Antimicrobials and methods of making and using same
Inventors
Duffy, Erin M. • Bhattacharjee, Ashoke • Kanyo, Zoltan F. • Ippolito, Joseph A.
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-10815237-B2
Publication Date
2020-10-27
Expiration Date
Abstract
The present disclosure relates generally to the field of antimicrobial compounds and to methods of making and using them. These compounds are useful for treating, preventing, reducing the risk of, and delaying the onset of microbial infections in humans and animals. In some embodiments, the present disclosure provides a compound of Formula (I) or a tautomer thereof or a pharmaceutically acceptable salt of the compound or tautomer.
Core Innovation
The disclosure relates to compounds of Formula (I), including a tautomer thereof and a pharmaceutically acceptable salt of the compound or tautomer. Formula (I) defines a set of variable substituents (R1-R11), the core variable W, and additional structural selections involving X, RN, RA, RB, and ring-formation relationships among substituents. The compounds are defined by a polycyclic heteroaromatic core with variable substituents and related analogs, including Formula (II) embodiments and closely related Formula (A), Formula (Ia), Formula (Ia-1) through Formula (Id-2).
The embodiments present a shared scaffold with variable substituent choices, including halo, C1-6 alkyl, C1-4 haloalkyl, ORa, SRa, and heterocycloalkyl substitutions. The structures include variations in halo and fluoro-containing substituents and other heteroatom-containing groups, with examples of fluorinated motifs, methoxy, hydroxyl, sulfur-containing substituents, and aminated side-chain groups. The variable groups are expressed through R-group definitions, and the heteroatom X is part of the core definition.
The disclosure further describes compound embodiments by reference to specific listed examples, including compounds in Tables 1, 1a, and 1b, and corresponding ESI [M+H]+ m/z values for several numbered compounds. It also states that the compounds bind bacterial ribosomes and inhibit protein synthesis, and that such compounds provide antimicrobial activity. The background context frames pharmaceutical uses and compositions for treating or preventing microbial infections, including infections associated with ESKAPE pathogens and other listed microorganisms.
Claims Coverage
The independent claim coverage centers on a Formula (I) compound, including tautomers and pharmaceutically acceptable salts, with multiple variable positions (R1-R11) plus W, X, RN, RA, and RB. The coverage is driven by defined substituent sets across the scaffold and includes ring-closure relationships involving R6/R7 and heterocycloalkyl ring formation involving RA/RB. Overall, the claim coverage combines broad genus language with structural constraints distributed across the scaffold.
Formula (I) compound with tautomer or pharmaceutically acceptable salt
A compound of Formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer.
Defined substituent sets for R1, R2, R3, W, and X
R1 is selected from H and halo; R2 is selected from H, halo, C1-6 alkyl, C1-4 haloalkyl, and ORa1; R3 is selected from H, C1-6 alkyl, and C1-4 haloalkyl; W is selected from N and CR4; and X is selected from O and NRN.
Substituent definitions at R4, R5, R6, and R7 with ring formation
R4 is selected from H, halo, ORa2, SRa2, 5-6 membered heterocycloalkyl, C1-6 alkyl, and C2-6 alkenyl, with C1-6 alkyl optionally substituted with ORa2; R5 is selected from H, halo, C1-6 alkyl, and C2-6 alkenyl, with C1-6 alkyl optionally substituted with ORa2; R6 is selected from H, C1-6 alkyl, and C2-6 alkenyl, with said C1-6 alkyl optionally substituted with ORa3; and R7 is selected from H and C1-6 alkyl, or R6 and R7 together with the carbon atoms to which they are attached and the nitrogen atom connecting said two carbon atoms form a ring of formula.
Heterocycloalkyl ring formation for RA and RB
RA is H; RB is H; or RA and RB together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocycloalkyl ring containing 1 or 2 heteroatoms selected from N, O and S, wherein said 5- to 6-membered heterocycloalkyl is optionally substituted with halo.
Substituent scope for R8, R9, R10, and R11
R8 is selected from H, C1-6 alkyl, and C1-4 haloalkyl; R9 is selected from C1-6 alkyl, C2-6 alkenyl, C3-5 cycloalkyl, with said C1-6 alkyl optionally substituted with ORa3 and SRa3; R10 is selected from H, C2-4 alkenyl, C1-4 haloalkyl, and C1-4 alkyl optionally substituted with amino, C1-4 alkoxy, C3-5 cycloalkyl, and 3- to 6-membered heterocycloalkyl; and R11 is H or C1-3 alkyl, with the C1-3 alkyl optionally substituted with OH.
Independent selection of auxiliary substituents
Each Ra1, Ra2, and Ra3 is independently selected from H, C1-6 alkyl and C1-4 haloalkyl.
Overall, the claim coverage protects a Formula (I) chemical genus with tightly specified substituent-selection rules at multiple positions, optional heteroatom-containing substituents, and alternative ring-forming constraints involving R6/R7 and RA/RB.
Stated Advantages
Treating or preventing microbial infections.
Compounds bind bacterial ribosomes and inhibit protein synthesis.
Antimicrobial evaluation includes MIC and antimicrobial activity assessment.
In vivo efficacy model types are described for antimicrobial performance.
Documented Applications
Pharmaceutical uses/compositions for treating or preventing microbial infections, including ESKAPE pathogens and other listed pathogens.
Ribosome binding and protein synthesis inhibition characterization, including ribosome binding and translation-only assay (70S ribosomes) context.
Antimicrobial evaluation including MIC (minimum inhibitory concentration) evaluation.
In vivo animal model efficacy evaluation types, including murine pneumonia and murine thigh, and peritonitis sepsis.
Interested in licensing this patent?