&bgr;-lactamase inhibiting compounds

Details &bgr;-lactamase inhibiting compounds &bgr;-lactamase inhibiting compounds

2000-04-13

2002-06-18

Berch, Mark L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S202000, C514S203000, C514S204000, C514S206000, C514S207000, C514S209000, C540S215000, C540S222000, C540S225000, C540S226000, C540S228000, C540S230000

Reexamination Certificate

active

06407091

ABSTRACT:

BACKGROUND OF THE INVENTION
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 P-99
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 possesses a class C enzyme, is now the third greatest cause of nosocomial 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 this 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 the product sold under the trademark AUGMENTIN (amoxicillin, clavulanate potassium), which contains the antibiotic amoxicillin and the &bgr;-lactamase inhibitor, clavulanate potassium.
There is a continued need for novel &bgr;-lactamase inhibitors, and in particular, for &bgr;-lactamase inhibitors that can be coadministered with a &bgr;-lactam antibiotic.
SUMMARY OF THE INVENTION
The invention provides a compound of formula I:
wherein:
R
1
, R
2
, R
5
, and R
6
are each independently hydrogen, (C
1
-C
10
)alkyl, (C
2
-C
10
)alkenyl, (C
2
-C
10
)alkynyl, (C
3
-C
8
)cycloalkyl, (C
1
-C
10
)alkoxy, (C
1
-C
10
)alkanoyl, (C
1
-C
10
)alkanoyloxy, (C
1
-C
10
)alkoxycarbonyl, aryl, heterocycle, halo, cyano, nitro, —COOR
a
, —C(═O)NR
b
R
c
, —OC(═O)NR
b
R
c
, NR
b
R
c
, or —S(O)
n
R
d
; or R
1
and R
2
together with the carbon to which they are attached are (C
3
-C
8
)cycloalkyl or a heterocycle, wherein each (C
3
-C
8
)cycloalkyl or heterocycle is optionally substituted with (C
1
-C
10
)alkyl, hydroxy, halo, (C
1
-C
10
)alkoxy, (C
1
-C
10
)alkanoyloxy, or (C
1
-C
10
)alkoxycarbonyl; or R
5
and R
6
together with the carbon to which they are attached are (C
3
-C
8
)cycloalkyl or a heterocycle, wherein each (C
3
-C
8
)cycloalkyl or heterocycle is optionally substituted with (C
1
-C
10
)alkyl, hydroxy, halo, (C
1
-C
10
)alkoxy, (C
1
-C
10
)alkanoyloxy, or (C
1
-C
10
)alkoxycarbonyl;
R
3
is hydrogen, (C
1
-C
10
)alkyl, (C
2
-C
10
)alkenyl, (C
2
-C
10
)alkynyl, (C
3
-C
8
)cycloalkyl, (C
1
-C
10
)alkoxy, (C
1
-C
10
)alkanoyl, (C
1
-C
10
)alkanoyloxy, (C
1
-C
10
)alkoxycarbonyl, halo, cyano, nitro, aryl, heterocycle, —COOR
a
, —C(═O)NR
b
R
c
, —OC(═O)NR
b
R
c
, NR
b
R
c
, or —S(O)
n
R
d
;
R
4
is hydrogen;
A is thio (S), sulfinyl (SO), or sulfonyl (SO
2
);
each n is independently 0, 1, or 2;
each R
a
is independently hydrogen, or (C
1
-C
10
)alkyl;
each R
b
and R
c
is independently hydrogen, (C
1
-C
10
)alkyl, (C
1
-C
10
)alkoxy, phenyl, benzyl, phenethyl, or (C
1
-C
10
)alkanoyl;
each R
d
is independently (C
1
-C
10
)alkyl, (C
1
-C
10
)alkanoyl, aryl, heterocycle, aryl(C
1
-C
6
)alkyl, heterocycle, or heterocycle(C
1
-C
6
)alkyl;
wherein any (C
1
-C
10
)alkyl, (C
2
-C
10
)alkenyl, (C
2
-C
10
)alkynyl, (C
3
-C
8
)cycloalkyl, (C
1
-C
10
)alkoxy, (C
1
-C
10
)alkanoyl, (C
1
-C
10
)alkanoyloxy, or (C
1
-C
10
)alkoxycarbonyl of R
1
, R
2
, R
3
, R
5
, and R
6
is optionally substituted with one or more (e.g. 1, 2, 3, or 4) substituents independently selected from halo, hydroxy, cyano, cyanato, nitro, mercapto, oxo, aryl, heterocycle, (C
