Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1997-03-14
2001-10-16
Pak, Michael (Department: 1646)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S201000, C514S204000, C514S205000, C514S207000, C514S208000, C514S209000, C540S221000, C540S222000, C540S226000, C540S227000, C540S228000, C540S229000, C540S230000
Reexamination Certificate
active
06303592
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to novel compounds which are &bgr;-lactamase inhibitors, pharmaceutical compositions containing the same and methods of inhibiting &bgr;-lactamases. More specifically this invention is concerned with novel 7-alkylidene cephalosporins and pharmaceutically acceptable salts thereof.
2. Description of the Background
The most important mechanism of microbial resistance to &bgr;-lactam antibiotics is the bacterial production of &bgr;-lactamases, enzymes which hydrolytically destroy &bgr;-lactam antibiotics, such as penicillins and cephalosporins. This type of resistance can be transferred horizontally by plasmids that are capable of rapidly spreading the resistance, not only to other members of the same strain, but even to other species. Due to such rapid gene transfer, a patient can become infected with different organisms, each possessing the same &bgr;-lactamase.
&bgr;-lactamase enzymes have been organized into four molecular classes: A, B, C, and D based on amino acid sequence. Class A, which includes RTEM and the &bgr;-lactamase of
Staphylococcus aureus
, class C, which includes the lactamase derived from P99
Enterobacter cloacae
, and class D are serine hydrolases. Class A enzymes have a molecular weight of about 29 kDa and preferentially hydrolyze penicillins. The class B lactamases are metalloenzymes and have a broader substrate profile than the proteins in the other classes. Class C enzymes include the chromosomal cephalosporinases of gram-negative bacteria and have molecular weights of approximately 39 kDa. The recently recognized class D enzymes exhibit a unique substrate profile which differs significantly from both class A and class C.
The class C cephalosporinases, in particular, are responsible for the resistance of gram-negative bacteria to a variety of both traditional and newly designed antibiotics. The Enterobacter species, which possess a class C enzyme, are now the third greatest cause of hospital-acquired infections in the United States. This class of enzymes often has poor affinities for inhibitors of the class A enzymes, such as clavulanic acid, a commonly prescribed inhibitor, and to common in vitro inactivators, such as 6-&bgr;-iodopenicillanate.
One strategy for overcoming rapidly evolving bacterial resistance is the synthesis and administration of &bgr;-lactamase inhibitors. Frequently, &bgr;-lactamase inhibitors do not possess antibiotic activity themselves and are thus administered together with an antibiotic. One example of such a synergistic mixture is “augmentin which is a registered trademark of the Smithkline Beechom Corporation”, which contains the antibiotic amoxicillin and the &bgr;-lactamase inhibitor, clavulanic acid.
It is thus desirable to find novel &bgr;-lactamase inhibitors which can be coadministered with a &bgr;-lactam antibiotic.
SUMMARY OF THE INVENTION
Accordingly, one object of the present invention is to provide novel &bgr;-lactamase inhibitors.
It is another object of the present invention to provide pharmaceutical compositions useful for inhibiting a &bgr;-lactamase.
It is another object of the present invention to provide pharmaceutical compositions with increased &bgr;-lactam antibiotic activity.
It is another object of the present invention to provide methods of inhibiting a &bgr;-lactamase.
It is another object of the present invention to provide methods of enhancing the biological activity of a &bgr;-lactam antibiotic.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors' discovery that compounds of the formula (1)
wherein n is 0 or 1 (the sulfide or the sulfone, respectively);
R
1
and R
2
are the same or different and are selected from the group consisting of
a) hydrogen;
b) linear or branched C
1-10
-alkyl;
c) halogen;
d) hydroxy-C
1-10
-alkyl;
e) C
1-10
-alkoxy;
f) C
2-10
-alkanoyloxy;
g) C
2-10
-alkene;
h) C
2-10
-alkene substituted with one or more groups selected from the group consisting of chlorine, fluorine, bromine or phenyl;
i) C
1-10
-alkoxycarbonyl;
j) C
1-10
-alkoxycarbamido;
k) N-C
1-10
-alkoxy-N-C
1-10
-alkylaminocarbonyl;
l) halo-C
1-10-
-alkyl;
m) C
6-10
-aryl;
n) C
6-10
-aryl substituted with one or more groups selected from the group consisting of ethyl, n-propyl, isopropyl, amino, methylamino and dimethylamino;
o) a C
2-10
-heterocycle having from 1-3 heteroatoms selected from the group consisting of O, N and S; and,
p) —COOH or —COOY, wherein Y is pharmaceutically acceptable cation;
R
3
is selected from the group consisting of
1) —COOH;
2) chlorine or fluorine;
3) trifluoromethyl;
4) —CHO; and,
5) —CH
2
M where M is selected from the group consisting of
a) hydrogen;
b) halogen;
c) hydroxy;
d) C
1-10
-alkoxy;
e) C
6-10
-aryloxy;
f) C
6-10
-aryl-C
1-10
-alkoxy;
g) mercapto;
h) mercapto substituted with one or more groups selected from the group consisting of methyl, ethyl or phenyl;
i) C
2-10
-acylthio;
j) C
2-10
-acyloxy or carbamoyloxy;
k) C
2-10
-acyloxy or carbamoyloxy substituted with one or more groups selected from the group consisting of —COOH, aminophenyl, phenyl, C
1-6
-alkyl, chlorine, bromine or fluorine;
1) a quaternary ammonium salt;
m) amino or amido; and,
n) amino or amido substituted with one or more groups selected from the group consisting of C
1-10
-alkyl groups;
R
4
is selected from the group consisting of
a) hydrogen; and,
b) pharmaceutically acceptable cations; are effective &bgr;-lactamase inhibitors.
