878672-00-5

Usage

Uses

Used in Pharmaceutical Industry:
RDEA 594 is used as a URAT1 inhibitor for the treatment of gout and hyperuricaemia.
It is used in combination therapy with xanthine oxidase inhibitors to enhance the efficacy of reducing uric acid levels in patients with gout.
Used in Gout Treatment:
RDEA 594 is used as an adjunctive therapy in combination with xanthine oxidase inhibitors to treat hyperuricaemia associated with gout. This combination helps in managing the symptoms and complications of gout more effectively.
Used in Drug Synthesis:
RDEA 594 is used to synthesize febuxostat, a non-purine analog inhibitor of xanthine oxidase. Febuxostat is approved by the European Medicines Agency and the US Food and Drug Administration for treating gout, providing an alternative treatment option for patients.

Synthesis

The synthesis of lesinurad began with commercial 1- bromonaphthalene (138). A Kumada coupling between this bromide and cyclopropyl Grignard delivered 139, which after selective nitration to give 140, delivered the oxylate salt 141 (which now is commercially available). Treatment of 141 with KOH followed by thiophosgene at 5 °C delivered isothiocyanate 142 in 63% yield. Reaction of 142 with formyl hydrazine followed by addition of potassium bicarbonate and mild heating resulted in thio-1,2,4-triazole 144 by the intermediacy of 143. Quantitative alkylation of triazolothiol 144 resulted in α-mercaptan 145, and this was followed by NBS bromination to afford bromotriazole 146. Ester saponification followed by acidification secured lesinurad (XVII) in a good yield over the final three steps.

Upstream product

• 2298-07-9 4-Bromo-1-naphthylamine 
• 1158970-76-3 5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole-3-thiol 
• 776-34-1 1-amino-4-nitronaphthalene 
• 79-08-3 bromoacetic acid 

Relevant academic research and scientific papers

Characterization of stereoselective metabolism, inhibitory effect on uric acid uptake transporters, and pharmacokinetics of lesinurad atropisomers

Lesinurad [Zurampic; 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)], a selective inhibitor of uric acid reabsorption transporters approved for the treatment of gout, is a racemate of two atropisomers. The objective of this investigation was to evaluate the stereoselectivity of metabolism, the inhibitory potency on kidney uric acid reabsorption transporters (URAT1 and OAT4), and the clinical pharmacokinetics of the lesinurad atropisomers. Incubations with human liver microsomes (HLM), recombinant CYP2C9, and recombinant CYP3A4 were carried out to characterize the stereoselective formation of three metabolites: M3 (hydroxyl-ation), M4 (a dihydrodiol metabolite), and M6 (S-dealkylation). The formation of M3 in HLM with atropisomer 1 was approximately twice as much as that with atropisomer 2, whereas formation of M4 with atropisomer 1 was 8- to 12-fold greater than that with atropisomer 2. There were no significant differences in the plasma protein binding among lesinurad and the atropisomers. Following oral administration of 400 mg lesinurad once daily for 14 days to healthy human volunteers, the systemic exposure (Cmax at steady state and area under the concentration-time curve from time zero to the time of dosing interval) of atropisomer 1 was approximately 30% lower than that of atropisomer 2, whereas renal clearance was similar. In vitro cell-based assays using HEK293 stable cells expressing URAT1 and OAT4 demonstrated that atropisomer 2 was approximately 4-fold more potent against URAT1 than atropisomer 1 and equally active against OAT4. In conclusion, lesinurad atropisomers showed stereoselectivity in clinical pharmacokinetics, metabolism, and inhibitory potency against URAT1.

RESOLUTION METHOD FOR AXIS CHIRAL ENANTIOMERS OF LESINURAD

A resolution method of axial chiral enantiomers of lesinurad (2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid) adopts inexpensive and readily available quinoline natural products and derivatives thereof, such as quinine, cinchonine, quinidine or cinconidine as resolving agents to react with lesinurad racemate in an organic solvent to form a salt, and the salt is dissociated by acidification so as to obtain optically pure (R)- or (S)-2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid. The method can give axial chiral enantiomer of lesinurad in R configuration with a chiral purity ee of up to 100% and a total yield of 90% or more. The obtained axial chiral enantiomer of lesinurad in S configuration can reach a chiral purity ee of up to 99.9% and a total yield of 80% or more.

