CN106317049A - 2-[5-(氮唑-1-基)噻唑-2-亚氨基]-5-亚苄基-4-噻唑啉酮作为na抑制剂的应用 - Google Patents
2-[5-(氮唑-1-基)噻唑-2-亚氨基]-5-亚苄基-4-噻唑啉酮作为na抑制剂的应用 Download PDFInfo
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- GNNILMDCYQGMRH-UHFFFAOYSA-N formyl benzoate Chemical compound O=COC(=O)C1=CC=CC=C1 GNNILMDCYQGMRH-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—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
- C07D417/14—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 three or more hetero rings
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Abstract
本发明涉及化学结构式Ⅰ所示的2-[5-(氮唑-1-基)噻唑-2-亚氨基]-5-亚苄基-4-噻唑啉酮:其中,R1选自:氢、C1~C2烷基、C3~C4直链或支链烷基;X、Y选自:CH或N;Z选自:氰基、C1~C2烷氧羰基、C3~C4直链烷氧羰基、C3~C4支链烷氧羰基或羧基。2-[5-(氮唑-1-基)噻唑-2-亚氨基]-5-亚苄基-4-噻唑啉酮在制备流感病毒神经氨酸酶抑制剂中的应用。
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-[5-(氮唑-1-基)噻唑-2-亚氨基]-5-亚苄基-4-噻唑啉酮的制备及其在作为流感病毒神经氨酸酶(NA)抑制剂的应用。
背景技术
禽流感病毒可引起禽类的呼吸器官或全身性感染,高致病性禽流感病毒可直接感染禽类,也能直接或间接感染人类。高致病性禽流感病毒是在人群中引发流感的一个潜在危险因素,并会严重地威胁人类健康。2003年7月之后,H5N1禽流感疫情呈现前所未有的暴发,波及亚洲、北美洲、欧洲和非洲17个国家和地区,造成数百人感染及死亡,直接经济损失高达100亿美元。2003年3月,荷兰发生H7N7型禽流感并波及整个欧洲,人类感染者达83例,不仅造成了人类的伤亡,同时重创了家禽养殖业。2009年3月底,墨西哥暴发人感染H1N1型猪流感疫情并扩散到世界各地,据世界卫生组织于2010年2月26日发布的甲型H1N1流感全球情况报告,至少有213个国家和地区的16226例病人死于这场大流感[曾祥兴,李康生。医学与社会,2010,11,4-6。]。经过基因序列分析,H1N1型病毒包含人流感病毒、北美禽流感病毒和北美、欧、亚猪流感病毒基因片段,为几种不同物种流感病毒的混合毒株,而非单独一种猪流感或禽流感病毒。2013年3月,我国首次发现人感染H7N9禽流感病例,截止2015年1月25日,世界卫生组织公布的H7N9禽流感确诊494人,死亡221人。抗禽流感病毒药物的研发,已成为世界各国政府及卫生防疫部门日益关注重大问题之一。
以NA为作用靶标,通过抑制NA活性来抑制流感病毒复制和毒性的NA抑制剂是抗禽流感病毒的第一线药物,代表药物有Zanamivir、Oseltamivir和Peramivir及其衍生物,其中Oseltamivir应用广泛。但已有研究发现一些病毒株对Oseltamivir产生了耐药性。
