Sulfonamidomethyl phosphonate inhibitors of beta-lactamase

Details Sulfonamidomethyl phosphonate inhibitors of beta-lactamase Sulfonamidomethyl phosphonate inhibitors of beta-lactamase

2000-07-05

2002-10-29

Huang, Evelyn Mei (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S272000, C514S301000, C514S307000, C514S314000, C514S333000, C514S335000, C514S336000, C514S337000, C514S338000, C514S342000, C514S343000, C514S351000, C514S363000, C514S367000, C514S369000, C514S374000, C514S378000, C514S389000, C514S397000, C514S418000, C514S422000, C514S428000, C514S443000, C514S445000, C514S468000, C514S470000, C514S473000, C514S604000, C546S023000, C546S024000, C546S025000, C544S243000, C548S112000, C548S113000, C549S006000, C549S220000, C549S222000, C558S175000

Reexamination Certificate

active

06472406

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. Brief Summary of the Related Art
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) teaches 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 numerous presently used antibiotics. More recently, Dudley, Pharmacotherapy 15: 9S-14S (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) discloses two semi-synthetic inhibitors, sulbactam and tazobactam, presently available. Coulton et al. (supra) also teaches 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.
Li et al., Bioorg. Med. Chem. 5 (9): 1783-1788 (1997), discloses that &bgr;-lactamase enzymes are inhibited by phosphonate monoesters. Li et al. teaches that better inhibitory activity is achieved by compounds with amido side-chains, but that such compounds suffer the disadvantage of hydrolytic instability. Li et al. discloses that benzylsulfonamidomethyl phosphonate monoesters exhibit better hydrolytic stability, but also significantly weaker potency against &bgr;-lactamase enzymes, than do the corresponding benzylamidomethyl phosphonate monoesters. Dryjanski and Pratt, Biochemistry 34:3569-3575 (1995) teaches that p-nitrophenyl [(dansylamido)methyl]phosphonate irreversibly inactivates the P99 &bgr;-lactamase enzyme, and describes its use as a mechanistic probe for studying the interaction of ligands with a second binding site of the enzyme.
The availability of only a few &bgr;-lactamase inhibitors, 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.
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 require a &bgr;-lactam pharmacophore.
In a first aspect, therefore, the invention provides novel &bgr;-lactamase inhibitors. In one embodiment of the invention, the novel &bgr;-lactamase inhibitor is a compound of Formula (I):
or a pro-drug or pharmaceutically acceptable salt thereof, wherein
R
1
is aryl or heteroaryl, wherein the aryl or heteroaryl group may be optionally substituted;
n is 0, 1, or 2;
R
2
is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aralkyl, and aryl;
R
3
is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aralkyl, aryl, heteroaryl, and (heteroaryl)alkyl, any of which groups may be optionally substituted;
R
4
is selected from the group consisting of OH, F, SR
7
, and N(R
7
)
2
; and
R
5
is selected from the group consisting of F, OR
6
, SR
7
, and N(R
7
)
2
,
where R
6
is selected from the group consisting of alkyl, cycloalkyl, aryl, aralkyl, (heteroaryl)alkyl, and heteroaryl, wherein the aryl or heteraryl portion of any such group may be optionally substituted, and where R
7
at each occurrence is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aralkyl, and aryl;
provided that R
4
and R
5
are not both F, and further provided that R
1
is not 5-dimethylamino-1-naphthyl when R
2
and R
3
are both H, R
4
is OH, and R
5
is 4-nitrophenoxy.
In another embodiment, the novel &bgr;-lactamase inhibitor is a compound of Formula (I):
or a pro-drug or pharmaceutically acceptable salt thereof, wherein
R
1
is aryl or heteroaryl, wherein the aryl or heteroaryl group may be optionally substituted;
n is 0, 1, or 2;
R
2
is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aralkyl, and aryl, wherein the aryl portion of any such group may be optionally substituted;
R
3
is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aralkyl, aryl, heteroaryl, and (heteroaryl)alkyl, wherein the aryl or heteroaryl portion of any such group may be optionally substituted;
R
4
is OR
8
, where R
8
is selected from the group consisting of phenyl substituted with at least one chloro, nitro, or fluoro substituent; heteroaryl; and substituted heteroaryl; and
R
5
is OR
6
, where R
6
is selected from the group consisting of H, alkyl, cycloalkyl, aryl, aralkyl, (heteroaryl)alkyl, and heteroaryl, wherein the aryl or heteraryl portion of any such group may be optionally substituted.
In yet another embodiment, the novel &bgr;-lactamase inhibitor is a compound of Formula (II):
or a pro-drug or pharmaceutically acceptable salt thereof, wherein
R
1
is aryl or heteroaryl, wherein the aryl or heteroaryl group may be optionally substituted;
n is 0, 1, or 2;
Y is O, NR
7
, or S;
R
2
is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aralkyl, and aryl;
R
4
and R
5
are independently selected from the group consisting of OH, F, SR
7
, N(R
7
)
2
, OR
6
,
where R
6
is selected from the group consisting of alkyl, cycloalkyl, aryl, aralkyl, (heteroaryl)alkyl, and heteroaryl, wherein the aryl or heteroaryl portion of any such group may be optionally substituted, and where R
7
at each occurrence is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aralkyl, and aryl;
provided that R
4
and R
5
are not both F or both OH.
In a second aspect, the invention provides pharmaceutical compositions comprising a compound of Formula (I) or Formula (II), or a pro-drug or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
In a third aspect, the invention provides methods for inhibiting bacterial growth, such methods comprising administering to a bacterial cell culture, or to a bacterially infected cell culture, tissue,: or organism, a &bgr;-lactamase inhibitor of Formula (I) or Formula (II).


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