Penicillanic acid derivative compounds and methods of making

Details Penicillanic acid derivative compounds and methods of making Penicillanic acid derivative compounds and methods of making

2002-06-05

2004-08-03

Berch, Mark L. (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06770759

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, includes RTEM and the &bgr;-lactamase of
Staphylococcus aureus
, class C, 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 that differs significantly from the profile of both class A and class C enzymes.
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 “AUGMENTIN” (a registered trademark of Smithkline Beecham Inc), which contains the antibiotic amoxicillin and the &bgr;-lactamase inhibitor, clavulanic acid.
Thus, there is a continuing need for novel &bgr;-lactamase inhibitors.
SUMMARY OF THE INVENTION
The present invention provides novel penicillin derivatives that are potent inhibitors of &bgr;-lactamase enzymes. Accordingly, the invention provides a compound of formula (I):
wherein
R
1
and R
2
are each independently hydrogen, (C
1
-C
10
)alkyl, (C
3
-C
8
)cycloalkyl, (C
2
-C
10
)alkenyl, (C
2
-C
10
)alkynyl, —COOR
a
, —CON
b
R
c
, cyano, —C(═O)R
d
, —OR
e
, aryl, heteroaryl, oxazolidinyl, isoxazolidinyl, morpholinyl, —S(O)
m
R
f
, —NR
g
R
h
, azido, or halo;
R
3
is (C
3
-C
10
)alkyl, (C
2
-C
10
)alkenyl, (C
2
-C
10
)alkynyl, (C
1
-C
10
)alkanoyl, (C
3
-C
8
)cycloalkyl, aryl, heteroaryl, aryl(C
1
-C
10
)alkyl, heteroaryl(C
1
-C
10
)alkyl, or —CH
2
R
i
, wherein R
i
is halo, cyano, cyanato, —OR
j
, —NR
k
R
l
, azido, —SR
m
, or (C
3
-C
8
)cycloalkyl;
R
4
is hydrogen, (C
1
-C
10
)alkyl, (C
3
-C
8
)cycloalkyl, (C
2
-C
10
)alkenyl, (C
2
-C
10
)alkynyl, aryl, or heteroaryl;
m and n are each independently 0, 1, or 2;
each R
a
-R
f
is independently hydrogen, (C
1
-C
10
)alkyl, (C
3
-C
8
)cycloalkyl, (C
2
-C
10
)alkenyl, (C
2
-C
10
)alkynyl, aryl, heteroaryl, oxazolidinyl, isoxazolidinyl, or morpholinyl;
each R
g
or R
h
is independently hydrogen, (C
1
-C
10
)alkyl, (C
3
-C
8
)cycloalkyl, (C
2
-C
10
)alkenyl, (C
2
-C
10
)alkynyl, (C
1
-C
10
)alkanoyl, aryl, benzyl, phenethyl, heteroaryl oxazolidinyl, isoxazolidinyl, or morpholinyl; or R
g
and R
h
together with the nitrogen to which they are attached are triazolyl, imidazolyl, oxazolidinyl, isoxazolidinyl, pyrrolyl, morpholino, piperidino, pyrrolidino, pyrazolyl, indolyl, or tetrazolyl;
R
j
is hydrogen, (C
1
-C
10
)alkyl, (C
3
-C
8
)cycloalkyl, (C
2
-C
10
)alkenyl, (C
2
-C
10
)alkynyl, —C(═O)N(R
p
)
2
, aryl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, or (C
1
-C
10
)alkanoyl, wherein each R
p
is independently hydrogen, (C
1
-C
10
)alkyl, aryl, benzyl, phenethyl, or heteroaryl;
each R
k
or R
l
is independently hydrogen, (C
1
-C
10
)alkyl, (C
3
-C
8
)cycloalkyl, (C
2
-C
10
)alkenyl, (C
2
-C
10
)alkynyl, (C
1
-C
10
)alkanoyl, —C(═O)N(R
q
)
2
, aryl, benzyl, phenethyl, heteroaryl oxazolidinyl, isoxazolidinyl, or morpholinyl, wherein each R
q
is independently hydrogen, (C
1
-C
10
)alkyl, aryl, benzyl, phenethyl, or heteroaryl; or R
k
and R
l
together with the nitrogen to which they are attached are triazolyl, imidazolyl, oxazolidinyl, isoxazolidinyl, pyrrolyl, morpholino, piperidino, pyrrolidino, pyrazolyl, indolyl, or tetrazolyl; and
R
m
is hydrogen, (C
1
-C
10
)alkyl, (C
3
-C
8
)cycloalkyl, (C
2
-C
10
)alkenyl, (C
2
-C
10
)alkynyl, cyano, aryl, benzyl, phenethyl, heteroaryl, oxazolidinyl, isoxazolidinyl, or morpholinyl;
wherein any (C
1
-C
10
)alkyl, (C
3
-C
8
)cycloalkyl, (C
2
-C
10
)alkenyl, (C
2
-C
10
)alkynyl, (C
1
-C
10
)alkanoyl, aryl, benzyl, phenethyl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, oxazolidinyl, isoxazolidinyl, or morpholinyl of R
1
-R
4
, R
a
-R
m
, or R
p
-R
q
may optionally be substituted with 1, 2, or 3 Z; and each Z is independently halo, nitro, cyano, hydroxy, (C
1
-C
10
)alkyl, (C
3
-C
8
)cycloalkyl, (C
1
-C
10
)alkoxy, (C
1
-C
10
)alkanoyl, (C
2
-C
10
)alkanoyloxy, trifluoromethyl, aryl, aryloxy, heteroaryl, or —SR
n
, wherein R
n
is hydrogen, (C
1
-C
10
)alkyl, (C-C
8
)cycloalkyl, aryl, benzyl, phenethyl, or heteroaryl;
and further wherein any aryl, aryloxy, heteroaryl, benzyl, or phenethyl of Z may optionally be substituted with 1, 2, or 3 substituents selected from the group consisting of halo, nitro, cyano, hydroxy, (C
1
-C
10
)alkyl, (C
3
-C
8
)cycloalkyl, (C
1
-C
10
)alkoxy, (C
1
-C
10
)alkanoyl, (C
2
-C
10
)alkanoyloxy, benzyloxy, 4-methoxybenzyloxy, and trifluoromethyl;
or a pharmaceutically acceptable salt thereof.


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