CN1145614C - 酪氨酸激酶的不可逆抑制剂,其制药用途及药物组合物 - Google Patents
酪氨酸激酶的不可逆抑制剂,其制药用途及药物组合物 Download PDFInfo
- Publication number
- CN1145614C CN1145614C CNB97194458XA CN97194458A CN1145614C CN 1145614 C CN1145614 C CN 1145614C CN B97194458X A CNB97194458X A CN B97194458XA CN 97194458 A CN97194458 A CN 97194458A CN 1145614 C CN1145614 C CN 1145614C
- Authority
- CN
- China
- Prior art keywords
- amino
- quinazoline
- phenyl
- alkyl
- bromo
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 142
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- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/94—Nitrogen atoms
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- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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Abstract
本发明提供了作为酪氨酸激酶不可逆抑制剂的化合物。本发明也提供了治疗癌症、动脉粥样硬化、再狭窄、子宫内膜异位或牛皮癣的方法,本发明还提供了一种包含作为酪氨酸激酶不可逆抑制剂的化合物的药物组合物。
Description
发明领域
本发明涉及作为酪氨酸激酶不可逆抑制剂的化合物。本发明也涉及治疗癌症、动脉粥样硬化、再狭窄、子宫内膜异位或牛皮癣的方法,本发明还涉及一种包含作为酪氨酸激酶不可逆抑制剂的化合物的药物组合物。
发明背景
癌症被认为是细胞内信号传导系统或信号传导机制的疾病。细胞接受许多来自细胞外的指令,指导细胞是否增殖。信号传导系统的目的是接受细胞表面的这些或其它信号,将其导入细胞内,然后将这些信号传递到细胞核、细胞骨架,以及转运和蛋白合成结构。
癌症的最常见病因是一系列的缺损,所述缺损可以是这些蛋白质的缺损(当其突变时),或者是对细胞内蛋白质的量的调节的缺损,从而使蛋白过度产生或产生不足。通常,在细胞内存在重要损伤,该损伤导致组成型状态,由此使细胞核收到增殖信号,而事实上这些信号并不存在。这可以通过多种机制发生。有时细胞会在不应该的情况下开始生产其自身受体的真正的生长因子,所谓的自分泌环机制。细胞表面受体的突变(该突变通常通过酪氨酸激酶将信号传递到细胞内)可导致激酶在缺乏配体的条件下被激活,并传递事实上并不存在的信号。或者,许多表面激酶可在细胞表面过度表达,导致对弱信号的过强响应。在细胞内存在许多水平,在这些水平上,突变或过度表达可导致在细胞内产生同样的假信号,并且有许多涉及癌症的其它种类的信号传导缺陷。本发明针对由上述三种机制引起的、涉及表皮生长因子受体酪氨酸激酶家族(EGFR)的细胞表面受体的癌症。该家族由EGF受体(Erb-B1)、Erb-B2受体、其组成性活性癌基因蛋白突变种Neu、Erb-B3受体和Erb-B4受体组成。此外,其它通过受体的EGF家族成员的生理学过程也可以用下述的本发明化合物进行治疗。
EGFR有两种重要的配体,表皮生长因子(EGF)和转化生长因子α(TGFα)。该受体在成人中仅有非常弱的功能,但似乎与大部分癌症的疾病进程有关,特别是结肠癌和乳腺癌。密切相关的Erb-B2、Erb-B3和Erb-B4受体有一类Heregulins作为其主要的配体,受体的过度表达和突变已被明确证实是预后不好的乳腺癌的主要危险因素。此外,已证实该受体家族的所有四个成员均可与该家族的其它成员形成异源二聚体的信号传导复合物,如果该家族中有一个以上成员在恶性肿瘤中过度表达,便可导致协同的信号传导作用。一种以上家族成员的过度表达在人体恶性肿瘤中显示出相当普遍。
除癌症外,再狭窄也是由于不利的细胞增殖所引起的疾病。再狭窄涉及血管平滑肌细胞的增殖。再狭窄是与冠状动脉血管成形术及其它医疗方法有关的主要临床问题。再狭窄通常在约0至约6个月内,以约30%-50%的发病率发生在经气囊血管成形术清除闭塞的冠状动脉以治疗由于动脉闭塞所引起的心脏病的患者中。形成的再狭窄会引起患者在疾病和健康护理方面的大量花销。
再狭窄的进程是由血管、包括动脉和静脉的损伤所引发,随后释放出凝血酶原、血管活性和促有丝分裂因子。内皮和深部血管的损伤导致血小板凝集、血栓形成、炎症、以及巨噬细胞和平滑肌细胞的激活。这些事件引起生长因子和细胞因子的产生和释放,这些因子随后又促进其自身的合成和从靶细胞的释放。因此,引发了涉及生长因子如EGF、血小板衍生的生长因子(PDGF)或成纤维细胞生长因子(FGFs)的自持过程。因此,非常需要信号传导通路、特别是酪氨酸激酶如EGF、PDGF、FGF或src酪氨酸激酶的不可逆抑制剂。
对于增殖性皮肤病牛皮癣目前还没有好的治疗方法。通常用抗癌剂如甲氨蝶呤进行治疗,该药物有非常严重的副作用,并且在必须使用的毒性极限剂量下并不十分有效。据信TGFα是牛皮癣中过度产生的主要生长因子,这是因为过度表达TGFα的转基因小鼠中有50%产生了牛皮癣。这表明EGFR信号传导的良好抑制剂可用作抗牛皮癣剂,该药物优选、但并非必须通过局部给药。
与可逆性抑制剂相比,不可逆的酪氨酸激酶抑制剂具有非常突出的优点,因为不可逆抑制剂可长时间抑制酪氨酸激酶,这种作用仅受受体再合成(也称为恢复)的正常速率的限制。
关于src酪氨酸激酶在涉及癌症和再狭窄的生理学进程中的作用的其它信息可以参见如下文献,这些文献均引入本文作为参考。
Benjamin C.W.和Jones D.a,“血小板衍生的生长因子刺激结合蛋白质-2的生长因子受体与血管平滑肌细胞中Src的缔合”,JBC.1994;269:30911-30916。
Kovalenko M等,“选择性血小板衍生的生长因子受体激酶阻断剂逆转顺-反形成”,Cancer Res,1994;54:6106-6114。
Schwartz R.S.等,“The Restenosis Paradigm Revisted:另一种对细胞机理的建议”,J Am Coll Cardio,1992;20:1284-1293。
Libby P.等,“再狭窄的链模型-一种动脉硬化进程的特定情形”,Circulation,1992;86:47-52。
其它有关EGF酪氨酸激酶在生物过程中对癌症和再狭窄作用的信息可以参见如下文献,这些文献均引入本文作为参考。
Jonathan Blay和Morley D.Hollenberg,“经培养的主动脉平滑肌细胞EGF受体功能的异源调节”,Eur J Pharmacal,Mol PharmacolSect,1989;172(1):1-7。
抗体对EGF或EGFR显示体内抗肿瘤活性的信息可以参见如下文献,这些文献均引入本文作为参考。
Modjtahedi H.,Eccles S.,Box G.,Styles J.,Dean C,“用阻断生长因子-受体作用的大鼠抗体对过度表达EGF受体的人体肿瘤异种移植的免疫治疗”,Br J Cancer,1993;67:254-261。
Kurachi H.,Morishige K.I.,Amemiya K.,Adachi H.,Hirota K.,Miyake A.,Tanizawa O,“在体内卵巢癌细胞系中转化生长因子α/表皮生长因子受体自分泌生长机理的重要性”,Cancer Res,1991;51:5956-5959。
Masui H.,Moroyama T.,Mendelsohn J,“具有不同的同型标本的抗表皮生长因子受体单克隆抗体在小鼠内抗肿瘤活性的机理”,CancerRes,1986;46:5592-5598。
Rodeck U.,Herlyn M.,Herlyn.D.,Molthoff C.,Atkinson B.,Varello M.,Steplewski Z.,Koprowski H.,“通过表皮生长因子受体单克隆抗体对肿瘤生长的调制”,Cancer Res,1987;47:3692-3696。
Guan E.,Zhou T.,Wang J.,Huang P.,Tang W.,Zhao M.,ChenY.,Sun Y,“通过抗表皮生长因子受体单克隆抗体对在无胸腺小鼠中人体鼻咽癌的生长抑制”,Internat J Cell Clon,1989;7:242-256。
Masui H.,Kawamoto T.,Sato J.D.,Wolf B.,Sato G.,MendelsohnJ,“通过抗表皮生长因子受体单克隆抗体对无胸腺小鼠中人体肿瘤细胞的生长抑制”,Cancer Res,1984;44:1002-1007。
此外,下述文献也明示出蛋白酪氨酸激酶抑制剂的抗肿瘤活性。这些文献引入本文作参考。
Buchdunger E.,Trinks U.,Mett H.,Regenass U.,Muller M.,Meyer T.,McGlynn E.,Pinna L.A.Traxler P.,Lydon N.B.“4,5-二苯氨基邻苯二甲酰胺:一种具有对表皮生长因子受体信号传导通路的选择性的蛋白酪氨酸激酶抑制剂”及体内抗肿瘤活性作用,Proc Natl AcadSci USA,1994;91:2334-2338。
Buchdunger E.,Mett H.,Trinks U.,Regenass U.,Muller M.,Meyer T.,Beilstein P.,Wirz B.,Schneider P.,Traxler P.,Lydon N.“4.5-二(4-氟苯氨基)邻苯二甲酰胺:一种具有有效体内Mdd抗肿瘤活性的对表皮生长因子受体信号传导通路的选择性抑制剂”,ClinicalCancer Research,1995;1:813-821。
作为酪氨酸激酶可逆抑制剂的化合物下在述专利文献中有述:US5,457,105、5,475,001和5,409,930,以及PCT申请WO9519774和WO9519970。本发明公开的化合物与上述文献所述的酪氨酸激酶抑制剂具有不同的结构,本发明的化合物为酪氨酸激酶的不可逆抑制剂。
发明概述
本发明提供了具有下式I的化合物和其药学上可接受的盐、酯、酰胺和其前药,
其中,X为-D-E-F,Y为-SR4、卤素、-OR4、-NHR3或氢,或者X为-SR4、卤素、-OR4、-NHR3或氢,Y为-D-E-F;
D为
R1为氢、卤素、C1-C6烷基;
R2、R3和R4独立地为氢、C1-C6烷基、-(CH2)n-N-哌啶基、-
(CH2)n-N-哌嗪基、-(CH2)n-N1-哌嗪基[N4-(C1-C6)烷基]、-
(CH2)n-N-吡咯烷基、-(CH2)n-吡啶基、-(CH2)n-N-咪唑基、-
(CH2)n-咪唑基、-(CH2)n-N-吗啉代基、-(CH2)n-N-硫代吗啉代
基、-(CH2)n-N-六氢吖庚因或取代的C1-C6烷基,其中取代基
-(CH2)nOH、-(CH2)n-N-哌啶基、-(CH2)n-N-哌嗪基、-(CH2)n-N1-
哌嗪基[N4-(C1-C6)烷基]、-(CH2)n-N-吡咯烷基、-(CH2)n-吡啶
基、-(CH2)n-N-咪唑基或-(CH2)n-咪唑基;Z1、Z2或Z3独立地为氢、卤素、C1-C6烷基、C3-C8环烷基、
C1-C6烷氧基、C3-C8环烷氧基、硝基、C1-C6全氟烷基、羟
基、C1-C6酰氧基、-NH2、-NH(C1-C6烷基)、-N(C1-C6烷基)2、
-NH(C3-C8环烷基)、-N(C3-C8环烷基)2、羟甲基、C1-C6酰基、
氰基、叠氮基、C1-C6硫代烷基、C1-C6亚磺酰基烷基、C1-
C6磺酰基烷基、C3-C8硫代环烷基、C3-C8亚磺酰基环烷基、
C3-C8磺酰基环烷基、巯基、C1-C6烷氧羰基、C3-C8环烷氧
羰基、C2-C4链烯基、C4-C8环链烯基或C2-C4链炔基;和R5为氢、卤素、C1-C6全氟烷基、1,1-二氟(C1-C6)烷基、C1-C6
烷基、-(CH2)n-N-哌啶基、-(CH2)n-哌嗪基、-(CH2)n-哌嗪基
[N4-(C1-C6)烷基]、-(CH2)n-N-吡咯烷基、-(CH2)n-吡啶基、-
(CH2)n-N-咪唑基、-(CH2)n-N-吗啉代基、-(CH2)n-N-硫代吗啉
代基、-CH=CH2、-CH=CH-C1-C6烷基、-(CH2)n-N-六氢
吖庚因、-(CH2)n-NH2、-(CH2)n-NH(C1-C6烷基)、-(CH2)n-
N(C1-C6烷基)2、-1-氧代(C1-C6)烷基、羧基、(C1-C6)烷氧羰基、
N-(C1-C6)烷基氨甲酰基、苯基或取代的苯基,其中取代的苯基
可具有1-3个取代基,该取代基独立地选自Z1、Z2、Z3或单
环杂芳基团,并且R5中上述每一个(C1-C6)烷基可被-OH、
-NH2或-NAB取代,其中A和B如前定义,R6为氢或C1-C6烷
基;和n为1-4,p为0或1。
在式I化合物的优选实施方案中,Z1和Z2为氢,Z3为卤素。
在式I化合物的另一优选实施方案中,Z3为溴。
在式I化合物的另一优选实施方案中,溴位于苯环的3位或间位。
在式I化合物的另一优选实施方案中,Z1为氢,Z2为F,Z3为Cl。
在式I化合物的另一优选实施方案中,Z1为氢,Z2为F,Z3为Cl,其中Z2位于苯环的4位,Z3位于苯环的3位。
在式I化合物的另一优选实施方案中,
X为
且Y为氢,或
X为氢,且Y为
在式I化合物的另一优选实施方案中,Y为-D-E-F,-D-E-F为
在式I化合物的另一优选实施方案中,X为-D-E-F,-D-E-F为
在式I化合物的另一优选实施方案中,R2为氢。
在式I化合物的另一优选实施方案中,Y为-D-E-F,X为-O-(CH2)n-吗啉代基。
在式I化合物的另一优选实施方案中,R5为羧基、(C1-C6)烷氧羰基或C1-C6烷基。
在式I化合物的另一优选实施方案中,Y为-D-E-F,X为-O-(CH2)n-吗啉代基。
在式I化合物的另一优选实施方案中,Y为-D-E-F,X为-O-(CH2)n-N1-哌嗪基[N4-(C1-C6)烷基]。
在式I化合物的另一优选实施方案中,Y为-D-E-F,X为-O-(CH2)n-咪唑基。
在另一实施方案中,本发明提供了一种下式II的化合物和其药学上可接受的盐、酯、酰胺和其前药,
其中Q为
p为0或1;
X为-D-E-F,Y为-SR4、-OR4、-NHR3或氢,或者X为-SR4、-OR4、-NHR3或氢,Y为-D-E-F;
E为
F为
条件是当E为
不是
R1为氢、卤素、C1-C6烷基;R2、R3和R4独立地为氢、C1-C6烷基、-(CH2)n-N-哌啶基、-
(CH2)n-N-哌嗪基、-(CH2)n-N1-哌嗪基[N4-(C1-C6)烷基]、-
(CH2)n-N-吡咯烷基、-(CH2)n-吡啶基、-(CH2)n-N-咪唑基、-
(CH2)n-咪唑基、-(CH2)n-N-吗啉代基、-(CH2)n-N-硫代吗啉代
基、-(CH2)n-N-六氢吖庚因或取代的C1-C6烷基,其中取代基
-(CH2)nOH、-(CH2)n-N-哌啶基、-(CH2)n-N-哌嗪基、-(CH2)n-
N1-哌嗪基[N4-(C1-C6)烷基]、-(CH2)n-N-吡咯烷基、-(CH2)n-吡
啶基、-(CH2)n-N-咪唑基或-(CH2)n-咪唑基;E1、E2或E3独立地为卤素、C1-C6烷基、C3-C8环烷基、C1-C6
烷氧基、C3-C8环烷氧基、硝基、C1-C6全氟烷基、羟基、
C1-C6酰氧基、-NH2、-NH(C1-C6烷基)、-N(C1-C6烷基)2、-
NH(C3-C8环烷基)、-N(C3-C8环烷基)2、羟甲基、C1-C6酰基、
氰基、叠氮基、C1-C6硫代烷基、C1-C6亚磺酰基烷基、C1-
C6磺酰基烷基、C3-C8硫代环烷基、C3-C8亚磺酰基环烷基、
C3-C8磺酰基环烷基、巯基、C1-C6烷氧羰基、C3-C8环烷氧
羰基、C2-C4链烯基、C4-C8环链烯基或C2-C4链炔基;和R5为氢、卤素、C1-C6全氟烷基、1,1-二氟(C1-C6)烷基、C1-C6
烷基、-(CH2)n-N-哌啶基、-(CH2)n-哌嗪基、-(CH2)n-哌嗪基
[N4-(C1-C6)烷基]、-(CH2)n-N-吡咯烷基、-(CH2)n-吡啶基、-
(CH2)n-N-咪唑基、-(CH2)n-N-吗啉代基、-(CH2)n-N-硫代吗啉
代基、-CH=CH2、-CH=CH-C1-C6烷基、-(CH2)n-N-六氢
吖庚因、-(CH2)n-NH2、-(CH2)n-NH(C1-C6烷基)、-(CH2)n-
N(C1-C6烷基)2、-1-氧代(C1-C6)烷基、羧基、(C1-C6)烷氧羰基、
N-(C1-C6)烷基氨甲酰基、苯基或取代的苯基,其中取代的苯基
可具有1-3个取代基,该取代基独立地选自E1、E2、E3或单
环杂芳基团,并且每一个(C1-C6)烷基可被-OH、-NH2或-NAB
取代,其中A和B如前定义,R6为氢或C1-C6烷基;和n为1-4,p为0或1。
在式II化合物的优选实施方案中,E1和E2为氢,E3为卤素。
在式II化合物的另一优选实施方案中,卤素为溴。
在式II化合物的另一优选实施方案中,溴位于苯环的3位或间位。
在式II化合物的另一优选实施方案中,E1为氢,E2为氯,E3为氟。
在式II化合物的另一优选实施方案中,Q为
在式II化合物的另一优选实施方案中,Q为
在式II化合物的另一优选实施方案中,Q为
在式II化合物的另一优选实施方案中,Q为
在式II化合物的另一优选实施方案中,X为
在式II化合物的另一优选实施方案中,X为
在另一实施方案中,本发明提供了一种下式III的化合物和其药学上可接受的盐、酯、酰胺和其前药,
p为0或1;
X为-D-E-F,Y为-SR4、-OR4、-NHR3或氢,或者X为-SR4、-OR4、-NHR3或氢,Y为-D-E-F;
E为
F为
条件是当E为
不是
R1为氢、卤素、C1-C6烷基;
R2、R3和R4独立地为氢、C1-C6烷基、-(CH2)n-N-哌啶基、-
(CH2)n-N-哌嗪基、-(CH2)n-N1-哌嗪基[N4-(C1-C6)烷基]、-
(CH2)n-N-吡咯烷基、-(CH2)n-吡啶基、-(CH2)n-N-咪唑基、-
(CH2)n-咪唑基、-(CH2)n-N-吗啉代基、-(CH2)n-N-硫代吗啉代
基、-(CH2)n-N-六氢吖庚因或取代的C1-C6烷基,其中取代基
选自-OH、-NH2或
;A和B独立地为氢、C1-C6烷基、
-(CH2)nOH、-(CH2)n-N-哌啶基、-(CH2)n-N-哌嗪基、-(CH2)n-
N1-哌嗪基[N4-(C1-C6)烷基]、-(CH2)n-N-吡咯烷基、-(CH2)n-吡
啶基、-(CH2)n-N-咪唑基或-(CH2)n-咪唑基;E1、E2或E3独立地为卤素、C1-C6烷基、C3-C8环烷基、C1-C6
烷氧基、C3-C8环烷氧基、硝基、C1-C6全氟烷基、羟基、
C1-C6酰氧基、-NH2、-NH(C1-C6烷基)、-N(C1-C6烷基)2、-
NH(C3-C8环烷基)、-N(C3-C8环烷基)2、羟甲基、C1-C6酰基、
氰基、叠氮基、C1-C6硫代烷基、C1-C6亚磺酰基烷基、C1-
C6磺酰基烷基、C3-C8硫代环烷基、C3-C8亚磺酰基环烷基、
C3-C8磺酰基环烷基、巯基、C1-C6烷氧羰基、C3-C8环烷氧
羰基、C2-C4链烯基、C4-C8环链烯基或C2-C4链炔基;和R5为氢、卤素、C1-C6全氟烷基、1,1-二氟(C1-C6)烷基、C1-C6
烷基、-(CH2)n-N-哌啶基、-(CH2)n-哌嗪基、-(CH2)n-哌嗪基
[N4-(C1-C6)烷基]、-(CH2)n-N-吡咯烷基、-(CH2)n-吡嗪基、-
(CH2)n-N-咪唑基、-(CH2)n-N-吗啉代基、-(CH2)n-N-硫代吗啉
代基、-CH=CH2、-CH=CH-C1-C6烷基、-(CH2)n-N-六氢
吖庚因、-(CH2)n-NH2、-(CH2)n-NH(C1-C6烷基)、-(CH2)n-
N(C1-C6烷基)2、-1-氧代(C1-C6)烷基、羧基、(C1-C6)烷氧羰基、
N-(C1-C6)烷基氨甲酰基、苯基或取代的苯基,其中取代的苯基
可具有1-3个取代基,该取代基独立地选自E1、E2、E3或单
环杂芳基团,并且每一个(C1-C6)烷基可被-OH、-NH2或-NAB
取代,其中A和B如前定义,R6为氢或C1-C6烷基;和n为1-4。
在式III化合物的另一优选实施方案中,Q为
在式III化合物的另一优选实施方案中,Q为
在式III化合物的另一优选实施方案中,X为
在式III化合物的另一优选实施方案中,E1和E2为氢,E3为溴。
在式III化合物的另一优选实施方案中,E1为氢,E2为氯,E3为氟。
在式III化合物的另一优选实施方案中,X为
在另一优选实施方案中,Q为6-取代的苯并噻吩并[3,2-d]嘧啶-4-基。
本发明也提供了包含式I、II或III化合物的药学上可接受的组合物。
本发明也提供了一种治疗癌症的方法,该方法包括向癌症患者给予治疗有效量的式I、II或III化合物。
本发明也提供了一种治疗或预防再狭窄的方法,该方法包括向再狭窄患者或有可能患再狭窄的患者给予治疗有效量的式I、II或III化合物。
本发明也提供了一种治疗牛皮癣的方法,该方法包括向牛皮癣患者给予治疗有效量的式I、II或III化合物。
本发明也提供了一种治疗动脉粥样硬化的方法,该方法包括向动脉粥样硬化患者给予治疗有效量的式I、II或III化合物。
本发明也提供了一种治疗子宫内膜异位的方法,该方法包括向子宫内膜异位患者给予治疗有效量的式I、II或III化合物。
本发明也提供了一种不可逆抑制酪氨酸激酶的方法,该方法包括向需要酪氨酸激酶抑制的患者给予酪氨酸激酶抑制量的式I、II或III化合物。
本发明提供了下述的化合物:
N-[4-(3-溴-苯基氨基)-吡啶并[4,3-d]-嘧啶-7-基]-N-(3-吗啉-4-基-丙基)-丙烯酰胺;
N-[4-(3-溴-苯基氨基)-吡啶并[3,4-d]-嘧啶-6-基]-N-(3-吗啉-4-基-丙基)-丙烯酰胺;
N-[4-(3-溴-苯基氨基)-喹唑啉-7-基]-丙烯酰胺;
N-[4-(3-溴-苯基氨基)-喹唑啉-7-基]-N-[3-吗啉代基丙基]丙烯酰胺;
3-[4-(3-溴-苯基氨基)-喹唑啉-7-基-氨甲酰基]丙烯酸;
3-[4-(3-溴-苯基氨基)-喹唑啉-7-基-氨甲酰基]丙烯酸乙酯;
丁-2-烯酸[4-(3-溴-苯基氨基)-喹唑啉-7-基]酰胺;
N-[4-[(3-溴-苯基氨基)-6-(3-吗啉-4-基-丙基氨基)-喹唑啉-7-基]-丙烯酰胺;
N-[4-[(3-溴-苯基)氨基]-喹唑啉-6-基]-丙烯酰胺;
N-[4-(3-甲基-苯基氨基)-喹唑啉-7-基]-丙烯酰胺;
N-[4-(3-氯-苯基氨基)-喹唑啉-7-基]-丙烯酰胺;
N-[4-(3-溴-苯基氨基)-喹唑啉-7-基]甲基丙烯酰胺;
N-[4-(3-溴-苯基氨基)-喹唑啉-7-基]乙烯基磺酰胺;
N-[4-[(3-氯-苯基)氨基]-喹唑啉-6-基]-丙烯酰胺;
N-[4-(3-甲基-苯基氨基)-喹唑啉-6-基]-丙烯酰胺;
N-[4-[(3-(三氟甲基)苯基)氨基]-喹唑啉-6-基]-丙烯酰胺;
N-[4-[(3-溴苯基)氨基]-7-[3-(4-吗啉代基)-丙氧基]-喹唑啉-6-基]丙烯酰胺;
N-[4-[(3-甲基苯基)氨基]-7-[3-(4-吗啉代基)-丙氧基]-喹唑啉-6-基]丙烯酰胺;
N-[4-[(3-甲基苯基)氨基]-7-[3-(4,N-甲基-1,N-哌嗪基)-丙氧基]-喹唑啉-6-基]丙烯酰胺;
N-[4-[(3-溴苯基)氨基]-7-[3-(4,N-甲基-1,N-哌嗪基)-丙氧基]-喹唑啉-6-基]丙烯酰胺;
N-[4-[(3-溴苯基)氨基]-7-[3-(1,N-咪唑基)-丙氧基]-喹唑啉-6-基]丙烯酰胺;
N-[4-[(3-溴苯基)氨基]-7-[4-(N,N-二甲基-氨基)丁氧基]-喹唑啉-6-基]丙烯酰胺;
N-[4-[(3-溴苯基)氨基]-喹唑啉-6-基]-N-[3-吗啉代丙基]丙烯酰胺;
N-[4-[(3-溴-苯基)氨基]-喹唑啉-6-基]甲基丙烯酰胺;
N-[4-(3-溴-苯基氨基)-喹唑啉-7-基]乙烯基磺酰胺;
N-[4-[(3-溴-苯基)氨基]-喹唑啉-6-基]-E-丁-2-烯酰胺;
N-[4-[(3-溴-苯基)氨基]-喹唑啉-6-基]-4,4,4-三氟-E-丁-2-烯酰胺;
N-[4-[(3-溴-苯基)氨基]-喹唑啉-6-基]-丙炔酰胺;
N-[4-[(3-溴-苯基)氨基]-喹唑啉-6-基]-丁-2-炔酰胺;
N-[4-[(3-溴-苯基氨基)-吡啶并[4,3-d]嘧啶-7-基]-丙烯酰胺;
N-[4-[(3-溴-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-丙烯酰胺;
N-[4-[(3-甲基-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-丙烯酰胺;
N-[4-[(3-溴-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-N-甲基丙烯酰胺;
N-[4-[(3-溴-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]甲基丙烯酰胺;
N-[4-[(3-溴-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]乙烯基磺酰胺;
N-[4-[(3-溴-苯基氨基)-吡啶并[3,2-d]嘧啶-6-基]丙烯酰胺;
N-[4-[(3-溴-苯基氨基)-苯并[b]噻吩并[3,2-d]嘧啶-8-基]-丙烯酰胺;
N-[4-[(3-溴-苯基氨基)-苯并[b]噻吩并[3,2-d]嘧啶-6-基]-丙烯酰胺;
N-[4-[(3-溴-苯基氨基)-苯并[b]噻吩并[3,2-d]嘧啶-7-基]-丙烯酰胺;
N-[4-[(3-溴-苯基)氨基]喹唑啉-6-基]丁-2,3-二烯酰胺;
N-[4-[(3-溴-苯基)氨基]喹唑啉-6-基]-E,4-氧代戊-2-烯酰胺;
N-[4-[(3-溴-苯基)氨基]喹唑啉-6-基]-E,4-乙氧基-4-氧代丁-2-烯酰胺;
N-[4-[(3-溴-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]戊-2,4-二烯酰胺;
N-[4-[(3-溴-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-N-(2-N,N-二甲基氨基)乙基)丙烯酰胺;
N-[4-[(3-溴-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]E-丁-2-烯酰胺;
N-[4-[(3-溴-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]肉桂酰胺;
N-[4-[(3-溴-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-E,3-氯-丙烯酰胺;
N-[4-[(3-溴-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]丙炔酰胺;
N-[4-[(3-溴苯基)氨基]-喹唑啉-6-基]-E,4-(3-(N,N-二甲基氨基)丙氧基-4-氧代丁-2-烯酰胺三三氟乙酸酯;
3-[4-(3-溴-苯基氨基)-喹唑啉-6-基-氨甲酰基]丙烯酸(Z);
N-[4-[(3-溴苯基)氨基]-喹唑啉-6-基]-E,4-(3-(N,N-二甲基氨基)丙基氨基-4-氧代丁-2-烯酰胺;
4-[(3-溴-苯基)氨基]-6-(亚乙基磺酰基)吡啶并[3,4-d]嘧啶;
1-[4-(3-溴苯基氨基)-喹唑啉-6-基]吡咯-2,5-二酮;
1-[4-(3-溴苯基氨基)-喹唑啉-6-基]丙-2-烯-1-酮;
丙烯酸4-(3-溴苯基氨基)-喹唑啉-6-基酯;
N-[4-[(3-溴苯基)氨基]-P-乙烯基-吡啶并[3,4-d]嘧啶-6-基]-膦酰胺甲酯;
丙烯酸4-(3-溴苯基氨基)-喹唑啉-7-基酯;
1-[4-(3-溴苯基氨基)-喹唑啉-6-基]丁-3-烯-2-酮;
丙烯酸4-(3-氯-4-氟-苯基氨基)-7-甲氧基-喹唑啉-6-基酯;
N-[4-(3-溴苯基氨基)-7-(3-吗啉-4-基-丙氧基)-吡啶并[3,2-d]嘧啶-6-基]-丙烯酰胺;
戊-2,3-二烯酸[4-(3-溴苯基氨基)-喹唑啉-6-基]酰胺;
丙-1,2-二烯-1-磺酸[4-(3-溴苯基氨基)-喹唑啉-6-基]酰胺;
N-[4-[(3-溴苯基)氨基]-6-喹唑啉基]-P-(1,2-丙二烯基)膦酰胺甲酯;
N-[1-(3-溴苯基氨基)-9H-2,4,9-三氮杂芴-7-基]-丙烯酰胺;
N-[4-(3-溴苯基氨基)-9H-1,3,9-三氮杂芴-6-基]-丙烯酰胺;
N-[4-(3-氯-4-氟苯基氨基)-喹唑啉-6-基]-丙烯酰胺;
N-(4-苯基甲基氨基-喹唑啉-6-基)-丙烯酰胺;
(S)-N-[4-(1-苯基乙基氨基)-喹唑啉-6-基]-丙烯酰胺;
(R)-N-[4-(1-苯基乙基氨基)-喹唑啉-6-基]-丙烯酰胺;
丁-2-烯二酸[4-(3-氯-4-氟苯基氨基)-喹唑啉-6-基]-酰胺(3-二甲基氨基-丙基)-酰胺;
N-[4-(3-氯-4-氟-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-丙烯酰胺;
N-[4-(3-氯-4-氟-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-N-甲基-丙烯酰胺;
丁-2-烯二酸[4-(3-氯-4-氟苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺(3-二甲基氨基-丙基)-酰胺;
丁-2-烯二酸[4-(3-氯-4-氟苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺(3-咪唑-1-基-丙基)-酰胺;
4,4-二氟-8-吗啉-4-基-辛-2-烯酸[4-(3-氯-4-氟苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺;
8-二甲基氨基-4,4-二氟-辛-2-烯酸[4-(3-氯-4-氟苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺;
7-二甲基氨基-4,4-二氟-庚-2-烯酸[4-(3-氯-4-氟苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺;
4,4-二氟-7-吗啉-4-基-庚-2-烯酸[4-(3-氯-4-氟苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺;
6-二甲基氨基-己-2-炔酸[4-(3-氯-4-氟苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺;
6-吗啉-4-基-己-2-炔酸[4-(3-氯-4-氟苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺;
7-二甲基氨基-庚-2-炔酸[4-(3-氯-4-氟苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺;
7-吗啉-4-基-庚-2-炔酸[4-(3-氯-4-氟苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺;
5-二甲基氨基-戊-2-炔酸[4-(3-氯-4-氟苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺;