2
-C
6
)alkenyl, (C
2
-C
6
)alkynyl, (C
1
-C
6
)alkoxy, (C
1
-C
6
)alkanoyl, (C
1
-C
6
)alkanoyloxy, aryl(C
1
-C
6
)alkanoyloxy, halo(C
1
-C
6
)alkanoyloxy, heterocycle(C
1
-C
6
)alkanoyloxy, aryloxy, (heterocycle)oxy, —COOR
a
, (C
3
-C
8
)cycloalkyl, —C(═O)NR
b
R
c
, —OC(═O)NR
b
R
c
, NR
b
R
c
, and —S(O)
n
R
d
; and
wherein any aryl is optionally substituted with one or more (e.g. 1, 2, 3, or 4) substituents independently selected from halo, hydroxy, cyano, trifluoromethyl, nitro, trifluoromethoxy, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkanoyl, (C
1
-C
6
)alkanoyloxy, (C
1
-C
6
)alkoxycarbonyl, —COOR
a
, —C(═O)NR
b
R
c
, —OC(═O)NR
b
R
c
, NR
b
R
c
, and —S(O)
n
R
d
;
or a pharmaceutically acceptable salt thereof.
The invention also provides a compound of formula IV:
wherein:
R
7
and R
8
are each independently hydrogen, (C
1
-C
10
)alkyl, (C
2
-C
10
)alkenyl, (C
2
-C
10
)alkynyl, (C
3
-C
8
)cycloalkyl, (C
1
-C
10
)alkoxy, (C
1
-C
10
)alkanoyl, (C
1
-C
10
)alkanoyloxy, (C
1
-C
10
)alkoxycarbonyl, aryl, heterocycle, halo, cyano, nitro, —COOR
e
, —C(═O)NR
f
R
g
, —OC(═O)NR
f
R
g
, NR
f
R
g
, or —S(O)
n
R
h
;
R
9
is cyano, —CH═NOR
i
, or a radical of the following formula
R
10
is hydrogen;
A is thio, sulfinyl, or sulfonyl;
each n is independently 0, 1, or 2;
each R
e
is independently hydrogen, or (C
1
-C
10
)alkyl;
each R
f
and R
g
is independently hydrogen, (C
1
-C
10
)alkyl, (C
1
-C
10
)alkoxy, phenyl, benzyl, phenethyl, or (C
1
-C
10
)alkanoyl;
each R
h
is independently (C
1
-C
10
)alkyl, phenyl, aryl(C
1
-C
6
)alkyl, heterocycle, or heterocycle(C
1
-C
6
)alkyl;
R
i
is hydrogen or (C
1
-C
6
)alkyl; and
R
j
and R
k
are each independently hydrogen, halo, cyano, nitro, aryl, heterocycle, (C
2
-C
6
)alkenyl, —COOR
e
, —C(═O)NR
f
R
g
, —OC(═O)NR
f
R
g
, NR
f
R
g
, or —S(O)
n
R
h
;
wherein any (C
1
-C
10
)alkyl, (C
2
-C
10
)alkenyl, (C
2
-C
10
)alkynyl, (C
3
-C
8
)cycloalkyl, (C
1
-C
10
)alkoxy, (C
1
-C
10
)alkanoyl, (C
1
-C
10
)alkanoyloxy, or (C
1
-C
10
)alkoxycarbonyl of R
7
, R
8
, R
j
and R
k
is optionally substituted with one or more (e.g. 1, 2, 3, or 4) substituents independently selected from halo, hydroxy, cyano, cyanato, nitro, mercapto, oxo, aryl, heterocycle, (C
2
-C
6
)alkenyl, (C
2
-C
6
)alkynyl, (C
1
-C
6
)alkoxy, (C
1
-C
6
)alkanoyl, (C
1
-C
6
)alkanoyloxy, aryl(C
1
-C
6
)alkanoyloxy, halo(C
1
-C
6
)alkanoyloxy, heterocycle(C
1
-C
6
)alkanoyloxy, aryloxy, (heterocycle)oxy, (C
3
-C
8
)cycloalkyl, —COOR
e
, —C(═O)NR
f
R
g
; —OC(═O)NR
f
R
g
, NR
h
R
i
, or —S(O)
n
R
k
; and
wherein any aryl is optionally substituted with one or more (e.g. 1, 2, 3, or 4) substituents independently selected from halo, hydroxy, cyano, trifluoromethyl, nitro, trifluoromethoxy, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkanoyl, (C
1
-C
6
)alkanoyloxy, (C
1
-C
6
)alkoxycarbonyl, —COOR
e
, —C(═O)NR
f
R
g
, —OC(═O)NR
f
R
g
, NR
h
R
i
, or —S(O)
n
R
k
;
or a pharmaceutically acceptable salt thereof.
The invention also provides a pharmaceutical composition comprising a compound of formula I or IV, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable diluent or carrier, as well as such a pharmaceutical composition that further comprises a &bgr;-lactam antib

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