CN104356108B - 芳杂环二苯并呫吨化合物以及制备方法及应用 - Google Patents
芳杂环二苯并呫吨化合物以及制备方法及应用 Download PDFInfo
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Abstract
本发明公开了芳杂环二苯并呫吨化合物以及制备方法及应用，其结构式为：
Description
技术领域
本发明涉及芳杂环二苯并呫吨化合物以及制备方法及应用。
背景技术
恶性肿瘤的危害已成为全球性的卫生问题，它是一种死亡率仅次于心脑血管疾病的高危疾病。但对许多实体瘤如肝癌等恶性肿瘤仍缺乏疗效明显的药物，因此，寻找选择性强、毒副作用小而价格低廉的特效抗癌药物仍是化学界、生物学界、医学界、药物学界的一个重要课题。
Tan
D-M等（Tan D-M，Li
H-H，Wang B，Liu
H-B，Xu Z-L，Chin.J.Chem.,2001,19:91）在进行模拟氧化酶的研究中，发现1,1’-联-2-萘酚在铜胺络合物的催化下，被氧气氧化为1-氧代-13c-烷氧基-1,13c-二氢-二苯并[a,kl]呫吨。体外药理试验表明，上述结构化合物用作抗肿瘤药物，对肝癌、肺癌等具有明显的抗肿瘤活性，具有良好的抗肿瘤药物开发应用前景。
发明内容
本发明的目的在于提供芳杂环二苯并呫吨化合物以及制备方法及应用。
本发明所采取的技术方案是：
芳杂环二苯并呫吨化合物，其结构式如下：
其中，X为CN、Cl、CH2COCH3、CH(COCH3)COOCH3、CH(COCH3)COOC2H5、CH(COCH3)COOCH(CH3)2中的一种。
芳杂环二苯并呫吨化合物的合成方法，其是利用二苯并[a,kl]呫吨在酸性条件下与亲核试剂发生亲核取代反应制备得到的，亲核试剂为Si(CH3)3CN、HCl、丙酮、乙酰乙酸甲酯、乙酰乙酸乙酯、乙酰乙酸异丙酯中的一种。
亲核取代反应的时间为5-30min。
亲核取代反应的温度为20-30℃。
芳杂环二苯并呫吨化合物在制备抗癌药物中的应用。
芳杂环二苯并呫吨化合物在制备抗肝癌药物中的应用。
芳杂环二苯并呫吨化合物在制备抗宫颈癌药物中的应用。
芳杂环二苯并呫吨化合物在制备抗骨肉瘤药物中的应用。
芳杂环二苯并呫吨化合物在制备抗肺癌药物中的应用。
本发明的有益效果是：本发明提供了一种新的亲核取代反应制备芳杂环二苯并呫吨化合物，反应条件温和，速度快，得到的系列化合物具有较高的抗肿瘤活性，在制备抗肿瘤药物中具有较好的前景。
具体实施方式
芳杂环二苯并呫吨化合物，其结构式如下：
其中，X为CN、Cl、CH2COCH3、CH(COCH3)COOCH3、CH(COCH3)COOC2H5、CH(COCH3)COOCH(CH3)2中的一种。
芳杂环二苯并呫吨化合物的合成方法，其是利用二苯并[a,kl]呫吨在酸性条件下与亲核试剂发生亲核取代反应制备得到的，亲核试剂为Si(CH3)3CN、HCl、丙酮、乙酰乙酸甲酯、乙酰乙酸乙酯、乙酰乙酸异丙酯中的一种。
优选的，其合成方法为：
将二苯并呫吨化合物1溶解在极性溶剂中，室温搅拌条件下加入亲核试剂，再加入磷酸溶液，搅拌10-15min，TLC监测反应进程，反应完成后除去溶剂，再有机溶剂萃取，所得有机物进行硅胶柱层析。
其中，所述的极性溶剂为乙腈、甲醇、乙醇、DMF、四氢呋喃、二甲亚砜中的至少一种，优选的，为乙腈；
所述的磷酸溶液的浓度为10-20wt%；
萃取用的有机溶剂为乙酸乙酯；
二苯并呫吨化合物1、亲核试剂、极性溶剂、磷酸溶液的用量比为：1
mmol:(1.8-2.2) mmol:(6-10) mL:(1-2) mL；
柱层析用洗脱剂为石油醚-乙酸乙酯（1:4-1:2/V:V）。
所涉及的反应方程式为：
下面结合具体实施例对本发明做进一步的说明：
合成实施例：
合成化合物2的通用方法：
称量0.942 g的二苯并呫吨化合物1加入到25 mL的乙腈溶剂中溶解，室温搅拌加入6 mmol的亲核试剂后再加入1-2 mL的浓度为15%的H3PO4，室温搅拌10-15
min，薄层点板跟踪反应完全，反应结束后减压蒸去大部分溶剂，并用乙酸乙酯萃取有机物，所得有机物用200-300目硅胶柱层析，洗脱剂为石油醚-乙酸乙酯（1:4-1:2/V:V），得到黄色固体化合物2。
按照以上方法，采用不同的亲核试剂进行亲核取代反应，所得产物产量、熔点等结果列于表1中，如下：
表
1
化合物的产量和熔点
结构表征例：
表征数据：
化合物
2a
的波谱数据：
1H-NMR (500 MHz, DMSO-d 6 )
δ: 8.14 (d, J = 9.0 Hz, 1H), 8.01
(d, J = 8.0 Hz, 1H), 7.78 (d, J = 10.0 Hz, 1H), 7.71 (d, J
= 8.5 Hz, 1H), 7.61-7.57 (m, 1H), 7.54-7.51 (m, 2H), 7.44 (dd, J = 9.0
