CN118063439A - 一种喹唑啉类化合物的制备及用途 - Google Patents
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Abstract
本发明涉及一种双靶向EGFRT790M/L858R和ACK1的喹唑啉类化合物制备及其应用,属于抗肿瘤药学技术领域。本发明解决的技术问题是提供一种作为双靶向EGFRT790M/L858R和ACK1抑制剂的化合物。该化合物包括如下所示的化合物或其药学上可接受的盐。本发明的化合物或其药学上可接受的盐,可以作为EGFRT790M/L858R和ACK1的抑制剂,具有抗肿瘤活性,能有效的抑制肿瘤细胞的生长。本发明化合物优选为抗肿瘤化合物,所对应肿瘤类型的特点为EGFRT790M/L858R和ACK1过度激活的肿瘤。
Description
技术领域
本发明涉及一种双靶向EGFRT790M/L858R和ACK1的喹唑啉类化合物的制备及其应用,属于抗肿瘤药学技术领域。
背景技术
癌症是影响健康的主要慢性疾病之一,严重地影响着人类的健康生活,给社会和家庭带来了沉重的负担。肺癌是起源于肺部支气管黏膜或腺体的恶性肿瘤,发病率和死亡率增长最快,对人群健康和生命威胁最大的恶性肿瘤之一,其中非小细胞肺癌(NSCLC)占所有肺癌比例超过80%,并且NSCLC患者5年生存率比较低,大多数患者都会出现局部晚期或者其他转移性疾病。在最近的十年中,科学家已经对NSCLC不同分子和遗传亚群的研究取得了重大进展,并极大的改变了患者的临床评估和治疗方法。
表皮生长因子受体(epithelial growth factor receptor,EGFR)是HER家族成员之一。EGFR为原癌基因c-erbB-1的表达产物,是一种跨膜酪氨酸激酶受体。EGFR通过影响PI3K/AKT等下游信号通路在细胞的生长、增殖和分化等生理过程发挥重要的作用。EGFR的功能缺失或活性异常均会引起肿瘤、糖尿病、免疫缺陷及心血管疾病的发生。EGFR也已被确定为非小细胞肺癌的一个关键靶标。具有结合EGFR敏感突变和T790M突变位点优势的第三代抑制剂已经成功上市,但耐药性的出现导致其难以发挥理想的抗肿瘤作用。
研究表明ACK1会在第三代EGFR抑制剂出现耐药现象后磷酸化激活,进一步旁路激活EGFR的下游底物AKT,从而挽救肿瘤细胞的增殖。本发明设计并合成了一种靶向EGFRT790M /L858R和ACK1的喹唑啉类抑制剂。该抑制剂能够选择性地抑制EGFRL858R/T790M、ACK1及下游信号通路,并在相应肿瘤细胞中表现出良好的抗增殖活性。双靶向EGFRT790M/L858R-ACK1抑制剂为非小细胞肺癌治疗提供了一个克服耐药的潜在策略,具有广阔的研究前景。
发明内容
本发明解决的技术问题是提供一种作为双靶向EGFRT790M/L858R和ACK1新型抑制剂的化合物。
本发明提供如下所示的化合物或其药学上可接受的盐:
其中,R1为
R2为
R3为
R4为H、CH3、OCH3、F、Br、I、CF3、Cl。
本发明还提供上述化合物或其药学上可接受的盐在制备抗肿瘤药物中的用途。
进一步的,所述抗肿瘤药物优选为双靶向EGFRT790M/L858R和ACK1的抑制剂类药物。
所述抗肿瘤药物优选为抗肿瘤的药物,所对应的肿瘤为具有EGFRT790M/L858R和ACK1过度激活特点的肿瘤。
