Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-09-21
2004-04-20
Berch, Mark L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S204000, C540S224000, C540S225000, C540S226000, C540S227000
Reexamination Certificate
active
06723716
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel cephalosporin antibiotics and their methods of production and use, as well as prodrugs thereof. These compounds exhibit antibiotic activity against a wide spectrum of organisms, including organisms which are resistant to conventional &bgr;-lactam antibiotics.
BACKGROUND OF THE INVENTION
The following review of the background of the invention is merely provided to aid in the understanding of the present invention and neither it nor any of the references cited within it are admitted to be prior art to the present invention.
Over the past three decades a large variety of antibiotics has become available for clinical use. One class of antibiotics which has seen remarkable growth are the cephalosporins, over 70 of which have entered clinical use for the treatment of bacterial infections in mammals since 1965. The cephalosporins exhibit their antibacterial activity by inhibiting bacterial peptidoglycan biosynthesis, and have been extremely effective in treating a wide variety of bacterial infections. Cephalosporins that are said to have antibacterial activity are described in U.S. Pat. No. 3,992,377 and U.S. Pat. No. 4,256,739.
Unfortunately, the wide-spread and indiscriminant use of these antibiotics has led to a rapid increase in the number of bacterial strains which are resistant to these compounds. Most importantly, this resistance has emerged among clinically important microorganisms which threaten to limit the utility of presently available cephalosporin antibiotics. In particular, resistant strains of Salmonella,
S. pneumonœ
, Enterobacteriaceoe,
Staphylococcus aureus
, and Pseudomonas have emerged which threaten to undo many of the strides made in reducing mortality and morbidity from bacterial infections.
Bacterial resistance to cephalosporins follows three major pathways: (a) the development of &bgr;-lactamases capable of inactivating the &bgr;-lactam ring of the cephalosporin; (b) decreased cephalosporin penetration into the bacteria due to changes in bacterial cell wall composition; and (c) poor binding to penicillin-binding proteins (PBPs). The latter pathway is especially important, as the binding of &bgr;-lactams to PBPs is essential for inhibiting bacterial cell-wall biosynthesis. Certain Gram-positive bacteria, namely methicillin-resistant
Staphylococcus aureus
(“MRSA”) and Enterococci are highly resistant to &bgr;-lactam antibiotics. Resistance in MRSA is due to the presence of high levels of an unusual PBP, PBP2a, which is insensitive, or binds poorly, to &bgr;-lactam antibiotics. The activity of &bgr;-lactam antibiotics against PBP2a-containing organisms has been shown to correlate well with the binding affinity of the antibiotic to PBP2a. Currently, the glycopeptides vancomycin and teicoplanin are primarily used for MRSA bacteremia. The quinolone antibacterials and some carbapenems, such as imipenem, have been reported to be active against a few MRSA strains, but their use is restricted due to emerging resistant MRSA strains.
Experimental compounds which may possess utility as anti-MRSA or anti-enterococcal bactericides include the glycylcyclines (see, e.g., P.-E. Sum et al., J. Med. Chem., 37, (1994)), FK-037 (see, e.g., H. Ohki et al., J. Antibiotics, 46:359-361 (1993)), RP-59,500 (see, e.g., S. K. Spangler et al., Antimicro. Agents Chemother., 36:856-9 (1992)), the everninomycin complex (see, e.g., W. E. Sanders et al., Antimicro. Agents Chemother., 6: 232-8 (1974)), the 2-(biaryl)carbapenems (see, e.g., U.S. Pat. No. 5,025,006), 3-(benzothiazolylthio)cephems (see, e.g., EP Application No. 527686), 3-(thiazolylthio)carbacephems (see, e.g., R. J. Ternansky et al., J. Med. Chem., 36:1971 (1993) and U.S. Pat. No. 5,077,287) and arbekacin (S. Kondo, et al. J. Antibiotics 46:531 (1993).
