CN109422724B - 一种吲哚取代的异喹啉化合物及其合成方法 - Google Patents
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Abstract
本发明公开了一种吲哚取代的异喹啉化合物及其制备方法和应用。该吲哚取代的异喹啉化合物如式I所示，其中R1为氢、卤素原子、烷基，R2与R3为氢、卤素原子、烷基或烷氧基。本发明通过2步反应合成目标产物，合成方法简洁、快速，且目标化合物收率较高，为进一步研究式I化合物或相关化合物提供了提供了必要基础。本发明的化合物对人类肿瘤细胞具有良好的抑制作用，在生物医药领域具有实际的应用价值。
Description
技术领域
本发明涉及药物化学领域，具体涉及一种吲哚取代的异喹啉化合物及其制备方法，以及该类化合物作为一类新的抗肿瘤药物先导化合物的应用。
背景技术
癌症是起源于上皮组织的恶性肿瘤，尽管其诊断和治疗技术已取得了很大的进步，但任然是人类致死疾病的三大主因之一，并且给人类社会带来巨大的精神与经济压力。在过去的几十年中，人们在研发癌症化疗试剂先到化合物方面做了非常多的工作，并且有多种化合物也已被证明具有良好的治疗效果。1974年，naphthyridinomycin化合物被分离出来，并且表现出很好的抗癌疗效，自此，异喹啉化合物作为一类特殊的生物碱而被应用于抗肿瘤研究中，并且被作为先导化合物不断开发出新的衍生物。
异喹啉类化合物是天然产物中一类，它们除了具有较好的抗癌活性，还具有抗糖尿病和抗微管蛋白等特殊的生物药理活性。它不仅是生物碱全合成的重要中间体，也是许多类天然分子与合成分子的亚结构单元。因此，我们可以通过多样性导向合成方法来合成异喹啉类化合物，对与化学合成、药理学及生物学都是具有重大意义的。
吲哚取代异喹啉化合物结合了吲哚与异喹啉两个特殊的结构单元，将会具有不可预料的潜在生物活性。吲哚取代的异喹啉肼盐化合物已有报道，但是裸露的肼基会具有较大的细胞毒性，不适合应用于药物研发中。因此，开发一种简洁、高效合成吲哚取代的异喹啉化合物的方法，并研究这些化合物的抗肿瘤活性，对于开发自主知识产权药物具有重要意义。
发明内容
本发明的目的在于提供一种吲哚取代的异喹啉化合物及其合成方法。
本发明的吲哚取代的异喹啉化合物，具有一定的抗癌活性，可以做为潜在的抗肿瘤药物或是做为抗糖尿病的候选药物，如式I所示：
I
其中，R1为氢、卤素原子或烷基，R2与R3为氢、卤素原子、烷基或烷氧基。
上述的吲哚取代的异喹啉化合物的合成方法，包括如下步骤：
(1)中间体化合物2的制备
取化合物1、质量分数为80%的水合肼溶于无水乙醇中，所述化合物2与水合肼物质的量之比为5:1-1:1，一定温度条件下搅拌1~2小时，固体完全析出，过滤，粗产物用无水乙醇重结晶，得到白色固体化合物2。
(2) 目标化合物的制备
取中间体2、吲哚化合物3，溶于有机溶剂中，所述中间体2、吲哚化合物、催化剂的物质的量之比为1：0.3-2：0.1-2， 20-100℃下反应，TLC检测反应进程，待反应完全，停止反应，将反应物冷却至室温，过滤掉后留滤液，并减压旋蒸除去溶剂，残留物进行柱层析，得到式I所示的目标产物；
以上各化合物均以反应式中各化合物下面序号加以区分，其中，R1为氢、卤素原子或烷基，R2与R3为氢、卤素原子、烷基或烷氧基。
进一步地， R1优选为H、Cl、Br、I、F、NO2、CN或Me。
进一步地， R2优选为H、Cl或Me。
进一步地， R3优选为H、Cl、F或Me。
进一步地，步骤（2）中，所述的有机溶剂优选二甲亚砜(DMSO)。
进一步地，步骤（2）中，所述的催化剂优选AgNO3。
进一步地，步骤（2）中，反应温度优选80℃。
本发明的有益效果在于：
（1）本发明提供了一种具有良好抗癌活性，可以做为潜在的抗肿瘤药物或是抗糖尿病候选药物的新型吲哚取代的异喹啉化合物。
（2）本发明的合成方法简洁、快速，催化剂廉价易得，且条件易于控制，目标化合物的收率较高，为进一步研究式I化合物或相关化合物提供了必要基础。