本发明制备的化合物或其药学上可接受的盐,可以作为双靶向EGFRT790M/L858R和ACK1抑制剂,具有一定的抗肿瘤活性,能有效的抑制癌细胞的生长。本发明化合物对多种肿瘤细胞,特别是EGFRT790M/L858R和ACK1均过度激活的非小细胞肺癌细胞系具有明显的抑制作用。
图表说明
表1为上述化合物的EGFRT790M/L858R和ACK1酶活性检测及其对H1975、MCF-7、第三代EGFR抑制剂奥希替尼耐药细胞系AZDR的抗增殖活性测试结果。
表1.关于式I相关化合物的体外酶活性检测和抗增殖活性结果
图1是本发明实施例中化合物1处理后裸鼠AZDR细胞异种移植模型的肿瘤体积的变化。
具体实施方
本发明提供如下所示的化合物或其药学上可接受的盐:
其中,R1为
R2为
R3为
R4为H、CH3、OCH3、F、Br、I、CF3、Cl。
下面是本发明的化合物的一些优选结构。
本发明还提供上述化合物或其药学上可接受的盐在制备抗肿瘤药物中的用途。
进一步的,所述抗肿瘤药物优选为双靶向EGFRT790M/L858R和ACK1的抑制剂类药物。
所述抗肿瘤药物优选为抗肿瘤的药物,所对应的肿瘤为具有EGFRT790M/L858R和ACK1过度激活特点的肿瘤。
本发明还提供一种药物组合物,它是包含有效剂量的上述化合物或其药学上可接受的盐的制剂。
可以通过本领域已知的方法可将本发明化合物制成以下形式:片剂、胶囊剂、水性或油性溶液剂、混悬剂、乳剂、乳膏剂、软膏剂、凝胶剂、喷鼻剂、栓剂、用于吸入的细小分散的粉剂或气雾剂或喷雾剂、用于胃肠道外(包括静脉内、肌内或输注)的无菌水性或油性溶液或混悬剂或无菌乳剂。可采用无菌水或水-丙二醇溶液作为溶剂来制备液体制剂,还可将活性组分配制在聚乙二醇水溶液中。用于口服给予的水性溶液可通过将活性组分溶解在水中并按需要加入合适的着色剂、矫味剂、稳定剂和增稠剂来制备。口服使用的水性混悬剂可通过将细小分散的活性组分与粘性物质一道分散在水中,所述粘性物质如为天然合成胶、树脂、甲基纤维素、羧甲基纤维素和其他药剂领域已知的悬浮剂。
药物组合物可为单位剂量形式。在这些形式中,将所述组合物分成含适量活性组分的单位剂量。该单位剂量形式可为包装制剂,包装中包括分隔量的制剂,例如盒装片剂、胶囊剂和在管形瓶或安瓿中的粉剂。单位剂量形式还可为胶囊剂、扁囊剂或片剂或其可为适当数量的任何这些包装形式。
本发明的药物组合物,其活性成分可仅为本发明的化合物,也可与其它抗肿瘤化合物组合作为活性成分。
在治疗肿瘤的过程中,可采用本发明的药物组合物与其他抗肿瘤药进行联合治疗。例如,与用于医学肿瘤学的抗增殖/抗肿瘤药、细胞生长抑制剂、抗入侵药物、生长因子功能抑制剂、抗血管生成剂、血管损伤剂等联用。
在治疗肿瘤时,可通过同时、序贯或单独给予各种治疗成分可实现这种联合治疗。此类组合产品应用有效剂量范围内的本发明化合物和准许剂量范围内的其他药学活性剂。
下面结合实施例对本发明的具体实施方式做进一步的描述,并不因此将本发明限制在所述的实施例范围之中。
实施例1优选化合物的合成
优选化合物采用如下反应式合成:
(a)m-nitroaniline,DIPEA,isopropanol,80℃;(b)N2H4·H2O,Renay-Ni,methanol,0℃;(c)acryloyl chloride,TEA,THF,0℃;(d)amino derivatives,TFA,sec-butanol,80℃.
