Oxazolidinone derivatives
Inventors
Rhee, Jae Keol • Im, Weon Bin • Cho, Chong Hwan • Choi, Sung Hak • Lee, Tae Ho
Assignees
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Publication Number
US-7816379-B2
Publication Date
2010-10-19
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 Staphylococi, Enterococci and Streptococi, 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, with an oxazolidinone core and defined substituents. R1 and R1′ are independently hydrogen or fluorine, R2 is selected from —NR5R6, —OR7, fluorine, alkylphosphate, monophosphate, or a metal salt of monophosphate, and R3 is hydrogen or a C1-3 or C1-4 alkyl group unsubstituted or substituted with cyano, —(CH2)m—OR7, or ketone.
The substituent definitions further constrain R5 and R6 as independently hydrogen or C1-4 alkyl, R7 as hydrogen, C1-3 alkyl, or acylated amino acid selected from alanine, glycine, proline, isoleucine, leucine, phenylalanine, β-alanine, or valine, and m as 0, 1, 2, 3, or 4. The document includes glycyloxymethyl, valyloxy, alanyloxy, prolinyloxy and related oxazolidin-2-one derivatives as trifluoroacetic-acid salts and hydrochloride salts, and phosphate prodrug forms including mono-/disodiumphosphate and mono-/phosphate derivatives.
The invention also provides methods for preparing an oxazolidinone derivative of Formula (I) or a pharmaceutically acceptable salt thereof by reacting a compound of Formula (III) wherein Y is halogen with a tin compound to provide a compound of Formula (IV), then reacting the compound of Formula (IV) with a compound of Formula (VI) under conditions selected to give a compound of Formula (V), and optionally reacting the compound of Formula (V) under conditions selected to give a compound of Formula (I). The invention includes conversion of the R2 hydroxy group of Formula (V) to R2 selected from —NR5R6, —OR7, fluorine, alkylphosphate, monophosphate, and a metal salt of monophosphate.
Claims Coverage
The consolidated material includes independent claim coverage for one product claim and two method claims. Across the independent claims, three main inventive features are covered: the Formula (I) oxazolidinone scaffold with defined substituent constraints, preparation from halogenated compounds using a tin compound, and conversion of the R2 hydroxy group of Formula (V) into the enumerated R2 substituents.
Oxazolidinone derivative of formula (I) or pharmaceutically acceptable salt
An oxazolidinone derivative of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R1 and R1′ are independently hydrogen or fluorine; R2 is —NR5R6, —OR7, fluorine, alkylphosphate, monophosphate, or a metal salt of monophosphate; R5 and R6 are independently hydrogen or C1-4 alkyl; R7 is hydrogen, C1-3 alkyl, or acylated amino acid selected from alanine, glycine, proline, isoleucine, leucine, phenylalanine, β-alanine, or valine; R3 is hydrogen or a C1-3 or C1-4 alkyl group unsubstituted or substituted with cyano, —(CH2)m—OR7, or ketone; and m is 0, 1, 2, 3, or 4.
Method for preparing oxazolidinone derivative of formula (I) via tin reaction and optional final conversion
Reacting a compound of Formula (III) wherein Y is halogen with a tin compound to provide a compound of Formula (IV); reacting the compound of Formula (IV) with a compound of Formula (VI) under conditions selected to give a compound of Formula (V); and optionally reacting the compound of Formula (V) under conditions selected to give the compound of Formula (I).
Method for converting the R2 hydroxy group of formula (V)
Reacting the R2 hydroxy group of Formula (V) under conditions selected to give R2 selected from —NR5R6, —OR7, fluorine, alkylphosphate, monophosphate, and a metal salt of monophosphate.
The claims define Formula (I) oxazolidinone derivatives with specified R1/R1′, R2, and R3 options, together with preparation methods that include halogen-to-C1-4 alkyl transformation using a tin compound and optional R2 hydroxy-group conversion.
Stated Advantages
Broad-spectrum antibacterial activity including MRSA and VRE.
Low toxicity.
Prodrug formation improves solubility and aqueous stability via esterase/phosphatase reversion.
General acute toxicity statement: LD50 > 1 g/kg.
Reduced toxicity compared with prior oxazolidinones (Zyvox/linezolid).
Improved water solubility.
Enables antibacterial activity against Gram-positive bacteria, anaerobic microorganisms, and acid-resistant microorganisms.
Documented Applications
Pharmaceutical composition and antibiotic use assertions for antibacterial treatment.
Method of treating bacterial infections caused by Gram-positive bacteria.
Use against broad-spectrum bacteria including Gram-positive bacteria and specific bacterial groups listed in the inputs, including Staphylococci, Enterococci, Streptococci, Bacteroides, Clostridia, Mycobacterium tuberculosis, Mycobacterium avium, MRSA, and VRE.
Antibiotic use for inhibiting broad-spectrum antibacterial activity against Gram-positive bacteria, anaerobic microorganisms, and acid-resistant microorganisms including Mycobacterium tuberculosis and Mycobacterium avium.
Treatment of bacterial infections caused by Gram-positive bacteria.
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