CN109134478B - 含连续三季碳的硫代吡咯酮拼接双螺环氧化吲哚化合物及其制备方法及应用 - Google Patents
含连续三季碳的硫代吡咯酮拼接双螺环氧化吲哚化合物及其制备方法及应用 Download PDFInfo
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Abstract
本发明公开了一种含连续三季碳的硫代吡咯酮拼接双螺环氧化吲哚化合物,本发明以各种取代的3‑NCS氧化吲哚与3‑丙二腈缩合的3‑烯氧化吲哚,按摩尔比为1:1的比例在二氯甲烷溶剂中,室温下进行3+2环加成反应,获得含连续三季碳的硫代吡咯酮拼接双螺环氧化吲哚化合物,可以为生物活性筛选提供化合物源,对药物的筛选和制药行业具有重要的应用价值。本发明操作简单易行,原料合成便宜易得,可以在各种有机溶剂中进行,也具有较好的空气稳定性,适用性广,对于各种取代基都有很好的兼容性。且该骨架化合物对人白血病细胞(K562)生长具有抑制活性。
Description
技术领域
本发明涉及化学技术领域,尤其是一种含连续三季碳的硫代吡咯酮拼接双螺环氧化吲哚化合物及其制备方法及应用。
背景技术
根据药物设计中药效团迁越原理,把具有生物活性基团拼接到具有活性分子骨架中,在有机化学和医药化学中是极其重要的研究领域。多官能团氧化吲哚广泛存在天然产物和合成药物分子中,其中,尤其3,3'-吡咯双螺环氧化吲哚因为具有广泛的生物活性,吸引了许多化学工作者及医药化学团队的广泛关注,例如,化合物I是具有抗细菌活性;化合物II具有抗真菌活性,化合物III具有抗肿瘤活性。根据药物设计中药效团迁越原理,鉴于3,3'-吡咯双螺环氧化吲哚骨架化合物具有潜在的生物活性。因此,在3,3'-吡咯双螺环氧化吲哚骨架上,增加药性官能团丙二腈以及吡咯环上增加官能团硫代酮,合成一系列新的潜在多活性官能团的氧化吲哚衍生物,可以为生物活性筛选提供化合物源,对药物的筛选和制药行业具有重要的应用价值(如附图10所示)。
发明内容
本发明的目的是:提供一种含连续三季碳的硫代吡咯酮拼接双螺环氧化吲哚化合物及其制备方法与应用,它是一类重要的医药中间体类似物和药物分子类似物,对药物筛选和制药行业具有重要的应用价值,且其合成方法非常经济简便。
本发明还发现该类化合物在制备防治肿瘤疾病药物中的应用。
本发明是这样实现的:含连续三季碳的硫代吡咯酮拼接双螺环氧化吲哚化合物,该化合物具有如下通式(I)的结构:
式中,R1为甲基、乙基或苄基;R2为甲基、H或卤素;R3为甲基、CH2CO2 tBu或CH2CO2Et;R4为甲基、H或卤素。
将各种取代的3-NCS氧化吲哚与3-丙二腈缩合的3-烯氧化吲哚,按摩尔比为1:1的比例在二氯甲烷溶剂中,室温下进行3+2环加成反应,获得含连续三季碳的硫代吡咯酮拼接双螺环氧化吲哚化合物。
合成路线如下:
反应机理如下:
其中各种取代的3-丙二腈缩合的3-烯氧化吲哚1以及3-NCS氧化吲哚2的结构式,其取代基满足R1为甲基、乙基或苄基;R2为甲基、H或卤素;R3为甲基、CH2CO2 tBu或CH2CO2Et;R4为甲基、H或卤素。
含连续三季碳的硫代吡咯酮拼接双螺环氧化吲哚化合物在制备防治肿瘤疾病药物中的应用。
通过采用上述技术方案,以各种取代的3-NCS氧化吲哚与3-丙二腈缩合的3-烯氧化吲哚,按摩尔比为1:1的比例在二氯甲烷溶剂中,室温下进行3+2环加成反应,获得含连续三季碳的硫代吡咯酮拼接双螺环氧化吲哚化合物,可以为生物活性筛选提供化合物源,对药物的筛选和制药行业具有重要的应用价值。且该化合物对人白血病细胞(K562)具有抑制活性的作用。本发明操作简单易行,原料合成便宜易得,可以在各种有机溶剂中进行,也具有较好的空气稳定性,适用性广,对于各种取代基都有很好的兼容性。此外,连续三季碳化合物的合成在有机化学合成领域是一个重要的挑战。
附图说明
附图1为本发明的实施例的化合物3aa单晶图;
附图2为本发明的实施例的化合物3bb单晶图;
附图3为本发明的实施例的化合物3cc单晶图;
附图4为本发明的实施例的化合物3db单晶图;
附图5为本发明的实施例的化合物3eb单晶图;
附图6为本发明的实施例的化合物3ga单晶图;
附图7为本发明的实施例的化合物3gb单晶图;
附图8为本发明的实施例的化合物3ib单晶图;
附图9为本发明的实施例的化合物3jc单晶图;
附图10为本发明的设计思路。
具体实施方式
本发明的实施例:在反应管中依次加入154.5mg 3-丙二腈缩合的3-烯氧化吲哚1a(0.5mmol),102.0mg 3-NCS氧化吲哚2a(0.5mmol)和5mL二氯甲烷,室温反应20min,TLC检测基本反应完全,过滤,二氯甲烷洗涤,纯化得化合物3aa,白色固体,熔点:112.2-113.6℃,>20:1dr;产率:236.0mg(92%)。核磁共振和高分辨质谱测试等结果如下:1H NMR(CD3COCD3,500MHz)δ:1.37(s,9H),3.10(s,3H),4.33(d,J=17.5Hz,1H),4.50(d,J=17.5Hz,1H),6.88(d,J=8.0Hz,1H),7.00(d,J=8.0Hz,1H),7.08-7.11(m,1H),7.24-7.27(m,1H),7.37-7.40(m,1H),7.45-7.49(m,2H),7.84(d,J=7.5Hz,1H),10.77(br s,1H).13C NMR(CD3COCD3,100MHz)δ:25.9,27.1,41.8,54.7,61.9,73.3,82.3,109.4,110.4,111.5,112.2,117.0,119.4,123.7,123.8,126.2,126.8,132.0,132.2,144.0,144.6,165.1,170.5,172.2,189.2.HRMS(ESI-TOF)m/z:Calcd.for C27H23N5NaO4S[M+Na]+:536.1363;Found:536.1364.
