CN105541859B - 二氢呋喃并色满酮衍生物及其制备方法与医药用途 - Google Patents
二氢呋喃并色满酮衍生物及其制备方法与医药用途 Download PDFInfo
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- CN105541859B CN105541859B CN201610098585.4A CN201610098585A CN105541859B CN 105541859 B CN105541859 B CN 105541859B CN 201610098585 A CN201610098585 A CN 201610098585A CN 105541859 B CN105541859 B CN 105541859B
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- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
Abstract
本发明公开了结构式Ⅰ所示的7,8‑二氢‑2H‑呋喃并[3,2‑h]色满‑6(3H)‑酮衍生物及其药学上可接受的盐,其制备方法和药物组合物以及其在制备流感病毒神经氨酸酶抑制剂中的应用。其中R选自:氢、氘、C1~C2烷基、C3~C5直链烷基或C3~C5支链烷基;X1、X5选自:氢、C1~C2烷基、C3~C4直链或支链烷基、羟基、甲氧基、乙氧基;X2、X4选自:氢、C1~C2烷基、C3~C4直链或支链烷基、硝基、羟基、甲氧基、乙氧基或氨基;X3选自:氢、C1~C2烷基、C3~C4直链或支链烷基,羟基、甲氧基、乙氧基、二甲氨基或羧基。
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7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮衍生物的制备与作为流感病毒神经氨酸酶抑制剂的应用。
背景技术
苯并吡喃酮类化合物在自然界分布广泛,其基本结构或类似物在许多生物的次生代谢产物中都能找到,说明这种结构对于有机体的生命活动具有至关重要的作用。近年来,许多课题组都经分离或合成手段得到了苯并吡喃酮的衍生物,同时也针对该类化合物进行了广泛的生物活性测试。Pal Perjési等[Eur.J.Med.Chem.,2008,43:839-845]设计合成了12种3-苯亚甲基-4-色满酮类衍生物,其中化合物A1对人肿瘤细胞株Molt4/C8和CEM的平均IC50值分别为5.22μM和4.81μM,显示其具有较强的抗癌活性,且对人体正常细胞具有较低的毒性,小鼠体内测试表明该类化合物优先杀死恶性肿瘤细胞,具有良好的体内相容性。
Alipour等[Daru.J.Pharm.Sci.,2014,22:41]以间苯二酚作为原料合成了一系列3-亚苄基取代的6,7-二氧亚甲基-4-色满酮,并测试了其对三种不同乳腺癌细胞MCF-7、T47D和MDA-MB-231的抑制活性。结果表明化合物A2表现出了对三种癌细胞良好的抑制活性(IC50≤9.3μg/mL)。
除抗癌活性外,许多苯并吡喃酮类化合物还被证实具有抗氧化活性,VidavalurSiddaiah等[Bioorg.Med.Chem.Lett.,2007,17:1288-1290]合成了一系列4-色满酮类似物,其中四羟基取代产物A3具有优异的NBT过氧化抑制活性和DPPH自由基清除活性,其IC50值分别为8.5μM和4.5μM,高于阳性对照组维生素C和BHA。
苯并吡喃酮类化合物还具有单胺氧化酶(MOA)抑制活性,Nicoletta Desideri等[J.Med.Chem.,2011,54:2155–2164]设计合成了一系列3-苯亚甲基-色满-4-酮类化合物,其中化合物A4和A5对hMAO-B具有优于阳性对照物selegiline的抑制活性。
2013年,Roy等[Eur.J.Med.Chem.,2013,66:499-507]从间苯二酚出发合成设计了一系列4-色满酮类化合物作为外排泵抑制对结核杆菌具有较好的抑制活性,其中化合物A6~A8最低抑菌浓度小于阳性对照物维拉帕米。
Lee W S等[Biol.Pharm.Bull.,2012,35(5):786-790]从一种苏木科Caesalpinia中提取分离得到12种多羟基苯并吡喃酮类化合物。通过化学发光检测法测试了12种化合物的神经氨酸酶(NA)抑制活性,其中化合物A9对流感病毒H1N1、H3N2、H9N2三种亚型神经氨酸酶具有较好的抑制活性,IC50值分别为0.7μM、1.1μM、1.0μM。
Ryu等[Bioorg.Med.Chem.Lett.,2009,19(17):4912-4915]研究发现了一系列苯并(二氢)吡喃酮类化合物,其中化合物A10具有纳摩尔级的抗流感活性(IC50=380nM),而且研究表明它在动力学上属于非竞争性抑制剂,故其作用机制可能与现有的抗流感药物不同,有望开发成对现有药物耐药病毒株强有效的神经氨酸酶抑制剂,因此对化合物A10的结构进行改造可能发现强有效的神经氨酸酶抑制剂。Dao等[Bioorg.Med.Chem.Lett.,2011,21(1):294-298]从甘草中分离出一种α,β不饱和酮化合物A11,它与奥司他韦联用时,可显著增强奥司他韦对H1N1(H274Y)型流感病毒的抑制活性。研究结果间接的表明它抗流感的作用机制与奥司他韦不同,因此它具有对抗耐奥司他韦流感病毒的潜力。
