CN118125961A - 一种1-(4-三氟甲基-苄基)-靛红衍生物及其制备方法与应用 - Google Patents
一种1-(4-三氟甲基-苄基)-靛红衍生物及其制备方法与应用 Download PDFInfo
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- CN118125961A CN118125961A CN202311322759.7A CN202311322759A CN118125961A CN 118125961 A CN118125961 A CN 118125961A CN 202311322759 A CN202311322759 A CN 202311322759A CN 118125961 A CN118125961 A CN 118125961A
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- Prior art keywords
- trifluoromethyl
- benzyl
- isatin
- isatin derivative
- derivative
- 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.)
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- OPPBIMDPCPZQQL-UHFFFAOYSA-N 1-[[4-(trifluoromethyl)phenyl]methyl]indole-2,3-dione Chemical class C1=CC(C(F)(F)F)=CC=C1CN1C2=CC=CC=C2C(=O)C1=O OPPBIMDPCPZQQL-UHFFFAOYSA-N 0.000 title claims abstract description 50
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 241000711573 Coronaviridae Species 0.000 claims abstract description 38
- 239000001257 hydrogen Substances 0.000 claims abstract description 31
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 31
- 150000001875 compounds Chemical class 0.000 claims abstract description 28
- 239000003814 drug Substances 0.000 claims abstract description 20
- JXDYKVIHCLTXOP-UHFFFAOYSA-N isatin Chemical compound C1=CC=C2C(=O)C(=O)NC2=C1 JXDYKVIHCLTXOP-UHFFFAOYSA-N 0.000 claims abstract description 17
- 229940079593 drug Drugs 0.000 claims abstract description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 8
- 239000000460 chlorine Substances 0.000 claims abstract description 7
- IKSNDOVDVVPSMA-UHFFFAOYSA-N 1-(bromomethyl)-4-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=C(CBr)C=C1 IKSNDOVDVVPSMA-UHFFFAOYSA-N 0.000 claims abstract description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims abstract description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 6
