1,2-雙酮化合物為一重要且廣用性的中間體可廣泛應用於有機合成、材料化學以及雜環分子合成。於本篇論文，我們關注於利用1,2-雙酮化合物作為中間體設計以quinoxaline及2,4,4-trisubstituted -1H-imidazol-5(4H)-one為骨架之具潛力之阿茲海默症相關藥物GSK3β及BACE1抑制劑。此外，這些化合物也具有其他生物活性例如抗癌抗發炎等。本篇論文首要任務是建立快速合成不對稱之1,2-雙酮化合物之方法並提供多個不對稱之1,2-雙酮化合物合成策略的探討，我們合成了一個新的系列2-thiol-4,4-diphenyl-1H-imidazol-5(4H)衍生物為主要架構之具潛力的BACE1抑制劑，結構中之硫醇官能基扮演了兩個重要的角色:(i)改變氫鍵之鍵結關係(將胺類置換成硫醇)以及(ii)使其更容易被其他親核試劑置換以便探討更多SAR關係。GSK3β抑制劑是由1,2-雙酮化合物與Diaminomaleonitrile縮合，再將nitrile化合物經水解並合環建構上方maleimide環，其中有一些化合物具有中度的抗癌活性。

1,2-Diketones is an important synthetic intermediate widely used for the synthesis of heterocycles, and have found wide applications in both medicinal and materials chemistry. In this thesis, we are interested in the use of 1,2-diketones moieties for the design of quinoxaline and 2,4,4-trisubstituted -1H-imidazol-5(4H)-one heterocycles as potential GSK3β and BACE1 inhibitors that are related to Alzheimer's disease. Furthermore these compounds also possesses other biological activities such as, anticancer and anti-inflammatory.The first task of this work involved a rapid access to a wide arrays of asymmetrically substituted 1,2-diketones and various routes have been explored. A new series of 2-thiol-4,4-diphenyl-1H-imidazol-5(4H) have been synthesized as potential BACE1 inhibitors. The 2-thiol moiety can play two important role: (i) by tuning hydrogen binding affinity (changing from nitrogen to sulfur), and (ii) readily replaced by other nucleophiles for SAR studies.
The GSK3β inhibitors were synthesized from the condensation of the 1,2-diketone with Diaminomaleonitrile, followed by conversion of the dinitrile to the 1H-pyrrole-2,5-dione (maleimide).Some of the synthesized compound showed moderate anticancer activities.

摘要 i
第一章 1
1.1前言 1
1.2 經由1,2-雙酮為中間體所衍生的異原子環 2
1.2.1 合成2-Aminol-1H-imidazol-5(4H)-one類似物與應用探討 2
1.2.2 合成2,5,5-triphenyl-1H-imidazol-4(5H)-one類似物之與應用探討 5
1.2.3 合成5,5-diphenylhydantoin類似物之應用與探討 7
1.2.4 合成5,5-diphenylhydantoin類似物之應用與探討 8
1.2.5合成pteridines 及pyridopyrazines類似物之應用與探討 10
1.2.6 合成5,6-diphenylpyrazinone類似物之應用與探討 13
1.2.7 合成5,6-diphenyl-1,2,4-triazine類似物之應用與探討 14
1.2.8 合成Canthin類似物之應用與探討 16
1.3 合成1.2-雙酮 17
1.4阿滋海默症介紹 23
1.5 肝醣合成酶激酶-(Glycogen synthase kinase 3β, GSK-3β) 23
1.5.1 GSK-3β與阿滋海默症的關係 24
1.5.2 肝醣合成酶激酶抑制劑(GSK-3beta β) 25
1.6 β-分泌酶(β-site APP cleaving enzyme, BACE1) 26
1.6.1 BACE1與阿滋海默症的關係 26
第二章 設計與合成BACE1與GSK3β抑制劑研究探討 27
2.1 前言 27
2.2 研究動機 27
2.3 逆合成分析 31
2.4合成與結果探討─1,2雙酮化合物 33
2.4.1 合成1,2-雙酮之途徑一: 33
2.4.2 合成1,2-雙酮之途徑二: 34
2.4.3 合成1,2-雙酮之途徑三: 36
2.4.4 合成1,2-雙酮之途徑四: 38
2.5合成與結果探討─BACE1抑制劑之合成 39
2.6合成與結果探討- GSK-3β抑制劑之合成 41
第四章 結論 43
第五章 實驗步驟 44
參考文獻 80

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