2010年,Mohan等设计并合成了一类含有三氮唑结构的Oseltamivir类似物,体外酶抑制剂活性测试筛选出一个对NAs(Nl)具有较高活性和选择性的抑制剂A[Mohan S.et al,J.Med.Chem.2010,53(20),7377-7391]。谢元超以L-羟脯氨酸的吡咯烷为基本母核,设计合成出一类含有三氮唑的化合物B显示有较好的NA抑制活性[谢元超,山东大学,2014]。
A Ki=0.07μM(N1),Ki=2.6μM(N2) B1:IC50=66.6μM B2:IC50=58.7μM
发明内容
本发明的目的在于提供化学结构式Ⅰ所示的2-[5-(氮唑-1-基)噻唑-2-亚氨基]-5-亚苄基-4-噻唑啉酮:
其中,R1选自:氢、C1~C2烷基、C3~C4直链或支链烷基;X、Y选自:CH或N;Z选自:2-氰基、3-氰基、4-氰基、2-C1~C2烷氧羰基、3-C1~C2烷氧羰基、4-C1~C2烷氧羰基、2-C3~C4直链烷氧羰基、3-C3~C4直链烷氧羰基、4-C3~C4直链烷氧羰基、2-C3~C4支链烷氧羰基、3-C3~C4支链烷氧羰基、4-C3~C4支链烷氧羰基、2-羧基、3-羧基或4-羧基。
本发明的目的在于提供的2-[5-(氮唑-1-基)噻唑-2-亚氨基]-5-亚苄基-4-噻唑啉酮选自2-{[4-叔丁基-5-(1H-1,2,4-三唑-1-基)噻唑-2-基]亚氨基}-5-(4-氰基亚苄基)-4-噻唑啉酮或2-{[4-叔丁基-5-(1H-1,2,4-三唑-1-基)噻唑-2-基]亚氨基}-5-(2-羧基亚苄基)-4-噻唑啉酮。
本发明的目的在于提供的2-[5-(氮唑-1-基)噻唑-2-亚氨基]-5-亚苄基-4-噻唑啉酮的制备方法,其特征在于它的制备反应如下:
其中,R1选自:氢、C1~C2烷基、C3~C4直链或支链烷基;X、Y选自:CH或N;Z选自:2-氰基、3-氰基、4-氰基、2-C1~C2烷氧羰基、3-C1~C2烷氧羰基、4-C1~C2烷氧羰基、2-C3~C4直链烷氧羰基、3-C3~C4直链烷氧羰基、4-C3~C4直链烷氧羰基、2-C3~C4支链烷氧羰基、3-C3~C4支链烷氧羰基、4-C3~C4支链烷氧羰基、2-羧基、3-羧基或4-羧基。
本发明的目的在于提供的2-[5-(氮唑-1-基)噻唑-2-亚氨基]-5-亚苄基-4-噻唑啉酮具有流感病毒神经氨酸酶抑制活性,在制备流感病毒神经氨酸酶(NA)抑制剂中的应用。
本发明与现有技术相比具有如下优点:
发明了2-[5-(氮唑-1-基)噻唑-2-亚氨基]-5-亚苄基-4-噻唑啉酮具有流感病毒神经氨酸酶抑制活性。
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-{[4-叔丁基-5-(1H-1,2,4-三唑-1-基)噻唑-2-基]亚氨基}-4-噻唑啉酮(2)的制备
11.25g(50mmol)4-叔丁基-5-(1H-1,2,4-三唑-1-基)噻唑-2-胺,100mL二氯甲烷,搅拌溶解,加入6.90g(50mmol)无水碳酸钾,常温搅拌30min,滴加4.0ml(50mmol)氯乙酰氯,常温反应2.5h。反应液倒入冰水,二氯甲烷萃取,饱和碳酸钠水溶液洗涤,合并有机相,无水硫酸钠干燥,脱溶,乙醇重结晶得13.50g白色固体1,收率93%,m.p.130~133℃。
10.25g化合物1,4.95g硫氰酸钾,100ml乙醇溶解,加热回流反应5.0h。冷却,析出固体,抽滤,干燥得9.50g淡黄色固体2-{[4-叔丁基-5-(1H-1,2,4-三唑-1-基)噻唑-2-基]亚氨基}-4-噻唑啉酮2,收率86%,m.p.182~185℃。1H NMR(CDCl3,400MHz)δ:1.19(s,9H,3×CH3),3.90(s,2H,CH2),8.11(s,1H,C2H2N33-H),8.28(s,1H,C2H2N35-H),12.01(s,1H,NH)。
