U.S. patent application number 10/756873 was filed with the patent office on 2004-08-12 for substituted biphenyl compounds for the treatment of inflammation.
This patent application is currently assigned to G.D. Searle & Co.. Invention is credited to Li, James J., Norton, Monica B., Reitz, David B..
Application Number | 20040158074 10/756873 |
Document ID | / |
Family ID | 25304989 |
Filed Date | 2004-08-12 |
United States Patent
Application |
20040158074 |
Kind Code |
A1 |
Reitz, David B. ; et
al. |
August 12, 2004 |
Substituted biphenyl compounds for the treatment of
inflammation
Abstract
A class of substituted biphenyl compounds is described for use
in treating inflammation and inflammation-related disorders.
Compounds of particular interest are defined by Formula III: 1
wherein each of R.sup.11 through R.sup.13 is independently selected
from hydrido, halo, lower alkoxy, lower haloalkyl, amino, lower
alkylamino, lower dialkylamino, and lower haloalkoxy; or wherein
R.sup.11 and R.sup.12 together form --O(CH.sub.2).sub.nO--; wherein
n is 1-2, inclusive; or a pharmaceutically-acceptable salt
thereof.
Inventors: |
Reitz, David B.;
(Chesterfield, MO) ; Li, James J.; (Pennington,
NJ) ; Norton, Monica B.; (Kissimmee, FL) |
Correspondence
Address: |
MCDONNELL BOEHNEN HULBERT & BERGHOFF LLP
300 S. WACKER DRIVE
32ND FLOOR
CHICAGO
IL
60606
US
|
Assignee: |
G.D. Searle & Co.
|
Family ID: |
25304989 |
Appl. No.: |
10/756873 |
Filed: |
January 13, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10756873 |
Jan 13, 2004 |
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09772595 |
Jan 30, 2001 |
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6677488 |
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09772595 |
Jan 30, 2001 |
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08849069 |
Nov 17, 1997 |
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08849069 |
Nov 17, 1997 |
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PCT/US95/14943 |
Nov 29, 1995 |
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Current U.S.
Class: |
546/290 ;
546/304; 548/541; 548/557; 564/440; 564/443; 568/660; 568/67;
568/717 |
Current CPC
Class: |
A61K 31/36 20130101;
C07C 317/22 20130101; C07D 319/18 20130101; C07C 317/32 20130101;
A61K 31/277 20130101; A61K 31/44 20130101; C07C 311/39 20130101;
C07D 213/34 20130101; C07C 311/29 20130101; A61K 31/10 20130101;
C07C 317/14 20130101; C07D 317/56 20130101; A61K 31/135 20130101;
C07C 311/16 20130101 |
Class at
Publication: |
546/290 ;
546/304; 548/541; 548/557; 564/440; 564/443; 568/067; 568/660;
568/717 |
International
Class: |
C07D 207/34; C07C
323/29 |
Claims
What is claimed is:
1. A compound of Formula I 74wherein A is selected from aryl and
heteroaryl, wherein A is optionally substituted with one or more
radicals seleceted from alkyl, halo, alkoxy, alkylthio, cyano,
haloalkyl, amino, alkylamino, carboxyl, haloalkoxy, hydroxyalkyl,
alkoxyalkyl, hydroxyl and mercapto; wherein each of R.sup.1 through
R.sup.4 is independently selected from hydrido, halo, and alkoxy;
and wherein each of R.sup.5 through R.sup.9 is independently
selected from hydrido, alkyl, halo, alkoxy, alkylthio, cyano,
haloalkyl, amino, alkylamino, haloalkoxy, hydroxyalkyl,
alkoxyalkyl, hydroxyl, mercapto, aminosulfonyl and alkylsulfonyl;
or a pharmaceutically-acceptable salt thereof.
2. Compound of claim 1 wherein A is selected from phenyl, naphthyl,
5-membered heteroaryl and 6-membered heteroaryl, wherein A is
optionally substituted with one or more radicals seleceted from
lower alkyl, halo, lower alkoxy, lower alkylthio, cyano, lower
haloalkyl, amino, lower alkylamino, lower dialkylamino, lower
haloalkoxy, lower hydroxyalkyl, lower alkoxyalkyl, hydroxyl and
mercapto; wherein each of R.sup.1 through R.sup.4 is independently
selected from hydrido and halo; or wherein R.sup.2 and R.sup.3
together form --O(CH.sub.2).sub.nO--; wherein n is 1 or 2,
inclusive; and wherein each of R.sup.5 through R.sup.9 is
independently selected from hydrido, lower alkyl, halo, lower
alkoxy, lower alkylthio, cyano, lower haloalkyl, amino, lower
alkylamino, lower dialkylamino, lower haloalkoxy, lower
hydroxyalkyl, lower alkoxyalkyl, hydroxyl, mercapto, aminosulfonyl
and lower alkylsulfonyl; or a pharmaceutically-acceptable salt
thereof.
3. Compound of claim 2 wherein A is selected from phenyl, naphthyl,
5-membered heteroaryl and 6-membered heteroaryl, wherein A is
optionally substituted with one or more radicals seleceted from
lower alkyl, halo, lower alkoxy, lower haloalkyl and lower
dialkylamino; wherein each of R.sup.1 through R.sup.4 is
independently selected from hydrido and halo; or wherein R.sup.2
and R.sup.3 together form --O(CH.sub.2).sub.nO--; wherein n is 1 or
2, inclusive; wherein each of R.sup.5, R.sup.6, R.sup.8 and R.sup.9
is hydrido; and wherein R.sup.7 is selected from aminosulfonyl and
lower alkylsulfonyl; or a pharmaceutically-acceptable salt
thereof.
4. Compound of claim 3 wherein A is selected from phenyl, naphthyl,
5-membered heteroaryl and 6-membered heteroaryl, wherein A is
optionally substituted with one or more radicals seleceted from
lower alkyl, halo, lower alkoxy, lower haloalkyl and lower
dialkylamino; wherein each of R.sup.1 through R.sup.4 is
independently selected from hydrido and halo; or wherein R.sup.2
and R.sup.3 together form --OCH.sub.2O--; and wherein R.sup.7 is
aminosulfonyl; or a pharmaceutically-acceptable salt thereof.
5. Compound of claim 4 wherein A is selected from phenyl, thienyl,
furyl, pyrazolyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl,
isothiazolyl, triazolyl and pyridyl, wherein A is optionally
substituted with one or more radicals seleceted from methyl, ethyl,
fluoro, chloro, bromo, methoxy, ethoxy, propoxy, n-butoxy,
methylenedioxy, ethylenedioxy, fluoromethyl, difluoromethyl,
difluorochloromethyl, trifluoromethyl, dichloroethyl,
dichlorofluoromethyl, chloromethyl, dichloromethyl,
trichloromethyl, pentafluoroethyl, heptafluoropropyl,
difluoroethyl, difluoropropyl, dichloropropyl,
N-ethyl-N-methylamino, N,N-dimethylamino and N,N-diethylamino;
wherein each of R.sup.1 through R.sup.4 is independently selected
from hydrido, fluoro, chloro and bromo; or wherein R.sup.2 and
R.sup.3 together form --OCH.sub.2O--; wherein R.sup.5, R.sup.6,
R.sup.8 and R.sup.9 are hydrido; and wherein R.sup.7 is
aminosulfonyl; or a pharmaceutically-acceptable salt thereof.
6. Compound of claim 5 selected from compounds, and their
pharmaceutically acceptable salts, of the group consisting of
4-[2-(4-methylphenyl)phenyl]- benzenesulfonamide;
4-[2-(3-fluoro-4-methylphenyl)phenyl]benzenesulfonamid- e;
4-[2-(3-chloro-4-methylphenyl)phenyl]benzenesulfonamide;
4-[2-(4-methoxyphenyl)phenyl]benzenesulfonamide;
4-[2-(3-fluoro-4-methoxy- phenyl)phenyl]benzenesulfonamide;
4-[2-(3-chloro-4-methoxyphenyl)phenyl]be- nzenesulfonamide;
4-[2-(4-fluorophenyl)phenyl]benzenesulfonamide;
4-[2-(3,4-difluorophenyl)phenyl]benzenesulfonamide;
4-[2-(3-chloro-4-fluorophenyl)phenyl]benzenesulfonamide;
4-[2-(4-chlorophenyl)phenyl]benzenesulfonamide;
4-[2-(4-chloro-3-fluoroph- enyl)phenyl]benzenesulfonamide;
4-[2-(3,4-dichlorophenyl)phenyl]benzenesul- fonamide;
4-[2-(4-trifluoromethylphenyl)phenyl]benzenesulfonamide;
4-[2-(3-fluoro-4-trifluoromethylphenyl)phenyl]benzenesulfonamide;
4-[2-(3-chloro-4-trifluoromethylphenyl)phenyl]benzenesulfonamide;
4-[2-[4-(N,N-dimethylamino)phenyl]phenyl]benzenesulfonamide;
4-[2-[3-fluoro-4-(N,N-dimethylamino)phenyl]phenyl]benzenesulfonamide;
4-[2-[3-chloro-4-(N,N-dimethylamino)phenyl]phenyl]benzenesulfonamide;
4-[6-(4-fluorophenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-(3,4-difluorophenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-(3-chloro-4-fluorophenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[6-[4-(N,N-dimethylamino)phenyl]-1,3-benzodioxol-5-yl]benzenesulfonamid-
e;
4-[6-[4-(N,N-dimethylamino)-3-fluorophenyl]-1,3-benzodioxol-5-yl]benzen-
esulfonamide;
4-[6-[3-chloro-4-(N,N-dimethylamino)phenyl]-1,3-benzodioxol--
5-yl]benzenesulfonamide;
4-[6-(3,5-difluoro-4-methylphenyl)-1,3-benzodioxo-
l-5-yl]benzenesulfonamide;
4-[6-(3,5-dichloro-4-methylphenyl)-1,3-benzodio-
xol-5-yl]benzenesulfonamide;
4-[6-(3,5-difluoro-4-methoxyphenyl)-1,3-benzo-
dioxol-5-yl]benzenesulfonamide;
4-[6-(3,5-dichloro-4-methoxyphenyl)-1,3-be-
nzodioxol-5-yl]benzenesulfonamide;
4-[4,5-difluoro-2-(4-methylphenyl)pheny- l]benzenesulfonamide;
4-[4,5-difluoro-2-(3-fluoro-4-methylphenyl)phenyl]be-
nzenesulfonamide;
4-[2-(3-chloro-4-methylphenyl)-4,5-difluorophenyl]benzen-
esulfonamide;
4-[4,5-difluoro-2-(4-methoxyphenyl)phenyl]benzenesulfonamide- ;
4-[4,5-difluoro-2-(3-fluoro-4-methoxyphenyl)phenyl]benzenesulfonamide;
4-[2-(3-chloro-4-methoxyphenyl)-4,5-difluorophenyl]benzenesulfonamide;
4-[4,5-difluoro-2-(4-fluorophenyl)phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-(3,4-difluorophenyl)phenyl]benzenesulfonamide;
4-[2-(3-chloro-4-fluorophenyl)-4,5-difluorophenyl]benzenesulfonamide;
4-[4,5-difluoro-2-(4-fluoro-3-methylphenyl)phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-(4-fluoro-3-methoxyphenyl)phenyl]benzenesulfonamide;
4-[2-(4-chlorophenyl)-4,5-difluorophenyl]benzenesulfonamide;
4-[2-(4-chloro-3-methylphenyl)-4,5-difluorophenyl]benzenesulfonamide;
4-[2-(4-chloro-3-fluorophenyl)-4,5-difluorophenyl]benzenesulfonamide;
4-[2-(3,4-dichlorophenyl)-4,5-difluorophenyl]benzenesulfonamide;
4-[2-(4-chloro-3-methoxyphenyl)-4,5-difluorophenyl]benzenesulfonamide;
4-[4,5-difluoro-2-(4-methoxy-3-methylphenyl)phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-(3,4-dimethoxyphenyl)phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-[4-(N,N-dimethylamino)phenyl]phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-[4-(N,N-dimethylamino)-3-methylphenyl]phenyl]benzenesul-
fonamide;
4-[4,5-difluoro-2-[4-(N,N-dimethylamino)-3-fluorophenyl]phenyl]b-
enzenesulfonamide;
4-[2-[3-chloro-4-(N,N-dimethylamino)phenyl]-4,5-difluor-
ophenyl]benzenesulfonamide;
4-[4,5-difluoro-2-[4-(N,N-dimethylamino)-3-met-
hoxyphenyl]phenyl]benzenesulfonamide;
4-[2-(1,3-benzodioxol-5-yl)-4,5-difl-
uorophenyl]benzenesulfonamide;
4-[2-(2,3-dihydro-1,4-benzodioxin-6-yl)-4,5-
-difluorophenyl]benzenesulfonamide;
4-[4,5-difluoro-2-(5-methylpyridin-2-y-
l)phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-(6-methylpyridin-3-yl)pheny-
l]benzenesulfonamide;
4-[4,5-difluoro-2-(3,4,5-trimethylphenyl)phenyl]benz-
enesulfonamide;
4-[4,5-difluoro-2-(3,4-dimethylphenyl)phenyl]benzenesulfon- amide;
4-[2-(3,5-dichloro-4-methoxyphenyl)-4,5-difluorophenyl]benzenesulfo-
namide;
4-[4,5-difluoro-2-(3,5-difluoro-4-methylphenyl)phenyl]benzenesulfo-
namide;
4-[2-(3,5-dichloro-4-methylphenyl)-4,5-difluorophenyl]benzenesulfo-
namide;
4-[4,5-difluoro-2-(3,5-dimethoxy-4-methylphenyl)phenyl]benzenesulf-
onamide;
4-[4,5-difluoro-2-(3,5-dimethyl-4-methoxyphenyl)phenyl]benzenesul-
fonamide;
4-[4,5-difluoro-2-(3,5-difluoro-4-methoxyphenyl)phenyl]benzenesu-
lfonamide;
4-[2-(3,5-dichloro-4-methoxyphenyl)-4,5-difluorophenyl]benzenes-
ulfonamide;
4-[4,5-difluoro-2-(3,4,5-trimethoxyphenyl)phenyl]benzenesulfon-
amide;
4-[4,5-difluoro-2-(3,5-dimethyl-4-fluorophenyl)phenyl]benzenesulfon-
amide;
4-[4,5-difluoro-2-(3,4,5-trifluorophenyl)phenyl]benzenesulfonamide;
4-[2-(3,5-dichloro-4-fluorophenyl)-4,5-difluorophenyl]benzenesulfonamide;
4-[4,5-difluoro-2-(3,5-dimethoxy-4-fluorophenyl)phenyl]benzenesulfonamide-
;
4-[2-(4-chloro-3,5-dimethylphenyl)-4,5-difluorophenyl]benzenesulfonamide-
;
4-[2-(4-chloro-3,5-difluorophenyl)-4,5-difluorophenyl]benzenesulfonamide-
;
4-[4,5-difluoro-2-(3,4,5-trichlorophenyl)phenyl]benzenesulfonamide;
4-[2-(4-chloro-3,5-dimethoxyphenyl)-4,5-difluorophenyl]benzenesulfonamide-
;
4-[4,5-difluoro-2-[3,5-dimethyl-4-(N,N-dimethylamino)phenyl]phenyl]benze-
nesulfonamide;
4-[4,5-difluoro-2-[3,5-difluoro-4-(N,N-dimethylamino)phenyl-
]phenyl]benzenesulfonamide;
4-[2-[3,5-dichloro-4-(N,N-dimethylamino)phenyl-
]-4,5-difluorophenyl]benzenesulfonamide;
4-[2,3,4,5-tetrafluoro-6-(4-methy-
lphenyl)phenyl]benzenesulfonamide;
4-[2,3,4,5-tetrafluoro-6-(3-fluoro-4-me-
thylphenyl)phenyl]benzenesulfonamide;
4-[2,3,4,5-tetrafluoro-6-(3-chloro-4-
-methylphenyl)phenyl]benzenesulfonamide;
4-[2,3,4,5-tetrafluoro-6-(4-metho-
xyphenyl)phenyl]benzenesulfonamide;
4-[2,3,4,5-tetrafluoro-6-(4-methoxy-3--
methylphenyl)phenyl]benzenesulfonamide;
4-[2,3,4,5-tetrafluoro-6-(3-fluoro-
-4-methoxyphenyl)phenyl]benzenesulfonamide;
4-[2,3,4,5-tetrafluoro-6-(3-ch-
loro-4-methoxyphenyl)phenyl]benzenesulfonamide;
4-[2,3,4,5-tetrafluoro-6-(-
3,4-dimethoxyphenyl)phenyl]benzenesulfonamide;
4-[2,3,4,5-tetrafluoro-6-(4-
-fluorophenyl)phenyl]benzenesulfonamide;
4-[2,3,4,5-tetrafluoro-6-(4-fluor-
o-3-methylphenyl)phenyl]benzenesulfonamide;
4-[2,3,4,5-tetrafluoro-6-(3,4--
difluorophenyl)phenyl]benzenesulfonamide;
4-[2,3,4,5-tetrafluoro-6-(3-chlo-
ro-4-fluorophenyl)phenyl]benzenesulfonamide; and
4-[2,3,4,5-tetrafluoro-6--
(4-fluoro-3-methoxyphenyl)phenyl]benzenesulfonamide.
