Design, Synthesis and Evaluation of Neurotrophic Modulators
| Autor: | Fei-Chiao Kuo, 郭斐荍 |
|---|---|
| Rok vydání: | 2009 |
| Druh dokumentu: | 學位論文 ; thesis |
| Popis: | 97 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. |
| Databáze: | Networked Digital Library of Theses & Dissertations |
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