文档介绍：广东药学院硕士研究生学位论文
Study on the Synthesis of the Dipeptidyl
Peptidase-Ⅳ Inhibitor K579

Name: Tan Hong’mei
Supervior: Associate Professor Ma Yuzhuo
ABSTRACT
Type-2 diabetes mellitus is a chronic metabolic disease and a growing global public
health concern. In the world, more than 285 million adults and children have diabetes.
Current oral treatment modalities for type-2 diabetes are aimed at suppressing hepatic
glucose output, stimulating insulin release, mitigating glucose absorption, and increasing
peripheral glucose utilization. Inhibition of the dipeptidyl peptidase-4 (DPP-4), a member
of the prolyl oligopeptidase family of serine protease, prolongs and enhances the activity of
incretins that play an important role in insulin secretion and blood glucose control
regulation. Inhibition of DPP-4 enzyme by small molecules has emerged as one of the key
approaches for the treatment of type-2 diabetes. A large number of DPP-4 inhibitors have
been reported in the literature.
K579, [(S)-1-[4-methyl-1-(2-pyrimidinyl)-4-piperidylamino]acetyl-2-pyrrolidine carb
onitrile], is a DPP-4 inhibitor discovered by researchers at Kyowa Hakko Kyogo. It didn't
only have improved chemical stability but also a longer-lasting action. That long-lasting
action was most likely due to slow dissociation of the enzyme-plex and an
active oxide metabolite that undergoes enterohepatic circulation. The discovery of the
active oxide was in fact a large breakthrough as it led to the development of vildagliptin
and saxagliptin. Presently, saxagliptin is available for clinical use and vildagliptin has been
launched in Europe only.
The key intermediate tert-butyl-4-amino-4-methylpiperidine-1-carboxylate was prep
-ared starting from ethyl piperidine-4-carboxylate via N-Boc protection, alkylation,
amidation and Hofmann rearrangement. After condensation with two key intermediates
which are 2-Chloropyrimidine and (S)-1-(2-chloroa