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Bicyclo[3.1.0]hexane containing oxazolidinone antibiotics and derivatives thereof

Inactive Publication Date: 2005-09-15
KYORIN PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The oxazolidinones are synthetic antibacterial compounds that are orally or intravenously active against problematic multidrug resistant Gram positive organisms and are not cross-resistant with other antibiotics.

Method used

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  • Bicyclo[3.1.0]hexane containing oxazolidinone antibiotics and derivatives thereof
  • Bicyclo[3.1.0]hexane containing oxazolidinone antibiotics and derivatives thereof
  • Bicyclo[3.1.0]hexane containing oxazolidinone antibiotics and derivatives thereof

Examples

Experimental program
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Effect test

example 51

N-[5(S)-3-[4-[(1α,5α,6α)-6-Azidomethyl-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

[0451] A suspension of N-[5(S)-3-[4-[(1α,5α,6α)-6-bromomethyl-3-azabicyclo [3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (213 mg) and sodium azide (114 mg) in DMF (3 mL) was heated at 70° C. for 48 hours. After diluting the mixture with ethyl acetate, the solution was washed water and brine. The organic extracts were dried over anhydrous sodium sulfate, filtered, and then concentrated in vacuo. Flash chromatography (silica, ethyl acetate:methanol=15:1) of the residue gave N-[5(S)-3-[4-[(1α,5α,6α)-6-azidomethyl-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (160 mg).

[0452] MS (EI+) m / z: 388 (M+).

[0453] HRMS (EI+) for C18H21FN6O3 (M+): calcd, 388.1659; found, 388.1697.

example 52

N-[5(S)-3-[4-[(1α,5α,6α)-6-Aminomethyl-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide

[0454] A uspension of N-[5(S)-3-[4-[(1α,5α,6α)-6-azidomethyl-3-azabicyclo [3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (153 mg) and palladium catalyst (10% on charcoal, 31 mg) in methanol (5 mL) and dichloromethane (1 mL) was hydrogenated at 1 atm for 4.5 hours at room temperature. After filtration of the catalyst, the filtrate was concentrated in vacuo. Treatment of the residue with ethanol-diisopropyl ether gave N-[5(S)-3-[4-[(1α,5α,6α)-6-aminomethyl-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluoro phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (132 mg).

[0455] MS (EI+) m / z: 362 (M+).

[0456] HRMS (EI+) for C18H23FN4O3 (M+): calcd, 362.1754; found, 362.1782.

example 53

N-[5(S)-3-[3-Fluoro-4-[(1α,5α,6α)-6-(pyridin-2-yl)amino-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

[0457] The mixture of N-[5(S)-3-[4-[(1α,5α,6α)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (348 mg), 2-pyridyl triflate (295 mg) and triethylamine (209 μL) in DMSO (2 mL) was heated at 100° C. for 36 hours. After diluting the mixture with dichloromethane-methanol (10:1), the mixture was washed with water, dried over anhydrous sodium sulfate, filtered, and then concentrated in vacuo. Flash chromatography (silica, ethyl acetate:methanol=12:1) of the residue gave N-[5(S)-3-[3-fluoro-4-[(1α,5α,6α)-6-(pyridin-2-yl)amino-3-azabicyclo[3.1.0]hexan-3-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (76.5 mg).

[0458]1H NMR (DMSO-d6) δ 1.76 (s, 2H), 1.82 (s, 3H), 3.27-3.40 (m, 5H), 3.64-3.74 (m, 3H), 4.04 (t, J=9.0 Hz, 1H), 4.67 (m, 1H), 6.53-6.57 (m, 2H), 6.74-6.80 (m, 2H), 7.09 (dd, J=8.8, 2.4 Hz, 1H), 7.37-7.47 (m,...

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Abstract

Oxazolidinones having a bicyclic[3.1.0]hexane containing moiety, which are effective against aerobic and anerobic pathogens such as multi-resistant staphylococci, streptococci and enterococci, Bacteroides spp., Clostridia spp. species, as well as acid-fast organisms such as Mycobacterium tuberculosis and other mycobacterial species. The compounds are represented by structural formula I: its enantiomer, diastereomer, or pharmaceutically acceptable salt or ester thereof, and wherein the variables R1, R2, R3, R4, R4a, A, Ar, HAr, n, r, and s are as defined herein.

Description

CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to Provisional Application Ser. No., ______, filed Mar. 14, 2002, and Provisional Application Ser. No. 60 / 283,956, filed Apr. 17, 2001.BACKGROUND OF THE INVENTION [0002] Oxazolidinones represent the first new class of antibacterials to be developed since the quinolones. The oxazolidinones are synthetic antibacterial compounds that are orally or intravenously active against problematic multidrug resistant Gram positive organisms and are not cross-resistant with other antibiotics. See Riedl et al, Recent Developments with Oxazolidinone Antibiotics, Exp. Opin. Ther. Patents (1999) 9(5), Ford et al., Oxazolidinones: New Antibacterial Agents, Trends in Microbiology 196 Vol. 5, No. 5, May 1997 and WO 96 / 35691. [0003] This invention relates to new oxazolidinones having a bicyclic[3.1.0]hexane containing moiety, which are effective against aerobic and anerobic pathogens such as multi-resistant staphylococci, str...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D263/20A61K31/421A61K31/422A61P31/04C07D263/10C07D263/24C07D405/10C07D413/10C07D413/14
CPCC07D263/10C07D413/10C07D405/10
Inventor FUKUDA, YASUMICHIHAMMOND, MILTON L.
Owner KYORIN PHARMA CO LTD
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