| Summary: | 碩士 === 台北醫學院 === 藥學研究所 === 88 === Abstract
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.
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