Study On Triazole-bearing Carboxylic Acids As URAT1 Inhibitors For The Treatment Of Gout And Hyperuricemia

Gout is a disease of both metabolism and inflammation/immunity.Gout pathogenesis requires the intersection of two distinct processes:(1)the intrinsic formation of uric acid,in the form of urate,at levels(serum uric acid>408 ?mol/L or 6.8 mg/dL)sufficient to drive the precipitation of urate into crystallized forms(monosodium urate,MSU)and(2)an inflammatory response to the crystals so formed.Hyperuricemia is defined as the condition where the serum uric acid concentration exceeds the dissolution threshold of 6.8 mg/dL at physiological circumstance.Patients with hyperuricemia may develop gout due to the MSU precipitation gradually accumulated,or may not show any symptoms,but their serum uric acid concentrations should be significantly higher than that for the normal people.The gouty patients need treatment immediately,and the hyperuricemia patients are also the potential objects for gout medication,because once the physical condition has changed,they may easily get a gout attack due to the increased burden on the body.With the rapid growth of Chinese economy,a substantial increase in living standards,food intake of purines and therefore the number of gout patients was observed.A nationwide epidemiological statistics showed that the current incidence of gout and hyperuricemia in China were 1.1%and 13.3%,corresponding to 14 million people and 170 million people,respectively.Such a large number of people are suffering from gout or have the potential to develop gout.However,the drugs currently available suffer from a lot of drawbacks,such as weak efficacy and poor safety profiles,and therefore novel drugs are in great need in clinics.According to statistics,more than 90%of gout patients are due to reduced uric acid excretion,so the uricosuric agents are the most promising agents to lower the serum uric acid.The newly discovered uric acid transporter URAT1 is the most important carrier protein involved in the reabsorption process of uric acid.Inhibition of URAT1 can block the reabsorption of uric acid and increase the uric acid excretion to reduce the concentration of serum uric acid.URAT1 has thus become a hot therapeutic target for the development of drugs to treat hyperuricemia and gout,with dozens of URAT1 inhibitors that have been in clinical trials.The first URAT1 selective inhibitor lesinurad is currently available in the US and Europe.The first chapter of this dissertation is the background of our research.In chapter 2,a practical synthetic route to URAT1 inhibitor lesinurad starting from 1-bromonaphthalene and cyclopropylmagnesium bromide in 10 steps in 18%total yield was developed.A new synthetic route to the key intermediate 3-amino-4-(4-cyclopropylnaphthalen-l-yl)-1H-1,2.4-triazole-5(4H)-thione(II-7)starting from 4-cyclopropylnaphthalen-1-yl isothiocyanate(II-4)was developed with significantly improved yield.Then,in order to further understand the structure-activity relationship(SAR)of a lesinurad-based hit ?-24 that was derived from the replacement of S atom in lesinurad with CH2,18 novel compounds were designed,synthesized and subjected to in vitro URAT1 inhibitory assay.The systematic SAR exploration eventually led to the discovery of a highly potent flexible URAT1 inhibitor,?-68c,which was 31-fold more potent than parent lesinurad(IC50?0.23 ?M against human URAT1 for ?-68c vs 7.18 ?M for lesinurad).This section of work discovered a novel flexible molecular scaffold as represented by ?-68c that might serve as a promising prototype scaffold for further development of potent URAT1 inhibitors,and also demonstrated that the S atom in lesinurad was not indispensable for its URAT1 inhibitory activity.Chapter 3 deals with the development of new synthetic routes to the two URAT1 inhibitors bearing alkoxy group-substituted triazoles ?-1a and ?-1b discovered in chapter 1.The synthetic approach reported in the first chapter to them suffers from relatively more reaction steps and quite low overall yields(3.3%and 3.0%for ?-1a and ?-1b,respectively).In order to further explore the structure-activity relationship(SAR)of ?-1a and ?-1b,synthetic approach with relatively fewer synthetic steps and higher overall yield is urgently needed.In this chapter,two efficient synthetic approaches to them were developed(approaches A and B),with CuCl-catalyzed nucleophilic aromatic substitution(SNAr)reaction of bromotriazole with sodium alkoxides and SNAr reaction of methylsulfonyltriazole with alkoxides as key steps,and the reaction conditions for some important steps were fully optimized.The two synthetic approaches are characterized by relatively fewer reaction steps and dramatically higher yields,and not only valuable to the further SAR exploration of?-1a and ?-1b but also very helpful to the synthesis of heterocycles with alkoxyl groups.Chapter 4 describes a facile 3-step synthetic approach to 3-halo-4-substituted-1,5?dihydro-4H-1,2,4-triazoline-5-thiones ?-1a??-1k starting from corresponding unhalogenated ?-8a??-8i based on the strategy of retro-Michael addition,with the key steps being regioselective S-alkylation of ?-8a??-8i with ethyl 3-iodopropionate(?-12c)and subsequently alkaline cleavage of the propionate protecting group via retro-Michael addition.The reaction conditions for alkylation of thione ?-8i were systematically and intensively screened and the optimal condition was finally obtained.The synthetic approach was characterized by simplicity of operation and wide substrate scope.In conclusion,the thesis carried out a systematic SAR exploration of a lesinurad-based hit,leading to the discovery of a highly potent flexible URAT1 inhibitor as well as a flexible molecular scaffold for the design of potent URAT1 inhibitors,and developed useful synthetic routes to alkoxy group-substituted triazoles and 3-halo-4-substituted-1,5-dihydro-4H-1,2,4-triazoline-5-thiones.