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6-o-carbamoyl ketolide antibacterials

An alkyl and alkynyl technology, applied in the field of macrolide compounds, can solve the problems of low stability, poor absorption, instability, etc.

Inactive Publication Date: 2004-11-03
ORTHO MCNEIL PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to low stability in acidic environment, they often have various side effects such as oral absorption is usually poor and unstable

Method used

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  • 6-o-carbamoyl ketolide antibacterials
  • 6-o-carbamoyl ketolide antibacterials
  • 6-o-carbamoyl ketolide antibacterials

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0072]

[0073] Formula I'

[0074] where R 1 , R 2 , R 3 and R 4 as above. More specifically R 2 and R 3 is hydrogen and R 4 For fluorine.

[0075] The compound of formula 1 shown in formula 1 " further constitutes an embodiment of the present invention:

[0076]

[0077] Formula I"

[0078] where R 1 , R 2 , R 3 and R 4 as above. More specifically R 2 and R 3 are all hydrogen, and R 4 For fluorine.

[0079] where R 5 Compounds of formula 1 selected from acyl and aroyl form further embodiments of the invention.

[0080] The invention also provides methods of preparing the compounds of the invention.

[0081] Compounds of formula I can be prepared using readily available starting materials such as erythromycin and erythromycin derivatives known in the art. Schemes 1-18 describe representative methods for preparing inventive compounds:

[0082] plan 1

[0083]

[0084] Scheme 1 illustrates the precurso...

Embodiment 1

[0170] Embodiment 1. compound 6 (formula 1': R 1 for H, R 2 for H, R 3 for H, R 4 for H)

[0171]

[0172] Formula 1'

[0173] Step A

[0174] Triethylamine (42.0 mL, 301 mmol), DMAP (0.6 g, 4.9 mmol) and acetic anhydride (28.5 mL, 302 mmol). The temperature of the mixture was allowed to return to room temperature naturally, and stirred for 18 hours. Methanol (10 mL) was added and stirring was continued for 5 minutes. The mixture was diluted with ether (750 mL), followed by saturated NaHCO 3 Washed with aqueous solution, water and brine (500 mL each), dried (MgSO 4 ), the title compound was obtained as a colorless foam after concentration. The product was used directly in the next step without further purification. MS 860(M+H) + .

[0175] Step B

[0176] To a solution of Step A compound (50.0 mmol) in THF (500 mL) at 0° C. was added sodium hexamethyldisilazide (1.0 M in THF, 60.0 mL, 60.00 mmol) over 25 minutes. After 2 h at 0°C, the mixture w...

Embodiment 2

[0187] Example 2. Compound 106 (Formula 1': R 1 for H, R 2 for H, R 3 for H, R 4 for F)

[0188] To a solution of the compound from Example 1, Step F (520 mg, 0.76 mmol) in DMF (8 mL) was added sodium hexamethyldisilazide (1.0 M in THF, 1.14 mL, 1.14 mmol). After 30 minutes at -60°C, add SELECTFLUOR TM (324 mg, 0.91 mmol). The resulting mixture was stirred at -60°C for 10 min, diluted with ethyl acetate, washed with water and brine, dried (MgSO 4 ),concentrate. The resulting material was placed in methanol for 24 hours, then concentrated. Chromatography (SiO 2 , 3-5% methanol / dichloromethane + 0.1% concentrated NH 4 OH) and subsequent secondary chromatography (SiO 2 , acetone) to afford 201 mg (40%) of the title compound. MS 660(M+H) + .

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Abstract

6-0-carbamoyl ketolide antibacterials of the formula: wherein R<1>, R<2>, R<3>, R<4>, R<5>, R6, X, X', Y, and Y' are as described herein and in which the substituents have the meaning indicated in the description. These compounds are useful as antibacterial agents.

Description

field of invention [0001] The present invention relates to the field of macrolide compounds with antibacterial activity, pharmaceutical compositions containing such compounds and methods of using these compounds to treat bacterial infections. Background of the invention [0002] Erythromycins are known antibacterial agents widely used in the treatment and prevention of bacterial infections caused by Gram-positive and Gram-negative bacteria. However, they often have various side effects such as poor oral absorption and instability due to low stability in acidic environments. As is the case with other antimicrobial agents, strains with resistance or reduced susceptibility to erythromycin have now been developed and identified in patients with: community-acquired pneumonia, upper and lower respiratory tract infections, skin and soft tissue infections, meningitis, hospital-acquired lung infections, and bone and joint infections. Particularly serious pa...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/7056A61P31/04C07H17/08
CPCC07H17/08A61P31/04A61K31/70
Inventor T·C·亨宁格X·C·徐
Owner ORTHO MCNEIL PHARM INC
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