Oxazolidinone compounds, liposome compositions comprising oxazolidinone compounds and method of use thereof
Inventors
Drummond, Daryl C. • Tipparaju, Suresh K. • Noble, Charles O. • Koshkaryev, Alexander • Kirpotin, Dmitri B.
Assignees
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Publication Number
US-11555033-B2
Publication Date
2023-01-17
Expiration Date
Abstract
Compositions and methods for the treatment of tuberculosis, as well as other mycobacterial and gram positive bacterial infections are disclosed. These compositions contain a highly potent and selective oxazolidinone encapsulated with high efficiency to maximize dosing potential of low toxicity drugs, and are stable in the presence of plasma. The compositions are long circulating and retain their encapsulated drug while in the circulation following intravenous dosing to allow for efficient accumulation at the site of the bacterial or mycobacterial infection. The high doses that can be achieved when combined with the long circulating properties and highly stable retention of the drug allow for a reduced frequency of administration when compared to daily or twice daily administrations of other drugs typically utilized to treat these infections.
Core Innovation
The disclosure relates to compounds of Formula I and pharmaceutically acceptable salt forms, including aminoalkyl oxazolidinone compounds and tedizolid-based fluorinated oxazolidinone derivatives with varied substituted patterns. The framework defines a tetrazole ring substituted at position 2′ with an aminoalkyl, with R2 being an amine, including NH2, or an acetamide.
The document characterizes a series of oxazolidinone/tetrazole-linked compounds, including AKG-21, AKG-22-1/AKG-22, AKG-23-1/AKG-23, AKG-24, AKG-25, AKG-26, AKG-27-1/AKG-27, AKG-28 to AKG-31, and AKG-38 to AKG-40. The described structural variations include oxazolidinone and tetrazole-linked motifs together with defined aminoalkyl substitution patterns and salt forms.
The disclosure addresses identification and optimization of compounds showing activity against Mycobacterium tuberculosis, evaluated in vitro by Mycobacterium tuberculosis MIC using Alamar Blue (MABA). It also reports liposomal formulations comprising liposome vesicles entrapping Formula I compounds, with transmembrane-gradient active loading, intraliposomal polyanions or sulfates, phospholipids, cholesterol, and optional PEG-lipid.
Claims Coverage
The consolidated claims coverage identifies five independent inventive-feature groupings across the input items: Formula I compounds with tetrazole-substituted aminoalkyl R1 and amine R2; a free base form with tertiary aminoalkyl R1 and NH2; a hydrochloric acid salt form with R2 = NH3+Cl− and selected R1; a hydrochloric acid salt claim narrowed to specific illustrated compounds; and liposomal entrapment of Formula I compounds. The recurring core is the Formula I framework with salt/free-base and selected-structure limitations.
Tetrazole-substituted aminoalkyl formula I compound
A compound of Formula I or a pharmaceutically acceptable salt thereof, wherein R1 is a tetrazole ring substituted at position 2′ with an aminoalkyl, and R2 is an amine.
Free base form with tertiary aminoalkyl and NH2
A free base form of a compound of Formula I, wherein R1 is a tetrazole ring substituted at position 2′ with a di-alkyl-substituted (tertiary) aminoalkyl, and R2 is NH2.
Hydrochloric acid salt with R2 as NH3+Cl−
A hydrochloric acid salt of a compound of Formula I, wherein R1 is selected from the group consisting of [specified structures], and R2 is NH3+Cl−.
Specific illustrated hydrochloric acid salt compounds
The hydrochloric acid salt claim is narrowed to specific illustrated compounds AKG-28, AKG-29, AKG-30, and AKG-31.
Liposomal entrapment of Formula I compounds
Liposomal formulations comprising liposome vesicles entrapping Formula I compounds, including transmembrane-gradient-based active loading, intraliposomal polyanions or sulfates, phospholipids, cholesterol, and optional PEG-lipid.
The claim coverage centers on Formula I tetrazole-substituted aminoalkyl oxazolidinones and their specified free base and hydrochloric acid salt forms, with one claim set further narrowed to specific named compounds. A separate inventive theme covers liposomal entrapment of Formula I compounds using gradient-based active loading and selected membrane and intraliposomal components.
Stated Advantages
High selectivity of the aminoalkyl oxazolidinone derivatives against Mycobacterium tuberculosis versus mammalian cells, expressed using selectivity index values.
High selectivity versus VERO cells (SI ≥1,000).
Potent antimycobacterial activity including MIC values reported as MIC <0.1 µg/mL against Mycobacterium (including Mycobacterium tuberculosis).
High drug-to-lipid ratios enabled by transmembrane-gradient-based active loading.
Prolonged circulation with blood retention at a stated time point.
Improved or at least matching antimycobacterial activity versus less encapsulation-optimized analogs.
Reduced dosing frequency for treatment of TB and other gram-positive/mycobacterial infections, once weekly to once every six weeks.
Quantitative liposome loading efficiency and reduced aqueous solubility in the vesicle.
Improved formulation performance via liposomes, including a loading rationale based on amphiphilic weak-base properties and intraliposomal polyanion trapping concepts.
Enhanced pharmacokinetics for tuberculosis/mycobacterial infections via liposomal use.
Aqueous solubility advantages are described for certain salts/free bases.
Enables analytical characterization of the described compounds by 1H/13C NMR and MS.
Reports in vitro biological evaluation including Mycobacterium tuberculosis MIC results.
Reports cytotoxicity and IC50 assays and selectivity indices (SI).
Reports mitochondrial protein synthesis (MPS) inhibition measurements with an MPS selectivity index (SI-MPS).
Documented Applications
Treatment of Mycobacterium tuberculosis (TB).
Treatment of other gram-positive/mycobacterial infections.
Tuberculosis/mycobacterial infections, including enhanced pharmacokinetics associated with liposomal use.
Antimicrobial activity assays against Mycobacterium (including Mycobacterium tuberculosis) and MRSA, including MIC/IC50 reporting guidance and comparison to linezolid.
In vitro evaluation against Mycobacterium tuberculosis, including MIC results for selected AKG series compounds and strain-specific comparisons (e.g., M.tb H37Rv and M.tb Erdman).
Cytotoxicity and IC50 measurement in Vero cells and HepG2 cells, with computed selectivity indices (SI).
Assessment of mitochondrial protein synthesis (MPS) inhibition and reporting of MPS selectivity index (SI-MPS) for selected compounds.
In vitro Mycobacterium tuberculosis MIC evaluation using Alamar Blue (MABA), including benchmark antibiotics (linezolid, tedizolid, bedaquiline) and testing against Mycobacterium tuberculosis (H37Rv and Erdman).
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