Carbapenem antibacterial compounds, compositions containing...

Details Carbapenem antibacterial compounds, compositions containing... Carbapenem antibacterial compounds, compositions containing...

1999-10-19

2001-08-21

Berch, Mark L (Department: 1611)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C540S302000

Reexamination Certificate

active

06277843

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to carbapenem antibacterial agents in which the carbapenem nucleus is substituted at the 2-position with an aryl platform, linked through a CH
2
—O— group. The aryl platform is further substituted with various substituent groups, typically including at least one cationic group
The carbapenems of the present invention are useful against gram positive microorganisms, especially methicillin resistant
Staphylococcus aureus
(MRSA), methicillin resistant
Staphylococcus epidermidis
(MRSE), and methicillin resistant coagulase negative Staphylococci (MRCNS). The antibacterial compounds of the present invention thus comprise an important contribution to therapy for treating infections caused by these difficult to control pathogens.
There is an increasing need for agents effective against such pathogens (MRSA/MRCNS) which are at the same time relatively free from undesirable side effects.
SUMMARY OF THE INVENTION
The present invention relates to a compound represented by formula I:
or a salt or hydrate thereof, wherein:
R
1
represents H or methyl;
CO
2
M represents a carboxylic acid, a carboxylate anion, a pharmaceutically acceptable ester group or a carboxylic acid protected by a protecting group;
P represents hydrogen, hydroxyl, F or hydroxyl protected by a hydroxyl-protecting group;
X is present or absent, and when present, represents members selected from the group consisting of: CH
2
, C(R)
2
, C═CR
2
, O, S(O)x, with x equal to 0, 1 or 2, C(O), CO
2
, OCO and NR;
each R group is independently selected from: hydrogen; halo; —CN; —N
2
; —NR
a
R
b
; —OR
c
; —SR
c
; —C(O)NR
a
R
b
; —C(O)OR
h
; —S(O)R
c
; —SO
2
R
c
; —SO
2
NR
a
R
b
; —NR
a
SO
2
R
b
; —C(O)R
a
; —OC(O)R
a
; —OC(O)NR
a
R
b
; —NR
a
C(O)NR
b
R
c
; —NR
a
CO
2
R
h
; —OCO
2
R
h
; —NR
a
C(O)R
b
; —C
1-6
straight- or branched-chain alkyl, unsubstituted or substituted with one to four R
d
groups; —A—(CH
2
)
n
—Q and —C
3-7
cycloalkyl, unsubstituted or substituted with one to four R
d
groups;
A represents O, S or —CH
2
—;
n represents an integer 0-3;
each R
a
, R
b
and R
c
independently represents hydrogen,
—C
1-6
straight- or branched-chain alkyl, unsubstituted or substituted with one to four R
d
groups, or —C
3-7
cycloalkyl, unsubstituted or substituted with one to four R
d
groups;
or R
a
and R
b
taken together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one or more of O, S, NR
c
, with R
c
as defined above, or —C(O)—, said ring being unsubstituted or substituted with one to four R
i
groups;
or R
b
and R
c
taken together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one to three of O, S, NR
a
, with R
a
as defined above, or —C(O)—, said ring being unsubstituted or substituted with one to four R
i
groups;
each R
d
independently represents halo; —CN; —NO
2
; —NR
e
R
f
; —OR
g
; —SR
g
; —CONR
e
R
f
; —COOR
g
; —SOR
g
; —SO
2
R
g
; —SO
2
NR
e
R
f
; —NR
e
SO
2
R
f
; —COR
e
; —NR
e
COR
f
; —OCOR
e
; —OCONR
e
R
f
; —NR
e
CONR
f
R
g
; —NR
e
CO
2
R
h
; —OCO
2
R
h
; —C(NR
e
)NR
f
R
g
; —NR
e
C(NH)NR
f
R
g
or —NR
e
C(NR
f
)R
g
;
R
e
, R
f
and R
g
represent hydrogen; —R*; —C
1-6
straight- or branched-chain alkyl unsubstituted or substituted with one to four R
i
groups;
or R
e
and R
f
taken together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one to three of O, S, —C(O)— or NR
g
with R
g
as defined above, said ring being unsubstituted or substituted with one to four R
i
groups;
each R
i
independently represents halo; —CN; —NO
2
; phenyl; —NHSO
2
R
h
; —OR
h
, —SR
h
; —N(R
h
)
2
; —N
+
(R
h
)
3
; —C(O)N(R
h
)
2
; —SO
2
N(R
h
)
2
; heteroaryl; heteroarylium; —CO
2
R
h
; —C(O)R
h
; —OCOR
h
; —NHCOR
h
; guanidinyl; carbamimidoyl or ureido;
each R
h
