Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-08-31
2001-08-21
Lambkin, Deborah C. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S376000, C546S271400, C548S229000
Reexamination Certificate
active
06277868
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 epidermis
, 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, pp175-194). 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 eperezoid 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 its principle embodiment, therefore, 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, pertluoroalkyl, 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, perifluoroalkyl, perfluoroalkoxy, perfluoroalkoxyalkyl, perfluoroalkoxyalkcnyl 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 selccted from alkyl, alkoxy, carboxy, azido, carboxaldehyde, halo, hydroxy, perfluoroalkyl, and perfluoroalkoxy;
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, and pefluoroalkoxy;
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, and perfluoroalkoxy; 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 combinations wherein A is phenyl, R
4
is NHR
5
wherein R
5
is alkanoyl, and R
3
is unsubstituted alkyl, are excluded therefrom; and
with the proviso that combinations wherein A is phenyl, R
4
is methoxy, and R
3
is optionally substituted phenyl are excluded therefrom.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of this invention are substituted oxazolidinones which are useful for treating bacterial infections, psoriasis, arthritis, toxicity due to chemotherapy, and obesity. In its principle embodiment, the invention is directed to compounds of formula (I)
or therapeutically acceptable salts thereof, wherein A, R
1
, R
2
, R
3
and R
4
are defined hereinabove.
The compounds of the invention comprise oxazolidinones connected through the nitrogen atom in the oxazolidinone ring to a substituted alkyne through ring A. Ring A is a stable, aromatic, monocyclic group substituted through carbon atoms in the ring. Preferably, ring A is phenyl, although heteroaryl rings such as furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl are within the scope of the invention. Ring A can be further substituted by independent replacement of one or two hydrogen atoms thereon by substituents defined by R
1
and R
2
so that, for instance and by way of example only, ring A can be substituted by halo, preferably fluorine. Lines drawn into ring A (such as from R
1
and R
2
) indicate that the bonds can be attached to any substitutable ring carbon atom. Preferred substituents include, but are not limited to, alkoxycarbonyl and the like.
It is intended that the definition of any substituent or variable at a particular location in a molecule be independent of its de
Djuric Stevan W.
Pliushchev Marina
Sciotti Richard J.
Abbott Laboratories
D'Souza Andrea
Lambkin Deborah C.
Sickert Dugal S.
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