Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-04-23
2001-08-07
Berch, Mark L. (Department: 1609)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S195000, C540S310000
Reexamination Certificate
active
06271222
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 penem compounds in which the releaseable liphophilic aromatic side-chain, tethered to the penem nucleus via a methylene linker, necessary for anti-MRSA activity replaces the non-releaseable liphophilic side-chains found in 2-aryl and 2-benzothiazolylthio carbapenem compounds. The present invention replaces the common simple ether based found in EPO 416,953, substituted carbon atoms found in EPO 507,313, and substituted amines found in WO 9523149. 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 penem antibiotics containing releaseable aromatic based side-chains. The releaseable side-chain imparts MRSA activity by preventing or lessening the likelihood of immune-mediated toxicity previously associated with the 2-aryl linked and 2-benzothiazolylthio carbapenems.
The compounds of the invention are represented by formula
or a pharmaceutically acceptable salt thereof, wherein:
CO
2
M represents a carboxylic acid, a carboxylate anion or cation, a pharmaceutically acceptable ester group or a carboxylic acid protected by a protecting group;
P represents hydrogen, hydroxyl, fluoro or hydroxyl protected by a hydroxyl-protecting group;
each R is independently selected from: —R*; A—(CH
2
)
n
—Q; —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;
A represents O, S or CH
2
; n=0-3;
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;
wherein when —OR
g
is OH, the OH group can be optionally protected by a hydroxyl protecting group;
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
)
n
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; —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 or terminated by one or two of O, S, SO, SO
2
, NR
w
Ayler Sylvia A.
Berch Mark L.
Daniel Mark R.
Merck & Co. , Inc.
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