independently represents hydrogen, a —C
1-6
straight or branched-chain alkyl group, a —C
3
-C
6
cycloalkyl group or phenyl, or when two R
h
groups are present, said R
h
groups may be taken in combination and represent a 4-6 membered saturated ring, optionally interrupted by one or two of O, S, SO
2
, —C(O)—, NH and NCH
3
;
Q is selected from the group consisting of:
wherein:
a and b are 1, 2 or 3;
L− is a pharmaceutically acceptable counterion;
&agr; represents O, S or NR
s
;
&bgr;, &dgr;, &lgr;, &mgr; and &sgr; represent CR
t
, N or N
+
R
s
, provided that no more than one of &bgr;, &dgr;, &lgr;, &mgr; and &sgr; is N
+
R
s
;
each R
s
independently represents hydrogen; phenyl or —C
1-6
straight- or branched-chain alkyl, unsubstituted or substituted with one to four R
i
groups;
each R
t
independently represents hydrogen; halo; phenyl; —CN; —NO
2
; —NR
u
R
v
; —OR
u
; —SR
u
; —CONR
u
R
v
; —COOR
h
; —SOR
u
; —SO
2
R
u
; —SO
2
NR
u
R
v
; —NR
u
SO
2
R
v
; —COR
u
; —NR
u
COR
v
; —OCOR
u
; —OCONR
u
R
v
; —NR
u
CO
2
R
v
; —NR
u
CONR
v
R
w
; —OCO
2
R
v
; —C
1-6
straight- or branched chain alkyl, unsubstituted or substituted with one to four R
i
groups;
R
u
and R
v
represent hydrogen or —C
1-6
straight- or branched-chain alkyl, unsubstituted or substituted with one to four R
i
groups;
or R
u
and R
v
together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one or more of O, S, NR
w
or —C(O)—, said ring being unsubstituted or substituted with one to four R
i
groups;
each R
w
independently represents hydrogen; —C
1-6
straight- or branched chain alkyl, unsubstituted or substituted with one to four R
i
groups; C
3-6
cycloalkyl optionally substituted with one to four R
i
groups; phenyl optionally substituted with one to four R
i
groups, or heteroaryl optionally substituted with 1-4 R
i
groups;
or R
h
and R
w
taken together with any intervening atoms represent a 5-6 membered saturated ring, optionally interrupted by one or two of O, S, SO
2
, NH or NCH
3
;
R
x
represents hydrogen or a C
1-8
straight- or branched-chain alkyl, optionally interrupted by one or two of O, S, SO, SO
2
, NR
w
, N
+
R
h
R
w
, or —C(O)—, said chain being unsubstituted or substituted with one to four of halo, CN, NO
2
, OR
w
, SR
w
, SOR
w
, SO
2
R
w
, NR
h
R
w
, N
+
(R
h
)
2
R
w
, —C(O)—R
w
, C(O)NR
h
R
w
, SO
2
NR
h
R
w
, CO
2
R
w
, OC(O)R
w
, OC(O)NR
h
R
w
, NR
h
C(O)R
w
, NR
h
C(O)NR
h
R
w
, or a phenyl or heteroaryl group which is in turn optionally substituted with from one to four R
i
groups or with one to two C
1-3
straight- or branched-chain alkyl groups, said alkyl groups being unsubstituted or substituted with one to four R
i
groups;
R
y
and R
z
represent hydrogen; phenyl; —C
1-6
straight or branched chain alkyl, unsubstituted or substituted with one to four R
i
groups, and optionally interrupted by O, S, NR
w
, N
+
R
h
R
w
or —C(O)—;
or R
x
and R
y
together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by O, S, SO
2
, NR
w
, N
+
R
h
R
w
or —C(O)—, unsubstituted or substituted with 1-4 R
i
groups,
and when R
x
and R
y
together represent a 4-6 membered ring as defined above, R
z
is as defined above or R
z
represents an additional saturated 4-6 membered ring fused to the ring represented by R
x
and R
y
taken together, optionally interrupted by O, S, NR
w
or —C(O)—, said rings being unsubstituted or substituted with one to four R
i
groups.
Pharmaceutical compositions and methods of treatment are also included.
DETAILED DESCRIPTION OF THE INVENTION
The invention is described herein in detail using the terms defined below unless otherwise specified.
Carboxylate anion refers to a negatively charged group —COO—.
The term “alkyl” refers to a monovalent alkane (hydrocarbon) derived radical containing from 1 to 10 carbon atoms unless otherwise defined. It may be straight, branched or cyclic. Preferred alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, cyclopentyl and cyclohexyl. When substituted, alkyl groups may be substituted with up to four substituent groups, selected from R
d
and R
i
, as defined, a

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