CN113087693B - 含氮联芳环类化合物、制备方法和应用 - Google Patents
含氮联芳环类化合物、制备方法和应用 Download PDFInfo
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Abstract
本发明涉及含氮联芳环类化合物、制备方法和应用,即以化合物为有效成分组成的药物组合物,制备方法,以及该类化合物在抗肝癌中的应用。本发明合成的一系列结构新颖的含氮联芳环类化合物,通过调节TRBP诱导miRNA的生成,并表现出良好的抗肝癌作用,该类小分子对肝癌细胞的增殖具有较强的抑制作用,个别化合物甚至比依诺沙星更具疗效,在此之前尚未有类似结构具有此作用,具有良好的开发前景。
Description
技术领域
本申请涉及含氮联芳环类化合物、衍生物、合成方法、应用、药物,属于化学及药物领域。
背景技术
肝癌在癌症相关死亡率排名第四,在世界所有癌症发病率中排名第六。肝病患者容易发生肝细胞癌,主要是由于乙型肝炎或丙型病毒感染或乙肝感染。在这些条件下,DNA突变经常发生。然而,系统性小分子药物抑制受体酪氨酸激酶,并不直接针对这些突变的基因或蛋白质。多激酶抑制剂已被批准用于治疗肝癌,包括一线治疗索拉非尼和伦伐替尼;然而,患者的1年中位生存期仍然较低。目前正在开发的治疗方法包括血管生成抑制剂和免疫检查点抑制剂,它们与服用索拉非尼的患者的1年中位生存期相似。因此,必须探索更多创新的药物和有效的肝细胞癌治疗目标。MicroRNAs(miRNA)与多种疾病有关,它通过协调在转录后水平上的基因表达参与各种生理过程。积累的证据表明,肝癌患者和健康患者的miRNAs表达存在显著差异,这种异常表达促进了肝癌细胞的增殖、侵袭和转移。此外,临床研究表明,不同miRNA 可用作肝癌发展或预测治疗结果的预后生物标志物。因此,miRNAs作为一个新靶点,在治疗肝癌的方面具有很大的吸引力。
其中,TRBP是microRNA诱导沉默复合物(RISC)的一个关键组成部分,它通过在RNA密集的环境中确保前体miRNA被高效和准确的处理,或者通过调节RISC组装和Ago2诱导的miRNA稳定性来影响miRNA的生成。依诺沙星(Enoxacin)是一种氟喹诺酮类抗菌药物,也是目前已知的唯一一种增强miRNA 生物合成和抑制肿瘤生长的TRBP激动剂。然而依诺沙星对TRBP的亲和力不够高(KD~12.56μM),对肝癌细胞的抑制能力仍不够强。开发新的靶向TRBP调节miRNA从而抑制肝癌细胞的增殖和转移的小分子仍然十分必要。
发明内容
本发明正是为了解决上述问题缺陷,提供一种含氮联芳环类化合物、制备方法和应用。本发明采用如下技术方案实现。
含氮联芳环类化合物,本发明该化合物具有如下通式:
其中,R1选自NHCH2CH2CH3,NHPh,或其它仲胺NHR。
进一步为,本发明该化合物的衍生物具有如下任一的结构式:
上述本发明化合物的制备方法,包括以下步骤:
化合物A通过酰胺化作用得到化合物(Ⅰ):
所用的缩合剂为1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(EDCI),1-羟基苯并三氮唑(HOBt),二环己基碳二亚胺(DCC),羰基咪唑(CDI),O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸(TBTU),二氯亚砜(SOCl2),草酰氯(C2Cl2O2)中任意一或两种;
所用催化剂为吡啶,4-二甲氨基吡啶(DMAP),三乙胺(EtN3),N,N-二异丙基乙胺(DIPEA)中任意一种;
所用溶剂为二氯甲烷,氯仿或N,N-二甲基甲酰胺(DMF)中任意一种;
所取温度为0℃-50℃之间,反应时间为8-15h。
上述步骤:取化合物A,将其用二氯甲烷溶解,随后加入缩合剂,反应3h,再加入R1H和催化剂;反应8h,萃取,浓缩,过硅胶柱得到结构为(Ⅰ)的化合物。
含氮联芳环类化合物,本发明该化合物具有如下通式:
其中,R2选自F,Cl,Br,I或OCH3;
R3选自H,CH3CO,PhCO,或其它酰基RCO,CH3SO2,PhSO2或其它磺酰基RSO2。
进一步为,本发明该化合物的衍生物具有如下任一的结构式:
上述本发明化合物的制备方法,包括以下步骤:
化合物B通过选择性脱甲基得到化合物C:
所用试剂为氯甲酸-1-氯乙酯(ACE-Cl),所用溶剂为氯仿/甲醇或氯仿/乙醇;
所取温度为60℃-90℃之间,反应时间为24-72h;
所用的缩合剂为1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(EDCI),1-羟基苯并三氮唑(HOBt),二环己基碳二亚胺(DCC),羰基咪唑(CDI),O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸(TBTU),二氯亚砜(SOCl2),草酰氯(C2Cl2O2)中任意一或两种;
所用催化剂为吡啶,4-二甲氨基吡啶(DMAP),三乙胺(EtN3),N,N-二异丙基乙胺(DIPEA)中任意一种;
所用溶剂为二氯甲烷,氯仿或N,N-二甲基甲酰胺(DMF)中任意一种;
所取温度为0℃-50℃之间,反应时间为5-12h。
上述步骤:取化合物B,将其用氯仿溶解,随后加入ACE-Cl,70℃反应12h,再加入甲醇,70℃再反应12h;萃取,浓缩,过硅胶柱得到化合物C;化合物C再通过酰胺化作用和酰氯或磺酰氯R3Cl或羧酸 R3OH得到化合物(Ⅱ);
取化合物C,将其用二氯甲烷溶解,随后加入R3Cl和吡啶,反应6h;或取化合物C,将其用二氯甲烷溶解,随后加入缩合剂和R3OH,反应12h;萃取,浓缩,重结晶或过硅胶柱得到结构为(Ⅱ)的化合物。
上述化合物(包含化合物、衍生物、制备方法中的中间产物、最终产物,等等)用以制备抗肝癌药物。