化合物3ab至3ka的制备方法同化合物3aa,投料比与化合物3aa相同,可得到化合物3ab至3ka,反应产率和非对映选择性见表1-3,但需强调的是本发明的化合物不限于表1-3所表示的内容。
表1为一种含连续三季碳的硫代吡咯酮拼接双螺环氧化吲哚化合物的化学结构
表2为一种含连续三季碳的硫代吡咯酮拼接双螺环氧化吲哚化合物的化学结构
表3为一种含连续三季碳的硫代吡咯酮拼接双螺环氧化吲哚化合物的化学结构
本实施例制备化合物3ab:白色固体;熔点:160.3-161.7℃;产率:234.6mg(89%),>20:1dr;核磁共振和高分辨质谱测试等结果如下:1H NMR(DMSO-d6,500MHz)δ:0.99-1.01(m,3H),1.34(s,9H),3.53-3.60(m,1H),3.72-3.78(m,1H),4.41-4.51(m,2H),7.02(d,J=7.5Hz,1H),7.06-7.12(m,2H),7.26-7.29(m,1H),7.36(d,J=7.5Hz,1H),7.39-7.42(m,1H),7.48-7.51(m,1H),7.73(d,J=7.5Hz,1H),12.34(br s,1H).13C NMR(DMSO-d6,125MHz)δ:12.6,27.8,35.3,42.2,55.2,61.6,73.6,82.6,110.3,111.2,111.9,112.5,116.7,119.6,124.1,124.3,126.4,127.1,132.4,132.8,143.6,144.0,165.7,170.7,171.9,188.2.HRMS(ESI-TOF)m/z:Calcd.forC28H25N5NaO4S[M+Na]+:550.1519;Found:550.1515.
本实施例制备化合物3ba:白色固体;熔点:132.1-134.0℃;产率:225.6mg(93%),>20:1dr;核磁共振和高分辨质谱测试等结果如下:1H NMR(CD3COCD3,500MHz)δ:1.11-1.14(m,3H),3.10(s,3H),4.04-4.13(m,2H),4.46(d,J=17.5Hz,1H),4.56(d,J=17.5Hz,1H),6.89(d,J=8.0Hz,1H),7.01(d,J=8.0Hz,1H),7.08-7.11(m,1H),7.25-7.28(m,1H),7.38-7.41(m,1H),7.45-7.49(m,2H),7.84(d,J=8.0Hz,1H),10.77(br s,1H).13C NMR(CD3COCD3,125MHz)δ:13.4,25.9,41.2,54.7,61.4,62.0,73.3,109.4,110.3,111.5,112.1,117.1,119.4,123.7,123.9,126.3,126.8,132.1,132.2,143.9,144.6,166.1,170.6,172.3,189.2.HRMS(ESI-TOF)m/z:Calcd.for C25H19N5NaO4S[M+Na]+:508.1050;Found:508.1054.
本实施例制备化合物3bb:白色固体;熔点:155.4-156.9℃;产率:219.6mg(88%);核磁共振和高分辨质谱测试等结果如下:1H NMR(DMSO-d6,500MHz)δ:0.95-0.98(m,3H),1.07-1.10(m,3H),3.50-3.57(m,1H),3.68-3.76(m,1H),3.99-4.07(m,2H),4.50-4.58(m,2H),6.98(d,J=8.0Hz,1H),7.03-7.09(m,2H),7.23-7.27(m,1H),7.33(d,J=8.0Hz,1H),7.35-7.39(m,1H),7.44-7.47(m,1H),7.70(d,J=8.0Hz,1H),12.31(br s,1H).13C NMR(DMSO-d6,125MHz)δ:12.2,13.8,34.9,41.2,54.7,61.2,61.3,73.1,109.9,110.7,111.4,112.0,116.3,119.1,123.7,124.0,126.0,126.6,132.1,132.3,143.1,143.3,166.3,170.2,171.4,187.7.HRMS(ESI-TOF)m/z:Calcd.for C26H21N5NaO4S[M+Na]+:522.1206;Found:522.1208.
本实施例制备化合物3ca:白色固体;熔点:163.7-164.9℃;产率:250.4mg(95%),>20:1dr;核磁共振和高分辨质谱测试等结果如下:1H NMR(CD3COCD3,500MHz)δ:1.37(s,9H),2.36(s,3H),3.11(s,3H),4.28(d,J=17.5Hz,1H),4.46(d,J=17.5Hz,1H),6.87(d,J=8.0Hz,2H),7.07-7.10(m,1H),7.28(d,J=8.0Hz,1H),7.37-7.40(m,1H),7.46(d,J=8.0Hz,1H),7.67(s,1H),10.74(br s,1H).13C NMR(CD3COCD3,125MHz)δ:20.4,25.9,27.2,41.9,54.6,62.1,73.4,82.2,109.4,110.1,111.6,112.3,117.1,119.5,123.7,126.7,126.8,132.2,132.3,133.5,141.7,144.6,165.2,170.5,172.3,189.3.HRMS(ESI-TOF)m/z:Calcd.for C28H25N5NaO4S[M+Na]+:550.1519;Found:550.1524.
