Combination therapy to treat Mycobacterium diseases
Inventors
Locher, Christopher Phillip • Bennani, Youssef Laafiret • Grillot, Anne-Laure • O'Dowd, Hardwin • Perola, Emanuele • Le Tiran, Arnaud • Charifson, Paul S.
Assignees
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Publication Number
US-9572809-B2
Publication Date
2017-02-21
Expiration Date
Abstract
The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof wherein X and R are as defined herein. The compounds of formula (I) are useful as gyrase and/or topoisomerase IV inhibitors for treating bacterial infections. The compounds of formula (I) either possess a broad range of anti-bacterial activity and advantageous toxicological properties or are prodrugs of compounds having said activity.
Core Innovation
The invention relates to controlling, treating or reducing the advancement, severity or effects of a mycobacterium disease by administering a therapeutically effective amount of a compound of formula (I) together with one or more antibiotic compounds. In formula (I), R is hydrogen or fluorine, and X is hydrogen, —PO(OH)2, —PO(OH)O−M+, —PO(O−)2.2M+, or —PO(O−)2.D2+, where M+ is a pharmaceutically acceptable monovalent cation and D2+ is a pharmaceutically acceptable divalent cation, or a pharmaceutically acceptable salt thereof.
The core approach combines the compound of formula (I) with one or more specified antibiotic compounds, including diarylquinolone, rifapentine, rifalazil, nitroimidazole, benzothiazinone, capreomycin, clofazimine, cycloserine, dapsone, thiocarbamide, ethambutol, DC-159a, nitrobenzthiazole, sutezolid (PNU-100480), AZD-5847, posizolid (AZD-2563), para-aminosalicylic acid, SQ-109, SQ-609, capuramycin, caprazene nucleoside, isothiazoloquinolone, thioridazine, thiacetazone, dirithromycin, roxithromycin, telithromycin, azithromycin, clarithromycin, erythromycin, amikacin, kanamycin, streptomycin, levofloxacin, moxifloxacin, gatifloxacin, linezolid, meropenem, clavulanate, PA 824, pyrazinamide, TMC-207, oxazolidinine, and isoniazid.
A proviso further refines the combination by requiring that, when certain antibiotics are used, an additional antibiotic is also present in the combination. The claims extend this concept to tuberculosis, including treating tuberculosis by administering a therapeutically effective amount of the formula (I) compound in combination with specified antibiotic compounds.
Claims Coverage
The document includes two independent claims. Across these claims, the core inventive coverage centers on administering a therapeutically effective amount of a defined formula (I) compound in combination with specified antibiotic compounds, with a proviso that certain selected antibiotics require an additional antibiotic in the combination.
Mycobacterium disease control with formula I plus specified antibiotics
A method of controlling, treating or reducing the advancement, severity or effects of a mycobacterium disease by administering to a patient a therapeutically effective amount of a compound of formula (I), wherein R is hydrogen or fluorine and X is hydrogen, —PO(OH)2, —PO(OH)O−M+, —PO(O−)2.2M+, or —PO(O−)2.D2+, where M+ is a pharmaceutically acceptable monovalent cation and D2+ is a pharmaceutically acceptable divalent cation, or a pharmaceutically acceptable salt thereof, in combination with one or more antibiotic compounds comprising named antibiotic agents, with a proviso that when certain listed antibiotics are used, an additional antibiotic is also present.
Tuberculosis treatment with formula I plus specified antibiotics
A method of treating tuberculosis by administering a therapeutically effective amount of a compound of formula (I), wherein R is hydrogen or fluorine and X is hydrogen, —PO(OH)2, —PO(OH)O−M+, —PO(O−)2.2M+, or —PO(O−)2.D2+, where M+ is a pharmaceutically acceptable monovalent cation and D2+ is a pharmaceutically acceptable divalent cation, or a pharmaceutically acceptable salt thereof, in combination with one or more antibiotic compounds comprising named antibiotic agents, with a proviso that when certain listed antibiotics are used, an additional antibiotic is also present.
Across both independent claims, the inventive coverage consistently requires the same conceptual combination: a defined formula (I) compound with specified R and X substituent/cation conditions, administered in combination with specified antibiotics, and a proviso that in certain named antibiotic selections an additional antibiotic must also be included.
Stated Advantages
Controls, treats or reduces the advancement, severity or effects of a mycobacterium disease.
Treats tuberculosis.
Addresses shortcomings of existing tuberculosis treatment, particularly in controlling drug-sensitive and drug-resistant mycobacteria.
Targets bacterial DNA gyrase/topoisomerase IV, including GyrB/ParE, with described selectivity considerations versus eukaryotic targets.
Aims to improve treatment against drug-sensitive and drug-resistant mycobacteria.
Documented Applications
Controlling, treating or reducing advancement, severity or effects of a mycobacterium disease by administering a compound of formula (I) in combination with specified antibiotic compounds.
Treating tuberculosis by administering a compound of formula (I) in combination with specified antibiotic compounds.
MIC profiling across multiple Mycobacterium species/strains.
Rat and monkey toxicity/toxicokinetics studies.
Pharmacokinetic assessment and in vivo conversion studies.
Enzymology assessment of DNA gyrase/TopoIV inhibition.
Mouse lung infection efficacy testing.
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