具体实施方式
本发明的实施例1:3,3′-双取代氧化吲哚与3-烯键氧化吲哚拼接衍生物的制备;化合物3aa: 在圆底烧瓶中,依次加入92.7 毫克 (0.3 mmol) N-Boc-3-苯基氧化吲哚1a,69.4 毫克 (0.2 mmol) N-甲基氧化吲哚MBH碳酸甲酯2a,12.9 毫克 TBAB (20 mol %),溶解在5.0 mL甲苯中,再加入24 毫克 NaOH (3.0 eq),室温下充分搅拌反应24小时,TLC检测反应完全,减压蒸馏除掉溶剂,残留油状物硅胶柱层析(300-400目)分离(石油醚:乙酸乙酯=3:1),得到淡黄色固体,产率61%,熔点:149.1-150.4 oC,核磁共振和高分辨质谱测试结果如下:1H NMR (CDCl3, 400 MHz) δ: 1.63 (s, 9 Hz), 3.15 (s, 3H), 3.60 (s, 3H),4.27 (d, J = 13.6 Hz, 1H), 4.74 (d, J = 13.6 Hz, 1H), 6.73 (d, J = 7.6 Hz,1H), 6.87 (t, J = 7.8 Hz, 1H), 7.02 (d, J = 7.6 Hz, 1H), 7.10 (t, J = 7.6 Hz,1H), 7.22-7.33 (m, 5H), 7.43 (d, J = 7.8 Hz, 2H), 7.48 (d, J = 7.6 Hz, 1H).7.90 (d, J = 8.4 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ: 25.9, 28.1, 35.4, 52.3,56.8, 84.1, 108.0, 115.3, 120.0, 122.2, 122.6, 124.0, 126.0, 127.2, 127.8,128.6, 128.7, 130.2, 139.4, 139.9, 142.9, 149.3, 167.1, 168.1, 175.8. HRMS(ESI-TOF) m/z: Calcd. for C32H30N2NaO6 [M+Na]+: 561.2002; Found: 561.2008.
附图中核磁共振和高分辨质谱图由现有技术软件生成,本领域技术人员可以通过图中曲线中的波峰值即可了解各化合物属性,对于图中个坐标数字可能因提交原因不是很清晰,但不影响本发明的完全公开。
通过实施例制备的化合物3ab~3aa-1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~3aa-1,反应产率见表1,但需强调的是本发明的化合物不限于表1所表示的内容。
本实施例制备化合物3ab:淡黄色固体, 产率63%; 熔点: 156.0-156.9 oC; 核磁共振和高分辨质谱测试结果如下:1H NMR (CDCl3, 400 MHz) δ: 1.53 (s, 9H), 3.06 (s,3H), 3.55 (s, 3H), 4.22 (d, J = 13.6 Hz, 1H), 4.64 (d, J = 13.6 Hz, 1H), 6.56(d, J = 8.0 Hz, 1H), 6.90 (d, J = 2.0 Hz, 1H). 7.01-7.05 (m, 1H), 7.10-7.13(m. 1H), 7.17-7.25 (m, 4H), 7.33-7.39 (m, 3H), 7.83 (d, J = 8.0 Hz, 1H); 13CNMR (CDCl3, 100 MHz) δ: 26.0, 28.1, 35.6, 52.5, 56.7, 84.2, 108.9, 115.2,121.3, 123.1, 124.0, 125.9, 127.1, 127.6, 127.9, 128.6, 128.7, 128.9, 129.9,139.2, 139.9, 141.0, 141.3, 149.2, 166.6, 167.7, 175.6. HRMS (ESI-TOF) m/z:Calcd. for C32H29ClN2NaO6 [M+Na]+: 595.1612; Found: 595.1613.