具体实施方式
以下通过具体实施例对本发明做进一步地详细说明，但不应将此理解为本发明上述主题的范围仅限于以下的实施例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
本发明所用仪器与试剂：
核磁共振仪：Bruker AV-II 500 MHz NMR，TMS为内标，DMSO-d 6 为溶剂；红外光谱仪：TFS-40型，KBr压片;熔点仪：XT-4型熔点测定仪。
所用试剂均为市售化学纯或分析纯。
实施例1
本发明化合物的合成
本发明化合物制备途径如下：
(1) 中间体化合物2a的合成：
取化合物1a(R2与R3均为H) 2.0 mmol、质量分数为80%的水合肼1.0 mmol溶于5 mL无水乙醇中，室温条件下搅拌1小时，固体完全析出，过滤，粗产物用无水乙醇重结晶，得到白色固体化合物2a。
(2) 目标化合物4的合成与表征：
取0.225 mmol中间体2、0.3mmol吲哚化合物3，溶于2 mL的二甲亚砜中， 80 ℃下反应，TLC检测反应进程，待反应完全，停止反应，将反应物冷却至室温，过滤掉后留滤液，并减压旋蒸除去溶剂，残留物进行柱层析，得到式I所示的目标产物；
1-（1H-3-吲哚）-3-苯基异喹啉 (4a)，浅黄色固体, 熔点 234-236 oC. IR (KBr)ν/cm-1: 3162, 1619, 1551, 1492, 1400, 1242, 1135. 1H NMR (DMSO-d 6 , 500 MHz)δ:11.74 (s, 1H), 8.46 (d, J = 8.5 Hz,1H), 8.32 – 8.20 (m, 3H), 8.09 – 7.92 (m,3H), 8.01 (s, 1H), 7.79 (t, J = 7.5 Hz,1H), 7.66 (t, J = 7.5 Hz,1H), 7.58 –7.54 (m, 3H), 7.45 (t, J = 7.5 Hz,1H), 7.24 (t, J = 7.5 Hz,1H), 7.17 (t, J =7.5 Hz,1H),. 13C NMR (DMSO-d 6 , 125 MHz) δ: 155.1, 148.8, 139.1, 137.7, 136.5,130.2, 128.8, 128.5, 127.9, 127.7, 127.3, 127.1, 126.8, 126.5, 125.4, 121.9,120.6, 120.0, 113.6, 111.8. HRMS (ESI) calcd for C23H17N2, 321.1392 (M+H)+;Found, 321.1396.
1-（5-氯-1H-3-吲哚）-3-苯基异喹啉 (4b), 橙色固体, 熔点 220-222 oC. IR(KBr) cm-1 3129, 1619, 1554, 1400, 1137, 956, 873. 1H NMR (DMSO-d 6 , 500 MHz)δ11.84 (s, 1H), 8.40 – 8.31 (m, 1H), 8.26 – 8.15 (m, 3H), 8.04 (d, J = 7.5 Hz,2H), 7.96 (d, J = 8.0 Hz, 1H), 7.67 (t, J = 7.5 Hz, 1H), 7.59 – 7.41 (m, 4H),7.34 (t, J = 7.5 Hz, 1H), 7.20 – 7.11 (m, 1H). 13C NMR (DMSO-d 6 , 125 MHz) δ154.4, 148.6, 139.1, 137.6, 134.9, 130.1 , 129.4, 128.7, 128.5, 127.9, 127.7,127.4, 126.7, 126.3, 125.2, 124.7, 121.9, 120.0, 113.8, 113.7, 113.41. HRMS(ESI) calcd for C23H16ClN2, 355.1002 (M+H)+; Found, 355.1008.
