240,1212,1146,1067,1044,987,926,844,777,617;M/z:469.2([M+H]+,100%).Elem.Anal.Calcd:C,61.52;H,6.88;N,17.94.Found C,61.83;H,6.87;N,17.32.
实施例3:3-(7-甲氧基-6-(3-吡咯丙氧基)喹唑啉-4-氨基)-1H-吡咯-2-甲酸乙酯(GI-3)
具体实施方法参照实施例1,以吡咯代替吗啉,得黄色粉末0.48克,收率64%。mp:192-194℃;1H-NMR(CDCl3)δ:1.36(t,3H),1.79(b,4H),2.16(p,2H),2.57(b,4H),2.72(t,2H),4.00(s,3H),4.28(t,2H),4.406(q,2H),6.86(t,1H),7.17(s,1H),7.22(s,1H),7.41(t,1H),8.68(s,1H),9.10(b,1H),9.95(b,1H);13C-NMR(CDCl3)δ:14.69,23.53,28.56,52.97,54.21,56.07,60.05,67.93,101.20,103.68,107.88,108.39,109.34,122.29,147.13,149.02,153.79,155.13,155.24,161.70;IR(cm-1):3410,3302,3043,2959,2863,1665,1622,1598,1557,1508,1433,1309,1208,1143,1072,1044,896,835,774;M/z:440.2([M+H]+,100%);Elem.Anal.Calcd:C,62.85;H,6.65;N,15.93.Found C,62.70;H,6.62;N,15.07。
实施例4:3-(7-甲氧基-6-(3-哌啶丙氧基)喹唑啉-4-氨基)-1H-吡咯-2-甲酸乙酯(GI-4)
具体实施方法参照实施例1,以哌啶代替吗啉,得白色粉末0.58克,收率74%。mp:188-190℃;1H-NMR(CDCl3)δ:1.41(t,5H),1.61(m,5H),2.16(b,2H),2.46(b,4H),2.60(b,2H),4.00(s,3H),4.28(t,2H),4.43(q,2H),7.24(s,1H),7.29(s,1H),7.46(d,1H),8.61(b,1H),8.70(d,1H),9.45-10.20(b,1H);13C-NMR(CDCl3)δ:14.76,24.45,25.95,26.45,54.61,55.85,56.15,60.19,68.05,101.12,103.73,107.92,109.34,122.27,147.18,149.00,153.87,155.10,155.27;IR(cm-1):3324,2925,1655,1623,1594,1557,1513,1471,1433,1395,1310,1242,1211,1143,1070,1046,980,926,777,628;M/z:452.3([M-H]+,100%);Elem.Anal.Calcd:C,63.56;H,6.89;N,15.44.FoundC,63.63;H,6.85;N,14.69.
实施例5:3-(7-甲氧基-6-(3-(二乙胺基)丙氧基)喹唑啉-4-氨基)-1H-吡咯-2-甲酸乙酯(GI-5)
具体实施方法参照实施例1,以二乙胺代替吗啉,,得白色粉末0.62克,收率76%。mp:195-196℃;1H-NMR(CDCl3)δ:1.05(t,6H),1.40(t,3H),2.09(p,2H),2.57(q,4H),2.71(t,2H),4.00(s,3H),4.28(t,2H),4.43(q,2H),6.90(t,1H),7.21(s,1H),7.24(s,1H),7.46(t,1H),8.72(s,1H),8.86(b,1H),9.82(b,1H);13C-NMR(CDCl3)δ:11.83,14.69,26.62,47.05,49.18,56.10,60.10,67.85,100.93,103.62,107.79,108.34,109.32,122.29,147.07,149.03,153.79,155.04,155.23,161.73;IR(cm-1):2959,2810,1736,1665,1624,1602,1559,1515,1473,1413,1398,1383,1317,1244,1211,1147,1066,928,843,779,614;M/z:442.2([M+H]+,100%).Elem.Anal.Calcd:C,62.57;H,7.08;N,15.86.Found C,62.44;H,7.22;N,14.85.
实施例6:3-(7-甲氧基-6-(3-(4-甲基哌啶-1-基)丙氧基)喹唑啉-4-氨基)-1H-吡咯-2-甲酸乙酯(GI-6)
具体实施方法参照实施例1,以4-甲基哌啶代替吗啉,得白色粉末0.52克,收率68%。mp:186-189℃;1H-NMR(CDCl3)δ:0.91(d,3H),1.25-1.41(m,6H),1.62(d,2H),1.98(b,2H),2.08(t,2H),2.60(b,2H),2.94(d,2H),4.00(s,3H),4.27(t,2H),4.02(q,2H),6.90(t,1H),7.19(s,1H),7.23(s,1H),7.45(s,1H),8.71(s,1H),8.86(b,1H),9.88(b,1H);13C-NMR(CDCl3)δ:14.72,21.83,26.64,30.83,34.38,54.05,55.47,56.11,60.13,68.06,101.16,103.71,107.89,109.34,122.29,147.15,149.02,153.83,155.12,155.26,161.71;IR(cm-1):2946,2911,1659,1624,1603,1559,1509,1471,1437,1413,1385,1316,1240,1212,1143,1066,1040,923,844,777,649;M/z:467.1([M+H]+,100%);Elem.Anal.Calcd:C,64.22;H,7.11;N,14.98.Found C,63.96;H,7.11;N,14.44.
实施例7:3-(7-甲氧基-6-(3-(2-甲基哌啶-1-基)丙氧基)喹唑啉-4-氨基)-1H-吡咯-2-甲酸乙酯(GI-7)
具体实施方法参照实施例1,以2-甲基哌啶代替吗啉,得类白色粉末0.47克,收率57%。mp:131-133℃;1H-NMR(CDCl3)δ:1.11(d,3H),1.30-1.38(m,2H),1.60-1.68(m,4H),2.11(p,2H),2.23(t,2H),2.50(b,1H),2.56-2.62(m,2H),3.00(p,1H),4.01(s,3H),4.31(t,2H),6.58(t,1H),7.25(s,1H),7.47(d,1H),8.10(s,1H),9.53(s,1H),10.79(b,1H);13C-NMR(CDCl3)δ:18.86,23.93,25.47,25.91,26.12,34.58,50.37,52.20,54.69,56.04,56.25,67.80,67.91,104.39,106.31,108.86,113.81,115.52,130.30,136.55,138.58,143.25,145.74,149.78,151.07,154.11;IR(cm-1):3193,2932,1696,1623,1609,1552,1470,1441,1424,1394,1299,1215,1136,1115,1038,866,784,741;M/z:467.1([M+H]+,100%).Elem.Anal.Calcd:C,64.22;H,7.11;N,14.98.Found C,65.15;H,6.43;N,15.18.
