Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-08-17
2004-06-15
Rotman, Alan L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S094000, C546S095000
Reexamination Certificate
active
06750224
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to optically pure S-(−)-benzoquinolizine carboxylic acids, their derivatives, salts, pseudopolymorphs, polymorphs and hydrates thereof, substantially free of their R-(+)-isomers, to processes for preparation of the optically pure S-(−)-benzoquinolizine carboxylic acids, their derivatives, salts, pseudopolymorphs, polymorphs and hydrates thereof substantially free of their R-(+)-isomers, and to pharmaceutical compositions comprising the S(−)-benzoquinolizine carboxylic acids, their derivatives, salts, pseudopolymorphs, polymorphs and hydrates thereof. These compounds and compositions can be used to systemically and topically treat bacterial Gram-positive, Gram-negative and anaerobic infections, specially resistant Gram-positive organism infections, Gram-negative organism infections, mycobacterial infections and emerging nosocomial pathogen infections, while avoiding toxic effects associated with the administration of the racemic mixture of RS-(±)-benzoquinolizine carboxylic acid. The compounds and compositions of this invention can also be used to treat diseases and disorders caused by Gram-positive, Gram-negative and anaerobic bacteria, and diseases and disorders caused by resistant Gram-positive organisms, Gram-negative organisms, mycobacteria and nosocomial pathogens.
BACKGROUND OF THE INVENTION
Bacterial resistance to antibiotics is an increasingly recurrent phenomenon. Of grave concern has been the development of methicillin-resistant
Staphylococcus aureus
(MRSA) and methicillin-resistant
Streptococcus epidermidis
(MRSE) strains, which because of the phenomenon of cross-resistance, are now also resistant to the larger class of &bgr;-lactam antibiotics including the cephalosporins and carbapenems. Of even graver concern is the development of resistance in MRSA strains against the class of anti-bacterial agents known as fluoroquinolones. Several reports are known of MRSA strains displaying resistance to fluoroquinolone agents such as ciprofloxacin, sparfloxacin and even the more recently introduced trovafloxacin. In addition, for trovafloxacin and for newer introductions like grepafloxacin, moxifloxacin and gatifloxacin, a concern has been expressed about their checkered safety records. The use of trovafloxacin has been suspended or severely curtailed because of its association with liver side effects. Grepafloxacin was withdrawn worldwide because of severe cardiovascular side effects. The labelling on gatifloxacin and moxifloxacin warns that they may prolong the QTc interval on electrocardiograms in some patients.
The last line of defense against such fluoroquinolone-resistant MRSA strains is the class of glycopeptide antibiotics represented by vancomycin and teicoplanin. These glycopeptide antibiotics are, however, laden with several limitations. Vancomycin is encumbered with lack of oral bioavailability, nephrotoxic potential, toxic effects such as phlebitis and red-men syndrome. Moreover, the recent disturbing wide spread emergence of Vancomycin resistant enterococci (VRE) followed by the alarming reports of Vancomycin intermediate resistance
Staphylococcus aureus
(VISA) strains from Japan and USA have cast a shadow over the future of glycoside antibiotics in clinical practice. In time, there is a relatively wide-spread emergence of staphylococci, enterococci, pneumococci and streptococci, which have become resistant to currently used first-and second-line antibacterial agents such as penicillin, oxacillin, vancomycin and erythromycin (SENTRY Programme: Antimicrobial Agents & Chemotherapy 42 1762-1770, 1998).
