N-formyl hydroxylamine compounds, preparation method, and use thereof

A technology of compounds and mixtures, applied in the field of medicine, can solve the problems of high polarity and easy interconversion of hydroxime groups

Inactive Publication Date: 2012-05-16
TIANJIN INSTITUTE OF PHARMA RESEARCH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] However, the polarity of the hydroxamic group in this

Method used

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  • N-formyl hydroxylamine compounds, preparation method, and use thereof
  • N-formyl hydroxylamine compounds, preparation method, and use thereof
  • N-formyl hydroxylamine compounds, preparation method, and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0081] Example 1 Preparation of 2-[(N-benzyloxy-N-formylamino)methyl]hexanoic acid

[0082] Preparation of acetone oxime: Add 20 mL of water and 6.95 g (0.1 mol) of hydroxylamine hydrochloride to a 100 mL round bottom flask, stir to dissolve the solid, drop in 6.38 g (0.11 mol) of acetone, react at room temperature for 1.5 hours, cool in an ice-water bath, and batch 4.0 g (0.1 mol) of sodium hydroxide was added one at a time, stirred for 0.5 hours, extracted with ether (30 mL×3), dried, and distilled off ether to obtain 6.79 g of white solid, yield 93%, m.p.61-62°C.

[0083] Preparation of oxybenzylacetone oxime: add 8.0 g (0.348 mol) of sodium metal into 150 mL of absolute ethanol, and cool down after all the sodium metal is dissolved. The solution obtained by dissolving 25.4g (0.348mol) of acetone oxime in 100mL of absolute ethanol was added dropwise to sodium ethoxide, and stirred for 1 hour. Then 44.1 g (0.348 mol) benzyl chloride was slowly added dropwise to the reacti...

Embodiment 2

[0092] Example 2 Preparation of 3-phenyl-5-aminomethylisoxazole

[0093] This example is the raw material used to prepare the compound of the present invention: 3-phenyl-5-aminomethylisoxazole, which is one of the compounds represented by formula III.

[0094] The chemical reaction is as follows:

[0095]

[0096] Preparation of benzaldoxime: Add 150mL of water, 50mL of methanol and 10.6g (0.10mol) of benzaldehyde into a 500mL Erlenmeyer flask, stir well and add 8.34g (0.12mol) of NH 2 After OH·HCl was completely dissolved, 6.36 g (0.06 mol) of sodium carbonate was added slowly, stirred at room temperature for 4 h, then 200 mL of water was added, and dichloromethane (60 mL×4) was extracted. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 11.2 g of a white solid. Yield 97%, m.p. 128-130°C. 1 H NMR (300MHz, CDCl 3 , δppm): 7.40-7.50 (m, 3H, Ar-H), 7.58-7.65 (m, 2H, Ar-H), 8.24 (s, 1H, OH).

[009...

Embodiment 3

[0101] Example 3 Preparation of N-[4-amino-2-carbonyl-(4-phenyl)butyl]-2-[(N-hydroxy-N-formylamino)methyl]hexanamide

[0102]

[0103] To a 50 mL round bottom flask was added 1.0 g (5.72 mmol) CDMT and 1.45 g (5.20 mmol) 2-[(N-benzyloxy-N-formylamino)methyl]hexanoic acid dissolved in dry dichloromethane (30 mL ), add dropwise 683mg (6.76mmol) N-methylmorpholine under ice-salt bath, after reacting for 4 hours, add 2.26g (5.20mmol) 3-phenyl-5-aminomethylisoxazole, After reacting for 2 hours, react overnight at room temperature. Remove the precipitate by filtration, wash the precipitate with a small amount of dichloromethane, combine the washing liquid and the filtrate, and successively wash with 0.5mol / L hydrochloric acid, saturated NaHCO 3 , saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated on a silica gel column (dichloromethane:methanol=20:1) to obtain 1.56 g of a white solid, with a yield of ...

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Abstract

The present invention relates to N-formyl hydroxylamine compounds, a preparation method and a use thereof. The present invention provides a compound represented by a formula (I), or a pharmaceutically-acceptable salt of the compound, or an enantiomer of the compound, or a raceme mixture of the compound, wherein R1 is H, linear or branched alkyl containing 1 to 5 carbon atoms, R2 and R3 independently represent H, linear alkyl containing 1 to 5 carbon atoms, -OR', -SR', -halogen, -CN, -CONR', -COOR' or -COR', wherein R' is H, linear or branched alkyl containing 1 to 5 carbon atoms. The present invention further provides a method for preparing the compounds, a drug composition containing the compounds, and a use of the compounds. The compounds of the present invention have effects of prevention and/or treatment of infectious diseases, and can be used for preparation of antimicrobial drugs.

Description

technical field [0001] The invention belongs to the technical field of medicine, in particular, the invention relates to N-formyl hydroxylamine compounds as inhibitors of peptide deformylase (PDF) and its preparation method and application. Background technique [0002] In my country, the incidence of infection is relatively high. In recent years, due to the widespread use of antibiotics, drug-resistant bacteria have increased and spread, making the market life of new antibiotics shorter and shorter. It is urgent to strengthen the rational use of antibiotics to reduce the incidence of drug-resistant bacteria. At the same time, it should also accelerate the development of new structural antibiotics. [0003] Peptide deformylase (PDF) is a metallopeptidase present in prokaryotes such as bacteria, and the peptide deformylation catalyzed by it is an essential process in the metabolism of Escherichia coli and most bacteria. This process is absent in the mitochondria of mammals an...

Claims

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Application Information

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IPC IPC(8): C07C259/06A61K31/166A61K31/16A61P31/00A61P31/04
Inventor 王建武孟凡翠贾炯徐为人尹玲汤立达刘巍赵桂龙
Owner TIANJIN INSTITUTE OF PHARMA RESEARCH
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