新型吲唑类HCV抑制剂构效关系和杂环骨架合成新方法研究
发布时间：2018-09-03 16:16
【摘要】：本论文工作包括两个部分:第一部分是新型吲唑类HCV抑制剂的构效关系研究;第二部分是金属催化的类药性杂环骨架合成与修饰新方法研究。1.新型吲唑类HCV抑制剂构效关系研究基于本组发现的具有HCV抑制活性的吲唑类先导化合物2,我们依次对区域I~V进行了改造,得到了8个IC50小于20 n M化合物,在组内工作基础上初步完成了构效关系研究和可修饰位点探索。对优选化合物做了初步的大鼠口服药代动力学研究,为进一步的药代动力学性质优化奠定了良好的基础。2.金属催化的杂环骨架合成新方法研究我们课题组对于构建杂环小分子库具有浓厚的兴趣,因此我们希望建立一些直接高效的构建杂环骨架的新方法。我们基于C H活化和串联反应的策略,采用RhIII、IrIII和CuI做催化剂建立了合成异吲哚酮、吡咯酮、吲哚酮的新方法;实现了芳香环的选择性硫醚化、sp3 C H官能团化和吲哚啉C 7位的多样性氨基化修饰。1)通过RhIII催化活化芳烃或烯烃C H键,与异氰酸酯发生串联反应,建立了合成3 亚甲基异吲哚酮类和5 亚甲基吡咯酮类化合物的新方法。我们分离得到了反应中间体,对反应机理进行了合理的解释。该方法直接将定位基转化为目标分子的一部分,不需要额外的定位基脱除步骤。我们应用该方法进行了衍生化合成,展示出潜在的应用价值。2)通过IrIII催化活化吲哚啉C 7位C H键,与叠氮试剂发生反应,建立了吲哚啉C 7位的直接磺胺基化,芳香氨基化和酰胺基化的新方法。该方法条件温和,官能团耐受性好。通过该方法我们实现了吲哚啉C 7位与天然产物分子脱氢松香酸甲酯的连接,得到了新化合物18,这为天然产物的修饰提供了新的思路,展示出潜在的应用价值。3)通过RhIII催化活化芳烃C H键,与二硫醚发生反应,我们首次实现了三价铑催化的C S键的构建,通过控制反应条件,可以实现单硫化和双硫化的控制。4)通过RhIII催化活化sp3 C H键,与重氮试剂发生反应,我们完成了具有挑战性的sp3 C H官能团化。通过控制反应条件和重氮底物的类型,我们分别得到了质子化产物和β-H消除产物。该方法官能团耐受性好,放大至2克的规模反应仍很稳健。同时,我们的产物经过氢化可以直接转化为有机发光体Julolidine的衍生物,展示出潜在应用价值。我们将机理研究实验和DFT计算相结合,对机理进行了合理的推测。5)基于高碘试剂的特殊亲电性质,我们通过Cu Cl催化的5 exo trig串联关环反应,建立了合成3,3 二取代 2 吲哚酮骨架的新方法。该方法底物范围广泛,官能团耐受性好。我们应用该方法合成了具有抗稻瘟病作用的化合物39的衍生物35l,完成了天然产物(±) Physovenine和(±) Physostigmine的形式合成,展示出潜在的应用价值。
[Abstract]:This thesis includes two parts: the first part is the study of the structure-activity relationship of the novel indazole HCV inhibitors, the second part is the metal catalyzed synthesis and modification of heterocyclic frameworks. Study on Structure-Activity relationship of New Indazole HCV Inhibitors based on the HCV inhibitory activity of indazole lead compound 2, we modified the region I V in turn, and obtained 8 IC50 < 20nM compounds. On the basis of intragroup work, the study of structure-activity relationship and the exploration of modifiable sites were preliminarily completed. The primary pharmacokinetics of the selected compounds in rats was studied, which laid a good foundation for the further optimization of pharmacokinetic properties. 2. A New method of Metallic catalyzed heterocyclic Skeleton Synthesis our team is very interested in constructing heterocyclic small molecular libraries, so we hope to establish some new methods to construct heterocyclic skeletons directly and efficiently. Based on the strategies of C-H activation and series reaction, a new method for the synthesis of isoindole ketone, pyrrolidone and indole ketone was established using RhIII,IrIII and CuI as catalysts. The selective sulfidization of aromatic rings and the modification of the 7 position diversity of indoline C ~ (2 +) were realized. The aromatic hydrocarbons or alkenes were activated by RhIII, and the isocyanate was reacted in series with isocyanate in series. A new method for the synthesis of 3-methylene isoindole ketones and 5-methylene pyrrolidone compounds was established. The reaction intermediates were separated and the reaction mechanism was explained reasonably. In this method, the localization base is transformed directly into a part of the target molecule, and no additional removal steps are required. We have used this method to synthesize the derivatives, showing the potential application value of .2) the direct sulfonamination of indoline C ~ (7) is established by IrIII catalytic activation of C ~ (7) C ~ (-H) bond with azide reagent. A New method of Aminoamination and Amidylation of aromatic compounds. The conditions of this method are mild and the functional groups have good tolerance. By using this method, we have realized the connection of indoline C ~ (7) with natural product molecular dehydrogenation rosin acid methyl ester, and obtained a new compound 18, which provides a new way of thinking for the modification of natural products. It shows the potential application value of 3. 3) through RhIII catalytic activation of aromatics C-H bond and reaction with disulfide, we first realized the construction of trivalent rhodium-catalyzed C / S bond by controlling the reaction conditions. The control of monovulcanization and double vulcanization can be achieved. The RhIII catalyzes the activation of sp3 C-H bonds and reacts with diazo reagents. We have completed the challenging sp3 C-H functionalization. By controlling the reaction conditions and the types of diazo substrates, we obtained protonation products and 尾 -H elimination products, respectively. The functional groups of this method are well tolerated, and the response to 2 g scale is still robust. At the same time, our products can be directly converted into derivatives of organic luminescent Julolidine after hydrogenation, which shows potential application value. Based on the special electrophilic properties of iodide reagents, we combined the mechanism research experiments with DFT calculations. Based on the special electrophilic properties of iodide reagents, we used Cu Cl to catalyze the 5 exo trig series closed ring reaction. A new method for the synthesis of 3 ~ (3 +) ~ (3) ~ (3) disubstituted indoleones was established. This method has a wide range of substrates and good tolerance of functional groups. The derivatives of compound 39 with resistance to rice blast were synthesized by this method, and the natural products (卤) Physovenine and (卤) Physostigmine were synthesized in the form of (卤) Physovenine and (卤) Physostigmine, which showed potential application value.