本发明的有益效果为:1)本发明提供了含氮联芳环类化合物、衍生物、制备方法和应用,该类化合物用途是作为抗艾滋病药物候选物,或者是作为不同剂型的抗肝癌药物组合物的活性成分。2)本申请提供的化合物和/或衍生物可根据需要制备为所需剂型的药物,并能在该药物中发挥对肝癌细胞增殖和转移的抑制作用。3)在将上述的含氮联芳环类衍生物制成各类剂型时,本领域技术人员可根据需要添加合理使用范围内的各类辅料或药学上可接受的载体。例如注射流体、气雾剂、乳膏、凝胶剂、片剂、丸剂、胶囊剂、糖浆剂或透皮贴剂剂型。加入辅料及载体后,不影响该药物效果的发挥。该药物可单独使用或与其他药物联合使用,或与其他组分制成药物组合物。给药方式口服给药、皮下注射、肌肉注射、静脉注射、舌下给药、直肠给药、经皮给药或喷雾吸入。4)本发明合成的一系列结构新颖的含氮联芳环类化合物,通过调节TRBP诱导miRNA的生成,并表现出良好的抗肝癌作用,该类小分子对肝癌细胞的增殖具有较强的抑制作用,个别化合物甚至比依诺沙星更具疗效,在此之前尚未有类似结构具有此作用,具有良好的开发前景。
下面结合附图和具体实施方式本发明做进一步解释。
附图说明
图1为本发明化合物对肝癌细胞的抑制能力测试图。
具体实施方式
下例实施例是本发明方法的举例说明而不是对其进行限制。对本领域技术人员显而易见的多种条件和参数的其他修改和适应性的改变,均包含在本发明的实质和范围内。
实施例1:
本发明含氮类联芳环衍生物的制备方法可概述如下:
(a)对于结构式为(I)型的化合物:
取化合物A(0.1mmol)于一25mL圆底烧瓶中,将其用10mL二氯甲烷溶解,随后加入SOCl2(0.12mmol), 45℃回流反应3h,再加入伯胺R1H(0.12mmol),Et3N(0.12mmol)和吡啶(0.01mmol),常温反应8h。反应完毕后将反应液倒入水中,用3×25mL CH2Cl2萃取,合并有机相后将其用食盐水3×25mL洗涤,接着用无水Na2SO4干燥,用旋转蒸发仪将其浓缩拌样,过100-200目的硅胶柱得到结构为(Ⅰ)的化合物,即实施例2-6的化合物1-5。
伯胺R1H是商业可得的原料,由Adamas,Acros或Sigma-Aldrich公司购买得到化合物A由以下路线得到:
化合物A的合成是以3,4,5-三羟基苯甲酸甲酯为起始原料,经过醚化关环,溴代反应,酚羟基甲醚化,Suzuki偶联,最后水解反应得到化合物A。
(b)对于结构式为(Ⅱ)型的化合物:
取化合物B(0.1mmol)于一25mL圆底烧瓶中,将其用8mL氯仿溶解,随后加入ACE-Cl(0.12mmol), 70℃回流反应12h,再加入甲醇16mL,70℃再回流反应12h。反应完毕后将反应液倒入水中,用3×25mL CH2Cl2萃取,合并有机相后将其用食盐水3×25mL洗涤,接着用无水Na2SO4干燥,用旋转蒸发仪将其浓缩拌样,过100-200目的硅胶柱得到结构为化合物(C)的化合物,即实施例7-8的化合物6-7。
取化合物C(0.1mmol),将其用10mL二氯甲烷溶解,随后加入R3Cl(0.12mmol)和吡啶(0.01mmol),常温反应6h。反应完毕后将反应液倒入水中,用3×25mL CH2Cl2萃取,合并有机相后将其用食盐水3× 25mL洗涤,接着用无水Na2SO4干燥,用旋转蒸发仪将其浓缩,丙酮/石油醚重结晶得到结构为化合物(Ⅱ) 的化合物,即实施例9-14的化合物8-13。
取化合物C(0.1mmol),将其用10mL二氯甲烷溶解,随后加入R3OH(0.12mmol),EDCI(0.12mmol) 和DMAP(0.01mmol)常温反应12h。反应完毕后将反应液倒入水中,用3×25mLCH2Cl2萃取,合并有机相后将其用食盐水3×25mL洗涤,接着用无水Na2SO4干燥,用旋转蒸发仪将其浓缩拌样,过100-200 目的硅胶柱得到结构为化合物(Ⅱ)的化合物,即实施例15-21的化合物14-20。
酰氯或磺酰氯R3Cl,羧酸R3OH是商业可得的原料,由Adamas,Acros或Sigma-Aldrich公司购买得到化合物B由以下路线得到:
化合物B的合成是以3,4,5-三羟基苯甲酸甲酯为起始原料,经过醚化关环,溴代反应,酚羟基甲醚化,最后通过Suzuki偶联得到化合物B。
实施例2:
取实施例1所得的含氮联芳基酸即化合物(A)于一25mL圆底烧瓶中,将其用10mL二氯甲烷溶解,随后加入SOCl2(0.12mmol),45℃回流反应3h,再加入二乙基乙二胺(CAS:100-36-7)(0.12mmol),Et3N (0.12mmol)和吡啶(0.01mmol),常温反应8h。反应完毕后将反应液倒入水中,用3×25mL CH2Cl2萃取,合并有机相后将其用食盐水3×25mL洗涤,接着用无水Na2SO4干燥,用旋转蒸发仪将其浓缩拌样,过100-200目的硅胶柱(PE:EA=4:1)得到黄色固体的化合物1。1H-NMR(300MHz,CDCl3):δ7.18-7.15(2H, d,J=8.7Hz),6.97(1H,s),6.74-6.71(2H,d,J=8.7Hz),6.00(2H,s),5.60(1H,s),3.76(3H, s),3.13-3.10(2H,q,J=5.1Hz),2.97(6H,s),2.35-2.28(4H,q,J=7.2Hz),2.18-2.14(2H,t, J=6.5Hz),0.88-0.83(6H,t,J=7.2Hz).13C NMR(75MHz,CDCl3):δ168.94,149.91,148.18,141.02, 138.94,131.22,130.87,127.46,123.18,112.26,103.97,101.64,60.09,51.12,46.23,40.52,37.53,11.35ppm.HRMS-ESI:m/z calcd for C23H32N3O4(M+H)+414.2387,found 414.2387.