本实施例制备化合物3ac:淡黄色固体, 产率72%; 熔点: 156.2-156.3 oC; 1HNMR (CDCl3, 400 MHz) δ: 1.61 (s, 9H), 3.14 (s, 3H), 3.63 (s, 3H), 4.28-4.32(m, 1H), 4.74 (d, J = 13.2Hz, 1H), 6.62-6.66 (m, 1H), 6.76-6.80 (m, 1H),6.92-6.97 (m, 1H), 7.09-7.13 (m, 1H), 7,24-7.33 (m, 4H), 7.41-7.48 (m, 3H),7.91(d, J = 8.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ: 26.0, 28.0, 35.5, 52.5,56.7, 84.2, 108.3, 108.4, 110.6 (d, J CF = 26.7 Hz), 115.2, 116.5 (d, J CF =23.7 Hz), 120.8, 124.0, 125.7, 125.9, 126.8, 127.1, 127.8, 128.5, 128.6,128.8, 138.9, 139.1, 139.9, 140.8, 149.2, 158.6 (d, J CF = 238.1 Hz), 166.8,167.7, 175.7. HRMS (ESI-TOF) m/z: Calcd. for C32H29FN2NaO6 [M+Na]+: 579.1907;Found: 579.1908.
本实施例制备化合物3ad:淡黄色固体, 产率69%; 熔点: 164.2-165.0 oC; 1HNMR (CDCl3, 400 MHz) δ: 1.64 (s, 9H), 2.13 (s, 3H), 3.06 (s, 3H), 3.54 (s,3H), 4.18 (d, J = 13.6 Hz, 1H), 4.69 (d, J = 13.6 Hz, 1H), 6.54 (d, J = 8.0Hz, 1H), 6.73 (s, 1H), 6.95-7.04 (m, 2H), 7.18-7.26 (m, 4H), 7.34-7.42(m,3H), 7.83 (d, J = 8.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ: 21.2, 25.9, 28.1,35.4, 52.3, 56.7, 84.1, 107.7, 115.1, 120.0, 123.4, 124.0, 126.0, 127.2,127.3, 127.7, 128.6, 128.7, 130.6, 131.4, 139.0, 139.4, 139.9, 140.7, 149,3,167.1, 168.2, 175.8, 177.3. HRMS (ESI-TOF) m/z: Calcd. for C33H32N2NaO6 [M+Na]+:575.2158; Found: 575.2159.
本实施例制备化合物3ae:淡黄色固体, 产率74%; 熔点: 153.0-154.9 oC; 1HNMR (CDCl3, 400 MHz) δ: 1.61 (s, 9H), 3.54 (s, 3H), 3.60 (s, 3H), 4.24 (d, J= 13.2 Hz, 1H), 4.77 (d, J = 13.2 Hz, 1H), 6.77 (t, J = 7.8 Hz, 1H), 6.89-6.91 (m, 1H). 7.10-7.16 (m, 2H), 7.24-7.33 (m, 4H), 7.39-7.42 (m, 2H), 7.45-7,47 (m, 1H), 7.91 (d, J = 8.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ: 28.0,29.3, 35.6, 52.5, 56.7, 84.2, 115.1, 115.6, 120.9, 122.6, 122.7, 124.0,125.8, 125.9, 127.1, 127.8, 128.5, 128.6, 128.8, 132.3, 138.6, 139.2, 139.8,140.7, 149.2, 167.2, 168.0, 175.6. HRMS (ESI-TOF) m/z: Calcd. forC32H29ClN2NaO6 [M+Na]+: 595.1612; Found: 595.1612.
本实施例制备化合物3af:淡黄色固体, 产率72%; 熔点: 158.8-158.9 oC; 1HNMR (CDCl3, 400 MHz)δ: 1.65 (s, 9H), 3.66 (s, 3H), 4.30 (d, J = 13.6 Hz, 1H),4.83-4.94 (m, 3H), 6.64 (d, J = 7.6 Hz, 1H), 6.85-6.89 (m 1H), 7.07-7.16 (m,3H), 7.23(t, J = 4.2 Hz, 2H), 7.28-7.37 (m, 7H), 7.47-7.49 (m 2H), 7.55-7.57(m, 1H), 7.95 (d, J = 8.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ: 28.1, 35.5,43.3, 52.4, 56.9, 84.2, 108.9, 115.2, 122.3, 122.7, 124.0, 126.1, 127.1,127.2, 127.7, 127.8, 128.6, 128.7, 128.8, 130.2, 135.6, 139.2, 139.8, 139.9,142.0, 149.3, 167.2, 168.2, 175.8. HRMS (ESI-TOF) m/z: Calcd. for C38H34N2NaO6 [M+Na]+: 637.2315; Found: 637.2317.