实施例8:3-(7-甲氧基-6-(3-(4-乙基哌嗪-1-基)丙氧基)喹唑啉-4-氨基)-1H-吡咯-2-甲酸乙酯(GI-9)
具体实施方法参照实施例1,以4-乙基哌嗪代替吗啉,得白色粉末0.62克,收率71%。mp:175-177℃;1H-NMR(CDCl3)δ:1.09(t,3H),1.41(t,2H),2.14(p,2H),2.38-2.71(m,10H),4.00(s,3H),4.28(t,2H),4.26(q,2H),6.91(t,1H),7.20(s,1H),7.24(s,1H),7.46(t,1H),8.71(s,1H),8.88(b,1H);13C-NMR(CDCl3)δ:11.94,14.73,26.52,52.30,52.87,53.28,55.09,56.11,56.27,60.13,67.79,67.92,101.28,103.76,104.43,106.29,107.96,108.41,108.89,109.35,122.31,130.09,136.64,147.21,149.03,1153.85,155.17,155.28,161.74;IR(cm-1):3441,2964,2875,1812,1701,1643,1624,1596,1558,1512,1437,1415,1382,1317,1278,1213,1162,1145,1068,1045,960,778,639;M/z:483.3([M+H]+,100%).Elem.Anal.Calcd:C,62.22;H,7.10;N,17.41;.Found C,62.12;H,6.92;N,62.12.
实施例9:3-(7-甲氧基-6-(3-(4-苯基哌嗪-1-基)丙氧基)喹唑啉-4-氨基)-1H-吡咯-2-甲酸乙酯(GI-10)
具体实施方法参照实施例1,以4-苯基哌嗪代替吗啉,得白色粉末0.59克,收率79%。mp:242-243℃;1H-NMR(CDCl3)δ:1.37(t,3H),2.16(p,2H),2.68-2.72(m,6H),3.23(t,4H),4.00(s,3H),4.30-4.43(m,4H),6.82-6.93(m,4H),7.25-7.28(m,4H),7.46(t,1H),8.72(s,1H),8.85(b,1H);13C-NMR(CDCl3)δ:14.68,26.49,49.16,53.30,55.06,56.15,60.16,67.82,101.31,103.77,107.98,108.43,109.38,116.00,119.63,122.31,129.10,147.22,149.02,151.38,153.89,155.17,155.31,161.79;IR(cm-1):3423,3334,2947,2879,2822,2733,1663,1624,1601,1600,1472,1436,1413,1397,1317,1242,1211,1148,1066,1044,930,845,780,690;M/z:531.3([M+H]+,100%).Elem.Anal.Calcd:C,65.64;H,6.46;N,15.84.Found C,64.86;H,6.34;N,15.53.
实施例10:3-(6-甲氧基-7-(3-吗啉丙氧基)喹唑啉-4-氨基)-1H-吡咯-2-甲酸乙酯(GII-1)
3-(6-(3-氯丙氧基)-7-甲氧基喹唑啉-4-氨基)-1H-吡咯-2-甲酸乙酯(GII-Cl,0.79g,2mmol),吗啉5ml,DMF(15ml),70℃反应30分钟,减压除去剩余吗啉,以60ml氯仿溶解残留物,20ml水洗涤2次,无水硫酸镁干燥,200-300目硅胶柱层析,乙酸乙酯∶三乙胺=20∶1洗脱,得白色粉末0.68克,收率75%。mp:202-203℃;1H-NMR(CDCl3)δ:1.37(t,3H),2.03-2.14(m,2H),2.47(t,4H),2.56(t,2H),3.71(t,4H),4.05(s,3H),4.23(t,2H),4.40(q,2H),6.88(t,1H),7.15(s,1H),7.23(s,1Hr),7.44(t,1H),8.70(s,1H),9.11(b,1H),9.90(b,1H);13C-NMR(CDCl3)δ:14.65,26.02,53.73,55.28,56.25,60.10,66.98,67.30,67.43,99.95,103.66,108.36,108.66,109.21,122.29,147.16,149.83,153.82,154.13,155.23,161.80;IR(cm-1):3459,3089,2991,1934,1659,1622,1595,1513,1455,1385,1312,1201,1147,1118,1069,859,777,621;M/z:456.2([M+H]+,100%).Elem.Anal.Calcd:C,60.65;H,6.42;N,15.37.Found C,60.22;H,6.40;N,14.69.
实施例11:3-(6-甲氧基-7-(3-(4-甲基哌嗪-1-基)丙氧基)喹唑啉-4-氨基)-1H-吡咯-2-甲酸乙酯(GII-2)
具体实施方法参照实施例10,以4-甲基哌嗪代替吗啉,得白色粉末0.56克,收率67%。mp:183-185℃;1H-NMR(CDCl3)δ:1.40(t,3H),2.11(p,2H),2.30(s,3H),2.48-2.61(m,1H),4.06(s,3H),4.23(t,2H),4.40(q,2H),6.89(s,1H),7.15(s,1H),7.21(d,1H),7.44(t,1H),8.70(s,1H),9.21(b,1H),9.94(b,1H);13C-NMR(CDCl3)δ:14.68,26.36,45.98,53.19,54.81,55.18,56.27,56.30,60.10,67.44,99.98,103.68,108.37,108.70,109.22,122.29,147.21,149.87,153.82,154.19,155.25,161.80;IR(cm-1):3422,3337,3113,2939,2797,1656,1620,1592,1513,1454,1386,1314,1204,1151,1074,1042,1013,895,826,777;M/z:469.3([M+H]+,100%).Elem.Anal.Calcd:C,61.52;H,6.88;N,17.94.Found C,60.91;H,6.84;N,17.10.
实施例12:3-(6-甲氧基-7-(3-吡咯丙氧基)喹唑啉-4-氨基)-1H-吡咯-2-甲酸乙酯(GII-3)
具体实施方法参照实施例10,以吡咯代替吗啉,得浅黄色粉末0.47克,收率59%。mp:189-191℃;1H-NMR(CDCl3)δ:1.39(t,3H),1.82(b,4H),2.16(p,2H),2.59(b,4H),2.74(t,2H),4.06(s,3H),4.21(t,2H),4.44(q,2H),6.85(t,1H),7.11(s,1H),7.14,(s,1H),7.37(t,1H),8.67(s,1H),9.44(b,1H),9.78(b,1H);13C-NMR(CDCl3)δ:14.71,23.54,28.35,52.76,54.15,56.27,56.29,60.08,67.39,99.89,103.66,108.33,108.67,109.19,122.28,147.20,149.83,153.80,154.11,155.17,161.80;IR(cm-1):3423,3323,3067,2952,2879,1658,1622,1595,1557,1511,1453,1387,1314,1206,1143,1072,1045,895,831,779,639;M/z:440.3([M+H]+,100%).Elem.Anal.Calcd:C,62.85;H,6.65;N,15.93.Found C,62.14;H,6.64;N,15.20.
实施例13:3-(6-甲氧基-7-(3-哌啶丙氧基)喹唑啉-4-氨基)-1H-吡咯-2-甲酸乙酯(GII-4)
具体实施方法参照实施例10,以哌啶代替吗啉,得白色粉末0.61克,收率72%。mp:199-202℃;1H-NMR(CDCl3)δ:1.38-1.48(m,5H),1.60(t,4H),2.10(p,2H),2.44(b,4H),2.55(d,2H),4.06(s,3H),4.22(t,2H),4.41(q,2H),6.62(d,1H),6.88(s,1H),7.19(s,1H),7.42(t,1H),8.69(s,1H),9.19(b,1H),9.80(b,1H);13C-NMR(CDCl3)δ:14.69,24.47,26.00,26.39,54.63,55.62,56.29,60.11,67.63,99.96,103.70,108.34,108.72,109.20,122.27,147.24,149.89,153.81,154.20,155.23,161.77;IR(cm-1):3061,2932,1657,1622,1595,1558,1512,1454,1411,1382,1312,1245,1211,1143,1070,1045,922,898,827,777,628;M/z:454.3([M+H]+,100%).Elem.Anal.Calcd:C,63.56;H,6.89;N,15.44.Found C,63.57;H,6.86;N,14.85.
