CN108864110B - 萘醌并吡喃衍生物及其合成方法与应用 - Google Patents

萘醌并吡喃衍生物及其合成方法与应用 Download PDF

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CN108864110B
CN108864110B CN201810680134.0A CN201810680134A CN108864110B CN 108864110 B CN108864110 B CN 108864110B CN 201810680134 A CN201810680134 A CN 201810680134A CN 108864110 B CN108864110 B CN 108864110B
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苑睿
许江飙
张鹏
宛瑜
吴翚
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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    • B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78—Ring systems having three or more relevant rings
    • C07D311/92—Naphthopyrans; Hydrogenated naphthopyrans
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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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
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Abstract

萘醌并吡喃衍生物及其合成方法与应用，所述萘醌并吡喃衍生物结构式如下式7或9所示，其是由2‑羟基‑1,4‑萘醌、苯并噻唑‑2‑乙腈与芳醛或取代靛红在乙醇中进行加热反应制得。本发明的萘醌并吡喃衍生物对三阴性乳腺癌(MDA‑MB‑231)，乳腺癌(MCF‑7)，人肺癌(A549)细胞株具有较好的抑制效果，具有抗癌活性，且对正常人体细胞的毒性较低，在制备新一代抗肺癌和乳腺癌特异性药物方面具有潜在的应用前景。

Description

萘醌并吡喃衍生物及其合成方法与应用
技术领域
本发明属于化学合成及生物医药领域，具体涉及萘醌并吡喃衍生物及其合成方法与应用。
背景技术
癌症，尤其是一些恶性肿瘤，是科学家久攻不破的难点，目前，化疗是治疗癌症主要的有效措施之一。但是，临床上可供选择的化疗药物的数量非常有限，因此发现新的可以用于临床使用的化疗药物是目前癌症研究中的热点。其中，萘醌并吡喃衍生物是极具潜力的先导药物分子骨架。
萘醌衍生物具有抗癌、抗疟、抗血小板、抗寄生虫、抗菌、抗真菌、抗炎等活性。萘醌骨架广泛存在于天然产物中，如β-拉帕醌(A)、去氢-α-拉帕醌(B)，展座盘菌素(C)、WS-5995A(D)、链黑菌素(E)等。吡喃骨架广泛存在于天然产物中，如维生素E、生物碱、花青素和黄酮类等。最近，许多吡喃衍生物被应用到医药化学及有机合成，其中一些可以用作利尿剂、抗痉挛药、抗癌药、抗凝剂等。萘醌并吡喃衍生物由于其潜在的生物活性和广泛的应用前景，近年来受到人们的广泛关注。
萘醌并吡喃衍生物由于其潜在的生物活性和广泛的应用前景，近年来受到人们的广泛关注，因此大量的合成方法被报道出来。使用的催化剂主要有三乙胺、DBU、邻苯二甲酰亚胺钾盐、Fe3O4纳米颗粒、[bmim]OH离子液体、Zn(L-proline)2、脂肪酶、尿素、微波等等。但是，这些方法仍旧存在一定局限性和缺点，如催化剂量大、合成步骤繁琐、催化剂毒性大、产率低等。因此，开发一种新型高效、低毒的合成方法具有一定的研究价值和应用前景。
发明内容
发明人通过大量实验研究研发了一种萘醌并吡喃衍生物的合成方法，并设计合成了多种萘醌并吡喃衍生物。体外实验表明，本发明的多种萘醌并吡喃衍生物对肿瘤细胞株具有较好的抑制效果，在制备抗肿瘤药物方面具有潜在的应用前景。
具体而言，本发明的萘醌并吡喃衍生物，其结构式为下式之一：
Figure GDA0002222374480000021
其中，
Figure GDA0002222374480000022
上述式7所示萘醌并吡喃衍生物的合成方法，包括，在催化剂存在下，式4所示2-羟基-1,4-萘醌、式5所示芳醛和式6所示乙腈类化合物于有机溶剂中反应得目标化合物7
Figure GDA0002222374480000031
其中，
Figure GDA0002222374480000032
上述式9所示萘醌并吡喃衍生物的合成方法，包括步骤：在催化剂存在下，式4所示2-羟基-1,4-萘醌、式8所示取代靛红和式6所示乙腈类化合物于有机溶剂中反应得目标化合物9
Figure GDA0002222374480000033
其中，
Figure GDA0002222374480000041
本发明的萘醌并吡喃衍生物合成方法，所用有机溶剂为乙醇。
本发明的萘醌并吡喃衍生物合成方法，所用催化剂为下式3h所示化合物
Figure GDA0002222374480000042
本发明的萘醌并吡喃衍生物合成方法，其后处理过程如下：反应结束后，冷却至室温，旋干多余溶剂得到粗产物，柱层析纯化得纯化产物。
本发明还提供了上述萘醌并吡喃衍生物在制备抗肿瘤药物中的应用。
与现有技术相比，本发明的有益效果：本发明的萘醌并吡喃衍生物合成工艺所需反应条件温和、反应时间短、产率高，具有广阔的工业化/规模化应用前景；本发明的萘醌并吡喃衍生物对三阴性乳腺癌(MDA-MB-231)，乳腺癌(MCF-7)，人肺癌(A549)细胞株具有较好的抑制效果，具有抗癌活性，且对正常人体细胞的毒性较低，在制备新一代抗肺癌和乳腺癌特异性药物方面具有潜在的应用前景。
具体实施方式：
实施例1酰胺-朝格尔碱衍生物3a、3b的合成
Figure GDA0002222374480000043
干燥的双颈瓶中加入氮杂环胺2(2mmol)，氢化钠(60％石蜡混合物，4mmol)，氩气保护下加入无水四氢呋喃(10mL)，室温下搅拌反应2h，将中间体1(1mmol)溶解在5mL无水四氢呋喃中，再将溶液缓慢滴入双颈瓶中，滴完后转移至油浴锅，氩气保护下加热回流24h(TLC跟踪)。减压蒸干溶剂，加水用1M NaHSO4溶液调节pH至中性，二氯甲烷萃取三次(每次100mL)，合并有机相，无水硫酸钠干燥，旋干溶剂，得粗产物，柱层析纯化(V乙酸乙酯:V甲醇＝5:1)，得到纯产物3a或3b。
实施例2酰胺-朝格尔碱衍生物3c、3d、3e、3f的合成
Figure GDA0002222374480000051
干燥的双颈瓶中加入氮杂环胺2a(2mmol)，氢化钠(60％石蜡混合物，4mmol)，氩气保护下加入无水四氢呋喃(10mL)，室温下搅拌反应2h，将中间体1(1mmol)溶解在5mL无水四氢呋喃中，再将溶液缓慢滴入双颈瓶中，滴完后转移至油浴锅，氩气保护下加热回流24h(TLC跟踪)。减压蒸干溶剂，加水用1M NaHSO4溶液调节pH至中性，二氯甲烷萃取三次(每次100mL)，合并有机相，无水硫酸钠干燥，旋干溶剂，得粗产物，柱层析纯化(V乙酸乙酯:V甲醇＝5:1)，得到纯产物3c、3d、3e或3f。
实施例3酰胺-朝格尔碱衍生物3g、3h的合成
Figure GDA0002222374480000052
干燥的双颈瓶中加入氮杂环胺2b(2mmol)，氢化钠(60％石蜡混合物，4mmol)，氩气保护下加入无水DMF(10mL)，室温下搅拌反应2h，将中间体1(1mmol)溶解在5mL无水DMF中，再将溶液缓慢滴入双颈瓶中，滴完后转移至油浴锅，氩气保护下100℃加热24h(TLC跟踪)。减压蒸干溶剂，加水用1M NaHSO4溶液调节pH至中性，过滤得到粗产物，柱层析纯化(V乙酸乙酯:V甲醇＝5:1)，得到纯产物3g或3h。
实施例4萘醌并吡喃衍生物7的合成
Figure GDA0002222374480000061
将2-羟基-1,4-萘醌4(1.0mmol)、芳醛5(1mmol)、乙腈类化合物6(1.0mmol)、实施例3中的催化剂3h(10mol％)和乙醇(5mL)加入干燥的圆底烧瓶中，加热搅拌回流，反应结束(TLC跟踪)，冷却至室温，旋干多余溶剂得到粗产物，以V石油醚:V乙酸乙酯＝1:2的展开剂进行柱层析纯化，得目标化合物7。
实施例5萘醌并吡喃衍生物9的合成
Figure GDA0002222374480000062
其中，
Figure GDA0002222374480000071
将2-羟基-1,4-萘醌4(1.0mmol)、取代靛红8(1mmol)、乙腈类化合物6(1.0mmol)、实施例3中的催化剂3h(10mol％)和乙醇(5mL)加入干燥的圆底烧瓶中，加热搅拌回流，反应结束(TLC跟踪)，冷却至室温，旋干多余溶剂得到粗产物，以V石油醚:V乙酸乙酯＝1:2的展开剂进行柱层析纯化，得目标化合物9。
实施例6产物结构表征
3a
8-(吡啶-2-基氨基甲酰基)-6H,12H-5,11-亚甲基二苯并[b,f][1,5]二氮芳辛-2-甲酸乙酯
Figure GDA0002222374480000072
黄色固体,熔点158.1-159.3℃,1H NMR(400MHz,DMSO-d6)δ10.57(s,1H),8.35(d,J＝3.7Hz,1H),8.14(d,J＝8.3Hz,1H),7.81(t,J＝8.2Hz,2H),7.76-7.65(m,2H),7.61(s,1H),7.30-7.18(m,2H),7.17-7.08(m,1H),4.80-4.65(m,2H),4.37-4.18(m,6H),1.26(t,J＝7.0Hz,3H).13C NMR(100MHz,CDCl3)δ166.45,166.02,152.66,149.17,148.62,147.79,136.94,130.79,129.54,129.32,129.20,129.13,127.32,125.55,120.85,119.08,115.69,114.86,113.91,67.99,60.92,60.22,57.66,14.68.HRMS(ESI)m/z:calcd for C24H22N4O3[M+H]+:415.1770；found:415.1781.
3b
N2,N8二(吡啶-2-基)-6H,12H-5,11-亚甲基二苯并[b,f][1,5]二氮芳辛-2,8-二甲酰胺
Figure GDA0002222374480000081
黄色固体,熔点165.0-166.2℃,1H NMR(400MHz,DMSO-d6)δ10.58(s,2H),8.35(d,J＝3.7Hz,2H),8.15(d,J＝8.3Hz,2H),7.81(t,J＝9.7Hz,4H),7.71(s,2H),7.26(d,J＝8.4Hz,2H),7.18-7.07(m,2H),4.75(d,J＝16.7Hz,2H),4.29(d,J＝18.5Hz,4H).13C NMR(100MHz,DMSO-d6)δ165.39,152.21,151.56,147.86,138.00,128.93,127.76,127.23,126.84,124.50,119.58,114.44,65.87,58.08.HRMS(ESI)m/z:calcd for C24H22N4O3[M+H]+:463.1882；found:463.1888.
3c
N2,N8-双(3-甲基异恶唑-5-基)-6H,12H-5,11-亚甲基二苯并[b,f][1,5]二氮芳辛-2,8-二甲酰胺
Figure GDA0002222374480000082
黄色固体,熔点287.3-289.6℃,1H NMR(400MHz,DMSO-d6)δ11.71(s,2H),7.79(d,J＝9.2Hz,2H),7.67(s,2H),7.29(d,J＝8.5Hz,2H),6.25(s,2H),4.75(d,J＝16.3Hz,2H),4.31(d,J＝19.2Hz,4H),2.19(s,6H).13C NMR(100MHz,DMSO-d6)δ162.95,161.55,160.59,152.07,128.03,127.38,127.33,126.92,124.74,112.71,89.35,58.05,11.33.HRMS(ESI)m/z:calcd for C25H22N6O4[M+H]+:471.1781；found:471.1796.
3d
N2,N8-双(1-甲基-1H-吡唑-5-基)-2,8-二甲酰胺-6H,12H-5,11-亚甲基二苯并[b,f][1,5]二氮芳辛
Figure GDA0002222374480000083
黄色固体,熔点245.7-246.9℃,1H NMR(400MHz,DMSO-d6)δ10.14(s,2H),7.77(d,J＝7.9Hz,2H),7.63(s,2H),7.37(s,2H),7.30(d,J＝8.2Hz,2H),6.17(s,2H),4.76(d,J＝16.6Hz,2H),4.32(d,J＝22.5Hz,4H),3.63(s,6H).13C NMR(100MHz,DMSO-d6)δ165.04,151.62,137.29,136.25,128.27,127.98,127.05,126.72,124.68,100.32,65.89,58.20,35.56.HRMS(ESI)m/z:calcd for C25H24N8O2[M+H]+:469.2100；found:469.2108.
3e
N2,N8-二(4H-1,2,4-三唑-4-基)-6H,12H-5,11-亚甲基二苯并[b,f][1,5]二氮芳辛-2,8-二甲酰胺
Figure GDA0002222374480000091
黄色固体,熔点>300℃,1H NMR(400MHz,DMSO-d6)δ11.84(s,2H),8.72(s,4H),7.73(d,J＝8.1Hz,2H),7.60(s,2H),7.34(d,J＝8.4Hz,2H),4.77(d,J＝16.8Hz,2H),4.40-4.26(m,4H).13C NMR(100MHz,DMSO-d6)δ170.31,152.27,143.83,128.29,127.11,126.55,125.62,124.90,65.81,58.19.HRMS(ESI)m/z:calcd forC21H18N10O2[M+H]+:443.1692；found:443.1685.
3f
N2,N8双(4-甲基嘧啶-2-基)-2,8-二甲酰胺-6H,12H-5,11-亚甲基二苯并[b,f][1,5]二氮芳辛
Figure GDA0002222374480000092
黄色固体,熔点252.3-253.8℃,1H NMR(400MHz,DMSO-d6)δ10.71(s,2H),8.53(d,J＝4.8Hz,2H),7.75(d,J＝8.2Hz,2H),7.64(s,2H),7.24(d,J＝8.4Hz,2H),7.10(d,J＝4.7Hz,2H),4.74(d,J＝16.6Hz,2H),4.29(d,J＝18.9Hz,4H),2.41(s,6H).13C NMR(100MHz,DMSO-d6)δ168.04,164.74,157.90,157.76,151.64,129.13,127.73,127.43,127.03,124.47,116.50,65.83,58.04,23.47.HRMS(ESI)m/z:calcd forC27H24N8O2[M+H]+:493.2100；found:493.2110.
3g
N2,N8-双(4-氧代-4,5-二氢-1,3,5-三嗪-2-基)-6H,12H-5,11-亚甲基二苯并[b,f][1,5]二氮芳辛-2,8-二甲酰胺
Figure GDA0002222374480000093
黄色固体,熔点238.2-240.7℃,1H NMR(400MHz,DMSO-d6)δ10.25(s,2H),9.10(s,2H),7.71(t,J＝7.6Hz,2H),7.59(d,J＝9.2Hz,2H),7.42-7.16(m,4H),4.80-4.64(m,2H),4.29-4.20(m,4H).13C NMR(100MHz,DMSO-d6)δ166.09,158.22,128.49,128.17,128.10,127.91,127.50,126.90,124.88,124.71,65.71,58.02.HRMS(ESI)m/z:calcd for C23H18N10O4[M+H]+:499.1591；found:499.1609.
3h
N2,N8-二(1H-四唑-5-基)-6H,12H-5,11-亚甲基二苯并[b,f][1,5]二氮芳辛-2,8-二甲酰胺
Figure GDA0002222374480000101
黄色固体,熔点250.5-252.0℃,1H NMR(400MHz,DMSO-d6)δ11.99(s,2H),7.87(d,J＝6.8Hz,2H),7.81-7.67(m,2H),7.58(s,2H),7.36-7.18(m,2H),4.74(t,J＝17.1Hz,2H),4.30(d,J＝13.8Hz,4H),2.41(s,6H).13C NMR(100MHz,DMSO-d6)δ164.78,152.28,151.31,128.53,128.00,127.61,127.12,124.74,65.73,58.01.HRMS(ESI)m/z:calcd forC19H16N12O2[M+H]+:445.1597；found:445.1584
7l
2-氨基-5,10-二氧代-4-(对甲苯基)-5,10-二氢-4H-苯并[g]苯并吡喃-3-羧酸乙酯
Figure GDA0002222374480000102
红色固体,熔点206.4-208.2℃,1H NMR(400MHz,DMSO-d6)δ8.03(d,J＝4.0Hz,1H),7.96-7.74(m,5H),7.15(d,J＝7.1Hz,2H),7.03(d,J＝7.1Hz,2H),4.86(s,1H),4.10-3.86(m,2H),2.20(s,3H),1.14(t,J＝6.6Hz,3H).13C NMR(100MHz,DMSO-d6)δ182.76,177.02,167.70,158.90,148.38,141.94,135.52,134.47,134.07,131.04,130.52,128.63,128.00,125.99,125.79,125.22,76.57,59.03,34.00,20.54,14.22.HRMS(ESI)m/z:calcd for C23H19NO5[M+H]+:390.1341；found:358.1350.
7m
2-氨基-4-(3-氯苯基)-5,10-二氧代-5,10-二氢-4H-苯并[g]苯并吡喃-3-羧酸乙酯
Figure GDA0002222374480000103
橙红色固体,熔点198.9-200.1℃,1H NMR(400MHz,DMSO-d6)δ8.04(d,J＝4.4Hz,1H),7.98-7.75(m,5H),7.36-7.15(m,4H),4.86(s,1H),4.00(q,J＝9.0,7.3Hz,2H),1.13(t,J＝6.9Hz,3H).13C NMR(100MHz,DMSO-d6)δ182.77,176.89,167.49,158.84,148.83,147.31,134.42,134.09,132.44,130.99,130.68,129.91,128.22,126.97,126.43,126.01,125.81,123.83,75.93,59.10,34.58,14.13.HRMS(ESI)m/z:calcd forC22H16ClNO5[M+H]+:410.0795；found:410.0786.
7n
2-氨基-4-(3-硝基苯基)-5,10-二氧代-5,10-二氢-4H-苯并[g]苯并吡喃-3-羧酸乙酯
Figure GDA0002222374480000111
橙红色固体,熔点215.6-217.1℃,1H NMR(400MHz,DMSO-d6)δ8.11(s,1H),8.07-7.91(m,4H),7.91-7.69(m,4H),7.53(t,J＝7.9Hz,1H),4.98(s,1H),3.99(q,2H),1.10(t,J＝6.9Hz,3H).13C NMR(100MHz,DMSO-d6)δ182.75,176.87,167.36,158.86,148.98,147.36,147.08,135.13,134.42,134.10,130.96,130.68,129.52,125.99,125.79,123.27,123.07,121.53,75.61,59.18,34.88,14.05.HRMS(ESI)m/z:calcd for C22H16N2O7[M+H]+:421.1036；found:421.1042.
7o
2-氨基-4-(4-氰基苯基)-5,10-二氧代-5,10-二氢-4H-苯并[g]苯并吡喃-3-羧酸乙酯
Figure GDA0002222374480000112
橙色固体,熔点220.2-221.9℃,1H NMR(400MHz,DMSO-d6)δ8.04(d,J＝5.4Hz,1H),7.96(s,2H),7.91-7.76(m,3H),7.71(d,J＝8.0Hz,2H),7.49(d,J＝8.1Hz,2H),4.92(s,1H),3.99(q,J＝6.8Hz,2H),1.11(t,J＝7.0Hz,3H).13C NMR(100MHz,DMSO-d6)δ182.70,176.84,167.39,158.88,150.43,148.91,134.46,134.13,131.98,130.93,130.63,129.45,126.02,125.79,123.52,118.79,109.19,75.51,59.15,35.09,14.15.HRMS(ESI)m/z:calcd for C23H16N2O5[M+H]+:401.1137；found:401.1145.
7p
2-氨基-4-(4-溴苯基)-5,10-二氧代-5,10-二氢-4H-苯并[g]苯并吡喃-3-羧酸乙酯
Figure GDA0002222374480000113
橙色固体,熔点239.7-241.5℃,1H NMR(400MHz,DMSO-d6)δ8.05(d,J＝7.3Hz,1H),7.97-7.78(m,5H),7.43(d,J＝8.0Hz,2H),7.24(d,J＝8.0Hz,2H),4.88(s,1H),3.56(s,3H).13C NMR(100MHz,DMSO-d6)δ182.36,176.41,157.38,150.01,145.73,134.67,134.16,131.41,130.89,130.57,129.90,126.03,125.68,121.19,119.97,119.19,75.49,56.91,36.00.HRMS(ESI)m/z:calcd for C21H14BrNO5[M+H]+:440.0134；found:440.0141.
7q
2-氨基-4-(3-氯苯基)-5,10-二氧代-5,10-二氢-4H-苯并[g]苯并吡喃-3-羧酸乙酯
Figure GDA0002222374480000121
橙色固体,熔点212.3-214.4℃,1H NMR(400MHz,DMSO-d6)δ8.07-7.90(m,1H),7.90(d,J＝8.3Hz,3H),7.86-7.77(m,2H),7.34-7.14(m,4H),4.88(s,1H),3.56(s,3H).13C NMR(100MHz,DMSO-d6)δ182.73,176.85,167.79,159.02,148.82,147.20,134.40,134.08,132.65,130.97,130.67,129.99,127.84,126.88,126.54,125.99,125.82,124.00,75.75,50.76,34.40.HRMS(ESI)m/z:calcd for C21H14ClNO5[M+H]+:396.0639；found:396.0650.
7r
2-氨基-4-(3-硝基苯基)-5,10-二氧代-5,10-二氢-4H-苯并[g]苯并吡喃-3-羧酸乙酯
Figure GDA0002222374480000122
橙色固体,熔点218.7-219.9℃,1H NMR(400MHz,DMSO-d6)δ8.12-7.92(m,5H),7.91-7.71(m,4H),7.54(t,J＝7.9Hz,1H),5.00(s,1H),3.55(s,3H).13C NMR(100MHz,DMSO-d6)δ182.73,176.86,167.66,159.00,148.95,147.57,146.94,135.02,134.42,134.10,130.95,130.68,129.56,125.99,125.81,123.41,122.75,121.61,75.47,50.79,34.73.HRMS(ESI)m/z:calcd for C21H14N2O7[M+H]+:407.0879；found:407.0885.
7s
2-氨基-4-(4-氰基苯基)-5,10-二氧代-5,10-二氢-4H-苯并[g]苯并吡喃-3-羧酸乙酯
Figure GDA0002222374480000123
橙色固体,熔点231.8-233.1℃,1H NMR(400MHz,DMSO-d6)δ8.04(d,J＝5.9Hz,1H),7.95(s,2H),7.92-7.78(m,3H),7.71(d,J＝8.0Hz,2H),7.49(d,J＝8.0Hz,2H),4.95(s,1H),3.55(s,3H).13C NMR(100MHz,DMSO-d6)δ182.68,176.81,167.70,158.98,150.31,148.97,134.46,134.14,132.10,130.93,130.64,129.24,126.02,125.81,123.61,118.76,109.27,75.40,50.76,34.94.HRMS(ESI)m/z:calcd for C22H14N2O5[M+H]+:387.0981；found:387.0992.
