CN105061442A - 含磺酰基哌嗪的香豆素并吡唑类化合物及其制备与在抑制肿瘤细胞中的应用 - Google Patents
含磺酰基哌嗪的香豆素并吡唑类化合物及其制备与在抑制肿瘤细胞中的应用 Download PDFInfo
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- CN105061442A CN105061442A CN201510416346.4A CN201510416346A CN105061442A CN 105061442 A CN105061442 A CN 105061442A CN 201510416346 A CN201510416346 A CN 201510416346A CN 105061442 A CN105061442 A CN 105061442A
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- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
Abstract
含磺酰基哌嗪的香豆素并吡唑类化合物,它具有如下通式。实验证明,含磺酰基哌嗪的香豆素并吡唑类化合物对人结肠癌细胞株(HCT-116),人体肺癌细胞株(A549),肝癌细胞(Huh7)和人脊髓白血病M3细胞株(HL60)都有不同程度的抑制作用。因此它们可能用于制备抗癌药物。本发明公开了含磺酰基哌嗪的香豆素并吡唑类化合物的制法。其中R为:
Description
技术领域
本发明涉及含磺酰基哌嗪的香豆素并吡唑类化合物及其制备与在抑制肿瘤细胞中的应用。
背景技术
天然和合成的香豆素类化合物具有多种生物活性,其作为抗凝剂和抗血栓药已被人们所了解。一些衍生物被报道具有光敏化,抗HIV,降脂、抗炎、抗肿瘤和抗氧化的作用,能够抑制脂质过氧化,清除自由基,松弛血管,调节心血管功能。研究发现,许多香豆素类化合物对哺乳动物的癌细胞系具有细胞毒性作用。最近一系列芳香基磺酰脲香豆素类化合物被报道在低浓度能有效抑制各种肿瘤细胞的增殖。而Manojkumar等也报道一些合成的杂环香豆素类化合物对DLA和EAC细胞具有细胞毒作用。芳香酶是雄激素转化为雌激素的关键酶,而雌激素通过雌激素受体刺激乳腺癌细胞的增殖。因此,一些合成的香豆素类芳香酶抑制剂,如来曲唑、依希美坦等被证明对内分泌激素引起的乳腺癌有效。香豆素的磷肼类衍生物具有体外抗P388白血病的作用,与氨甲喋呤合用在鼠类白血病细胞系L1210上能够观察到抗肿瘤作用。香豆素和7-羟基香豆素在体内和体外都具有抗肿瘤作用,能够通过诱导细胞周期停滞于G1期而抑制所有的肺癌细胞系细胞生长,和其它抗新生瘤的药物合用能够增强对非小细胞肺癌的治疗作用。
本发明基于香豆素的抗癌活性,对其引入不同取代基的磺酰基哌嗪进行修饰,合成出一系列含磺酰基哌嗪的香豆素并吡唑类化合物,并对它们进行抗癌活性测试。
发明内容
本发明涉及含磺酰基哌嗪的香豆素并吡唑类化合物及其制备与在抑制肿瘤细胞中的应用。
本发明的技术方案如下:
一类含磺酰基哌嗪的香豆素并吡唑类化合物,其特征是它有如下通式:
其中R为:
-CF3,-CH3,-CH2CH3,-CH2CH2CH3,-CH2CH2CH2CH3,-CH2CH2Cl,-CH2CH2CH2Cl。
一种制备上述的含磺酰基哌嗪的香豆素并吡唑类化合物的方法,其特征是它由下列步骤组成:
将4-羟基香豆素0.06mmol溶解在46.2ml的无水N,N-二甲基甲酰胺中,将此反应液冷却至0℃以下。在0℃以下条件下,边搅拌边缓慢滴加POCl30.18mmol,待POCl3加毕,将反应液缓慢升温至室温条件下搅拌0.5h后,然后升温至65-70℃搅拌反应6h。用TLC跟踪监测反应,当反应完毕后,将反应液倒入200g的冰水混合物中并剧烈搅拌,有大量浅黄色固体1析出。将固体抽滤,并用5%的Na2CO3水溶液洗涤,将所得固体干燥,即得到中间体。
将步骤一中所得固体1mmol溶解在10ml乙醇中,加完搅拌使其溶解充分,然后冷却至15-20℃,将配置好的溶液(85%的水合肼2mmol+三乙胺4mmol+60%乙醇10ml)在搅拌条件下,保持温度在15-20℃,缓慢滴加至反应液中。滴加毕,保持温度不超过25℃,搅拌反应12h。用TLC跟踪监测反应。将所得固体减压浓缩,所得固体用乙醇重结晶,即得到中间体2。