实施例14:3-(6-甲氧基-7-(3-(二乙胺基)丙氧基)喹唑啉-4-氨基)-1H-吡咯-2-甲酸乙酯(GII-5)
具体实施方法参照实施例10,以二乙胺代替吗啉,得白色粉末0.63克,收率76%。mp:175-177℃;1H-NMR(CDCl3)δ:1.04(t,6H),1.41(t,3H),2.10(p,2H),2.55(q,4H),2.67(t,2H),4.06(s,3H),4.23(t,2H),4.42(q,2H),6.91(t,1H),7.17(s,1H),7.25(s,1H),7.46(t,1H),8.70(d,1H),8.81(b,1H),9.86(b,1H);13C-NMR(CDCl3)δ:11.75,11.87,14.69,26.72,47.03,47.10,49.29,56.32,56.47,60.15,67.63,67.77,99.98,103.78,104.48,105.30,108.74,109.20,109.79,122.58,136.58,147.30,149.94,153.82,154.35,155.30;IR(cm-1):3345,319,2968,1697,1659,1623,1597,1556,1495,1453,1409,1382,1313,1287,1242,1199,1138,1070,1044,930,863,775,632;M/z:442.1([M+H]+,100%).Elem.Anal.Calcd:C,62.57;H,7.08;N,15.86.Found C,62.20;H,6.93;N,15.46.
实施例15:3-(6-甲氧基-7-(3-(4-甲基哌啶-1-基)丙氧基)喹唑啉-4-氨基)-1H-吡咯-2-甲酸乙酯(GII-6)
具体实施方法参照实施例10,以4-甲基哌啶代替吗啉,得类白色粉末0.51克,收率69%。mp:176-178℃;1H-NMR(CDCl3)δ:0.92(d,3H),1.26(m,2H),1.40(m,3H),1.63(d,2H),1.98(b,2H),2.13(t,2H),2.58(b,2H),2.95(d,2H),4.04(s,3H),4.23(t,2H),4.21(q,2H),6.88(s,1H),7.12(s,1H),7.43(t,1H),8.69(s,1H),9.14(s,1H),9.87(b,1H);13C-NMR(CDCl3)δ:14.70,21.80,26.50,30.84,34.10,34.28,34.36,54.03,55.16,55.25,56.29,56.38,60.10,67.58,99.92,103.66,104.31,105.25,108.32,109.18,113.85,115.31,122.30,130.15,136.60,147.98,150.87,153.80,154.15,155.20,161.79;IR(cm-1):3165,3157,2945,2930,2841,2071,1698,1655,1623,1597,1586,1558,1511,1493,1452,1411,1382,1313,1276,1201,1143,1070,1044,770;M/z:467.1([M+H]+,100%).Elem.Anal.Calcd:C,64.22;H,7.11;N,14.98.Found C,64.06;H,6.92;N,15.50.
实施例16:3-(6-甲氧基-7-(3-(2-甲基哌啶-1-基)丙氧基)喹唑啉-4-氨基)-1H-吡咯-2-甲酸乙酯(GII-7)
具体实施方法参照实施例10,以2-甲基哌嗪代替吗啉,得类白色粉末0.48克,收率58%。mp:227-230℃;1H-NMR(CDCl3)δ:1.10(d,3H),1.57-1.67(m,4H),2.10(m,2H),2.30(t,1H),2.40(b,1H),2.56(t,1H),2.92-3.00(m,2H),3.00(p,1H),4.01(s,3H),4.25(t,2H),4.45(q,2H),6.58(t,1H),7.25(s,1H),7.47(d,1H),8.10(s,1H),9.53(s,1H),10.79(b,1H);13C-NMR(CDCl3)δ:18.61,23.77,25.44,26.12,50.28,52.01,55.89,56.39,67.81,104.20,105.13,109.66,113.78,115.24,130.81,136.51,138.48,143.04,145.81,150.56,151.06,153.09;IR(cm-1):3125,2902,1699,1622,1608,1574,1489,1445,1382,1300,1213,1132,1116,1042,869,786,745;M/z:467.1([M+H]+,100%).Elem.Anal.Calcd:C,64.22;H,7.11;N,14.98.Found C,65.06;H,6.73;N,15.16.7
实施例17:3-(6-甲氧基-7-(3-(4-乙基哌嗪-1-基)丙氧基)喹唑啉-4-氨基)-1H-吡咯-2-甲酸乙酯(GII-9)
具体实施方法参照实施例10,以4-乙基哌嗪代替吗啉,得白色粉末0.59克,收率73%。mp:236-238℃;1H-NMR(CDCl3)δ:1.08(t,3H),1.40(t,2H),2.17(p,2H),2.41(q,3H),2.55-2.66(m,10),4.04(s,3H),4.23(q,2H),4.42(q,2H),6.64(t,1H),7.11(s,1H),7.23(s,1H),7.50(t,1H),8.69(s,1H),9.24(b,1H);13C-NMR(CDCl3)δ:11.91,14.70,26.33,52.27,52.76,52.81,53.24,54.81,54.87,56.37,60.11,67.43,99.90,103.66,104.22,105.18,108.65,109.67,122.34,130.46,136.58,138.49,145.65,149.84,150.50,153.02,154.15,155.20,161.98;IR(cm-1):3452,3167,2929,1700,1620,1602,1552,1494,1394,1277,1210,1107,948,897,780,738;M/z:483.3([M+H]+,75%).Elem.Anal.Calcd:C,62.22;H,7.10;N,17.41.Found C,61.90;H,6.77;N,17.94.
实施例18:3-(6-甲氧基-7-(3-(4-苯基哌嗪-1-基)丙氧基)喹唑啉-4-氨基)-1H-吡咯-2-甲酸乙酯(GII-10)
具体实施方法参照实施例10,以4-苯基哌嗪代替吗啉,得白色粉末0.65克,收率81%。mp:221-223℃;1H-NMR(CDCl3)δ:1.41(t,3H),2.17(t,2H),2.63-2.69(m,6H),3.23(t,4H),4.07(s,3H),4.27(t,2H),4.42(q,2H),6.85(t,1H),6.90(d,2H),6.95(s,1H),7.17(s,1H),7.23-7.29(m,4H),7.46(t,1H),8.71(s,1H),8.85(b,1H);13C-NMR(CDCl3)δ:14.69,26.33,49.16,53.28,53.40,54.96,56.31,60.16,67.45,99.97,103.77,105.45,108.39,108.73,109.25,116.09,119.64,122.27,129.08,136.70,147.19,149.88,151.37,153.05,153.83,154.18,155.27,161.80;IR(cm-1):3423,3326,3249,3136,2937,2820,1693,1659,1624,1599,1583,1558,1499,1453,1394,1383,1312,1238,1211,1201,1141,1071,1043,1010,991,926,863,780,650;M/z:531.3([M+H]+,100%).Elem.Anal.Calcd:C,65.64;H,6.46;N,15.84.Found C,64.84;H,6.13;N,15.35.
