Polymorph of axially chiral enantiomer of URAT1 inhibitor

A technology of polymorphism and axial chirality, applied in the field of polymorph I and its application in the field of medicine, can solve the problems of difficult drug preparation and storage, thermodynamic instability, poor fluidity, etc.

Inactive Publication Date: 2017-10-20
ZHEJIANG JINGXIN PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] There are significant activity differences between the two axial chiral enantiomers, and the R or S configuration enantiomers disclosed in this patent application exist in an amorphous form
In the course of their research, the inventors found that 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl Thio)acetic acid axial chiral enantiomer has defects in stability, such as thermodynamic instability, poor fluidity, strong hygroscopicity, etc., which brings certain difficulties to the preparation and storage of drugs

Method used

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  • Polymorph of axially chiral enantiomer of URAT1 inhibitor
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  • Polymorph of axially chiral enantiomer of URAT1 inhibitor

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Effect test

Embodiment 1

[0076] The preparation of embodiment 1 polymorph I

[0077] Take 0.2g sample of amorphous (S)-2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid , added to 40mL cyclohexane, heated to 50°C to dissolve for 2 hours to make a saturated solution, stirred and cooled to 10°C for crystallization, filtered, and baked at 45°C for 2 hours to obtain 0.15g of (S)-2-(5- A sample of polymorph I of bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid.

Embodiment 2

[0078] The preparation of embodiment 2 polymorph I

[0079] Take 0.2g sample of amorphous (S)-2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid , added to 50mL of heptane, heated and dissolved at 60°C for 2 hours to make a saturated solution, stirred and cooled to 10°C for crystallization, filtered, and baked at 45°C for 2 hours to obtain 0.13g of (S)-2-(5-bromo- A sample of polymorph I of 4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid.

Embodiment 3

[0080] The preparation of embodiment 3 polymorph I

[0081] Take 0.2g sample of amorphous (S)-2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid , added to 50mL of n-hexane, heated and dissolved at 60°C for 2 hours to make a saturated solution, stirred and cooled to 10°C for crystallization, filtered, and baked at 45°C for 2 hours to obtain 0.17g of (S)-2-(5-bromo- A sample of polymorph I of 4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid.

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Abstract

The invention discloses a polymorph I of an S-configuration axially chiral enantiomer of 2-(5-bromo-4-(4-cyclopropylnaphthalene-1-yl)-4H-1,2,4-triazole-3-yl-thio)acetic acid, and CuKalpha radiation based X-ray powder diffraction spectrum represented with the angle 2theta at least have diffraction peaks at 7.02 degrees plus or minus 0.2 degrees, 11.14 degrees plus or minus 0.2 degrees, 14.10 degrees plus or minus 0.2 degrees, 14.60 degrees plus or minus 0.2 degrees, 15.44 degrees plus or minus 0.2 degrees, 16.98 degrees plus or minus 0.2 degrees, 20.98 degrees plus or minus 0.2 degrees, 21.86 degrees plus or minus 0.2 degrees and 28.02 degrees plus or minus 0.2 degrees. Compared with an amorphous form, the polymorph I is good in stability, almost has no hygroscopicity, is high in crystal form purity, and facilitates drug preparation, storage and transportation.

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) the crystal form of the axial chiral enantiomer, especially polymorph I of the S configuration enantiomer and its application in the field of medicine. Background technique [0002] Ardea Biosciences has developed a novel URAT1 inhibitor, lesinurad, whose structure is shown in formula I, chemical name: 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1, 2,4-triazol-3-ylthio)acetic acid, or 2-[[5-bromo-4-(4-cyclopropyl-1-naphthalene)-4H-1,2,4-triazole-3 -yl]thio]acetic acid, CAS: 878672-00-5. Lesinurad is an oral uricosurgic agent that inhibits the renal proximal tubule uric acid transporter URAT1 for the treatment of gouty patients with hyperuricemia. [0003] [0004] Chinese patent application 201510918016.5 discloses lesinurad axial chiral enantiomers as shown in formula I...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D249/12A61K31/4196A61P19/06
CPCC07D249/12C07B2200/07C07B2200/13
Inventor 黄悦叶佳丽胡秀荣余红
Owner ZHEJIANG JINGXIN PHARMA
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