7t
2-氨基-5,10-二氧代-4-(对甲苯基)-5,10-二氢-4H-苯并[g]苯并吡喃-3-羧酸乙酯
Figure GDA0002222374480000131
橙红色固体,熔点225.5-227.0℃,1H NMR(400MHz,DMSO-d6)δ8.08-8.00(m,1H),7.94-7.80(m,5H),7.15(d,J＝7.4Hz,2H),7.04(d,J＝7.5Hz,2H),4.87(s,1H),3.55(s,3H),2.20(s,3H).13C NMR(100MHz,DMSO-d6)δ182.77,177.01,168.02,159.04,148.37,141.82,135.61,134.49,134.11,131.02,130.51,128.78,127.81,126.01,125.81,125.32,76.38,50.72,33.84,20.53.HRMS(ESI)m/z:calcd for C22H17NO5[M+H]+:376.1185；found:376.1193.
7u
2-氨基-3-(苯并[d]噻唑-2-基)-4-苯基-4H-苯并[g]苯并吡喃-5,10-二酮
Figure GDA0002222374480000132
紫色固体,熔点240.5-241.1℃,1H NMR(400MHz,DMSO-d6)δ8.72(s,2H),8.08-8.02(m,1H),8.00-7.89(m,3H),7.86-7.82(m,2H),7.46(d,J＝7.4Hz,2H),7.28(t,J＝7.5Hz,2H),7.19-7.10(m,3H),4.99(s,1H).13C NMR(100MHz,DMSO-d6)δ182.70,177.05,167.73,153.87,152.68,147.78,142.76,134.57,134.14,131.45,128.71,128.32,127.70,127.10,126.80,126.12,125.88,125.71,123.96,123.05,121.42,120.21,79.97,37.85.HRMS(ESI)m/z:calcd for C26H16N2O3S[M+H]+:437.0960；found:437.0967.
7v
2-氨基-3-(苯并[d]噻唑-2-基)-4-(3-氯苯基)-4H-苯并[g]苯并吡喃-5,10-二酮
Figure GDA0002222374480000133
紫色固体,熔点225.5-227.0℃,1H NMR(400MHz,DMSO-d6)δ8.77(s,2H),8.07(s,1H),8.01-7.92(m,2H),7.90-7.79(m,3H),7.42(m,3H),7.32(t,J＝7.7Hz,1H),7.24(d,J＝6.3Hz,2H),5.01(s,1H).13C NMR(100MHz,DMSO-d6)δ182.72,176.94,167.47,153.91,152.65,148.11,145.14,134.53,134.16,132.85,131.40,131.01,130.65,130.17,128.47,127.61,127.20,126.19,126.06,125.91,123.13,122.92,121.49,120.27,79.38,37.71.HRMS(ESI)m/z:calcd for C26H15ClN2O3S[M+H]+:471.0570；found:471.0581.
7w
2-氨基-3-(苯并[d]噻唑-2-基)-4-(3-溴苯基)-4H-苯并[g]苯并吡喃-5,10-二酮
Figure GDA0002222374480000141
紫色固体,熔点241.4-242.9℃,1H NMR(400MHz,DMSO-d6)δ8.76(s,2H),8.05(d,J＝7.8Hz,1H),8.00-7.78(m,6H),7.44(m,5H),4.99(s,1H).13C NMR(100MHz,DMSO-d6)δ182.70,173.93,172.93,167.50,153.86,153.66,152.66,147.91,142.11,134.58,134.17,131.90,131.40,131.19,130.98,130.56,126.17,126.07,125.88,123.21,123.11,121.45,120.26,112.70,79.46,37.44.HRMS(ESI)m/z:calcd forC26H15BrN2O3S[M+H]+:515.0065；found:5115.0074.
7x
2-氨基-3-(苯并[d]噻唑-2-基)-4-(3-硝基苯基)-4H-苯并[g]苯并吡喃-5,10-二酮
Figure GDA0002222374480000142
紫色固体,熔点224.0-226.1℃,1H NMR(400MHz,DMSO-d6)δ8.83(s,2H),8.03(d,J＝8.3Hz,2H),7.99-7.77(m,7H),7.60(t,J＝7.1Hz,1H),7.38(t,J＝7.3Hz,1H),7.21(t,J＝7.3Hz,1H),5.13(s,1H).13C NMR(100MHz,DMSO-d6)δ182.70,176.92,167.28,153.98,152.64,148.26,147.66,144.82,135.77,135.60,134.52,134.16,131.35,130.98,130.65,129.74,126.22,126.04,125.91,123.22,122.41,122.28,121.50,120.31,79.10,37.84.HRMS(ESI)m/z:calcd for C26H15N3O5S[M+H]+:482.0811；found:482.0803.
7y
4-(2-氨基-3-(苯并[d]噻唑-2-基)-5,10-二氧代-5,10-二氢-4H-苯并[g]苯并吡喃-4-基)苄腈
Figure GDA0002222374480000143
紫色固体,熔点228.8-230.4℃,1H NMR(400MHz,DMSO-d6)δ8.81(s,2H),8.04(d,J＝10.9Hz,1H),7.96-7.86(m,2H),7.86-7.72(m,5H),7.65(d,J＝7.9Hz,2H),7.36(t,J＝7.4Hz,1H),7.20(t,J＝7.3Hz,1H),5.04(s,1H).13C NMR(100MHz,DMSO-d6)δ182.60,176.87,167.31,153.92,152.65,148.23,134.55,134.19,132.89,132.23,131.34,130.94,130.48,129.88,126.21,126.07,125.89,123.37,123.15,122.59,121.43,120.29,109.90,79.09,38.15.HRMS(ESI)m/z:calcd for C27H15N3O3S[M+H]+:462.0912；found:462.0921.
