CN114949241A - 一种聚乙二醇-s-217622结合物及其药物组合物 - Google Patents
一种聚乙二醇-s-217622结合物及其药物组合物 Download PDFInfo
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- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
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- A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
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Abstract
本发明涉及一种四臂聚乙二醇‑S‑217622结合物或其药学上可接受的盐,及其制备方法和在制备抗新冠肺炎药物中的应用。该结合物能提升药物负载率和溶解性,减缓由酶介导的药物代谢速度,延长半衰期,减缓药物的代谢分解,能够有效的起到治疗的作用,在治疗新冠肺炎上具有良好的应用前景。同时,本发明上述四臂聚乙二醇‑S‑217622结合物的制备方法具有合成线路短、反应条件温和、高收率、高纯度、后处理简单、底物适应性强和环境友好的优点。
Description
技术领域
本发明属于制药领域,具体涉及一种四臂聚乙二醇-S-217622组合物、药物 组合物及其制备方法和应用。
背景技术
3c-like蛋白酶(3CLpro)是一种半胱氨酸蛋白酶,负责切割多蛋白的11个不同 位点,转化为成熟的功能蛋白。3CLpro在病毒复制中起着关键作用,抑制该蛋白 酶将会抑制复制必需酶的形成,如RNA依赖的RNA聚合酶,从而抑制病毒复 制。3CLpro是小分子口服疗法治疗COVID-19的一个有吸引力的靶点,而 S-217622(式I-1)是第一个口服非肽非共价小分子SARS-CoV-2 3CL蛋白酶抑 制剂的临床候选药物。
目前市场已经获批和正在开发的针对COVID-19(SARS-CoV-2)的制剂聚 焦于口服制剂,该类制剂存在普遍首过效应,S-217622虽然表现出针对 SARS-CoV-2Mpro病毒有极好的抑制作用,口服生物利用度高,但S-217622水溶 性极差导致吸收较慢,药物半衰期相对较短,而病毒发展进程往往较快,对于一 些消化代谢障碍或者重症行动不便的急症患者无法口服,开发起效迅速的注射剂 等剂型变得紧迫而有必要。
发明内容
针对上述问题,本发明提供一种四臂聚乙二醇-S-217622结合物,该结合物 能提升药物负载率和溶解性,减缓由酶介导的药物代谢速度,延长半衰期,减缓 药物的代谢分解。
为了实现上述目的,本发明的第一个方面提供一种由下列式I-2表示的四臂 聚乙二醇-S-217622结合物:
其中:
m代表四臂聚乙二醇片段中CH2CH2O的个数;n代表碳的个数;G代表丁 二酰亚胺上的取代基;m是30-230的整数,n为1-5的整数。
在一些实施方式中,所述式(I-2)中四臂聚乙二醇的数均分子量为5000- 40000道尔顿。
在一些实施方式中,G代表丁二酰亚胺上的取代基,所述G选自溴、甲基、 三氟甲基以及氢中的一种,具体选自式II-V式中的任意一种:
可以理解,S-217622结构中包含有氯代芳香结构,氯可以直接与硫代乙酸 发生取代反应并经盐酸水解得到含有巯基的中间体,该中间体的巯基与四臂聚乙 二醇化的马来酰亚胺结合形成特异性偶联,从而获得了四臂聚乙二醇-S-217622 结合物。在这种结合物中,每一个四臂聚乙二醇的端基可以与4个S-217622残 基相连,药物的负载率大大提高,溶解性大大提高,该结合物不需要与利托那韦 联用,就能够减缓由酶介导的药物代谢速度,延长半衰期,减缓药物的代谢分解, 让高药物浓度在患者体内保持更长时间,更好地对抗病毒。可以进一步提升 S-217622抗病毒的临床效果和应用价值。
本发明的第二个方面,提供了一种四臂聚乙二醇-S-217622结合物的制备方 法,包括以下步骤:
(1)对S-217622进行改性,引入活性官能团巯基;
(2)S-217622引入的巯基与四臂聚乙二醇马来酰亚胺发生特异性偶联得到 四臂PEG化的S-217622。
一般而言,本文描述的化合物可通过化学技术领域中已知的方法制备,尤其 鉴于本文所含的描述制备。用于制备本文描述的化合物的某些方法作为实施方案 的其他特征提供且举例说明于如下提供的反应方案中和实验部分中。