7. Compound of claim 5 selected from compounds, and their
pharmaceutically acceptable salts, of the group consisting of
4-[4,5-difluoro-2-(4-fluoro--
3-methylphenyl)phenyl]benzenesulfonamide;
4-[2-(4-chloro-3-methylphenyl)-4-
,5-difluorophenyl]benzenesulfonamide;
4-[4,5-difluoro-2-(3,4-dimethylpheny- l)phenyl]benzenesulfonamide;
4-[2-(3,5-dichloro-4-methoxyphenyl)-4,5-diflu-
orophenyl]benzenesulfonamide;
4-[4,5-difluoro-2-(4-methoxy-3-methylphenyl)-
phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-(3,4-dimethoxyphenyl)phenyl]b- enzenesulfonamide;
4-[2-(2,3-dihydro-1,4-benzodioxin-6-yl)-4,5-difluorophe-
nyl]benzenesulfonamide;
4-[4,5-difluoro-2-(5-methylpyridin-2-yl)phenyl]ben-
zenesulfonamide;
4-[4,5-difluoro-2-(6-methylpyridin-3-yl)phenyl]benzenesul-
fonamide;
4-[2-(3-Chloro-4-fluorophenyl)-4,5-difluorophenyl]benzenesulfona-
mide; 4-[2-(4-fluorophenyl)phenyl]benzenesulfonamide;
4-[2-(4-chlorophenyl)phenyl]benzenesulfonamide;
4-[2-(3-fluoro-4-methoxyp- henyl)phenyl]benzenesulfonamide;
4-[2-(3-chloro-4-methoxyphenyl)phenyl]ben- zenesulfonamide;
4-[2-(4-trifluoromethylphenyl)phenyl]benzenesulfonamide;
4-[2-(3-chloro-4-fluorophenyl)phenyl]benzenesulfonamide;
4-[4,5-difluoro-2-(4-fluorophenyl)phenyl]benzenesulfonamide;
4-[2,3,4,5-tetrafluoro-6-(4-fluorophenyl)phenyl]benzenesulfonamide;
4-[2-(3-chloro-4-methoxyphenyl)-4,5-difluorophenyl]benzenesulfonamide;
4-[4,5-difluoro-2-(3-fluoro-4-methoxyphenyl)phenyl]benzenesulfonamide;
4-[6-(4-fluorophenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
4-[4,5-difluoro-2-(4-methylphenyl)phenyl]benzenesulfonamide;
4-[2-(1,3-benzodioxol-5-yl)-4,5-difluorophenyl]benzenesulfonamide;
4-[2-(3-chloro-4-methylphenyl)-4,5-difluorophenyl]benzenesulfonamide;
and
4-[2-[3-chloro-4-(N,N-dimethylamino)phenyl]-4,5-difluorophenyl]benzenesul-
fonamide.
8. Compound of claim 5 where the compound is
4-[4,5-difluoro-2-(3-chloro-4-
-fluorophenyl)phenyl]benzenesulfonamide, or a
pharmaceutically-acceptable salt thereof.
9. Compound of claim 5 where the compound is
4-[2-(3-chloro-4-methoxypheny- l)phenyl]benzenesulfonamide, or a
pharmaceutically-acceptable salt thereof.
10. Compound of claim 3 wherein A is selected from phenyl,
naphthyl, 5-membered heteroaryl and 6-membered heteroaryl, wherein
A is optionally substituted with one or more radicals seleceted
from lower alkyl, halo, lower alkoxy, lower haloalkyl and lower
dialkylamino; wherein each of R.sup.1 through R.sup.4 is
independently selected from hydrido and halo; or wherein R.sup.2
and R.sup.3 together form --OCH.sub.2O--; and wherein R.sup.7 is
lower alkylsulfonyl; or a pharmaceutically-acceptable salt
thereof.
11. Compound of claim 10 wherein A is selected from phenyl,
thienyl, furyl, pyrazolyl, pyrrolyl, thiazolyl, oxazolyl,
isoxazolyl, isothiazolyl, triazolyl and pyridyl, wherein A is
optionally substituted with one or more radicals seleceted from
methyl, ethyl, fluoro, chloro, bromo, methoxy, ethoxy, propoxy,
n-butoxy, methylenedioxy, ethylenedioxy, fluoromethyl,
difluoromethyl, difluorochloromethyl, trifluoromethyl,
dichloroethyl, dichlorofluoromethyl, chloromethyl, dichloromethyl,
trichloromethyl, pentafluoroethyl, heptafluoropropyl,
difluoroethyl, difluoropropyl, dichloropropyl,
N-ethyl-N-methylamino, N,N-dimethylamino and N,N-diethylamino;
wherein each of R.sup.1 through R.sup.4 is independently selected
from hydrido, fluoro, chloro and bromo; or wherein R.sup.2 and
R.sup.3 together form --OCH.sub.2O--; wherein R.sup.5, R.sup.6,
R.sup.8 and R.sup.9 are hydrido; and wherein R.sup.7 is
methylsulfonyl; or a pharmaceutically-acceptable salt thereof.
12. Compound of claim 11 selected from compounds, and their
pharmaceutically acceptable salts, of the group consisting of
1,2-difluoro-4-(4-fluoro-3-methylphenyl)-5-[4-(methylsulfonyl)phenyl]benz-
ene;
4-(4-chloro-3-methylphenyl)-1,2-difluoro-5-[4-(methylsulfonyl)phenyl]-
benzene;
1,2-difluoro-4-(3,4-dimethylphenyl)-5-[4-(methylsulfonyl)phenyl]b-
enzene;
1,2-difluoro-4-(4-methoxy-3-methylpheny)-5-[4-(methylsulfonyl)phen-
yl]benzene;
1,2-difluoro-4-(3,4-dimethoxypheny)-5-[4-(methylsulfonyl)pheny-
l]benzene;
6-[4,5-difluoro-2-[4-(methylsulfonyl)phenyl]-2,3-dihydro-1,4-be-
nzodioxin;
1,2-dichloro-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]ben-
zene;
2-[4,5-difluoro-4'-(methylsulfonyl)-(1,1'-biphenyl)-2-yl]-5-methylpy-
ridine;
5-[4,5-difluoro-4'-(methylsulfonyl)-(1,1'-biphenyl)-2-yl]-2-methyl-
pyridine; 1-(4-fluorophenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
1-(4-chlorophenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
2-chloro-1-methoxy-4-[2-[4-(methylsulfonyl)phenyl]phenyl]benzene;
2-fluoro-1-methoxy-4-[2-[4-(methylsulfonyl)phenyl]phenyl]benzene;
2-chloro-1-fluoro-4-[2-[4-(methylsulfonyl)phenyl]phenyl]benzene;
5-(4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodioxole;
1,2-difluoro-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]benzene;
1,2-difluoro-4-(4-methylphenyl)-5-[4-(methylsulfonyl)phenyl]benzene;
1-(3-chloro-4-methoxyphenyl)-4,5-difluoro-2-[4-(methylsulfonyl)phenyl]ben-
zene;
1,2-difluoro-4-(3-fluoro-4-methoxyphenyl)-5-[4-(methylsulfonyl)pheny-
l]benzene;
1-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-[4-(methylsulfonyl)p-
henyl]benzene;
1-(3,5-dichloro-4-methoxyphenyl)-4,5-difluoro-2-[4-(methyls-
ulfonyl)phenyl]benzene;
1-(3,5-difluoro-4-methoxyphenyl)-4,5-difluoro-2-[4-
-(methylsulfonyl)phenyl]benzene;
5-[4,5-difluoro-2-[4-(methylsulfonyl)phen-
yl]phenyl]-1,3-benzodioxole;
1-(3-chloro-4-methylphenyl)-4,5-difluoro-2-[4-
-(methylsulfonyl)phenyl]benzene; and
2-chloro-4-[4,5-difluoro-2-[4-(methyl-
sulfonyl)phenyl]phenyl]-N,N-dimethylbenzeneamine.
13. A compound of Formula II 75wherein A is selected from 76wherein
each of R.sup.2 and R.sup.3 is independently selected from hydrido
and halo; or wherein R.sup.2 and R.sup.3 together form
--OCH.sub.2O--; wherein each of R.sup.10 through R.sup.14 is
independently selected from hydrido, lower alkyl, halo, lower
alkoxy, lower haloalkyl, and lower dialkylamino; or wherein
R.sup.11 and R.sup.12 together form --O(CH.sub.2).sub.nO--; wherein
n is 1-2, inclusive; and wherein R.sup.7 is selected from lower
alkylsulfonyl and aminosulfonyl; or a pharmaceutically-acceptable
salt thereof.
14. A compound of Formula III 77wherein each of R.sup.11 through
R.sup.13 is independently selected from hydrido, halo, lower
alkoxy, lower haloalkyl, amino, lower alkylamino, lower
dialkylamino, and lower haloalkoxy; or wherein R.sup.11 and
R.sup.12 together form --O(CH.sub.2).sub.nO--; wherein n is 1-2,
inclusive; or a pharmaceutically-acceptable salt thereof.
15. A compound of Formula IV 78wherein Y is CR.sup.11 or N; wherein
Z is CR.sup.10 or N; wherein each of R.sup.10 through R.sup.12 is
independently selected from hydrido and lower alkyl; wherein
R.sup.7 is aminosulfonyl or methylsulfonyl; provided one of Y and Z
is N; or a pharmaceutically-acceptable salt thereof.
16. A pharmaceutical composition comprising a
therapeutically-effective amount of a compound, said compound
selected from a family of compounds of claim 1; or a
pharmaceutically-acceptable salt thereof.
17. A pharmaceutical composition comprising a
therapeutically-effective amount of a compound, said compound
selected from a family of compounds of claim 2; or a
pharmaceutically-acceptable salt thereof.
18. A pharmaceutical composition comprising a
therapeutically-effective amount of a compound, said compound
selected from a family of compounds of claim 3; or a
pharmaceutically-acceptable salt thereof.
19. A pharmaceutical composition comprising a
therapeutically-effective amount of a compound, said compound
selected from a family of compounds of claim 4; or a
pharmaceutically-acceptable salt thereof.
20. A pharmaceutical composition comprising a
therapeutically-effective amount of a compound, said compound
selected from a family of compounds of claim 5; or a
pharmaceutically-acceptable salt thereof.
21. A pharmaceutical composition comprising a
therapeutically-effective amount of a compound, said compound
selected from a family of compounds of claim 6; or a
pharmaceutically-acceptable salt thereof.
22. A pharmaceutical composition comprising a
therapeutically-effective amount of a compound, said compound
selected from a family of compounds of claim 7; or a
pharmaceutically-acceptable salt thereof.
23. A pharmaceutical composition comprising a
therapeutically-effective amount of a compound, said compound
selected from a family of compounds of claim 8; or a
pharmaceutically-acceptable salt thereof.
24. A pharmaceutical composition comprising a
therapeutically-effective amount of a compound, said compound
selected from a family of compounds of claim 9; or a
pharmaceutically-acceptable salt thereof.
25. A pharmaceutical composition comprising a
therapeutically-effective amount of a compound, said compound
selected from a family of compounds of claim 10; or a
pharmaceutically-acceptable salt thereof.
26. A pharmaceutical composition comprising a
therapeutically-effective amount of a compound, said compound
selected from a family of compounds of claim 11; or a
pharmaceutically-acceptable salt thereof.
27. A pharmaceutical composition comprising a
therapeutically-effective amount of a compound, said compound
selected from a family of compounds of claim 12; or a
pharmaceutically-acceptable salt thereof.
28. A pharmaceutical composition comprising a
therapeutically-effective amount of a compound, said compound
selected from a family of compounds of claim 13; or a
pharmaceutically-acceptable salt thereof.
29. A pharmaceutical composition comprising a
therapeutically-effective amount of a compound, said compound
selected from a family of compounds of claim 14; or a
pharmaceutically-acceptable salt thereof.
30. A pharmaceutical composition comprising a
therapeutically-effective amount of a compound, said compound
selected from a family of compounds of claim 15; or a
pharmaceutically-acceptable salt thereof.
31. A method of treating inflammation or an inflammation-associated
disorder in a subject, said method comprising treating the subject
having or susceptible to said disorder with a
therapeutically-effective amount of a compound of claim 1; or a
pharmaceutically-acceptable salt thereof.
32. A method of treating inflammation or an inflammation-associated
disorder in a subject, said method comprising treating the subject
having or susceptible to said disorder with a
therapeutically-effective amount of a compound of claim 2; or a
pharmaceutically-acceptable salt thereof.