取无水哌嗪3mmol溶解在30ml无水二氯甲烷中冷却至0℃以下,然后加入三乙胺4ml,搅拌一段时间后,加入磺酰氯3mmol,在0℃以下搅拌反应2-4h,反应毕,有机层用水洗(30ml×3)后,用无水硫酸钠干燥,减压蒸干溶剂,所得固体3减压干燥后,直接用于下一步反应。
取上述所得固体3mmol,化合物21mmol加热溶解在20-25ml的无水乙醇中,待溶解充分后,冷却至室温下,向反应液中缓慢加入40%的甲醛溶液300μl,室温下搅拌反应4-6h,有大量固体析出。过滤,所得固体用冷的乙醇洗涤,然后将固体干燥,用乙醇重结晶,即得到含磺酰胺氮杂环的香豆素并吡唑衍生物。
本发明的含磺酰基哌嗪的香豆素并吡唑类化合物对肿瘤细胞具有明显的抑制作用。因此本发明的含磺酰基哌嗪的香豆素并吡唑类化合物可以应用于制备抗癌药物。
具体实施方式
通过以下实施例进一步详细说明本发明,但本发明的范围并不受这些实施例的任何限制。
实施例一:2-((4-(苯磺酰基)哌嗪-1-基)甲基)色烯并[4,3-c]吡唑-4(2H)-酮(化合物1)的制备
将4-羟基香豆素0.06mmol溶解在46.2ml的无水N,N-二甲基甲酰胺中,将此反应液冷却至0℃以下。在0℃以下条件下,边搅拌边缓慢滴加POCl30.18mmol,待POCl3加毕,将反应液缓慢升温至室温条件下搅拌0.5h后,然后升温至65-70℃搅拌反应6h。用TLC跟踪监测反应,当反应完毕后,将反应液倒入200g的冰水混合物中并剧烈搅拌,有大量浅黄色固体1析出。将固体抽滤,并用5%的Na2CO3水溶液洗涤,将所得固体干燥,即得到中间体。
将步骤一中所得固体1mmol溶解在10ml乙醇中,加完搅拌使其溶解充分,然后冷却至15-20℃,将配置好的溶液(85%的水合肼2mmol+三乙胺4mmol+60%乙醇10ml)在搅拌条件下,保持温度在15-20℃,缓慢滴加至反应液中。滴加毕,保持温度不超过25℃,搅拌反应12h。用TLC跟踪监测反应。将所得固体减压浓缩,所得固体用乙醇重结晶,即得到中间体2。
取无水哌嗪3mmol溶解在30ml无水二氯甲烷中冷却至0℃以下,然后加入三乙胺4ml,搅拌一段时间后,加入磺酰氯3mmol,在0℃以下搅拌反应2-4h,反应毕,有机层用水洗(30ml×3)后,用无水硫酸钠干燥,减压蒸干溶剂,所得固体减压干燥后,直接用于下一步反应。
取上述所得固体1mmol,化合物21mmol加热溶解在20-25ml的无水乙醇中,待溶解充分后,冷却至室温下,向反应液中缓慢加入40%的甲醛溶液300μl,室温下搅拌反应4-6h,有大量固体析出。过滤,所得固体用冷的乙醇洗涤,然后将固体干燥,用乙醇重结晶,即得到终产物。产物为白色粉末,产率63%。Mp:199-200℃.1HNMR(400MHz,CDCl3):8.20(s,1H,ArH),8.04(d,J=7.60Hz,1H,ArH),7.72(d,J=7.28Hz,2H,ArH),7.57-7.47(m,4H,ArH),7.38(d,J=8.24Hz,1H,ArH),7.32(t,J=7.48Hz,1H,ArH),5.05(s,2H,CH2),3.07(s,4H,-CH2CH2),2.74(s,4H,-CH2CH2).MS(ESI):425.33(C21H21N4O4S,[M+H]+).Anal.CalcdforC21H20N4O4S:C,59.42;H,4.75;N,13.20%.Found:C,59.43;H,4.74;N,13.21%.
实施例二:2-((4-甲苯磺酰基哌嗪-1-基)甲基)色烯并[4,3-c]吡唑-4(2H)-酮(化合物2)的制备
制备方法同实施例一。产物为白色粉末状固体。产率57%。Mp:176-177℃.1HNMR(400MHz,CDCl3):8.20(s,1H,ArH),8.05(d,J=7.72Hz,1H,ArH),7.61(d,J=7.92Hz,2H,ArH),7.49(t,J=7.70Hz,1H,ArH),7.38(d,J=8.28Hz,1H,ArH),7.31(t,J=9.66Hz,3H,ArH),5.04(s,2H,-CH2),3.05(s,4H,-CH2CH2),2.75(t,J=4.38Hz,4H,-CH2CH2),2.40(s,3H,CH3).MS(ESI):439.32(C22H23N4O4S,[M+H]+).Anal.CalcdforC22H22N4O4S:C,60.26;H,5.06;N,12.78%.Found:C,60.27;H,5.08;N,12.76%.
