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Oxazolidinones having sulfoximine functionality and their use as antimicrobial agents

A technology of oxazolidine and alkyl, applied in the field of oxazolidinone containing sulfonimide functional group, can solve problems such as inactivity

Inactive Publication Date: 2003-01-15
PHARMACIA & UPJOHN CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] However, useful levels of oxazolidinones are generally inactive against aerobic Gram-negative bacteria
Therefore, the use of these oxazolidinone antimicrobials is limited to infections caused by Gram-positive bacteria

Method used

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  • Oxazolidinones having sulfoximine functionality and their use as antimicrobial agents

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0073] Example Preparation 1: N-({(5S)-3-[3-fluoro-4-(1-imino-1-oxo bridge-1λ 4 ,4-thiazidin-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide (2)

[0074] ((S)-N-[[3-[3-fluoro-4-(1-oxothiomorpholin-4-yl)phenyl]-2-oxo -5-oxazolidinyl]methyl]acetamide (compound 1, prepared according to the method described in Example 3 of WO95 / 07271) (1.01g, 2.73mmol) and sodium azide (0.38g, 5.8mmol) Add pyrophosphoric acid (40g), warm the mixture at 50-55°C for 6 hours, and at 60°C for 4 hours. Slowly cool to 0°C, add water (20ml) and a sufficient amount of 50% (w / w) Sodium hydroxide raises the pH to 10.5-11.0. The mixture is diluted with sufficient water to obtain a solution which is extracted with chloroform. The extract is dried (sodium sulfate) and concentrated. The residue is chromatographed on silica gel Purification, eluting with a mixture of methanol-chloroform containing 2-3% methanol, gave 691 mg of product. The product was crystallized in acetone...

Embodiment 2

[0085] Found: C 47.98; H 5.34; N 14.01 Example 2: N-({(5S)-3-[3-fluoro-4-(1-imino-1-oxo-1λ 4 ,4-thiazidin-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)thiopropionamide (5)

[0086] Compound 3 was reacted with ethyl dithiopropionate and triethylamine in methanol in the manner described in Example 1, step 2 to afford compound 5, which crystallized in methanol. Melting point: 189-190°C; HRMS (FAB): C 17 h 24 FN 4 o 3 S 2 (M+H + ) calculated value: 415.1273

[0087] Measured value: 415.1278C 17 h 23 FN 4 o 3 S 2 Anal. Calcd for: C 49.26; H 5.59; N 13.52;

Embodiment 3

[0088] Found: C 49.89; H 5.81; N 13.18 Example 3: N-({(5S)-3-[3-fluoro-4-(1-imino-1-oxo-1λ 4 ,4-thiazidin-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)cyclopropanethiocarboxamide (6)

[0089] Compound 3 was reacted with ethyl dithiocyclopropanecarboxylate and triethylamine in methanol in the manner described in step 2 of Example 1 to give compound 6 which crystallized in methanol. Melting point: 209-210°C (decomposition); HRMS (FAB): C 18 h 24 FN4 o 3 S 2 (M+H + ) calculated value: 427.1273

[0090] Measured value: 427.1289C 18 h 23 FN 4 o 3 S 2 Analytical calculated values ​​for: C 50.69; H 5.43; N 13.14;

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Abstract

The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof wherein: A is a structure i, ii, iii, or iv; B is (a), (b), (c) W is NHC(=X)R1, or -Y-het; provided that when A is a structure iv, W is not -Y-het; Z is S(=O)(=N-R5); and R2 and R3 are independently H, F, CI, methyl or ethyl; which have potent activities against Gram-positive and Gram-negative bacteria.

Description

field of invention [0001] The present invention relates to novel oxazolidinones containing sulfoximino functional groups and processes for their preparation. These compounds have strong activity against Gram-positive and Gram-negative bacteria. Background of the invention [0002] Oxazolidinone antibacterial agents are a new class of synthetic fungicides that are highly active against many pathogenic bacteria in humans and animals, including Gram-positive aerobic bacteria such as multidrug-resistant staphylococci and streptococci, anorexia Aerobic bacteria such as Bacteroides and Clostridium and acid-fast bacteria such as Mycobacterium tuberculosis and Mycobacterium avium. [0003] However, useful levels of oxazolidinones are generally inactive against aerobic Gram-negative bacteria. Therefore, the use of these oxazolidinone antibacterial agents is limited to infections caused by Gram-positive bacteria. Accordingly, it is an object of the presen...

Claims

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Application Information

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IPC IPC(8): C07D263/20A61K31/422A61K31/541A61P17/00A61P27/02A61P31/00A61P31/04C07D413/10C07D417/10
CPCC07D413/10C07D417/10A61P17/00A61P27/02A61P31/00A61P31/04
Inventor J·B·小海斯特D·L·阿莱克安德
Owner PHARMACIA & UPJOHN CO
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