实施例3:
取实施例1所得的含氮联芳基酸即化合物(A)于一25mL圆底烧瓶中,将其用10mL二氯甲烷溶解,随后加入EDCI(0.12mmol)和HOBt(0.12mmol),再加入苄胺(CAS:100-46-9)(0.12mmol)和DMAP (0.01mmol),常温反应8h。反应完毕后将反应液倒入水中,用3×25mLCH2Cl2萃取,合并有机相后将其用食盐水3×25mL洗涤,接着用无水Na2SO4干燥,用旋转蒸发仪将其浓缩拌样,过100-200目的硅胶柱 (PE:EA=6:1)得到白色固体的化合物2。1H-NMR(300MHz,CDCl3):δ7.18-7.16(3H,m),7.12(1H, s),7.09-7.08(1H,m),6.86-6.85(2H,m),6.67-6.64(2H,d,J=8.7Hz),5.99(2H,s),5.43(1H,s), 4.24-4.22(2H,d,J=5.1Hz),3.74(3H,s),3.97(6H,s).13C NMR(75MHz,CDCl3):δ168.43,149.99, 148.29,141.06,139.13,137.64,130.79,130.32,128.42,127.94,127.69,127.28,122.83, 112.32,104.25,101.70,60.08,44.44,40.45ppm.HRMS-ESI:m/zcalcd for C24H25N2O4(M+H)+405.1809,found 405.1805.
实施例4:
取实施例1所得的含氮联芳基酸即化合物(A)于一25mL圆底烧瓶中,将其用10mL二氯甲烷溶解,随后加入SOCl2(0.12mmol),45℃回流反应3h,再加入苯胺(CAS:62-53-3)(0.12mmol),Et3N(0.12mmol) 和吡啶(0.01mmol),常温反应8h。反应完毕后将反应液倒入水中,用3×25mL CH2Cl2萃取,合并有机相后将其用食盐水3×25mL洗涤,接着用无水Na2SO4干燥,用旋转蒸发仪将其浓缩拌样,过100-200目的硅胶柱(PE:EA=5:1)得到白色固体的化合物3。1H-NMR(300MHz,CDCl3):δ7.24-7.15(5H,m), 7.03-6.99(4H,m),7.80-7.77(2H,d,J=8.7Hz),6.03(2H,s),3.79(3H,s),2.98(6H,s).13C NMR (75MHz,CDCl3):δ166.10,150.46,148.52,141.02,139.64,137.99,131.06,130.03,128.70, 127.89,124.05,122.55,120.11,112.90,104.91,101.85,60.14,40.61ppm.HRMS-ESI:m/zcalcd forC23H23N2O4(M+H)+391.1652,found 391.1650.
实施例5:
取实施例1所得的含氮联芳基酸即化合物(A)于一25mL圆底烧瓶中,将其用10mL二氯甲烷溶解,随后加入SOCl2(0.12mmol),45℃回流反应3h,再加入3-甲氧基苯胺(CAS:536-90-3)(0.12mmol),Et3N (0.12mmol)和吡啶(0.01mmol),常温反应8h。反应完毕后将反应液倒入水中,用3×25mL CH2Cl2萃取,合并有机相后将其用食盐水3×25mL洗涤,接着用无水Na2SO4干燥,用旋转蒸发仪将其浓缩拌样,过100-200目的硅胶柱(PE:EA=5:1)得到黄色固体的化合物4。
1H-NMR(300MHz,CDCl3):δ7.24-7.21(2H,d,J=8.7Hz),7.06-7.01(2H,m),6.81-6.78(2H, d,J=8.7Hz),6.68(1H,s),6.57-6.54(2H,m),6.04(2H,s),3.80(3H,s),3.71(3H,s),2.98(6H, s).13C NMR(75MHz,CDCl3):δ165.97,159.94,150.40,148.57,141.03,139.70,139.16,131.12, 129.90,129.37,127.93,122.50,112.83,112.36,110.49,105.23,104.97,101.88,60.16,55.19, 40.52ppm.HRMS-ESI:m/z calcd for C24H25N2O5(M+H)+421.1758,found 421.1757.