1-（5-碘-1H-3-吲哚）-3-苯基异喹啉(4c), 橙色固体, 熔点208-210 oC. IR(KBr) cm-1 3127, 1617, 1555, 1493, 1440, 1140, 955, 875. 1H NMR (DMSO-d 6 , 500MHz) δ 11.85 (s, 1H), 8.52 (s, 1H), 8.43 – 8.37 (m, 1H), 8.26 (d, J = 6.0 Hz,3H), 8.01 (d, J = 8.5 Hz, 2H), 7.72 (t, J = 7.5 Hz, 1H), 7.60 (t, J = 7.5 Hz,1H), 7.49 (t, J = 7.5 Hz, 2H), 7.44 (d, J = 8.5 Hz, 1H), 7.42 – 7.36 (m, 2H).13C NMR (DMSO-d 6 , 125 MHz) δ 154.3, 148.5, 139.0, 137.6, 135.5, 130.2, 129.8,129.5, 129.4, 128.8, 128.7, 128.6, 127.7, 127.4, 126.7, 126.3, 125.2, 114.3,113.6, 113.3, 84.0. HRMS (ESI) calcd for C23H16IN2, 447.0358 (M+H)+; Found,447.0353.
1-（6-氟-1H-3-吲哚）-3-苯基异喹啉(3d), 橙色固体, 熔点240-241 oC. IR(KBr) cm-1 3131, 1619, 1542, 1492, 1400, 1291, 1141, 957, 832. 1H NMR (DMSO-d 6 ,500 MHz) δ 11.70 (s, 1H), 8.38 (d, J = 8.5 Hz, 1H), 8.31 – 8.15 (m, 3H), 8.07– 7.90 (m, 3H), 7.69 (t, J = 7.5 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.47 (t,J = 7.5 Hz, 2H), 7.36 (t, J = 7.0 Hz, 1H), 7.31 – 7.23 (m, 1H), 7.01 – 6.86(m, 1H). 13C NMR (DMSO-d 6 , 125 MHz) δ 170.7, 160.5, 158.6, 155.2, 149.2,139.6, 138.1, 136.8, 136.7, 130.6, 129.2, 128.9, 128.8, 128.8, 128.1, 127.8,127.3, 126.9, 125.8, 124.1, 122.3, 122.2, 114.6, 114.1, 109.1, 108.9, 98.3,98.1. HRMS (ESI) calcd for C23H16FN2, 339.1298 (M+H)+; Found, 339.1305.
3-苯基-1-（1H-3-吡咯[2,3-b]吡啶）异喹啉(4e), 黄色固体，熔点 278-280 oC.IR (KBr) cm-1 3415, 3135, 1618, 1556, 1526, 1494, 1400, 1300, 1134. 1H NMR(DMSO-d 6 , 500 MHz)δ 12.19 (s, 1H), 8.44-8.35 (m, 2H), 8.29 (d, J = 4.5 Hz,1H), 8.26 – 8.19 (m, 3H), 8.09 (s, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.71 (t, J= 7.5 Hz, 1H), 7.58 (t, J = 7.5 Hz, 1H), 7.50 -7.44 (m, 2H), 7.36 (t, J = 7.5Hz, 1H), 7.20 -7.13 (m, 1H). 13C NMR (DMSO-d 6 , 125 MHz) δ 154.2, 148.7, 148.6,143.4, 139.0, 137.6, 130.3, 129.1, 128.8, 128.5, 128.0, 127.7, 127.5, 126.5,126.4, 125.1, 119.2, 116.7, 113.8, 112.9. HRMS (ESI) calcd for C22H16N3,322.1344 (M+H)+; Found, 322.1338.