除非另外说明,方案A中的变量具有如本文所定义的相同含义。
方案A:
如方案A中所例举,S-217622结构中氯直接与硫代乙酸发生取代反应并经 水解得到含有巯基的中间体,该中间体的巯基与四臂聚乙二醇化的马来酰亚胺结 合形成特异性偶联,从而获得了四臂聚乙二醇-S-217622结合物。本文中具体可 参考实施例。
相较于现有技术,所述化合物的制备方法,具有以下优点:1)合成路线较 短,共二步反应;2)反应条件温和;3)后处理无需柱层析纯化,常规沉降结晶 及干燥即可得到高收率和高纯度的产物,方便快捷;4)底物适应性强;5)由于 没有使用柱纯化,只是常规的沉降结晶,产生的废水少,环境友好。
对于本文上述制备本发明化合物的方法的一些步骤,有必要保护不希望反应 的潜在反应性官能团,并因此裂解所述保护基。在此类情况下,可以使用任何相 容的保护基。
前述方法中使用的新颖起始物质的所有上述反应和制备是用于其表现或制 备的常规和适当的试剂和反应条件,并且用于分离期望产物的程序将是本领域技 术人员通过参考文献先例以及其实施例和制备例所众所周知的。
本发明第三个方面,提供了包含前述四臂聚乙二醇-S-217622结合物以及药 学上可接受的载体、赋形剂、辅剂、媒介物或它们的任意组合的药物组合物。
在一些实施方式中,本发明的结合物可以纯化合物形式或适宜的药物组合物 形式进行给药,可采用任何可接受的给药方式或用于类似的用途的试剂进行。
在一些实施方式中,采用的给药方式可选择通过口、鼻内、局部、透皮方式, 其形式为固体、半固体、冻干粉或液体药剂形式给药,例如,散剂、栓剂、注射 剂、溶液剂、混悬剂、膏剂、贴剂、雾化剂等。
在一些实施方式中,采用适用于精确剂量的注射给药的单元剂量形式。
本发明的另一个方面,提供了前述四臂聚乙二醇-S-217622结合物在制备抗 新冠病毒COVID-19(SARSCoV-2)药物中的应用。
本发明的技术方案中,提供一种新型的四臂聚乙二醇-S-217622结合物,该 结合物提高了药物负载率和溶解性,延长半衰期,减缓药物的代谢分解,能够有 效的起到治疗的作用。因此本发明的四臂聚乙二醇-S-217622结合物在治疗新冠 肺炎上具有良好的应用前景。同时,本发明上述四臂聚乙二醇-S-217622结合物 的制备方法具有合成线路短、反应条件温和、高收率、高纯度、后处理简单、底 物适应性强和环境友好的优点。
在本说明书的描述中,参考术语“一个实施例”、“一些实施例”、“示例”、“具 体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结 构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中,对 上述术语的示意性表述不必须针对的是相同的实施例或示例。而且,描述的具体 特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结 合。此外,在不相互矛盾的情况下,本领域的技术人员可以将本说明书中描述的 不同实施例或示例以及不同实施例或示例的特征进行结合和组合。
本发明中,如“化合物A”和“式A所示的化合物”和“式A”的表述,表示的 是同一个化合物。
具体实施方式
实施例1 S-217622的巯基化
往500mL单口瓶中,依次加入10.62g S-217622和200ml THF,充分溶解 后在-10℃下滴加10ml 10%的NaOH水溶液。滴加完毕后反应体系在30℃温度 下搅拌2小时,然后在30℃温度下滴加硫代乙酸1.5g,使反应继续搅拌12小 时,TLC监控反应进程。反应结束后,减压旋蒸除去溶剂,粗品用200ml 2M的 盐酸和100ml DMF混合溶液溶解,反应液持续搅拌12小时,通过TLC检测反 应进程,反应结束后,将反应液过滤,滤液加入到1000ml二氯甲烷中,用100mL 水、100mL饱和NaHCO3溶液、100mL水分别洗涤后,将有机相减压浓缩除去 二氯甲烷。粗品通过乙酸乙酯/正己烷重结晶得到巯基化的中间体S-217622-SH 7.62g。收率:72%。1H NMR(400MHz,DMSO-d6)δ:3.32(s,1H),3.92(s,3H),4.15 (s,3H),5.08(s,2H),5.25(s,2H),7.46(m,1H),7.52-7.65(m,2H),7.73(s,1H),8.43 (s,1H),9.32(s,1H).