实施例6:
取实施例1所得的含氮联芳基酸即化合物(A)于一25mL圆底烧瓶中,将其用10mL二氯甲烷溶解,随后加入SOCl2(0.12mmol),45℃回流反应3h,再加入2-碘苯胺(CAS:615-43-0)(0.12mmol),Et3N(0.12mmol) 和吡啶(0.01mmol),常温反应8h。反应完毕后将反应液倒入水中,用3×25mL CH2Cl2萃取,合并有机相后将其用食盐水3×25mL洗涤,接着用无水Na2SO4干燥,用旋转蒸发仪将其浓缩拌样,过100-200目的硅胶柱(PE:EA=5:1)得到黄色固体的化合物5。1H-NMR(300MHz,CDCl3):δ8.14-8.11(1H,d,J=6.9 Hz),7.65-7.63(1H,d,J=7.8Hz),7.29-7.24(4H,m),7.05(1H,s),6.78-6.73(1H,t,J=7.5Hz), 6.71-6.68(2H,d,J=8.4Hz),6.04(2H,s),3.80(3H,s),2.91(6H,s).13C NMR(75MHz,CDCl3): δ167.39,150.33,148.33,141.19,139.65,138.94,131.31,130.63,129.02,127.98,125.79,122.18,122.00,112.59,104.21,101.86,89.85,60.13,40.58ppm.HRMS-ESI:m/zcalcd forC23H22IN2O4 (M+H)+517.0619,found 517.0618.
实施例7:
取实施例1所得的化合物B(0.1mmol)于一25mL圆底烧瓶中,将其用8mL氯仿溶解,随后加入ACE-Cl(CAS:50893-53-3)(0.12mmol),70℃回流反应12h,再加入甲醇16mL,70℃再回流反应12h。反应完毕后将反应液倒入水中,用3×25mL CH2Cl2萃取,合并有机相后将其用食盐水3×25mL洗涤,接着用无水Na2SO4干燥,用旋转蒸发仪将其浓缩拌样,过100-200目的硅胶柱(PE:EA=2:1)得到黄色固体的化合物6。1H-NMR(300MHz,CDCl3):δ6.98-6.95(2H,d,J=8.4Hz),6.95(1H,s),6.56-6.54(2H, d,J=8.7Hz),5.96(2H,s),3.69(3H,s),3.49(3H,s),2.79(3H,s).13C NMR(75MHz,CDCl3): δ168.36,148.28,147.68,141.40,140.13,131.19,130.32,125.80,125.02,111.76,104.39, 101.73,59.99,51.89,30.68ppm.HRMS-ESI:m/zcalcd for C17H18NO5(M+H)+316.1179,found 316.1174.
实施例8:
取实施例1所得的化合物B(0.1mmol)于一25mL圆底烧瓶中,将其用8mL氯仿溶解,随后加入 ACE-Cl(CAS:50893-53-3)(0.12mmol),70℃回流反应12h,再加入甲醇16mL,70℃再回流反应12h。反应完毕后将反应液倒入水中,用3×25mL CH2Cl2萃取,合并有机相后将其用食盐水3×25mL洗涤,接着用无水Na2SO4干燥,用旋转蒸发仪将其浓缩拌样,过100-200目的硅胶柱(PE:EA=2:1)得到黄色固体的化合物7。1H-NMR(300MHz,CDCl3):δ7.13(1H,s),7.03-6.99(2H,m),6.66-6.63(1H,d,J=8.1Hz), 6.02(2H,s),4.37(1H,s),3.79(3H,s),3.79(3H,s),2.92(3H,s).13C NMR(75MHz,CDCl3): δ168.08,148.16,144.06,141.54,140.22,130.10,130.00,129.25,125.87,129.25,118.48, 109.98,104.60,101.95,60.12,52.04,30.50ppm.HRMS-ESI:m/zcalcd for C17H17ClNO5(M+H)+350.0790, found 350.0789.
实施例9:
取实施例1所得的取化合物C(0.1mmol),将其至于25mL圆底烧瓶中,用10mL二氯甲烷溶解,随后加入苯甲酰氯(CAS:98-88-4)(0.12mmol)和吡啶(0.01mmol),常温反应6h。反应完毕后将反应液倒入水中,用3×25mL CH2Cl2萃取,合并有机相后将其用食盐水3×25mL洗涤,接着用无水Na2SO4干燥,用旋转蒸发仪将其旋干,使用丙酮/石油醚重结晶得到黄色固体的化合物8。1H-NMR(300MHz,CDCl3):δ 7.29-7.27(2H,d,J=6.3Hz),7.26(1H,s),7.16-7.11(3H,m),6.98-6.97(5H,m),5.95(2H, s),3.6(3H,s),3.47(3H,s),3.35(3H,s).13C NMR(75MHz,CDCl3):δ170.76,167.48,148.47, 143.55,141.01,140.36,135.20,130.35,129.92,129.52,128.87,127.75,126.18,125.24, 104.77,102.07,59.98,51.84,38.43ppm.HRMS-ESI:m/zcalcd for C24H22NO6(M+H)+420.1442,found 420.1438.
实施例10:
取实施例1所得的取化合物C(0.1mmol),将其至于25mL圆底烧瓶中,用10mL二氯甲烷溶解,随后加入苯磺酰氯(CAS:98-09-9)(0.12mmol)和吡啶(0.01mmol),常温反应6h。反应完毕后将反应液倒入水中,用3×25mL CH2Cl2萃取,合并有机相后将其用食盐水3×25mL洗涤,接着用无水Na2SO4干燥,用旋转蒸发仪将其旋干,使用丙酮/石油醚重结晶得到白色固体的化合物9。1H-NMR(300MHz,CDCl3):δ 7.58-7.55(3H,m),7.48-7.46(2H,d,J=7.2Hz),7.11-7.10(5H,m),6.06(2H,s),3.78(3H,s),3.56(3H, s),3.22(3H,s).13C NMR(75MHz,CDCl3):δ148.58,140.21,136.06,132.89,130.10,128.79, 128.04,125.69,125.45,104.90,102.13,60.14,51.95,38.11ppm.HRMS-ESI:m/zcalcd for C23H22NO7S (M+H)+456.1111,found 456.1110.
