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研究生:吳瑞蓉
研究生(外文):Rang-rong Wu
論文名稱:3-取代基-6-胺基-1,2,4-三唑[3,4-f][1,2,4]三氮肼-8(7H)-酮及3-芳香基-5-胺基-1,2,4-三唑[4,3-d][1,2,4]三氮肼衍生化合物之合成研究及生物活性測試
論文名稱(外文):Synthesis Study and Bioactivity Evaluation of 6-Amino-3-substituted-1,2,4-triazolo[3,4-f][1,2,4] triazin-8(7H)-ones and 5-Amino-3-aryl-1,2,4- triazolo[4,3-d][1,2,4]triazines
指導教授:黃龍池
指導教授(外文):Long-chih Hwang
學位類別:碩士
校院名稱:高雄醫學大學
系所名稱:藥學研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2002
畢業學年度:90
語文別:中文
中文關鍵詞:3-取代基-6-胺基-124-三唑[34-f] [124]三氮肼-8(7H)-酮3-芳香基-5-胺基-124-三唑[43-d][124]三氮肼衍生化合物
外文關鍵詞:3-substituted-6-amino-124-triazolo[34-f][124]triazin-8(7H)-5-amino-3-aryl-124-triazolo[43-d][124]triazines
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壹、中 文 摘 要
本研究合成出雙環雜環3-取代基-6-胺基-1,2,4-三唑[3,4-f][1,2,4]三氮肼-8(7H)-酮及3-芳香基-5-胺基-1,2,4-三唑[4,3-d][1,2,4]三氮肼兩大系列衍生化合物。前者3-取代基部分包括3-烷基-與3-芳香基-、3-烷胺基-、3-芳香胺基-及3-烷硫基-的6-胺基-1,2,4-三唑[3,4-f][1,2,4]三氮肼-8(7H)-酮等三類五種雙環雜環衍生化合物。
由單環雜環3-胺基-6-肼基-1,2,4-三氮肼-5(2H)-酮,各別與氯醯酸類經親核性取代反應得到醯肼基(-NHNHCOR)取代基,與醛類經縮合脫水反應得到亞甲基肼基(-NHN=CHR)取代基,及與異硫氰酸酯類化合物經親核性加成反應而得到4-N-取代硫半芐肼基(-NHNHCSNHR)取代基之1,2,4-三氮肼單環雜環取代衍生化合物。並探討經由不同反應條件達到環合效果,獲得雙環雜環衍生化合物製備的新途徑。
本研究成功地合成雙環雜環3-烷基-與3-芳香基-6-胺基-1,2,4-三唑[3,4-f][1,2,4]三氮肼-8(7H)-酮的新途徑及方法:(1)以矽化方法將單環醯肼基取代化合物進行矽化環合反應而得到3-取代基雙環雜環,此矽化環合方法方便,產率高及純化容易。(2)由3-胺基-6-溴基- 1,2,4-三氮肼-5(2H)-酮於二甲亞碸溶媒中與醯肼類化合物迴流反應,此方法乃一個步驟完成反應,得到最後產物。(3)由亞甲基肼基於四醋酸鉛或溴/氯化鐵催化下進行環合反應,得到最終產物,其中以四醋酸鉛的催化反應產率高、易純化,此方法可增加3-芳香基上多樣化的取代。上述各種反應的反應機制也提出探討。
3-烷胺基-與3-芳香胺基-6-胺基-1,2,4-三唑[3,4-f][1,2,4]三氮肼-8(7H)-酮雙環雜環衍生化合物未能成功地由4-N-取代硫半芐肼基取代基化合物直接環合而得,可由3-硫基-6-胺基-1,2,4-三唑[3,4-f][1,2,4]三氮肼-8(7H)-酮經矽化反應所得之矽化中間體,以芳香胺類進行親核性芳香族取代反應而得。
3-取代硫基-6-胺基-1,2,4-三唑[3,4-f][1,2,4]三氮肼-8(7H)-酮雙環雜環衍生化合物則由3-硫基-6-胺基-1,2,4-三唑[3,4-f][1,2,4]三氮肼-8(7H)-酮於氨/甲醇鹼性條件下與溴化烷類化合物進行親核性取代反應而得。第二系列雙環雜環衍生化合物,也成功地將單環雜環3-胺基-5-醯肼基-1,2,4-三氮肼經矽化環合反應而獲得,成功地運用矽化反應於取代與環合反應中。
本研究合成出的單環及雙環雜環衍生化合物取23個分別進行抗癌(人類大腸癌細胞SW480、COLO205及人類肺癌細胞H520)測試,資料顯示化合物31對H520細胞有較好的細胞毒殺效果(39%)。6個雙環雜環衍生化合物(35、38、39、49、50及52)對嘌呤核苷磷酸酶(purine nucleoside phosphorylase,PNP)的抑制表現,資料顯示39、49、50及52具有抑制效果,其中以化合物49 表現最佳(47.69%)。

英 文 摘 要
This study has synthesized two series of bicycloheterocyclic derivatives, 3-substituted-6-amino-1,2,4-triazolo[3,4-f][1,2,4]triazin-8(7H)-
ones and 5-amino-3-aryl-1,2,4-triazolo[4,3-d][1,2,4]triazines. The former includes 3-alkyl-, 3-aryl-, 3-alkylamino-, 3-arylamino- and 3-alkylsulfanyl-6-amino-1,2,4-trizolo[3,4-f][1,2,4]triazin-8(7H)-ones. The later is 3-alkyl-5-amino- and 5-amino-3-aryl-1,2,4-triazolo[4,3-d][1,2,4] triazines. We have obtained nineteen bicycloheterocyclic compounds in five types from both series.
