新型N1-取代-1,8-萘啶-3-甲酰胺类ASBT抑制剂的设计、合成及活性研究  

Design, synthesis, and evaluation of N-(3,5-difluorophenyl)-1-(alkoxyphenyl)-7-dimethylamino-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamides as inhibitors of ASBT

作　　者：赵跃[1] 高梦远 刘洪涛[1,3] 李文燕[2] 何红伟[1] 王菊仙[1] ZHAO Yue;GAO Meng-yuan;LIU Hong-tao;LI Wen-yan;HE Hong-wei;WANG Ju-xian(Organic Synthesis Chamber,Institute of Medicinal Biotechnology,Chinese Academy of Medical Sciences&Peking Union Medical College,Beijing 100050,China;College of Chemistry and Material Science,Hebei Normal University,Shijiazhuang 050024,China;Department of Pharmacy,Hebei General Hospital,Shijiazhuang 050051,China)

机构地区：[1]中国医学科学院北京协和医学院医药生物技术研究所有机合成室,北京100050 [2]河北师范大学化学与材料科学学院,石家庄050024 [3]河北省人民医院药学部,石家庄050051

出　　处：《中国医药生物技术》2018年第4期305-312,共8页Chinese Medicinal Biotechnology

基　　金：国家自然科学基金(81473098、1473099);河北省自然科学基金(H2018307055)

摘　　要：目的设计、合成新型N1-取代-7-N,N-二甲氨基-4-氧代-1,4-二氢-1,8-萘啶-3-N-(3,5-二氟苯基)甲酰胺类化合物,测定其对顶端钠依赖性胆酸转运体(ASBT)的抑制活性,考察N1位取代基对化合物活性的影响。方法以2,6-二氯烟酰乙酸乙酯为起始原料,经缩合、亲和取代、环合、水解等9步反应制备目标化合物,其结构均经质谱和核磁氢谱分析确证。以S-1647为阳性对照,利用放射性结合试验(RBA)法测定目标化合物的ASBT抑制活性。结果合成了N1-取代-7-N,N-二甲氨基-4-氧代-1,4-二氢-1,8-萘啶-3-N-(3,5-二氟苯基)甲酰胺类化合物48个,活性结果表明目标化合物均具有较好的ASBT抑制活性,其中7个化合物10b_2、10c_3、10c_6、10d_2、10d_3、10d_6和10d_7在10μmol/L浓度下对ASBT的抑制率均大于90%,抑制活性明显高于阳性对照物S-1647(76.1%)。结论目标化合物中N1位连接链的长度对活性有较大的影响,当烷基链为5～7个碳原子时化合物的ASBT抑制活性较好,其中烷基链的碳原子数为7的化合物10d的ASBT抑制活性最好;连接链末端为季铵盐取代的化合物ASBT抑制活性明显优于叔胺取代的化合物。Objective To design,synthesize and evaluate N-(3,5-difluorophenyl)-1-(alkoxyphenyl)-7-dimethylamino-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamides as inhibitors of the apical sodium-dependent bile salt transporter(ASBT).Methods The target compounds were synthesized from ethyl nicotinoylacetate,via condensation reaction,affinity substitution reaction,cyclization reaction,hydrolysis reaction and other nine-step reactions.Their structures were confirmed by MS and 1H-NMR.The ASBT inhibitory activity of the target compound was determined using the radioactive binding assay(RBA)method with S-1647 as a positive control.Results Forty-eight N-(3,5-difluorophenyl)-1-(alkoxyphenyl)-7-dimethylamino-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamides were synthesized and evaluated activity against ASBT.Most of the newly synthesized derivatives exhibited ASBT inhibitory activity and eighteen of them showed better activity than the positive control S-1647(76.1%).In particular,compounds 10b2,10c3,10c6,10d2,10d3,10d6 and 10d7 exhibited excellent potency against ASBT with more than 90%inhibition at 10μmol/L.Conclusion The length of N1 position linker in the target compound has a great influence on the activity.When the alkyl chain has 5-7 carbon atoms,the ASBT inhibitory activity of the compound is better,and compound 10d with 7 carbon atoms in the alkyl chain has best ASBT inhibitory activity.The ASBT inhibitory activity of the quaternary ammonium salt-substituted compound at the end of the linker linkage is significantly better than that of the tertiary amine-substituted compound.

关 键 词：化学技术 合成 N1-取代-7-N N-二甲氨基-4-氧代-1 4-二氢-1 8-萘啶-3-N-(3 5-二氟苯基)甲酰胺 顶端钠依赖性胆酸转运体 抗胆固醇血症药 

分 类 号：R91[医药卫生—药学]