Compounds
Inventors
PORRAS DE FRANCISCO, Esther • Remuiñan-Blanco, Modesto Jesús • BOUROTTE, Marilyne • Deprez, Benoit • Willand, Nicolas
Assignees
Bioversys AG • GlaxoSmithKline Intellectual Property Development Ltd
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11969423-B2
Publication Date
2024-04-30
Expiration Date
Abstract
The invention relates to compounds of Formula (I) and their use in therapy, for example in the treatment of mycobacterial infections or in the treatment of diseases caused by mycobacterium, such as tuberculosis.
Core Innovation
The invention relates to a combination comprising 4,4,4-trifluoro-1-(4-(2-(trifluoromethyl)pyridin-4-yl)piperidin-1-yl)butan-1-one, or a pharmaceutically acceptable salt thereof. The combination further includes at least one anti-tuberculosis agent selected from a specified group of anti-tuberculosis agents, and at least one anti-viral agent selected from a specified group of anti-viral agents.
The disclosure relates to compounds of Formula (I) and related Formula (II), including substituted piperidinyl or related ring linked to a 4,4,4-trifluorobutan-1-one moiety. It further describes a fluorinated butanone scaffold with substituted heteroaryl analogs, including pyridyl, pyrimidyl, and pyrazinyl ring substitutions and additional halogen or fluoro substituents.
The document also presents key intermediates and transformations among heteroaryl-piperidine building blocks and related fluorinated fragments. Examples include tert-butyl 4-hydroxy-4-[4-(trifluoromethyl)-2-pyridyl]piperidine-1-carboxylate and tert-butyl 4-(5-chloropyridin-3-yl)-4-fluoropiperidine-1-carboxylate, together with characterization data and tabulated results for selected analogs and intermediates.
The partial content also describes biological evaluation context including rat oral bioavailability and in vivo mouse liver safety/PPAR marker results. Anti-tuberculosis potentiation of ethionamide is described with M. tuberculosis H37Rv-GFP and ethionamide-resistant W4-E1-GFP strains, including EC50_H37Rv and EC50_Mutant rankings.
Claims Coverage
The independent claim set centers on one specific fluorinated piperidinyl ketone compound or pharmaceutically acceptable salt, together with at least one anti-tuberculosis agent and at least one anti-viral agent. Across the merged claim coverage, there are 3 core inventive features.
Specific fluorinated piperidinyl butanone compound or salt
A compound that is 4,4,4-trifluoro-1-(4-(2-(trifluoromethyl)pyridin-4-yl)piperidin-1-yl)butan-1-one, or a pharmaceutically acceptable salt thereof.
Combination with at least one anti-tuberculosis agent
At least one anti-tuberculosis agent selected from the listed group comprising isoniazid, rifampin, pyrazinamide, ethambutol, moxifloxacin, rifapentine, clofazimine, ethionamide, prothionamide, isoxyl, thiacetazone, rifabutin, a diarylquinoline, nitroimidazo-oxazine PA-824, delamanid (OPC-67683), an oxazolidinone, EMB analogue SQ109, OPC-167832, GSK3036656 (GSK070), GSK2556286, GSK3211830, a benzothiazinone, an azaindole, a dinitrobenzamide, and a beta-lactam.
Combination with at least one anti-viral agent
At least one anti-viral agent selected from the listed group comprising zidovudine, didanosine, lamivudine, zalcitabine, abacavir, stavudine, adefovir, adefovir dipivoxil, fozivudine, todoxil, emtricitabine, alovudine, amdoxovir, elvucitabine, nevirapine, delavirdine, efavirenz, loviride, immunocal, oltipraz, capravirine, lersivirine, GSK2248761, TMC-278, TMC-125, etravirine, saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, fosamprenavir, brecanavir, darunavir, atazanavir, tipranavir, palinavir, lasinavir, enfuvirtide, T-20, T-1249, PRO-542, PRO-140, TNX-355, BMS-806, BMS-663068, BMS-626529, 5-Helix, raltegravir, elvitegravir, GSK1349572, GSK1265744, vicriviroc (Sch-C), Sch-D, TAK779, maraviroc, TAK449, tenofovir, lopinavir, and darunavir.
The claim coverage centers on a combination defined by the presence of the specified fluorinated butanone, or a pharmaceutically acceptable salt, together with selected anti-tuberculosis and anti-viral agents selected from the enumerated lists.
Stated Advantages
Treatment of mycobacterial infections, including tuberculosis caused by Mycobacterium tuberculosis and drug-resistant variants, including multidrug-resistant tuberculosis and ethionamide-resistant variants.
Rat oral bioavailability and in vivo mouse liver safety/PPAR marker results are described.
Anti-tuberculosis potentiation of ethionamide is described with M. tuberculosis H37Rv-GFP and ethionamide-resistant W4-E1-GFP strains.
Documented Applications
Treatment of mycobacterial infections, particularly tuberculosis caused by Mycobacterium tuberculosis and drug-resistant variants.
Combination therapy that includes at least one anti-tuberculosis agent and at least one anti-viral agent.
Anti-tuberculosis evaluation with M. tuberculosis H37Rv-GFP and ethionamide-resistant W4-E1-GFP strains.
Interested in licensing this patent?