1.中间体1-3的合成通法
将2,4,6-三氯喹唑啉(10.0mmol)溶解在异丙醇(100mL)中,然后加入3-硝基苯胺(1.11g,8.0mmol),二异丙基乙胺(6.61mL,40.0mmol)加热至80℃反应,TLC显示3-硝基苯胺反应完毕时,减压抽滤,将滤饼经过柱层析色谱(石油醚/乙酸乙酯,2/1)纯化得中间体1。
将中间体1(4.0mmol),水合肼(497μL,16.0mmol),雷尼镍(0.47g,8.0mmol)加入甲醇中,冰浴条件下反应,TLC检测反应显示中间体1反应完毕时,减压抽滤,浓缩,经柱层析色谱纯化后得到中间体2。
向溶解有中间体2(2.0mmol)的四氢呋喃(15mL)溶液中加入丙烯酰氯(304μL,4.0mmol)和TEA(834μL,6.0mmol),冰浴条件下搅拌反应,TLC检测显示中间体2反应完毕。减压浓缩,通过柱层析色谱(石油醚/乙酸乙酯,2/1)分离得中间体3。
2.化合物1-10的合成通法
将中间体3(0.5mmol),4-(1H-吡唑-1-基)苯胺(0.06g,0.4mmol)和TFA(111μL,1.5mmol)加入仲丁醇中,80℃搅拌反应,使用TLC监测反应,当3反应完全时,经过柱层析色谱分离得到黄色固体目标化合物1-10。
化合物1,黄色固体,收率为44%;1H NMR(400MHz,DMSO-d6)δ10.62(d,J=196.7Hz,3H),8.61(s,1H),7.94(d,J=79.7Hz,2H),7.75(s,1H),7.56(s,2H),7.46(s,2H),7.34(s,1H),6.48(dd,J=16.9,10.2Hz,1H),6.28(d,J=19.0Hz,1H),5.78(d,J=12.0Hz,1H),4.00(d,J=91.3Hz,2H),1.29(d,J=52.2Hz,3H).13C NMR(100MHz,DMSO)δ163.8,159.4,159.2,150.0,135.5,134.8,132.3,131.3,129.3,127.7,121.0,46.9,16.0;HR-ESI-MS[M+H]+:m/z434.1491。
化合物2,黄色固体,收率为35%;1H NMR(400MHz,DMSO-d6)δ10.2-10.0(m,1H),9.3(s,1H),9.1(s,1H),8.5(s,1H),7.9(s,1H),7.6(d,J=8.9Hz,2H),7.4(s,3H),7.3(t,J=8.0Hz,1H),6.9(s,1H),6.5-6.4(m,1H),6.3-6.2(m,1H),5.7(dd,J=18.9,11.1Hz,1H),1.5(s,9H).13C NMR(100MHz,DMSO)δ163.6,163.5,139.7,133.6,132.4,129.9,129.3,127.4,123.6,123.0,116.6,67.6,29.9;HR-ESI-MS[M+H]+:m/z 462.1804。
化合物3,浅黄色固体,收率为31%;1H NMR(400MHz,DMSO-d6)δ10.20(s,1H),9.67(s,1H),9.11(s,1H),8.56(d,J=31.9Hz,1H),8.16(s,2H),7.80(d,J=15.0Hz,1H),7.68-7.41(m,4H),7.36(s,1H),6.49(dd,J=17.0,10.1Hz,1H),6.28(d,J=17.0Hz,1H),5.78(d,J=12.1Hz,1H),3.73(dq,J=52.4,7.1,6.3Hz,4H),3.23(s,3H).13C NMR(100MHz,DMSO)δ163.7,140.2,135.3,133.6,132.5,130.4,129.2,127.2,123.9,123.0,120.6,118.0,116.3,107.5,97.6,71.2,58.4,51.6;HR-ESI-MS[M+H]+:m/z 464.1596。
化合物4,黄色固体,收率为34%;1H NMR(400MHz,DMSO-d6)δ10.19(s,1H),9.67(s,1H),9.22(s,1H),8.54(s,1H),8.35(s,1H),8.07(s,1H),7.72(s,1H),7.67(d,J=8.9Hz,1H),7.42(d,J=27.6Hz,3H),7.36(d,J=8.0Hz,1H),6.49(dd,J=16.9,10.1Hz,1H),6.29(d,J=16.9Hz,1H),5.78(d,J=12.1Hz,1H),5.08(s,2H).13C NMR(100MHz,DMSO-d6)δ163.7,151.3,140.0,139.7,133.6,132.5,132.4,129.3,127.4,125.0,123.0,121.5,51.9;HR-ESI-MS[M+H]+:m/z 488.1208。
