U.S. patent application number 09/884735 was filed with the patent office on 2002-04-18 for oxazolidinone chemotherapeutic agents.
Invention is credited to Djuric, Stevan W., Pliushchev, Marina, Sciotti, Richard J..
Application Number | 20020045625 09/884735 |
Document ID | / |
Family ID | 27096306 |
Filed Date | 2002-04-18 |
United States Patent
Application |
20020045625 |
Kind Code |
A1 |
Sciotti, Richard J. ; et
al. |
April 18, 2002 |
OXAZOLIDINONE CHEMOTHERAPEUTIC AGENTS
Abstract
Compounds of the formula 1 or therapeutically acceptable salts
or prodrugs thereof, are useful for treating bacterial infections,
psoriasis, arthritis, and toxicity due to chemotherapy. Preparation
of the compounds, compositions containing the compounds, and
treatment of diseases using the compounds are disclosed.
Inventors: |
Sciotti, Richard J.;
(Gurnee, IL) ; Djuric, Stevan W.; (Libertyville,
IL) ; Pliushchev, Marina; (Vernon Hills, IL) |
Correspondence
Address: |
Steven F. Weinstock
Abbott Laboratories
100 Abbott Park Road
Abbott Park
IL
60064-6050
US
|
Family ID: |
27096306 |
Appl. No.: |
09/884735 |
Filed: |
June 19, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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09884735 |
Jun 19, 2001 |
|
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09652504 |
Aug 31, 2000 |
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Current U.S.
Class: |
514/252.05 ;
514/255.05; 514/256; 514/340; 514/365; 514/376; 544/238; 544/330;
544/405; 546/271.4; 548/190; 548/229 |
Current CPC
Class: |
A61P 31/04 20180101;
C07D 263/20 20130101; A61P 17/06 20180101; A61P 43/00 20180101;
A61K 31/421 20130101; A61K 31/4439 20130101; A61P 19/02 20180101;
C07D 263/24 20130101; A61K 31/422 20130101; C07D 413/10
20130101 |
Class at
Publication: |
514/252.05 ;
514/255.05; 514/256; 514/340; 514/365; 514/376; 546/271.4; 548/190;
548/229; 544/405; 544/330; 544/238 |
International
Class: |
A61K 031/506; A61K
031/501; A61K 031/497; A61K 031/4439; A61K 031/421; A61K
031/427 |
Claims
What is claimed is:
1. A compound of the formula 12or 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.sup.1 and R.sup.2 are
independently selected from hydrogen, alkyl, cycloalkyl, hydroxy,
amino, halo, haloalkyl, and perfluoroalkyl; R.sup.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 is selected from NHR.sup.5,
N(R.sup.6)C(O)OR.sup.7, N(R.sup.6)C(O)N(R.sup.6)2, OR.sup.7,
SR.sup.7, S(O)R.sup.7, and SO.sub.2R.sup.7; R.sup.5 is selected
from alkanoyl, aryloyl, thioalkanoyl, heteroaryl, heteroarylalkyl,
(heteroaryl)oyl, heterocycle, and (heterocycle)alkyl, wherein the
groups defining R.sup.5 can be optionally substituted with 1-5
substituents independently selected from alkyl, alkoxy, carboxy,
azido, carboxaldehyde, halo, hydroxy, perfluoroalkyl,
perfluoroalkoxy, and amino; R.sup.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.sup.7is 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, perfluoroalkoxy, and amino; all of the foregoing
with the proviso that when A is phenyl and R.sup.4 is NHR.sup.5
wherein R.sup.5 is alkanoyl, R.sup.3 is not unsubstituted alkyl;
and with the proviso that when A is phenyl and R.sup.4 is methoxy,
R.sup.3 is not optionally substituted phenyl.
2. A compound set forth in claim 1 of formula (II) 13or a
therapeutically acceptable salt or prodrug thereof, wherein
R.sup.1, R.sup.2, and R.sup.3 are defined therein.
3. A compound set forth in claim 1 wherein R.sup.1 and R.sup.2 are
hydrogen.
4. A compound set forth in claim 1 wherein R.sup.1 is hydrogen and
R.sup.2 is halo.
5. A compound set forth in claim 1 wherein R.sup.4 is --NHR.sup.5
and R.sup.5 is defined therein.
6. A compound set forth in claim 5 wherein R.sup.5 is alkanoyl.
7. A composition comprising a compound of claim 1, or a
therapeutically acceptable salt or prodrug thereof, and a
therapeutically acceptable excipient.
8. A method for treating bacterial infections, psoriasis,
arthritis, and toxicity due to chemotherapy in a patient comprising
administering to the patient a therapeutically acceptable amount of
a compound of the formula: 14or a therapeutically acceptable salt
or prodrug 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.sup.1 and R.sup.2 are
independently selected from hydrogen, alkyl, cycloalkyl, hydroxy,
amino, halo, haloalkyl, and perfluoroalkyl; R.sup.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.sup.4 is selected from NHR.sup.5,
N(R.sup.6)C(O)OR.sup.7, N(R.sup.6)C(O)N(R.sup.6).sub.2, OR.sup.7,
SR.sup.7, S(O)R.sup.7, and SO.sub.2R.sup.7; R.sup.5 is selected
from alkanoyl, aryloyl, thioalkanoyl, heteroaryl, heteroarylalkyl,
(heteroaryl)oyl, heterocycle, and (heterocycle)alkyl, wherein the
groups defining R.sup.5 can be optionally substituted with 1-5
substituents independently selected from alkyl, alkoxy, carboxy,
azido, carboxaldehyde, halo, hydroxy, perfluoroalkyl,
perfluoroalkoxy, and amino; R.sup.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.sup.7is 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,
9. A compound selected from:
N-(((5S)-3-(3-fluoro-4-(4-(carbomethoxyphenyl-
)ethynyl)phenyl)-2-oxo-1,3-oxazolidin-5-yl)methyl)acetamide,
N-(((5S)-3-(3-fluoro-4-(1H-pyrrol-2-ylethynyl)phenyl)-2-oxo-1,3-oxazolidi-
n-5-yl)methyl)acetamide,
N-(((5S)-3-(3-fluoro-4-(7H-purin-6-ylethynyl)phen-
yl)-2-oxo-1,3-oxazolidin-5-yl)methyl)acetamide,
N-(((S)-3-(4-((5-(aminosul-
fonyl)thien-2-yl)ethynyl)-3-fluorophenyl)-2-oxo-1,3-oxazolidin-5-yl)methyl-
)acetamide,
N-(((5S)-3-(3-fluoro-4-((1-oxo-2,3-dihydro-1H-inden-5-yl)ethyn-
yl)phenyl)-2-oxo-1,3-oxazolidin-5-yl)methyl)acetamide,
5-((4-((5S)-5-((acetylamino)methyl)-2-oxo-1,3-oxazolidin-3-yl)-2-fluoroph-
enyl)ethynyl)-2,3-dihydro-1-benzofuran-7-carboxylic acid,
N-(((5S)-3-(4-((1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl)ethynyl)-3-fluorop-
henyl)-2-oxo-1,3-oxazolidin-5-yl)methyl)acetamide,
N-(((5S)-3-(4-((5-cyano-
pyridin-3-yl)ethynyl)-3-fluorophenyl)-2-oxo-1,3-oxazolidin-5-yl)
methyl)acetamide,
N-(((5S)-3-(3-fluoro-4-(1,8-naphthyridin-2-ylethynyl)ph-
enyl)-2-oxo-1,3-oxazolidin-5-yl) methyl)acetamide,
N-(((5S)-3-(3-fluoro-4--
((4-(hydroxymethyl)phenyl)ethynyl)phenyl)-2-oxo-1,3-oxazolidin-5-yl)methyl-
)acetamide,
N-(((5S)-3-(3-fluoro-4-(1,8-naphthyridin-2-ylethynyl)phenyl)-2-
-oxo-1,3-oxazolidin-5-yl) methyl)acetamide,
N-(((5S)-3-(3-fluoro-4-((4-met-
hoxy-3-pyridinyl)ethynyl)phenyl)-2-oxo-1,3-oxazolidin-5-yl)methyl)acetamid-
e,
N-(((5S)-3-(4-((2-aminopyrimidin-5-yl)ethynyl)-3-fluorophenyl)-2-oxo-1,-
3-oxazolidin-5-yl)methyl)acetamide,
N-(((5S)-3-(3-fluoro-4-(pyrimidin-5-yl-
ethynyl)phenyl)-2-oxo-1,3-oxazolidin-5-yl)methyl)acetamide,
N-(((5S)-3-(4-((3-aminophenyl)ethynyl)-3-fluorophenyl)-2-oxo-1,3-oxazolid-
in-5-yl)methyl)acetamide, methyl
3-((4-((5S)-5-((acetylamino)methyl)-2-oxo-
-1,3-oxazolidin-3-yi)-2-fluorophenyl)ethynyl)benzoate,
N-(3-(2-(4-((5S)-5-((acetylamino)methyl)-2-oxo-1,3-oxazolidin-3-yl)-2-flu-
orophenyl)ethynyl)phenyl)acetamide,
N-(((5S)-3-(4-((3-(aminomethyl)phenyl)-
ethynyl)-3-fluorophenyl)-2-oxo-1,3-oxazolidin-5-yl)methyl)acetamide,
N-(((5S)-3-(3-fluoro-4-((4-hydroxyphenyl)ethynyl)phenyl)-2-oxo-1,3-oxazol-
idin-5-yl)methyl)acetamide, and
N-(((5S)-3-(3-fluoro-4-((2-oxo-2,3-dihydro-
-1,3-benzothiazol-6-yl)ethynyl)phenyl)-2-oxo-1,3-oxazolidin-5-yl)methyl)ac-
etamide.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part of pending U.S.
application Ser. No. 09/652,504, filed Aug. 31, 2000.
TECHNICAL FIELD
[0002] 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
[0003] 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, X, 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.
[0004] 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.).
[0005] 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.
[0006] 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
[0007] 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) 2
[0008] or therapeutically acceptable salts or prodrugs thereof,
wherein
[0009] A is selected from
[0010] (a) phenyl,
[0011] (b) a five-membered aromatic ring containing one or two
atoms selected from N, O, and S, and the remaining atoms are
carbon,
[0012] wherein the groups defining (b) are substituted on a
substitutable carbon or nitrogen atom in the ring, and
[0013] (c) a six-membered aromatic ring containing one or two
nitrogen atoms, and the remaining atoms are carbon;
[0014] wherein the groups defining (c) are substituted on a
substitutable carbon atom in the ring;
[0015] R.sup.1 and R.sup.2 are independently selected from
hydrogen, alkyl, cycloalkyl, hydroxy, amino, halo, haloalkyl, and
perfluoroalkyl;
[0016] R.sup.3 is selected from
[0017] (a) alkyl, alkanoyl, carboxamido, cycloalkyl,
cyclothioalkoxy, cycloalkylsulfinyl, cycloalkoxycarbonyl,
alkylsulfonyl, alkoxycarbonyl, cycloalkenyl,
cycloalkenylsulfonyl,
[0018] 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,
[0019] (b) aryl, arylalkyl, arylthio, arylsulfinyl,
aryloxycarbonyl, heteroaryl, heteroarylalkyl, heteroarylsulfonyl,
heteroaryloxycarbonyl, heterocycle, (heterocycle)alkyl,
(heterocycle)sulfonyl, and (heterocycle)oxycarbonyl,
[0020] 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,
[0021] 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;
[0022] R.sup.4 is selected from NHR.sup.5, N(R.sup.6)C(O)OR.sup.7,
N(R.sup.6)C(O)N(R.sup.6).sub.2, OR.sup.7, SR.sup.7, S(O)R.sup.7,
and SO.sub.2R.sup.7;
[0023] R.sup.5 is selected from alkanoyl, aryloyl, thioalkanoyl,
heteroaryl, heteroarylalkyl, (heteroaryl)oyl, heterocycle, and
(heterocycle)alkyl,
[0024] wherein the groups defining R.sup.5 can be optionally
substituted with 1-5 substituents independently selected from
alkyl, alkoxy, carboxy, azido, carboxaldehyde, halo, hydroxy,
perfluoroalkyl, perfluoroalkoxy, and amino;
[0025] R.sup.6 is selected from
[0026] (a) hydrogen,
[0027] (b) alkyl,
[0028] wherein the alkyl can be optionally substituted with 1-5
substituents independently selected from alkoxy, carboxy, azido,
carboxaldehyde, halo, hydroxy, perfluoroalkyl, and
perfluoroalkoxy;
[0029] (c) cycloalkyl, cycloalkylalkyl, aryl, heteroaryl,
heteroarylalkyl, heterocycle, and (heterocycle)alkyl;
[0030] 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
[0031] R.sup.7 is selected from
[0032] (a) alkyl,
[0033] wherein the alkyl can be optionally substituted with 1-5
substituents independently selected from alkoxy, carboxy, azido,
carboxaldehyde, halo, hydroxy, perfluoroalkyl, and
perfluoroalkoxy,
[0034] (b) cycloalkyl, cycloalkylalkyl, aryl, heteroaryl,
heteroarylalkyl, heterocycle, and (heterocycle)alkyl;
[0035] 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,
[0036] all of the foregoing with the proviso that when A is phenyl
and R.sup.4 is NHR.sup.5 wherein R.sup.5 is alkanoyl, R.sup.3 is
not unsubstituted alkyl; and
[0037] with the proviso that when A is phenyl and R.sup.4 is
methoxy, R.sup.3 is not optionally substituted phenyl.
