Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-07-24
2002-11-05
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S355000
Reexamination Certificate
active
06476015
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a novel class of monocyclic &bgr;-lactam compounds and compositions comprising a single, 4-membered azetidinone ring, which exhibit wide-ranging antibacterial activity, wherein the N
1
nitrogen atom of the azetidinone ring is bonded to sulfur but is not sulfonated. Specifically, compounds are disclosed that inhibit growth of diverse strains of bacteria wherein substitutions at positions C
3
and C
4
of the azetidinone ring, and at the sulfur atom, produce antibacterial agents of varying bacterial specificity and efficacy. Additionally, the invention relates to methods for the synthesis of the aforementioned compounds.
BACKGROUND OF THE INVENTION
The clinical use of antibiotics in the 20
th
century has substantially decreased morbidity from bacterial infections. The early success of penicillin was extended by various sulfonamide drugs developed in the 1930s, and subsequently by a “golden” period of discovery, between 1945 and 1970, during which a wide array of highly effective agents were discovered and developed. See: Chopra, I., Hodgson, J., Metcalf, B. & Poste, G. “The Search for Antimicrobial Agents Effective against Bacteria Resistant to Multiple Antibiotics” (1997)
Antimicrobial Agents and Chemotherapy
41:497-503.
However, since the 1980s the introduction of new antibiotics has slowed, and, concurrently, there has been an alarming increase in bacterial resistance to existing agents that now constitutes a serious threat to public health. See: Brown, A. G. (1987) “Discovery and Development of New &bgr;-Lactum Antibiotics”
Pure & Appl. Chem.
59:475-484. Hospitals, nursing homes and infant day care centers have become breeding grounds for the most tenacious drug-resistant pathogens. See: “Frontiers in Biotechnology” (1994)
Science
264:359-393. There has been an alarming rise in drug resistant staphylococci, enterococci, streptococci, and pneumococci infections, and an increase in tuberculosis, influenza and sepsis.
For several decades, &bgr;-lactam antibiotics have been widely used to control bacterial infections. Since the discovery of penicillin, countless numbers of analogues have been prepared and tested (see for example: U.S. Pat. No. 5,142,039 to Blaszczak et al., and U.S. Pat. No. 5,338,861 to Botts et al.), and a variety of successful modifications have been made to the five-membered ring, including (1) replacement of the sulfur atom with carbon or oxygen, (2) oxidation of the sulfur to the sulfoxide or sulfone, (3) enlargement to a larger ring, (4) incorporation of unsaturation, (5) attachment of additional fused rings, and (6) removal of the five membered ring. As a result, new &bgr;-lactam ring systems have been introduced, including the penems, cephalosporins, carbapenems, oxapenems, oxacephams, as well as monocyclic, spirocyclic , and multicyclic &bgr;-lactams. In the case of monocyclic &bgr;-lactams (see: Sykes, R. B., Cimarusti, C. M., Bonner, D. P., Bush, K., Floyd, D. M., Georgopapadakou, N. H., Koster, W. H., Trejo, W. H. & Wells, J. S. (1981) “Monocyclic &bgr;-Lactam Antibiotics Produced by Bacteria”
Nature
291:489-490), which directly relates to the present invention, removal of the five-membered ring leaves a four-membered &bgr;-lactam ring, the structural core of which is 2-azetidinone (1):
Monocyclic antibiotics successfully developed by derivatization of this core structure include the monobactams (see: Slusarchyk, W. A., Dejneka, T., Gordon, E. M., Weaver, E. R. & Koster, W. H. “Monobactams: Ring Activating N-1-Substituents in Monocyclic &bgr;-Lactam Antibiotics” (1984)
Heterocycles
21:191-209.), which have 2-oxoazetidine sulfonic acid as their characteristic structure. A key feature of the monobactams is the activation of the &bgr;-lactam ring towards nucleophilic attack by bacterial transpeptidases that is caused by the electron-withdrawing potential of the sulfonated nitrogen atom. Alternative activating groups for monobactam derivatives have been discovered, including phosphate, phosphonate, and analogues in which a spacer atom is interposed between the ring nitrogen and activating group (see: Breuer, H., Straub, H., Treuner, U. D., Drossard, J.-M., Höhn, H. & Lindner, K. R. “[(2-oxo-1-azetidinyl)oxy]acetic acids: a new class of synthetic monobactams” (1985)
J. Antibiotics
38:813-818, and Slusarchyk, W. A., Dejneka, T., Gordon, E. M., Weaver, E. R. & Koster, W. H. “Monobactams: Ring Activating N-1-Substituents in Monocyclic &bgr;-Lactam Antibiotics” (1984)
Heterocycles
21:191-209).