实施例11:
取实施例1所得的取化合物C(0.1mmol),将其至于25mL圆底烧瓶中,用10mL二氯甲烷溶解,随后加入4-氟苯磺酰氯(CAS:349-88-2)(0.12mmol)和吡啶(0.01mmol),常温反应6h。反应完毕后将反应液倒入水中,用3×25mL CH2Cl2萃取,合并有机相后将其用食盐水3×25mL洗涤,接着用无水Na2SO4干燥,用旋转蒸发仪将其旋干,使用丙酮/石油醚重结晶得到黄色固体的化合物10。1H-NMR(300MHz,CDCl3): δ7.58-7.53(2H,m),7.16-7.10(7H,m),6.06(2H,s),3.79(3H,s),3.58(3H,s),3.22(3H,s).13C NMR(75MHz,CDCl3):δ167.32,148.60,141.11,140.31,139.99,136.27,132.37,130.76,130.64, 130.17,125.60,125.29,116.17,115.87,104.89,102.13,60.09,51.90,38.03ppm.HRMS-ESI: m/zcalcd forC23H21FNO7S(M+H)+474.1017,found 474.1022.
实施例12:
取实施例1所得的取化合物C(0.1mmol),将其至于25mL圆底烧瓶中,用10mL二氯甲烷溶解,随后加入4-硝基苯磺酰氯(CAS:98-74-8)(0.12mmol)和吡啶(0.01mmol),常温反应6h。反应完毕后将反应液倒入水中,用3×25mL CH2Cl2萃取,合并有机相后将其用食盐水3×25mL洗涤,接着用无水Na2SO4干燥,用旋转蒸发仪将其旋干,使用丙酮/石油醚重结晶得到黄色固体的化合物11。1H-NMR(300MHz, CDCl3):δ8.31-8.28(2H,d,J=8.7Hz),7.71-6.68(2H,d,J=8.7Hz),7.13-7.09(5H,m),6.07(2H,s), 3.81(3H,s),3.63(3H,s),3.27(3H,s).13CNMR(75MHz,CDCl3):δ166.97,150.23,148.68,141.82, 141.09,140.29,139.27,136.87,130.41,129.25,125,47,124.03,104.96,102.16,60.10, 51.98,38.16ppm.HRMS-ESI:m/zcalcd for C23H21N2O9S(M+H)+501.0962,found 501.0960.
实施例13:
取实施例1所得的取化合物C(0.1mmol),将其至于25mL圆底烧瓶中,用10mL二氯甲烷溶解,随后加入4-溴苯磺酰氯(CAS:98-58-8)(0.12mmol)和吡啶(0.01mmol),常温反应6h。反应完毕后将反应液倒入水中,用3×25mL CH2Cl2萃取,合并有机相后将其用食盐水3×25mL洗涤,接着用无水Na2SO4干燥,用旋转蒸发仪将其旋干,使用丙酮/石油醚重结晶得到黄色固体的化合物12。1H-NMR(300MHz,CDCl3): δ7.60-7.58(2H,d,J=8.7Hz),7.40-7.38(1H,d,J=8.4Hz),7.12-7.10(5H,m),6.07(2H,s),3.79(3H, s),3.58(3H,s),3.22(3H,s).13CNMR(75MHz,CDCl3):δ167.35,148.63,141.13,140.32,139.88, 136.36,135.29,132.09,130.23,129.56,127.95,125.61,125.33,104.92,102.14,60.13,51.96, 38.08ppm.HRMS-ESI:m/zcalcd for C23H21BrNO7S(M+H)+534.0217,found 534.0211.
实施例14:
取实施例1所得的取化合物C(0.1mmol),将其至于25mL圆底烧瓶中,用10mL二氯甲烷溶解,随后加入甲磺酰氯(CAS:124-63-0)(0.12mmol)和吡啶(0.01mmol),常温反应6h。反应完毕后将反应液倒入水中,用3×25mL CH2Cl2萃取,合并有机相后将其用食盐水3×25mL洗涤,接着用无水Na2SO4干燥,用旋转蒸发仪将其旋干,使用丙酮/石油醚重结晶得到黄色固体的化合物13。1H-NMR(300MHz,CDCl3):δ 7.40-7.37(2H,d,J=8.4Hz),7.23-7.20(2H,d,J=8.4Hz),7.11(1H,s),6.06(2H,s),3.80(3H, s),3.52(3H,s),3.37(3H,s),2.87(3H,s).13C NMR(75MHz,CDCl3):δ167.46,148.52,141.04, 140.08,135.97,130.45,129.77,125.31,125.06,104.72,102.00,60.02,51.86,38.05,35.20 ppm.HRMS-ESI:m/zcalcd forC18H20NO7S(M+H)+394.0955,found 394.0947.
