臺灣博碩士論文加值系統

為了開發抗過敏藥物，本研究室根據生物等價性原理設計，並合成出一系列2, 7-雙取代硫兩苯并化合物 (36∼56)。本系列化合物可利用2, 5-雙取代苯甲酸(18∼35)分別與硫酸進行環化，再利用2,7-雙取代硫兩苯并化合物(36∼39)與鐵/氯化銨在乙醇/水中迴流進行還原反應來獲得2-胺基取代衍生化合物 (53∼56)。
所得化合物其結構之正確性都經由 IR , MS , UV ,1H-NMR 和13C-NMR等光譜分析資料來綜合確認。
這類化合物18~56之IR光譜其C=O之吸收在1637~1709cm-1之間，-NO2之吸收在1518~1347 cm-1之間，-NH2之吸收在3420~3349 cm-1之間，-OH之吸收在3368 cm-1左右。而UV光譜一般有三個主要吸收譜帶其大致範圍為339nm、263nm及203nm左右。
所有合成出及經結構判定正確的化合物，部分化合物分別以肥滿細胞去顆粒作用、嗜中性球去顆粒作用及嗜中性球過氧化物生成作用等之抑制試驗來評估其抗過敏活性。而從目前之體外測試結果，對於Compound48/80誘導的肥滿細胞去顆粒作用之抑制試驗、fMLP誘導的嗜中性球過氧化物生成作用(Neutrophil superoxide formation)及PMA誘導的嗜中性球過氧化物生成作用 (Neutrophil superoxide formation)之抑制試驗中，化合物 36、41-45、48-51及53，皆無明顯的抑制活性。簡言之;即硫兩苯并結構上第二位置之高氧化態取代基(如-COOH, -CH2OH, -CHO)對其抗過敏活性可能是必要的。故此結果可提供我們日後從事此類化合物之合成及抗過敏活性研究時的參考，以期進一步建立 2,7-雙取代硫兩苯并之結構與生理活性間的關係。

For bioisosteric designing antiallergic agents , a series of 2, 7-disubstituted thioxanthen-9-ones (36∼56) have been synthesized by the cyclization of 2, 5-disubstituted benzoic acids (18∼35) with concentrated sulfuric acid and then reduced of 2, 7-disubstituted thioxanthen-9-ones (36∼39) with iron/ammonium chloride in ethanol/water under reflux conditions to give only the corresponding 2-amino substituted derivatives (53∼56).
Structures of these products were fully identified by IR , MS , UV , 1H-NMR and 13C-NMR spectral analyses .
The stturated thioxanthen-9-one derivative's (18~56) IR spectral analyses have the carbonyl group (C=O) absorptivity between 1637~1709 cm-1, the nitro group (-NO2) absorptivity between 1518~1347 cm-1, the amino group (-NH2) absorptivity between 3420~3349 cm-1, and the hydroxyl group (-OH) absorptivity about 3368 cm-1. The UV spectral analyses generally have three major absorptivity bands those are at about 339 nm, 263 nm, and 203 nm.
Some of these synthetic compounds were evaluated for antiallergic activity by inhibition tests of mast cell degranulation , neutrophil degranulation , and neutrophil superoxide formation. Among these tested compounds, compounds 36, 41-45 and 48-53, showed no inhibitory activity on compound 48/80 induced mast cell degranulation. Compounds 36, 41-45 and 48-53, showed no inhibitory activity on fMLP and PMA induced neutrophil superoxide formations, too. It may conclude that 2-substituents with high oxidation state (such as -COOH, -CH2OH, -CHO) of thioxanthen-9-one should be essential for their antiallergic activities. These results will provide us a guide to study of synthesis and antiallergic activity of these series of compounds, and further generalize the structure-activity relationships of 2, 7-disubstituted thioxanthen-9-ones.

謝誌…………………………………………………………………………ii
中文摘要……………………………………………………………………iii
英文摘要……………………………………………………………………iv
第一章 緒論………………………………………………………………..1
第一節 抗過敏活性概述………………………………………………..1
第二節 抗過敏活性藥物之研究概況…………………………………..4
壹.前言……………………………………………………………….4
貳.研究動機與目的………………………………………………….8
第二章 研究經過、結果與討論…………………………………………9
壹.化學合成部分…………………………………………………….9
甲. 2-Methylthioxanthen-9-one (16) 之合成……………………......9
乙. 5-Nitro-2-(p-tolylmercapto)benzoic acid (18) 之合成……............11
丙. 2-(p-Substituted phenylmercapto)-5-substituted benzoic acid (19~35) 之合成.12
丁. 2, 7-Disubstituted thioxanthen-9-one (35~52) 之合成……….......13
戊. 2-Amino-7-substituted thioxanthen-9-one (53~56) 之合成…........15
貳.藥理活性試驗…………………………………………………….22
甲.對於Compound48/80誘導的肥滿細胞去顆粒作用抑制試驗..23
乙.對於fMLP 誘導的嗜中性球去顆粒作用抑制試驗…………..27
丙.對於fMLP 誘導的嗜中性球過氧化物生成作用抑制試驗…..31
丁.對於 PMA 誘導的嗜中性球過氧化物生成作用抑制試驗…..35
第三章 結論………………………………………………………………..39
第四章 實驗部份…………………………………………………………41
第一節 材料與儀器………………………………………………………41
壹.試劑與溶劑……………………………………………………….41
貳.儀器……………………………………………………………….43
第二節 實驗方法………………………………………………………..44
壹.化學合成部分…………………………………………………….44
貳.藥理試驗方法…………………………………………………….83
第五章 參考文獻…………………………………………………………..84
附錄（圖譜部分）…………………………………………………………86

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