5-吗啉-4-基-戊-2-炔酸[4-(3-氯-4-氟苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺;
5-咪唑-1-基-戊-2-炔酸[4-(3-氯-4-氟苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺;
5-(4-甲基哌嗪-1-基-戊-2-炔酸[4-(3-氯-4-氟苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺;
4-[4-(3-氯-4-氟苯基氨基)-吡啶并[3,4-d]嘧啶-6-基氨甲酰基]-丁-3-烯酸2-(4-甲基哌嗪-1-基)-乙酯;
4-[4-(3-氯-4-氟苯基氨基)-吡啶并[3,4-d]嘧啶-6-基氨甲酰基]-丁-3-烯酸2-(2-咪唑-1-基)-乙酯;
戊-2-烯二酸1-{[4-(3-氯-4-氟苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺}5-[(3-吗啉-4-基-丙基)-酰胺];
戊-2-烯二酸1-{[4-(3-氯-4-氟苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺}5-[(3-二乙基氨基-丙基)-酰胺];
4-[4-(3-氯-4-氟苯基氨基)-吡啶并[3,4-d]嘧啶-6-基氨甲酰基]-丁-3-烯酸2-吗啉-4-基-乙酯;
戊-2-烯二酸1-{[4-(3-氯-4-氟苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺}5-{[3-(4-甲基-哌嗪-1-基)-丙基]酰胺};
(3-氯-4-氟苯基)-{6-[2-(3-二甲基氨基丙氧基)乙磺酰基]-吡啶并[3,4-d]嘧啶-4-基}-胺;
(3-氯-4-氟苯基)-(6-{2-[4-(4-甲基哌嗪-1-基)丁基氨基]-乙磺酰基}-吡啶并[3,4-d]嘧啶-4-基}-胺;
(3-氯-4-氟苯基)-[6-(5-吗啉-4-基-戊-1-烯-1-磺酰基]-吡啶并[3,4-d]嘧啶-4-基]-胺;
(3-氯-4-氟苯基)-(6-乙烯基亚磺酰基-吡啶并[3,4-d]嘧啶-4-基]-胺;
3-[4-(1-苯基乙基氨基)喹唑啉-6-基氨甲酰基]丙烯酸2-吗啉-4-基-乙酯;
丁-2-烯二酸(4-咪唑-1-基-丁基)-酰胺[4-(1-苯基-乙基氨基)喹唑啉-6-基]-酰胺;
4-[4-(1-苯基乙基氨基)-喹唑啉-6-基氨甲酰基]-丁-3-烯酸3-二乙基氨基丙酯;
戊-2-烯二酸5-{[2-(4-甲基哌嗪-1-基)乙基]-酰胺}1-{[4-(1-苯基-乙基氨基)-喹唑啉-6-基]-酰胺};
4,4-二氟-7-吗啉-4-基-庚-2-烯酸[4-(1-苯基-乙基氨基)-喹唑啉-6-基]-酰胺;
7-二甲基氨基-4,4-二氟-庚-2-烯酸[4-(1-苯基-乙基氨基)-喹唑啉-6-基]-酰胺;
7-咪唑-1-基-庚-2-炔酸[4-(1-苯基-乙基氨基)-喹唑啉-6-基]-酰胺;
6-二甲基氨基-己-2-炔酸[4-(1-苯基-乙基氨基)-喹唑啉-6-基]-酰胺;
丁-2-烯二酸[4-(3-溴-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺(3-二甲基氨基-丙基)-酰胺;
丁-2-烯二酸[4-(3-溴-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺(3-咪唑-1-基-丙基)-酰胺;
4,4-二氟-8-吗啉-4-基-辛-2-烯酸[4-(3-溴-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺;
8-二甲基氨基-4,4-二氟-辛-2-烯酸[4-(3-溴-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺;
7-二甲基氨基-4,4-二氟-庚-2-烯酸[4-(3-溴-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺;
4,4-二氟-7-吗啉-4-基-庚-2-烯酸[4-(3-溴-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺;
6-二甲基氨基-己-2-炔酸[4-(3-溴-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺;
6-吗啉-4-基-己-2-炔酸[4-(3-溴-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺;
7-二甲基氨基-庚-2-炔酸[4-(3-溴-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺;
7-吗啉-4-基-庚-2-炔酸[4-(3-溴-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺;
5-二甲基氨基-戊-2-炔酸[4-(3-溴-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺;
5-吗啉-4-基-戊-2-炔酸[4-(3-溴-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺;
5-咪唑-1-基-戊-2-炔酸[4-(3-溴-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺;
5-(4-甲基-哌嗪-1-基)-戊-2-炔酸[4-(3-溴-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺;
4-[4-(3-溴-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基氨甲酰基]-丁-3-烯酸2-(4-甲基-哌嗪-1-基)-乙酯;
4-[4-(3-溴-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基氨甲酰基]-丁-3-烯酸2-咪唑-1-基-乙酯;
戊-2-烯二酸1-{[4-(3-溴苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺}5-[(3-吗啉基-4-基-丙基)-酰胺];
戊-2-烯二酸1-{[4-(3-溴苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺}5-[(3-二乙基氨基-丙基)-酰胺];
4-[4-(3-溴-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基氨甲酰基]-丁-3-烯酸2-吗啉-4-基-乙酯;
戊-2-烯二酸1-{[4-(3-溴苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺}5-{[3-(4-甲基-哌嗪-1-基)-丙基]-酰胺};
(3-溴-苯基)-{6-[2-(3-二甲基氨基-丙氧基)-乙磺酰基]-吡啶并[3,4-d]嘧啶-4-基}-胺;
(3-溴-苯基)-(6-{2-[4-(4-甲基哌嗪-1-基)-丁基氨基]-乙磺酰基}-吡啶并[3,4-d]嘧啶-4-基}-胺;
(3-溴-苯基)-[6-(5-吗啉-4-基-戊-1-烯-1-磺酰基)-吡啶并[3,4-d]嘧啶-4-基]-胺;
(3-溴-苯基)-(6-亚乙基-亚磺酰基)-吡啶并[3,4-d]嘧啶-4-基]-胺;
丁-2-烯二酸[4-(3-氯-4-氟苯基氨基)-喹唑啉-6-基]-酰胺(3-二甲基氨基-丙基)-酰胺;
丁-2-烯二酸[4-(3-氯-4-氟苯基氨基)-喹唑啉-6-基]-酰胺(3-咪唑-1-基-丙基)-酰胺;
4,4-二氟-8-吗啉-4-基-辛-2-烯酸[4-(3-氯-4-氟-苯基氨基)-喹唑啉-6-基]-酰胺;
8-二甲基氨基-4,4-二-氟-辛-2-烯酸[4-(3-氯-4-氟-苯基氨基)-喹唑啉-6-基]-酰胺;
7-二甲基氨基-4,4-二氟-庚-2-烯酸[4-(3-氯-4-氟-苯基氨基)-喹唑啉-6-基]-酰胺;
4,4-二氟-7-吗啉-4-基-庚-2-烯酸[4-(3-氯-4-氟-苯基氨基)-喹唑啉-6-基]-酰胺;
6-二甲基氨基-己-2-炔酸[4-(3-氯-4-氟-苯基氨基)-喹唑啉-6-基]-酰胺;
6-吗啉-4-基-己-2-炔酸[4-(3-氯-4-氟-苯基氨基)-喹唑啉-6-基]-酰胺;
7-二甲基氨基-庚-2-炔酸[4-(3-氯-4-氟-苯基氨基)-喹唑啉-6-基]-酰胺;
7-吗啉-4-基-庚-2-炔酸[4-(3-氯-4-氟-苯基氨基)-喹唑啉-6-基]-酰胺;
5-二甲基氨基-戊-2-炔酸[4-(3-氯-4-氟-苯基氨基)-喹唑啉-6-基]-酰胺;
5-吗啉-4-基-戊-2-炔酸[4-(3-氯-4-氟-苯基氨基)-喹唑啉-6-基]-酰胺;
5-咪唑-1-基-戊-2-炔酸[4-(3-氯-4-氟-苯基氨基)-喹唑啉-6-基]-酰胺;
5-(4-甲基-哌嗪-1-基)-戊-2-炔酸[4-(3-氯-4-氟-苯基氨基)-喹唑啉-6-基]-酰胺;
戊-2-烯二酸1-{[4-(3-氯-4-氟-苯基氨基)-喹唑啉-6-基]-酰胺}5-[(3-吗啉基-4-基-丙基)-酰胺];
戊-2-烯二酸1-{[4-(3-氯-4-氟-苯基氨基)-喹唑啉-6-基]-酰胺}5-[(3-二乙基氨基-丙基)-酰胺];
4-[4-(3-氯-4-氟-苯基氨基)-喹唑啉-6-基氨甲酰基]-丁-3-烯酸2-吗啉-4-基-乙酯;
戊-2-烯二酸1-{[4-(3-氯-4-氟-苯基氨基)-喹唑啉-6-基]-酰胺}5-{[3-(4-甲基-哌嗪-1-基)-丙基]-酰胺};
(3-氯-4-氟-苯基)-{6-[2-(3-二甲基氨基-丙氧基)-乙磺酰基]-喹唑啉-4-基}-胺;
(3-氯-4-氟-苯基)-(6-{2-[4-(4-甲基哌嗪-1-基)-丁基氨基]-乙磺酰基}-喹唑啉-4-基}-胺;
丁-2-烯二酸[4-(3-溴-苯基氨基)-喹唑啉-6-基]-酰胺(3-二甲基氨基-丙基)-酰胺;
丁-2-烯二酸[4-(3-溴-苯基氨基)-喹唑啉-6-基]-酰胺(3-咪唑-1-基-丙基)-酰胺;
4,4-二氟-8-吗啉-4-基-辛-2-烯酸[4-(3-溴-苯基氨基)-喹唑啉-6-基]-酰胺;
8-二甲基氨基-4,4-二氟-辛-2-烯酸[4-(3-溴-苯基氨基)-喹唑啉-6-基]-酰胺;
7-二甲基氨基-4,4-二氟-庚-2-烯酸[4-(3-溴-苯基氨基)-喹唑啉-6-基]-酰胺;
4,4-二氟-7-吗啉-4-基-庚-2-烯酸[4-(3-溴-苯基氨基)-喹唑啉-6-基]-酰胺;
6-二甲基氨基-己-2-炔酸[4-(3-溴-苯基氨基)-喹唑啉-6-基]-酰胺;
6-吗啉-4-基-己-2-炔酸[4-(3-溴-苯基氨基)-喹唑啉-6-基]-酰胺;
7-二甲基氨基-庚-2-炔酸[4-(3-溴-苯基氨基)-喹唑啉-6-基]-酰胺;
7-吗啉-4-基-庚-2-炔酸[4-(3-溴-苯基氨基)-喹唑啉-6-基]-酰胺;
5-二甲基氨基-戊-2-炔酸[4-(3-溴-苯基氨基)-喹唑啉-6-基]-酰胺;
5-吗啉-4-基-戊-2-炔酸[4-(3-溴-苯基氨基)-喹唑啉-6-基]-酰胺;
5-咪唑-1-基-戊-2-炔酸[4-(3-溴-苯基氨基)-喹唑啉-6-基]-酰胺;
5-(4-甲基-哌嗪-1-基)-戊-2-炔酸[4-(3-溴-苯基氨基)-喹唑啉-6-基]-酰胺;
4-[4-(3-溴-苯基氨基)-喹唑啉-6-基氨甲酰基]-丁-3-烯酸2-(4-甲基-哌嗪-1-基)-乙酯;
4-[4-(3-溴-苯基氨基)-喹唑啉-6-基氨甲酰基]-丁-3-烯酸2-咪唑-1-基-乙酯;
戊-2-烯二酸1-{[4-(3-溴苯基氨基)-喹唑啉-6-基]-酰胺}5-[(3-吗啉基-4-基-丙基)-酰胺];
戊-2-烯二酸1-{[4-(3-溴苯基氨基)-喹唑啉-6-基]-酰胺}5-[(3-二乙基氨基-丙基)-酰胺];
4-[4-(3-溴-苯基氨基)-喹唑啉-6-基氨甲酰基]-丁-3-烯酸2-吗啉-4-基-乙酯;
戊-2-烯二酸1-{[4-(3-溴苯基氨基)-喹唑啉-6-基]-酰胺}5-{[3-(4-甲基-哌嗪-1-基)-丙基]-酰胺};
3-[4-(1-苯基乙基氨基)-吡啶并[3,4-d]嘧啶-6-基氨甲酰基]丙烯酸2-吗啉-4-基-乙酯;
丁-2-烯二酸(4-咪唑-1-基-丁基)-酰胺[4-(1-苯基-乙基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺;
4-[4-(1-苯基乙基氨基)-吡啶并[3,4-d]嘧啶-6-基氨甲酰基]-丁-3-烯酸3-二乙基氨基丙酯;
戊-2-烯二酸5-{[2-(4-甲基哌嗪-1-基)乙基]-酰胺}1-{[4-(1-苯基-乙基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺};
4,4-二氟-7-吗啉-4-基-庚-2-烯酸[4-(1-苯基-乙基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺;
7-二甲基氨基-4,4-二氟-庚-2-烯酸[4-(1-苯基-乙基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺;
7-咪唑-1-基-庚-2-炔酸[4-(1-苯基-乙基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺;
6-二甲基氨基-己-2-炔酸[4-(1-苯基-乙基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺;
丁-2-烯二酸(4-(3-氯-4-氟苯基氨基)-7-氟喹唑啉-6-基]-酰胺(3-二甲基氨基丙基)酰胺;
丁-2-烯二酸(7-氯-4-(3-氯-4-氟苯基氨基)喹唑啉-6-基]-酰胺(3-二甲基氨基丙基)酰胺;
N-[4-[3-(溴苯基)氨基]-5-氟-7-[3-(4-吗啉代)丙氧基]喹唑啉-6-基]-丙烯酰胺;和
N-[4-[(3-(氯-4-氟苯基)氨基]-5-氟-7-[1,N-咪唑基)丙氧基]喹唑啉-6-基]-丙烯酰胺。
发明详述
本发明提供了一种下式I的化合物和其药学上可接受的盐、酯、酰胺和其前药,
其中,X为-D-E-F,Y为-SR4、卤素、-OR4、-NHR3或氢,或者X为-SR4、卤素、-OR4、-NHR3或氢,Y为-D-E-F;
D为
条件是当E为
不是
R1为氢、卤素、C1-C6烷基;
R2、R3和R4独立地为氢、C1-C6烷基、-(CH2)n-N-哌啶基、-
(CH2)n-N-哌嗪基、-(CH2)n-N1-哌嗪基[N4-(C1-C6)烷基]、-
(CH2)n-N-吡咯烷基、-(CH2)n-吡啶基、-(CH2)n-N-咪唑基、-
(CH2)n-咪唑基、-(CH2)n-N-吗啉代基、-(CH2)n-N-硫代吗啉代
基、-(CH2)n-N-六氢吖庚因或取代的C1-C6烷基,其中取代基
-(CH2)nOH、-(CH2)n-N-哌啶基、-(CH2)n-N-哌嗪基、-(CH2)n-
N1-哌嗪基[N4-(C1-C6)烷基]、-(CH2)n-N-吡咯烷基、-(CH2)n-吡
啶基、-(CH2)n-N-咪唑基或-(CH2)n-咪唑基;Z1、Z2或Z3独立地为氢、卤素、C1-C6烷基、C3-C8环烷基、
C1-C6烷氧基、C3-C8环烷氧基、硝基、C1-C6全氟烷基、羟
基、C1-C6酰氧基、-NH2、-NH(C1-C6烷基)、-N(C1-C6烷基)2、
-NH(C3-C8环烷基)、-N(C3-C8环烷基)2、羟甲基、C1-C6酰基、
氰基、叠氮基、C1-C6硫代烷基、C1-C6亚磺酰基烷基、C1-
C6磺酰基烷基、C3-C8硫代环烷基、C3-C8亚磺酰基环烷基、
C3-C8磺酰基环烷基、巯基、C1-C6烷氧羰基、C3-C8环烷氧
羰基、C2-C4链烯基、C4-C8环链烯基或C2-C4链炔基;和R5为氢、卤素、C1-C6全氟烷基、1,1-二氟(C1-C6)烷基、C1-C6
烷基、-(CH2)n-N-哌啶基、-(CH2)n-哌嗪基、-(CH2)n-N1-哌嗪
基[N4-(C1-C6)烷基]、-(CH2)n-N-吡咯烷基、-(CH2)n-吡啶基、
-(CH2)n-N-咪唑基、-(CH2)n-N-吗啉代基、-(CH2)n-N-硫代吗啉
代基、-CH=CH2、-CH=CH-C1-C6烷基、-(CH2)n-N-六氢
吖庚因、-(CH2)n-NH2、-(CH2)n-NH(C1-C6烷基)、-(CH2)n-
N(C1-C6烷基)2、-1-氧代(C1-C6)烷基、羧基、(C1-C6)烷氧羰基、
N-(C1-C6)烷基氨甲酰基、苯基或取代的苯基,其中取代的苯基
可具有1-3个取代基,该取代基独立地选自Z1、Z2、Z3或单
环杂芳基团,并且每一个(C1-C6)烷基可被-OH、-NH2或-NAB
取代,其中A和B如前定义,R6为氢或C1-C6烷基;R13为氢或
卤素;和
n为1-4,p为0或1。
在另一实施方案中,本发明提供了一种下式II的化合物和其药学上可接受的盐、酯、酰胺和其前药,
其中Q为
p为0或1;
X为-D-E-F,Y为-SR4、-OR4、-NHR3或氢,或者X为-SR4、-OR4、-NHR3或氢,Y为-D-E-F;
E为
F为
R1为氢、卤素、C1-C6烷基;R2、R3和R4独立地为氢、C1-C6烷基、-(CH2)n-N-哌啶基、-
(CH2)n-N-哌嗪基、-(CH2)n-N1-哌嗪基[N4-(C1-C6)烷基]、-
(CH2)n-N-吡咯烷基、-(CH2)n-吡啶基、-(CH2)n-N-咪唑基、-
(CH2)n-咪唑基、-(CH2)n-N-吗啉代基、-(CH2)n-N-硫代吗啉代
基、-(CH2)n-N-六氢吖庚因或取代的C1-C6烷基,其中取代基
选自-OH、-NH2或
A和B独立地为氢、C1-C6烷基、
-(CH2)nOH、-(CH2)n-N-哌啶基、-(CH2)n-N-哌嗪基、-(CH2)n-
N1-哌嗪基[N4-(C1-C6)烷基]、-(CH2)n-N-吡咯烷基、-(CH2)n-吡
啶基、-(CH2)n-N-咪唑基或-(CH2)n-咪唑基;E1、E2或E3独立地为卤素、C1-C6烷基、C3-C8环烷基、C1-C6
烷氧基、C3-C8环烷氧基、硝基、C1-C6全氟烷基、羟基、
C1-C6酰氧基、-NH2、-NH(C1-C6烷基)、-N(C1-C6烷基)2、-
NH(C3-C8环烷基)、-N(C3-C8环烷基)2、羟甲基、C1-C6酰基、
氰基、叠氮基、C1-C6硫代烷基、C1-C6亚磺酰基烷基、C1-
C6磺酰基烷基、C3-C8硫代环烷基、C3-C8亚磺酰基环烷基、
C3-C8磺酰基环烷基、巯基、C1-C6烷氧羰基、C3-C8环烷氧
羰基、C2-C4链烯基、C4-C8环链烯基或C2-C4链炔基;和
R5为氢、卤素、C1-C6全氟烷基、1,1-二氟(C1-C6)烷基、C1-C6
烷基、-(CH2)n-N-哌啶基、-(CH2)n-哌嗪基、-(CH2)n-哌嗪基
[N4-(C1-C6)烷基]、-(CH2)n-N-吡咯烷基、-(CH2)n-吡啶基、-
(CH2)n-N-咪唑基、-(CH2)n-N-吗啉代基、-(CH2)n-N-硫代吗啉
代基、-CH=CH2、-CH=CH-C1-C6烷基、-(CH2)n-N-六氢
吖庚因、-(CH2)n-NH2、-(CH2)n-NH(C1-C6烷基)、-(CH2)n-
N(C1-C6烷基)2、-1-氧代(C1-C6)烷基、羧基、(C1-C6)烷氧羰基、
N-(C1-C6)烷基氨甲酰基、苯基或取代的苯基,其中取代的苯基
可具有1-3个取代基,该取代基独立地选自E1、E2、E3或单
环杂芳基团,并且每一个(C1-C6)烷基可被-OH、-NH2或-NAB
取代,其中A和B如前定义,R6为氢或C1-C6烷基;和
n为1-4,p为0或1。
在另一实施方案中,本发明也提供了一种下式III的化合物和其药学上可接受的盐、酯、酰胺和其前药,
其中Q为
p为0或1;
X为-D-E-F,Y为-SR4、-OR4、-NHR3或氢,或者X为-SR4、-OR4、-NHR3或氢,Y为-D-E-F;
R1为氢、卤素、C1-C6烷基;R2、R3和R4独立地为氢、C1-C6烷基、-(CH2)n-N-哌啶基、-
(CH2)n-N-哌嗪基、-(CH2)n-N1-哌嗪基[N4-(C1-C6)烷基]、-
(CH2)n-N-吡咯烷基、-(CH2)n-吡啶基、-(CH2)n-N-咪唑基、-
(CH2)n-咪唑基、-(CH2)n-N-吗啉代基、-(CH2)n-N-硫代吗啉代
基、-(CH2)n-N-六氢吖庚因或取代的C1-C6烷基,其中取代基
-(CH2)nOH、-(CH2)n-N-哌啶基、-(CH2)n-N-哌嗪基、-(CH2)n-
N1-哌嗪基[N4-(C1-C6)烷基]、-(CH2)n-N-吡咯烷基、-(CH2)n-吡
啶基、-(CH2)n-N-咪唑基或-(CH2)n-咪唑基;
E1、E2或E3独立地为卤素、C1-C6烷基、C3-C8环烷基、C1-C6
烷氧基、C3-C8环烷氧基、硝基、C1-C6全氟烷基、羟基、
C1-C6酰氧基、-NH2、-NH(C1-C6烷基)、-N(C1-C6烷基)2、-
NH(C3-C8环烷基)、-N(C3-C8环烷基)2、羟甲基、C1-C6酰基、
氰基、叠氮基、C1-C6硫代烷基、C1-C6亚磺酰基烷基、C1-
C6磺酰基烷基、C3-C8硫代环烷基、C3-C8亚磺酰基环烷基、
C3-C8磺酰基环烷基、巯基、C1-C6烷氧羰基、C3-C8环烷氧
羰基、C2-C4链烯基、C4-C8环链烯基或C2-C4链炔基;和
R5为氢、卤素、C1-C6全氟烷基、1,1-二氟(C1-C6)烷基、C1-C6
烷基、-(CH2)n-N-哌啶基、-(CH2)n-哌嗪基、-(CH2)n-哌嗪基
[N4-(C1-C6)烷基]、-(CH2)n-N-吡咯烷基、-(CH2)n-吡啶基、-
(CH2)n-N-咪唑基、-(CH2)n-N-吗啉代基、-(CH2)n-N-硫代吗啉
代基、-CH=CH2、-CH=CH-C1-C6烷基、-(CH2)n-N-六氢
吖庚因、-(CH2)n-NH2、-(CH2)n-NH(C1-C6烷基)、-(CH2)n-
N(C1-C6烷基)2、-1-氧代(C1-C6)烷基、羧基、(C1-C6)烷氧羰基、
N-(C1-C6)烷基氨甲酰基、苯基或取代的苯基,其中取代的苯基
可具有1-3个取代基,该取代基独立地选自E1、E2、E3或单
环杂芳基团,并且每一个(C1-C6)烷基可被-OH、-NH2或-NAB
取代,其中A和B如前定义,R6为氢或C1-C6烷基;和
n为1-4。
术语“烷基”是指直链或支链的烃基。烷基的代表性实例为甲基、乙基、丙基、异丙基、异丁基、丁基、叔丁基、仲丁基、戊基和己基。
术语“烷氧基”是指连接氧原子的烷基。烷氧基的代表性实例为甲氧基、乙氧基、叔丁氧基、丙氧基和异丁氧基。
术语“卤素”包括氯、氟、溴和碘。
术语“链烯基”是指具有一个或多个碳-碳双键的直链或支链的烃基。
术语“环烷基”是指环状烃基。环烷基的实例包括环丙基、环丁基、环戊基和环己基。
术语“环烷氧基”是指连接氧原子的环烷基。
术语“全氟烷基”是指所有的氢原子均被氟原子取代的烷基。
术语“酰基”是指由有机酸除去羟基(-OH)后得到的基团。
术语“酰氧基”是指连接氧原子的酰基。
术语“硫代烷基”是指连接硫原子的烷基。
术语“亚磺酰基烷基”是指连接烷基的亚磺酰基。
术语“磺酰基烷基”是指连接烷基的磺酰基。
术语“硫代环烷基”是指连接硫原子的环烷基。
术语“亚磺酰基环烷基”是指连接环烷基的亚磺酰基。
术语“磺酰基环烷基”是指连接环烷基的磺酰基。
术语“巯基”是指-SH基团。
术语“烷氧羰基”是指连接羰基的烷氧基。
术语“环烷氧羰基”是指连接羰基的环烷氧基。
术语“环链烯基”具有一个或多个碳-碳双键的环烃基。
术语“链炔基”是指具有一个或多个碳-碳叁键的烃基。
术语“单环杂芳基”是指仅具有一个环结构的杂环芳基化合物。环状化合物为芳族,并包含一个或多个杂原子。杂原子的实例包括但不限于:氮、氧、硫和磷。单环杂芳基的实例包括但不限于:吡啶、噻吩和咪唑。
符号“-”表示共价键。
式I、II和III的化合物为酪氨酸激酶的不可逆抑制剂,特别是EGF酪氨酸激酶的不可逆抑制剂。治疗有效量的式I、II或III化合物可给药于癌症患者、再狭窄患者或有可能患再狭窄的患者、牛皮癣患者、动脉粥样硬化患者或子宫内膜异位患者。本领域的技术人员易于识别癌症患者、再狭窄患者、牛皮癣患者、动脉粥样硬化患者或子宫内膜异位患者,或有可能患再狭窄的患者。术语“患者”是指动物如狗、猫、牛、羊,也包括人。
本发明的化合物可给药于人和动物,可以口服、直肠、肠胃外(静脉内、肌肉内或皮下)、脑池内、阴道内、腹膜内、膀胱内、局部给药(粉剂、软膏剂或滴剂),或者以口或鼻喷剂给药。所述化合物可以单独给药,或者作为包含可成药赋形剂的药学上可接受的组合物的一部分。需要指出,超过一种的式I、II、III的化合物可以同时给药或顺序给药。
适用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇(丙二醇、聚乙二醇、甘油等,及其适宜的混合物,植物油(如橄榄油)及可注射的有机酯如油酸乙酯。使用包衣材料如卵磷脂,通过保持在分散液中所要求的颗粒尺寸以及使用表面活性剂可保持适当的流动性。
这些组合物也可包含各种助剂,如防腐剂、润湿剂、乳化剂、分散剂。通过各种杀菌剂和杀真菌剂可确保防止微生物活动,这些杀菌剂和杀真菌剂的实例是,对羟基苯甲酸酯、氯丁醇、苯酚、山梨酸等。同样,组合物也可包括等渗剂,如糖、氯化钠等。可以采用延缓吸收剂如单硬脂酸铝和明胶以使可注射药物形式延长吸收。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中,活性化合物与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:(a)填料或增容剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如,羧甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶;(c)保湿剂,例如,甘油;(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠;(e)缓溶剂,例如石蜡;(f)吸收加速剂,例如,季铵化合物;(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如,高岭土和膨润土;和(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
类似类型的固体组合物也可使用诸如乳糖的赋形剂,以及高分子量聚乙二醇等用作在软填充胶囊和硬填充胶囊中的填料。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆和酏剂。除了活性化合物外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例如,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苄醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油,甘油、四羟基呋喃醇、聚乙二醇和脱水山梨醇脂肪酸酯,或这些物质的混合物等。
除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝、膨润土、琼脂和黄蓍胶,或这些物质的混合物等。
用于直肠给药的组合物优选为栓剂,其可通过使本发明的化合物与适宜的无刺激性赋形剂或载体混合而制得,所述赋形剂或载体如可可脂、聚乙二醇或栓剂蜡,其在常温下为固体,而在体温下为液体,因而可在直肠或阴道内熔化并释放出活性成分。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂,或必要时可能需要的推进剂一起混合。眼制剂、眼药膏、散剂和溶液剂也在本发明的保护范围之内。
本文中,术语“药学上可接受的盐、酯、酰胺和前药”是指本发明化合物的羧酸盐、氨基酸加成盐、酯、酰胺和前药,这些物质从药物方面考虑,应适于与患者的组织接触,不会产生毒性、刺激性、过敏反应等,并与合理的效益/风险比相称,能够有效地发挥其作用,如果可能的话,还可为本发明化合物的两性离子形式。术语“盐”是指相对无毒的本发明化合物的无机酸加成盐和有机酸加成盐。这些盐可在化合物最后的分离和提纯过程中现场制备,或者是另使纯化的化合物以其游离碱形式与适宜的有机或无机酸进行反应,再将形成的盐分离而制成的。代表性盐包括氢溴酸盐、盐酸盐、硫酸盐、亚硫酸盐、硝酸盐、乙酸盐、草酸盐、戊酸盐、油酸盐、棕榈酸盐、硬脂酸盐、月桂酸盐、硼酸盐、苯甲酸盐、乳酸盐、磷酸盐、甲苯甲酸盐、柠檬酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、萘甲酸盐、甲磺酸盐、葡庚糖酸盐、乳糖酸盐和月桂基磺酸盐等。它们可包含基于碱金属和碱土金属的阳离子,如钠、锂、钾、钙、镁等,以及无毒铵、季铵和胺阳离子,包括但不限于:铵、四甲基铵、四乙基铵、甲胺、二甲胺、三甲胺、三乙胺、乙胺等(如可参见:S.M.Berge等,“药物盐”J Pharm Sci,1977;66:1-19,该文献引入本文作为参考)。
本发明化合物的药学上可接受的无毒性酯的实例包括C1-C6烷基酯,其中,烷基基团为直链或支链基团。可接受的酯也包括C5-C7环烷基酯及芳基烷基酯,例如,但不限于苄酯。优选C1-C4烷基酯。本发明化合物的酯可以按照常规方法制备。
本发明化合物的药学上可接受的无毒性酰胺的实例包括由氨、C1-C6烷基伯胺、C1-C6二烷基仲胺得到的酰胺,其中,烷基基团为直链或支链基团。在仲胺的情形下,胺也可为包含一个氮原子的5-或6-元杂环形式。优选由氨、C1-C3烷基伯胺、C1-C2二烷基仲胺得到的酰胺。本发明化合物的酰胺可以按照常规方法制备。
术语“前药”是指例如通过在血液中水解可迅速在体内转化成上式的母体化合物的那些化合物。有关的详细讨论可参见下述文献:T.Higuchi和V.Stella,“作为新传递系统的前药”Vol.14 of the A.C.S.Symposium Series,以及Bioreversible Carriers in Drug Design,ed.Edward B.Roche,American Pharmaceutical Association andPergamon Press,1987,这些文献均引入本文作参考。
本发明的化合物向患者的给药剂量为约0.1-1000mg/天。对体重为约70kg的普通成年人而言,约0.01-100mg/天/kg体重就足已。当然,具体采用的剂量是可以改变的。例如,剂量可根据以下的多种因素改变,包括患者的需求、被治疗的病症的严重程度、所采用化合物的药物活性。如何确定特定患者的最佳剂量是本领域的技术人员公知的。
本发明的化合物根据其不对称中心的存在情况而以不同的立体异构形式存在。可以理解,化合物的所有立体异构形式及其混合物,包括其外消旋混合物,构成了本发明的一部分。
此外,本发明的化合物可与药学上可接受的溶剂以非溶剂化形式及溶剂化形式存在,所述溶剂例如水、乙醇等。一般说来,就本发明的用途而言,溶剂化形式被认为是与非溶剂化形式等价的。
本发明式I、II或III的化合物可以通过合成方法生产或通过生物方法生产。
下述实施例说明了本发明的具体实施方案,但它们并非对本发明的说明书和权利要求书的限定。
通用合成路线
氨基-连接的烷基化Michael受体侧链
胺通过在偶联剂如EDAC存在下用酸进行酰化,或者通过酰氯进行酰化。胺则通过还原相应的硝基化合物、用胺或氨等价物取代卤素或者在吡啶并[4,3-d]嘧啶时在合成过程中直接引入而制得。当用酰基胺和过量的叔胺碱处理时,2-卤代烷基磺酰卤形成乙烯基磺酰胺。
C/N是指碳或氮原子存在于该位置上。
---是指单键或无键。
氧-连接的烷基化Michael受体侧链
