中樞神經興奮性化合物之合成研究

Abstract

第一部分 乙二型興奮劑檢驗標準品之合成 近年在臺灣發現以化合物1 (飆妥巴胺，buctopamine) 或化合物2 (苯乙胺醇A，phenylethanolamine A) 違法替代萊克多巴胺 (ractopamine) 作為「瘦肉精」。因此，本研究旨在合成高純度化合物1及化合物2供定性定量檢驗之標準品。化合物1由 4-hydroxyacetophenone經四步合成，總產率為50%；而化合物2由1-methyl-3-phenyl-propylamine經三步合成，總產率為30%。 第二部分10-Desmethyltetrabenazine (10-dmTBZ) 衍生物之合成及藥理活性研究 Tetrabenazine 是第一個也是唯一用於治療亨丁頓氏症的藥物，其右旋化合物藥效較左旋化合物強，在體內代謝成具活性之dihydrotetrabenazine。化合物(+/-)-3以(+)-2,3-dibenzoyl tartaric acid進行光學分割可得到化合物(+)-3；而隨之留下的化合物(-)-3，可經由異構化反應再次得到(+/-)-3。以化合物(+)-3為起始物，可合成得到化合物(+)-4、(+)-5與(+)-6。化合物(+/-)-7經還原反應可得到化合物(+/-)-C8。在這些10-dmTBZ衍生物中，化合物(+)-3、(+)-4及(+)-6對於第二型囊泡單胺轉運體有高親合力(Ki < 10 nM)。此外，由動物行為測試中發現，(+)-3可有效減低對小鼠自我給予安非他命之行為。

Part 1 Synthesis of Potential beta-2 Receptor Agonists as Reference Standards Recenly, compound 1 (buctopamine) and compound 2 (phenylethanolamine A) were illegally used as alternatives of ractopamine for growth promotion of livestock in Taiwan. Therefore, it is necessary to obtain compound 1 and compound 2 in high purity as reference standards for qualitative and quantitative analysis. Starting from 4-hydroxyacetophenone, compound 1 was prepared in four steps in an overall yield of 50%. Compound 2 was prepared from 1-methyl-3-phenyl-propylamine in three steps in an overall yield of 30%. Part 2 Synthesis and Pharmacological Activities of 10-Desmethyltetrabenazine (10-dmTBZ) Derivatives (+/-)-Tetrabenazine ((+/-)-TBZ) was the first and only drug used clinically to treat Huntington’s disease. The (+)-TBZ was more potent than (-)-TBZ and dihydrotetrabenazine (DTBZ) was the major active metabolite of TBZ. Compound (+)-3 was obtained by optical resolution of (+/-)-3 with (+)-2,3-dibenzoyltartaric acid, and (-)-3 could be epimerized to give (+/-)-3. Compounds (+)-4, (+)-5 and (+)-6 were synthesized starting from (+)-3. The (+/-)-7 was reduced to afford (+/-)-8. Among these 10-dmTBZ derivatives, (+)-3, (+)-4 and (+)-6 had high binding affinity to VMAT2 (Ki < 10 nM). It is found that (+)-3 effectively decreased d-methamphetamine self-administration in mouse behavior study.