实施例2
2-{[4-叔丁基-5-(1H-1,2,4-三唑-1-基)噻唑-2-基]亚氨基}-5-(4-氰基亚苄基)-4-噻唑啉酮的制备
30ml乙酸、12.0mmol乙酸钠、4.0mmol中间体2和8.0mmol 4-氰基苯甲醛,加热回流反应10h。冷却,倒入饱和食盐水中,抽滤,水洗,乙醇重结晶得黄色固体2-{[4-叔丁基-5-(1H-1,2,4-三唑-1-基)噻唑-2-基]亚氨基}-5-(4-氰基亚苄基)-4-噻唑啉酮,收率75%,m.p.250~253℃。1H NMR(DMSO,400MHz)δ:1.19(s,9H,3×CH3),7.76(d,J=8.0Hz,2H,C6H42,6-H),7.99(d,J=8.0Hz,2H,C6H43,5-H),8.08(s,1H,=CH),8.29(s,1H,C2H2N33-H),9.03(s,1H,C2H2N35-H),13.00(s,1H,NH)。
实施例3
2-{[4-叔丁基-5-(1H-1,2,4-三唑-1-基)噻唑-2-基]亚氨基}-5-(2-羧基亚苄基)-4-噻唑啉酮的制备
30ml乙酸、12.0mmol乙酸钠、4.0mmol中间体2和8.0mmol邻甲酰基苯甲酸,加热回流反应10h。冷却,倒入饱和食盐水中,抽滤,水洗,乙醇重结晶得黄色固体2-{[4-叔丁基-5-(1H-1,2,4-三唑-1-基)噻唑-2-基]亚氨基}-5-(2-羧基亚苄基)-4-噻唑啉酮,收率79%,m.p.258~260℃。1H NMR(DMSO,400MHz)δ:1.10(s,9H,3×CH3),7.57~7.61(m,1H,C6H44-H),7.71~7.72(m,2H,C6H45,6-H),8.02(d,J=7.6Hz,1H,C6H43-H),8.29(s,1H,C2H2N33-H),8.34(s,1H,=CH),9.01(s,1H,C2H2N35-H),12.88(s,1H,NH),13.39(s,1H,COOH)。
实施例4
2-{[4-叔丁基-5-(1H-1,2,4-三唑-1-基)噻唑-2-基]亚氨基}-5-(4-羧基亚苄基)-4-噻唑啉酮的制备
30ml乙酸、12.0mmol乙酸钠、4.0mmol中间体2和8.0mmol对甲酰基苯甲酸,加热回流反应10h。冷却,倒入饱和食盐水中,抽滤,水洗,乙醇重结晶得黄色固体2-{[4-叔丁基-5-(1H-1,2,4-三唑-1-基)噻唑-2-基]亚氨基}-5-(4-羧基亚苄基)-4-噻唑啉酮,收率82%,m.p.>300℃。1H NMR(DMSO,400MHz)δ:1.19(s,9H,3×CH3),7.78(d,J=8.0Hz,2H,C6H42,6-H),7.81(s,1H,=CH),8.05(d,J=8.0Hz,2H,C6H43,5-H),8.29(s,1H,C2H2N33-H),9.03(s,1H,C2H2N35-H),12.96(s,1H,NH),13.25(s,1H,COOH)。
实施例5
2-{[4-叔丁基-5-(1H-1,2,4-三唑-1-基)噻唑-2-基]亚氨基}-5-(4-甲氧羰基亚苄基)-4-噻唑啉酮的制备
30ml乙酸、16.0mmol乙酸钠、4.0mmol中间体2和8.0mmol对甲酰基苯甲酸甲酯,加热回流反应10h。冷却,倒入饱和食盐水中,抽滤,水洗,乙醇重结晶得黄色固体2-{[4-叔丁基-5-(1H-1,2,4-三唑-1-基)噻唑-2-基]亚氨基}-5-(4-甲氧羰基亚苄基)-4-噻唑啉酮,收率72%,m.p.246~248℃。1H NMR(CDCl3,400MHz)δ:1.26(s,9H,3×CH3),3.96(s,3H,CO2CH3),7.66(d,J=7.2Hz,2H,C6H42,6-H),7.85(s,1H,=CH),8.14(s,1H,C2H2N33-H),8.16(d,J=7.2Hz,2H,C6H43,5-H),8.33(s,1H,C2H2N35-H),12.03(s,1H,NH)。
