臺灣博碩士論文加值系統

中文摘要
本研究主旨在於設計與合成喹類衍生物作為非肽腎上腺皮質素促進釋放激素(CRH1)受體的拮抗劑。依據一系列已知CRH1拮抗劑之構造與結構關係以及前導化合物CP154526-1（12）的結構，以環取代前導化合物的喀嘧啶環，設計標的化合物8-aryl-4-(N- cyclopropylmethyl-N-propylamino)-2-methylquinazoline (36-38, 40)。由2-bromoaniline（20）為起始物，加入chloral hydrate以及hydroxylamine形成2-bromoisonitrosoacetanilide（21），再以濃硫酸處理形成7-bromoisatin（22），在鹼性條件下以雙氧水進行脫反應製得2-amino-3-bromobenzoic acid（23），再以triphosgene進行環合反應，接著在鹼性條件下處理形成2-amino-3-bromobenzamide （25），再以2,4-pentadione在酸性條件下催化形成8-bromo-2-methyl-3H-quinazolin-4-one（26）。於quinazoline第4位進行氯化反應，所得的8-bromo-4-chloro-2-methylquinazoline（27）隨之與N-propyl-N-cyclopropylmethylamine進行親核性取代反應得到主要中間化合物8-bromo-4-(N-cyclopropylmethyl-N-propylamino)-2-methylquinazoline (19)。最後製備標的化合物4-(N-cyclopropylmethyl-N-propylamino)-8- mesityl-2-methylquinazoline (36)、4-(N-cyclopropylmethyl-N-propylamino)-8- (2,4-dimethoxyphenyl)-2-methyl-quinazoline (37)、8-(4-bromophenyl)-4- (N-cyclopropylmethyl-N-propylamino)-2-methylquinazoline (38)和4-(N-cyclopropylmethyl-N-propylamino)-8-pyridyl-2-methylquinazoline (40)乃是應用金屬鈀催化所進行的耦合反應。初步結果顯示標的化合物36和37對腎上腺皮質素促進釋放激素CRH1受體有良好選擇性及結合力，其Ki值分別為13 nM和50 nM 。此結果證實我們所設計的標的物36和37為有潛力之選擇性非肽CRH1拮抗劑。

Abstract
This thesis is aimed to design and synthesize substituted arylquinazoline derivatives as potential non-peptide corticotropin-releasing hormone 1 (CRH1) receptor antagonists. According to the structure-activity relationship of a series of known CRH1 antagonists and the lead compound CP154526-1 (12), quinazoline core was intended to replace the pyrrolopyrimidine ring leading to the target compounds 8-aryl-4-(N-cyclopropylmethyl-N-propylamino)- 2-methylquinazol-ines (36-38, 40). 2-Bromoaniline (20) was the starting material to prepare 2-bromoisonitrosoacetamilide (21) which was cyclized by concentrated H2SO4 to give 7-bromoisatin (22). Accordingly, 22 was decarboxylated by hydrogen peroxide to afford 2-amino-3-bromobenzoic acid (23). Condensation of 23 with triphosgene and then treatment under basic condition gave 2-amino-3-bromobenzamide (25). 8-Bromo-2-methyl-3H- quinazolin-4-one (26) was formed by condensation of 25 and 2,4-pentadione with p-toluenesulfonic acid catalysis. Chlorination of 26 with phosphorus oxychloride gave the 8-bromo-4-chloro-2-methylquinazoline (27). The key intermediate, 8-bromo-4-(N-cyclopropylmethyl-N-propylamino)-2-methyl- quinazoline (19) was obtained by nucleophilic substitution of 27 by the corresponding amine. Palladium-catalyzed cross-coupling reaction was employed in the final step to afford the target compounds 4-(N-cyclopropylmethyl-N-propylamino)-8-mesityl-2-methylquinazoline (36)、4-(N-cyclopropylmethyl-N-propylamino)-8-(2,4-dimthoxyphenyl)-2-methylquinazoline (37)、8-(4-bromophenyl)-4-(N-cyclopropylmethyl-N-propylamino)-2- methylquinazoline (38) and 4-(N-cyclopropylmethyl-N-propylamino)-8- pyridyl-2-methylquinazoline (40). Preliminary results showed that target compounds 36 and 37 were selective CRH1 antagonists with Ki = 13 nM and Ki = 50 nM, respectively. The results demonstrated that designed targets 36 and 37 are potential non-peptide selective CRH1 antagonists.

目錄
圖表目錄……………………………………………………………………..ii-iii
反應圖示目錄……………………..…………………………..……………….iv
中文摘要…………………………..………………………………………..…..v
Abstract………………………………...…………………………………...….vii
壹、緒論 1
貳、藥物設計 13
第一節、結構與活性關係的探討 13
第二節、設計構想: 14
參、結果與討論 16
第一節、標的化合物之合成策略 16
第二節、8-Bromo-4-(N-cyclopropylmethyl-N-propylamino)-2-methyl quinazoline (19)之合成 17
第三節、不同取代benzeneboronic acid之合成 21
第四節、標的化合物36-38及40之合成 24
第五節、藥理活性 27
肆、結論……………………….……………………….………………….…..29
伍、實驗 30
第一節、檢驗方法與實驗儀器 30
第二節、試藥、溶媒、材料 30
第三節、合成步驟 31
陸、參考文獻 44
柒、附錄 各化合物之核磁共振光譜…………..………….…………………50

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