2012年,胡艾希等[CN 102399229B,2013-9-4]报道了一类含苯并吡喃和苯并呋喃环N-酰基吡唑鱼藤酚A12及其制备方法与应用,优选N-氯乙酰基吡唑鱼藤酚在反应系统中检测浓度为40ug/ml,其对神经氨酸酶的抑制率为40%。
发明内容
本发明解决的技术问题是提供一类7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮衍生物、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提供了一类如化学结构式Ⅰ所示的7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮衍生物及其药学上可接受的盐:
其中R选自:氢、氘、C1~C2烷基、C3~C5直链烷基或C3~C5支链烷基;X1、X5选自:氢、C1~C2烷基、C3~C4直链或支链烷基、羟基、甲氧基、乙氧基;X2、X4选自:氢、C1~C2烷基、C3~C4直链或支链烷基、硝基、羟基、甲氧基、乙氧基或氨基;X3选自:氢、C1~C2烷基、C3~C4直链或支链烷基,羟基、甲氧基、乙氧基、二甲氨基或羧基。
进一步的,优选的化合物选自:
7-(3-羟基亚苄基)-2,2-二甲基-7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮、7-(4-羟基亚苄基)-2,2-二甲基-7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮、7-(3,4-二羟基亚苄基)-2,2-二甲基-7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮、7-(3-甲氧基亚苄基)-2,2-二甲基-7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮、7-(4-甲氧基亚苄基)-2,2-二甲基-7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮、7-(3,4,5-三甲氧基亚苄基)-2,2-二甲基-7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮、7-(4-羟基-3-甲氧基亚苄基)-2,2-二甲基-7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮、7-(3-羟基-4-甲氧基亚苄基)-2,2-二甲基-7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮、7-(2-羟基-3-甲氧基亚苄基)-2,2-二甲基-7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮、7-(2-硝基亚苄基)-2,2-二甲基-7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮、7-(3-硝基亚苄基)-2,2-二甲基-7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮、7-(4-硝基亚苄基)-2,2-二甲基-7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮、7-(2-氨基亚苄基)-2,2-二甲基-7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮、7-(3-氨基亚苄基)-2,2-二甲基-7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮、7-(4-氨基亚苄基)-2,2-二甲基-7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮、7-(4-羧基亚苄基)-2,2-二甲基-7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮、7-(4-二甲氨基亚苄基)-2,2-二甲基-7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮。
本发明技术方案的第二方面是提供了第一方面所述结构式I所示的7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮衍生物的制备方法,其特征在于它的制备反应如下:
其中R选自:氢、氘、C1~C2烷基、C3~C5直链烷基或C3~C5支链烷基;X1、X5选自:氢、C1~C2烷基、C3~C4直链或支链烷基、羟基、甲氧基、乙氧基;X2、X4选自:氢、C1~C2烷基、C3~C4直链或支链烷基、硝基、羟基、甲氧基、乙氧基或氨基;X3选自:氢、C1~C2烷基、C3~C4直链或支链烷基,羟基、甲氧基、乙氧基、二甲氨基或羧基。