【学位授予单位】：中国科学院上海药物研究所
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R914.5
，
本文编号：2220502
[Abstract]:This thesis includes two parts: the first part is the study of the structure-activity relationship of the novel indazole HCV inhibitors, the second part is the metal catalyzed synthesis and modification of heterocyclic frameworks. Study on Structure-Activity relationship of New Indazole HCV Inhibitors based on the HCV inhibitory activity of indazole lead compound 2, we modified the region I V in turn, and obtained 8 IC50 < 20nM compounds. On the basis of intragroup work, the study of structure-activity relationship and the exploration of modifiable sites were preliminarily completed. The primary pharmacokinetics of the selected compounds in rats was studied, which laid a good foundation for the further optimization of pharmacokinetic properties. 2. A New method of Metallic catalyzed heterocyclic Skeleton Synthesis our team is very interested in constructing heterocyclic small molecular libraries, so we hope to establish some new methods to construct heterocyclic skeletons directly and efficiently. Based on the strategies of C-H activation and series reaction, a new method for the synthesis of isoindole ketone, pyrrolidone and indole ketone was established using RhIII,IrIII and CuI as catalysts. The selective sulfidization of aromatic rings and the modification of the 7 position diversity of indoline C ~ (2 +) were realized. The aromatic hydrocarbons or alkenes were activated by RhIII, and the isocyanate was reacted in series with isocyanate in series. A new method for the synthesis of 3-methylene isoindole ketones and 5-methylene pyrrolidone compounds was established. The reaction intermediates were separated and the reaction mechanism was explained reasonably. In this method, the localization base is transformed directly into a part of the target molecule, and no additional removal steps are required. We have used this method to synthesize the derivatives, showing the potential application value of .2) the direct sulfonamination of indoline C ~ (7) is established by IrIII catalytic activation of C ~ (7) C ~ (-H) bond with azide reagent. A New method of Aminoamination and Amidylation of aromatic compounds. The conditions of this method are mild and the functional groups have good tolerance. By using this method, we have realized the connection of indoline C ~ (7) with natural product molecular dehydrogenation rosin acid methyl ester, and obtained a new compound 18, which provides a new way of thinking for the modification of natural products. It shows the potential application value of 3. 3) through RhIII catalytic activation of aromatics C-H bond and reaction with disulfide, we first realized the construction of trivalent rhodium-catalyzed C / S bond by controlling the reaction conditions. The control of monovulcanization and double vulcanization can be achieved. The RhIII catalyzes the activation of sp3 C-H bonds and reacts with diazo reagents. We have completed the challenging sp3 C-H functionalization. By controlling the reaction conditions and the types of diazo substrates, we obtained protonation products and 尾 -H elimination products, respectively. The functional groups of this method are well tolerated, and the response to 2 g scale is still robust. At the same time, our products can be directly converted into derivatives of organic luminescent Julolidine after hydrogenation, which shows potential application value. Based on the special electrophilic properties of iodide reagents, we combined the mechanism research experiments with DFT calculations. Based on the special electrophilic properties of iodide reagents, we used Cu Cl to catalyze the 5 exo trig series closed ring reaction. A new method for the synthesis of 3 ~ (3 +) ~ (3) ~ (3) disubstituted indoleones was established. This method has a wide range of substrates and good tolerance of functional groups. The derivatives of compound 39 with resistance to rice blast were synthesized by this method, and the natural products (卤) Physovenine and (卤) Physostigmine were synthesized in the form of (卤) Physovenine and (卤) Physostigmine, which showed potential application value.
【学位授予单位】：中国科学院上海药物研究所
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R914.5
，
本文编号：2220502
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