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 6
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Abstract
本发明公开了一种1‑(4‑三氟甲基‑苄基)‑靛红衍生物及其制备方法与应用,属于生物医药领域。本发明的1‑(4‑三氟甲基‑苄基)‑靛红衍生物的结构如式(I)所示,其中,R1‑R4各自独立地选自氟、氯、溴、碘、氢中的一种。通过将靛红或靛红衍生物与4‑三氟甲基苄溴在碱的作用下于反应溶剂中反应,即可得到1‑(4‑三氟甲基‑苄基)‑靛红衍生物,其制备方法工艺简单,易于产业化。本发明的1‑(4‑三氟甲基‑苄基)‑靛红衍生物对新型冠状病毒(SARS‑CoV‑2)3CL蛋白酶具有良好的抑制作用,其中某些化合物活性与阳性对照药Ebselen相当,且毒性小,可用于制备抗新型冠状病毒药物。
Description
技术领域
本发明属于生物医药领域,具体涉及一种1-(4-三氟甲基-苄基)-靛红衍生物及其制备方法与应用。
背景技术
新型冠状病毒感染是继严重急性呼吸道综合症(SARS)和中东呼吸综合征(MERS)之后又一高传染性、高致病性的传染病。随着病毒的传播,新冠病毒变异株不断出现,主要包括阿尔法(Alpha)、贝塔(Beta)、伽玛(Gamma)、德尔塔(Delta)和奥密克戎(Omicron)等变体。其中,Delta型和Omicron型变异株因具有更高的传播能力和强致病性受到全球广泛关注,亟需探索行之有效的治疗方法及开发针对不同变异株均有效的特效药物。
3CL蛋白酶在新型冠状病毒中高度保守,与刺突蛋白相比,不容易发生突变;其活性中心的氨基酸为SARS-CoV-2特有,与人类蛋白酶的同源性低,对人体没有细胞毒性和生殖毒性,可以大大提高此类药的安全性,临床安全性要高于RNA聚合酶抑制剂。3CL蛋白酶在病毒复制中的关键作用及其高度保守性,3CL蛋白酶被认为是冠状病毒药物研发最具吸引力的靶标。随着辉瑞公司新冠病毒口服药Paxlovid的上市,3CL蛋白酶靶点广受关注,国内外多家企业开始积极布局。目前报道的冠状病毒3CL蛋白酶抑制剂按照化合物结构类型可将其分为拟肽类与非肽类抑制剂。目前3CL蛋白酶抑制剂为开发口服抗新型冠状病毒的重要靶点,全球上市的有帕罗韦德和日本盐野义制药的恩赛特韦,全球开发的品种有歌礼制药的ASC11、众生睿创的RAY003、先声药业的SIM0417和前沿药业的FB2001等10余个品种,许多已进入II/III期临床试验。目前新冠病毒3CL蛋白酶抑制剂的研究仍然处于早期阶段,但上市品种少,其临床疗效和安全性还有待观察,而临床需求巨大,是世界范围内药物研究工作者关注的重要课题之一。
由蒋华良院士、饶子和院士领衔的科研团队在美国国立卫生院(NIH)下属的临床药物库中发现镇痛“老药”Ebselen对3CL蛋白酶具有较强的结合能力,并在细胞实验中展现出优异的抗病毒效果(IC50=0.67μM,EC50=4.67μM)。依布硒啉用于新型冠状病毒感染中度及重症患者治疗的Ⅱ期临床试验正在进行中(美国,NCT04484025/NCT04483973)。本发明经筛选发现了一些新的三氟甲基靛红衍生物,其抑制SARS-CoV-2的3CL蛋白酶活性与依布硒啉(Ebselen)活性相当,且毒性小,显示了较好的开发应用前景。
发明内容
针对现有技术的不足,本发明的目的在于提供一种具有抑制新型冠状病毒3CL蛋白酶活性的1-(4-三氟甲基-苄基)-靛红衍生物及其制备方法与应用。
本发明的1-(4-三氟甲基-苄基)-靛红衍生物以1-(4-三氟甲基-苄基)-靛红为先导化合物,其对新型冠状病毒3CL蛋白酶有很强的抑制活性,某些化合物活性与阳性对照药依布硒啉(Ebselen)活性相当,且毒性小。
本发明为制备治疗新型冠状病毒和/或新型冠状病毒突变株所引起的疾病的药物提供了新策略。
本发明的目的通过下述技术方案实现:
一种1-(4-三氟甲基-苄基)-靛红衍生物,其具有如下式(I)所示结构:
其中,R1、R2、R3、R4各自独立地选自氟、氯、溴、碘、氢中的一种。
