Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-06-17
2004-08-17
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S274000, C544S310000, C544S312000, C544S320000, C544S321000
Reexamination Certificate
active
06777420
ABSTRACT:
FIELD OF THE INVENTION
This invention is generally in the field of heterocyclic organic molecules that have antibacterial activity.
BACKGROUND OF THE INVENTION
Bacterial pathogens continue to pose a serious threat to public health as indicated by a worldwide resurgence of bacterial diseases. One aspect of this resurgence appears to be the result of prior widespread, and largely effective, therapeutic and prophylactic use of antibiotics, which, unfortunately, over time has also selected for resistant strains of various bacterial pathogens. Of particular concern to the public health has been the emergence and proliferation of bacterial strains that are resistant to multiple antibiotics in the current arsenal of antimicrobial agents. Such multi-antibiotic resistant (“MAR”) bacterial strains include species of Gram positive bacteria, such as, antibiotic resistant strains of
Staphylococcus aureus, Enterococcus fecalis
, and
Enterococcus fecium
, which, along with antibiotic resistant Gram negative strains of
Escherichia coli
, constitute the most frequent etiological agents of nosocomial (hospital-acquired) diseases, such as septicemia, endocarditis, and infections of wounds and the urinary tract.
S. aureus
is currently the most frequent cause of nosocomial bacteremia and skin or wound infection.
Streptococcus pneumoniae
causes several serious and life-threatening diseases, including a contagious meningitis, bacteremia, and otitis media. Annual mortality from
S. pneumoniae
infection alone is estimated at between 3-5 million persons globally. More recently, clinical accounts of highly aggressive skin and tissue infections by “flesh-eating” strains of Group A streptococcus bacteria, such as Streptococcus pyogenes, has heightened the concern and need for new or improved antibacterial agents.
Recently, a group of organic compounds has been described which are structural analogs of deoxynucleotides, such as N
3
-substituted uracil and isocytosine and 9-substituted guanine and adenine compounds. Such compounds have been classified as “HPUra” (for “6-(p-hydroxyphenylazo)uracil)-like class of anti-microbial compounds or the 6-anilinouracil (“AU”) family of compounds, which are non-traditional antibiotics in that they specifically bind and inhibit the bacterial DNA polymerase IIIC (“Pol IIIC”) that is required for DNA replication in the “low G-C” eubacteria, which include mycoplasmas and the low G-C, Gram positive bacteria such as Streptococcus, Enterococcus, Staphylococcus, Bacillus, Clostridium, and Listeria (see, e.g., Wright et al.,
Curr. Opin. Anti
-
Infective Investig. Drugs,
1: 45-48 (1999); Tarantino et al.,
J. Med. Chem.,
42: 2035-2040 (1999); U.S. Pat. No. 5,516,905). Accordingly, these compounds are antibiotics capable of inhibiting Gram positive bacteria and mycoplasmas (see, e.g., U.S. Pat. No. 5,516,905).
Another approach to developing improved antibiotics has been the synthesis of hybrid molecules, such as the family of hybrid molecules consisting of a fluoroquinolone antibiotic molecule (see, e.g., Domagala et al.,
J. Med. Chem.,
29: 394-404 (1986)) linked to a &bgr;-lactam antibiotic molecule (see, e.g., Hamilton-Miller,
J. Antimicrobial Chemotherapy,
33: 197-202 (1994)). Such hybrid molecules are “dual-action” antibiotics in that they offer the benefit of a fluoroquinolone component, which can inhibit bacterial type II topoisomerase (Topo II), and a &bgr;-lactam component, such as cephalosporins and penicillins, which inhibit bacterial cell wall synthesis (see, e.g, Hamilton-Miller,
J. Antimicrobial Chemotherapy,
33: 197-202 (1994)). The fluoroquinolone and &bgr;-lactam components may be linked to one another via an ester linkage in a “pro-drug” form, which can undergo hydrolysis after administration to an individual (often catalyzed by esterase) to provide the two active component antibiotics. Alternatively, linkages less susceptible to spontaneous hydrolysis may be used to enhance the half-life of the hybrid molecule after administration. In this latter case, the fluoroquinolone active segment may be released in the presence of a &bgr;-lactamase, such as produced by P-lactam resistant bacteria, or when the &bgr;-lactam antibiotic is acylated during its mode of action (Id.).
