1-(烷氧苯基)-6-氟-7-二甲氨基-1,8萘啶-3-甲酰胺类衍生物的合成及活性

Synthesis and Activity Evaluation of 1-(2,4-bifluorophenyl)-6-fluoro-7-dialkylamino-1,8-naphthyridine-3-carboxamides

以-5-氟-2,6-二氯烟酰乙酸乙酯为起始原料,经缩合、亲核取代、环合、水解、酰化等9步反应合成了20个1(烷氧苯基)-6-氟-7-二甲氨基1,8萘啶-3-甲酰胺类衍生物,结构均经质谱和核磁氢谱确证.以S1647为阳性对照,采用放射性结合试验法测定目标化合物对顶端钠依赖性胆酸转运体(ASBT)的抑制活性.活性结果表明,多数目标化合物具有一定的ASBT抑制活性,其中化合物10c1在10μmol/L浓度下对ASBT的抑制率为67.9%,与阳性对照物S1647相当.初步构效关系表明,6位氟取代对活性不利,侧链长度以5~6个碳链长度为宜,链末端对称季铵盐形式对活性并无明显影响.

Twenty1-(2,4-bifluorophenyl)-6-fluoro-7-dialkylamino- 1,8-naphthyridine-3-carboxamides were sequentially obtained through a nine-steps process,such as condensation,substitution,cyclization, hydrolysis and acylation from ethyl-2,6-dichloro-5-fluoropyridine-3-acetoacetate.The inhibitory activity of these compounds was tested in vitrOagainst ASBT by a radioisotope-based assay with S -1647 as a positive control.Most of compounds demonstrated potency against ASBT transport of bile acids.Particularly,compound10c1 was found tOhave the best activity,resulting in 67.9 % inhibition of ASBT at10 μmol/L,which was equivalent tOthe positive control drug S -1647.The structure-activity relationship of these target compounds was summarized.Fluorine substituted at 6-position of the1,8-naphthyridine scaffold was considered unfavorable and 5~6 carbon chain lengths’ linker were suitable,while the symmetric quaternary ammonium salt form in the linker’end had nOsignificant effect on activity.