The primary targets of &bgr;-lactams are the penicillin binding proteins, a group of bacterial proteins that mediate the final step of bacterial cell wall biosynthesis in which a terminal alanine-alanine linkage of a peptidoglycan strand is cleaved by an active site serine and crosslinked to another peptidoglycan fragment, thus strengthening the bacterial cell wall. Penicillin interrupts this crosslinking step by acylating the serine with its reactive &bgr;-lactam ring. Following acylation, ring opening results in further chemical fragmentations that are deleterious to the enzyme. Also among the penicillin binding proteins are the &bgr;-lactamases: enzymes that degrade &bgr;-lactams. Clavulinic acid targets these enzymes, and is therefore useful in conjunction with established penicillins in combination therapies for combating certain resistant strains of bacteria. See: Chopra, I., Hodgson, J., Metcalf, B. & Poste, G. “The Search for Antimicrobial Agents Effective against Bacteria Resistant to Multiple Antibiotics” (1997)
Antimicrobial Agents and Chemotherapy
41:497-503.
There is a clear need for new antibacterial agents to combat pathogenic bacteria that have become resistant to current antibiotics. Towards this end, a novel class of derivatized, N-thiolated, monocyclic &bgr;-lactams have been developed in the present invention, that exhibit strong antibacterial activity against a wide variety of species and strains.
SUMMARY OF THE INVENTION
The invention comprises a novel class of monocyclic &bgr;-lactam antibacterial and antibiotic agents, herein termed N-1 thiolated monolactams, of the general structure:
independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, alkenyl, or alkynyl; X is H, C or O;and n=0 to 3.
It is an object of the present invention to provide these compounds, including their salts, hydrates, and in combinations with suitable pharmaceutical carriers, as antibacterial and antibiotic agents.
It is a further object of this invention to provide such compounds, wherein R
4
and R
5
are hydrogen, and —C(R
1
)
3
is methyl or benzyl (—CH
2
Ph).
It is yet a further object of the invention to provide antibacterial and antibiotic agents with varying bacterial strain specificities and efficacies, by the expedient means of varying substituents of the 2-azetidinone ring, including but not limited to nitrogen (N-1) thiomethyl or thiobenzyl moieties, and substitutions at the C
3
and C
4
positions.
In another embodiment, it is a further object of this invention to provide methods for inhibiting the growth of bacteria by administering the compounds of the present invention, and to provide methods for the treatment of bacterial infections of a patient, in which one or more doses of an effective amount of the compounds and compositions of the present invention are administered to a patient.
It is yet a further objective of the present invention to provide compounds and compositions suitable for the treatment of gonorrhea.
The present invention confers numerous advantages over the compounds of the prior art, including the following: ease of synthesis, whereby compounds with diverse substituents may be synthesized and tested for antibacterial and antibiotic activity; the invention provides novel antibacterial and antibiotic agents to which bacterial pathogens have not yet acquired resistance; and the invention provides novel compounds for the treatment of increasingly common and resistant diseases such as gonorrhea. Surprisingly, the inventors have found that antibacterial an
Carpenter Edward T.
Dickey Sonja S.
Lim Daniel V.
Long Timothy
Turos Edward
McKenzie Thomas C
Saliwanchik Lloyd & Saliwanchik
University of South Florida
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