A crystal-type HCV inhibitor, a preparing method thereof and applications of the inhibitor

A crystalline form, isopropyl technology, applied in the field of drug development, can solve the problem that amorphous API is difficult to prepare pharmaceutical preparations

Active Publication Date: 2017-11-10
JIANGSU HANSOH PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, since the compound of the formula disclosed in Example 24 of patent WO2015101183A1 is recrystallized and purified in CH2Cl2, it is still an amorphous solid, and it is difficult to prepare an amorphous API into a pharmaceutical preparation suitable for clinical use. Therefore, it is urgent to develop a stable , crystals with good solubility to meet the needs of clinical drug development

Method used

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  • A crystal-type HCV inhibitor, a preparing method thereof and applications of the inhibitor
  • A crystal-type HCV inhibitor, a preparing method thereof and applications of the inhibitor
  • A crystal-type HCV inhibitor, a preparing method thereof and applications of the inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0066] Weigh 50mg of the compound of formula I (amorphous) and place it in a 10.0mL glass bottle, then add 3.0mL of positive solvent methyl tert-butyl ether, stir to dissolve, slowly add 5.0mL of anti-solvent n-heptane, at room temperature (20- 25°C) magnetic stirring for 48 hours, solid-liquid separation to obtain the compound of crystalline formula I (crystal form I), its powder X-ray diffraction pattern is as follows figure 1 shown.

[0067] The obtained crystal form I of the compound of formula I was thermally analyzed by differential scanning calorimeter (DSC) and thermogravimetric analyzer (TGA), respectively. The DSC instrument model used was TA Q2000, and the TGA instrument model was TA Q5000. DSC, TGA analysis method parameters are as follows: the temperature range is room temperature to 300 degrees Celsius, the scan rate is 10 degrees Celsius per minute, and the protective gas is nitrogen (flow rate 25 ml / min). DSC analysis chart see image 3 , see the TGA analysis...

Embodiment 2

[0069] Weigh 30mg of the compound of formula I (amorphous) into a 10.0mL glass bottle, then add 2.0mL of positive solvent ethyl acetate, stir to dissolve, slowly add 5.0mL of anti-solvent n-heptane, at room temperature (20-25°C) Magnetic stirring for 48 hours, solid-liquid separation to obtain crystalline formula I compound (crystal form II), its powder X-ray diffraction pattern is as follows figure 2 shown.

[0070] The obtained crystalline form II of the compound of formula I was thermally analyzed by differential scanning calorimeter (DSC) and thermogravimetric analyzer (TGA). The DSC instrument model used was TA Q2000, and the TGA instrument model was TA Q5000. DSC, TGA analysis method parameters are as follows: the temperature range is room temperature to 300 degrees Celsius, the scan rate is 10 degrees Celsius per minute, and the protective gas is nitrogen (flow rate 25 ml / min). DSC analysis chart see Figure 5 , see the TGA analysis chart Figure 6 .

Embodiment 3

[0072] Weigh 200mg of the compound of formula I (amorphous) into a 20.0mL glass bottle, then add 5.0mL of normal solvent isopropyl ether, stir to dissolve, slowly add 10.0mL of anti-solvent n-hexane, at room temperature (20-25°C) magnetic Stir for 48 hours, solid-liquid separation to obtain the crystalline formula I compound (crystal form I), its powder X-ray diffraction pattern is as shown in figure 1 Basically the same.

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PUM

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Abstract

The invention relates to a crystal-type HCV inhibitor, a preparing method thereof and applications of the inhibitor. The chemical name of the HCV inhibitor is isopropyl((S)-(4-cyclopropylphenoxy)(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)-L-alanine. The HCV inhibitor can be adopted as an inhibitor of HCV NS5B polymerase and an HCV replication inhibitor, can be used for treating hepatitis C infection of mammals, has a broad application prospect and is expected to be developed into an antiviral drug of a new generation.

Description

technical field [0001] The invention belongs to the technical field of drug development, and in particular relates to a crystalline HCV inhibitor and its preparation method and application. Background technique [0002] The viruses of the Flaviviridae family include at least three distinct genera: pestiviruses, which cause disease in cattle and pigs; and flaviviruses, which are the primary cause of diseases such as dengue fever and yellow fever and the genus hepaciviruses, the only member of which is HCV. The Flavivirus genus includes more than 68 members, grouped based on serological relatedness. Clinical symptoms vary and include fever, encephalitis, and hemorrhagic fever. Flaviviruses of global concern for association with human disease include dengue hemorrhagic fever virus (DHF), yellow fever virus, shock syndrome virus, and Japanese encephalitis virus. Because the HCV genome is similar to human flaviviruses and pestiviruses in structure and phenotypic characteristic...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/06C07H1/00A61K31/7072A61P31/12A61P31/14
CPCC07B2200/13C07H1/00C07H19/06Y02A50/30
Inventor 李响陈中科包如迪
Owner JIANGSU HANSOH PHARMA CO LTD
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