9e
2-氨基5’-甲氧基-2’,5,10-三氧代-5,10-二氢螺[苯并[g]苯并吡喃-4,3’-二氢吲哚]-3-甲腈
Figure GDA0002222374480000151
灰色固体,熔点259.8-261.2℃,1H NMR(400MHz,DMSO-d6)δ10.47(s,1H),8.11(s,2H),8.03(d,J＝5.2Hz,1H),7.82(s,3H),7.15-7.00(m,2H),6.79(d,J＝7.5Hz,2H),3.32(s,3H).13C NMR(100MHz,DMSO-d6)δ177.36,165.86,160.06,155.27,139.92,139.14,135.01,134.81,127.56,125.71,124.06,122.21,121.48,120.30,118.06,117.35,114.06,110.77,110.49,60.63,55.30,48.80.
9f
2-氨基-2’,5,10-三氧代-5,10-二氢螺[苯并[g]苯并吡喃-4,3’-二氢吲哚]-3-甲酸乙酯
Figure GDA0002222374480000152
橙色固体,熔点253.1-254.9℃,1H NMR(400MHz,DMSO-d6)δ10.47(s,1H),8.11(s,2H),8.03(d,J＝4.4Hz,1H),7.81(s,3H),7.17-7.01(m,2H),6.79(d,J＝7.3Hz,2H),3.32(s,3H).13C NMR(100MHz,DMSO-d6)δ181.63,179.34,176.56,167.34,158.73,149.26,143.46,135.69,134.76,134.14,130.84,129.94,128.01,126.04,125.91,123.51,121.65,120.82,108.51,75.71,50.34,47.95.HRMS(ESI)m/z:calcd for C22H14N2O6[M+H]+:403.0930；found:403.0921.
9g
2-氨基-5’-氟-2’,5,10-三氧代-5,10-二氢螺[苯并[g]苯并吡喃-4,3’-二氢吲哚]-3-甲酸乙酯
Figure GDA0002222374480000153
橙色固体,熔点257.3-259.1℃,1H NMR(400MHz,DMSO-d6)δ10.51(s,1H),8.17(s,2H),8.09-8.01(m,1H),7.83(s,3H),7.04(d,J＝6.0Hz,1H),6.93(t,J＝7.7Hz,1H),6.81-6.73(m,1H),3.34(s,3H).13C NMR(100MHz,DMSO-d6)δ181.69,179.34,176.54,167.24,158.75,156.45,149.45,139.83,137.32,134.76,134.16,130.83,129.95,126.06,125.90,120.97,114.07,111.67,108.79,75.37,50.38,48.44.HRMS(ESI)m/z:calcd for C22H13FN2O6[M+H]+:421.0836；found:421.0844.
9h
2-氨基-5’-溴-2’,5,10-三氧代-5,10-二氢螺[苯并[g]苯并吡喃-4,3’-二氢吲哚]-3-甲酸乙酯
Figure GDA0002222374480000161
橙红色固体,熔点258.7-259.2℃,1H NMR(400MHz,DMSO-d6)δ10.62(s,1H),8.17(s,2H),8.04(d,J＝1.1Hz,1H),7.82(s,3H),7.29(d,J＝11.8Hz,2H),6.76(d,J＝6.3Hz,1H),3.35(s,3H).13C NMR(100MHz,DMSO-d6)δ181.78,179.02,176.49,167.16,158.76,149.59,142.94,138.02,134.72,134.17,130.81,130.64,130.03,126.49,126.07,125.90,120.74,112.37,110.33,75.29,50.43,48.13.HRMS(ESI)m/z:calcd forC22H13BrN2O6[M+H]+:481.0035；found:481.0029.
9i
2-氨基-5’-甲基-2’,5,10-三氧代-5,10-二氢螺[苯并[g]苯并吡喃-4,3’-二氢吲哚]-3-甲酸乙酯
Figure GDA0002222374480000162
棕色固体,熔点204.2-205.9℃,1H NMR(400MHz,DMSO-d6)δ10.79(s,1H),8.10(d,J＝5.9Hz,2H),7.95-7.80(m,4H),7.12(s,1H),6.99(d,J＝7.6Hz,1H),6.79(d,J＝7.7Hz,1H),3.35(s,3H)2.09(s,3H).13C NMR(100MHz,DMSO-d6)δ182.38,181.65,177.15,176.26,149.78,140.82,134.89,134.47,133.76,130.78,130.17,130.08,130.00,129.37,126.17,126.15,125.58,120.57,108.90,87.77,51.05,47.31,20.49.HRMS(ESI)m/z:calcd for C23H16N2O6[M+H]+:417.1087；found:417.1093.
9j
2-氨基-5’-硝基-2’,5,10-三氧代-5,10-二氢螺[苯并[g]苯并吡喃-4,3’-二氢吲哚]-3-甲酸乙酯
Figure GDA0002222374480000163
橙色固体,熔点254.8-256.2℃,1H NMR(400MHz,DMSO-d6)δ11.26(s,1H),8.24(s,2H),8.17-8.08(m,2H),8.04(d,J＝6.4Hz,1H),7.80(s,3H),7.01(d,J＝8.4Hz,1H),3.36(s,3H).13C NMR(100MHz,DMSO-d6)δ182.00,180.00,176.41,166.93,158.89,150.27,150.00,141.69,136.54,134.67,134.23,130.73,130.10,126.06,125.94,125.69,120.06,119.49,108.43,74.86,56.00,50.53.HRMS(ESI)m/z:calcd for C22H13N3O8[M+H]+:448.0781；found:448.0792.