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7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮衍生物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7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮衍生物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流感病毒神经氨酸酶抑制剂方面的应用。
有益技术效果:
本发明的7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮衍生物是一类新结构类型的具有流感病毒神经氨酸酶抑制活性的化合物。
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
2,2-二甲基-7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮的制备
(1)3-((2,2-二甲基-2,3-二氢苯并呋喃-7-基)氧基)丙腈的制备
8.2g(50mmol)呋喃酚,26.5g(500mmol)丙烯腈,0.7g(5mmol)碳酸钾,0.37g(5mmol)叔丁醇,氮气保护。升温至回流,反应48h。停止加热后,加入0.46g(4mmol)85%磷酸淬灭反应。减压蒸馏回收丙烯腈14.27g,加入二氯甲烷溶解搅拌,抽滤后取滤液。用50mL浓度为2mol/L的氢氧化钠溶液和3mL DMSO混合溶液洗涤两次,50mL二氯甲烷再反萃一次。饱和食盐水洗两次。无水硫酸钠干燥后,减压蒸馏去除二氯甲烷,得到白色晶体3-((2,2-二甲基-2,3-二氢苯并呋喃-7-基)氧基)丙腈。收率75.1%,m.p.56~58℃。1H NMR(400M Hz,DMSO)δ:1.42(s,6H,2×CH3),2.97(t,J=6.0Hz,2H,CNCH2),3.00(s,2H,CH2),4.15(s,2H,OCH2),6.71~6.84(m,3H,C6H3)。
(2)3-((2,2-二甲基-2,3-二氢苯并呋喃-7-基)氧基)丙酸的制备
4.34g(20mmol)3-((2,2-二甲基-2,3-二氢苯并呋喃-7-基)氧基)丙腈,30mL浓盐酸,回流2h。停止反应后,将混合液倒入100mL冰水中,静置,抽滤,将滤饼溶于200mL5%的碳酸氢钠溶液中,二氯甲烷洗涤3次,用5%的碳酸氢钠溶液反萃取一次,用18%的盐酸将pH值调到中性,将析出的固体抽滤,干燥,得到橘红色固体3-((2,2-二甲基-2,3-二氢苯并呋喃-7-基)氧基)丙酸,收率80.0%。
(3)2,2-二甲基-7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮的制备
30mL多聚磷酸,搅拌升温至60℃,加入4.72g(20mmol)3-((2,2-二甲基-2,3-二氢苯并呋喃-7-基)氧基)丙酸,反应1.5h。停止反应后,将反应温度降至10℃以下,加入100mL冰水至反应体系中继续搅拌0.5h。用150mL乙酸乙酯萃取,再用200mL2mol/L氢氧化钠洗涤。减压蒸馏除去乙酸乙酯,柱层析[V石油醚:V乙酸乙酯=2:1]得黄绿色固体。收率36.5%,m.p.138~140℃。1H NMR(400M Hz,CDCl3)δ:1.54(s,6H,2×CH3),2.82(t,J=6.4Hz,2H,COCH2),3.07(s,2H,CH2),4.60(t,J=6.4Hz,2H,OCH2),6.82(d,J=7.9Hz,1H,C6H2),7.43(d,J=7.9Hz,1H,C6H2)。
实施例2
7-(3-羟基亚苄基)-2,2-二甲基-7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮的制备
将1.5mmol 2,2-二甲基-7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮、1.55mmol4-羟基苯甲醛加入到100mL三口瓶中,然后加入8mL 85%磷酸,磁力搅拌升温至80℃。TLC监测原料反应完全后,停止加热,待反应混合物冷却后,加入适量冰水搅拌数分钟,用适量乙酸乙酯萃取粗产物,饱和碳酸氢钠洗涤有机层,饱和食盐水洗,干燥,脱溶,乙醇重结晶得到棕黄色固体,收率63.9%,m.p.204~207℃。1H NMR(400MHz,DMSO)δ:1.45(s,6H,2×CH3),3.09(s,2H,CH2),5.37(s,2H,OCH2),6.80~6.90(m,3H,C6H4),6.97(d,J=8.0Hz,1H,C6H2),7.28~7.34(m,1H,C6H4),7.39(d,J=8.0Hz,1H,C6H2),7.65(s,1H,=CH),9.74(s,1H,OH);13C NMR(100MHz,DMSO)δ:28.06,42.96,67.60,88.88,116.75,117.12,118.84,119.21,121.49,122.00,130.34,130.98,135.23,136.10,137.11,145.60,146.44,157.41,181.53。