Recent advances in the compounds, compositions and methods useful for treating infections in mammals arising from &bgr;-lactam antibiotic resistant bacteria are described in commonly owned International Application No. PCT/US95/03976 and U.S. patent applications Ser. No. 08/222,262, filed Apr. 1, 1994; Ser. No. 08/369,798, filed Jan. 6, 1995; Ser. Nos. 08/413,713, 08/413,714, 08/415,065, 08/413,712, 08/415,064, and Ser. No. 08/415,069, all of which were filed on Mar. 29, 1995; Ser. No. 08/455,969, filed May 31, 1995; Ser. No. 08/457,673, filed Jun. 1, 1995; Ser. Nos. 08/940,508 and 08/937,812, both of which were filed Sep. 29, 1997; Ser. Nos. 08/730,041, 08/730,039, 08/728,232, 08/430,042, 08/728,233, and 08/730,040, all of which were filed Oct. 1, 1996; and Ser. No. 08/842,915, filed Apr. 17, 1997; all of which are incorporated herein by reference in their entirety, including any drawings.
SUMMARY OF THE INVENTION
The present invention includes compounds, compositions and methods effective to treat infections in mammals arising from &bgr;-lactam antibiotic resistant bacteria. Preferred compounds will have a minimum inhibitory concentration (MIC) that is less that 50%, more preferably less than 10%, and most preferably less than 1% of the MIC of cefotaxime or imipenem for a beta-lactam resistant organism, preferably a methicillin-resistant Staphylococcal organism. Other preferred compounds will be able to prevent or reduce mortality in mice infected with the beta-lactam resistant organism to a greater extent than cefotaxime or imipenem.
Compounds from the class of 7-acylamino-3-heteroarylthio-3-cephem carboxylic acids of this invention have higher chemical reactivity and lower stability towards chemical or enzymatic decomposition than other cephalosporin compounds known in the art. Without wishing to be bound by any particular theory of operation of the invention, it is believed that this is due to an unusual type of substitution at the 3-position of the cephalosporin system. One aspect of the present invention features certain compounds from the class of 7-acylamino-3-heteroarylthio-3-cephem carboxylic acids which display an unexpected advantage over other compounds of this class, by virtue of lowered susceptibility to decomposition by enzymes present in mammalian serum. Compounds having this property are described below, and data is presented showing their improved stability in mammalian serum. In addition to this increased stability, there is also an improvement in pharmacokinetic parameters of such compounds and especially a lowered clearance of such compounds from the body. Pharmacological data demonstrating this lowered clearance is shown below, as well as improved efficacy in an animal model of infection due to this lowered clearance. One aspect of the present invention features certain compounds from the class of 7-acylamino-3-heteroarylthio-3-cephem carboxylic, acids which combine the above mentioned improved characteristics of increased stability in mammalian serum and lowered clearance with low binding to human serum proteins.
In one aspect the invention features compounds of Formula I or II:
or a pharmaceutically acceptable salt thereof, where
R
1
is selected from the group consisting of optionally substituted aryl and optionally substituted heterocycle,
where the heterocycle is selected from the group consisting of pyridyl, thiadiazolyl, and thiazolyl; and
where the aryl and heterocycle are each independently and optionally substituted with substituents selected from the group consisting of hydroxyl, bromo, fluoro, chloro, iodo, mercapto, cyano, alkylthio, carboxyl, oxo, alkoxycarbonyl, alkyl, alkenyl, nitro, amino, alkoxyl, and carboxamido;
R
2
is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, optionally substituted aralkyl, and trialkylsilyl;
where the alkyl, alkenyl, and aryl are each independently and optionally substituted with substituents selected from the group consisting of hydroxyl, bromo, fluoro, chloro, iodo, mercapto, cyano, alkylthio, carboxyl, oxo, alkoxycarbonyl, alkyl, alkenyl, nitro, amino, alkoxyl, and carboxamido;
R
11
is selected from the group consisting of hydrogen, halogen, hydroxy, op
Calkins Trevor
Cho Aesop
Glinka Tomasz W.
Hecker Scott J.
Lee Ving J.
Berch Mark L.
Bingham & McCutchen LLP
Essential Therapeutics, Inc.
Rose, Esq. Bernard F.
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