本实施例制备化合物3ag:淡黄色固体, 产率53%; 熔点: 155.4-156.6 oC; 1HNMR (CDCl3, 400 MHz) δ: 1.61 (s, 9H), 3.65 (s, 3H), 4.28 (d, J = 13.2 Hz,1H), 4.78-4.91 (m, 3H), 6.49-6.53 (m 1H), 6.76-6.85 (m, 2H), 7.07-7.11 (m,1H), 7.16-7.25 (m, 2H), 7.25-7.36 (m, 7H), 7.35-7.50 (m, 2H), 7.49-7.52 (m,1H), 7.92 (d, J = 8.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ: 28.0, 35.5, 43.3,52.6, 84.2, 109.3, 109.4, 110.7 (d, J CF = 25.9 Hz), 115.2, 116.5 (d, J CF =23.6 Hz), 120.9, 123.9, 126.0, 126.7, 127.0, 127.1, 127.7, 127.8, 128.5,128.6, 128.8, 135.2, 137.9, 138.9, 139.9, 141.2, 149.2, 158.6 (d, J CF = 238.1Hz), 166.9, 167.7, 175.7. HRMS (ESI-TOF) m/z: Calcd. for C38H33FN2NaO6 [M+Na]+:655.2220; Found: 655.2229.
本实施例制备化合物3ah:淡黄色固体, 产率71%; 熔点: 150.7-150.9 oC; 1HNMR (CDCl3, 400 MHz) δ: 1.62 (s, 9H), 3.65 (s, 3H), 4.28 (d, J = 13.2 Hz,1H), 4.78-4.91 (m, 3H), 6.52 (d, J = 8.8 Hz, 1H), 6.99 (d, J = 1.6 Hz, 1H),7.07-7.11 (m, 2H), 7.15 (d, J = 6.8 Hz, 2H), 7.25-7.35 (m, 7H), 7.42-7.44 (m,2H), 7.48-7.50 (m, 1H), 7.93 (d, J = 8.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ:28.0, 35.6, 43.3, 52.6, 56.8, 84.2, 109.8, 115.2, 121.3, 123.2, 123.9, 125.9,126.2, 127.0, 127.1, 127.7, 127.8, 127.9, 128.4, 128.6, 128.8, 129.9, 135.1,138.9, 139.9, 140.3, 141.4, 149.2, 166.7, 167.7, 175.7. HRMS (ESI-TOF) m/z:Calcd. for C38H33ClN2NaO6 [M+Na]+: 671.1925; Found: 671. 1917.
本实施例制备化合物3ai:淡黄色固体, 产率64%; 熔点: 257.8-258.4 oC; 1HNMR (CDCl3, 400 MHz) δ: 1H NMR (CDCl3, 400 MHz) δ: 1. 54 (s, 9H), 2.09 (s,3H), 3.56 (s, 3H), 4.16 (d, J = 13.6 Hz, 1H), 4,70-4.82 (m, 3H), 6.42 (d, J =8.0 Hz, 1H), 6.48 (t, J = 9.0 Hz, 1H), 6.74 (s, 1H), 6.84 (t, J = 4.0 Hz,1H), 6.90-7.01 (m, 2H), 7.07-7.25 (m, 6H), 7,35-7.46 (m 4H), 7.84(d, J = 8.0Hz, 1H); 13C NMR (CDCl3, 100 MHz)δ: 21.2, 27.7, 28.1, 35.5, 43.3, 52.3, 56.9,84.2, 108.7, 115.2, 123.5, 123.9, 126.2, 127.1, 127.2, 127.6, 127.7, 127.8,128.6, 128.7, 128.8, 130.6, 131.5, 135.7, 139.4, 149.3, 167.2, 168.3, 175.8.HRMS (ESI-TOF) m/z: Calcd. for C39H36N2NaO6 [M+Na]+: 651.2471; Found: 651.2472.