实施例3
7-(4-羟基亚苄基)-2,2-二甲基-7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮的制备
按例2方法,反应12h,粗品经柱层析[V石油醚:V乙酸乙酯=2:1]得到黄色固体,收率57.1%,m.p.203~205℃。1H NMR(400MHz,DMSO)δ:1.44(s,6H,2×CH3),3.08(s,2H,CH2),5.39(s,2H,OCH2),6.89(d,J=8.0Hz,2H,C6H4),6.95(d,J=7.8Hz,1H,C6H2),7.33(d,J=8.0Hz,2H,C6H4),7.36(d,J=7.8Hz,1H,C6H2),7.66(s,1H,=CH),10.14(s,1H,OH);13C NMR(100MHz,DMSO)δ:28.07,42.93,67.79,88.79,116.03,118.68,119.12,122.15,125.15,128.02,133.03,135.76,137.35,145.39,146.39,159.19,181.41。
实施例4
7-(3,4-二羟基亚苄基)-2,2-二甲基-7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮的制备
按例2方法,反应11h,乙醇重结晶得到黄色固体,收率44.8%,m.p.214~216℃。1HNMR(400MHz,DMSO)δ:1.44(s,6H,2×CH3),3.07(s,2H,CH2),5.38(s,2H,OCH2),6.75~6.90(m,3H,C6H3),6.94(d,J=7.8Hz,1H,C6H2),7.35(d,J=7.8Hz,1H,C6H2),7.57(s,1H,=CH),9.26(s,1H,OH),9.66(s,1H,OH)。
实施例5
7-(3-甲氧基亚苄基)-2,2-二甲基-7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮的制备
按例2方法,反应11.5h,粗品经柱层析[V石油醚:V乙酸乙酯=8:1]得黄色固体,收率57.5%,m.p.119~121℃。1H NMR(400MHz,CDCl3)δ:1.54(s,6H,2×CH3),3.08(s,2H,CH2),3.83(s,3H,OCH3),5.39(s,2H,OCH2),6.80~6.91(m,3H,C6H2,C6H4),6.92~6.99(m,1H,C6H4),7.32~7.38(m,1H,C6H4),7.56(d,J=8.0Hz,1H,C6H2),7.83(s,1H,=CH)。
实施例6
7-(4-甲氧基亚苄基)-2,2-二甲基-7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮的制备
按例2方法,反应10.5h,粗品经柱层析[V石油醚:V乙酸乙酯=8:1]得淡黄色固体,收率46.6%,m.p.132~134℃。1H NMR(400MHz,CDCl3)δ;1.54(s,6H,2×CH3),3.08(s,2H,CH2),3.86(s,3H,OCH3),5.42(s,2H,OCH2),6.87(d,J=8.0Hz,1H,C6H2),6.97(d,J=8.8Hz,2H,C6H4),7.28(d,J=8.8Hz,2H,C6H4),7.56(d,J=8.0Hz,1H,C6H2),7.83(s,1H,=CH)。
实施例7
7-(3,4,5-三甲氧基亚苄基)-2,2-二甲基-7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮的制备
按例2方法,反应10h,粗品经柱层析[V石油醚:V乙酸乙酯=8:1]得到棕色固体,收率46.2%,m.p.125~127℃。1H NMR(400MHz,CDCl3)δ:1.54(s,6H,2×CH3),3.09(s,2H,CH2),3.88(s,6H,2×OCH3),3.91(s,3H,OCH3),5.46(s,2H,OCH2),6.54(s,2H,C6H4),6.89(d,J=8.0Hz,1H,C6H2),7.56(d,J=8.0Hz,1H,C6H2),7.79(s,1H,=CH)。
实施例8
7-(4-羟基-3-甲氧基亚苄基)-2,2-二甲基-7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮的制备
按例2方法,反应11h,粗品经柱层析[V石油醚:V乙酸乙酯=4:1]得黄色固体,收率55.3%,m.p.136~138℃。1H NMR(400MHz,DMSO)δ:1.54(s,6H,2×CH3),3.08(s,2H,CH2),3.92(s,3H,OCH3),5.44(s,2H,OCH2),6.83~6.89(m,3H,C6H3),6.98(d,J=8.0Hz,1H,C6H2),7.56(d,J=8.0Hz,1H,C6H2),7.80(s,1H,=CH)。