[0038] 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) 3
[0039] or therapeutically acceptable salts or prodrugs thereof,
wherein
[0040] A is selected from
[0041] (a) phenyl,
[0042] (b) a five-membered aromatic ring containing one or two
atoms selected from N, O, and S, and the remaining atoms are
carbon,
[0043] wherein the groups defining (b) are substituted on a
substitutable carbon or nitrogen atom in the ring, and
[0044] (c) a six-membered aromatic ring containing one or two
nitrogen atoms, and the remaining atoms are carbon;
[0045] wherein the groups defining (c) are substituted on a
substitutable carbon atom in the ring;
[0046] R.sup.1 and R.sup.2 are independently selected from
hydrogen, alkyl, cycloalkyl, hydroxy, amino, halo, haloalkyl, and
perfluoroalkyl;
[0047] R.sup.3 is selected from
[0048] (a) alkyl, alkanoyl, carboxamido, cycloalkyl,
cyclothioalkoxy, cycloalkylsulfinyl, cycloalkoxycarbonyl,
alkylsulfonyl, alkoxycarbonyl, cycloalkenyl,
cycloalkenylsulfonyl,
[0049] 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,
[0050] (b) aryl, arylalkyl, arylthio, arylsulfinyl,
aryloxycarbonyl, heteroaryl, heteroarylalkyl, heteroarylsulfonyl,
heteroaryloxycarbonyl, heterocycle, (heterocycle)alkyl,
(heterocycle)sulfonyl, and (heterocycle)oxycarbonyl,
[0051] 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,
[0052] 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;
[0053] R.sup.4 is selected from NHR.sup.5, N(R.sup.6)C(O)OR.sup.7,
N(R.sup.6)C(O)N(R.sup.6).sub.2, OR.sup.7, SR.sup.7, S(O)R.sup.7,
and SO.sub.2R.sup.7;
[0054] R.sup.5 is selected from alkanoyl, aryloyl, thioalkanoyl,
heteroaryl, heteroarylalkyl, (heteroaryl)oyl, heterocycle, and
(heterocycle)alkyl,
[0055] wherein the groups defining R.sup.5 can be optionally
substituted with 1-5 substituents independently selected from
alkyl, alkoxy, carboxy, azido, carboxaldehyde, halo, hydroxy,
perfluoroalkyl, perfluoroalkoxy, and amino;
[0056] R is selected from
[0057] (a) hydrogen,
[0058] (b) alkyl,
[0059] wherein the alkyl can be optionally substituted with 1-5
substituents independently selected from alkoxy, carboxy, azido,
carboxaldehyde, halo, hydroxy, perfluoroalkyl, and
perfluoroalkoxy;
[0060] (c) cycloalkyl, cycloalkylalkyl, aryl, heteroaryl,
heteroarylalkyl, heterocycle, and (heterocycle)alkyl;
[0061] 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
[0062] R.sup.7 is selected from
[0063] (a) alkyl,
[0064] wherein the alkyl can be optionally substituted with 1-5
substituents independently selected from alkoxy, carboxy, azido,
carboxaldehyde, halo, hydroxy, perfluoroalkyl, and
perfluoroalkoxy,
[0065] (b) cycloalkyl, cycloalkylalkyl, aryl, heteroaryl,
heteroarylalkyl, heterocycle, and (heterocycle)alkyl;
[0066] 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.
DETAILED DESCRIPTION OF THE INVENTION
[0067] 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) 4
[0068] or therapeutically acceptable salts thereof, wherein A,
R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are defined hereinabove.
[0069] 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 and
R.sup.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.sup.1 and R.sup.2) indicate that the bonds
can be attached to any substitutable ring carbon atom. Preferred
substituents include, but are not limited to, alkoxycarbonyl, halo,
and the like.
[0070] It is intended that the definition of any substituent or
variable at a particular location in a molecule be independent of
its definition elsewhere in that molecule. For example, for
substituents defined by R.sup.4, it is intended that the definition
of an R substituent at one location is independent of its
definition elsewhere. Thus, N(R.sup.6)C(O)N(R.sup.6).sub.2
represents, for instance, and by way of example only,
N(CH.sub.3)C(O)N(C.sub.2H.sub.5)(C.sub.3H.sub.7), and the like. In
a preferred embodiment of the invention, R.sup.4 is NHR.sup.5
wherein R.sup.5 is alkanoyl, preferably acetyl.
[0071] It is believed that when the compounds have attached thereto
a hydroxyl, amino, or carboxylic acid group, prodrugs can be
prepared from these compounds by attaching thereto a
prodrug-forming group to provide prodrug esters prodrug amides, and
prodrug esters, respectively. These prodrugs can then be rapidly
transformed in vivo to the parent compound, such as, for example,
by hydrolysis in blood. The term "therapeutically acceptable
prodrug," as used herein, refers to those prodrugs of the compounds
which are suitable for use in contact with the tissues of humans
and lower animals with undue toxicity, irritation, allergic
response, and the like, commensurate with a reasonable benefit/risk
ratio, and effective for their intended use, as well as the
zwitterionic forms, wherein possible, of the compounds.
[0072] The invention is based, in part, on the structure activity
relationship data provided hereinbelow. Therefore, another
embodiment of the invention encompasses any compound, including
metabolic precursors of the inhibitor compounds, which contain an
essential inhibitory group as disclosed herein. These inhibitory
groups can be in masked form or prodrug form and can be released by
metabolic or other processes after administration to a patient.
[0073] Because asymmetric centers exist in the compounds, the
invention contemplates stereoisomers and mixtures thereof.
Individual stereoisomers of compounds are prepared by synthesis
from starting materials containing the chiral centers or by
preparation of mixtures of enantiomeric products followed by
separation such as conversion to a mixture of diastereomers
followed by separation or recrystallization, chromatographic
techniques, or direct separation of the enantiomers on chiral
chromatographic columns. Starting compounds of particular
stereochemistry are either commercially available or are made by
the methods described below and resolved by techniques well-known
in the art.
[0074] Because carbon-carbon double bonds may also exist in the
compounds, the invention contemplates various geometric isomers and
mixtures thereof resulting from the arrangement of substituents
around these carbon-carbon double bonds. These substituents are
designated as being in the E or Z configuration wherein the term
"E" refers to higher order substituents on opposite sides of the
carbon-carbon double bond, and the term "Z" refers to higher order
substituents on the same side of the carbon-carbon double bond. A
thorough discussion of E and Z isomerism is provided in Advanced
Organic Chemistry. Reactions, Mechanisms, and Structure, 4th ed.,
John Wiley & Sons, New York, 1992, pp. 109-112.
[0075] Accordingly, it will be seen by those skilled in the art
that another embodiment of compounds of formula (I) are compounds
of formula (II) 5
[0076] or therapeutically acceptable salts or prodrugs or thereof,
wherein R.sup.1, R.sup.2, and R.sup.3 are defined hereinabove.
[0077] In another embodiment of the invention is disclosed a
composition comprising a compound of formula (I) or formula (II),
or a therapeutically acceptable salt or prodrug thereof, and a
therapeutically acceptable excipient.
[0078] In another embodiment of the invention is disclosed a
composition comprising a compound of formula (I) or formula (II),
or a therapeutically acceptable salt or prodrug thereof, and a
therapeutically acceptable excipient.
[0079] In another embodiment of the invention is disclosed a method
for treating bacterial infections, psoriasis, arthritis, and
toxicity due to chemotherapy in a patient comprising administering
to the patient a therapeutically acceptable amount of a compound of
formula (I) 6
[0080] or a therapeutically acceptable salt or prodrug thereof,
wherein
[0081] A is selected from
[0082] (a) phenyl,
[0083] (b) a five-membered aromatic ring containing one or two
atoms selected from N, O, and S, and the remaining atoms are
carbon,
[0084] wherein the groups defining (b) are substituted on a
substitutable carbon or nitrogen atom in the ring, and
[0085] (c) a six-membered aromatic ring containing one or two
nitrogen atoms, and the remaining atoms are carbon;
[0086] wherein the groups defining (c) are substituted on a
substitutable carbon atom in the ring;
[0087] R.sup.1 and R.sup.2 are independently selected from
hydrogen, alkyl, cycloalkyl, hydroxy, amino, halo, haloalkyl, and
perfluoroalkyl;
[0088] R.sup.3 is selected from
[0089] (a) alkyl, alkanoyl, carboxamido, cycloalkyl,
cyclothioalkoxy, cycloalkylsulfinyl, cycloalkoxycarbonyl,
alkylsulfonyl, alkoxycarbonyl, cycloalkenyl,
cycloalkenylsulfonyl,
[0090] 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,
[0091] (b) aryl, arylalkyl, arylthio, arylsulfinyl,
aryloxycarbonyl, heteroaryl, heteroarylalkyl, heteroaryisulfonyl,
heteroaryloxycarbonyl, heterocycle, (heterocycle)alkyl,
(heterocycle)sulfonyl, and (heterocycle)oxycarbonyl,
[0092] 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,
[0093] 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;
[0094] R.sup.4 is selected from NHR.sup.5, N(R.sup.6)C(O)OR.sup.7,
N(R.sup.6)C(O)N(R.sup.6).sub.2, OR.sup.7, SR.sup.7, S(O)R.sup.7,
and SO.sub.2R.sup.7;
[0095] R.sup.5 is selected from alkanoyl, aryloyl, thioalkanoyl,
heteroaryl, heteroarylalkyl, (heteroaryl)oyl, heterocycle, and
(heterocycle)alkyl,
[0096] wherein the groups defining R.sup.5 can be optionally
substituted with 1-5 substituents independently selected from
alkyl, alkoxy, carboxy, azido, carboxaldehyde, halo, hydroxy,
perfluoroalkyl, perfluoroalkoxy, and amino;
[0097] R.sup.6 is selected from
[0098] (a) hydrogen,
[0099] (b) alkyl,
[0100] wherein the alkyl can be optionally substituted with 1-5
substituents independently selected from alkoxy, carboxy, azido,
carboxaldehyde, halo, hydroxy, perfluoroalkyl, and
perfluoroalkoxy;
[0101] (c) cycloalkyl, cycloalkylalkyl, aryl, heteroaryl,
heteroarylalkyl, heterocycle, and (heterocycle)alkyl;
[0102] 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
[0103] R.sup.7 is selected from
[0104] (a) alkyl,
[0105] wherein the alkyl can be optionally substituted with 1-5
substituents independently selected from alkoxy, carboxy, azido,
carboxaldehyde, halo, hydroxy, perfluoroalkyl, and
perfluoroalkoxy,
[0106] (b) cycloalkyl, cycloalkylalkyl, aryl, heteroaryl,
heteroarylalkyl, heterocycle, and (heterocycle)alkyl;
[0107] 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.
[0108] all of the foregoing with the proviso that when A is phenyl
and R.sup.4 is NHR.sup.5 wherein R.sup.5 is alkanoyl, R.sup.3 is
not unsubstituted alkyl.
[0109] In another embodiment of the invention is disclosed a method
for treating bacterial infections, psoriasis, arthritis, and
toxicity due to chemotherapy in a patient comprising administering
to the patient a therapeutically acceptable amount of a compound of
formula (I) 7
[0110] or a therapeutically acceptable salt or prodrug thereof,
wherein
[0111] A is selected from
[0112] (a) phenyl,
[0113] (b) a five-membered aromatic ring containing one or two
atoms selected from N, O, and S, and the remaining atoms are
carbon,
[0114] wherein the groups defining (b) are substituted on a
substitutable carbon or nitrogen atom in the ring, and
[0115] (c) a six-membered aromatic ring containing one or two
nitrogen atoms, and the remaining atoms are carbon;
[0116] wherein the groups defining (c) are substituted on a
substitutable carbon atom in the ring;
[0117] R.sup.1 and R.sup.2 are independently selected from
hydrogen, alkyl, cycloalkyl, hydroxy, amino, halo, haloalkyl, and
perfluoroalkyl;
[0118] R.sup.3 is selected from
[0119] (a) alkyl, alkanoyl, carboxamido, cycloalkyl,
cyclothioalkoxy, cycloalkylsulfinyl, cycloalkoxycarbonyl,
alkylsulfonyl, alkoxycarbonyl, cycloalkenyl,
cycloalkenylsulfonyl,
[0120] 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,
[0121] (b) aryl, arylalkyl, arylthio, arylsulfinyl,
aryloxycarbonyl, heteroaryl, heteroarylalkyl, heteroarylsulfonyl,
heteroaryloxycarbonyl, heterocycle, (heterocycle)alkyl,
(heterocycle)sulfonyl, and (heterocycle)oxycarbonyl,
[0122] 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,
[0123] 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;
[0124] R.sup.4 is selected from NHR.sup.5, N(R.sup.6)C(O)OR.sup.7,
N(R.sup.6)C(O)N(R.sup.6).sub.2, OR.sup.7, SR.sup.7, S(O)R.sup.7,
and SO.sub.2R.sup.7;
[0125] R.sup.5 is selected from alkanoyl, aryloyl, thioalkanoyl,
heteroaryl, heteroarylalkyl, (heteroaryl)oyl, heterocycle, and
(heterocycle)alkyl,
[0126] wherein the groups defining R.sup.5 can be optionally
substituted with 1-5 substituents independently selected from
alkyl, alkoxy, carboxy, azido, carboxaldehyde, halo, hydroxy,
perfluoroalkyl, perfluoroalkoxy, and amino;
[0127] R.sup.6 is selected from
[0128] (a) hydrogen,
[0129] (b) alkyl,
[0130] wherein the alkyl can be optionally substituted with 1-5
substituents independently selected from alkoxy, carboxy, azido,
carboxaldehyde, halo, hydroxy, perfluoroalkyl, and
perfluoroalkoxy;
[0131] (c) cycloalkyl, cycloalkylalkyl, aryl, heteroaryl,
heteroarylalkyl, heterocycle, and (heterocycle)alkyl;
[0132] 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
[0133] R.sup.7 is selected from
[0134] (a) alkyl,
[0135] wherein the alkyl can be optionally substituted with 1-5
substituents independently selected from alkoxy, carboxy, azido,
carboxaldehyde, halo, hydroxy, perfluoroalkyl, and
perfluoroalkoxy,
[0136] (b) cycloalkyl, cycloalkylalkyl, aryl, heteroaryl,
heteroarylalkyl, heterocycle, and (heterocycle)alkyl;
[0137] 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.