33. A method of treating inflammation or an inflammation-associated
disorder in a subject, said method comprising treating the subject
having or susceptible to said disorder with a
therapeutically-effective amount of a compound of claim 3; or a
pharmaceutically-acceptable salt thereof.
34. A method of treating inflammation or an inflammation-associated
disorder in a subject, said method comprising treating the subject
having or susceptible to said disorder with a
therapeutically-effective amount of a compound of claim 4; or a
pharmaceutically-acceptable salt thereof.
35. A method of treating inflammation or an inflammation-associated
disorder in a subject, said method comprising treating the subject
having or susceptible to said disorder with a
therapeutically-effective amount of a compound of claim 5; or a
pharmaceutically-acceptable salt thereof.
36. A method of treating inflammation or an inflammation-associated
disorder in a subject, said method comprising treating the subject
having or susceptible to said disorder with a
therapeutically-effective amount of a compound of claim 6; or a
pharmaceutically-acceptable salt thereof.
37. A method of treating inflammation or an inflammation-associated
disorder in a subject, said method comprising treating the subject
having or susceptible to said disorder with a
therapeutically-effective amount of a compound of claim 7; or a
pharmaceutically-acceptable salt thereof.
38. A method of treating inflammation or an inflammation-associated
disorder in a subject, said method comprising treating the subject
having or susceptible to said disorder with a
therapeutically-effective amount of a compound of claim 8; or a
pharmaceutically-acceptable salt thereof.
39. A method of treating inflammation or an inflammation-associated
disorder in a subject, said method comprising treating the subject
having or susceptible to said disorder with a
therapeutically-effective amount of a compound of claim 9; or a
pharmaceutically-acceptable salt thereof.
40. A method of treating inflammation or an inflammation-associated
disorder in a subject, said method comprising treating the subject
having or susceptible to said disorder with a
therapeutically-effective amount of a compound of claim 10; or a
pharmaceutically-acceptable salt thereof.
41. A method of treating inflammation or an inflammation-associated
disorder in a subject, said method comprising treating the subject
having or susceptible to said disorder with a
therapeutically-effective amount of a compound of claim 11; or a
pharmaceutically-acceptable salt thereof.
42. A method of treating inflammation or an inflammation-associated
disorder in a subject, said method comprising treating the subject
having or susceptible to said disorder with a
therapeutically-effective amount of a compound of claim 12; or a
pharmaceutically-acceptable salt thereof.
43. A method of treating inflammation or an inflammation-associated
disorder in a subject, said method comprising treating the subject
having or susceptible to said disorder with a
therapeutically-effective amount of a compound of claim 13; or a
pharmaceutically-acceptable salt thereof.
44. A method of treating inflammation or an inflammation-associated
disorder in a subject, said method comprising treating the subject
having or susceptible to said disorder with a
therapeutically-effective amount of a compound of claim 14; or a
pharmaceutically-acceptable salt thereof.
45. A method of treating inflammation or an inflammation-associated
disorder in a subject, said method comprising treating the subject
having or susceptible to said disorder with a
therapeutically-effective amount of a compound of claim 15; or a
pharmaceutically-acceptable salt thereof.
46. The method of claim 31 for use in treatment of
inflammation.
47. The method of claim 31 for use in treatment of an
inflammation-associated disorder.
48. The method of claim 47 wherein the inflammation-associated
disorder is arthritis.
49. The method of claim 47 wherein the inflammation-associated
disorder is pain.
50. The method of claim 47 wherein the inflammation-associated
disorder is fever.
Description
FIELD OF THE INVENTION
[0001] This invention is in the field of anti-inflammatory
pharmaceutical agents and specifically relates to compounds,
compositions and methods for treating inflammation and
inflammation-associated disorders, such as arthritis.
BACKGROUND OF THE INVENTION
[0002] Prostaglandins play a major role in the inflammation process
and the inhibition of prostaglandin production, especially
production of PGG.sub.2, PGH.sub.2 and PGE.sub.2, has been a common
target of anti-inflammatory drug discovery. However, common
non-steroidal anti-inflammatory drugs (NSAIDs) that are active in
reducing the prostaglandin-induced pain and swelling associated
with the inflammation process are also active in affecting other
prostaglandin-regulated processes not associated with the
inflammation process. Thus, use of high doses of most common NSAIDs
can produce severe side effects, including life threatening ulcers,
that limit their therapeutic potential. An alternative to NSAIDs is
the use of corticosteroids, which have even more drastic side
effects, especially when long term therapy is involved.
[0003] Previous NSAIDs have been found to prevent the production of
prostaglandins by inhibiting enzymes in the human arachidonic
acid/prostaglandin pathway, including the enzyme cyclooxygenase
(COX). The recent discovery of an inducible enzyme associated with
inflammation (named "cyclooxygenase-2 (COX-2)" or "prostaglandin
G/H synthase II") provides a viable target of inhibition which more
effectively reduces inflammation and produces fewer and less
drastic side effects.
[0004] Substituted biphenyl compounds have been reported as
components in photographic materials. U.S. Pat. No. 5,238,790, to
Shimura et al., describes the use of biphenyl compounds as
dispersion agents in photographic materials. U.S. Pat. No.
5,294,530, to Seto et al., describes photographic materials
containing biphenyl compounds as anti-fading agents.
[0005] U.S. Pat. No. 4,990,647, to Himmler et al., describes a
method for the preparation of unsymmetric biaryl compounds.
[0006] Substituted biphenyl compounds have been reported as having
activity as angiotensin II antagonists. Heterocyclo-substituted
biphenyl compounds are described by D. Kim, et al. [Bioorg. Med.
Chem. Lett., 4, 41-44 (1994)]. U.S. Pat. No. 5,254,546, to Ardecky
et al., describes tetrazole substituted biphenyl compounds. U.S.
Pat. No. 5,240,928, to Allen et al., describes
aminosulfonyl-substituted biphenyl compounds.
[0007] Recently, a terphenyl compound has been described as an
anti-inflammatory agent [R. Copeland et al., Med. Chem. Res., 5.,
384-393 (1995)].
DESCRIPTION OF THE INVENTION
[0008] A class of compounds useful in treating inflammation-related
disorders is defined by Formula I: 2
[0009] wherein A is selected from aryl and heteroaryl, wherein A is
optionally substituted with one or more radicals selected from
alkyl, halo, alkoxy, alkylthio, cyano, haloalkyl, amino,
alkylamino, carboxyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl,
hydroxyl and mercapto; wherein each of R.sup.1 through R.sup.4 is
independently selected from hydrido, halo, and alkoxy; and wherein
each of RS through R.sup.9 is independently selected from hydrido,
alkyl, halo, alkoxy, alkylthio, cyano, haloalkyl, amino,
alkylamino, haloalkoxy, hydroxyalkyl, alkoxyalkyl, hydroxyl,
mercapto, aminosulfonyl and alkylsulfonyl; or a
pharmaceutically-acceptab- le salt thereof.
[0010] Compounds of Formula I would be useful for, but not limited
to, the treatment of inflammation in a subject, and for treatment
of other inflammation-associated disorders, such as, as an
analgesic in the treatment of pain and headaches, or as an
antipyretic for the treatment of fever. For example, compounds of
the invention would be useful to treat arthritis, including but not
limited to rheumatoid arthritis, spondyloarthopathies, gouty
arthritis, osteoarthritis, systemic lupus erythematosus and
juvenile arthritis. Such compounds of the invention would be useful
in the treatment of asthma, bronchitis, menstrual cramps,
tendinitis, bursitis, and skin-related conditions such as
psoriasis, eczema, burns and dermatitis. Compounds of the invention
also would be useful to treat gastrointestinal conditions such as
inflammatory bowel disease, Crohn's disease, gastritis, irritable
bowel syndrome and ulcerative colitis and for the prevention or
treatment of cancer, such as colorectal cancer. Compounds of the
invention would be useful in treating inflammation in such diseases
as vascular diseases, migraine headaches, periarteritis nodosa,
thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma,
rheumatic fever, type I diabetes, myasthenia gravis, multiple
sclerosis, sarcoidosis, nephrotic syndrome, Behcet's syndrome,
polymyositis, gingivitis, hypersensitivity, swelling occurring
after injury, myocardial ischemia, and the like. The compounds
would also be useful in the treatment of ophthalmic diseases such
as retinitis, retinopathies, uveitis, conjunctivitis, and of acute
injury to the eye tissue. The compounds would also be useful in the
treatment of pulmonary inflammation, such as that associated with
viral infections and cystic fibrosis. The compounds would also be
useful for the treatment of certain central nervous system
disorders such as Alzheimer's disease and dementia. The compounds
of the invention are useful as anti-inflammatory agents, such as
for the treatment of arthritis, with the additional benefit of
having significantly less harmful side effects. These compounds
would also be useful in the treatment of allergic rhinitis,
respiratory distress syndrome, endotoxin shock syndrome,
atherosclerosis and central nervous system damage resulting from
stroke, ischemia and trauma.
[0011] Besides being useful for human treatment, these compounds
are also useful for veterinary treatment of mammals, including
companion animals and farm animals, such as, but not limited to,
horses, dogs, cats, sheep and pigs.
[0012] The present compounds may also be used in co-therapies,
partially or completely, in place of other conventional
anti-inflammatories, such as together with steroids, NSAIDs,
5-lipoxygenase inhibitors, LTB.sub.4 antagonists and LTA.sub.4
hydrolase inhibitors.
[0013] Suitable LTB.sub.4 inhibitors include, among others,
ebselen, Bayer Bay-x-1005, Ciba Geigy compound CGS-25019C, Leo
Denmark compound ETH-615, Lilly compound LY-293111, Ono compound
ONO-4057, Terumo compound TMK-688, Lilly compounds LY-213024,
264086 and 292728, ONO compound ONO-LB457, Searle compound
SC-53228, calcitrol, Lilly compounds LY-210073, LY223982, LY233469,
and LY255283, ONO compound ONO-LB-448, Searle compounds SC-41930,
SC-50605 and SC-51146, and SK&F compound SKF-104493.
Preferably, the LTB.sub.4 inhibitors are selected from ebselen,
Bayer Bay-x-1005, Ciba Geigy compound CGS-25019C, Leo Denmark
compound ETH-615, Lilly compound LY-293111, Ono compound ONO-4057,
and Terumo compound TMK-688.
[0014] Suitable 5-LO inhibitors include, among others, masoprocol,
tenidap, zileuton, pranlukast, tepoxalin, rilopirox, flezelastine
hydrochloride, enazadrem phosphate, and bunaprolast.
[0015] The present invention preferably includes compounds which
selectively inhibit cyclooxygenase-2 over cyclooxygenase-1.
Preferably, the compounds have a cyclooxygenase-2 IC.sub.50 of less
than about 0.2 .mu.M, and also have a selectivity ratio of
cyclooxygenase-2 inhibition over cyclooxygenase-1 inhibition of at
least 50, and more preferably of at least 100. Even more
preferably, the compounds have a cyclooxygenase-1 IC.sub.50 of
greater than about 1 .mu.M, and more preferably of greater than 10
.mu.M. Such preferred selectivity may indicate an ability to reduce
the incidence of common NSAID-induced side effects.
[0016] A preferred class of compounds consists of those compounds
of Formula I wherein A is selected from phenyl, naphthyl,
5-membered heteroaryl and 6-membered heteroaryl, wherein A is
optionally substituted with one or more radicals selected from
lower alkyl, halo, lower alkoxy, lower alkylthio, cyano, lower
haloalkyl, amino, lower alkylamino, lower dialkylamino, lower
haloalkoxy, lower hydroxyalkyl, lower alkoxyalkyl, hydroxyl and
mercapto; wherein each of R.sup.1 through R.sup.4, is independently
selected from hydrido and halo; or wherein R.sup.2 and R.sup.3
together form --O(CH.sub.2).sub.nO--; wherein n is 1 or 2,
inclusive; and wherein each of R.sup.5 through R.sup.9 is
independently selected from hydrido, lower alkyl, halo, lower
alkoxy, lower alkylthio, cyano, lower haloalkyl, amino, lower
alkylamino, lower dialkylamino, lower haloalkoxy, lower
hydroxyalkyl, lower alkoxyalkyl, hydroxyl, mercapto, aminosulfonyl
and lower alkylsulfonyl; or a pharmaceutically-acceptable salt
thereof.
[0017] A more preferred class of compounds consists of those
compounds of Formula I wherein A is selected from phenyl, naphthyl,
5-membered heteroaryl and 6-membered heteroaryl, wherein A is
optionally substituted with one or more radicals selected from
lower alkyl, halo, lower alkoxy, lower haloalkyl and lower
dialkylamino; wherein each of R.sup.1 through R.sup.4 is
independently selected from hydrido and halo; or wherein R.sup.2
and R.sup.3 together form --O(CH.sub.2).sub.nO--; wherein n is 1 or
2, inclusive; wherein each of R.sup.5, R.sup.6, R.sup.8 and R.sup.9
is hydrido; and wherein R.sup.7 is selected from aminosulfonyl and
lower alkylsulfonyl; or a pharmaceutically-acceptable salt
thereof.
[0018] Within Formula I there is a subclass of compounds which
consists of compounds wherein A is selected from phenyl, naphthyl,
5-membered heteroaryl and 6-membered heteroaryl, wherein A is
optionally substituted with one or more radicals selected from
lower alkyl, halo, lower alkoxy, lower haloalkyl and lower
dialkylamino; wherein each of R.sup.1 through R.sup.4 is
independently selected from hydrido and halo; or wherein R.sup.2
and R.sup.3 together form --OCH.sub.2O--; and wherein R.sup.7 is
aminosulfonyl; or a pharmaceutically-acceptable salt thereof.
[0019] A class of compounds of particular interest consists of
those compounds of Formula I wherein A is selected from phenyl,
thienyl, furyl, pyrazolyl, pyrrolyl, thiazolyl, oxazolyl,
isoxazolyl, isothiazolyl, triazolyl and pyridyl, wherein A is
optionally substituted with one or more radicals selected from
methyl, ethyl, fluoro, chloro, bromo, methoxy, ethoxy, propoxy,
n-butoxy, methylenedioxy, ethylenedioxy, fluoromethyl,
difluoromethyl, difluorochloromethyl, trifluoromethyl,
dichloroethyl, dichlorofluoromethyl, chloromethyl, dichloromethyl,
trichloromethyl, pentafluoroethyl, heptafluoropropyl,
difluoroethyl, difluoropropyl, dichloropropyl,
N-ethyl-N-methylamino, N,N-dimethylamino and N,N-diethylamino;
wherein each of R.sup.1 through R.sup.4 is independently selected
from hydrido, fluoro, chloro and bromo; or wherein R.sup.2 and
R.sup.3 together form --OCH.sub.2O--; wherein R.sup.5, R.sup.6,
R.sup.8 and R.sup.9 are hydrido; and wherein R.sup.7 is
aminosulfonyl; or a pharmaceutically-acceptable salt thereof.
