CN107827877B - 二烷基氨基喹唑啉类化合物及其在制备抗肿瘤药物中的应用 - Google Patents
二烷基氨基喹唑啉类化合物及其在制备抗肿瘤药物中的应用 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- Chemical & Material Sciences (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
技术领域
本发明涉及一类新型的喹唑啉类化合物;并涉及该类化合物的制备方法和它们在制备抗肿瘤药物方面的用途。
背景技术
肿瘤极大的危害着人类的健康,肿瘤的治疗是一个重大的难题。临床上常用的抗肿瘤药物主要是细胞毒类药物,具有难以避免的毒副作用。随着科技的发展,近年来靶向肿瘤治疗给肿瘤患者带来福音。靶向肿瘤治疗药物进入体内能特异性地与致癌靶标相结合而发挥作用,使肿瘤细胞特异性死亡,而不会伤及周围的正常细胞。研究表明多种肿瘤均表现出表皮生长因子受体(EGFR)酪氨酸激酶的过度表达,抑制EGFR的活性对肿瘤的治疗具有积极的作用,因此EGFR已成为治疗肿瘤的重要靶点。随着人们对EGFR信号转导通路的认知,现阶段已经开发出了一些靶向EGFR的肿瘤治疗药物,包括单克隆抗体、小分子酪氨酸激酶抑制剂、反义寡核苷酸、抗霉素轭合物等,其中小分子酪氨酸激酶抑制剂是最具潜力且应用最为广泛的EGFR抑制剂。
4-芳氨基喹唑啉是一类较早发现的表皮生长因子受体酪氨酸激酶的抑制剂。一系列的报道表明4-芳氨基喹唑啉化合物可通过与EGFR的ATP结合位点结合,高度选择性地抑制EGFR的磷酸化,进而达到抑制肿瘤细胞增殖的效果。4-芳氨基喹唑啉类化合物Gefitinib、Erlotinib、Icotinib(LiuD,Zhang L,WuY,etal.Lung Cancer,2015,89(3):262-267.)等为第一代EGFR抑制剂。这些第一代EGFR抑制剂在肿瘤治疗的过程中,会产生EGFR的T790M突变,这种突变会对第一代EGFR抑制剂产生耐药性。T790M突变是由苏氨酸Thr790变成体积更大的蛋氨酸Met790,改变了EGFR激酶域的构象,增强了ATP与EGFR激酶口袋的结合能力,降低了第一代EGFR抑制剂与激酶口袋的结合能力(Susumu K,BoggonT J,Tajhal D,etal.New EnglandJournal of Medicine,2005,352(8):786-792.)。针对这种突变,药物化学家开发出了第二代不可逆型EGFR抑制剂。作为不可逆型EGFR抑制剂,这些药物包含了一个Michael受体,与位于ATP结合口袋入口处的半胱氨酸残基(Cys797)发生共价键结合,产生不可逆抑制酪氨酸激酶的活性作用(Chang S,Zhang L,XuS,etal.Journal ofMedicinal Chemistry,2012,55(6):2711-2723.)。第二代不可逆EGFR抑制剂中以Afatinib(Dungo RT,Keating G M.Drug,2013,73(13):1503-1515.)、Dacomitinib、Neratinib(Hwei-ruT,etal.Journal of Medicinal Chemistry,2005,48(4):1107-1131.)为代表,虽然它们在治疗T790M突变的非小细胞肺癌有较好的疗效,但其与剂量相关的副作用较为严重,如腹泻、皮疹等(WenjunZ,DaliaE,Liang C,etal.Nature,2009,462(7276):1070-1074.)。基于以上原因,第三代EGFR抑制剂便应运而生,如CO-1686及AZD9291等。尽管目前第三代EGFR抑制剂的临床研究中展现出高的活性,但接受AZD9291治疗的患者中有近三分之一出现了EGFRC797S(第三次点突变)的新突变。这种新出现的EGFRC797S突变对第三代EGFR抑制剂产生了新的耐药性(ZopiaP,etal.Cancer Discovery,2015,5(7):713-722.),因此,继续开发新型高效的EGFR抑制剂具有极其重要的意义。