[0138] The present invention is also directed to compounds selected
from the group consisting of:
[0139]
N-(((5S)-3-(3-fluoro-4-(4-(carbomethoxyphenyl)ethynyl)phenyl)-2-oxo-
-1,3-oxazolidin-5-yl)methyl)acetamide,
[0140]
N-(((5S)-3-(3-fluoro-4-(1H-pyrrol-2-ylethynyl)phenyl)-2-oxo-1,3-oxa-
zolidin-5-yl)methyl)acetamide,
[0141]
N-(((5S)-3-(3-fluoro4-(7H-purin-6-ylethynyl)phenyl)-2-oxo-1,3-oxazo-
lidin-5-yl)methyl)acetamide,
[0142]
N-(((5S)-3-(4-((5-(aminosulfonyl)thien-2-yl)ethynyl)-3-fluorophenyl-
)-2-oxo-1,3-oxazolidin-5-yl)methyl)acetamide,
[0143] N-(((5S)-3-(3-fluoro-4-((1-oxo-2,3-dihydro- I
H-inden-5-yJ)ethynyl)phenyl)-2-oxo-1,3-oxazolidin-5-yl)methyl)acetamide,
[0144]
5-((4-((5S)-5-((acetylamino)methyl)-2-oxo-1,3-oxazolidin-3-yl)-2-fl-
uorophenyl)ethynyl)-2,3-dihydro-1-benzofuran-7-carboxylic acid,
[0145]
N-(((5S)-3-(4-((1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl)ethynyl)-3-f-
luorophenyl)-2-oxo-1,3-oxazolidin-5-yl)methyl)acetamide,
[0146]
N-(((5S)-3-(4-((5-cyanopyridin-3-yl)ethynyl)-3-fluorophenyl)-2-oxo--
1,3-oxazolidin-5-yl)methyl)acetamide,
[0147]
N-(((5S)-3-(3-fluoro-4-(18-naphthyridin-2-ylethynyl)phenyl)-2-oxo-1-
,3-oxazolidin-5-yl)methyl)acetamide,
[0148]
N-(((5S)-3-(3-fluoro-4-((4-(hydroxymethyl)phenyl)ethynyl)phenyl)-2--
oxo-1,3-oxazolidin-5-yl)methyl)acetamide,
[0149] N-(((5S)-3-(3-fluoro-4-(1,
8-naphthyridin-2-ylethynyl)phenyl)-2-oxo-
-1,3-oxazolidin-5-yl)methyl)acetamide,
[0150]
N-(((5S)-3-(3-fluoro-4-((4-methoxy-3-pyridinyl)ethynyl)phenyl)-2-ox-
o-1,3-oxazolidin-5-yl)methyl)acetamide,
[0151]
N-(((5S)-3-(4-((2-aminopyrimidin-5-yl)ethynyl)-3-fluorophenyl)-2-ox-
o-1,3-oxazolidin-5-yl)methyl)acetamide,
[0152]
N-(((5S)-3-(3-fluoro-4-(pyrimidin-5-ylethynyl)phenyl)-2-oxo-1,3-oxa-
zolidin-5-yl)methyl)acetamide,
[0153]
N-(((5S)-3-(4-((3-aminophenyl)ethynyl)-3-fluorophenyl)-2-oxo-1,3-ox-
azolidin-5-yl)methyl)acetamide, methyl
3-((4-((5S)-5-((acetylamino)methyl)-
-2-oxo-1,3-oxazolidin-3-yl)-2-fluorophenyl)ethynyl)benzoate,
[0154]
N-(3-(2-(4-((5S)-5-((acetylamino)methyl)-2-oxo-1,3-oxazolidin-3-yl)-
-2-fluorophenyl)ethynyl)phenyl)acetamide,
[0155]
N-(((5S)-3-(4-((3-(aminomethyl)phenyl)ethynyl)-3-fluorophenyl)-2-ox-
o-1,3-oxazolidin-5-yl)methyl)acetamide,
[0156]
N-(((5S)-3-(3-fluoro-4-((4-hydroxyphenyl)ethynyl)phenyl)-2-oxo-1,3--
oxazolidin-5-yl)methyl)acetamide, and
[0157]
N-(((5S)-3-(3-fluoro-4-((2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)et-
hynyl)phenyl)-2-oxo-1,3-oxazolidin-5-yl)methyl)acetamide.
[0158] As used throughout the specification, the following terms
have the meanings indicated:
[0159] The term "alkanoyl," as used herein, refers to an alkyl
group, as defined herein, attached to the parent molecular group
through a carbonyl group.
[0160] The term "alkanoyloxy," as used herein, refers to an
alkanoyl group, as defined herein, attached to the parent molecular
group through an oxygen atom.
[0161] The term "alkanoyloxyalkyl," as used herein, refers to an
alkyl group, as defined herein, to which is attached at least one
alkanoyloxy substituent.
[0162] The term "alkanoyloxyalkenyl," as used herein, refers to an
alkenyl group, as defined herein, to which is attached at least one
alkanoyloxy substituent.
[0163] The term "alkenyl," as used herein, refers to a monovalent
straight or branched chain hydrocarbon having from two to six
carbons and at least one carbon-carbon double bond.
[0164] The term "alkoxy," as used herein, refers to an alkyl group,
as defined herein, attached to the parent molecular group through
an oxygen atom.
[0165] The term "alkoxyalkyl," as used herein, refers to an alkyl
group, as defined herein, to which is attached at least one alkoxy
substituent.
[0166] The term "alkoxyalkenyl," as used herein, refers to an
alkenyl group, as defined herein, to which is attached at least one
alkoxy substituent.
[0167] The term "alkoxycarbonyl," as used herein, refers to an
alkoxy group, as defined herein, attached to the parent molecular
group through a carbonyl group.
[0168] The term "alkoxycarbonylalkyl," as used herein, refers to an
alkyl group, as defined herein, to which is attached at least one
alkoxycarbonyl substituent.
[0169] The term "alkoxycarbonylalkenyl," as used herein, refers to
an alkenyl group, as defined herein, to which is attached at least
one alkoxycarbonyl substituent.
[0170] The term "alkyl," as used herein, refers to a saturated,
monovalent straight or branched chain hydrocarbon having from one
to six carbons. The alkyl groups of this invention can be
optionally substituted with 1-5 substituents 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. The substituted aryl, substituted heteroaryl, and
substituted heterocycle groups substituting the alkyl groups of
this invention are substituted with at least one substituent
selected from alkyl, alkoxy, carboxy, azido, carboxaldehyde, halo,
hydroxy, perfluoroalkyl, and perfluoroalkoxy.
[0171] The term "alkylsulfinyl," as used herein, refers to an alkyl
group, as defined herein, attached to the parent molecular group
through an --S(O)-- group.
[0172] The term "alkylsulfinylalkyl," as used herein, refers to an
alkyl group, as defined herein, to which is attached at least one
alkylsulfinyl substituent.
[0173] The term "alkylsulfinylalkenyl," as used herein, refers to
an alkenyl group, as defined herein, to which is attached at least
one alkylsulfinyl substituent.
[0174] The term "alkylsulfonyl," as used herein, refers to an alkyl
group, as defined herein, attached to the parent molecular group
through a sulfonyl group.
[0175] The term "alkylsulfonylalkyl," as used herein, refers to an
alkyl group, as defined herein, to which is attached at least one
alkylsulfonyl substituent.
[0176] The term "alkylsulfonylalkenyl," as used herein, refers to
an alkenyl group, as defined herein, to which is attached at least
one alkylsulfonyl substituent.
[0177] The term "amino," as used herein, refers to --NH.sub.2 or
derivatives thereof formed by independent replacement of one or
both hydrogen atoms thereon with a substituent or substituents
independently selected from alkyl, alkanoyl, aryl, arylalkyl,
cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, and an
amino protecting group.
[0178] The term "aminoalkyl," as used herein, refers to an alkyl
group, as defined herein, to which is attached at least one amino
substituent.
[0179] The term "aminoalkenyl," as used herein, refers to an
alkenyl group, as defined herein, to which is attached at least one
amino substituent.
[0180] The terms "amino protecting group," or "nitrogen protecting
group," as used herein, refer to selectively introducible and
removable groups which protect amino groups against undesirable
side reactions during synthetic procedures. Examples of amino
protecting groups include methoxycarbonyl, ethoxycarbonyl,
trichloroethoxycarbonyl, benzyloxycarbonyl (Cbz), chloroacetyl,
trifluoroacetyl, phenylacetyl, benzoyl (Bn), benzyl (Bz),
dimethoxybenzyl, tert-butoxycarbonyl (Boc),
para-methoxybenzyloxycarbonyl, isopropoxycarbonyl, phthaloyl,
succinyl, diphenylmethyl, triphenylmethyl (trityl),
methanesulfonyl, para-toluenesulfonyl, trimethylsilyl,
triethylsilyl, triphenylsilyl, and the like. Preferred amino or
nitrogen protecting groups of this invention are phthalyl and
2,4-dimethoxybenzyl. Amino protecting group can also be used as
prodrug-forming groups.
[0181] The term "aminosulfonyl," as used herein, refers to an amino
group, as defined herein, attached to the parent molecular group
through a sulfonyl group.
[0182] The term "arylsulfonylalkyl," as used herein, refers to an
alkyl group, as defined herein, to which is attached at least one
arylsulfonyl substituent.
[0183] The term "arylsulfonylalkenyl," as used herein, refers to an
alkenyl group, as defined herein, to which is attached at least one
arylsulfonyl substituent.
[0184] The term "aryl," as used herein, refers to groups containing
at least one aromatic, carbocyclic ring. Aryl groups of this
invention are exemplified by phenyl, naphthyl, indenyl, indanyl,
dihydronaphthyl, tetrahydronaphthyl, and the like. The aryl groups
of this invention 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. The substituted aryl,
heteroaryl, and heterocycle groups substituting the aryl groups of
this invention are substituted with at least one substituent
selected from alkyl, alkoxy, carboxy, azido, carboxaldehyde, halo,
hydroxy, perfluoroalkyl, and perfluoroalkoxy.
[0185] The term "arylalkyl," as used herein, refers to an alkyl
group, as defined herein, to which is attached at least one aryl
substituent.
[0186] The term "arylalkenyl," as used herein, refers to an alkenyl
group, as defined herein, to which is attached at least one aryl
substituent.
[0187] The term "aryloyl," as used herein, refers to an aryl group,
as defined herein, attached to the parent molecular group through a
carbonyl group.
[0188] The term "arylsulfinyl," as used herein, refers to an aryl
group, as defined herein, attached to the parent molecular group
through an --S(O)-- group.
[0189] The term "arylsulfinylalkyl," as used herein, refers to an
alkyl group, as defined herein, to which is attached at least one
arylsulfinyl substituent.
[0190] The term "arylsulfinylalkenyl," as used herein, refers to an
alkenyl group, as defined herein, to which is attached at least one
arylsulfonyl substituent.
[0191] The term "arylsulfonyl," as used herein, refers to an alkyl
group, as defined herein, attached to the parent molecular group
through a sulfonyl group.
[0192] The term "arylsulfonylalkyl," as used herein, refers to an
alkyl group, as defined herein, to which is attached at least one
arylsulfonyl substituent.
[0193] The term "arylsulfonylalkenyl," as used herein, refers to an
alkenyl group, as defined herein, to which is attached at least one
arylsulfonyl substituent.
[0194] The term "arylthio," as used herein, refers to an aryl
group, as defined herein, attached to the parent molecular group
through a sulfur atom.