[0020] Within Formula I there is a second subclass of compounds of
high interest wherein A is selected from phenyl, naphthyl,
5-membered heteroaryl and 6-membered heteroaryl, wherein A is
optionally substituted with one or more radicals selected from
lower alkyl, halo, lower alkoxy, lower haloalkyl and lower
dialkylamino; wherein each of R.sup.1 through R.sup.4 is
independently selected from hydrido and halo; or wherein R.sup.2
and R.sup.3 together form --OCH.sub.2O--; and wherein R.sup.7 is
lower alkylsulfonyl; or a pharmaceutically-acceptable salt
thereof.
[0021] A class of compounds of particular interest consists of
those compounds of Formula I wherein A is selected from phenyl,
thienyl, furyl, pyrazolyl, pyrrolyl, thiazolyl, oxazolyl,
isoxazolyl, isothiazolyl, triazolyl and pyridyl, wherein A is
optionally substituted with one or more radicals selected from
methyl, ethyl, fluoro, chloro, bromo, methoxy, ethoxy, propoxy,
n-butoxy, methylenedioxy, ethylenedioxy, fluoromethyl,
difluoromethyl, difluorochloromethyl, trifluoromethyl,
dichloroethyl, dichlorofluoromethyl, chloromethyl, dichloromethyl,
trichloromethyl, pentafluoroethyl, heptafluoropropyl,
difluoroethyl, difluoropropyl, dichloropropyl,
N-ethyl-N-methylamino, N,N-dimethylamino and N,N-diethylamino;
wherein each of R.sup.1 through R.sup.4 is independently selected
from hydrido, fluoro, chloro and bromo; or wherein R.sup.2 and
R.sup.3 together form --OCH.sub.2O--; wherein R.sup.5, R.sup.6,
R.sup.8 and R.sup.9 are hydrido; and wherein R.sup.7 is
methylsulfonyl; or a pharmaceutically-acceptable salt thereof.
[0022] A family of specific compounds of particular interest within
Formula I consists of compounds and pharmaceutically-acceptable
salts thereof as follows:
[0023] 4-[2-biphenyl]benzenesulfonamide;
[0024] 4-[2-(3-methylphenyl)phenyl]benzenesulfonamide;
[0025] 4-[2-(3-methoxyphenyl)phenyl]benzenesulfonamide;
[0026] 4-[2-(3-fluorophenyl)phenyl]benzenesulfonamide;
[0027] 4-[2-(3-chlorophenyl)phenyl]benzenesulfonamide;
[0028] 4-[2-(3-trifluoromethylphenyl)phenyl]benzenesulfonamide;
[0029]
4-[2-[3-(N,N-dimethylamino)phenyl]phenyl]benzenesulfonamide;
[0030] 4-[2-(4-methylphenyl)phenyl]benzenesulfonamide;
[0031] 4-[2-(3,4-dimethylphenyl)phenyl]benzenesulfonamide;
[0032]
4-[2-(3-methoxy-4-methylphenyl)phenyl]benzenesulfonamide;
[0033] 4-[2-(3-fluoro-4-methylphenyl)phenyl]benzenesulfonamide;
[0034] 4-[2-(3-chloro-4-methylphenyl)phenyl]benzenesulfonamide;
[0035]
4-[2-(4-methyl-3-trifluoromethylphenyl)phenyl]benzenesulfonamide;
[0036]
4-[2-[3-(N,N-dimethylamino)-4-methylphenyl]phenyl]benzenesulfonamid-
e;
[0037] 4-[2-(4-methoxyphenyl)phenyl]benzenesulfonamide;
[0038]
4-[2-(4-methoxy-3-methylphenyl)phenyl]benzenesulfonamide;
[0039] 4-[2-(3,4-dimethoxyphenyl)phenyl]benzenesulfonamide;
[0040]
4-[2-(3-fluoro-4-methoxyphenyl)phenyl]benzenesulfonamide;
[0041]
4-[2-(3-chloro-4-methoxyphenyl)phenyl]benzenesulfonamide;
[0042]
4-[2-(4-methoxy-3-trifluoromethylphenyl)phenyl]benzenesulfonamide;
[0043]
4-[2-[3-(N,N-dimethylamino)-4-methoxyphenyl]phenyl]benzenesulfonami-
de;
[0044] 4-[2-(4-fluorophenyl)phenyl]benzenesulfonamide;
[0045] 4-[2-(4-fluoro-3-methylphenyl)phenyl]benzenesulfonamide;
[0046]
4-[2-(4-fluoro-3-methoxyphenyl)phenyl]benzenesulfonamide;
[0047] 4-[2-(3,4-difluorophenyl)phenyl]benzenesulfonamide;
[0048] 4-[2-(3-chloro-4-fluorophenyl)phenyl]benzenesulfonamide;
[0049]
4-[2-(4-fluoro-3-trifluoromethylphenyl)phenyl]benzenesulfonamide;
[0050]
4-[2-[3-(N,N-dimethylamino)-4-fluorophenyl]phenyl]benzenesulfonamid-
e;
[0051] 4-[2-(4-chlorophenyl)phenyl]benzenesulfonamide;
[0052] 4-[2-(4-chloro-3-methylphenyl)phenyl]benzenesulfonamide;
[0053]
4-[2-(4-chloro-3-methoxyphenyl)phenyl]benzenesulfonamide;
[0054] 4-[2-(4-chloro-3-fluorophenyl)phenyl]benzenesulfonamide;
[0055] 4-[2-(3,4-dichlorophenyl)phenyl]benzenesulfonamide;
[0056]
4-[2-(4-chloro-3-trifluoromethylphenyl)phenyl]benzenesulfonamide;
[0057]
4-[2-[4-chloro-3-(N,N-dimethylamino)phenyl]phenyl]benzenesulfonamid-
e;
[0058] 4-[2-(4-trifluoromethylphenyl)phenyl]benzenesulfonamide;
[0059]
4-[2-(3-methyl-4-trifluoromethylphenyl)phenyl]benzenesulfonamide;
[0060]
4-[2-(3-methoxy-4-trifluoromethylphenyl)phenyl]benzenesulfonamide;
[0061]
4-[2-(3-fluoro-4-trifluoromethylphenyl)phenyl]benzenesulfonamide;
[0062]
4-[2-(3-chloro-4-trifluoromethylphenyl)phenyl]benzenesulfonamide;
[0063]
4-[2-[3,4-di(trifluoromethyl)phenyl]phenyl]benzenesulfonamide;
[0064]
4-[2-[3-(N,N-dimethylamino)-4-trifluoromethylphenyl]phenyl]benzenes-
ulfonamide;
[0065]
4-[2-[4-(N,N-dimethylamino)phenyl]phenyl]benzenesulfonamide;
[0066]
4-[2-[4-(N,N-dimethylamino)-3-methylphenyl]phenyl]benzenesulfonamid-
e;
[0067]
4-[2-[4-(N,N-dimethylamino)-3-methoxyphenyl]phenyl]benzenesulfonami-
de;
[0068]
4-[2-[4-(N,N-dimethylamino)-3-fluorophenyl]phenyl]benzenesulfonamid-
e;
[0069]
4-[2-[3-chloro-4-(N,N-dimethylamino)phenyl]phenyl]benzenesulfonamid-
e;
[0070]
4-[2-[4-(N,N-dimethylamino)-3-trifluoromethylphenyl]phenyl]benzenes-
ulfonamide;
[0071]
4-[2-[3,4-di(N,N-dimethylamino)phenyl]phenyl]benzenesulfonamide;
[0072] 4-[2-(3,5-dimethylphenyl)phenyl]benzenesulfonamide;
[0073] 4-[2-(3,5-dimethoxyphenyl)phenyl]benzenesulfonamide;
[0074] 4-[2-(3,5-difluorophenyl)phenyl]benzenesulfonamide;
[0075] 4-[2-(3,5-dichlorophenyl)phenyl]benzenesulfonamide;
[0076]
4-[2-[3,5-di(trifluoromethyl)phenyl]phenyl]benzenesulfonamide;
[0077]
4-[2-[3,5-di(N,N-dimethylamino)phenyl]phenyl]benzenesulfonamide;
[0078] 4-[2-(3,4,5-trimethylphenyl)phenyl]benzenesulfonamide;
[0079]
4-[2-(3,5-dimethoxy-4-methylphenyl)phenyl]benzenesulfonamide;
[0080]
4-[2-(3,5-difluoro-4-methylphenyl)phenyl]benzenesulfonamide;
[0081]
4-[2-(3,5-dichloro-4-methylphenyl)phenyl]benzenesulfonamide;
[0082]
4-[2-[3,5-di(trifluoromethyl)-4-methylphenyl]phenyl]benzenesulfonam-
ide;
[0083]
4-[2-[3,5-di(N,N-dimethylamino)-4-methylphenyl]phenyl]benzenesulfon-
amide;
[0084]
4-[2-(3,5-dimethyl-4-methoxyphenyl)phenyl]benzenesulfonamide;
[0085] 4-[2-(3,4,5-trimethoxyphenyl)phenyl]benzenesulfonamide;
[0086]
4-[2-(3,5-difluoro-4-methoxyphenyl)phenyl]benzenesulfonamide;
[0087]
4-[2-(3,5-dichloro-4-methoxyphenyl)phenyl]benzenesulfonamide;
[0088]
4-[2-[3,5-di(trifluoromethyl)-4-methoxyphenyl]phenyl]benzenesulfona-
mide;
[0089]
4-[2-[3,5-di(N,N-dimethylamino)-4-methoxyphenyl]phenyl]benzenesulfo-
namide;
[0090]
4-[2-(3,5-dimethyl-4-fluorophenyl)phenyl]benzenesulfonamide;
[0091]
4-[2-(3,5-dimethoxy-4-fluorophenyl)phenyl]benzenesulfonamide;
[0092] 4-[2(3,4,5-trifluorophenyl)phenyl]benzenesulfonamide;
[0093]
4-[2-(3,5-dichloro-4-fluorophenyl)phenyl]benzenesulfonamide;
[0094]
4-[2-[3,5-di(trifluoromethyl)-4-fluorophenyl]phenyl]benzenesulfonam-
ide;
[0095]
4-[2-[3,5-di(N,N-dimethylamino)-4-fluorophenyl]phenyl]benzenesulfon-
amide;
[0096]
4-[2-(4-chloro-3,5-dimethylphenyl)phenyl]benzenesulfonamide;
[0097]
4-[2-(4-chloro-3,5-dimethoxyphenyl)phenyl]benzenesulfonamide;
[0098]
4-[2-(4-chloro-3,5-difluorophenyl)phenyl]benzenesulfonamide;
[0099] 4-[2-(3,4,5-trichlorophenyl)phenyl]benzenesulfonamide;
[0100]
4-[2-[4-chloro-3,5-di(trifluoromethyl)phenyl]phenyl]benzenesulfonam-
ide;
[0101]
4-[2-[4-chloro-3,5-di(N,N-dimethylamino)phenyl]phenyl]benzenesulfon-
amide;
[0102]
4-[2-(3,5-dimethyl-4-trifluoromethylphenyl)phenyl]benzenesulfonamid-
e;
[0103]
4-[2-(3,5-dimethoxy-4-trifluoromethylphenyl)phenyl]benzenesulfonami-
de;
[0104]
4-[2-(3,5-difluoro-4-trifluoromethylphenyl)phenyl]benzenesulfonamid-
e;
[0105]
4-[2-(3,5-dichloro-4-trifluoromethylphenyl)phenyl]benzenesulfonamid-
e;
[0106]
1-[2-[3,4,5-tri(trifluoromethyl)-phenyl]phenyl]benzenesulfonamide;
[0107]
4-[2-[3,5-di(N,N-dimethylamino)-4-trifluoromethylphenyl]phenyl]benz-
enesulfonamide;
[0108]
4-[2-[3,5-dimethyl-4-(N,N-dimethylamino)phenyl]phenyl]benzenesulfon-
amide;
[0109]
4-[2-[3,5-dimethoxy-4-(N,N-dimethylamino)phenyl]phenyl]benzenesulfo-
namide;
[0110]
4-[2-[3,5-difluoro-4-(N,N-dimethylamino)phenyl]phenyl]benzenesulfon-
amide;
[0111]
4-[2-[3,5-dichloro-4-(N,N-dimethylamino)phenyl]phenyl]benzenesulfon-
amide;
[0112]
4-[2-[4-(N,N-dimethylamino)-3,5-di(trifluoromethyl)phenyl]phenyl]be-
nzenesulfonamide;
[0113]
4-[2-[3,4,5-tri(N,N-dimethylamino)phenyl]phenyl]benzenesulfonamide;
[0114] 4-[6-phenyl-1,3-benzodioxol-5-yl]benzenesulfonamide;
[0115]
4-[6-(3-methylphenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
[0116]
4-[6-(3-fluorophenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
[0117]
4-[6-(3-chlorophenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
[0118]
4-[6-(3-methoxyphenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
[0119]
4-[6-(3-trifluoromethylphenyl)-1,3-benzodioxol-5-yl]benzenesulfonam-
ide;
[0120]
4-[6-[3-(N,N-dimethylamino)phenyl]-1,3-benzodioxol-5-yl]benzenesulf-
onamide;
[0121]
4-[6-(4-methylphenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
[0122]
4-[6-(3,4-dimethylphenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
[0123]
4-[6-(3-fluoro-4-methylphenyl)-1,3-benzodioxol-5-yl]benzenesulfonam-
ide;
[0124]
4-[6-(3-chloro-4-methylphenyl)-1,3-benzodioxol-5-yl]benzenesulfonam-
ide;
[0125]
4-[6-(3-methoxy-4-methylphenyl)-1,3-benzodioxol-5-yl]benzenesulfona-
mide;
[0126]
4-[6-(4-methyl-3-trifluoromethylphenyl)-1,3-benzodioxol-5-yl]benzen-
esulfonamide;
[0127]
4-[6-[3-(N,N-dimethylamino)-4-methylphenyl]-1,3-benzodioxol-5-yl]be-
nzenesulfonamide;
[0128]
4-[6-(4-methoxyphenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
[0129]
4-[6-(4-methoxy-3-methylphenyl)-1,3-benzodioxol-5-yl]benzenesulfona-
mide;
[0130]
4-[6-(3-fluoro-4-methoxyphenyl)-1,3-benzodioxol-5-yl]benzenesulfona-
mide;
[0131]
4-[6-(3-chloro-4-methoxyphenyl)-1,3-benzodioxol-5-yl]benzenesulfona-
mide;
[0132]
4-[6-(3,4-dimethoxyphenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
[0133]
4-[6-(4-methoxy-3-trifluoromethylphenyl)-1,3-benzodioxol-5-yl]benze-
nesulfonamide;
[0134]
4-[6-[3-(N,N-dimethylamino)--4-methoxyphenyl]-1,3-benzodioxol-5-yl]-
benzenesulfonamide;
[0135]
4-[6-(4-fluorophenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
[0136]
4-[6-(4-fluoro-3-methylphenyl)-1,3-benzodioxol-5-yl]benzenesulfonam-
ide;
[0137]
4-[6-(3,4-difluorophenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
[0138]
4-[6-(3-chloro-4-fluorophenyl)-1,3-benzodioxol-5-yl]benzenesulfonam-
ide;
[0139]
4-[6-(4-fluoro-3-methoxyphenyl)-1,3-benzodioxol-5-yl]benzenesulfona-
mide;
[0140]
4-[6-(4-fluoro-3-trifluoromethylphenyl)-1,3-benzodioxol-5-yl]benzen-
esulfonamide;
[0141]
4-[6-[3-(N,N-dimethylamino)-4-fluorophenyl]-1,3-benzodioxol-5-yl]be-
nzenesulfonamide;
[0142]
4-[6-(4-chlorophenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
[0143]
4-[6-(4-chloro-3-methylphenyl)-1,3-benzodioxol-5-yl]benzenesulfonam-
ide;
[0144]