Hz 1.0 Hz, 1H), 7.41 (d, J = 7.5 Hz, 1H), 7.27 (d, J = 8.5 Hz,
1H), 6.63 (d, J = 10.0 Hz, 1H). 13C-NMR (125 MHz, DMSO -d 6 )
δ: 190.60, 148.54, 148.32, 142.18, 133.04,
131.99, 130.72, 130.67, 128.91, 126.93, 125.67, 125.28, 125.15, 125.11, 118.02,
117.85, 117.71, 112.39, 104.34, 44.42, 39.84. LC-MS, m/z: 309 ([M]-).
Anal.calcd for C21H11NO2 . C 81.54,
H 3.58; found C 81.33, H 3.55.
化合物
2b
的波谱数据：
1H-NMR (500 MHz, Acetone-d 6 )
δ: 8.08-8.05 (m, 1H),7.96 (d, J =
9.0 Hz, 1H), 7.89-7.86 (m, 1H), 7.47-7.42 (m, 3H), 7.37 (d, J = 9.0 Hz,
1H), 7.32 (t, J = 10.2 Hz, 1H), 7.21-7.14 (m, 2H), 6.27 (d, J =
10.2 Hz, 1H). 3C-NMR (125 MHz, Acetone-d 6 ) δ: 198.87, 149.89, 138.94, 132.92, 132.46, 131.03, 130.74,
130.51, 128.14, 127.79, 125.47, 124.96, 124.11, 124.00, 119.44, 117.14, 117.02,
116.42, 111.41, 68.73. LC-MS, m/z: 317 ([M]-). Anal.calcd for C20H11ClO2 .
C 75.36, H 3.48; found C 75.21, H 3.45.
化合物
2c
的波谱数据：
1H-NMR (500 MHz, Acetone-d 6 )
δ: 7.89 (d, J = 9.0 Hz, 1H),
7.86-7.84 (m, 2H), 7.43 (d, J = 10.0 Hz, 1H), 7.39-7.37 (m, 2H), 7.33
(t, J = 8.0 Hz, 1H), 7.27 (d, J = 8.5 Hz, 1H), 7.16 (d, J
= 7.5 Hz, 1H), 7.04 (d, J = 8.5 Hz, 1H), 6.28 (d, J = 9.5 Hz, 1H),
4.16 (d, J = 16.5 Hz, 1H), 3.80 (d, J = 16.5 Hz, 1H), 1.64 (s,
3H). 13C-NMR (125 MHz, Acetone-d 6 ) δ: 203.43, 200.38, 151.00, 150.03, 139.74, 132.18, 131.70,
131.47, 130.61, 129.04, 128.78, 127.55, 125.83, 125.20, 123.78, 123.73, 121.47,
117.75, 116.06, 111.79, 51.05, 49.79, 30.54. LC-MS, m/z: 341 ([M+H]+)
. Anal.calcd for C23H16O3 . C 81.16,
H 4.74; found C 81.23, H 4.66.
化合物
2d
的波谱数据：
1H-NMR (500 MHz, CDCl3) δ: 8.05 (d, J = 8.5 Hz, 1H), 7.85 (d, J =
9.0 Hz, 1H), 7.83 (dd, J = 7.5 Hz 1.5 Hz, 1H), 7.46-7.32 (m, 5H), 7.24
(d, J = 7.5 Hz, 1H), 7.15 (d, J = 7.5 Hz, 1H), 6.63 (d, J
= 10.0Hz, 1H), 4.45 (s, 1H), 3.46 (s, 3H), 1.68 (s, 3H). 13C-NMR
(125 MHz, CDCl3) δ: 201.1, 198.5,
168.7, 152.7, 152.4, 140.7, 131.7, 131.6, 130.8, 130.6, 129.1, 128.7, 128.5,
126.4, 25.7, 124.4, 124.2, 118.0, 117.6, 116.7, 114.7, 68.7, 52.7, 52.2, 29.2.
LC-MS, m/z: 397 ([M-H]-). Anal.calcd for C25H18O5 .
