Biodefense agents
Inventors
Bhattacharjee, Ashoke • Duffy, Erin M. • Grossman, Trudy • Ippolito, Joseph A. • Kanyo, Zoltan F.
Assignees
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Publication Number
US-12152031-B2
Publication Date
2024-11-26
Expiration Date
Abstract
The present disclosure relates to methods of treating, preventing, reducing the risk of, or delaying the onset of microbial infections in humans and animals that are caused by or involves one or more microorganisms which are capable of being used as biological weapons, the method including administering a pyrrolocytosine compound or a tautomer thereof or a pharmaceutically acceptable salt of the compound or tautomer.
Core Innovation
The invention relates to a method of treating, preventing, reducing the risk of, or delaying the onset of a microbial infection in a subject by administering a therapeutically effective amount of a compound of Formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer. Formula (I) is defined by multiple substituent variables, including R1 through R11, W, X, RN, RA, and RB, with optional ring-forming arrangements and defined selections for halo, alkyl, haloalkyl, ORa groups, sulfur-containing groups, and heterocycloalkyl groups.
The structural scope includes defined selections for W as N or CR4 and X as O or NRN, together with constrained substituent options for R2, R3, R4, R5, R6, R7, R8, R9, R10, and R11. The definition also includes optional ring formation where R6 and R7 together with the carbon atoms to which they are attached and the nitrogen atom connecting the two carbon atoms form a ring, and where RA and RB together with the nitrogen atom form a 5- to 6-membered heterocycloalkyl ring containing 1 or 2 heteroatoms selected from N, O and S, optionally substituted with halo.
The disclosed embodiments further refer to representative Formula (I), Formula (II), and Formula (II-1) compounds, including enumerated compound sets in Tables 1, 1a, 1b, 1c, 2, 2a, and 2b, as well as related sub-formulae and example structures. The described structures include substituted bicyclic or heteroaromatic scaffolds, fluoro and chloro substituents, sulfur-containing motifs, and variations in terminal side-chain functionality, together with stereoisomers, geometric isomers, tautomers, isotopically labeled compounds, N-oxides, and metabolites where stated.
Claims Coverage
The consolidated claim coverage centers on a single independent method claim for administering a therapeutically effective amount of a Formula (I) compound, including a tautomer or a pharmaceutically acceptable salt, to treat, prevent, reduce the risk of, or delay the onset of microbial infection. The claim is defined by extensive structural restrictions across the Formula (I) scaffold and by microorganism limitations involving biological-weapon-capable microorganisms and extremely-drug resistant Gram-positive or Gram-negative pathogens.
Therapeutically effective administration of Formula (I) compounds
A method of treating, preventing, reducing the risk of, or delaying the onset of a microbial infection in a subject by administering to the subject a therapeutically effective amount of a compound of Formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer.
Defined Formula (I) substituent and ring constraints
Formula (I) is defined by selections for R1 through R11, W, X, RN, RA, and RB, including halo, alkyl, haloalkyl, ORa groups, sulfur-containing groups, heterocycloalkyl, and optional ring formation involving R6 and R7 with the nitrogen atom and optional 5- to 6-membered heterocycloalkyl ring formation from RA and RB.
Target microorganism context
The infection is caused by or involves one or more microorganisms capable of being used as biological weapons or extremely-drug resistant Gram-positive or Gram-negative pathogens.
Biodefense category and enumerated microorganism limitations
Dependent claims further limit the microorganisms by biodefense category A or biodefense category B and by listed pathogenic bacteria and related microorganisms, including Bacillus anthracis, Yersinia pestis, Francisella tularensis, Burkholderia pseudomallei, Coxiella burnetii, Brucella species, Burkholderia mallei, Chlamydia psittaci, Rickettsia prowazekii, diarrheagenic E. coli, pathogenic Vibrios, Shigella species, Salmonella, Listeria monocytogenes, Campylobacter jejuni, and Yersinia enterocolitica.
Overall, the claims combine administration of a tightly defined Formula (I) compound family with microorganism restrictions tied to biological-weapon capability, biodefense classification, and extreme drug resistance, while dependent claims narrow the scope to listed compound sets and enumerated pathogen examples.
Stated Advantages
Treating, preventing, reducing the risk of, or delaying the onset of a microbial infection in a subject.
Targets infections caused by or involving microorganisms capable of being used as biological weapons or extremely-drug resistant Gram-positive or Gram-negative pathogens.
Reduced cross-resistance is suggested, with equivalent or improved in vitro efficacy versus one or more comparators.
Effectiveness of most compounds against Category A pathogens and Category B pathogens is indicated by MIC testing results.
Many MIC90 values are reported in low μg/mL ranges for many of the compounds tested.
Documented Applications
Treatment, prevention, reduction of risk, or delaying the onset of microbial infection in a subject caused by or involving microorganisms capable of being used as biological weapons or extremely-drug resistant Gram-positive or Gram-negative pathogens.
Use against infections associated with biodefense category A or biodefense category B microorganisms.
Use against listed pathogenic bacteria and related microorganisms, including Bacillus anthracis, Yersinia pestis, Francisella tularensis, Burkholderia mallei, Burkholderia pseudomallei, Coxiella burnetii, Brucella species, Chlamydia psittaci, Rickettsia prowazekii, diarrheagenic E. coli, pathogenic Vibrios, Shigella species, Salmonella, Listeria monocytogenes, Campylobacter jejuni, and Yersinia enterocolitica.
MIC testing of Formula (I) variants and table-enumerated compounds against pathogenic bacteria and related microorganisms.
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