实施例2四臂聚乙二醇(数均分子量5000)-乙酰胺-溴代丁二酰亚胺-S-217622结合物(PM-1)的制备
往500mL单口瓶中,依次加入0.53g S-217622-SH和200ml DMSO/乙酸 乙酯混合溶液,充分溶解后在常温下滴加溶解有5g四臂聚乙二醇(数均分子量 5000)-乙酰胺-溴代马来酰亚胺的DMSO溶液。滴加完毕后反应体系在30℃温度 下搅拌2小时,然后在30℃温度下滴加三乙胺0.1g,使反应常温继续搅拌12 小时,TLC监控反应进程。反应结束后,减压旋蒸除去溶剂,粗品用200ml二 氯甲烷溶解,将不溶性固体过滤除去,滤液用100mL水、100mL饱和NaHCO3溶液、100mL水分别洗涤后,将有机相减压浓缩除去大部分二氯甲烷。粗品倒 入甲基叔丁基醚中沉降析晶得到白色固体PM-1共计4.6g,收率:79.3%。1H NMR (400MHz,CDCl3)δ:8.93(s,1H),7.92(s,1H),7.86(s,1H),7.74(s,1H),7.12(s, 1H),7.06(s,1H),6.52(s,1H),5.70(s,1H),5.56(d,J=10.7Hz,2H),5.32(s,1H), 4.70(s,1H),4.42(s,1H),4.23(s,2H),3.95(s,3H),3.80(s,3H),3.72(s,2H),3.66(m, 28H),3.46(s,2H),3.41(s,3H),3.29(s,2H).
实施例3四臂聚乙二醇(数均分子量20000)-乙酰胺-溴代丁二酰亚胺-S-217622结合物(PM-2)的制备
往500mL单口瓶中,依次加入0.53g S-217622-SH和200ml DMSO/乙酸 乙酯混合溶液,充分溶解后在常温下滴加溶解有20g四臂聚乙二醇(数均分子量 5000)-乙酰胺-溴代马来酰亚胺的DMSO溶液。滴加完毕后反应体系在30℃温度 下搅拌2小时,然后在30℃温度下滴加三乙胺0.1g,使反应常温继续搅拌12 小时,TLC监控反应进程。反应结束后,减压旋蒸除去溶剂,粗品用200ml二 氯甲烷溶解,将不溶性固体过滤除去,滤液用100mL水、100mL饱和NaHCO3溶液、100mL水分别洗涤后,将有机相减压浓缩除去大部分二氯甲烷。粗品倒 入冰冷的乙酸乙酯中沉降析晶得到白色固体PM-2共计14.2g,收率:67.6%。1H NMR(400MHz,CDCl3)δ:8.73(s,1H),7.95(s,1H),7.89(s,1H),7.75(s,1H), 7.11(s,1H),7.02(s,1H),6.48(s,1H),5.73(s,1H),5.58(d,J=10.7Hz,2H),5.36(s, 1H),4.72(s,1H),4.44(s,1H),4.25(s,2H),3.94(s,3H),3.78(s,3H),3.67(s,2H), 3.63(m,462H),3.46(s,2H),3.40(s,3H),3.28(s,2H).