The monocycloheterocyclic 3-amino-6-hydrazino-1,2,4-triazin-5(2H)-
one(4) reacted with acyl chlorides via nucleophilic substitution would afford 6-acylhydrazino (6-NHNHCOR) substituted compounds. Compound 4 condensed with aldehydes would gain 6-methylidenehydrazino (6-NHN=CHR) substituted compounds. Compound 4 underwent nucleophilic addition reaction with isothiocynates could give 6-(4-N-substitutedthiosemicarbazido) (6-NHNHCSNHR) substituted derivatives. We explored new processes to gain bicycloheterocyclic derivatives through different reaction modes of cyclization of above monocycloheterocyclic substituted compounds.
The new processes to synthesize 3-alkyl-6-amino- and 6-amino-3-aryl-1,2,4-triazolo[3,4-f][1,2,4]triazin-8(7H)-ones included (1) the sililated cyclization of 6-acylhydrazino substituted compounds, a rather convenient way to acquire high yield rate as well as purity of the products, (2) the nucleophilic substitution and then cyclization of 3-amino-6-bromo-1,2,4-triazin-5(2H)-one with acylhydrazines refluxed under DMSO solvent, which was an one-step reaction, (3) the cyclization of 6-methylenehydrazino substituted compounds catalyzed by Pb(OAc)4 or Br2/FeCl3, with products via Pb(OAc)4 being easier to purify and higher yield. The mechanisms of above reactions will also be proposed.
3-Alkylamino-6-amino- and 6-amino-3-arylamino-1,2,4-triazolo-
[3,4-f][1,2,4]triazin-8(7H)-ones could not be gained by cyclization of 6-(4-N-substitutedthiosemicarbazido) substituted derivatives; howerer, they could be obtained by nucleophilic aromatic substitution of sililated intermediate of 6-amino-3-thio(2H)-1,2,4-trizolo[3,4-f][1,2,4]triazin- 8(7H)-one reacted with alkylamine or arylamine.
6-Amino-3-alkylsulfanyl-1,2,4-triazolo[3,4-f][1,2,4]triazin-8(7H)-ones was obtained through nucleophilic substitution of 6-amino-3-thio(2H)-1,2,4-triazolo[3,4-f][1,2,4]triazin-8(7H)-one reacted with alkylbromide under methanoic ammonium. On the other hand, 5-amino-3-aryl-1,2,4-triazolo[4,3-d][1,2,4]triazines was successfully gained by sililated cyclization of 3-amino-5-acylhydrazino-1,2,4-triazines.
The synthesized products of monocycles and bicycloheterocycles in this study were tested on the bioactivity of anti-cancer properties against colon cancer SW480、COLO205 and human lung cancer cells H520. Compound 31 showed potent cytotoxicity(39%) against H520. Compounds 25, 38, 39, 49, 50 and 52 were evaluated on the inhibition of purine nucleoside phosphorylase (PNP), with 39, 49 and 52 owing the better inhibitory effects.