C 75.37, H 4.55; found C 75.30, H 4.51.
化合物
2e
的波谱数据：
1H-NMR (500 MHz, CDCl3) δ: 8.10 (d, J = 8.5 Hz, 1H), 7.82 (d, J =
8.5 Hz, 1H), 7.78 (dd, J = 8.0 Hz 1.5 Hz, 1H), 7.43-7.38 (m, 2H),
7.34-7.30 (m, 2H), 7.22 (d, J = 10.0 Hz, 1H), 7.15 (dd, J = 8.5
Hz 1.5 Hz, 1H), 7.10 (d, J = 8.5 Hz, 1H), 6.53 (d, J = 10.0Hz,
1H), 4.56 (s, 1H), 3.75-3.72 (m, 1H), 3.67-3.63 (m, 1H), 2.00 (s, 3H), 0.68 (t,
J = 7.0 Hz, 1H, 3H). 13C-NMR (125 MHz, CDCl3) δ: 202.3, 198.2, 167.7, 151.9, 151.3, 138.3, 132.4, 131.5,
131.1, 128.9, 128.7(2C), 128.6, 127.1, 125.9, 124.2, 120.0, 123.3, 117.8,
116.8, 113.2, 70.4, 61.6, 52.0, 30.3, 12.9. LC-MS, m/z: 411 ([M-H]-).
Anal.calcd for C26H20O5 . C 75.72, H
4.89; found C 75.68, H 4.83.
化合物
2f
的波谱数据：
1H-NMR (500 MHz, CDCl3) δ: 8.11 (d, J = 8.5 Hz, 1H), 7.81 (d, J =
8.5 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.42-7.28 (m, 4H), 7.24 (d, J
= 10.0 Hz, 1H), 7.15 (d, J = 8.5 Hz, 1H), 7.10 (d, J = 7.5 Hz,
1H), 6.55 (d, J = 10.0 Hz, 1H), 4.58-4.55 (m, 1H), 4.53 (s, 1H), 2.01
(s, 3H), 0.81 (d, J = 6.5 Hz, 3H), 0.59 (d, J = 6.5 Hz, 3H). 13C-NMR
(125 MHz, CDCl3) δ: 202.5, 198.2,
167.1, 151.9, 151.5, 138.5, 132.5, 131.7, 131.6, 130.9, 128.9, 128.5 (2C),
127.1, 126.4, 125.9, 125.8, 124.4, 124.0, 117.8, 116.9, 70.8, 69.4, 51.8, 30.3,
20.7, 20.5. LC-MS, m/z: 425 ([M-H]-). Anal.calcd for C27H22O5 .
C 76.04, H 5.20; found C 76.13, H 5.15.
测试例：
化合物2a~2f体外抗癌试验和细胞毒性试验（MTT比色法）
把3×104/mL的细胞株接种于96孔培养板中，每孔加入200 μL，用10％ MEM培养基培养。温箱中培养24 h后去掉培养液，加入新配制培养液，并分别加入一系列浓度的待测药物的DMSO溶液，每孔加入200 μl，加药后暗箱挂白炽灯60W光照1 h，每剂量组设三个平行样本，培养48 h后每孔加入2 mg/ml的MTT溶液20 μL，培养40 h。完全吸出孔内培养液，各加入150 μL的DMSO，震荡10分钟使结晶物溶解。用酶联检测仪检测各孔OD值（=490
nm）；以OD值对药物浓度的对数作图，从图上求出令半数细胞死亡的药物浓度即IC50。
结果如表2：
表
2
抗肿瘤活性测试结果
体外药理实验结果表明，2a~2f这六个化合物对肝癌细胞(Bel-7402)、宫颈癌细胞（Hela）、人骨头肉瘤细胞(MG-63)和肺癌细胞(A549)具有明显的抗肿瘤活性。
Claims (5)
1.芳杂环二苯并呫吨化合物，其特征在于：其结构式如下：
其中，X为Cl、CH(COCH3)COOCH3、CH(COCH3)COOC2H5、CH(COCH3)COOCH(CH3)2中的一种。
2.权利要求1所述的芳杂环二苯并呫吨化合物的合成方法，其特征在于：其是利用二苯并[a,kl]呫吨在酸性条件下与亲核试剂发生亲核取代反应制备得到的，亲核试剂为、HCl、乙酰乙酸甲酯、乙酰乙酸乙酯、乙酰乙酸异丙酯中的一种。
3.根据权利要求2所述的芳杂环二苯并呫吨化合物的合成方法，其特征在于：亲核取代反应的时间为5-30min。
4.根据权利要求2所述的芳杂环二苯并呫吨化合物的合成方法，其特征在于：亲核取代反应的温度为20-30℃。
5.权利要求1所述的芳杂环二苯并呫吨化合物在制备抗肺癌药物中的应用。
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