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-12145928-B2
Publication Date
2024-11-19
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 document describes oxazolidinone-containing analogs and aminoalkyl oxazolidinone compounds defined by formula frameworks with R and R1 substituents, including R as NHAc and R1 as specified cyclic diamine-derived substituents or aminoalkyl groups such as 2-(N,N-dimethylamino)ethyl, 2-(N,N-diethylamino)ethyl, and 2-(N,N-diethylamino)propyl. The disclosure includes oxazolidinone variants identified as AKG-21 through AKG-40, including AKG-23, AKG-28, AKG-38, AKG-39, and AKG-40, with additional depicted variants and salt or bromine-containing forms.
The document further characterizes preparation compositions and a method of making oxazolidinone compounds in which a first intermediate having R as NHAc is reacted with a second intermediate so that the R1 group in the product matches the R1 group in the second intermediate. The disclosed process uses Pd(dppf)Cl2-catalyzed C–N/C–C coupling with K3PO4 in dioxane/H2O, and selected compounds are characterized by 1H NMR, 13C NMR, and mass spectrometry including ESI+ MS.
The disclosure links these compounds and formulations to biological activity against Mycobacterium tuberculosis, with MIC and selectivity index measurements versus mammalian cells such as VERO and HepG2. It also describes liposome-encapsulated oxazolidinone therapy for tuberculosis and Gram-positive infections, including amphiphilic weak bases used for transmembrane-gradient loading, high solubility prior to encapsulation, and liposomal oxazolidinones exemplified by Ls-AKG28 and Ls-AKG38 with in vivo pharmacokinetic, retention, tolerability, and pegylated liposome findings.
Claims Coverage
The consolidated claim coverage includes independent claims directed to compositions for the preparation of oxazolidinones and a method of making such compounds. Across the independent claims, there are 3 inventive-feature groupings centered on formula-defined compounds with R as NHAc and R1 selected from specific aminoalkyl substituents, with the method requiring that the product R1 matches the R1 of the second intermediate.
Oxazolidinone preparation composition with NHAc and specified aminoalkyl R1
A composition for the preparation of an oxazolidinone comprising a compound of a formula wherein R is NHAc, and a compound of a formula wherein R1 is 2-(N,N-dimethylamino)ethyl, 2-(N,N-diethylamino)ethyl, or 2-(N,N-diethylamino)propyl, with R is NHAc.
Oxazolidinone preparation composition with specified diamine-derived R1
A composition for the preparation of an oxazolidinone comprising a compound where R1 is —(CH2)2N(Me)2 or —(CH2)2N(Et)2, and a compound where R is NHAc.
Method of making an oxazolidinone by reacting a first intermediate with a second intermediate to set R1
A method of making a compound of formula wherein R is NHAc and R1 is —(CH2)2N(Me)2, —(CH2)2N(Et)2, or —(CH2)3N(Et)2, comprising reacting a first intermediate compound wherein R is NHAc with a second intermediate of formula wherein R1 is one of those aminoalkyl groups to produce the compound; wherein R1 in the compound is the same as the R1 in the second intermediate compound.
The independent claims define preparation compositions that combine an NHAc-containing compound with specified R1 substituent-bearing compounds, and a method in which an NHAc first intermediate is reacted with a second intermediate so that the product R1 matches the second intermediate’s R1.
Stated Advantages
Enables transmembrane-gradient loading to achieve high solubility prior to encapsulation.
Provides high drug/lipid loading ratios.
Provides long-circulating stable formulations.
Provides entrapment efficiencies greater than about 85% to about 95%.
Higher exposure and prolonged persistence versus linezolid based on AUC measures.
Dose-proportional linear pharmacokinetics.
Multi-dose pharmacokinetics over weeks without increased clearance or accelerated blood clearance (ABC) for pegylated liposomes.
Demonstrated in vivo drug retention of liposome-associated payload in mice using a drug-to-liposome phospholipid (DL) ratio.
Tolerability in mice and rats with reported body weight, hematology/biochemistry, and histopathology findings.
In vivo therapeutic performance in infection models including reductions in ICF/CFU reported in tuberculosis and relapse dosing effect in rabbit MRSA endocarditis.
Selective anti-mycobacterium tuberculosis activity versus mammalian cells, with reported high selectivity ranges and selectivity index values.
Reduced dosing frequency, described as once weekly to once every six weeks.
Aqueous solubility advantage in HCl/water conditions relative to linezolid.
Documented Applications
In vitro Mycobacterium tuberculosis MIC/MABA testing comparing activity across oxazolidinone/tetrazole side-chain substitutions, including acetamide versus amine at C5 and aminoalkyl substituent variations, using H37Rv and reference strains.
Treatment of mycobacterial infections, including Mycobacterium tuberculosis.
Liposome-encapsulated oxazolidinone therapy for tuberculosis.
Liposome-encapsulated oxazolidinone therapy for Gram-positive infections, including mycobacteria and Gram-positive bacteria such as MRSA.
Tuberculosis pulmonary infection in a C3HeB/FeJ (Kramnik) mouse model, with described lesion context and regimens including comparison involving substitution of linezolid in BPaL/BPaM regimens.
Chronic tuberculosis in a Balb/c chronic TB model, with reported log10 CFU reductions in regimens.
Rabbit MRSA endocarditis relapse dosing, including a described relapse dosing effect with daptomycin (DAP) comparator context.
Non-tuberculosis mycobacteria (NTM) MIC testing and biological activity context reported as ICF/CFU reductions in TB regimens.
Use for mycobacteria and gram-positive bacteria, including MRSA (Staphylococcus aureus).
Intravenous parenteral administration of liposomal formulations.
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