壹、N-溴代丁二醯亞胺作為催化劑在有機合成上的應用; 貳、磷化物在有機合成上之應用；參、合成含有1,2,4-噁二唑之吡唑類衍生物在CB1受體拮抗劑之生物活性研究

(I) Novel synthetic strategy for the synthesis of biologically active N-heterocycles catalyted by N-bromosuccinimide (II) Application of phosphous reagent in organic synthesis (III) SAR study on novel series of oxadiazoles as CB1 cannabinoid receptor antagonists

郭俊偉(Chun-Wei Kuo)

指導教授 ： 姚清發 博士 ； 夏克山 博士

國立臺灣師範大學/理學院/化學系/博士(2008年)

摘要

本論文共分成三部分
第一部分以便宜易取得之N-溴代丁二醯亞胺 (NBS) 試劑，分別催化合成具生物活性1,5-benzodiazepines衍生物以及吲哚基硝基烷化合物，此高效催化效率皆可使反應順利進行，並得到高產率的產物。
第二部分以磷化物試劑，二氯化磷酸乙酯 (ethyl dichlorophosphate)或是二氯化磷酸苯酯 (phenyl dichlorophosphate)進行官能基的轉變及Beckmann 重排反應，反應順利可在室溫下進行並且得到高產率的產物。
第三部分為探討含1,2,4-噁二唑為新型CB1受體拮抗劑之抗肥胖藥物的開發研究，以Rimonabant（SR141716A, Acomplia™）作為先導化合物進行pyrazole-C3位置的官能基修飾，依生物同質性概念成功引入1,2,4-噁二唑取代之新型化合物並顯現高度之CB1受體親和力、功能活性與CB2/1選擇性。發現具高度CB1親和力與CB2/1選擇性的化合物如11g, 11h等，將適合針對減重機制與抗肥胖藥物的特性進一步深入研究動物體內活性（in vivo efficacy）、藥物動力學（pharmacokinetics）及毒理試驗（toxicology）期能獲得具有潛力治療肥胖症的先導藥物或候選藥物。

關鍵字

N-溴代丁二醯亞胺 ； 催化劑 ； 磷化物 ； 1,2,4-噁二唑 ； 吡唑 ； CB1受體拮抗劑

並列摘要

In the first part of this dissertation, we have focused on the use of relatively low toxic, inexpensive reagents such as N-bromosuccinimide for carrying out the catalytic synthetic methodology. Various biologically important 1,5-benzodiazepine derivatives were efficiently synthesized in excellent yields. Furthermore, 3-indolyl-nitroalkane derivatives can be synthesized utilizing this newly development catalytic system as well.

The second part is focused on ethyl dichlorophosphate mediates functional group transormation from primary amides into nitriles under mild condition. However, phenyl dichlorophosphate also promotes Beckmann rearrangement at room temperature with highly efficiently to afford products in good to high yields.

Finally, a novel series of 1,2,4-oxadiazole as potent and selective CB1 cannabinoid receptor antagonists has been developed. Replacing the conventional pyrazole 3-aryl substituent of rimonabant with the 1,2,4-oxadiazole moiety, a novel class of 1,2,4-oxadiazole-pyrazole derivatives, behaving as highly potent CB1 receptor antagonists with good CB2/1 selectivity, was discovered.

並列關鍵字

N-bromosuccinimide ； catalyst ； phosphorus reagent ； 1,2,4-oxadiazole ； pyrazole ； CB1 receptor antagonist

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