[0195] The term "azido," as used herein, refers to --N.sub.3.
[0196] The term "carbonyl," as used herein, refers to
--C(.dbd.O)--.
[0197] The term "carboxamido," as used herein, refers to an amide;
e.g., an amino group, as defined herein, attached to the parent
molecular group through a carbonyl group.
[0198] The term "carboxamidoalkyl," as used herein, refers to an
alkyl group, as defined herein, to which is attached at least one
carboxamido substituent.
[0199] The term "carboxamidoalkenyl," as used herein, refers to an
alkenyl group, as defined herein, to which is attached at least one
carboxamido substituent.
[0200] The term "carboxy," as used herein, refers to --CO.sub.2H or
a derivative thereof formed by replacement of the hydrogen atom
thereon by a carboxy protecting group.
[0201] The term "carboxyalkyl," as used herein, refers to an alkyl
group, as defined herein, to which is attached at least one carboxy
substituent.
[0202] The term "carboxyalkenyl," as used herein, refers to an
alkenyl group, as defined herein, to which is attached at least one
carboxy substituent.
[0203] The term "carboxy protecting group," as used herein, refers
to selectively introducible and removable groups which protect
carboxy groups against undesirable side reactions during synthetic
procedures and includes all conventional carboxy protecting groups.
Examples of carboxy protecting groups include methyl, ethyl,
n-propyl, isopropyl, 1,1-dimethylpropyl, n-butyl, tert-butyl,
phenyl, naphthyl, benzyl, diphenylmethyl, triphenylmethyl (trityl),
para-nitrobenzyl, para-methoxybenzyl, acetylmethyl, benzoylmethyl,
para-nitrobenzoylmethyl, para-bromobenzoylmethyl,
2-tetrahydropyranyl, 2-tetrahydrofuranyl, 2,2,2-trichloroethyl,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxymethyl,
methoxyethoxymethyl, arylalkoxyalkyl, benzyloxymethyl,
1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, and the like.
Carboxy protecting group can also be used as prodrug-forming
groups.
[0204] The term "cyano," as used herein, refers to --CN.
[0205] The term "cyanoalkyl," as used herein, refers to an alkyl
group, as defined herein, to which is attached at least one cyano
substituent.
[0206] The term "cyanoalkenyl," as used herein, refers to an
alkenyl group, as defined herein, to which is attached at least one
cyano substituent. The term "cycloalkenyl," as used herein, refers
to a monovalent cyclic or bicyclic hydrocarbon of three to fifteen
carbons and at least one carbon-carbon double bond.
[0207] The term "cycloalkenylsulfinyl," as used herein, refers to a
cycloalkenyl group, as defined herein, attached to the parent
molecular group through a --S(O)-- group.
[0208] The term "cycloalkenylsulfonyl," as used herein, refers to a
cycloalkenyl group, as defined herein, attached to the parent
molecular group through a --S(O).sub.2- group.
[0209] The term "cycloalkoxy," as used herein, refers to a
cycloalkyl group, as defined herein, attached to the parent
molecular group through an oxygen atom.
[0210] The term "cycloalkoxycarbonyl," as used herein, refers to an
cycloalkoxy group, as defined herein, attached to the parent
molecular group through a carbonyl group.
[0211] The term "cycloalkyl," as used herein, refers to a
monovalent saturated cyclic or bicyclic hydrocarbon of three to
fifteen carbons. The cycloalkyl groups of this invention 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. The substituted aryl, substituted
heteroaryl, and substituted heterocycle substituting the cycloalkyl
groups of this invention are substituted with 1-5 substituents
independently selected from alkyl, alkoxy, carboxy, azido,
carboxaldehyde, halo, hydroxy, perfluoroalkyl, and
perfluoroalkoxy.
[0212] The term "cycloalkylsulfinyl," as used herein, refers to a
cycloalkyl group, as defined herein, attached to the parent
molecular group through an --S(O)-- group.
[0213] The term "cycloalkylsulfonyl," as used herein, refers to a
cycloalkyl group, as defined herein, attached to the parent
molecular group through an --SO.sub.2-- group.
[0214] The term "cycloalkylalkyl," as used herein, refers to an
alkyl group, as defined herein, to which is attached at least one
cycloalkyl substituent.
[0215] The term "cycloalkylalkenyl," as used herein, refers to an
alkenyl group, as defined herein, to which is attached at least one
cycloalkyl substituent.
[0216] The term "cyclothioalkoxy," as used herein, refers to a
cycloalkyl group, as defined herein, attached to the parent
molecular group through a sulfur atom.
[0217] The term "halo" as used herein, refers to F, Cl, or Br.
[0218] The term "haloalkyl," as used herein, refers to an alkyl
group, as defined herein, to which is attached at least one halo
substituent.
[0219] The term "haloalkenyl," as used herein, refers to an alkenyl
group, as defined herein, to which is attached at least one halo
substituent.
[0220] The term "heteroaryl," as used herein, refers to cyclic,
aromatic five- and six-membered groups, wherein at least one atom
is selected from the group consisting of N, O, and S, and the
remaining atoms are carbon. The five-membered rings have two double
bonds, and the six-membered rings have three double bonds. The
heteroaryl groups of the invention are connected to the parent
molecular group through a substitutable carbon or nitrogen in the
ring. Heteroaryls are exemplified by furanyl, thienyl, pyrrolyl,
oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl,
oxadiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl,
pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, triazinyl, and the
like. The heteroaryl groups of this invention can be fused to an
aryl group, a heterocycle, or another heteroaryl. The heteroaryl
groups of this invention 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. The substituted aryl,
heteroaryl, and heterocycle substituting the heteroaryl groups of
this invention are substituted with at least one substituent
selected from alkyl, alkoxy, carboxy, azido, carboxaldehyde, halo,
hydroxy, perfluoroalkyl, and perfluoroalkoxy.
[0221] The term "heteroarylalkyl," as used herein, refers to an
alkyl group, as defined herein, to which is attached at least one
heteroaryl substituent.
[0222] The term "heteroarylalkenyl," as used herein, refers to an
alkenyl group, as defined herein, to which is attached at least one
heteroaryl substituent.
[0223] The term "(heteroaryl)oyl," as used herein, refers to a
heteroaryl group, as defined herein, attached to the parent
molecular group through a carbonyl.
[0224] The term "heterocycle," as used herein, refers to cyclic,
non-aromatic, four-, five-, six-, or seven-membered rings
containing at least one atom selected from the group consisting of
oxygen, nitrogen, and sulfur. The four-membered rings have zero
double bonds, the five-membered rings have zero or one double
bonds, and the six- and seven-membered rings have zero, one, or two
double bonds. Heterocycle groups of the invention are exemplified
by dihydropyridinyl, morpholinyl, piperazinyl, pyrrolidinyl,
tetrahydropyridinyl, piperidinyl, thiomorpholinyl, 1,3-dioxolanyl,
1,4-dioxanyl, 1,3-dioxanyl, and the like. The heterocycle groups of
this invention can be fused to an aryl group or a heteroaryl group.
The heterocycle groups of the invention are connected to the parent
molecular group through a substitutable carbon or nitrogen atom in
the heterocycle ring or the aryl or hereroaryl ring to which it is
fused. The heterocycle groups of this invention 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. The substituted aryl,
heteroaryl, and heterocycle groups substituting the heterocycle
groups of this invention are substituted with at least one
substituent selected from alkyl, alkoxy, carboxy, azido,
carboxaldehyde, halo, hydroxy, perfluoroalkyl, and
perfluoroalkoxy.
[0225] The term "(heterocycle)alkyl," as used herein, refers to an
alkyl group, as defined herein, to which is attached at least one
heterocycle substituent.
[0226] The term "(heterocycle)oxy," as used herein, refers to a
heterocycle, as defined herein, connected to the parent molecular
group through an oxygen atom.
[0227] The term "(heterocycle)oxycarbonyl," as used herein, refers
to a (heterocycle)oxy group, as defined herein, connected to the
parent molecular group through a carbonyl group.
[0228] The term "(heterocycle)sulfinyl," as used herein, refers to
a heterocycle group, as defined herein, connected to the parent
molecular group through an --S(O)-- group.
[0229] The term "(heterocycle)sulfonyl," as used herein, refers to
a heterocycle group, as defined herein, connected to the parent
molecular group through an --SO.sub.2-- group.
[0230] The term "hydroxy," as used herein, refers to --OH or a
derivative thereof formed by replacement of the hydrogen atom
thereon with a hydroxy protecting group.
[0231] The term "hydroxyalkyl," as used herein, refers to an alkyl
group, as defined herein, to which is attached at least one hydroxy
substituent.
[0232] The term "hydroxyalkenyl," as used herein, refers to an
alkenyl group, as defined herein, to which is attached at least one
hydroxy substituent.
[0233] The term "hydroxy protecting group," as used herein, refers
to selectively introducible and removable groups which protect
hydroxy groups against undesirable side reactions during synthetic
procedures. Examples of hydroxy protecting groups include
benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl,
4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,
methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl,
diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbony- l,
2-(trimethylsilyl)-ethoxycarbonyl, 2-furfuryloxycarbonyl,
allyloxycarbonyl, acetyl, formyl, chloroacetyl, trifluoroacetyl,
methoxyacetyl, phenoxyacetyl, benzoyl, methyl, tert-butyl,
2,2,2-trichloroethyl, 2-trimethylsilylethyl,
1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, benzyl,
para-methoxybenzyldiphenylmethyl, triphenylmethyl (trityl),
tetrahydrofuryl methoxymethyl, methylthiomethyl, benzyloxymethyl,
2,2,2-trichloroethoxymethyl, 2-(trimethylsilyl)ethoxymethyl,
methanesulfonyl, para-toluenesulfonyl, trimethylsilyl,
triethylsilyl, triisopropylsilyl, and the like. Hydroxy protecting
group can also be used as prodrug-forming groups.
[0234] The term "oxo," as used herein, refers to a group formed by
the replacement of two hydrogen atoms on the same carbon atom with
a single oxygen atom.
[0235] The term "perfluoroalkoxy," as used herein, refers to a
perfluoroalkyl group attached to the parent group through an oxygen
atom.
[0236] The term "perfluoroalkoxyalkyl," as used herein, refers to
an alkyl group, as defined herein, to which is attached at least
one perfluoroalkoxy substituent.
[0237] The term "perfluoroalkoxyalkenyl," as used herein, refers to
an alkenyl group, as defined herein, to which is attached at least
one perfluoroalkoxy substituent.
[0238] The term "perfluoroalkyl," as used herein, refers to an
alkyl group in which all of the hydrogen atoms have been replaced
with fluorine atoms.
[0239] The term "thioalkanoyl," as used herein, refers to an alkyl
group, as defined herein, connected to the parent molecular group
through a thiocarbonyl.
[0240] The term "thioalkoxy," as used herein, refers to an alkyl
group, as defined herein, attached to the parent molecular group
through a sulfur atom.
[0241] The term "thioalkoxyalkyl," as used herein, refers to an
alkyl group, as defined herein, to which is attached at least one
thioalkoxy substituent.
[0242] The term "thioalkoxyalkenyl," as used herein, refers to an
alkenyl group, as defined herein, to which is attached at least one
thioalkoxy substituent.
[0243] The term "thiocarbonyl," as used herein, refers to
--C(.dbd.S)--.
[0244] The term "thiocycloalkenyloxy," as used herein, refers to a
cycloalkenyl group, as defined herein, attached to the parent
molecular group through a sulfur atom.
[0245] The compounds of the invention can exist as therapeutically
acceptable salts. The term "therapeutically acceptable salt," as
used herein, refers to salts or zwitterionic forms of the compounds
of the invention which are water or oil-soluble or dispersible,
which are suitable for treatment of diseases without undue
toxicity, irritation, and allergic response, which are commensurate
with a reasonable benefit/risk ratio, and which are effective for
their intended use. The salts can be prepared during the final
isolation and purification of the compounds or separately by
reacting an amino group with a suitable acid. Representative acid
addition salts include acetate, adipate, alginate, citrate,
aspartate, benzoate, benzenesulfonate, bisulfate, butyrate,
camphorate, camphorsulfonate, digluconate, glycerophosphate,
hemisulfate, heptanoate, hexanoate, formate, fumarate,
hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate
(isethionate), lactate, maleate, mesitylenesulfonate,
methanesulfonate, naphthylenesulfonate, nicotinate,
2-naphthalenesulfonate, oxalate, palmoate, pectinate, persulfate,
3-phenylpropionate, picrate, pivalate, propionate, succinate,
tartrate, trichloroacetic, trifluoroacetic, phosphate, glutamate,
bicarbonate, para-toluenesulfonate, and undecanoate. Also, amino
groups in the compounds of the invention can be quaternized with as
methyl, ethyl, propyl, and butyl chlorides, bromides and iodides;
dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl,
myristyl, and stearyl chlorides, bromides, and iodides; benzyl and
phenethyl bromides. Examples of acids which can be employed to form
therapeutically acceptable acid addition salts include inorganic
acids such as hydrochloric, hydrobromic, sulphuric, and phosphoric
and organic acids such as oxalic, maleic, succinic, and citric.