化合物5,黄色固体,收率为29%;1H NMR(400MHz,DMSO-d6)δ10.26(s,1H),9.89-8.74(m,2H),8.57(s,1H),7.98(d,J=114.8Hz,3H),7.70(s,3H),7.48(s,4H),7.37(t,J=8.OHz,2H),7.27(t,J=7.5Hz,1H),6.46(s,1H),6.26(d,J=16.9Hz,1H),5.76(d,J=4.9Hz,1H).13C NMR(100MHz,DMSO)δ163.7,156.0,140.2,139.8,133.8,1323,129.9,127.4,126.3,126.0,123.0,118.1,116.8.HPLCpurity:95.84%;HR-ESI-MS[M+H]+:m/z482.1491。
化合物6,黄色固体,收率为33%;1H NMR(400MHz,DMSO-d6)δ10.19(s,1H),9.62(s,1H),9.15(s,1H),8.52(s,1H),8.18(d,J=77.1Hz,2H),7.78(s,1H),7.68-7.41(m,4H),7.38-7.17(m,6H),6.48(dd,J=16.9,10.2Hz,1H),6.29(d,J=16.9Hz,1H),5.77(d,J=12.2Hz,1H),5.30(s,2H).13C NMR(100MHz,DMSO-d6)δ163.7,132.4,130.7,129.3,128.9,127.9,127.9,127.4,124.3,123.0,120.3,55.4;HR-ESI-MS[M+H]+:m/z 496.1647。
化合物7,黄色固体,收率为28%;1H NMR(400MHz,DMSO-d6)δ10.2(s,1H),9.6(s,1H),9.1(s,1H),8.5(s,1H),8.2(d,J=35.6Hz,1H),7.8(d,J=78.8Hz,1H),7.6(d,J=8.9Hz,3H),7.4(t,J=10.0Hz,2H),7.2(s,1H),6.5(dd,J=16.9,10.1Hz,1H),6.3(d,J=16.9Hz,1H),5.8(d,J=12.1Hz,1H),4.4(s,1H),3.9(s,2H),3.4(s,2H),1.9(s,4H).13C NMR(100MHz,DMSO)δ163.7,157.9,139.7,133.9,133.6,132.4,130.1,127.5,123.6,123.0,118.3,66.4,57.6,33.4,31.7,30.3;HR-ESI-MS[M+H]+:m/z 490.1753。
化合物8,黄色固体,收率为31%;1H NMR(400MHz,DMSO-d6)δ10.3(s,1H),9.6(s,1H),9.2(s,1H),8.5(s,1H),8.2(s,1H),7.8-7.6(m,3H),7.5(s,2H),7.4(s,2H),6.5(t,J=11.6Hz,1H),6.3(d,J=19.0Hz,1H),5.8(d,J=12.2Hz,1H),4.1(s,1H),3.0(s,3H),2.3(s,4H),1.9(d,J=85.6Hz,4H).13C NMR(100MHz,DMSO)δ163.7,158.6,158.3,140.2,139.8,139.5,139.1,132.5,130.1,127.2,123.7,123.0,119.2,118.3,117.9,116.2,57.6,54.2,45.4,31.8;HR-ESI-MS[M+H]+:m/z 503.2069。
化合物9,黄色固体,收率为27%;1H NMR(400MHz,DMSO-d6)δ10.20(s,1H),9.61(s,1H),9.11(s,1H),8.52(s,1H),8.11(s,1H),7.78(s,1H),7.70-7.19(m,6H),6.49(dd,J=16.9,10.1Hz,1H),6.29(d,J=19.1Hz,1H),5.78(d,J=12.1Hz,1H),4.07(d,J=93.5Hz,2H),3.54(s,4H),2.69(s,2H),2.40(s,4H).13C NMR(100MHz,DMSO)δ163.7,161.9,133.6,132.4,130.2,129.3,127.4,123.8,123.0,120.5,66.6,58.4,53.6,49.3;HR-ESI-MS[M+H]+:m/z519.2018。
