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Bicyclic nitroimidazoles covalently linked to substituted phenyl oxazolidinones

A nitroimidazole ring, unsubstituted technology, applied in the field of bicyclic nitroimidazoles covalently linked to substituted phenyl oxazolidinones, which can solve the problems of no references to be published

Active Publication Date: 2011-02-02
TENNOR THERAPEUTICS (SUZHOU) LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] although Oxazolidinones and bicyclic nitroimidazoles are known, but no reference discloses making phenyl The oxazolidinone is covalently bonded to the bicyclic nitroimidazole pharmacophore and the phenyl substituted with the resulting bicyclic nitroimidazole Oxazolidinones as antimicrobial agents against aerobic and anaerobic Gram-positive and Gram-negative bacteria, especially mycobacteria and Clostridia

Method used

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  • Bicyclic nitroimidazoles covalently linked to substituted phenyl oxazolidinones
  • Bicyclic nitroimidazoles covalently linked to substituted phenyl oxazolidinones
  • Bicyclic nitroimidazoles covalently linked to substituted phenyl oxazolidinones

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0132] (S, S)-N-{3-[3-fluoro-4-(4-{2-[4-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b ][1,3] Oxyzin-6-yloxymethyl)-phenoxy]-acetyl}-piperazin-1-yl)-phenyl]-2-oxo- Oxazolidin-5-ylmethyl}-acetamide:

[0133]

[0134] Step 1. (4-Hydroxymethyl-phenoxy)-tert-butyl acetate. 4-Hydroxymethylphenol (3.70g, 30mmol), tert-butyl bromoacetate (6.0mL, 40mmol), K 2 CO 3 (16.6g, 120mmol) suspension in acetonitrile (100mL) in N 2 Stirred at 60°C for 16h. The reaction mixture was filtered and the solvent was removed under reduced pressure to give a crude product which was purified by flash chromatography with EtOAc / hexanes to give the title product as an oil (6.22 g, 87%).

[0135] 1 H NMR (400MHz, CDCl 3 )δ7.29(d, J=8.0Hz, 2H), 6.88(d, J=8.4Hz, 2H), 4.62(d, J=5.6Hz, 2H), 4.52(s, 2H), 1.49(s, 9H).

[0136] Step 2. (4-Chloromethyl-phenoxy)-tert-butyl acetate. at 0°C in N 2 To a stirred solution of (4-hydroxymethyl-phenoxy)-tert-butyl acetate (2.38 g, 10 mmol) in dichloromethane (50 mL) ...

Embodiment 2

[0142] (S,S)-N-(3-{3-fluoro-4-[4-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3] Oxyzin-6-yloxymethyl)-benzyloxy]-phenyl}-2-oxo- Oxazolidin-5-ylmethyl)-acetamide:

[0143]

[0144] Step 1.6 (S)-(4-Chloromethyl-benzyloxy)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3] Zinc. To stirred 2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3] To a solution of azin-6(S)-ol (0.1 g, 0.54 mmol) in anhydrous DMF (1 mL) was added NaH (60% dispersion in oil, 26.0 mg, 0.65 mmol) and stirred at 0 °C 30 minutes. 1,4-Dichloromethylbenzene (472 mg, 2.7 mmol) in anhydrous DMF (0.5 mL) was added to the reaction mixture and stirred at 0 °C for 30 minutes and at room temperature for another 3 hours. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine. Anhydrous Na for organic layer 2 SO 4 Dry, filter and evaporate. The residue was washed with hexane to obtain the title compound (65 mg, 37%) as a solid.

[0145] ESI MS m / z 324 (M+H + ); 1 H NMR (400MHz, CDCl 3 ...

Embodiment 3

[0149] (S,S)-N-(3-{3-fluoro-4-[3-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3] Oxyzin-6-yloxymethyl)-benzyloxy]-phenyl}-2-oxo- Oxazolidin-5-ylmethyl)-acetamide:

[0150]

[0151] Step 1.6 (S)-(3-Chloromethyl-benzyloxy)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3] Zinc. The title compound was prepared by the same method as described in the preparation of Example 2, except that 1,3-bis-(chloromethyl)-benzene was used in place of 1,4-bis-(chloromethyl)-benzene.

[0152] ESI MS m / z 473 (M+H + ); 1 HNMR (400MHz, CDCl 3 )δ7.38(s, 1H), 7.32-7.19(m, 4H), 4.71(d, J=30Hz, 1H), 4.60(d, J=21Hz, 2H), 4.33(d, J=30.0Hz, 1H), 4.15(m, 3H), 3.45(s, 2H), 3.41(s, 4H), 2.37(s, 4H), 1.44(s, 9H).

[0153] Step 2. (S,S)-N-(3-{3-fluoro-4-[3-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1 ,3] Oxyzin-6-yloxymethyl)-benzyloxy]-phenyl}-2-oxo- oxazolidin-5-ylmethyl)-acetamide. The title compound was prepared by the same method as described in the preparation of Example 2, except that the starting m...

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Abstract

The current invention provides a series of bicyclic nitroimidazole- substituted phenyl oxazolidinones in which a bicyclic nitroimidazole pharmacophore is covalently bonded to a phenyl oxazolidinone, their pharmaceutical compositions, and the method of use of the compositions for prevention and treatment of bacterial infections. The bicyclic nitroimidazole-substituted phenyl oxazolidinones possess surprising antibacterial activity against wild- type and resistant strains of pathogens, and are therefore useful for the prevention, control and treatment of a number of human and veterinary bacterial infections caused by these pathogens, such as Mycobacterium tuberculosis.

Description

technical field [0001] This application claims priority to US Provisional Patent Application Serial No. 61 / 070,855, entitled "Bicyclic Nitroimidazole-Substituted Phenyl Oxazolidinones," filed March 26, 2008, the entire contents of which are hereby incorporated by reference. Background technique [0002] The present invention relates to phenyl substituted by bicyclic nitroimidazole Oxazolidinones, in which the bicyclic nitroimidazole pharmacophore is covalently bonded to the phenyl Chemical attachment of oxazolidinone pharmacophores. [0003] The disturbing increase in bacterial resistance to existing antimicrobials is a major clinical challenge. Accordingly, there is a need in the art for compounds, compositions and methods for treating warm-blooded animals with bacterial infections that are resistant to conventional antimicrobial therapy. The rise of multidrug resistant tuberculosis ("MDRTB") poses a profound public threat. Tuberculosis ("TB") is highly contagious. T...

Claims

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Application Information

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IPC IPC(8): A61K31/5365C07D498/04A61P31/04A61P31/06
CPCC07D498/04A61P31/04A61P31/06A61P31/10
Inventor 丁照中陆根良基思·科姆布林克陈殿军宋民秀王建成马振坤布赖恩·德斯蒙德·帕尔默亚德里恩·布拉泽安德鲁·M·托姆普松伊韦塔·克门托娃哈米什·斯科特·萨瑟兰威廉·亚历山大·丹尼
Owner TENNOR THERAPEUTICS (SUZHOU) LTD
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