[0246] Basic addition salts can be prepared during the final
isolation and purification of the compounds by reacting a carboxy
group with a suitable base such as the hydroxide, carbonate, or
bicarbonate of a metal cation or with ammonia or an organic
primary, secondary or tertiary amine. Therapeutically acceptable
salts cations based on lithium, sodium, potassium, calcium,
magnesium, and aluminum and nontoxic quaternary ammonia and amine
cations such as ammonium, tetramethylammonium, tetraethylammonium,
methylamine, dimethylamine, trimethylamine, triethylamine,
diethylamine, ethylamine, tributylamine, pyridine,
N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine,
dicyclohexylamine, procaine, dibenzylamine,
N,N-dibenzylphenethylamine, 1-ephenamine, and
N,N'-dibenzylethylenediamine. Other representative organic amines
useful for the formation of base addition salts include
ethylenediamine, ethanolamine, diethanolamine, piperidine, and
piperazine.
[0247] The term "sulfonyl," as used herein, refers to
--SO.sub.2--.
[0248] In accordance with pharmaceutical compositions and methods
of treatment, the compounds can be administered alone or in
combination with other antibacterial, anti-psoriasis,
anti-arthritis, and anti-chemotherapeutic toxicity agents. The
therapeutically effective dose level depends on factors such as the
disorder being treated and the severity of the disorder; the
activity of the compound used; the composition employed; the age,
body weight, general health, sex, and diet of the patient; the time
of administration; the route of administration; the rate of
excretion of the compound; the duration of treatment; and drugs
used in combination with or coincidentally with the compounds. The
compounds can be administered orally, parenterally, nasally,
rectally, vaginally, or topically in unit dosage formulations
containing therapeutically acceptable excipients such as carriers,
adjuvants, diluents, vehicles, or combinations thereof. The term
"parenteral" includes infusion, subcutaneous, intravenous,
intramuscular, and intrastemal injection.
[0249] The antibacterial, anti-psoriasis, anti-arthritis, and
anti-chemotherapeutic toxicity effect of parenterally administered
compounds can be controlled by slowing their absorption, such as,
for example, by administration of injectable suspensions of
crystalline, amorphous, or otherwise water-insoluble forms of the
compounds; administration of the compounds as oleaginous solutions
or suspensions; or administration of microencapsulated matrices of
the compounds trapped within liposomes, microemulsions, or
biodegradable polymers. In each case, the ratio of compound to
excipient and the nature of the excipient influences the rate of
release of the compound. Transdermal patches also provide
controlled delivery of compounds using rate-controlling membranes.
Conversely, absorption enhancers can be used to increase absorption
of the compounds.
[0250] Solid dosage forms for oral administration of the compounds
include capsules, tablets, pills, powders, and granules. These
compositions can contain diluents, lubricants, and buffering
agents. Tablets and pills can be prepared with release-controlling
coatings, and sprays can optionally contain propellants.
[0251] Liquid dosage forms for oral administration of the compounds
include emulsions, microemulsions, solutions, suspensions, syrups,
and elixirs. These compositions can also contain adjuvants such as
wetting, emulsifying, suspending, sweetening, flavoring, and
perfuming agents.
[0252] Topical dosage forms of the compounds include ointments,
pastes, creams, lotions, gels, powders, solutions, sprays, and
inhalants. Suppositories for rectal or vaginal administration
comprise compounds with a suitable nonirritating excipient.
Ophthalmic formulations such as eye drops and eye are also
contemplated as being within the scope of this invention.
[0253] The total daily dose of the compounds administered to a
patient in single or divided doses can be in amounts from about 0.1
to about 200 mg/kg body weight or preferably from about 0.25 to
about 100 mg/kg body weight. Single dose compositions contain these
amounts or submultiples thereof to make up the daily dose.
[0254] Determination of Antibacterial Activity
[0255] The minimum inhibitory concentrations (MIC's) of the
compounds for the microorganisms listed in Table 1 were determined
by the procedure described in National Committee for Clinical
Laboratory Standards. 2000. Methods for Dilution Antimicrobial
Susceptibility Tests for Bacteria That Grow Aerobically, 5th ed.
Approved Standard: M7-A5 (NCCLS, Wayne, PA). Briefly, the compounds
were dissolved in DMSO to 2 mg/mL and diluted in the appropriate
susceptibility test medium to a concentration of 256 .mu.g/mL.
Serial two-fold dilutions were made in microtiter plates to achieve
a final volume of 50 .mu.L. Inocula for each organism were prepared
by making a standard suspension in sterile saline with turbidity
equivalent to that of a 0.5 McFarland Standard from an 18 to 24
hour culture grown on agar plates at 35.degree. C. The standard
suspension of each organism was diluted 100-fold in the appropriate
medium and further diluted 2-fold by adding 50 .mu.L to the medium
containing antibiotic to achieve a final density of
5.times.10.sup.5 CFU/mL. Microdilution plates were incubated for 16
to 20 hours at 35.degree. C. in ambient air. Each plate was
visually inspected, and MIC's were recorded as the lowest
concentration of drug which yielded no growth, a slight haze, or
sparsely isolated colonies on the inoculum spot as compared to the
growth control. The compounds inhibited the growth of these
bacteria with MIC's in a range of about 1 .mu.g/mL to about 64
.mu.g/mL; in a more preferred range, the compounds inhibited the
growth of bacteria with MIC's in a range of about 1 .mu.g/mL to
about 8 .mu.g/mL; and in a most preferred range, the compounds
inhibited the growth of bacteria with MIC's in a range of about 1
.mu.g/mL to about 4 .mu.g/mL.
[0256] Thus, the compounds are useful for treating bacterial
infections for which these microorganisms are responsible.
1 TABLE 1 Microorganism Staphylococcus aureus NCTC10649M
Staphylococcus epidermidis 3519 Moraxella catarrhalis 2604
Enterococcus faecium ATCC GYR 1632 Streptococcus pneumonia
ATCC6303
[0257] Preparation of the Compounds of the Invention
[0258] The compounds can be prepared by employing reactions shown
in Schemes 1-4. It will be readily apparent to one of ordinary
skill in the art that the compounds can be synthesized by
substitution of the appropriate reactants in these syntheses, and
that the steps themselves can be conducted in varying order. It
will also be apparent that protection and deprotection steps can be
performed to successfully complete the syntheses of the compounds.
A thorough discussion of protecting groups is provided in
Protective Groups in Organic Synthesis, 3rd edition, John Wiley
& Sons, New York (1999).
[0259] Abbreviations used in the schemes and the examples are as
follows: BINAP for 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl; DME
for dimethoxyethane; DMF for N,N-dimethylformamide; DMSO for
dimethylsulfoxide; m-CPBA for meta-chloroperbenzoic acid; THF for
tetrahydrofuran; PCC for pyridinium chlorochromate; PDC for
pyridinium dichromate; DEAD for diethyl azodicarboxylate; DIAD for
diisopropyl azodicarboxylate. 8
[0260] Conversion of 5-(hydroxymethyl)-1,3-oxazolidin-2-one (i) to
compounds of formula (v) can be accomplished by treatment of the
former with a hydroxyl activating group precursor such as
para-toluenesulfonyl chloride (R.sup.C is 4-methylphenyl),
methanesulfonyl chloride (R.sup.C is methyl),
2-nitrobenzenesulfonyl chloride (RC is 2-nitrophenyl), or
trifluoromethanesulfonyl chloride (R.sup.C is trifluoromethyl) and
a base such as diisopropylethylamine, pyridine, triethylamine,
sodium carbonate, potassium carbonate, or cesium carbonate,
followed by treatment of the compounds of formula (v) with the
appropriate R.sup.4 introduction agent. For example, compounds of
formula (vi) can be obtained by treatment of compounds of formula
(v) with compounds of formula (M).sup.+(XR.sup.7).sup.- wherein M
is lithium, sodium or potassium, and X is O or S. The reactions are
conducted at about 0.degree. C. to about 30.degree. C.; and the
reaction times are from about 1 to about 24 hours. Solvents useful
for this reaction include benzene, toluene, THF, dioxane, DME, or
mixtures thereof.
[0261] Conversion of compounds of formula (vi), wherein X is S, to
compounds wherein X is S(O) or SO.sub.2 can be accomplished by
treatment of the former with a oxidizing agent such as m-CPBA,
potassium permanganate, or potassium peroxymonosulfate
(Oxone.RTM.). The reactions are conducted at about 0.degree. C. to
about 30.degree. C.; and the reaction times are from about 1 to
about 10 hours, each depending on the degree of oxidation desired.
Solvents useful for this reaction include benzene, toluene, THF,
dioxane, dichloromethane, chloroform, DMe, or mixtures thereof.
[0262] Conversion of compounds of formula (v) to compounds of
formula (iii) can be accomplished by treatment of the former with
an excess of the appropriately substituted amine wherein R.sup.A
and R.sup.B are independently selected from hydrogen or
unsubstituted or substituted alkyl, aryl, arylalkyl, cycloalkyl,
cycloalkylalkyl, heteroaryl, and heteroarylalkyl. The reactions are
conducted at about 20.degree. C. to about 110.degree. C.; and the
reaction times are from about 1 to about 24 hours. Solvents useful
for this reaction include the amines themselves, benzene, toluene,
THF, dioxane, acetonitrile, DME, DMSO, or mixtures thereof.
[0263] Conversion of compounds of formula (v) to compounds of
formula (iii) can be accomplished by treatment of the former with
compounds of formula (M).sup.+(NR.sup.AR.sup.B) wherein R.sup.A and
R.sup.B, together with the nitrogen to which they are attached, are
phthalimide and M is Na or K. The reactions are conducted at about
0.degree. C. to about 50.degree. C.; and the reaction times are
from about 1 to about 24 hours. Solvents useful for this reaction
include dichloromethane, toluene, THF, dioxane, DME, DMF, or
mixtures thereof.
[0264] Conversion of compounds of formula (i) to compounds of
formula (iii) can also be accomplished by treatment of the former
with phthalimide under Mitsunobu conditions (triphenylphosphine and
DEAD or DIAD). The reactions are conducted at about -10.degree. C.
to about 30.degree. C.; and the reaction times are from about 1 to
about 10 hours. Solvents useful for this reaction include benzene,
toluene, THF, dioxane, DME, dichloromethane, chloroform, or
mixtures thereof.
[0265] Conversion of compounds of formula (iii), wherein R.sup.A
and R.sup.B, together with the nitrogen to which they are attached,
are phthalimide, to compounds of formula (iv) can be accomplished
by treatment of the former with hydrazine. The reactions are
conducted at about 50.degree. C. to about 110.degree. C.; and the
reaction times are from about 1 to about 10 hours. Solvents useful
for this reaction include ethanol, toluene, THF, dioxane, DME, or
mixtures thereof. 9
[0266] Conversion of compounds of formula (x) to compounds of
formula (xii) can be accomplished by treatment of the former with
compounds of formula (xi), a palladium catalyst such as
tris(dibenzylideneacetone)dipa- lladium, palladium(II) acetate,
bis(triphenylphosphine)palladium(II) chloride, or
tetrakis(triphenylphosphine)palladium, and, optionally, an additive
such as tributylphosphine, triphenylphosphine,
(2-(diphenylphosphino)ethyl)(diphenyl)phosphine,
(3-(diphenylphosphino)pr- opyl)(diphenyl)phosphine,
tri-tert-butylphosphine or BINAP, and a base such as sodium
carbonate, potassium carbonate, or cesium carbonate. The reactions
are conducted at about 50.degree. C. to about 110.degree. C.; and
the reaction times are from about 1 to about 24 hours. Solvents
useful for this reaction include benzene, toluene, THF, dioxane,
DME, water or mixtures thereof.
[0267] As shown in Scheme 3, conversion of compounds of formula
(xii) to compounds of formula (xiii) can be accomplished by
treatment of the former with carbon tetrabromide and
triphenylphosphine or polystyrene-supported triphenylphosphine. The
reactions are typically conducted at about -15.degree. C. to about
0.degree. C.; and the reaction times are typically from about I to
about 5 hours. Solvents useful for this reaction include
dichloromethane, and chloroform.
[0268] Conversion of compounds of formula (xiii) to compounds of
formula (lb) can be accomplished by treatment of the former with
compounds of formula M.sup.1-R.sup.3 (M.sup.1 is trialkyl or
triarylstannyl, boronic acid or ester, zinc, or zirconium; and
R.sup.3 is unsubstituted or substituted aryl, unsubstituted or
substituted heteroaryl, unsubstituted or substituted alkenyl, or
unsubstituted or substituted cycloalkenyl), a palladium catalyst
such as tris(dibenzylideneacetone)dipalladium,
trans-dichlorobis(triphenylphosphine)palladium(II),
palladium(II)acetate or tetrakis(triphenylphosphine)palladium, and,
optionally, an additive such as tributylphosphine,
triphenylphosphine, triphenylarsine, tri-t-butylphosphine,
tri-2-furylphosphine (2-(diphenylphosphino)ethyl)(d-
iphenyl)phosphine,
(3-(diphenylphosphino)propyl)(diphenyl)phosphine, or BINAP, and a
base such as sodium carbonate, potassium carbonate, or cesium
carbonate. The reactions are conducted at about 50.degree. C. to
about 110.degree. C.; and the reaction times are from about 1 to
about 48 hours. Solvents useful for this reaction include benzene,
toluene, THF, dioxane, DME, water or mixtures thereof. 10
[0269] Conversion of compounds of formula (xii) to compounds of
formula (Ic), can be accomplished by treatment of the former with
compounds of formula (xiv) (where R.sup.C is methyl or ethyl and
R.sup.D is H or alkanoyl), a base such as potassium tert-butoxide,
sodium tert-butoxide, potassium carbonate, sodium carbonate,
potassium bis(trimethyl)silyl amide in a solvent such as methanol,
THF, dioxane or mixtures thereof. The reactions are typically
conducted at about -78.degree. C. to about 40.degree. C.; and the
reaction times are typically from about 1 to about 36 hours (Synth.