1-（5-硝基-1H-3-吲哚）-3-苯基异喹啉(4f), 黄色固体, 熔点255-256 oC. IR(KBr) cm-1 3342, 2915, 1623, 1560, 1487, 1326, 1097, 738, 680. 1H NMR (DMSO-d 6 ,500 MHz)δ 12.42 (s, 1H), 9.23 (s, 1H), 8.53 (d, J = 10.0 Hz, 1H), 8.40 -8.36(m, 4H), 8.17- 8.12 (m, 2H), 7.83 (t, J = 5.0 Hz, 1H), 7.83 (t, J = 5.0 Hz,1H), 7.74 (d, J = 10.0 Hz, 1H), 7.57 (t, J = 5.0 Hz, 2H), 7.48 (t, J = 5.0Hz, 1H). 13C NMR (DMSO-d 6 , 125 MHz) δ 153.6, 148.7, 141.6, 139.6, 138.9,137.7, 131.4, 130.4, 128.8, 128.7, 127.9, 127.7, 126.5, 126.4, 126.3, 118.2,117.3, 116.1, 114.2, 112.4. HRMS (ESI) calcd for C23H16N3O2, 366.1243 (M+H)+;Found, 366.1239.
1-（5-溴-1H-3-吲哚）-3-苯基异喹啉(4g), 黄色固体, 熔点232-234 oC. IR(KBr) cm-1 3124, 2923, 2854, 1616, 1553, 1433, 1137, 953, 877, 765, 686. 1HNMR (DMSO-d 6 , 500 MHz)δ 11.95 (s, 1H), 8.48 (d, J = 8.5 Hz, 1H), 8.34 – 8.32(m, 4H), 8.14-8.12 (m, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.80 (t, J = 7.5 Hz,1H), 7.67(t, J = 7.5 Hz, 1H), 7.59- 7.55 (m, 3H), 7.47 (t, J = 7.5 Hz, 1H),7.39-7.37 (m, 1H). 13C NMR (DMSO-d 6 , 125 MHz) δ 154.3, 148.6, 139.1, 137.7,135.2, 130.2, 129.3, 128.8, 128.7, 128.6, 127.8, 127.5, 126.7, 126.4, 125.2,124.4, 123.1, 113.9, 113.7, 112.7. HRMS (ESI) calcd for C23H16BrN2, 399.0497 (M+H)+; Found, 399.0496.
1-（2-甲基-1H-3-吲哚）-3-苯基异喹啉(4h), 黄色固体, 熔点170-172 oC. IR(KBr) cm-1 3174, 3054, 2924, 1617, 1556, 1495, 1462, 1436, 741, 687. 1H NMR(DMSO-d 6 , 500 MHz)δ 11.54 (s, 1H), 8.38 (s, 1H), 8.30 (d, J = 8.0 Hz, 2H),8.10 (d, J = 8.0 Hz, 1H), 7.98 (d, J = 8.5 Hz, 1H), 7.51 (t, J = 7.5 Hz, 1H),7.57 - 7.52 (m, 3H), 7.48 (d, J = 8.0 Hz, 1H), 7.45 (t, J = 7.5 Hz, 1H), 7.29(d, J = 8.0 Hz, 1H), 7.13 (t, J = 7.5 Hz, 1H), 7.01 (t, J = 7.5 Hz, 1H), 2.50(s, 3H). 13C NMR (DMSO-d 6 , 125 MHz) δ 155.7, 149.0, 139.2, 137.4, 135.9,135.2, 130.2, 128.7, 128.4, 128.1, 127.6, 127.5, 126.9, 126.4, 126.2, 120.7,119.4, 118.7, 114.2, 111.5, 110.9, 12.8. HRMS (ESI) calcd for C24H19N2,335.1548 (M+H)+; Found, 335.1551.
