Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-07-21
2002-07-02
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S376000, C548S229000, C548S232000, C548S234000, C548S454000, C546S271400
Reexamination Certificate
active
06413981
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the field of phenyl oxazolidinone compounds having antibacterial activity against Gram-positive and Gram-negative bacteria, 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), glycopeptide-intermediate resistant
Staphylococcus aureus
(GISA), vancomycin-resistant enterocci (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. Exemplary 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, including indolyl substituted compounds useful as antibacterial agents.
WO 98/54161 (Hester et al.) discloses amides, thioamides, ureas, and thioureas which are antibacterial agents.
WO 95/07271 (Barbachyn et al.) discloses 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 multiple-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.
WO 93/09103 (Barbachyn et al.) discloses substituted aryl- and heteroarylphenyloxazolidinones which are useful as antibacterial agents.
SUMMARY OF THE INVENTION
The invention provides phenyl oxazolidinone compounds of Formula I:
wherein:
R is selected from the group consisting of OH, N
3
, OR′, O-Aryl, O-Heteroaryl OSO
2
R″, —NR′″R″″, or
wherein:
(i) R′ is straight-chain or branched acyl having up to 6 carbon atoms or benzyl;
(ii) R″ is straight-chain or branched alkyl, having up to 5 carbon atoms, phenyl or tolyl; and
(iii) R′″ and R″″ are independently selected from the group consisting of H, cycloalkyl having 3 to 6 carbon atoms, phenyl or tert-butoxycarbonyl, fluorenyloxycarbonyl, benzyloxycarbonyl, straight-chain or branched alkyl having up to 6 carbon atoms which is optionally substituted by cyano or alkoxycarbonyl having up to 4 carbon atoms, —CO
2
—R
1
, —CO—R
1
, —CO—SR
1
, —CS—R
1
, P(O)(OR
2
)(OR
3
), and —SO
2
—R
4
, in which
R
1
is selected from the group consisting of H, cycloalkyl having 3 to 6 carbon atoms, trifluoromethyl or phenyl, benzyl, or acyl each having up to 5 carbon atoms, straight-chain or branched alkyl having up to 6 carbon atoms, said alkyl optionally substituted by straight-chain or branched alkoxycarbonyl having up to 5 carbon atoms, OH, cyano, up to 3 halogen atoms, and —NR
5
R
6
in which R
5
and R
6
are identical or different and are selected from H, phenyl or straight-chain or branched alkyl having up to 4 carbon atoms;
R
2
and R
3
are identical or different and are selected from hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms; and
R
4
is selected from straight-chain or branched alkyl having up to 4 carbon atoms or phenyl and;
R
4a
is CN, COR
4c
, COOR
4c
, CONHR
4c
, CO—NR
4c
R
4d
, SO
2
R
4c
, SO
2
NHR
4c
, SO
2
—NR
4c
R
4d
, or NO
2
;
R
4b
is H, alkyl, OR
4c
, SR
4c
, amino, NHR
4c
, NR
4c
,R
4d
, C1-C8-alkylaryl or mono-, di-, tri-, and per-halo C1-C8-alkyl;
R
4c
and R
4d
are independently selected from H, alkyl, aryl, or in the case of any NR
4c
R
4d
group R
4c
and R
4d
taken together with the nitrogen atom to which they are attached form a unsubstituted or substituted pyrrolidinyl, piperidinyl or morpholinyl group;
X is 0 to 4 members independently selected from the group consisting of halogen, OH, mercapto, nitro, halo-C
1-8
-alkyl, C
1-8
alkoxy, 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, 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
Y is a radical of Formulae II or III:
wherein
R
5
, R
6
, R
7
, and R
8
are each independently H, alkyl, CN, nitro, C
1-8
alkyl, halo-C
1-8
-alkyl, formyl, carboxy, alkoxycarbonyl, carboxamide, aryl, substituted-aryl, heteroaryl, substituted-heteroaryl, or R
5
and R
6
and/or R
7
and R
8
together form an oxo group;
R
9
, and R
10
are each independently H, halogen, alkyl, OH, CN, mercapto, nitro, C
1-8
alkyl, halo-C
1-8
-alkyl, C
1-8
alkoxy, thio-C
1-8
-alkyl, amino, 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, or amine;
A, B, C, and D are selected from C, S, O, and N to form any five to ten membered aromatic or heteroaromatic ring, said heteroaromatic ring having one to four members selected from the group consisting of S, O, and N;
Z is selected from halogen, alkyl, aryl, substituted-aryl, heteroaryl, substituted-heteroaryl, CN, CHO, COalkyl, amine, (dialkylamino)alkyl, said dialkylamino consisting of straight-chain or branched alkyl having up to 6 carbon atoms or phenyl or constituting a ring of 2 to 5 carbons having 0 to 2 atoms selected from S, O and N or alkoxy, or NHCO—(C
1
-C
8
-alkyl); and
m is or 1,
and the 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 mammal 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 of the phenyl oxazolidinone compounds of the present invention, the following definitions apply.
Unless specified otherwise, the terms “alkyl”, “alkenyl”, and “alkynyl” may be straight or branched groups with 1-8 carbon atoms.
“Acyl” means an organic radical having the designated number of carbon atoms, derived from an organic acid by the removal of a hydroxyl group having the formula RCO, as in the case of acetyl where R is CH
3
.
“Aryl” is an unsubstituted carbocyclic aromatic group including, but not limited to, phenyl, 1- or 2-naphthyl and the like. “Heteroaryl” refers to a cyclic aromatic radical having from five to ten atoms in the ring; where one to three ring atoms are independent heteroatoms such as S, O, and N, and the remaining ring atoms are carbon, for example, a pyridinyl, pyrazinyl, pyrimidinyl, pyrroyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thienyl, furanyl, quinolinyl, or isoquinolinyl, radical and the like.
Hlasta Dennis
Paget Steven
Ortho-McNeil Pharamceutical, Inc.
Patel Sudhaker B.
Raymond Richard L.
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