实施例4四臂聚乙二醇(数均分子量5000)-丙酰胺-甲基丁二酰亚胺-S-217622结合物(PM-3)的制备
往500mL单口瓶中,依次加入0.53g S-217622-SH和200ml DMSO/乙酸 乙酯混合溶液,充分溶解后在常温下滴加溶解有5g四臂聚乙二醇(数均分子量 5000)-丙酰胺-甲基马来酰亚胺的DMSO溶液。滴加完毕后反应体系在30℃温度 下搅拌2小时,然后在30℃温度下滴加三乙胺0.1g,使反应常温继续搅拌12 小时,TLC监控反应进程。反应结束后,减压旋蒸除去溶剂,粗品用200ml二 氯甲烷溶解,将不溶性固体过滤除去,滤液用100mL水、100mL饱和NaHCO3溶液、100mL水分别洗涤后,将有机相减压浓缩除去大部分二氯甲烷。粗品倒 入乙酸乙酯中沉降析晶得到白色固体PM-3共计4.2g,收率:84%。1H NMR(400 MHz,CDCl3)δ:8.73(s,1H),7.96(s,1H),7.89(s,1H),7.77(s,1H),6.87(s,1H), 6.75(s,1H),6.02(s,1H),5.56(s,1H),5.30(s,1H),4.68(s,1H),4.25(s,2H),4.04(s, 1H),3.94(s,3H),3.79(d,J=9.0Hz,4H),3.67(s,2H),3.63(m,115H),3.46(s,2H), 3.40(s,3H),3.25(d,J=13.0Hz,3H),2.66(s,2H),1.17(s,3H).
实施例5四臂聚乙二醇(数均分子量40000)-丙酰胺-甲基丁二酰亚胺-S-217622结合物(PM-4)的制备
往500mL单口瓶中,依次加入0.53g S-217622-SH和200ml DMSO/乙酸 乙酯混合溶液,充分溶解后在常温下滴加溶解有40g四臂聚乙二醇(数均分子量 40000)-丙酰胺-甲基马来酰亚胺的DMSO溶液。滴加完毕后反应体系在30℃温 度下搅拌2小时,然后在30℃温度下滴加三乙胺0.1g,使反应常温继续搅拌 12小时,TLC监控反应进程。反应结束后,减压旋蒸除去溶剂,粗品用200ml二 氯甲烷溶解,将不溶性固体过滤除去,滤液用100mL水、100mL饱和NaHCO3溶液、100mL水分别洗涤后,将有机相减压浓缩除去大部分二氯甲烷。粗品倒 入乙酸乙酯中沉降析晶得到白色固体PM-4共计34.7g,收率:85%。1H NMR(400 MHz,CDCl3)δ:8.76(s,1H),8.06(s,1H),7.92(s,1H),7.75(s,1H),6.89(s,1H), 6.74(s,1H),6.05(s,1H),5.58(s,1H),5.32(s,1H),4.69(s,1H),4.27(s,2H),4.08(s, 1H),3.97(s,3H),3.82(d,J=9.0Hz,4H),3.66(s,2H),3.64(m,910H),3.46(s,2H), 3.42(s,3H),3.26(d,J=13.0Hz,3H),2.68(s,2H),1.18(s,3H).