羟基在偶联剂如EDAC存在下用酸进行酰化,或者通过酰氯进行酰化。羟基化合物则通过使相应的甲基醚化合物的解离制备。3-甲基硫代链烷酸或其酰氯可用于酰化氧,随后进行S-烷基化或氧化及碱或热消除。
Ar和R代表芳基,R代表本文举例的有机基团。
碳
-连接的烷基化Michael受体侧链
Stille和Suzuki偶联反应可用于偶联侧链至一个适宜的取代喹唑啉/吡啶并嘧啶/嘧啶并嘧啶/三环上。这些物质可以通过本领域中公知的方法以芳基卤制得,或为通过上述的羟基化合物的三氟甲基磺酸化以三氟甲基磺酸芳酯制得,用六甲基二锡烷通过上述三氟甲基磺酸酯的反应以芳基锡烷制得,或者通过将芳基碘转化成芳基有机金属化物,随后用硼酸酯处理和水解,以芳基硼酸制得。或者,芳基碘可转化为芳基锌物质,再与活性卤偶联。
硫-连接的烷基化Michael受体侧链
在吡啶并嘧啶和嘧啶并嘧啶中的活性卤可被适宜的2-羟基硫醇盐取代,它们又会被氧化成砜,然后通过用甲磺酰氯和几当量的碱处理除去水。对喹唑啉和要求保护的三环化合物而言,或者活性卤如氟可用于对吡啶并嘧啶所述的顺序中,或者酰基碘前体可被金属化,用硫或适宜的硫亲电反应物淬火,然后将形成的芳基硫醇用于打开末端环氧化物,得到2-羟基硫醚,其可通过前述的氧化及水消除过程转化成乙烯基砜。
肼基-连接的烷基化Michael受体侧链
在吡啶并嘧啶和嘧啶并嘧啶中的活性卤和适度取代的喹唑啉可被(N-烷基)肼取代。或者,所需环核的氨基衍生物可被重氮化,然后还原成肼。然后,可通过本领域技术人员公知的方法对肼的末端氮进行酰化、磺酰化或磷酰化。
羟基氨基-O-连接的烷基化Michael受体侧链
在吡啶并嘧啶和嘧啶并嘧啶中的活性卤和适度取代的喹唑啉可被适宜的O保护的(N-烷基)羟基胺取代。或者,所需环核的硝基衍生物可合成,然后在适宜的温和还原条件下还原为羟基胺。然后,可通过本领域技术人员公知的方法对羟基胺的氧进行酰化、磺酰化或磷酰化。
在吡啶并嘧啶和嘧啶并嘧啶中的活性卤和适度取代的喹唑啉可被氰化物取代,优选在铜或镍盐催化下进行。或者,所需环核的氨基衍生物可重氮化,然后转化成如上所述的腈。在某些情况下,在合成的早期可将腈官能团引入杂环中,或者以其自身,或者经羧酸或酸酐,本领域技术人员易于将两者转化成腈化合物。随后,可通过本领域技术人员公知的方法进行氮酰化、磺酰化或磷酰化,实现腈向亚甲基胺的还原。
亚甲基氧基-O-连接的烷基化Michael受体侧链
羟甲基化合物可按照本领域技术人员公知的多种方式引入适宜的杂环化合物中。例如,碘代喹唑啉可在Heck反应中羰基化,然后用NaBN4还原成所需前体。氨基吡啶并嘧啶可被重氮化,转化成腈,部分还原成亚胺,水解,形成的醛还原成羟基甲基化合物。羟基甲基化合物的氧再通过本领域技术人员公知的方法酰化、磺酰化或磷酰化。
桥亚乙基-连接的烷基化Michael受体侧链
如果需要的话,将由碘代喹唑啉经有机锌酸盐得到的铜酸盐进行Michael加成至二乙烯基酮上,或者适宜的单掩蔽衍生物上,随后,通过第二不饱和官能团的去掩蔽,将给出所需类型的化合物。由如前所述的吡啶并嘧啶或嘧啶并嘧啶得到的醛可通过各种技术如由本领域技术人员说明的那些技术经容许反应(homologate)生成所需化合物。
氨基甲基-C-连接的烷基化Michael受体侧链
由本申请所述类型的氨基杂环可通过1-溴-丁-3-烯-2-酮的各种双键掩蔽的等价物被烷基化,随后,通过本领域技术人员公知的方法进行不饱和的去掩蔽。
羟甲基-C-连接的烷基化Michael受体侧链
如前所述由甲氧基-杂环制备的羟基杂环可通过1-溴-丁-3-烯-2-酮的各种双键掩蔽的等价物被烷基化,随后,通过本领域技术人员公知的方法进行不饱和的去掩蔽。另外,苯酚的烷基化可用氯代乙酸来完成,再转化成酰氯,以及酰卤与适宜链烯基锡烷的Stille偶联。
硫甲基-C-连接的烷基化Michael受体侧链
适宜的巯基-杂环可通过活化卤在杂芳环上的取代而制得,其可通过1-溴-丁-3-烯-2-酮的各种双键掩蔽的等价物被烷基化。然后,通过本领域技术人员公知的方法进行不饱和的去掩蔽。另外,硫醇的烷基化可用氯代乙酸来完成,再转化成酰氯,以及酰卤与适宜链烯基锡烷的Stille偶联。
实施例1N-[4-(3-溴-苯基氨基)-吡啶并[4,3-d]嘧啶-7-基]-N-(3-吗啉-4-基丙基)-丙 烯酰胺
通用方法A:
按照本领域技术人员公知的方法,可对7-氨基-4-[(3-溴苯基)氨基]-吡啶并[4,3-d]嘧啶进行酰基化[J Med Chem,1995:3780],制得N-[4-(3-溴-苯基氨基)-吡啶并[4,3-d]嘧啶-7-基]-N-(3-吗啉-4-基丙基)-丙烯酰胺。例如,采用丙烯酸的酰化过程可通过使用标准缩合试剂如1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺HCl(EDAC)或通过使用丙烯酰氯和一种叔碱如二异丙基乙基胺作为酸清除剂而实现。
然后,-丙烯酰胺的N-烷基化反应可通过本领域技术人员公知的方法实现。例如,用标准试剂如氢化钠进行处理将酰胺转化成其单阴离子,随后,通过用适宜的卤化物如N-(3-氯丙基)吗啉或N-(4-氯丁基)吗啉进行取代,得到所需的烷基化酰胺。
通用方法B:
N-[4-(3-溴-苯基氨基)-吡啶并[4,3-d]嘧啶-7-基]-N-(3-吗啉-4-基丙基)-丙烯酰胺也可以这样进行制备:用二甲基亚砜中的N-(3-氨基丙基)吗啉对7-氟-4-[(3-溴苯基)氨基]-吡啶并[4.3-d]嘧啶进行处理,再用丙烯酸和一种偶联试剂如1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺HCl(EDAC)或丙烯酰氯和一种叔碱如二异丙基乙基胺按照本领域技术人员公知的方法进行酰化。参见,例如,WO9519774A1。
实施例2N-[4-(3-溴-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-N-(3-吗啉-4-基丙基)-丙 烯酰胺
在0℃及氮气氛下,向搅拌中的4-[(3-溴-苯基)氨基]-6-[(3-吗啉代丙基)氨基]吡啶并[3,4-d]嘧啶(400mg,0.90mmol)(由4-[(3-溴-苯基)氨基]-6-氟吡啶并[3,4-d]嘧啶和3-吗啉代丙-1-基胺)、DMAP(40mg)和Et3N(过量,2.0mL)的溶液中加入丙烯酰氯(1.2摩尔当量,1.08mmol,89μL)。搅拌1小时后,在2小时内,再加入另两份酰氯(各89μL),将反应混合物在20℃下搅拌1小时,用水稀释,用乙酸乙酯萃取。合并后的有机萃取液用盐水洗涤,用无水硫酸钠干燥,减压浓缩,再用硅胶色谱处理,用甲醇/乙酸乙酯(1∶9)至甲醇/乙酸乙酯(1∶5)作为洗脱液,得到N-[4-(3-溴-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-N-(3-吗啉代丙基)-丙烯酰胺(142mg,32%),为乳白色粉末,mp(二氯甲烷/己烷)178-180℃。1H NMR[(CD3)2SO]:δ10.15(s,1H,NH),9.15(s,1H,芳族),8.80(s,1H,芳族),8.47(s,1H,芳族),8.21(br s,1H,H-2′),7.92(br d,J=7.6Hz,1H,H-6′),7.41(t,J=8.0Hz,1H,H-5′),7.37(dt,J=8.1Hz,J=1.6Hz,J=1.6Hz,1H,H-4′),6.25(m,2H,CH2CHCO,CH2CHCO),5.66(m,1H,CH2CHCO),3.98(t,J=7.5Hz,2H,CH2NRCO),3.46(t,J=4.5Hz,4H,吗啉代亚甲基),2.29(t,J=7.1Hz,2H,CH2CH2CH2NRCO),2.24(br s,4H,
吗啉代亚甲基),1.73(五重峰,J=7.2Hz,2H,CH2CH2CH2).13C NMR:δ164.84,156.69,155.80,151.83,150.05,143.01,140.02,130.51,129.27,127.88,126.76,124.32,121.19,120.82,113.02,66.02(×2),55.05,53.02(×2),45.85,24.63.对C23H25BrN6O2·H2O的元素分析:计算值:C,53.6;H,5.3;N,16.3%。实测值:C,53.8;H,5.0;N,16.3%。
实施例3
N-[4-(3-溴-苯基氨基)-喹唑啉-7-基]-丙烯酰胺
向7-氨基-4-(3-溴苯胺基)喹唑啉(0.158g(0.5mM))[J Med Chem1995:3482]和丙烯酸(0.108g)的无水二甲基甲酰胺(DMF,5.0mL)的冰冷却溶液中加入1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺盐酸盐(EDAC)(0.288g)。搅拌5分钟后,混合物变成溶液,除去冰浴。将反应混合物在室温下再搅拌3小时。然后,将反应混合物倒入冰与水的混合物中,加入饱和碳酸氢钠溶液使其成碱性。将这种含水混合物用乙酸乙酯萃取三次,将合并后的萃取液用硫酸镁干燥。将溶液过滤,真空浓缩,得到一种浅黄色固体。将该固体溶解于100mL的甲醇中,过滤,真空浓缩至大约10毫升。收集从溶液中沉淀出的固体,在80℃下真空干燥,得到50mg的N-[4-(3-溴-苯基氨基)-喹唑啉-7-基]-丙烯酰胺,mp>265℃。化学电离质谱:m/e 369。1H NMR(D6-二甲亚砜):δ5.86(dd,1H,J=10.1,J=1.9),6.36(dd,1H,J=17.0,J=1.9),6.51(dd,1H,J=16.9,J=10.1),7.30(m,1H),7.36(t,1H,J=8.1),7.82(dd,1H,J=9.2,J=2.2),7.9(d,1H,J=8.0),8.25(dd,1H,J=3.6,J=1.9),8.50(d,1H,J=8.9),8.61(s,1H),9.79(s,1H,-NH),10.61(s,1H,-NH).对C17H13BrN4O的元素分析:计算值:C,55.30;H,3.55;N,15.17。实测值:C,55.49;H,3.63;N,15.26。
实施例4
N-[4-(3-溴-苯基氨基)-喹唑啉-7-基]-N-[3-吗啉代丙基]-丙烯酰胺向4-[(3-溴-苯基)氨基]-7-氟喹唑啉(0.60g,1.89mmol)的二甲亚砜(DMSO)(10mL)溶液中加入4-(3-氨基丙基)吗啉(7.54mmol,1.10mL)。将反应混合物于110℃下加热26小时,然后用水稀释,用饱和碳酸氢钠碱化,用乙酸乙酯萃取。合并后的有机萃取液用盐水洗涤,用无水硫酸钠干燥,真空浓缩。在III级氧化铝上进行柱色谱处理,用乙酸乙酯至乙酸乙酯/甲醇(98∶2)进行梯度洗脱,再用乙酸乙酯/己烷进行重结晶,得到4-[(3-溴-苯基)氨基]-7-[(3-吗啉代丙基)氨基]-喹唑啉(0.65g,78%),为乳白色结晶,mp 162-162.5℃。
1H NMR[(CD3)2SO,200MHz]:δ9.41(s,1H,NH),8.43(s,1H,H-2),8.24(br s,1H,H-2′),8.18(d,J=9.2Hz,1H,H-5),7.87(br d,J=8.1Hz,1H,H-6′),7.35-7.18(m,2H,H-4′,5′),6.88(dd,J=1.9Hz,J=9.1Hz,1H,H-6′),6.65(t,J=5.3Hz,1H,CH2NH),6.62(br s,1H,H-8),3.60(t,J=4.6Hz,4H,吗啉代亚甲基),3.19(dt,J=6.4Hz,J=6.4Hz,J=5.8Hz,1H,CH2CH2NH),2.43-2.33(m,6H,
吗啉代亚甲基,CH2CH2CH2NH),1.75(五重峰,J=6.8Hz,1H,CH2CH2CH2).13C NMR:δ156.56,154.27,152.41,152.32,141.60,130.15,124.90,123.41,123.31,121.06,119.87,116.51,105.68,102.21,66.13(×2),55.81,53.31(×2),40.46,25.14在氮气氛下,向上述4-[(3-溴-苯基)氨基]-7-[(3-吗啉代丙基)氨基]-喹唑啉(0.10g,0.230mmol)的无水DMF(5.0ml)溶液中加入丙烯酸(0.565mmol,39μL)、三乙胺(100μL)和1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺盐酸盐(EDCI·HCl)(0.565mmol,108mg),将反应混合物在室温下搅拌4天,每天加入丙烯酸(40μL)、三乙胺(100μL)和EDCI·HCl(100mg)。然后,真空除去DMF,将形成的残余物用饱碳酸氢钠稀释,用乙酸乙酯萃取。合并后的有机萃取液用盐水洗涤,用无水硫酸钠干燥,减压浓缩。用硅胶柱色谱处理,用甲醇/乙酸乙酯/二氯甲烷(1∶4∶5)至甲醇/乙酸乙酯/二氯甲烷(2∶4∶4)进行梯度洗脱,在高Rf下得到,N-[4-(3-溴-苯基氨基)-喹唑啉-7-基]-N-[3-吗啉代丙基]-丙烯酰胺(39mg,35%),为白色粉末,mp(乙酸乙酯/己烷)86-88℃(分解)。
1H NMR[(CD3)2SO,200MHz]:δ9.96(s,1H,NH),8.68(s,1H,H-2),8.63(d,J=8.7Hz,1H,H-5),8.23(br s,1H,H-2′),7.91(dt,J=7.3Hz,J=2.0Hz,J=2.0Hz,1H,H-6′),7.68-7.58(m,2H,芳族),7.42-7.31(m,2H,芳族),6.18(m,2H,CH2CHCO,CH2CHCO),5.63(dd,J=2.0Hz,J=10.0Hz,1H,CH2CHCO),3.90(t,J=7.1Hz,2H,CH2CH2CH2NCO),3.51(t,J=4.3Hz,4H,吗啉代亚甲基),2.50(br s,2H,CH2CH2CH2NCO),2.28(br s,4H,吗啉代亚甲基),1.67(五重峰,J=6.5Hz,2H,CH2CH2CH2).在低Rf下,回收原料,4-[(3-溴-苯基)氨基]-7-[(3-吗啉代丙基)氨基]-喹唑啉(34%),与可信样品相同。
实施例5
3-[4-(3-溴-苯基氨基)-喹唑啉-7-基氨甲酰基]丙烯酸
向5℃下的7-氨基-4-(3-溴苯胺基)喹唑啉(0.158g)[J Med Chem1995:3482]的四氢呋喃(10ml)溶液中加入马来酸酐(0.059g)。将该冷溶液搅拌15分钟,然后除去冰浴。将反应混合物升温至室温,继续搅拌15小时。在回流下,将悬浮液加热30分钟,然后,再在室温下搅拌15小时。再加入马来酸酐(0.059g)和四氢呋喃(20ml),将反应混合物再回流2小时。再在室温下处理15小时后,将反应混合物回流15小时。将反应混合物过滤,将浅褐色固体首先通过二甲基甲酰胺进行重结晶,再由甲醇进行重结晶,得到0.036g的所需产物。1H NMR[(CD3)2SO]:δ12.95(br s,1H,与D2O交换),11.04(br s,1H,与D2O交换),9.81(br s,1H,与D2O交换),8.62(s,1H),8.49(d,J=9.2Hz,1H),8.24(s,1H),8.17(d,J=1.7Hz,1H),7.90(d,J=8.4Hz,1H),7.78(d,J=9.2Hz,1H),7.36(t,J=8.1Hz,1H),7.30(dd,J=1Hz,9Hz,1H),6.50(d,J=12.1Hz,1H),6.37(d,J=11.8Hz,1H);CIMS m/z(相对%):411.3(95),412.3(23),413.3(100),414.3(21).对C18H13BrN4O3的元素分析:计算值:C,52.32;H,3.17;N,13.56。实测值:C,52.57;H,3.51;N,13.16。
实施例6
3-[4-(3-溴-苯基氨基)-喹唑啉-7-基氨甲酰基]丙烯酸乙酯
向冰冷却下的7-氨基-4-(3-溴苯胺基)-喹唑啉(0.158g)与富马酸单乙酯(0.216g)的无水二甲基甲酰胺(3ml)溶液中加入1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺盐酸盐(EDAC)(0.288g)。7-氨基-4-(3-溴苯胺基)-喹唑啉按照本领域技术人员公知的方法制备。参见:J Med Chem,1995:3482,该文献引入本文作为参考。在5℃下搅拌5分钟后,除去冰浴,将反应混合物升温至室温,再搅拌15小时。将反应混合物倒入冷水中,加入饱和碳酸氢钠溶液使悬浮液碱化。通过过滤收集形成的固体,用水洗涤,用50ml的乙醇进行重结晶,得到0.052g的所需产物,mp>260℃。1H NMR[(CD3)2SO]:δ10.99(br s,1H,与D2O交换),9.82(br s,1H,与D2O交换),8.62(s,1H),8.52(d,J=8.9Hz,1H),8.24(s,2H),7.90(d,J=8.2Hz,1H),7.81(dd,J=1.7Hz,8.9Hz,1H),7.34(m,2H),7.26(d,J=15.7Hz,1H),6.79(d,J=15.4Hz,1H),3.33(q,J=7.0Hz,14.2Hz,2H),1.28(t,J=7.0Hz,3H);CIMS m/z(相对%):440(19%),441(100),442(37),443(78).对C20H17BrN4O3的元素分析:计算值:C,54.44;H,3.88;N,12.70;Br,18.11。实测值:C,54.32;H,3.85;N,12.76;Br,17.89。
实施例7
N-(3-溴-苯基)-喹唑啉-4-基-胺
N-(3-溴-苯基)-喹唑啉-4-基-胺按照本领域技术人员公知的方法制备。如参见:J Med Chem,1995:3482-3487。
实施例8
4-(3-溴-苯基氨基)-6,7-二甲氧基喹唑啉
4-(3-溴-苯基氨基)-6,7-二甲氧基喹唑啉按照本领域技术人员公知的方法制备。如参见:EP 566 226 A1。
实施例9
丁-2-烯酸[4-(3-溴-苯基氨基)-喹唑啉-7-基]酰胺
向冰冷却下的7-氨基-4-(3-溴苯胺基)-喹唑啉(0.158g)(J Med Chem,1995:3482)的四氢呋喃(5ml)溶液中滴加巴豆酰氯(0.105g)的四氢呋喃(5ml)溶液。当滴加完成后,除去冰浴,将反应混合物在室温下搅拌15小时。将反应混合物过滤,滤出黄色固体,将其用四氢呋喃洗涤,用20ml沸腾的甲醇进行重结晶,得到0.060g的所需产物,mp>250℃。1H NMR[(CD3)2SO]:δ11.44(br s,1H,与D2O交换),11.04(s,1H,与D2O交换),8.92(s,1H),8.78(d,J=9.2Hz,1H),8.52(d,J=1.9Hz,1H),8.05(t,J=1.8Hz,1H),7.91(dd,J=2.1Hz,9.3Hz,1H),7.76(m,1H),7.52(m,1H),7.45(t,J=8.0Hz,1H),6.70(m,1H),6.28(dd,J=1.7Hz,15.1Hz,1H),1.92(dd,J=1.6Hz,6.9Hz,3H);CIMS:382(21),383(100),384(34),385(64).对C18H15BrN4O·1HCl·0.5H2O的元素分析:计算值:C,50.43;H,4.00;N,13.07;Br,18.64;Cl,8.27。实测值:C,50.71;H,4.00;N,12.98;Br,18.93;Cl,7.51。
实施例10
N-[4-(3-溴-苯基氨基)-6-(3-吗啉-4-基-丙基氨基)-喹唑啉-7-基]酰胺
用亚硫酰氯或POCl3对6-氯-7-硝基喹唑啉-4-酮进行处理(Aust JChem,1995;48:227-232),得到4,6-二氯-7-硝基喹唑啉。与3-溴苯胺反应,得到4-(3-溴苯基氨基)-6-氯-7-硝基喹唑啉和4-氯-6-(3-溴苯基氨基)-7-硝基喹唑啉,通过柱色谱将它们分离开。用N-(3-氨基丙基)吗啉处理所需的4-(3-溴苯基氨基)-6-氯-7-硝基喹唑啉,随后再使硝基官能团与例如乙酸中的铁反应,得到7-氨基-4-(3-溴-苯基氨基)-6-(3-吗啉4-基-丙基氨基)喹唑啉。按照实施例3的方法实行酰化,得到-丙烯酰胺。
实施例11
N-[4-(3-溴-苯基氨基)喹唑啉-6-基]丙烯酰胺
在氮气氛下,向6-氨基-4-[(3-溴苯基)氨基]-喹唑啉(2.0g,6.35mmol)的无水DMF(20ml)溶液中加入丙烯酸(12.7mmol,0.87ml)。将形成的溶液冷却至0℃,再加入1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺盐酸盐(EDCI·HCl)(7.62mmol,1.46g)。在0℃下将反应混合物搅拌15分钟,然后使其升温至室温,再搅拌2小时,此后,再加入丙烯酸(0.30ml)和(EDCI·HCl)(0.30g)。再搅拌2小时后,通过TLC确定反应完成,减压除去溶剂,形成的残余物用饱和碳酸氢钠稀释,重复用乙酸乙酯进行萃取。合并后的有机萃取液用盐水洗涤,用无水硫酸钠干燥,减压浓缩。经III级氧化铝上进行柱色谱处理,用乙酸乙酯/甲醇(95∶5)进行洗脱,再用乙酸乙酯/己烷进行重结晶,得到海绵状白色固体,经几个小时高真空,得到N-[4-(3-溴苯基)氨基]喹唑啉-6-基]-丙烯酰胺(1.06g,45%),为乳白色粉末,mp 258-261℃。1H NMR[(CD3)2SO,200MHz]:δ10.51(s,1H,CONH),9.93(s,1H,NH),8.83(br s,1H,H-5),8.59(s,1H,H-2),8.18(br s,1H,H-2′),7.94-7.78(m,3H,H-6′,8,5′),7.40-7.27(m,2H,H-7,4′),6.54(dd,J=9.8Hz,J=17.0Hz,1H,CH2CHCO),6.36(dd,J=2.1Hz,J=16.9Hz,1H,CH2CHCO),5.85(dd,J=2.0Hz,J=9.7Hz,1H,CH2CHCO).
质谱(CI):371(95,81BrMH+),370(53,81BrM+),369(100,79BrMH+),368(33,79BrM+).
对C17H13BrN4O的元素分析:
计算值:C,55.30;H,3.55;N,15.17%。实测值:C,55.19;H,3.34;N,14.88%。
实施例12
N-[4-(N,N-二甲基氨基)-喹唑啉-6-基]-丙烯酰胺
将6-硝基喹唑酮(3.50g,18.5mmol)在含两滴DMF的纯SOCl2(30ml)中的悬浮液回流3小时,直至其澄清。减压除去过量的SOCl2,加入无水苯,减压蒸发以除去所有痕量的SOCl2。将形成的粗产物4-氯-6-硝基喹唑啉溶解于无水二氯甲烷(50ml)中,用饱和碳酸钠洗涤2次,然后,将该溶液加至含三乙胺(过量,7.0ml)的4-氨基-2-溴-N,N-二甲基苄基胺(20.3mmol,4.64g)的异丙醇(60ml)溶液中。将形成的反应混合物加热回流3小时,然后减压浓缩,用水稀释,用乙酸乙酯萃取。合并后的有机萃取液用无水硫酸钠干燥,减压浓缩,用硅胶色谱处理,用二氯甲烷/乙酸乙酯(1∶1)至甲醇/二氯甲烷/乙酸乙酯(2∶9∶9)进行洗脱,得到4-N,N-二甲基氨基-6-硝基喹唑啉(2.56g,64%),为黄色结晶,mp(二氯甲烷)131-132℃。1H NMR[(CD3)2SO],(400MHz):δ9.02(d,J=2.4Hz,1H,H-5),8.59(s,1H,H-2),8.47(dd,J=2.5Hz,J=9.2Hz,1H,H-7),7.85(d,J=9.2Hz,1H,H-8),3.46(s,6H,N(CH3)2).
进一步洗脱得到2-溴-N,N-二甲基-4-(6-硝基喹唑啉-4-基)苄基胺(0.62g,8%),为黄色粉末,mp(二氯甲烷)198-200℃。1H NMR[(CD3)2SO],(400MHz):δ10.47(br s,1H,NH),9.66(d,J=2.4Hz,1H,H-5),8.77(s,1H,H-2),8.57(dd,J=9.2Hz,J=2.5Hz,1H,H-7),8.21(d,J=2.0Hz,1H,H-2′),7.95(d,J=9.1Hz,1H,H-8),7.91(dd,J=8.4Hz,1H,H-6′),7.49(d,J=8.5Hz,1H,H-5′),3.46(s,2H,CH2N(CH3)2),2.22(s,6H,N(CH3)2).
对C17H16BrN5O2·1.5H2O的元素分析:计算值:C,47.6;H,4.5;N,16.3%。实测值:C,47.7;H,4.2;N,15.7%。
向回流下的、含有冰醋酸(4.0ml)的、上述4-N,N-二甲基氨基-6-硝基喹唑啉胺(1.20g,5.50mmol)的乙醇/水(2∶1,90ml)溶液中分批加入刚洗涤过(用1N盐酸,再用蒸馏水)的铁粉(4摩尔当量,1.24g)。重复上述相同的反应过程,经硅胶色谱处理,用二氯甲烷/乙酸乙酯(1∶1)至甲醇/二氯甲烷/乙酸乙酯(1∶4∶5)洗脱,得到4-N,N-二甲基氨基-6-氨基喹唑啉(0.87g,84%),为浅棕色粉末,mp(来自甲醇/乙醚的二盐酸盐)258-261℃。1H NMR(二盐酸盐),[(CD3)2SO],(400MHz):δ14.8(br s,1H,NH+),8.65(s,1H,H-2),7.79(m,2H,H-5,H-8),7.57(dd,J=2.1Hz,J=8.9Hz,1H,H-7),5.70(br s,3H,NH3 +),3.55(s,6H,N(CH3)2).
在氮气氛下,向搅拌中的、包含上述4-N,N-二甲基氨基-6-氨基喹唑啉(0.65g,3.45mmol)、丙烯酸(4摩尔当量,13.8mmol,0.95ml)和吡啶(过量,1.3ml)的DMA(20ml)溶液中加入1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺盐酸盐(EDCI·HCl)(2摩尔当量,6.90mmol,1.32g)。进行上述标准过程,经硅胶色谱处理,用二氯甲烷/乙酸乙酯(1∶1)至甲醇/二氯甲烷/乙酸乙酯(1∶4∶5)洗脱,得到[4-(N,N-二甲基氨基)喹唑啉-6-基]-丙烯酰胺(350mg,42%),为乳油色粉末,mp(二氯甲烷/己烷)204-206℃。1H NMR[(CD3)2SO],(400MHz):δ10.49(s,1H,CONH),8.80(d,J=2.2Hz,1H,H-5),8.46(s,1H,H-2),7.88(dd,J=2.4Hz,J=9.1Hz,1H,H-7),7.73(d,J=9.0Hz,1H,H-8),6.47(dd,J=17.0Hz,J=10.1Hz,1H,CH2CHCO),6.34(dd,J=17.0Hz,J=2.0Hz,1H,CH2CHCO),5.83(dd,J=10.1Hz,J=2.0Hz,1H,CH2CHCO),3.32(s,6H,N(CH3)2).
实施例13
N-[4-(3-甲基-苯基氨基)-喹唑啉-7-基]-丙烯酰胺
在0℃下,向搅拌下的7-氨基-4-[(3-甲基苯基)氨基]喹唑啉(123mg,0.49mmol)、丙烯酸(0.04ml,0.58mmol)、三乙胺(0.15ml,1.1mmol)的DMF(1.5ml)溶液中加入1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺盐酸盐(123mg,0.64mmol)。将形成的浅黄色混合物在25℃下搅拌20小时,用水使反应停止。收集固体,用二氯甲烷/乙酸乙酯/甲醇的混合物通过声处理进行纯化,得到所需产物(75mg,49%),为黄色固体,mp269.7-270℃。1H NMR[(CD3)2SO]:δ10.63(s,1H,NH),9.68(s,1H,NH),8.58(s,1H,H2),8.54(d,J=9.3Hz,1H,H6),8.25(d,J=2.2Hz,1H,H8),7.83(dd,J=9.0,1.9Hz,1H,H5),7.71(m,2H,H2′,H6′),7.32(t,J=8.3Hz,1H,H5′),6.99(d,J=7.1Hz,1H,H4′),6.56(dd.J=16.8,10.0Hz,1H,CH=CH2),6.40(dd.J=17.1,5.0Hz,1H,CH=CH2),5.9(dd,J=10.3,2.0Hz,1H,CH=CH2),2.39(s,3H,CH3).
质谱(CI):305(100,MH+),304(31.84,M+).对C18H16N4O·0.4H2O的元素分析:计算值:C,69.39;H,5.44;N,17.94%。实测值:C,69.19;H,5.19;N,17.67%。
实施例14
N-[4-(3-氯-苯基氨基)-喹唑啉-7-基]-丙烯酰胺
在0℃和氮气氛下,向搅拌中的6-氨基-4-[(3-氯苯基)氨基]喹唑啉(136mg,0.5mmol)和丙烯酸(108mg,1.5mmol)的DMF(5ml)溶液中加入1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺盐酸盐(288mg,1.5mmol)。15分钟后,在25℃下搅拌18小时,然后将其倒入冰水(50ml)中,1小时后,通过布氏漏斗过滤收集沉淀。将残余物淋洗,空气干燥,溶解于少量25℃下的甲醇(60ml)中。在25℃下减压浓缩至少于10ml,在0℃下重结晶,得到N-[4-(3-氯-苯基氨基)-喹唑啉-7-基]-丙烯酰胺(33mg,20%),为浅橙色固体,mp296.5-298.5℃。对C17H13ClN4O·0.08CH3OH·0.25H2O的元素分析:计算值:C,61.82;H,4.20;N,116.89%。实测值:C,69.19;H,4.23;N,116.72%。1H NMR[(CD3)2SO]:δ10.61(brs,1H,NH),9.80(s,1H,NH),8.62(s,1H,H2), 8.50(d,J=9.0Hz,H5),8.25(d,J=2.0Hz,1H,H8),8.13(t,J=2.0Hz,1H,H2′),7.87-7.78(m,2H,H6 & H6′),7.42(t,J=8.2Hz,1H,H5′),7.16(dd,J=2.2,7.9Hz,1H,H4′),6.51(dd,J=10.0,17.1Hz,1H,CH=CH2),6.35(dd,J=1.8,17.1Hz,1H,CH=CH2),5.86(dd,J=1.8,10.1Hz,1H,CH=CH2).
质谱(CI)327(32,37ClMH+),326(25,37ClM+,13C 35ClMH+),325(100,35ClMH+),322(22,35ClMH+).
实施例15
N-[4-(3-溴-苯基氨基)-喹唑啉-7-基]-甲基丙烯酰胺
向搅拌下的7-氨基-4-[(3-溴苯基)氨基]喹唑啉(J Med Chem,1995;38:3482)(150mg,0.48mmol)的无水DMF(20ml)溶液中加入甲基丙烯酸(200mg)和加入1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺盐酸盐(EDCI·HCl)(228mg,2.5mmol)。在反应混合物过夜搅拌后再加EDCI·HCl(230mg)和甲基丙烯酸(200mg)。再过2天后,真空除去溶剂,残余物用和饱和碳酸氢钠稀释,用乙酸乙酯进行萃取,将合并后的有机萃取液用无水硫酸钠干燥,减压浓缩,用硅胶色谱处理,用甲醇/二氯甲烷/乙酸乙酯(5∶45∶50)至甲醇/二氯甲烷/乙酸乙酯(10∶40∶50)洗脱,得到N-[4-(3-溴-苯基氨基)-喹唑啉-7-基]-甲基丙烯酰胺(43mg,24%),为浅棕色固体,mp(二氯甲烷/己烷)255-259℃。
1H NMR[(CD3)2SO],(400MHz)δ10.22(s,1H,CONH),
9.76(s,1H,NH),8.61(s,1H,H-2),8.48(d,
J=9.2Hz,1H,H-5),8.26(m,2H,H-2′,8),7.92(m,
2H,H-6′,6),7.36(t,J=8.0Hz,1H,H-5′),7.30
(br d,J=8.3Hz,1H,H-4′),5.92(s,1H,
CH2C(CH3)CO),5.63(s,1H,CH2C(CH3)CO),2.00(s,3H,
CH2C(CH3)CO).