1-（6-氰基-1H-3-吲哚）-3-苯基异喹啉(4i), 黄色固体, 熔点228-230 oC. IR(KBr) cm-1 3034, 2923, 2853, 2217, 1619, 1554, 1526, 1495, 1448, 956, 817,693. 1H NMR (DMSO-d 6 , 500 MHz)δ 12.27 (s, 1H), 8.41-8.30 (m, 5H), 8.21 (d, J =8.0 Hz, 1H), 8.11-9.09 (m, 2H), 7.81 (t, J = 7.0 Hz, 1H), 7.67 (t, J = 7.5Hz, 1H), 7.57-7.45 (m, 4H). 13C NMR (DMSO-d 6 , 125 MHz) δ 154.0, 148.8, 139.0,137.6, 135.3, 131.8, 130.3, 130.0, 128.8, 128.7, 128.6, 127.8, 127.5, 126.7,126.4, 125.4, 122.7, 121.7, 120.4, 116.9, 114.8, 114.1 103.4. HRMS (ESI)calcd for C24H16N3, 346.1344 (M+H)+; Found, 346.1343.
1-（7-甲基-1H-3-吲哚）-3-苯基异喹啉(4j), 黄色固体, 熔点142-144 oC. IR(KBr) cm-1 3338, 3044, 2924, 1613, 1549, 1526, 1491, 1426, 1125, 772, 746,690. 1H NMR (DMSO-d 6 , 500 MHz)δ 11.68 (s, 1H), 8.45 (d, J = 8.5 Hz, 1H), 8.32-8.30 (m, 3H), 8.07 (d, J = 8.0 Hz, 1H), 7.97-7.96 (m, 1H), 7.88 (d, J = 7.5Hz, 1H), 7.78 (t, J = 7.5 Hz, 1H), 7.64 (t, J = 7.5 Hz, 1H), 7.54 (t, J = 7.5Hz, 2H), 7.43 (t, J = 7.5 Hz, 1H), 7.07-7.02 (m, 2H), 2.59 (s, 3H). 13C NMR(DMSO-d 6 , 125 MHz) δ 155.3, 148.7, 139.2, 137.6, 135.9, 130.1, 128.7, 128.5,127.6, 127.4, 127.2, 127.0, 126.6, 126.4, 125.5, 122.3, 121.0, 120.2, 118.2,114.7, 113.5, 16.9. HRMS (ESI) calcd for C24H19N2, 335.1548 (M+H)+; Found,335.1551.
1-（1H-3-吲哚）-3-(4-甲氧基苯基)异喹啉(4k), 黄色固体, 熔点256-257 oC.IR (KBr) cm-1 3145, 2924, 2854, 1608, 1551, 1513, 1432, 1244, 1177, 827, 743.1H NMR (DMSO-d 6 , 500 MHz)δ 11.71 (s, 1H), 8.45 (d, J = 8.5 Hz, 1H), 8.30 (d, J= 8.5 Hz, 2H), 8.20 (s, 1H), 8.10 (s, J = 8.0 Hz, 1H), 8.03-8.00 (m, 2H),7.74 (t, J = 7.5 Hz, 1H), 7.61-7.57 (m, 2H), 7.25 (t, J = 7.5 Hz, 1H), 7.17(t, J = 7.5 Hz, 1H), 7.11 (d, J = 8.5 Hz, 2H), 3.84 (s, 3H). 13C NMR (DMSO-d 6 ,125 MHz) δ 159.7, 155.0, 148.6, 137.8, 136.5, 131.7, 130.0, 127.7, 127.6,127.5, 127.0, 126.9, 126.8, 125.1, 121.9, 120.6, 120.0, 114.3, 114.1, 112.2,111.8, 55.2. HRMS (ESI) calcd for C24H19N2O, 351.1497 (M+H)+; Found, 351.1497.