DETAILED DESCRIPTION OF THE INVENTION
Thus, in a first embodiment, the present invention provides novel compounds of the formula (1)
wherein n is 0 or 1;
R
1
and R
2
are the same or different and are selected from the group consisting of
a) hydrogen;
b) linear or branched C
1-10
-alkyl, preferably, C
1-6
-alkyl, more preferably, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, cyclopropyl, cyclopentyl, or cyclohexyl, most preferably t-butyl;
c) halogen, preferably Br or Cl;
d) hydroxy-C
1-10
-alkyl, preferably, hydroxy-C
1-6
-alkyl, more preferably, hydroxymethyl, 1-hydroxyethyl or 2-hydroxyethyl;
e) C
1-10
-alkoxy, preferably, C
1-6
-alkoxy, more preferably, t-butoxy or methoxy;
f) C
2-10
-alkanoyloxy, preferably, C
2-6
-alkanoyloxy, more preferably, acetoxy or propanoyloxy;
g) C
2-10
-alkene, preferably, C
2-6
-alkene, more preferably, ethylene, 1-propylene or 2-propylene;
h) substituted C
2-10
-alkene, preferably, C
2-6
-alkene, more preferably ethylene, 1-propylene or 2-propylene, wherein said substituents are one more groups selected from the group consisting of chlorine, fluorine, bromine or phenyl;
i) C
1-10
-alkoxycarbonyl, preferably, C
1-6
-alkoxycarbonyl, more preferably, methoxycarbonyl or t-butoxycarbonyl;
j) C
1-10
-alkoxycacbamido, preferably, C
1-6
-alkoxycarbamido, more preferably, methoxycarbamido, ethoxycarbamido or n-propoxycarbamido;
k) N-C
1-10
-alkoxy-N-C
1-10
-alkylaminocarbonyl, preferably, N-C
1-6
-alkoxy-N-C
1-6
-alkylaminocarbonyl, more preferably, N-methoxy-N-methylaminocarbonyl, N-ethoxy-N-methylaminocarbonyl, N-methoxy-N-ethylaminocarbonyl or N-ethoxy-N-ethylaminocarbonyl;
1) halo-C
1-10
-alkyl, preferably, halo-C
1-6
-alkyl, more preferably, chloromethyl, 1-chloroethyl or 2-chloroethyl;
m) C
6-10
-aryl group, preferably, phenyl, tolyl, anisoyl, mesityl, and xylyl;
n) substituted C
1-10
-alkyl, preferably, phenyl, tolyl, anisoyl, mesityl, and xylyl, wherein said substituents are one or more groups selected from the group consisting of ethyl, n-propyl, isopropyl, amino, methylamino and dimethylamino;
o) a C
2-10
-heterocycle having from 1-3 heteratoms selected from the group consisting of O, N and S, preferably, triazolyl, triazinyl, oxazoyl, isoxazolyl, oxazolidinoyl, isoxazolidinoyl, thiazolyl, isothiazoyl, pyrazolyl, imidazolyl, pyrrolyl, pyrazinyl, pyridinyl, morpholinyl, quinolinyl, isoquinolinyl, indolyl, and pyrimidinyl, more preferably, pyridinyl; and,
p) —COOH or —COOY, wherein Y is a pharmaceutically acceptable cation, preferably, sodium, potassium,
Bachmann Brian
Buynak John D.
Pak Michael
Research Corporation Technologies Inc.
Shwegman, Lundberg, Woessner & Kluth, P.A.
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