合成3α-Hydroxy-3β-methoxymethyl-5α-pregnan-20-one類化合物作為GABAA之抑制劑; Synthesis of  3α-Hydroxy-3β-methoxymethyl-5α-pregnan-20-one Derivatives for GABAA Modulators

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题名:	合成3α-Hydroxy-3β-methoxymethyl-5α-pregnan-20-one類化合物作為GABAA之抑制劑;Synthesis of 3α-Hydroxy-3β-methoxymethyl-5α-pregnan-20-one Derivatives for GABAA Modulators
作者:	張泊暐;Po-Wei Chang
贡献者:	中國醫藥大學：藥物化學研究所碩士班
关键词:	類固醇;荷爾蒙;γ-胺基丁酸;氯離子;steroid;hormone;GABA;chloroanion
日期:	2009-06-11
上传时间:	2009-08-13 09:37:21 (UTC+8)
摘要:	3α-hydroxy-3β-methoxymethyl-5α-pregnan-20-one 為新型的GABAA之異位調控劑，在先前文獻的3α-hydroxy-3β-methoxy- methyl-5α-pregnan-20-one structure-activity relationship，本實驗合成之3α-hydroxy-3β-methoxymethyl-5α-pregnan-20-one，其經動物藥理測試，因代謝快速，其每日給藥量皆>200 mg/day。因此，本實驗主要在改善其代謝速度。本實驗研究內容主分三部分，第一部分將3α-hydroxy-3β-meth-oxy-methyl-5α-pregnan-20-one C21位置加成piperazine，探討mono-substituted及di-substituted的方法。第二部分在C21位置延伸amino acid與guanidine等具有強hydrogen bonding之官能基。第三部分發明了以Cesium formate做為3α-bromo-3β-methoxy- methyl-5α-pregnan-20-one的水解反應試劑，其產物3α-hydroxy-3β-methoxy-methyl-5α-pregnan-20-one 做為在C21加成sugar的前驅物，以增加水溶性及hydrogen bonding，延長代謝。 Following the previous literature, 3α-hydroxy-3β-methoxymethyl-5α-pregnan-20-one derivatives were the new GABAA inhibitors. We were also synthesized 21-Imidazolyl-3α-hydroxy-3β-ethoxymethyl-5α-pregnan-20-one and investigated the reaction mechanism and bioactivity. When the bioactivity was determined the animal study, we found the amounts of daily dosage is more than 200mg/day. As a result, we will modified the skeleton of 3α-hydroxy-3β-methoxy-methyl-5α-pregnan-20-one derivatives to improve the metabolism by the intermolecular hydrogen bonding. This investigation contains three sections: In first section, we have synthesized the moni- and di- substituted 21-piperazinyl-3α-hydroxy-3β-methoxymethyl-5α-pregnan-20-one . In second section, 21-bromo-3α-hydroxy-3β-methoxy- methyl-5α-pregnan-20-one was treated with amino acid and guanidine to perform substituted reaction on the C-21 position. Finally, we developed a new hydrolysis ethodology by used HCO2Cs to give 21-hydroxy-3α-hydroxy-3β-methoxy- methyl-5α-pregnan-20-one. Then 21-hydroxy-3α-hydroxy-3β-meth-oxymethyl-5α-pregnan-20-one was reacted with β-D-Galactose to give the corresponding product β-D- galacto-pyranoside. Those 3α-hydroxy-3β-methoxymethyl-5α-pregnan-20-one derivatives will be perform the bioactivity study in the future work.
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