CN107141267B - N-(5-酰基噻唑-2-基)酰胺及其制备方法与应用 - Google Patents
N-(5-酰基噻唑-2-基)酰胺及其制备方法与应用 Download PDFInfo
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- CN107141267B CN107141267B CN201710482345.9A CN201710482345A CN107141267B CN 107141267 B CN107141267 B CN 107141267B CN 201710482345 A CN201710482345 A CN 201710482345A CN 107141267 B CN107141267 B CN 107141267B
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Abstract
本发明公开了结构式Ⅰ所示的N‑(5‑酰基噻唑‑2‑基)酰胺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。
Description
技术领域
本发明涉及一类新化合物、其制备方法与应用，具体是N-(5-酰基噻唑-2-基)酰胺、其制备方法及其在制备抗流感病毒神经氨酸酶抑制剂的应用。
背景技术
Ye等[European Journal of Medicinal Chemistry,2012,54(12):764-770]描述了吗啉修饰的扎那米韦类似物对流感NA的抑制活性，其中A对H3N2的IC50值分别为566.8±76.9μM，对H5N1的IC50值分别为517.0±105μM。Wen等[Bioorganic&Medicinal Chemistry,2010,18(11):4074-84]描述了C-4位修饰的扎那米韦类似物对流感病毒神经氨酸酶的抑制活性。其中化合物B对H1N1NA的IC50值为33.3μM，EC50值为37.6μM。
尤启冬等[CN 102659615B.2014.05.07]描述了奥司他韦衍生物的制备方法以及其在抗流感病毒中的作用；其中，化合物C对流感病毒H1N1和H3N2神经氨酸酶的抑制活性IC50分别为1.9μM和2.3μM；其乙酯D对流感病毒H1N1和H3N2神经氨酸酶的抑制活性IC50分别为1.2μM和0.9μM。
Sokoloova等[Med.Chem.,2017,2(11):960-963]描述了冰片类杂环化合物的制备，并在MDCK细胞中测试了其对流感病毒的抑制活性；其中含有吗啉片段的化合物E～G有较好的抗流感病毒活性，IC50分别是7.1μM、12.2μM和7.8μM。
发明内容
本发明解决的技术问题是提供一类N-(5-酰基噻唑-2-基)酰胺、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结构式Ⅰ所示的N-(5-酰基噻唑-2-基)酰胺及其在药学上可接受的盐：
式中R1选自：H、C1～C2烷基、C3～C4直链烷基或C3～C4支链烷基；R2选自：C1～C2烷基、C3～C4直链烷基或C3～C4支链烷基、C1～C2烷氧基、C3～C4直链烷氧基或C3～C4支链烷氧基；R3选自：H、C1～C2烷基、C3～C6直链烷基；R4选自：H、C1～C2烷基、C3～C4直链烷基；Z选自：O，S或CH2；n选自：1、2、3、4、5或6。
进一步的，优选的化合物选自：N-(5-乙酰基-4-甲基噻唑-2-基)-2-(吗啉-1-基)乙酰胺、N-(5-乙酰基-4-甲基噻唑-2-基)-3-(吗啉-1-基)丙酰胺或N-(5-乙酰基-4-甲基噻唑-2-基)-2-(哌啶-1-基)乙酰胺。
本发明技术方案的第二方面是提供了第一方面所述通式I所示的N-(5-酰基噻唑-2-基)酰胺的制备方法，其特征在于它的制备反应如下：
式中R1选自：H、C1～C2烷基、C3～C4直链烷基或C3～C4支链烷基；R2选自：C1～C2烷基、C3～C4直链烷基或C3～C4支链烷基、C1～C2烷氧基、C3～C4直链烷氧基或C3～C4支链烷氧基；R3选自：H、C1～C2烷基、C3～C6直链烷基；R4选自：H、C1～C2烷基、C3～C4直链烷基；Z选自：O，S或CH2；n选自：1、2、3、4、5或6；X选自：氯、溴或碘。
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N-(5-酰基噻唑-2-基)酰胺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N-(5-酰基噻唑-2-基)酰胺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N-(5-酰基噻唑-2-基)酰胺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
N-(5-乙酰基-4-甲基噻唑-2-基)-2-(吗啉-1-基)乙酰胺的制备
0.86mmol N-(5-乙酰基-4-甲基噻唑-2-基)-2-氯乙酰胺、5mL THF、0.86mmol吗啉，0.86mmol TEA，常温搅拌，TLC监测，反应18h；脱溶，二氯甲烷溶解，饱和食盐水洗涤，收集、合并有机层，无水硫酸钠干燥，脱溶，加石油醚析出固体，乙醇重结晶，抽滤，滤饼用石油醚和冰乙醇洗涤，干燥后得白色粉末状固体N-(5-乙酰基-4-甲基噻唑-2-基)-2-(吗啉-1-基)乙酰胺0.12g，收率49.3％，m.p.142～145℃，1HNMR(400MHz，CDCl3)δ：2.52(s，3H，CH3)，2.64(t，J＝4.4Hz，4H，CH2NCH2)，2.66(s，3H，CH3CO)，3.29(s，2H，COCH2)，3.79(t，J＝4.4Hz，4H，CH2OCH2)。