本实施例制备化合物3cb:白色固体;熔点:178.3-179.7℃;产率:246.2mg(91%),>20:1dr;核磁共振和高分辨质谱测试等结果如下:1H NMR(DMSO-d6,500MHz)δ:0.95-0.97(m,3H),1.30(s,9H),2.29(s,3H),3.50-3.54(m,1H),3.73-3.77(m,1H),4.33-4.44(m,2H),6.92(d,J=8.5Hz,1H),6.99(d,J=8.0Hz,1H),7.04-7.07(m,1H),7.27(d,J=8.0Hz,1H),7.32(d,J=7.5Hz,1H),7.35-7.38(m,1H),7.49(s,1H),12.27(br s,1H).13C NMR(DMSO-d6,125MHz)δ:12.1,20.8,27.4,35.8,41.8,54.6,60.8,72.9,82.1,109.8,110.6,111.5,112.0,116.3,119.2,123.7,126.3,126.6,132.2,132.3,132.8,141.2,143.1,162.3,165.3,170.1,171.5,187.8.HRMS(ESI-TOF)m/z:Calcd.for C29H27N5NaO4S[M+Na]+:564.1676;Found:564.1681.
本实施例制备化合物3cc:白色固体;熔点:168.3-169.9℃;产率:257.1mg(95%),>20:1dr;核磁共振和高分辨质谱测试等结果如下:1H NMR(CD3COCD3,500MHz)δ:1.39(s,9H),2.28(s,3H),2.35(s,3H),3.09(s,3H),4.35(d,J=17.5Hz,1H),4.45(d,J=17.5Hz,1H),6.76(d,J=8.0Hz,1H),6.87(d,J=8.0Hz,1H),7.18(d,J=7.5Hz,1H),7.28(s,2H),7.66(s,1H),10.69(br s,1H).13C NMR(CD3COCD3,125MHz)δ:19.8,25.4,26.6,41.4,54.2,61.6,72.8,81.7,108.6,109.5,111.0,111.8,116.6,118.9,126.2,127.1,131.7,131.8,132.9,133.0,141.1,141.6,164.7,170.0,171.6,188.7.HRMS(ESI-TOF)m/z:Calcd.forC29H27N5NaO4S[M+Na]+:564.1676;Found:564.1671.
本实施例制备化合物3da:白色固体;熔点:168.7-170.2℃;产率:239.0mg(90%),>20:1dr;核磁共振和高分辨质谱测试等结果如下:1H NMR(CD3COCD3,500MHz)δ:1.41(s,9H),3.19(s,3H),4.42(d,J=17.5Hz,1H),4.56(d,J=17.5Hz,1H),6.98(d,J=8.0Hz,1H),7.11-7.13(m,1H),7.16(d,J=7.5Hz,1H),7.33-7.37(m,1H),7.45-7.48(m,1H),7.51(d,J=8.0Hz,1H),7.64-7.67(m,1H),10.83(br s,1H).13C NMR(CD3COCD3,125MHz)δ:26.0,27.1,41.9,54.5,61.4,73.2,82.4,109.6,111.4,111.8,111.9(d,JCF=23.8Hz),113.9(d,JCF=27.5Hz),118.5,118.6,118.7,119.2,123.9,126.9,132.4,140.4,144.6,159.2(d,JCF=238.8Hz),165.0,170.3,172.1,188.7.HRMS(ESI-TOF)m/z:Calcd.for C27H22FN5NaO4S[M+Na]+:554.1269;Found:554.1264.
本实施例制备化合物3bd:白色固体;熔点:158.9-160.3℃;产率:253.5mg(93%),>20:1dr;核磁共振和高分辨质谱测试等结果如下:1H NMR(DMSO-d6,500MHz)δ:1.09-1.12(m,3H),3.05(s,3H),3.98-4.09(m,2H),4.58-4.66(m,2H),6.98-7.01(m,1H),7.04-7.07(m,2H),7.24-7.30(m,2H),7.46-7.50(m,1H),7.64-7.66(m,1H),12.38(br s,1H).13C NMR(DMSO-d6,125MHz)δ:14.3,27.1,41.7,55.3,61.8,73.5,105.4,111.5,111.6,112.4,115.0(d,JCF=238.8Hz),116.6,119.1(d,JCF=23.8Hz),120.9,121.0,124.6,126.1,132.8,140.7,143.7,159.2(d,JCF=27.5Hz),166.8,170.5,172.2,188.0.HRMS(ESI-TOF)m/z:Calcd.for C25H18FN5NaO4S[M+Na]+:526.0956;Found:526.0958.
本实施例制备化合物3dc:白色固体;熔点:135.1-136.9℃;产率:242.6mg(89%),>20:1dr;核磁共振和高分辨质谱测试等结果如下:1H NMR(DMSO-d6,500MHz)δ:1.32(s,9H),2.23(s,3H),3.05(s,3H),4.42-4.51(m,2H),6.86(d,J=8.0Hz,1H),7.09-7.13(m,2H),7.20(d,J=8.0Hz,1H),7.38-7.43(m,2H),12.35(br s,1H).13C NMR(DMSO-d6,125MHz)δ:20.6,26.5,27.4,27.5,41.9,54.8,61.1,73.4,82.3,109.8,111.3,111.9,112.3,113.1(d,JCF=26.3Hz),117.9,118.0,118.8,118.9(d,JCF=23.8Hz),127.1,132.5,133.3,140.0,141.5,158.5(d,JCF=238.8Hz),165.2,170.0,171.6,187.3.HRMS(ESI-TOF)m/z:Calcd.forC28H24FN5NaO4S[M+Na]+:568.1425;Found:568.1429.