实施例9
7-(3-羟基-4-甲氧基亚苄基)-2,2-二甲基-7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮的制备
按例2方法,反应11h,乙醇重结晶得到棕黄色固体,收率59.6%,m.p.194~196℃。1H NMR(400MHz,DMSO)δ:1.45(s,6H,2×CH3),3.09(s,2H,CH2),3.85(s,3H,OCH3),5.40(s,2H,OCH2),6.90~6.92(m,2H,C6H32,6-H),6.96(d,J=8.0Hz,1H,C6H2),7.05(d,J=8.4Hz,1H,C6H35-H),7.37(d,J=8.0Hz,1H,C6H2),7.61(s,1H,=CH),9.36(s,1H,OH);13C NMR(100MHz,DMSO)δ:28.13,42.97,55.89,67.77,88.72,112.33,117.32,118.65,119.11,122.18,123.28,126.80,128.80,135.69,137.13,145.45,146.45,146.51,149.58,181.19。
实施例10
7-(2-羟基-3-甲氧基亚苄基)-2,2-二甲基-7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮的制备
按例2方法,反应11h,粗品经柱层析[V石油醚:V乙酸乙酯=3:1]得到黄色固体,收率48.1%,m.p.178~180℃。1H NMR(400MHz,DMSO)δ:1.43(s,6H,2×CH3),3.08(s,2H,CH2),3.84(s,3H,OCH3),5.26(s,2H,OCH2),6.70~6.73(m,1H,C6H3),6.87(t,J=8.0Hz,1H,C6H34-H),6.93~6.97(m,1H,C6H3),7.08(d,J=8.0Hz,1H,C6H2),7.38(d,J=8.0Hz,1H,C6H2),7.84(s,1H,=CH),9.41(s,1H,OH)。
实施例11
7-(2-硝基亚苄基)-2,2-二甲基-7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮的制备
按例2方法,反应11h,乙醇重结晶得到淡黄色固体,收率57.1%,m.p.142~145℃。1H NMR(400MHz,CDCl3)δ:1.44(s,6H,2×CH3),3.10(s,2H,CH2),5.17(s,2H,OCH2),7.00(d,J=8.0Hz,1H,C6H2),7.42(d,J=8.0Hz,1H),7.43~7.48(m,1H,C6H4),7.72~7.78(m,1H,C6H4),7.85~7.90(m,1H,C6H4),7.93(s,1H,=CH),8.25~8.31(m,1H,C6H4)。
实施例12
7-(3-硝基亚苄基)-2,2-二甲基-7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮的制备
1.5mmol 2,2-二甲基-7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮、5mL乙醇和适量5%NaOH溶液,室温搅拌,缓慢加入1.55mmol 3-硝基苯甲醛,TLC跟踪反应,视反应情况补加适量5%NaOH水溶液。TLC监测反应完全后,向反应液中加入适量冰水搅拌15分钟,析出黄色沉淀,抽滤,冰水洗涤滤饼,冰乙醇淋洗滤饼,乙醇重结晶得到黄色固体,收率68.0%,m.p.231~234℃。1H NMR(400MHz,DMSO)δ:1.44(s,6H,2×CH3),3.09(s,2H,CH2),5.41(s,2H,OCH2),6.99(d,J=8.0Hz,1H,C6H2),7.40(d,J=8.0Hz,1H,C6H2),7.79~7.89(m,3H,C6H4),8.26~8.34(m,2H,C6H4,=CH)。
实施例13
7-(4-硝基亚苄基)-2,2-二甲基-7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮的制备
按例2方法,反应10h,乙酸乙酯重结晶得到黄色固体,收率61.9%,m.p.238~241℃。1H NMR(400MHz,DMSO)δ:1.44(s,6H,2×CH3),3.09(s,2H,CH2),5.39(s,2H,OCH2),6.99(d,J=8.0Hz,1H,C6H2),7.40(d,J=8.0Hz,1H,C6H2),7.73(d,J=8.0Hz,2H,C6H42,6-H),7.81(s,1H,=CH),8.32(d,J=8.0Hz,2H,C6H43,5-H)。
实施例14
7-(2-氨基亚苄基)-2,2-二甲基-7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮的制备