发明内容
本发明所要解决的技术问题在于提供一类具有抗肿瘤活性的二烷基氨基喹唑啉类化合物,以及这些化合物在制备抗肿瘤药物中的用途。
解决上述技术问题所采用的技术方案是:该类具有抗肿瘤活性的二烷基氨基喹唑啉类化合物为结构式如下的化合物:
式中R1代表氢、卤素、乙炔基、丙烯-1-基或卤代的苄氧基;n为1~3的整数;m为1~4的整数;R2、R3各自独立的代表C1~C4烷基。
本发明二烷基氨基喹唑啉类化合物优选为下列化合物1~4中的任意一种:
化合物1:4-[3-氯-4-(3-氟苄氧基)苯氨基]-6-[5-((N,N-二乙氨基乙基)氨甲基)呋喃-2-基]喹唑啉
化合物2:4-(3-乙炔基苯氨基)-6-[5-((N,N-二乙氨基乙基)氨甲基)呋喃-2-基]喹唑啉
化合物3:4-[4-(E)-丙烯基苯氨基]-6-[5-((N,N-二乙氨基乙基)氨甲基)呋喃-2-基]喹唑啉
化合物4:4-(3-氯-4-氟苯氨基)-6-[5-((N,N-二乙氨基乙基)氨甲基)呋喃-2-基]喹唑啉
上述二烷基氨基喹唑啉类化合物是以式I所示的4-芳氨基-6-(5-甲酰基呋喃-2-基)喹唑啉和式II所示的二烷氨基烷基胺为原料,在氰基硼氢化钠的存在下,通过还原胺化反应制得。具体合成反应如下:
本发明二烷基氨基喹唑啉类化合物在制备抗肿瘤药物中的用途,其按常规药用制剂,与药学上可接受的载体按照各种制剂的常规制备工艺制成,可以是片剂、颗粒剂、胶囊剂。
本发明的二烷基氨基喹唑啉类化合物对肿瘤细胞的增殖具有良好的抑制作用,大多数化合物活性明显优于现临床使用的抗肿瘤药物吉非替尼和拉帕替尼,表明其可用于制备抗肿瘤药物。该类化合物既可以独自用药,也可与其它药物联合使用,也可以其盐或溶剂化物的形式用于抗肿瘤药物的制备。
具体实施方式
下面结合实施例对本发明作进一步详细说明,但本发明的保护范围不仅限于这些实施例。
下面实施例中所用的4-芳氨基-6-(5-甲酰基呋喃-2-基)喹唑啉参考文献(ZhangY L,Zhang Y,Liu J,etal.Bioorganic&Medicinal Chemistry Letters,2017,27,1584-1587.)方法合成。所用其他试剂均为分析纯。化合物结构确定所用的核磁共振数据由Bruker Avance 600超导核磁共振仪测定,TMS作为内标;红外光谱数据采用Bruker Tensor2733红外光谱仪测定;熔点采用X-6显微熔点测定仪(北京泰克仪器有限公司)测定(温度未进行校正);质谱数据用Bruker Esquire3000plus质谱仪测定。
实施例1
合成化合物1:4-[3-氯-4-(3-氟苄氧基)苯氨基]-6-[5-((N,N-二乙氨基乙基)氨甲基)呋喃-2-基]喹唑啉
将0.09g(0.75mmol)式II-1所示的N,N-二乙氨基乙胺、5.0mL甲醇加入到50mL单口瓶中,用甲酸调节pH为5-6,然后加入0.28g(2.00mmol)无水硫酸钠、0.06g(1.00mmol)氰基硼氢化钠,搅拌下将0.24g(0.50mmol)式I-1所示的4-[3-氯-4-(3-氟苄氧基)苯胺基]-6-(5-甲酰基呋喃-2-基)喹唑啉和5mL四氢呋喃的混合物滴入到反应体系中,滴加完后,室温搅拌反应30分钟,再加入0.06g(1.00mmol)氰基硼氢化钠,继续搅拌反应90分钟,用氢氧化钠水溶液调节pH至9-10,抽滤,将滤液蒸除溶剂,残留物用硅胶柱色谱分离(甲醇:氯仿=1:15,V/V),得到0.24g浅黄色固体化合物1,收率为82.0%,其m.p.:103.5-104.7℃;HRMS(C32H33ClFN5O2)m/z[M+H]+:574.2379(计算值:574.2385);1H