对C18H15BrN4O的元素分析:计算值:C,56.4;H,4.0;N,14.6%。实测值:C,56.1;H,4.0;N,14.1%。
实施例16
N-[4-(3-溴-苯基氨基)-喹唑啉-7-基]乙烯基-磺酰胺
在氮气氛及搅拌下,使7-氨基-4-[(3-溴苯基)氨基]喹唑啉(J MedChem,1995;38:3482)(500mg,1.59mmol)、三乙胺(0.60ml)和二甲胺吡啶(DMAP)(催化量)的四氢呋喃(THF)(30ml)溶液与氯乙烷磺酰氯(1.6摩尔当量,2.54mmol,265μL)在25℃下反应1小时。反应混合物用饱和碳酸氢钠稀释,用乙酸乙酯萃取。合并后的有机萃取液用盐水洗涤,用无水硫酸钠干燥,减压浓缩,用硅胶色谱处理,用甲醇/二氯甲烷/乙酸乙酯(3∶47∶50)洗脱。用二氯甲烷/己烷进行重结晶,得到N-[4-(3-溴-苯基氨基)-喹唑啉-7-基]乙烯基-磺酰胺(80mg,12%),为乳油色粉末,mp218℃分解(dec)。
1H NMR[(CD3)2SO],(400MHz)δ10.73(s,1H,SO2NH),
9.80(s,1H,NH),8.59(s,1H,H-2),8.47(d,
J=9.1Hz,1H,H-5),8.21(br s,1H,H-2′),7.87(br
d,J=8.0Hz,1H,H-6′),7.47(d,J=2.1Hz,1H,
H-8),7.40(dd,J=9.0Hz,J=2.2Hz,1H,H-6),7.36
(t,J=8.0Hz,1H,H-5′),7.30(br d,J=8.0Hz,1H,
H-4′),6.93(dd,J=16.4Hz,J=9.9Hz,1H,
CH2CHSO2),6.28(d,J=16.4Hz,1H,CH2CHSO2),6.15
(d,J=9.9Hz,1H,CH2CHSO2).
对C16H13BrN4O2S的元素分析:计算值:C,47.4;H,3.2%。实测值:C,47.3;H,3.5%。
实施例17
N-[4-(3-溴-苯基氨基)-喹唑啉-7-基]-丙酰胺
在氮气氛及25℃下,向搅拌中的7-氨基-4-[(3-溴苯基)氨基]喹唑啉(163mg,0.52mmol)的无水THF(3ml)溶液中滴加丙酰氯(0.05ml,0.58mmmol)。立即形成黄色固体。1小时后,通过布氏漏斗过滤收集固体,用乙醚洗涤,干燥。用湿甲醇进行重结晶,得到所需产物(81mg,38%),为亮黄色固体,mp282-283℃。1H NMR[(CD3)2SO]:δ11.4(brs,1H,NH),10.76(s,1H,NH),8.90(s,1H,H8),8.64(d,J=9.0Hz,1H,H6),8.42(s,1H,H2),8.06(s,1H,H2′),7.80(dd,J=9.2,1.9Hz,1H,H5),7.74(d,J=7.8Hz,1H,H4′),7.50(d,J=8.0Hz,1H,H6′),7.45(t,J=8.0Hz,1H,H5′),2.48(q,J=7.6Hz,2H,CH2),1.13(t,J=7.5Hz,3H,CH3).
质谱(APCI):373(100,81BrMH+),372(21,81BrM+),371(96,79BrMH+).对C17H15BrO·HCl·0.2H2O的元素分析:计算值:C,49.64;H,4.02;N,13.63%。实测值:C,49.48;H,3.91;N,13.57%。
实施例18
N-[4-[3-氯-苯基)氨基]喹唑啉-6-基]-丙烯酰胺
在0℃及氮气氛下,将1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺盐酸盐(1902mg,1mmol)加至搅拌中的6-氨基-4-[(3-氯苯基)氨基]喹唑啉(136mg,0.5mmol)、丙烯酸(74mg,1.0mmol)和吡啶(201mg,2.5mmol)的THF/DMF(4∶1,2.5ml)溶液中。20分钟后,将反应混合物在25℃下再搅拌3小时,然后倒入水(12.5ml)中,用乙酸乙酯萃取(2×10ml)。合并后的萃取液用稀盐酸(0.5M,10ml)处理,通过布氏漏斗过滤收集沉淀,用水(10ml)和乙醚(2×10ml)洗涤,在空气中干燥,得到N-[4-[3-氯-苯基)氨基]喹唑啉-6-基]-丙烯酰胺盐酸盐(93mg,48%),为暗黄色固体,mp 223-227℃。对C18H13ClN4O·HCl·1.5H2O的元素分析:计算值:C,52.59;H,4.41;N,14.43%。实测值:C,52.43;H,4.37;N,14.27%。1H NMR[(CD3)2SO]:δ11.46(brs,1H,NH),11.05(s,1H,NH),9.13(d,J=2.0Hz,1H,H5),8.90(s,1H,H2),8.12(dd,J=2.0,9.0Hz,1H,H7),7.99(d,J=9.0Hz,1H,H8),7.88(t,J=2.0Hz,1H,H2′),7.68(dd,J=6.1,1.0Hz,1H,H6′),7.51(t,J=8.0Hz,1H,H5′),7.37(dd,J=8.1,1.2Hz,1H,H-4′),6.63(dd,J=10.3,17.1Hz,1H,CH=CH2),6.37(dd,J=1.6,17.1Hz,1H,CH=CH2),5.87(dd,J=1.7,10.Hz,1H,CH=CH2).
质谱,化学电离(CI):327(8,37ClMH+),325(37,35ClMH+),
135(100).
实施例19
N-[4-(3-甲基苯基)氨基]-喹唑啉-6-基]-丙烯酰胺
在0℃及氮气氛下,在20分钟内,将氯甲酸异丁酯(20.35g,0.15mol)滴加至搅拌中的丙烯酸(10.82g,0.15mol)和三乙胺(30.19g,0.30mol)的THF(400ml)溶液中。将浆液在该温度下搅拌30分钟,然后在45分钟内,滴加6-氨基-4-[(3-甲基苯基)氨基]喹唑啉(27.71mg,107mmol)的DMF(80ml)溶液。4小时后,再一次性加入混合酸酐(来自丙烯酸(3.61g,50mmol)、氯甲酸异丁酯(6.80g,50mmol)和三乙胺(10.1g,100mmol)的THF(100ml))(0℃)。15分钟后,将反应混合物在25℃下搅拌30分钟,然后倒入冰水(1L)中。加入乙醚(200ml),进行相分离。水层用乙酸乙酯(500ml)萃取,合并后的有机相用水(500ml)和饱和盐水(250ml)洗涤。溶液用无水硫酸镁搅拌2分钟,过滤,加入硅胶(150g)。将混合物汽提至干,作为快速硅胶色谱柱(700g)的上样原料,用丙酮/二氯甲烷(25%4L,35%8L,40%4L)洗脱。通过适宜成分汽提溶剂,将残余物悬浮于乙酸乙酯(200ml)中,回流5分钟,在60℃下用声波处理20分钟,然后通过布氏漏斗过滤收集,用乙酸乙酯(3×25ml)洗涤,在75℃下于真空炉中干燥16小时,得到N-[4-(3-甲基苯基)氨基]-喹唑啉-6-基]-丙烯酰胺(11.38g,35%),为浅黄色固体,mp247-8℃。
对C18H16N4O·0.1H2O的元素分析:计算值:C,70.61;H,5.33;N,18.30%。实测值:C,70.33;H,5.19;N,18.17%。1H NMR[(CD3)2SO]:δ10.49(brs,1H,NH),9.76(brs,1H,NH),8.75(d,J=2.5Hz,1H,H5),8.52(s,1H,H2),7.89(dd,J=2.0,9.2Hz,1H,H7),7.77(d,J=8.9Hz,1H,H8),7.64-7.60(m,2H,H6′& H2′),7.26(dt,Jd=1.4Hz,Jt=7.5Hz,1H,H5′),6.94(d,J=7.2Hz,1H,H4′),6.53(dd,J=10.1,16.9Hz,1H,CH=CH2),6.34(dd,J=1.9,16.9Hz,1H,CH=CH2),5.84(dd,J=1.9,10.1Hz,1H,CH=CH2)2.34(s,3H,Me).
质谱(CI)305(100,MH+),304(49,M+).
实施例20
N-[4-[(3-(三氟甲基)苯基氨基]-喹唑啉-6-基]-丙烯酰胺在0℃及氮气氛下,将1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺盐酸盐(212mg,1.1mmol)加至6-氨基-4-[(3-(三氟甲基)苯基)氨基]喹唑啉(153mg,0.5mmol)、丙烯酸(73mg,1.0mol)和吡啶(206mg,2.5mmol)的THF/DMF(4∶1,2.5ml)溶液中,搅拌。15分钟后,将反应混合物在25℃下搅拌1小时,然后再冷却至0℃。加入稀盐酸(0.5M,10ml),15分钟后,通过布氏漏斗过滤收集沉淀。残余物用水(5ml)和乙醚(2×5ml)洗涤,在75℃真空炉中过夜干燥,得到N-[4-[(3-(三氟甲基)苯基氨基]-喹唑啉-6-基]-丙烯酰胺盐酸盐(87mg,45%),为浅绿色固体,mp195-199℃。
对C18H13F3N4O·HCl·0.5H2O的元素分析:计算值:C,53.54;H,3.74;N,13.88%。实测值:C,53.70;H,3.72;N,13.73%。1H NMR[(CD3)2SO]:δ11.59(brs,1H,NH),10.99(s,1H,NH),9.17(d,J=2.0Hz,H5),8.92(s,1H,H2),8.12(s,1H,H2′),8.10(dd,J=2.0,9.2Hz,1H,H7),8.04(d,J=8.0Hz,1H,H6′),7.98(d,J=9.0Hz,1H,H8),7.74(t,J=7.9Hz,1H,H5′),7.68(d,J=7.8Hz,1H,H4′),6.60(dd,J=10.1,16.9Hz,1H,CH=CH2),6.38(dd,J=1.6,16.9Hz,1H,CH=CH2),5.89(dd,J=1.6,10.1Hz,1H,CH=CH2).
质谱(CI)359(45,MH+),134(100).
实施例21
N-[4-[(3-溴苯基)氨基]-7-[3-(4-吗啉代)丙氧基]-喹唑啉-6-基]-丙烯酰胺
在氮气氛下,将金属钠(27.6mmol,0.63g)加至3-吗啉代丙-1-醇(22.0mmol,3.20g)的THF(60ml)溶液中。将所得悬浮液在20℃下搅拌2小时,然后,在氮气氛下用套管加至4-[(3-溴苯基)氨基]-7-氟-6-硝基喹唑啉(J Med Chem,1996(39):918)(2.0g,5.51mmol)的THF(50ml)溶液中。然后,将溶液加热回流24小时,再用水稀释,用乙酸乙酯萃取。合并后的有机萃取液用无水硫酸钠干燥,减压浓缩,在氧化铝柱上进行色谱处理,用乙酸乙酯/己烷(1∶1)至甲醇/二氯甲烷/乙酸乙酯(2∶3∶5)洗脱,得到N-[4-[(3-溴苯基)氨基]-7-[3-(4-吗啉代)丙氧基]-6-硝基喹唑啉(1.75g,65%),为黄色粉末,mp(甲醇)216-220℃。1H NMR[(CD3)2SO]:δ10.12(s,1H,NH),9.24(s,1H,芳族),8.69(s,1H,芳族),8.19(t,J=1.8Hz,1H,H-2′),7.88(dt,Jd=7.8Hz,Jt=1.4Hz,1H,H-6′),7.49(s,1H,芳族),7.38(t,J=8.0Hz,1H,H-5′),7.34(dt,Jd=8.1Hz,Jt=1.4Hz,1H,H-4′),4.35(t,J=6.2Hz,2H,CH2CH2CH2O),3.58(t,J=4.6Hz,4H,吗啉代亚甲基),2.45(t,J=7.0Hz,2H,NCH2CH2CH2),2.37(br s,4H,吗啉代亚甲基),1.94(五重峰,J=6.6Hz,2H,CH2CH2CH2).13C NMR:δ157.76,157.26,153.76,153.21,140.32,138.86,130.37,126.38,124.26,121.70,121.13,120.72,110.11,107.88,67.87,66.13(×2),54.42,53.28(×2),25.30.
对C21H22BrN5O4·0.75H2O的元素分析:计算值:C,50.3;H,4.7;N,14.0%。实测值:C,50.3;H,4.4;N,13.8%。
将新洗涤过(1N盐酸,再用蒸馏水)的铁粉(12mmol,0.686g)分批加至含冰乙酸(2.0ml)的上述硝基喹唑啉(1.50g,3.07mmol)的乙醇/水(2∶1,80ml)的回流溶液中。将形成的悬浮液在剧烈搅拌下加热回流20分钟,然后冷却,加入浓氨水碱化,用硅藻土垫进行过滤,用乙醇洗涤该垫,滤液经减压浓缩,用水稀释,用乙酸乙酯萃取。合并后的有机萃取液用无水硫酸钠干燥,减压浓缩,用III级氧化铝柱进行色谱处理,用二氯甲烷/乙酸乙酯(1∶1)至甲醇/乙酸乙酯(2∶98)洗涤,得到6-氨基-4-[(3-溴苯基)氨基]-7-[(3-吗啉代)丙氧基]-喹唑啉(1.08g,77%),为浅棕色粉末,mp(乙酸乙酯/己烷)158-160℃。1H NMR[(CD3)2SO],(400MHz):δ9.37(s,1H,NH),8.40(s,1H,芳族),8.24(t,J=1.9Hz,1H,H-2′),7.86(ddd,J=8.2,0.8,1.8Hz,1H,H-6′),7.42(s,1H,芳族),7.30(t,J=8.1Hz,1H,H-5′),7.21(ddd,J=8.2,1.0,1.9Hz,1H,H-4′),7.09(s,1H,芳族),5.36(s,2H,NH2),4.20(t,J=6.2Hz,2H,CH2CH2CH2O),3.59(t,J=4.6Hz,4H,吗啉代亚甲基),2.50(t,J=7.3Hz,2H,NCH2CH2CH2),2.39(br s,4H,吗啉代亚甲基),1.99(五重峰,J=6.7Hz,2H,CH2CH2CH2).13C NMR:δ154.88,151.94,150.19,144.84,141.94,138.50,130.16,124.66,123.02,121.09,119.65,110.42,106.37,100.81,66.45,66.14(×2),54.77,53.29(×2),25.50.
对C21H24BrN5O2·0.25H2O的元素分析:计算值:C,54.5;H,5.3;N,15.1%。实测值:C,54.6;H,5.5;N,15.0%。
在氮气氛下,向搅拌中的上述6-氨基-喹唑啉(0.50g,1.09mmol)、丙烯酸(6.54mmol,449μL)和三乙胺(过量,2.0ml)的DMF(20ml)溶液中加入1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺盐酸盐(EDCI·HCl)(3mol,3.27mmol,627mg)。将反应混合物在0℃下搅拌15分钟,然后升温至室温,再搅拌2小时。减压除去溶剂,将形成的残余物用饱和碳酸氢钠稀释,重复用乙酸乙酯萃取。合并后的有机萃取液用盐水洗涤,用无水硫酸钠干燥,减压浓缩。用III级氧化铝柱进行色谱处理,用乙酸乙酯/己烷(9∶1)至甲醇/乙酸乙酯(2∶98)洗涤,得到N-[4-[(3-溴苯基)氨基]-7-[3-(4-吗啉代)丙氧基]-喹唑啉-6-基]-丙烯酰胺(329mg,59%),为乳油色粉末,mp(乙酸乙酯/己烷)170-172℃。1H NMR[(CD3)2SO]:δ 9.78(s,1H,CONH),9.62(s,1H,NH),8.89(s,1H,芳族),8.56(s,1H,芳族),8.18(t,J=1.9Hz,1H,H-2′),7.88(br d,J=8.2Hz,1H,H-6′),7.34(t,J=8.1Hz,1H,H-5′),7.30(s,1H,芳族),7.27(ddd,J=7.9,1.4,0.8Hz,1H,H-4′),6.72(dd,J=17.0,10.2Hz,1H,CH2CHCO),6.33(dd,J=17.0,1.9Hz,1H,CH2CHCO),5.83(dd,J=10.2,1.9Hz,1H,CH2CHCO),4.27(t,J=6.3Hz,2H,CH2CH2CH2O),3.58(t,J=4.6Hz,4H,吗啉代亚甲基),2.48(t,J=7.1Hz,2H,NCH2CH2CH2),2.38(br s,4H,吗啉代亚甲基),1.99(五重峰J=6.7Hz,2H,CH2CH2CH2).13C NMR:δ163.49,156.68,154.96,153.92,149.19,141.20,131.58,130.19,127.16,126.95,125.52,123.97,121.03,120.52,116.78,108.80,107.28,66.96,66.14(×2),54.54,53.28(×2).25.31.
对C24H26BrN5O3·0.5H2O的元素分析:计算值:C,55.3;H,5.2;N,13.4%。实测值:C,55.3;H,4.9;N,13.3%。
实施例22
N-[4-[(3-甲基苯基)氨基]-7-[3-(4-吗啉代)丙氧基]-喹唑啉-6-基]-丙烯酰胺
将包含2滴DMF的7-氟-6-硝基喹唑酮(2.40g,11.48mmol)的纯SOCl2(25ml)悬浮液回流3小时,直至其澄清。然后,真空除去过量的SOCl2,向残余物中加入无水苯,然后减压蒸馏以除去所有痕量的SOCl2,得到粗品4-氯-7-氟-6-硝基喹唑啉,将其溶解于无水二氯甲烷(50ml)中,并加至搅拌中的间甲苯胺的异丙醇(30ml)溶液中。将反应混合物在20℃下搅拌30分钟,然后加入己烷(200ml),沉淀出作为盐酸盐的产物。滤出沉淀,用己烷洗涤,然后,在温和加热下,将其溶解于甲醇/水(4∶1,150ml)。然后,向溶液中加入过量的三乙胺,再加入水(400ml)以沉淀出游离碱,然后,将这种游离碱滤出,用水洗涤,减压干燥,得到7-氟-4-[(3-甲基苯基)-氨基]-6-硝基喹唑啉(3.01g,88%),为黄色粉末,mp(二氯甲烷/己烷)191-192℃。1H NMR[(CD3)2SO]:δ10.38(s,1H,NH),9.62(d,J=8.1Hz,1H,H-5),8.67(s,1H,H-2),7.80(d,J=12.6Hz,1H,H-8),7.63(br d,J=8.2Hz,1H,H-6′),7.60(br s,1H,H-2′),7.31(t,J=7.8Hz,1H,H-5′),7.03(br d,J=7.5Hz,1H,H-4′),2.35(s,3H,ArCH3).对C15H11FN4O2的元素分析:计算值:C,60.4;H,3.7;N,18.8%。实测值:C,60.6;H,3.6;N,19.0%。
在氮气氛下,向3-吗啉代丙-1-醇(8.40mmol,1.22g)的THF(40ml)溶液中加入金属钠(11.8mmol,0.27g)。将形成的悬浮液在20℃下搅拌2小时,然后,在氮气氛下,将其用套管加至7-氟-4-[(3-甲基苯基)-氨基]-6-硝基喹唑啉(0.70g,2.35mmol)的THF(30ml)溶液中。在上述的反应和处理后,在硅胶上进行色谱处理,用甲醇/二氯甲烷/乙酸乙酯(5∶45∶50)至甲醇/二氯甲烷/乙酸乙酯(3∶7∶10)洗脱,得到4-[(3-甲基苯基)氨基]-7-[(3-吗啉代)丙氧基]-6-硝基-喹唑啉(0.87g,88%),为黄色粉末,mp(二氯甲烷/己烷)169-170℃。1H NMR[(CD3)2SO]:δ10.00(s,1H,NH),9.26(s,1H,芳族),8.62(s,1H,芳族),7.64(br d,J=8.1Hz,1H,H-6′),7.62(br s,1H,H-2′),7.45(s,1H,芳族),7.29(t,J=7.8Hz,1H,H-5′),6.99(br d,J=7.5Hz,1H,H-4′),4.34(t,J=6.1Hz,2H,CH2CH2CH2O),3.58(t,J=4.6Hz,4H,吗啉代亚甲基),2.46(t,J=7.0Hz,2H,NCH2CH2CH2),2.38(br s,4H,吗啉代亚甲基),2.35(s,3H,CH3Ar),1.94(五重峰,J=6.6Hz,2H,CH2CH2CH2).对C22H25N5O4的元素分析:计算值:C,62.4;H,6.0;N,16.5%。实测值:C,62.2;H,6.1;N,16.5%。
将上述硝基喹唑啉(0.71g,1.68mmol)的甲醇/乙酸乙酯(2∶1,60ml)溶液在Pd-C进行氢化(60psi)6小时,然后通过硅藻土过滤。减压浓缩滤液,得到6-氨基-4-[(3-甲基苯基)氨基]-7-[(3-吗啉代)丙氧基]-喹唑啉,其可不经进一步处理而使用。向这种喹唑啉(0.7g,1.8mmol)、丙烯酸(6mol,10.8mmol,776μL)、三乙胺(过量,4.0ml)的搅拌中溶液中加入1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺盐酸盐(EDCI·HCl)(3mol,5.38mmol,1.03g)。进行上述标准过程,经硅胶色谱处理,用二氯甲烷/乙酸乙酯(1∶1)至甲醇/二氯甲烷/乙酸乙酯(3∶7∶10)洗脱,得到N-[4-[(3-甲基苯基)氨基]-7-[3-(4-吗啉代)丙氧基]-喹唑啉-6-基]-丙烯酰胺(175mg,22%),为乳油色粉末,mp(乙酸乙酯/乙醚)69-72℃。1H NMR[(CD3)2SO],(400MHz):δ9.60(s,1H,可交换),9.59(s,1H,NH), 8.86(s,1H,H5),8.48(s,1H,H2),7.62(br d,J=8.0Hz,1H,H-6′),7.61(br s,1H,H-2′),7.26(s,1H,H8),7.25(t,J=7.8Hz,1H,H-5′),6.92(br d,J=7.4Hz,1H,H-4′),6.70(dd,J=16.9,10.2Hz,1H,CH2CHCO),6.32(dd,J=16.9,1.9Hz,1H,CH2CHCO),5.82(dd,J=10.2,1.9Hz,1H,CH2CHCO),4.26(t,J=6.3Hz,2H,CH2CH2CH2O),3.58(t,J=4.6Hz,4H,吗啉代亚甲基),2.48(t,J=7.1Hz,2H,NCH2CH2CH2),2.38(br s,4H,吗啉代亚甲基),2.33(s,3H,CH3Ar),1.99(五重峰,J=6.7Hz,2H,CH2CH2CH2).对C25H29N5O3·0.25H2O的元素分析:计算值:C,66.4;H,6.6;N,15.5%。实测值:C,66.3;H,6.9;N,15.9%。
实施例23
N-[4-[(3-甲基苯基)氨基]-7-[3-(4,N-甲基-1,N-哌嗪基)丙氧基]-喹唑啉-6-
基]-丙烯酰胺
在氮气氛下,向3-N-(4-甲基哌嗪基)丙-1-醇(6.71mmol,1.06g)的THF(15ml)溶液中加入金属钠(10.1mmol,0.23g)。将形成的悬浮液在20℃下搅拌2小时,然后,在氮气氛下,将其用套管加至7-氟-4-[(3-甲基苯基)-氨基]-6-硝基喹唑啉(0.50g,1.68mmol)的THF(20ml)溶液中。将暗红色的溶液加热回流24小时,再用水稀释,用乙酸乙酯萃取。合并后的有机萃取液用无水硫酸钠干燥,减压浓缩,在氧化铝上进行色谱处理,用乙酸乙酯/己烷(1∶1)至乙酸乙酯(2∶3∶5)洗脱,得到4-[(3-甲基苯基)氨基]-7-[3-N-(4-甲基哌嗪基)丙氧基]-6-硝基-喹唑啉(0.67g,91%),为黄色粉末,mp(乙醚/己烷)155-156℃。1H NMR[(CD3)2SO]:δ10.00(s,1H,NH),9.26(s,1H,H5,H2H5),8.61(s,1H,H2),7.64(br d,J=8.4Hz,1H,H-6′),7.62(br s,1H,H-2′),7.43(s,1H,H8),7.29(t,J=7.8Hz,1H,H-5′),6.99(br d,J=7.4Hz,1H,H-4′),4.32(t,J=6.0Hz,2H,CH2CH2CH2O),2.44(t,J=7.0Hz,2H,NCH2CH2CH2),2.39-2.28(br s,8H,哌嗪基亚甲基),2.34(s,3H,CH3Ar),2.14(s,3H,CH3N),1.92(五重峰,J=6.6Hz,2H,CH2CH2CH2).
对CH28N6O3的元素分析:计算值:C,63.3;H,6.5;N,19.3%。实测值:C,63.4;H,6.8;N,19.6%。
将上述硝基喹唑啉(0.61g,1.40mmol)的甲醇/乙酸乙酯(2∶1,50ml)溶液在Pd-C进行氢化(60psi)5小时,然后通过硅藻土过滤。减压浓缩滤液,用III级氧化铝进行色谱处理,用甲醇/乙酸乙酯(5∶95)洗脱,得到6-氨基-4-[(3-甲基苯基)氨基]-7-[3-N-(4-甲基哌嗪基)丙氧基]-喹唑啉(361mg),其表现出可迅速脱色,可不经进一步处理而使用。向搅拌中的这种喹唑啉(0.36g,0.89mmol)、丙烯酸(6mol,5.53mmol,366μL)、三乙胺(过量,2.0ml)的DMF(20ml)溶液中加入1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺盐酸盐(EDCI·HCl)(3mol,2.66mmol,511mg)。进行上述标准过程,经III级氧化铝色谱处理,用乙酸乙酯至甲醇/乙酸乙酯(2∶98)洗脱,得到N-[4-[(3-甲基苯基)氨基]-7-[3-N-(4-甲基哌嗪基)丙氧基]-喹唑啉-6-基]-丙烯酰胺(65mg,16%),为无色玻璃状,mp(乙醚/己烷)60-66℃。1H NMR[(CD3)2SO]:δ9.60(s,1H,NH),9.59(s,1H,NH),8.86(s,1H,H5),8.48(s,1H,H2),7.62(br d,J=8.0Hz,1H,H-6′),7.62(br s,1H,H-2′),7.25(t,J=8.1Hz,1H,H-5′),7.25(s,1H,H8),6.92(br d,J=7.5Hz,1H,H-4′),6.70(dd,J=17.0Hz,J=10.2Hz,1H,CH2CHCO),6.31(dd,J=16.9,1.8Hz,1H,CH2CHCO),5.83(dd,J=10.2,1.8Hz,1H,CH2CHCO),4.24(t,J=6.3Hz,2H,CH2CH2CH2O),2.47(t,J=7.1Hz,2H,NCH2CH2CH2),2.41-2.28(br s,8H,哌嗪基亚甲基),2.33(s,3H,CH3Ar),2.15(s,3H,CH3N),1.97(五重峰,J=6.8Hz,2H,CH2CH2CH2).EI HRMS(M+)C26H32N6O2计算值:460.2587。
实测值:460.2576。
实施例24N-[4-[(3-溴苯基)氨基]-7-[3-(4,N-甲基-1,N-哌嗪基)丙氧基]-喹唑啉-6-基]- 丙烯酰胺
在氮气氛下,向3-N-(4-甲基哌嗪基)丙-1-醇(8.81mmol,1.39g)的THF(40ml)溶液中加入金属钠(13.2mmol,0.30g)。将形成的悬浮液在20℃下搅拌2小时,然后,在氮气氛下,将其用套管加至4-[(3-溴苯基)-氨基]-7-氟-6-硝基喹唑啉[J Med Chem,1996(39):918](0.80g,2.20mmol)的THF(30ml)溶液中。进行与前述实施例相同的过程,在硅胶上进行色谱处理,用甲醇/二氯甲烷/乙酸乙酯(1∶9∶10)至甲醇/二氯甲烷/乙酸乙酯(2∶3∶5)洗脱,得到4-[(3-溴苯基)氨基]-7-[3-N-(4-甲基哌嗪基)丙氧基]-6-硝基-喹唑啉(0.36g,33%),为黄色粉末,mp(三盐酸盐)(甲醇/乙醚)233℃(dec)。1H NMR(游离碱,(CD3)2SO]:δ10.12(s,1H,NH),9.24(s,1H,H5),8.69(s,1H,H2),8.19(br s,1H,H-2′),7.88(br d,J=7.8Hz,1H,H-6′),7.47(s,1H,H8),7.38(t,J=7.8Hz,1H,H-5′),7.34(dt,Jd=8.0,Jt=1.3Hz,1H,H-4′),4.33(t,J=6.1Hz,2H,CH2CH2CH2O),2.45(t,J=7.0Hz,2H,NCH2CH2CH2),2.42-2.29(br s,8H,哌嗪基亚甲基),2.15(s,3H,CH3N),1.92(五重峰,J=6.7Hz,2H,CH2CH2CH2).对C22H25BrN6O3·3HCl·H2O的元素分析:计算值:C,42.0;H,4.8;N,13.4;Cl,16.9%。实测值:C,42.1;H,4.5;N,13.3;Cl,16.9%。
将新洗涤过(1N盐酸,再用蒸馏水)的铁粉(4摩尔当量,0.138g)分批加至含冰乙酸(1.0ml)的上述硝基喹唑啉(0.31g,0.62mmol)的乙醇/水(2∶1,50ml)的回流溶液中。将形成的悬浮液在剧烈搅拌下加热回流20分钟,然后冷却,加入浓氨水碱化,用硅藻土垫进行过滤,用乙醇洗涤该垫,滤液经减压浓缩,用水稀释,用乙酸乙酯萃取。合并后的有机萃取液用无水硫酸钠干燥,减压浓缩,用III级氧化铝柱进行色谱处理,用甲醇/乙酸乙酯(5∶95)洗涤,得到6-氨基-4-[(3-溴苯基)氨基]-7-[(3-N-(4-甲基哌嗪基)丙氧基]-喹唑啉(238mg,82%),为乳油色粉末,mp(二氯甲烷)171-172℃。1H NMR[(CD3)2SO]:δ9.36(s,1H,NH),8.38(s,1H,H2),8.22(t,J=1.9Hz,1H,H-2′),7.86(ddd,J=8.2,0.8,1.9Hz,1H,H-6′),7.40(s,1H,H5),7.30(t,J=8.0Hz,1H,H-5′),7.20(ddd,J=8.3,1.0,1.9Hz,1H,H-4′),7.09(s,1H,H8),5.34(s,2H,NH2),4.19(t,J=6.2Hz,2H,CH2CH2CH2O),2.49(模糊的t,J=7Hz,2H,NCH2CH2CH2),2.43-2.29(br s,8H,哌嗪基亚甲基),2.16(s,3H,CH3N),1.97(五重峰,J=6.8Hz,2H,CH2CH2CH2).
对C22H27BrN6O·1.25H2O的元素分析:计算值:C,53.5;H,6.0;N,17.0%。实测值:C,53.5;H,5.7;N,17.0%。
在氮气氛下,向搅拌中的丙烯酸(6mol,2.84mmol,195μL)、三乙胺(过量,1.0ml)的DMA(20ml)溶液中加入上述氨基喹唑啉(233mg,0.47mmol)和1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺盐酸盐(EDCI·HCl)(3mol,1.42mmol,273mg)。进行上述标准过程,经III级氧化铝色谱处理,用乙酸乙酯/己烷(1∶1)至甲醇/乙酸乙酯(2∶98)洗脱,得到N-[4-[(3-溴苯基)氨基]-7-[3-N-(4-甲基哌嗪基)丙氧基]-喹唑啉-6-基]-丙烯酰胺(145mg,58%),为乳油色粉末,mp(二氯甲烷/乙醚/己烷)105-107℃。1H NMR[(CD3)2SO]:δ9.78(s,1H,CONH),9.61(s,1H,NH),8.89(s,1H,H5),8.56(s,1H,H2),8.17(t,J=1.9Hz,1H,H-2′),7.87(br d,J=8.5Hz,1H,H-6′),7.34(t,J=8.1Hz,1H,H-5′),7.28(s,1H,H8),7.27(br dt,Jd=8Hz,Jt=1Hz,1H,H-4′),6.72(dd,J=17.0,10.3Hz,1H,CH2CHCO),6.32(dd,J=17.0,1.9Hz,1H,CH2CHCO),5.83(dd,J=10.2,1.9Hz,1H,CH2CHCO),4.26(t,J=6.3Hz,2H,CH2CH2CH2O),2.47(t,J=7.1Hz,2H,NCH2CH2CH2),2.42-2.27(br s,8H,哌嗪基亚甲基),2.15(s,3H,CH3N),1.98(五重峰,J=6.7Hz,2H,CH2CH2CH2).对C25H29BrN6O2·0.5H2O的元素分析:计算值:C,56.2;H,5.7;N,15.7%。实测值:C,56.3;H,5.6;N,15.5%。
实施例25
N-[4-[(3-溴苯基)氨基]-7-[3-(1,N-咪唑基)丙氧基]-喹唑啉-6-基]-丙烯酰胺
通过套管向经己烷预洗涤过的氢化钠(5.50mmol,220mg,60%矿物油的分散液)在THF(20ml)的悬浮液中加入3-N-(咪唑基)丙-1-醇(4.84mmol,0.61g)的THF(30ml)溶液。在氮气氛及20℃下,将形成的悬浮液搅拌2小时,期间,从溶液中部分沉淀出所需的醇钠,然后,向该悬浮液中加入固体4-[(3-溴苯基)-氨基]-7-氟-6-硝基喹唑啉[J Med Chem,1996(39):918](0.80g,2.20mmol),得到一种暗红色溶液,将其加热回流24小时,再用水稀释,用乙酸乙酯萃取。合并后的有机萃取液用无水硫酸钠干燥,减压浓缩,用硅胶进行色谱处理,用二氯甲烷/乙酸乙酯(1∶1)至甲醇/二氯甲烷/乙酸乙酯(3∶7∶10)洗脱,得到4-[(3-溴苯基)氨基]-7-[3-N-(咪唑基)丙氧基]-6-硝基-喹唑啉(524mg,51%),为黄色粉末,mp(二氯甲烷/己烷)212-215℃。1H NMR[(CD3)2SO]:δ10.16(s,1H,NH),9.30(s,1H,H5),8.70(s,1H,H2),8.19(t,J=1.6Hz,1H,H-2′),7.88(dt,Jd=7.8Hz,Jt=1.5Hz,1H,H-6′),7.63(s,1H,咪唑基次甲基),7.48(s,1H,H8),7.39(t,J=7.9Hz,1H,H-5′),7.35(dt,Jd=8.0Hz,Jt=1.6Hz,1H,H-4′),7.21(s,1H,咪唑基次甲基),6.90(s,1H,咪唑基次甲基),4.22(t,J=6.0Hz,2H,CH2CH2CH2),4.18(t,J=6.8Hz,2H,CH2CH2CH2),2.26(五重峰,J=6.4Hz,2H,CH2CH2CH2).