Commun. 1989, 19, 561-564 and J. Org. Chem. 1971, 36,
1379-1385).
[0270] Conversion of compounds of formula (Ic) to compounds of
formula (Ib) can be accomplished by treatment of the former with
compounds of formula R.sup.3-Q.sup.1 (R.sup.3 is unsubstituted or
substituted alkenyl, unsubstituted or substituted cycloalkenyl,
unsubstituted or substituted aryl or unsubstituted or substituted
heteroaryl, and Q.sup.1 is bromide, iodide, or
trifluoromethanesulfonate), a palladium catalyst such as
tris(dibenzylideneacetone)dipalladium, palladium(II) acetate,
transdichlorobis(triphenylphosphine)palladium(II), or
tetrakis(triphenylphosphine)palladium, and, optionally, an additive
such as triphenylphosphine or tri-tert-butylphosphine and
optionally a co-catalyst such as copper(I) iodide and optionally a
base such as n-butyl amine, diethyl amine, triethyl amine,
diisopropyl amine, or piperidine. The reactions are conducted at
about 25.degree. C. to about 110.degree. C.; and the reaction times
are from about 1 to about 48 hours. Solvents useful for this
reaction include toluene, DMF, THF, N-methyl pyrrolidine, dioxane,
diethyl ether or mixtures thereof. 11
[0271] Conversion of compounds of formula (Ic) to compounds of
formula (Id), can be accomplished by treatment of the former with a
base such as n-butyl lithium, lithium diisopropylamide, sodium
bis(trimethyl)silyl amide, lithium bis(trimethyl)silyl amide then
with compounds of formula R.sup.3-X.sup.1-Q.sup.2 (wherein Q.sup.2
is Cl, Br, I, arylsulfonate or alkylsulfonate and X is a covalent
bond or C(O)), in a solvent such as THF, DME, dioxane or mixtures
thereof. The reactions are typically conducted at about -78.degree.
C. to about 40.degree. C.; and the reaction times are typically
from about 1 to about 24 hours.
[0272] In addition to the chemistry discussed above, other standard
manipulations can be used to prepare compounds of the invention.
Amino groups can be reacted with acid chlorides, acid anhydrides,
isocyanates, chloroformates, and aldehydes under reductive
alkylation conditions (sodium borohydride, sodium cyanoborohydride)
to provide variety of substituent groups. Carboxamido groups can be
reacted with Lawesson's reagent or P.sub.4S.sub.10Na.sub.2CO.sub.3
to provide thioamides.
[0273] Heteroaryl substituents such as furan or thiazole can be
converted to carboxylic acids by hydrolytic or oxidative means
well-known in the art. Once formed, the carboxylic acid groups can
be converted to alkoxycarbonyl, carboxamide, or cyano groups by
esterification, coupling, and dehydration procedures.
[0274] A thorough discussion of reactions are described in Larock,
Comprehensive Organic Transformations. A Guide to Functional Group
Preparations, John Wiley & Sons (1999).
[0275] The invention will now be described in connection with
preferred embodiments of Schemes 1-4, which are not intended to
limit its scope. On the contrary, the invention covers all
alternatives, modifications, and equivalents which are included
within the scope of the claims. Thus, the following examples show
an especially preferred practice of the invention, it being
understood that the examples are for the purposes of illustration
of certain preferred embodiments and are presented to provide what
is believed to be the most useful and readily understood
description of its procedures and conceptual aspects.
EXAMPLE 1
[0276]
N-(((5S)-3-(3-fluoro-4-(4-(carbomethoxyphenyl)ethynyl)phenyl)-2-oxo-
-1,3-oxazolidin-5-yl)methyl)acetamide
EXAMPLE 1A
[0277] ((5R)-2-oxo-1,3-oxazolidin-5-yl)methyl
4-methylbenzenesulfonate
[0278] A solution of (5R)-5-(hydroxymethyl)-1,3-oxazolidin-2-one
(10.0 g), prepared as described in Tetrahedron: Asymmetry 1995, 6,
1181-1190, in pyridine (60 mL) at -10.degree. C. was treated with
para-toluenesulfonyl chloride (21.2 g), stirred for 2 hours, poured
into 1:1 brine/water (100 mL), and extracted with ethyl acetate.
The extract was washed with 1:1 saturated sodium bicarbonate/water
and 1:1 brine/water, and the washes were back extracted with ethyl
acetate. The combined extracts was dried (MgSO.sub.4), filtered,
and concentrated to provide the desired product. MS (ESI(+)) m/e
272 (M+H).sup.+; .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.80 (d,
2H), 7.39 (d, 2H), 4.80 (m, 1H), 4.18 (d, 2H), 3.70 (t, 1H), 3.50
(dd, 1H), 2.45 (s, 3H).
EXAMPLE 1B
[0279] 2-(((5R)-2-oxo-1,3-oxazolidin-5-yl)methyl)-1H-isoindole-1,3
(2H)-dione
[0280] A solution of Example 1A (22.16 g) in DMF (163 mL) at room
temperature was treated with potassium phthalimide (16.7 g), heated
to 80.degree. C., stirred for 5 hours, poured into 1:1 brine/water
(200 mL), and extracted with dichloromethane. The extract was dried
(MgSO.sub.4), filtered, and concentrated. The concentrate was
treated with ethyl acetate (200 mL), cooled to 5.degree. C., and
filtered. The mother liquor was concentrated, treated with ethyl
acetate (100 mL), cooled to 5.degree. C., filtered, and combined
with the first crop to provide the desired product. MS (ESI(+)) m/e
247 (M+H).sup.+; .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.88 (m,
2H), 7.75 (m, 2H), 4.98 (m, 1H), 4.10 (dd, 1H), 3.90 (dd, 1H), 3.73
(t, 1H), 3.49 (dd, 1H).
EXAMPLE 1C
[0281]
4-((5S)-5-((1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl)-2-oxo-1,-
3-oxazolidin-3-yl)-2-fluorobenzaldehyde
[0282] A suspension of Example 1B (2.5 g) in toluene (20 mL) in a
sealable tube was degassed with nitrogen and treated with
4-bromo-2-fluorobenzalde- hyde (2.03 g), BINAP (498 mg), cesium
carbonate (4.56 g), and tris(dibenzylideneacetone)dipalladium (366
mg). The tube was sealed, and the mixture was heated at 100.degree.
C. for 24 hours, cooled, poured into 1:1 saturated ammonium
chloride/water (200 mL), and extracted with ethyl acetate. The
extract was dried (MgSO.sub.4), filtered, and concentrated. The
concentrate was treated with dichloromethane (100 mL), cooled to
5.degree. C., and filtered. The filtrate was concentrated, treated
with dichloromethane (70 mL), cooled to 5.degree. C., filtered, and
combined with the first crop to provide the desired product. mp
167-169.degree. C.; MS (ESI(+)) m/e 369 (M+H).sup.+; .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 10.27 (s, 1H), 7.88 (m, 3H), 7.75 (m,
2H), 7.63 (dd, 1H), 7.27 (dd, 1H), 5.04 (m, 1H), 4.16 (m, 2H), 4.00
(m, 2H).
EXAMPLE 1D
[0283]
2-(((5S)-3-(4-(2,2-dibromovinyl)-3-fluorophenyl)-2-oxo-1,3-oxazolid-
in-5-yl)methyl)-1H-isoindole-1,3(2H)-dione
[0284] Polymer-supported triphenylphosphine (10.0 g of 3 mmol/g, 2%
divinylbenzene cross-linked polystyrene resin) was swelled in
dichloromethane (100 mL) and cooled to -10.degree. C. The mixture
was treated with carbon tetrabromide (4.97 g), warmed to -5.degree.
C., stirred for 30 minutes, treated portionwise with Example 1C
(1.84 g), stirred for 20 minutes, treated with methanol (50 mL) and
filtered. The resin was washed with dichloromethane (100 mL), 1:1
dichloromethane/methanol (100 mL), and methanol (3.times.100 mL).
The washes were combined, and the solution was concentrated. The
concentrate was dissolved in dichloromethane (150 mL) and washed
with 1:1 saturated sodium bicarbonate/water and 1:1 brine/water.
The aqueous washes were back extracted with dichloromethane and the
combined extracts were dried (MgSO.sub.4), filtered, and
concentrated to provide the desired product. MS (ESI(+)) m/e 542
(M+NH.sub.4).sup.+; .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.89
(m, 2H), 7.77 (m, 3H), 7.50 (s, 1H), 7.46 (dd, 1H), 7.23 (dd, 1H),
5.01 (m, 1H), 4.16 (m, 2H), 3.98 (m, 2H).
EXAMPLE 1E
[0285]
N-(((5S)-3-(4-(2,2-dibromovinyl)-3-fluorophenyl)-2-oxo-1,3-oxazolid-
in-5-yl)methyl)acetamide
[0286] A suspension of Example 1D (2.45 g) in 1:1 THF/ethanol (36
mL) was heated to 70.degree. C., and treated with hydrazine
monohydrate (3.times.227 .mu.L) at I hour intervals. One hour after
the final addition, the mixture was cooled to 25.degree. C., and
filtered. The filtrate was concentrated, dissolved in a mixture of
pyridine (10 mL) and dichloromethane (25 mL), cooled to -5.degree.
C., treated with acetic anhydride (880 .mu.L), warmed to room
temperature, stirred for 5 minutes, and concentrated to provide
crude product. The crude product was dissolved in 4:1
THF/dichloromethane (75 mL) and washed with 1:1 brine/water. The
aqueous wash was extracted with dichloromethane (25 mL), and the
combined extracts were dried over MgSO.sub.4. Next the mixture was
filtered and concentrated. The residue was dissolved in acetone (20
mL) and filtered. The filtrate was concentrated and the residue
triturated with hexanes to provide the desired product. mp
177-179.degree. C.; MS (ESI(+)) m/e 437 (M+H).sup.+; .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 7.81 (t, 1H), 7.50 (s, 1H), 7.47 (dd,
1H), 7.20 (dd, 1H), 5.92 (br t, 1H), 4.80 (m, 1H), 4.06 (t, 1H),
3.77 (dd, 1H), 3.75-3.55 (m, 2H), 2.02 (s, 3H).
EXAMPLE 1F
[0287] methyl
4-((4-((5S)-5-((acetylamino)methyl)-2-oxo-1,3-oxazolidin-3-y-
l)-2-fluorophenyl)ethynyl)benzoate
[0288] A mixture of Example 1E (55 mg),
4-methoxycarbonylphenylboronic acid (27.2 mg), and
tris(dibenzylideneacetone)dipalladium (15 mg) in degassed
dimethoxyethane (1.3 mL) was treated with 2N aqueous
Na.sub.2CO.sub.3 (0.1 mL), heated to 70.degree. C. for 20 hours,
and concentrated. The concentrate was dissolved in dichloromethane
(2 mL), filtered, and concentrated. The concentrate was purified by
flash column chromatography on silica gel with 1:1 hexanes/acetone
to provide the desired product. MS (ESI(+)) in/e 411 (M+H).sup.+;
MS (ESI(-)) m/e 409 (M-H).sup.-; .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 8.00 (d, 2H), 7.61 (d, 2H), 7.55 (dd, 1H), 7.50 (t, 1H),
7.20 (dd, 1H), 6.0 (br t, 1H), 4.80 (m, 1H), 4.07 (t, 1H), 3.93 (s,
3H), 3.85-3.75 (dd, 1H), 3.60-3.50 (m, 2H), 2.05 (s, 3H).
EXAMPLE 2
[0289]
N-(((5S)-3-(3-fluoro-4-(1H-pyrrol-2-ylethynyl)phenyl)-2-oxo-1,3-oxa-
zolidin-5-yl)methyl)acetamide
[0290] The desired product was prepared by substituting
1-(tert-butoxycarbonyl)-pyrrole-2-boronic acid for
4-methoxycarbonylphenylboronic acid in Example 1F to afford the
tert-butoxycarbonyl-bromo olefin which was treated with sodium
methoxide in methanol (0.25 mL) for 10 minutes and concentrated.
