Nitroheteroaryl-containing rifamycin derivatives

Inventors

Ding, Charles Z. • Kim, In Ho • Wang, Jiancheng • Ma, Zhenkun • Jin, Yafei • Combrink, Keith D. • Lu, Genliang • Lynch, A. Simon

Assignees

TenNor Therapeutics Suzhou Ltd

Abstract

Substituted rifamycin derivatives in which a nitroimidazole, nitrothiazole or nitrofuran pharmacophore is covalently bonded to a rifamycin, methods of using the rifamycin derivatives, and pharmaceutical compositions containing the rifamycin derivatives are disclosed. Methods of synthesizing these substituted rifamycin derivatives are also disclosed. The rifamycin derivatives possess antibacterial activity, and are effective against a number of human and veterinary pathogens in the treatment of bacterial diseases.

Core Innovation

The invention relates to compounds of structural formula (I) and pharmaceutically acceptable salts thereof, including nitroheteroaryl-containing rifamycin hybrid antibacterial agents in which a nitroimidazole, nitrothiazole, nitrofuran, or nitro-imidazo[2,1-b][1,3]oxazine related pharmacophore is covalently linked to a rifamycin scaffold. The compounds include a group G defined as formula II, III, IV or V, with R1 hydrogen or acetyl and Q as N or CR2 bonded to linkage group L.

The linkage group L is a bond or a linker group selected from specified combinations of two to five linker moieties, including (C1-C6)alkylene, (C3-C8)cycloalkylene, arylene, heteroarylene, heterocycloalkylene containing 1 to 3 heteroatoms, and moieties including —C(═O)—, —C(═N—O—R3)—, —C≡N—, —O—, and —S(O)n—. The linker group is further constrained by substitution rules on carbon or nitrogen atoms, and R3 and R4 are independently selected from hydrogen, substituted or unsubstituted (C1-C6)alkyl, aryl, heteroaryl, or heterocycloalkyl group.

The compounds further include a structural portion defined as structural formula VI, VII, VIII or IX, in which Y is bonded to the linkage group L and Z is selected from a carbon form, carbonyl, amide, sulfonamide, or a heteroatom selected from N, O, S, SO or SO2. The ring-forming allowance permits R5 and R6 to join together, and R7 and R8 to join together to form a five to seven-member ring system optionally containing one to three heteroatoms.

Claims Coverage

The document includes two independent claims and covers three inventive features in the main structural claim, plus a separate selection claim. Coverage spans a broad chemical class of rifamycin S or rifamycin SV derivatives with nitroheteroaryl-linked frameworks and a finite list of specifically named compounds.

Claim coverage is directed to a general structural formula covering nitroheteroaryl-linked rifamycin scaffold compounds, a separate selection claim reciting a finite list of specifically named derivatives, and a pharmaceutical composition for treating bacterial infections.

Stated Advantages

Documented Applications