Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1999-05-17
2001-06-26
Celsa, Bennett (Department: 1627)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S019300, C514S237500, C514S255010, C514S336000, C514S350000, C514S376000, C562S560000
Reexamination Certificate
active
06251869
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to methods and compositions for enhancing the effectiveness of oxazolidinone antibacterial agents against gram-negative organisms by using an arginine derivative.
BACKGROUND OF THE INVENTION
The oxazolidinone antibacterial agents are a novel synthetic class of antimicrobials with potent activity against a number of human and veterinary pathogens, including gram-positive aerobic bacteria such as multiply-resistant staphylococci and streptococci, anaerobic organisms such as bacteroides and clostridia species, and acid-fast organisms such as
Mycobacterium tuberculosis
and
Mycobacterium avium.
In particular, the oxazolidinone compounds of structures I-V have been found especially effective.
However, certain oxazolidinones generally have poor activity at a useful level against aerobic gram-negative organisms such as
E. coli, Haemophilus influenzae, Moraxella catarrhalis, Pseudomonas aeruginosa,
or
Klebsiella pneumoniae.
Thus, the use of these oxazolidinone antibacterial agents alone is limited to infectious states due to gram-positive bacteria. Accordingly, it is among the objects of the present invention to provide a process for enhancing the inhibitory spectrum of the oxazolidinones. We have now discovered that when the oxazolidinone antibacterial agents are administered with an arginine derivative, a pronounced synergic effect against gram-negative organisms is produced. The effective amount of an oxazolidinone antibacterial agent to be fully efficacious against aerobic gram-negative organisms is much lower than would be needed if an oxazolidinone was administered without these arginine derivatives.
INFORMATION DISCLOSURE
International publication No. WO 96/33285 discloses methods for screening inhibitors of microbial efflux pumps, including those which export antibiotics. The screening methods are based on the increase in the intracellular concentration of a compound, such as an antibiotic or a dye, when the bacterial cells are contacted with an efflux pump inhibitor. In addition, this invention provides pharmaceutical compositions containing such efflux pump inhibitors, including certain arginine derivatives, and methods for treating microbial infections and enhancing the antimicrobial activity of certain antimicrobial agents.
The abstract of the 36th ICAAC, presented by Pharmacia and Upjohn, Inc. discloses mutation of the AcrAB antibiotic efflux pump in
E. coli
confers susceptibility to oxazolidinone antibacterial agents.
SUMMARY OF THE INVENTION
The present invention presents a method and a composition for treating gram-negative organisms infections in mammal which comprises administration of an effective amount of an oxazolidinone antibacterial agent and an arginine derivative of formula A
wherein
R
1
is
a) aryl, optionally substituted with C
1-4
alky, C
1-4
alkoxy, C
1-4
alkythio, halo, or —NH
2
,
b) —(CH
2
)
i
—aryl, in which aryl is substituted with C
1-4
alkyl, C
1-4
alkoxy, C
1-4
alkythio, halo, or —NH
2
,
c) thienyl, furyl, pyridyl, benzofuranyl, or benzothienyl;
Z is R
2
, or —CHWR
2
;
R
2
is
a) aryl, optionally substituted with one or two C
1-4
alkyl, C
1-4
alkoxy, C
1-4
alkythio, halo, —NH
2
, C
1-4
alkylamino, C
1-4
dialkylamino, or —NHOH,
b) C
1-4
alkyl, optionally substituted with fluoro,
c) C
1-4
alkoxy, C
1-4
alkythio,
d) halo,
e) thienyl, furanyl, or pyridyl;
W is H, —NH
2
, C
1-4
alkylamino, C
1-4
dialkylamino, halo, hydroxyl, C
1-4
alkoxy, alkylthio, or azaheterocycle;
aryl is phenyl, or naphthyl;
azaheterocycle is n-morpholinyl, n-piperazinyl, n-pyrrolidinyl, n-imidazolyl, n-pyrrolyl, n-pyrazolyl, n-triazolyl, or n-tetrazolyl;
i is 0, 1, or 2; and pharmaceutically acceptable salts.
REFERENCES:
patent: 5977373 (1999-11-01), Gadwood et al.
patent: 5989832 (1999-11-01), Trias et al.
patent: 6998406 (1999-12-01), Hestter, Jr.
patent: WO99/17791 (1999-04-01), None
Barbachyn et al. J. Med. Chem. vol. 39, No. 3 pp. 680-685, Feb. 1996.*
Brickner et al. J. Med. Chem. vol. 39, No. 3 pp. 673-679, Feb. 1996.
Celsa Bennett
Pharmacia & Upjohn Company
Yang Lucy X.
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