Novel Human Urate Transporter 1 Inhibitors as Hypouricemic Drug Candidates with Favorable Druggability

Lesinurad, a human urate transporter 1 (URAT1) inhibitor approved as a medication for the treatment of hyperuricemia associated with gout in 2015, can cause liver and renal toxicity. Here, we modified all three structural components of lesinurad by applying scaffold hopping, bioisosterism, and substituent-decorating strategies. In a mouse model of acute hyperuricemia, 21 of the synthesized compounds showed increased serum uric acid (SUA)-reducing activity; SUA was about 4-fold lower in animals treated with 44, 54, and 83 compared with lesinurad or benzbromarone. In the URAT1 inhibition assay, 44 was over 8-fold more potent than lesinurad (IC50: 1.57 μM vs 13.21 μM). Notably, 83 also displayed potent inhibitory activity (IC50 = 31.73 μM) against GLUT9. Furthermore, we also preliminarily explored the effect of chirality on the potency of the promising derivatives 44 and 54. Compounds 44, 54, and 83 showed favorable drug-like pharmacokinetics and appear to be promising candidates for the treatment of hyperuricemia and gout.

Synthesis of lesinurad via a multicomponent reaction with isocyanides and disulfides

An efficient synthesis of Lesinurad a selective uric acid reabsorption (URAT1) inhibitor, is described in this article. The route to synthesis of Lesinurad avoids the use of thiophosgene and the formation of thiols. The key reaction in this synthesis is construction of the 1,2,4-Triazole ring in 72percent yield. The title product is obtained in 45percent yield over 5 steps.

Refining method of Lesinured

The invention relates to a refining method of Lesinured. The method comprises the following steps: adding a Lesinured crude product into a solvent which is heated to boil, heating to dissolve, addingactivated carbon, filtering, dropwise adding n-hexane, slowly cooling to 35-45 DEG C, crystallizing for 1-2 h, slowly cooling to 0-10 DEG C, crystallizing for 2-3 h, filtering, and drying under reduced pressure to obtain a high-purity finished product. Compared with the prior art, the method provided by the invention has the advantages of good refining effect, common solvent used in the refining process, simple industrial operation, and high yield and purity of the refined target product, and is suitable for industrial mass production.

Method for purifying Lesinurad impurity

The invention relates to a method for purifying a Lesinurad impurity. The purification route is shown in the specification. The method is simple and safe in operation, good in yield, high in product purity, good in economic effect and suitable for industrial production.

Method for preparing

The reaction of the intermediate, with 1 - bromo - 4 4-cyclopropylnaphthalene and S - (5 - oxo - 4444185-dihydro - 111111111, 2, 4-triazole - 3 3-yl) thiocarboxylic acid ester to obtain the intermediate 3, greatly improves the route efficiency 4, and reduces the process cost 5, and also reduces the production S - of the finished product. The method, is suitable for amplifying and producing; products . The reaction yield is high, obtained by the reaction of the intermediates, through; alkylation reaction with sodium chlorfenac to obtain a Retnatid product according to the present invention as shown in Table, The present invention discloses a method, for producing a. rasid product.

In Situ Activation of Disulfides for Multicomponent Reactions with Isocyanides and a Broad Range of Nucleophiles

Activation of disulfides with N-halogen succinimide in the presence of TEMPO allows insertion reaction by an isocyanide, the product of which can further accept a wide range of nucleophiles for the generation of isothioureas and related molecular moieties. This new procedure overcomes previous methods that accept essentially only aryl amines as the third nucleophilic component. The diverse nucleophiles usable in our new protocol make this approach a general method for de novo synthesis of many S-containing heterocycles.

Preparing method of Lesinurad impurities

The invention belongs to the technical field of medicines, and relates to a preparing method of Lesinurad impurities. The preparing method includes the following steps of firstly, making 5-bromo-4-(4-cyclopropyl naphthalene-1-yl)-4H-1,2,4-triazolyl-3-thiol as the initial raw material have a substitution reaction with 2,2-methyl dibromoacetate(ethyl ester and other esters); secondly, making the obtained product have a hydrolysis reaction with a water solution of lithium hydrate to obtain 2-bromo-2-((5-bromo-4-(4-cyclopropyl naphthalene-1-yl)-4H-1,2,4-triazolyl-3-yl)sulfo)acetic acid.

Preparation method of Roxadustat

The invention discloses a preparation method of Roxadustat. The chemical name of Roxadustat is 2-[[5-bromo-4-(4-cyclopropyl-1-naphthalene)-4H-1,2,4-triazole-3-yl] sulfo] acetic acid. The molecular formula is C17H14BrN3O2S. The preparation process is concise, raw materials are easily available and the preparation process is economical and environmentally friendly, industrialization is achieved favorably, the economical technical development of bulk pharmaceutical chemicals of Roxadustat can be promoted, the production cost is lowered, the yield is high, the environmental pollution is slight, and the method is suitable for large-scaled production.