NMR(600MHz,DMSO-d6)δ(ppm):9.96(s,1H),8.76(s,1H),8.57(s,1H),8.14(dd,J=8.7,1.3Hz,1H),8.04(d,J=1.9Hz,1H),7.81-7.77(m,2H),7.48(dd,J=14.0,7.7Hz,1H),7.36-7.32(m,2H),7.28(d,J=9.0Hz,1H),7.21-7.17(m,1H),7.05(d,J=3.1Hz,1H),6.46(d,J=3.1Hz,1H),5.28(s,2H),3.83(s,4H),2.64(t,J=6.4Hz,2H),2.47-2.44(m,4H),0.93(t,J=7.1Hz,6H);13C NMR(151MHz,DMSO-d6)δ(ppm):162.2(d,1JC-F=243.7Hz),157.5,155.3,154.1,151.4,149.7,148.8,139.6(d,3JC-F=7.5Hz),133.2,130.5(d,3JC-F=8.3Hz),129.7,129.6,129.6,129.5,128.5,128.4,127.7,124.2,123.2(d,4JC-F=2.6Hz),122.4,121.1,116.3,115.4,114.6(d,2JC-F=20.9Hz),114.2,114.0(d,2JC-F=21.9Hz),109.3,107.8,69.4,52.1,46.5,46.2,45.8,11.6;IRνmax(KBr)cm-1:3405,1660,1492,1449,1440,1025,994,827,769.
实施例2
合成化合物2:4-(3-乙炔基苯氨基)-6-[5-((N,N-二乙氨基乙基)氨甲基)呋喃-2-基]喹唑啉
将0.09g(0.75mmol)式II-1所示的N,N-二乙氨基乙胺、5.0mL甲醇加入到50mL单口瓶中,用甲酸调节pH为5-6,然后加入0.28g(2.00mmol)无水硫酸钠、0.06g(1.00mmol)氰基硼氢化钠,搅拌下将0.17g(0.50mmol)式I-2所示的4-(3-乙炔基苯氨基)-6-(5-甲酰基呋喃-2-基)喹唑啉和5mL四氢呋喃的混合物滴入到反应体系中,滴加完后,室温搅拌反应30分钟,再加入0.06g(1.00mmol)氰基硼氢化钠,继续搅拌反应90分钟,用氢氧化钠水溶液调节pH至9-10,抽滤,将滤液蒸除溶剂,残留物用硅胶柱色谱分离(甲醇:氯仿=1:15,V/V),得到0.18g浅黄色固体化合物2,收率为79.7%,其m.p.:81.4-82.3℃;HRMS(C27H29N5O)m/z[M+H]+:440.2464(计算值:440.2450);1H NMR(600MHz,DMSO-d6)δ(ppm):10.08(s,1H),8.90(s,1H),8.61(s,1H),8.18(dd,J=8.7,1.7Hz,1H),8.11(brs,1H),8.01-7.98(m,1H),7.82(d,J=8.7Hz,1H),7.43(t,J=7.9Hz,1H),7.27-7.24(m,1H),7.12(d,J=3.2Hz,1H),6.50(d,J=3.2Hz,1H),4.22(s,1H),3.87(s,2H),2.73(t,J=6.0Hz,2H),2.69(t,J=6.0Hz,2H),2.64-2.60(m,4H),1.00(t,J=7.1Hz,6H);13C NMR(151MHz,DMSO-d6)δ(ppm):157.6,154.5,154.1,151.5,148.9,139.5,128.9,128.6,128.5,128.4,126.9,125.2,123.0,121.7,116.7,115.5,109.8,108.0,83.5,80.6,51.4,46.5,45.4,45.2,40.1,21.1,10.8;IRνmax(KBr)cm-1:3452,3061,2963,1631,1610,1569,1529,1481,1199,891.
