such as (R)-5'-[3-{1-(4-{1-[1-(3-Carboxy-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-8-yl)-pyrrolidin-3-yl-cyclopropyl]-methylamino}-piperidin-1-yl]-3'-hydroxy-benzoxazinorifamycin, useful as bactericides for the treatment of bacterial infections
Inventors
Ding, Charles Z. • Jin, Yafei • Combrink, Keith • Kim, In Ho
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-7884099-B2
Publication Date
2011-02-08
Expiration Date
Abstract
The compounds include substituted rifamycin derivatives in which a quinolone carboxylic acid pharmacophore is covalently bonded to a benzoxazinorifamycin or a spiropiperidinorifamycin. The rifamycin derivatives are useful as antimicrobial agents and are effective against a number of human and veterinary Gram positive and Gram negative pathogens. The advantage of the inventive compounds is that both the rifamycin and quinolone antibacterial pharmacophores are co-delivered with matched pharmacokinetics to the targeted pathogens of interests. Delivery of multiple antibacterial pharmacophores simultaneously to the targeted pathogens has the maximum chance of achieving synergy and minimizing the development of resistance to the antibiotics given.
Core Innovation
The invention relates to quinolone carboxylic acid-substituted rifamycin hybrids formed by covalently linking a quinolone antibacterial pharmacophore to a 3,4-fused benzoxazinorifamycin or to a spiropiperidinorifamycin. The hybrid compounds are defined by a structural formula (I) in which X1, X2, Q, Y, Z, R1-R8 and a linker group L are varied within stated substituent and bonding constraints, and the compounds may be provided as pharmaceutically acceptable salts.
A central aspect of the invention is the linker group L connecting the quinolone pharmacophore and the rifamycin framework, where L is selected as a bond or from a defined set of linker groups including (C1-C6)alkylene, (C3-C8)cycloalkylene, arylene, heteroarylene, heterocycloalkylene containing 1 to 3 heteroatoms, and functional linkers such as —C(=O)—, —C(=N—O—R6)—, —C(≡N)—, —O—, and —S(O)n—. The linker atoms may be optionally substituted by substituents including (C1-C6)alkyl and amino-related substituents, along with hydroxyl, (C1-C6)alkoxy, and heterocycloalkyl groups.
The document identifies specific compound embodiments defined as rifamycin S/rifamycin analog structures and related stereochemical variants. It also includes downstream embodiments in which the compound is used as an antibacterial agent in a pharmaceutical antibacterial composition, and in methods for treating a bacterial infection in a patient by administration of the composition.
Claims Coverage
The partial content provides one independent compound claim and dependent claims that refine the compound features and add pharmaceutical composition and method-of-treatment coverage. Across the inventive features, the compound definition emphasizes a hybrid quinolone carboxylic acid-substituted rifamycin scaffold with a defined structural formula (I), a selectable covalent linker L connecting the pharmacophores, and optional salt formation.
Quinolone carboxylic acid-substituted rifamycin hybrid scaffold
A compound of structural formula (I) or a pharmaceutically acceptable salt thereof, wherein X1 is NH, NR4, O or S; X2 is N or CR5; Q is N or CR8; Y and Z are independently selected from C or N; R1 is H or acetyl group; R2, R4, R5, R6, R7 are independently a group selected from hydrogen, (C1-C6)alkyl, (C3-C7)cycloalkyl, aryl, heteroaryl, and heterocycloalkyl groups that are all optionally substituted; R3 is H, —OH or —SH; and R8 is H, F, Cl, CN, CH3, OCH3, OCHF2 or CF3.
Linker group L connecting pharmacophore portions via defined covalent linkage options
L is a bond, or a linker group selected from one or a combination of two to three of the following groups: (C1-C6)alkylene; (C3-C8)cycloalkylene; arylene; heteroarylene; heterocycloalkylene containing 1 to 3 heteroatoms; —C(=O)—; —C(=N—O—R6)—; —C(≡N)—; —O—; —S(O)n—, wherein n is number between 0 and 2; —N(R7)—.
Optional substitution on linker atoms by selected substituent set
The carbon or nitrogen atoms of the linker L group are optionally substituted by 1 to 3 substituents selected from (C1-C6)alkyl, substituted (C1-C6)alkyl, amino, (C1-C6)alkylamino, di(C1-C6)alkylamino, hydroxyl, (C1-C6)alkoxy, and heterocycloalkyl group.
Specific stereochemical and named rifamycin/analog embodiments within the structural formula
A compound according to claim 1 is specified by selection from the listed (R)-, (R/S)-, and rifamycin S/rifamycin analog structures including the enumerated 3,4-fused benzoxazinorifamycin or spiropiperidinorifamycin-based hybrid forms.
Pharmaceutical antibacterial composition including a pharmaceutically effective amount
A pharmaceutical antibacterial composition that includes a pharmaceutically effective amount of a compound as defined in claim 1, formulated with a pharmaceutically acceptable carrier.
Method for treating bacterial infection by administering the antibacterial composition
A method for treating a bacterial infection in a patient by administering a pharmaceutical composition as specified in claim 5.
Overall claim coverage centers on a defined structural formula (I) that constrains the heteroatom choices, substituent options, and a selected linker group L from a defined set, with optional substitution on the linker atoms. Dependent claim refinements further specify particular stereochemical and rifamycin S/rifamycin analog embodiments, followed by composition and treatment use in related dependent claims.
Stated Advantages
Provides multifunctional/combination pharmacology by combining targets described in the provided summary context (RNA polymerase inhibition, DNA gyrase inhibition, and topoisomerase inhibition).
Reports activity against diverse Gram-positive and Gram-negative pathogens, including rifamycin- and quinolone-resistant strains.
Claims reduced resistance development via the multifunctional hybrid approach as characterized in the provided summary content (combination pharmacology with matched co-delivery).
Documented Applications
Pharmaceutical antibacterial composition including a pharmaceutically effective amount of the compound of structural formula (I) with a pharmaceutically acceptable carrier.
Method of treating a bacterial infection in a patient by administering the pharmaceutical composition.
Interested in licensing this patent?