Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-06-15
2003-08-12
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S058200, C544S058700, C544S060000
Reexamination Certificate
active
06605609
ABSTRACT:
FILED OF THE INVENTION
The present invention describes a novel compound, N-({(5S)-3-[4-(1,1-dioxido-4-thiomorpholinyl)-3,5-difluorophenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide, a new antimicrobial combination therapy for infective diseases caused by gram-positive and gram-negative bacteria, and compositions particularly useful for oral and intravenous administration.
BACKGROUND OF THE INVENTION
The oxazolidinone antibacterial agents are a novel synthetic class of antimicrobials with broad activity against a number of human and veterinary pathogens, including gram-positive aerobic bacteria such as multiply-resistant staphylococci and streptococci, gram-negative aerobic bacteria such as
H. influenzae
and
M. catarrhalis
, as well as anaerobic organisms such as bacteroides and clostridia species, and acid-fast organisms such as
Mycobacterium tuberculosis
and
Mycobacterium avium
. It is also known that as a chemical compound class, oxazolidinones generally inhibit to some extent monoamine oxidase (MAO), the enzyme responsible for preventing acute blood pressure elevation by the endogenous and dietary amine, tyramine, and other sympathomimetic amines. Accordingly, there is a demand to discover oxazolidinone antibiotics that possess minimum MAO inhibitory activity to eliminate the related side effects from potential drug-drug interactions.
The present invention provides N-({(5S)-3-[4-(1,1-dioxido-4-thiomorpholinyl)-3,5-difluorophenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide. This compound has potent activity against gram-positive human and veterinary pathogens. In particular, it has unexpectedly weak MAO inhibitory activity, which indicates that this compound possesses the capacity to minimize or eliminate potential drug-drug interactions since strong inhibition of monoamine oxidase can result in altered clearance rates for other compounds normally metabolized by it.
In addition, many gram-positive organisms have developed significant levels of resistance to other antibiotics. However, N-({(5S)-3-[4-(1,1-dioxido-4-thiomorpholinyl)-3,5-difluorophenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide exhibits potent activity against gram-positive pathogens that are resistant to other gram-positive antibiotics. Therefore, it is beneficiary in a medical treatment to combine the compound of the present invention with other gram-positive antibiotics to achieve broad coverage and synergistic interactions. The present invention provides a method for treating gram-positive infection in a mammal by using the compound of the present invention, either individually, or in combination with other gram-positive antibiotics.
Furthermore, in medical treatments, a physician often does not know for sure whether the infections are caused by gram-positive bacteria, or gram-negative bacteria or both. Therefore, a need remains for combination therapy to assure coverage of all pathogens in a potentially mixed infection. The present invention provides a combination therapy by using the compound of the present invention in combination with other gram-negative antibiotics.
The present invention further provides compositions suitable for oral and intravenous administrations.
U.S. Pat. No. 5,880,118 discloses substituted oxazine and thiazine oxazolidinone antimicrobials. U.S. Pat. No. 6,968,962 discloses phenyloxazolidinones having a C—C bond to 4-8 membered heterocyclic rings. U.S. Pat. No. 5,981,528 discloses antibiotic oxazolidinone derivatives. PCT patent application, Ser. No. PCT/US00/28872 disclose admixture of linezolid and other antibacterial agents.
None of the references cited above specifically contemplates the compound of the present invention, its combination therapy and its novel compositions.
SUMMARY OF THE INVENTION
The present invention provides a novel oxazolidinone compound of formula I
or its pharmaceutically acceptable salt.
The present invention further provides a method for treating gram-positive bacterial infections which comprises administration to a mammal being treated a pharmaceutically effective amount of the compound of formula I, either individually, or in combination with other gram-positive antibiotics.
The present invention further provides a method for treating gram-positive and gram-negative bacterial infections which comprises administration to a mammal being treated a pharmaceutically effective amount of the compound of formula I in combination with at least one other gram-negative antibiotic.
The present invention further provides compositions for treating gram-positive bacterial infections wherein the compositions comprise a pharmaceutically effective amount of the compound of formula I and at least one other gram-positive antibiotic.
The present invention further provides compositions for treating gram-positive and gram-negative bacterial infections wherein the compositions comprise a pharmaceutically effective amount of the compound of formula I and at least one other gram-negative antibiotic.
The present invention further provides an aqueous composition suitable for intravenous administration for the treatment of gram-positive and/or gram-negative bacterial infections wherein the composition comprises a pharmaceutically effective amount of the compound of formula I and at least one other gram-negative antibiotic.
The present invention further provides a composition suitable for oral administration for the treatment of gram-positive and/or gram-negative bacterial infections wherein the composition comprises a pharmaceutically effective amount of the compound of formula I and at least one other gram-negative antibiotic.
The present invention further provides a use of the compound of formula I to prepare a medicament, for treating gram-positive and/or gram-negative bacterial infections.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
The term “antibiotic” refers to an antibacterial agent other than the compound of the present invention.
Specifically, they refer to Amikacin, Gentamicin, Spectinomycin, Tobramycin, Imipenem, Meropenem, Cefadroxil, Cefazolin, Cephalexin, Cefaclor, Cefotetan, Cefoxitin, Cefprozil, Cefuroxime, Loracarbef, Cefdinir, Cefixime, Cefoperazone, Cefotaxime, Cefpodoxime, Ceftazidime, Ceftibuten, Ceftozoxime, Ceftriaxone, Cefepime, Azithromycin, Clarithromycin, Dirithromycin, Penicillin G, Cloxacillin, Dicloxacillin, Nafcillin, Oxacillin, Amoxicillin, Amoxicillin, Ampicillin, Mezlocillin, Piperacillin, Nalidixic Acid, Ciprofloxacin, Enoxacin, Lomefloxacin, Norfloxacin, Ofloxacin, Levofloxacin, Sparfloxacin, Alatrofloxacin, Gatifloxacin, Moxifloxacin, Trimethoprim, Sulfisoxazole, Sulfamethoxazole, Doxycycline, Minocycline, Tetracycline, Aztreonam, Chloramphenicol, Clindamycin, Quinupristin, Fosfomycin, Metronidazole, Nitrofurantoin, Rifampin, Trimethoprim, and Vancomycin. All of them are known. They can be either obtained commercially or be prepared according to the references cited in PHYSICIANS' DESK REFERENCE, the 53
rd
Edition (1999) and the US FDA's Orange book.
The term “gram-positive antibiotic” refers to an antibacterial agent active against gram-positive bacterial organisms.
The term “gram-negative antibiotic” refers to an antibacterial agent active against gram-negative bacterial organisms.
Methods for Preparation
The compound of the present invention, N-({(5S)-3-[4-(1,1-dioxido-4-thiomorpholinyl)-3,5-difluorophenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide, can be prepared according to the procedures described herein below.
Method 1
Step 1 Preparation of 4-(2,6-difluoro-4-nitrophenyl)thiomorpholine
2,6-Difluoro-4-nitrophenyl trifluoromethanesulfonate (992 mg, 3.23 mmol) is dissolved in dry tetrahydrofuran (15 mL) and then treated dropwise with thiomorpholine (0.487 mL, 4.85 mmol). The reaction is then heated to reflux (70° C.) under nitrogen for 16 hours. The reaction is then allowed to cool to room temperature, stirring over the weekend (56 hours) under nitrogen. At this time, the reaction is found to be complete by thin layer chromatograph
Barbachyn Michael Robert
Zurenko Gary Edward
O'Brien Jonathan P.
Pharmacia & Upjohn Company
Yang Lucy X.
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