优选的,所述的1-(4-三氟甲基-苄基)-靛红衍生物选自下列化合物:R1为氢、R2为氯、R3为氢、R4为氢的化合物1;R1为氢、R2为氟、R3为氢、R4为氢的化合物2;R1为氢、R2为溴、R3为氢、R4为氢的化合物3;R1为氯、R2为氢、R3为氢、R4为氢的化合物4;R1为氢、R2为氢、R3为氯、R4为氢的化合物5;R1为碘、R2为氢、R3为氢、R4为氢的化合物6;R1为氢、R2为溴、R3为氢、R4为溴的化合物7;R1为氯、R2为氢、R3为氯、R4为氢的化合物8;R1为氟、R2为氯、R3为氢、R4为氢的化合物9;R1为氢、R2为氢、R3为氢、R4为氢的化合物10。所述化合物1-10的结构如下:
所述的1-(4-三氟甲基-苄基)-靛红衍生物的制备方法,其反应式如下,包括如下步骤:
靛红或靛红衍生物与4-三氟甲基苄溴在碱的作用下于反应溶剂中反应,得到1-(4-三氟甲基-苄基)-靛红衍生物。其中,所述的碱包括氢氧化钠、氢氧化钾、碳酸钠,碳酸钾、氢化钠和氢化钾等,所述的反应溶剂包括N,N-二甲基甲酰胺(DMF)、四氢呋喃、甲醇、乙醇等,所述的反应优选在0-5℃下进行。
优选地,所述的1-(4-三氟甲基-苄基)-靛红衍生物的制备方法,包括如下步骤:在0-5℃下,将靛红或靛红衍生物溶于N,N-二甲基甲酰胺(DMF)中,向体系中加入NaOH,在0-5℃下搅拌10-30min,再加入4-三氟甲基苄溴,反应30-60min,反应完成后,通过TLC进行监测。用萃取试剂萃取,萃取层用饱和盐水洗,乙酸乙酯层经干燥后浓缩,再经过硅胶柱分离得到1-(4-三氟甲基-苄基)-靛红衍生物。所述的萃取试剂包括乙酸乙酯、氯仿、二氯甲烷等。
一种上述1-(4-三氟甲基-苄基)-靛红衍生物药学上可接受的盐。所述的盐由上述1-(4-三氟甲基-苄基)-靛红衍生物与无机酸或有机酸反应得到。优选地,所述的无机酸选自盐酸、氢溴酸、氢氟酸、硫酸、硝酸和磷酸中的至少一种;所述的有机酸选自甲酸、乙酸、丙酸、柠檬酸、甲磺酸、乙磺酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、草酸和酒石酸中的至少一种。
一种含有上述1-(4-三氟甲基-苄基)-靛红衍生物或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剂量的本发明1-(4-三氟甲基-苄基)-靛红衍生物和/或其药用盐,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。可通过将本发明的1-(4-三氟甲基-苄基)-靛红衍生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。本发明的1-(4-三氟甲基-苄基)-靛红衍生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。
本发明的1-(4-三氟甲基-苄基)-靛红衍生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。
本发明的1-(4-三氟甲基-苄基)-靛红衍生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。
为了将本发明的1-(4-三氟甲基-苄基)-靛红衍生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的1-(4-三氟甲基-苄基)-靛红衍生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的1-(4-三氟甲基-苄基)-靛红衍生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。
为将本发明的1-(4-三氟甲基-苄基)-靛红衍生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调节剂、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调节剂可以是磷酸盐、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。
上述1-(4-三氟甲基-苄基)-靛红衍生物和/或其药学上可接受的盐和/或上述药物组合物在制备新型冠状病毒3CL蛋白酶抑制剂中的应用。
上述1-(4-三氟甲基-苄基)-靛红衍生物和/或其药学上可接受的盐和/或上述药物组合物在制备抗新冠病毒药物中的应用。
上述1-(4-三氟甲基-苄基)-靛红衍生物或其药学上可接受的盐或上述药物组合物在制备治疗新型冠状病毒所引起的疾病的药物中的应用。
