CN111848585A - 一种2,4-二取代喹唑啉类衍生物及其制备方法和在抗肿瘤药物中的应用 - Google Patents
一种2,4-二取代喹唑啉类衍生物及其制备方法和在抗肿瘤药物中的应用 Download PDFInfo
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- CN111848585A CN111848585A CN202010776079.2A CN202010776079A CN111848585A CN 111848585 A CN111848585 A CN 111848585A CN 202010776079 A CN202010776079 A CN 202010776079A CN 111848585 A CN111848585 A CN 111848585A
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- disubstituted quinazoline
- disubstituted
- reaction
- derivative
- hydrogen
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Classifications
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- C—CHEMISTRY; METALLURGY
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- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
本发明属于药物技术领域，尤其涉及一种2,4‑二取代喹唑啉类衍生物及其在抗肿瘤药物中的应用。具体为抗肺癌、抗胃癌、抗卵巢癌、抗乳腺癌、抗直肠癌等抗肿瘤作用效果。MTT实验显示，本发明合成的FAK抑制剂对肿瘤细胞的抑制率比较理想，具有临床开发抗肿瘤药物的前景。
Description
技术领域
本发明属药物合成领域，涉及2,4-二取代喹唑啉类衍生物，以及所述化合物的药学可接受的盐、水合物、溶剂化物或前药，它们的制备方法及其作为治疗剂特别是作为FAK抑制剂的用途。
背景技术
恶性肿瘤是临床上常见的高发病，它严重威胁着人类的健康，肿瘤治疗已经成为一个世界性的难题，高效低毒的抗肿瘤药物的研发迫在眉睫。靶向药物凭借其特异性好、有效性强、毒副反应作用低等特点，在肿瘤治疗中发挥着巨大的作用。
黏着斑激酶(focal adhesion kinase,FAK)是非受体酪氨酸激酶家族中的一员，位于细胞与细胞之间的连接处，当细胞外基质(extracellularmatrix,ECM)通过整合素受体群与细胞发生连接后，调节整合素受体下游信号通路。大量研究表明，FAK的激活会对多种不同的细胞行为产生影响，在肿瘤细胞扩散的附着、迁移、侵袭等过程中发挥关键作用。这些功能特性表明，FAK与肿瘤的生长、增殖、转移以及凋亡之间存在密切的联系，抑制FAK表达能有效抑制肿瘤细胞的生长，同时防止疾病的发生。
FAK抑制剂的开发现已成为药物学家关注的焦点，目前已有些FAK抑制剂正进行临床或临床前研究，主要分为两大类，一类为ATP依赖性FAK抑制剂，另一类为ATP非依懒性FAK抑制剂。为了获得高活性、骨架新颖的FAK抑制剂，我们设计并合成了一系列2,9-二取代嘌呤类衍生物，具有突出的FAK抑制活性。
发明内容
本发明针对现有技术的不足，提供一种2,4-二取代喹唑啉类衍生物，几何异构体或其药学上可接受的盐、水合物、溶剂化物或前药，及其作为FAK抑制剂的应用。
其中，
R1选自氢、卤素，C1-C6烷基、C1-C6烷氧基、羟基、氨基、硝基；
R2选自氢、氨基、硝基、羟基、卤素、C1-C6烷基，C1-C6烷氧基，N-烷基酰胺基、二甲基氧磷基。
本发明优选通式(I)所示的2,4-二取代喹唑啉类衍生物，
其中，R1选自氢、卤素、C1-C6烷基、C1-C6烷氧基；R2选自氢、C1-C6烷氧基，N-烷基酰胺基、二甲基氧磷基。
本发明所述的2,4-二取代喹唑啉类衍生物，选自：