实施例三:2-((4-((4-甲氧基苯基)磺酰基)哌嗪-1-基)甲基)色烯并[4,3-c]吡唑-4(2H)-酮(化合物3)的制备
制备方法同实施例一。产物为白色粉末状固体。产率54%。Mp:182-184℃.1HNMR(400MHz,CDCl3):8.20(s,1H,ArH),8.05(d,J=7.64Hz,1H,ArH),7.66(d,J=8.36Hz,2H,ArH),7.48(t,J=5.76Hz,1H,ArH),7.38(d,J=8.24Hz,1H,ArH),7.32(t,J=7.52Hz,1H,ArH),6.96(d,J=8.52Hz,2H,ArH),5.05(s,2H,-CH2),3.85(s,3H,OCH3),3.05(s,4H,-CH2CH2),2.74(d,J=4.32Hz,4H,-CH2CH2).MS(ESI):455.37(C22H23N4O5S,[M+H]+).Anal.CalcdforC22H22N4O5S:C,58.14;H,4.88;N,12.33%.Found:C,58.15;H,4.91;N,4.86%.
实施例四:2-((4-((4-(叔丁基)苯基)磺酰基)哌嗪-1-基)甲基)色烯并[4,3-c]吡唑-4(2H)-酮(化合物4)的制备
制备方法同实施例一。产物为白色结晶状固体。产率58%。Mp:264-266℃.1HNMR(400MHz,CDCl3):8.22(s,1H,ArH),8.05(d,J=7.76Hz,1H,ArH),7.65(d,J=8.44Hz,2H,ArH),7.52(d,J=8.32Hz,2H,ArH),7.47(d,J=7.28Hz,1H,ArH),7.37(d,J=8.24Hz,1H,ArH),7.32(t,J=7.50Hz,1H,ArH),5.05(s,2H,-CH2),3.06(s,4H,-CH2CH2),2.77(t,J=4.66Hz,4H,-CH2CH2),1.33(s,9H,3CH3).MS(ESI):481.44(C25H29N4O4S,[M+H]+).Anal.CalcdforC25H28N4O4S:C,62.48;H,5.87;N,11.66%.Found:C,62.47;H,5.89;N,11.65%.
实施例五:2-((4-((4-氟苯基)磺酰基)哌嗪-1-基)甲基)色烯并[4,3-c]吡唑-4(2H)-酮(化合物5)的制备
制备方法同实施例一。产物为黄色粉末状固体。产率55%。Mp:202-205℃.1HNMR(400MHz,CDCl3):8.20(s,1H,ArH),8.05(m,1H,ArH),7.78(d,J=8.04Hz,2H,ArH),7.31(d,J=8.44Hz,2H,ArH),7.49(m,1H,ArH),7.37(d,J=7.88Hz,1H,ArH),7.33(t,J=7.54Hz,1H,ArH),7.31(d,J=8.44Hz,2H,ArH),5.04(s,2H,CH2),3.08(s,4H,-CH2CH2),2.76(t,J=4.56Hz,4H,-CH2CH2).MS(ESI):443.35(C21H20FN4O4S,[M+H]+).Anal.CalcdforC21H19FN4O4S:C,57.00;H,4.33;N,12.66%.Found:C,57.03;H,4.31;N,12.67%.
实施例六:2-((4-((4-氯苯基)磺酰基)哌嗪-1-基)甲基)色烯并[4,3-c]吡唑-4(2H)-酮(化合物6)的制备
制备方法同实施例一。产物为浅黄色粉末状固体。产率61%。Mp:229-230℃.1HNMR(400MHz,CDCl3):8.20(s,1H,ArH),8.05(d,J=7.72Hz,1H,ArH),7.67(d,J=8.44Hz,2H,ArH),7.48(m,3H,ArH),7.38(d,J=8.32Hz,1H,ArH),7.32(t,J=7.48Hz,1H,ArH),5.06(s,2H,-CH2),3.07(s,4H,-CH2CH2),2.76(t,J=4.52Hz,4H,-CH2CH2).MS(ESI):459.81(C21H20ClN4O4S,[M+H]+).Anal.CalcdforC21H19ClN4O4S:C,54.96;H,4.17;N,12.21%.Found:C,54.99;H,4.16;N,12.20%.
实施例七:2-((4-((4-溴苯基)磺酰基)哌嗪-1-基)甲基)色烯并[4,3-c]吡唑-4(2H)-酮(化合物7)的制备
制备方法同实施例一。产物为浅黄色粉末状固体。产率57%。Mp:250-251℃.1HNMR(400MHz,CDCl3):8.19(s,1H,ArH),8.05(m,1H,ArH),7.67(d,J=8.16Hz,2H,ArH),7.59(d,J=8.56Hz,2H,ArH),7.49(m,1H,ArH),7.38(d,J=7.92Hz,1H,ArH),7.33(t,J=7.50Hz,1H,ArH),5.06(s,2H,CH2),3.07(s,4H,-CH2CH2),2.76(t,J=4.84Hz,4H,-CH2CH2).MS(ESI):504.27(C21H20BrN4O4S,[M+H]+).Anal.CalcdforC21H19BrN4O4S:C,50.11;H,3.80;N,11.13%.Found:C,50.13;H,3.81;N,11.11%.
