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1,6-diazabicyclo[3,2,1]octanes (DBOs)

The bridged 1,6-diazabicyclo[3.2.1]ocatan-7-ones (DBOs, Figure 1) were conceived as potential b-lactam analogs by chemists at Hoechst Marion Roussel in the mid-1990s [1]. The initial examples lacked antibacterial activity, but showed inhibitory activity versus classes A and C b-lactamases. The initial patents were filed in 2001 - 2004 [2-5] and the structure selected for development became known as AVE1330A
[6]. In 2004 Novexel was formed as a spin-out of Sanofi-Aventis anti-infectives unit, and the compound renamed NXL104.
 

Figure 1. Schematic representation of 1,6-Diazabicyclo[3.2.1]ocatan-7-ones (DBOs) b-lactamase inhibitors.

Structurally related DBOs have been patented as b-lactamase inhibitors (e.g., WO2009133442) [7,8]. Wockhard Ltd reports a DBO nitrile (Figure 1) with inhibitory activity equivalent to avibactam but also exhibits synergy with meropenem against class D ESBL producing strains of A. baumannii [9].

DBOs having independent antibacterial activity against P. aeruginosa and/or E. coli have been patented and are shown in Figure 2 [10-15].

Figure 2. DBOs having antibacterial activity.

 


1. Coleman K. Diazabicyclooctanes (DBOs): a potent new class of non-betalactambeta-lactamase inhibitors. Curr. Opin. Microbiol. 14: 550-5, 2011.

2. Lampilas M, Aszodi J, Rowlands DA, Fromentin C. "Azabicyclic compounds, including 1,3-diazabicyclo[2.2.1]heptan2-one and 1,6-diazabicyclo[3.2.1]octan-7one
derivatives, preparation thereof, and use as medicines, in particular as antibacterial agents". WO2002010172; 2002.

3. Aszodi J, Lampilas M, Musicki B, et al. "Preparation of fused-ring diazepines, method of preparation and use as anti-bacterial agents". WO2002100860; 2002.

4. Aszodi J, Lampilas M, Fromentin C, Rowlands DA. "Preparation of azabicycles as inhibitors of beta-lactamases and their use in pharmaceutical compositions containing beta-lactam antibiotics". FR2835186; 2003.

5. Lampilas M, Musicki B, Klich M, Rowlands DA. "Preparation of fused-ring diazepines as anti-bacterial drugs and inhibitors of beta-lactamases". FR2848210; 2004.

6. Bonnefoy A, Dupuis-Hamelin C, Steier V, et al. "In vitro activity of AVE1330A, an innovative broad-spectrum non-beta-lactam beta-lactamase inhibitor". J. Antimicrob. Chemother. 54: 410-17, 2004.

7. Ledoussal B, Gourdel ME. "Preparation of azabicycles as inhibitors of beta-lactamases and their use in pharmaceutical compositions containing beta-lactam antibiotics". FR2930553; 2009.

8. Ledoussal B, Gourdel M-E. "Preparation of azabicycles as inhibitors of beta-lactamases and their use in pharmaceutical compositions containing beta-lactam antibiotics". WO2009133442; 2009.

9. Patil VT, Tadiparthi R, Birajdar S, Bhagwat S. "Preparation of trans-7-oxo-6(sulfoxy)-1,6-diazabicyclo[3.2.1]octane-2carbonitrile salts for the treatment of bacterial infections". WO2013038330; 2013.

10. Lampilas M, Rowlands DA, Kebsi A, et al. "New nitrogen-heterocyclic compounds, their preparation and their use as antibacterial drugs". WO2008142285; 2008.

11. Lampilas M, Rowlands D, Ledoussal B, et al. "New nitrogen-heterocyclic compounds, especially fused-ring diazepines, their preparation and their use as antibacterial drugs". WO2010038115; 2010.

12. Levasseur P, Pace JL, Coleman K, Lowther J. "Antibacterial nitrogen-heterocyclic compounds, especially fused-ring diazepines, their preparation and their synergistic effect in combinations with other antibacterial antibiotics". WO2010041112; 2010.

13. Ledoussal B, Gourdel M-E, Renaud E, et al. "New nitrogen-heterocyclic compounds, especially fused-ring diazepines, their preparation and their use as antibacterial drugs". WO2010041108; 2010.

14. Patel MV, Deshpand PK, Bhawasar S, et al. "Nitrogen containing compound 1,6-diazabicyclo[3,2,1]octan-7-one derivatives and their use in the treatment of bacterial infections". WO2013030733; 2013.

15. Bhagwat S, Deshpande PK, Bhawasar S, et al. "Preparation of diazabicyclooctanone derivatives for use as antibacterial agents". WO2013030735; 2013.


 

 

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