对C20H17BrN6O3的元素分析:计算值:C,51.2;H,3.6;N,17.9%。实测值:C,51.0;H,3.6;N,17.6%。
将新洗涤过(1N盐酸,再用蒸馏水)的铁粉(4mol,0.241g)分批加至含冰乙酸(0.7ml)的上述6-硝基喹唑啉(0.51g,1.08mmol)的乙醇/水(2∶1,60ml)的回流溶液中。进行与前述实施例相同的反应和处理过程,用III级氧化铝柱进行色谱处理,用甲醇/乙酸乙酯(5∶95)洗脱,得到6-氨基-4-[(3-溴苯基)氨基]-7-[3-N-(咪唑基)丙氧基]-喹唑啉(389mg,82%),为灰白色粉末,mp(二氯甲烷/乙醚)178-180℃。1H NMR[(CD3)2SO]:δ9.37(s,1H,NH),8.38(s,1H,H2),8.22(t,J=1.8Hz,1H,H-2′),7.86(br d,J=8.1Hz,1H,H-6′),7.66(s,1H,咪唑基次甲基),7.40(s,1H,H5),7.30(t,J=8.1Hz,1H,H-5′),7.23(s,1H,咪唑基次甲基),7.21(br d,J=7.7Hz,1H,H-4′),7.06(s,1H,H8),6.90(s,1H,咪唑基次甲基),5.45(s,2H,NH2),4.28(t,J=7.1Hz,2H,CH2CH2CH2),4.10(t,J=5.8Hz,2H,CH2CH2CH2),2.27(五重峰,J=6.5Hz,2H,CH2CH2CH2).
对C20H19BrN6O·0.5H2O的元素分析:计算值:C,53.6;H,4.5;N,18.7%。实测值:C,53.6;H,4.5;N,18.6%。
在氮气氛下,向搅拌中的6-氨基-4-[(3-溴苯基)氨基]-7-[3-N-(咪唑基)丙氧基]-喹唑啉(383mg,0.87mmol)、丙烯酸(6mol,5.23mmol,359μL)、吡啶(过量,1.0ml)的DMA(20ml)溶液中加入1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺盐酸盐(EDCI·HCl)(5mol,4.36mmol,838mg)。进行上述标准过程,经III级氧化铝色谱处理,用乙酸乙酯/己烷(1∶1)至甲醇/乙酸乙酯(5∶95)洗脱,得到N-[4-[(3-溴苯基)氨基]-7-[3-N-(咪唑基)丙氧基]-喹唑啉-6-基]-丙烯酰胺(9mg,2%),为乳油色粉末,mp(二氯甲烷/乙醚/己烷)235-237℃。1H NMR[(CD3)2SO]:δ9.79(s,1H,CONH),9.60(s,1H,NH),8.88(s,1H,H5),8.55(s,1H,H2),8.18(t,J=1.9Hz,1H,H-2′),7.87(ddd,J=8.2,1.8,1.0Hz,1H,H-6′),7.64(s,1H,咪唑基次甲基),7.34(t,J=8.0Hz,1H,H-5′),7.28(br dt,Jd=8.0Hz,Jt=1.2Hz,1H,H-4′),7.27(s,1H,H8),7.21(t,J=1.3Hz,1H,咪唑基次甲基),6.89(br s,1H,咪唑基次甲基),6.73(dd,J=17.0,10.2Hz,1H,CH2CHCO),6.34(dd,J=17.0,1.8Hz,1H,CH2CHCO),5.85(dd,J=10.2,1.8Hz,1H,CH2CHCO),4.22(t,J=6.9Hz,2H,CH2CH2CH2),4.14(t,J=6.0Hz,2H,CH2CH2CH2),2.27(五重峰,J=6.4Hz,2H,CH2CH2CH2).对C23H21BrN6O2·0.75H2O的元素分析:计算值:C,54.5;H,4.5;N,16.6%。实测值:C,54.5;H,4.4;N,16.2%。
实施例26N-[4-[(3-溴苯基)氨基]-7-[4-(N,N-二甲基氨基)丁氧基]-喹唑啉-6-基]-丙烯 酰胺
通过套管向经己烷预洗涤过的氢化钠(11.0mmol,440mg,60%矿物油的分散液)于THF(20ml)的悬浮液中加入4-(N,N-二甲基氨基)丁-1-醇(8.80mmol,1.03g)的THF(30ml)溶液。在氮气氛及20℃下,将形成的悬浮液搅拌2小时,然后,向该悬浮液中用套管加入4-[(3-溴苯基)-氨基]-7-氟-6-硝基喹唑啉[J Med Chem,1996(39):918-928](0.80g,2.20mmol)于THF(30ml)中的溶液。将得到的暗红色溶液过夜加热回流。进行与前相同的处理过程,再用III级氧化铝进行色谱处理,用乙酸乙酯至甲醇/乙酸乙酯(5∶95)洗脱,得到6-氨基-4-[(3-溴苯基)氨基]-7-[4-(N,N-二甲基氨基)丁氧基]-喹唑啉(310mg,33%),为浅棕色粉末,mp(二氯甲烷/己烷)155-156℃。1H NMR[(CD3)2SO],(400MHz):δ9.36(s,1H,NH),8.39(s,1H,芳族),8.23(t,J=2.0Hz,1H,H-2′),7.86(br d,J=8.0Hz,1H,H-6′),7.41(s,1H,芳族),7.30(t,J=8.1Hz,1H,H-5′),7.20(ddd,J=8.2Hz,J=0.8Hz,J=1.8Hz,1H,H-4′),7.09(s,1H,芳族),5.32(s,2H,NH2),4.17(t,J=6.2Hz,2H,CH2CH2CH2CH2O),2.47(t,J=7.3Hz,2H,NCH2CH2CH2CH2),2.15(s,6H,N(CH3)2),1.84(五重峰,J=6.4Hz,2H,CH2CH2CH2CH2),1.62(五重峰,J=6.9Hz,2H,CH2CH2CH2CH2).对C20H24BrN5O·0.5H2O的元素分析:计算值:C,54.7;H,5.7;N,15.9%。实测值:C,54.3;H,5.8;N,15.8%。
在氮气氛下,向搅拌中的上述6-氨基喹唑啉(276mg,0.64mmol)、丙烯酸(6摩尔当量,3.85mmol,264μL)、三乙胺(过量,1.0ml)的DMA(10ml)溶液中加入1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺盐酸盐(EDCI·HCl)(3摩尔当量,1.92mmol,369mg)。进行上述标准过程,经III级氧化铝色谱处理,用乙酸乙酯/己烷(1∶1)至甲醇/乙酸乙酯(3∶97)洗脱,得到N-[4-[(3-溴苯基)氨基]-7-[4-(N,N-二甲基氨基)丁氧基]-喹唑啉-6-基]-丙烯酰胺(98mg,32%),为乳油色粉末,mp(二氯甲烷/乙醚)112-115℃。1H NMR[(CD3)2SO],(400MHz):δ9.77(s,1H,CONH),9.62(s,1H,NH),8.88(s,1H,芳族),8.56(s,1H,芳族),8.17(t,J=1.9Hz,1H,H-2′),7.87(ddd,J=8.2Hz,J=1.8Hz,J=1.0Hz,1H,H-6′),7.34(t,J=8.0Hz,1H,H-5′),7.29(s,1H,芳族),7.27(ddd,J=8.2Hz,J=1.8Hz,J=1.0Hz,1H,H-4′),6.71(dd,J=17.1Hz,J=10.2Hz,1H,CH2CHCO),6.32(dd,J=17.0Hz,J=1.9Hz,1H,CH2CHCO),5.82(dd,J=10.2Hz,J=1.9Hz,1H,CH2CHCO),4.24(t,J=6.6Hz,2H,CH2CH2CH2CH2O),2.27(t,J=7.2Hz,2H,NCH2CH2CH2CH2),2.12(s,6H,N(CH3)2),1.85(五重峰,J=6.9Hz,2H,CH2CH2CH2CH2),1.60(五重峰,J=7.4Hz,2H,CH2CH2CH2CH2).
对C23H26BrN5O2·1.25H2O的元素分析:计算值:C,54.5;H,5.7;N,13.8%。实测值:C,54.5;H,5.3;N,13.7%。
实施例27
N-[4-[(3-溴-苯基)氨基]-喹唑啉-6-基]-N-[3-吗啉代丙基]丙烯酰胺
将搅拌中的N-[4-[(3-溴-苯基)氨基]-喹唑啉-6-基]-丙烯酰胺(1.78g,4.82mmol)、吗啉(过量,4.0ml)和对甲苯磺酸(催化量)的THF(50ml)溶液在50℃下加热4小时,减压浓缩,用水稀释,用乙酸乙酯萃取。将合并后的有机萃取液用盐水洗涤,用无水硫酸钠干燥,减压浓缩,用硅胶色谱处理,用甲醇/二氯甲烷/乙酸乙酯(15∶40∶45)洗脱,得到N-[4-[(3-溴-苯基)氨基]-喹唑啉-6-基]-3-吗啉代丙基酰胺(1.86g,78%),为乳油色粉末,mp(乙酸乙酯)184-186℃。1H NMR[(CD3)2SO]:δ10.37(s,1H,CONH),9.91(s,1H,NH),8.72(d,J=1.9Hz,1H,H-5),8.58(s,1H,H-2),8.17(t,J=2.1Hz,1H,H-2′),7.86(m,2H,H-7,6′),7.78(d,J=8.9Hz,1H,H-8),7.35(t,J=8.0Hz,1H,H-5′),7.29(dt,Jt=1.2Hz,Jd=8.0Hz,1H,H-4′),3.40(t,J=4.6Hz,4H,吗啉代亚甲基),2.69(t,J=6.6Hz,2H,NCH2CH2CONH),2.58(t,J=6.6Hz,2H,NCH2CH2CONH),2.44(br s,4H,吗啉代亚甲基).13C NMR:δ170.24,157.18,152.86,146.48,141.13,136.87,130.21,128.39,127.01,125.74,124.21,121.03,120.79,115.40,111.46,66.09(×2),54.04,53.00(×2),33.66.
对C21H22BrN5O2的元素分析:计算值:C,55.3;H,4.9;N,15.3%。实测值:C,55.1;H,5.2;N,15.2%。
在氮气氛及0℃下,向搅拌中的上述酰胺(0.85g,1.86mmol)的THF(30ml)溶液中滴加BH3·DMS(2摩尔当量,372μL,10M溶液)。将形成的溶液升温至25℃,搅拌2小时,加入1N盐酸(40ml)使反应停止。然后,将反应混合物在50℃下搅拌2小时,用饱和碳酸钠碱化,用乙酸乙酯萃取。将合并后的有机萃取液用盐水洗涤,用无水硫酸钠干燥,减压浓缩,用硅胶色谱处理,用甲醇/二氯甲烷/乙酸乙酯(3∶8∶8)洗脱,得到N-[4-[(3-溴-苯基)氨基]-6-[(3-吗啉代丙基)氨基]喹唑啉(130mg,16%),为黄色玻璃状物(约90%纯,NMR)。该产物不经纯化即可使用。1H NMR[(CD3)2SO]:δ9.40(s,1H,NHAr),8.37(s,1H,H-2),8.17(t,J=1.9Hz,1H,H-2′),7.91(br d,J=8.2Hz,1H,H-6′),7.54(d,J=9.0Hz,1H,H-8),7.34(t,J=8.0Hz,1H,H-5′),7.27(m,2H,H-4′,7),7.16(d,J=2.2Hz,1H,H-5),6.25(t,J=5.1Hz,1H,CH2NH),3.59(t,J=4.5Hz,4H,吗啉代亚甲基),3.22(q,J=6.0Hz,1H,CH2NH),2.45(t,J=6.9Hz,2H,CH2CH2CH2NH),2.39(br s,4H,吗啉代亚甲基),1.82(五重峰,J=7.0Hz,2H,CH2CH2CH2).
在氮气氛下,向搅拌中的上述胺(133mg,0.30mmol)、丙烯酸(4摩尔当量,1.20mmol,83μL)和三乙胺(过量,0.50ml)的DMF(5.0ml)溶液中加入1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺盐酸盐(EDCI·HCl)(2.0mol,0.60mmol,115mg)。进行上述标准过程,经硅胶色谱处理,用乙酸乙酯/二氯甲烷(1∶1)至甲醇/二氯甲烷/乙酸乙酯(3∶7∶10)洗脱,得到N-[4-[(3-溴苯基)氨基]--喹唑啉-6-基]-N-[3-吗啉代丙基]丙烯酰胺(39mg,26%),为乳油色粉末,mp(二氯甲烷/己烷)171-175℃。1H NMR[(CD3)2SO]:δ9.86(s,1H,NH),8.70(s,1H,H-2),8.52(d,J=2.0Hz,1H,H-5),8.20(t,J=1.9Hz,1H,H-2′),7.91(br d,J=8.6Hz,1H,H-6′),7.89(d,J=8.9Hz,1H,H-8),7.79(dd,J=8.8Hz,J=2.1Hz,1H,H-7),7.38(t,J=7.9Hz,1H,H-5′),7.33(dt,Jd=8.4Hz,Jt=1.7Hz,1H,H-4′),6.22(dd,J=16.7,2.3Hz,1H,CH2CHCO),6.05(br s,1H,CH2CHCO),5.61(br d,J=8.8Hz,1H,CH2CHCO),3.87(t,J=7.4Hz,2H,CH2NRCO),3.49(t,J=4.5Hz,4H,吗啉代亚甲基),2.28(t,J=7.1Hz,2H,CH2CH2CH2NRCO),2.27(br s,4H,吗啉代亚甲基),1.69(五重峰,J=7.3Hz,2H,CH2CH2CH2)·DEI HRMS(M+).对C24H26BrN5O2的计算值:497.1249。实测值:497.1250。
实施例28
N-[4-(3-溴-苯基氨基)-喹唑啉-6-基]-丙酰胺
在氮气氛及25℃下,向6-氨基-4-[(3-溴苯基)氨基]喹唑啉(157mg,0.5mmol)的无水THF(3ml)溶液中滴加丙酰氯(0.05ml,0.58mmol)。立即形成黄色固体。45分钟后,过滤收集固体,用乙醚洗涤,干燥。用湿甲醇重结晶,得到所需产物(97mg,47%),mp265-266℃。1H NMR[(CD3)2SO]:δ11.3(brs,1H,NH),10.53(s,1H,NH),9.02(s,1H,H5),8.88(s,1H,H2),8.00-7.97(m,2H,H7,H2′),7.89(d,J=9.1Hz,1H,H8),7.71(d,J=7.8Hz,1H,H6′),7.50(d,J=8.3Hz,1H,H4′),7.45(t,J=8.1Hz,1H,H5′),2.45(q,J=7.3Hz,2H,CH2),1.15(t,J=7.5Hz,3H,CH3).
质谱(CI):373(84,81BrMH+),372(43,81BrM+),371(100,79BrMH+),370(28,79BrM+).
对C17H15N4BrO·HCl·0.5H2O的元素分析:计算值:C,49.00;H,4.11;N,13.45%。实测值:C,48.89;H,3.97;N,13.36%。
实施例29
N-[4-[(3-溴-苯基)氨基]-喹唑啉-6-基]-甲基丙烯酰胺
在氮气氛下,向搅拌下的6-氨基-4-[(3-溴苯基)氨基]喹唑啉(J MedChem,1995;38:3482)(0.50g,1.59mmol)的THF(20ml)溶液中滴加入三乙胺(过量,1.0ml)、催化量的DMAP和甲基丙烯酰氯(1.1摩尔当量,1.75mmol,171μL)。将反应混合物在25℃下搅拌1.5小时,期间两次加入甲基丙烯酰氯(每次50μL)。将反应混合物用饱和碳酸氢钠稀释,用乙酸乙酯萃取。将合并后的有机萃取液用无水硫酸钠干燥,减压浓缩,用硅胶色谱处理,用二氯甲烷/乙酸乙酯(1∶1)至甲醇/二氯甲烷/乙酸乙酯(5∶45∶50)洗脱。由乙酸乙酯重结晶,得到N-[4-[(3-溴-苯基)氨基]-喹唑啉-6-基]-2-甲基丙烯酰胺(195mg,32%),为乳油色粉末,mp 244-245℃。1H NMR[(CD3)2SO]:δ10.15(s,1H,CONH),9.90(s,1H,NH),8.80(br s,1H,H-5),8.60(s,1H,H-2),8.20(br s,1H,H-2′),7.97(br d,J=8.6Hz,1H,H-7),7.89(br d,J=7.7Hz,1H,H-6′),7.80(d,J=8.9Hz,1H,H-8),7.35(t,J=8.0Hz,1H,H-5′),7.30(br d,J=7.5Hz,1H,H-4′),5.94(s,1H,CH2C(CH3)CO),5.62(s,1H,CH2C(CH3)CO),2.02(s,3H,CH2C(CH3)CO).13C NMR:δ166.71,157.17,153.07,146.69,141.09,139.93,136.62,130.23,128.24,128.11,125.73,124.11,121.04,120.66,120.51,115.19,113.28,18.60.
对C18H15BrN4O的元素分析:计算值:C,56.4;H,4.0;N,14.6%。实测值:C,56.1;H,3.9;N,14.5%。
实施例30
N-[4-(3-溴-苯基氨基)-喹唑啉-6-基]-乙烯基磺酰胺
在氮气氛下,向搅拌下的6-氨基-4-[(3-溴苯基)氨基]喹唑啉(J MedChem,1995;38:3482)(0.30g,0.95mmol)的THF(20ml)溶液中滴加入三乙胺(3.5摩尔当量,3.33mmol,245μL)、催化量的DMAP和氯乙磺酰氯(1.2摩尔当量,1.14mmol,119μL)。将反应混合物在25℃下搅拌1小时,将反应混合物用饱和碳酸氢钠稀释,用乙酸乙酯萃取。将合并后的有机萃取液用无水硫酸钠干燥,减压浓缩,用硅胶色谱处理,用甲醇/二氯甲烷/乙酸乙酯(3∶47∶50)洗脱。由二氯甲烷/己烷重结晶,得到N-[4-[(3-溴-苯基)氨基]-喹唑啉-6-基]-乙烯基磺酰胺(210mg,542%),为乳油色粉末,mp 217℃(dec)。1H NMR[(CD3)2SO]:δ10.31(s,1H,SO2NH),9.96(s,1H,NH),8.60(s,1H,H-2),8.20(d,J=2.0Hz,1H,H-5),8.14(br s,1H,H-2′),7.85(br d,J=7.9Hz,1H,H-6′),7.81(d,J=8.9Hz,1H,H-8),7.67(dd,J=8.9,2.1Hz,1H,H-7),7.37(t,J=8.0Hz,1H,H-5′),7.32(br d,J=8.1Hz,1H,H-4′),6.90(dd,J=16.4,9.8Hz,1H,CH2CHSO2),6.17(d,J=16.4Hz,1H,CH2CHSO2),6.06(d,J=9.8Hz,1H,CH2CHSO2).13C NMR:δ157.18,153.47,147.17,140.83,136.02,135.48,130.25,129.03,128.44,127.77,126.08,124.60,121.18,121.03,115.43,114.01.
对C16H13BrN4O2S的元素分析:计算值:C,47.4;H,3.2;N,13.8%。实测值:C,47.7;H,3.1;N,13.8%。
实施例31
N-[4-(3-溴-苯基氨基)-喹唑啉-6-基]-E-丁-2-烯酰胺
在0℃及氮气氛下,向搅拌中的6-氨基-4-[(3-溴苯基)氨基]喹唑啉(316mg,1.0mmol)的THF(6ml)溶液中加入反式-巴豆酰氯。加入后即形成黄色固体。2.5小时后,通过布氏漏斗过滤收集固体并用乙酸乙酯进行声处理,得到标题化合物(216mg,52%),mp279-281℃。1H NMR[(CD3)2SO]:δ11.55(brs,1H,NH),10.78(s,1H,NH),9.17(d,J=1.9Hz,1H,H5),8.97(s,1H,H2),8.12(dd,J=9.1,2.0Hz,1H,H7),8.05(t,J=1.9Hz,1H,H2′),7.99(d,J=9.0Hz,1H,H8),7.76(dd,J=8.1,2.0Hz,1H,H6′),7.58(dd,J=8.6,1.7Hz,1H,H4′),7.52(t,J=8.1Hz,1H,H5'),7.03-6.94(m,1H,[(CO)CH=],6.34(dd,J=15.1,1.7Hz,1H,CH=CHCH3),1.98(dd,J=6.8,1.4Hz,3H,CH3).
质谱(CI):385(89,81BrMH+),384(51,81BrM+),383(100,79BrMH+),382(37,79BrM+).
对C18H15N4BrO·HCl的元素分析:计算值:C,51.51;H,3.84;N,13.35%。实测值:C,51.29;H,3.52;N,13.13%。
实施例32
N-[4-(3-溴-苯基氨基)-喹唑啉-6-基]-4,4,4三氟-E-丁-2-烯酰胺
在0℃及氮气氛下,向搅拌中的6-氨基-4-[(3-溴苯基)氨基]喹唑啉(158mg,0.5mmol)和4,4,4-三氟丁-2-烯酸(153mg,1.1mmol)的THF/DMF(4∶1,2.5ml)溶液中加入1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺盐酸盐(192mg,1.0mmol)。1小时后,加入水(10ml),在15分钟后,通过布氏漏斗过滤收集沉淀。残余物用水(2×5ml)和乙醚(10ml)洗涤,空气干燥。将固体悬浮于乙酸乙酯(10ml)中,迅速回流,用声波处理10分钟,再通过布氏漏斗过滤收集固体,用乙酸乙酯(5ml)洗涤,在75℃的真空炉中干燥1.5小时,得到N-[4-(3-溴-苯基氨基)-喹唑啉-6-基]-4,4,4三氟-丁-2-烯酰胺0.4盐酸盐(76mg,33%),为浅黄色固体,mp273-278℃。
对C18H13BrF3N4O·0.4HCl的元素分析:计算值:C,47.85;H,2.77;N,12.40%。实测值:C,47.89;H,2.66;N,12.27%。1H NMR[(CD3)2SO]:δ11.09(brs,1H,NH),10.43(s,1H,NH),8.90(s,1H,H2),8.70(s,1H,H5),8.11(s,1H,H2′),7.97(dd,J=2.5,9.2Hz,1H,H7),7.87(d,J=9.0Hz,1H,H8),7.81(d,J=6.9Hz,1H,H6′),7.41-7.33(m,2H,H5′& H4′),7.11(d,J=16.4Hz,1H,CH=CHCF3),7.03(dq,Jd=16.4Hz,Jq=6.4Hz,1H,CH=CHCF3).
质谱(CI)439(78 81BrM+),437(100 79BrM+).
实施例33
N-[4-(3-溴-苯基氨基)-喹唑啉-6-基]-丙炔酰胺
在0℃及氮气氛下,向搅拌中的6-氨基-4-[(3-溴苯基)氨基]喹唑啉(158mg,0.5mmol)和丙炔酸(0.08ml,1.1mmol)的DMF(1.5ml)溶液中加入1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺盐酸盐(200mg,1.04mmol)。将形成的溶液在0℃下搅拌30分钟,用水使反应停止。通过布氏漏斗过滤收集形成的细固体,然后将其溶解于甲醇中,通过硅胶上的制备TLC进行纯化,用10%甲醇/氯仿洗脱。经分离得到标题化合物,为黄色固体(21mg,12%),mp>310℃。1H NMR[(CD3)2SO]:δ11.18(brs,1H,NH),9.94(s,1H,NH),8.75(s,1H,H5),8.59(s,1H,H2),8.15(s,1H,H2′),7.85-7.79(m,3H,H7,H8,H6′),7.37-7.28(m,2H,H5′,H4′),4.53(s,1H,CH).
质谱(CI):369(47,81BrMH+),368(24,81BrM+),367(50,79BrMH+),366(13,79BrM+),91(100).Calculated for C17H11N4BrO:对C17H11BrN4O的元素分析:计算值:C,55.61;H,3.02;N,15.26%。实测值:C,55.40;H,2.84;N,15.18%。
实施例34
N-[4-(3-溴-苯基氨基)-喹唑啉-6-基]-丁-2-炔酰胺
向在25℃下搅拌了20分钟的2-丁炔酸(196mg,2.3mmol)和1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺盐酸盐(385mg,2.0mmol)的DMF(5ml)溶液中加入6-氨基-4-[(3-溴苯基)氨基]喹唑啉(316mg,1.0mmol)。将形成的溶液在25℃及氮气氛下搅拌14小时,再加入1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺盐酸盐(206mg,1.0mmol)和2-丁炔酸(82mg,1.0mmol)。8小时后,再向反应混合物中加入1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺盐酸盐(197mg,1.0mmol)和2-丁炔酸(93mg,1.0mmol)。再于25℃搅拌12小时后,用水使反应停止。收集形成的黄色沉淀,然后将其用丙酮进行声处理,再用三乙胺处理,通过硅胶上的制备TLC进行纯化,用1∶1乙酸乙酯/丙酮洗脱。经分离得到所需产物,为黄色固体(20mg,4.7%),mp>281-283℃。1H NMR[(CD3)2SO]:δ10.97(brs,1H,NH),9.93(s,1H,NH),8.76(s,1H,H5),8.57(s,1H,H2),8.14(s,1H,H2′),7.84-7.76(m,3H,H7,H8,H4′),7.34(t,J=8.1Hz,1H,H5′),7.29(d,J=7.8Hz,1H,H6′),2.09(s,3H,CH3).
质谱(APCI):383(100,81BrMH+),382(23,81BrM+),381(95,79BrMH+).对C18H13BrN4O·0.3HCl·0.6C3H6O的元素分析:计算值:C,55.69;H,3.99;N,13.12%。实测值:C,55.67;H,3.96;N,12.93%。
实施例35
N-[4-(3-溴-苯基氨基)-吡啶并[4,3-d]嘧啶-7-基]-丙烯酰胺
在0℃及氮气氛下,在4个小时内,向搅拌中的7-氨基-4-[(3-溴苯基)氨基]-吡啶并[4,3-d]嘧啶[J Med Chem,1995:3780](140mg,0.46mmol)、DMAP(14mg)和三乙胺(过量,2.0ml)的溶液中滴加丙烯酰氯(4.8摩尔当量,182μL)。然后,将反应混合物在20℃下搅拌,用水稀释,用乙酸乙酯萃取。将合并后的有机萃取液用盐水洗涤,用无水硫酸钠干燥,减压浓缩,用硅胶色谱处理,用甲醇/二氯甲烷/乙酸乙酯(5∶45∶50)洗脱,得到N-[4-(3-溴-苯基氨基)-吡啶并[4,3-d]嘧啶-7-基]-丙烯酰胺(12mg,7%),为乳油色粉末,mp(二氯甲烷/己烷)215-220℃(dec)。1H NMR[(CD3)2SO]:δ11.15(s,1H,CONH),10.25(s,1H,NH),9.67(s,1H,H5),8.71(s,1H,H2),8.40(s,1H,H8),8.21(t,J=1.9Hz,1H,H-2′),7.88(dt,Jd=7.6Hz,Jt=1.5Hz,1H,H-6′),7.38(t,J=7.7Hz,1H,H-5′),7.36(dt,Jd=7.7Hz,Jt=1.5Hz,1H,H-4′),6.68(dd,J=17.1,10.2Hz,1H,CH2CHCO),6.39(dd,J=17.0,1.8Hz,1H,CH2CHCO),5.86(dd,J=10.1,1.8Hz,1H,CH2CHCO).
实施例36
N-[4-(3-溴-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-丙烯酰胺
将6-氟吡啶并[3,4-d]嘧啶-4(3H)-酮(U.S.专利申请08/358,352,1994)(1.65g)的亚硫酰氯(50ml)悬浮液与几滴二甲基甲酰胺加热回流直至得到澄清的溶液(20分钟),然后,再处理30分钟。减压除去挥发性物质,将残余物溶解于二氯甲烷中,用碳酸钠水溶液洗涤。将溶剂干燥除去,得到4-氯-6-氟吡啶并[3,4-d]嘧啶粗产物,将其溶解于包含3-溴苯胺(2.1g)的2-丙醇(50ml)中。将混合物加热回流15分钟,得到一种沉淀,将其再通过加入三乙胺溶解。加入水后,将溶液浓缩并冷却,得到4-[(3-溴-苯基)氨基]-6-氟吡啶并[3,4-d]嘧啶(2.29g),mp(甲醇)219.5-221℃。
将4-[(3-溴-苯基)氨基]-6-氟吡啶并[3,4-d]嘧啶(0.48g)与4-甲氧基苄基胺(10.3g)在乙醇(50ml)中的混合物加热至100℃加热5天。形成的产物用硅胶色谱处理,用二氯甲烷∶乙酸乙酯(3∶1)洗脱,得到4-[(3-溴-苯基)氨基]-6-[(4-甲氧基苯基)甲基氨基]吡啶并[3,4-d]嘧啶(0.18g),mp(含水甲醇),178-179.5℃。将0.10g的该产物溶解于5ml的三氟乙酸中,加热回流1小时,将混合物蒸发至干。使残余物在乙酸乙酯与氨水间分配,粗产物用氧化铝进行色谱处理,用二氯甲烷∶甲醇(97∶3)洗脱,得到6-氨基-4-[(3-溴苯基)氨基]-吡啶并[3,4-d]嘧啶(0.040g),mp(二氯甲烷)241.5-242℃。
在0℃及氮气氛下,向6-氨基-4-[(3-溴苯基)氨基]-吡啶并[3,4-d]嘧啶(J Med Chem,1996;39:1823)(455mg,1.50mmol)的无水THF(50ml)溶液中加入三乙胺(22.5mmol,1.61ml)、催化量的DMAP(45mg)和丙烯酰氯(4.50mmol,366μL)。将反应混合物搅拌1小时,再加入丙烯酰氯(100μL),使反应混合物升温至室温,再搅拌1小时,如前述实施例进行处理,用硅胶色谱柱色谱处理,用甲醇/乙酸乙酯(5∶95)洗脱,得到N-[4-(3-溴-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-丙烯酰胺(20mg,37%),为乳油色粉末,mp(乙酸乙酯/甲醇)238-245℃(dec.)。1H NMR[(CD3)2SO]:δ11.07(s,1H,CONH),10.33(s,1H,NH),9.05(s,1H,H5 or H2),9.03(s,1H,H2 orH5),8.66(s,1H,H8),8.18(br s,1H,H-2′),7.89(brd,J=7.6Hz,1H,H-6′).7.40-7.33(m,2H,H-4′,5′),6.70(dd,J=17.0,10.2Hz,1H,CH2CHCO),6.41(dd,J=1.2,16.9Hz,1H,CH2CHCO),5.87(dd,J=1.2,10.1Hz,1H,CH2CHCO).13C NMR:δ163.35,156.82,154.13,150.87,147.92,141.64,140.40,131.25,130.26,127.86,126.49,124.76,121.30,121.02,120.97,103.43.对C16H12BrN5O·1.25H2O的元素分析:计算值:C,51.3;H,3.4;N,18.7%。实测值:C,51.1;H,3.1;N,18.4%。
实施例37
N-[4-(3-甲基-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-丙烯酰胺
在0℃及氮气氛下,向搅拌中的6-氨基-4-[(3-甲基苯基)氨基]吡啶并[3,4-d]嘧啶(如前实施例所述,由间甲苯胺和4-氯-6-氟吡啶并[3,4-d]嘧啶以及随后的对甲氧基苄基胺和三氟乙酸制得)(140mg,0.56mmol)、DMAP(14mg)和三乙胺(过量,0.5ml)的溶液中,在3小时内,滴加入丙烯酰氯(2.7摩尔当量,123μL)。然后,将反应混合物在20℃下搅拌1小时,用水稀释,用乙酸乙酯萃取。将合并后的有机萃取液用盐水洗涤,用无水硫酸钠干燥,减压浓缩,用硅胶色谱处理,用二氯甲烷/乙酸乙酯(1∶1)至甲醇/二氯甲烷/乙酸乙酯(2∶48∶50)洗脱,得到N-[4-(3-甲基-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-丙烯酰胺(41mg,24%),为乳油色粉末,mp(乙酸乙酯/己烷)221-223℃(dec.)。1H NMR[(CD3)2SO]:δ11.03(s,1H,CONH),10.18(s,1H,NH),9.02(s,1H,H5 or H2),9.01(s,1H,H2 orH5),8.59(s,1H,H8),7.63(m,2H,H-2′,6′),7.29(m,1H,H-5′),6.89(br d,J=7.5Hz,1H,H-4′),6.69(dd,J=17.0,10.2Hz,1H,CH2CHCO),6.37(dd,J=17.0,1.9Hz,1H,CH2CHCO),5.85(dd,J=10.2,1.9Hz,1H,CH2CHCO),2.35(s,3H,CH3Ar).对C17H15N5O的元素分析:计算值:C,66.9;H,5.0;N,22.9%。实测值:C,67.3;H,5.2;N,22.9%。
实施例38
N-[4-(3-溴-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-N-甲基丙烯酰胺
在0℃及氮气氛下,向搅拌中的44(3-溴苯基)氨基]-6-甲基氨基吡啶并[3,4-d]嘧啶(100mg,0.3mmol)、再蒸馏的丙烯酸(75μL,1.05mmol)、吡啶(0.3ml)的THF/DMA(3∶2,1.8ml)溶液中一次性加入1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺盐酸盐(294mg,1.5mmol)。30分钟后,将反应混合物升温至25℃,3.75小时后再加入丙烯酸(25μL),再将溶液搅拌3小时。用水使反应停止,收集固体,空气干燥。固体在热二氯甲烷∶乙酸乙酯中研制,收集,得到产物(67mg,56%),mp 215-223℃(dec)。1H NMR[(CD3)2SO]:δ10.11(s,与D2O交换),9.14(s,1H),8.80(s,1H),8.45(s,1H),8.22(s,1H),7.91(br d,J=7.7Hz,1H),7.43-7.36(m,2H),6.36-6.23(m,2H),5.66(dd,J=9.5,3.0Hz,1H),3.44(s,3H).CIMS m/z(相对%)383(23),384(100),385(40),386(99),387(20).
