摘要
目的 对本课题组前期发现的具有优秀体内外抗流感病毒活性的吲哚并喹啉硼酸候选化合物IQB-6进行合成工艺、溶解性及稳定性研究.方法 针对物料投料比、溶剂量、反应时间、反应温度、后处理及纯化方法等一系列反应条件,进行合成工艺优化,提高IQB-6产率及纯度;测试IQB-6在正己烷、水、乙醇、二甲基亚砜(DMSO)等8种溶剂中的溶解性;考察IQB-6在高温、高湿、光照、酸、碱及氧化条件下的稳定性,并且测试其在人工胃液、肠液及体外SD大鼠血浆中的稳定性.结果 通过7步反应得到纯度大于99％的IQB-6产物,总产率可达到25％;溶解性研究表明,IQB-6在DMSO中溶解性最好,在其他有机溶剂中均有一定的溶解性,在水中最差;此外,在高温、高湿、光照等条件下的稳定性研究发现IQB-6具有一定的稳定性.结论 优化后的工艺成本低、易操作,便于放大.IQB-6的溶解特性可为进一步的制剂研究提供指导.IQB-6理化性质稳定,便于储藏、运输和给药,相关稳定性试验则为后期的质量标准、药代动力学等研究提供一定的指导.
Abstract
Objective To study synthesis process,solubility and stability of IQB-6,an indole quinolineboronic acid candidate compound with excellent in vitro and in vitro anti-influenza virus activity discovered by our research group.Methods Firstly,for purpose of improving the yield and purity of IQB-6,a series of reaction conditions were optimized by controlling the material feeding ratio,solvent volume,reaction time,reaction temperature,post-treatment and purification methods.Secondly,the solubility of IQB-6 in eight solvents such as n-hexane,water,ethanol and DMSO was tested.Finally,the stability of IQB-6 solid under high temperature,high humidity,light,acid,alkali and oxidation conditions was investigated,and the stability of IQB-6 solid in artificial gastric and intestinal fluids,plasma of SD rats was tested.Results The IQB-6 product with purity greater than 99％was obtained through seven steps,and the overall yield was 25％.Studies on the solubility of IQB-6 in organic solvents mentioned above showed that the solubility of IQB-6 in DMSO was the best and that in water was the worst,and it only had a certain solubility in others.In addition,stability studies under high temperature,high humidity,light and other conditions found that IQB-6 solid had a certain stability.Conclusion The optimized process had the advantages of low cost,simple operation and simple amplification.The dissolution characteristics of IQB-6 could provide guidance for further preparation research.The physical and chemical properties of IQB-6 were stable,which was convenient for storage,transportation and administration.The relevant stability test could provide certain guidance for the later quality standard and drug metabolism research.
基金项目
国家自然科学基金(82003583)
国家自然科学基金(82073759)
新药创制国家科技重大专项(2018ZX09735004)
大湾区精准医学研究院(广州)基金(IPM2021C009)
NETL
NSTL
万方数据