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Monocycle gyrase and topoisomerase IV inhibitor

A technology of stereoisomers and heterocyclic groups, applied in medical preparations containing active ingredients, organic active ingredients, organic chemistry, etc., can solve problems such as poor solubility, poor penetration of bacterial outer membrane, and lack of clinical application

Active Publication Date: 2016-11-30
BEIJING SIHUAN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Quinolones mainly act on the GyrA subunit for the DNA gyrase target, and mainly act on the ParC subunit for the topoisomerase. However, there are few reports about the mutations of GyrB subunit and PaerE subunit, so the clinical application of quinolone antibiotics is limited to a certain extent.
Coumarin compounds, such as novobiocin, chlorobiocin, and coumarin, mainly target DNA gyrase. These compounds have problems such as poor solubility and poor penetration of bacterial outer membranes, so they are not Not widely used clinically

Method used

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  • Monocycle gyrase and topoisomerase IV inhibitor
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  • Monocycle gyrase and topoisomerase IV inhibitor

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0124] The present invention also provides the preparation method of above-mentioned compound:

[0125]

[0126] Reaction steps:

[0127] (1) Preparation of intermediate 1

[0128] Add raw materials 2, 1,4-dioxane, BiPin to the reaction flask 2 , KAc, palladium catalyst (such as Pd(dppf)Cl 2 ) and halogenated organic solvents (such as dichloromethane, chloroform), heating under nitrogen protection, cooling, adding sodium bicarbonate, water, raw material 1, palladium catalyst (such as Pd(dppf)Cl 2 ) and halogenated organic solvents (such as dichloromethane, chloroform), continue to react for about 4h. The reaction solution was concentrated and purified to obtain Intermediate I. Y represents halogen.

[0129] (2) Preparation of Intermediate 2

[0130] Add intermediate 1 into a mixed organic solvent (such as methanol, ethanol, tetrahydrofuran, triethylamine), add palladium on carbon, and stir under hydrogen atmosphere until the reaction is complete. Suction filtration a...

experiment example 1

[0169] The in vitro antibacterial activity of experimental example 1 compound of the present invention

[0170] Tested strains: All the clinically isolated strains used in the test were purchased from public institutions.

[0171] LRE and LRS strains were obtained from Peking University First Hospital; MRSA, MRSE, PRSP and other strains were purchased from Jinan Central Hospital, Renji Hospital Affiliated to Shanghai Jiao Tong Fourth Hospital and the Affiliated Hospital of the Third Military Medical University.

[0172] Test items: compounds 1, 2, 3, 15, 17, 20, 55, 56, 57, 59;

[0173] Compound of the present invention, its chemical name and structural formula see embodiment;

[0174] Experimental method: agar dilution method, refer to National Committee for Clinical Laboratory Standards.2006.Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard--Seventh Edition M7-A7.Vol26, no.2, Wayne, PA: Clinical And Laboratory S...

experiment example 2

[0183] Rat Pharmacokinetic Experiment of Experimental Example 2 Compound of the present invention

[0184] Test samples: Compound 2, Compound 20, Compound 55, and Compound 57 of the present invention are self-made, and their chemical names and preparation methods are shown in the preparation examples of each compound.

[0185] Test animals: male SD rats, 3 / administration dose / test product, body weight 210-290g / rat.

[0186] Preparation of the test solution:

[0187] Preparation of blank solvent:

[0188] Preparation of 28% Captisol solution: Weigh 8.4g of Captisol, add a small amount of purified water to dissolve it ultrasonically, then dilute to 30mL with purified water, vortex and mix to obtain the product.

[0189] Preparation of 28% and 40% HP-β-CD solutions: Weigh 2.8g and 4.0g of HP-β-CD, prepare 10mL solutions with sterilized water for injection, and vortex to obtain the solution.

[0190](1) Compound 2, intravenous injection (iv) prescription: 5% DMSO+10% PEG400+85%...

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Abstract

The invention belongs to the technical field of medicines, and in particular relates to a gyrase and topoisomerase IV inhibitor compound of formula (I) as shown in the specification, and a pharmaceutically acceptable salt, an ester or stereoisomers thereof. In the formula, R1, R2, R3 and cycle A are defined as in the specification. The invention further relates to preparation methods, medicinal preparations, medicinal compositions and applications of the compounds in preparing medicines for treating and / preventing bacterium infectious diseases.

Description

1. Technical field [0001] The invention belongs to the field of medical technology, and specifically relates to gyrase and topoisomerase IV dual-target inhibitor compounds, pharmaceutically acceptable salts, esters or stereoisomers thereof; the invention also relates to preparation methods of these compounds, Pharmaceutical preparations, pharmaceutical compositions and applications in the preparation of medicines for treating and / preventing bacterial infectious diseases. 2. Background technology [0002] With the extensive use of antibiotics, especially non-indication use, inappropriate selection of backup antimicrobials, overtreatment and frequent replacement of antibiotics, the frequency of bacterial resistance to drugs is increasing. In particular, the emergence of some specific bacterial strains, such as: Streptococcus pneumoniae, Mycobacterium tuberculosis and Enterococcus, have made various clinically widely used antibiotics ineffective to varying degrees. Therefore, t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/14C07D409/14A61K31/4439A61K31/506A61K31/454A61K31/4545A61K45/00A61P31/04A61P31/06
CPCC07D405/14C07D409/14
Inventor 吴永谦田玉伟
Owner BEIJING SIHUAN PHARMA
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