所述的新型冠状病毒包括新型冠状病毒、新型冠状病毒突变株;所述的新型冠状病毒突变株包括阿尔法(Alpha)、贝塔(Beta)、伽玛(Gamma)、德尔塔(Delta)、奥密克戎(Omicron)和EG.5.1等新变体中的一种或多种,同时并不局限于上述新型冠状病毒及其突变株。
本发明的优点和有益效果:
1、本发明的1-(4-三氟甲基-苄基)-靛红衍生物对新型冠状病毒3CL蛋白酶具有良好的抑制活性,部分化合物的活性与依布硒啉(Ebselen)活性相当。
2、本发明的1-(4-三氟甲基-苄基)-靛红衍生物急性毒性小,药物安全性高,可作为抗新型冠状病毒药物在临床应用。
3、本发明的1-(4-三氟甲基-苄基)-靛红衍生物,可制备药物组合物,用于抗新型冠状病毒药物在临床应用。
具体实施方式
下面通过具体实施方式来进一步说明本发明的技术方案。本领域技术人员应该明了,所述实施例仅仅是帮助理解本发明,不应视为对本发明的具体限制。
实施例1 1-(4-三氟甲基-苄基)-5-氯-吲哚啉-2,3-二酮(化合物1)的合成
在0℃下,将5-氯-靛红(87.15mg,0.48mmol)溶于10mL DMF中,向体系中加入NaOH(19.2mg,0.48mmol),在0-5℃下搅拌30min,再加DMF溶解的4-三氟甲基苄溴(172.10mg,0.72mmol),反应30min后,用乙酸乙酯50mL萃取,乙酸乙酯层用饱和盐水50mL洗三次,乙酸乙酯层经无水硫酸钠干燥后浓缩,再经过硅胶柱(100目,柱层层析硅胶;洗脱剂,石油醚:乙酸乙酯=100:1-10:1)分离得到化合物1,橙黄色粉末122.69mg,收率75.4%,mp:150-152℃。1H NMR(600MHz,CDCl3):δH 7.62(d,J=8.1Hz,2H),7.60(d,J=2.1Hz,1H),7.47(dd,J=8.1,2.2Hz,1H),7.44(d,J=8.1Hz,2H),6.69(d,J=8.4Hz,1H),4.99(s,2H).13CNMR(151MHz,CDCl3):δC 181.9,157.8,148.6,138.3,137.9,131.0,130.3,127.8,127.8,126.3,125.7,124.8,123.0,118.7,112.1,43.8.HRMS(ESI+):m/z calcd C16H9ClF3NO2 for[M+Na]+362.0172,found 362.0170。
实施例2 1-(4-三氟甲基-苄基)-5-氟-吲哚啉-2,3-二酮(化合物2)的合成
合成方法同实施例1,不同之处在于用5-氟靛红替代5-氯靛红,得到化合物2,橙黄色粉末,收率78.5%,mp:129-131℃。1H NMR(600MHz,CDCl3):δH 7.60(d,J=8.2Hz,2H),7.44(d,J=8.1Hz,2H),7.31(dd,J=6.4,2.7Hz,1H),7.21(td,J=8.6,2.7Hz,1H),6.70(dd,J=8.6,3.6Hz,1H),4.98(s,2H).13C NMR(151MHz,CDCl3):δC 182.3,162.7,160.4,158.7,158.1,146.4,138.4,127.8,127.8,126.2,125.0,124.8,118.4,112.8,112.0,43.8.HRMS(ESI+):m/z calcd C16H9F4NO2 for[M+Na]+346.0467,found 346.0456。
实施例3 1-(4-三氟甲基-苄基)-5-溴-吲哚啉-2,3-二酮(化合物3)的合成
合成方法同实施例1,不同之处在于用5-溴靛红替代5-氯靛红,得到化合物3,黄色粉末,收率77.4%,mp:158-160℃。1H NMR(600MHz,CDCl3):δH 7.68(d,J=2.1Hz,1H),7.60(d,J=8.3Hz,2H),7.59(d,J=8.4Hz,1H),7.44(d,J=8.1Hz,2H),6.67(dd,J=8.3Hz,1H),4.98(s,2H).13C NMR(151MHz,CDCl3):δC 181.8,157.6,149.0,140.7,138.3,130.7,128.4,127.8,127.8,126.2,124.8,123.0,118.9,117.1,112.6,43.7.HRMS(ESI+):m/z calcdC16H9BrF3NO2for[M+Na]+405.9666,found 405.9664。
