Application of chiral chloroquine, hydroxychloroquine or salt of the chiral chloroquine and hydroxychloroquine as anti-coronavirus drug target 3CL hydrolase inhibitor for reducing cardiotoxicity

A coronavirus and hydrolytic enzyme technology, applied in antiviral agents, drug combinations, medical preparations containing active ingredients, etc., can solve problems such as prolonged QT interval, tachycardia, and sudden death

Active Publication Date: 2020-10-23
SOUTH UNIVERSITY OF SCIENCE AND TECHNOLOGY OF CHINA +1
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Usually, among the toxic and side effects caused by drugs, cardiotoxicity is a very important detection index. The main reason is: blocking the rapid delayed rectification current of the heart, causing the prolongation of the QT interval in the cardiac action potential time course, and then inducing the peak Torsades ventricular tachycardia, which can cause sudden death in severe cases

Method used

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  • Application of chiral chloroquine, hydroxychloroquine or salt of the chiral chloroquine and hydroxychloroquine as anti-coronavirus drug target 3CL hydrolase inhibitor for reducing cardiotoxicity
  • Application of chiral chloroquine, hydroxychloroquine or salt of the chiral chloroquine and hydroxychloroquine as anti-coronavirus drug target 3CL hydrolase inhibitor for reducing cardiotoxicity
  • Application of chiral chloroquine, hydroxychloroquine or salt of the chiral chloroquine and hydroxychloroquine as anti-coronavirus drug target 3CL hydrolase inhibitor for reducing cardiotoxicity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] Preparation of Chiral Chloroquine by Chiral High Performance Liquid Chromatography

[0066] The racemic chloroquine phosphate 1 purchased from the market is converted into free racemic chloroquine 2 under alkaline conditions.

[0067]

[0068] At 0°C, 13.0 g of chloroquine phosphate was dissolved in 75 mL of water, then 50 mL of 12% NaOH aqueous solution was added, after stirring for half an hour, 25 mL of ethyl acetate was added, and stirring was continued for half an hour. The reaction solution was naturally raised to room temperature, extracted three times with 100 mL of ethyl acetate, combined the organic phases, washed with 150 mL of saturated brine and water successively, dried by adding anhydrous sodium sulfate, and filtered to remove sodium sulfate. The organic solvent was removed with a rotary evaporator to obtain 7.6 g of free chloroquine in the form of light yellow viscous liquid, with a yield of 94%.

[0069] 1 H NMR (600MHz, Chloroform-d) δ8.50 (d, J =...

Embodiment 2

[0073] Preparation of Optically Pure Chloroquine Phosphate

[0074] R and S Free State Chloroquine Converted to Optically Pure Chloroquine Phosphate

[0075]

[0076]Dissolve 640 mg of S-chloroquine in 4 mL of ethanol and heat to reflux. 0.25 mL of 85% phosphoric acid was added dropwise to the above solution, and the reaction was refluxed for two hours. At this time, a large amount of white solids were precipitated. After the reaction solution was cooled to room temperature, it was filtered, and the filter cake was washed three times with 1 mL of ethanol to obtain 868 mg of white S-chloroquine phosphate solid, with a yield of 84%, [α] D 27.8 =79.7(c=0.5,H 2 O).

[0077]

[0078] Dissolve 640 mg of R-chloroquine in 4 mL of ethanol and heat to reflux. 0.25 mL of 85% phosphoric acid was added dropwise to the above solution, and the reaction was refluxed for two hours. At this time, a large amount of white solids were precipitated. After the reaction solution was coole...

Embodiment 3

[0080] Preparation of Chiral Chloroquine Phosphate by Chiral Synthesis

[0081] Weigh 72g (0.46mol) of the side chain of chloroquine (chemical name: (±)-2-amino-5-diethylaminopentane), add it to a 250mL round bottom flask, then add 100mL of isopropanol, and stir to dissolve it; Add 36.5 g (0.24 mol) of D-(-)-mandelic acid (R-(-)-mandelic acid) into the reaction flask, stir at room temperature, and a large amount of white solid precipitates; stir for 3 hours to complete the salt formation, filter with suction, and use Wash the solid with isopropanol three times, 50 mL each time; combine the mother liquors and concentrate to 100 mL, add a small amount of the solid obtained by suction filtration as a seed crystal, so that the unprecipitated solid crystallizes; filter with suction, and wash with isopropanol three times, 50 mL each time. Combine the white solids obtained by suction filtration twice, put in a 250mL flask, pour 50mL of isopropanol, stir under reflux, slowly add isopr...

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Abstract

The invention discloses an application of chiral chloroquine, hydroxychloroquine or pharmaceutically acceptable salts of the chiral chloroquine and hydroxychloroquine in preparation of drugs used forpreventing and / or treating coronavirus pneumonia by using a coronavirus key drug target 3CL hydrolase (Mpro) as an action target. The chiral chloroquine and hydroxychloroquine have high bonding strength with the Mpro causing inflammation of the lung and the like; the activity of the Mpro can be significantly inhibited; and the chiral chloroquine and hydroxychloroquine are indicated to have the effect of preventing and treating pneumonia caused by coronaviruses and be able to be used as anti-pneumonia drugs. Through evaluation on the inhibitory activity of an hERG potassium ion channel, the concentration at which the chloroquine, hydroxychloroquine and enantiomers of the chloroquine and hydroxychloroquine are likely to generate cardiotoxicity to the hERG potassium ion channel is provided. The chiral chloroquine and hydroxychloroquine are prepared through chiral high-performance liquid chromatography and chiral synthesis; S-configuration chloroquine, hydroxychloroquine or salts of the chloroquine and hydroxychloroquine can be selected as a drug independently, or form a pharmaceutical composition for treating diseases caused by the coronaviruses; and due to higher activity and low cardiotoxicity of the chloroquine, hydroxychloroquine or salts of the chloroquine and hydroxychloroquine, the administration dosage range is greatly widened.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to the use of chiral chloroquine, hydroxychloroquine or a salt thereof as an anti-coronavirus drug target 3CL hydrolase inhibitor for reducing cardiotoxicity. Background technique [0002] The 2019 novel coronavirus pneumonia (COVID-19), which first broke out in December 2019, was caused by a new type of coronavirus, also known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Its clinical features are fever, dry cough, fatigue, and gradually progress to asthma, fatigue and other symptoms. Although some mild patients can recover spontaneously, there are still many patients with rapid disease progression in the later stage, developing acute respiratory distress syndrome (ARDS), sepsis, renal failure, metabolic acidosis that is difficult to correct, and hemorrhage and coagulation obstacle. The disease is mainly transmitted by respiratory droplets and contact, and t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4706A61P31/14A61P11/00C07D215/46C07B57/00A61K31/7052A61K33/30
CPCA61K31/4706A61P31/14A61P11/00C07D215/46C07B57/00A61K31/7052A61K33/30C07B2200/07A61K2300/00
Inventor 张绪穆罗海彬张彦涛李迎君李官官史永杰黄仪有李哲邹永陈新滋
Owner SOUTH UNIVERSITY OF SCIENCE AND TECHNOLOGY OF CHINA
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