4-[6-(4-chloro-3-fluorophenyl)-1,3-benzodioxol-5-yl]benzenesulfonam-
ide;
[0145]
4-[6-(3,4-dichlorophenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
[0146]
4-[6-(4-chloro-3-methoxyphenyl)-1,3-benzodioxol-5-yl]benzenesulfona-
mide;
[0147]
4-[6-(4-chloro-3-trifluoromethylphenyl)-1,3-benzodioxol-5-yl]benzen-
esulfonamide;
[0148]
4-[6-[4-chloro-3-(N,N-dimethylamino)phenyl]-1,3-benzodioxol-5-yl]be-
nzenesulfonamide;
[0149]
4-[6-(4-trifluoromethylphenyl)-1,3-benzodioxol-5-yl]benzenesulfonam-
ide;
[0150]
4-[6-(3-methyl-4-trifluoromethylphenyl)-1,3-benzodioxol-5-yl]benzen-
esulfonamide;
[0151]
4-[6-(3-fluoro-4-trifluoromethylphenyl)-1,3-benzodioxol-5-yl]benzen-
esulfonamide;
[0152]
4-[6-(3-chloro-4-trifluoromethylphenyl)-1,3-benzodioxol-5-yl]benzen-
esulfonamide;
[0153]
4-[6-(3-methoxy-4-trifluoromethylphenyl)-1,3-benzodioxol-5-yl]benze-
nesulfonamide;
[0154]
4-[6-[3,4-di(trifluoromethyl)phenyl]-1,3-benzodioxol-5-yl]benzenesu-
lfonamide;
[0155]
4-[6-[3-(N,N-dimethylamino)-4-trifluoromethylphenyl]-1,3-benzodioxo-
l-5-yl]benzenesulfonamide;
[0156]
4-[6-[4-(N,N-dimethylamino)phenyl]-1,3-benzodioxol-5-yl]benzenesulf-
onamide;
[0157]
4-[6-[4-(N,N-dimethylamino)-3-methylphenyl]-1,3-benzodioxol-5-yl]be-
nzenesulfonamide;
[0158]
4-[6-[4-(N,N-dimethylamino)-3-fluorophenyl]-1,3-benzodioxol-5-yl]be-
nzenesulfonamide;
[0159]
4-[6-[3-chloro-4-(N,N-dimethylamino)phenyl]-1,3-benzodioxol-5-yl]be-
nzenesulfonamide;
[0160]
4-[6-[4-(N,N-dimethylamino)-3-methoxyphenyl]-1,3-benzodioxol-5-yl]b-
enzenesulfonamide;
[0161]
4-[6-[4-(N,N-dimethylamino)-3-trifluoromethylphenyl]-1,3-benzodioxo-
l-5-yl]benzenesulfonamide;
[0162]
4-[6-[3,4-di(N,N-dimethylamino)phenyl]-1,3-benzodioxol-5-yl]benzene-
sulfonamide;
[0163]
4-[6-(3,5-dimethylphenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
[0164]
4-[6-(3,5-difluorophenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
[0165]
4-[6-(3,5-dichlorophenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
[0166]
4-[6-(3,5-dimethoxyphenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide;
[0167]
4-[6-[3,5-di(trifluoromethyl)phenyl]-1,3-benzodioxol-5-yl]benzenesu-
lfonamide;
[0168]
4-[6-[3,5-di(N,N-dimethylamino)phenyl]-1,3-benzodioxol-5-yl]benzene-
sulfonamide;
[0169]
4-[6-(3,4,5-trimethylphenyl)-1,3-benzodioxol-5-yl]benzenesulfonamid-
e;
[0170]
4-[6-(3,5-difluoro-4-methylphenyl)-1,3-benzodioxol-5-yl]benzenesulf-
onamide;
[0171]
4-[6-(3,5-dichloro-4-methylphenyl)-1,3-benzodioxol-5-yl]benzenesulf-
onamide;
[0172]
4-[6-(3,5-dimethoxy-4-methylphenyl)-1,3-benzodioxol-5-yl]benzenesul-
fonamide;
[0173]
4-[6-[3,5-di(trifluoromethyl)-4-methylphenyl]-1,3-benzodioxol-5-yl]-
benzenesulfonamide;
[0174]
4-[6-[3,5-di(N,N-dimethylamino)-4-methylphenyl]-1,3-benzodioxol-5-y-
l]benzenesulfonamide;
[0175]
4-[6-(3,5-dimethyl-4-methoxyphenyl)-1,3-benzodioxol-5-yl]benzenesul-
fonamide;
[0176]
4-[6-(3,5-difluoro-4-methoxyphenyl)-1,3-benzodioxol-5-yl]benzenesul-
fonamide;
[0177]
4-[6-(3,5-dichloro-4-methoxyphenyl)-1,3-benzodioxol-5-yl]benzenesul-
fonamide;
[0178]
4-[6-(3,4,5-trimethoxyphenyl)-1,3-benzodioxol-5-yl]benzenesulfonami-
de;
[0179]
4-[6-[3,5-di(trifluoromethyl)-4-methoxyphenyl]-1,3-benzodioxol-5-yl-
]benzenesulfonamide;
[0180]
4-[6-[3,5-di(N,N-dimethylamino)-4-methoxyphenyl]-1,3-benzodioxol-5--
yl]benzenesulfonamide;
[0181]
4-[6-(3,4,5-trimethylphenyl)-1,3-benzodioxol-5-yl]benzenesulfonamid-
e;
[0182]
4-[6-(3,5-difluoro-4-fluorophenyl)-1,3-benzodioxol-5-yl]benzenesulf-
onamide;
[0183]
4-[6-(3,5-dichloro-4-fluorophenyl)-1,3-benzodioxol-5-yl]benzenesulf-
onamide;
[0184]
4-[6-(3,5-dimethoxy-4-fluorophenyl)-1,3-benzodioxol-5-yl]benzenesul-
fonamide;
[0185]
4-[6-[3,5-di(trifluoromethyl)-4-fluorophenyl]-1,3-benzodioxol-5-yl]-
benzenesulfonamide;
[0186]
4-[6-[3,5-di(N,N-dimethylamino)-4-fluorophenyl]-1,3-benzodioxol-5-y-
l]benzenesulfonamide;
[0187]
4-[6-(4-chloro-3,5-dimethylphenyl)-1,3-benzodioxol-5-yl]benzenesulf-
onamide;
[0188]
4-[6-(4-chloro-3,5-difluorophenyl)-1,3-benzodioxol-5-yl]benzenesulf-
onamide;
[0189]
4-[6-(3,4,5-trichlorophenyl)-1,3-benzodioxol-5-yl]benzenesulfonamid-
e;
[0190]
4-[6-(4-chloro-3,5-dimethoxyphenyl)-1,3-benzodioxol-5-yl]benzenesul-
fonamide;
[0191]
4-[6-[4-chloro-3,5-di(trifluoromethyl)phenyl]-1,3-benzodioxol-5-yl]-
benzenesulfonamide;
[0192]
4-[6-[4-chloro-3,5-di(N,N-dimethylamino)phenyl]-1,3-benzodioxol-5-y-
l]benzenesulfonamide;
[0193]
4-[6-(3,5-dimethyl-4-trifluoromethylphenyl)-1,3-benzodioxol-5-yl]be-
nzenesulfonamide;
[0194]
4-[6-(3,5-difluoro-4-trifluoromethylphenyl)-1,3-benzodioxol-5-yl]be-
nzenesulfonamide;
[0195]
4-[6-(3,5-dichloro-4-trifluoromethylphenyl)-1,3-benzodioxol-5-yl]be-
nzenesulfonamide;
[0196]
4-[6-(3,5-dimethoxy-4-trifluoromethylphenyl)-1,3-benzodioxol-5-yl]b-
enzenesulfonamide;
[0197]
4-[6-[3,4,5-tri(trifluoromethyl)phenyl]-1,3-benzodioxol-5-yl]benzen-
esulfonamide;
[0198]
4-[6-[3,5-di(N,N-dimethylamino)-4-trifluoromethylphenyl]-1,3-benzod-
ioxol-5-yl]benzenesulfonamide;
[0199]
4-[6-[3,5-dimethyl-4-(N,N-dimethylamino)phenyl]-1,3-benzodioxol-5-y-
l]benzenesulfonamide;
[0200]
4-[6-[4-(N,N-dimethylamino)-3,5-difluorophenyl]-1,3-benzodioxol-5-y-
l]benzenesulfonamide;
[0201]
4-[6-[3,5-dichloro-4-(N,N-dimethylamino)phenyl]-1,3-benzodioxol-5-y-
l]benzenesulfonamide;
[0202]
4-[6-[3,5-dimethoxy-4-(N,N-dimethylamino)phenyl]-1,3-benzodioxol-5--
yl]benzenesulfonamide;
[0203]
4-[6-[4-(N,N-dimethylamino)-3,5-di(trifluoromethyl)phenyl]-1,3-benz-
odioxol-5-yl]benzenesulfonamide;
[0204]
4-[6-[3,4,5-tri(N,N-dimethylamino)phenyl]-1,3-benzodioxol-5-yl]benz-
enesulfonamide;
[0205] 4-[4,5-difluoro-2-biphenyl]benzenesulfonamide;
[0206]
4-[4,5-difluoro-2-(3-methylphenyl)phenyl]benzenesulfonamide;
[0207]
4-[4,5-difluoro-2-(3-fluorophenyl)phenyl]benzenesulfonamide;
[0208]
4-[2-(3-chlorophenyl)-4,5-difluorophenyl]benzenesulfonamide;
[0209]
4-[4,5-difluoro-2-(3-methoxyphenyl)phenyl]benzenesulfonamide;
[0210]
4-[4,5-difluoro-2-(3-trifluoromethylphenyl)phenyl]benzenesulfonamid-
e;
[0211]
4-[4,5-difluoro-2-[3-(N,N-dimethylamino)phenyl]phenyl]benzenesulfon-
amide;
[0212]
4-[4,5-difluoro-2-(4-methylphenyl)phenyl]benzenesulfonamide;
[0213]
4-[4,5-difluoro-2-(3,4-dimethylphenyl)phenyl]benzenesulfonamide;
[0214]
4-[4,5-difluoro-2-(3-fluoro-4-methylphenyl)phenyl]benzenesulfonamid-
e;
[0215]
4-[2-(3-chloro-4-methylphenyl)-4,5-difluorophenyl]benzenesulfonamid-
e;
[0216]
4-[4,5-difluoro-2-(3-methoxy-4-methylphenyl)phenyl]benzenesulfonami-
de;
[0217]
4-[4,5-difluoro-2-(4-methyl-3-trifluoromethylphenyl)phenyl]benzenes-
ulfonamide;
[0218]
4-[4,5-difluoro-2-[3-(N,N-dimethylamino)-4-methylphenyl]phenyl]benz-
enesulfonamide;
[0219]
4-[4,5-difluoro-2-(4-methoxyphenyl)phenyl]benzenesulfonamide;
[0220]
4-[4,5-difluoro-2-(4-methoxy-3-methylphenyl)phenyl]benzenesulfonami-
de;
[0221]
4-[4,5-difluoro-2-(3-fluoro-4-methoxyphenyl)phenyl]benzenesulfonami-
de;
[0222]
4-[2-(3-chloro-4-methoxyphenyl)-4,5-difluorophenyl]benzenesulfonami-
de;
[0223]
4-[4,5-difluoro-2-(3,4-dimethoxyphenyl)phenyl]benzenesulfonamide;
[0224]
4-[4,5-difluoro-2-(4-methoxy-3-trifluoromethylphenyl)phenyl]benzene-
sulfonamide;
[0225]
4-[4,5-difluoro-2-[3-(N,N-dimethylamino)-4-methoxyphenyl]phenyl]ben-
zenesulfonamide;
[0226]
4-[4,5-difluoro-2-(4-fluorophenyl)phenyl]benzenesulfonamide;
[0227]
4-[4,5-difluoro-2-(4-fluoro-3-methylphenyl)phenyl]benzenesulfonamid-
e;
[0228]
4-[4,5-difluoro-2-(3,4-difluorophenyl)phenyl]benzenesulfonamide;
[0229]
4-[4,5-difluoro-2-(3-chloro-4-fluorophenyl)phenyl]benzenesulfonamid-
e;
[0230]
4-[4,5-difluoro-2-(4-fluoro-3-methoxyphenyl)phenyl]benzenesulfonami-
de;
[0231]
4-[4,5-difluoro-2-(4-fluoro-3-trifluoromethylphenyl)phenyl]benzenes-
ulfonamide;
[0232]
4-[4,5-difluoro-2-[3-(N,N-dimethylamino)-4-fluorophenyl]phenyl]benz-
enesulfonamide;
[0233]
4-[2-(4-chlorophenyl)-4,5-difluorophenyl]benzenesulfonamide;
[0234]
4-[2-(4-chloro-3-methylphenyl)-4,5-difluorophenyl]benzenesulfonamid-
e;
[0235]
4-[2-(4-chloro-3-fluorophenyl)-4,5-difluorophenyl]benzenesulfonamid-
e;
[0236]
4-[2-(3,4-dichlorophenyl)-4,5-difluorophenyl]benzenesulfonamide;
[0237]
4-[2-(4-chloro-3-methoxyphenyl)-4,5-difluorophenyl]benzenesulfonami-
de;
[0238]
4-[2-(4-chloro-3-trifluoromethylphenyl)-4,5-difluorophenyl]benzenes-
ulfonamide;
[0239]
4-[2-[4-chloro-3-(N,N-dimethylamino)phenyl]-4,5-difluorophenyl]benz-
enesulfonamide;
[0240]
4-[4,5-difluoro-2-[4-(trifluoromethyl)phenyl]phenyl]benzenesulfonam-
ide;
[0241]
4-[4,5-difluoro-2-(3-methyl-4-trifluoromethylphenyl)phenyl]benzenes-
ulfonamide;
[0242]
4-[4,5-difluoro-2-(3-fluoro-4-trifluoromethylphenyl)phenyl]benzenes-
ulfonamide;
[0243]
4-[2-(3-chloro-4-trifluoromethylphenyl)-4,5-difluorophenyl]benzenes-
ulfonamide;
[0244]
4-[4,5-difluoro-2-[3-methoxy-4-(trifluoromethyl)phenyl]phenyl]benze-
nesulfonamide;
[0245]
4-[4,5-difluoro-2-[3,4-di(trifluoromethyl)phenyl]phenyl]benzenesulf-
onamide;
[0246]
4-[4,5-difluoro-2-[3-(N,N-dimethylamino)-4-trifluoromethylphenyl]ph-
enyl]benzenesulfonamide;
[0247]
4-[4,5-difluoro-2-[4-(N,N-dimethylamino)phenyl]phenyl]benzenesulfon-
amide;
[0248]
4-[4,5-difluoro-2-[4-(N,N-dimethylamino)-3-methylphenyl]phenyl]benz-
enesulfonamide;
[0249]
4-[4,5-difluoro-2-[4-(N,N-dimethylamino)-3-fluorophenyl]phenyl]benz-
enesulfonamide;
[0250]
4-[2-[3-chloro-4-(N,N-dimethylamino)phenyl]-4,5-difluorophenyl]benz-
enesulfonamide;
[0251]
4-[4,5-difluoro-2-[4-(N,N-dimethylamino)-3-methoxyphenyl]phenyl]ben-
zenesulfonamide;
[0252]
4-[4,5-difluoro-2-[4-(N,N-dimethylamino)-3-(trifluoromethyl)phenyl]-
phenyl]benzenesulfonamide;
[0253]
4-[4,5-difluoro-2-[3,4-di(N,N-dimethylamino)phenyl]phenyl]benzenesu-
lfonamide;
[0254]
4-[4,5-difluoro-2-(3,5-dimethylphenyl)phenyl]benzenesulfonamide;
[0255]
4-[4,5-difluoro-2-(3,5-difluorophenyl)phenyl]benzenesulfonamide;
[0256]
4-[2-(3,5-dichlorophenyl)-4,5-difluorophenyl]benzenesulfonamide;
[0257]
4-[4,5-difluoro-2-(3,5-dimethoxyphenyl)phenyl]benzenesulfonamide;
[0258]
4-[4,5-difluoro-2-[3,5-di(trifluoromethyl)phenyl]phenyl]benzenesulf-
onamide;
[0259]
4-[4,5-difluoro-2-[3,5-di(N,N-dimethylamino)phenyl]phenyl]benzenesu-
lfonamide;
[0260]
4-[4,5-difluoro-2-(3,4,5-trimethylphenyl)phenyl]benzenesulfonamide;
[0261]
4-[4,5-difluoro-2-(3,5-difluoro-4-methylphenyl)phenyl]benzenesulfon-
amide;
[0262] 4-[2-(3,5-dichloro-4-methylphenyl)
4,5-difluorophenyl]benzenesulfon- amide;
[0263]
4-[4,5-difluoro-2-(3,5-dimethoxy-4-methylphenyl)phenyl]benzenesulfo-
namide;
[0264]
4-[4,5-difluoro-2-[3,5-di(trifluoromethyl)-4-methylphenyl]phenyl]be-
nzenesulfonamide;
[0265]
4-[4,5-difluoro-2-[3,5-di(N,N-dimethylamino)-4-methylphenyl]phenyl]-
benzenesulfonamide;
[0266]
4-[4,5-difluoro-2-(3,5-dimethyl-4-methoxyphenyl)phenyl]benzenesulfo-
namide;
[0267]
4-[4,5-difluoro-2-(3,5-difluoro-4-methoxyphenyl)phenyl]benzenesulfo-
