Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-03-13
2001-06-26
Berch, Mark L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S302000, C540S543000, C544S071000, C544S231000, C546S017000, C546S018000, C546S064000, C548S208000
Reexamination Certificate
active
06251890
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 naphthosultam linked through a CH
2
group. The naphthosultam 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 compounds of the invention are represented by formula I:
or a pharmaceutically acceptable salt thereof, wherein:
CO
2
M represents a carboxylic acid, a carboxylate anion, a pharmaceutically acceptable ester group or a carboxylic acid protected by a protecting group;
R
1
represents H or methyl;
P represents hydrogen, hydroxyl, F or hydroxyl protected by a hydroxyl-protecting group;
R
2
represents:
wherein:
each R is independently selected from: —R*; 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;
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*;
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; C
1-6
straight or branched chain alkyl; —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, —C
1-6
straight or branched-chain alkyl group, —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, said saturated ring being optionally interrupted by one or two of O, S, SO
2
, —C(O)—, NH and NCH
3
;
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;
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
w
independently represents hydrogen; —C
1-6
straight- or branched-chain alkyl, C
3-6
cycloalkyl, said alkyl or cycloalkyl being optionally substituted with 1-4 R
i
groups; phenyl, or heteroaryl, said phenyl and heteroaryl being 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
;
each R
x
independently 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 alkyl 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
, phenyl or heteroaryl, said phenyl or heteroaryl 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;
or two R
x
groups taken together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by O, S, SO
2
, NR
w
, N
+
R
w
R
w
or —C(O)—, said saturated ring being unsubstituted or substituted with 1-4 R
i
groups, where R
w
and R
i
are defined above,
or two R
w
groups taken together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by O, S, SO
2
, NR
h
, N
+
R
h
R
h
or —C(O)—, said saturated ring being unsubstituted or substituted with 1-4 R
i
groups, where R
h
and R
i
are defined above.
Pharmaceutical compositions and methods of treatment are also included herein.
DETAILED DESCRIPTION OF THE INVENTION
The invention is described herein in detail using the terms defined below unless otherwise specified.
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, at any available point of attachment. When the alkyl group is said to be substituted with an alkyl group, this is used interchangeably with “branched alkyl group”.
Cycloalkyl is a specie of alkyl containing from 3 to 15 carbon atoms, without alternating or resonating double bonds between carbon atoms. It may contain from 1 to 4 rings which are fused.
Aryl refers to aromatic rings e.g., phenyl, substituted phenyl and the like, as well as rings which are fused, e.g., naphthyl, phenanthrenyl and the like. An aryl group thus contains at least one ring havi
Blizzard Timothy A.
Morgan, II Jerry D.
Ratcliffe Ronald W.
Wilkening Robert R.
Ayler Sylvia A.
Berch Mark L.
Daniel Mark R.
Merck & Co. , Inc.
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