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6-O-acyl ketolide derivatives of erythromycine useful as antibacterials

An alkynyl and alkyl technology, applied in the field of macrolide compounds, can solve the problems of low stability and unstable oral absorption of erythromycin

Inactive Publication Date: 2005-02-23
ORTHO MCNEIL PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the low stability of erythromycin in an acidic environment, it often produces negative reactions such as poor and unstable oral absorption

Method used

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  • 6-O-acyl ketolide derivatives of erythromycine useful as antibacterials
  • 6-O-acyl ketolide derivatives of erythromycine useful as antibacterials
  • 6-O-acyl ketolide derivatives of erythromycine useful as antibacterials

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0212] Compound IX

[0213] Step A

[0214] Triethylamine (42.0 mL, 301 mmol), DMAP (0.6 g, 4.9 mmol) and acetic anhydride (28.5 mL, 302 mmol) were added to suspend erythromycin (36.7 g, 50 mmol) in dichloromethane (250 mL) at 0° C. in the liquid. The mixture was allowed to warm to room temperature and stirred for 18 hours. Methanol (10 mL) was added and stirring was continued for 5 minutes. The mixture was diluted with diethyl ether (750 mL), washed with saturated aqueous sodium bicarbonate, water and brine (500 mL each), dried (magnesium sulfate) and concentrated to afford the title compound as a colorless foam. The material was used directly in the next step without further purification. MS860(M+H) + .

[0215] Step B

[0216] Sodium hexamethyldisilylamide (1.0 M in tetrahydrofuran, 60.0 mL, 60.00 mmol) was added to a solution of the compound from Step A (50.0 mmol) in THF (500 mL) at 0° C. over 25 minutes. After 2 hours at 0 °C, the mixture was diluted with water (...

Embodiment 2

[0228] Compound 2 (formula 1a: R 5 for H, R 6 for H)

[0229] A solution of compound IX (1.00 g, 1.56 mmol), 2,5-dimethoxytetrahydrofuran (0.40 mL, 3.09 mmol) and trifluoroacetic acid (0.60 mL, 7.79 mmol) in acetonitrile (10 mL) was stirred at room temperature for 24 hours . Water (5 mL) was added and the solution was stirred for 20 hours. The reaction mixture was diluted with ethyl acetate (75 mL), washed with saturated aqueous sodium bicarbonate (50 mL) and brine (50 mL), dried over magnesium sulfate and concentrated. Purified by chromatography (SiO 2 , 95:5:0.2 dichloromethane / methanol / conc. ammonia) afforded 550 mg (51%) of the title compound. MS 692(M+H) + .

Embodiment 3

[0231] Compound 3 (formula 1a: R 5 is C(O)H, R 6 for H)

[0232] A solution of compound IX (500 mg, 0.78 mmol), 2,5-dimethoxy-3-tetrahydrofurfuraldehyde (625 mg, 3.90 mmol) and trifluoroacetic acid (0.60 mL, 7.79 mmol) in acetonitrile (5 mL) was stirred at room temperature 18 hours. The reaction mixture was diluted with ethyl acetate (50 mL), washed with saturated aqueous sodium bicarbonate (50 mL) and brine (50 mL), dried over sodium carbonate and concentrated. Purified by chromatography (SiO 2 , 95:5:0.5 dichloromethane / methanol / conc. ammonia) afforded 255 mg (45%) of the title compound. MS 720(M+H) + .

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Abstract

6-O-Acyl ketolide antibacterials of the formula (I), wherein R1, R2, R3, R4, W, 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

[0001] Cross References to Related Applications [0002] This application claims the benefit under 35 U.S.C. § 119(e) of provisional patent serial nos. 60 / 392,513, filed June 28, 2002, and 60 / 338,566, filed December 5, 2001, both provisional applications Both are incorporated herein by reference. field of invention [0003] The field of the invention relates to macrolide compounds having antibacterial activity, to pharmaceutical compositions containing such compounds, and to methods of using such compounds to treat bacterial infections. Background of the invention [0004] Erythromycin is well known as an antibacterial agent widely used in the treatment and prevention of bacterial infections caused by Gram-positive and Gram-negative bacteria. However, due to the low stability of erythromycin in an acidic environment, negative reactions such as poor and unstable oral absorption often occur. As with other types of antimicrobials,...

Claims

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Application Information

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IPC IPC(8): A61K31/7048A61P31/04C07D498/04C07H17/08
CPCC07D498/04C07H17/08A61P31/04
Inventor T·C·亨宁格尔M·J·马切拉M·A·滕纳库恩X·徐
Owner ORTHO MCNEIL PHARM INC
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