实施例6四臂聚乙二醇(数均分子量10000)-丁酰胺-三氟甲基丁二酰亚胺 -S-217622结合物(PM-5)的制备
往500mL单口瓶中,依次加入0.53g S-217622-SH和200ml DMSO/乙酸 乙酯混合溶液,充分溶解后在常温下滴加溶解有10g四臂聚乙二醇(数均分子量 10000)-丁酰胺-三氟甲基马来酰亚胺的DMSO溶液。滴加完毕后反应体系在30℃ 温度下搅拌2小时,然后在30℃温度下滴加三乙胺0.1g,使反应常温继续搅拌 12小时,TLC监控反应进程。反应结束后,减压旋蒸除去溶剂,粗品用200ml二 氯甲烷溶解,将不溶性固体过滤除去,滤液用100mL水、100mL饱和NaHCO3溶液、100mL水分别洗涤后,将有机相减压浓缩除去大部分二氯甲烷。粗品倒 入乙酸乙酯中沉降析晶得到白色固体PM-5共计8.8g,收率:88%。1H NMR(400 MHz,CDCl3)δ:8.79(s,1H),8.04(s,1H),7.88(d,J=12.7Hz,2H),7.32(s,1H), 7.12(s,1H),5.64(s,1H),5.37(s,1H),5.26(s,1H),5.13(s,1H),4.42(s,1H),4.25(s, 2H),3.94(s,3H),3.78(s,3H),3.67(s,2H),3.63(s,230H),3.48(s,2H),3.46(s, 2H),3.28(s,2H),3.18(s,2H),2.34(s,2H),1.93(s,2H),1.13(s,3H).
实施例7四臂聚乙二醇(数均分子量30000)-丁酰胺-三氟甲基丁二酰亚胺 -S-217622结合物(PM-6)的制备
往500mL单口瓶中,依次加入0.53g S-217622-SH和200ml DMSO/乙酸 乙酯混合溶液,充分溶解后在常温下滴加溶解有30g四臂聚乙二醇(数均分子量 30000)-丁酰胺-三氟甲基马来酰亚胺的DMSO溶液。滴加完毕后反应体系在30℃ 温度下搅拌2小时,然后在30℃温度下滴加三乙胺0.1g,使反应常温继续搅拌 12小时,TLC监控反应进程。反应结束后,减压旋蒸除去溶剂,粗品用200ml二 氯甲烷溶解,将不溶性固体过滤除去,滤液用100mL水、100mL饱和NaHCO3溶液、100mL水分别洗涤后,将有机相减压浓缩除去大部分二氯甲烷。粗品倒 入乙酸乙酯中沉降析晶得到白色固体PM-6共计23.5g,收率:73.4%。1H NMR (400MHz,CDCl3)δ:8.82(s,1H),8.06(s,1H),7.90(d,J=12.2Hz,2H),7.34(s, 1H),7.15(s,1H),5.66(s,1H),5.39(s,1H),5.24(s,1H),5.15(s,1H),4.44(s,1H), 4.28(s,2H),3.96(s,3H),3.80(s,3H),3.69(s,2H),3.65(s,683H),3.50(s,2H), 3.46(s,2H),3.29(s,2H),3.19(s,2H),2.36(s,2H),1.95(s,2H),1.16(s,3H).
实施例8四臂聚乙二醇(数均分子量8000)-戊酰胺-丁二酰亚胺-S-217622结合物(PM-6)的制备
往500mL单口瓶中,依次加入0.53g S-217622-SH和200ml DMSO/乙酸 乙酯混合溶液,充分溶解后在常温下滴加溶解有8g四臂聚乙二醇(数均分子量 8000)-戊酰胺-马来酰亚胺的DMSO溶液。滴加完毕后反应体系在30℃温度下搅 拌2小时,然后在30℃温度下滴加三乙胺0.1g,使反应常温继续搅拌12小时, TLC监控反应进程。反应结束后,减压旋蒸除去溶剂,粗品用200ml二氯甲烷 溶解,将不溶性固体过滤除去,滤液用100mL水、100mL饱和NaHCO3溶液、 100mL水分别洗涤后,将有机相减压浓缩除去大部分二氯甲烷。粗品倒入乙酸乙酯中沉降析晶得到白色固体PM-1共计6.3g,收率:76.8%。1H NMR(400MHz, CDCl3)δ:8.76(s,1H),7.97(d,J=13.2Hz,2H),7.86(s,1H),7.13(s,1H),6.90(s, 1H),5.80(s,1H),5.63(s,1H),5.34(s,1H),5.25(s,1H),4.26(s,2H),3.96(s,3H), 3.78(s,3H),3.65(m,184H),3.49(d,J=15.0Hz,10H),3.46(s,2H),3.32(d,J=15.2 Hz,3H),3.16(d,J=14.4Hz,3H),2.34(s,2H),1.96(s,2H),1.14(s,3H).