实施例八:2-((4-((4-硝基苯基)磺酰基)哌嗪-1-基)甲基)色烯并[4,3-c]吡唑-4(2H)-酮(化合物8)的制备
制备方法同实施例一。产物为浅黄色粉末状固体。产率59%。Mp:252-254℃.1HNMR(400MHz,DMSO):8.80(s,1H,ArH),8.43(d,J=8.76Hz,1H,ArH),8.35(d,J=8.76Hz,2H,ArH),7.97(d,J=8.76Hz,2H,ArH),7.56(m,1H,ArH),7.43(d,J=8.12Hz,1H,ArH),7.38(t,J=7.50Hz,1H,ArH),5.19(s,2H,-CH2),3.04(s,4H,-CH2CH2),2.66(d,J=4.28Hz,4H,-CH2CH2).MS(ESI):470.38(C21H20N5O6S,[M+H]+).Anal.CalcdforC21H19N5O6S:C,53.73;H,4.08;N,14.92%.Found:C,53.74;H,4.10;N,14.90%.
实施例九:2-((4-((3-硝基苯基)磺酰基)哌嗪-1-基)甲基)色烯并[4,3-c]吡唑-4(2H)-酮(化合物9)的制备
制备方法同实施例一。产物为黄色粉末状固体。产率43%。Mp:231-233℃.1HNMR(400MHz,CDCl3):8.20(s,1H,ArH),8.11(s,1H,ArH),8.05(d,J=7.52Hz,1H,ArH),7.79(m,2H,ArH),7.68(d,J=8.48Hz,1H,ArH),7.51(t,J=7.88Hz,1H,ArH),7.37(d,J=8.40Hz,1H,ArH),7.33(t,J=7.42Hz,1H,ArH),5.11(s,2H,-CH2),3.12(s,4H,-CH2CH2),2.78(s,4H,-CH2CH2).MS(ESI):470.38(C21H20N5O6S,[M+H]+).Anal.CalcdforC21H19N5O6S:C,53.73;H,4.08;N,14.92%.Found:C,53.71:H,4.09;N,14.95%.
实施例十:2-((4-((2-硝基苯基)磺酰基)哌嗪-1-基)甲基)色烯并[4,3-c]吡唑-4(2H)-酮(化合物10)的制备
制备方法同实施例一。产物为黄色粉末状固体。产率37%。Mp:218-219℃.1HNMR(400MHz,CDCl3):8.22(s,1H,ArH),8.14(m,1H,ArH),8.04(d,J=7.60Hz,1H,ArH),7.72(m,2H,ArH),7.50(t,J=7.76Hz,1H,ArH),7.42(m,1H,ArH),7.39(d,J=8.44Hz,1H,ArH),7.33(t,J=7.46Hz,1H,ArH),5.09(s,2H,-CH2),3.10(s,4H,-CH2CH2),2.77(s,4H,-CH2CH2).MS(ESI):470.38(C21H20N5O6S,[M+H]+).Anal.CalcdforC21H19N5O6S:C,53.73;H,4.08;N,14.92%.Found:C,53.74;H,4.11;N,14.91%.
实施例十一:2-((4-((4-(三氟甲基)苯基)磺酰基)哌嗪-1-基)甲基)色烯并[4,3-c]吡唑-4(2H)-酮(化合物11)的制备
制备方法同实施例一。产物为浅黄色粉末状固体。产率46%。Mp:189-291℃.1HNMR(400MHz,CDCl3):8.19(s,1H,ArH),8.04(m,1H,ArH),7.70(d,J=8.20Hz,2H,ArH),7.62(d,J=8.32Hz,2H,ArH),7.48(m,1H,ArH),7.38(d,J=7.96Hz,1H,ArH),7.32(t,J=7.64Hz,1H,ArH),5.06(s,2H,CH2),3.06(d,J=4.72Hz,4H,-CH2CH2),2.75(t,J=4.84Hz,4H,-CH2CH2).MS(ESI):493.31(C22H20F3N4O4S,[M+H]+).Anal.CalcdforC22H19F3N4O4S:C,53.66;H,3.89;F,11.57;N,11.38%.Found:C,53.63:H,3.91;N,11.39%.
实施例十二:2-((4-((2,5-二甲基苯基)磺酰基)哌嗪-1-基)甲基)色烯并[4,3-c]吡唑-4(2H)-酮(化合物12)的制备
制备方法同实施例一。产物为白色粉末状固体。产率58%。Mp:223-225℃.1HNMR(400MHz,CDCl3):8.19(s,1H,ArH),8.05(m,1H,ArH),7.56(d,J=8.44Hz,1H,ArH),7.47(m,1H,ArH),7.36(d,J=7.92Hz,1H,ArH),7.33(t,J=7.56Hz,1H,ArH),7.23(m,2H,ArH),5.08(s,2H,CH2),3.07(s,4H,-CH2CH2),2.78(t,J=4.56Hz,4H,-CH2CH2)2.60(s,3H,CH3),2.45(s,3H,CH3).MS(ESI):453.41(C23H25N4O4S,[M+H]+).Anal.CalcdforC23H24N4O4S:C,61.05;H,5.35;N,12.38%.Found:C,61.01;H,5.37;N,12.36%.
