Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
2001-06-19
2002-06-25
Higel, Floyd D. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
C544S335000, C546S271400, C548S180000, C548S232000
Reexamination Certificate
active
06410728
ABSTRACT:
TECHNICAL FIELD
This invention is directed to compounds useful for treating bacterial infections, psoriasis, arthritis, and toxicity due to chemotherapy; preparation of the compounds; chemotherapeutic compositions comprising the compounds; and methods for treating diseases using the compounds.
BACKGROUND OF THE INVENTION
The escalation of resistance to antibiotics once useful for treatment of bacterial infections resulting from pathogens such as
Staphylococcus aureus, Staphylococcus epidermidis
, and
Enterococcus faecium
is problematic in the United States and Europe (
Drugs Exp. Clin. Res
. 1994, XX, 215-224
; Am. J. Surg
. 1995, 5A (Suppl.), 8S-12S;
Drugs
, 1994, 48, 678-688; and
Current Pharmaceutical Design
, 1996, Vol.2, No.2, 175-194). Thus, the development of new broad-spectrum synthetic and semi-synthetic antibacterial compounds is the subject of constant current research.
One such class of compounds are synthetic oxazolidinones, exemplified by eperezolid and linezolid, which constitute a class of orally active, synthetic antibacterial agents (
Current Pharmaceutical Design
, op. cit.).
U.S. Pat. No. 6,040,306, the disclosure of which is hereinafter incorporated by reference into this specification, also teaches the use of oxazolidinones for treatment of psoriasis, arthritis, and toxicity due to chemotherapy.
Given these and other reports on the therapeutic benefit of oxazolidinone antibacterials, the loss of activity among antibacterials which were once efficacious for treatment of certain Gram-positive bacteria, and the continuing need for treatment of a diseases such as psoriasis, arthritis, and toxicity due to chemotherapy, there is a continuing need for the development of novel oxazolidinone drugs with modified or improved profiles of activity.
SUMMARY OF THE INVENTION
In another embodiment, the instant invention is directed to compounds which can be useful for treating bacterial infections, psoriasis, arthritis, and toxicity due to chemotherapy, said compounds having structural formula (I)
or therapeutically acceptable salts or prodrugs thereof, wherein
A is selected from
(a) phenyl,
(b) a five-membered aromatic ring containing one or two atoms selected from N, O, and S, and the remaining atoms are carbon,
wherein the groups defining (b) are substituted on a substitutable carbon or nitrogen atom in the ring, and
(c) a six-membered aromatic ring containing one or two nitrogen atoms, and the remaining atoms are carbon;
wherein the groups defining (c) are substituted on a substitutable carbon atom in the ring;
R
1
and R
2
are independently selected from hydrogen, alkyl, cycloalkyl, hydroxy, amino, halo, haloalkyl, and perfluoroalkyl;
R
3
is selected from
(a) alkyl, alkanoyl, carboxamido, cycloalkyl, cyclothioalkoxy, cycloalkylsulfinyl, cycloalkoxycarbonyl, alkylsulfonyl, alkoxycarbonyl, cycloalkenyl, cycloalkenylsulfonyl,
wherein the groups defining (a) can be optionally substituted with 1-5 substituents independently selected from alkoxy, alkanoyloxy, alkoxycarbonyl, amino, azido, carboxamido, carboxy, cyano, halo, hydroxy, nitro, perfluoroalkyl, perfluoroalkoxy, oxo, thioalkoxy, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heterocycle,
(b) aryl, arylalkyl, arylthio, arylsulfinyl, aryloxycarbonyl, heteroaryl, heteroarylalkyl, heteroarylsulfonyl, heteroaryloxycarbonyl, heterocycle, (heterocycle)alkyl, (heterocycle)sulfonyl, and (heterocycle)oxycarbonyl,
wherein the groups defining (b) can be optionally substituted with 1-5 substituents independently selected from alkyl, alkoxy, alkoxyalkyl, alkoxyalkenyl, alkanoyl, alkanoyloxy, alkanoyloxyalkyl, alkanoyloxyalkenyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylalkenyl, alkylsulfonyl, alkylsulfonylalkyl, alkylsulfonylalkenyl, amino, aminoalkyl, aminoalkenyl, aminosulfonyl, aminosulfonylalkyl, aminosulfonylalkenyl, azido, carboxaldehyde, (carboxaldehyde)alkyl, (carboxaldehyde)alkenyl, carboxamido, carboxamidoalkyl, carboxamidoalkenyl, carboxy, carboxyalkyl, carboxyalkenyl, cyano, cyanoalkyl, cyanoalkenyl, halo, haloalkyl, haloalkenyl, hydroxy, hydroxyalkyl, hydroxyalkenyl, nitro, oxo, perfluoroalkyl, perfluoroalkoxy, perfluoroalkoxyalkyl, perfluoroalkoxyalkenyl thioalkoxy, thioalkoxyalkyl, thioalkoxyalkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heterocycle,