namide;
[0268]
4-[2-(3,5-dichloro-4-methoxyphenyl)-4,5-difluorophenyl]benzenesulfo-
namide;
[0269]
4-[4,5-difluoro-2-(3,4,5-trimethoxyphenyl)phenyl]benzenesulfonamide-
;
[0270]
4-[4,5-difluoro-2-[3,5-di(trifluoromethyl)-4-methoxyphenyl]phenyl]b-
enzenesulfonamide;
[0271]
4-[4,5-difluoro-2-[3,5-di(N,N-dimethylamino)-4-methoxyphenyl]phenyl-
]benzenesulfonamide;
[0272]
4-[4,5-difluoro-2-(3,5-dimethyl-4-fluorophenyl)phenyl]benzenesulfon-
amide;
[0273]
4-[4,5-difluoro-2-(3,4,5-difluorophenyl)phenyl]benzenesulfonamide;
[0274]
4-[2-(3,5-dichloro-4-fluorophenyl)-4,5-difluorophenyl]benzenesulfon-
amide;
[0275]
4-[4,5-difluoro-2-(3,5-dimethoxy-4-fluorophenyl)phenyl]benzenesulfo-
namide;
[0276]
4-[4,5-difluoro-2-[3,5-di(trifluoromethyl)-4-fluorophenyl]phenyl]be-
nzenesulfonamide;
[0277]
4-[4,5-difluoro-2-[3,5-di(N,N-dimethylamino)-4-fluorophenyl]phenyl]-
benzenesulfonamide;
[0278]
4-[2-(4-chloro-3,5-dimethylphenyl)-4,5-difluorophenyl]benzenesulfon-
amide;
[0279]
4-[2-(4-chloro-3,5-difluorophenyl)-4,5-difluorophenyl]benzenesulfon-
amide;
[0280]
4-[4,5-difluoro-2-(3,4,5-trichlorophenyl)phenyl]benzenesulfonamide;
[0281]
4-[2-(4-chloro-3,5-dimethoxyphenyl)-4,5-difluorophenyl]benzenesulfo-
namide;
[0282]
4-[2-[4-chloro-3,5-di(trifluoromethyl)phenyl]-4,5-difluorophenyl]be-
nzenesulfonamide;
[0283]
4-[2-[4-chloro-3,5-di(N,N-dimethylamino)phenyl]-4,5-difluorophenyl]-
benzenesulfonamide;
[0284]
4-[4,5-difluoro-2-[3,5-dimethyl-4-(trifluoromethyl)phenyl]phenyl]be-
nzenesulfonamide;
[0285]
4-[4,5-difluoro-2-[3,5-difluoro-4-(trifluoromethyl)phenyl]phenyl]be-
nzenesulfonamide;
[0286]
4-[2-[3,5-dichloro-4-(trifluoromethyl)phenyl]-4,5-difluorophenyl]be-
nzenesulfonamide;
[0287]
4-[4,5-difluoro-2-[3,5-dimethoxy-4-(trifluoromethyl)phenyl]phenyl]b-
enzenesulfonamide;
[0288]
4-[4,5-difluoro-2-[3,4,5-tri(trifluoromethyl)-phenyl]phenyl]benzene-
sulfonamide;
[0289] 4-[4,5-difluoro-2-[3,5-di
(N,N-dimethylamino)-4-(trifluoromethyl)ph-
enyl]phenyl]benzenesulfonamide;
[0290]
4-[4,5-difluoro-2-[3,5-dimethyl-4-(N,N-dimethylamino)phenyl]phenyl]-
benzenesulfonamide;
[0291]
4-[4,5-difluoro-2-[3,5-difluoro-4-(N,N-dimethylamino)phenyl]phenyl]-
benzenesulfonamide;
[0292]
4-[2-[3,5-dichloro-4-(N,N-dimethylamino)phenyl]-4,5-difluorophenyl]-
benzenesulfonamide;
[0293]
4-[4,5-difluoro-2-[3,5-dimethoxy-4-(N,N-dimethylamino)phenyl]phenyl-
] benzenesulfonamide;
[0294]
4-[4,5-difluoro-2-[3,5-di(trifluoromethyl)-4-(N,N-dimethylamino)phe-
nyl]phenyl]benzenesulfonamide;
[0295] 4-[4,5-difluoro-2-[3,4,5-tri(N,N-dimethylamino)phenyl]phenyl
]benzenesulfonamide;
[0296] 4-[3,4,5,6-tetrafluoro-2-biphenyl]benzenesulfonamide;
[0297]
4-[2-(3-methylphenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
[0298]
4-[2-(3-fluorophenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
[0299]
4-[2-(3-chlorophenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
[0300]
4-[2-(3-methoxyphenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonamide-
;
[0301]
4-[3,4,5,6-tetrafluoro-2-[3-(trifluoromethyl)phenyl]phenyl]benzenes-
ulfonamide;
[0302]
4-[2-[3-(N,N-dimethylamino)phenyl]-3,4,5,6-tetrafluorophenyl]benzen-
esulfonamide;
[0303]
4-[2-(4-methylphenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
[0304]
4-[2-(3,4-dimethylphenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonam-
ide;
[0305]
4-[2-(3-fluoro-4-methylphenyl)-3,4,5,6-tetrafluorophenyl]benzenesul-
fonamide;
[0306]
4-[2-(3-chloro-4-methylphenyl)-3,4,5,6-tetrafluorophenyl]benzenesul-
fonamide;
[0307]
4-[2-(3-methoxy-4-methylphenyl)-3,4,5,6-tetrafluorophenyl]benzenesu-
lfonamide;
[0308]
4-[2-[4-methyl-3-(trifluoromethyl)phenyl]-3,4,5,6-tetrafluorophenyl-
]benzenesulfonamide;
[0309]
4-[2-[3-(N,N-dimethylamino)-4-methylphenyl]-3,4,5,6-tetrafluorophen-
yl]benzenesulfonamide;
[0310]
4-[2-(4-methoxyphenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonamide-
;
[0311]
4-[2-(3-methyl-4-methoxyphenyl)-3,4,5,6-tetrafluorophenyl]benzenesu-
lfonamide;
[0312]
4-[2-(3-fluoro-4-methoxyphenyl)-3,4,5,6-tetrafluorophenyl]benzenesu-
lfonamide;
[0313]
4-[2-(3-chloro-4-methoxyphenyl)-3,4,5,6-tetrafluorophenyl]benzenesu-
lfonamide;
[0314]
4-[2-(3,4-dimethoxyphenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfona-
mide;
[0315]
4-[2-[4-methoxy-3-(trifluoromethyl)phenyl]-3,4,5,6-tetrafluoropheny-
l]benzenesulfonamide;
[0316]
4-[2-[3-(N,N-dimethylamino)-4-methoxyphenyl]-3,4,5,6-tetrafluorophe-
nyl]benzenesulfonamide;
[0317]
4-[2-(4-fluorophenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
[0318]
4-[2-(4-fluoro-3-methylphenyl)-3,4,5,6-tetrafluorophenyl]benzenesul-
fonamide;
[0319]
4-[2-(3,4-difluorophenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonam-
ide;
[0320]
4-[2-(3-chloro-4-fluorophenyl)-3,4,5,6-tetrafluorophenyl]benzenesul-
fonamide;
[0321]
4-[2-(4-fluoro-3-methoxyphenyl)-3,4,5,6-tetrafluorophenyl]benzenesu-
lfonamide;
[0322]
4-[2-[4-fluoro-3-(trifluoromethyl)phenyl]-3,4,5,6-tetrafluorophenyl-
]benzenesulfonamide;
[0323]
4-[2-[3-(N,N-dimethylamino)-4-fluorophenyl]-3,4,5,6-tetrafluorophen-
yl]benzenesulfonamide;
[0324]
4-[2-(4-chlorophenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonamide;
[0325]
4-[2-(4-chloro-3-methylphenyl)-3,4,5,6-tetrafluorophenyl]benzenesul-
fonamide;
[0326]
4-[2-(4-chloro-3-fluorophenyl)-3,4,5,6-tetrafluorophenyl]benzenesul-
fonamide;
[0327]
4-[2-(3,4-dichlorophenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonam-
ide;
[0328]
4-[2-(4-chloro-3-methoxyphenyl)-3,4,5,6-tetrafluorophenyl]benzenesu-
lfonamide;
[0329]
4-[2-(4-chloro-3-trifluoromethylphenyl)-3,4,5,6-tetrafluorophenyl]b-
enzenesulfonamide;
[0330]
4-[2-[4-chloro-3-(N,N-dimethylamino)phenyl]-3,4,5,6-tetrafluorophen-
yl]benzenesulfonamide;
[0331]
4-[3,4,5,6-tetrafluoro-2-[4-(trifluoromethyl)phenyl]phenyl]benzenes-
ulfonamide;
[0332]
4-[2-[3-methyl-4-(trifluoromethyl)phenyl]-3,4,5,6-tetrafluorophenyl-
]benzenesulfonamide;
[0333]
4-[2-[3-fluoro-4-(trifluoromethyl)phenyl]-3,4,5,6-tetrafluorophenyl-
]benzenesulfonamide;
[0334]
4-[2-[3-chloro-4-(trifluoromethyl)phenyl]-3,4,5,6-tetrafluorophenyl-
]benzenesulfonamide;
[0335]
4-[2-[3-methoxy-4-(trifluoromethyl)phenyl]-3,4,5,6-tetrafluoropheny-
l]benzenesulfonamide;
[0336]
4-[2-[3,4-di(trifluoromethyl)phenyl]-3,4,5,6-tetrafluorophenyl]benz-
enesulfonamide;
[0337]
4-[2-[3-(N,N-dimethylamino)-4-(trifluoromethyl)phenyl]-3,4,5,6-tetr-
afluorophenyl]benzenesulfonamide;
[0338]
4-[2-[4-(N,N-dimethylamino)phenyl]-3,4,5,6-tetrafluorophenyl]benzen-
esulfonamide;
[0339]
4-[2-[4-(N,N-dimethylamino)-3-methylphenyl]-3,4,5,6-tetrafluorophen-
yl]benzenesulfonamide;
[0340]
4-[2-[4-(N,N-dimethylamino)-3-fluorophenyl]-3,4,5,6-tetrafluorophen-
yl]benzenesulfonamide;
[0341]
4-[2-[3-chloro-4-(N,N-dimethylamino)phenyl]-3,4,5,6-tetrafluorophen-
yl]benzenesulfonamide;
[0342]
4-[2-[4-(N,N-dimethylamino)-3-methoxyphenyl]-3,4,5,6-tetrafluorophe-
nyl]benzenesulfonamide;
[0343]
4-[2-[4-(N,N-dimethylamino)-3-(trifluoromethyl)phenyl]-3,4,5,6-tetr-
afluorophenyl]benzenesulfonamide;
[0344]
4-[2-[3,4-di(N,N-dimethylamino)phenyl]-3,4,5,6-tetrafluorophenyl]be-
nzenesulfonamide;
[0345]
4-[2-(3,5-dimethylphenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonam-
ide;
[0346]
4-[2-(3,5-difluorophenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonam-
ide;
[0347]
4-[2-(3,5-dichlorophenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfonam-
ide;
[0348]
4-[2-(3,5-dimethoxyphenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfona-
mide;
[0349]
4-[2-[3,5-di(trifluoromethyl)phenyl]-3,4,5,6-tetrafluorophenyl]benz-
enesulfonamide;
[0350]
4-[2-[3,5-di(N,N-dimethylamino)phenyl]-3,4,5,6-tetrafluorophenyl]be-
nzenesulfonamide;
[0351]
4-[2-(3,4,5-trimethylphenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfo-
namide;
[0352]
4-[2-(3,5-difluoro-4-methylphenyl)-3,4,5,6-tetrafluorophenyl]benzen-
esulfonamide;
[0353] 4-[2-(3,5-dichloro-4-methylphenyl)
3,4,5,6-tetrafluorophenyl]benzen- esulfonamide;
[0354]
4-[2-(3,5-dimethoxy-4-methylphenyl)-3,4,5,6-tetrafluorophenyl]benze-
nesulfonamide;
[0355]
4-[2-[3,5-di(trifluoromethyl)-4-methylphenyl]-3,4,5,6-tetrafluoroph-
enyl]benzenesulfonamide;
[0356]
4-[2-[3,5-di(N,N-dimethylamino)-4-methylphenyl]-3,4,5,6-tettafluoro-
phenyl]benzenesulfonamide;
[0357]
4-[2-(3,5-dimethyl-4-methoxyphenyl)-3,4,5,6-tetrafluorophenyl]benze-
nesulfonamide;
[0358]
4-[2-(3,5-difluoro-4-methoxyphenyl)-3,4,5,6-tetrafluorophenyl]benze-
nesulfonamide;
[0359]
4-[2-(3,5-dichloro-4-methoxyphenyl)-3,4,5,6-tetrafluorophenyl]benze-
nesulfonamide;
[0360]
4-[2-(3,4,5-trimethoxyphenyl)-3,4,5,6-tetrafluorophenyl]benzenesulf-
onamide;
[0361]
4-[2-[3,5-di(trifluoromethyl)-4-methoxyphenyl]-3,4,5,6-tetrafluorop-
henyl]benzenesulfonamide;
[0362]
4-[2-[3,5-di(N,N-dimethylamino)-4-methoxyphenyl]-3,4,5,6-tetrafluor-
ophenyl]benzenesulfonamide;
[0363]
4-[2-(3,5-dimethyl-4-fluorophenyl)-3,4,5,6-tetrafluorophenyl]benzen-
esulfonamide;
[0364]
4-[2-(3,4,5-trifluorophenyl)-3,4,5,6-tetrafluorophenyl]benzenesulfo-
namide;
[0365]
4-[2-(3,5-dichloro-4-fluorophenyl)-3,4,5,6-tetrafluorophenyl]benzen-
esulfonamide;
[0366]
4-[2-(3,5-dimethoxy-4-fluorophenyl)-3,4,5,6-tetrafluorophenyl]benze-
nesulfonamide;
[0367]
4-[2-[3,5-di(trifluoromethyl)-4-fluorophenyl]-3,4,5,6-tetrafluoroph-
enyl]benzenesulfonamide;
[0368]
4-[2-[3,5-di(N,N-dimethylamino)-4-fluorophenyl]-3,4,5,6-tetrafluoro-
phenyl]benzenesulfonamide;
[0369]
4-[2-(4-chloro-3,5-dimethylphenyl)-3,4,5,6-tetrafluorophenyl]benzen-
esulfonamide;
[0370]
4-[2-(4-chloro-3,5-difluorophenyl)-3,4,5,6-tetrafluorophenyl]benzen-
esulfonamide;
[0371]
4-[3,4,5,6-tetrafluoro-2-(3,4,5-trichlorophenyl)phenyl]benzenesulfo-
namide;
[0372]
4-[2-(4-chloro-3,5-dimethoxyphenyl)-3,4,5,6-tetrafluorophenyl]benze-
nesulfonamide;
[0373]
4-[2-[4-chloro-3,5-di(trifluoromethyl)phenyl]-3,4,5,6-tetrafluoroph-
enyl]benzenesulfonamide;
[0374]
4-[2-[4-chloro-3,5-di(N,N-dimethylamino)phenyl]-3,4,5,6-tetrafluoro-
phenyl]benzenesulfonamide;
[0375]
4-[2-[3,5-dimethyl-4-(trifluoromethyl)phenyl]-3,4,5,6-tetrafluoroph-
enyl]benzenesulfonamide;
[0376]
4-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]-3,4,5,6-tetrafluoroph-
enyl]benzenesulfonamide;
[0377]
4-[2-[3,5-dichloro-4-(trifluoromethyl)phenyl]-3,4,5,6-tetrafluoroph-
enyl]benzenesulfonamide;
[0378]
4-[2-[3,5-dimethoxy-4-(trifluoromethyl)phenyl]-3,4,5,6-tetrafluorop-
henyl]benzenesulfonamide;
[0379]
4-[2-[3,4,5-tri(trifluoromethyl)phenyl]-3,4,5,6-tetrafluorophenyl]b-
enzenesulfonamide;
[0380]
4-[2-[3,5-di(N,N-dimethylamino)-4-(trifluoromethyl)phenyl]-3,4,5,6--
tetrafluorophenyl]benzenesulfonamide;
[0381]
4-[2-[3,5-dimethyl-4-(N,N-dimethylamino)phenyl]-3,4,5,6-tetrafluoro-
phenyl]benzenesulfonamide;
[0382]
4-[2-[3,5-difluoro-4-(N,N-dimethylamino)phenyl]-3,4,5,6-tetrafluoro-