The concentrate was purified by flash column chromatography on
silica gel with 97:3 dichloromethane/methanol to provide the
desired product. MS (ESI(+)) m/e 342 (M+H).sup.+; .sup.1H NMR (300
MHz, CD.sub.3OD) .delta. 7.56 (dd, 1H), 7.46 (t, 1H), 7.27 (dd,
1H), 6.78 (m, 11H), 6.43 (dd, 1H), 6.12 (dd, 11H), 4.80 (m, 1H),
4.15 (t, 1H), 3.82 (dd, 1H), 3.56 (d, 2H), 1.96 (s, 3H).
[0291]
N-(((5S)-3-(3-fluoro-4-(7H-purin-6-ylethynyl)phenyl)-2-oxo-1,3-oxaz-
olidin-5-yl)methyl)acetamide
EXAMPLE 3A
[0292]
2-(3-(4-Ethynyl-3-fluoro-phenyl)-2-oxo-oxazolidin-5-ylmethyl)-isoin-
dole-1,3-dione
[0293] To a -78.degree. C. solution of potassium t-butoxide (7.7 mL
of a 1.0 M solution in THF) was added a -78.degree. C. THF (4 mL)
solution of dimethyl diazomethylphosphonate (1.15 g, prepared
according to the procedure described in J Org. Chem. 1971, 36,
1379-1385). The mixture was stirred at -78.degree. C. for 10
minutes, then a -78.degree. C. solution of Example 1C (2.18 g) in
THF (100 mL) was added via cannula over 20 minutes. The reaction
mixture was stirred for 24 hours gradually warming to room
temperature. The mixture was quenched with 1:1 saturated ammonium
chloride/water (100 mL) and extracted with dichloromethane (50 mL).
The aqueous layer was extracted with 4:1 THF/dichloromethane
(3.times.100 mL). The combined extracts were washed with 1:1
saturated sodium bicarbonate/water (100 mL), and then with 1:1
brine/water (100 mL). The organic extracts were dried over
MgSO.sub.4, filtered, and concentrated to provide crude product.
The crude product was purified by flash column chromatography on
silica gel with 98:2 dichloromethane/methanol to provide the
desired product.MS (ESI(+)) m/e 365 (M+H).sup.+; .sup.1H NMR (300
MHz, DMSO) .delta. 7.85-7.95 (m, 4H), 7.45-7.64 (m, 2H), 7.25-7.35
(dd, J=2.1, 8.7 Hz, 1H), 4.97 (m, 1H), 4.22 (t, J=9 Hz, 1H),
3.9-4.1 (m, 3H), 3.30 (s, 1H).
EXAMPLE 3B
[0294]
N-(((5S)-3-(4-ethynyl-3-fluorophenyl)-2-oxo-1,3-oxazolidin-5-yl)met-
hyl)acetamide
[0295] A 50.degree. C. suspension of Example 3A (1.65 g) in 1:1
THF/ethanol (34 mL) was treated with hydrazine monohydrate
(3.times.240 .mu.L) at I hour intervals. One hour after the final
addition the mixture was cooled to 25.degree. C. and filtered. The
filtrate was concentrated in vacuo. The resultant material was
dissolved in a mixture of pyridine (17 mL) and dichloromethane (17
mL), cooled to -5.degree. C., and treated with acetic anhydride
(854 .mu.L). The reaction mixture was warmed to room temperature,
stirred for 5 minutes, and concentrated to provide crude product.
The crude product was dissolved in 4:1 THF/dichloromethane (75 mL)
and washed with 1:1 brine/water. The aqueous wash was extracted
with dichloromethane (25 mL), and the combined extracts were dried
over MgSO.sub.4. Next the mixture was filtered and concentrated.
The residue was dissolved in acetone (20 mL) and filtered. The
filtrate was concentrated and the residue triturated with hexanes
to provide the desired product. MS (ESI(+)) m/e 277 (M+H).sup.+;
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.5-7.4 (m, 2H),
7.16-7.19 (dd, J=2.4, 8.4 Hz, 1H), 5.93 (bt, 1H), 4.8 (m, 1H), 4.05
(t, J=9 Hz, 1H), 3.8-3.6 (m, 3H), 3.28 (s, 1 H), 2.02 (s, 3H).
EXAMPLE 3C
[0296]
N-(3-(3-Fluoro-4-(7H-purin-6-ylethynyl)-phenyl)-2-oxo-oxazolidin-5--
ylmethyl)-acetamide
[0297] To a suspension of Example 3B (100 mg) and diisopropylamine
(0.25 mL) in degassed DMF (1 mL) was added sequentially
6-iodopurine (89 mg), copper iodide (3.5 mg) and
tetrakis(triphenylphosphine)palladium (21 mg). The mixture was
heated to 60.degree. C. for 4 hours. Next, the reaction mixture was
cooled to room temperature and concentrated. The resultant material
was dissolved in dichloromethane (4 mL), then filtered. The
precipitate was washed with water (10 mL), then cold acetone (3 mL)
to provide the desired solid. MS (ESI(+)) m/e 395 (M+H).sup.+;
.sup.1H NMR (300 MHz, DMSO) .delta. 8.91 (s, 1H), 8.69 (s, 1H),
8.25 (t, J=5.7 Hz, 1H), 7.89 (m, 1H), 7.82 (t, J=9 Hz, 1H), 7.7
(dd, J=2.1, 12.3 Hz, 1H), 7.5 (dd, J=2.1, 9 Hz, 1H), 4.78 (m, 1H),
4.19 (t, J=9 Hz, 1H), 3.8 (dd, J=6.3, 9.6 Hz,1H), 3.44 (t, J=5.7
Hz, 2H), 1.84 (s, 3H).
EXAMPLE 4
[0298]
N-(((5S)-3-(4-((5-(aminosulfonyl)thien-2-yl)ethynyl)-3-fluorophenyl-
)-2-oxo-1,3-oxazolidin-5-yl) methyl)acetamide
[0299] The desired product was prepared as in Example 3C but with
heating at 35.degree. C. for I hour and substituting
5-bromo-thiophene-2-sulfonic acid amide for 6-iodopurine. MS
(ESI(+)) m/e 438 (M+H).sup.+; .sup.1H NMR (300 MHz, DMSO) .delta.
8.24 (t, J=5.7 Hz, 1H), 7.86 (s, 2H), 7.69 (t, J=8.4 Hz, 1H), 7.65
(dd, J=1.8, 12.0 Hz, 1H), 7.52 (d, J=4.2 Hz, 1H), 7.45 (d, J=3.9
Hz, 1 H), 7.42 (dd, J=1.8, 8.7 Hz, 1H), 4.76 (m, 1H), 4.16 (t, J=9
Hz, 1H), 3.78 (dd, J=6.3, 9.6 Hz,1H), 3.42 (t, J=5.7 Hz, 2H), 1.83
(s, 3H).
EXAMPLE 5
[0300]
N-(((5S)-3-(3-fluoro-4-((1-oxo-2,3-dihydro-1H-inden-5-yl)ethynyl)ph-
enyl)-2-oxo-1,3-oxazolidin-5-yl)methyl)acetamide
[0301] The desired product was prepared as in Example 3C but with
heating at 40.degree. C. for 3 hours and substituting
5-bromo-indan-1-one for 6-iodopurine. MS (ESI(+)) m/e 407
(M+H).sup.+; .sup.1H NMR (300 MHz, DMSO) .delta. 8.23 (t, J=5.7 Hz,
1H), 7.77 (s, 1H), 7.55-7.72 (m, 4H), 7.42 (dd, J=2.1, 9 Hz, 1H),
4.76 (m, 1H), 4.17 (t, J=9 Hz, 1H), 3.78 (dd, J=6.3, 9.6 Hz,1H),
3.43 (t, J=5.7 Hz, 2H), 3.13 (t, J=6 Hz, 2H), 2.67 (m, 2H), 1.84
(s, 3H).
EXAMPLE 6
[0302]
5-((4-((5S)-5-((acetylamino)methyl)-2-oxo-1,3-oxazolidin-3-yl)-2-fl-
uorophenyl)ethynyl)-2,3-dihydro-1-benzofuran-7-carboxylic acid
[0303] The desired product was prepared as in Example 3C but with
heating at 60.degree. C. for 8 hours and substituting
5-bromo-2,3-dihydrobenzofur- an-7-carboxylic acid for
6-iodopurine.MS (ESI(+)) m/e 461 (M+23).sup.+;.sup.1H NMR (300 MHz,
DMSO) .delta. 8.23 (t, J=6.3 Hz, 1H), 7.88 (m, 2H), 7.72 (t, J=9
Hz, 1H), 7.66 (dd, J=2.1, 12.3 Hz, 1H), 7.4 (dd, J=2.1, 9 Hz, 1H),
4.76 (m, 1H), 4.17 (t, J=9 Hz, 1H), 3.78 (dd, J=6.3, 9.6 Hz,1H),
3.43 (t, J=5.7 Hz, 2H), 3.13 (t, J=6 Hz, 2H), 2.67 (m, 2H), 1.84
(s, 3H).
EXAMPLE 7
[0304]
N-(((5S)-3-(4-((1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl)ethynyl)-3-f-
luorophenyl)-2-oxo-1,3-oxazolidin-5-yl)methyl)acetamide
[0305] The desired product was prepared as in Example 3C but with
heating at 60.degree. C. for 8 hours and by substituting
5-bromo-isoindole-1,3-di- one for 6-iodopurine. MS (ESI(+)) m/e 422
(M+H).sup.+; .sup.1H NMR (300 MHz, DMSO) .delta. 11.5 (s, 1H), 8.25
(t, J=5.7 Hz, 1H), 7.85-8.00 (m, 3H), 7.73 (t, J=8.4 Hz, 1H), 7.67
(dd, J=2.1, 12.3 Hz, 1H), 7.45 (dd, J=2.1, 8.4 Hz, 1H), 4.78 (m,
1H), 4.19 (t, J=9 Hz, 1H), 3.8 (dd, J=6.3, 9.6 Hz,1H), 3.44 (t,
J=5.7 Hz, 2H), 1.84 (s, 3H).
EXAMPLE 8
[0306]
N-(((5S)-3-(4-((5-cyanopyridin-3-yl)ethynyl)-3-fluorophenyl)-2-oxo--
1,3-oxazolidin-5-yl) methyl)acetamide
[0307] The desired product was prepared as in Example 3C but with
heating at 35.degree. C. for 2 hours and by substituting
5-bromo-nicotinonitrile for 6-iodopurine.MS (ESI(+)) m/e 379
(M+H).sup.+; .sup.1H NMR (300 MHz, DMSO) .delta. 9.02 (dd, J=2.1,
5.1 Hz, 2H), 8.57 (t, J=2.1 Hz,1H), 8.23 (t, J=5.7 Hz, 1H), 7.7 (t,
J=8.4 Hz, 1H), 7.67 (dd, J=2.4, 12.3 Hz, 1H), 7.4 (dd, J=2.4, 8.4
Hz, 1H), 4.76 (m, 1H), 4.17 (t, J=9 Hz, 1H), 3.78 (dd, J=6.3, 9.6
Hz,1H), 3.43 (t, J=5.7 Hz, 2H), 1.83 (s, 3H).
EXAMPLE 9
[0308]
N-(((5S)-3-(3-fluoro-4-(1,8-naphthyridin-2-ylethynyl)phenyl)-2-oxo--
1,3-oxazolidin-5-yl)methyl)acetamide
[0309] The desired product was prepared as in Example 3C but with
heating at 60.degree. C. for 4 hours and substituting
2-bromo-[1.8]naphthyridine for 6-iodopurine. MS (ESI(+)) m/e 405
(M+H).sup.+; .sup.1H NMR (300 MHz, DMSO) .delta. 9.04 (dd,
J=1.5,4.2 Hz, 1H), 8.45 (t, J=8.7 Hz, 2H), 8.24 (t, J=5.7 Hz, 1H),
7.97 (d, J=8.7 Hz, 1H), 7.86 (t, J=4.5 Hz, 1H), 7.8 (t, J=8.7 Hz,
1H), 7.66 (dd, J=2.1, 12.3 Hz, 1H), 7.45 (dd, J=2.1, 8.7 Hz, 1H),
4.76 (m, 1H), 4.18 (t, J=9 Hz, 1H), 3.79 (dd, J=6.3, 9.6 Hz,1H),
3.44 (t, J=5.7 Hz, 2H), 1.83 (s, 3H).
EXAMPLE 10
[0310]
N-(((5S)-3-(3-fluoro-4-((4-(hydroxymethyl)phenyl)ethynyl)phenyl)-2--
oxo-1,3-oxazolidin-5-yl)methyl)acetamide
[0311] The desired product was prepared by substituting
4-hydroxymethylphenylboronic acid for
4-methoxycarbonylphenylboronic acid in Example 1F. MS (ESI(+)) m/e
383 (M+H).sup.+; .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.60
(dd, 1H), 7.50 (d, 2H), 7.38 (d, 2H), 7.30 (m, 2H), 4.80 (m, 1H),
4.17 (t, 1H), 3.84 (dd, 1H), 3.56 (d, 2H), 1.96 (s, 3H).
