Antibiotics with improved solubility, lower toxicity; potent antibacterial activity; includes Torezolid phosphate
Inventors
Rhee, Jae Keol • Im, Weon Bin • Cho, Chong Hwan • Choi, Sung Hak • Lee, Tae Ho
Assignees
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Publication Number
US-8420676-B2
Publication Date
2013-04-16
Expiration Date
Abstract
The present invention relates to novel derivatives of oxazolidinone, a method thereof and pharmaceutical compositions comprising the derivatives for use in an antibiotic. The oxazolidinone derivatives of the present invention show inhibitory activity against a broad spectrum of bacteria and lower toxicity. The prodrugs, prepared by reacting the compound having hydroxyl group with amino acid or phosphate, have an excellent efficiency on solubility thereof against water. Further, the derivatives of the present invention may exert potent antibacterial activity versus various human and animal pathogens, including Gram-positive bacteria such as, Staphylococci, Enterococci and Streptococci anaerobic microorganisms such as Bacteroides and Clostridia, and acid-resistant microorganisms such as Mycobacterium tuberculosis and Mycobacterium avium. Accordingly, the compositions comprising the oxazolidinone are used in an antibiotic.
Core Innovation
The invention relates to oxazolidinone derivatives of Formula (I) and pharmaceutically acceptable salts thereof. The derivatives include a Het substituent selected from tetrazolyl and oxadiazolyl, and a ring A that is unsubstituted or has at least one fluorine substituent. The compound structure is further characterized by defined substituent options for R7, R3, and m within the stated formula relationships.
Within Formula (I), R7 is H or a phosphate/phosphonate-type substituent represented as PO(OH)2 or PO(O)2−(M+)2, where M+ is a pharmaceutically acceptable metal cation. R3 is hydrogen, a C1-4 alkyl group that is unsubstituted, or substituted with cyano, —(CH2)m—OR7, or ketone, and m is 0, 1, 2, 3, or 4. The document also describes specific oxazolidinone examples and salt forms, including hydroxymethyl and glycyloxymethyl variants and amino-acid oxy substituents.
Claims Coverage
The consolidated claim coverage centers on one independent claim directed to an oxazolidinone derivative of Formula (I), or a pharmaceutically acceptable salt thereof, defined by four main inventive features: Het selection, ring A fluorination status, R7 phosphate/phosphonate options with a pharmaceutically acceptable metal cation, and defined R3 and m options. A separate closed selection claim lists specific named compounds, including compounds 16), 27), 39), 48), 51), 52), 53), 54), 55), 56), 57), 58), and 60).
Oxazolidinone derivative of Formula (I) or pharmaceutically acceptable salt
An oxazolidinone derivative of Formula (I), or a pharmaceutically acceptable salt thereof, having a structural framework defined by Het, ring A, R7, R3, and m.
Het selected from tetrazolyl or oxadiazolyl
Het is selected from the group consisting of tetrazolyl and oxadiazolyl.
Ring A unsubstituted or fluorinated
Ring A is unsubstituted or has at least one fluorine substituent.
R7 as H or phosphate/phosphonate with pharmaceutically acceptable metal cation
R7 is either H, or PO(OH)2, or PO(O)2−(M+)2, wherein M+ is a pharmaceutically acceptable metal cation.
R3 and m defined substitution options
R3 is hydrogen, a C1-4 alkyl group that is unsubstituted, or substituted with cyano, —(CH2)m—OR7, or ketone; and m is 0, 1, 2, 3, or 4.
Closed list selection of specific named compounds
A compound selected from the group consisting of Compounds 16), 27), 39), 48), 51), 52), 53), 54), 55), 56), 57), 58), and 60).
Overall, the claim scope centers on a Formula (I) oxazolidinone scaffold constrained by Het (tetrazolyl or oxadiazolyl), optional fluorination on ring A, phosphate/phosphonate-type R7 substituents optionally paired with pharmaceutically acceptable metal cations, and defined R3 substitution modes governed by m. A separate claim narrows coverage to a closed set of specifically named compounds and related salt forms.
Stated Advantages
Broad-spectrum antibacterial activity, including MRSA and VRE.
Improved solubility for amino-acid/phosphate-derived prodrugs.
In-water and acid stability with enzymatic reversion in blood (esterase/phosphatase).
Low acute toxicity, reported LD50 greater than 1 g/kg.
Improves solubility versus Zyvox.
Reduces toxicity versus Zyvox.
Documented Applications
Treating bacterial infections, including Gram-positive bacterial infections, with specified genera such as Staphylococcus, Enterococcus, Streptococcus, Bacteroides, Clostridium, and Mycobacterium.
Use against Gram-positive bacteria, including Staphylococci, Enterococci, and Streptococci.
Use against anaerobes including Bacteroides and Clostridia.
Use against acid-resistant Mycobacterium tuberculosis and Mycobacterium avium.
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