1-（1H-3-吲哚）-3-(4-氟苯基)异喹啉(4l), 黄色固体, 熔点218-220 oC. IR(KBr) cm-1 3198, 2924, 1617, 1550, 1528, 1508, 1428, 1222, 1132, 949, 829,728. 1H NMR (DMSO-d 6 , 500 MHz)δ 11.72 (s, 1H), 8.45 (d, J = 8.5 Hz, 1H), 8.37-8.35 (m, 2H), 8.28 (s, 1H), 8.05 (t, J = 7.5 Hz, 2H), 8.01-8.00 (m, 1H), 7.77(t, J = 7.5 Hz, 1H), 7.63 (t, J = 7.5 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H),7.37-7.35 (m, 2H), 7.24 (t, J = 7.5 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H). 13C NMR(DMSO-d 6 , 125 MHz) δ 163.5, 161.5, 155.1, 147.7, 137.6, 136.5, 135.7, 128.5,128.4, 127.9, 127.6, 121.9, 120.5, 120.0, 115.6, 115.5, 114.1, 113.3, 111.9.HRMS (ESI) calcd for C23H16FN2, 339.1298 (M+H)+; Found, 339.1305.
1-（1H-3-吲哚）-7-甲基3-苯基异喹啉(4m), 黄色固体, 熔点226-228 oC. IR(KBr) cm-1 3205, 3051, 2920, 1615, 1552, 1530, 1495, 1433, 1321, 1103, 871,743, 690. 1H NMR (DMSO-d 6 , 500 MHz)δ 11.67 (s, 1H), 8.31 (d, J = 7.5 Hz, 1H),8.24-8.23 (m, 2H), 8.08 (d, J = 8.0 Hz, 2H), 8.01-8.00 (m, 1H), 7.97 (d, J =8.0 Hz, 1H), 7.61-7.57 (m, 2H), 7.53 (t, J = 7.5 Hz, 2H), 7.42 (t, J = 7.5Hz, 1H), 7.24 (t, J = 7.5 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H), 3.40 (s, 3H). 13CNMR (DMSO-d 6 , 125 MHz) δ 154.5, 148.0, 139.3, 136.7, 136.4, 135.8, 132.2,128.7, 128.3, 127.6, 127.5, 127.0, 126.3, 125.8, 125.7, 121.8, 120.6, 119.9,114.3, 113.3, 111.8, 21.6. HRMS (ESI) calcd for C24H19N2, 335.1548 (M+H)+;Found, 335.1551.
1-（4-氯-1H-3-吲哚）-3-苯基异喹啉(4n), 黄色固体, 熔点189-191 oC. IR(KBr) cm-1 3158, 2923, 2855, 1619, 1563, 1488, 1441, 1341, 1189, 771, 743,699. 1H NMR (DMSO-d 6 , 500 MHz)δ 11.91 (s, 1H), 8.40 (s, 1H), 8.27 (d, J = 7.5Hz, 2H), 8.07 (d, J = 8.0 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.78-7.72 (m,2H), 7.58 (d, J = 7.5 Hz, 1H), 7.54-7.49 (m, 3H), 7.42 (t, J = 7.5 Hz, 1H),7.20 (t, J = 7.5 Hz, 1H), 7.08 (t, J = 7.5 Hz, 1H). 13C NMR (DMSO-d 6 , 125 MHz)δ 155.7, 148.5, 139.1, 137.4, 136.5, 130.1, 128.7, 128.6, 128.4, 128.1,127.7, 127.6, 127.2, 126.9, 126.6, 124.7, 122.3, 120.2, 115.0, 113.9, 111.1.HRMS (ESI) calcd for C23H16ClN2, 355.1002 (M+H)+; Found, 355.1008.