实施例9四臂聚乙二醇(数均分子量15000)-戊酰胺-丁二酰亚胺-S-217622结合物(PM-8)的制备
往500mL单口瓶中,依次加入0.53g S-217622-SH和200ml DMSO/乙酸 乙酯混合溶液,充分溶解后在常温下滴加溶解有15g四臂聚乙二醇(数均分子量 15000)-戊酰胺-马来酰亚胺的DMSO溶液。滴加完毕后反应体系在30℃温度下 搅拌2小时,然后在30℃温度下滴加三乙胺0.1g,使反应常温继续搅拌12小 时,TLC监控反应进程。反应结束后,减压旋蒸除去溶剂,粗品用200ml二氯 甲烷溶解,将不溶性固体过滤除去,滤液用100mL水、100mL饱和NaHCO3溶液、100mL水分别洗涤后,将有机相减压浓缩除去大部分二氯甲烷。粗品倒 入乙酸乙酯中沉降析晶得到白色固体PM-8共计12.9g,收率:81.6%。1H NMR (400MHz,CDCl3)δ:8.78(s,1H),8.02(d,J=10.7Hz,2H),7.90(s,1H),7.15(s, 1H),6.92(s,1H),5.82(s,1H),5.63(s,1H),5.34(s,1H),5.26(s,1H),4.27(s,2H), 3.96(s,3H),3.78(s,3H),3.64(m,341H),3.52(d,J=13.6Hz,10H),3.33(d,J= 14.2Hz,3H),3.15(d,J=12.5Hz,3H),2.36(s,2H),1.98(s,2H),1.16(s,3H).
实施例10不同四臂聚乙二醇S-217622结合物在水以及各种溶剂中的溶解性
称取约1g样品置100ml容量瓶,先加0.8ml水(在极易溶解范围内:1g在不 到1ml溶剂中溶解),按药典试验方法30分钟内观察溶解情况,如果未完全溶解, 则接着往里加约8ml水(在易溶范围内:1g在1-10ml溶剂中溶解),继续同法试验 30分钟内观察溶解情况,如还未完全溶解,再往后加约20ml水(在溶解范围内) 因为采用的是100ml容量瓶,则当加到90ml水时(在略溶范围内)如还未完全溶 解,则需要重新配制样品继续往下做,这时可以适当减少药物称样量,也可节约 溶剂用量,比如称取约10mg样品置100ml容量瓶,加9ml水(在微溶范围内),同 法操作,如还未完全溶解,则接着往里加约80ml水(在极微溶解范围内),如还未 完全溶解,则接着往里加水至刻度(在几乎不溶范围内)。按照此方法我们测试了S-217622以及上述实施例中的各种PEG化S-217622的溶解性情况如下:
表1 S-217622以及上述实施例中的各种PEG化S-217622的溶解性
可以看出,PEG修饰后的S-217622在溶解性方面有极大提升,尤其是四臂 聚乙二醇修饰的S-217622溶解性极好。
实施例11不同四臂聚乙二醇S-217622结合物对3CLpro蛋白酶的抑制作用研究
3CL蛋白酶抑制试验在384孔板(Thermo Scientific)中进行。先将待测溶液(10mM DMSO溶液)用DMSO稀释3倍,然后逐步稀释至250μmol/L的溶液。 最后,将该溶液与20mmol/L Tris-HCl(pH7.5)充分混合作为一种复合溶液。往孔 板的每个孔中分别手动添加10μL复合物溶液,然后加入5μL 16μM的缓冲液(包 含2mMEDTA,20mMDTT,0.02%BSA,20mMTris-HCl,pH=7.5)。在上述配 制的抑制缓冲液中加入5μL 12nM的3CL蛋白酶,室温孵育3h。生化筛检:化合 物筛选试验在384孔板(Thermo Scientific)中进行。通过HAMILTONPB600-1取 样器向每个孔中加入150nL不同浓度的待测化合物。接下来,每孔中加入 7.5μL8μM底物(Dabcyl-KTSAVLQSGFRKME-Edans)。