臺灣博碩士論文加值系統

中文摘要
本研究之目的旨在探討過去本研究室所開發之2-phenyl-1,8-naphthyridin-4-one (PN) 類化合物 : 此論文重點分成兩部份，其中第一部份著重於尋找確切穩定合成2-phenyl-1,8-naphthyridin-4-one之條件，解決350 ℃嚴苛反應條件，改善過去後繼者無法大量合成之困難，著者利用傳統給熱，於沙浴中反覆檢討加熱方式而獲得穩定合成條件，合成一系列PN衍生物。另一方面試圖以微波照射解決產率不佳問題，經反覆實驗證實，CEM 300 Walt微波儀器無法順利反應。也試圖利用本研究室過去所用之合成方法，開發有別於一般PN類化合物合成方法。
合成之化合物ㄧ些為文獻已載化合物，ㄧ些為未載化合物，提供這些化合物對HL-60、A549、HA22T及NCI-H226等癌細胞株抑制活性的探討，供建立完整SAR，並發現化合物28及34具有進一步研究的價值。
第二部份則為改善PN類化合物溶解度不佳問題，過去PN類化合物雖具有強力的細胞致毒活性，但是其脂溶性皆偏高( log P 7~8之間) 以致於應用困難，於是著者在本研究中就將所合成的主要中間體PN進一步衍生成可形成sodium salt之前藥(prodrugs)以供動物試驗之用。著者成功合成化合物42等前藥，以供將來PK試驗。

Astract
The purpose of this research was to seek for the accurately synthetic method and condition of the PN compounds that our laboratory had developed in the past.
This paper was divided into two parts with emphasis. The first part was focused on the way of the heat. The traditional heat was used with the sand bath, and the stable synthetic condition was obtained. In this condition, a series of PN compounds were synthesized. On the other hand, the microwave was used for attempting to enhance the yield. Confirmed after repeated experiments, the CEM 300 Walt instrument was not responed for improvements of the severe synthetic condition . The synthetic methods, our laboratory used in the past, were utilized to substitute for the general synthetic method of PN compounds in this study.
In this study, some compounds were known in previous papers ; some were not published. The cytotoxicity of compounds for HL-60、A549、HA22T and NCI-H226, were discussed in this study. The data was used to establish a complete SAR. The compounds, 28 and 34, were discovered for the further development.
The emphasis of the second was to solve the problem for the poor solubility of PN compounds. Although the PN compounds possessed strong cytotoxicity for the test in vitro, the PN compounds was too lipophilic to use. For the reason, the prodrugs of PN compounds were further synthesizd as the sodium salt derivatives. The prodrug compound, 42, was synthesized successfully for the PK test by the author.

目錄
中文摘要-------------------------------------------------------------------------1
英文摘要-------------------------------------------------------------------------2
第一章 緒論
第一節 2-Phenyl-1,8-naphthyridin-4-one之研究概況與背景---------- 3
第二節 微管(Microtubulin)簡介--------------------------------------------8
第三節 2-PQ類緣衍生物合成方法簡介---------------------------------11
第四節 研究目的與動機----------------------------------------------------17
第二章 結果與討論
第一節 化學合成-------------------------------------------------------------18
Substituted ethyl benzoylacetates (7-12)之合成---------------19
2-Arylpyrido[1,2-α]pyrimidin-4-ones (17-26)之合成-------20
化合物22之結構鑑定--------------------------------------------21
化合物17-26之合成機轉----------------------------------------25
2-Aryl-1,8-naphthyridin-4(1H)-ones (27-35)之合成----------26
化合物32之結構鑑定--------------------------------------------27
N-(5-Chloropyridine-2-yl)-3-fluorobenzamide (38)-----------37
7-Chloro-2-(3''-fluorophenyl)pyrido[1,2-α]pyrimidin-4-one-3-
carboxylate (40)之合成--------------------------------------------38
第二節 水溶性前藥類衍生物之合成-------------------------------------44
第三節 利用微波照射方法改良反應-------------------------------------50
第四節 藥理活性試驗結果-------------------------------------------------55
Table 1. Cytotoxicity for compounds 27-34 against HL-60、A549、HA22T、NCI-H226---------------------------56
第三章 結論--------------------------------------------------------------59
第四章 實驗部分
第一節 試藥與溶媒--------------------------------------------------------61
第二節 重要儀器-----------------------------------------------------------65
第三節 藥理試驗方法-----------------------------------------------------66
第四節 化合物之製備
Substituted ethyl benzoylactates (7-12)之合成---------------69
2-Arylpyrido[1,2-α]pyrimidin-4-ones (17-26)之合成------71
2-Aryl-1,8-naphthyridin-4(1H)-ones (27-35)之合成---------81
圖譜
化合物17之IR、NMR圖譜----------------------------------95
化合物18之質譜、IR、NMR圖譜--------------------------96
化合物19之質譜、IR、NMR圖譜--------------------------98
化合物20之質譜、IR、NMR圖譜-------------------------100
化合物21之IR、NMR圖譜---------------------------------102
化合物22之質譜、IR、NMR圖譜-------------------------104
化合物23之質譜、IR、NMR圖譜-------------------------106
化合物24之質譜、IR、NMR圖譜-------------------------107
化合物25之質譜、IR、NMR圖譜-------------------------109
化合物26之IR、NMR圖譜--------------------------------111
化合物27之IR、NMR圖譜--------------------------------113
化合物28之質譜、IR、NMR圖譜------------------------114
化合物29之IR、NMR圖譜--------------------------------115
化合物30之質譜、IR、NMR圖譜------------------------116
化合物31之IR、NMR圖譜--------------------------------118
化合物32之質譜、IR、NMR圖譜------------------------120
化合物33之IR、NMR圖譜--------------------------------124
化合物34之質譜、IR、NMR圖譜------------------------126
化合物40之質譜、IR、NMR圖譜------------------------128
化合物42之IR、NMR圖譜--------------------------------130
參考文獻---------------------------------------------------------132

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