实施例4 1-(4-三氟甲基-苄基)-4-氯-吲哚啉-2,3-二酮(化合物4)的合成
合成方法同实施例1,不同之处在于用4-氯靛红替代5-氯靛红,得到化合物4,橙黄色粉末,收率78.5%,mp:177-179℃。1H NMR(600MHz,CDCl3):δH 7.61(d,J=8.1Hz,2H),7.44(d,J=8.1Hz,2H),7.42(t,J=8.1Hz,1H),7.06(d,J=8.2Hz,1H),6.65(d,J=7.8Hz,1H),5.00(s,2H).13C NMR(151MHz,CDCl3):δC 179.7,157.5,151.4,138.7,138.4,134.3,130.9,127.8,127.8,126.3,125.9,124.8,123.0,114.9,109.1,43.8.HRMS(ESI+):m/zcalcd C16H9ClF3NO2 for[M+Na]+362.0172,found 362.0160。
实施例5 1-(4-三氟甲基-苄基)-6-氯-吲哚啉-2,3-二酮(化合物5)的合成
合成方法同实施例1,不同之处在于用6-氯靛红替代5-氯靛红,得到化合物5,黄色粉末,收率74.2%,mp:129-131℃。1H NMR(600MHz,CDCl3):δH 7.59(d,J=8.1Hz,2H),7.51(d,J=8.0Hz,1H),7.45(d,J=8.1Hz,2H),7.05(dd,J=8.0,1.6Hz,1H),6.77(d,J=1.7Hz,1H),4.96(s,2H).13C NMR(151MHz,CDCl3):δC 181.4,158.3,151.3,144.9,138.3,130.6,127.7,127.7,126.6,126.1,124.8,124.4,122.9,116.0,111.4,43.6.HRMS(ESI+):m/zcalcd C16H9ClF3NO2for[M+Na]+,362.0172,found 362.0161。
实施例6 1-(4-三氟甲基-苄基)-4-碘-吲哚啉-2,3-二酮(化合物6)的合成
合成方法同实施例1,不同之处在于用4-碘靛红替代5-氯靛红,得到化合物6,橙黄色粉末,收率78.5%,mp:175-177℃。1H NMR(600MHz,CDCl3):δH 7.61(d,J=8.0Hz,2H),7.55(d,J=8.1Hz,1H),7.44(d,J=8.0Hz,2H),7.14(t,J=1.9Hz,1H),6.72(d,J=7.9Hz,1H),4.99(s,2H).13C NMR(151MHz,CDCl3):δC 181.2,157.6,152.2,138.4,138.2,135.5,130.8,127.8,127.8,126.2,124.7,123.0,119.4,110.3,93.4,43.5.HRMS(ESI+):m/zcalcd C16H9F3INO2 for[M+Na]+453.9528,found 453.9508。
实施例7 1-(4-三氟甲基-苄基)-5,7-二溴-吲哚啉-2,3-二酮(化合物7)的合成
合成方法同实施例1,不同之处在于用5,7-二溴靛红替代5-氯靛红,得到化合物7,橙黄色粉末,收率70.3%,mp:124-126℃。1H NMR(600MHz,CDCl3):δH 7.81(d,J=2.0Hz,1H),7.71(d,J=2.0Hz,1H),7.59(d,J=8.2Hz,2H),7.36(t,J=8.1Hz,2H),5.44(s,2H).13CNMR(151MHz,CDCl3):δC 181.0,158.3,146.4,145.4,140.0,130.2,127.8,126.8,126.8,126.0,124.9,123.1,121.5,117.6,105.1,44.5.HRMS(ESI+):m/z calcd C16H8Br2F3NO2 for[M+Na]+485.8751,found 485.8748。
实施例8 1-(4-三氟甲基-苄基)-4,6-二氯-吲哚啉-2,3-二酮(化合物8)的合成
