Study on the Synthetic Process and Design, Synthesis and Biological Evaluation of New Compounds as DPP-4 Inhibitors Related to Type Ⅱ Diabetes Mellitus

Author:Ma Yu Heng

Supervisor:sun bai wang


Degree Year:2017





After tumor and cardiovascular diseases,diabetes has become the third harm to human life and health.In view of GLP-1 analogs in anti-diabetes,by inhibiting its degrading enzyme DPP-4,it brings new ideas to the treatment and drug development of diabetes.As anti-diabetic drug Alogliptin is protected by patents,the API has no legitimate source.Because of this situation,it is very important to study the synthesis process and quality research.At present,the existing DPP-4 small molecule inhibitors have short action time,poor patient compliance and many other issues.In order to avoid these shortcomings,the future direction must be a long-term mechanism of small molecules and formulation.Guiding by the concept of imitation and innovation,this paper try to explore long-term mechanism,based on the development of a series of new salt and new compounds.The specific research contents are as follows:(1)Development and quality of API technology:We have developed the synthesis process of Alogliptin benzoate.The key process steps and parameters were studied in detail.In addition,the impurity spectra were analyzed and studied.After 5 steps reaction and 1 step crystallization,the Alogliptin benzoate of pharmaceutical grade was obtained and the purity can reach more than 99.90%.In the follow-up quality research,the physical and chemical properties related to the Alogliptin benzoate were studied,and the related traits were checked and compared.Four items as wettability,solubility,melting point and specific rotation were selected.According to the characteristics of compound structure,ultraviolet spectrophotometry and high performance liquid chromatography were used to identify and compare.In the experiment of the inspection project,mainly related to the crystal determination,by differential scanning calorimetry to carny out indirect judgments.A total of 9 related substances were examined.In the destructive test,through a more complete forced degradation test,a comprehensive understanding of the stability of Alogliptin benzoate was obtained.It not only provided a useful information for the formulation of prescription,the design of the product and the product storage conditions,but also laid a solid foundation for the follow-up application of Alogliptin benzoate.(2)Development of new salt type:52 different acids and Alogliptin bases were screened.The structure was confirmed by NMR.The thermodynamic properties of the Alogliptin base in combination with various acids were investigated by DSC/TGA.In the influencing factors experiment,more intense conditions were used to test.Under the conditions of high temperature,high humidity and strong light,the impurity level of new salt type was investigated.Finally,through the in vitro dissolution test,by comparing the whole dissolution curve,Alogliptin p-methylbenzoate is preferred as follow-up development.(3)The development of new compounds:Based on the classical structure of listed drugs,we have optimized various different effective pharmacophores by skeleton jumping strategy,and designed a new three series,total of 44 compounds.The inhibitory activity of DPP-4 was determined by in vitro DPP-4 enzyme kinetic model.At the same time,we also introduced a computer-aided evaluation method,which help us predict DPP-4 inhibitory activity.In the compound series 3,the inhibitory activity value of DPP-4 was consistent with our predicted value,and the activity reached the nanomolar level.When the pyrimidinedione and cyanopyrrolidine are connected with N atoms and the N atoms are separated by two or four C atoms,the activity is better.This discovery has laid a good foundation for the subsequent development.