实施例2
N-(5-乙酰基-4-甲基噻唑-2-基)-3-氯丙酰胺的制备
75mmol 3-氯丙酸和75mmol DCC溶于60mL二氯甲烷，投入催化剂DMAP 2g，室温下搅拌10分钟，加入2-氨基-4-甲基噻唑-5-乙酮的氢溴酸盐4.8g，黄色消失，室温搅拌约48h，抽滤，二氯甲烷洗涤滤饼，滤液依次用饱和食盐水和饱和NaHCO3洗涤数次，水层用二氯甲烷萃取，合并有机层，无水硫酸钠干燥，脱溶，柱层析(V石油醚：V乙酸乙酯＝2:1)，得白色粉末N-(4-甲基-5-乙酰基噻唑-2-基)-3-氯丙酰胺5.84g，收率70.3％，m.p.163～166℃，1HNMR(400MHz，CDCl3)δ：2.52(s，3H，CH3)，2.64(s，3H，CH3)，2.96(t，J＝6.3Hz，2H，COCH2)，3.90(t，J＝6.2Hz，2H，CH2)。
实施例3
N-(5-乙酰基-4-甲基噻唑-2-基)-3-(吗啉-1-基)丙酰胺的制备
0.813mmol N-(5-乙酰基-4-甲基噻唑-2-基)-3-氯丙酰胺、5mL THF、0.813mmol吗啉，0.86mmol TEA，常温搅拌，TLC监测，反应18h；脱溶，二氯甲烷溶解，饱和食盐水洗涤，收集、合并有机层，无水硫酸钠干燥，脱溶，加石油醚析出固体，乙醇重结晶，抽滤，滤饼用石油醚和冰乙醇洗涤，干燥后得白色粉末状固体N-(5-乙酰基-4-甲基噻唑-2-基)-3-(吗啉-1-基)丙酰胺0.16g，收率66.7％，m.p.154～156℃，1HNMR(400MHz，CDCl3)δ：2.50(s，3H，CH3)，2.68～2.61(m，9H，CH3CO+CH2NCH2+COCH2)，2.78(t，J＝5.6Hz，2H，CH2)，3.87(s，J＝4.4Hz，4H，CH2OCH2)，12.66(s，1H，NH)。
实施例4
N-(5-乙酰基-4-甲基噻唑-2-基)-2-(哌啶-1-基)乙酰胺的制备
1.07mmol N-(5-乙酰基-4-甲基噻唑-2-基)-2-氯乙酰胺溶于5mL THF、1.61mmol哌啶、1.07mmol TEA，常温反应，TLC监测，反应23h；反应完后，脱溶，二氯甲烷溶解，饱和食盐水洗，收集、合并有机层，无水硫酸钠干燥，脱溶，加石油醚析出固体，乙醇重结晶，抽滤，滤饼用石油醚和冰乙醇洗涤，干燥得白色粉末状固体N-(5-乙酰基-4-甲基噻唑-2-基)-2-(哌啶-1-基)乙酰胺0.14g，收率46.6％，m.p.120～122℃，1HNMR(400MHz，CDCl3)δ：1.49～1.50(m，2H，哌啶4-H)，1.64～1.69(m，4H，哌啶3，5-H)，2.52(s，3H，CH3)，2.55(m，4H，哌啶2，6-H)，2.66(s，3H，CH3CO)，3.22(s，2H，COCH2)。
实施例5
N-(5-酰基噻唑-2-基)酰胺及其盐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：实施例化合物
4.活性结果
实施例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及其IC50值列入下表1：
表1 N-(5-酰基噻唑-2-基)酰胺对神经氨酸酶的抑制活性
N-(5-酰基噻唑-2-基)酰胺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 (6)
1.一类化学结构式Ⅰ所示的N-(5-酰基噻唑-2-基)酰胺及其药学上可接受的盐：
式中R1选自：H、C1～C2烷基、C3～C4直链烷基或C3～C4支链烷基；R2选自：C1～C2烷基、C3～C4直链烷基或C3～C4支链烷基、C1～C2烷氧基、C3～C4直链烷氧基或C3～C4支链烷氧基；R3选自：H、C1～C2烷基、C3～C6直链烷基；R4选自：H、C1～C2烷基、C3～C4直链烷基；Z选自：O，S或CH2；n选自：1、2、3、4、5或6。
2.权利要求1所述的N-(5-酰基噻唑-2-基)酰胺及其药学上可接受的盐，其特征在于，所述的化合物选自：
N-(5-乙酰基-4-甲基噻唑-2-基)-3-(吗啉-1-基)丙酰胺或N-(5-乙酰基-4-甲基噻唑-2-基)-2-(哌啶-1-基)乙酰胺。
3.权利要求1所述的N-(5-酰基噻唑-2-基)酰胺的制备方法，其特征在于它的制备反应如下：
式中，Z,n,R1～R4如权利要求1所述；X选自：氯、溴或碘。
4.权利要求1所述的N-(5-酰基噻唑-2-基)酰胺在制备流感病毒神经氨酸酶抑制剂中的应用。
5.权利要求2所述的N-(5-酰基噻唑-2-基)酰胺在制备流感病毒神经氨酸酶抑制剂中的应用。
6.一种药物组合物，包括权利要求1或2至少一种化合物和制药学上可用的载体。
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| CN105669589A (zh) * | 2016-01-21 | 2016-06-15 | 湖南大学 | 2-(5-酰基噻唑-2-亚氨基)-4-噻唑啉酮及其制备方法与应用 |
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| CN105669589A (zh) * | 2016-01-21 | 2016-06-15 | 湖南大学 | 2-(5-酰基噻唑-2-亚氨基)-4-噻唑啉酮及其制备方法与应用 |
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