臺灣博碩士論文加值系統

以鉀離子通道促進劑cromakalim為引導化合物，在本研究中合成了一系列具有光學活性的六氫-苯駢喃[3,4-b][1,4]的衍生物（(+)-37a-c，(-)-38f-o及(-)-52），並以老鼠肝門靜脈和膀胱逼尿肌進行活性測試， 觀察其是否有抑制收縮的活性。

目標化合物中的(+)-37a-c為(4aR,10bS)-1,2,3,4a,5,10b-六氫-5,,5-二甲基-1-苯駢喃[3,4-b][1,4]-9((+)-41)的醯化產物，合成起始物環氧化合物(-)- 39是由6-氰基-2,2-二甲基-2H-1-苯駢喃經以Mn(salen)為催化劑的不齊氧化反應而來。接著以乙二醇胺( ethanolamine) 進行開環反應， 得到雙醇化合物(+)-40 。 再對雙醇中間體進行Mitsunobu 分子內環化， 則得到三環中間體 (+)-41 。化合物41分別與甲酸乙酸，丙酸和異丁醯氯反應則得到37a-c 。 本實驗室先前之研究發現(4aR,10bR)-N-苯甲醯1,2,3,4a,5,10b-六氫-5,,5-二甲-1-苯駢喃[3,4-b][1,4]-9(38e) 對膀胱具有選擇性的抑制收縮的活性。為了探討苯環上取代基的效應， 乃合成了化合物(-)-38f-o，化合物38f-n是由其(4a,10b)反式異構物((+)-50f-n)經鹼催化反應而得，化合物(-)-38o則是經由(-)-38j以三溴化硼進行去甲基化反應而得。目標化合物(-)-52為(-)-38e的類似物其合成是經由中間體(-)38b用鹽酸將其乙醯基水解後得到類化合物(-)-46，再與苯醯氯進行醯化反應而得。


依藥理活性結果38e對膀胱活性為 8.15 mM其選擇性(IC50,門靜脈/ IC50,膀胱 = 4.2倍) 。化合物38f-o在苯環上之不同取代基其對鉀離子通道活性有顯著影響，其中間位有甲基取代的38g對肝門靜脈有最高的活性(0.54mM)及選擇性( IC50 rato = 0.002) 。而對位有含未鍵接電子取代者對膀胱逼尿肌的活性較好， 如4-溴衍生物38k ( 2.0 mM )及4-基衍生物38o (3.8 mM)，38o之選擇性最高(IC50 ratio = 19.6)，苯磺化合物52在膀胱之活性僅比38e略低(11.6 mM)但選擇性較高(IC50 ratio =10.3)。

As rigid analogs of the prototype potassium channel opener (POC) cromakalim, a series of optically active hexahydro benzopyrano[3,4-b][1,4] oxazine derivatives have been synthesized. The PCO activity of target compounds were evaluated in vitro with preparations of spontaneous contracting rat portal vein and KCl-stimulated rat detrusor strip.

Target compounds (+)-37a-c are acylation products of (4aR,10aS)-1,2,3,4a,5,10b-hexahydro-5,5-dimethyl-1-benzopyrano[3,4-b][1,4] oxazine-9-carbonitrile ((+)-41). The starting epoxide (-)-39, prepared form 6-cyano-2,2-dimethyl-2H-1-benzopyran via Mn(salen) catalyzed asymmetric epoxidation, was subjected to ring-opening by 2-aminoethanol to give the diol intermediate (+)-40. Compound (+)-40 underwent intramoleculor cyclization under Mitsunobu condition to form the tricyclic intermediate (+)-41. Acylation of 41 with acetic formic anhydride, propionic anhydride, and isobutyryl chloride respectively, provided the target compounds (+)-37a-c. Earlier studies in our laboratory resulted in the identification of (4aR,10aR)-N-benzoxyl-1,2,3,4a,5,10b-hexahydro-5,5-dimethyl-1-benzopyrano[3,4-b][1,4]oxazine-9-carbonitrile ((-)-38e) as a bladder-selective potassium channel opener. To study the effects on PCO activity of different substitutents on the benzene ring of 38e, compounds (-)-38f-o were synthesized. Compound 38f-n were prepared from their corresponding (4aS,10aR)- or trans isomers (+)-50f-n. Compound 38o was obtained form 38j via O-demethylation with boron tribromide. Compound 52, the sulfonamide analog of amide(-)-38e, was obtained form 38b via hydrolysis with HCl and the subsequent reaction with benzenesulfonyl chloride.

Among the target compounds, 38g with a meta-methyl - substituent showed the highest potency (IC50 = 0.54 mM ) and selectivity (IC50, portal vein / IC 50,bladder =0.002) on the portal vein. Compounds with para-substituents having lone-pair electrons showed improved activity on the bladder, such as the 4-bromo analog 38k (IC50,bladder = 2.0 mM; IC50 ratio = 4 ) and the 4-OH analog 38o (IC50,bladder = 3.8 mM; IC50 ratio = 19.6). Benzenesulfonamide 52 was found to be bio-isosteric with benzamide 38e, with slightly lower IC50 (11.6 mM) and higher selectivity (IC50 ratio = 10.3).

中文摘要 1
英文摘要 3
一‧背景及動機 6
二‧結果與討論 26
化學合成 26
藥理 39
三‧結論 43
四‧實驗部分 45
溶劑及藥品來源 45
一般儀器及方法 46
合成步驟 49
藥理實驗 79
五‧參考文獻 81
六‧附圖 89
圖 目 錄


圖1: 鉀離子通道促進劑與心肌或平滑肌細胞之間的電生理效應 9
圖2: Cromakalim 類似化合物之結構通式14
圖3: Cromakalim的X-光繞射晶體結構25
圖4: 化合物37a的X-光繞射晶體結構28
圖5: 化合物38k的X-光繞射晶體結構34
圖6: 化合物38n的X-光繞射晶體結構35
圖7: 51e和38e分子最低能量構形36
表 目 錄

表一:化合物37a-c及其相關化合物影響老鼠肝門靜脈和膀胱逼尿
肌收縮的藥理活性41
表二:化合物38e-f和化合物52抑制老鼠肝門靜脈和膀胱逼尿肌
縮的藥理活性42
路 徑 目 錄

路徑1: 目標化合物37a-c的合成27
路徑2: 化合物38a-e的合成30
路徑3: 化合物47的合成31
路徑4: 目標化合物38e-o的合成33
路徑5: 目標化合物52的合成之一 37
路徑6: 目標化合物52的合成之二 38

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