本实施例制备化合物3dd:白色固体;熔点:182.3-184.1℃;产率:241.6mg(88%),>20:1dr;核磁共振和高分辨质谱测试等结果如下:1H NMR(DMSO-d6,500MHz)δ:1.33(s,9H),3.09(s,3H),4.48-4.56(m,2H),7.02-7.07(m,2H),7.13-7.15(m,1H),7.28-7.32(m,1H),7.38-7.45(m,2H),12.42(br s,1H).13C NMR(DMSO-d6,125MHz)δ:26.8,27.4,27.5,41.9,54.9,61.0,73.1,82.4,111.1,111.4,111.8,112.5,112.6,113.2(d,JCF=26.3Hz),114.8(d,JCF=26.3Hz),117.6,117.7,118.9(d,JCF=23.8Hz),119.2(d,JCF=22.5Hz),120.3,120.4,139.9,140.2,158.6(d,JCF=240.1Hz),158.9(d,JCF=238.8Hz),165.1,169.9,171.7,187.2.HRMS(ESI-TOF)m/z:Calcd.for C27H21F2N5NaO4S[M+Na]+:572.1175;Found:572.1176.
本实施例制备化合物3ea:白色固体;熔点:133.5-135.1℃;产率:259.8mg(95%),>20:1dr;核磁共振和高分辨质谱测试等结果如下:1H NMR(DMSO-d6,500MHz)δ:1.30(s,9H),3.07(s,3H),4.40-4.49(m,2H),6.97(d,J=8.0Hz,1H),7.07-7.12(m,2H),7.30(d,J=7.5Hz,1H),7.38-7.41(m,1H),7.58-7.61(m,2H),12.40(br s,1H).13C NMR(DMSO-d6,125MHz)δ:26.5,27.4,41.9,54.5,60.9,73.5,82.4,110.1,111.3,111.8,112.6,118.2,118.7,124.1,125.3,126.4,127.9,132.2,132.5,142.6,143.8,165.1,169.8,171.8,187.3.HRMS(ESI-TOF)m/z:Calcd.for C27H22ClN5NaO4S[M+Na]+:570.0973;Found:570.0977.
本实施例制备化合物3eb:白色固体;熔点:159.3-161.1℃;产率:238.4mg(85%),>20:1dr;核磁共振和高分辨质谱测试等结果如下:1H NMR(DMSO-d6,500MHz)δ:0.98-1.01(m,3H),1.30(s,9H),3.49-3.53(m,1H),3.79-3.83(m,1H),4.41-4.50(m,2H),7.02-713(m,3H),7.31(d,J=7.5Hz,1H),7.32-7.41(m,1H),7.60-7.64(m,2H),12.37(br s,1H).13C NMR(DMSO-d6,125MHz)δ:12.2,27.5,34.9,41.9,54.5,60.7,73.1,82.4,110.1,111.3,111.8,112.7,118.1,118.9,124.0,125.8,126.6,127.8,132.1,132.5,142.6,143.0,165.1,169.8,171.4,187.3.HRMS(ESI-TOF)m/z:Calcd.for C28H24ClN5NaO4S[M+Na]+:584.1130;Found:584.1135.
本实施例制备化合物3ec:白色固体;熔点:163.1-164.3℃;产率:263.7mg(94%),>20:1dr;核磁共振和高分辨质谱测试等结果如下:1H NMR(DMSO-d6,500MHz)δ:1.09(s,9H),1.99(s,3H),2.81(s,3H),4.18-4.28(m,2H),6.62(d,J=8.0Hz,1H),6.86(d,J=8.8Hz,2H),6.95(d,J=7.6Hz,1H),7.35(d,J=8.4Hz,2H),12.13(br s,1H).13C NMR(DMSO-d6,125MHz)δ:21.1,26.9,27.9,42.3,55.1,61.4,73.9,82.8,110.2,111.6,112.3,112.9,118.7,119.2,125.8,127.5,128.3,132.5,132.9,133.7,141.8,142.9,165.5,170.2,172.1,187.6.HRMS(ESI-TOF)m/z:Calcd.for C28H24ClN5NaO4S[M+Na]+:584.1130;Found:584.1135.
本实施例制备化合物3ed:白色固体;熔点:137.8-138.4℃;产率:262.8mg(93%),>20:1dr;核磁共振和高分辨质谱测试等结果如下:1H NMR(DMSO-d6,500MHz)δ:1.33(s,9H),3.09(s,3H),4.49-4.56(m,2H),7.02-7.05(m,2H),7.13(d,J=8.0Hz,1H),7.28-7.32(m,1H),7.61-7.63(m,2H),12.45(br s,1H).13C NMR(DMSO-d6,125MHz)δ:27.1,27.8,27.9,42.3,55.2,61.3,73.6,82.9,111.5,111.8,111.9,112.2,113.2,115.1(d,JCF=27.5Hz),118.4,119.3(d,JCF=23.8Hz),120.7,120.8,125.9,128.5,132.8,140.5,142.9,159.3(d,JCF=240.3Hz),165.5,170.1,172.2,187.6.HRMS(ESI-TOF)m/z:Calcd.forC27H21ClFN5NaO4S[M+Na]+:588.0879;Found:588.0874.