本实施例制备化合物3aj:淡黄色固体, 产率66%; 熔点: 150.8-152.5 oC; 1HNMR (CDCl3, 400 MHz) δ: 1H NMR (CDCl3, 400 MHz) δ: 1.22-1.30 (m, 3H), 1.61 (s,9H), 3.54 (s, 3H), 3.99-4.05 (m, 2H), 4.27 (d, J = 13.6 Hz, 1H), 4.77 (d, J =13.6 Hz, 1H), 6.77 (t, J = 8.0 Hz., 1H), 6.95-6.97 (m, 1H), 7.10-7.17 (m,2H), 7.24-7.33 (m, 4H), 7.40-7.47 (m, 3H), 7.91 (d, J = 8.0 Hz, 1H); 13C NMR(CDCl3, 100 MHz) δ: 13.6, 28.0. 29.3, 35.6, 56.7, 62.0, 84.1, 115.2, 115.5,121.1, 122.6, 122.8, 124.1, 125.6, 125.8, 127.1, 127.8, 128.6, 128.7, 128.8,132.2, 138.6, 139.3, 139.9, 141.3, 149.3, 167.3, 167.6, 175.7. HRMS (ESI-TOF)m/z: Calcd. for C33H31ClN2NaO6 [M+Na]+: 609.1768; Found: 609.1769.
本实施例制备化合物3ak:淡黄色固体, 产率83%; 熔点: 148.7-149.8oC; 1H NMR(CDCl3, 400 MHz) δ: 1.06 (t, J = 7.2 Hz, 3H), 1.60 (d, J = 7.6 Hz, 18H),2.19-2.28 (m, 1H), 3.45-3.53 (m, 1H), 3.83-3.87 (m, 2H), 6.97 (t, J = 7.6 Hz,1H), 7,04 (t, J = 7.6 Hz, 1H), 7.20 (d, J = 7.6 Hz, 1H), 7.25-7.32 (m, 5H),7.43 (t, J = 6.6 Hz, 3H), 7.79 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 8.4Hz, 1H).13C NMR (CDCl3, 100 MHz) δ: 13.2, 28.0, 28.1, 39.1, 55.9, 61.7, 84.5, 84.6,114.9, 115.3, 120.7, 123.7, 123.9, 124.4, 126.0, 127.2, 127.3, 127.8, 128.1,128.7, 129.1, 130.4, 137.9, 139.8, 140.2, 140.4, 148.7, 149.1, 163.6, 168.6,175.2. HRMS (ESI-TOF) m/z: Calcd. for C37H38N2NaO8 [M+Na]+: 661.2526; Found:661.2527.
本实施例制备化合物3ba:淡黄色固体, 产率60%; 熔点: 177.2-177.3 oC; 1HNMR (CDCl3, 400 MHz)δ: 1.52 (s, 9H), 2.22 (s, 3H), 3.07 (s, 3H), 3.53 (s,3H), 4.17 (d, J = 13.6 Hz, 1H), 4.66 (d, J = 13.6 Hz, 1H), 6.64 (d, J = 8.0Hz, 1H), 6.77-6.81 (m, 1H), 6.94 (d, J = 7.6 Hz, 1H), 7.01-7.04 (m, 3H),7.12-7.23 (m, 4H), 7,39-7.41 (m, 1H), 7.81 (d, J = 8.0 Hz, 1H); 13C NMR(CDCl3, 100 MHz) δ: 20.9, 25.9, 28.1, 35.4, 52.3, 56.5, 84.0, 108.0, 115.1,120.1, 122.1, 122.6, 123.9, 125.9, 127.0, 128.6, 128.9, 129.3, 130.2, 136.5,137.5, 139.5, 139.9, 142.9, 149.3, 167.1, 168.2, 175.9. HRMS (ESI-TOF) m/z:Calcd. for C33H32N2NaO6 [M+Na]+: 575.2158; Found: 575.2159.