实施例十三:2-((4-((4-氯-3-硝基苯基)磺酰基)哌嗪-1-基)甲基)色烯并[4,3-c]吡唑-4(2H)-酮(化合物13)的制备
制备方法同实施例一。产物为浅黄色粉末状固体。产率39%。Mp:247-248℃.1HNMR(400MHz,CDCl3):8.20(s,2H,ArH),8.05(d,J=7.56Hz,1H,ArH),7.85(d,J=8.12Hz,1H,ArH),7.74(d,J=8.48Hz,1H,ArH),7.50(t,J=7.76Hz,1H,ArH),7.39(d,J=8.44Hz,1H,ArH),7.33(t,J=7.46Hz,1H,ArH),5.09(s,2H,-CH2),3.14(s,4H,-CH2CH2),2.80(s,4H,-CH2CH2).MS(ESI):504.73(C21H19ClN5O6S,[M+H]+).Anal.CalcdforC21H18ClN5O6S:C,50.05;H,3.60;N,13.90%.Found:C,50.07;H,3.61;N,13.87%.
实施例十四:2-((4-(三甲磺酰基)哌嗪-1-基)甲基)色烯并[4,3-c]吡唑-4(2H)-酮(化合物14)的制备
制备方法同实施例一。产物为白色粉末状固体。产率67%。Mp:217-219℃.1HNMR(400MHz,CDCl3):8.20(s,1H,ArH),8.05(m,1H,ArH),7.48(m,1H,ArH),7.38(d,J=7.92Hz,1H,ArH),7.32(t,J=7.52Hz,1H,ArH),7.04(m,2H,ArH),5.06(s,2H,CH2),3.07(t,J=4.58Hz,4H,-CH2CH2),2.76(t,J=4.82Hz,4H,-CH2CH2),2.71(s,6H,2CH3),2.29(s,3H,CH3).MS(ESI):467.39(C24H27N4O4S,[M+H]+).Anal.CalcdforC24H26N4O4S:C,61.78;H,5.62;N,12.01%.Found:C,61.80;H,5.64;N,11.99%.
实施例十五:2-((4-((2,4,6-三异丙基苯基)磺酰基)哌嗪-1-基)甲基)色烯并[4,3-c]吡唑-4(2H)-酮(化合物15)的制备
制备方法同实施例一。产物为白色粉末状固体。产率65%。Mp:238-240℃.1HNMR(400MHz,CDCl3):8.20(s,1H,ArH),8.03(d,J=7.64Hz,1H,ArH),7.48(t,J=7.70Hz,1H,ArH),7.38(d,J=8.36Hz,1H,ArH),7.31(t,J=7.48Hz,1H,ArH),7.09(s,2H,ArH),5.12(s,2H,CH2),4.05(m,2H,2-CH),3.24(s,4H,-CH2CH2),2.85(m,1H,-CH),2.71(s,4H,-CH2CH2),1.21(d,J=6.96Hz,6H,2CH3),1.14(d,J=6.68Hz,12H,4CH3).MS(ESI):551.42(C30H39N4O4S,[M+H]+).Anal.CalcdforC30H38N4O4S:C,65.43;H,6.95;N,10.17%.Found:C,65.41;H,6.97;N,10.18%.
实施例十六:2-((4-((三氟甲基)磺酰基)哌嗪-1-基)甲基)色烯并[4,3-c]吡唑-4(2H)-酮(化合物16)的制备
制备方法同实施例一。产物为浅黄色粉末状固体。产率41%。Mp:167-169℃.1HNMR(400MHz,CDCl3):8.20(s,1H,ArH),8.05(d,J=7.76Hz,1H,ArH),7.50(t,J=7.64Hz,1H,ArH),7.37(d,J=8.56Hz,1H,ArH),7.33(t,J=7.64Hz,1H,ArH),5.10(s,2H,-CH2),2.78(t,J=4.18Hz,4H,-CH2CH2),2.57(s,4H,-CH2CH2).MS(ESI):417.28(C16H16F3N4O4S,[M+H]+).Anal.CalcdforC16H15F3N4O4S:C,46.15;H,3.63;N,13.46%.Found:C,46.18;H,3.62;N,13.49%.
实施例十七:2-((4-(甲基磺酰基)哌嗪-1-基)甲基)色烯并[4,3-c]吡唑-4(2H)-酮(化合物17)的制备
制备方法同实施例一。产物为白色粉末状固体。产率59%。Mp:191-194℃.1HNMR(400MHz,CDCl3):8.20(s,1H,ArH),8.04(d,J=7.88Hz,1H,ArH),7.51(t,J=7.60Hz,1H,ArH),7.38(d,J=8.52Hz,1H,ArH),7.33(t,J=7.52Hz,1H,ArH),5.10(s,2H,-CH2),2.97(s,3H,CH3),2.79(t,J=4.22Hz,4H,-CH2CH2),2.61(s,4H,-CH2CH2).MS(ESI):363.32(C16H19N4O4S,[M+H]+).Anal.CalcdforC16H18N4O4S:C,53.03;H,5.01;N,15.46%.Found:C,53.01;H,5.03;N,15.44%.
