Oxazolidinone compounds and compositions and methods related thereto

A compound and alkyl technology, applied in the field of oxazolidinone antibacterial compounds, can solve the problems of undescribed antibacterial activity and MAOi activity, and achieve the effect of weak inhibitory activity

Inactive Publication Date: 2007-08-29
菲尔诺国际公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These documents do not describe antibacterial activity and MAOi activity

Method used

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  • Oxazolidinone compounds and compositions and methods related thereto
  • Oxazolidinone compounds and compositions and methods related thereto
  • Oxazolidinone compounds and compositions and methods related thereto

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0107] (a) Preparation of amide compound (I, X=O):

[0108] Formally, the amides are prepared by condensation of the active form of the acid (III) with the corresponding aminomethyl derivative (II). The acid can previously be converted to a reactive acylating reagent either by isolation or by in situ preparation. Acid halides, imidazolides, p-nitrophenyl esters or 2,4,5-trichlorophenyl esters are more commonly used isolatable acylated species prepared directly from carboxylic acids. These activation methods generate acid halides in situ in the presence of nucleophiles such as refluxing carboxylic acids, triphenylphosphine, trichloromethyl bromide, and the amines. Other coupling reagents convert carboxylic acids into reactive intermediates that react with nucleophilic amines. Many such reagents can be used, some of them are as follows: dicyclohexylcarbodiimide, 2-chloropyridinium cation, 3-chloroisoxazolium cation, diphenylphosphoryl Azide, N-hydroxybenzotriazole (HOBt), 2-(...

Embodiment 1

[0145] Example 1: N-[[(5S)-3-[3-fluoro-4-(4-morpholinyl)-phenyl]-2-oxo-5-oxazolidinyl]methyl]furan-2 -yl-amide

[0146]

[0147] In 5 ml of dichloromethane (DCM), 57 mg (1.5 equivalents) of 2-furanoic acid, 21 mg (0.5 equivalents) of 4-(dimethylamino)pyridine (DMAP), 97 mg of 1-ethyl-3-(3′-dimethyl A solution of aminopropyl)carbodiimide hydrochloride (EDCI.HCl, 1.5 equiv) was stirred at room temperature under argon for 30 minutes. Then, 100 mg (1 equivalent) of N-[[(5S)-3-[3-fluoro-4-(4-morpholinyl)-phenyl]-2-oxo-5-oxazole was added to 5 ml DCM Alkyl]methyl]amine and stirring was continued for 12 hours when complete conversion of the starting amine was observed by TLC. The crude mixture was washed with 5% HOAc solution, saturated NaHCO 3 and washed with brine. The combined organic layers were dried (MgSO 4 ) and concentrated under vacuum to give 125 mg of N-[[(5S)-3-[3-fluoro-4-(4-morpholinyl)-phenyl]-2-oxo-5-oxazolidinyl] Methyl]furan-2-yl-amide (Yield = 95%).

[01...

Embodiment 2

[0151] Example 2: N-[[(5S)-3-[3-fluoro-4-(4-morpholinyl)-phenyl]-2-oxo-5-oxazolidinyl]methyl]furan-2 -yl-thioamide

[0152]

[0153] 87mg N-[[(5S)-3-[3-fluoro-4-(4-morpholinyl)-phenyl]-2-oxo-5-oxazole in 4ml 1,4-dioxane A solution of alkyl]methyl]furan-2-yl-amide, 271.3 mg (3 eq) of Lawesson's reagent was heated at 65°C for 3 hours and at 100°C for 1 h. The solvent was removed under reduced pressure and the crude product was purified by column chromatography (Merck silica gel, DCM / MeOH 99 / 1) to obtain 87 mg of the title product (Yield = 96%).

[0154] HPLC (t, %): 11.3 min, 96%.

[0155] MS(ESI)m / z=406(M+1)

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Abstract

The invention provides new oxazolidinones of formula (I), where R1, R2, R3 and R4 are independently selected from hydrogen, F and Cl; A is selected from certain heterocycles optionally substituted; X is selected from O, S, NRs and CR8Rg; Y is selected from O, S, SO, SO2, NO, NR11 and CR11R12; and n is selected from 0 and 1. The invention also provides different processes for the preparation of such compounds. Oxazolidinone compounds of formula (I) are active against Gram-positive and some Gram-negative human and veterinary pathogens with a weak monoamine oxidase (MAO) inhibitory activity. They are useful for the treatment of bacterial infections.

Description

technical field [0001] The present invention relates to an oxazolidinone antibacterial compound, which can effectively fight against Gram-positive bacteria and some Gram-negative bacteria, and has weak monoamine oxidase (MAO) inhibitory activity. Background of the invention [0002] Oxazolidinones are prominent among the new Gram-positive antimicrobials now becoming effective. Oxazolidinones bind to the 50S subunit of prokaryotic ribosomes, preventing the formation of the initiation complex for protein synthesis. This is a new way of working. Other protein synthesis inhibitors either block elongation of the polypeptide or cause misreading of the mRNA. Linezolid (N-[[(5S)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide is The first antibacterial oxazolidinone approved for clinical use in the United States and elsewhere. [0003] [0004] Linezolid [0005] According to the test method, the minimum inhibitory concentration (MICs) of linezolid...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/00A61P31/04A61K31/541
CPCC07D413/14C07D413/12A61P31/04A61P43/00C07D413/00A61K31/541
Inventor M·卡诺A·帕洛莫A·古列塔
Owner 菲尔诺国际公司
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