wherein for the groups defining (a) and (b), the substituted aryl, the substituted heteroaryl, and the substituted heterocycle are substituted with 1-5 substituents independently selected from alkyl, alkoxy, carboxy, azido, carboxaldehyde, halo, hydroxy, perfluoroalkyl, perfluoroalkoxy, and amino;
R
4
is selected from NHR
5
, N(R
6
)C(O)OR
7
, N(R
6
)C(O)N(R
6
)
2
, OR
7
, SR
7
, S(O)R
7
, and SO
2
R
7
;
R
5
is selected from alkanoyl, aryloyl, thioalkanoyl, heteroaryl, heteroarylalkyl, (heteroaryl)oyl, heterocycle, and (heterocycle)alkyl,
wherein the groups defining R
5
can be optionally substituted with 1-5 substituents independently selected from alkyl, alkoxy, carboxy, azido, carboxaldehyde, halo, hydroxy, perfluoroalkyl, perfluoroalkoxy, and amino;
R
6
is selected from
(a) hydrogen,
(b) alkyl,
wherein the alkyl can be optionally substituted with 1-5 substituents independently selected from alkoxy, carboxy, azido, carboxaldehyde, halo, hydroxy, perfluoroalkyl, and perfluoroalkoxy;
(c) cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heteroarylalkyl, heterocycle, and (heterocycle)alkyl;
wherein the groups defining (c) can be optionally substituted with 1-5 substituents independently selected from alkyl, alkoxy, carboxy, azido, carboxaldehyde, halo, hydroxy, perfluoroalkyl, perfluoroalkoxy, and amino; and
R
7
is selected from
(a) alkyl,
wherein the alkyl can be optionally substituted with 1-5 substituents independently selected from alkoxy, carboxy, azido, carboxaldehyde, halo, hydroxy, perfluoroalkyl, and perfluoroalkoxy,
(b) cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heteroarylalkyl, heterocycle, and (heterocycle)alkyl;
wherein the groups defining (b) can be optionally substituted with 1-5 substituents independently selected from alkyl, alkoxy, carboxy, azido, carboxaldehyde, halo, hydroxy, perfluoroalkyl, and perfluoroalkoxy,
all of the foregoing with the proviso that when A is phenyl and R
4
is NHR
5
wherein R
5
is alkanoyl, R
3
is not unsubstituted alkyl; and
with the proviso that when A is phenyl and R
4
is methoxy, R
3
is not optionally substituted phenyl.
In another embodiment, the instant invention is directed to compounds which can be useful for treating bacterial infections, psoriasis, arthritis, and toxicity due to chemotherapy, said compounds having structural formula (I)
or therapeutically acceptable salts or prodrugs thereof, wherein
A is selected from
(a) phenyl,
(b) a five-membered aromatic ring containing one or two atoms selected from N, O, and S, and the remaining atoms are carbon,
wherein the groups defining (b) are substituted on a substitutable carbon or nitrogen atom in the ring, and
(c) a six-membered aromatic ring containing one or two nitrogen atoms, and the remaining atoms are carbon;
wherein the groups defining (c) are substituted on a substitutable carbon atom in the ring;
R
1
and R
2
are independently selected from hydrogen, alkyl, cycloalkyl, hydroxy, amino, halo, haloalkyl, and perfluoroalkyl;
R
3
is selected from
(a) alkyl, alkanoyl, carboxamido, cycloalkyl, cyclothioalkoxy, cycloalkylsulfinyl, cycloalkoxycarbonyl, alkylsulfonyl, alkoxycarbonyl, cycloalkenyl, cycloalkenylsulfonyl,
wherein the groups defining (a) can be optionally substituted with 1-5 substituents independently selected from alkoxy, alkanoyloxy, alkoxycarbonyl, amino, azido, carboxamido, carboxy, cyano, halo, hydroxy, nitro, perfluoroalkyl, perfluoroalkoxy, oxo, thioalkoxy, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heterocycle,
(b) aryl, arylalkyl, arylthio, arylsulfinyl, aryloxycarbonyl, heteroaryl, heteroarylalkyl, heteroarylsulfonyl
Djuric Stevan W.
Pliushchev Marina
Sciotti Richard J.
Abbott Laboratories
Donner B. Gregory
Higel Floyd D.
Small Andrea D.
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