本实施例制备化合物3bb:淡黄色固体, 产率60%; 熔点: 172.9-173.1 oC; 1HNMR (CDCl3, 400 MHz) δ: 1.60 (s, 9H), 2.30 (s, 3H), 3.14 (s, 3H), 3.63 (s,3H), 4.27(d, J = 13.2 Hz, 1H), 4.70 (d, J = 13.6 Hz, 1H), 6.64 (d, J = 8.0Hz, 1H), 6.98 (d, J = 2.0 Hz, 1H), 7.08-7.12 (m, 3H), 7.19-7.21 (m, 1H),7.26-7.33 (m, 3H), 7.43-7.45 (m, 1H), 7.90 (d. J = 8.0 Hz, 1H); 13C NMR(CDCl3, 100 MHz) δ: 20.9, 26.0, 28.0, 35.5, 52.5, 56.4, 84.1, 108.8, 115.1,121.2, 123.1, 123.9, 125.8, 126.3, 127.0, 127.5, 128.6, 128.7, 129.3, 129.8,136.2, 137.6, 139.8, 141.1, 141.2, 149.2, 166.6, 167.7, 175.7. HRMS (ESI-TOF)m/z: Calcd. for C33H31ClN2NaO6 [M+Na]+: 609.1768; Found: 609.1773.
本实施例制备化合物3bh:淡黄色固体, 产率61%; 熔点: 166.9-167.7 oC; 1HNMR (CDCl3, 400 MHz) δ: 1.61 (s, 9H), 2.29 (s, 3H), 3.66 (s, 3H), 4.14 (d, J = 13.2 Hz, 1H), 4.90 (d, J = 13.6 Hz, 1H), 5.29-5.39 (m, 2H), 6.78 (t, J =8.0 Hz, 1H), 6.94-6.96 (m, 1H), 7.02-7.04 (m, 1H), 7.06-7.12 (m, 5H), 7.24-7.27 (m, 2H), 7.28-7.38 (m, 4H), 7,45-7.47 (m, 1H), 7.90 (d, J = 8.0 Hz, 1H);13C NMR (CDCl3, 100 MHz) δ: 20.9, 28.1, 35.7, 44.5, 52.5, 56.6, 84.1, 115.1,115.5, 121.1, 122.8, 122.9, 123.9, 125.4, 125.9, 126.3, 126.9, 127.1, 128.5,128.6, 128.7, 129.3, 132.5, 136.2, 137.2, 137.6, 137.8, 139.8, 141.5, 149.3,167.6, 168.1, 175.9. HRMS (ESI-TOF) m/z: Calcd. for C39H35ClN2NaO6 [M+Na]+:685.2081; Found: 685.2085.
本实施例制备化合物3ca:淡黄色固体, 产率56%; 熔点: 291.0-292.5 oC; 1HNMR (CDCl3, 400 MHz) δ: 1.61 (s, 9H), 2.24-2.28 (m, 6H), 3.16 (s, 3H), 3.64(s, 3H), 4.16 (d, J = 13.6 Hz, 1H), 4.82 (d, J = 13.6 Hz, 1H), 6.72 (d, J =8.0 Hz, 1H), 6.84-6.89 (m, 2H), 7.02 (t, J = 7.8 Hz, 3H), 7.07-7.11 (m, 1H),7.21-7.31 (m, 2H), 7.45-7.47 (m, 1H), 7.89 (d, J = 8.0 Hz, 1H); 13C NMR(CDCl3, 100 MHz) δ: 21.5, 25.8, 28.1, 35.3, 52.3, 56.6, 84.0, 107.9, 115.0,120.0, 122.1, 122.5, 123.9, 124.8, 126.0, 126.9, 128.6, 128.9, 129.4, 130.1,138.0, 139.3, 139.7, 139.8, 142.8, 149.3, 167.0, 168.1, 175.9. HRMS (ESI-TOF)m/z: Calcd. for C34H34N2NaO6 [M+Na]+: 589.2315; Found: 589.2311.
本实施例制备化合物3ch:淡黄色固体, 产率75%; 熔点: 151.9-152.7 oC; 1HNMR (CDCl3, 400 MHz) δ: 1.62 (s. 9H), 2.23 (s. 6H), 3.69 (s. 3H), 4.06 (d, J = 13.6 Hz, 1H), 5.01 (d, J = 13.6 Hz, 1H), 5.29-5.39 (m, 2H), 6.76-6.80 (m,1H), 6.88 (s, 1H), 6.94-6.96 (m, 3H), 7.02-7.06 (m, 1H), 7.07-7.12 (m, 3H).7.24-7.33 (m, 4H), 7.44-7,46 (m, 1H), 7.90 (d, J = 8.0 Hz, 1H) ; 13C NMR(CDCl3, 100 MHz) δ: 21.4, 28.2, 35.7, 44.5, 52.5, 56.8, 84.1, 115.1, 115.5,121.1, 122.8, 122.9, 123.9, 124.7, 125.3, 126.0, 126.2, 126.9, 127.1, 128.5,128.7, 128.8, 129.5, 132.5, 137.3, 137.8, 138.0, 139.1, 139.8, 141.7, 149.3,167.7, 168.1, 176.0. HRMS (ESI-TOF) m/z: Calcd. for C40H37ClN2NaO6 [M+Na]+:699.2238; Found: 699.2238.
