Z-halo-6-o-substituted ketolide derivatives

A technology of substituents and compounds, applied in the field of semi-synthetic macrolides, can solve problems such as erythromycin resistance or insufficient sensitivity

Inactive Publication Date: 2001-02-07
ABBOTT LAB INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] However, it is recognized that, as with other antimicrobials, strains are resistant or have insufficient susceptibility to erythromycin

Method used

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  • Z-halo-6-o-substituted ketolide derivatives
  • Z-halo-6-o-substituted ketolide derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0189] Compound of formula (I): R p is H, R 1 Be methyl, X is F step 1a formula (I) compound: R p is benzoyl, R 1 is methyl, X is F

[0190] Scheme 3 compound 12 at 0°C (wherein R p is benzoyl, R 1 NaH (60% in oil, 108mg, 2.70mmol) was added to a solution of NaH (60% in oil, 108mg, 2.70mmol), and the mixture was stirred for 30 minutes . N-Fluorobenzenesulfonylimide (510 mg, 1.62 mmol, Aldrich) was added to the solution, and the mixture was stirred at 0°C for 3 hours. The mixture was taken up in 2-propyl acetate and washed successively with aqueous sodium bicarbonate and brine, dried over sodium sulfate and concentrated in vacuo. Chromatography on silica gel (eluting with 2:1 hexane:acetone) gave the title compound (615 mg). Step 1b Compound of formula (I): R p is H, R 1 is methyl, X is F

[0191] A sample (600mg, 0.791mmol) of the compound obtained in step 1a (solution) in methanol (25ml) was heated at reflux for 24 hours to remove the 2'-benzoyl group. The me...

Embodiment 2

[0195] In scheme 3 compound 12 (wherein R p is H, R 1 is methyl) (130mg, 0.204mmol, prepared according to U.S. Patent 5,631,355) in N-methylpyrrolidone (1.5ml) was added hexachloroethane (50mg, 0.214mmol) and sodium carbonate (43mg, 0.408 mmol). The mixture was stirred at room temperature for 3 days, further hexachloroethane (50 mg) and sodium carbonate (50 mg) were added, and the mixture was stirred at 60°C for 24 hrs. The mixture was dissolved in 2-propanol and washed sequentially with 5% aqueous sodium bicarbonate and brine, dried over sodium sulfate, and concentrated in vacuo. Chromatography on silica gel (eluting with acetone) gave the title compound (67 mg).

[0196] MS m / z672(M+H) + ;

[0197] 13 C NMR (75MHz, CDCl 3 )δ201.3, 181.0.165.8, 155.9, 104.1, 81.4, 80.7, 79.3, 80.0, 74.2, 70.4, 69.6, 65.9, 60.5, 49.6, 48.4, 42.8, 42.3, 42.2, 40.2, 38.9, 36.2, 31.8 .28.2, 22.1, 21.1, 19.7, 18.7, 16.5, 13.0, 11.0, 10.5;

[0198] HRMS m / z(M+H) + Analysis C 33 h 55 ClN...

Embodiment 3

[0200] Scheme 3 compound 12 at 0°C (wherein R p is H, R 1 is methyl) (500mg, 0.785mmol, prepared according to US Pat. 3 (352 mg, 1.10 mmol). The mixture was stirred at room temperature overnight, and pyridine·HBr was added 3 (2 equivalents), and the mixture was stirred at room temperature for 5 hours. The mixture was quenched with aqueous sodium carbonate and saturated aqueous sodium thiosulfate, pH 10. The mixture was extracted with dichloromethane, then washed successively with aqueous sodium carbonate and brine, dried over sodium sulfate, and concentrated in vacuo. Silica gel chromatography (with 3-5% (2M NH 3 methanol) and dichloromethane) to give the title compound (226 mg). MS (DCI / NH 3 )m / z 716( 79 Br(M+H) + ) and 718 ( 81 Br(M+H) + ); 13 C NMR (75 MHz, CDCl 3 )δ 201.6, 181.1, 166.1, 155.8, 103.6, 81.4, 80.1, 79.8, 78.8, 70.3, 69.4, 66.0, 65.8, 60.3, 49.4, 48.5, 44.0, 42.8, 42.2, 40.2, 38.8, 36.0, 32.5, 28.2, 20.0, 21.1, 19.6, 18.8, 17.4, 14.0, 13.0, 10.9,...

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Abstract

The present invention relates to novel 2-halogenated-6-O-substituted ketolide derivatives of formula (I) or (II) with antibacterial activity and pharmaceutically acceptable salts and esters thereof, containing a therapeutically effective amount of the compound of the present invention Compositions with pharmaceutically acceptable carriers combined therewith, methods for treating bacterial infections by administering to mammals a pharmaceutical composition containing a therapeutically effective amount of the compound of the present invention, and methods for their preparation.

Description

technical field [0001] The present invention relates to novel semi-synthetic macrolides with antibacterial activity, pharmaceutical compositions and medical methods containing these compounds. More particularly, the present invention relates to novel 2-halo-6-O-substituted ketolide derivatives, processes for their preparation, compositions containing these compounds, and methods of using these compositions to treat bacterial infections. Background of the invention [0002] Erythromycins A to D represented by the formula (E) are known effective antibacterial agents and have been widely used in the treatment and prevention of bacterial infections. [0003] However, it is recognized that, as with other antimicrobials, strains are resistant or have insufficient susceptibility to erythromycin. Furthermore, erythromycin A has only weak activity against Gram-negative bacteria. Therefore, there is still a need to recognize new erythromycin derivatives with improved antibacterial...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/7042A61K31/7048A61P31/04C07H17/08
CPCC07H17/08Y02P20/55A61P31/04A61K31/7048
Inventor T·范利Y·S·沃尔D·T·楚J·J·普拉特纳陈燕R·F·克拉克
Owner ABBOTT LAB INC
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