实施例3
合成化合物3:4-[4-(E)-丙烯基苯氨基]-6-[5-((N,N-二乙氨基乙基)氨甲基)呋喃-2-基]喹唑啉
将0.09g(0.75mmol)式II-1所示的N,N-二乙氨基乙胺、5.0mL甲醇加入到50mL单口瓶中,用甲酸调节pH为5-6,然后加入0.28g(2.00mmol)无水硫酸钠、0.06g(1.00mmol)氰基硼氢化钠,搅拌下将0.18g(0.50mmol)式I-3所示的4-[4-(E)-丙烯基苯氨基]-6-(5-甲酰基呋喃-2-基)喹唑啉和5mL四氢呋喃的混合物滴入到反应体系中,滴加完后,室温搅拌反应30分钟,再加入0.06g(1.00mmol)氰基硼氢化钠,继续搅拌反应90分钟,用氢氧化钠水溶液调节pH至9-10,抽滤,将滤液蒸除溶剂,残留物用硅胶柱色谱分离(甲醇:氯仿=1:15,V/V),得到0.19g浅黄色固体化合物3,收率为82.6%,其m.p.:89.9-91.3℃;HRMS(C28H33N5O)m/z[M+H]+:456.2758(计算值:456.2763);1H NMR(600MHz,DMSO-d6)δ(ppm):9.95(s,1H),8.80(d,J=1.5Hz,1H),8.55(s,1H),8.15(dd,J=8.7,1.8Hz,1H),7.85-7.78(m,3H),7.42(d,J=8.7Hz,2H),7.07(d,J=3.2Hz,1H),6.47(d,J=3.2Hz,1H),6.42(dd,J=15.8,1.5Hz,1H),6.30-6.24(m,1H),3.84(s,2H),2.67(t,J=6.4Hz,2H),2.57(t,J=5.6Hz,2H),2.55-2.51(m,4H),1.87(dd,J=6.6,1.5Hz,3H),0.95(t,J=7.1Hz,6H);13C NMR(151MHz,DMSO-d6)δ(ppm):157.6,155.1,154.2,151.5,148.9,137.8,133.1,130.5,128.5,128.4,128.3,125.7,124.4,122.6,116.5,115.5,109.4,107.8,51.9,51.8,46.5,45.8,45.6,40.1,18.3,11.4;IRνmax(KBr)cm-1:3447,3238,2992,1638,1618,1486,1396,1350,1173,1120,1001,784.
实施例4
合成化合物4:4-(3-氯-4-氟苯氨基)-6-[5-((N,N-二乙氨基乙基)氨甲基)呋喃-2-基]喹唑啉
将0.09g(0.75mmol)式II-1所示的N,N-二乙氨基乙胺、5.0mL甲醇加入到50mL单口瓶中,用甲酸调节pH为5-6,然后加入0.28g(2.00mmol)无水硫酸钠、0.06g(1.00mmol)氰基硼氢化钠,搅拌下将0.18g(0.50mmol)式I-4所示的4-(3-氯-4-氟苯氨基)-6-(5-甲酰基呋喃-2-基)喹唑啉和5mL四氢呋喃的混合物滴入到反应体系中,滴加完后,室温搅拌反应30分钟,再加入0.06g(1.00mmol)氰基硼氢化钠,继续搅拌反应90分钟,用氢氧化钠水溶液调节pH至9-10,抽滤,将滤液蒸除溶剂,残留物用硅胶柱色谱分离(甲醇:氯仿=1:15,V/V),得到0.19g浅黄色固体化合物4,收率为78.1%,其m.p.:98.3-99.8℃;HRMS(C25H27ClFN5O)m/z[M+H]+:468.1959(计算值:468.1966);1H NMR(600MHz,DMSO-d6)δ(ppm):10.19(s,1H),8.93(s,1H),8.61(s,1H),8.26(dd,J=6.8,2.4Hz,1H),8.18(dd,J=8.7,1.6Hz,1H),7.96-7.92(m,1H),7.83(d,J=8.7Hz,1H),7.49-7.45(m,1H),7.13(d,J=3.2Hz,1H),6.52(d,J=3.2Hz,1H),3.90(s,2H),2.79(brs,4H),2.75-2.70(d,4H),1.04(t,J=7.2Hz,6H);13C NMR(151MHz,DMSO-d6)δ(ppm):157.5,154.0,153.4(d,1JC-F=243.4Hz),151.6,148.9,136.5(d,4JC-F=2.5Hz),128.7,128.5,128.4,123.9,122.8(d,3JC-F=7.1Hz),118.7(d,2JC-F=18.6Hz),116.8,116.5(d,2JC-F=21.3Hz),115.4,115.4,110.0,108.0,50.9,50.9,46.5,45.2,40.1,10.3;IRνmax(KBr)cm-1:3441,3064,2968,1631,1611,1574,1498,1418,1018,841.
