Carbapenem antibacterial compounds, compositions containing...

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

1998-10-05

2001-03-27

Berch, Mark L. (Department: 1611)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C540S302000

Reexamination Certificate

active

06207823

ABSTRACT:

BACKGROUND OF THE INVENTION
Infections caused by methicillin resistant
Staphylococcus aureus
(MRSA) and related gram positive pathogens are a growing medical concern. Vancomycin, a glycopeptide antibiotic, is currently the agent of choice for combating these infections which are predominantly encountered in hospital settings. With the increased usage of Vancomycin, the emergence of resistant stains of staphylococci is inevitable, and the first confirmed report of vancomycin resistance in
Staphylococcus epidermidis
was disclosed at the 36th Interscience Conference on Antimicrobial Agents and Chemotherapy, New Orleans, La., 1996. Consequently, there is a dire need to develop new agents with an alternative mode of action.
The present invention relates to novel tricyclic carbapenem compounds (trinems) in which the lipophilic side-chain necessary for anti-MRSA activity replaces the common simple ether based substitutents found in EPO 416,953, substituted carbon atoms found in EPO 507,313, and substituted amines found in WO9523149. 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 anti-MRSA tricyclic carbapenem antibiotics containing aromatic based side-chains. The side-chain imparts MRS activity previously unassociated with the trinem skeleton.
The compounds of the invention are represented by formula I:
Z represents
or a pharmaceutically acceptable salt thereof, wherein:
X represents CH
2
, CHR, C=CHR, O, S, SO, SO
2
, CO, CO
2
, OCO, or NR;
CO
2
M represents a carboxylic acid, a carboxylate anion counter balanced by a counterion, a pharmaceutically acceptable ester group or a carboxylic acid protected by a protecting group;
Rrr represents hydrogen, —C
1-6
straight- or branched-chain alkyl, unsubstituted or substituted with one to four R
i
groups;
P represents hydrogen, hydroxyl, F or hydroxyl protected by a hydroxyl-protecting group;
each R is independently selected from: —R
*
; —Q; hydrogen; halo; —CN; —NO
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; and —C
3-7
cycloalkyl, unsubstituted or substituted with one to four R
d
groups;
with the proviso that at least one R is present which contains at least one positive charge;
each R
a
, R
b
and R
c
independently represents hydrogen, —R
*
, —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
; —NR
e
C(NR
f
)R
g
; —R
*
or —Q;
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
;
R
*
is selected from the group consisting of:
wherein:
d represents O, S or NR
k
;
e, g, x, y and z represent CR
m
, N or N
+
R
k
, provided that no more than one of e, g, x, y and z in any given structure represents N
+
R
k
;
R
k
represents hydrogen; —C
1-6
straight- or branched-chain alkyl, unsubstituted or substituted with one to four R
i
groups; or —(CH
2
)
n
Q where n=1, 2 or 3 and Q is as previously defined;
each R
m
independently represents a member selected from the group consisting of: hydrogen; halo; —CN; —NO
2
; —NR
n
R
o
; —OR
n
; —SR
n
; —CONR
n
R
o
; —COOR
h
; —SOR
n
; —SO
2
R
n
; —SO
2
NR
n
R
o
; —NR
n
SO
2
R
o
; —COR
n
; —NR
n
COR
o
; —OCOR
n
; —OCONR
n
R
o
; —NR
n
CO
2
R
h
; —NR
n
CONR
o
R
h
; —OCO
2
R
h
; —CNR
n
NR
o
R
h
; —NR
n
CNHNR
o
R
h
; —NR
n
C(NR
o
)R
h
; —C
1-6
straight- or branched-chain alkyl, unsubstituted or substituted with one to four R
i
groups; —C
3-7
cycloalkyl, unsubstituted or substituted with one to four R
i
groups; and —(CH
2
)Q where n and Q are as defined above;
R
n
and R
o
represent hydrogen, phenyl; —C
1-6
straight- or branched-chain alkyl unsubstituted or substituted with one to four R
i
groups;
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; —C1-6 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 or terminated 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
, S

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