本实施例制备化合物3fa:白色固体;熔点:168.9-170.0℃;产率:232.0mg(93%),>20:1dr;核磁共振和高分辨质谱测试等结果如下:1H NMR(CD3COCD3,500MHz)δ:1.15-1.18(m,3H),2.40(s,3H),3.16(s,3H),4.08-4.16(m,2H),4.45(d,J=17.5Hz,1H),4.57(d,J=17.5Hz,1H),6.92(d,J=7.5Hz,2H),7.12-7.15(m,1H),7.31(d,J=8.5Hz,1H),7.41-7.44(m,1H),7.48(d,J=8.0Hz,1H),7.71(s,1H),10.80(br s,1H).13C NMR(CD3COCD3,125MHz)δ:13.4,20.3,25.9,41.2,54.7,61.3,61.9,73.3,109.4,110.0,111.5,112.2,117.1,119.4,123.7,126.7,126.8,132.2,132.3,133.6,141.5,144.6,166.1,170.5,172.3,189.3.HRMS(ESI-TOF)m/z:Calcd.forC26H21N5NaO4S[M+Na]+:522.1206;Found:522.1211.
本实施例制备化合物3fb:白色固体;熔点:151.1-153.2℃;产率:225.7mg(88%),>20:1dr;核磁共振和高分辨质谱测试等结果如下:1H NMR(DMSO-d6,500MHz)δ:0.95-0.98(m,3H),1.07-1.09(m,3H),2.29(s,3H),3.49-3.56(m,1H),3.72-3.79(m,1H),3.97-4.08(m,2H),4.46-4.54(m,2H),6.92(d,J=8.5Hz,1H),6.98(d,J=8.0Hz,1H),7.05-7.08(m,1H),7.26(d,J=8.5Hz,1H),7.32(d,J=7.5Hz,1H),7.35-7.38(m,2H),7.49(s,1H),12.28(br s,1H).13CNMR(DMSO-d6,125MHz)δ:12.1,13.8,20.8,34.8,41.2,45.7,54.9,61.3,73.3,109.8,110.4,111.5,112.1,116.4,119.4,123.6,126.4,126.6,132.2,132.3,132.9,141.0,143.1,166.3,170.2,171.6,187.5.HRMS(ESI-TOF)m/z:Calcd.for C27H23N5NaO4S[M+Na]+:536.1363;Found:536.1361.
本实施例制备化合物3fc:白色固体;熔点:170.3-171.9℃;产率:230.9mg(90%),>20:1dr;核磁共振和高分辨质谱测试等结果如下:1H NMR(DMSO-d6,500MHz)δ:1.09-1.12(m,3H),2.22(s,3H),2.30(s,3H),3.03(s,3H),3.97-4.10(m,2H),4.49-4.57(m,2H),6.82(d,8.0Hz,1H),6.93(d,J=8.5Hz,1H),7.11(s,1H),7.17(d,J=8.0Hz,1H),7.26(d,J=8.0Hz,1H),7.45(s,1H),12.28(br s,1H).13C NMR(DMSO-d6,125MHz)δ:13.9,20.6,20.8,26.4,41.2,54.7,61.3,73.4,109.5,110.4,111.4,112.1,116.5,119.0,127.0,132.2,133.1,133.2,141.0,141.5,166.3,170.1,171.8,187.7.HRMS(ESI-TOF)m/z:Calcd.forC27H23N5NaO4S[M+Na]+:536.1363;Found:536.1366.
本实施例制备化合物3fd:白色固体;熔点:153.1-154.8℃;产率:232.6mg(90%),>20:1dr;核磁共振和高分辨质谱测试等结果如下:1H NMR(DMSO-d6,500MHz)δ:1.09-1.12(m,3H),2.31(s,3H),3.06(s,3H),3.98-4.08(m,2H),4.53-4.62(m,2H),6.95(d,J=8.0Hz,1H),6.98-7.01(m,1H),7.03-7.06(m,1H),7.25-7.30(m,2H),7.45(s,1H),12.36(br s,1H).13C NMR(DMSO-d6,125MHz)δ:14.3,21.2,27.1,41.7,55.3,61.8,73.5,111.0,111.6,111.7,112.4,115.0(d,JCF=26.3Hz),116.7,119.0(d,JCF=23.8Hz),126.4,133.0,133.9,140.6,141.3,159.1(d,JCF=240.5Hz),166.8,170.4,172.3,188.0.HRMS(ESI-TOF)m/z:Calcd.for C26H20FN5NaO4S[M+Na]+:540.1112;Found:540.1112.
本实施例制备化合物3ga:白色固体;熔点:163.3-165.1℃;产率:218.8mg(87%),>20:1dr;核磁共振和高分辨质谱测试等结果如下:1H NMR(DMSO-d6,500MHz)δ:1.06-1.09(m,3H),3.08(s,3H),3.98-4.06(m,2H),4.53-4.60(m,2H),6.98(d,J=8.0Hz,1H),7.08-7.15(m,2H),7.32(d,J=8.0Hz,1H),7.39-7.42(m,3H),12.40(br s,1H).13C NMR(DMSO-d6,125MHz)δ:13.8,26.5,41.4,54.6,60.8,61.4,73.4,110.1,111.2,111.8,112.3,113.2(d,JCF=27.5Hz),117.9,118.7,119.1(d,JCF=22.5Hz),124.0,126.5,132.4,139.8,143.9,158.5(d,JCF=240.0Hz),166.2,170.0,171.7,187.3.HRMS(ESI-TOF)m/z:Calcd.forC25H18FN5NaO4S[M+Na]+:526.0956;Found:526.0958.