此外，按照本发明所属领域的一些通常方法，本发明中通式(I)的部分化合物具有碱性基团，可以与酸生成药学上可接受的盐。可药用加成盐包括无机酸和有机酸加成盐，与下列酸加成的盐是特别优选的：盐酸、氢溴酸、硫酸、磷酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘二磺酸、乙酸、丙酸、乳酸、三氟乙酸、马来酸、柠檬酸、富马酸、草酸、酒石酸、苯甲酸等。最优选为盐酸。
本发明的“水合物”是指溶剂分子是水所形成的缔合物。
本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括，但并不限于，水，异丙醇，乙醇，甲醇，二甲亚砜，乙酸乙酯，乙酸和氨基乙醇。
本发明还包括本发明衍生物的前药。本发明衍生物的前药是通式(I)的衍生物，它们自身可能具有较弱的活性甚至没有活性，但是在给药后，在生理条件下(例如通过代谢、溶剂分解或另外的方式)被转化成相应的生物活性形式。
通式(I)所示的化合物可以以非溶剂化形式和含有药学上可接受的溶剂(如水、乙醇等)的溶剂化形式。通式(I)所示的化合物可以含有不对称或手性中心，因此可以以不同立体异构形式存在。本发明的所有立体异构形式，包括但不限于非对映异构体、对映异构体和阻转异构体以及它们的混合物(如外消旋混合物)，均包括在本发明的范围内。
通式(I)所示的化合物可以以不同的互变异构体形式存在，所有这些形式均包括在本发明的范围内。术语“互变异构体”或“互变异构形式”是指经由低能垒互相转化的不同能量的结构异构体。
本发明中“烷基”是指直链或支链的烷基，其中C1-C6基团是指该部分中具有1-6个碳原子，即基团包含1、2、3、4、5或6个碳原子。
本发明的“烷氧基”是指烷基醚基烷基，例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基和叔丁氧基等。
本发明中的术语“环烷基”是指任选取代的一价饱和烃环，其包含3-6个成环碳原子，也可包括作为取代基的其他非成环原子(例如：甲基环丙基)。
本发明中所述的“卤素”是指氟、氯、溴或碘代。
本发明可以含有通式(I)的衍生物，及其药学上可接受的盐、水合物、溶剂化物或前药作为活性成份，与药学上可接受的载体或赋型剂混合制备成组合物，并制备成临床上可接受的剂型，上述药学上可接受的赋型剂是指任何可用于药学领域的稀释剂、辅助剂和/或载体。本发明的衍生物可以与其他活性成份组合使用，只要它们不产生其他不利的作用，例如过敏反应。
本发明的药用组合物可配制成若干种剂型，其中含有药物领域中一些常用的赋形剂。如上所述的若干种剂型可以采用注射剂、片剂、胶囊剂、气雾剂、栓剂、膜剂、滴丸剂、外用搽剂、软膏剂等剂型药物。
用于本发明药物组合物的载体是药物领域中可得到的常见类型，包括：粘合剂、润滑剂、崩解剂、助溶剂、稀释剂、稳定剂、悬浮剂、无色素、矫味剂、防腐剂、加溶剂和基质等。药物制剂可以经口服或胃肠外方式(例如静脉内、皮下、腹膜内或局部)给药，如果某些药物在胃部条件下不稳定的，可将其配制成肠衣片剂。
本发明所述衍生物的制备方法，均可按照下列路线的方法进行合成。
路线中试剂和条件：(a)DIPEA,DMF,0℃；(b)5-amino-1,3-dihydroindol-2-one,HCl,EtOH,120℃。
如上述路线所示，目标化合物的合成主要有以下两个步骤：
步骤1、以取代的2,4-二氯喹唑啉为原料与不同取代的苯胺在碱性条件下进行亲核取代反应得到中间体2，反应溶剂可为二氯甲烷、三氯甲烷、四氢呋喃、DMF等，优选DMF。
步骤2、合成的中间体2与5-氨基二氢吲哚-2-酮在反应溶剂里发生取代反应，取代反应条件可以为质子酸或者碱催化，优选HCl，反应溶剂可为四氢呋喃、乙醇、DMF等，优选乙醇，反应温度为50-130℃，优选90-130℃。
本发明所述的抗肿瘤具体为乳腺癌、前列腺癌、肺癌。
本发明显著的技术效果。
本发明酶活性实验显示，本发明人合成的2,4-二取代喹唑啉类衍生物具有较强的抗肿瘤活性优点，可用于制备抗肿瘤药物。MTT实验显示，本发明合成的FAK抑制剂对肿瘤细胞的抑制率比较理想，具有临床开发抗肿瘤药物的前景。
具体实施方法
下述实施例旨在阐述而不是限制本发明的范围。化合物的核磁共振氢谱用BrukerARX-400测定，质谱用Agilent 1100LC/MS测定；所用试剂均为分析纯或化学纯。