EXAMPLE 11
[0312]
N-(((5S)-3-(3-fluoro-4-(1,8-naphthyridin-2-ylethynyl)phenyl)-2-oxo--
1,3-oxazolidin-5-yl)methyl)acetamide
EXAMPLE 11A
[0313]
2-(3-(4-Acetyl-3-fluoro-phenyl)-2-oxo-oxazolidin-5-ylmethyl)-isoind-
ole-1,3-dione
[0314] Example 1C (5 g) in dichloromethane (130 mL) was treated
sequentially with diazomethane (3.times.60 mL of a 0.4 M solution
in diethyl ether) at 24 hours intervals. The mixture was stirred at
room temperature for 5 days, then concentrated and used directly in
the next step.
EXAMPLE 11B
[0315]
2-(3-(3-Fluoro-4-prop-1-ynyl-phenyl)-2-oxo-oxazolidin-5-ylmethyl)-i-
soindole-1,3-dione
[0316] To a -78.degree. C. solution of potassium t-butoxide (17 mL
of a 1.0 M solution in THF) was added a -78.degree. C. THF (4 mL)
solution of dimethyl diazomethylphosphonate (2.53 g, prepared
according to the procedure described in J Org. Chem. 1971, 36,
1379-1385). The mixture was stirred at -78.degree. C. for 10
minutes then a -78.degree. C. solution of Example 3A (5.19 g) in
THF (100 mL) was added via cannula over 20 minutes. The reaction
mixture was stirred for 24 hours, gradually warming to room
temperature. The mixture was quenched with 1:1 saturated ammonium
chloride/water (200 mL) and extracted with dichloromethane (50 mL).
The aqueous layer was extracted with 4:1 THF/dichloromethane (250
mL), and the combined extracts were washed with 1:1 saturated
sodium bicarbonate/water (200 mL) and 1:1 brine/water (200 mL). The
organic extracts were dried over MgSO.sub.4, filtered, and
concentrated to provide crude product. The crude product was
purified by flash column chromatography on silica gel eluting with
4:1 hexanes/acetone to provide the desired product. MS (ESI(+)) m/e
379 (M+H).sup.+;
[0317] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.9 (m, 2H), 7.77
(m, 2H), 7.45 (dd, J=2.4, 9 Hz, 1H), 7.36 (d, J=7.2 Hz, 1H),
7.25-7.35 (dd, J=2.4, 8.7 Hz, 1H), 4.97 (m, 1H), 4.07-4.18 (m, 2H),
3.87-4.01 (m, 2H), 2.09 (s, 3H).
EXAMPLE 11C
[0318]
N-(((5S)-3-(3-fluoro-4-(1,8-naphthyridin-2-ylethynyl)phenyl)-2-oxo--
1,3-oxazolidin-5-yl) methyl)acetamide
[0319] A 50.degree. C. suspension of Example 11B (2.0 g) in 1:1
THF/ethanol (20 mL) was treated with hydrazine monohydrate
(3.times.240 .mu.L) at 1 hour intervals. One hour after the final
addition, the mixture was cooled to 25.degree. C. and filtered. The
filtrate was concentrated in vacuo. The resultant material was
dissolved in a mixture of pyridine (10 mL) and dichloromethane (10
mL), cooled to -5.degree. C., and treated with acetic anhydride
(990 .mu.L). The reaction mixture was warmed to room temperature,
stirred for 5 minutes, and concentrated to provide crude product.
The crude product was dissolved in 4:1 THF/dichloromethane (75 mL)
and washed with 1:1 brine/water. The aqueous wash was extracted
with dichloromethane (25 mL), and the combined extracts were dried
over MgSO.sub.4. Next the mixture was filtered and concentrated.
The residue was dissolved in acetone (20 mL) and filtered. The
filtrate was concentrated and the residue triturated with hexanes
to provide the desired product. MS (ESI(+)) m/e 291 (M+H).sup.+;
.sup.1H NMR (300 MHz, DMSO) .delta. 8.22 (t, J=5.7 Hz, 1H), 7.56
(dd, J=2.1, 12.3 Hz, 1H), 7.47 (t, J=8.7 Hz, 1H), 7.3 (dd, J=2.1,
8.7 Hz, I H), 4.73 (m, I H), 4.12 (t, J=9 Hz, 1H), 3.74 (dd, J=6.3,
9.6 Hz,1H), 3.41 (t, J=5.7 Hz, 2H), 2.07 (s, 3H), 1.83 (s, 3H).
EXAMPLE 12
[0320]
N-(((5S)-3-(3-fluoro-4-((4-methoxy-3-pyridinyl)ethynyl)phenyl)-2-ox-
o-1,3-oxazolidin-5-yl)methyl)acetamide
[0321] The desired product was prepared by substituting
2-methoxy-5-pyridineboronic acid for 4-methoxycarbonylphenylboronic
acid in Example 1F. MS (ESI(+)) m/e 384 (M+H).sup.+; .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 8.37 (d, 1H), 7.70 (dd, 1H), 7.50 (m,
1H), 7.21 (dd, 1H), 6.73 (dd, 1H), 5.91(b t, 1H), 4.79 (m, 11H),
4.07 (t, I1H), 3.97 (s, 3H), 3.81 (dd, 1H), 3.75-3.60 (m, 2H), 2.03
(s, 3H).
EXAMPLE 13
[0322]
N-(((5S)-3-(4-((2-aminopyrimidin-5-yI)ethynyl)-3-fluorophenyl)-2-ox-
o-1,3-oxazolidin-5-yl)methyl)acetamide
[0323] A solution of Example 1F (41 mg) in degassed DME (1.3 mL)
was treated with
5-(4,4,5,5-tetramethyl-(1,3,2)dioxaborolan-2-yl)-pyrimidin-2-
-ylamine (41.5mg, prepared according to the procedure described in
Tetrahedron Letters, 1997, 38, 3447-3450),
tetrakis(triphenylphosphine)pa- lladium (12 mg) and a degassed 2 N
solution of potassium carbonate in water (0.2 mL). The tube was
sealed, heated to 70.degree. C., and stirred for 20 hours. The
reaction mixture was then cooled to room temperature, concentrated,
and diluted with dichloromethane (4 mL). The precipitate was
removed by filtration and washed with water (10 mL) and then cold
acetone (3 mL) to provide the desired product. MS (ESI(+)) m/e 370
(M+H).sup.+; .sup.1H NMR (300 MHz, MeOH) .delta. 8.49 (s, 2H), 7.61
(dd, J=2.1, 12 Hz, 1H), 7.57 (t, J=8.4 Hz, I H), 7.32 (dd, J=2.1,
8.7 Hz, 11H), 4.8 (m, 1H), 4.16 (t, J=9 Hz, 1H), 3.83 (dd, J=6.3,
9.6 Hz,1H), 3.56(d, J=5.4 Hz, 2H), 1.96 (s, 3H).
EXAMPLE 14
[0324]
N-(((5S)-3-(3-fluoro-4-(pyrimidin-5-ylethynyl)phenyl)-2-oxo-1,3-oxa-
zolidin-5-yl)methyl)acetamide
[0325] The desired product was prepared as in Example 13 with
substitution of
5-(4,4,5,5-tetramethyl-(1,3,2)dioxaborolan-2-yl)-pyrimidine (38.7
mg, prepared according to the procedure described in Tetrahedron
Letters, 1997, 38, 3447-3450), for
5-(4,4,5,5-tetramethyl-(1,3,2)dioxaborolan-2-yl-
)-pyrimidin-2-ylamine. MS (ESI(+)) m/e 355 (M+H).sup.+; .sup.1H NMR
(300 MHz, MeOH) .delta. 9.11 (s, 1H), 8.93 (s, 2H), 7.65 (dd,
J=2.1, 12 Hz, 1H), 7.62 (t, J=8.4 Hz, 1H), 7.38 (dd, J=2.1, 8.4 Hz,
1H), 4.8 (m, 1H), 4.18 (t, J=9 Hz, 1H), 3.85 (dd, J=6.3, 9.6 Hz,
1H), 3.57(d, J=5.4 Hz, 2H), 1.96 (s, 3H).
EXAMPLE 15
[0326]
N-(((5S)-3-(4-((3-aminophenyl)ethynyl)-3-fluorophenyl)-2-oxo-1,3-ox-
azolidin-5-yl)methyl)acetamide
[0327] The desired product was prepared by substituting
3-aminophenylboronic acid hydrate for
4-methoxycarbonylphenylboronic acid in Example 1F. MS (ESI(+)) m/e
368 (M+H).sup.+; .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 7.63
(dd, 1H), 7.55 (t, 1H), 7.48 (d, 2H), 7.40 (s, 1H), 7.33 (dd, 1H),
7.26 (m, 1H), 4.80 (m, 1H), 4.17 (t, 1H), 3.85 (dd, 1H), 3.57 (d,
2H), 1.96 (s, 3H).
EXAMPLE 16
[0328] methyl
3-((4-((5S)-5-((acetylamino)methyl)-2-oxo-1,3-oxazolidin-3-y-
l)-2-fluorophenyl)ethynyl)benzoate
[0329] The desired product was prepared by substituting
3-methoxycarbonylphenylboronic acid for
4-methoxycarbonylphenylboronic acid in Example 1F. MS (ESI(+)) m/e
411 (M+H).sup.+; .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.20 (t,
1H), 8.01 (d, 1H), 7.71 (d, 11H), 7.51 (s, 1H), 7.46 (m, 2H), 7.20
(dd, 1H), 6.05 (b t, 1H), 4.80 (m, 1H), 4.07 (t, 1H), 3.94 (s, 3H),
3.81 (dd, 1H), 3.75-3.60 (m, 2H), 2.04 (s, 3H).
EXAMPLE 17
[0330]
N-(3-(2-(4-((5S)-5-((acetylamino)methyl)-2-oxo-1,3-oxazolidin-3-yl)-
-2-fluorophenyl)ethynyl)phenyl)acetamide
[0331] The desired product was prepared by substituting
3-acetamidophenylboronic acid for 4-methoxycarbonylphenylboronic
acid in Example 1F. MS (ESI(+)) m/e 410 (M+H).sup.+; .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 7.65 (m, 1H), 7.54-7.46 (m, 3H),
7.31-7.27 (m, 3H), 7.20 (dd, 1H), 5.97 (b t, 1H), 4.80 (m, 1H),
4.06 (t, 1H), 3.80 (dd, 1H), 3.75-3.60 (m, 2H), 2.19 (s, 3H), 2.03
(2, 3H).
EXAMPLE 18
[0332]
N-(((5S)-3-(4-((3-(aminomethyl)phenyl)ethynyl)-3-fluorophenyl)-2-ox-
o-1,3-oxazolidin-5-yl)methyl)acetamide
[0333] The desired product was prepared by substituting
3-aminomethylphenylboronic acid, hydrochloride for
4-methoxycarbonylphenylboronic acid in Example 1F. MS (ESI(+)) m/e
382 (M+H).sup.+; .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 7.64 (s,
1H), 7.60-7.45 (m, 5H), 7.35 (dd, 1H), 4.80 (m, 1H), 4.20 (m, 1H),
4.14 (s, 2H), 3.84 (dd, 1H), 3.58 (m, 2H), 1.96 (s, 3H).
EXAMPLE 19
[0334]
N-(((5S)-3-(3-fluoro-4-((4-hydroxyphenyl)ethynyl)phenyl)-2-oxo-1,3--
oxazolidin-5-yl)methyl)acetamide
[0335] The desired product was prepared by substituting
4-hydroxyphenylboronic acid, pinacol ester for
4-methoxycarbonylphenylbor- onic acid in Example 1F. MS (ESI(+))
m/e 386 (M+NH.sub.4).sup.+; .sup.1H NMR (300 MHz, CD.sub.3OD)
.delta. 7.55 (dd, 1H), 7.34 (d, 2H), 7.30 (m, 2H), 6.77 (d, 2H),
4.78 (m, 1H), 4.16 (t, 1H), 3.82 (dd 1H), 3.56 (d, 2H), 1.96 (s,
3H).
EXAMPLE 20
[0336]
N-(((5S)-3-(3-fluoro-4-((2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)et-
hynyl)phenyl)-2-oxo-1,3-oxazolidin-5-yl)methyl)acetamide
[0337] The desired product was prepared as in Example 3C but with
heating at 60.degree. C. for 8 hours and substituting
6-bromo-3H-benzothiazol-2-o- ne for 6-iodopurine.MS (ESI(+)) m/e
426 (M+H).sup.+; .sup.1H NMR (300 MHz, DMSO) .delta. 12.1 (s, 1H),
8.23 (t, J=6 Hz, 11H), 7.88 (m, 1H), 7.82 (s,1H), 7.64 (m, 1H), 7.4
(m, 2H), 7.16 9(d, J=8.7 Hz, 11H), 4.76 (m, 1H), 4.15 (t, J=9 Hz,
1H), 3.78 (dd, J=6.3, 9.6 Hz,1H), 3.42 (t, J=5.7 Hz, 2H), 1.83 (s,
3H).
[0338] It will be evident to one skilled in the art that the
invention is not limited to the forgoing examples, and that it can
be embodied in other specific forms without departing from the
essential attributes thereof. Thus, it is desired that the examples
be considered as illustrative and not restrictive, reference being
made to the claims, and that all changes which come within the
meaning and range of equivalency of the claims be embraced
therein.
* * * * *