Synthesis And Biological Activity Of N-aryl-1-deoxynojirimycin Derivatives

With the development of social economy and improvement of living standards,human beings have paid more and more attention to health issues.Among these issues,diabetes has become the third major noncommunicable disease which threaten human health seriously after cancer and angiocardiopathy.People have attached great importance to this disease.Relative to the diabetes itself,the complications(Such as atherosclerosis,stroke,kidney disease,retinopathy,neuropathy and so on)it caused do a greater harm to people's health,and chronic hyperglycemia is a major risk factor for the further damage of insulin secretion and insulin resistance of peripheral tissue.There are many clinical diabetes drugs now,however,these drugs have different limitations,such as mechanism of action(Relying on the remaining islet functions,etc),varies of side effects(Hypoglycemia,gastrointestinal tract reaction,liver and kidney impairment,allergies,the workload on the heart,etc)and so on.Meanwhile,they can hardly completely cure diabetes,which promotes pharmaceutical chemistry workers to seek more safe and effective medicines to control the blood sugar.A new kind of hypoglycemic drugs--Dapagliflozin was approved by European Drug Administration(EDA)on November 12,2012.This drug was the first sodium-glucose cotransporters 2(SGLT2)inhibitor to be approved for the treatment of type 2 diabetes in the world.Then some of SGLT2 inhibitors,such as canagliflozin and empagliflozin,have been developed.SGLT2 is mainly expressed in S1 segments of glomerular proximal convoluted tubule and is responsible for 90%of renal glucose reabsorption.Simultaneously,they have the advantages of losing weight,improving the cure of cardiovascular disease and so on.Therefore,SGLT2 inhibitor is popular among diabetes patients since approved.1-deoxynojirimycin has been demonstrated to be an effective a-glycosidase inhibitor.By using marketed SGLT2 inhibitors and 1-deoxynojirimycin as the references,a series of N-aryl-1-deoxynojirimycin derivatives were firstly designed and synthesized.We hope these designed compounds will have better effects for the treatment of diabetes.This thesis mainly contains the following sections.Firstly,we summarized the research progress of diabetes,the treatment of diabetes status,the research progress of SGLT2 inhibitors,the synthesis methods of dapagliflozin,canagliflozin and empagliflozin,and put forward the research content of this subject.Secondly,a series of intermediates were prepared using 2-chloro-4-nitrobenzoic acid,2-chloro-5-nitrobenzoic acidand 2-methyl-5-nitrobenzoic acid,respectively,as the materials by a synthetic route including chlorination of carboxylic acid,Friedel-Crafts acylation,reduction of carbonyl,reduction of nitro.Meanwhile,5-keto-D-glucose was obtained from 1,2-O-isopropylidene-a-D-glucofuranose by oxidation and hydrolyzation.Then these intermediate compounds could react with 5-keto-D-glucose by double reductive amination to give the mixture of N-aryl-l-deoxynojirimycin.For the purification,the crude mixture was treated with acetic anhydride to yield tetraacetyl-N-aryl-l-deoxynojirinmycin.Pure tetraacetyl-N-aryl-l-deoxynojirinmycin was obtained by the isolation of column chromatography.Then they could be hydrolyzed to give the pure compound N-aryl-l-deoxynojirinmycin.The target compounds were confirmed and characterized by 1H-NMR,13C-NMR,HRMS,IR and melting point determination.Thirdly,preliminarily testing the activities of target compounds.(1)By measuring blood glucose,urine volume and urine glucose after dosing orally the target compounds to SD rats,it was found that all compounds could decrease the SD rats' blood glucose,increase urine volume and the excretion of urine glucose.Among these compounds,compound J had the best hypoglycemic effect,followed by compound H and L.(2)Testing the inhibition activity of target compounds on hSGLT1 and hSGLT2 in vitro,and exploring their selective of hSGLT1 and hSGLT2.The results shown that all the compounds had no obvious selective.(3)Testing the inhibition activity of target compounds on a-glycosidase by means of pNPG.The data suggested that compound B had a better inhibition activity.(4)In consideration of the correlation between diabetes and cancer,the antitumor activities of target compounds on A431,A549,SW480 and NCI-H1975 were tested preliminarily by MTT method.The results indicated antitumor activitives of compound G and H were better than the other compounds.In conclusion,all subjects had certain function to reduce the blood sugar,and part of them had good inhibition activities on tumor.