实施例5
本发明二烷基氨基喹唑啉类化合物在制备抗肿瘤药物中的应用
发明人分别将上述实施例合成的化合物1~4作为受试化合物,测试其对肿瘤细胞的生长抑制的作用,具体试验情况如下:
1、细胞株
人皮肤鳞状细胞癌细胞株A431、人非小细胞肺癌细胞株A549、人结肠癌细胞株SW480,人肺癌细胞株NCI-H1975(EGFRT790M/L858R双突变)均购自中国科学院上海细胞库。
2、试剂和材料
MTT(MPBIO)、96孔细胞培养板(Costar)、胎牛血清(Gibco)、培养基(Gibco)、酶标仪(PerkinElmer EnSpire)。
3、实验步骤
化合物1~4对肿瘤细胞的生长抑制活性利用MTT法进行测定。分别取对数生长期的人肿瘤细胞SW480、A549、A431、NCI-H1975,用0.25%的胰蛋白酶消化液消化、离心、重悬后计数,制备细胞悬液,调整细胞悬液浓度为2×104~5×104个/mL。取细胞悬液接种于96孔细胞培养板中(100μL/孔),置饱和湿度、37℃和5%CO2培养箱中培养24h。用培养基稀释受试化合物至所需浓度,加入已接种人肿瘤细胞的96孔细胞培养板中(100μL/孔),DMSO终浓度为0.5%,置于培养箱中培养72h。将MTT加入96孔板中(20μL/孔),培养箱中反应4h。吸弃孔内液体,加入DMSO(150μL/孔),摇床上震荡10min,使甲臜完全溶解。然后用酶标仪测定570nm波长处的吸光度(OD570),630nm波长处的吸光度(OD630)作为参比,以相应溶剂作为对照,计算细胞生长抑制率。
受试化合物对肿瘤细胞生长抑制率的计算方式如下:
肿瘤细胞生长抑制率%=[1-(ODs-ODNC)/(ODPC-ODNC)]×100%
其中:ODS表示样品孔的吸光度值(细胞+待测化合物+MTT);ODPC表示对照孔的吸光度值(细胞+DMSO+MTT);ODNC表示调零孔的吸光度值(培养基+DMSO+MTT);ODs=OD570s-OD630s;ODPC=OD570PC-OD630PC;ODNC=OD570NC-OD630NC。
受试化合物对肿瘤细胞生长抑制曲线的拟合及IC50的计算:
采用Graphpad Prism5拟合受试化合物对肿瘤细胞生长的抑制曲线,并得出IC50值。每组设置3个复孔,实验至少重复3次。
4、实验结果
以临床使用的抗肿瘤药物吉非替尼(Gefitinib)和拉帕替尼(Lapatinib)为阳性对照,实验结果如表1所示。
表1受试化合物抑制肿瘤细胞增殖的IC50(μmol/L)
由表1中实验数据可见,受试化合物对4种肿瘤细胞株的增殖都具有很好的抑制作用,这些化合物的效果明显优于临床抗肿瘤药物Gefitinib和Lapatinib。
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