設計與合成4-芳香基-1-苯甲基喹唑啉酮衍生物作為第四型與第五型磷酸二酯酶雙效抑制劑

Abstract

本實驗室在之前的研究發現1-（4-溴苯甲基）-4-（3-氯苯基）-7-甲氧基喹唑啉酮（24）對第四與第五型磷酸二酯酶具雙效抑制劑的表現，為了深入探討第四與第五型磷酸二酯酶雙效抑制的結構與活性關係研究以化合物24作為先導化合物並合成一系列4-芳香基-1-苯甲基喹唑啉酮衍生物。在這些目標化合物的合成策略中，4-芳香基-喹唑啉酮衍生物經由化合物35與鎂反應生成的格里納試劑與化合物30與31進行合環反應得到。目標化合物經由4-芳香基-喹唑啉酮衍生物與4-溴苯基溴進行縮合反應得到。 在這些目標化合物中，化合物37b、37c、37e與37j展現比化合物24更卓越的磷酸二酯酶雙效性抑制效果。根據結構與活性關係研究的分析，在喹唑啉酮第四位置上芳香基的第三與第四位置獲得官能基的特徵包含小的結構立體效應、強大的推電子基與扮演氫鍵提供者明顯地增強對磷酸二酯酶雙效性能力與其他磷酸二酯酶的選擇性。此外，在探索喹唑啉酮的第1位置取代基對於雙效型抑制劑的結果中，官能基的脂溶性有著有利的影響對於第五型磷酸二酯酶的抑制能力與對其他磷酸二酯酶的選擇性。 此外，在化合物37b與37c的主結構喹唑啉酮第六位置接上一個溴原子進行修飾所合成之化合物48b與48a，化合物48b與48a出人意料地增強了對於抑制第五型磷酸二酯酶並且展現對於其他磷酸二酯酶卓越的選擇性在臨床上與目前知名的第五型磷酸二酯酶抑制劑相較之下。 其他的新穎化合物1-（4-溴苯甲基）-4-（3-氯苯基）-3-（2-羥乙基）-7-甲氧基喹啉酮（26），經由多個步驟合成包含酸水解經由格里納試劑與化合物30反應產生的中間體得到化合物49、化合物49與4-溴苯醛進行亞胺還原反應產生化合物50與化合物50與γ-丁內酯經由克諾維納蓋爾縮合反應的環化反應獲得化合物26。結果顯示化合物26展現強效抑制對於第四型與第五型磷酸二酯酶而且對於第七型磷酸二酯酶具附加抑制效果。因此，化合物26是被認為具潛力的先導化合物進行更進一步的最佳化修飾在發展第四型、第五型與第七型磷酸二酯酶抑制劑。

In our previous investigation, 1-(4-bromobenzyl)-4-(3-chlorophenyl)-7-methoxy-1H-quinazolin-2-one（24）has been identified as a dual PDE4 and PDE5 inhibitor. to explore further structure-activity relationship taking 24 as lead compound and synthesized a series of 4-aryl-1-benzyl-1H-quinazolin-2-ones were. In the synthetic strategy leading to targeted compounds, 4-aryl-1H-quinazolin-2-ones were prepared from Grignard reagent, obtained by a reaction of 35 and magnesium, following a cyclization with 30 and 31. Targeted compounds were obtained by a condensation of 4-aryl-1H-quinazolin-2-ones and 4-bromobenzyl bromide. Among them, 37b, 37c, 37e and 37j displayed superior activities of dual PDE 4/5 inhibitiory activity by comparing with 24. On the basis of SAR analysis, the C-3’ and C-4’ position of aryl group attached to the C-4 of 1H-quinazolin-2-one resulted in a characteristic features with small steric effect, strong electron-donating group and hydrogen bond donors obviously favor dual PDE 4/5 inhibitions and selectivity over other PDEs. Besides, to investigate the effect of the C-1 substituent of 1H-quinazolin-2-one on dual inhibitors, it demonstrated that the lipophilicity of functional groups have the favorable effect with PDE5 inhibitory activity and selectivity over other PDEs. Furthermore, compound 37b and 37c were induced a bromo atom at the C-6 of 1H-quinazolin-2-one to generate 48b and 48a. Surprisingly, 48a and 48b illustrated the potent activity against PDE5 and better selectivity toward other PDEs in compared with current known selective PDE5 inhibitors in the clinics. Another novel class of compound, 1-(4-bromobenzyl)-4-(3-chlorophenyl)-3-(2-hydroxyethyl)-7-methoxy-1H -quinolin-2-one（26）, was synthesized via multiple steps including the acid hydrolysis of the intermediate, maded by the reaction of Grignard reagent and 30 to provide 49, the imine reduction of 49 and 4-bromobenzaldehyde to provide 50 and the cyclization of 50 with γ-butyrolactone via Knoevenagel condensation to obtain 26. In the result, 26 exhibited potent inhibitions against PDE4/5 and the additional inhibition against PDE7. Therefore, 26 is considered as a potential lead for further optimizations in the development of PDE4, PDE5 and PDE7 inhibitors.