合成方法同实施例1,不同之处在于用4,6-二氯靛红替代5-氯靛红,得到化合物8,橙黄色粉末,收率58.9%,mp:156-158℃。1H NMR(600MHz,CDCl3):δH 7.62(d,J=8.1Hz,2H),7.44(d,J=8.0Hz,2H),7.05(d,J=1.5Hz,1H),6.69(d,J=1.6Hz,1H),4.98(s,2H).13CNMR(151MHz,CDCl3):δC 178.4,157.5,152.0,144.9,138.0,134.9,130.8,127.7,127.7,126.3,125.6,124.8,123.0,113.3,109.9,43.9.HRMS(ESI+):m/z calcd C16H8Cl2F3NO2for[M+Na]+395.9782,found 395.9782。
实施例9 1-(4-三氟甲基-苄基)-4-氟-5-氯-吲哚啉-2,3-二酮(化合物9)的合成
合成方法同实施例1,不同之处在于用4-氟-5-氯靛红替代5-氯靛红,得到化合物9,橙黄色粉末,收率59.4%,mp:152-153℃。1H NMR(600MHz,CDCl3):δH 7.64(d,J=8.1Hz,2H),7.45(d,J=8.1Hz,2H),7.42(d,J=6.7Hz,1H),6.79(d,J=5.2Hz,1H),4.97(s,2H).13CNMR(151MHz,CDCl3):δC 181.1,157.9,156.2,146.6,138.0,131.8,131.0,127.8,127.8,126.4,124.8,123.0,116.6,113.6,113.0,43.9.HRMS(ESI+):m/z calcd C16H8ClF4NO2for[M+Na]+380.0077,found 380.0070。
实施例10 1-(4-三氟甲基-苄基)-吲哚啉-2,3-二酮(化合物10)的合成
合成方法同实施例1,不同之处在于用靛红替代5-氯靛红,得到化合物10,橙黄色粉末,收率67.8%,mp:193-195℃。1H NMR(600MHz,CDCl3)δ7.62(m,2H),7.51(t,J=7.8Hz,1H),7.47(s,1H),7.45(s,2H),7.12(td,J=7.6,2.8Hz,1H),6.74(dd,J=8.0,3.0Hz,1H),4.99(s,2H).13C NMR(151MHz,CDCl3)δ182.9,158.4,150.4,138.8,138.6,130.7,127.8,127.8,126.2,125.8,124.9,124.3,124.3,123.1,117.8,43.7.HRMS(ESI+):m/z calcdC16H10F3NO2 for[M+Na]+328.0561,found 328.0544。
实施例11 1-(4-三氟甲基-苄基)-靛红衍生物对新型冠状病毒(2019-nCoV)Mpro/3CLpro抑制实验
新型冠状病毒(2019-nCoV)Mpro/3CLpro抑制剂筛选试剂盒由碧云天生物技术有限公司提供,其采用荧光共振能量转移(fluorescence resonance energy transfer,FRET)的方法。
一、实验方法
1.样品的准备:取适量待测定的1-(4-三氟甲基-苄基)-靛红衍生物,用AssayBuffer或DMSO等适当的溶剂配制成适宜浓度的溶液,如果有必要可配制成适当的浓度梯度待用。
2.阳性对照的准备:本试剂盒提供的阳性对照抑制剂Ebselen浓度为10mM,配制在DMSO中,可以根据需要使用与1-(4-三氟甲基-苄基)-靛红衍生物一样的溶剂稀释成所需浓度或浓度梯度。
3.样品测定
a.根据样品数量(含相关对照),参考说明书要求配制适量的Assay Reagent。注:由于2019-nCoV Mpro/3CLpro的甘油含量较高,微量吸取时要注意避免吸头吸附损失并吹打完全,加入2019-nCoV M pro/3CLpro后需要注意充分混匀。
b.使用96孔黑板设置各组别,并按照说明书要求依次加入检测试剂和样品。加入待测样品后,混匀。为获得更加可靠的检测结果,建议每个样品至少应该进行2个重复孔的检测。
c.各孔快速加入Substrate 2μL,混匀。注:加入Substrate后反应会立即开始,如果孔数较多的情况下,建议在低温或使用排枪操作以减小各孔间加入Substrate的时间差而导致的误差,混匀操作可在培养板振荡器上进行。