实施例15:
取实施例1所得的取化合物C(0.1mmol),将其至于25mL圆底烧瓶中,用10mL二氯甲烷溶解,随后加入BOC-甘氨酸(CAS:4530-20-5)(0.12mmol),EDCI(0.12mmol)和DMAP(0.01mmol),常温反应12h。反应完毕后将反应液倒入水中,用3×25mL CH2Cl2萃取,合并有机相后将其用食盐水3×25mL洗涤,接着用无水Na2SO4干燥,用旋转蒸发仪将其浓缩拌样,过100-200目的硅胶柱(PE:EA=2:1)得到白色固体的化合物14。1H-NMR(300MHz,CDCl3):δ7.24-7.22(4H,m),7.12(1H,s),6.07(2H,s), 5.43(1H,s),3.83(3H,s),3.72-3.71(2H,d,J=3.9Hz),3.54(3H,s),3.34(3H,s),1.42(9H, s).13C NMR(75MHz,CDCl3):δ168.75,167.54,155.79,148.67,140.99,140.61,140.06,137.48, 131.28,129.39,126.35,125.41,104.78,102.04,79.43,59.98,51.97,43.07,37.54,28.35 ppm.HRMS-ESI:m/zcalcd for C24H29N2O8(M+H)+473.1918,found 473.1911.
实施例16:
取实施例1所得的取化合物C(0.1mmol),将其至于25mL圆底烧瓶中,用10mL二氯甲烷溶解,随后加入BOC-甲基甘氨酸(CAS:13734-36-6)(0.12mmol),EDCI(0.12mmol)和DMAP(0.01mmol),常温反应12h。反应完毕后将反应液倒入水中,用3×25mL CH2Cl2萃取,合并有机相后将其用食盐水3×25mL 洗涤,接着用无水Na2SO4干燥,用旋转蒸发仪将其浓缩拌样,过100-200目的硅胶柱(PE:EA=2:1)得到黄色固体的化合物15。1H-NMR(300MHz,CDCl3):δ7.28-7.19(4H,m),7.13(1H,s),6.07(2H,s), 3.81(4H,s),3.72(1H,s),3.53(3H,s),3.32(3H,s),2.90(3H,s),1.47(6H,s),1.45(3H, s).13C NMR(75MHz,CDCl3):δ168.88,168.58,167.43,156.57,148.72,141.45,141.15,140.26, 137.19,131.26,129.84,126.62,126.37,125.37,104.92,102.13,79.80,60.09,51.91,51.56, 51.06,37.57,36.00,28.51ppm.HRMS-ESI:m/zcalcd for C25H31N2O8(M+H)+487.2075,found 487.2080.
实施例17:
取实施例1所得的取化合物C(0.1mmol),将其至于25mL圆底烧瓶中,用10mL二氯甲烷溶解,随后加入BOC-L-丙氨酸(CAS:15761-38-3)(0.12mmol),EDCI(0.12mmol),HOBt(0.12mmol)和DMAP (0.01mmol),常温反应12h。反应完毕后将反应液倒入水中,用3×25mLCH2Cl2萃取,合并有机相后将其用食盐水3×25mL洗涤,接着用无水Na2SO4干燥,用旋转蒸发仪将其浓缩拌样,过100-200目的硅胶柱 (PE:EA=2:1)得到黄色油状的化合物16。1H-NMR(300MHz,CDCl3):δ7.28(4H,s),7.12(1H,s), 6.07(2H,s),5.43-5.41(1H,d,J=8.1Hz),4.44-4.40(1H,t,J=6.9Hz),3.82(3H,s),3.52(3H, s),3.33(3H,s),1.45(3H,s),1.42(6H,s),1.15-1.13(3H,d,J=6.6Hz).13C NMR(75MHz, CDCl3):δ173.51,167.82,155.09,148.74,141.41,141.07,140.23,137.22,131.25,129.55, 126.65,125.62,104.94,102.12,60.10,51.96,47.11,38.06,28.48,18.96ppm.HRMS-ESI:m/zcalcd for C25H31N2O8(M+H)+487.2075,found 487.2079.
实施例18:
取实施例15所取得的化合物14(0.1mmol),将其至于25mL圆底烧瓶中,用10mL乙酸乙酯溶解,随后加入1mL浓盐酸,常温反应6h。反应完毕后,用饱和的NaHCO3溶液将反应液的pH调成中性,再将其倒入水中,用3×25mL乙酸乙酯萃取,合并有机相后将其用食盐水3×25mL洗涤,接着用无水Na2SO4干燥,用旋转蒸发仪将其旋干后用二氯甲烷/石油醚重结晶后得到白色固体的化合物17。1H-NMR(300MHz, CDCl3):δ7.26-7.24(4H,m),7.11(1H,s),6.06(2H,s),5.43(1H,s),3.78(3H,s),3.63(2H,s), 3.51(3H,s),3.29(3H,s).13C NMR(75MHz,CDCl3):δ167.52,166.21,148.93,141.18,140.44, 139.26,138.55,131.82,129.68,126.07,124.90,105.04,102.24,59.99,51.99,41.07,37.69 ppm.HRMS-ESI:m/zcalcd forC19H21N2O6(M+H)+373.1394,found 373.1393.
实施例19:
取实施例16所取得的化合物15(0.1mmol),将其至于25mL圆底烧瓶中,用10mL乙酸乙酯溶解,随后加入1mL浓盐酸,常温反应6h。反应完毕后,用饱和的NaHCO3溶液将反应液的pH调成中性,再将其倒入水中,用3×25mL乙酸乙酯萃取,合并有机相后将其用食盐水3×25mL洗涤,接着用无水Na2SO4干燥,用旋转蒸发仪将其旋干后用二氯甲烷/石油醚重结晶后得到黄色固体的化合物18。1H-NMR(300MHz, CDCl3):δ7.28-7.17(4H,m),7.13(1H,s),6.08(2H,s),3.82(3H,s),3.53(3H,s),3.35(3H,s), 3.15(2H,s),2.36(3H,s),2.23(1H,s).13CNMR(75MHz,CDCl3):δ171.33,167.49,148.72, 141.51,141.08,140.27,137.10,131.11,129.75,126.42,125.35,104.92,102.13,60.09,52.89, 51.88,37.35,36.41ppm.HRMS-ESI:m/zcalcd for C20H23N2O6(M+H)+387.1551,found 387.1549.
