目的对阿伐那非合成工艺中具有警示结构的潜在有关物质进行致突变性评价研究,为阿伐那非有关物质的分类分级提供指导和依据。方法通过化学方法定向合成阿伐那非含警示结构的潜在遗传毒性杂质E(impurity E,Imp-E),按照国际人用药品注册...目的对阿伐那非合成工艺中具有警示结构的潜在有关物质进行致突变性评价研究,为阿伐那非有关物质的分类分级提供指导和依据。方法通过化学方法定向合成阿伐那非含警示结构的潜在遗传毒性杂质E(impurity E,Imp-E),按照国际人用药品注册技术协调会(The InternationalCouncil for Harmonisation of Technical Requirementsfor Pharmaceuticals for Human Use,ICH)M7指导原则对其进行评价和分类。分别采用基于专家规则和统计学原理的2种互补的定量构效关系(quantitative structure-activity relationship,QSAR)评价系统(Derek和Sarah)对Imp-E的遗传毒性进行初步预测,并展开Ames试验对Imp-E进一步验证。结果Imp-E的Derek预测结果为阳性,依据ICH M7指导原则的分类为第3类。在Ames验证试验中,受试物剂量为每皿62.5~1000μg时,无论S9存在与否的情况下,回复突变菌落数均未超过溶剂对照组菌落数的2倍且不呈剂量-反应关系,试验结果显阴性。结论Imp-E的致突变性为阴性,推翻了Derek预测的阳性结果,依据ICH M7中的第5类即非突变性杂质进行控制。展开更多
Trimethoxybenzoyloxysolanesylamide（8） was first synthesized from solanesol in four steps. Thus, solanesyl bromide（5） prepared by the reaction of solanesol（4） and PBr3 was reacted with potassium phthalimide to gi...Trimethoxybenzoyloxysolanesylamide（8） was first synthesized from solanesol in four steps. Thus, solanesyl bromide（5） prepared by the reaction of solanesol（4） and PBr3 was reacted with potassium phthalimide to give N-solanesylphthalimide（6）, which was refluxed with N2H4·H2O in 95%EtOH to give solanesylamine（7）. Compound 7 was then reacted with 3,4,5-trimethoxybenzoyloxyl chloride to give the title compound. Its structure has been confirmed by IR, 1H NMR, MS and elemental analysis.展开更多
文摘目的对阿伐那非合成工艺中具有警示结构的潜在有关物质进行致突变性评价研究,为阿伐那非有关物质的分类分级提供指导和依据。方法通过化学方法定向合成阿伐那非含警示结构的潜在遗传毒性杂质E(impurity E,Imp-E),按照国际人用药品注册技术协调会(The InternationalCouncil for Harmonisation of Technical Requirementsfor Pharmaceuticals for Human Use,ICH)M7指导原则对其进行评价和分类。分别采用基于专家规则和统计学原理的2种互补的定量构效关系(quantitative structure-activity relationship,QSAR)评价系统(Derek和Sarah)对Imp-E的遗传毒性进行初步预测,并展开Ames试验对Imp-E进一步验证。结果Imp-E的Derek预测结果为阳性,依据ICH M7指导原则的分类为第3类。在Ames验证试验中,受试物剂量为每皿62.5~1000μg时,无论S9存在与否的情况下,回复突变菌落数均未超过溶剂对照组菌落数的2倍且不呈剂量-反应关系,试验结果显阴性。结论Imp-E的致突变性为阴性,推翻了Derek预测的阳性结果,依据ICH M7中的第5类即非突变性杂质进行控制。
文摘Trimethoxybenzoyloxysolanesylamide（8） was first synthesized from solanesol in four steps. Thus, solanesyl bromide（5） prepared by the reaction of solanesol（4） and PBr3 was reacted with potassium phthalimide to give N-solanesylphthalimide（6）, which was refluxed with N2H4·H2O in 95%EtOH to give solanesylamine（7）. Compound 7 was then reacted with 3,4,5-trimethoxybenzoyloxyl chloride to give the title compound. Its structure has been confirmed by IR, 1H NMR, MS and elemental analysis.
