Axially chiral enantiomers of drug Lesinurad

An enantiomer and axial chiral technology, applied in the field of R-configuration enantiomer, hyperuricemia and gout, can solve problems such as difficult to develop compounds, no great progress, slow development, etc., to achieve prevention of tissue Abnormal uric acid level symptoms, excellent suppression effect

Inactive Publication Date: 2016-03-16
ZHEJIANG JINGXIN PHARMA +1
View PDF3 Cites 42 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, the therapeutic effect of high doses and the nephrotoxicity caused by high doses are a pair of contradictions that are difficult to reconcile
[0010] At present, the development of therapeutic drugs for t

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Axially chiral enantiomers of drug Lesinurad
  • Axially chiral enantiomers of drug Lesinurad
  • Axially chiral enantiomers of drug Lesinurad

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0083] Preparation of racemic lesinurad

[0084] Referring to WO2014008295A1, lesinurad was synthesized. Proceed as follows:

[0085]

[0086] Add 4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole-3-thiol (Compound A, 5g, 0.018mol), potassium carbonate (3.74 g, 0.027mol, 1.5eq), DMF (50ml). Ethyl bromoacetate (3.3 g, 0.022 mol, 1.2 eq) was added dropwise with stirring. After dropping, stir the reaction at room temperature for 1.5h. After the reaction of the raw materials was detected by sampling, 100 ml of ice water was dripped into the reaction solution under stirring, and a white solid was precipitated. Stir for 30min, filter with suction and wash with water. After the filter cake was dried, it was recrystallized with ethyl acetate to obtain 4 g of white solid, namely Intermediate B.

[0087] 1HNMR(CDCl3)δ8.54(dd,J=8Hz,1H),8.31(S,1H),7.66(m,1H),7.57(m,1H),7.40(dd,J=8Hz,1H),7.34 (m,2H),4.08(m,2H),3.72(s,3H),2.42(m,1H),1.16(m,2H),0.85(m,2H)

[0088] ESI(M+H): 340 ...

Embodiment 2

[0097] Preparative liquid phase separation of lesinurad axial chiral enantiomers

[0098] The R configuration axis and the S configuration axis chiral enantiomer of the lesinurad obtained in Example 1 were separated using a preparative liquid chromatograph.

[0099] Instrument: SFC-80 (Thar, Waters), preparative chiral column model: OJ column 20×250mm, 5μm (Dacel),

[0100] Column temperature: 35°C, mobile phase: CO 2 / MeOH=75 / 25, flow rate: 80g / min,

[0101] Detection wavelength: 214nm, column pressure: 100bar, injection volume: 0.2mL,

[0102] Cycle time: 2.5min,

[0103] Sample preparation method: Dissolve 6000mg of racemic lesinurad in 50mL of methanol.

[0104] figure 1 High performance liquid chromatography (HPLC) diagram for the separation of the R-configuration and S-configuration axial chiral enantiomers of lesinurad.

[0105] Enrichment and collection of peak components with a retention time of t=3.72min to obtain amorphous lesinurad whose axial chirality is S-...

Embodiment 3

[0115] The HEK293 cell line stably transfected with URAT1 (uric acid transporter) gene was used to determine the inhibitory activity of compounds on uric acid transporter.

[0116] Experimental Materials

[0117] (1) HEK293-pcDNA3.1-URAT1-4, HEK293-pcDNA3.1-5 cells: the HEK293 cell line stably transfected with URAT1 gene, the HEK293 cell line transfected with empty expression vector pcDNA3.1. The two cell lines were constructed by Shanghai WuXi AppTec New Drug Development Co., Ltd.

[0118] (2) Compounds to be tested: R-lesinurad (Formula II), S-lesinurad (Formula III), and lesinurad (Formula I), prepared with 100% DMSO solution to prepare 250 mM mother liquor for temporary storage in a nitrogen cabinet.

[0119] See Table 1 for other reagents.

[0120] Table 1. List of Reagents

[0121]

[0122]

[0123] experimental method

[0124] Cell treatment: add the cells HEK293-pcDNA3.1-URAT1-4 and HEK293-pcDNA3.1-5 to the 24-well plate coated with rat tail collagen, and the...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

No PUM Login to view more

Abstract

The invention discloses an axially chiral R-enantiomer and an axially chiral S-enantiomer of the drug Lesinurad. The axially chiral R-enantiomer shows excellent URAT1 inhibition effect, overcomes the problems that a high dosage of Lesinurad racemate leads to renal toxicity and a low dosage Lesinurad racemate cannot produce additional drug effect, and can be applied to treatment or prevention of symptoms of abnormal tissue uric acid levels.

Description

technical field [0001] The invention belongs to the field of pharmacy, in particular to medicine Lesinurad (2-(5-bromo-4-(4-cyclopropylnaphthalene-1-yl)-4H-1,2,4-triazol-3-ylsulfanyl) ) acetic acid), especially related to the R configuration enantiomer, and its use in the preparation of medicines, which can be used to treat or prevent abnormal tissue uric acid levels, especially hyperuricemia and gout. Background technique [0002] Uric acid is a product of xanthine oxidation. Abnormal levels of uric acid metabolism can lead to many conditions, including gout, hyperuricemia, polycythemia, myeloid metaplasia, recurrent gout attacks, gouty arthritis, hypertension, cardiovascular disease, coronary heart disease, Lesch-Nye Grain syndrome, Kelly-Semmeller syndrome, kidney disease, kidney stones, renal failure, joint inflammation, arthritis, urolithiasis, lead poisoning, hyperparathyroidism, psoriasis or sarcoidosis, etc. . In recent years, due to changes in people's modern li...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
IPC IPC(8): C07D249/12A61K31/4196A61P19/06C07B57/00
CPCC07B57/00C07B2200/07C07D249/12
Inventor 黄悦徐辉张喻彬郑飞
Owner ZHEJIANG JINGXIN PHARMA
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap