Polymyxin compounds
Inventors
Brown, Pamela • Dawson, Michael • Simonovic, Mona • Boakes, Steven • Duperchy, Esther • RIVERS, DEAN • LESTER, ROY • Coleman, Scott
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11459357-B2
Publication Date
2022-10-04
Expiration Date
Abstract
The invention provides a polymyxin compound of formula (I) and salts, solvates and protected forms thereof, pharmaceutical compositions comprising the compounds of formula (I), and the use of the compounds and compositions in methods of treatment, such as methods for the treatment of microbial infections. The compounds of formula (I) are represented thus:wherein —R15 is a group:and —R16 is hydrogen; —R17 is hydrogen -L- is a covalent bond or methylene; and —Ar is optionally substituted aryl. The groups —X—, —R1, —R2, —R3, —R4, and —R8 are as defined herein.
Core Innovation
The disclosure concerns polymyxin-derived nonapeptide compounds of formula I with a modified or deacylated polymyxin core. The position-3 residue is Dap, the polymyxin nonapeptide scaffold includes an N-terminal moiety of the form —NH—X—R15 or —X—R15, and X is —C(O)— in one description. The disclosure further includes stereochemical variants, defined R-group residues, and optionally substituted aryl, aralkyl, phenyl, and heteroaryl options on the substituted scaffold.
The compounds further define amino-acid residues within the polymyxin nonapeptide framework through residues R1, R2, R3, R4 and R8 at specified positions. R1 is selected to include D-amino acid residues such as D-Phe, D-Leu, and D-norleucine, R2 is defined as a C1-4 alkyl or related residue at position 7, R3 is threonine, R4 is Dap, and R8 is H or methyl corresponding to Ser/Thr. The disclosure also describes stereoisomer definitions associated with faster- versus slower-eluting stereoisomers.
The invention provides pharmaceutically acceptable salts, solvates, protected forms, prodrug forms, and pharmaceutical compositions containing the compounds. The documented use is for treating or prophylaxis of microbial infections, with emphasis on Gram-negative bacterial infections. The disclosure also describes combination use with a second active agent, including rifampicin, rifabutin, rifalazil, rifapentine, rifaximin, beta-lactams, tetracyclines, aminoglycosides, and quinolones.
Claims Coverage
The claim coverage includes formula-defined polymyxin-derivative compounds and dependent refinements that add pharmaceutical compositions and therapeutic methods for treating infections, specifically narrowing from microbial infection to bacterial infection to Gram-negative bacterial infection, and further to selected Gram-negative taxa. Across the independent claim set, the inventive coverage is centered on formula-defined polymyxin-derivative compounds plus salts, solvates, protected forms, and prodrugs in one family.
Formula-defined polymyxin-derivative compounds with salts, solvates, and protected forms
A compound of the formula and salts, solvates and protected forms thereof.
Formula-defined polymyxin-derivative compounds with salts, solvates, prodrugs, and protected forms
A compound of the formula and salts, solvates, prodrug and protected forms thereof.
Pharmaceutical composition including the formula-defined compound or derivative forms
A pharmaceutical composition is claimed that contains a compound according to the independent compound claim, or a salt, solvate, or protected form of that compound, optionally with one or more pharmaceutically acceptable carriers.
Treating a microbial infection with administration of the formula-defined compound or derivative forms
A method for treating a microbial infection by administering a therapeutically effective amount of a compound according to the independent compound claim, or one of its salt, solvate, or protected forms, to a subject in need.
Treating bacterial infection by administration of the formula-defined compound
The method is wherein the infection treated is a bacterial infection.
Treating Gram-negative bacterial infection by administration of the formula-defined compound
The method is further limited such that the bacterial infection is a Gram-negative bacterial infection.
Treating Gram-negative infection selected from listed taxa
The method specifies that the Gram-negative bacterial infection is selected from the listed genera and species.
Overall, the independent claim families cover formula-defined compounds and include derivative forms (salts, solvates, protected forms, and prodrugs in one family). Dependent claim coverage provides formulation and therapeutic methods that narrow infection type from microbial infection to bacterial infection, then to Gram-negative bacterial infection, with an optional selection restricted to named Gram-negative genera and species.
Stated Advantages
The patent reports biological performance, including MIC determination against Gram-negative bacteria, HK-2 renal cytotoxicity assessment relative to polymyxin B, in vivo kidney drug level measurements, neutropenic murine thigh and lung infection models, log reductions in CFU compared to vehicle and polymyxin B, rifampicin synergy supported by MIC data, and renal toxicity comparison using urinary biomarkers and histopathology.
The problem addressed is to obtain polymyxin-derived nonapeptide compounds intended to achieve a favorable combination of low cytotoxicity and acceptable kidney drug levels after parenteral dosing.
Documented Applications
Pharmaceutical administration of compounds by topical, intranasal, pulmonary, ocular, rectal, vaginal, and parenteral routes.
Kit concepts in which the compound is provided together with instructions and optionally a second active agent.
Evaluation against Gram-negative bacteria, including E. coli, K. pneumoniae, P. aeruginosa, and A. baumannii.
In vivo kidney exposure and efficacy studies using mouse infection models and kidney drug level measurements.
Treating or prophylaxis of microbial infections, particularly Gram-negative bacterial infections, including infections caused by listed Gram-negative bacterial genera and species.
Interested in licensing this patent?