支氣管擴張劑 BDTI 類似物之合成研究
Synthesis of BDTI Analogues as Brinchodilator
中文摘要
支氣管擴張劑BDTI 類似物之合成研究
支氣管擴張劑可做為呼吸道阻塞或氣喘的治療與預防藥物，依藥理作用原理可分為 adrenergic drugs，antimuscarnic drugs，glucorticosteroids，antihistamine
drugs，phosphodiesterase inhibitors，leukotriene antagonists 等六大類。理想交感神
經興奮之支氣管擴張劑應對β2 有選擇性，避免 β1 興奮而引起心悸副作用發生。具選擇性交感
神經β2 興奮之支氣管擴張劑有 metaproterol (3)、terbutaline (4)、salbutamol (5) 等均屬 phenylethylamine 衍生物。
本研究室發現BDTI (1-Benzyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline) (16)具 β2 選擇性支氣管擴張作用，其化學構造屬isoquinoline 衍生物，但卻隱含 phenylethylamine 部分，於C-1 有 benzyl 取代基，而 C-1 的立體配位對藥效十分重要，本研究室曾發現 R(-)- BDTI (18) 之支氣管擴張為 S(+)-BDTI (19)的 168 倍，可見 benzyl 取代對其活性具有重要 的影響。另曾發現BDTI (16)對交感 B2 受體興奮選擇性比 salbutamol (5)為高。今擬以 BDTI 為先導化合物進行化學構造修飾，並合成一系列衍生物 22、 25、 28、 31、 34、 37、 40、
43、 46、 49、 52 和 55；研討其化學構造變化對藥效之影響。
BDTI 及其衍生物係以不同的 phenylacetic acid 類與 phenylethylamine 類經縮合反應而成 醯胺類，再由此不同醯胺為中間體，經傳統的Bischler - Napieralski 反應以 phosphorus oxychloride 為催化劑環化，再經 sodium borhydride 還原，可得 1-substituted
isoquinolines，再經氫溴酸去除甲基即可得具 catechol isoquinolines 衍生物共 12 種 22、
25、 28、 31、 34、 37、 40、 43、 46、 49、 52 和 55。各別化學構造均經融點測定、紅外 光譜、氫譜、碳譜、質譜及元素分析等確認。
經天竺鼠離體之氣管平滑肌鬆弛作用顯示化合物34、 40 和 43 皆比 BDTI (16)為佳；再以化 合物 34 和 40 進行天竺鼠離體之心肌收縮力實驗，結果對心肌收縮力並無明顯增強，因此 34、 40 和 43 對氣管平滑肌鬆弛具有選擇性作用。
英文摘要
SYNTHESIS OF BDTI ANALOGUES AS BRONCHODILATOR
Bronchodilators are used for the treatment and prevention of airway obstructive and asthma, and they can be classified into six categories including adrenergic drugs、antimuscarinic drugs、glucorticosteroids、antihistamine
drugs 、phosphodiesterase inhibitors and leukotriene antagonists. An ideal bronchodilator should have high selectivity onβ2 adrenergic receptor and avoid tachycardia by stimulation onβ1receptor. Selective adrenergic bronchodilators usedclinicallyare metaproterol (3)、terbutaline (4) and salbutamol (5), which are belonging to the phenylethylamine derivatives.
BDTI (1-Benzyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline) (16), was found recently to be a selective adreneregicβ2 agonist in our laboratory. Benzyl substituted at C1 on isoquinoline nucleus made a greater contribution to theβ2 effect. R(-)BDTI (18) was about 168 times more active than its enantiomers, S(+)BDTI (19) to stimulateβ2 adrenergic receptor. Furthermore, BDTI (16) is more selective than salbutamol (5) on the stimulation of adrenergicβ2 and β1 receptors.
In order to study the structure and activity relationship (SAR) of these compounds, a series of BDTI analogues, 22、25、28、31、34、37、40、43、46、49、52 and 55 are prepared and their bronchodilation activity were be evaluated.
BDTI (16) and their analogues were prepared by the usual procedure for the synthesis of isoquinolines. Condensation of 3,4-dihydroxyl acetyl chloride and various phenylethylamines gave the benzylamides, which were then cyclized by Bischler-Napieralski reaction catalyzed by phosphorus oxychloride to give dihydroisoquinolines. Sodium borhydride reduction of the dihydroisoquinolines and then O-demethylation by HBr yielded the target analogues
22 、25 、28 、31 、34 、37、40、43、46、49、52 and 55 . All these analogues were characterized by M.P. , IR, 1H-NMR, 13C-NMR, mass spectrometry and element analysis. Fifteen compounds were evaluated by the isolated trachea preparation from guinea-pig to determine the smooth muscle relaxation effects. The result indicated that compounds 34、 40 and 43 showed more potent than BDTI (16) to relax the trachea smooth muscle. 34 and 40 also evaluated their inotropic effect by the cardiac muscle isolated from guinea-pig . Compounds 34 and 40 showed a selective relaxation effect in trachea smooth muscle without great stimulation on trachea muscle.