实施例19:5-(6-(3-吗啉丙氧基)-7-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯(BI-1)
5-(6-(3-氯丙氧基)-7-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯(0.80g,2mmol),吗啉5ml,DMF(15ml),70℃反应30分钟,减压除去剩余吗啉,以60ml氯仿溶解残留物,20ml水洗涤2次,无水硫酸镁干燥,200-300目硅胶柱层析,乙酸乙酯∶三乙胺=20∶1洗脱,得白色粉末0.81克,收率77%。mp:192-194℃;1H-NMR(CDCl3)δ:1.43(t,3H),2.12(dd,2H),2.49(t,4H),2.58(t,2H),3.72(t,4H),4.00(s,3H),4.19(t,2H),4.42(q,2H),7.13(s,1H),7.37(s,1H),7.70(d,1H),7.85(d,1H),8.04(s,1H,HAr),8.30(d,1H),8.67(s,1H);13C-NMR(CDCl3)δ:14.21,26.23,35.79,55.40,56.22,60.39,66.96,67.76,100.79,108.19,109.04,118.07,122.71,123.14,130.22,135.19,136.07,138.23,139.48,147.67,149.15,153.63,155.29,156.47,162.74;IR(cm-1):3445,3367,3027,2976,2870,2109,1710,1621,1592,1526,1503,1424,1391,1240,1141,1110,996,957,857,754;M/z:523.2([M+H]+,100%).Elem.Anal.Calcd:C,62.05;H,5.79;N,10.72.Found C,61.57;H,6.04;N,10.09.
实施例20:5-(6-(3-(4-甲基哌嗪-1-基)丙氧基)-7-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯(BI-2)
具体实施方法参照实施例19,以4-甲基哌嗪代替吗啉,得白色粉末0.72克,收率68%。mp:169-171℃;1H-NMR(CDCl3)δ:1.42(t,3H),2.10(q,2H),2.27(s,3H),2.45-2.54(b,8H),2.55(t,2H),3.99(s,3H),4.22(t,2H),4.42(q,2H),7.23(s,1H),7.34(s,1H),7.73(dd,1H),7.82(d,1H),7.95(b,1H),8.02(s,1H,HAr),8.31(d,1H),8.65(s,1H);13C-NMR(CDCl3)δ:14.29,26.43,45.98,53.20,54.87,55.05,56.16,61.62,67.84,100.90,108.04,118.07,122.76,123.06,130.22,136.08,149.10,153.59;IR(cm-1):3406,3235,3209,2941,2806,2149,1708,1624,1593,1522,1510,1428,1237,1147,1070,1008,962,866,756;M/z:536.2([M+H]+,100%).Elem.Anal.Calcd:C,62.78;H,6.21;N,13.07.Found C,62.09;H,6.25;N,13.25.
实施例21:5-(6-(3-吡咯丙氧基)-7-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯(BI-3)
具体实施方法参照实施例19,以吡咯代替吗啉,得浅黄色粉末0.52克,收率58%。mp:162-164℃;1H-NMR(CDCl3)δ:1.41(t,3H),1.81(m,4H),2.12(p,2H),2.54(b,4H),2.65(t,2H),3.98(s,3H),4.17(t,2H),4.40(q,2H),7.18(s,1H),7.53(s,1H),7.71(dd,1H),7.84(d,1H),8.02(s,1H),8.30(d,1H),8.67(s,1H);13C-NMR(CDCl3)δ:14.30,23.45,28.28,52.90,54.25,56.16,61.60,67.91,101.12,107.91,109.16,118.04,122.77,122.96,130.27,134.92,136.23,138.04,139.39,147.43,148.97,153.54,155.09,156.59,162.76;IR(cm-1):3452,3313,3280,2871,2186,1705,1624,1587,1513,1438,1413,1288,1225,1140,921,855;M/z:507.2([M+H]+,100%).Elem.Anal.Calcd:C,64.01;H,5.97;N,11.06.Found C,63.59;H,6.05;N,10.85.
实施例22:5-(6-(3-哌啶丙氧基)-7-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯(BI-4)
具体实施方法参照实施例19,以哌啶代替吗啉,得白色粉末0.67克,收率71%。mp:153-155℃;1H-NMR(CDCl3)δ:1.40-1.46(m,5H),1.57-1.65(m,4H),2.12(t,2H),2.44(b,4H),2.53(t,2H),4.00(s,3H),4.19(t,2H),4.43(q,2H),7.20(s,1H),7.51(s,1H),7.73(dd,1H),7.85(d,1H),8.04(s,1H),8.32(d,1H),8.67(s,1H);13C-NMR(CDCl3):14.35,24.35,25.90,26.52,54.68,55.67,56.21,61.64,68.13,100.98,108.13,109.10,118.08,122.78,123.09,130.28,135.09,136.14,138.18,139.47,147.62,149.15,153.60,155.29,156.49,162.76;IR(cm-1):3466,2930,2850,2071,1706,1622,1594,1525,1507,1427,1390,1238,1194,1147,1065,1010,951,862,756;M/z:521.3([M+H]+,100%).Elem.Anal.Calcd:C,64.59;H,6.20;N,10.76.Found C,64.24;H,6.17;N,10.91.
实施例23:5-(6-(3-(二乙胺基)丙氧基)-7-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯(BI-5)
具体实施方法参照实施例19,以二乙胺代替吗啉,得白色粉末0.56克,收率69%。mp:144-146℃;1H-NMR(CDCl3)δ:1.01(t,6H),1.41(t,3H),2.02(p,2H),2.57(hex,6H),3.97(s,3H),4.14(t,2H),4.40(q,2H),7.24(s,1H),7.67(s,1H),7.70(dd,1H),7.82(d,1H),8.00(s,1H),8.26(d,1H),8.67(s,1H);13C-NMR(CDCl3)δ:11.62,14.28,26.82,46.99,49.07,56.12,61.60,67.79,100.81,107.90,109.09,118.06,122.74,122.99,130.20,134.97,136.09,138.09,139.37,147.44,149.14,153.49,155.20,156.51,162.73;IR(cm-1):2950,2795,1711,1623,1574,1521,1445,1425,1389,1232,1192,1142,1065,1009,954,867,759;M/z:509.2([M+H]+,100%).Elem.Anal.Calcd:C,63.76;H,6.34;N,11.02.Found C,63.89;H,6.34;N,11.61.
实施例24:5-(6-(3-(4-甲基哌啶-1-基)丙氧基)-7-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯(BI-6)
具体实施方法参照实施例19,以4-甲基哌啶代替吗啉,得白色粉末0.61克,收率64%。mp:170-172℃;1H-NMR(CDCl3)δ:0.90(d,3H),1.20-1.23(m,2H),1.34(m,1H),1.41(t,3H),1.60(d,2H),1.90(t,2H),2.06(p,2H),2.46(t,2H),2.86(d,2H),3.96(s,3H),4.12(t,2H),4.40(q,2H),7.22(s,1H),7.23(s,1H),7.70(dd,1H),7.74(s,1H),7.80(d,1H),7.99(d,1H),8.27(d,1H);13C-NMR(CDCl3)δ:14.29,21.79,26.63,30.75,34.30,54.04,55.27,61.60,68.00,100.92,107.88,109.10,118.12,122.79,122.97,130.20,13.95,136.09,138.09,139.36,147.44,149.07,153.30,155.18,156.54,162.73;IR(cm-1):3282,3094,2944,2913,1713,1624,1577,1527,1516,1451,1428,1393,1295,1241,1202,1146,1066,1003,920,886,857,752;M/z:535.2([M+H]+,100%).Elem.Anal.Calcd:C,65.14;H,6.41;N,10.48.Found C,65.02;H,6.39;N,10.79.