本实施例制备化合物3cj:淡黄色固体, 产率60%; 熔点: 169.8-169.9 oC; 1HNMR (CDCl3, 400 MHz) δ: 1.24 (t, J = 7.2 Hz, 3H), 1.61 (s, 9H), 2.26 (s, 6H),1.54 (s, 3H), 4.03-4.08 (m, 2H), 4.15 (d, J = 13.2 Hz, 1H), 4.83 (d, J = 13.2Hz, 1H), 6.76 (t, J = 7.8 Hz, 1H), 6.89 (s, 1H), 6.94-6.97 (m, 3H), 7.08-7.16(m, 2H), 7.26-7.32 (m, 1H), 7.42-7.44 (m, 1H),7.91(d, J = 8.0 Hz, 1H); 13C NMR(CDCl3, 100 MHz) δ: 13.6, 21.5, 28.0, 29.3, 35.5, 56.6, 62.0, 84.0, 115.0,115.5, 121.0, 122.6, 122.8, 123.9, 124.7, 125.4, 125.8, 128.6, 128.9, 129.5,132.1, 138.0, 138.5, 139.3, 139.9, 141.6, 149.3, 167.3, 167.6, 175.8. HRMS(ESI-TOF) m/z: Calcd. for C35H35ClN2NaO6 [M+Na]+: 637.2081; Found: 637.2084.
本实施例制备化合物3da:淡黄色固体, 产率52%; 熔点: 211.4-212.5 oC; 1HNMR (CDCl3, 400 MHz) δ: 1.53 (s, 9H), 3.09 (s, 3H), 3.58 (s, 3H), 4.06 (d, J= 13.6 Hz, 1H), 4.79(d, J = 13.2 Hz, 1H), 6.66 (d, J = 8.0 Hz, 1H), 6.79-6.83(m, 1H), 6.89-6.96 (m, 2H), 7.14-7.27 (m, 5H), 7.32-7.34 (m, 2H), 7.80-7.83(m, 1H) ; 13C NMR (CDCl3, 100 MHz) δ: 25.9, 28.1, 35.2, 52.4, 57.1, 84.3,108.2, 113.4 (d, J CF = 37.5 Hz), 115.3, 115.5, 116.4, 119.9, 122.4 (d, J CF =24.8 Hz), 127.0, 128.0, 128.8, 130.4, 130.6, 135.9, 138.8, 142.9, 159.5 (d,J CF = 241.4 Hz), 167.1, 168.1, 175.5. HRMS (ESI-TOF) m/z: Calcd. forC32H29FN2NaO6 [M+Na]+: 579.1907; Found: 579.1909.
本实施例制备化合物3ea:淡黄色固体, 产率54%; 熔点: 246.1-246.4 oC; 1HNMR (CDCl3, 400 MHz) δ: 1 .62 (s, 9H), 2.17 (s, 3H), 3.18 (s, 3H), 3,65 (s,3H), 4.17 (d, J = 13.6Hz, 1H), 4.78 (d, J = 13.6 Hz, 1H), 6.75 (d, J = 7.6Hz, 1H), 6.88-6.92 (m, 1H), 7.05 (d, J = 7.6 Hz, 1H), 7.10-7.12 (m, 1H),7.23-7.35 (m, 5H), 7.46 (t, J = 4.4 Hz, 2H), 7.78 (d, J = 8.4 Hz, 1H); 13C NMR(CDCl3, 100 MHz) δ: 21.1, 25.8, 28.1, 35.4, 52.3, 57.0, 83.9, 107.9, 114.9,120.1, 122.1, 122.7, 126.5, 127.2, 127.7, 128.6, 128.7, 129.2, 130.2, 133.4,137.6, 139.4, 139.6, 142.8, 149.3, 167.1, 168.1, 175.9. HRMS (ESI-TOF) m/z:Calcd. for C33H32N2NaO6 [M+Na]+: 575.2158; Found: 575.2168.
