設計與合成喹唑啉-2-酮衍生物作為潛能第五型磷酸二 酯酶抑制劑之可行性評估

Abstract

本論文以4-(4-胺苯基)-1-(4-溴苯甲基)-7-甲氧基喹唑啉-2-酮 (16) 的PDE4/5雙效抑制，及在主結構喹唑啉-2-酮的第六位置接上一個溴原子的化合物15a-b為先導化合物，期望能發展成具有選擇性的PDE5抑制劑，來治療臨床上，像是勃起功能障礙、良性攝護腺肥大等等疾病。為了進一步探討在主環第六位置接上溴原子的化合物的結構與活性關係，在這些目標化合物的合成策略中，主結構4-芳香基-喹唑啉-2-酮可經由一系列反應生成的格林納試劑，再與含溴的苯甲腈化合物以及氯甲酸甲酯進行合環反應獲得，目標化合物則由4-芳香基-喹唑啉-2-酮衍生物進行烷基化即可得到。根據體外酵素活性測試結果顯示，在主環第一位置氮上的苯甲基環，如果將拉電子基移到間位位置上，可維持對PDE5的抑制能力，但也會些微抑制PDE6，而同時在鄰位與對位上作拉電子基取代，發現對整體的抑制效果沒有太大的影響，但如果將其以其它疏水性基團如六元環作為取代，發現可以選擇性抑制PDE5。在第四位置苯環上則以對位胺基、甲胺基和間位甲氧基取代有較好的抑制效果，其立體障礙的大小也是影響的關鍵之一。而如果在第六位置置入碘原子取代，可以維持PDE5的抑制能力，但也增強了PDE4和6的抑制效果，足見此位置在對PDE5選擇性上扮演了重要的關鍵角色。此外，在第七位置上的修飾，得知此位置所能容忍的取代基大小有限，最後發現以三氟甲氧基的取代，不論在選擇性還是抑制程度上，都表現的非常卓越。綜觀來說，結合六元環和三氟甲氧基取代的化合物54a，是這一系列化合物中最強效的PDE5抑制劑。

4-(4-Aminophenyl)-1-(4-bromobenzyl)-7-methoxy-1H-quinazolin-2-one (16), a potential dual PDE4/5 inhibitor, and compounds 15a-b which contain bromo atom on the 6-position of 1H-quinazolin-2-one were chosen as lead compounds for this investigation as potential PDE5 selective inhibitors. These selective inhibitors may be used to treat clinical diseases, such as erectile dysfunction, benign prostatic hyperplasia, etc. To explore further structure-activity relationship, the main structure, 4-aryl-1H- quinazolin-2-ones, were prepared from phenylation, followed by the cyclization of bromo substituted o-aminobenzonitriles and methyl chloroformate. Final tartget compounds were synthesized from alkylation of 4-aryl-1H-quinazolin- 2-ones. According to preliminary result of in vitro enzyme inhibitory activity assay, if the electro-withdrawing group was introduced to the meta position on benzyl ring of the 1-position of main structure, the ability of inhibition on PDE5 will be maintained, but the inhibition of PDE6 will be slightly increased. However, it has no significant effect when the electro-withdrawing groups were placed to ortho and para position at the same time. Moreover, it also has been found that the replacement of other hydrophobic substitution on the 1-position like cyclohexylmethyl ring shows good selectivity on PDE5 with moderate potency. The amino, methylamine group on para and methoxy group on meta position in the benzene ring of 4-position of the main structure show better inhibiton, and the steric hindrance here also plays a vital role in this position. If the iodo atom was placed to the 6-position of the main ring, it will not only enhance the ability of inhibiton on PDE5, but also on PDE4 and 6. So it is reasonable to conclude that this position plays an important role in attaining selectivity on PDE5. Furthermore, the modification on 7-position indicated that it has limitless on the size of substitution here. Finally, the trifluoromethoxy group on 7-position lead to the amazing selectivity and inhibiton on PDE5.In summary, compound 54a with the substitution of trifluoromethoxy group and cyclohexylmethyl ring is the most potent PDE5 inhibitors in this series of compounds.