新型吲唑類HCV抑制劑構效關系和雜環(huán)骨架合成新方法研究
發(fā)布時間：2018-09-03 16:16
【摘要】：本論文工作包括兩個部分:第一部分是新型吲唑類HCV抑制劑的構效關系研究;第二部分是金屬催化的類藥性雜環(huán)骨架合成與修飾新方法研究。1.新型吲唑類HCV抑制劑構效關系研究基于本組發(fā)現(xiàn)的具有HCV抑制活性的吲唑類先導化合物2,我們依次對區(qū)域I~V進行了改造,得到了8個IC50小于20 n M化合物,在組內(nèi)工作基礎上初步完成了構效關系研究和可修飾位點探索。對優(yōu)選化合物做了初步的大鼠口服藥代動力學研究,為進一步的藥代動力學性質(zhì)優(yōu)化奠定了良好的基礎。2.金屬催化的雜環(huán)骨架合成新方法研究我們課題組對于構建雜環(huán)小分子庫具有濃厚的興趣,因此我們希望建立一些直接高效的構建雜環(huán)骨架的新方法。我們基于C H活化和串聯(lián)反應的策略,采用RhIII、IrIII和CuI做催化劑建立了合成異吲哚酮、吡咯酮、吲哚酮的新方法;實現(xiàn)了芳香環(huán)的選擇性硫醚化、sp3 C H官能團化和吲哚啉C 7位的多樣性氨基化修飾。1)通過RhIII催化活化芳烴或烯烴C H鍵,與異氰酸酯發(fā)生串聯(lián)反應,建立了合成3 亞甲基異吲哚酮類和5 亞甲基吡咯酮類化合物的新方法。我們分離得到了反應中間體,對反應機理進行了合理的解釋。該方法直接將定位基轉(zhuǎn)化為目標分子的一部分,不需要額外的定位基脫除步驟。我們應用該方法進行了衍生化合成,展示出潛在的應用價值。2)通過IrIII催化活化吲哚啉C 7位C H鍵,與疊氮試劑發(fā)生反應,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。該方法條件溫和,官能團耐受性好。通過該方法我們實現(xiàn)了吲哚啉C 7位與天然產(chǎn)物分子脫氫松香酸甲酯的連接,得到了新化合物18,這為天然產(chǎn)物的修飾提供了新的思路,展示出潛在的應用價值。3)通過RhIII催化活化芳烴C H鍵,與二硫醚發(fā)生反應,我們首次實現(xiàn)了三價銠催化的C S鍵的構建,通過控制反應條件,可以實現(xiàn)單硫化和雙硫化的控制。4)通過RhIII催化活化sp3 C H鍵,與重氮試劑發(fā)生反應,我們完成了具有挑戰(zhàn)性的sp3 C H官能團化。通過控制反應條件和重氮底物的類型,我們分別得到了質(zhì)子化產(chǎn)物和β-H消除產(chǎn)物。該方法官能團耐受性好,放大至2克的規(guī)模反應仍很穩(wěn)健。同時,我們的產(chǎn)物經(jīng)過氫化可以直接轉(zhuǎn)化為有機發(fā)光體Julolidine的衍生物,展示出潛在應用價值。我們將機理研究實驗和DFT計算相結合,對機理進行了合理的推測。5)基于高碘試劑的特殊親電性質(zhì),我們通過Cu Cl催化的5 exo trig串聯(lián)關環(huán)反應,建立了合成3,3 二取代 2 吲哚酮骨架的新方法。該方法底物范圍廣泛,官能團耐受性好。我們應用該方法合成了具有抗稻瘟病作用的化合物39的衍生物35l,完成了天然產(chǎn)物(±) Physovenine和(±) Physostigmine的形式合成,展示出潛在的應用價值。
[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 (鹵) Physovenine and (鹵) Physostigmine were synthesized in the form of (鹵) Physovenine and (鹵) Physostigmine, which showed potential application value.
【學位授予單位】：中國科學院上海藥物研究所
【學位級別】：博士
【學位授予年份】：2016
【分類號】：R914.5
，
本文編號：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 (鹵) Physovenine and (鹵) Physostigmine were synthesized in the form of (鹵) Physovenine and (鹵) Physostigmine, which showed potential application value.
【學位授予單位】：中國科學院上海藥物研究所
【學位級別】：博士
【學位授予年份】：2016
【分類號】：R914.5
，
本文編號：2220502
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