CN108440468A - 2-(苯并呋喃-5-基)苯酚及其作为抗癌药物的应用 - Google Patents
2-(苯并呋喃-5-基)苯酚及其作为抗癌药物的应用 Download PDFInfo
- Publication number
- CN108440468A CN108440468A CN201810340899.XA CN201810340899A CN108440468A CN 108440468 A CN108440468 A CN 108440468A CN 201810340899 A CN201810340899 A CN 201810340899A CN 108440468 A CN108440468 A CN 108440468A
- Authority
- CN
- China
- Prior art keywords
- phenol
- alkyl
- benzofuran
- pharmaceutically acceptable
- chain alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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- 125000000217 alkyl group Chemical group 0.000 claims abstract description 30
- 150000003839 salts Chemical class 0.000 claims abstract description 20
- JABJLTLPOVTUPG-UHFFFAOYSA-N 2-(1-benzofuran-5-yl)phenol Chemical class O1C=CC2=C1C=CC(=C2)C1=C(C=CC=C1)O JABJLTLPOVTUPG-UHFFFAOYSA-N 0.000 claims abstract description 15
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Abstract
本发明涉及一类如化学结构式Ⅰ所示的2‑(苯并呋喃‑5‑基)苯酚及其在药学上可接受的盐： 其中，R选自：氢、C1～C2烷基、C3～C4直链烷基或支链烷基；R1选自：C1～C2烷基、C3～C6直链烷基或支链烷基。2‑(苯并呋喃‑5‑基)苯酚及其在药学上可接受的盐在制备抗人肺腺癌细胞A549药物中的应用。
Description
技术领域
本发明涉及一类新化合物的制备与应用；具体是2-(苯并呋喃-5-基)苯酚及其作为抗癌药物的应用。
背景技术
中国发明专利[CN201610052934.9]描述了1-(4-羟基-3-芳基苯基)-2-丙酮的制备方法；中国发明专利[CN201610100379.2和CN2016101038556]描述了含苯并呋喃环的酰腙衍生物及其对于流感病毒的抑制作用。
发明内容
本发明解决的技术问题是提供一类2-(苯并呋喃-5-基)苯酚、其制备方法、药物组合物和用途。
为解决本发明的技术问题，本发明提供如下技术方案：
本发明技术方案的第一方面是化学结构式Ⅰ所示的2-(苯并呋喃-5-基)苯酚及其在药学上可接受的盐：
其中，R选自：氢、C1～C2烷基、C3～C4直链烷基或支链烷基；R1选自：C1～C2烷基、C3～C6直链烷基或支链烷基。
进一步的，优选的化合物选自：4-烯丙基-2-(2-甲基苯并呋喃-5-基)-6-((4-甲基哌嗪-1-基)甲基)苯酚、4-烯丙基-2-(2-甲基苯并呋喃-5-基)-6-((4-乙基哌嗪-1-基)甲基)苯酚、4-烯丙基-2-(2-甲基苯并呋喃-5-基)-6-((4-丙基哌嗪-1-基)甲基)苯酚或4-烯丙基-2-(2-乙基苯并呋喃-5-基)-6-((4-甲基哌嗪-1-基)甲基)苯酚。
本发明技术方案的第二方面是提供了第一方面所述的2-(苯并呋喃-5-基)苯酚的制备方法，其特征在于它的制备反应如下：
R选自：R选自：氢、C1～C2烷基、C3～C4直链烷基或支链烷基；R1选自：C1～C2烷基、C3～C6直链烷基或支链烷基。
本发明技术方案的第三方面是提供含有第一方面所述化合物及其药学上可接受的盐的药物组合物，该药物组合物含有治疗有效量的本发明的2-(苯并呋喃-5-基)苯酚及其药学上可接受的盐，以及任选的含有药用载体。其中所述的药用载体指药学领域常用的药用载体；该药物组合物可根据本领域公知的方法制备。可通过将本发明化合物及其药学上可接受的盐与一种或多种药学上可接受的固体或液体赋形剂和/或辅剂组合，制成适于人或动物使用的任何剂型。本发明化合物及其药学上可接受的盐在其药物组合物中的含量通常为0.1％～95％重量百分比。