实施例1。
步骤1中间体2的合成
将2,4,-二氯喹唑啉(465mg，2.0mmol)溶于10mL DMF中，冰浴降温至0℃。加入邻甲氧基苯胺(267mg，2.0mmol)和DIEA(0.39mL,2.4mmol)。0℃条件下继续搅拌反应3h。TLC检测反应完成后将反应液倾入100mL水中，析出固体。抽滤干燥得淡黄色固体423mg,收率72％。
步骤2目标化合物的合成
将中间体2(196mg,0.67mmol)和5-氨基二氢吲哚-2-酮加入封管中，加入10mL乙醇和10μL浓盐酸，升温至120℃反应15h。TLC检测反应完成，降至室温，减压浓缩除去溶剂，然后加入30mL乙酸乙酯萃取，分别用水和饱和食盐水洗涤有机层，Na2SO4干燥过夜。滤除干燥剂，减压蒸除溶剂，残余物经硅胶柱层析纯化，得白色固体221mg,收率72％。
1H-NMR(400MHz,DMSO-d6)δ10.59(s,1H),10.31(s,1H),10.05(s,1H),8.14(d,J＝8.0Hz,1H),7.84–7.81(m,2H),7.63–7.58(m,3H),7.25–7.21(m,2H),7.02–6.98(m,3H),3.86(s,3H),3.59(s,2H).ESI-MS m/z:398.2[M+H]+.
按照实施例1的方法，分别使用以取代的2,4-二氯喹唑啉为原料与不同取代的苯胺经取代反应，再与5-氨基二氢吲哚-2-酮发生取代反应制备得到实施例2-8。
实施例2。
1H-NMR(400MHz,DMSO-d6)δ10.59(s,1H),10.30(s,1H),10.04(s,1H),8.73(d,J＝4.4Hz,1H),8.12(d,J＝8.1Hz,1H),7.96(d,J＝8.4Hz,1H),7.84–7.81(m,2H),7.74(d,J＝7.8Hz,1H),7.64–7.58(m,4H),7.28(d,J＝8.3Hz,1H),7.02–6.98(m,1H),3.59(s,2H),2.83(d,J＝4.6Hz,3H).ESI-MS m/z:425.2[M+H]+.
实施例3。
1H-NMR(400MHz,DMSO-d6)δ10.58(s,1H),10.32(s,1H),10.06(s,1H),8.12(d,J＝8.4Hz,1H),7.84–7.81(m,2H),7.63–7.58(m,3H),7.28–7.21(m,4H),7.02–6.98(m,1H),3.59(s,2H),1.84(d,J＝13.2Hz,6H).ESI-MS m/z:444.1[M+H]+.
实施例4。
1H-NMR(400MHz,DMSO-d6)δ10.59(s,1H),10.31(s,1H),10.05(s,1H),8.15(d,J＝7.8Hz,1H),7.63–7.59(m,2H),7.46–7.41(m,2H),7.25–7.20(m,2H),7.02–6.97(m,3H),3.86(s,3H),3.81(s,3H),3.58(s,2H).ESI-MS m/z:428.1[M+H]+.
实施例5。
1H-NMR(400MHz,DMSO-d6)δ10.59(s,1H),10.30(s,1H),10.04(s,1H),8.73(d,J＝4.4Hz,1H),8.15(d,J＝8.1Hz,1H),7.96(d,J＝8.4Hz,1H),7.74(d,J＝7.8Hz,1H),7.63–7.59(m,3H),7.46–7.41(m,2H),7.28(d,J＝8.3Hz,1H),7.03–6.98(m,1H),3.81(s,3H),3.58(s,2H),2.82(d,J＝4.4Hz,3H).ESI-MS m/z:455.2[M+H]+.
实施例6。
1H-NMR(400MHz,DMSO-d6)δ10.58(s,1H),10.32(s,1H),10.06(s,1H),8.14(d,J＝8.0Hz,1H),7.63–7.58(m,2H),7.46–7.41(m,2H),7.28–7.20(m,4H),7.02–6.98(m,1H),3.82(s,3H),3.60(s,2H),1.86(d,J＝13.4Hz,6H).ESI-MS m/z:474.2[M+H]+.