本实施例制备化合物3gb:白色固体;熔点:163.4-164.8℃;产率:245.6mg(95%),>20:1dr;核磁共振和高分辨质谱测试等结果如下:1H NMR(DMSO-d6,500MHz)δ:0.96-0.99(m,3H),1.06-1.09(m,3H),3.51-3.58(m,1H),3.75-3.82(m,1H),3.97-4.07(m,2H),4.53-4.60(m,2H),7.02(d,J=8.0Hz,1H),7.07-7.15(m,2H),7.32(d,J=8.0Hz,1H),7.38-7.45(m,3H),12.32(br s,1H).13C NMR(DMSO-d6,125MHz)δ:12.2,13.8,34.9,41.3,54.6,60.9,61.4,73.2,110.0,111.3,111.7,112.3,113.6(d,JCF=27.5Hz),117.7,118.9,119.0,123.9,126.7,132.5,139.8,143.0,158.5(d,JCF=238.8Hz),166.2,170.0,171.4,187.3.HRMS(ESI-TOF)m/z:Calcd.for C26H20FN5NaO4S[M+Na]+:540.1112;Found:540.1115.
本实施例制备化合物3gc:白色固体;熔点:150.3-151.8℃;产率:245.5mg(95%),>20:1dr;核磁共振和高分辨质谱测试等结果如下:1H NMR(DMSO-d6,500MHz)δ:1.10(s,3H),2.23(s,3H),3.06(s,3H),3.98-4.09(m,2H),4.55-4.63(m,2H),6.86(d,J=8.0Hz,1H),7.12(s,1H),7.13-7.15(m,1H),7.38-7.41(m,2H).13C NMR(DMSO-d6,125MHz)δ:13.9,20.6,26.5,41.3,54.7,61.0,61.4,73.4,109.8,111.2,111.9,112.3,113.1,113.3,117.9,118.0,118.7,118.9,119.1,127.1,132.5,133.3,139.8,141.5,157.5,159.4,166.2,170.0,171.6,187.3.HRMS(ESI-TOF)m/z:Calcd.for C26H20FN5NaO4S[M+Na]+:540.1112;Found:540.1112.
本实施例制备化合物3gd:白色固体;熔点:170.3-171.1℃;产率:226.6mg(87%),>20:1dr;核磁共振和高分辨质谱测试等结果如下:1H NMR(DMSO-d6,500MHz)δ:1.09-1.12(m,3H),3.09(s,3H),3.96-4.01(m,1H),4.04-4.10(m,1H),4.59-4.67(m,2H),7.01-7.07(m,2H),7.14-7.16(m,1H),7.29-7.33(m,1H),7.38-7.45(m,2H),12.44(br s,1H).13C NMR(DMSO-d6,125MHz)δ:14.3,27.2,41.8,55.3,61.5,61.9,73.6,111.5,111.8,112.2,112.9,113.0,113.7(d,JCF=26.3Hz),115.1(d,JCF=26.3Hz),118.1,119.3(d,JCF=22.5Hz),119.7(d,JCF=23.8Hz),120.7,120.8,140.2,140.6,159.0(d,JCF=240.0Hz),159.2(d,JCF=238.8Hz),166.7,170.3,172.1,187.6.HRMS(ESI-TOF)m/z:Calcd.for C25H17F2N5NaO4S[M+Na]+:544.0862;Found:544.0867.
本实施例制备化合物3ha:白色固体;熔点:161.1-162.5℃;产率:230.8mg(89%),>20:1dr;核磁共振和高分辨质谱测试等结果如下:1H NMR(DMSO-d6,500MHz)δ:1.07-1.09(m,3H),3.07(s,3H),3.98-4.06(m,2H),4.53-4.60(m,2H),6.98(d,J=8.0Hz,1H),7.08-7.13(m,2H),7.29(d,J=7.5Hz,1H),7.39-7.42(m,1H),7.58-7.61(m,2H),12.41(br s,1H).13C NMR(DMSO-d6,125MHz)δ:13.9,26.5,41.4,54.5,60.9,61.4,73.5,110.1,111.2,111.7,112.5,118.3,118.7,124.1,125.4,126.4,128.0,132.3,132.5,142.4,143.8,166.1,169.8,171.8,187.3.HRMS(ESI-TOF)m/z:Calcd.for C25H18ClN5NaO4S[M+Na]+:542.0660;Found:542.0665.
本实施例制备化合物3ib:白色固体;熔点:165.3-167.0℃;产率:245.1mg(92%),>20:1dr;核磁共振和高分辨质谱测试等结果如下:1H NMR(DMSO-d6,500MHz)δ:0.98-1.10(m,3H),1.06-1.09(m,3H),3.44-3.55(m,1H),3.78-3.85(m,1H),3.98-4.07(m,2H),4.58(s,2H),7.03(d,J=8.0Hz,1H),7.07-7.11(m,1H),7.13(d,J=8.5Hz,1H),7.31(d,J=7.5Hz,1H),7.39-7.42(m,1H),7.60(d,J=8.5Hz,1H),7.64(s,1H),12.39(br s,1H).13CNMR(DMSO-d6,125MHz)δ:12.2,13.8,35.0,41.3,54.5,60.7,61.4,73.1,110.1,111.3,111.7,112.7,118.1,118.8,124.0,125.9,126.6,127.9,132.2,132.6,142.4,143.0,166.1,169.8,171.4,187.3.HRMS(ESI-TOF)m/z:Calcd.for C26H20ClN5NaO4S[M+Na]+:556.0817;Found:556.0817.
本实施例制备化合物3ie:白色固体;熔点:132.0-133.8℃;产率:267.6mg(90%),>20:1dr;核磁共振和高分辨质谱测试等结果如下:1H NMR(DMSO-d6,500MHz)δ:1.04-1.07(m,3H),3.96-4.06(m,2H),4.61(s,2H),4.75(d,J=16.0Hz,1H),5.03(d,J=16.0Hz,1H),6.79(d,J=8.0Hz,1H),7.01-7.03(m,2H),7.06-7.09(m,1H),7.17(d,J=8.0Hz,1H),7.24-7.26(m,3H),7.30-7.36(m,2H),7.64(d,J=8.0Hz,1H),7.68-7.69(m,1H),12.48(br s,1H).13C NMR(DMSO-d6,125MHz)δ:8.7,13.8,41.4,43.3,45.8,61.4,110.8,112.6,126.1,126.8,127.7,128.3,128.7,134.5,142.5,143.3,166.2,170.0,172.0.HRMS(ESI-TOF)m/z:Calcd.forC31H22ClN5NaO4S[M+Na]+:618.0973;Found:618.0977.