化合物10,黄色固体,收率为43%;1H NMR(400MHz,DMSO-d6)δ12.38(s,1H),10.18(s,1H),9.62(s,1H),9.12(s,1H),8.53(s,1H),8.12(s,1H),7.88(s,1H),7.77(s,1H),7.64(d,J=6.6Hz,1H),7.45(s,3H),7.34(t,J=8.1Hz,1H),6.50(dd,J=16.9,10.1Hz,1H),6.28(d,J=19.0Hz,1H),5.77(d,J=12.1Hz,1H).13C NMR(101MHz,DMSO)δ163.6,157.8,156.5,151.2,140.1,139.7,133.5,132.4,129.2,127.3,123.4,123.0,115.4,114.0;HR-ESI-MS[M+H]+:m/z 406.1178。
试验例1 化合物1对NCI-H1975,MCF-7,AZDR细胞抗增殖试验
在NCI-H1975,MCF-7,AZDR细胞中进行抗增值活性试验:
取对数生长期的NCI-H1975,MCF-7,AZDR细胞分别接种在96孔板中(每孔大约5×103个细胞)。培养24小时,待细胞贴壁生长后,分别加入指定浓度的各个化合物,并孵育24小时。使用PBS溶解MTT至终浓度为0.5%,随后每孔添加20μL的MTT溶液。在37℃,5%CO2的细胞培养箱中避光孵育3-4小时,随后弃去已有培养基,每孔添加150μL的DMSO,通过酶标仪检测490nM波长下对应的OD值,利用SPSS分析各化合物对细胞增殖的影响,评估各化合物的抗增殖活性,其结果见表1,可以明显看出,该系列化合物对肿瘤细胞具有显著的较强的抗增殖活性。其中优选化合物1对EGFRL858R/T790M和ACK1过度激活的细胞具有显著的较强的抗增殖活性,对NCI-H1975,MCF-7,AZDR细胞半数抑制浓度分别为0.67±0.08μM,1.04±0.15μM,1.27±0.12μM。
试验例2:化合物1的体内抗肿瘤活性实验
本实验的目的是检测本发明的优选化合物的体内抗肿瘤效果。在奥希替尼耐药的AZDR细胞异种移植小鼠模型中,将化合物1进行腹腔注射,剂量为20、40或60mg/kg,每天1次;并将ACK1抑制剂达沙替尼、第三代EGFR抑制剂奥希替尼、及两种药物的联用,剂量均为10mg/kg作为阳性对照。
实验测定的肿瘤生长曲线如图1所示,口服奥希替尼和达沙替尼诱导了一定程度的肿瘤消退。而化合物1以剂量依赖的方式发挥显著的体内抗肿瘤活性,在60mg/kg条件下化合物1展现出较达沙替尼(10mg/kg)与奥希替尼(10mg/kg)联用组更优的体内抗肿瘤活性。
综合以上实验,我们获得了能够有效抑制EGFRL858R/T790M和ACK1发挥抗癌作用的抑制剂,该类抑制剂能够为治疗EGFRL858R/T790M和ACK1过度激活的肿瘤提供了一种好的方法,针对于此类抑制剂的开发,具有很广阔的研究前景。
Claims (7)
1.一种通式(I)所示的化合物,或其在药学上可接受的盐:
其中,R1为
R2为
R3为
R4为H、CH3、OCH3、F、Br、I、CF3、Cl。
2.根据权利要求1所述的化合物或其药学上可接受的盐,其特征在于:结构式如式I或式II所示。
3.根据权利要求1或2所述的化合物或其药学上可接受的盐,其特征在于:
R1为
R2为
R3为
R4为H、CH3、OCH3、F、Br、I、CF3、Cl。
4.权利要求1~3任一项所述的化合物或其药学上可接受的盐在制备抗肿瘤药物中的用途。
5.根据权利要求4所述的用途,其特征在于:所述抗肿瘤药物为双靶向EGFRT790M/L858R和ACK1的抑制剂类药物。
6.根据权利要求5所述的用途,其特征在于:所述抗肿瘤药物为治疗具有EGFRT790M/L858R和ACK1过度激活特点的肿瘤类型的药物。
7.一种药物组合物,其特征在于:它是包含有效剂量的权利要求1~3任一项所述的化合物或其药学上可接受的盐的制剂。
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