Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-11-30
2003-03-18
Travers, Russell (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S312000
Reexamination Certificate
active
06534508
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to novel compositions of matter containing optically pure (S)-lomefloxacin. These compositions possess potent activity in treating various infections while avoiding adverse effects associated with racemic lomefloxacin including but not limited to headache, stomach discomfort, gastrointestinal disorders, hypoglycemia, renal and hepatic dysfunction, allergic reactions and respiratory distress, and arthropathy, such as cartilage lesions and erosion and abnormalities in bone growth in immature patients. Additionally, these novel compositions of matter containing optically pure (S)-lomefloxacin are useful in treating infection in those patients with impaired renal function. Also disclosed are methods for treating the above-described conditions in a human while avoiding adverse effects that are associated with the racemic mixture of lomefloxacin, by administering the (S)-isomer of lomefloxacin to said human.
BACKGROUND OF THE INVENTION
Steric Relationship and Drug Action
Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1 or (+) and (−) are employed to designate the sign of rotation of plane-polarized light by the compound, with (−) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these compounds, called stereoisomers, are identical except that they are mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture.
Stereochemical purity is of importance in the field of pharmaceuticals, where 12 of the 20 most prescribed drugs exhibit chirality. A case in point is provided by the L-form of the &bgr;-adrenergic blocking agent, propranolol, which is known to be 100 times more potent than the D-enantiomer.
Furthermore, optical purity is important since certain isomers may actually be deleterious rather than simply inert. For example, it has been suggested that the D-enantiomer of thalidomide was a safe and effective sedative when prescribed for the control of morning sickness during pregnancy, and that the corresponding L-enantiomer was a potent teratogen.
Racemic Lomefloxacin
Lomefloxacin is described in U.S. Pat. No. 4,528,287 and Japan Patent Publication No. 64979 (1985). Lomefloxacin is currently available commercially in the United States as MAXAQUIN® as well as in Argentina, Japan, Mexico and certain countries in Asia and Eastern Europe, as the racemic mixture, i.e., it is a 1:1 mixture of optical isomers. It is the optically pure, or substantially optically pure (S)-isomer of lomefloxacin, which is the subject of the present invention, hereinafter referred to as (S)-lomefloxacin.
Racemic lomefloxacin, having the chemical name 1-ethyl-6,8-difluoro-1,4-dihydro-7-(3-methyl-lpiperazinyl)-4-oxo-3-quinolinecarboxylic acid, belongs to the quinoline class of antibiotics. The quinoline antibiotics, in general, exhibit a broad spectrum of antibacterial action, demonstrating effectiveness against both Gram-positive and Gram-negative bacterial strains. Quinoline antibiotics have been shown to be effective in treating infections of the respiratory, genito-urinary, and gastrointestinal tracts. They have also demonstrated utility in the treatment of patients with cystic fibrosis and pulmonary infections. Effectiveness has also been demonstrated in the treatment of intra-abdominal, bone and joint, skin, soft-tissue, pelvic, and eye, ear, nose, and throat infections.
Examples of Gram-positive bacteria include but are not limited to Streptococcus, Staphlococcus, Mycobacteria, Listeriaceae, Bacillus and Nocardia. A number of Gram-positive bacteria cause respiratory tract infections including, but not limited to,
Streptococcus pneumoniae
and Mycobacteria. The majority of clinically diagnosed cases of pneumonia are caused by
Streptococcus pneumoniae.
However, recently there has been an increase in the number of pneumonias caused by Mycobacteria. Three different species of Mycobacteria,
Mycobacteria tuberculosis
(
M. tuberculosis
),
Mycobacteria bovis
(
M. bovis
), and
Mycobacteria africanum
(
M. africanum
) can cause a disease state commonly known as tuberculosis. Tuberculosis is a highly contagious disease which is most commonly transmitted by aerosolized respiratory secretions. While infection usually begins in the lungs, mycobacteria can easily spread to other organs as well, including eyes, intestine, pericardium, peritoneum, bone and joints, urinary tract, and lymphatic system. See The Merck Manual, 16th ed., pp. 131-146, Merck Sharpe & Dohme.
In addition to
M. tuberculosis, M. bovis,
and
M. africanum,
other species of Mycobacteria include
M. chelonei, M. Marinum, M. avium
and
M. kansasii.
The quinoline antibiotics derive their activity through inhibition of the bacterial enzyme, DNA gyrase, which is responsible for catalyzing the bacterial DNA supercoiling necessary to pack DNA filaments into bacterial cells. This inhibition causes irreversible chromosome damage leading to bacterial cell death. The selectivity of quinoline antibiotics for bacterial cells is the result of the supercoiling mechanism in eukariotic cells being mediated by a different set of enzymes not susceptible to quinoline inhibition. Quinoline antibiotics are also thought to interfere with proper bacterial cell membrane function, also contributing to cell death.
The first quinoline antibiotic to be commercialized, nalidixic acid, was discovered following the observation that the structurally similar 6-chloro-1H-ethyl-4-oxoquinolone-3-carboxylic acid, a minor by-product of the commercial production of the antimalarial agent chloroquine, exhibited weak antibacterial action. Since the discovery of nalidixic acid, some 7,000 analogues belonging to approximately 16 different ring systems have been synthesized and tested for antibacterial action. From this data, a comprehensive structure/activity relationship has been elucidated.
Structural activity studies have demonstrated that substitution,at position 1 and a carbonyl substitution at position 4 on the quinoline ring appear to be required for antimicrobial activity. No substitution at position 2 and a carboxyl function at position 3 also appear to be required for activity. The only exception appears to be a thiazolidone ring fused at positions 2 and 3. Depending on modification, the presence of additional fused rings, as well as various ring substitutions can be either beneficial or detrimental to activity.
Racemic lomefloxacin exhibits a broad spectrum of antibacterial action, demonstrating effectiveness against both Gram-positive and Gram-negative bacterial strains. Lomefloxacin has shown to be more effective against Gram-negative bacteria. In particular, lomefloxacin has shown excellent bacteriocidal activity against strains of Enterobacteriaceae,
Haemophilus influenzas, Neisseria gonorrhoeae, Branhamella catarrhalis, L. pneumophilia,
and good-to-moderate activity against strains of Acinetobacter,
Pseudomonas aeruginosa, Staphylococcus aureus
and
Staphylococcus epidermidis,
but poor activity against
Pseudomonas cepacia.
There is only a low propensity for bacteria to develop a resistance to lomefloxacin by spontaneous mutation. However, development of resistance is facilitated when bacteria are exposed to sub-inhibitory concentrations of the antibiotic.
Lomefloxacin has an average elimination half-life of approximately 8 hours with peak plasma concentrations occurring at approximately 1 hour after oral dosing in humans. Its long half-life and dose proportionality have lead to introduction of lomefloxacin as the first, once-daily 4-quinoline antibiotic.
Furthermore, unlike c
Aberg A. K. Gunnar
Young James W.
Sepracor Inc.
Travers Russell
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