实施例25:5-(6-(3-(2-甲基哌啶-1-基)丙氧基)-7-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯(BI-7)
具体实施方法参照实施例19,以2-甲基哌嗪代替吗啉,得白色粉末0.56克,收率59%。mp:177-178℃;1H-NMR(CDCl3)δ:1.05(d,3H),1.25-1.30(m,2H),1.41(t,3H),1.60-1.66(m,2H),2.02(t,2H),2.13(t,1H),2.42(b,1H),2.44(p,1H),2.54(s,2H),2.85(p,2H),3.95(s,3H),4.06-4.14(m,2H),4.40(q,2H),7.22(s,1H),7.32(s,1H),7.73(dd,1H),7.99(s,1H),8.06(d,1H),8.28(d,1H),8.65(d,1H);13C-NMR(CDCl3)δ:14.28,23.76,25.35,25.96,34.38,50.20,52.11,56.11,61.59,68.00,101.30,107.76,109.21,118.09,122.82,122.91,130.24,136.24,138.01,139.34,147.37,148.92,153.51,156.67,162.76;IR(cm-1):3331,2977,2931,2849,2156,1704,1626,1595,1577,1524,1453,1427,1392,1290,1235,1221,1191,1142,1077,1014,942,887,862,754;M/z:535.2([M+H]+,100%).Elem.Anal.Calcd:C,65.14;H,6.41;N,10.48.Found C,65.17;H,6.60;N,10.34.
实施例26:5-(6-(3-(二甲胺基)丙氧基)-7-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯(BI-8)
具体实施方法参照实施例19,以二甲胺代替吗啉,得白色粉末0.47克,收率61%。mp:201-203℃;1H-NMR(CDCl3)δ:1.14(t,3H),2.07(t,2H),2.25(s,6H),2.45(t,3H),3.98(s,3H),4.17(t,2H),4.40(q,2H),7.24(s,1H),7.67(s,1H),7.70(dd,1H),7.82(d,1H),8.01(s,1H),8.29(d,1H),8.67(s,1H);13C-NMR(CDCl3)δ:14.21,27.22,45.56,56.16,56,21,61.65,67.74,100.85,108.05,109.15,118.04,122.71,123.06,130.28,136.14,138.12,139.45,147.49,149.17,153.58,155.16,156.50,162.78;IR(cm-1):3452,3281,3089,2962,2753,2099,1702,1625,1579,1517,1473,1430,1395,1292,1233,1148,1067,993,888,862,754;M/z:509.2([M+H]+,100%).Elem.Anal.Calcd:C,62.48;H,5.87;N,11.66.Found C,62.42;H,5.93;N,10.92.
实施例27:5-(6-(3-(4-乙基哌嗪-1-基)丙氧基)-7-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯(BI-9)
具体实施方法参照实施例19,以4-乙基哌嗪代替吗啉,得白色粉末0.54克,收率65%。mp:174-175℃;1H-NMR(CDCl3)δ:1.06(t,3H),1.41(t,3H),2.08(t,3H),2.35-2.53(m,12H),3.97(s,3H),4.15(t,2H),4.41(q,2H),7.19(s,1H),7.24(s,1H),7.61(b,1H),7.70(d,1H),7.83(d,1H),8.01(s,1H),8.28(s,1H),8.67(s,1H);13C-NMR(CDCl3)δ:11.94,14.30,26.56,52.29,52.83,53.32,54.95,56.15,61.61,67.96,100.99,108.13,109.08,118.06,122.73,123.04,130.18,136.14,138.17,139.45,147.63,149.19,153.58,155.35,156.50,162.71;IR(cm-1):3296,3181,3117,2965,2934,2810,1710,1625,1578,1522,1506,1472,1450,1428,1393,1332,1233,1199,1144,1066,994,923,845,752,639;M/z:550.3([M+H]+,100%).Elem.Anal.Calcd:C,63.37;H,6.42;N,12.74.Found C,62.95;H,6.32;N,12.84.
实施例28:5-(6-(3-(4-苯基哌嗪-1-基)丙氧基)-7-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯(BI-10)
具体实施方法参照实施例19,以4-苯基哌嗪代替吗啉,得白色粉末0.61克,收率59%。mp:204-206℃;1H-NMR(CDCl3)δ:1.41(t,3H),1.97(b,2H),2.13(p,2H),2.59-2.65(m,6H),3.20(t,4H),3.99(s,3H),4.20(t,2H),4.41(q,2H),6.82-6.89(m,3H),7.20-7.23(m,3H),7.58(s,1H),7.68(dd,1H),7.80(d,1H),8.00(s,1H),8.27(d,1H),8.67(s,1H);13C-NMR(CDCl3)δ:14.30,26.51,49.13,53.33,54.90,56.17,61.60,67.90,101.22,108.20,109.13,116.04,118.06,119.80,122.72,123.05,129.10,130.20,136.16,139.46,147.69,149.16,151.22,153.62,155.38,162.70;IR(cm-1):3454,3347,2968,2815,1697,1678,1623,1597,1574,1528,1508,1473,1434,1392,1240,1219,1142,1076,1008,916,866,758,692;M/z:598.2([M+H]+,100%).Elem.Anal.Calcd:C,66.31;H,5.90;N,11.72.Found C,65.32;H,5.79;N,11.81.
实施例29:5-(7-(3-吗啉丙氧基)-6-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯(BII-1)
5-(6-(3-氯丙氧基)-6-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯(0.78g,2mmol),吗啉5ml,DMF(15ml),70℃反应30分钟,减压除去剩余吗啉,以60ml氯仿溶解残留物,20ml水洗涤2次,无水硫酸镁干燥,200-300目硅胶柱层析,乙酸乙酯∶三乙胺=20∶1洗脱,得白色粉末0.71克,收率68%。mp:155-157℃;1H-NMR(CDCl3)δ:1.41(t,3H),2.09(t,2H),2.48(t,4H),2.54(t,2H),3.72(t,4H),3.97(s,3H),4.21(t,2H),4.40(q,2H),7.13(s,1H),7.55(s,1H),7.69(d,1H),7.83(d,1H),8.01(s,1H),8.26(d,1H),8.6(s,1H);13C-NMR(CDCl3)δ:14.27,25.92,53.67,55.24,56.32,61.62,66.93,67.38,99.60,108.67,108.88,118.07,122.73,123.03,130.16,135.04,136.01,138.15,139.37,147.47,149.84,153.48,154.34,156.46,162.71;IR(cm-1):3780,3456,2953,2853,2064,1706,1679,1629,1521,1453,1416,1228,1114,1069,1010,858;M/z:523.2([M+H]+,100%).Elem.Anal.Calcd:C,62.05;H,5.79;N,10.72.Found C,61.77;H,6.05;N,9.99.