实施例6
2-[5-(氮唑-1-基)噻唑-2-亚氨基]-5-亚苄基-4-噻唑啉酮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,可产生450nm荧光,荧光强度的变化可以灵敏地反映神经氨酸酶活性。酶均来自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。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:2-[5-(氮唑-1-基)噻唑-2-亚氨基]-5-亚苄基-4-噻唑啉酮(Ⅰ)
其中,R1选自:氢、C1~C2烷基、C3~C4直链或支链烷基;X、Y选自:CH或N;Z选自:2-氰基、3-氰基、4-氰基、2-C1~C2烷氧羰基、3-C1~C2烷氧羰基、4-C1~C2烷氧羰基、2-C3~C4直链烷氧羰基、3-C3~C4直链烷氧羰基、4-C3~C4直链烷氧羰基、2-C3~C4支链烷氧羰基、3-C3~C4支链烷氧羰基、4-C3~C4支链烷氧羰基、2-羧基、3-羧基或4-羧基。
4.活性结果
2-[5-(氮唑-1-基)噻唑-2-亚氨基]-5-亚苄基-4-噻唑啉酮在反应系统中检测浓度40.0μg/mL时对神经氨酸酶的抑制率及其IC50值列入表1:
表12-[5-(氮唑-1-基)噻唑-2-亚氨基]-5-亚苄基-4-噻唑啉酮对神经氨酸酶的抑制活性
2-[5-(氮唑-1-基)噻唑-2-亚氨基]-5-亚苄基-4-噻唑啉酮具有良好的抗流感病毒神经氨酸酶活性,可用于制备流感病毒神经氨酸酶抑制剂。
Claims (4)
1.化学结构式Ⅰ所示的2-[5-(氮唑-1-基)噻唑-2-亚氨基]-5-亚苄基-4-噻唑啉酮:
其中,R1选自:氢、C1~C2烷基、C3~C4直链或支链烷基;X、Y选自:CH或N;Z选自:2-氰基、3-氰基、4-氰基、2-C1~C2烷氧羰基、3-C1~C2烷氧羰基、4-C1~C2烷氧羰基、2-C3~C4直链烷氧羰基、3-C3~C4直链烷氧羰基、4-C3~C4直链烷氧羰基、2-C3~C4支链烷氧羰基、3-C3~C4支链烷氧羰基、4-C3~C4支链烷氧羰基、2-羧基、3-羧基或4-羧基。
2.权利要求1所述的2-[5-(氮唑-1-基)噻唑-2-亚氨基]-5-亚苄基-4-噻唑啉酮选自2-{[4-叔丁基-5-(1H-1,2,4-三唑-1-基)噻唑-2-基]亚氨基}-5-(4-氰基亚苄基)-4-噻唑啉酮或2-{[4-叔丁基-5-(1H-1,2,4-三唑-1-基)噻唑-2-基]亚氨基}-5-(2-羧基亚苄基)-4-噻唑啉酮。
3.权利要求1所述的2-[5-(氮唑-1-基)噻唑-2-亚氨基]-5-亚苄基-4-噻唑啉酮的制备方法,其特征在于它的制备反应如下:
式中,R1、X、Y、Z如权利要求1所述。
4.权利要求1~2中任一项所述2-[5-(氮唑-1-基)噻唑-2-亚氨基]-5-亚苄基-4-噻唑啉酮在制备流感病毒神经氨酸酶抑制剂中的应用。
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VATHAN KUMAR ET AL.: "Identification, Synthesis, and Evaluation of New Neuraminidase Inhibitors", 《ORGANIC LETTERS》 * |
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