本发明化合物及其药学上可接受的盐或含有它的药物组合物可以单位剂量形式给药，给药途径可为肠道或非肠道，如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、阴道、直肠等。
给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等；固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等；半固体剂型可以是软膏剂、凝胶剂、糊剂等。
本发明化合物及其药学上可接受的盐可以制成普通制剂、也制成是缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
为了将本发明化合物及其药学上可接受的盐制成片剂，可以广泛使用本领域公知的各种赋形剂，包括稀释剂、黏合剂、润湿剂、崩解剂、润滑剂、助流剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等；湿润剂可以是水、乙醇、异丙醇等；粘合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等；崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等；润滑剂和助流剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。
还可以将片剂进一步制成包衣片，例如糖包衣片、薄膜包衣片、肠溶包衣片，或双层片和多层片。
为了将给药单元制成胶囊剂，可以将有效成分本发明化合物及其药学上可接受的盐与稀释剂、助流剂混合，将混合物直接置于硬胶囊或软胶囊中。也可将有效成分本发明化合物及其药学上可接受的盐先与稀释剂、黏合剂、崩解剂制成颗粒或微丸，再置于硬胶囊或软胶囊中。用于制备本发明化合物及其药学上可接受的盐片剂的各稀释剂、黏合剂、润湿剂、崩解剂、助流剂品种也可用于制备本发明化合物及其药学上可接受的盐的胶囊剂。
为将本发明化合物及其药学上可接受的盐制成注射剂，可以用水、乙醇、异丙醇、丙二醇或它们的混合物作溶剂并加入适量本领域常用的增溶剂、助溶剂、pH调剂剂、渗透压调节剂。增溶剂或助溶剂可以是泊洛沙姆、卵磷脂、羟丙基-β-环糊精等；pH调剂剂可以是磷酸盐、醋酸盐、盐酸、氢氧化钠等；渗透压调节剂可以是氯化钠、甘露醇、葡萄糖、磷酸盐、醋酸盐等。如制备冻干粉针剂，还可加入甘露醇、葡萄糖等作为支撑剂。
此外，如需要，也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其它添加剂。
为达到用药目的，增强治疗效果，本发明的药物或药物组合物可用任何公知的给药方法给药。
本发明技术方案的第四方面是提供本发明第一方面所述2-(苯并呋喃-5-基)苯酚及其药学上可接受的盐以及第三方面所述药物组合物在制备抗人肺腺癌细胞A549药物中的应用。
有益技术效果：
本发明的2-(苯并呋喃-5-基)苯酚是一类新结构类型的具有抗癌活性的化合物。
具体实施方式
以下实施例旨在说明本发明而不是对本发明的进一步限定。
实施例1
4-烯丙基-2-(2-甲基苯并呋喃-5-基)-6-((4-甲基哌嗪-1-基)甲基)苯酚的制备
2.0mmol 4-烯丙基-2-(2-甲基苯并呋喃-5-基)苯酚、10mL甲醇、6.0mmol 4-甲基哌嗪和6.0mmol 37％甲醛水溶液，60℃反应6h。反应液脱溶，经柱层析提纯，得4-烯丙基-2-(2-甲基苯并呋喃-5-基)-6-((4-甲基哌嗪-1-基)甲基)苯酚，收率68.0％；淡黄色油状液体；1H NMR(400MHz，CDCl3)δ7.65(s，1H，苯并呋喃环4-H)，7.45～7.39(m，2H，苯并呋喃环6,7-H)，7.10(s，1H，C6H23-H)，6.80(s，1H，C6H25-H)，6.38(s，1H，苯并呋喃环3-H)，5.97(dt，J＝16.6，7.0Hz，1H，CH)，5.29(br，1H，OH)，5.12～5.02(m，2H，＝CH2)，3.75(s，2H，CH2)，3.33(d，J＝7.0Hz，2H，CH2)，2.62(br，8H，哌嗪基2,3,5,6-H)，2.46(s，3H，NCH3)，2.29(s，3H，CH3)；13C NMR(101MHz，CDCl3)δ155.59，153.97，152.98，137.91，133.02，130.50，130.41，129.31，129.16，127.78，124.77，121.32，120.86，115.52，110.06，102.82，61.61，54.51，52.10，45.52，39.48，14.14。