使用赛默飞 Multidrop Combi/SMART自动分液器添加缓冲液(包括100mM氯化钠, 1m Methylene diaminetetraacetic acid[EDTA],10mMDL-二硫苏糖醇(DTT),0.01% 牛血清白蛋白和20mM Tris-HCl,pH7.5)。在上述实验缓冲体系中加入7.5μL 6 或0.6nM 3CL蛋白酶引发反应,室温孵育3h。孵育后,依次加入45μL含0.1% 甲酸的水溶液、10%乙腈和0.05μmol/L内标肽(Dabcyl-KTSAVLeu[13C6,15N]-Q 以终止反应。使用安捷伦6550精确质量四极杆飞行时间质谱仪进行质谱分析。 使用RapidFire Integrator(Agilent Technologies)对峰值区域进行采集和分析。IC50 值通过绘制化合物浓度与抑制的关系图并使用四参数逻辑曲线拟合数据的方法 来确定。
表2 PEG化S-217622对来源于SARSCoV-2的3CLpro蛋白酶的抑制作用
通过上述S-217622以及PEG化S-217622对3CLpro的半抑制浓度对比,不 难看出S-217622经4Arm-PEG修饰后依然具有普遍的高度选择性,对3CLpro蛋 白酶显示出较低的半抑制浓度值,检测显示,PM-6对相关3CLpro蛋白酶(半抑 制浓度=0.646μM)有有效的抑制作用。提示所有PEG化合物均有统计学显著的抗 3CLpro蛋白酶作用。
实施例12药物血浆半衰期的测定实验
材料与方法
实验动物健康的家狗1只,雌雄不拘,体重为2-4千克。7号头皮针、三通 管、注射器、试管;500U/ml肝素钠生理盐水溶液;分光光度计、台式离心机。
实验目的
根据绝大多数药物在体内按一级动力学消除的规律,用给药后各时间点测出 的家狗血药浓度数据测定药物血浆半衰期。
实验方法
取试管7支,按0-6编号,在0号管加入生理盐水3ml,其余各管均加入生 理盐水4ml。取家狗一只,称重,将家狗固定于兔盒中。使用充满肝素的7号头 皮针从家狗耳中央的小动脉插入,用输液夹固定。从三通管往小动脉方向注入 500U/ml肝素钠生理盐水溶液1ml/kg,致使家狗全身肝素化,以抗凝。用连接在 三通管上的注射器反复抽吸3-5次后,从三通管处(动脉方向)准确抽取药前血 0.2ml于1号管中作为药前对照管。用注射器从家狗耳缘静脉注入0.5μM前药溶 液2ml/kg。分别于给药后5、10、20、40、60分钟时,从三通管(动脉方向)准确 吸取血样0.2ml于2、3、4、5、6号试管中,摇匀,静置,记录取到血样的时间。 因三通管内含有上次残存血样,所以每次取血前应用注射器反复抽吸3-5次。将 各试管离心速度为3000转/分,离心时间为5分钟。精确吸取离心后的上清液3ml 分别放入另一组编好号的试管中,以0号管为对照,用分光光度计测定给药后各 管上清液的光密度值。在半对数座标纸上,以时间为横座标(等方格),血药浓度 为纵座标(对数值),将6次测算的浓度值作点连线,即为药时曲线,在此线上找 出血药浓度下降一半所对应的时间即为该药的血浆半衰期。
表3 PEG化S-217622的血浆半衰期
S-217622在静脉给药后消除半衰期(t1/2)为30.2h,而PEG化后的S-217622 前药静脉给药后半衰期普遍超过50h以上,可见PEG修饰S-217622可以显著延 长药物半衰期。
Claims (10)
2.根据权利要求1所述的结合物或其药学上可接受的盐,其特征在于,所述四臂聚乙二醇的数均分子量为5000-40000道尔顿。
3.根据权利要求1所述的结合物或其药学上可接受的盐,其特征在于,所述G选自溴、甲基、三氟甲基以及氢中的一种。
