神經滋養調控劑之合成設計與生物活性評估

Abstract

本研究主旨在於設計與合成isoquinolinone 衍生物作為調控神經軸突之藥物以及糖尿病的抑制劑。以methyl 2-cyanomethylbenzoate (10)作為起始物，氫氧化鈉水溶液水解得到2-cyanomethylbenzoic acid (9)，再以secondary amine 作親核加成，經電子轉移得到isoquinolinone類似物 (8, 17, 18, 19)。化合物8四號碳上的取代可用NXS作鹵素取代；或用氫化鈉拔去二號氮上的氫，再經電子轉移，在四號碳上作親核加成，用以接上拉電子基團。Quinazoline類似物則是以methyl 2-aminobenzoate (36)作為起始物，在高溫下和尿素反應，環化成quinazoline-2,4(1H,3H)-dione (37)，再以三氯氧磷作氯化反應得到2,4-dichloroquinazoline (38)，四號碳上的氯經由氫氧化鈉水溶液水解為羰基，quinazoline二號碳上的取代則是以酒精在封管、高溫下和二級胺反應 (43)。經體外神經細胞實驗及DPP 4 活性測試中發現，3-(piperidin-1-yl)isoquinolin-1(2H)-one (17)及其類似物，(R)-3-(3-(N-Boc-amino)piperidin-1-yl)isoquinolin-1(2H)-one (8)，於sub-μM 濃度範圍內能顯著地促進神經軸突延長的現象，卻無法有效抑制DPP 4 的活性。具有此種類似結構之化合物亦有促進神經軸突延展之功能，未來經進一步優化後能更有效地應用於對抗神經退化性疾病以及糖尿病的治療。

This thesis is aimed to majorly design a series of isoquinolinone derivatives as neurite outgrowth modulators and perhaps also as dipeptidyl peptidase 4 (DPP 4) inhibitor. The synthesis of isoquinolinone derivatives were started from commercially available methyl 2-cyanomethylbenzoate (10) which was hydrolyzed by sodium hydroxide to give 2-cyanomethylbenzoic acid (9). Subsequently, compound 9 was condensed with a variety of amines to afford isoquinolinone derivatives (8, 17, 18, and 19). The treatment of compound 8 with alkyl halides or benzyl halides in the presence of sodium hydride got C4-alkylated isoquinolinone derivatives. However, the synthesis of quinazoline derivatives began with a condensation of methyl 2-aminobenzoate (36) with urea under high temperature. The cyclized product, quinazoline-2,4(1H,3H)-dione (37), was then treated with phosphorus oxychloride to obtain 2,4-dichloroquinazoline (38). Compound 38 was treated with sodium hydroxide solution lead to the formation of 39. Subsequently, compound 40 was provided by the sealed tube reaction of secondary amines with 39 under high temperature. The designed isoquinolinone derivatives were subjected to neurite outgrowth evaluation. The preliminary results demonstrated that 3-(piperidin-1-yl) isoquinolin-1(2H)-one (17) and its derivatives such as (R)-3-(3-(N-Boc-amino)piperidin-1-yl)isoquinolin-1(2H)-one (8), significantly promote in vivo neurite outgrowth at sub-μM range but less activity of DPP 4 inhibition. These isoquinolinone derivatives provide an alternative strategy which may be applied to therapeutically interest for handling neurodegenerative disorders and diabetes mellitus after better optimization.