一种非肽CCK拮抗剂的设计和合成

Design and Novel Synthesis of a Nonpeptide Cholecystokynin Antagonist

缩胆囊素是肽类激素 ,在消化道和神经传导方面起重要作用。许多非肽类物质与缩胆囊素受体也有很强的亲合力 ,成为人们感兴趣的研究课题。该文用四氢嘧啶酮环系替代吡咯环 ,设计合成了非肽缩胆囊素拮抗剂 (+)RP6 6 80 3的类似物。合成反应以天冬酰胺叔丁酯为起始原料 ,先与苯甲醛形成亚胺 ,再与甘氨酸酰氯发生环化缩合 ,生成中间体 3-苯基 - 4-氨甲基羰基 - 5 -叔丁氧羰基四氢嘧啶酮 ,最后与间甲苯异氰酸酯反应 ,即得目标产物。以天冬酰胺叔丁酯计总收率为 42 %。

Cholecystokynin(cck) is a polypeptide hormone which plays an important role in the digestive tract where it predominantly interacts with cck A receptor,and also in the central nervous system where it essentially acts as a neurotransmitter through cck B type receptors.Some non peptide compounds also possess the affinity for cck receptors and become the subject of intense research.Herein the design and synthesis of similar compounds of the non peptide cck antagonist (+) RP66803 containing tetrahydropyrimidinone ring instead of pyrrolidine ring were reported.The synthesis started with asparagine t butyl ester,which reacted with benzaldehyde toform an imine.Treating the imine with glycine chloride led to coupling and cyclization to form an intermediate,3 phenyl 4 aminomethylcarbonyl 5 t butyl carbonyl tetrahydropyrimidinone,and then reacted with m tolylisocyanate to form the desired product in 42% overall yield(based on asparagine t butyl ester).