A dual-action antibiotic directed against two different targets in a bacterial cell is an attractive strategy as the probability of the appearance of a resistant strain in a treated bacterial population should be quite low, i.e., equal to the product of the probabilities of occurrence of two, spontaneous and separate, resistant mutations in a single bacterial cell. The impact that currently available, hybrid antibiotics, such as the “cephaloquins” (or “quinocephs”), as described above, will have clinically remains to be determined. Moreover, as is well known, the search and development of a variety of antibiotics will continue to be necessary as it is unlikely that any one class of antibiotics will be effective against a sufficiently wide spectrum of bacteria as to treat all bacterial diseases or to be used in all patients. Thus, in addition to having an antimicrobial action against one or more clinically significant strains of bacterial pathogens, the successful development of any new and useful antibiotic depends not only on the frequency with which resistant strains may arise, but also on an understanding of such pharmaceutically and pharmacologically relevant properties as solubility, potency, patient toxicity, and the susceptibility of the antibiotic to degradation or clearance when administered to a patient by a particular route.
Clearly, needs remain for compounds that can serve as antibiotics against pathogenic bacterial species as well as for compounds that provide the structural foundation for developing future generations of new anti-microbial agents.
SUMMARY OF THE INVENTION
The invention provides a new family of molecules, which are heterocyclic compounds that have antibacterial activity against pathogenic bacterial strains and/or that provide a structural foundation (i.e., are parent molecules) for developing additional new antibacterial agents.
In one embodiment, the invention provides a compound having the formula:
P-L-T,
wherein P is a segment of the compound that selectively binds and inhibits bacterial DNA polymerase IIIC in the presence of a DNA template and that is linked, directly or indirectly, to segment T of the compound; L is absent or is a linker segment of the compound comprising 1 to 10 atoms in contiguous linear connectivity that links the P and T segments; and T is a segment that is linked, directly or indirectly, to segment P and that selectively inhibits a type II bacterial topoisomerase; and wherein the compound binds and inhibits polymerase IIIC and type II bacterial topoisomerase; and pharmaceutically acceptable salts, esters, and hydrates thereof.
In another embodiment, the invention provides a compound having formula (1) or (2):
wherein the notation
signifies an optionally substituted 5-10 membered mono or bicyclic heterocycle in which the ring members are, independently, selected from the group consisting of carbon, nitrogen, sulfur, and oxygen, and wherein any carbon may be optionally substituted with a lower alkyl, amino, carbonyl and thiocarbonyl; and wherein:
A-B is a segment characterized by an ability to selectively bind bacterial type II topoisomerase;
C is absent or a linker segment comprising 1-10 atoms in contiguous linear connectivity;
G is selected from the group consisting of H, aryl, arylalkyl, alkyl, acyl, and an amino protecting group;
Y is absent or selected from the group consisting of lower alkylidene, NH, and CO;
Z is aryl, which may be optionally substituted with alkyl, halo, amino, nitro, acyl, alkylamino, alkylaminoalkyl, alkoxy, alkoxyalkyl, alkylthio, alkylthioalkyl, oxo, nitro, hydroxyl, cyano, carbocyclyl, carbocyclylalkyl, carbocyclyloxy, carbocyclyloxyalkyl, carbocyclylamino, carbocyclylaminoalkyl, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocycloyloxyalkyl, heterocyclylamino, and heterocyclylaminoal
Wright George E.
Zhi Chengxin
Berka Thomas R.
McKenzie Thomas
Microbiotix, Inc.
Raymond Richard L.
Yankwich Leon R.
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