1-（1H-3-吲哚）-3-(4-氯苯基)异喹啉(4o), 黄色固体, 熔点225-227 oC. IR(KBr) cm-1 3210, 2958, 2925, 2856, 1729, 1615, 1550, 1529, 1459, 1275, 1128,957, 824, 744. 1H NMR (DMSO-d 6 , 500 MHz)δ 11.91 (s, 1H), 8.45 (s, 1H), 8.34-8.32 (m, 3H), 8.07-7.99 (m, 3H), 7.78 (d, J = 7.5 Hz, 1H), 7.64 (t, J = 7.5Hz, 1H), 7.60-7.56 (m, 3H), 7.23 (t, J = 7.5 Hz, 1H), 7.15 (t, J = 7.5 Hz,1H). 13C NMR (DMSO-d 6 , 125 MHz) δ 155.3, 147.5, 138.1, 137.6, 136.4, 133.2,130.2, 128.7, 128.1, 127.9, 127.7, 127.4, 127.0, 126.8, 125.5, 121.9, 120.5,120.1, 114.1, 113.7, 111.8. HRMS (ESI) calcd for C23H16ClN2, 355.1002 (M+H)+;Found, 355.1008.
7-氯-1-（1H-3-吲哚）-3-苯基异喹啉 (4p), 黄色固体，熔点 215-216 oC. IR(KBr) cm-1 3283, 2954, 1588, 1556, 1544, 1534, 1480, 1424, 1242, 1088, 874,743, 689. 1H NMR (DMSO-d 6 , 500 MHz)δ 11.75 (s, 1H), 8.39-8.36 (m, 2H), 8.32(d, J = 7.5 Hz, 2H), 8.13 (d, J = 8.5 Hz, 2H), 8.07-8.03 (m, 2H), 7.82 (d, J= 7.5 Hz, 1H), 7.59-7.54 (m, 2H), 7.46 (t, J = 7.5 Hz, 1H), 7.25 (t, J = 7.5Hz, 1H), 7.18 (t, J = 7.5 Hz, 1H). 13C NMR (DMSO-d 6 , 125 MHz) δ 154.4, 149.3,138.8, 136.5, 136.2, 131.5, 130.7, 130.0, 128.8, 128.7, 128.0, 126.7, 126.5,125.9, 125.8, 122.0, 120.4, 120.2, 113.7, 113.2, 111.9. HRMS (ESI) calcd forC23H16ClN2, 355.1002 (M+H)+; Found, 355.1007.
7-氯-3-（1H-3-吲哚）-3-(4-氯苯基)异喹啉 (4q), 黄色固体，熔点 217-218 oC.IR (KBr) cm-1 3243, 2923, 1595, 1541, 1455, 1425, 1241, 1088, 876, 829, 742.1H NMR (DMSO-d 6 , 500 MHz)δ 11.76 (s, 1H), 8.38 (s, 2H), 8.33 (s, J = 8.0 Hz,2H), 8.11 (d, J = 8.5 Hz, 2H), 8.07-8.06 (m, 1H), 8.01 (d, J = 8.0 Hz, 1H),7.82 (d, J = 7.5 Hz, 1H), 7.62-7.57 (m, 2H), 7.25 (t, J = 7.5 Hz, 1H), 7.17(t, J = 7.5 Hz, 1H). 13C NMR (DMSO-d 6 , 125 MHz) δ 154.5, 148.0, 137.7, 136.5,136.0, 133.5, 131.7, 130.8, 130.0, 128.8, 128.1, 126.6, 126.0, 125.8, 122.0,120.3, 120.2, 113.6, 113.4, 112.0. HRMS (ESI) calcd for C23H15Cl2N2, 389.0612(M+H)+; Found, 389.0615.
