Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-06-23
2002-02-12
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
06346526
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 1,1 dioxo-2,3-dihydro-naphtho[1,8-de][1,2]thiazin-2-yl group or 1,1,3 trioxo-2,3-dihydro-naphtho[1,8-de][1,2]thiazin-2-yl group linked through a CH
2
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:
including pharmaceutically acceptable salts thereof, wherein:
R
1
represents H or methyl;
CO
2
M represents a carboxylic acid, a pharmaceutically acceptable carboxylic acid salt, carboxylate anion, a pharmaceutically acceptable ester group or a carboxylic acid protected by a protecting group;
X represents CH
2
or C═O;
P represents hydrogen, hydroxyl, F or hydroxyl protected by a hydroxyl-protecting group;
Each R independently represents R
b
,
—Het(R
b
)
3
, C
2-6
alkenyl, or a group L—Q—R
q
with the proviso that only one R group of the type L—Q—R
q
can be present or one R group may be taken with L, if present, and any intervening atoms to represent a 5-6 membered ring;
L is C
1-4
straight or branched alkylene, uninterrupted, interrupted or terminated by 1-2 of O, S, NR
a
, C(O), CO
2
and C(O)NR
a
;
Q represents:
Y
−
is a charge balancing group;
n is a value from 0 to 2 selected to maintain overall charge neutrality;
R
a
is H or C
1-6
alkyl;
R
q
is C
1-6
alkyl, straight or branched, uninterrupted, interrupted or terminated by 1-2 of O, S, NR
a
, C(O), C(O)O, C(O)NR
a
, —CH═CH—, —Het(R
b
)
3
—, —C(O)Het(R
b
)
3
—, —C(O)NR
a
Het(R
b
)
3
—,
said R
q
being unsubstituted or substituted with 1-3 R
c
groups;
Het is a heteroaryl group;
each R
b
is independently selected from H, halo, OR
a
, OC(O)R
a
, C(O)R
a
, CN, C(O)NR
a
R
d
, NO
2
, NR
a
R
d
, SO
2
NR
a
R
d
and C
1-4
alkyl unsubstituted or substituted with 1-3 groups selected from R
e
;
each R
c
is independently selected from halo, OR
f
, OC(O)R
f
, SR
f
, S(O)R
f
, SO
2
R
f
, CN, C(O)R
f
, CO
2
R
f
, NR
f
R
g
, N
+
R
a
R
f
R
g
Z
31
, C(O)NR
a
R
f
, —Het(R
b
)
3
, C(═N
+
R
a
R
f
)R
a
Z
−
, C(═N
+
R
a
R
f
)NR
a
R
f
Z
−
, NR
a
C(═N
+
R
a
R
f
)R
a
Z
−
, NR
a
C(═N
+
R
a
R
f
)NR
a
R
f
Z
−
, heteroarylium(R
b
)
3
Z
−
, SO
2
NR
a
R
f
, OC(O)NR
a
R
f
, NR
a
C(O)R
f
, NR
a
C(O)NR
a
R
f
, and
or in the alternative, when 2 or more R
c
groups are present, 2 R
c
groups may be taken together with any intervening atoms to form a 3-6 membered carbocyclic ring, optionally interrupted with 1-3 of O, S, NR
g
, and C(O), said ring being unsubstituted or substituted with 1-3 R
e
groups;
R
d
is H or C
1-4
alkyl, or R
a
and R
d
taken together with any intervening atoms represent a 4-6 membered ring;
R
e
is selected from halo, OR
a
, NR
a
R
d
and CONR
a
R
d
;
R
f
is H; C
1-6
straight or branched chain alkyl, unsubstituted or substituted with 1-3 R
e
groups; —Het(R
b
)
3
; C
3-6
cycloalkyl, unsubstituted or substituted with 1-3 R
e
groups, and
or R
a
and R
f
together with an intervening atoms form a 4-6 membered ring, optionally interrupted by O, S, NR
a
or C(O); and
R
g
is H, C
1-6
alkyl, unsubstituted or substituted with 1-3 R
e
groups; C
3-6
cycloalkyl, unsubstituted or substituted with 1-3 R
e
groups; C(═N
+
R
a
R
f
)R
a
Z
− or C(═N
+
R
a
R
f
)NR
a
R
f
Z
−
;
or R
f
and R
g
together with any intervening atoms form a 4-6 membered ring optionally interrupted by O, S, NR
a
or C(O); and
Z
−
is a charge balancing group selected from Y, a monovalent anion such as acetate, benzoate, bromide, chloride or the like, or an internal anion such as CO
2
M, where M is a negative charge.
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 15 carbon atoms unless otherwise defined. It may be straight or branched. Preferred alkyl groups include methyl, ethyl, propyl, isopropyl, butyl and t-butyl. When substituted, alkyl groups may be substituted with up to 3 substituent groups, selected from R
c
or R
e
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. Preferred cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. When substituted, cycloalkyl groups may be substituted with up to 3 substituents selected from R
c
or R
e
as defined.
A C
1-4
alkylene group refers to an alkyl group which is attached through two bonds to two different atoms or substituents. The two bonds on the alkylene group can be on the same carbon atom or on different carbon atoms. See, e.g., the following:
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. The preferred aryl groups are phenyl, naphthyl and phenanthrenyl. Aryl groups may likewise be substituted as defined. Preferred substituted aryls include phenyl and naphthyl.
The term “heteroaryl” (Het) refers to a monocyclic aromatic hydrocarbon 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:
The group L—Q—R
q
, if present, is attached to either of the two phenyl rings of the 1,1dioxo-2,3-dihydro-naphtho[1,8-de][1,2]thiazin-2-yl or 1,1,3trioxo-2,3-dihydro-naphtho[1,8-de][1,2]thiazin-2-yl group, provided that no more than one L—Q—R
q
group is present.
Heteroarylium refers to heteroaryl groups bearing a quaternary nitrogen atom and thus a positive charge. Examples include the following:
When a charge is shown on a particular nitrogen atom in a ring which contains one or mo
Blizzard Timothy A.
Dykstra Kevin D.
Ratcliffe Ronald W.
Ayler Sylvia A.
Berch Mark L.
Daniel Mark R.
Merck & Co. , Inc.
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