d.37℃避光孵育5分钟后信号即趋于稳定,可在5-20分钟内使用多功能酶标进行荧光测定。激发波长为340nm,发射波长为490nm。当荧光读数偏低时,也可适当延长孵育时间至20-30分钟。注:也可在步骤a中将待测样品加入后37℃孵育10分钟,再将Substrate加入反应体系中。37℃孵育10分钟再加入Substrate可能会降低待测样品的IC50(半数抑制浓度)。先通过预实验确定待测样品比较适合的孵育时间。
4.计算
a.计算每个样品孔和空白对照孔的平均荧光值,可分别记录为RFU空白对照、RFU100%酶活性对照、RFU阳性对照和RFU样品。RFU,Relative Fluorescence Unit。
b.计算每个样品的抑制百分率。计算公式如下:抑制率(%)=(RFU100%酶活性对照-RFU样品)/(RFU100%酶活性对照-RFU空白对照)×100%。
c.对于检测发现有效的样品,通过检测该样品的剂量效应就可以计算出该样品的IC50(半数抑制浓度)。
二、实验结果
表1 1-(4-三氟甲基-苄基)-靛红衍生物对新型冠状病毒(2019-nCoV)Mpro/3CLpro抑制活性
从表1可知,本发明的1-(4-三氟甲基-苄基)-靛红衍生物均显示一定抑制新型冠状病毒(2019-nCoV)Mpro/3CLpro活性,值得注意的是化合物1、化合物3、化合物7、化合物8和化合物10均显示了很强的抑制活性,其中化合物7抑制活性与阳性对照药Ebselen相当,且毒性小,为寻找新的抗SARS-CoV-2药物提供了新思路。
实施例12 1-(4-三氟甲基-苄基)-靛红衍生物的急性毒性实验
选择活性较好的化合物7进行急性毒性实验,KM小鼠,雄性,体质量36±4g,SPF级,随机分为生理盐水组,低剂量组200mg/kg,高剂量组800mg/kg,每组6只小鼠,小鼠连续7天给药后,体重毛发没有明显变化,没有死亡现象出现,表明本发明的新型1-(4-三氟甲基-苄基)-靛红衍生物毒性小,可用于抗新型冠状病毒药物研究。
Claims (10)
1.一种1-(4-三氟甲基-苄基)-靛红衍生物,其特征在于,所述的1-(4-三氟甲基-苄基)-靛红衍生物具有如下式(I)所示结构:
其中,R1、R2、R3、R4各自独立地选自氟、氯、溴、碘、氢中的一种。
2.根据权利要求1所述的1-(4-三氟甲基-苄基)-靛红衍生物,其特征在于,选自结构如下所示的化合物:
3.一种权利要求1或2所述的1-(4-三氟甲基-苄基)-靛红衍生物的制备方法,其特征在于,反应式如下所示,包括如下步骤:
靛红或靛红衍生物与4-三氟甲基苄溴在碱的作用下于反应溶剂中反应,得到1-(4-三氟甲基-苄基)-靛红衍生物。
4.根据权利要求3所述的1-(4-三氟甲基-苄基)-靛红衍生物的制备方法,其特征在于,
所述的碱包括氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、氢化钠、氢化钾;
所述的反应溶剂包括N,N-二甲基甲酰胺、四氢呋喃、甲醇、乙醇;
所述的反应在0-5℃下进行。
5.根据权利要求3所述的1-(4-三氟甲基-苄基)-靛红衍生物的制备方法,其特征在于,包括如下步骤:在0-5℃下,将靛红或靛红衍生物溶于N,N-二甲基甲酰胺中,向体系中加入氢氧化钠,在0-5℃下搅拌10-30min,再加入4-三氟甲基苄溴反应,得到1-(4-三氟甲基-苄基)-靛红衍生物。
6.一种权利要求1或2所述的1-(4-三氟甲基-苄基)-靛红衍生物药学上可接受的盐,其特征在于,所述的盐由权利要求1或2所述的1-(4-三氟甲基-苄基)-靛红衍生物与无机酸或有机酸反应得到。
7.一种药物组合物,其特征在于,包含权利要求1或2所述的1-(4-三氟甲基-苄基)-靛红衍生物和/或其药学上可接受的盐中的至少一种化合物,以及制药学上可用的载体。
8.一种权利要求1或2所述的1-(4-三氟甲基-苄基)-靛红衍生物和/或其药学上可接受的盐和/或权利要求7所述的药物组合物在制备新型冠状病毒3CL蛋白酶抑制剂中的应用。
9.一种权利要求1或2所述的1-(4-三氟甲基-苄基)-靛红衍生物和/或其药学上可接受的盐和/或权利要求7所述的药物组合物在制备抗新型冠状病毒药物和/或治疗新型冠状病毒所引起的疾病的药物中的应用。
10.根据权利要求8或9所述的应用,其特征在于,所述的新型冠状病毒包括新型冠状病毒、新型冠状病毒突变株;所述的新型冠状病毒突变株包括阿尔法、贝塔、伽玛、德尔塔、奥密克戎和EG.5.1新变体中的一种或多种。
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