Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-05-24
2001-09-11
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
06288054
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 a 2-mercaptobenzothiazole moiety linked through a group —Z—CH
2
—. Z represents an trans-ethenediyl group, ethynediyl group or is absent. The mercaptobenzothiazole moiety is further substituted with various substituent groups 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 anti-MRSA carbapenem antibiotics containing heteroaromatic based side-chains. The side-chain imparts MRS activity previously unassociated with the carbapenem skeleton.
The compounds of the invention are represented by formula I:
or a pharmaceutically acceptable salt 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;
Z represents trans-ethenediyl, ethynediyl or is absent;
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
; —OC
2
R
h
; —NR
a
C(O)Rb
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;
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
)
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
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, S
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
DiNinno Frank P.
Dykstra Kevin D.
Hammond Milton L.
Ayler Sylvia A.
Berch Mark L.
Daniel Mark R.
Merck & Co. , Inc.
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