1.0mmol 7-(3-硝基亚苄基)-2,2-二甲基-7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮,10mL二氯甲烷和10ml乙酸搅拌溶解,加入适量铁粉和1mL水,室温搅拌反应6h。过滤,二氯甲烷洗滤饼,3×20mL水洗滤液,2×20mL饱和NaHCO3洗至无絮状物,干燥,脱溶,乙醇重结晶得棕黄色固体,收率82.2%,m.p.182~184℃。1H NMR(400MHz,DMSO)δ:1.43(s,6H,2×CH3),3.07(s,2H,CH2),5.26(s,2H,OCH2),5.49(s,2H,NH2),6.59(t,J=7.2Hz,1H,C6H4),6.70~6.89(m,2H,C6H4),6.95(d,J=7.8Hz,1H,C6H2),7.13(t,J=7.5Hz,1H,C6H4),7.39(d,J=7.8Hz,1H,C6H2),7.68(s,1H,=CH)。
实施例15
7-(3-氨基亚苄基)-2,2-二甲基-7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮的制备
按例14方法,乙醇重结晶得黄色固体,收率74.6%,m.p.152~155℃。1H NMR(400MHz,DMSO)δ:1.44(s,6H,2×CH3),3.08(s,2H,CH2),5.29(s,1H,OCH2),5.36(s,2H,NH2),6.69~6.52(m,3H,C6H4),6.96(d,J=7.8Hz,1H,C6H2),7.09~7.19(m,1H,C6H4),7.37(d,J=7.8Hz,1H,C6H2),7.58(s,1H,=CH)。
实施例16
7-(4-氨基亚苄基)-2,2-二甲基-7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮的制备
按例2方法,反应11.5h,乙醇重结晶得到橘黄色固体,收率44.5%,m.p.146~149℃。1H NMR(400MHz,DMSO)δ:1.45(s,6H,2×CH3),3.08(s,2H,CH2),5.40(s,2H,OCH2),5.95(s,2H,NH2),6.65(d,J=8.5Hz,2H,C6H4),6.93(d,J=8.0Hz,1H,C6H2),7.19(d,J=8.5Hz,2H,C6H4),7.34(d,J=8.0Hz,1H,C6H2),7.59(s,1H,=CH);13C NMR(100MHz,DMSO)δ:28.17,42.99,68.16,88.53,113.81,118.37,118.96,121.36,122.53,125.14,133.30,135.09,138.10,145.26,146.42,151.29,180.85。
实施例17
7-(4-羧基亚苄基)-2,2-二甲基-7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮的制备
按例2方法,反应10.5h,乙醇重结晶得黄色固体,收率55.2%,m.p.274~277℃。1HNMR(400MHz,DMSO)δ:1.44(s,6H,2×CH3),3.09(s,2H,CH2),5.39(s,2H,OCH2),6.98(d,J=8.0Hz,1H,C6H2),7.39(d,J=8.0Hz,1H,C6H2),7.57(d,J=8.0Hz,2H,C6H42,6-H),7.77(s,1H,=CH),8.03(d,J=8.0Hz,2H,C6H43,5-H)。
实施例18
7-(4-二甲氨基亚苄基)-2,2-二甲基-7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮的制备
按例2方法,反应12h,乙醇重结晶得橘黄色固体F28,收率57.8%,m.p.202~204℃。1H NMR(400MHz,DMSO)δ:1.44(s,6H,2×CH3),3.01(s,6H,2×CH3,C6H4),3.07(s,2H,CH2),5.42(s,2H,OCH2),6.79(d,J=8.4Hz,2H,C6H43,5-H),6.93(d,J=8.0Hz,1H,C6H2),7.34(m,3H,C6H2,C6H42,6-H),7.65(s,1H,=CH)。
实施例19
7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮衍生物的抗流感病毒神经氨酸酶活性
1.实验原理
化合物MUNANA是神经氨酸酶的特异性底物,在神经氨酸酶作用下产生的代谢产物在360nm照射激发下,可以产生450nm荧光,荧光强度的变化可以灵敏地反应神经氨酸酶活性。酶都来自A/PR/8/34(H1N1)病毒毒株。
2.实验方法
在酶反应体系中,一定浓度样品与流感病毒神经氨酸酶NA悬浮于反应缓冲液中(pH6.5),加入荧光底物MUNANA启动反应体系,37℃孵育40分钟后,加反应终止液终止反应。在激发波长360nm和发射波长为450nm的参数条件下,测定荧光强度值。反应体系的荧光强度可以反映酶的活性。根据荧光强度的减少量可以计算化合物对NA活性的抑制率。
3.检测样品:实施例化合物
