Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
2001-03-01
2003-07-29
Solola, Taofiq (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
C549S008000, C558S079000, C568S012000, C423S302000, C423S316000
Reexamination Certificate
active
06599889
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to bacterial antibiotic resistance. More particularly, the invention relates to compositions and methods for overcoming bacterial antibiotic resistance.
2. Background of the Invention
Bacterial antibiotic resistance has become one of the most important threats to modern health care. Cohen, Science 257:1051-1055 (1992) discloses that infections caused by resistant bacteria frequently result in longer hospital stays, higher mortality and increased cost of treatment. Neu, Science 257:1064-1073 (1992) discloses that the need for new antibiotics will continue to escalate because bacteria have a remarkable ability to develop resistance to new agents rendering them quickly ineffective.
The present crisis has prompted various efforts to elucidate the mechanisms responsible for bacterial resistance. Coulton et al. Progress in Medicinal Chemistry 31:297-349 (1994) teach that the widespread use of penicillins and cephalosporins has resulted in the emergence of &bgr;-lactamases, a family of bacterial enzymes that catalyze the hydrolysis of the &bgr;-lactam ring common to presently used antibiotics. More recently, Dudley, Pharmacotherapy 15: 9S14S (1995) has disclosed that resistance mediated by &bgr;-lactamases is a critical aspect at the core of the development of bacterial antibiotic resistance.
Attempts to address this problem through the development of &bgr;-lactamase inhibitors have had limited success. Sutherland, Trends Pharmacol Sci 12: 227-232 (1991) discusses the development of the first clinically useful &bgr;-lactamase inhibitor, clavulanic acid, which is a metabolite of
Streptomyces clavuligerus.
Coulton et al. (supra) disclose two other such semi-synthetic inhibitors, sulbactam and tazobactam presently available. Coulton et al. (supra) also teach that in combination with &bgr;-lactamase-susceptible antibiotics, &bgr;-lactamase inhibitors prevent antibiotic inactivation by &bgr;-lactamase enzymes, thereby producing a synergistic effect against &bgr;-lactamase producing bacteria.
Rahil and Pratt, Biochem. J. 275: 793-795 (1991), and Li et al., Bioorg. Med. Chem. 5: 1783-1788 (1997) teach that &bgr;-lactamase enzymes are inhibited by phosphonate monoesters. Song and Kluger, Bioorg. Med. Chem. Lett., 4, 1225-1228 (1994), teaches that
E. Coli
RTEM &bgr;-lactamase is inhibited by benzylpenicillin methyl phosphate.
Laird and Spence, J. C. S. Perkin Trans. II 1434 (1973), Kazlauskas and Whitesides, J. Org. Chem. 50: 1069-1076 (1985), Chantrenne, Compte. Rend. Trav. Lab. Carlsberg Ser. Chim. 26: 297 (1948), and Maracek and Griffith, J. Am. Chem. Soc. 92: 917-921 (1970), report synthesis and solvolysis studies of acyl phosphate and acyl phosphonate compounds. Kluger et al., Can. J. Chem. 74: 2395-2400 discloses that aminoacyl phosphates are useful as biomimetically activated amino acids.
The availability of only a few compounds however, is insufficient to counter the constantly increasing diversity of &bgr;-lactamases for which a variety of novel and distinct inhibitors has become a necessity. There is, therefore, a need for the ability to identify new &bgr;-lactamase inhibitors. The development of fully synthetic inhibitors would greatly facilitate meeting this need. Ideally, certain embodiments of such inhibitors would also bind bacterial DD-peptidases, thus potentially acting both as &bgr;-lactamase inhibitors and as antibiotic agents.
BRIEF SUMMARY OF THE INVENTION
The invention provides novel &bgr;-lactamase inhibitors, which are structurally unrelated to the natural product and semi-synthetic &bgr;-lactamase inhibitors presently available, and which do not possess &bgr;-lactam pharmacophore. These new inhibitors are preferably fully synthetic, allowing ready access to a wide variety of structurally related analogs. Certain embodiments of these new inhibitors also bind bacterial DD-peptidases, and thus potentially act both as &bgr;-lactamase inhibitors and as antibiotics.