9k
2-氨基-3-(苯并[d]噻唑-2-基)螺[苯并[g]苯并吡喃-4,3’-二氢吲哚]-2’,5,10-三酮
Figure GDA0002222374480000171
深棕色固体,熔点235.8-237.6℃,1H NMR(400MHz,DMSO-d6)δ11.03(s,1H),9.10(s,2H),8.07(d,J＝6.2Hz,1H),7.90-7.77(m,5H),7.37(t,J＝7.3Hz,1H),7.31-7.17(m,3H),6.99(d,J＝7.5Hz,1H),6.91-6.84(m,1H).13C NMR(100MHz,DMSO-d6)δ181.74,177.46,165.39,153.95,150.64,149.33,149.02,144.28,134.83,134.14,132.35,132.12,130.99,129.98,129.56,126.17,126.11,125.93,125.02,123.45,121.96,120.74,120.23,112.70,109.84,79.17,49.80.HRMS(ESI)m/z:calcd forC27H15N3O4S[M+H]+:478.0862；found:478.0856.
9l
2-氨基-3-(苯并[d]噻唑-2-基)-5’-氯螺[苯并[g]苯并吡喃-4,3’-二氢吲哚]-2’,5,10-三酮
Figure GDA0002222374480000172
绿色固体,熔点218.9-220.3℃,1H NMR(400MHz,DMSO-d6)δ9.12(s,1H),8.85(s,2H),8.18(s,1H),8.02(s,1H),7.72(s,3H),7.60(d,J＝5.0Hz,3H),7.52(d,J＝10.0Hz,2H),7.40(s,1H).13C NMR(100MHz,DMSO-d6)δ184.67,176.39,173.04,170.02,158.94,157.54,151.77,142.39,136.02,135.22,134.98,134.78,132.77,132.43,130.56,129.53,128.54,127.84,126.36,126.30,126.04,124.03,123.49,123.18,107.71,95.63,59.62.HRMS(ESI)m/z:calcd for C27H14ClN3O4S[M+H]+:512.0472；found:512.0481.
9m
2-氨基-3-(苯并[d]噻唑-2-基)-5’-溴螺[苯并[g]苯并吡喃-4,3’-二氢吲哚]-2’,5,10-三酮
Figure GDA0002222374480000173
绿色固体,熔点239.8-241.3℃,1H NMR(400MHz,DMSO-d6)δ11.11(s,1H),9.04(s,2H),8.01(d,J＝6.5Hz,1H),7.89-7.73(m,4H),7.37(d,J＝6.3Hz,1H),7.37-7.21(m,3H),6.97(d,J＝7.1Hz,1H),6.98-6.86(m,1H).13C NMR(100MHz,DMSO-d6)δ181.65,177.79,165.41,152.97,151.36,149.41,149.14,142.36,135.79,134.31,133.32,132.09,130.86,129.87,129.43,127.37,126.21,125.83,125.01,122.98,121.87,120.54,119.93,112.70,108.99,78.67,50.02.HRMS(ESI)m/z:calcd for C27H14BrN3O4S[M+H]+:555.9967；found:555.9960.
9n
2-氨基-3-(苯并[d]噻唑-2-基)-5’-甲基螺[苯并[g]苯并吡喃-4,3’-二氢吲哚]-2’,5,10-三酮
Figure GDA0002222374480000181
绿色固体,熔点209.7-210.2℃,1H NMR(400MHz,DMSO-d6)δ10.89(s,1H),8.60(s,1H),8.27(d,J＝7.4Hz,1H),8.18-8.02(m,2H),7.87(t,J＝14.4Hz,3H),7.72-7.57(m,3H),7.04(d,J＝7.6Hz,1H),6.83-6.68(m,2H),3.73(s,3H).13C NMR(100MHz,DMSO-d6)δ181.63,179.67,176.21,165.84,161.08,154.01,152.99,140.18,139.13,135.80,134.86,134.26,130.66,130.01,127.70,127.20,126.14,123.36,122.46,120.14,116.69,112.84,111.15,106.27,97.24,69.42,55.20,14.01.HRMS(ESI)m/z:calcdfor C28H17N3O4S[M+H]+:492.1018；found:492.1027.
9o
2-氨基-3-(苯并[d]噻唑-2-基)-5’-硝基螺[苯并[g]苯并吡喃-4,3’-二氢吲哚]-2’,5,10-三酮
Figure GDA0002222374480000182
红色固体,熔点>300℃,1H NMR(400MHz,DMSO-d6)δ10.96(s,1H),9.08(s,2H),8.12(d,J＝6.8Hz,1H),7.73-7.58(m,4H),7.37(d,J＝5.0Hz,1H),7.21-7.08(m,3H),6.99(d,J＝7.1Hz,1H).6.89-6.76(m,1H).13C NMR(100MHz,DMSO-d6)δ184.67,176.39,173.04,170.02,158.94,157.54,151.77,149.80,136.27,136.02,135.22,134.78,132.77,132.43,130.56,128.54,127.84,126.30,126.04,124.87,123.49,123.18,123.06,120.20,107.62,95.63,59.62.HRMS(ESI)m/z:calcd for C27H14N4O6S[M+H]+:523.0712；found:523.0724.
