Para-defovir mesylate related substance and application thereof

A related substance, methanesulfonic acid technology, applied in the field of medicine, can solve few problems and achieve the effect of low detection limit, good specificity and high sensitivity

Pending Publication Date: 2022-01-04
XIAN XINTONG PHARM RES CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, prior art reports on related substances of paladefovir mesylate are seldom

Method used

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  • Para-defovir mesylate related substance and application thereof
  • Para-defovir mesylate related substance and application thereof
  • Para-defovir mesylate related substance and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0104] Prescription Composition of Paradefovir Mesylate Tablets

[0105]

[0106] 1) Weighing and preparing materials: dry the silicified microcrystalline cellulose, pregelatinized starch, and silicon dioxide in an oven at 105° C. for 3 hours. Weigh and pulverize paradefovir mesylate, pass through an 80-mesh sieve; mix with silicon dioxide.

[0107] 2) Mixing: the mixed raw material and silicon dioxide mixture are mixed with silicified microcrystalline cellulose and pregelatinized starch for 10 minutes. Add stearic acid again and mix for 8 minutes, discharging.

[0108] 3) Tablet compression: Control the tablet weight according to the content of intermediates, and press plain tablets.

[0109] 4) Coating: the plain tablet is coated into a film-coated tablet.

Embodiment 2

[0111] Phase II clinical trial and preferred dosage

[0112] A randomized, double-blind, positive-drug parallel-controlled, multi-center, phase II dose-finding clinical trial design: with Tenofovir Disoproxil Fumarate Tablets as a control, to evaluate different doses of Paradefovir Mesylate Tablets Effectiveness in the treatment of chronic hepatitis B, evaluation of the safety of different doses of paradefovir mesylate tablets, and exploration of the best safe and effective dose of paradefovir mesylate tablets.

[0113] 240 subjects were divided into 5 groups, respectively 30mg / time, 45mg / time, 60mg / time and 75mg / time of paladefovir mesylate and 300mg / time of tenofovir fumarate Pifufurate positive control group, once a day, orally, the screening period was 14 days, the double-blind test period was 24 weeks, and the observation period was 4 weeks after the course of treatment.

[0114] The main curative effect index is the logarithmic value of serum HBV DNA (PCR method) decrea...

Embodiment 3

[0123] (+)-trans-9-{2-[4-[(S)-(3-Chlorophenyl)-2-oxo-1,3,2-dioxaphosphorin-2-methylene] The preparation of -1-ethyl} adenine mesylate (formula 1):

[0124]

[0125] Add adefovir (29g), NN-diethylformamide (13.2ml), dichloromethane (370ml) into a 1L three-necked flask, and add oxalyl chloride (40ml) dropwise while stirring, the system is white and turbid, and the reaction is refluxed for 2.5h , the system becomes clear. Concentrate at 40°C to obtain yellow semi-solid and semi-liquid. Add dichloromethane (230ml) to dissolve, lower the temperature to below 10°C, add pyridine (10.4ml) in batches, the color changes from brown to dark green, stir for later use, and obtain 2-(6-((diethylamino) Methylamino)-9H-purin-9-yl)ethoxy)methylphosphoryl dichloride.

[0126] Add (S)-1-(3-chlorophenyl)propyl-1,3-diol (20g) and dichloromethane (280ml) to another 1L three-necked flask, lower the temperature to -30°C, and control the temperature < At -20°C, a dichloromethane solution of 2-(6...

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Abstract

The invention provides a separated compound which is a para-defovir mesylate related substance. The invention also provides an application of the compound, wherein the compound is used for preparing the para-defovir mesylate or a composition containing the para-defovir mesylate.

Description

technical field [0001] The invention belongs to the technical field of medicines, specifically, the invention relates to related substances of paladefovir mesylate and applications thereof. Background technique [0002] Paradefovir mesylate is a liver-targeted adefovir (PMEA) prodrug that utilizes liver-targeting technology (HepDirect) to construct an aryl phosphate ring diester structure in the target active drug to form a bioequivalent . Its structural formula is: [0003] [0004] Paradefovir mesylate is effectively converted to PMEA through the action of hepatic cytochrome P450 isoenzyme CYP3A4. PMEA can effectively combine with the hepatitis B virus infection and replication site in the liver to achieve therapeutic effect. The drug is a potential specific drug for the treatment of hepatitis B. [0005] Chinese Patent No. 200510098771.X and No. 201210344333.7 disclose the preparation of paradefovir mesylate (crude drug). However, the present inventors found that ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): G01N30/88C07F9/6574C07F9/6561
CPCG01N30/88C07F9/657181C07F9/65616G01N2030/884
Inventor 王媛张登科金伟丽郭维博张艳侠高中强
Owner XIAN XINTONG PHARM RES CO LTD
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