In a first aspect, the invention provides novel acyl phosphate and acyl phosphonate &bgr;-lactamase inhibitors. Preferably, such inhibitors have the general mixed anhydride structure of Formula I:
or salts thereof;
wherein X is alkyl, aryl, aralkyl, or heterocyclic radical; Y is Z or OZ; and Z is alkyl, aryl, aralkyl, acyl, heterocyclic radical, or phosphonyl; provided, however, that when Y is Z, then Z is not phosphonyl; and further provided that when Y is OZ and Z is phenyl, then X is not methyl or phenyl; when Y is OZ and Z is alkyl or adenosyl, then X is not &agr;-aminoalkyl; and when Y is OZ and Z is benzoyl, then X is not phenyl.
In certain preferred embodiments, the mixed anhydride is an acyl phosphate, and Y is thus OZ. In certain other preferred embodiments, the mixed anhydride is an acyl phosphonate, and Y is thus Z.
In certain preferred embodiments, Y and X are taken together with the remaining atoms of the chain to form a cyclic structure of Formula II:
wherein Y is O or alkylene and X is alkylene, cycloalkylene, fused heterocycle, heteroarylene, or arylene, and wherein the alkylene, cycloalkylene, fused heterocycle, heteroarylene, and arylene groups may be optionally substituted; provided that X is not phenylethene.
In a second aspect, the invention provides pharmaceutical compositions comprising an acyl phosphate or acyl phosphonate &bgr;-lactamase inhibitor and a pharmaceutically acceptable carrier, excipient, or diluent. Preferably, such inhibitors have the general mixed anhydride structure (I):
or salts thereof;
wherein X is alkyl, aryl, aralkyl, or heterocyclic radical; Y is Z or OZ; and Z is alkyl, aryl, aralkyl, acyl, heterocyclic radical, or phosphonyl; provided that when Y is Z, then Z is not phosphonyl.
In certain preferred embodiments, Y and X are taken together with the remaining atoms of the chain to form a cyclic structure of Formula II:
wherein Y is O or alkylene and X is alkylene, cycloalkylene, fused heterocycle, heteroarylene, or arylene, and wherein the alkylene, cycloalkylene, fused heterocycle, heteroarylene, and arylene groups may be optionally substituted.
In a third aspect, the invention provides methods for inhibiting in vitro or in vivo &bgr;-lactamase activity, such methods comprising administering an acyl phosphate or acyl phosphonate &bgr;-lactamase inhibitor. Preferably, such inhibitors have the general mixed anhydride structure of Formula I:
or salts thereof;
wherein X is alkyl, aryl, aralkyl, or heterocyclic radical; Y is Z or OZ; and Z is alkyl, aryl, aralkyl, acyl, heterocyclic radical, or phosphonyl; provided that when Y is Z, then Z is not phosphonyl.
In certain preferred embodiments, X and Y are taken together with the remaining atoms of the chain to form a cyclic structure of Formula II:
wherein Y is O or alkylene and X is alkylene, cycloalkylene, fused heterocycle, heteroarylene, or arylene, and wherein the alkylene, cycloalkylene, fused heterocycle, heteroarylene, and arylene groups may be optionally substituted
In a fourth aspect, the invention provides a method for inhibiting bacterial growth, the method comprising administering an acyl phosphate or acyl phosphonate &bgr;-lactamase inhibitor. Preferably, such inhibitors have the general mixed anhydride structure of Formula I:
or salts thereof;
wherein X is alkyl, aryl, aralkyl, or heterocyclic radical; Y is Z or OZ; and Z is alkyl, aryl, aralkyl, acyl, heterocyclic radical, or phosphonyl; provided that when Y is Z, then Z is not phosphonyl.
In certain preferred embodiments, X and Y are taken together with the remaining atoms of the chain to form a cyclic structure of Formula II:
wherein Y is O or alkylene and X is alkylene, cycloalkylene, fused heterocycle, heteroarylene, or arylene, and wherein the alkylene, cycloalkylene, fused heterocycle, heteroarylene, and arylene groups may be optionally substituted
In one embodiment of such a method, &bgr;-lactamase inhibitor according to the invention is co-administered with an antibiotic. In another embodiment the &bgr;-lactamase inhibitor according to the invention has antibiot
Besterman Jeffrey M.
Pratt Rex
Rahil Jubrail
Keown & Associates
MethylGere, Inc.
Solola Taofiq
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