实施例30:5-(7-(3-(4-甲基哌嗪-1-基)丙氧基)-6-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯(BII-2)
具体实施方法参照实施例29,以4-甲基哌嗪代替吗啉,得白色粉末0.60克,收率62%。mp:173-174℃;1H-NMR(CDCl3)δ:1.42(t,3H),2.10(p,2H),2.31(s,3H),2.25(b,8H),2.57(t,2H),4.01(s,3H),4.24(t,2H),4.42(q,2H),7.07(s,1H),7.33(s,1H),7.70(dd,1H),7.86(d,1H),8.05(d,1H),8.31(d,1H),8.67(s,1H);13C-NMR(CDCl3)δ:14.35,26.35,46.00,53.13,54.85,55.16,56.45,61.67,67.61,99.45,108.89,108.95,118.02,122.69,123.14,130.23,136.08,138.22,139.49,147.71,149.98,153.59,154.49,156.40,162.75;IR(cm-1):3302,3181,3103,2940,2838,2241,1712,1624,1587,1521,1454,1417,1245,1229,1147,1057,1010,922,854,755;M/z:536.2([M+H]+,100%).Elem.Anal.Calcd:C,62.78;H,6.21;N,13.07.Found C,62.72;H,6.15;N,12.85.
实施例31:5-(7-(3-吡咯丙氧基)-6-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯(BII-3)
具体实施方法参照实施例29,以吡咯代替吗啉,得黄色粉末0.45克,收率51%。mp:205-207℃;1H-NMR(CDCl3)δ:1.48(t,3H),1.80(m,4H),2.14(s,2H),2.56(b,4H),2.68(q,2H),3.73(t,2H),4.02(s,3H),4.23(t,2H),7.24(s,1H),7.40(s,1H),7.51(dd,1H),7.68(d,1H),8.01(d,1H),8.16(d,1H),8.60(s,1H);13C-NMR(CDCl3)δ:14.29,23.54,24.17,26.62,47.44,49.28,52.93,54.25,56.57,67.62,100.73,108.59,109.20,118.56,122.43,122.66,125.79,136.07,136.47,139.56,136.89,139.56,139.89,147.50,149.80,153.65,154.29,157.05,162.74;IR(cm-1):3422,3332,3139,2869,2178,1706,1625,1588,1511,1450,1417,1296,1224,1140,913,852;M/z:507.2([M+H]+,100%).Elem.Anal.Calcd:C,64.01;H,5.97;N,11.06.Found C,63.59;H,6.34;N,10.58.
实施例32:5-(7-(3-哌啶丙氧基)-6-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯(BII-4)
具体实施方法参照实施例29,以哌啶代替吗啉,得类白色粉末0.64克,收率68%。mp:166-167℃;1H-NMR(CDCl3)δ:1.39-1.46(m,5H),1.57-1.65(m,4H),2.12(t,2H),2.44(b,4H),2.54(t,2H),4.00(s,3H),4.21(t,2H),4.41(q,2H),7.10(s,1H),7.41(s,1H),7.70(dd,1H),7.85(d,1H),8.04(s,1H),8.30(d,1H),8.66(s,1H);13C-NMR(CDCl3)δ:14.33,24.33,25.84,26.23,54.58,55.65,56.43,61.66,67.73,99.49,108.84,108.88,118.04,122.75,122.80,123.10,130.24,136.07,138.19,139.44,147.62,149.90,153.54,154.40,156.41,162.76;IR(cm-1):3466,3352,3110,2930,2856,2107,1708,1681,1628,1578,1526,1451,1419,1234,1219,1140,1067,1012,944,856,756;M/z:521.3([M+H]+,100%).Elem.Anal.Calcd:C,64.59;H,6.20;N,10.76.Found C,64.67;H,6.34;N,10.18.
实施例33:5-(7-(3-(二乙胺基)丙氧基)-6-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯(BII-5)
具体实施方法参照实施例29,以二乙胺代替吗啉,得白色粉末0.71克,收率72%。mp:181-183℃;1H-NMR(CDCl3)δ:1.03(t,6H),1.42(t,3H),2.05(m,2H),2.55(q,4H),2.65(t,3H),3.99(s,3H),4.21(t,2H),4.42(q,2H),7.12(s,1H),7.50(s,1H),7.70(dd,1H),7.84(d,1H),8.02(d,1H),8.28(d,1H),8.67(s,1H);M/z:509.2,([M+H]+,100%);13C-NMR(CDCl3)δ:11.86,14.22,14.34,26.61,47.09,47.15,49.17,56.43,61.67,67.68,99.57,108.86,108.90,118.06,122.76,123.10,130.24,135.11,136.13,138.18,139.46,147.70,149.98,153.57,154.54,156.47,162.77;IR(cm-1):3453,3281,3198,3093,2957,2165,1705,1625,1577,1522,1450,1417,1234,1194,1147,1065,1018,955,869,753;M/z:509.2([M+H]+,100%).Elem.Anal.Calcd:C,63.76;H,6.34;N,11.02.Found C,63.64;H,6.34;N,10.60.
实施例34:5-(7-(3-(4-甲基哌啶-1-基)丙氧基)-6-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯(BII-6)
具体实施方法参照实施例29,以4-甲基哌啶代替吗啉,得白色粉末0.62克,收率65%。mp:166-168℃;1H-NMR(CDCl3)δ:0.91(d,3H),1.23-1.26(m,2H),1.35(m,1H),1.41(t,3H),1.61(d,2H),1.95(t,2H),2.09(p,2H),2.51(t,2H),2.89(d,2H),3.97(s,3H),4.19(t,2H),4.41(q,2H),7.11(s,1H),7.50(s,1H),7.69(dd,1H),7.83(s,1H),8.01(s,1H),8.27(d,1H),8.75(s 1H);13C-NMR(CDCl3)δ:14.30,21.83,26.48,30.80,34.32,54.02,55.29,56.37,61.63,67.80,99.59,108.76,108.87,118.06,122.74,123.05,130.21,136.08,139.41,153.51,156.45;IR(cm-1):3431,3359,2947,2918,2861,2171,1709,1680,1627,1579,1525,1453,1419,1236,1143,1067,1015,980,849,756;M/z:535.2([M+H]+,100%).Elem.Anal.Calcd:C,65.14;H,6.41;N,10.48.Found C,65.04;H,6.67;N,10.00.
实施例35:5-(7-(3-(2-甲基哌啶-1-基)丙氧基)-6-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯(BII-7)
具体实施方法参照实施例29,以2-甲基哌嗪代替吗啉,得类白色粉末0.51克,收率60%。mp:160-161℃;1H-NMR(CDCl3)δ:1.06(d,3H),1.26-1.32(m,2H),1.42(t,3H),1.51-1.67(m,4H),2.01-2.21(m,4H),2.54(p,1H),2.90(p,2H),3.97(s,3H),4.10-4.20(m,2H),4.41(q,2H),7.12(s,1H),7.55(s,1H),7.69(dd,1H),7.84(d,1H),8.02(s,1H),8.27(s,1H),8.67(s,1H);13C-NMR(CDCl3)δ:14.34,19.02,23.98,25.31,26.20,34.66,50.23,52.25,54.66,55.96,56.42,61.67,67.84,99.66,108.82,108.92,118.09,122.77,123.09,130.24,135.10,136.13,138.19,139.45,147.67,149.98,153.57,154.53,156.60,162.78;IR(cm-1):3450,3253,3076,2928,2166,1725,1702,1621,1576,1525,1506,1452,1418,1242,1222,1146,1067,1008,958,852,752;M/z:535.2([M+H]+,100%).Elem.Anal.Calcd:C,65.14;H,6.41;N,10.48.Found C,64.48;H,6.40;N,10.17.
实施例36:5-(7-(3-(二甲胺基)丙氧基)-6-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯(BII-8)
具体实施方法参照实施例29,以二甲胺代替吗啉,得白色粉末0.47克,收率52%。mp:176-178℃;1H-NMR(CDCl3)δ:1.43(t,3H),2.37(t,2H),2.76(s,6H),3.15(d,3H),4.05(s,3H),4.26(t,2H),4.41(q,2H),7.18(s,1H),7.60(s,1H),7.84-7.91(m,2H),8.05(s,1H),8.43(s,1H),8.54(s,1H);13C-NMR(CDCl3)δ:13.70,24.31,38.96,39.51,35.79,42.97,54.90,56.04,60.88,65.57,101.83,107.50,109.19,118.04,121.92,123.05,129.63,133.94,136.27,136.97,138.55,146.06,148.74,152.84,156.47,162.00;IR(cm-1):3487,2825,2662,1709,1622,1587,1513,1453,1418,1230,1146,1065,1015,958,859,756;M/z:509.2([M+H]+,100%).Elem.Anal.Calcd:C,62.48;H,5.87;N,11.66.Found C,62.02;H,5.51;N,11.92.
实施例37:5-(7-(3-(4-乙基哌嗪-1-基)丙氧基)-6-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯(BII-9)
具体实施方法参照实施例29,以4-乙基哌嗪代替吗啉,得白色粉末0.56克,收率67%。mp:155-156℃;1H-NMR(CDCl3)δ:1.07(t,2H),1.38(t,2H),2.06(p,2H),2.20(t,2H),2.37-2.55(m,12H),3.93(s,3H),4.17(t,2H),4.39(q,2H),7.17(s,1H),7.24(s,1H),7.67(dd,1H),7.71(s,1H),7.80(d,1H),7.97(s,1H),8.23(d,1H),8.64(s,1H);13C-NMR(CDCl3)δ:11.87,14.26,26.31,52.25,52.77,53.15,54.84,56.34,61.60,67.57,99.86,108.72,108.95,118.09,122.77,122.97,130.17,135.01,136.14,138.12,139.37,147.57,149.89,153.49,154.44,156.54,162.73;IR(cm-1):3420,3335,2975,2948,2808,1719,1697,1626,1596,1579,1527,1511,1453,1419,1395,1237,1220,1201,1162,1145,1061,1012,923,866,756,649;M/z:550.3([M+H]+,100%).Elem.Anal.Calcd:C,63.37;H,6.42;N,12.74.Found C,63.33;H,6.32;N,12.40.
实施例38:5-(7-(3-(4-苯基哌嗪-1-基)丙氧基)-6-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯(BII-10)
具体实施方法参照实施例29,以4-苯基哌嗪代替吗啉,得白色粉末0.48克,收率59%。mp:170-172℃;1H-NMR(CDCl3)δ:1.43(t,3H),1.69(b,2H),2.16(p,2H),2.61-2.67(m,6H),3.22(t,4H),4.02(s,3H),4.27(t,2H),4.42(q,2H),6.86(t,31),6.92(s,1H),6.95(s,1H),7.09(s,1H),7.24-7.30(m,2H),7.34(s,1H),7.70(dd,1H),7.85(d,1H),8.04(s,1H),8.30(d,1H),8.67(s,1H);13C-NMR(CDCl3)δ:14.30,26.37,49.20,53.30,54.94,56.45,61.61,67.58,70.47,99.64,109.04,116.08,119.65,122.64,123.09,129.09,130,17,136.12,138.21,139.49,147.73,150.01,151.39,153.58,154.50,156.42,162.70;IR(cm-1):3428,3329,3180,2939,2820,1693,1624,1599,1557,1494,1453,1395,1384,1313,1278,1238,1212,1139,1042,1011,927,898,783,694;M/z:598.3([M+H]+,100%).Elem.Anal.Calcd:C,66.31;H,5.90;N,11.72.Found C,65.35;H,5.99;N,12.50。
Claims (4)
1.一种4-芳香氨基喹唑啉衍生物,包括下列化合物或其与药学上可接受的酸所成的盐:
3-(7-甲氧基-6-(3-吗啉丙氧基)喹唑啉-4-氨基)-1H-吡咯-2-甲酸乙酯
3-(7-甲氧基-6-(3-(4-甲基哌嗪-1-基)丙氧基)喹唑啉-4-氨基)-1H-吡咯-2-甲酸乙酯
3-(7-甲氧基-6-(3-吡咯丙氧基)喹唑啉-4-氨基)-1H-吡咯-2-甲酸乙酯
3-(7-甲氧基-6-(3-哌啶丙氧基)喹唑啉-4-氨基)-1H-吡咯-2-甲酸乙酯
3-(7-甲氧基-6(3-(二乙胺基)丙氧基)喹唑啉-4-氨基)-1H-吡咯-2-甲酸乙酯
3-(7-甲氧基-6-(3-(4-甲基哌啶-1-基)丙氧基)喹唑啉-4-氨基)-1H-吡咯-2-甲酸乙酯
3-(7-甲氧基-6-(3-(2-甲基哌啶-1-基)丙氧基)喹唑啉-4-氨基)-1H-吡咯-2-甲酸乙酯
3-(7-甲氧基-6-(3-(4-乙基哌嗪-1-基)丙氧基)喹唑啉-4-氨基)-1H-吡咯-2-甲酸乙酯
3-(7-甲氧基-6-(3-(4-苯基哌嗪-1-基)丙氧基)喹唑啉-4-氨基)-1H-吡咯-2-甲酸乙酯
3-(6-甲氧基-7-(3-吗啉丙氧基)喹唑啉-4-氨基)-1H-吡咯-2甲酸乙酯
3-(6-甲氧基-7-(3-(4-甲基哌嗪-1-基)丙氧基)喹唑啉-4-氨基)-1H-吡咯2甲酸乙酯
3-(6-甲氧基-7-(3-吡咯丙氧基)喹唑啉-4-氨基)-1H-吡咯-2-甲酸乙酯
3-(6-甲氧基-7-(3-哌啶丙氧基)喹唑啉-4-氨基)-1H-吡咯-2-甲酸乙酯
3-(6-甲氧基-7(3-(二乙胺基)丙氧基)喹唑啉-4-氨基)-1H-吡咯-2-甲酸乙酯
3-(6-甲氧基-7-(3-(4-甲基哌啶-1-基)丙氧基)喹唑啉-4-氨基)-1H-吡咯-2-甲酸乙酯
3-(6-甲氧基-7-(3-(2-甲基哌啶-1-基)丙氧基)喹唑啉-4-氨基)-1H-吡咯-2-甲酸乙酯
3-(6-甲氧基-7-(3-(4-乙基哌嗪-1-基)丙氧基)喹唑啉-4-氨基)-1H-吡咯-2-甲酸乙酯
3-(6-甲氧基-7-(3-(4-苯基哌嗪-1-基)丙氧基)喹唑啉-4-氨基)-1H-吡咯-2-甲酸乙酯
5-(6-(3-吗啉丙氧基)-7-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯
5-(6-(3-(4-甲基哌嗪-1-基)丙氧基)-7-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯
5-(6-(3-吡咯丙氧基)-7-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯
5-(6-(3-哌啶丙氧基)-7-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯
5-(6-(3-(二乙胺基)丙氧基)-7-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯
5-(6-(3-(4-甲基哌啶-1-基)丙氧基)-7-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯
5-(6-(3-(2-甲基哌啶-1-基)丙氧基)-7-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯
5-(6-(3-(二甲胺基)丙氧基)-7-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯
5-(6-(3-(4-乙基哌嗪-1-基)丙氧基)-7-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯
5-(6-(3-(4-苯基哌嗪-1-基)丙氧基)-7-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯
5-(7-(3-吗啉丙氧基)-6-甲氧基喹唑啉-4氨基)苯[b]并噻吩-2-甲酸乙酯
5-(7-(3-(4-甲基哌嗪-1-基)丙氧基)-6-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯
5-(7-(3-吡咯丙氧基)-6-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯
5-(7-(3-哌啶丙氧基)-6-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯
5-(7-(3-(二乙胺基)丙氧基)-6-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯
5-(7-(3-(4-甲基哌啶-1-基)丙氧基)-6-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯
5-(7-(3-(2-甲基哌啶-1-基)丙氧基)-6-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯
5-(7-(3-(二甲胺基)丙氧基)-6-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯
5-(7-(3-(4-乙基哌嗪-1-基)丙氧基)-6-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯
5-(7-(3-(4-苯基哌嗪-1-基)丙氧基)-6-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯。
2.根据权利要求1所述的4-芳香氨基喹唑啉衍生物,选自下列化合物或其与药学上可接受的酸所成的盐:
3-(7-甲氧基-6-(3-(4-甲基哌嗪-1-基)丙氧基)喹唑啉-4-氨基)-1H-吡咯-2-甲酸乙酯,
3-(7-甲氧基-6-(3-吡咯丙氧基)喹唑啉-4-氨基)-1H-吡咯-2-甲酸乙酯,
3-(7-甲氧基-6-(3-哌啶丙氧基)喹唑啉-4-氨基)-1H-吡咯-2-甲酸乙酯,
3-(7-甲氧基-6-(3-(二乙胺基)丙氧基)喹唑啉-4-氨基)-1H-吡咯-2-甲酸乙酯,
3-(7-甲氧基-6-(3-(4-甲基哌啶-1-基)丙氧基)喹唑啉-4-氨基)-1H-吡咯-2-甲酸乙酯,
3-(6-甲氧基-7-(3-吗啉丙氧基)喹唑啉-4-氨基)-1H-吡咯-2-甲酸乙酯,
3-(6-甲氧基-7-(3-(4-甲基哌嗪-1-基)丙氧基)喹唑啉-4-氨基)-1H-吡咯-2-甲酸乙酯,
3-(6-甲氧基-7-(3-吡咯丙氧基)喹唑啉-4-氨基)-1H-吡咯-2-甲酸乙酯,
3-(6-甲氧基-7-(3-哌啶丙氧基)喹唑啉-4-氨基)-1H-吡咯-2-甲酸乙酯,
3-(6-甲氧基-7-(3-(二乙胺基)丙氧基)喹唑啉-4-氨基)-1H-吡咯-2-甲酸乙酯,
5-(6-(3-(4-甲基哌嗪-1-基)丙氧基)-7-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯
5-(6-(3-吡咯丙氧基)-7-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯,
5-(6-(3-哌啶丙氧基)-7-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯,
5-(6-(3-(二乙胺基)丙氧基)-7-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯,
5-(6-(3-(4-甲基哌啶-1-基)丙氧基)-7-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯,
5-(6-(3-(2-甲基哌啶-1-基)丙氧基)-7-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯,
5-(6-(3-(二甲胺基)丙氧基)-7-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯
5-(7-(3-(4-甲基哌嗪-1-基)丙氧基)-6-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯,
5-(7-(3-(二乙胺基)丙氧基)-6-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯,
5-(7-(3-(2-甲基哌啶-1-基)丙氧基)-6-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯,
5-(7-(3-(二甲胺基)丙氧基)-6-甲氧基喹唑啉-4-氨基)苯[b]并噻吩-2-甲酸乙酯。
3.根据权利要求2所述的4-芳香氨基喹唑啉衍生物,其特征在于药学上可接受的盐是所述特定化合物与盐酸、氢溴酸、硫酸、硝酸、磷酸、琥珀酸、马来酸、富马酸、醋酸、枸橼酸、酒石酸、苯甲酸、苯磺酸或萘磺酸形成的盐。
4.权利要求2所述的4-芳香氨基喹唑啉衍生物在制备治疗肺癌、胃癌或肝癌药物方面的应用。
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CN101857588B (zh) * | 2010-06-08 | 2013-11-27 | 东南大学 | 4-芳香胺基喹唑啉类衍生物及其用途 |
CN102911125B (zh) * | 2011-08-05 | 2016-03-02 | 浙江九洲药业股份有限公司 | 一种吉非替尼中间体的制备方法 |
CN102898384A (zh) * | 2012-08-14 | 2013-01-30 | 邓俐丽 | 制备吉非替尼的中间体及所述中间体的制备方法 |
JP6669499B2 (ja) | 2013-02-15 | 2020-03-18 | カラ ファーマシューティカルズ インコーポレイテッド | 治療用化合物 |
EP2958895B1 (en) | 2013-02-20 | 2020-08-19 | Kala Pharmaceuticals, Inc. | Therapeutic compounds and uses thereof |
US9688688B2 (en) | 2013-02-20 | 2017-06-27 | Kala Pharmaceuticals, Inc. | Crystalline forms of 4-((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)-1-(2-oxa-7-azaspiro[3.5]nonan-7-yl)butan-1-one and uses thereof |
CN103539789A (zh) * | 2013-09-09 | 2014-01-29 | 苏州东南药业股份有限公司 | 一种酪氨酸激酶抑制剂喹唑啉衍生物的制备方法 |
MX355330B (es) | 2013-11-01 | 2018-04-16 | Kala Pharmaceuticals Inc | Formas cristalinas de compuestos terapeuticos y sus usos. |
US9890173B2 (en) | 2013-11-01 | 2018-02-13 | Kala Pharmaceuticals, Inc. | Crystalline forms of therapeutic compounds and uses thereof |
TWI567063B (zh) * | 2014-09-05 | 2017-01-21 | 國立交通大學 | 用於促進癌細胞凋亡的化合物、其醫藥組成物及其用途 |
CN106083836B (zh) * | 2016-06-26 | 2021-08-20 | 徐州医学院 | 基于喹唑啉结构的h2s供体化合物及其应用 |
MX2019002629A (es) | 2016-09-08 | 2019-10-07 | Kala Pharmaceuticals Inc | Formas cristalinas de compuestos terapéuticos y usos de los mismos. |
US10253036B2 (en) | 2016-09-08 | 2019-04-09 | Kala Pharmaceuticals, Inc. | Crystalline forms of therapeutic compounds and uses thereof |
US10392399B2 (en) | 2016-09-08 | 2019-08-27 | Kala Pharmaceuticals, Inc. | Crystalline forms of therapeutic compounds and uses thereof |
CN110092781A (zh) * | 2018-01-31 | 2019-08-06 | 河南省医药科学研究院 | 一种新型喹唑啉类egfr抑制剂及其制备和应用 |
CN109438423A (zh) * | 2018-09-12 | 2019-03-08 | 通化师范学院 | 一种肺癌靶向化合物azd-3759的合成工艺的新方法 |
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