Also, for primary skin infections such as impetigo and folliculitis, and for secondary infections in humans such as infected dermatitis, wounds and bums, as well as to eliminate nasal carriage of MRSA in healthcare workers and patients, a special antibiotic used topically is Mupirocin. Mupirocin has high in vitro anti-staphylococcal and anti-streptococcal activity. There has, however, been an increase of organisms, specially staphylococci, developing resistance to Mupirocin. The emergence of Mupirocin-resistant Methicillin-resistant
Staphylococcus aureus
(MRSA) in infected patients in different countries like Canada, Western Australia, UK, Spain and Switzerland is described in different references in the medical and scientific literature viz. J. Hosp. Infect. 39(1), 19-26 (1998); J. Hosp. Infect. 26(3),157-165 (1994); Infect Control Epidemiol 17(2), 811-813 (1996); 38
th
Annual ICAAC Abstract C-75, 90 (1998); 38
th
ICAAC Abstract 12-25, 507 (1998).
Furthermore, Gram-positive pathogens such as Staphylococci, enterococci and Gram-negative pathogens
E. coli
, Klebsiella, Proteus, Serratia, Citrobacter and Pseudomonas, frequently encountered in urinary tract infections are susceptible to the known fluoroquinolones, such as ciprofloxacin, levofloxacin, ofloxacin and norfloxacin. The potency of these fluoroquinolones, however, markedly deteriorates under the acidic conditions likely to be encountered in urinary tract infections, rendering them inadequate.
Furthermore, multidrug-reistant (MDR) mycobacterial strains have emerged displaying resistance to first-line antimycobacterial agents such as rifampicin, pyrazinamide and INH etc. thus severely curtailing therapeutic options available for the management of infections due to such strains. Usually, the antimycobacterial drug regimen involves treatment spread over several months, and hence the drug has to be tolerated well by the patients. Among the fluoroquinolone antibiotics, sparfloxacin is reported to be highly active against mycobacteria. It is not quite suitable, however, for long-term therapy because of its potential to cause phototoxic side effects in humans and laboratory animals such as mice and guinea-pigs.
Furthermore, in the worldwide management of nosocomial infections, besides the problematic strains of staphylococci and enterococci, including MRSA, strains of Chryseobacteria have recently emerged as new members of nosocomial pathogens causing neonatal meningitis and pneumonia, as well as sepsis, in immuno-compromised patients being treated in intensive care units. Chryseobacteria are intrinsically resistant to &bgr;-lactam antibiotics including third-generation cephalosporins and carbapenems. These factors reduce the treatment options available to the clinicians.
The highly pressing need for other agents and methods of treatment for infections arising from such emerging resistant microorganisms, Gram-negative pathogens in acidic environments, mycobacteria and nosocomial pathogens thus assumes great significance.
Among other agents, one particular class of compounds the benzoquinolizine carboxylic acids are of particular relevance. Nadifloxacin is an example of a benzo-quinolizine carboxylic acid. Nadifloxacin is racemic [(±)-9-fluoro-8-(4-hydroxypiperidin-1-yl)-5-methyl-6,7-dihydro-1-oxo-1H-5H-benzo[i,j]quinolizine-2-carboxylic acid and is disclosed in JP Patent No. 58,90,511 and U.S. Pat. No. 4,399,134. Nadifloxacin has an asymmetric carbon atom at the 5-position thereof. RS-(±)-Nadifloxacin comprises two optically active isomers. In describing an optically active compound, the prefixes R and S or D and L are used to denote the absolute configuration of the molecule about its chiral centre(s). The prefixes (+) and (−) or d and l are employed to designate the sign of rotation of plane-polarized light by the compound, with (−) or l meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. Compounds having a single chiral centre exist as a pair of enantiomers, which are identical except that they are non-superimposable mirror images of one another. A one-to-one mixture of enantiomers is often referred to as a racemic mixture. Racemic RS-(±)-Nadifloxacin derives its biological activity primarily from the S-(−)-enantiomer. The optically active S-(−)-Nadifloxacin [&agr;]
20
D
=−312.0 is
Agarwal Shivkumar
Chaturvedi Nishith
De Souza Noel John
Kandepu Sreenivas
Khorakiwala Habil Fakhruddin
Ladas & Parry
Rotman Alan L.
Truong Tamthom N.
Wockhardt Limited
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