4.活性结果
优选化合物在反应系统中检测浓度40.0μg/mL时对神经氨酸酶的抑制率和IC50列入下表:
表17,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮衍生物(40.0μg/mL)对神经氨酸酶的抑制率和IC50(μg/mL)
由表中数据可知7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮对神经氨酸酶具有较好的抑制活性,可应用于制备神经氨酸酶抑制剂。
Claims (5)
1.一类化学结构式Ⅰ所示的7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮衍生物及其药学上可接受的盐:
其中R选自:氢、氘、C1~C2烷基、C3~C5直链烷基或C3~C5支链烷基;X1、X5选自:氢、C1~C2烷基、C3~C4直链或支链烷基、羟基、甲氧基、乙氧基;X2、X4选自:氢、C1~C2烷基、C3~C4直链或支链烷基、硝基、羟基、甲氧基、乙氧基或氨基;X3选自:氢、C1~C2烷基、C3~C4直链或支链烷基,羟基、甲氧基、乙氧基、二甲氨基或羧基。
2.权利要求1所述的7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮衍生物及其药学上可接受的盐,其特征在于,所述的化合物选自:
7-(3-羟基亚苄基)-2,2-二甲基-7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮、
7-(4-羟基亚苄基)-2,2-二甲基-7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮、
7-(3,4-二羟基亚苄基)-2,2-二甲基-7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮、
7-(3-甲氧基亚苄基)-2,2-二甲基-7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮、
7-(4-甲氧基亚苄基)-2,2-二甲基-7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮、
7-(3,4,5-三甲氧基亚苄基)-2,2-二甲基-7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮、
7-(4-羟基-3-甲氧基亚苄基)-2,2-二甲基-7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮、
7-(3-羟基-4-甲氧基亚苄基)-2,2-二甲基-7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮、
7-(2-羟基-3-甲氧基亚苄基)-2,2-二甲基-7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮、
7-(2-硝基亚苄基)-2,2-二甲基-7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮、
7-(3-硝基亚苄基)-2,2-二甲基-7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮、
7-(4-硝基亚苄基)-2,2-二甲基-7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮、
7-(2-氨基亚苄基)-2,2-二甲基-7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮、
7-(3-氨基亚苄基)-2,2-二甲基-7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮、
7-(4-氨基亚苄基)-2,2-二甲基-7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮、
7-(4-羧基亚苄基)-2,2-二甲基-7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮或
7-(4-二甲氨基亚苄基)-2,2-二甲基-7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮。
3.权利要求1所述的7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮衍生物的制备方法,其特征在于它的制备反应如下:
式中,R、X1~X5如权利要求1所述。
4.权利要求1或2所述的7,8-二氢-2H-呋喃并[3,2-h]色满-6(3H)-酮衍生物在制备流感病毒神经氨酸酶抑制剂中的应用。
5.一种药物组合物,包括权利要求1~2至少一种化合物和制药学上可用的载体。
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