| Due to the high morbility and lethality,chronic kidney disease(CKD)has become one of the most serious disease along with tumor and cardiovascular disease.The most common complications of CKD include hyperphosphatemia,chronic renal failure and chronic fibrosis.The main treatment of CKD is to control and relieve these complications.As for hyperphosphatemia,this paper focused on the research of industrial synthesis and dry suspension preparation of sevelamer carbonate,a drug of phosphate binder,which was widely used in USA,Japan,Canada and so on,but has not been approved into market of China.Therefore,the synthesis and dry suspension preparation of sevelamer carbonate were studied in this thesis.As for chronic renal failure,considering the poor solubility,low bioavailability and other shortcomings of nicousamide,a clinical candidate drug with anti-renal failure profile,further structural modification was performed based on the structure of nicousamide.Concretely,29 novel coumarin amide derivatives were synthesized and biological evaluated to obtain more potent compounds.On the whole,this thesis is divided into two parts(Part Ⅰ and Part Ⅱ):Part Ⅰ.Industrialization of Sevelamer Carbonate for the Control of Chronic RenalFailureThe first section in Part Ⅰ is to introduce the background of chronic kidney disease,including the epidemiological investigation of chronic renal failure,the pathogenesis of chronic renal failure,current treatment methods for chronic renal failure,and the current research progress of anti-chronic renal failure.Finally,we propose the basis of the thesis and design the research content.The second section in Part Ⅰ is to study the industrialization of sevelamer carbonate and study on its dry-suspension agent.Firstly,the background of the industrial preparation of sevelamer carbonate was introduced.On the basis of summarizing the existing synthesis technology of sevelamer carbonate,an indirect method was chosen to synthesize the sevelamer carbonate.The synthesis process such as post processing of cross-linking,the amount of epichlorohydrin,salt formation process,etc.has been optimized.What’s more,the industrialized preparation of sevelamer carbonate was carried out and optimized.The control methods such as polypropylene amine,sevelamer base,other materials and solvents had been established.The quality standards of initial compounds such as polypropylene amine,sevelamer base had been established,and the key steps and the key parameters in industrial preparation process had been analyzed.Secondly,the structural confirmation and physicochemical properties of sevelamer carbonate were investigated.The structure of the synthesized compounds was verified by elemental analysis,nuclear magnetic resonance and mass spectrometry.The physical and chemical properties of sevelamer raw materials such as traits,solubility,primability,and swelling index were also studied.Thirdly,the quality study of sevelamer carbonate raw materials were studied.Through integrating the existing analysis method of sevelamer carbonate,we established a quality analysis method for raw materials and verified the analytical methods of propylene amines,soluble oligomers,epichlorohydrin,carbonates,total titratable amines,residual solvents,etc.Three batches of pilot samples were all examined according to the established quality standards.Finally,the paper also investigated the formulation and industrialization of sevelamer carbonate suspension,which includes the study of raw materials,formulation of prescriptions and processes,packaging materials,and so on.Based on the above achievement results,Shandong Xinhua Pharmaceutical Co.,Ltd.,the author’s affiliation,has obtained the clinical test approval of Sevelamer Carbonate and two specifications of dry suspensions from the China Food and Drug Administration(CFDA).Part Ⅱ.Design,Synthesis and Bioactivity Evaluation of Novel Coumarin Amides for the Control of Chronic Renal FailureThis part(namely,the third chapter)includes the design and synthesis of coumarin amides and their pharmacological activity against renal failure.In this chapter,taking nicousamide as lead compound,a total of 32 target compounds of 6-nitro-2H-benzopyran-2-one were designed and synthesized derived from the structure of coumarin.All these synthesized target compounds were confirmed by LC-MS and 1H-NMR.Then these compounds were evaluated for the curative activity for renal disease using rat fibroblasts(NRK-49F)for renal fibrosis model and human proximal tubular epithelial cell lines(HKC)for renal failure model.The results demonstrated that several compounds showed anti-renal fibrosis activity on TGF-β1 induced NRK-49F cell.The IC50 values of active compounds were listed as follows:DW-16(34.09 μM),DW-20(30.94μM),DW-23(35.40 μM),DW-25(9.35 μM),DW-27(12.40 μM),DW-28(35.52 μM),DW-29(17.96 μM).Researches on mechanism of action indicated that DW-16,DW-20 and DW-26 might prevent renal fibrosis through Wnt/β-catenin pathway.However,DW-29,DW-25,DW-27 might use ERK1/2 or JNK,TGF-β/Smad or JNK,TGF-β/Smad or ERK1/2 pathway respectively for the treatment of renal fibrosis.In the model of LPS induced HKC,several compounds showed anti renal failure activity,the IC50 values of which were listed:DW-14(31.19 μM),DW-16(34.09 μM),DW-18(13.89 μM),DW-25(10.43,M),DW-26(14.69 μM),these compounds may delay renal failure by inhibition of the expression of apoptosis gene Bax,and thus lead to promotion of antiapoptotic gene expression of Bcl-2 and prevention of apoptosis.The fourth chapter is the summary and perspectives.On one hand,this thesis provides optimization schemes for industrialization of sevelamer carbonate.On the other hand,two series of novel coumarin amides compounds were synthesized and evaluated for in-vitro anti-renal fibrosis and renal failure activities,resulting in the discovery of novel lead compounds for treatment of renal disease.To sum up,this research may pave the way for further development of anti-renal failure drugs. |
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