实施例20:
取实施例17所取得的化合物16(0.1mmol),将其至于25mL圆底烧瓶中,用10mL乙酸乙酯溶解,随后加入1mL浓盐酸,常温反应6h。反应完毕后,用饱和的NaHCO3溶液将反应液的pH调成中性,再将其倒入水中,用3×25mL乙酸乙酯萃取,合并有机相后将其用食盐水3×25mL洗涤,接着用无水Na2SO4干燥,用旋转蒸发仪将其旋干后用二氯甲烷/石油醚重结晶后得到黄色油状的化合物19。1H-NMR(300MHz, CDCl3):δ7.28-7.19(4H,m),7.13(1H,s),6.08(2H,s),3.81(3H,s),3.58(1H,s),3.52(3H, s),3.33(3H,s),1.77(2H,s),1.16-1.14(3H,d,J=6.6Hz).13CNMR(75MHz,CDCl3):δ176.84, 167.53,148.74,142.00,141.08,140.27,137.05,131.13,129.69,126.56,125.39,104.94,102.14, 60.10,51.88,47.39,37.85,21.71.HRMS-ESI:m/zcalcd for C20H23N2O6(M+H)+387.1551,found 387.1551.
实施例21:
取实施例1所得的取化合物C(0.1mmol),将其至于25mL圆底烧瓶中,用10mL二氯甲烷溶解,随后加入生物素标记的氨基己酸(CAS:72040-64-3)(0.12mmol),EDCI(0.12mmol),HOBt(0.12mmol)和 DMAP(0.01mmol),常温反应12h。反应完毕后将反应液倒入水中,用3×25mL CH2Cl2萃取,合并有机相后将其用食盐水3×25mL洗涤,接着用无水Na2SO4干燥,用旋转蒸发仪将其浓缩拌样,过100-200目的硅胶柱(EA:CH3OH:H2O=20:1:1)得到白色固体的化合物20。1H-NMR(400MHz,CDCl3):δ7.22-7.20(2H,d,J= 7.6Hz),7.16-7.14(2H,d,J=8.0Hz),7.10(1H,s),6.06(2H,s),4.49(1H,s),4.28(1H,s),3.79(3H,s),3.51(3H, s),3.28(3H,s),3.16-3.11(3H,m),2.90-2.86(1H,dd,J1=12.4Hz,J2=4.4Hz),2.74-2.71(1H,d,J=12.8Hz), 2.18-2.13(4H,m),1.69-1.57(5H,m),1.41(4H,s).13C NMR(100MHz,CDCl3):δ173.32,173.29,167.43,167.43, 148.60,142.70,141.01,140.22,136.58,130.89,129.77,126.43,125.25,104.80,102.06,61.76,60.28,60.02, 55.75,51.79,40.49,39.10,37.31,36.05,33.84,29.03,28.30,28.11,26.50,25.83,25.00ppm.HRMS-ESI: m/zcalcd for C33H42N4O8SNa(M+Na)+677.2616,found 677.2618.
实施例22:
化合物1-20的体外抗肝癌活性实验
本申请中公开的化合物1-20经中国科学院成都生物研究所进行抗肝癌活性筛选,具体实验方法和结果如下所述:
所用细胞:SK-Hep-1(人肝癌细胞),QSG-7701(人肝细胞),RPMI-1640培养基(含10%胎牛血清) 培养,2天传代一次,实验开始前1天,1:2传代,以保证细胞状态。
化合物的配制:96孔板内,对化合物1a从最大浓度400μmol/L(μM)做5倍梯度稀释,100μl/孔,共6 个稀释度,每个稀释度设3个重复孔。
药物的抗肝癌活性检测:
1)96孔板内,对化合物1b从最大浓度400μM做5倍梯度稀释,100μl/孔,共6个稀释度,每个稀释度设3 个重复孔。
2)将SK-Hep-1细胞250×g离心5min后,用新鲜的生长培养基悬浮,吹打均匀,Trypan Blue染色计数,确定细胞浓度,活细胞百分数必须大于95%方可进行下一步实验。
3将上述细胞加到含有化合物的96孔板中,100μl/孔,设置不含化合物的阳性对照孔和不含病毒的阴性对照孔。在37℃,5%CO2条件下与化合物共培3d。
4)在倒置显微镜下(100×)计数合胞体的形成。计算EC50,即化合物抑制50%合胞体形成时的药物浓度。
结果处理:药物的抗病毒活性表示为:药物的抗病毒活性%=(测试值-最低均值)/(最高均值-最低均值)×100,用Median Equation方法计算EC50。
量效关系曲线采用Graphpad Prism 5.0软件生成。统计分析采用SPSS 15.0软件。
实施例23:
上述实施例所制得的化合物抗肝癌活性测试结果如下
样品名称 | EC50(μM)against SK-Hep-1 | EC50(μM)against QSG-7701 |
Enoxacin | 25.03 | 72.35 |
化合物1 | >100 | >100 |
化合物2 | 23.57 | 56.35 |
化合物3 | 38.43 | 58.45 |
化合物4 | 31.56 | 64.38 |
化合物5 | 35.78 | 56.89 |
化合物6 | 24.45 | 67.23 |
化合物7 | 22.68 | 50.32 |
化合物8 | 19.43 | 48.35 |
化合物9 | 26.67 | 61.35 |