目 錄
誌 謝--------------------------------------------------- Ⅰ縮 寫--------------------------------------------------- Ⅱ
表目錄--------------------------------------------------- Ⅲ
圖目錄--------------------------------------------------- Ⅳ
壹、中文摘要--------------------------------------------- 1
英文摘要-------------------------------------------- 3貳、緒 論
一、導論---------------------------------------------- 5二、合成動機------------------------------------------- 18
參、合成方法、結構鑑定、結果與討論
一、合成方法大綱--------------------------------------- 19
甲、起始原料之合成略圖
乙、3-Alkyl-6-amino-與6-amino-3-aryl-1,2,4-triazolo-
[3,4-f][1,2,4]triazin-8(7H)-ones之合成略圖
丙、3-Alkylamino-6-amino-與6-amino-3-arylamino-
1,2,4-triazolo[3,4-f][1,2,4]triazin-8(7H)-ones
之合成略圖
丁、3-Alkylsulfanyl-6-amino-1,2,4-triazolo-
[3,4-f][1,2,4]triazin-8(7H)-ones之合成略圖
戊、5-Amino-3-aryl-1,2,4-triazolo-
[4,3-d][1,2,4]triazines之合成略圖
二、合成各論
甲、單環雜環1,2,4-triazine環上取代衍生化合物之合成
(一)6-(2-Acylhydrazino)-3-amino-1,2,4-triazin-
5(2H)-ones衍生化合物之合成﹑結構鑑定﹑結果與
討論------------------------------------------- 23
(二)3-Amino-6-(2-substitutedmethylenehydrazino)-
1,2,4-triazin-5(2H)-ones衍生化合物之合成﹑結構
鑑定﹑結果與討論-------------------------------- 30
(三)3-Amino-6-(4-N-substitutedthiosemicarbazido)-
1,2,4-triazin-5(2H)-ones衍生化合物之合成﹑結構
鑑定﹑結果與討論-------------------------------- 37
(四)5-(2-Acylhydrazino)-3-amino-1,2,4-triazines衍生
化合物之合成﹑結構鑑定﹑結果與討論-------------- 43
乙、雙環雜環6-Amino-3-substituted-1,2,4-triazolo-
[3,4-f][1,2,4]triazin-8(7H)-ones 衍生化合物之合成
(一)3-Alkyl-6-amino-與6-amino-3-aryl-1,2,4-triazolo-
[3,4-f][1,2,4]triazin-8(7H)-ones衍生化合物之合成、
結構鑑定、結果與討論----------------------------- 49
(二)3-Alkylamino-6-amino-與6-amino-3-arylamino-1,2,4-
triazolo[3,4-f][1,2,4]triazin-8(7H)-ones衍生化合
物之合成、結構鑑定、結果與討論------------------ 63
(三)3-Alkylsulfanyl-6-amino-與6-amino-3-arylsulfanyl-
1,2,4-triazolo[3,4-f][1,2,4]triazin-8(7H)-ones衍生
化合物之合成、結構鑑定、結果與討論-------------- 66
丙、雙環雜環5-Amino-3-aryl-1,2,4-triazolo-
[4,3-d][1,2,4]triazines衍生化合物之合成、結構鑑定、
結果與討論-------------------------------------- 74肆、實驗部分
一、儀器及試藥部分-------------------------------------- 82
二、合成部分-------------------------------------------- 86
甲、單環雜環1,2,4-triazine及其環上取代衍生化合物之製備
(一)起始原料之製備---------------------------------- 86
(二)6-(2-Acylhydrazino)-3-amino-1,2,4-triazin-
5(2H)-ones衍生化合物之製備---------------------- 88
(三)3-Amino-6-(2-substitutedmethylenehydrazino)-
1,2,4-triazin-5(2H)-ones衍生化合物之製備-------- 91
(四)3-Amino-6-(4-N-substitutedthiosemicarbazido)-
1,2,4-triazin-5(2H)-ones衍生化合物之製備-------- 98
(五)5-(2-Acylhydrozino)-3-amino-1,2,4-triazines
衍生化合物之製備------------------------------- 100
乙、雙環雜環6-Amino-3-substituted-1,2,4-triazolo-
[3,4-f][1,2,4]triazin-8(7H)-ones衍生化合物之製備
(六)3-Alkyl-6-amino-1,2,4-triazolo-
[3,4-f][1,2,4]triazin-8(7H)-ones衍生化合物
之製備------------------------------------------ 103
(七)6-Amino-3-aryl-1,2,4-triazolo-
[3,4-f][1,2,4]triazin-8(7H)-ones衍生化合物
之製備----------------------------------------- 105
(八)3-Alkylamino-6-amino-1,2,4-triazolo-
[3,4-f][1,2,4]triazin-8(7H)-ones衍生化合物
之製備----------------------------------------- 106
(九)6-Amino-3-arylamino-1,2,4-triazolo-
[3,4-f][1,2,4]triazin-8(7H)-ones衍生化合物
之製備----------------------------------------- 107
(十)3-Alkylsulfanyl-6-amino-1,2,4-triazolo-
[3,4-f][1,2,4]triazin-8(7H)-ones 衍生化合物
之製備----------------------------------------- 107
丙、雙環雜環5-Amino-3-aryl-1,2,4-triazolo-
[4,3-d][1,2,4]triazines衍生化合物之製備-------- 109
伍、生物活性測試----------------------------------------- 113
陸、參考文獻--------------------------------------------- 121柒、附錄------------------------------------------------- 124

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