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-11566023-B2
Publication Date
2023-01-31
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 invention relates to novel aminoalkyl oxazolidinone compounds defined by Formula I and pharmaceutically acceptable salts. In the compounds, R1 is a tetrazole ring substituted at position 2′ with an aminoalkyl, including aminoethyl and aminopropyl, and R2 is an acetamide, represented as —NHCOCH3. Exemplified Formula 1a–1e compounds are described, including the AKG series and named embodiments such as AKG-28 and AKG-38.
The document further describes variants with di-alkyl-substituted (tertiary) amino groups at R1 and ties specific compound embodiments to Formula variants including Formula 1c, 1d, and 1e. The disclosure also describes pharmaceutical compositions that include these Formula I compounds or pharmaceutically acceptable salts, and formulations using liposome vesicles, trapping agents, phospholipids, cholesterol or sterols, and optional PEG-lipids.
The patent further describes liposome-encapsulation and transmembrane-gradient-driven loading of aminoalkyl oxazolidinone (Formula I) compounds. It reports improved aqueous solubility, amphiphilic weak base properties, plasma stability, retained drug-to-lipid ratio, burst-release stability metrics, and prolonged circulation compared with a linezolid comparator.
Claims Coverage
The independent claims cover three inventive features: a Formula I compound, a corresponding pharmaceutical composition, and a method of treating MRSA infection. The claims are defined by structural selection constraints on R1 and R2, with R1 as a tetrazole ring substituted at position 2′ with an aminoalkyl and R2 fixed as —NHCOCH3, and with further narrowing in the composition claim to aminoethyl and aminopropyl.
Formula I compound with tetrazole-aminoalkyl and acetamide
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 acetamide.
Pharmaceutical composition with di-alkyl-substituted tertiary aminoalkyl (aminoethyl or aminopropyl) and acetamide
A pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof wherein R1 is a tetrazole ring substituted at position 2′ with a di-alkyl-substituted (tertiary) aminoalkyl selected from an aminoethyl and an aminopropyl; and R2 is —NHCOCH3.
Method of treating MRSA infection by administering Formula I tetrazole-aminoalkyl acetamide compound
A method of treating a methicillin-resistant Staphylococcus aureus (MRSA) infection comprising the step of administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof wherein R1 is selected from the group consisting of specified options and R2 is —NHCOCH3.
Across the independent claims, the inventive concept centers on Formula I compounds in which R1 is a tetrazole ring substituted at position 2′ with an aminoalkyl and R2 is fixed as —NHCOCH3. The composition claim narrows R1 to aminoethyl or aminopropyl, and the method claim applies the structurally defined compounds to treating MRSA infection.
Stated Advantages
Improved aqueous solubility of the compounds.
Amphiphilic weak base properties enable high-efficiency transmembrane-gradient liposome loading.
Long circulating liposomal formulations aimed at extended circulation and plasma stability.
Retention of drug-to-lipid ratio (DL ratio) in liposomal formulations.
High microbiological potency against Mycobacterium tuberculosis, including MIC values less than 0.1 μg/mL as stated.
High microbiological potency against MRSA, including MIC values less than 2 μg/mL as stated.
High in vitro selectivity against Mycobacterium tuberculosis versus mammalian cells, including SI ranges.
Prolonged circulation compared with a linezolid comparator.
High encapsulation efficiency and retention behavior under low or zero dextrose conditions.
Linear pharmacokinetics and low clearance changes.
Documented Applications
Liposomal formulations and compounds for tuberculosis/mycobacterial infections.
Liposomal formulations and compounds for gram-positive infections, including methicillin-resistant Staphylococcus aureus (MRSA) treatment.
Parenteral administration and intravenous dosing contexts for the disclosed formulations.
Treating a methicillin-resistant Staphylococcus aureus (MRSA) infection by administering a therapeutically effective amount of a Formula I compound or pharmaceutically acceptable salt.
Use of liposomes for encapsulation and transmembrane-gradient-driven loading of aminoalkyl oxazolidinone (Formula I) compounds.
Treatment context for tuberculosis (Mycobacterium tuberculosis), MRSA, and other mycobacteria/gram-positive bacteria.
Efficacy studies in pulmonary Mycobacterium tuberculosis models, including comparisons to combination regimens and monotherapy studies.
Additional efficacy in an MRSA endocarditis model.
In vitro MIC testing against nontuberculous mycobacteria and MDR Mycobacterium tuberculosis isolates.
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