本实施例制备化合物3ic:白色固体;熔点:191.3-192.5℃;产率:247.8mg(93%),>20:1dr;核磁共振和高分辨质谱测试等结果如下:1H NMR(DMSO-d6,500MHz)δ:1.09-1.12(m,3H),2.23(s,3H),3.05(s,3H),3.98-4.08(m,2H),4.56-4.64(m,2H),6.86(d,J=8.0Hz,1H),7.10(s,1H),7.13(d,J=8.5Hz,1H),7.19-7.21(m,1H),7.58-7.61(m,2H),12.37(brs,1H).13C NMR(DMSO-d6,125MHz)δ:13.9,20.6,26.5,41.3,54.6,60.9,61.4,73.4,109.8,111.2,111.8,112.6,118.3,118.6,125.4,127.0,128.0,132.5,133.4,141.4,142.4,166.1,169.8,171.6,187.3.HRMS(ESI-TOF)m/z:Calcd.for C26H20ClN5NaO4S[M+Na]+:556.0817;Found:556.0819.
本实施例制备化合物3bc:白色固体;熔点:151.7-153.2℃;产率:217.1mg(87%),>20:1dr;核磁共振和高分辨质谱测试等结果如下:1H NMR(DMSO-d6,500MHz)δ:1.09-1.12(m,3H),2.23(s,3H),3.01(s,3H),3.99-4.09(m,2H),4.52-4.61(m,2H),6.81(d,J=8.0Hz,1H),7.05(d,J=8.0Hz,1H),7.11(s,1H),7.18(d,J=8.0Hz,1H),7.22-7.25(m,1H),7.44-7.47(m,1H),7.65(d,J=7.5Hz,1H),12.30(br s,1H).13C NMR(DMSO-d6,125MHz)δ:13.9,20.6,26.5,41.2,54.8,61.3,73.3,109.5,110.7,111.4,112.1,116.5,119.0,124.0,125.6,127.0,132.1,132.3,133.1,141.6,143.3,166.3,170.3,171.7,187.6.HRMS(ESI-TOF)m/z:Calcd.forC26H21N5NaO4S[M+Na]+:522.1206;Found:522.1207.
本实施例制备化合物3db:白色固体;熔点:167.3-169.5℃;产率:221.4mg(88%),>20:1dr;核磁共振和高分辨质谱测试等结果如下:1H NMR(DMSO-d6,500MHz)δ:0.99-1.02(m,3H),1.34(s,9H),3.54-3.61(m,1H),3.78-3.85(m,1H),4.44-4.53(m,2H),7.06(d,J=8.0Hz,1H),7.10-7.17(m,2H),7.36(d,J=7.5Hz,1H),7.42-7.48(m,2H),12.42(br s,1H).13C NMR(DMSO-d6,125MHz)δ:12.2,27.4,34.9,41.9,54.4,60.7,73.1,82.3,110.1,111.3,111.8,112.5,113.5(d,JCF=27.5Hz),117.7,119.0,123.9,126.7,132.5,140.0,143.0,158.4(d,JCF=238.8Hz),165.2,170.0,171.4,187.3.HRMS(ESI-TOF)m/z:Calcd.forC28H24FN5NaO4S[M+Na]+:568.1425;Found:568.1429.
本实施例制备化合物3jc:白色固体;熔点:163.3-165.1℃;产率:230.2mg(95%),>20:1dr;核磁共振和高分辨质谱测试等结果如下:1H NMR(DMSO-d6,500MHz)δ:2.23(s,3H),3.02(s,3H),3.56(s,3H),4.59(s,2H),6.82(d,J=8.0Hz,1H),7.05(d,J=8.0Hz,1H),7.11(s,1H),7.16-7.19(m,1H),7.23-7.26(m,1H),7.44-7.47(m,1H),7.65(d,J=8.0Hz,1H),10.77(br s,1H).13C NMR(DMSO-d6,125MHz)δ:20.6,26.5,41.1,52.3,54.8,61.3,73.4,109.6,110.7,111.4,112.1,116.4,118.9,124.0,125.6,127.1,132.2,132.3,133.1,141.6,143.3,166.9,170.2,171.7,187.7.HRMS(ESI-TOF)m/z:Calcd.for C25H19N5NaO4S[M+Na]+:508.1050;Found:508.1054.
本实施例制备化合物3ka:白色固体;熔点:138.1-139.5℃;产率:183.8mg(89%),>20:1dr;核磁共振和高分辨质谱测试等结果如下:1H NMR(DMSO-d6,400MHz)δ:3.00(s,3H),3.03(s,3H),6.89-6.91(m,1H),7.02(d,J=8.0Hz,1H),7.06-7.10(m,1H),7.18-7.22(m,1H),7.33-7.37(m,2H),7.42-7.46(m,1H),7.60(d,J=7.6Hz,1H),12.31(br s,1H).13C NMR(DMSO-d6,100MHz)δ:26.9,27.0,55.1,62.1,73.9,110.4,110.8,111.9,113.0,117.1,119.6,124.1,124.4,125.9,126.6,132.8,132.9,144.5,144.6,170.5,172.4,188.4.HRMS(ESI-TOF)m/z:Calcd.forC22H15N5NaO2S[M+Na]+:436.0839;Found:436.0845.