对C17H14N5OBr·0.4H2O的元素分析:计算值:C,52.16;H,3.81;N,17.89%。实测值:C,52.25;H,3.51;N,17.76%。
实施例39
N-[4-(3-溴-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-甲基丙烯酰胺
在氮气氛下,向6-氨基-4-[(3-溴苯基)氨基]-吡啶并[3,4-d]嘧啶(J MedChem,1996;39:1823)(250mg,0.82mmol)、三乙胺(过量,2.0ml)和DMAP(催化量)的THF(20ml)溶液中加入甲基丙烯酰氯(3×1.1摩尔当量,共264μL),反应条件与处理过程同前,经柱色谱和硅胶上的制备性薄层色谱处理,用乙酸乙酯/二氯甲烷(1∶1)洗脱,得到N-[4-(3-溴-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-甲基丙烯酰胺(18mg,6%),为乳油色粉末,mp(二氯甲烷/己烷)177-178℃。1H NMR[(CD3)2SO]:δ10.61(s,1H,CONH),10.29(s,1H,NH),9.06(s,1H,H5),8.93(s,1H,H2),8.67(s,1H,H8),8.19(t,J=1.6Hz,1H,H-2′),7.91(dt,Jd=7.6Hz,Jt=1.6Hz,1H,H-6′),7.38(t,J=7.9Hz,1H,H-5′),7.34(dt,Jd=8.1Hz,Jt=1.4Hz,1H,H-4′),6.04(s,1H,CH2C(CH3)CO),5.64(s,1H,CH2C(CH3)CO),2.03(s,1H,CH2C(CH3)CO)EI HRMS(M+)C17H14BrN5O计算值:385.0361。
实测值:385.0360。
实施例40
N-[4-(3-溴-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-乙烯基磺酰胺
6-氨基-4-[(3-溴苯基)氨基]-吡啶并[3,4-d]嘧啶(J Med Chem,1996;39:1823)(250mg,0.82mmol)、三乙胺(0.23ml)和DMAP(催化量)的THF(20ml)溶液与氯乙烷磺酰氯(1.4摩尔当量,1.15mmol,120μL)如前述进行反应,经硅胶色谱处理,用甲醇/二氯甲烷/乙酸乙酯(2∶48∶50)洗脱,用CH2Cl2/乙烷重结晶得到N-[4-(3-溴-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-乙烯基磺酰胺(53mg,16%),为乳油色粉末,mp261-265℃。1H NMR[(CD3)2SO]:δ11.02(s,1H,SO2NH),10.25(s,1H,NH),9.02(s,1H,H5),8.67(s,1H,H2),8.15(br s,1H,H-2′),8.00(s,1H,H8),7.87(dt,Jd=7.2Hz,Jt=1.9Hz,1H,H-6′),7.40(br t,J=7.9Hz,1H,H-5′),7.37(br dt,Jd=7.8Hz,Jt=1.9Hz,1H,H-4′),7.07(dd,J=16.5,9.9Hz,1H,CH2CHSO2),6.30(d,J=16.5Hz,1H,CH2CHSO2),6.09(d,J=9.9Hz,1H,CH2CHSO2).13C NMR:δ156.59,154.34,151.23,147.43,141.54,140.18,137.02,130.36,127.06,126.73,124.88,121.43,121.24,121.07,103.57.
对C15H12BrN5O2S·0.25H2O的元素分析:计算值:C,43.9;H,3.1;N,17.0%。实测值:C,44.2;H,3.0;N,16.5%。
实施例41
N-[4-(3-溴-苯基氨基)-吡啶并[3,2-d]嘧啶-6-基]-丙烯酰胺
在氮气氛下,向搅拌中的6-氨基-4-[(3-溴苯基)氨基]-吡啶并[3,2-d]嘧啶(J Med Chem,1996;39:1823)(46mg,0.15mmol)和丙烯酸(6摩尔当量,0.91mmol,62μL)的DMA(5.0ml)溶液中加入1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺盐酸盐(EDCI·HCl)(4.0摩尔当量,0.61mmol,116mg)。将反应混合物搅拌48小时,再在12小时内加入附加量的丙烯酸与EDCI·HCl(62μL/116mg),然后进行如前的处理,再用硅胶色谱处理,用乙酸乙酯∶二氯甲烷(1∶1)至甲醇/二氯甲烷/乙酸乙酯(2∶48∶50)洗脱,得到N-[4-(3-溴-苯基氨基)-吡啶并[3,2-d]嘧啶-6-基]-丙烯酰胺(14mg,26%),为乳油色粉末,mp(二氯甲烷/己烷)226-228℃。1H NMR[(CD3)2SO]:δ11.13(s,1H,CONH),9.57(s,1H,NH),8.72(s,1H,H2),8.69(d,J=9.1Hz,1H,H8),8.43(t,J=1.9Hz,1H,H-2′),8.30(d,J=9.1Hz,1H,H7),7.87(br d,J=6.9Hz,1H,H-6′),7.39(t,J=8.1Hz,1H,H-5′),7.33(dt,Jd=8.2Hz,Jt=1.3Hz,1H,H-4′),6.68(dd,J=17.0,10.2Hz,1H,CH2CHCO),6.43(dd,J=17.0,1.8Hz,1H,CE2CHCO),5.91(dd,J=10.2,1.8Hz,1H,CH2CHCO).
对C16H12BrN5O的元素分析:计算值:C,51.9;H,3.3;N,18.9%。实测值:C,51.7;H,3.3;N,18.8%。
实施例42
N-[4-(3-溴-苯基氨基)-苯并[b]噻吩并[3,2-d]嘧啶-8-基]-丙烯酰胺
在25℃及氮气氛下,向搅拌中的8-氨基4-[(3-溴苯基)氨基]-苯并噻吩并嘧啶(见WO专利申请95/19970,1995)(100mg,0.26mm0l)和丙烯酸(0.04ml,0.58mmol)和三乙胺(0.07ml,0.5mmol)的DMF(1.5ml)溶液中加入1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺盐酸盐(0.66mmol,127mg)。24小时后,将反应混合物用水停止反应,通过布氏漏斗过滤收集浅褐色沉淀,通过硅胶制备性TLC纯化,用10%甲醇/氯仿洗脱,得到所需产物(25mg,23%),为褐色固体,mp 249.0-250.5℃。1H NMR[(CD3)2SO]:δ10.50(s,1H,NH),9.86(s,1H,NH),8.86(d,J=2.0Hz,1H,H9),8.79(s,1H,H2),8.19(s,1H,H2′),8.17(dd,J=8.0,1.9Hz,1H,H7),7.91(dd,J=8.8,2.2Hz,1H,H6),7.84(d,J=8.1Hz,1H,H6′),7.35(t,J=8.1Hz,1H,H5′),7.29(d,J=8.0Hz,1H,H4′),6.50(dd,J=16.9,10Hz,1H,=CH),6.33(dd,J=16.8,2.1Hz,1H,=CH2),5.82(dd,J=10,1.9Hz,1H,=CH2).
质谱(APCI):427(100,81BrMH+),426(21,81BrM+),425(93,79BrMH+).
对C19H13BrN4OS·0.3HCl·0.25C3H6O的元素分析:计算值:C,52.49;H,3.18;N,12.19%。实测值:C,52.62;H,3.31;N,12.40%。
实施例43
N-[4-(3-溴-苯基氨基)-苯并[b]噻吩并[3,2-d]嘧啶-6-基]-丙烯酰胺6-氨基-4-(3-溴苯胺)苯并噻吩并[3,2-d]嘧啶
2-氯-3-硝基苯甲酰胺:在25℃及氮气氛下,将DMF(3滴)加至2-氯-3-硝基苯甲酸(0.99g,4.9mmol)、草酰氯(0.47ml,5.4mmol)在二氯甲烷(20ml)中的混合物中。在气体形成停止后,所有固体溶解于溶液中。3小时后,减压除去溶剂,得到一种浅黄色固体,将其用冷的氢氧化铵进行处理(20ml)。收集2-氯-3-硝基苯甲酰胺(1.02g,100%),为灰白色固体。1H NMR[(CD3)2SO]:δ8.12(brs,1H,NH2),8.06(dd,J=8.0,1.7Hz,1H,H4),7.87(brs,1H,NH2),7.73(dd,J=7.8,1.7Hz,1H,H6),7.63(t,J=8.1Hz,1H,H5).
2-氯-3-硝基苄腈:将2-氯-3-硝基苯甲酰胺(1.02g,4.9mmol)的P2O5/(TMS)2O/1,2-二氯乙烷(30ml)的溶液在85℃下加热18小时。在将其冷却至25℃后,通过硅胶(60ml)管塞进行过滤,用5%甲醇/氯仿(400ml)洗脱。合并后的洗液进行减压浓缩,得到2-氯-3-硝基苄腈(0.66g,74%),为灰白色固体。1H NMR[(CD3)2SO]:δ8.42(dd,J=8.1,1.5Hz,1H,H4),8.33(dd,J=8.1,1.7Hz,1H,H6),7.81(t,J=8.3Hz,1H,H5).
3-氨基-7-硝基苯并噻吩-2-甲酸甲酯:在25℃氮气氛下,在搅拌下,将三乙胺(0.16ml,1.15mmol)滴加至2-氯-3-硝基苄腈(191mg,1.05mmol)和硫代乙酸甲酯(0.1ml,1.1mmol)的DMSO(3ml)溶液中。溶液的颜色变为暗橙色。30分钟后,用冰水使反应停止。通过布氏漏斗过滤收集形成的固体,空气干燥,得到3-氨基-7-硝基苯并噻吩-2-甲酸甲酯(244mg,92%),为橙红色固体。1H NMR[(CD3)2SO]:δ8.67(dd,J=8.1,1.0Hz,1H,H6),8.58(dd,J=7.8,0.8Hz,1H,H4),7.72(t,J=7.8Hz,1H,H5),7.37(brs,2H,NH2).
将6-硝基苯并噻吩并[3,2-d]嘧啶酮:向3-氨基-7-硝基苯并噻吩-2-甲酸甲酯(242mg,0.96mmol)和乙酸甲脒(0.51g,4.9mmol)的混合物加热至185℃,向其中加入1.5ml的甲酰胺。在185℃下加热1小时后,将反应混合物冷却至25℃。收集固体并用水洗涤,然后,干燥。分离后得到6-硝基苯并噻吩并[3,2-d]嘧啶酮(161.5mg,68%),为黄色固体。1H NMR[(CD3)2SO]:δ8.72(d,J=8.1Hz,2H,H7,H9),8.45(s,1H,H2),7.91(t,J=7.8Hz,H8).
4-氯-6-硝基苯并噻吩并[3,2-d]嘧啶:将无水DMF(5滴)加至6-硝基苯并噻吩并[3,2-d]嘧啶酮(161mg,0.65mmol)和草酰氯(0.28ml,3.2mmol)在1,2-二-氯乙烷(5ml)中的混合物中。将反应混合物在85℃下加热7.5小时,然后冷却至25℃。通过布氏漏斗滤出固体,用二氯甲烷洗涤,空气干燥。得到4-氯-6-硝基苯并噻吩并[3,2-d]嘧啶(166mg,96%粗产物),为灰色固体。1H NMR[(CD3)2SO]:69.33(s,1H,H2),8.99(dd,J=7.9,1.3Hz,1H,H7),8.87(dd,J=8.1,1.0Hz,1H,H9),8.03(t,J=7.8Hz,1H,H8).
4-([3-溴苯基]氨基-6-硝基苯并噻吩并[3,2-d]嘧啶:将于异丙醇(4.5ml)中的4-氯-6-硝基苯并噻吩并嘧啶(166mg,0.62mmol)、间溴苯胺(0.08ml,0.73mmol)和间溴苯胺盐酸盐(144mg,0.69mmol)的混合物在氮气氛及搅拌下在85℃下加热7.5小时。通过布氏漏斗过滤收集深棕色的固体,用异丙醇洗涤,空气干燥,得到4-([3-溴苯基]氨基-6-硝基苯并噻吩并[3,2-d]嘧啶(145mg,67%),mp247.0-248.1℃。1H NMR[(CD3)2SO]:δ10.21(s,1H,NH),8.89(s,1H,H2),8.84(dd,J=7.6,1.1Hz,1H,H7),8.75(dd,J=8.0,0.9Hz,1H,H9),8.25(s,1H,H2′),7.92(t,J=7.8Hz,1H,H8),7.89(d,J=6.6Hz,1H,H4′),7.39-7.31(m,2H,H5′,H6′).MS(APCI):403(100,81Br,MH+),402(17.45,81Br,M+),401(93.01,79Br,MH+).
对C16H9BrN4O2S·HCl的元素分析:计算值:C,43.90;H,2.30;N,12.80%。实测值:C,44.00;H,2.43;N,12.48%。
6-氨基-4-[(3-溴苯基)氨基]苯并噻吩并[3,2-d]嘧啶:在25℃下用阮内镍(0.07g)对4-([3-溴苯基]氨基-6-硝基苯并噻吩并[3,2-d]嘧啶(160mg,0.4mmol)的甲醇(10ml)溶液进行氢化30小时。反应完成后,减压除去溶剂,得到一种暗棕色固体。由湿甲醇重结晶得到6-氨基-4-[(3-溴苯基)氨基]苯并噻吩并[3,2-d]嘧啶(70mg,43%),为棕色固体,mp217.6-218.8℃。1H NMR[(CD3)2SO]:δ9.89(s,1H,NH),8.77(s,1H,H2),8.19(t,J=1.9Hz,H2′),7.85(ddd,J=8.1,2.9,1.2Hz,1H,H4′),7.64(dd,J=7.9,1.0Hz,1H,H9),7.34(t,J=7.6Hz,2H,H8,H5′),7.28(td,J=8.1,1.5Hz,1H,H6′),6.95(dd,J=7.4,1.0Hz,1H,H7),5.71(brs,2H,NH2).MS(APCI):373(100,81Br,MH+),372(19.5,81Br,M+),371(96.87,79Br,MH+).对C16H11BrN4S·0.3HCl·0.7CH3OH的元素分析:计算值:C,49.57;H,3.51;N,13.85%。实测值:C,49.47;H,3.56;N,13.84%。
在0℃及氮气氛下,向搅拌中的6-氨基-4-[(3-溴苯基)氨基]苯并噻吩并喹唑啉(130mg,0.35mmol)、丙烯酸(0.05ml,0.73mmol)和三乙胺(0.1ml,0.72mmol)的DMF(3ml)溶液中加入1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺盐酸盐(144mg,0.75mmol)。将反应混合物逐渐升温至25℃,20小时后,用水使反应停止。收集形成的黄色固体,用丙酮进行声处理而纯化,得到所需产物(40mg,27%),mp216.4-217.2℃。1H NMR[(CD3)2SO]:δ10.64(s,1H,NH),9.84(s,1H,NH),8.77(s,1H,H2),8.73(d,J=1.5Hz,1H,H6),8.31(d,1H,J=8.8Hz,H8),8.20(s,1H,H2′),7.84(d,J=8.3Hz,1H,H6′),7.67(dd,J=8.6,1.7Hz,1H,H9),7.34(t,J=7.8Hz,1H,H5′),7.28(d,J=8.1Hz,1H,H4′),6.50(dd,J=16.9,10.0Hz,1H,=CH),6.34(dd,J=17.1,1.7Hz,1H,=CH2),5.83(dd,J=10,1.7Hz,1H=CH2).
质谱(APCI):426.7(100,81BrMH+),425.7(26.28,81BrM+),424.7(92,79BrMH+).
对C19H13BrN4OS·0.3HCl·0.8H2O的元素分析:计算值:C,52.28;H,3.62;N,12.26%。实测值:C,52.42;H,3.49;N,12.41%。
实施例44
N-[4-(3-溴-苯基氨基)-苯并[b]噻吩并[3,2-d]嘧啶-7-基]-丙烯酰胺7-硝基-苯并[b]噻吩并[3,2-d]-3H-嘧啶-4-酮
2-氟-4-硝基苯甲酸:[25]向重铬酸钠(3.87g,13mmol)的乙酸(20ml)溶液中分批加入2-氟-4-硝基甲苯(1.55g,10mmol),随后再滴加浓硫酸(10g)。可观察至强的放热(100℃),颜色从橙色变为绿色。将反应混合物在90℃下再加热1小时,冷却至25℃。将反应混合物溶解于水(30ml)中,在0℃下冷却后形成白色结晶。通过过滤收集白色固体,用冷水洗涤,干燥,得到2-氟-4-硝基苯甲酸(0.99g,53%)。1H NMR(DMSO-d6)δ:8.16(dd,J=10.0,2.0Hz,1H),8.10-8.03(m,2H).
2-氟-4-硝基苯甲酰胺:在25℃及氮气氛下,将DMF(3滴)加至2-氟-4-硝基苯甲酸(0.98g,5.3mol)、草酰氯(0.48ml,5.5mmol)在二氯甲烷(25ml)中的混合物中。气体释放!固体缓慢地溶解,4小时后,减压除去挥发性物质。向残余物中加入饱和氨水(5ml),将混合物搅拌10分钟。固体用氯仿(3×20ml)萃取。将合并后的有机萃取液用水、饱和盐水洗涤,干燥(硫酸镁)。减压除去溶剂,得到2-氟-4-硝基苯甲酰胺(0.83g,85%),为浅黄色固体。1H NMR(DMSO-d6):δ8.15(dd.J=10.0,2.2Hz,1H),8.06(dd,J=8.5,2.2Hz,1H),8.02(brs,1H),7.88(brs,1H),7.81(dd,J=8.3,7.0Hz,1H).
2-氟-4-硝基苄腈:在氮气氛下,将2-氟-4-硝基苯甲酰胺(0.83g,4.6mmol)和P2O5/六甲基二硅氧烷在1,2-二氯乙烷(20ml)中的混合物在100℃下加热4小时。在将其冷却后,将溶液倒入硅胶管塞中用己烷(200ml)洗涤,再用5%甲醇/氯仿(400ml)洗脱。收集甲醇/氯仿洗液,进行减压浓缩,得到2-氟-4-硝基苄腈(0.71g,95%),为浅白色固体。1H NMR(DMSO-d6):δ8.46(dd,J=9.5,2.0Hz,1H),8.37-8.22(m,2H).
3-氨基-6-硝基苯并噻吩-2-甲酸甲酯:在25℃氮气氛下,在搅拌下,将硫代乙醇酸甲酯(0.08ml,0.85mmol)加至2-氟-4-硝基苄腈(145mg,0.87mmol)和三乙胺(0.14ml,1.0mmol)的乙腈(20ml)溶液。3小时后,再向溶液中加入三乙胺(0.28ml,2.0mmol),在25℃下再搅拌16小时。减压除去溶剂,得到一种棕色残余物,将其与氯仿研制,沉淀出3-氨基-6-硝基苯并噻吩-2-甲酸甲酯(103mg,54%),为棕红色固体,mp228.5-229.5℃。1H NMR(DMSO-d6):δ8.87(d,J=2.0Hz,1H),8.32(d,J=9.0Hz,1H),8.15(dd,J=8.8,2.0Hz,1H),7.26(brs,2H),3.77(s,3H).
质谱(CI):253(100,MH+),252(52,M+)
7-硝基苯并[b]噻吩并[3,2-d]-3H-嘧啶-4-酮:将3-氨基-6-硝基苯并噻吩-2-甲酸甲酯(20mg,0.08mmol)和乙酸甲脒(59mg,0.57mmol)的混合物在190℃加热5小时,然后,将反应混合物冷却至25℃。反应残余物用水研制,通过布氏漏斗过滤,得到7-硝基苯并[b]噻吩并[3,2-d]-3H-嘧啶4-酮(7mg,36%),为暗棕固体,mp>320℃。1H NMR(DMSO-d6):δ9.21(d,J=1.7Hz,1H),8.39(d,J=8.5Hz,1H),8.38(s,1H),8.32(dd,J=8.8,2.0Hz,1H).
质谱(CI):248(100,MH+),247(30,M+).对C10H5BrN3O3S的元素分析:计算值:C,48.58;H,2.04;N,17.00%。实测值:C,48.19;H,2.09;N,16.77%。
在0℃及氮气氛下,向搅拌中的7-氨基-4-[(3-溴苯基)氨基]苯并噻吩并嘧啶(88mg,0.24mmol)、丙烯酸(0.03ml,0.44mmol)和三乙胺(0.09ml,0.64mmol)的DMF(3ml)溶液中加入1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺盐酸盐(84mg,0.44mmol)。逐渐将反应混合物升温至25℃,24小时后,用水使反应停止。收集浅棕色沉淀,用丙酸通过声处理进行纯化。经分离后,得到所需产物(59mg,37%),为米色固体,mp251.0-252.4℃。1H NMR[(CD3)2SO]:δ10.58(s,1H,NH),9.92(s,1H,NH),8.84(s,1H,H2),8.28-8.24(m,2H,H6,H2′),7.88(d,1H,J=6.8Hz,H6′),7.70(dd,J=7.6,1.2Hz,1H,H8),7.65(t,J=7.6Hz,1H,H9),7.33(t,J=8.0Hz,1H,H5′),7.28(dd,J=6.9,1.8Hz,1H,H4′),6.60(dd,J=16.8,10.0Hz,1H,=CH),6.36(dd,J=17.1,1.9Hz,1H,=CH2),5.88(dd,J=10.3,1.7Hz,1H,=CH2).
质谱(APCI):426.7(100,MH+),425.7(18.68,M+).
对C19H13BrN4OS·H2O的元素分析:计算值:C,51.47;H,3.41;N,12.64%。实测值:C,51.42;H,3.39;N,12.40%。
实施例45
N-[4-[(3-溴苯基)氨基]-喹唑啉-6-基]-丁-2,3-二烯酰胺
在0℃及氮气氛下,向搅拌中的6-氨基-4-[(3-溴苯基)氨基]喹唑啉(316mg,1.0mmol)和3-丁炔酸(173mg,2.06mmol)的DMF(5ml)溶液中加入1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺盐酸盐(384mg,2.0mmol)。1.5小时后,用0.1M的盐酸溶液(10ml)使反应停止。通过布氏漏斗过滤,用水洗涤,再用丙酮洗涤,收集黄色沉淀。加入三乙胺将固体溶解于丙酮中。形成的溶液用2-英寸的硅胶进行过滤,用50%的丙酮/二氯甲烷洗脱。收集滤液,减压浓缩,得到标题化合物(247mg,56%),为黄色固体,mp 268-270℃。1H NMR[(CD3)2SO]:δ10.39(s,1H,NH),9.93(s,1H,NH),8.76(d,J=2.2Hz,1H,H5),8.58(s,1H,H2),8.18(s,1H,H2′),7.87(dt,J=9.0,1.9Hz,2H,H7,H8),7.79(d,J=8.8Hz,1H,H6′),7.34(t,J=7.9Hz,1H,H5′),7.29(d,J=8.3Hz,1H,H4′),6.07(t,J=6.5Hz,1H,CH=C=CH2),5.49(d,J=6.6Hz,2H,=C=CH2).
质谱(APCI):382.8(88,81BrMH+),381.8(19,81BrM+),380.7(100,79BrMH+).
对C18H13BrN4O·0.8H2O·0.8C3H6O的元素分析:计算值:C,55.42;H,4.42;N,12.68%。实测值:C,55.13;H,4.17;N,12.87%。
实施例46
N-[4-[(3-溴苯基)氨基]-喹唑啉-6-基]-E,4-氧代戊-2-烯酰胺
在25℃及氮气氛下,向搅拌中的E,4-氧代戊-2-烯酸(171mg,1.5mmol)和EDAC·HCl(288mg,1.5mmol)的THF/DMF(3∶1,4ml)的溶液中加入6-氨基-4-[(3-溴苯基)氨基]喹唑啉(0.23g,0.75mmol)和N-乙基二异丙基胺(0.26ml,1.5mmol)。除去冰浴,将反应混合物在25℃下搅拌4小时,再加入N-乙基二异丙基胺(0.13ml,0.75mmol)、E,4-氧代戊-2-烯酸(86mg,0.75mmol)和EDAC·HCl(144mg,0.75mmol)。在25℃下再搅拌14小时,将反应混合物滴加至搅拌中的冷水(100ml)中。收集固体,将其溶解于甲醇(50ml)中,硅胶干燥(3g)。将其用作硅胶快速柱(80g)的上样原料,用10%甲醇/二氯甲烷洗脱。减压下浓缩纯级分,得到N-[4-[(3-溴苯基)氨基]-喹唑啉-6-基]-E,4-氧代戊-2-烯酰胺(0.14g,45%),为黄色固体,mp 230℃(dec.)。1H NMR[(CD3)2SO]:δ10.91(s,1H,NH),9.99(s,1H,NH),8.87(d,J=1.9Hz,1H,H5),8.60(s,1H,H2),8.17(t,J=1.9Hz,1H,H2′),7.85(m,3H,H7,H8,H6'),7.37(m,2H,H5′,H4′),7.15(d,J=15.7Hz,1H,H3-戊烯基),6.99(d,J=15.7Hz,1H,H2-戊烯基),2.40(s,3H,Me).
质谱(APCI):412.7(100,81BrMH+),410.8(98,79BrMH+).
对C19H15BrN4O2的元素分析:计算值:C,55.49;H,3.68;N,13.62%。实测值:C,55.21;H,3.72;N,13.35%。
实施例47
N-[4-[(3-溴苯基)氨基]-喹唑啉-6-基]-E,4-乙氧基-4-氧代丁-2-烯酰胺
在25℃及氮气氛下,向搅拌中的E,4-乙氧基-4-氧代丁-2-烯酸(216mg,1.5mmol)和EDAC·HCl(288mg,1.5mmol)的THF/DMF(3∶1,4ml)的溶液中加入6-氨基-4-[(3-溴苯基)氨基]喹唑啉(0.23g,0.75mmol)和N-乙基二异丙基胺(0.26ml,1.5mmol)。除去冰浴,将反应混合物在25℃下搅拌4小时,再加入N-乙基二异丙基胺(0.13ml,0.75mmol)、E,4-乙氧基-4-氧代丁-2-烯酸(108mg,0.75mmol)和EDAC·HCl(144mg,0.75mmol)。在25℃下再搅拌14小时,将反应混合物滴加至搅拌中的冷水(100ml)中。收集固体,将其溶解于甲醇(50ml)中,硅胶干燥(3g)上。将其用作硅胶快速柱(80g)的上样原料,用10%甲醇/二氯甲烷洗脱。减压下浓缩纯化的级分,得到N-[4-[(3-溴苯基)氨基]-喹唑啉-6-基]-E,4-乙氧基-4-氧代丁-2-烯酰胺(0.19g,58%),为黄色固体,mp>255℃。1H NMR[(CD3)2SO]:δ10.93(s,1H,NH),9.99(s,1H,NH),8.89(d,J=1.9Hz,1H,H5),8.60(s,1H,H2),8.16(t,J=1.9Hz,1H,H2′),7.85(m,3H,H7,H8,H6′),7.33(m,3H,H5′,H4′,H3-戊烯基),6.79(d,J=15.4Hz,1H,H2-戊烯基),4.24(q,J=7.1Hz,CH2),1,29(t,J=7.1Hz,3H,Me).
质谱(APCI):442.8(99,81BrMH+),440.8(100,79BrMH+).对C20H17BrN4O3的元素分析:计算值:C,55.44;H,3.88;N,12.70%。实测值:C,55.59;H,3.83;N,12.67%。
实施例48
N-[4-[(3-溴苯基)氨基]-吡啶并[3,4-d]嘧啶-6-基]戊-2,4--二烯酰胺
在氮气氛下,向0-5℃搅拌中的6-氨基-4-[(3-溴苯基)氨基]-吡啶并[3,4-d]嘧啶(160mg,0.5mmol)、80%反-2,4-戊二烯酸(245mg,2mmol)和吡啶(0.5ml)的THF/DMA(2∶1,3ml)溶液中一次性加入1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺盐酸盐(490mg,2.5mmol)。除去冷浴,将粘性混合物在25℃下搅拌。23小时后,向混合物中再加入反-2,4-戊二烯酸(125mg)、1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺盐酸盐(240mg)和THF/DMA(2∶1,2ml)。再搅拌19小时后,用水和乙酸乙酯稀释混合物。将两相混合物升温,然后通过硅藻土用滤垫过滤,用水和热的乙酸乙酯充分洗涤。滤液用乙酸乙酯萃取3次,将合并后的有机萃取液用盐水洗涤,干燥(硫酸镁),浓缩至固体。将该固体溶解于热乙酸乙酯中,溶液用快速硅胶柱色谱纯化,用乙酸乙酯洗脱。将产物各级分合并,浓缩至固体,将其在热乙酸乙酯中研制。冷却后,收集固体,干燥,得到产物(27mg,13%),mp 210-215℃。1H NMR[(CD3)2SO]:δ11.04(s,1H,与D2O交换),10.34(s,1H,与D2O交换),9.04(s,1H),9.02(s,1H),8.66(s,1H),8.17(t,J=1.9Hz,1H),7.89(dt,J=7.7,1.7Hz,1H),7.40-7.27(m,3H),6.60(dt,J=16.9,10.6Hz,1H),6.53(d,J=15.2Hz,1H),5.75(d,J=16.9Hz,1H),5.56(d,J=11.1Hz,1H).
质谱(APCI)m/z(相对%):395.9(89),396.9(20),397.9(100),398.9(20).
对C18H14N5OBr·0.3H2O·0.2C4H8O2的元素分析:计算值:C,53.86;H,3.89;N,16.70%。实测值:C,54.02;H,3.77;N,16.33%。
实施例49N-[4-[(3-溴苯基)氨基]-吡啶并[3,4-d]嘧啶-6-基]-N-(2-(N,N-二甲基氨基)乙 基)丙烯酰胺
在氮气氛下,向0-5℃搅拌中的4-[(3-溴苯基)氨基]-6-(2-二甲基氨基乙基)氨基吡啶并[3,4-d]嘧啶(387mg,1mmol)和再蒸馏的丙烯酸(0.25ml,3.6mmol)的吡啶(5ml)溶液中加入1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺盐酸盐(980mg,5mmol)。30分钟后,除去冷浴,将混合物搅拌45分钟。用1%碳酸氢钠水溶液对溶液进行稀释,用乙酸乙酯萃取4次。合并后的有机萃取液用盐水洗涤,干燥(硫酸镁),浓缩,得到一种油,将其用乙酸乙酯在5℃下过夜结晶,得到产物(122mg,28%),mp>160℃(dec)。1H NMR[(CD3)2SO]:δ10.16(s,1H,与D2O交换),9.15(s,1H),8.80(s,1H),8.43(s,1H),8.22(s,1H),7.93(d,J=7.7Hz,1H),7.42-7.35(m,2H),6.29-6.22(m,2H),5.66(dd,J=9.0,3.5Hz,1H),4.05(t,J=7.1Hz,2H)2.42(t,J=7.1Hz,2H),2.11(s,6H).