本实施例制备化合物3eb:淡黄色固体, 产率64%; 熔点: 168.9-169.0 oC; 1HNMR (CDCl3, 400 MHz) δ: 1.60 (s, 9H), 2.25 (s, 3H), 3.15 (s, 3H), 3.64 (s,3H), 4.29 (d, J = 13.2 Hz, 1H), 4.69(d, J = 13.2 Hz, 1H), 6.65 (d, J = 8.4Hz, 1H), 6.99 (d, J = 2.0 Hz, 1H), 7.09-7.12 (m, 1H), 7.19-7.22 (m, 1H),7.25-7.34 (m, 4H). 7.41-7.44 (m, 2H), 7.76 (d, J = 8.4 Hz, 1H); 13C NMR(CDCl3, 100 MHz) δ: 21.0, 25.9, 28.0, 35.5, 52.5, 55.9, 84.0, 108.7, 114.9,121.2, 123.2, 126.4, 127.1, 127.5, 127.8, 128.5, 128.6, 129.3, 129.8, 133.4,137.5, 139.3, 141.0, 141.2, 149.2, 166.6, 167.7, 175.7. HRMS (ESI-TOF) m/z:Calcd. for C33H31ClN2NaO6 [M+Na]+: 609.1768; Found: 609.1781.
本实施例制备化合物3fh:淡黄色固体, 产率72%; 熔点: 120.4-123.2oC; 1H NMR(CDCl3, 400 MHz) δ: 1.53 (s, 9H), 3.14 (d, J = 12.8 Hz, 1H), 3.27 (d, J =12.8 Hz, 1H), 3.61 (d, J = 13.2 Hz, 1H), 3.74 (s, 3H), 4.94 (d, J = 13.6 Hz,1H), 5.36-5.49 (m, 2H), 6.70-6.78 (m, 3H), 6.91 (d, J = 0.8 Hz, 1H), 6.91-6.93 (m, 5H), 6.98-6. 7.17 (m, 3H), 7.25-7.35 (m, 3H), 7.45-7.48 (m, 2H); 13CNMR (CDCl3, 100 MHz) δ: 28.0, 34.0, 44.6, 47.3, 52.5, 55.5, 83.5, 114.4,115.5, 121.0, 122.8, 123.8, 124.2, 124.8, 126.2, 126.8, 127.1, 127.5, 128.1,128.4, 128.6, 129.7, 132.4, 134.1, 137,1, 137.7, 139.7, 141.5, 148.5, 168.0,177.0. HRMS (ESI-TOF) m/z: Calcd. for C39H35ClN2NaO6 [M+Na]+: 685.2081; Found:685.2081.
本实施例制备化合物3aa-1:淡黄色固体, 产率24%; 熔点: 218.2-218.7oC; 1HNMR (DMSO-d 6 , 400 MHz) δ: 3.12 (s, 3H), 3.50 (s, 3H), 4.08 (d, J = 13.2 Hz,1H), 4.52 (d, J = 13.2 Hz, 1H), 6.86 (d, J = 7.2 Hz, 1H), 6.88-6.95 (m, 3H),6.98 (d, J = 8.0 Hz, 1H), 7.14-7.18 (m, 1H), 7.25-7.39 (m, 7H), 10.54 (br s,1H); 13C NMR (DMSO-d 6 , 100 MHz) δ: 25.9, 33.8, 52.2, 56.3, 108.9, 109.8,119.1, 121.3, 121.9, 122.2, 125.4, 125.8, 126.5, 127.4, 128.5, 130.5, 130.6,139.9, 140.4, 142.3, 142.5, 166.4, 167.5, 178.2. HRMS (ESI-TOF) m/z: Calcd.for C27H22N2NaO4 [M+Na]+: 461.1477; Found: 461.1468.