实施例7。
1H-NMR(400MHz,DMSO-d6)δ10.59(s,1H),10.31(s,1H),10.05(s,1H),8.62(d,J＝2.1Hz,1H),7.85(dd,J＝2.2,8.9Hz,1H),7.70(d,J＝8.9,1H),7.63–7.58(m,2H),7.25–7.21(m,2H),7.02–6.97(m,3H),3.85(s,3H),3.58(s,2H).ESI-MS m/z:432.1[M+H]+.
实施例8。
1H-NMR(400MHz,DMSO-d6)δ10.59(s,1H),10.30(s,1H),10.04(s,1H),8.73(d,J＝4.4Hz,1H),8.62(d,J＝2.1Hz,1H),7.96(d,J＝8.4Hz,1H),7.85(dd,J＝2.2,8.9Hz,1H),7.70(d,J＝8.9,1H),7.74(d,J＝7.8Hz,1H),7.62–7.58(m,3H),7.26(d,J＝8.4Hz,1H),7.01–6.98(m,1H),3.58(s,2H),2.83(d,J＝4.6Hz,3H).ESI-MS m/z:459.1[M+H]+.
实施例9。
1H-NMR(400MHz,DMSO-d6)δ10.56(s,1H),10.31(s,1H),10.04(s,1H),8.62(d,J＝2.1Hz,1H),7.96(d,J＝8.4Hz,1H),7.85(dd,J＝2.2,8.9Hz,1H),7.63–7.58(m,2H),7.28–7.21(m,4H),7.02–6.98(m,1H),3.61(s,2H),1.82(d,J＝13.0Hz,6H).ESI-MS m/z:478.1[M+H]+.
药理活性测试。
一、FAK抑制活性测试。
实验使用Promega公司的Kinase-Glo Plus luminescence kinase assay kit试剂盒，通过定量分析酶促反应后残留的ATP含量来检测激酶活性。测试中的荧光信号与ATP含量相关。
测试方法:配置50μL的反应液，包括40mM Tris,pH7.4,10mM MgCl2,0.l mg/mlBSA,1mM DTT,0.2mg/ml Poly(G1u,Tyr)substrate，10μM ATP和FAK激酶混合液。将待测化合物配成10％DMSO溶液，取5μL稀释到50μL上述反应液中，得到最终DMSO浓度为1％的反应液。酶先和化合物孵化30min，然后加入ATP和底物开始反应，所有酶催化反应都在30℃下进行40min。酶催化反应结束后，反应液中加入50μL Kinase-Glo Plus Luminescence kinaseassay solution(Promega)，继在室温孵化30min，酶标仪读取发光值。结果见表1。
表1 FAK抑制活性测试结果。
二、细胞增殖抑制实验(MTT assay)。
肿瘤细胞选择A549、MCF-7、PC3细胞，培养上述细胞至对数生长期，使用胰蛋白酶消化处理贴壁细胞，收集细胞至含10％胎牛血清的DMEM培养基中。离心细胞悬液(1000×rpm)，将细胞稀释至2.5-5.0×103个/mL，每孔加入2.0-3.0×103个细胞，37℃培养24h。加入2μL不同浓度药物溶液，37℃培养，分别于不同的时间点加入10μL MTT[3-(4，5-二甲基噻唑-2)-2，5-二苯基四氮唑溴盐]溶液。37℃温育4h，弃去培养基，每孔加入200μL DMSO，以溶解残留的甲臜结晶，15min后，在490nm处记录吸光值。结果见表2。
表2 MTT细胞增殖抑制率。
本发明中通式(I)的化合物可单独施用，但通常是和药用载体混合物给予，所述药用载体的选择要根据所需用药途径和标准药物实践，下面分别用该类化合物的各种药物剂型，例如片剂、胶囊剂、注射剂、气雾剂、栓剂、膜剂、滴丸剂、外用搽剂和软膏剂的制备方法，说明其在制药领域中的新应用。
实施例10：片剂
用含实施例1化合物10g，按照药剂学一般压片法加辅料20g混匀后，压制成100片，每片重300mg。