实施例十八:2-((4-(乙基磺酰基)哌嗪-1-基)甲基)色烯并[4,3-c]吡唑-4(2H)-酮(化合物18)的制备
制备方法同实施例一。产物为白色粉末状固体。产率52%。Mp:201-203℃.1HNMR(400MHz,CDCl3):8.20(s,1H,ArH),8.05(m,1H,ArH),7.50(t,J=7.68Hz,1H,ArH),7.38(d,J=8.44Hz,1H,ArH),7.32(t,J=7.58Hz,1H,ArH),5.11(s,2H,-CH2),3.36(m,2H,-CH2),2.76(t,J=4.30Hz,4H,-CH2CH2),2.57(d,J=4.12Hz,4H,-CH2CH2),1.22(t,J=7.48Hz,3H,CH3).MS(ESI):377.29(C17H21N4O4S,[M+H]+).Anal.CalcdforC17H20N4O4S:C,54.24;H,5.36;N,14.88%.Found:C,54.26;H,5.37;N,14.90%.
实施例十九:2-((4-(丙基磺酰基)哌嗪-1-基)甲基)色烯并[4,3-c]吡唑-4(2H)-酮(化合物19)的制备
制备方法同实施例一。产物为白色粉末状固体。产率56%。Mp:208-210℃.1HNMR(400MHz,CDCl3):8.21(s,1H,ArH),8.05(m,1H,ArH),7.51(t,J=7.42Hz,1H,ArH),7.37(d,J=8.32Hz,1H,ArH),7.33(t,J=7.46Hz,1H,ArH),5.08(s,2H,-CH2),3.26(t,J=7.62Hz,2H,-CH2),2.77(t,J=4.34Hz,4H,-CH2CH2),2.54(d,J=4.08Hz,4H,-CH2CH2),2.12(m,2H,-CH2),1.01(t,J=7.48Hz,3H,CH3).MS(ESI):391.24(C18H23N4O4S,[M+H]+).Anal.CalcdforC18H22N4O4S:C,55.37;H,5.68;N,14.35%.Found:C,55.41;H,5.69;N,14.37%.
实施例二十:2-((4-(丁基磺酰基)哌嗪-1-基)甲基)色烯并[4,3-c]吡唑-4(2H)-酮(化合物20)的制备
制备方法同实施例一。产物为白色粉末状固体。产率51%。Mp:211-213℃.1HNMR(400MHz,CDCl3):8.20(s,1H,ArH),8.04(m,1H,ArH),7.49(t,J=7.54Hz,1H,ArH),7.38(d,J=8.40Hz,1H,ArH),7.32(t,J=7.34Hz,1H,ArH),5.09(s,2H,-CH2),3.29(t,J=7.16Hz,2H,-CH2),2.79(t,J=4.28Hz,4H,-CH2CH2),2.55(d,J=4.16Hz,4H,-CH2CH2),1.98(m,2H,-CH2),1.34(m,2H,-CH2),0.97(m,3H,CH3).MS(ESI):405.26(C19H25N4O4S,[M+H]+).Anal.CalcdforC19H24N4O4S:C,56.42;H,5.98;N,13.85%.Found:C,56.46;H,5.97;N,13.87%.
实施例二十一:2-((4-(环丙基磺酰基)哌嗪-1-基)甲基)色烯并[4,3-c]吡唑-4(2H)-酮(化合物21)的制备
制备方法同实施例一。产物为白色粉末状固体。产率54%。Mp:194-196℃.1HNMR(400MHz,CDCl3):8.20(s,1H,ArH),8.05(m,1H,ArH),7.51(t,J=7.48Hz,1H,ArH),7.37(d,J=8.36Hz,1H,ArH),7.34(t,J=7.72Hz,1H,ArH),5.11(s,2H,-CH2),3.34(m,2H,-CH2),2.81(t,J=4.12Hz,4H,-CH2CH2),2.57(d,J=4.08Hz,4H,-CH2CH2),1.94(m,4H,2-CH2).MS(ESI):389.31(C18H21N4O4S,[M+H]+).Anal.CalcdforC18H20N4O4S:C,55.66;H,5.19;N,14.42%.Found:C,55.64;H,5.21;N,14.44%.
实施例二十二2-((4-((2-氯乙基)磺酰基)哌嗪-1-基)甲基)色烯并[4,3-c]吡唑-4(2H)-酮(化合物22)的制备
制备方法同实施例一。产物为白色粉末状固体。产率49%。Mp:187-189℃.1HNMR(400MHz,CDCl3):8.19(s,1H,ArH),8.05(m,1H,ArH),7.50(t,J=7.56Hz,1H,ArH),7.38(d,J=8.24Hz,1H,ArH),7.32(t,J=7.86Hz,1H,ArH),5.10(s,2H,-CH2),3.47(t,J=7.86Hz,2H,-CH2),3.38(t,J=7.78Hz,4H,2-CH2),2.79(t,J=4.18Hz,4H,-CH2CH2),2.58(d,J=4.10Hz,4H,-CH2CH2).MS(ESI):411.81(C17H20ClN4O4S,[M+H]+).Anal.CalcdforC17H19ClN4O4S:C,49.69;H,4.66;N,13.64%.Found:C,49.68;H,4.65;N,13.65%.
