Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-03-20
2002-06-04
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S334000
Reexamination Certificate
active
06399597
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 —A—Q—L—B.
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), and are also active against Gram negative bacteria. 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. The antibacterial compounds of the present invention thus comprise an important contribution to therapy for treating infections caused by these difficult to control pathogens.
SUMMARY OF THE INVENTION
The compounds of the invention are represented by formula I:
as well as pharmaceutically acceptable salts 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;
A—Q—L—B represents a side chain wherein:
A is a C
1-6
alkylene group, straight or branched, and optionally interrupted or terminated by 1-2 of —O—, —S—, NR
a
—, —C(O)— and —CH═CH—;
Q is selected from:
in which:
a is 1, 2 or 3;
b is 2 or 3;
and X− is a monovalent or divalent charge balancing counterion;
L represents a bond or a C
1-8
alkylene group, unsubstituted or substituted with 1-3 R
c
groups, uninterrupted, interrupted or terminated by 1-3 of —CH═CH—, —C(O)—, —C(O)NR
d
—, —Het(R
e
)—, —C(O)—Het(R
e
)—, —C(O)NR
a
—Het(R
e
)—, —O—, —S—, —S(O)—, —SO
2
—, —CO
2
—, —NR
a
—, —N
+
(R
a
)
2
—,
Het is a heteroaryl group;
B represents a member selected from the group consisting of:
4) a 4-7 membered, N-containing heterocycle selected from:
wherein c and d are independently 0-4, such that c+d equals from 2-5, and said heterocycle is optionally substituted on carbon atoms with 1-2 R
f
or R
g
groups, and is optionally interrupted by O, S, NR
f
or NR
g
;
wherein
and
represent quaternary an d non-quaternary 5-10 membered mono- or bicyclic, N-containing heteroaryl groups, respectively, optionally containing 1-4 additional heteroatoms selected from O, S and N; and
R
a
is H or C
1-6
alkyl;
R
b
is independently selected from NH
2
and C
1-6
alkyl unsubstituted or substituted with 1-3 groups selected from halo, OH, CN and C(O)NH
2
;
R
c
is independently selected from halo, OR
a
, SR
a
, OC(O)R
a
, CO
2
R
a
, CN, C(O)N(R
a
)
2
and C(O)R
a
,
R
d
is H or C
1-3
alkyl, or R
c
and R
d
taken together with any intervening atoms represent a 4-6 membered ring;
R
e
is H; R
c
; NO
2
, N(R
a
)
2
, SO
2
N(R
a
)
2
or C
1-4
alkyl, unsubstituted or substituted with 1-3 groups selected from halo, OH and C(O)NH
2
R
f
, R
g
and R
h
are independently selected from H; C
1-6
straight or branched chain alkyl, unsubstituted or substituted with 1-3 R
c
groups; C
3-6
cycloalkyl, unsubstituted or substituted with 1-3 R
c
groups; phenyl, unsubstituted or substituted with 1-3 R
e
groups and Het, unsubstituted or substituted with 1-3 R
e
groups, or
R
f
and R
g
taken together with the intervening N atom form a 4-6 membered ring, optionally interrupted by 1-2 of O, S, C(O) or NR
h
, and optionally substituted by 1-3 R
c
groups;
R
i
is H or R
b
;
R
j
and R
k
are C
1-4
alkyl or R
j
and R
k
taken together with the intervening S atom are a 5-6 membered ring;
and each R independently represents H; R
c
; NO
2
; N(R
a
)
2
; SO
2
N(R
a
)
2
or C
1-4
alkyl, unsubstituted or substituted with 1-3 groups selected from halo, OH and C(O)NH
2
, or
R together with A of the group —A—Q—L—B and any intervening atoms represent a 5-6 membered carbocyclic ring.
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 15 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
c
, R
f
and R
g
, or as otherwise 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 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, and in which 1-2 additional carbon atoms are optionally replaced by a heteroatom selected from O or S, and in which from 1-3 additional carbon atoms are optionally replaced by N, said heteroaryl group being optionally substituted as described herein. Examples include the following:
Heteroaryl includes protonated forms as well. It thus includes positively charged as well as non-charged groups. Examples include the groups shown above, having an additional H attached to a nitrogen atom.
The group A—Q—L—B is attached to one of the two phenyl rings shown.
Heteroarylium refers to heteroaryl groups bearing a quaternary or protonated atom and thus a positive charge. Examples include the following:
When a charge is shown on a particular nitrogen atom in a ring or in a nitrogen containing non-ring moiety which contains one or more additional nitrogen atoms, it is understood that the charge may reside on a different nitrogen atom than that shown in a particular drawing by virtue of charge resonance that occurs.
For example,
Likewise, when a basic nitrogen containing moiety is provided at an appropriately acidic pH, the moiety becomes protonated due to acid base reactivity. Both the protonated and non-protonated forms of the compounds of formula I are included in the present invention.
The term “heterocycloalkyl” refers to a cycloalkyl group (nonaromatic) in which one of the carbon atoms in the ring is replaced by a heteroatom selected from O, S or N, and in which up to three additional carbon atoms may be replaced by hetero atoms.
The terms “quaternary nitrogen” and “positive charge” refer to tetravalent, positively charged atoms including, e.g., the positivel
Cama Lovji D.
Ratcliffe Ronald W.
Sun Wanying
Wildonger Kenneth J.
Wilkening Robert R.
Ayler Sylvia A.
Daniel Mark R.
McKenzie Thomas
Merck & Co. , Inc.
Raymond Richard L.
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