实施例2
2-(苯并呋喃-5-基)苯酚的抗癌活性
1.抗肿瘤活性原理
MTT法又称MTT比色法，是一种用于确定活细胞中线粒体脱氢酶活性的经典方法。MTT分析法以活细胞代谢还原剂噻唑蓝[3-(4,5-二甲基-2-噻唑)-2,5二苯基溴化四氮唑；3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide,MTT]为基础。MTT是一种能接受氢原子的染料。活细胞线粒体中与NADP相关的脱氢酶在细胞内可将黄色的MTT转化为不溶性的蓝紫色甲瓒(formazn)，而死细胞则无此功能。用DMSO溶解甲瓒后，在一定波长下用酶标仪测定光密度值，即可定量测出细胞的存活率。根据光密度值的变化观察样品对肿瘤细胞株的抑制作用。
2.抗肿瘤活性实验
试样：实施例化合物
细胞系：人肺腺癌细胞株A549。
试剂：噻唑蓝(MTT)、RPMI 1640培养基、新生胎牛血清、新生牛血清、双抗(Gibco)；胰酶(Gibco)；96孔板；二甲亚砜(国药集团)。
仪器：HFsafe-1500型超净台、HF151UV型CO2培养箱(上海力申科学仪器有限公司)；XSP-15C型倒置显微镜(上海长方光学仪器有限公司)；Multiskan MK3型酶标仪(美国Thermo公司)；超纯水制备仪(美国Milli-Q公司)。
实验操作：试样对A549细胞的测试。试样作用于四种细胞的实验过程相同。每组实验设置空白对照组，试样分为5个浓度梯度，每个浓度设4个复孔，每组实验平行测定三次。设置波长为570nm检测各孔的OD值，并通过OD的变化计算试样对各细胞株的细胞毒活性。
3.抗肿瘤活性评价
1)细胞增殖抑制率计算：
2)IC50值计算
运用SPSS软件进行分析，样品浓度对数值与细胞抑制率线性回归，计算化合物对各细胞株的半数抑制浓度IC50值。4-烯丙基-2-(2-甲基苯并呋喃-5-基)-6-((4-甲基哌嗪-1-基)甲基)苯酚对A549细胞的IC50是25.15μM。
活性测试结果表明，2-(苯并呋喃-5-基)苯酚及其在药学上可接受的盐对人肺腺癌细胞A549具有良好的抑制活性，可用于制备抗癌药物。
Claims (4)
1.一类如化学结构式Ⅰ所示的2-(苯并呋喃-5-基)苯酚及其在药学上可接受的盐：
其中，R选自：氢、C1～C2烷基、C3～C4直链烷基或支链烷基；R1选自：C1～C2烷基、C3～C6直链烷基或支链烷基。
2.权利要求1所述的2-(苯并呋喃-5-基)苯酚选自：4-烯丙基-2-(2-甲基苯并呋喃-5-基)-6-((4-甲基哌嗪-1-基)甲基)苯酚、4-烯丙基-2-(2-甲基苯并呋喃-5-基)-6-((4-乙基哌嗪-1-基)甲基)苯酚、4-烯丙基-2-(2-甲基苯并呋喃-5-基)-6-((4-丙基哌嗪-1-基)甲基)苯酚或4-烯丙基-2-(2-乙基苯并呋喃-5-基)-6-((4-甲基哌嗪-1-基)甲基)苯酚。
3.权利要求1所述的2-(苯并呋喃-5-基)苯酚的制备方法，其特征在于，它的制备反应如下：
其中，R选自：氢、C1～C2烷基、C3～C4直链烷基或支链烷基；R1选自：C1～C2烷基、C3～C6直链烷基或支链烷基。
4.权利要求1所述的2-(苯并呋喃-5-基)苯酚及其在药学上可接受的盐在制备抗人肺腺癌细胞A549药物中的应用。
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| CN110950856A (zh) * | 2018-09-27 | 2020-04-03 | 湖南大学 | 8-(苯并呋喃-5-基)苯并噁嗪二酮及其作为抗癌药物的应用 |
| CN110950825A (zh) * | 2018-09-27 | 2020-04-03 | 湖南大学 | 6-(哌嗪甲基)-2-(苯并呋喃-5-基)苯酚及其应用 |
| CN110950825B (zh) * | 2018-09-27 | 2023-01-03 | 湖南大学 | 6-(哌嗪甲基)-2-(苯并呋喃-5-基)苯酚及其作为抗癌药物的应用 |
| CN110950856B (zh) * | 2018-09-27 | 2023-01-03 | 湖南大学 | 8-(苯并呋喃-5-基)苯并噁嗪二酮及其作为抗癌药物的应用 |
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