| 摘要: | 幾年前本研究所首次合成 1-benzyl-3-(5?-hyroxymethyl-2?-furyl) indazole (YC-1)，並經抗血小板活性試驗，發現其是不經由 NO (NO-independent) 而直接活化 soluble guanylate cyclase (sGC)，由於其機轉特殊，所以本論文是以YC-1 bioisostere 即1-benzyl-3-(5''''-hyroxymethyl-2''''-furyl)benzimidazole (9) 為 先導化合物合成一系列其類緣化合物供作抗血小板活性試驗。 在 cupric acetate 存在下，5-acetoxymethyl-2-furfural (1)與 o-phenylenediamine (2) 經縮合反應，可得主產物2-(5''-hyroxymethyl-2''-furyl) benzimidazole (3) 及副產物1-5''-hydroxymethyl-2''-furyl)methyl-2-(5''''-hyroxymethyl-2''''-furyl)benzimidazole (4)。主產物再與 benzyl chloride 反應，即可得1-benzyl-3-(5''''-hyroxymethyl-2''''-furyl) benzimidazole (9)，以化合物9 為先導化合物加以修飾，可合成一系列其類緣化合物10~12, 14, 17,18, 20, 23, 26和32~35 (32a~35a, 32b~35b)。 由抗血小板活性試驗結果，發現先導化合物9對AA, collagen 和PAF所誘發血小板凝集具有相當明顯的抑制活性，但對於thromin所誘發之凝集無抑制作用。當化合物9和33之 N?-benzyl group 消失時 (化合物3 和31)，其抗血小板活性之形式就有明顯的改變了，雖然它們對 collagen 所誘導之血小板凝集抑制仍然維持在與化合物9和33相同的強度，但是對AA 和 PAF所誘導之血小板凝集抑制活性卻大幅減弱。若化合物9的benzyl group之對位被F或Cl取代，得化合物10, 11，發現對 collagen 和 PAF所誘導之血小板凝集並沒有相當意義的抑制作用的改變，但是降低對AA 所誘導之血小板凝集的抑制作用。將化合物9, 10, 11 的第6位導入 fluoro group，分別得到化合物33, 34, 35 其所呈現的活性形式與相對應的化合物9, 10, 11相似，但是強度均稍微減弱。然而先導化合物9 之furan ring 上第5位之-CH2OH group 轉變為methyl group 得到化合物26 時，則N?-benzyl group 衍生物共同的抗血小板活性形式就改變了，只對AA 和 collagen 所誘發血小板凝集呈現明顯的活性而已，對PAF所引起的凝集抑制活性則大幅降低。 從以上之結構與活性的檢討中建立了下列初步的構效關係(SAR) : (1) 先導化合物9具有類似YC-1之抗血小板活性之形式，但強度稍弱。 (2) 先導化合物9 之 N ?-benzyl group上或第6位上有鹵素原子取代時 (如 10~12 和 33~35)，對抗血小板凝集活性都不 會有顯著的影響。 (3) 化合物之 N ?-benzyl group 及 5''''-CH2OH group 之-OH 是維持 類似 YC-1 抗血小板凝集活性形式的必要基團，當 N?-benzyl group 及5''''-CH2OH group 之-OH 消失時 (例如 3, 26, 31) 其 活性形式有明顯的變化。; 1-Benzyl-3-(5''-hydroxymethyl-2''-furyl)indazole (YC-1) was synthesized in our laboratory a few years ago. Biological studies revealed that YC-1 exhibited antiplatelet activity in vitro through NO-independent activation of soluble guanylate cyclase (sGC). Due to the unique mechanism of action as an antiplatelet agent, 1-benzyl-2-(5''''-hydroxymethyl-5''''-furyl)-benzimidazole (9), a YC-1 bioisostere, was used as a lead compound to pepare a series of its analogs for searching more active potent compound with the same mechanism of antiplatelet activity. 5-Acetoxymethyl-2-furfural (1) was condensed with o-phenylenediamine (2) in the presence of cupric acetate to afford 2-(5''-hydroxymethyl-2''-furyl)benzimidazole (3) as the major product and 1-(5''-hydroxymethyl-2''-furyl)methyl-2-(5''''-hydroxymethyl-2''''-furyl)- benzimidazole (4) as a minor product. The former product was reacted with benzyl chloride to yield 1-benzyl-2-(5''''-hydroxymethyl-2''''-furyl)- benzimidazole (9). Using compound 9 as the lead compound, a series of its derivatives 10~12, 14, 17, 18, 20, 23, 26 and 32~35 (32a~35a, 32b~35b) was synthesized. The antiplatelet activities of lead compound (9) inhibited significantly the aggregation induced by AA-, collagen- and PAF, but it did not inhibit thrombin-induced aggregation . When removing the N 1-benzyl group of compound 9 and 33 to obtain compound 3 and 31 respectively, it would be change the pattern of antiplatelet activity, only inhibited collagen-induced platelet aggregation, but it did not inhibit AA- and PAF induced aggregation. When introducing F and Cl atoms into the para position of the benzyl group of 9 to obtain 10 and 11 respectively. Such modification did not significantly affect the potency against collagen- and PAF-induced platelet aggregation, but resulted in reduction of the potency against AA-induced aggregation. The addition of fluoro atom at 6-position of 9, 10 and 11 had no significant affect on their antiplatelet activity too. However, when the 5''''-CH2OH group of compound 9 was replaced by methyl group, it resulted in compound with the different antiplatelet pattern, which was only inhibited AA and collagen-induced platelet aggregation, but it did not inhibit PAF-induced aggregation. Summarizng the above findings, led to the establishment of the following prelimina |