本发明的式(1)化合物具有重要的生物活性,体外对人前列腺(PC-3), 人肺癌细胞(A549)以及人白血病细胞(K562)共三株肿瘤细胞的细胞毒性试验表明:此类式(1)所示的结构的3,3′-双取代氧化吲哚与3-烯键氧化吲哚拼接衍生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。
本发明的式(1)化合物或其可药用盐及其溶剂化物可以与药学上常用的辅料或载体结合,制备得到具有肿瘤细胞生长抑制活性从而可以用于防治肿瘤的药物组合物。上述各类药物组合物可以采用注射剂、片剂、胶囊剂、气雾剂、膜剂、滴丸剂、外用搽剂、软膏剂等剂型药物,还可以采用现代制药界所公知的控释剂或缓释剂或纳米剂。
本发明的式(1)化合物或其可药用盐及其溶剂化物可以与现已上市的抗肿瘤药物如铂类药物顺铂(DDP)、喜树碱类药物伊立替康(Irinatecan、CPT-11)、长春花碱类药物失碳长春花碱(Vinorebine, NVB诺维本)、脱氧胞昔类药物吉西他滨(Gemcitabine, Gemzar,健择)、足叶乙甙(Etoposide)、紫杉醇(Paclitaxel)等联合使用,制备得到具有肿瘤生长抑制活性的细胞毒性组合物,可用于治疗肿瘤疾病。该类药物组合物可以采用注射剂、片剂、胶囊剂、气雾剂、膜剂、滴丸剂、外用搽剂、软膏剂等剂型药物,还可以采用现代制药界所公知的控释剂或缓释剂或纳米剂。
药理实施例1:化合物3aa、3ba或3ca对PC-3细胞的细胞毒性
PC-3(人前列腺癌)细胞用RPMI-1640培养基培养,培养基中含10%的胎牛血清,100U/mL 青霉素及100U/mL的链霉素。细胞以每孔5000个细胞的浓度加入到96孔中,在37oC 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3aa、3ba或3ca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6.25 μmol/L, 12.5 μmol/L, 25 μmol/L, 50 μmol/L 和100 μmol/L。48小时后,每孔加入10 μL MTT (5 mg/mL) 的磷酸盐缓冲液,再继续在37 oC 培养4小时后,离心5分钟除去未转化的MTT,每孔中加入150 μL 二甲基亚砜。以溶解还原的MTT 晶体甲臜(formazan),用酶标仪在490 nm波长测定OD值。其中化合物3aa、3ba或3ca对PC-3细胞半抑制浓度IC50由spss软件(19版本)分析得到。 化合物3aa对PC-3肿瘤细胞的IC50为29.8 μmol/L;化合物3ba对PC-3肿瘤细胞的IC50为30.9 μmol/L;化合物3ca对PC-3肿瘤细胞的IC50为30.4 μmol/L;而阳性对照顺铂对PC-3肿瘤细胞的IC50为28.4 μmol/L。
实验结论:PC-3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3,3′-双取代氧化吲哚与3-烯键氧化吲哚拼接化合物对PC-3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。
药理实施例2:化合物3aa、3ba或3ca对A549细胞的细胞毒性
A549(人非小细胞肺癌肺癌)用DMEM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4000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。具体方法如药理实施例1。化合物3aa对A549肿瘤细胞的IC50为49.1 μmol/L;化合物3ba对A549肿瘤细胞的IC50为50.9 μmol/L;化合物3ca对A549肿瘤细胞的IC50为60.4 μmol/L;而阳性对照顺铂对A540肿瘤细胞的IC50为24.5 μmol/L。
实验结论:A549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3,3′-双取代氧化吲哚与3-烯键氧化吲哚拼接化合物对A549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。
药理实施例3:化合物3aa、3ba或3ca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,100 U/mL的青霉素和100 U/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。具体方法如药理实施例1。化合物3aa对K562肿瘤细胞的IC50为72.1 μmol/L;化合物3ba对PC-3肿瘤细胞的IC50为31.3 μmol/L;化合物3ca对PC-3肿瘤细胞的IC50为52.5 μmol/L;而阳性对照顺铂对K562肿瘤细胞的IC50为20.6 μmol/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3,3′-双取代氧化吲哚与3-烯键氧化吲哚拼接化合物对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这三株肿瘤细胞都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。