本发明的式(1)化合物具有重要的生物活性,体外对人白血病细胞(K562)的细胞毒性试验表明:此类式(1)所示的结构含连续三季碳的硫代吡咯酮拼接双螺环氧化吲哚化合物对肿瘤细胞生长具有抑制作用,有可能发展成为新的防治肿瘤药物。但需强调的是本发明的化合物不限于人白血病细胞(K562)表示的细胞毒性。
药理实施例:化合物3dc,3gd,3ha,3ec和3ka对K562细胞的细胞毒性
K562(人慢性髓系白血病细胞)用RPMI-1640培养基培养,培养基中含10%的胎牛血清,100U/mL的青霉素和100U/mL链霉素。细胞以每孔5000个细胞的浓度加入到96孔中,在37℃含5%CO2潮湿空气的培养箱中培养24小时。
细胞存活率的测定用改良MTT法。细胞经过24小时的孵育后,分别将新配的化合物3dc,3gd,3ha,3ec和3ka的二甲基亚砜溶液以浓度梯度加入到各孔中,使孔中化合物最终浓度分别为5μmol/L,10μmol/L,20μmol/L,40μmol/L和80μmol/L。48小时后,每孔加入10μLMTT(5mg/mL)的磷酸盐缓冲液,再继续在37℃培养4小时后,离心5分钟除去未转化的MTT,每孔中加入150μL二甲基亚砜。以溶解还原的MTT晶体甲臜(formazan),用酶标仪在490nm波长测定OD值。其中化合物3dc,3gd,3ha,3ec和3ka对K562细胞半抑制浓度IC50由spss软件(19版本)分析得到。化合物3dc对K562肿瘤细胞的IC50为34.7μmol/L;化合物3gd对K562肿瘤细胞的IC50为57.6μmol/L;化合物3ha对K562肿瘤细胞的IC50为43.7μmol/L;化合物3ec对K562肿瘤细胞的IC50为57.1.8μmol/L;化合物3ka对K562肿瘤细胞的IC50为69.0μmol/L;而阳性对照顺铂对K562肿瘤细胞的IC50为27.8μmol/L。
实验结论:K562细胞是测试化合物对肿瘤细胞的细胞毒性的有效工具和评价指标。本实验表明此类式(1)所示的含连续三季碳的硫代吡咯酮拼接双螺环氧化吲哚化合物对K562细胞具有较强的细胞毒性,有可能发展成新的具有抗肿瘤作用的药物。
从以上药理实施例中我们可以看出这些化合物对人白血病细胞(K562)显示有一定的细胞毒性。可见这些化合物具有开发成为抗肿瘤药物的潜力,值得继续深入研究下去。
Claims (3)
3.一种如权利要求1所述的含连续三季碳的硫代吡咯酮拼接双螺环氧化吲哚化合物在制备防治肿瘤疾病药物中的应用。
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Publication number | Priority date | Publication date | Assignee | Title |
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CN106866686A (zh) * | 2017-03-30 | 2017-06-20 | 贵州大学 | 异恶唑拼接3,3′‑吡咯双螺环氧化吲哚化合物及其制备方法及应用 |
CN107383030A (zh) * | 2017-04-10 | 2017-11-24 | 贵州大学 | 姜黄酮拼接3,3’‑吡咯双螺环氧化吲哚化合物及其制备方法及应用 |
CN107857766A (zh) * | 2017-12-11 | 2018-03-30 | 皖南医学院 | 一种基于苯丙氨酸和多羰基类环酮化合物的螺旋吲哚类化合物的合成方法及其应用 |
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106866686A (zh) * | 2017-03-30 | 2017-06-20 | 贵州大学 | 异恶唑拼接3,3′‑吡咯双螺环氧化吲哚化合物及其制备方法及应用 |
CN107383030A (zh) * | 2017-04-10 | 2017-11-24 | 贵州大学 | 姜黄酮拼接3,3’‑吡咯双螺环氧化吲哚化合物及其制备方法及应用 |
CN107857766A (zh) * | 2017-12-11 | 2018-03-30 | 皖南医学院 | 一种基于苯丙氨酸和多羰基类环酮化合物的螺旋吲哚类化合物的合成方法及其应用 |
Non-Patent Citations (5)
Title |
---|
3-Isothiocyanato Oxindoles Serving as Powerful and Versatile Precursors to Structurally Diverse Dispirocyclic Thiopyrrolidineoxindoles through a Cascade Michael/Cyclization Process with Amino-Thiocarbamate Catalysts;Wen-Yong Han,等;《Chem. Eur. J.》;20130312;第19卷;第5551-5556页 * |
A Catalyst-Free Self-Catalyzed [3+2] Cycloaddition Reaction of 3-Isothiocyanato Oxindoles and Vinylpyridines;Hou-Ze Gui,等;《Eur. J. Org. Chem.》;20180716;第4905-4916页,尤其参见第4907页表4,第4910页左栏第2段 * |
Highly Efficient and Stereocontrolled Construction of 3,3’-Pyrrolidonyl Spirooxindoles via Organocatalytic Domino Michael/Cyclization Reaction;Xiong-Li Liu,等;《ORGANIC LETTERS》;20130301;第15卷(第6期);第1246-1249页 * |
Highly Efficient and Stereoselective Construction of Dispiro-[oxazolidine-2-thione]bisoxindoles and Dispiro [imidazolidine-2-thione]bisoxindoles;Yan-Yan Han,等;《ORGANIC LETTERS》;20120111;第14卷(第2期);第490-493页 * |
Molecular Hybridization-Guided One-Pot Multicomponent Synthesis of Turmerone Motif-Fused 3,3’-Pyrrolidinyl-dispirooxindoles via a 1,3-Dipolar Cycloaddition Reaction;Bing Lin,等;《Molecules》;20170417;第22卷(第4期);第645/1-645/27页 * |
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