phenyl]benzenesulfonamide;
[0383]
4-[2-[3,5-dichloro-4-(N,N-dimethylamino)phenyl]-3,4,5,6-tetrafluoro-
phenyl]benzenesulfonamide;
[0384]
4-[2-[3,5-dimethoxy-4-(N,N-dimethylamino)phenyl]3,4,5,6-tetrafluoro-
phenyl]benzenesulfonamide;
[0385]
4-[2-[3,5-di(trifluoromethyl)-4-(N,N-dimethylamino)phenyl]-3,4,5,6--
tetrafluorophenyl]benzenesulfonamide;
[0386]
4-[2-[3,4,5-tri(N,N-dimethylamino)phenyl]-3,4,5,6-tetrafluorophenyl-
]benzenesulfonamide;
[0387] 4-[2-(4-hydroxymethylphenyl)phenyl]benzenesulfonamide;
[0388] 4-[2-(4-methylthiophenyl)phenyl]benzenesulfonamide;
[0389] 4-[2-(4-cyanophenyl)phenyl]benzenesulfonamide;
[0390] 4-[2-(4-aminophenyl)phenyl]benzenesulfonamide;
[0391] 4-[2-(4-hydroxyphenyl)phenyl]benzenesulfonamide;
[0392] 4-[2-[4-(N-methylamino)phenyl]phenyl]benzenesulfonamide;
[0393] 4-[2-(4-methoxymethylphenyl)phenyl]benzenesulfonamide;
[0394]
4-[2-(1,3-benzodioxol-5-yl)-4,5-difluorophenyl]benzenesulfonamide;
[0395]
4-[2-(2,3-dihydro-1,4-benzodioxin-6-yl)-4,5-difluorophenyl]benzenes-
ulfonamide;
[0396]
4-[4,5-difluoro-2-(5-methylpyridin-2-yl)phenyl]benzenesulfonamide;
[0397]
4-[4,5-difluoro-2-(6-methylpyridin-3-yl)phenyl]benzenesulfonamide;
[0398] 4-[4,5-difluoro-2-(2-thienyl)phenyl]benzenesulfonamide;
[0399] 4-[4,5-difluoro-2-(3-furyl)phenyl]benzenesulfonamide;
[0400]
4-[4,5-difluoro-2-(4-hydroxymethylphenyl)phenyl]benzenesulfonamide;
[0401]
4-[4,5-difluoro-2-(4-methylthiophenyl)phenyl]benzenesulfonamide;
[0402]
4-[2-(4-cyanophenyl)-4,5-difluoro-phenyl]benzenesulfonamide;
[0403]
4-[2-(4-aminophenyl)4,5-difluoro-phenyl]benzenesulfonamide;
[0404]
4-[4,5-difluoro-2-(4-hydroxyphenyl)phenyl]benzenesulfonamide;
[0405]
4-[4,5-difluoro-2-[4-(N-methylamino)phenyl]phenyl]benzenesulfonamid-
e; and
[0406]
4-[4,5-difluoro-2-(4-methoxymethylphenyl)phenyl]benzenesulfonamide.
[0407] A second family of specific compounds of particular interest
within Formula I consists of compounds and
pharmaceutically-acceptable salts thereof as follows:
[0408] 2-[4-(methylsulfonyl)phenyl]-1-phenylbenzene;
[0409] 1-(3-methylphenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
[0410] 1-(3-methoxyphenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
[0411] 1-(3-fluorophenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
[0412] 1-(3-chlorophenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
[0413] 1-(4-methylphenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
[0414]
1-(3,4-dimethylphenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
[0415]
1-(3-methoxy-4-methylphenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
[0416]
1-(3-fluoro-4-methylphenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
[0417]
1-(3-chloro-4-methylphenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
[0418] 1-(4-methoxyphenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
[0419]
1-(3-methyl-4-methoxyphenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
[0420]
1-(3,4-dimethoxyphenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
[0421]
2-fluoro-1-methoxy-4-[2-[4-(methylsulfonyl)phenyl]phenyl]benzene;
[0422]
2-chloro-1-methoxy-4-[2-[4-(methylsulfonyl)phenyl]phenyl]benzene;
[0423] 1-(4-fluorophenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
[0424]
1-(4-fluoro-3-methylphenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
[0425]
1-(4-fluoro-3-methoxyphenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
[0426]
1-(3,4-difluorophenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
[0427]
2-chloro-1-fluoro-4-[2-[4-(methylsulfonyl)phenyl]phenyl]benzene;
[0428] 1-(4-chlorophenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
[0429]
1-(4-chloro-3-methylphenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
[0430]
1-(4-chloro-3-methoxyphenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
[0431]
1-(4-chloro-3-fluorophenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
[0432]
1-(3,4-dichlorophenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
[0433]
1-(3,5-dimethylphenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
[0434]
1-(3,5-dimethoxyphenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
[0435]
1-(3,5-difluorophenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
[0436]
1-(3,5-dichlorophenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
[0437]
1-(3,4,5-trimethylphenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
[0438]
1-(3,5-dimethoxy-4-methylphenyl)-2-[4-(methylsulfonyl)phenyl]benzen-
e;
[0439]
1-(3,5-difluoro-4-methylphenyl)-2-[4-(methylsulfonyl)phenyl]benzene-
;
[0440]
1-(3,5-dichloro-4-methylphenyl)-2-[4-(methylsulfonyl)phenyl]benzene-
;
[0441]
1-(3,5-dimethyl-4-methoxyphenyl)-2-[4-(methylsulfonyl)phenyl]benzen-
e;
[0442]
1-(3,4,5-trimethoxyphenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
[0443]
1-(3,5-difluoro-4-methoxyphenyl)-2-[4-(methylsulfonyl)phenyl]benzen-
e;
[0444]
1-(3,5-dichloro-4-methoxyphenyl)-2-[4-(methylsulfonyl)phenyl]benzen-
e;
[0445]
1-(3,5-dimethyl-4-fluorophenyl)-2-[4-(methylsulfonyl)phenyl]benzene-
;
[0446]
1-(3,5-dimethoxy-4-fluorophenyl)-2-[4-(methylsulfonyl)phenyl]benzen-
e;
[0447]
1-(3,4,5-trifluorophenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
[0448]
1-(3,5-dichloro-4-fluorophenyl)-2-[4-(methylsulfonyl)phenyl]benzene-
;
[0449]
1-(4-chloro-3,5-dimethylphenyl)-2-[4-(methylsulfonyl)phenyl]benzene-
;
[0450]
1-(4-chloro-3,5-dimethoxyphenyl)-2-[4-(methylsulfonyl)phenyl]benzen-
e;
[0451]
1-(4-chloro-3,5-difluorophenyl)-2-[4-(methylsulfonyl)phenyl]benzene-
;
[0452]
1-(3,4,5-trichlorophenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
[0453] 6-[4-(methylsulfonyl)phenyl]-5-phenyl-1,3-benzodioxole;
[0454]
5-(3-methylphenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodioxole;
[0455]
5-(3-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodioxole;
[0456]
5-(3-chlorophenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodioxole;
[0457]
5-(3-methoxyphenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodioxole;
[0458]
5-(4-methylphenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodioxole;
[0459]
5-(3,4-dimethylphenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodioxol-
e;
[0460]
5-(3-fluoro-4-methylphenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzod-
ioxole;
[0461]
5-(3-chloro-4-methylphenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzod-
ioxole;
[0462]
5-(3-methoxy-4-methylphenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzo-
dioxole;
[0463]
5-(4-methoxyphenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodioxole;
[0464]
5-(3-methyl-4-methoxyphenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzo-
dioxole;
[0465]
5-(3-fluoro-4-methoxyphenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzo-
dioxole;
[0466]
5-(3-chloro-4-methoxyphenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzo-
dioxole;
[0467]
5-(3,4-dimethoxyphenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodioxo-
le;
[0468]
5-(4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodioxole;
[0469]
5-(4-fluoro-3-methylphenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzod-
ioxole;
[0470]
5-(3,4-difluorophenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodioxol-
e;
[0471]
5-(3-chloro-4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzod-
ioxole;
[0472]
5-(4-fluoro-3-methoxyphenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzo-
dioxole;
[0473]
5-(4-chlorophenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodioxole;
[0474]
5-(4-chloro-3-methylphenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzod-
ioxole;
[0475]
5-(4-chloro-3-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzod-
ioxole;
[0476]
5-(3,4-dichlorophenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodioxol-
e;
[0477]
5-(4-chloro-3-methoxyphenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzo-
dioxole;
[0478]
5-(3,5-dimethylphenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodioxol-
e;
[0479]
5-(3,5-difluorophenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodioxol-
e;
[0480]
5-(3,5-dichlorophenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodioxol-
e;
[0481]
5-(3,5-dimethoxyphenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodioxo-
le;
[0482]
5-(3,4,5-trimethylphenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodio-
xole;
[0483]
5-(3,5-difluoro-4-methylphenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-be-
nzodioxole;
[0484]
5-(3,5-dichloro-4-methylphenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-be-
nzodioxole;
[0485]
5-(3,5-dimethoxy-4-methylphenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-b-
enzodioxole;
[0486]
5-(3,5-dimethyl-4-methoxyphenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-b-
enzodioxole;
[0487]
5-[3,5-difluoro-4-methoxyphenyl)-61(4-(methylsulfonyl)phenyl]-1,3-b-
enzodioxole;
[0488]
5-(3,5-dichloro-4-methoxyphenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-b-
enzodioxole;
[0489]
5-(3,4,5-trimethoxyphenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodi-
oxole;
[0490]
5-(3,5-dimethyl-4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-be-
nzodioxole;
[0491]
5-(3,4,5-trifluorophenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodio-
xole;
[0492]
5-(3,5-dichloro-4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-be-
nzodioxole;
[0493]
5-(3,5-dimethoxy-4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-b-
enzodioxole;
[0494]
5-(4-chloro-3,5-dimethylphenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-be-
nzodioxole;
[0495]
5-(4-chloro-3,5-difluorophenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-be-
nzodioxole;
[0496]
5-(3,4,5-trichlorophenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-benzodio-
xole;
[0497]
5-(4-chloro-3,5-dimethoxyphenyl)-6-[4-(methylsulfonyl)phenyl]-1,3-b-
enzodioxole;
[0498]
1,2-difluoro-5-[4-(methylsulfonyl)phenyl]-4-phenylbenzene;
[0499]
1,2-difluoro-4-(3-methylphenyl)-5-[4-(methylsulfonyl)phenyl]benzene-
;
[0500]
1,2-difluoro-4-(3-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]benzene-
;
[0501]
4-[3-chlorophenyl)-1,2-difluoro-5-[4-(methylsulfonyl)phenyl]benzene-
;
[0502]
1,2-difluoro-4-(3-methoxyphenyl)-5-[4-(methylsulfonyl)phenyl]benzen-
e;
[0503]
1,2-difluoro-4-(4-methylphenyl)-5-(4-(methylsulfonyl)phenyl]benzene-
;
[0504]
1,2-difluoro-4-(3,4-dimethylphenyl)-5-[4-(methylsulfonyl)phenyl]ben-
zene;
[0505]
1,2-difluoro-4-(3-fluoro-4-methylphenyl)-5-[4-(methylsulfonyl)pheny-
l]benzene;
[0506]
4-(3-chloro-4-methylphenyl)-1,2-difluoro-5-[4-(methylsulfonyl)pheny-
l]benzene;
[0507]
1,2-difluoro-4-(3-methoxy-4-methylphenyl)-5-[4-(methylsulfonyl)phen-
yl]benzene;
[0508]
1,2-difluoro-4-(4-methoxyphenyl)-5-[4-(methylsulfonyl)phenyl]benzen-
e;
[0509]