质谱(APCI)m/z(相对%):440.9(99),441.8(23),442.8(100),443.9(24).
对C20H21N6OBr的元素分析:计算值:C,54.43;H,4.80;N,19.04%。实测值:C,54.15;H,4.65;N,18.76%。
实施例50
N-[4-[(3-溴苯基)氨基]-吡啶并[3,4-d]嘧啶-6-基]-E-丁-2-烯酰胺
在氮气氛下,向0-5℃搅拌中的6-氨基-4-[(3-溴苯基)氨基]吡啶并[3,4-d]嘧啶(32mg,0.1mmol)、反式巴豆酸(35mg,0.4mmol)的吡啶(0.4ml)溶液中加入1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺盐酸盐(98mg,0.5mmol)。除去冷浴,将混合物在25℃下搅拌。2小时后,用水对溶液进行稀释,将悬浮液搅拌15分钟。收集固体,将其溶解于乙酸乙酯中。溶液用5%碳酸氢钠水溶液洗涤,干燥(硫酸镁),通过快速硅胶过滤。浓缩滤液至固体。将其在热乙酸乙酯中研制。收集固体,得到产物(11mg,28%),mp>260℃(dec)。1H NMR[(CD3)2SO]:δ10.87(s,1H,与D2O交换),10.31(s,1H,与D2O交换),9.03(s,1H),9.00(s,1H),8.65(s,1H),8.17(s,1H),7.89(d,J=7.5Hz,1H),7.39-7.33(m,2H),6.99-6.90(m,1H),6.39(dd,J=15.4,1.7Hz,1H),1.91(dd,J=7.0,1.4Hz,3H.
质谱(APCI)m/z(相对%):381.8(74),382.8(27),383.8(100),384.8(30),385.9(10).
对C17H14N5OBr·0.3H2O的元素分析:计算值:C,52.40;H,3.78;N,17.97%。实测值:C,52.37;H,3.65;N,17.70%。
实施例51
N-[4-[(3-溴苯基)氨基]-吡啶并[3,4-d]嘧啶-6-基]-肉桂酰胺
在氮气氛下,向0-5℃搅拌中的6-氨基-4-[(3-溴苯基)氨基]吡啶并[3,4-d]嘧啶(32mg,0.1mmol)、反式肉桂酸(60mg,0.4mmol)的吡啶(0.4ml)溶液中加入1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺盐酸盐(98mg,0.5mmol)。除去冷浴,将混合物在25℃下搅拌。2小时后,用水对溶液进行稀释,将悬浮液搅拌15分钟。收集固体,将其溶解于乙酸乙酯中。溶液用5%碳酸氢钠水溶液洗涤,干燥(硫酸镁),通过快速硅胶过滤。浓缩滤液至固体。将其在热乙酸乙酯中研制。收集固体,得到产物(23mg,51%),mp 253-256℃。1H NMR[(CD3)2SO]:δ11.07(s,1H,与D2O交换),10.36(s,1H,与D2O交换),9.06(s,2H;用D2O洗
叠并9.06[s,1H]and 9.02[s,1H]),8.67(s,1H),8.19(s,1H),7.90(d,J=7.7Hz,1H),7.72-7.65(m,3H),7.51-7.34(m,5H),7.14(d,J=15.7,1H).
质谱(APCI)m/z(相对%):445.9(97),446.9(24),447.9(100),448.9(26).对C22H16N5OBr·0.2H2O的元素分析:计算值:C,58.73;H,3.67;N,15.57%。实测值:C,58.79;H,3.66;N,15.37%。
实施例52
N-[4-[(3-溴苯基)氨基]-吡啶并[3,4-d]嘧啶-6-基]-E,3-氯丙烯酰胺
在氮气氛下,向-20℃搅拌中的6-氨基-4-[(3-溴苯基)氨基]吡啶并[3,4-d]嘧啶(128mg,0.4mmol)和顺式-3-氯丙烯酸(172mg,1.6mmol)的吡啶(2ml)溶液中加入1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺盐酸盐(392mg,1.5mmol)。4.5小时后,再加入顺式-3-氯丙烯酸(57mg)和1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺盐酸盐(130mg),将温度升至-10℃。在总反应时间7小时后,粘性暗黑色的混合物用DMF稀释,将形成的溶液倒入1∶1乙酸乙酯∶水中。将形成的混合物剧烈振动,进行相分离。水层再萃取2次,然后,将合并后的有机萃取液用盐水洗涤2次,干燥(硫酸镁),通过快速硅胶过滤。将滤液浓缩成固体,将其溶解于温热的乙酸乙酯中。将溶液用快速硅胶进行柱色谱纯化,用乙酸乙酯洗脱。合并产物级分并浓缩成固体,将其在1∶1乙酸乙酯∶叔丁基甲基醚中研制。收集固体,以0.1mm/25℃的速度干燥,得到产物(30mg,18%),mp 165-175℃(dec),再用乙酸乙酯进行重结晶。1H NMR[(CD3)2SO]:δ11.09(s,1H,与D2O交换),10.38(s,1H,与D2O交换),9.04(s,1H),9.00(s,1H),8.66(s,1H),8.16(t,J=1.9Hz,1H),7.88(dt,J=7.7,1.7Hz,1H),7.40-7.33(m,2H),7.07(d,J=8.0Hz,1H),6.77(d,J=8.0Hz,1H).
质谱(APCI)m/z(相对%):365.8(29),366.8(36),367.8(35),368.8(35),401.8(82),402.8(18),403.8(100),404.8(20),405.8(29).
对C16H11N5OBrCl·0.2H2O·0.2C4H8O2的元素分析:计算值:C,47.38;H,3.08;N,16.44%。实测值:C,47.53;H,3.15;N,16.25%。
实施例53
N-[4-[(3-溴苯基)氨基]-吡啶并[3,4-d]嘧啶-6-基]-丙炔酰胺
在氮气氛下,向-20℃搅拌中的6-氨基-4-[(3-溴苯基)氨基]吡啶并[3,4-d]嘧啶(94mg,0.3mmol)和丙炔酸(66μL,1.05mmol)的吡啶(1.2ml)溶液中加入1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺盐酸盐(294mg,1.5mmol)。2.25小时后,再向冷溶液中加入丙炔酸(33μL)和1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺盐酸盐(147mg)。在总反应时间7.5小时后,粘性暗黑色的混合物用DMF稀释,将形成的溶液倒入1∶1乙酸乙酯∶水中。将形成的混合物剧烈振动,进行相分离。水层再萃取2次,然后,将合并后的有机萃取液用盐水洗涤2次,干燥(硫酸镁),通过快速硅胶过滤。将滤液浓缩成固体,将其溶解于温热的乙酸乙酯中。将溶液用快速硅胶进行柱色谱纯化,用乙酸乙酯洗脱。合并产物级分并浓缩成固体,将其在1∶1乙酸乙酯∶叔丁基甲基醚中研制。收集固体,以0.1mm/25℃的速度干燥,得到产物(16mg,14%),mp>150℃(dec)。1H NMR[(CD3)2SO]:δ11.69(s,1H,与D2O交换),10.31(s,1H,与D2O交换),9.05(s,1H),8.83(s,1H),8.68(s,1H),8.15(s,1H),7.87(d,J=7.2Hz,1H),7.40-7.33(m,2H),4.54(s,1H).
质谱(APCI)m/z(相对%):365.8(69),366.8(28),367.8(100),368.9(50),369.9(14).
对C16H10N5OBr·0.1H2O·0.1C4H8O2的元素分析:计算值:C,52.00;H,2.93;N,18.49%。实测值:C,51.89;H,3.78;N,18.50%。
实施例54N-[4-[(3-溴苯基)氨基]喹唑啉-6-基]-E,4-(3-(N,N-二甲基氨基)丙氧基-4-氧 代丁-2-烯酰胺三三氟乙酸酯
在0℃及氮气氛下,在15分钟内,将6-氨基-4-[(3-溴苯基)氨基]喹唑啉(158mg,0.5mmol)的THF(10ml)溶液滴加至搅拌中的富马酰氯(382mg,2.5mmol)的THF(10ml)溶液中。在0℃下1小时后,使悬浮液静置,滗析出上清液。加入新鲜的THF(5ml),在0℃下搅拌该悬浮液,同时滴加3-(N,N-二甲基氨基)丙-1-醇(1.18ml,10mmol)的THF(5ml)溶液。在25℃下将悬浮液再搅拌1小时,减压汽提除去溶剂,将残余物用冷水处理。通过布氏漏斗过滤收集固体,将其溶解于少量DMF中,硅胶吸收(2g)并干燥。将该固体用作硅胶快速色谱(50g)的上样原料,用二氯甲烷/甲醇(2∶1)洗脱。合并最好的级分,汽提,溶解于乙酸/水(3∶2,2.5ml)中,使其通过0.45μ的过滤物,在Vidac C18218TP1022反相HPLC柱上通过HPLC进行纯化,用10%-50%梯度的0.1%TFA的水溶液/0.1%TFA的乙腈溶液在60分钟内洗脱。合并纯化的级分,并冻干,得到N-[4-[(3-溴苯基)氨基]-喹唑啉-6-基]-E,4-(3-(N,N-二甲基氨基)丙氧基-4-氧代丁-2-烯酰胺三三氟乙酸酯(51mg,12%),为黄色固体,mp 60℃。1H NMR[(CD3)2SO]:δ11.14(s,1H,NH),10.85(br s,1H,NH),9.57(br s,1H,NH),9.01(d,J=1.7Hz,1H,H5),8.79(s,1H,H2),8.07(s,1H,H2′),8.02(dd,J=2.1,9.0Hz,1H,H7),7.89(d,J=8.9Hz,1H,H8),7.78(d,J=6.5Hz,H6′),7.43(m,2H,H4′& H5′),7.34(d,J=15.4Hz,1H,H3-丁烯基),6.84(d,J=15.4Hz,1H,H2-丁烯基),4.26(t,J=6.2Hz,2H,OCH2),3.19(m,2H,CH2N),2.81(d,J=4.6Hz,6H,Me),2.05(m,2H,CH2).
质谱(APCI):499.8(100,81BrMH+),497.9(97,79BrMH+).
对C23H24BrN5O3·3CF3COOH的元素分析:计算值:C,40.15;H,3.49;N,8.07%。实测值:C,40.06;H,3.36;N,8.25%。
实施例55
3-[4-(3-溴-苯基氨基)-喹唑啉-6-基氨甲酰基]-丙烯酸(Z)
向6-氨基-4-[(3-溴苯基)氨基]-喹唑啉(0.78g,2.5mmol)的DMF(8ml)溶液中加入马来酸酐(0.266g,2.7mmol),将混合物在搅拌下于70℃油浴中加热2.5小时。将形成的悬浮液冷却至室温,然后用水稀释。收集固体,依次用甲苯/DMF(1∶1)、水和IPA洗涤。于60℃下真空干燥该固体16小时,得到3-[4-(3-溴-苯基氨基)-喹唑啉-6-基氨甲酰基]-丙烯酸(Z)(0.87g,86%),为浅黄色粉末,mp224-225℃(随气体挥发分解)。1H NMR[(CD3)2SO]:δ13.00(br s,1H,COOH),10.85(br s,1H,NH),9.96(br s,1H,NH),8.73(d,J=1.8Hz,1H,H5),8.54(s,1H,H2),8.11(br s,1H,Me2NCHO),7.91-7.75(m,4H),7.32-7.24(m,2H),6.46(d,J=12.0Hz,1H,CH=CH),6.35(d,J=12.0Hz,1H,CH=CH),2.84(s,3H,Me2NCHO),2.68(s,3H,Me2NCHO).
质谱(APCI):412.8(100,81BrM+),410.8(96,79BrM+);413.8(26,81BrMH+),411.8(24,79BrMH+).
对C18H13BrN4O3·0.81DMF的元素分析:计算值:C,51.94;H,3.98;N,14.26%。实测值:C,51.97;H,3.98;N,14.40%。
实施例56N-[4-[(3-溴苯基)氨基]-喹唑啉-6-基]-E,4-(3-(N,N-二甲基氨基)丙基氨基-4- 氧代丁-2-烯酰胺
在0℃及氮气氛下,在15分钟内,将6-氨基-4-[(3-溴苯基)氨基]喹唑啉(158mg,0.5mmol)的THF(10ml)溶液滴加至搅拌中的富马酰氯(382mg,2.5mmol)的THF(10ml)溶液中。在0℃下1小时后,使悬浮液静置,滗析出上清液。加入新鲜的THF(5ml),在0℃下搅拌该悬浮液,同时滴加3-(N,N-二甲基氨基)丙-1-基胺(1.26ml,10mmol)的THF(5ml)溶液。在25℃下将悬浮液再搅拌1小时,减压汽提除去溶剂,将残余物用冷水处理。通过布氏漏斗过滤收集固体,将其溶解于沸腾的甲醇(25ml)中,过滤,减压除去溶剂。再将残余物溶解于乙酸/水(3∶2,2.5ml)中,在Vidac C18218TP1022反相HPLC柱上通过HPLC进行纯化,用10%-50%梯度的0.1%TFA的水溶液/0.1%TFA的乙腈溶液在60分钟内洗脱。合并纯化的级分,并冻干,得到N-[4-[(3-溴苯基)氨基]-喹唑啉-6-基]-E,4-(3-(N,N-二甲基氨基)丙-1-基氨基-4-氧代丁-2-烯酰胺三三氟乙酸酯(154mg,37%),为黄色固体,mp 40℃。1H NMR[(CD3)2SO]:δ11.02(s,1H,NH),9.50(br s,1H,NH),9.02(d,J=1.7Hz,1H,H5),8.82(s,1H,H2),8.74(t,J=5.7Hz,1H,NH),8.05(s,1H,H2′),8.02(dd,J=2.1,9.0Hz,1H,H7),7.89(d,J=8.9Hz,1H,H8),7.76(d,J=7.2Hz,H6′),7.45(m,2H,H4′& H5′),7.17(d,J=14.9Hz,1H,H3-丁烯基),7.05(d,J=15.2Hz,1H,H2-丁烯基),3.26(m,2H,NCH2),3.08(m,2H,CH2N),2.79(d,J=4.8Hz,6H,Me),1.83(m,2H,CH2).
质谱(APCI):498.8(100,81BrMH+),496.9(97,79BrMH+).
对C23H25BrN6O2·3CF3COOH的元素分析:计算值:C,41.49;H,3.36;N,10.01%。实测值:C,41.44;H,3.60;N,10.33%。
实施例57
4-[(3-溴苯基)氨基]-6-(亚乙基磺酰基)吡啶并[3,4-d]嘧啶;
2-4-[(3-溴苯基)氨基]-吡啶并[3,4-d]嘧啶-6-基硫烷基(sulfanyl)]-乙醇;
用无水碳酸铯(3.26g,10mmol)处理氮气吹扫下的2-巯基乙醇(1.75ml,25mmol)和4-[(3-溴苯基)氨基]-6-氟吡啶并[3,4-d]嘧啶(1.6g,5mmol)的DMSO(10ml)溶液。将搅拌中的溶液在50℃下加热2小时,然后将其倾入2%的盐酸(180ml)水溶液中。将悬浮液搅拌15分钟后,收集固体,用水洗涤,溶解于DMF中。将溶液倒入1∶1水∶乙酸乙酯中,形成的混合物用乙酸乙酯萃取3次。合并后的有机萃取液用盐水洗涤,干燥(硫酸镁),通过快速硅胶过滤。浓缩滤液至固体,将该固体在乙酸乙酯中研制。收集固体得到头两批1.24g(66%)的产物,mp 182-185℃,第三批98mg(5%),mp179-183℃。1H NMR[(CD3)2SO]:δ10.03(s,1H,与D20交换),9.10(s,1H),8.69(s,1H),8.35(s,1H),8.22(t,J=1.9Hz,1H),7.91(dt,J=7.7,1.9Hz,1H),7.42-7.34(m,2H),5.04(t,J=5.5Hz,与D2O交换,1H),3.68(dd,J=6.8,5.7Hz,2H),3.36(t,J=6.8Hz,2H).
质谱(APCI)m/z(相对%):374.8(49),375.8(10),376.9(100),377.8(23),378.9(63),379.8(14).对C15H13N4OSBr的元素分析:计算值:C,47.76;H,3.47;N,14.85%。实测值:C,47.65;H,3.38;N,14.55%。
2-4-[(3-溴苯基)氨基]-吡啶并[3,4-d]嘧啶-6-磺酰基]-乙醇;
用间氯过苯甲酸(1.27g,57-86%)处理0-5℃搅拌中的2-4-[(3-溴苯基)氨基]-吡啶并[3,4-d]嘧啶-6-基-硫烷基]-乙醇(755mg,2mmol)的氯仿(30ml)悬浮液。在4小时内,将该悬浮液缓慢地升温至25℃。分别在14.5和17.5小时后,将该悬浮液用另一份氧化剂(720mg,720mg)处理。在总反应时间共19.5小时后,将稀的悬浮液冷却至0-5℃,用DMSO(2ml)处理。除去冷却,将溶液搅拌30分钟。然后,使混合物在乙酸乙酯与5%碳酸氢钠水溶液间进行分配。有机相用盐水洗涤,干燥(硫酸镁),浓缩以减少体积,再将其在快速硅胶柱色谱上进行纯化,用乙酸乙酯洗脱。合并产物级分,浓缩至固体,将其用乙酸乙酯结晶,得到产物(460mg,56%),mp 210-220℃。滤液进一步处理得到84mg(10%)的第二批产物,mp208-209℃。1H NMR(CF3CO2H):δ10.96(s,1H),10.90(s,1H),10.42(s,1H),9.47(s,1H),9.16(d,J=8.2Hz,1H),9.05(d,J=8.2Hz,1H),8.83(t,J=8.0,1H),5.81(t,J=5.2Hz,2H),5.43(t,J=5.2Hz,2H).
质谱(APCI)m/z(相对%):378.7(39),380.7(45),408.7(100),409.7(15),410.7(97),411.7(17).
对C15H13N4O3SBr的元素分析:计算值:C,44.02;H,3.20;N,13.69%。实测值:C,44.09;H,3.14;N,13.44%。
4-[(3-溴苯基)氨基]-6-(亚乙基磺酰基)吡啶并[3,4-d]嘧啶;
在氮气氛下,向0-5℃ 2-4-[(3-溴苯基)氨基]-吡啶并[3,4-d]嘧啶-6-磺酰基]-乙醇(41mg,0.1mmol)和三乙胺(31μL,0.22mmol)的二氯甲烷(0.5ml)的悬浮液中滴加甲磺酰氯(9.3μL,0.12mmol)。45分钟和1.5小时后,再加入甲磺酰氯(9.3μL,9.3μL),后一次加入时同时加入三乙胺(50μL)。总共反应2.5小时后,用5%碳酸氢钠水溶液使冷却的溶液停止反应,然后,用乙酸乙酯萃取2次。合并后的有机萃取液用硫酸镁干燥,通过快速硅胶热过滤。将滤液浓缩成固体,再将其用乙酸乙酯结晶,得到产物(17mg,44%),mp 214-217℃。1H NMR[(CD3)2SO]:δ10.64(s,1H,与D2O交换),9.30(s,1H),9.25(s,1H),8.87(s,1H),8.16(s,1H),7.89-7.85(m,1H),7.39-7.33(m,2H),7.17(dd,J=10.0,16.5Hz,1H),6.46(d,J=16.4Hz,1H),6.37(d,J=10.0Hz,1H).
实施例58
N-(3-溴苯基)-N-[6-2,5-二氢-吡咯-1-基)-喹唑啉-4-基]-乙酰胺
将乙酸钠(0.10g,1.2mmol)加至3-[4-(3-溴苯基氨基)-喹唑啉-6-基氨甲酰基]丙烯酸(Z)(0.25g,0.61mmol)的乙酸酐(5ml)悬浮液中,将混合物加热回流30分钟。冷却至室温后,将反应混合物过滤,将滤液真空浓缩至干。将残余物吸收进入乙酸乙酯中,依次用饱和碳酸氢钠、水和盐水洗涤。乙酸乙酯部分用硫酸镁干燥,过滤,浓缩,得到淡粉红色固体。将该固体由乙酸乙酯重结晶两次,得到N-(3-溴苯基)-N-[6-(2,5-二氢-吡咯-1-基)-喹唑啉-4-基]-乙酰胺(0.104g,39%),为灰白色粉末,mp 174-175℃。1H NMR[CDCl3]:δ9.24(s,1H,H2),8.16(d,J=9Hz,1H,H8),8.10(d,J=2Hz,1H,H5),8.03(dd,J=9Hz,J=2Hz,1H,H7),7.59(t,1H,J=2 Hz,H2′),7.45(m,1H,H4′),7.38(m,1H,H6′),7.27(d,1H,J=7Hz,H5′),6.91(s,2H,CH=CH),2.15(s,3H,CH3).
质谱(APCI):438.7(89,81BrMH+),436.7(79,79BrMH+);439.7(17,81BrM+),437.7(19,79BrM+);470.7(100,81BrM+MeOH),468.8(95,79BrM+MeOH).
对C20H13BrN4O3的元素分析:计算值:C,54.94;H,3.00;N,12.81%。实测值:C,54.90;H,2.97;N,12.61%。
使如前所述的反应路线和实施例可制备下述化合物:
1-[4-(3-溴苯基氨基)-喹唑啉-6-基]吡咯-2,5-二酮;
1-[4-(3-溴苯基氨基)-喹唑啉-6-基]丙-2-烯-1-酮;
丙烯酸4-(3-溴苯基氨基)-喹唑啉-6-基酯;
N-[4-[(3-溴苯基)氨基]-P-乙烯基-吡啶并[3,4-d]嘧啶-6-基]
膦酰胺甲酯;
丙烯酸4-(3-溴苯基氨基)-喹唑啉-7-基酯;
1-[4-(3-溴苯基氨基)-喹唑啉-6-基]丁-3-烯-2-酮;
丙烯酸4-(3-氯-4-氟-苯基氨基)-7-甲氧基-喹唑啉-6-基酯;
N-[4-(3-溴苯基氨基)-7-(3-吗啉-4-基-丙氧基)-吡啶并[3,2-d]嘧啶-6-基]-丙烯酰胺;
戊-2,3-二烯酸[4-(3-溴苯基氨基)-喹唑啉-6-基]酰胺;
丙-1,2-二烯-1-磺酸[4-(3-溴苯基氨基)-喹唑啉-6-基]酰胺;
N-[4-[(3-溴苯基)氨基]-6-喹唑啉基]-P-(1,2-丙二烯基)膦酰胺甲酯;
N-[1-(3-溴苯基氨基)-9H-2,4,9-三氮杂芴-7-基]-丙烯酰胺;
N-[4-(3-溴苯基氨基)-9H-1,3,9-三氮杂芴-6-基]-丙烯酰胺;
N-[4-(3-氯-4-氟苯基氨基)-喹唑啉-6-基]-丙烯酰胺;
N-(4-苯基甲基氨基-喹唑啉-6-基)-丙烯酰胺;
(S)-N-[4-(1-苯基乙基氨基)-喹唑啉-6-基]-丙烯酰胺;
(R)-N-[4-(1-苯基乙基氨基)-喹唑啉-6-基]-丙烯酰胺;
丁-2-烯二酸[4-(3-氯-4-氟苯基氨基)-喹唑啉-6-基]-酰胺(3-二甲基氨基-丙基)-酰胺;
N-[4-(3-氯-4-氟-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-丙烯酰胺;
N-[4-(3-氯-4-氟-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-N-甲基-丙烯酰胺;
丁-2-烯二酸[4-(3-氯-4-氟苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺(3-二甲基氨基-丙基)-酰胺;
丁-2-烯二酸[4-(3-氯-4-氟苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺(3-咪唑-1-基-丙基)-酰胺;
4,4-二氟-8-吗啉-4-基-辛-2-烯酸[4-(3-氯-4-氟苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺;
8-二甲基氨基-4,4-二氟-辛-2-烯酸[4-(3-氯-4-氟苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺;
7-二甲基氨基-4,4-二氟-庚-2-烯酸[4-(3-氯-4-氟苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺;
4,4-二氟-7-吗啉-4-基-庚-2-烯酸[4-(3-氯-4-氟苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺;
6-二甲基氨基-己-2-炔酸[4-(3-氯-4-氟苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺;
6-吗啉-4-基-己-2-炔酸[4-(3-氯-4-氟苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺;
7-二甲基氨基-庚-2-炔酸[4-(3-氯-4-氟苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺;
7-吗啉-4-基-庚-2-炔酸[4-(3-氯-4-氟苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺;
5-二甲基氨基-戊-2-炔酸[4-(3-氯-4-氟苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺;
5-吗啉-4-基-戊-2-炔酸[4-(3-氯-4-氟苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺;
5-咪唑-1-基-戊-2-炔酸[4-(3-氯-4-氟苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺;
5-(4-甲基哌嗪-1-基-戊-2-炔酸[4-(3-氯-4-氟苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺;
4-[4-(3-氯-4-氟苯基氨基)-吡啶并[3,4-d]嘧啶-6-基氨甲酰基]-丁-3-烯酸2-(4-甲基哌嗪-1-基)-乙酯;
4-[4-(3-氯-4-氟苯基氨基)-吡啶并[3,4-d]嘧啶-6-基氨甲酰基]-丁-3-烯酸2-(2-咪唑-1-基)-乙酯;
戊-2-烯二酸1-{[4-(3-氯-4-氟苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺}5-[(3-吗啉-4-基-丙基)-酰胺];
戊-2-烯二酸1-{[4-(3-氯-4-氟苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺}5-[(3-二乙基氨基-丙基)-酰胺];
4-[4-(3-氯-4-氟苯基氨基)-吡啶并[3,4-d]嘧啶-6-基氨甲酰基]-丁-3-烯酸2-吗啉-4-基-乙酯;
戊-2-烯二酸1-{[4-(3-氯-4-氟苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺}5-{[3-(4-甲基-哌嗪-1-基)-丙基]酰胺};
(3-氯-4-氟苯基)-{6-[2-(3-二甲基氨基丙氧基)乙磺酰基]-吡啶并[3,4-d]嘧啶-4-基}-胺;
(3-氯-4-氟苯基)-(6-{2-[4-(4-甲基哌嗪-1-基)丁基氨基]-乙磺酰基}-吡啶并[3,4-d]嘧啶-4-基}-胺;
(3-氯-4-氟苯基)-[6-(5-吗啉-4-基-戊-1-烯-1-磺酰基]-吡啶并[3,4-d]嘧啶-4-基]-胺;
(3-氯-4-氟苯基)-(6-乙烯基亚磺酰基-吡啶并[3,4-d]嘧啶-4-基]-胺;
3-[4-(1-苯基乙基氨基)喹唑啉-6-基氨甲酰基]丙烯酸2-吗啉-4-基-乙酯;
丁-2-烯二酸(4-咪唑-1-基-丁基)-酰胺[4-(1-苯基-乙基氨基)喹唑啉-6-基]-酰胺;
4-[4-(1-苯基乙基氨基)-喹唑啉-6-基氨甲酰基]-丁-3-烯酸3-二乙基氨基丙酯;
戊-2-烯二酸5-{[2-(4-甲基哌嗪-1-基)乙基]-酰胺}1-{[4-(1-苯基-乙基氨基)-喹唑啉-6-基]-酰胺};
4,4-二氟-7-吗啉-4-基-庚-2-烯酸[4-(1-苯基-乙基氨基)-喹唑啉-6-基]-酰胺;
7-二甲基氨基-4,4-二氟-庚-2-烯酸[4-(1-苯基-乙基氨基)-喹唑啉-6-基]-酰胺;
7-咪唑-1-基-庚-2-炔酸[4-(1-苯基-乙基氨基)-喹唑啉-6-基]-酰胺;
6-二甲基氨基-己-2-炔酸[4-(1-苯基-乙基氨基)-喹唑啉-6-基]-酰胺;
丁-2-烯二酸[4-(3-溴-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺(3-二甲基氨基-丙基)-酰胺;
丁-2-烯二酸[4-(3-溴-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺(3-咪唑-1-基-丙基)-酰胺;
4,4-二氟-8-吗啉-4-基-辛-2-烯酸[4-(3-溴-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺;
8-二甲基氨基-4,4-二氟-辛-2-烯酸[4-(3-溴-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺;
7-二甲基氨基-4,4-二氟-庚-2-烯酸[4-(3-溴-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺;
4,4-二氟-7-吗啉-4-基-庚-2-烯酸[4-(3-溴-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺;
6-二甲基氨基-己-2-炔酸[4-(3-溴-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺;
6-吗啉-4-基-己-2-炔酸[4-(3-溴-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺;
7-二甲基氨基-庚-2-炔酸[4-(3-溴-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺;
7-吗啉-4-基-庚-2-炔酸[4-(3-溴-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺;
5-二甲基氨基-戊-2-炔酸[4-(3-溴-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺;
5-吗啉-4-基-戊-2-炔酸[4-(3-溴-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺;
5-咪唑-1-基-戊-2-炔酸[4-(3-溴-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺;
5-(4-甲基-哌嗪-1-基)-戊-2-炔酸[4-(3-溴-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺;
4-[4-(3-溴-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基氨甲酰基]-丁-3-烯酸2-(4-甲基-哌嗪-1-基)-乙酯;
4-[4-(3-溴-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基氨甲酰基]-丁-3-烯酸2-咪唑-1-基-乙酯;
戊-2-烯二酸1-{[4-(3-溴苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺}5-[(3-吗啉基-4-基-丙基)-酰胺];
戊-2-烯二酸1-{[4-(3-溴苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺}5-[(3-二乙基氨基-丙基)-酰胺];
4-[4-(3-溴-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基氨甲酰基]-丁-3-烯酸2-吗啉-4-基-乙酯;
戊-2-烯二酸1-{[4-(3-溴苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺}5-{[3-(4-甲基-哌嗪-1-基)-丙基]-酰胺};
(3-溴-苯基)-{6-[2-(3-二甲基氨基-丙氧基)-乙磺酰基]-吡啶并[3,4-d]嘧啶-4-基}-胺;
(3-溴-苯基)-(6-{2-[4-(4-甲基哌嗪-1-基)-丁基氨基]-乙磺酰基}-吡啶并[3,4-d]嘧啶-4-基}-胺;
(3-溴-苯基)-[6-(5-吗啉-4-基-戊-1-烯-1-磺酰基)-吡啶并[3,4-d]嘧啶-4-基]-胺;
(3-溴-苯基)-(6-亚乙基-亚磺酰基)-吡啶并[3,4-d]嘧啶-4-基]-胺;
丁-2-烯二酸[4-(3-氯-4-氟苯基氨基)-喹唑啉-6-基]-酰胺(3-二甲基氨基-丙基)-酰胺;
丁-2-烯二酸[4-(3-氯-4-氟苯基氨基)-喹唑啉-6-基]-酰胺(3-咪唑-1-基-丙基)-酰胺;
4,4-二氟-8-吗啉-4-基-辛-2-烯酸[4-(3-氯-4-氟-苯基氨基)-喹唑啉-6-基]-酰胺;