测试例
选取上述得到的化合物3c、3d、3g、3h、3i、3j、3l、3m、3n、3o进行如下活性测定
实验材料:
1 人癌细胞株：均购自中科院上海细胞库；
2 受试药物：用DMSO溶解后，配置成10000微克每毫升最初浓度，备用；
3 0.9%生理盐水：批号201721112，规格250 mL：2.25 g，郑州永和制药有限公司产品；
4 5-氟尿嘧啶注射液（5-Fu），批号140107，规格10mL：0.25g/支，上海旭东海普药业有限公司产品。
实验方法
细胞常规接种于完全培养基中，经37℃，5%的CO2饱和湿度培养、扩增。细胞用0.25%胰蛋白酶消化后，加培养液稀释成1×105个/mL瘤细胞悬液（胎盼蓝染色，活细胞数均＞95%），供试验用。于96孔无菌培养板上设阴性对照孔和阳性对照孔、供试品不同浓度孔，浓度设定为64、32、16、8、4、2、1、0.5微克每毫升，同时每个浓度设3个复孔。将制备好的细胞悬液接种于96孔无菌培养板，培养24h后加入不同浓度的化合物。阴性对照孔内加入等量的培养液，置入培养箱中培养。分别于72h后取出，每孔加入 MTT 20μL，继续培养 4 h，取出后离心，吸弃上清。每孔加入 DMSO 150μL，震荡使紫蓝色甲瓒结晶完全溶解。用酶标仪测定各孔的OD值，通过SPSS计算其IC50。
实验结果
上述化合物对五种人类肿瘤细胞的抗肿瘤活性评价数据
实验结果表明：这几种化合物表现出优良的抗肿瘤活性，尤其是对SW620结肠癌细胞，化合物3c、3d、3n均表现出了优异的活性，同时表现出了广谱抗肿瘤活性，化合物3n对MCF-7乳腺癌、SW620结肠癌、PC-9肺腺癌等三种肿瘤细胞的活性均优于5-氟脲嘧啶，可作为进一步开发的候选或者先导化合物，应用于制备抗癌药物。
Claims (6)
1.一种吲哚取代的异喹啉化合物，如式I所示，
I
其中，R1为氢、卤素原子或甲基，R2与R3为氢、卤素原子、甲基、氰基、硝基或甲氧基。
2.权利要求1所述的吲哚取代的异喹啉化合物的合成方法，其特征在于，包括如下步骤：
(1)中间体化合物2的制备
取化合物1、质量分数为80%的水合肼溶于无水乙醇中，所述化合物2与水合肼物质的量之比为5:1-1:1，一定温度条件下搅拌1~2小时，固体完全析出，过滤，粗产物用无水乙醇重结晶，得到白色固体化合物2。
(2)目标化合物的制备
取中间体2、吲哚化合物3，溶于极性有机溶剂二甲亚砜中，所述中间体2、吲哚化合物、过渡金属催化剂硝酸银的物质的量之比为1：0.3-2：0.1-2，20-100℃下反应，TLC检测反应进程，待反应完全，停止反应，将反应物冷却至室温，过滤掉后留滤液，并减压旋蒸除去溶剂，残留物进行柱层析，得到式I所示的目标产物；
以上各化合物均以反应式中各化合物下面序号加以区分，其中，R1为氢、卤素原子或甲基，R2与R3为氢、卤素原子、甲基、氰基、硝基或甲氧基。
3.根据权利要求2所述的吲哚取代的异喹啉化合物的合成方法，其特征在于：R1为H、Cl或Me；R2为H、F、Cl、Br、CN、NO2或Me；R3为H、Cl、F、Me或甲氧基。
4.根据权利要求2所述的吲哚取代的异喹啉化合物的合成方法，其特征在于：步骤（1）中，化合物1与水合肼的物质的量之比为2:1。
5.根据权利要求2所述的吲哚取代的异喹啉化合物的合成方法，其特征在于：所述化合物2、化合物3、和AgNO3的物质的量之比为0.75：1：1。
6.根据权利要求2所述的吲哚取代的异喹啉化合物的合成方法，其特征在于：步骤（2）中，所述的反应温度为80℃。
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| WO2005123672A2 (en) * | 2004-06-14 | 2005-12-29 | Takeda San Diego, Inc. | Kinase inhibitors |
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| CN105503722A (zh) * | 2016-01-26 | 2016-04-20 | 湖南科技大学 | 一种异喹啉化合物的合成方法 |
| CN105541713A (zh) * | 2016-01-26 | 2016-05-04 | 湖南科技大学 | 一种异喹啉化合物及其合成方法 |
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