Bicyclic nitroimidazole-substituted phenyl oxazolidinones
Inventors
Ding, Charles Z. • Lu, Genliang • Combrink, Keith • Chen, Dianjun D. • Song, Minsoo • Wang, Jiancheng • Ma, Zhenkun • Palmer, Brian Desmond • Blaser, Adrian • Thompson, Andrew M. • Kmentova, Iveta • Sutherland, Hamish Scott • Denny, William Alexander
Assignees
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Publication Number
US-7666864-B2
Publication Date
2010-02-23
Expiration Date
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.
Core Innovation
The disclosed subject matter concerns compounds having a nitroimidazole ring, including pharmaceutically acceptable salts thereof, and defines variable substituent options for R1, X1 and X2, G, R2, and a linker group L that is a bond or a selected linker group. The compounds of structural formula (II) further define A1 through A6 and L1 and L2 from selected group types, and G is selected from —OH, substituted or unsubstituted triazole, or —NHCOCH3.
The patent also includes enumerated stereochemically defined compounds as members of specified groups, including nitroimidazo[2,1-b][1,3]oxazin- and related scaffolds linked to oxazolidin-2-one or 2-oxo-oxazolidin-5-ylmethyl acetamide motifs. These compounds include diverse aryl or heteroaryl substituent patterns and pharmaceutically acceptable salts.
The disclosed chemical matter is directed to treating bacterial infection via pharmaceutical compositions that contain a pharmaceutically effective amount of the compounds and a pharmaceutically acceptable carrier. The patent frames the problem as bacterial infections, including bacterial resistance and Mycobacterium tuberculosis and MDRTB, and states antibacterial utility under anaerobic growth conditions.
Claims Coverage
The consolidated claim coverage includes two independent compound claim groupings defined by structural formulae (I) and (II), plus independent enumeration claims for specific stereochemically defined compounds. Across these claims, the main inventive features are the nitroimidazole-containing scaffold with defined substituent options and linker group L, the alternative structural formula (II) with defined A1 through A6, L1/L2, and G selections, and the enumerated stereochemically defined oxazolidin-2-one/2-oxo-oxazolidin-5-ylmethyl acetamide derivatives with pharmaceutically acceptable salts.
Nitroimidazole structural formula with configurable linker L
A compound of structural formula (I) having a nitroimidazole ring, or a pharmaceutically acceptable salt thereof, wherein R1, X1, X2, G, R2, and L are defined selections, and L is a bond or a linker group selected from specified linker groups including alkylene, cycloalkylene, arylene, heteroarylene, heterocycloalkylene, —C(=O)—, —O—, —S(O)n—, —N(R3)—, or —C(R4)≡C(R5)— with defined substituent variability.
Structural formula (II) compound with defined scaffold and G options
A compound of structural formula (II), or a pharmaceutically acceptable salt thereof, wherein A1 through A6 are each independently selected from bond, a heteroatom, unsubstituted carbon, and substituted carbon; L1 and L2 are independently selected from bond and defined linker selections; and G is —OH, substituted or unsubstituted triazole, or —NHCOCH3.
Enumerated stereochemically defined oxazolidinone and nitroimidazole hybrids
A compound selected from enumerated stereochemically defined structures, including nitroimidazo[2,1-b][1,3]oxazin and oxazolidin-2-one/2-oxo-oxazolidin-5-ylmethyl acetamide frameworks, together with their pharmaceutically acceptable salts.
The claim coverage centers on nitroimidazole-containing compounds defined by structural formulae (I) and (II), with configurable substituent patterns and linker selections, and on enumerated stereochemically defined oxazolidinone-containing nitroimidazole hybrids. The provided claim set also connects these compounds to pharmaceutical compositions and treatment of bacterial infections by administering the relevant composition to a subject.
Stated Advantages
Improved potency.
Retained activity against resistant strains, including linezolid-resistant S. aureus and PA-824-resistant M. tuberculosis.
Antibacterial utility against bacterial infections.
Surprising activity/synergy versus wild-type and resistant strains.
Activity including under anaerobic growth conditions.
Utility addressing Mycobacterium tuberculosis and MDRTB.
No in vivo biotransformation.
Documented Applications
Treating bacterial infections by administering a pharmaceutical composition containing a compound of the claims to a subject in need of such treatment.
Application contexts mentioned for antibacterial utility include Mycobacterium tuberculosis, MDRTB, anaerobic growth conditions, Gram-positive and Gram-negative pathogens, Clostridium difficile, and Helicobacter pylori.
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