Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-07-21
2001-10-02
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S254020, C514S376000, C514S227800, C544S060000, C544S137000, C544S369000, C548S229000
Reexamination Certificate
active
06297242
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the field of phenyl oxazolidinone compounds having antibacterial activity, pharmaceutical compositions containing the compounds, and methods of treating bacterial infections with the compounds.
BACKGROUND OF THE INVENTION
Oxazolidinones have been identified, within the last twenty years, as a new class of antibacterials which are active against numerous multidrug-resistant gram positive organisms. Particularly problematic pathogens include methicillin-resistant
Staphylococcus aureus
(MRSA), vancomycin-resistant enterococci (VRE) and penicillin- and cephalosporin-resistant
Streptococcus pneumoniae.
As a class oxazolidinones exhibit a unique mechanism of action. Studies have shown that these compounds selectively bind to the 50S ribosomal subunit and inhibit bacterial translation at the initiation phase of protein synthesis. Examplary members of oxazolidinones are linezolid (see WO 95/07271) and eperezolid.
U.S. Pat. No. 5,792,765 to Riedl et al. discloses a series of substituted oxazolidinones (cyanoguanidine, cyanoamidines, and amidines) useful as antibacterial medicaments.
U.S. Pat. No. 5,910,504 to Hutchinson discloses a series of heteroaromatic ring substituted phenyl oxazolidinones.
WO 98/54161 (Hester et al.) discloses amides, thioamides, ureas, and thioureas which are antibacterial agents.
WO 95/07271 (Barbachyn et al.) oxazine and thiazine oxazolidinone derivatives such as linezolid and its analogs which are useful antimicrobial agents, effective against a number of human and veterinary pathogens, including gram-positive aerobic bacteria such as multiply-resistant staphylococci, streptococci and enterococci as well as anaerobic organisms such as Bacteroides spp. and Clostridia spp. species, and acid-fast organisms such as
Mycobacterium tuberculosis, Mycobacterium avium
and Mycobacterium spp.
SUMMARY OF THE INVENTION
The invention provides new oxazolidinone compounds of the formula I:
wherein:
R is H, alkyl, OR
1
, SR
1
, amino, NHR
1
, NR
1
R
2
, (C
1
-C
8
) alkylaryl or mono-, di-, tri-, and per- halo-(C
1
-C
8
) alkyl;
W is H, CN, COR
1
, COOR
1
, CONHR
1
, CO—NR
1
R
2
, SO
2
R
1
, SO
2
NHR
1
, SO
2
—NR
1
R
2
, or NO
2
,
R
1
and R
2
are independently selected from H, alkyl aryl, or, in the case of any —NR
1
R
2
group R
1
and R
2
taken together with the nitrogen group may form a cyclic amino derivative:
X is selected from H, CN, COR
1
, COOR
1
, CONHR
1
, CO—NR
1
R
2
, SOR
1
, SO
2
R
1
, SO
2
NHR
1
, SO
2
—NR
1
R
2
, NO
2
, (C
1
-C
8
) alkyl, OR
1
, SR
1
, amino, NHR
1
, NR
1
R
2
, aryl, (C
1
-C
8
) alkylaryl (such as benzyl), and (mono-, di-, tri-, and per-) halo-alkyl and heteroaryl;
Y is 0 to 4 members independently selected from the group consisting of H, halogen, OH, mercapto, nitro, halo-C
1-8
-alkyl, C
1-8
alkoxyl, thio-C
1-8
-alkyl, C
1-8
alkyl-amino, di(C
1-8
-alkyl-)amino, formyl, carboxy, alkoxycarbonyl, C
1-8
alkyl-CO—O—, C
1-8
alkyl-CO—NH—, carboxamide, aryl, substituted-aryl, heteroaryl, substituted-heteroaryl, CN, amine, alkoxy, NHCO—(C
1-8
alkyl), C
3-6
cycloalkyl, C
1-8
alkyl optionally substituted with one or more members selected from the group consisting of F, Cl, OH, C
1-8
alkoxyl and C
1-8
acyloxy; and optical isomers, enantiomers, diastereomers, racemates and racemic mixtures thereof, or pharmaceutically acceptable salts and esters thereof.
Compounds of the above formula are useful as antibacterial agents for the treatment of bacterial infections in humans and animals.
The present invention is also directed to a method of treating a subject having a condition caused by or contributed to by bacterial infection, which comprises administering to said subject a therapeutically effective amount of the compound of Formula I.
