Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-12-07
2001-07-03
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
06255300
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 iodo-substituted phenyl linked through a CH
2
—O— group. The iodo-substituted phenyl ring 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:
as well as salts and hydrates 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 hydroxyl-protecting group;
A represents O, S or —CH
2
— attached at position 3, 4 or 5;
n represents an integer 0-3;
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 NRS;
&bgr;, &dgr;, ↓, &mgr; and &sgr; represent CR
t
, N or N+R
s
, provided that no more than one of &bgr;, &dgr;, ↓, &mgr; and &sgr; is N+R
s
balanced by L;, as defined above;
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;
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
5
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
;
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, NRW 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
3-5
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, 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.
The term “alkenyl” refers to a hydrocarbon radical straight, branched or cyclic containing from 2 to 10 carbon atoms and at least one carbon to carbon double bond. Preferred alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl.
The term “alkynyl” refers to a hydrocarbon radical straight or branched, containing from 2 to 10 carbon atoms and at least one carbon to carbon triple bond. Preferred alkynyl groups include ethynyl, propynyl and butynyl.
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 having at least 6 atoms, with up to five such rings being present, containing up to 22 atoms therein, with alternating (resonating) double bonds between adjacent carbon atoms or suitable heteroatoms. The preferred aryl groups are phenyl, naphthyl and phenanthrenyl. Aryl groups may likewise be substituted as defined. Preferred substituted aryls include phenyl and napbthyl.
The term “heteroaryl” refers to a monocyclic aromatic group having 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing at least one heteroatom, O, S or N, in which a carbon or nitrogen atom is the point of attachment, and in which one or two additional carbon atoms is optionally replaced by a heteroatom selected from O or S, and in which from 1 to 3 additional carbon atoms are optionally replaced by nitrogen heteroatoms, said heteroaryl group being optionally substituted as described herein. Examples of this type are pyrrole, pyridine, oxazole, thiazole and oxazine. Additional nitrogen atoms may be present together with the first nitrogen and oxygen or sulfur, giving, e.g., thiadiazole. Examples include the following:
H
DiNinno Frank P.
Dykstra Kevin D.
Ayler Sylvia A.
Berch Mark L
Daniel Mark R.
Merck & Co. , Inc.
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