5.根据权利要求4所述的制备方法,其特征在于,所述I-1化合物结构中的氯直接与硫代乙酸发生取代反应并经盐酸水解得到含有巯基的中间体V-1化合物。
6.根据权利要求4所述的制备方法,其特征在于,所述V-1化合物的巯基与四臂聚乙二醇化的马来酰亚胺发生特异性偶联得到I-2化合物。
7.一种药物组合物,包含权利要求1-3任一项所述的结合物或其药学上可接受的盐及药学上可接受的载体、赋形剂、辅剂、媒介物或它们的任意组合。
8.根据权利要求7所述的药物组合物,其特征在于,所述药物组合物为散剂、栓剂、注射剂、溶液剂、混悬剂、膏剂、贴剂、雾化剂中的至少一种。
9.根据权利要求8所述的药物组合物,其特征在于,所述药物组合物采用适用于精确剂量的注射给药的单元剂量形式。
10.根据权利要求1-3任一项所述的结合物或其药学上可接受的盐或者根据权利要求7-9所述的组合物在制备抗新冠肺炎药物中的应用。
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103755949A (zh) * | 2009-12-25 | 2014-04-30 | 天津键凯科技有限公司 | 多臂聚乙二醇衍生物及其与药物的结合物和凝胶 |
WO2022035911A2 (en) * | 2020-08-11 | 2022-02-17 | Tutela Pharmaceuticals, Inc. | Methods of treating coronavirus infections by co-administering an fkbp ligand and an antiviral agent |
CN114259570A (zh) * | 2022-01-20 | 2022-04-01 | 长沙创新药物工业技术研究院有限公司 | 一种聚乙二醇修饰的抗肿瘤前药及其制备方法和应用 |
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103755949A (zh) * | 2009-12-25 | 2014-04-30 | 天津键凯科技有限公司 | 多臂聚乙二醇衍生物及其与药物的结合物和凝胶 |
WO2022035911A2 (en) * | 2020-08-11 | 2022-02-17 | Tutela Pharmaceuticals, Inc. | Methods of treating coronavirus infections by co-administering an fkbp ligand and an antiviral agent |
CN114259570A (zh) * | 2022-01-20 | 2022-04-01 | 长沙创新药物工业技术研究院有限公司 | 一种聚乙二醇修饰的抗肿瘤前药及其制备方法和应用 |
Non-Patent Citations (2)
Title |
---|
YUTO UNOH等: "Discovery of S 217622, a Noncovalent Oral SARS-CoV 2 3CL Protease Inhibitor Clinical Candidate for Treating COVID-19", J. MED. CHEM., vol. 65, pages 6499 - 6512, XP093007183, DOI: 10.1021/acs.jmedchem.2c00117 * |
滕再进等: "聚乙二醇前药设计原理与应用研究进展", 中国药业, vol. 23, no. 15, pages 1 - 4 * |
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