实施例11：胶囊剂
用含实施例1化合物10g，按照药剂学胶囊剂的要求将辅料20g混匀后，装入空心胶囊，每个胶囊重300mg。
实施例12：注射剂
用含实施例1化合物10g，按照药剂学常规方法，进行活性炭吸附，经0.65μm微孔滤膜过滤后，填入氮气罐制成水针制剂，每只装2mL，共灌装100瓶。
实施例13：气雾剂
用含实施例1化合物10g，用适量丙二醇溶解后，加入蒸馏水及其他辐料后，制成500mL的澄清溶液即得。
实施例14：栓剂
用含实施例1化合物10g，将之研细加入甘油适量，研匀后加入已熔化的甘油明胶，研磨均匀，倾入已涂润滑剂的模型中，制得栓剂50颗。
实施例15：膜剂
用含实施例1化合物10g，将聚乙烯醇、药用甘油、水等搅拌膨胀后加热溶解，80目筛网过滤，再将实施例18化合物加入到滤液中搅拌溶解，涂膜机制膜100片。
实施例16：滴丸剂
用含实施例1化合物为例10g，与明胶等基质50g加热熔化混匀后，滴入低温液体石蜡中，共制得滴丸1000丸。
实施例17：外用搽剂
用含实施例1化合物10g，按照常规药剂学方法与乳化剂等辅料2.5g混合研磨，再加蒸馏水至200mL制得。
实施例18：软膏剂
用含实施例1化合物10g，研细后与凡士林等油性基质500g研匀制得。
尽管已经通过特定实施方案描述了本发明，但修改和等价变化对于精通此领域的技术人员而言是显见的，且它们都包含在本发明范围。
Claims (9)
1.一种2,4-二取代喹唑啉类衍生物，及其几何异构体或其药学上可接受的盐、水合物、溶剂化物或前药，其特征在于，所述的衍生物的结构式如下：
其中，所述的R1选自氢、卤素、C1-C6烷基、C1-C6烷氧基、羟基、氨基、硝基；
R2选自氢、氨基、硝基、羟基、卤素、C1-C6烷基，C1-C6烷氧基，N-烷基酰胺基、二甲基氧磷基。
2.如权利要求1所述的2,4-二取代喹唑啉类衍生物，及其几何异构体或其药学上可接受的盐、水合物、溶剂化物或前药，其特征在于，所述R1选自氢、卤素，C1-C6烷基、C1-C6烷氧基；R2选自氢、C1-C6烷氧基，N-烷基酰胺基、二甲基氧磷基。
3.如权利要求1所述的2,4-二取代喹唑啉类衍生物，其特征在于，所述的衍生物选自：
4.如权利要求1-2任一所述的2,4-二取代喹唑啉类衍生物的制备方法，其特征在于，具体为以下两个步骤：
步骤1、以取代的2,4-二氯喹唑啉为原料与不同取代的苯胺在碱性条件下进行亲核取代反应得到中间体2；
步骤2、合成的中间体2与5-氨基二氢吲哚-2-酮在反应溶剂里发生取代反应。
5.如权利要求4所述的2,4-二取代喹唑啉类衍生物的制备方法，其特征在于，所述的反应溶剂为二氯甲烷、三氯甲烷、四氢呋喃或DMF；优选DMF。
6.如权利要求4所述的2,4-二取代喹唑啉类衍生物的制备方法，其特征在于，所述的步骤2中取代反应条件为质子酸或者碱催化，反应溶剂为四氢呋喃、乙醇或DMF；反应温度为50-130℃。
7.如权利要求6所述的2,4-二取代喹唑啉类衍生物的制备方法，其特征在于，所述的反应溶剂优选乙醇，反应温度优选90-130℃。
8.如权利要求1-2任一所述的2,4-二取代喹唑啉类衍生物用于制备抗肿瘤药物。
9.如权利要求8所述的2,4-二取代喹唑啉类衍生物用于制备抗肿瘤药物，其特征在于，所述的抗肿瘤具体为乳腺癌、前列腺癌或肺癌。
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| CHENZHOU HAO等: "Development of 2, 4-diaminoquinazoline derivatives as potent PAK4 inhibitors by the core refinement strategy", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
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