8-二甲基氨基-4,4-二氟-辛-2-烯酸[4-(3-氯-4-氟-苯基氨基)-喹唑啉-6-基]-酰胺;
7-二甲基氨基-4,4-二氟-庚-2-烯酸[4-(3-氯-4-氟-苯基氨基)-喹唑啉-6-基]-酰胺;
4,4-二氟-7-吗啉-4-基-庚-2-烯酸[4-(3-氯-4-氟-苯基氨基)-喹唑啉-6-基]-酰胺;
6-二甲基氨基-己-2-炔酸[4-(3-氯-4-氟-苯基氨基)-喹唑啉-6-基]-酰胺;
6-吗啉-4-基-己-2-炔酸[4-(3-氯-4-氟-苯基氨基)-喹唑啉-6-基]-酰胺;
7-二甲基氨基-庚-2-炔酸[4-(3-氯-4-氟-苯基氨基)-喹唑啉-6-基]-酰胺;
7-吗啉-4-基-庚-2-炔酸[4-(3-氯-4-氟-苯基氨基)-喹唑啉-6-基]-酰胺;
5-二甲基氨基-戊-2-炔酸[4-(3-氯-4-氟-苯基氨基)-喹唑啉-6-基]-酰胺;
5-吗啉-4-基-戊-2-炔酸[4-(3-氯-4-氟-苯基氨基)-喹唑啉-6-基]-酰胺;
5-咪唑-1-基-戊-2-炔酸[4-(3-氯-4-氟-苯基氨基)-喹唑啉-6-基]-酰胺;
5-(4-甲基-哌嗪-1-基)-戊-2-炔酸[4-(3-氯-4-氟-苯基氨基)-喹唑啉-6-基]-酰胺;
戊-2-烯二酸1-{[4-(3-氯-4-氟-苯基氨基)-喹唑啉-6-基]-酰胺}5-[(3-吗啉基-4-基-丙基)-酰胺];
戊-2-烯二酸1-{[4-(3-氯-4-氟-苯基氨基)-喹唑啉-6-基]-酰胺}5-[(3-二乙基氨基-丙基)-酰胺];
4-[4-(3-氯-4-氟-苯基氨基)-喹唑啉-6-基氨甲酰基]-丁-3-烯酸2-吗啉-4-基-乙酯;
戊-2-烯二酸1-{[4-(3-氯-4-氟-苯基氨基)-喹唑啉-6-基]-酰胺}5-{[3-(4-甲基-哌嗪-1-基)-丙基]-酰胺};
(3-氯-4-氟-苯基)-{6-[2-(3-二甲基氨基-丙氧基)-乙磺酰基]-喹唑啉-4-基}-胺;
(3-氯-4-氟-苯基)-(6-{2-[4-(4-甲基哌嗪-1-基)-丁基氨基]-乙磺酰基}-喹唑啉-4-基}-胺;
丁-2-烯二酸[4-(3-溴-苯基氨基)-喹唑啉-6-基]-酰胺(3-二甲基氨基-丙基)-酰胺;
丁-2-烯二酸[4-(3-溴-苯基氨基)-喹唑啉-6-基]-酰胺(3-咪唑-1-基-丙基)-酰胺;
4,4-二氟-8-吗啉-4-基-辛-2-烯酸[4-(3-溴-苯基氨基)-喹唑啉-6-基]-酰胺;
8-二甲基氨基-4,4-二氟-辛-2-烯酸[4-(3-溴-苯基氨基)-喹唑啉-6-基]-酰胺;
7-二甲基氨基-4,4-二氟-庚-2-烯酸[4-(3-溴-苯基氨基)-喹唑啉-6-基]-酰胺;
4,4-二氟-7-吗啉-4-基-庚-2-烯酸[4-(3-溴-苯基氨基)-喹唑啉-6-基]-酰胺;
6-二甲基氨基-己-2-炔酸[4-(3-溴-苯基氨基)-喹唑啉-6-基]-酰胺;
6-吗啉-4-基-己-2-炔酸[4-(3-溴-苯基氨基)-喹唑啉-6-基]-酰胺;
7-二甲基氨基-庚-2-炔酸[4-(3-溴-苯基氨基)-喹唑啉-6-基]-酰胺;
7-吗啉-4-基-庚-2-炔酸[4-(3-溴-苯基氨基)-喹唑啉-6-基]-酰胺;
5-二甲基氨基-戊-2-炔酸[4-(3-溴-苯基氨基)-喹唑啉-6-基]-酰胺;
5-吗啉-4-基-戊-2-炔酸[4-(3-溴-苯基氨基)-喹唑啉-6-基]-酰胺;
5-咪唑-1-基-戊-2-炔酸[4-(3-溴-苯基氨基)-喹唑啉-6-基]-酰胺;
5-(4-甲基-哌嗪-1-基)-戊-2-炔酸[4-(3-溴-苯基氨基)-喹唑啉-6-基]-酰胺;
4-[4-(3-溴-苯基氨基)-喹唑啉-6-基氨甲酰基]-丁-3-烯酸2-(4-甲基-哌嗪-1-基)-乙酯;
4-[4-(3-溴-苯基氨基)-喹唑啉-6-基氨甲酰基]-丁-3-烯酸2-咪唑-1-基-乙酯;
戊-2-烯二酸1-{[4-(3-溴苯基氨基)-喹唑啉-6-基]-酰胺}5-[(3-吗啉基-4-基-丙基)-酰胺];
戊-2-烯二酸1-{[4-(3-溴苯基氨基)-喹唑啉-6-基]-酰胺}5-[(3-二乙基氨基-丙基)-酰胺];
4-[4-(3-溴-苯基氨基)-喹唑啉-6-基氨甲酰基]-丁-3-烯酸2-吗啉-4-基-乙酯;
戊-2-烯二酸1-{[4-(3-溴苯基氨基)-喹唑啉-6-基]-酰胺}5-{[3-(4-甲基-哌嗪-1-基)-丙基]-酰胺};
3-[4-(1-苯基乙基氨基)-吡啶并[3,4-d]嘧啶-6-基氨甲酰基]丙烯酸2-吗啉-4-基-乙酯;
丁-2-烯二酸(4-咪唑-1-基-丁基)-酰胺[4-(1-苯基-乙基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺;
4-[4-(1-苯基乙基氨基)-吡啶并[3,4-d]嘧啶-6-基氨甲酰基]-丁-3-烯酸3-二乙基氨基丙酯;
戊-2-烯二酸5-{[2-(4-甲基哌嗪-1-基)乙基]-酰胺}1-{[4-(1-苯基-乙基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺};
4,4-二氟-7-吗啉-4-基-庚-2-烯酸[4-(1-苯基-乙基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺;
7-二甲基氨基-4,4-二氟-庚-2-烯酸[4-(1-苯基-乙基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺;
7-咪唑-1-基-庚-2-炔酸[4-(1-苯基-乙基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺;
6-二甲基氨基-己-2-炔酸[4-(1-苯基-乙基氨基)-吡啶并[3,4-d]嘧啶-6-基]-酰胺;
丁-2-烯二酸(4-(3-氯-4-氟苯基氨基)-7-氟喹唑啉-6-基]-酰胺(3-二甲基氨基丙基)酰胺;
丁-2-烯二酸(7-氯-4-(3-氯-4-氟苯基氨基)喹唑啉-6-基]-酰胺(3-二甲基氨基丙基)酰胺;
N-[4-[3-(溴苯基)氨基]-5-氟-7-[3-(4-吗啉代)丙氧基]喹唑啉-6-基]-丙烯酰胺;和
N-[4-[(3-(氯-4-氟苯基)氨基]-5-氟-7-[1,N-咪唑基)丙氧基]喹唑啉-6-基]-丙烯酰胺。
生物学方法
组织培养
A431人表皮样癌细胞是从美国典型培养物保藏中心(AmericanType Culture Collection),Rockville,MD得到的,并在包含10%胎牛血清的dMEM(Dulbecco’s改良eagle培养基)/F12,50∶50(Gibco/BRL)中作为单细胞层保存。对于生长抑制实验,指定的化合物的10μL稀释液放置在24孔Linbro平板(1.7×1.6cm,平底),随后,加入在2mL培养基中的细胞(2×104)。在潮湿的含5%二氧化碳的空气中将平板在37℃下培养72小时。用Coulter Model AM电子细胞计数仪(Coulter Electronics,Inc.,Hialeah,FL),通过细胞计数测量细胞生长。
表皮生长因子受体酪氨酸激酶的纯化
通过下述方法从A431人体表皮样癌细胞中分离出人体EGF受体酪氨酸激酶。细胞在滚瓶内包含10%胎牛血清的dMEM/F12培养基(Gibco/BRL)中生长。约109个细胞溶解于2体积缓冲液中,缓冲液包含20mM的N-[2-羟基乙基]-哌嗪-N′-[2-乙磺酸](Hepes),pH值为7.4,5mM的乙二醇-二(β-氨基乙基醚)N,N,N′,N′-四乙酸(EGTA)、1%的Triton X-100、10%的甘油、0.1mM的原钒酸钠、5mM氟化钠、4mM焦磷酸盐、4mM苯甲酰胺、1mM二硫苏糖醇(DTT)、80μg/mL抑酶肽、40μg/mL亮抑酶肽和1mM苯基甲基磺酰氟(PMSF)。在25,000xg下离心10分钟后,将上清液加至快速Q琼脂糖柱(Pharmacia biotech.,Inc.,Piscataway,NJ)中,用线性梯度为在50mM Hepes中0.1M氯化钠至0.4m氯化钠,10%甘油,pH7.4洗脱。合并酶活性级分,将其等分,贮存于-100℃下。通过本领域公知的方法制得成纤维细胞生长因子受体(FGFR)、血小板衍生生长因子(PDGF)、胰岛素和c-src酪氨酸激酶。例如,参见:Fry等,“具有抗肿瘤活性的新型酪氨酸激酶抑制剂的发现策略”,AnticancerDrug Design,1994;9:331-351。
酪氨酸激酶实验
对IC50测量的酶实验是在96孔滤板(Millipore MADVN6550,Millipore,Bedford,MA)中进行的。总体积为0.1mL,包含20mM Hepes,pH7.4,50μM的钒酸钠、40mM的氯化镁、包含0.5μCi[32P]ATP的10μM的腺苷三磷酸(ATP)、20μg的聚谷氨酸/酪氨酸(Sigma ChemicalC0.,St.Louis,MO),10ng的EGF受体酪氨酸激酶和适宜抑制剂的稀释液。除ATP外的所有成分均加至孔中,将平板在25℃及振动下培养10分钟。反应通过加入[32P]ATP开始,并将平板在25℃下培养10分钟。通过加入0.1mL的20%三氯乙酸(TCA)使反应停止。将平板保持在4℃下至少15分钟,使底物沉淀。然后,用0.2mL的10%TCA将孔洗涤5次,用Wallac β平板计数仪(Wallac,Inc.,Gaithersburg,PA)测量32P掺入。使用PDGF、FGF和胰岛素受体的胞内激酶结构域以及对c-src的那些结构域的实验如对EGF受体所述进行,只是在反应中包含10mM的氯化锰。
Western蛋白质印迹实验
提取液制备:将单细胞层溶解于0.2mL的沸腾Laemlli缓冲液(2%十二烷基硫酸钠,5%β-巯基乙醇,10%甘油和50mM三[羟甲基]氨基甲烷(Tris),pH),将溶胞产物在100℃下加热5分钟。溶胞产物中的蛋白质通过聚丙烯酰胺凝胶电泳分离并经电泳转移至硝基纤维素。膜在10mM Tris,pH7.2,150mM氯化钠,0.01%叠氮化物(TNA)中洗涤一次,并在包含5%牛血清白蛋白和1%卵清蛋白的TNA中过夜阻断。用抗磷酸酪氨酸抗体(UBI,1μg/mL的阻断缓冲液)将膜印迹2小时,然后用TNA洗涤2次,在含0.05%吐温-20洗涤剂和0.05%乙基苯基聚乙二醇(Nonidet P40)洗涤剂的TNA中洗涤1次,再用TNA洗涤2次。然后,将膜在包含0.1μCiml[125I]蛋白质A的阻断缓冲液中培养2小时,然后再如上所述进行洗涤。在将印迹干燥后,将其置于胶卷暗盒中,暴露于X-AR X-射线胶卷下1-7天(Eastman Kodak Co.,Rochester,NY)。用分子动力学激光光密度计测量带强度。
自磷酸化实验
A431人体表皮样癌细胞在6孔平板上生长至约80%融合,然后在无血清培养基中培养18小时。用各种浓度的欲测试的指定化合物作为抑制剂对一式两份的细胞处理15分钟。然后,用100ng/mL的EGF对细胞刺激5分钟,然后,如蛋白质印迹实验中所述得到提取液。
不可逆实验方法
A431人体表皮样癌细胞在6孔平板上生长至约80%汇合,然后在无血清培养基中培养18小时。用2μM的欲测试的指定化合物作为不可逆抑制剂对一式两份的细胞处理1或2小时。然后,将一组细胞用100ng/mL的EGF对细胞刺激5分钟,然后,如蛋白质印迹实验中所述得到提取液。另一组细胞用温热的无血清培养基洗至无化合物,培养2小时,再洗涤,再培养2小时,再洗涤,再次培养4小时。然后,将这组细胞用EGF刺激,并类似于第一组细胞得到提取液。
结果
表1的第1栏示出了各种化合物对于分离的EGF受体酪氨酸激酶抑制作用的IC50值,第2栏示出了在A431细胞中EGF受体由EGF刺激的自磷酸化抑制作用的IC50值。本发明的大多数化合物以低纳摩尔或亚纳摩尔的效力抑制分离的酶,当抑制细胞的自磷酸化时,大部分具有低纳摩尔效力。表2表明通过这些化合物,再通过从培养基中将它们除去而完成酶抑制后,A431细胞恢复EGF受体自磷酸化活性的能力。第1组细胞提取液(第2栏)表明,多数测试的化合物在开始2小时培养后,完全可抑制EGF受体自磷酸化。表2的第3栏表明,在如方法中所述的无化合物的培养基中,在洗涤和培养后,EGF受体自磷酸化作用的恢复百分数。至少30个化合物在经这种处理后,保留50%或更多的对激酶活性的抑制作用,而至少23个化合物显示出其原有酶活性90-100%的抑制作用。用所有其它的测试化合物处理过的细胞均能恢复86-100%其依赖EGF的自磷酸化活性。其中进行培养的可逆性研究进一步表明需要恢复50%活性所需时间为21小时(表3)。对不可逆相互作用特定的侧链要求由以下事实表明:与化合物3非常类似的化合物9是完全可逆的,对酶具有相同的潜在抑制活性。进而,在侧链上对共轭烯烃的需求由比较用化合物3和11及其饱和类似物17和28说明。在这些情况下,化合物均显示出类似的对分离酶的效能,并在自磷酸化实验中不能很好地区分,但化合物17和28在8小时洗涤后不具有抑制作用,而不可逆抑制剂化合物3和11此时的酶抑制率为89%和100%。
表4表明了化合物3随着暴露于其它酪氨酸激酶保留了非常高的对EGF受体酪氨酸激酶的专一性,并且表明,在实施例3中的活性侧链并不会与其它酶不经区别地进行作用。
最后,对化合物3抑制A431人体表皮样癌细胞的抑制增殖能力进行了测试。IC50值为0.30±0.09微摩尔表明其有能力停止肿瘤生长。
不可逆抑制剂的性能更为引人注意,这是因为其有助于克服或解决血浆短半衰期的效能问题和/或延长对靶物抑制作用的需求。在不可逆抑制剂的适宜剂量下一静脉浓注将可有效地足以完全破坏存在的靶物活性,这种活性的恢复将取决于靶物再合成的速度。由于A431细胞中EGF受体恢复的半衰期是20小时,抑制剂将可以通过一天给药一次或两次而保持对受体的抑制。这消除了多次注射或使用输液或渗透泵的需求。另外,由于受体活性不再受平衡结合条件的束缚,在多次或连续给药方式时为达到不可逆抑制剂的作用结果所使用的剂量可以降低。
表1
各实施例对分离的EGFR激酶活性的IC50值
和在A431细胞中的EGFR自磷酸化作用
EGFR酪氨酸激酶 自磷酸化作用
实施例 IC50值(nM) IC50值(nM)
2 2.7 156
3 0.36 14
4 89 2090
5 11
6 104
7 27 130
8 0.029 13
9 0.46 20
11 0.84 2.7
12 910 >10000
13 1.6 90
14 0.25 53
15 1.2 16
16 3.7 2450
17 1.9 60
18 1.6 2.3
19 0.42 4.7
20 0.91 4.5
21 3.6 5.3
22 1.5 27
23 2 18
24 4 7.9
25 3 21
26 1.7 3
27 3.3 194
28 0.52 15
29 1.2 28
30 1.4 2.7
31 0.55 8.7
32 1.75 35
33 0.89 10
34 0.47 5.5
35 0.54 108
36 0.91 3.4
37 0.48 8.3
38 0.17 13
39 1.6 44
表1(续)
各实施例对分离的EGFR激酶活性的IC50
值和在A431细胞中的EGFR自磷酸化作用
EGFR酪氨酸激酶 自磷酸化作用
实施例 IC50值(nM) IC50值(nM)
40 0.76 2.4
41 1.1 5.6
42 23 173
43 1.4 24
44 21 327
45 1.6 1039
46 1.2 120
47 2.7 67
48 1.1 27
49 4.2 2280
50 0.5 7.7
51 9.1 77
52 0.69 20
53 0.81 52
54 2.4 108
55 0.37 >500
56 0.44 59
57 0.43 >500
58 124 >500
表2
在暴露于2μM抑制剂后在A431细胞中
EGF受体自磷酸化作用活性的恢复
2小时培养后 在无药培养基培养8
实施例号 对照% 小时后的对照% 不可逆性
2 0 92 N
3 1 13 Y
4 55 98 N
5 N
6 N
7 N
8 0 95 N
9 0 99 N
11 0 0 Y
12 85 100 N
13 1 90 N
14 0 50 Y
15 0 85 N
16 30 85 N
17 0 100 N
18 0 0 Y
19 0 0 Y
20 0 0 Y
21 0 0 Y
22 0 0 Y
23 0 0 Y
24 0 0 Y
25 0 0 Y
26 0 0 Y
27 0 96 N
28 0 100 N
29 0 100 N
30 0 0 Y
31 0 35 Y
32 0 0 Y
33 0 0 Y
34 0 0 Y
35 0 20 Y
36 0 0 Y
37 0 0 Y
38 0 0 Y
39 0 80 N
40 0 0 Y
41 0 0 Y
表2(续)
在暴露于2μM抑制剂后在A431细胞中
EGF受体自磷酸化作用活性的恢复
2小时培养后 在无药培养基培养8
实施例号 对照% 小时后的对照% 不可逆性
42 12 50 Y
43 0 0 Y
44 13 42 Y
45 0 21 Y
46 19 59 Y
47 0 26 Y
48 0 53 Y
49 50 75 N
50 0 32 Y
51 12 32 Y
52 0 0 Y
53 0 0 Y
54 0 3 Y
55 32 32 Y
56 0 0 Y
57 43 39 Y
58 81 95 N
表3
在用2μM化合物3或化合物9抑制剂处理2小时的
A431细胞中EGF受体自磷酸化作用抑制剂的可逆性
在无药培养基中 化合物3 化合物9
的小时数 自磷酸化作用的对照% 自磷酸化作用的对照%
0 0 4
4 12 24
8 23 100
23 54 100
表4
实施例3对不同酪氨酸激酶抑制作用IC50(nM)的影响
EGFR C-SRC 胰岛素 PDGF FGF1
0.36 >2,500 >50,000 >50,000 >50,000
体内数据
在第0天,向18-20g的雌性裸鼠(Ncr nu/nu,Taconic Farms)的右腋窝区域中植入具有肿瘤片断(约30mg)的SC。用于本研究的肿瘤为用h-EGF受体转染的成纤维细胞NIH 3T3(Decker等,J Biol Chem,1990;265:7009-7015)。这种模型非常易于肿瘤发生,发生率为100%,在2天之内体积倍增。将实施例3的化合物通过腹膜内给药,在第3-7天每隔12小时给药一次,总共10次注射(每组5只小鼠)。赋形剂为6%的二甲基乙酰胺,50mM乳酸缓冲液中,pH4.0。通过测量单个肿瘤的长度和宽度,按照下式(a×b2)/2计算质量(毫克数),记录肿瘤的体积,每周3次,其中a和b分别为肿瘤的长度和宽度。按照具体测量天数时治疗组肿瘤的中等肿瘤体积与对照组肿瘤的中等肿瘤体积的比值计算百分比T/C(治疗组/对照组)。
由第7、10和12天的实验,以100和30mg/kg/注射量进行治疗可抑制肿瘤生长40-50%。而以10和3mg/kg/注射量则未观察到活性。在任何剂量水平下,均未观察到失重、死亡或临床毒性迹象。
%T/C
天
组 7 10 12
对照组 100 100 100
实施例3@100(mg/kg/注射) 57 70 57
实施例3@30(mg/kg/注射) 48 66 53
实施例3@30(mg/kg/注射) 115 138 113
附加体内试验
采用与前述类似的方法,只是每组有6只小鼠,给药计划如前所述,对若干个化合物进行了各种肿瘤异种移植试验。这些试验包括如前所述的h-EGF受体转染NIH 3T3-转染的成纤维细胞模型;A431人体表皮样癌,其严重地过度表达EGF受体;MCF7人体乳腺癌,其对EGF受体抑制剂是敏感的,并公知表达EGF受体和erbB-2和erbB-3;SK-OV-3人体卵巢癌,其主要过度表达erbB-2;AH-125小细胞肺癌,其过度表达EGF受体;鼠16/c乳腺癌。
实施例3
EGFR肿瘤腹膜内给药,第3-7天每天给药2次:
@100mg/kg引起4天的生长延迟。
@30mg/kg引起2.5天的生长延迟。腹膜内给药,第1-13天每天给药2次:
@300mg/kg无活性。
@190和120mg/kg引起1天的生长延迟。
@75mg/kg引起5天的生长延迟。
实施例11
MCF-7肿瘤腹膜内给药,第1-5天、第8-12天、第15-19天每天给药2次:
@47mg/kg引起17.4天的生长延迟。
@28mg/kg引起22.9天的生长延迟。
鼠16/C乳腺癌
每天给药2次,剂量超过120mg/kg无活性。
EGFR肿瘤
腹膜内给药,14天每天给药2次:
@75mg/kg引起8.7天的生长延迟。
@47mg/kg引起6.6天的生长延迟。
@29mg/kg引起2.3天的生长延迟。
@18mg/kg引起1.8天的生长延迟。
@150mg/kg有毒性。
@75mg/kg有毒性。腹膜内给药,第3-7天、第10-14天、第17-21天和第24-28天每天给药2次:
@75mg/kg引起19.9天的生长延迟。
@150mg/kg有毒性。腹膜内给药,第3-17天每天给药1次:
@75mg/kg引起11.7天的生长延迟。腹膜内给药,第3-7天、第10-14天、第17-21天每天给药1次:
@75mg/kg引起5.3天的生长延迟。
@150mg/kg有毒性。
A431肿瘤腹膜内给药,第7-11天、第4-18天、第21-25天每天给药2次:
@28mg/kg引起28.2天的生长延迟。口服给药,第7-21天每天1次:
@200mg/kg引起3.5天的生长延迟。
@100mg/kg引起2天的生长延迟。
SK-OV-3-肿瘤皮内给药,第10-14天、第17-21天、第24-28天每天给药2次:
@30mg/kg引起1.2天的生长延迟。
实施例19
EGFR肿瘤腹膜内给药,14天每天给药2次:
@124mg/kg引起11.8天的生长延迟。
@77mg/kg引起7.9天的生长延迟。
@48mg/kg引起6.4天的生长延迟。
@200mg/kg有毒性。
SK-OV-3-肿瘤皮内给药,第10-14天、第17-21天、第24-28天每天给药2次:
@30mg/kg引起1.3天的生长延迟。
A431肿瘤皮下输注(Alzet),第9-23天:
@24mg/kg/天引起14天的生长延迟。
@12mg/kg/天引起15天的生长延迟。
实施例21腹膜内给药,每天2次:
@48mg/kg有毒性。
EGFR肿瘤腹膜内给药,14天每天2次:
@12.5mg/kg引起16.8天的生长延迟。
@6.25mg/kg引起9.3天的生长延迟。
@25mg/kg有毒性。皮下输注(Alzet):
@200、124、77和48mg/kg/天有毒性。
AH-125肿瘤皮下输液(Alzet),第19-23天:
@20.6mg/kg/天引起10.0天的生长延迟。
@10.4mg/kg/天引起9.5天的生长延迟。
@5.5mg/kg/天引起9.5天的生长延迟。
A431肿瘤皮下输注(Alzet),第9-23天和第42-56天:
@48mg/kg/天引起55天的生长延迟。
@24mg/kg/天引起60天的生长延迟。
@12mg/kg/天引起51天的生长延迟。
实施例36
EGFR肿瘤腹膜内给药,7天每天给药2次:
@48mg/kg引起10.3天的生长延迟。腹膜内给药,14天每天给药2次:
@25mg/kg引起8.7天的生长延迟。
@12.5mg/kg引起3.5天的生长延迟。
@50mg/kg有毒性。皮下输注(Alzet):
@200、124、77mg/kg/天有毒性。
实施例40腹膜内给药,每天给药2次:
@48和20mg/kg有毒性。
EGFR肿瘤
@14天每天给药2次,10和5mg/kg无效。皮下输注(Alzet):
@200、124、77和48mg/kg/天有毒性。
Claims (32)
1、一种下式I的化合物和其药学上可接受的盐、酯、酰胺和其前药,
其中,X为-O(CH2)n-N-咪唑基、-O(CH2)n哌嗪基、-O(CH2)n-N-(C1-C6烷基)2、-O(CH2)n吗啉代基或氢,而Y为-D-E-F;
R1为氢或C1-C6烷基;
R2为氢、C1-C6烷基、-(CH2)n-N-吗啉代基或取代的C1-C6烷基,其
Z1、Z2或Z3独立地为氢、卤素、C1-C6烷基或三氟甲基;而
R5为氢、卤素、三氟甲基、C1-C6烷基、-CH=CH2、-(CH2)n-N(C1-C6
烷基)2、-1-氧代(C1-C6)烷基、羧基、(C1-C6)烷氧羰基、
N-(C1-C6)烷基氨甲酰基或苯基,并且每一个(C1-C6)烷基可
被
取代,其中A和B独立地为氢或C1-C6烷基,R6为
氢;和
n为1-4,p为0。
2、根据权利要求1的化合物,其中Z1和Z2为氢,Z3为卤素。
3、根据权利要求2的化合物,其中Z3为溴。
4、根据权利要求3的化合物,其中溴位于苯环的3位或间位。
5、根据权利要求1的化合物,其中R2为氢。
6、根据权利要求1的化合物,其中R2为-(CH2)n-N-吗啉代基。
7、根据权利要求1的化合物,其中R5为羧基、(C1-C6)烷氧羰基或C1-C6烷基。
8、一种下式II的化合物和其药学上可接受的盐、酯、酰胺和其前药,
其中Q为
其中,X为-D-E-F,Y为氢,其中
R1为氢或C1-C6烷基;
R2为氢、C1-C6烷基、-(CH2)n-N-吗啉代基、或取代的C1-C6烷基,
其中取代基选自
,A和B独立地为氢、C1-C6烷基;
E1、E2或E3独立地为氢、卤素、C1-C6烷基或三氟甲基;而
R5为氢、卤素、三氟甲基、C1-C6烷基、-CH=CH2、-(CH2)n-N(C1-C6
烷基)2、-1-氧代(C1-C6)烷基、羧基、(C1-C6)烷氧羰基、
N-(C1-C6)烷基氨甲酰基或苯基,并且每一个(C1-C6)烷基可
为氢;和
n为1-4,p为0。
9、根据权利要求8的化合物,其中E1和E2为氢,E3为卤素。
10、根据权利要求9的化合物,其中卤素为溴。
11、根据权利要求10的化合物,其中溴位于苯环的3位或间位。
12、根据权利要求8的化合物,其中Q为
13、根据权利要求8的化合物,其中Q为
15、根据权利要求13的化合物,其中X为
16、根据权利要求14的化合物,其中X为
17、根据权利要求14的化合物,其中X为
18、根据权利要求12的化合物,其中X为
Y为氢。
19、一种下式III的化合物和其药学上可接受的盐、酯、酰胺和其前药,
其中Q为
其中,X为氢,Y为-D-E-F;
F为
R1为氢或C1-C6烷基;
R2为氢、C1-C6烷基、-(CH2)n-N-吗啉代基或取代的C1-C6烷基,其
E1、E2或E3独立地为氢、卤素、C1-C6烷基或三氟甲基;而
R5为氢、卤素、三氟甲基、C1-C6烷基、-(CH2)n-N(C1-C6烷基)2、
-1-氧代(C1-C6)烷基、羧基、(C1-C6)烷氧羰基、N-(C1-C6)
烷基氨甲酰基或苯基,并且每一个(C1-C6)烷基可被-N-B取
代,其中A和B独立地为氢或C1-C6烷基,R6为氢或C1-C6
烷基;和
n为1-4,p为0。
20、根据权利要求19的化合物,其中E1和E2为氢,E3为溴。
21、权利要求1的化合物,它是
N-[4-(3-溴-苯基氨基)-喹唑啉-7-基]-丙烯酰胺;
N-[4-(3-氯-苯基氨基)-喹唑啉-7-基]-丙烯酰胺;
N-[4-[(3-氯-苯基)氨基]-喹唑啉-6-基]-丙烯酰胺;
N-[4-(3-甲基-苯基氨基)-喹唑啉-6-基]-丙烯酰胺;
N-[4-[(3-(三氟甲基)苯基)氨基]-喹唑啉-6-基]-丙烯酰胺;
N-[4-[(3-溴-苯基)氨基]-喹唑啉-6-基]-E-丁-2-烯酰胺;
N-[4-[(3-溴-苯基)氨基]-喹唑啉-6-基]-4,4,4-三氟-E-丁-2-烯酰胺;
N-[4-[(3-溴-苯基)氨基]-喹唑啉-6-基]-丙炔酰胺;
N-[4-[(3-溴-苯基)氨基]-喹唑啉-6-基]-丁-2-炔酰胺;
N-[4-[(3-溴-苯基)氨基]喹唑啉-6-基]-E,4-氧代戊-2-烯酰胺;
N-[4-[(3-溴-苯基)氨基]喹唑啉-6-基]-E,4-乙氧基-4-氧代丁-2-烯酰胺;
3-[4-(3-溴-苯基氨基)-喹唑啉-6-基-氨甲酰基]丙烯酸(Z);
N-[4-[(3-溴苯基)氨基]-7-[(3-(4-吗啉代)丙氧基]-喹唑啉-6-基]-丙烯酰胺;
N-[4-[(3-甲基苯基)氨基]-7-[(3-(4-吗啉代)丙氧基]-喹唑啉-6-基]-丙烯酰胺;
N-[4-[(3-溴苯基)氨基]-7-[(3-(4,N-甲基-1,N-哌嗪基)丙氧基]-喹唑啉-6-基]-丙烯酰胺;
N-[4-[(3-溴苯基)氨基]-7-[(3-(1,N-咪唑基)丙氧基]-喹唑啉-6-基]-丙烯酰胺;
N-[4-[(3-溴苯基)氨基]-7-[4-(N,N-二甲基氨基)丁氧基]-喹唑啉-6-基]-丙烯酰胺;
N-[4-[(3-溴苯基)氨基]-喹唑啉-6-基]-E,4-(3-(N,N-二甲基氨基)丙氧基-4-氧代丁-2-烯酰胺三氟乙酸酯;和
N-[4-[(3-溴苯基)氨基]-喹唑啉-6-基]-E,4-(3-(N,N-二甲基氨基)丙基氨基-4-氧代丁-2-烯酰胺。
22.根据权利要求8的化合物,它是
N-[4-[(3-溴-苯基氨基)-吡啶并[4,3-d]嘧啶-7-基]-丙烯酰胺;
N-[4-[(3-溴-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-丙烯酰胺;
N-[4-[(3-甲基-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-丙烯酰胺;
N-[4-[(3-溴-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-N-甲基丙烯酰胺;
N-[4-[(3-溴-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]戊-2,4-二烯酰胺;
N-[4-[(3-溴-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]E-丁-2-烯酰胺;
N-[4-[(3-溴-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]肉桂酰胺;
N-[4-[(3-溴-苯基氨基)-吡啶并[3,4-d]嘧啶-6-基]-E,3-氯-丙烯酰胺;
4-[(3-溴-苯基)氨基]-6-(亚乙基磺酰基)吡啶并[3,4-d]嘧啶。
23.根据权利要求19的化合物,它是
N-[4-[(3-溴-苯基氨基)-苯并[b]噻吩并[3,2-d]嘧啶-8-基]-丙烯酰胺;
N-[4-[(3-溴-苯基氨基)-苯并[b]噻吩并[3,2-d]嘧啶-6-基]-丙烯酰胺;
N-[4-[(3-溴-苯基氨基)-苯并[b]噻吩并[3,2-d]嘧啶-7-基]-丙烯酰胺。
24、一种包含权利要求1的化合物的药学上可接受的组合物。
25、一种包含权利要求8的化合物的药学上可接受的组合物。
26、一种包含权利要求19的化合物的药学上可接受的组合物。
27、权利要求1的化合物用于制备不可逆抑制酪氨酸激酶的药物的用途。
28.权利要求27的用途,其中所述药物可用于治疗或预防癌症、再狭窄、牛皮癣、动脉粥样硬化或子宫内膜异位。
29、权利要求8的化合物用于制备不可逆抑制酪氨酸激酶的药物的用途。
30、权利要求29的用途,其中所述药物可用于治疗或预防癌症、再狭窄、牛皮癣、动脉粥样硬化或子宫内膜异位。
31、权利要求19的化合物用于制备不可逆抑制酪氨酸激酶的药物的用途。
32、权利要求31的用途,其中所述药物可用于治疗或预防癌症、再狭窄、牛皮癣、动脉粥样硬化或子宫内膜异位。
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CNA2006101018277A Pending CN1923818A (zh) | 1996-04-12 | 1997-04-08 | 酪氨酸激酶的不可逆抑制剂 |
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BG (1) | BG63160B1 (zh) |
BR (1) | BR9708640B1 (zh) |
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DK (1) | DK0892789T4 (zh) |
EA (1) | EA001595B1 (zh) |
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PL (1) | PL190489B1 (zh) |
PT (1) | PT892789E (zh) |
RO (1) | RO121900B1 (zh) |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN100503580C (zh) * | 1996-04-12 | 2009-06-24 | 沃尼尔·朗伯公司 | 酪氨酸激酶的不可逆抑制剂 |
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