化合物10 | 31.68 | 67.89 |
化合物11 | 34.25 | 69.32 |
化合物12 | 28.65 | 62.35 |
化合物13 | 46.98 | 75.86 |
化合物14 | 39.65 | 63.25 |
化合物15 | 89.65 | >100 |
化合物16 | 40.91 | 59.47 |
化合物17 | >100.00 | >100.00 |
化合物18 | >100.00 | >100.00 |
化合物19 | 64.65 | 74.15 |
化合物20 | 28.32 | 57.35 |
从上表可以看出,该类化合物除了化合物1,15,17,18以外普遍具有较好的抗肝癌活性。其中化合物6,7,9和依诺沙星对肝癌细胞的抑制能力相当,8号化合物甚至比依诺沙星更具效力。除此之外,该类化合物对正常的肝脏细胞抑制不明显,表现出了较低的毒性。因而该类化合物具有良好的开发潜力。
在本说明书中所谈到的“一个实施例”、“另一个实施例”、“实施例”、“优选实施例”等,指的是结合该实施例描述的具体特征、结构或者特点包括在本申请概括性描述的至少一个实施例中。在说明书中多个地方出现同种表述不是一定指的是同一个实施例。进一步来说,结合任一实施例描述一个具体特征、结构或者特点时,所要主张的是结合其他实施例来实现这种特征、结构或者特点也落在本申请的范围内。尽管这里参照本申请的多个解释性实施例对本申请进行了描述,但是,应该理解,本领域技术人员可以设计出很多其他的修改和实施方式,这些修改和实施方式将落在本申请公开的原则范围和精神之内。更具体地说,在本申请公开、附图和权利要求的范围内,可以对主题组合布局的组成部件和/或布局进行多种变型和改进。除了对组成部件和/或布局进行的变形和改进外,对于本领域技术人员来说,其他的用途也将是明显的。
以上所述的仅是本发明的部分具体实施例(由于本发明的实施例不能穷举,本发明所记载的保护范围以本发明的记载范围和其他技术要点范围为准),由于本发明涉及化学领域,故有关化学实验中的数值参数并非唯一限制,本发明技术内涵旨意表示在理解技术方案的基础上,能够实现本发明技术方案的数值参数均纳入保护范围。方案中公知的具体内容或常识在此未作过多描述。应当指出,上述实施例不以任何方式限制本发明,对于本领域的技术人员来说,凡是采用等同替换或等效变换的方式获得的技术方案均落在本发明的保护范围内。本申请要求的保护范围应当以其权利要求的内容为准,说明书中的具体实施方式等记载可以用于解释权利要求的内容。
Claims (10)
3.如权利要求1所述化合物的制备方法,其特征在于,包括以下步骤:
化合物A通过酰胺化作用得到化合物(Ⅰ):
所用的缩合剂为1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(EDCI),1-羟基苯并三氮唑(HOBt),二环己基碳二亚胺(DCC),羰基咪唑(CDI),O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸(TBTU),二氯亚砜(SOCl2),草酰氯(C2Cl2O2)中任意一或两种;
所用催化剂为吡啶,4-二甲氨基吡啶(DMAP),三乙胺(EtN3),N,N-二异丙基乙胺(DIPEA)中任意一种;
所用溶剂为二氯甲烷,氯仿或N,N-二甲基甲酰胺(DMF)中任意一种;
所取温度为0℃-50℃之间,反应时间为8-15h。
4.根据权利要求3所述的化合物的制备方法,其特征在于,所述步骤为:
取化合物A,将其用二氯甲烷溶解,随后加入缩合剂,反应3h,再加入R1H和催化剂;反应8h,萃取,浓缩,过硅胶柱得到结构为(Ⅰ)的化合物。
7.如权利要求5所述化合物的制备方法,其特征在于,包括以下步骤:
化合物B通过选择性脱甲基得到化合物C:
所用试剂为氯甲酸-1-氯乙酯(ACE-Cl),所用溶剂为氯仿/甲醇或氯仿/乙醇;
所取温度为60℃-90℃之间,反应时间为24-72h;
所用的缩合剂为1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(EDCI),1-羟基苯并三氮唑(HOBt),二环己基碳二亚胺(DCC),羰基咪唑(CDI),O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸(TBTU),二氯亚砜(SOCl2),草酰氯(C2Cl2O2)中任意一或两种;
所用催化剂为吡啶,4-二甲氨基吡啶(DMAP),三乙胺(EtN3),N,N-二异丙基乙胺(DIPEA)中任意一种;
所用溶剂为二氯甲烷,氯仿或N,N-二甲基甲酰胺(DMF)中任意一种;
所取温度为0℃-50℃之间,反应时间为5-12h。
8.根据权利要求7所述的化合物的制备方法,其特征在于,所述步骤为:
取化合物B,将其用氯仿溶解,随后加入ACE-Cl,70℃反应12h,再加入甲醇,70℃再反应12h;萃取,浓缩,过硅胶柱得到化合物C;化合物C再通过酰胺化作用和酰氯或磺酰氯R3Cl或羧酸R3OH得到化合物(Ⅱ);
取化合物C,将其用二氯甲烷溶解,随后加入R3Cl和吡啶,反应6h;或取化合物C,将其用二氯甲烷溶解,随后加入缩合剂和R3OH,反应12h;萃取,浓缩,重结晶或过硅胶柱得到结构为(Ⅱ)的化合物。
9.如权利要求1或2或5或6所述的化合物的应用为制备抗肝癌药物。
10.如权利要求3或4或7或8所述制备方法得到的化合物的应用为制备抗肝癌药物。
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