The present invention is further directed to a method of preventing a subject from suffering from a condition caused by or contributed to by bacterial infection, which comprises administering to the subject a prophylactically effective dose of the pharmaceutical composition of a compound of Formula I.
Other objects and advantages will become apparent to those skilled in the art from a review of the ensuing specification.
DETAILED DESCRIPTION
Relative to the above description, certain definitions apply as follows.
Unless specified otherwise, the terms “alkyl”, “alkenyl”, and “alkynyl” may be normal or branched groups with 1-8 carbon atoms.
Aryl is a carbocyclic aromatic radical including, but not limited to, phenyl, 1- or 2-naphthyl and the like. The aromatic radical may be substituted by independent replacement of 1 to 3 of the hydrogen atoms thereon with halogen, OH, CN, mercapto, nitro, amino, alkyl, O-alkyl, S-alkyl, NH-alkyl, N(alkyl)
2
, (mono-, di-, tri-, and per-) halo-alkyl, formyl, COR
1
, COOR
1
, CONHR
1
, CO—NR
1
R
2
, SOR
1
, SO
2
R
1
, SO
2
NHR
1
, SO
2
—NR
1
R
2
, alkyl-CO—O—, alkyl-CO—NH—, or carboxamide or a second aryl group. Illustrative aryl radicals include, for example, phenyl, naphthyl, diphenyl, fluorophenyl, difluorophenyl, benzyl, benzoyloxyphenyl, carboethoxyphenyl, acetylphenyl, ethoxyphenyl, phenoxyphenyl, hydroxyphenyl, carboxyphenyl, trifluoromethylphenyl, methoxyethylphenyl, acetamidophenyl, tolyl, xylyl, dimethylcarbamylphenyl and the like.
The term “halo” or “halogen” means fluoro, chloro, bromo and iodo. (Mono-, di-, tri-, and per-) halo-alkyl is an alkyl radical substituted by independent replacement of the hydrogen atoms thereon with halogen.
Heteroaryl refers to a cyclic aromatic radical having from five to ten ring atoms of which one ring atom is selected from S, O, and N; 0-2 ring atoms are additional heteroatoms independently selected from S, O, and N; and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms, such as, for example, pyridinyl, pyrazinyl, pyrimidinyl, pyrroyl, pyrazolyl, imidazolyl, thiazolyi, oxazolyl, isoxazolyl, thiadiazolyl, triazolyl, oxadiazolyl, thienyl, furanyl, quinolinyl, isoquinolinyl, and the like. The heteroaryl group may be substituted by independent replacement of 1 to 3 of the hydrogen atoms thereon with halogen, OH, CN, mercapto, nitro, amino, alkyl, O-alkyl, S-alkyl, NH-alkyl, N(alkyl)
2
, (mono-, di-, tri-, and per-) halo-alkyl, formyl, COR
1
, COOR
1
, CONHR
1
, CO—NR
1
R
2
, SOR
1
, SO
2
R
1
, SO
2
NHR
1
, SO
2
—NR
1
R
2
, alkyl-CO—O—, alkyl-CO—NH—, or carboxamide. Heteroaryl may be substituted with a mono-oxo to give for example a 4-oxo-1H-quinoline.
A cyclic amino group is a 4 to 8 membered nitrogen containing cyclic group where the other remaining members are selected from carbon, nitrogen, oxygen or sulfur, for instance an azetidinyl group, pyrrolidinyl group, piperidinyl group, morpholino group, piperazinyl, or groups of the following formulae:
wherein m is −2 to 4 and n is 1-4;
The compounds of the instant invention are asymmetric in the oxazolidinone ring at the 5-position and thus exist as optical antipodes. As such, all possible optical antipodes, enantiomers or diastereomers resulting from additional asymmetric centers that may exist in optical antipodes, racemates and racemic mixtures thereof are also part of this invention. The antipodes can be separated by methods known to those skilled in the art such as, for example, fractional recrystallization of diastereomeric salts of enantiomerically pure acids. Alternatively, the antipodes can be separated by chromatography on a Pirkle column.
The phrase “pharmaceutically acceptable salts” denotes salts of the free base which possess the desired pharmacological activity of the free base and which are neither biologically nor otherwise undesirable. These salts may be derived from inorganic or organic acids. Examples of inorganic acids are hydrochloric acid, nitric acid, hydrobromic acid, sulfuric acid, or phosphoric acid. Examples of organic acids are acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,
Dow Kenneth J.
McKane Joseph K.
Ortho-McNeil Pharmaceutical , Inc.
Wright Sonya
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