实施例7抗肿瘤活性测定
采用MTT法分别测试实施例4中的化合物7a～7y，实施例5中的化合物9a～9o对人肺癌细胞(A549)、人三阳性乳腺癌细胞(MCF-7)、人三阴性乳腺癌细胞(MDA-MB-231)和正常的人支气管上皮细胞(HBE)的抑制作用。
测试步骤如下：
1.将解冻复苏的待试肿瘤细胞株接种于含10％新生牛血清的DMEM培养基中，置于37℃、5％的CO2饱和湿度培养箱中传代培养，取对数生长期细胞用于实验；
2.取对数生长期待试肿瘤细胞制成1×104/mL单细胞悬液，接种于96孔板中，每孔100uL，置37℃、5％CO2条件下培养24h，待细胞贴壁；
3.移去原培养液，加入5ug/mL浓度的待测化合物的培养基处理细胞，另设空白对照组；将培养板置37℃，5％CO2细胞培养箱常规培养24h；
4.实验终止4h以前，每孔加入5mg/mL的MTT溶液20uL，用PBS配制，pH＝7.4，0.22um滤膜过滤除菌，终止培养，吸弃孔内培养上清液。每孔加DCM 100uL/孔，室温下振荡10min；
5.在酶联免疫监测仪上测定各孔吸光度值，选择波长490nm，重复3次；
6.计算各化合物对肿瘤细胞的抑制率，其中抑制率的计算公式为：
抑制率％＝[1-(加药细胞OD-空白组OD)/(对照细胞OD-空白组OD)]×100％。
化合物7a～7y的测试结果如表1所示：
表1化合物7对肿瘤和正常细胞株的抑制率a(IC50，单位μg/mL)
Figure GDA0002222374480000191
aIC50大于等于50μg/mL标记为“-”
由表1可知，产物7c、7j、7k、7n、7r、7t对三种肿瘤细胞中的其中一种或两种具有很好的的抑制作用，但同时这些产物对人支气管上皮细胞(HBE)表现出了细胞毒性。产物7f、7g、7l、7m、7o对三种肿瘤细胞均有抑制作用，可能对肿瘤细胞具有普遍适用性，但是，这些产物也对人支气管上皮细胞(HBE)表现出了细胞毒性。因此，需要对其结构进行修饰以制备抗肿瘤药物。
产物7u只对人三阳性乳腺癌细胞(MCF-7)表现出很好的抑制作用，具有高度特异性，而且对正常人支气管上皮细胞(HBE)没有毒性。
三阳性乳腺癌是雌激素受体(ER)、孕激素受体(PR)和人类表皮生长因子受体(HER-2)均为阳性的乳腺癌，有调查表明：虽然在乳腺癌中占比较小，但三阳性乳腺癌具有肿块较大、生物学行为差、病理多分为III级、腋窝淋巴结转移、常有神经或脉管浸润、高肿瘤负荷和高增殖指数等病理特征。且三阳性乳腺癌相对阴性乳腺癌复发转移较早，总生存率和无病生存率较低。因此，开发三阳性乳腺癌的靶向药物，降低其复发转移率具有重要的意义。
产物7u的4号位芳环上没有取代、3号位是苯并噻唑基取代的产物，说明MCF-7细胞中的受体对空间位阻要求很高，4号位上的取代基可能会因为位阻破坏产物与受体的结合。同时，无取代基的苯并噻唑的空间位阻和结合位点的位置及电子效应等恰好符合该受体的要求。通过进一步的空间结合模式模拟以及详细的构效关系研究，结合专业手段，有望找到该化合物在MCF-7中的受体、明确其抑制MCF-7的机制，在制备高效低毒的治疗三阳性乳腺癌的药物方面具有广阔的应用前景。
产物7u只对人三阳性乳腺癌细胞(MCF-7)表现出很好的抑制作用，具有高度特异性，而且对正常人支气管上皮细胞(HBE)没有毒性。说明MCF-7细胞中的受体对空间位阻要求很高，4号位上的取代基可能会因为位阻破坏产物与受体的结合。同时，无取代基的苯并噻唑的空间位阻和结合位点的位置及电子效应等恰好符合该受体的要求。通过进一步的空间结合模式模拟以及详细的构效关系研究，结合专业手段，有望找到该化合物在MCF-7中的受体、明确其抑制MCF-7的机制，在制备高效低毒的治疗三阳性乳腺癌的药物方面具有较好的应用前景。
化合物9a～9o的测试结果如表2所示：
表2化合物9对三种癌细胞及正常细胞的抑制率a(IC50,μg/mL)
Figure GDA0002222374480000201
Figure GDA0002222374480000211
a IC50值高于50标记为“-”
表2测试结果表明：产物9c对人肺癌细胞(A549)表现出了抑制作用，但对正常人支气管上皮细胞(HBE)表现出了细胞毒性；产物9a、9b、9d、9f、9g、9h、9i、9j、9l、9m、9n、9o对三种肿瘤细胞均有很好的抑制作用，美中不足的是它们对正常细胞也表现出毒性。该系列产物绝大多数均表现出了很好的对肿瘤细胞的抑制作用，因此，需要对其结构进行修饰以制备抗肿瘤药物。
产物9k作为萘醌并吡喃衍生物，3号位取代基为苯并噻唑基，4号位为苯环上没有取代的靛红，其结构特征与7u颇为相似。该结果说明苯并噻唑和合适的空间位阻是两类产物具备抗肿瘤活性的必要条件。产物9k对三种肿瘤细胞均表现出了很好的抗肿瘤活性，同时对正常细胞没有毒性，在制备抗癌药物方面具有广阔的应用前景。

Claims (4)

1.式7所示萘醌并吡喃衍生物的合成方法，其特征在于，包括：在催化剂存在下，式4所示2-羟基-1,4-萘醌、式5所示芳醛和式6所示乙腈类化合物于有机溶剂中反应得目标化合物7
Figure FDA0002222374470000011
其中，
Figure FDA0002222374470000012
所述催化剂为式3h所示化合物
Figure FDA0002222374470000013
2.式9所示萘醌并吡喃衍生物的合成方法，其特征在于，包括步骤：在催化剂存在下，式4所示2-羟基-1,4-萘醌、式8所示取代靛红和式6所示乙腈类化合物于有机溶剂中反应得目标化合物9
Figure FDA0002222374470000021
其中，
Figure FDA0002222374470000022
所述催化剂为式3h所示化合物
Figure FDA0002222374470000023
3.根据权利要求1或2所述的合成方法，其特征在于，所述有机溶剂为乙醇。
4.根据权利要求1或2所述的合成方法，其特征在于，其后处理过程如下：反应结束后，冷却至室温，旋干多余溶剂得到粗产物，柱层析纯化得纯化产物。
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