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Novel oxazolidinone compound, as well as preparation method and application thereof

A technology for oxazolidinones and compounds, which is applied in the field of new oxazolidinones and their preparations, and can solve the problems of difficult cross-resistance, weak inhibitory activity of peptidyltransferase, single variety of oxazolidinine antibacterial drugs, etc. problems, to achieve the effect of solving the side effects of hypertensive crisis, improving the activity of dilating blood vessels, and having atom economy

Active Publication Date: 2014-02-26
GUANGXI WUZHOU PHARMA GRP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Oxazolidinone compounds are a new class of antibacterial drugs for the treatment of bacterial infections. Peptidyltransferase inhibitors (such as lincomycin and chloramphenicol) partially overlap in their sites of action, but their mechanisms of action are significantly different. The former selectively inhibits the initial stage of protein synthesis and has no effect on peptidyl transfer The enzyme inhibitory activity is extremely weak, so it is not easy to cross-resistance with other antibacterial drugs that inhibit protein synthesis
Although the oxazolidinone represented by this drug can be used to treat microbial infections, infections caused by linezolid-resistant Staphylococcus aureus and Enterococcus have appeared clinically after long-term use, and their application is due to severe limited by side effects
Such as the inhibitory effect of monoamine oxidase, it cannot be used simultaneously with many drugs, such as serotonin reuptake inhibitors or other antidepressants, and it is accompanied by side effects such as thrombocytopenia and bone marrow suppression. If it is used in combination with epinephrine drugs, hypertensive crisis
[0003] Clinically, the drug resistance of Gram-positive bacteria is becoming more and more serious, and the clinical use of oxazolidine antibiotics is single
As a new type of antibacterial drug, linezolid has played a certain role in overcoming bacterial resistance, but the drug resistance of linezolid is becoming more and more serious. Therefore, it is urgent to expand the clinical application varieties of oxazolidinone antibiotics, and develop antibacterial drugs that are highly effective against drug-resistant Gram-positive bacteria and have low toxic and side effects.

Method used

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  • Novel oxazolidinone compound, as well as preparation method and application thereof
  • Novel oxazolidinone compound, as well as preparation method and application thereof
  • Novel oxazolidinone compound, as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Example 1: Preparation of 2,3,5-trimethyl-6-((4-nitrophenoxy)methyl)pyrazine (A1)

[0047]

[0048] In the 50mL two-necked flask, add TMP-Br (1.188g, 5.52mmol, TMP-Br is made by known method, can refer to literature Journal of Fudan University, 1980,4:390-394.), p-nitrophenol ( 0.640g, 4.60mmol), potassium carbonate (1.279g, 9.20mmol), and add 5.5mL of anhydrous DMF to dissolve, heat to 85°C, stir for 5-7h, and stop the reaction. The reaction solution was cooled to room temperature, poured into 50 times the volume of ice water, and white flocs were precipitated, filtered to obtain a white solid, and dried in vacuo to obtain a yellowish (log color) solid A1 (1.173 g, 93.4%).

[0049] 1 H NMR (300MHz, CDCl 3 ):δ8.15(d,J=8.0Hz,2H),7.06(d,J=9.1Hz,2H),5.23(s,2H),2.56(s,3H),2.49(s,6H).

Embodiment 2

[0050] Example 2: Preparation of 2-((2-fluoro-4-nitrophenoxy)methyl)-3,5,6-trimethylpyrazine (B1)

[0051]

[0052] Using 2-fluoro-4-nitrophenol and TMP-Br as raw materials, the preparation method was the same as in Example 1 to obtain light yellow solid B2 (6.0 g, 95.2%).

[0053] 1 H NMR (300MHz, CDCl 3 ):δ8.01(ddd, J=9.0,2.6,1.4Hz,1H),7.95(dd,J=10.5,2.7Hz,1H),7.27(dd,J=11.3,5.8Hz,1H),5.33( s,2H),2.59(s,3H),2.50(d,J=2.2Hz,6H).

Embodiment 3

[0054] Example 3: Preparation of benzyl 4-((3,5,6-trimethylpyrazin-2-yl)methoxy)carbamate (A2)

[0055]

[0056] Add A1 (6.0g, 22mmol, the preparation method is the same as in Example 1) and 10%Pd / C (0.6g) into a 100mL two-necked round-bottomed flask, then add THF (35mL) and stir to dissolve. The reaction system was evacuated at 0° C. under a hydrogen atmosphere, replaced with nitrogen twice and once with hydrogen, and then stirred and reacted at room temperature for 24 hours. Filter through diatomaceous earth, wash with acetone 3 times, spin the filtrate to dryness under reduced pressure, and put it directly into the next step. Place the obtained product in the previous step into a 100 mL two-neck round bottom flask, and use 4 mL of H 2 O dissolved sodium carbonate (2.6g, 2.2mmol) into the reaction flask, then added 40mL of acetone, and slowly added benzyloxycarbonyl chloride (10mL, 66mmol) dropwise under a nitrogen atmosphere. After reacting at room temperature for 18 h...

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Abstract

The invention belongs to the field of medicines, and discloses a novel oxazolidinone compound, as well as a preparation method and application thereof. The compound has a chemical structure shown in the formula (I), wherein R1 and R2 are hydrogen, fluorine or chlorine; R3 is -OR4, -NR5R6, -NHCOR7, fluorine, azide group, primary amine group, triazole, triazole containing side chain radicals, mono-phosphate, metal phosphate, sulfonate or metal sulfonate. The novel oxazolidinone compound can be applied to preparation of antibacterial agents or active vasodilator agents.

Description

technical field [0001] The invention belongs to the field of medicine, in particular to a novel oxazolidinone compound and its preparation method and application. Background technique [0002] Due to the increase in antibiotic resistance, especially in Gram-positive bacteria, new types of antibacterial drugs with new structures and new modes of action are urgently needed in the treatment of bacterial infections. At present, Linezolid (ZyvoxR), the first oxazolidinone antibacterial agent, was approved for marketing in the United States in April 2000, and is used to treat infections caused by multidrug-resistant Gram-positive bacteria. Oxazolidinone compounds are a new class of antibacterial drugs for the treatment of bacterial infections. Peptidyltransferase inhibitors (such as lincomycin and chloramphenicol) partially overlap in their sites of action, but their mechanisms of action are significantly different. The former selectively inhibits the initial stage of protein syn...

Claims

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Application Information

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IPC IPC(8): C07D413/12C07D413/14A61P31/04A61P9/08
CPCC07D413/12C07D413/14
Inventor 陈卫民阮志雄陈艳皇甫德胜孙平华
Owner GUANGXI WUZHOU PHARMA GRP
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