实施例二十三:2-((4-((3-氯丙基)磺酰基)哌嗪-1-基)甲基)色烯并[4,3-c]吡唑-4(2H)-酮(化合物23)的制备
制备方法同实施例一。产物为白色粉末状固体。产率53%。Mp:189-192℃.1HNMR(400MHz,CDCl3):8.20(s,1H,ArH),8.04(m,1H,ArH),7.49(t,J=7.44Hz,1H,ArH),7.38(d,J=8.36Hz,1H,ArH),7.33(t,J=7.74Hz,1H,ArH),5.09(s,2H,-CH2),3.42(t,J=7.70Hz,2H,-CH2),3.36(t,J=7.46Hz,4H,2-CH2),2.78(t,J=4.34Hz,4H,-CH2CH2),2.55(d,J=4.24Hz,4H,-CH2CH2),2.11(m,2H,-CH2).MS(ESI):425.79(C18H22ClN4O4S,[M+H]+).Anal.CalcdforC18H21ClN4O4S:C,50.88;H,4.98;N,13.19%.Found:C,50.90;H,4.97;N,13.21%.
实施例二十四:含磺酰基哌嗪的香豆素并吡唑类化合物抗癌活性研究
1.实验材料和方法
1.1药品与试剂
采用MTT[3-(4,5)-双甲基-2-噻唑-(2,5)-苯基溴化四氮唑蓝]法来测定咖啡酸类衍生物对人乳腺癌细胞株(MCF-7),人体肺癌细胞株(A549)和小鼠黑色素瘤细胞(B16-F10)的半数抑制浓度(IC50)。
(1)培养液(每升)的配制:①悬浮细胞:RPMI-1640培养粉一袋(10.4g),新生牛血清100ml,青霉素溶液(20万U/ml)0.5ml,链霉素溶液(20万U/ml)0.5ml,加三蒸水溶解后,用5.6%的NaHCO3溶液调PH值至7.2-7.4,最后定容至1000ml。过滤灭菌。②贴壁细胞:同上,再加入NaHCO32.00g,HEPES2.38g。
(2)PBS缓冲液(每升)的配制:NaCl8.00g,KCl0.40g,Na2HPO4·12H2O0.06g,KH2PO40.06g,NaHCO30.35g。高压灭菌。
(3)胰蛋白酶液的配制:利用PBS缓冲液配成浓度为0.5%胰蛋白酶液。过滤除菌。
(4)实验药液的配制:将测试样品用少量的三蒸水溶解配成储备液,一般按实验最高浓度的10倍配制储备液。根据化合物溶解性不同,可用三蒸水直接溶解,或用少量DMSO助溶,再加三蒸水溶解。DMSO在培养液中的浓度不宜过大,加药后的每孔细胞悬液中DMSO的终浓度一般不超过0.05%-0.1%。储备液保存于-20℃冰箱中备用。
(5)人结肠癌细胞株HCT-116的培养:为贴壁生长细胞,常规培养于RPMI-1640培养液内(含10%小牛血清、100U/ml链霉素),置37℃、5%CO2培养箱中培养,每隔3-4天传代一次。传代时先弃去原培养液,再用PBS缓冲液洗涤;然后用0.5%胰蛋白酶消化30秒左右,加入少量新鲜培养液终止消化;吹打,使贴壁细胞从培养瓶壁上脱落下来;移取适量至新鲜培养瓶中,再补充新鲜培养液至原体积(培养液体积约为培养瓶容量的1/10)。
(6)人肺癌细胞A549的培养:为贴壁生长细胞,常规培养于RPMI-1640培养液内(含10%小牛血清、100U/ml链霉素),置37℃、5%CO2培养箱中培养,每隔3-4天传代一次。传代时先弃去原培养液,再用PBS缓冲液洗涤;然后用0.5%胰蛋白酶消化30秒左右,加入少量新鲜培养液终止消化;吹打,使贴壁细胞从培养瓶壁上脱落下来;移取适量至新鲜培养瓶中,再补充新鲜培养液至原体积(培养液体积约为培养瓶容量的1/10)。
(7)肝癌细胞Huh7的培养:为贴壁生长细胞,常规培养于RPMI-1640培养液内(含10%小牛血清、100U/ml链霉素),置37℃、5%CO2培养箱中培养,每隔3-4天传代一次。传代时先弃去原培养液,再用PBS缓冲液洗涤;然后用0.5%胰蛋白酶消化30秒左右,加入少量新鲜培养液终止消化;吹打,使贴壁细胞从培养瓶壁上脱落下来;移取适量至新鲜培养瓶中,再补充新鲜培养液至原体积(培养液体积约为培养瓶容量的1/10)。
(8)人脊髓白血病M3细胞株(HL60)的培养:为悬浮生长细胞,常规培养于RPMI-1640培养液内(含10%小牛血清、100U/ml链霉素),置37℃、5%CO2培养箱中培养,每隔3-4天传代一次。传代时先弃去原培养液,再用PBS缓冲液洗涤;然后用0.5%胰蛋白酶消化30秒左右,加入少量新鲜培养液终止消化;吹打,使贴壁细胞从培养瓶壁上脱落下来;移取适量至新鲜培养瓶中,再补充新鲜培养液至原体积(培养液体积约为培养瓶容量的1/10)。
(9)细胞孵育:取对数生长期的肿瘤细胞,调细胞悬液浓度为1-1.5×105个ml-1。在96孔培养板中每孔加细胞悬液100μl,置37℃,5%CO2培养箱中培养24h。培养24h后,分别按设计加入药液。
(10)加药:将测试药液按照最终浓度的浓度梯度分别加入到各个孔中,每个浓度设6个平行孔。实验分为药物试验组(分别加入不同浓度的测试药)、对照组(只加培养液和细胞,不加测试药)和空白组(只加培养液,不加细胞和测试药)。将加药后的96孔板置于37℃,5%CO2培养箱中培养48h。阳性对照药物的活性按照测试样品的方法测定。
(11)存活细胞的测定:在培养了48h后的96孔板中,每孔加MTT40μl(用PBS缓冲液配成4mg/ml)。在37℃放置4h后,移去上清液。每孔加150μlDMSO,振荡5min,使formazan结晶溶解。最后,利用自动酶标仪在570nm波长处检测各孔的光密度(OD值)。
抑制率的计算:细胞生长的抑制率按照下列公式计算:
生长抑制率=(1-存活率)×100%=[1-(OD实验-OD空白)/(OD对照-OD空 白)]×100%(OD实验表示测试药物组的平均光密度,OD对照表示对照组的平均光密度,OD空白表示对照组的平均光密度)。
半数抑制浓度(IC50)定义为当50%的肿瘤细胞存活时的药物浓度。根据测定的光密度(OD值),制作细胞生长抑制率的标准曲线,在标准曲线上求得其对应的药物浓度。
测得的IC50见表1所示。
2.实验结果
表1本发明所列含磺酰基哌嗪的香豆素并吡唑类化合物对癌细胞的抑制IC50值。
结果表明:含磺酰基哌嗪的香豆素并吡唑类化合物对人结肠癌细胞株(HCT-116),人体肺癌细胞株(A549),肝癌细胞(Huh7)和人脊髓白血病M3细胞株(HL60)都有不同程度的抑制作用。
Claims (3)
1.一类含磺酰基哌嗪的香豆素并吡唑类化合物,其特征是它具有以下通式:
其中R为:
2.一种权利要求1中所述的含磺酰基哌嗪的香豆素并吡唑类化合物的制法,其特征是它由以下步骤组成:
将4-羟基香豆素0.06mmol溶解在46.2ml的无水N,N-二甲基甲酰胺中,将此反应液冷却至0℃以下。在0℃以下条件下,边搅拌边缓慢滴加POCl30.18mmol,待POCl3加毕,将反应液缓慢升温至室温条件下搅拌0.5h后,然后升温至65-70℃搅拌反应6h。用TLC跟踪监测反应,当反应完毕后,将反应液倒入200g的冰水混合物中并剧烈搅拌,有大量浅黄色固体1析出。将固体抽滤,并用5%的Na2CO3水溶液洗涤,将所得固体干燥,即得到中间体。
将步骤一中所得固体1mmol溶解在10ml乙醇中,加完搅拌使其溶解充分,然后冷却至15-20℃,将配置好的溶液(85%的水合肼2mmol+三乙胺4mmol+60%乙醇10ml)在搅拌条件下,保持温度在15-20℃,缓慢滴加至反应液中。滴加毕,保持温度不超过25℃,搅拌反应12h。用TLC跟踪监测反应。将所得固体减压浓缩,所得固体用乙醇重结晶,即得到中间体2。
取无水哌嗪3mmol溶解在30ml无水二氯甲烷中冷却至0℃以下,然后加入三乙胺4ml,搅拌一段时间后,加入磺酰氯3mmol,在0℃以下搅拌反应2-4h,反应毕,有机层用水洗(30ml×3)后,用无水硫酸钠干燥,减压蒸干溶剂,所得固体3减压干燥后,直接用于下一步反应。
取上述所得固体3mmol,化合物21mmol加热溶解在20-25ml的无水乙醇中,待溶解充分后,冷却至室温下,向反应液中缓慢加入40%的甲醛溶液300μl,室温下搅拌反应4-6h,有大量固体析出。过滤,所得固体用冷的乙醇洗涤,然后将固体干燥,用乙醇重结晶,即得到含磺酰胺氮杂环的香豆素并吡唑衍生物。
3.权利要求1所述的含磺酰基哌嗪的香豆素并吡唑类化合物及其制备与在抑制肿瘤药物中的应用。
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