1,2-difluoro-4-(4-methoxy-3-methylphenyl)-5-[4-(methylsulfonyl)phen-
yl]benzene;
[0510]
1,2-difluoro-4-(3-fluoro-4-methoxyphenyl)-5-[4-(methylsulfonyl)phen-
yl]benzene;
[0511]
4-[3-chloro-4-methoxyphenyl)-1,2-difluoro-5-[4-(methylsulfonyl)phen-
yl]benzene;
[0512]
1,2-difluoro-4-(3,4-dimethoxyphenyl)-5-(4-(methylsulfonyl)phenyl]be-
nzene;
[0513]
1,2-difluoro-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]benzene-
;
[0514]
1,2-difluoro-4-(4-fluoro-3-methylphenyl)-5-[4-(methylsulfonyl)pheny-
l]benzene;
[0515]
1,2-difluoro-4-(3,4-difluorophenyl)-5-[4-(methylsulfonyl)phenyl]ben-
zene;
[0516]
4-[3-chloro-4-fluorophenyl)-1,2-difluoro-5-[4-(methylsulfonyl)pheny-
l]benzene;
[0517]
1,2-difluoro-4-(4-fluoro-3-methoxyphenyl)-5-(4-(methylsulfonyl)phen-
yl]benzene;
[0518]
4-(4-chlorophenyl)-1,2-difluoro-5-[4-(methylsulfonyl)phenyl]benzene-
;
[0519]
4-(4-chloro-3-methylphenyl)-1,2-difluoro-5-[4-(methylsulfonyl)pheny-
l]benzene;
[0520]
4-[4-chloro-3-fluorophenyl)-1,2-difluoro-5-(4-(methylsulfonyl)pheny-
l]benzene;
[0521]
4-(3,4-dichlorophenyl)-112-difluoro-5-[4-(methylsulfonyl)phenyl]ben-
zene;
[0522]
4-[4-chloro-3-methoxyphenyl)-1,2-difluoro-5-[4-(methylsulfonyl)phen-
yl]benzene;
[0523]
1,2-difluoro-4-(3,5-dimethylphenyl]-5-[4-(methylsulfonyl)phenyl]ben-
zene;
[0524]
1,2-difluoro-4-(3,5-difluorophenyl)-5-[4-(methylsulfonyl)phenyl]ben-
zene;
[0525]
4-(3,5-dichlorophenyl)-1,2-difluoro-5-[4-(methylsulfonyl)phenyl]ben-
zene;
[0526]
1,2-difluoro-4-(3,5-dimethoxyphenyl)-5-[4-(methylsulfonyl)phenyl]be-
nzene;
[0527]
1,2-difluoro-4-(3,4,5-trimethylphenyl)-5-[4-(methylsulfonyl)phenyl]-
benzene;
[0528]
1,2-difluoro-4-(3,5-difluoro-4-methylphenyl)-5-[4-(methylsulfonyl)p-
henyl]benzene;
[0529]
4-(3,5-dichloro-4-methylphenyl)-1,2-difluoro-5-[4-(methylsulfonyl)p-
henyl]benzene;
[0530]
1,2-difluoro-4-(3,5-dimethoxy-4-methylphenyl)-5-[4-(methylsulfonyl)-
phenyl]benzene;
[0531]
1,2-difluoro-4-(3,5-dimethyl-4-methoxyphenyl)-5-[4-(methylsulfonyl)-
phenyl]benzene;
[0532]
1,2-difluoro-4-(3,5-difluoro-4-methoxyphenyl)-5-[4-(methylsulfonyl)-
phenyl]benzene;
[0533]
4-(3,5-dichloro-4-methoxyphenyl)-1,2-difluoro-5-[4-(methylsulfonyl)-
phenyl]benzene;
[0534]
1,2-difluoro-4-(3,4,5-trimethoxyphenyl)-5-[4-(methylsulfonyl)phenyl-
]benzene;
[0535]
4-(3,5-dimethyl-4-fluorophenyl)-1,2-difluoro-5-[4-(methylsulfonyl)p-
henyl]benzene;
[0536]
1,2-difluoro-4-(3,4,5-trifluorophenyl)-5-[4-(methylsulfonyl)phenyl]-
benzene;
[0537]
4-(3,5-dichloro-4-fluorophenyl)-1,2-difluoro-5-[4-(methylsulfonyl)p-
henyl]benzene;
[0538]
1,2-difluoro-4-(3,5-dimethoxy-4-fluorophenyl)-5-[4-(methylsulfonyl)-
phenyl]benzene;
[0539]
4-(4-chloro-3,5-dimethylphenyl)-1,2-difluoro-5-[4-(methylsulfonyl)p-
henyl]benzene;
[0540]
4-(4-chloro-3,5-difluorophenyl)-1,2-difluoro-5-[4-(methylsulfonyl)p-
henyl]benzene;
[0541]
1,2-difluoro-4-(3,4,5-trichlorophenyl)-5-[4-(methylsulfonyl)phenyl]-
benzene;
[0542]
4-(4-chloro-3,5-dimethoxyphenyl)-1,2-difluoro-5-[4-(methylsulfonyl)-
phenyl]benzene;
[0543]
5-[4,5-difluoro-2-[4-(methylsulfonyl)phenyl]phenyl]-1,3-benzodioxol-
e;
[0544]
2-chloro-4-[4,5-difluoro-2-[4-(methylsulfonyl)phenyl]phenyl]-N,N-di-
methylbenzenamine;
[0545]
6-[4,5-difluoro-2-[4-(methylsulfonyl)phenyl]-2,3-dihydro-1,4-benzod-
ioxin;
[0546]
1,2-dichloro-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]benzene-
;
[0547]
2-[4,5-difluoro-4'-(methylsulfonyl)-(1,1'-biphenyl)-2-yl]-5-methylp-
yridine;
[0548]
5-[4,5-difluoro-4'-(methylsulfonyl)-(1,1'-biphenyl)-2-yl]-2-methylp-
yridine; and
[0549]
1,2-difluoro-5-[4-(methylsulfonyl)phenyl]-4-(2-thiazolyl)benzene.
[0550] Within Formula I there is a subclass of compounds of high
interest represented by Formula II: 3
[0551] wherein A is selected from 4
[0552] wherein each of R.sup.2 and R.sup.3 is independently
selected from hydrido and halo; or wherein R.sup.2 and R.sup.3
together form --OCH.sub.2O--; wherein each of R.sup.10 through
R.sup.14 is independently selected from hydrido, lower alkyl, halo,
lower alkoxy, lower haloalkyl, and lower dialkylamino; or wherein
R.sup.11 and R.sup.12 together form --O(CH.sub.2).sub.nO--; wherein
n is 1-2, inclusive; and wherein R.sup.7 is selected from lower
alkylsulfonyl and aminosulfonyl; or a pharmaceutically-acceptable
salt thereof.
[0553] Within Formula I there is a second subclass of compounds of
high interest represented by Formula III: 5
[0554] wherein each of R.sup.11 through R.sup.13 is independently
selected from hydrido, halo, lower alkoxy, lower haloalkyl, amino,
lower alkylamino, lower dialkylamino, and lower haloalkoxy; or
wherein R.sup.11 and R.sup.12 together form --O(CH.sub.2).sub.nO--;
wherein n is 1-2, inclusive; or a pharmaceutically-acceptable salt
thereof.
[0555] Within Formula I there is a third subclass of compounds of
high interest represented by Formula IV: 6
[0556] wherein Y is CR.sup.11 or N; wherein Z is CR.sup.10 or N;
wherein each of R.sup.10 through R.sup.12 is independently selected
from hydrido and lower alkyl; wherein R.sup.7 is aminosulfonyl or
methylsulfonyl; provided one of Y and Z is N; or a
pharmaceutically-acceptable salt thereof.
[0557] The term "hydrido" denotes a single hydrogen atom (H). This
hydrido radical may be attached, for example, to an oxygen atom to
form a hydroxyl radical or two hydrido radicals may be attached to
a carbon atom to form a methylene (--CH.sub.2--) radical. Where the
term "alkyl" is used, either alone or within other terms such as
"haloalkyl" and "alkylsulfonyl", it embraces linear or branched
radicals having one to about twenty carbon atoms or, preferably,
one to about twelve carbon atoms. More preferred alkyl radicals are
"lower alkyl" radicals having one to about ten carbon atoms. Most
preferred are lower alkyl radicals having one to about six carbon
atoms. Examples of such radicals include methyl, ethyl, n-propyl,
isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl,
isoamyl, hexyl and the like. The term "halo" means halogens such as
fluorine, chlorine, bromine or iodine atoms. The term "haloalkyl"
embraces radicals wherein any one or more of the alkyl carbon atoms
is substituted with halo as defined above. Specifically embraced
are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A
monohaloalkyl radical, for one example, may have either an iodo,
bromo, chloro or fluoro atom within the radical. Dihaloalkyl and
polyhaloalkyl radicals may have two or more of the same halo atoms
or a combination of different halo radicals. "Lower haloalkyl"
embraces radicals having one to six carbon atoms. Examples of
haloalkyl radicals include fluoromethyl, difluoromethyl,
trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,
trichloromethyl, pentafluoroethyl, heptafluoropropyl,
difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,
difluoropropyl, dichloroethyl and dichloropropyl. The term
"hydroxyalkyl" embraces linear or branched alkyl radicals having
one to about ten carbon atoms any one of which may be substituted
with one or more hydroxyl radicals. More preferred hydroxyalkyl
radicals are "lower hydroxyalkyl" radicals having one to six carbon
atoms and one or more hydroxyl radicals. Examples of such radicals
include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl
and hydroxyhexyl. The term "alkoxy" embraces linear or branched
oxy-containing radicals each having alkyl portions of one to about
ten carbon atoms, such as methoxy radical. More preferred alkoxy
radicals are "lower alkoxy" radicals having one to six carbon
atoms. Examples of such radicals include methoxy, ethoxy, propoxy,
butoxy, tert-butoxy, methylenedioxy and ethylenedioxy. The term
"alkoxyalkyl" embraces alkyl radicals having one or more alkoxy
radicals attached to the alkyl radical, that is, to form
monoalkoxyalkyl and dialkoxyalkyl radicals. More preferred
alkoxyalkyl radicals are "lower alkoxyalkyl", radicals having one
to six carbon atoms and one or two alkoxy radicals. Examples of
such radicals include methoxymethyl, methoxyethyl, ethoxyethyl,
methoxybutyl and methoxypropyl. The "alkoxy" radicals may be
further substituted with one or more halo atoms, such as fluoro,
chloro or bromo, to provide "haloalkoxy" and "lower haloalkoxy"
radicals. Examples of such radicals include fluoromethoxy,
chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy and
fluoropropoxy. The term "aryl", alone or in combination, means a
carbocyclic aromatic system containing one, two or three rings
wherein such rings may be attached together in a pendent manner or
may be fused. The term "aryl" embraces aromatic radicals such as
phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl. The term
"heterocyclic" embraces saturated, partially saturated and
unsaturated heteroatom-containing ring-shaped radicals, where the
heteroatoms may be selected from nitrogen, sulfur and oxygen.
Examples of saturated heterocyclic radicals include saturated 3 to
6-membered heteromonocylic group containing 1 to 4 nitrogen
atoms[e.g. pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl,
etc.]; saturated 3 to 6-membered heteromonocyclic group containing
1 to 2 oxygen atoms and 1 to 3-nitrogen atoms [e.g. morpholinyl,
etc.]; saturated 3 to 6-membered heteromonocyclic group containing
1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl,
etc.]. Examples of partially saturated heterocyclic radicals
include dihydrothiophene, dihydropyran, dihydrofuran and
dihydrothiazole. The term "heteroaryl" embraces unsaturated
heterocyclic radicals. Examples of heteroaryl radicals include
unsaturated 5 to 6 membered heteromonocyclic group containing 1 to
4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl,
pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl,
pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl,
1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.]tetrazolyl [e.g.
1H-tetrazolyl, 2H-tetrazolyl, etc.], etc.; unsaturated condensed
heterocyclic group containing 1 to 5 nitrogen atoms, for example,
indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl,
isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g.,
tetrazolo [1,5-b]pyridazinyl, etc.], etc.; unsaturated 3 to
6-membered heteromonocyclic group containing an oxygen atom, for
example, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5 to
6-membered heteromonocyclic group containing a sulfur atom, for
example, 2-thienyl, 3-thienyl, etc.; unsaturated 5- to 6-membered
heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3
nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl
[e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl,
etc.] etc.; unsaturated condensed heterocyclic group containing 1
to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. benzoxazolyl,
benzoxadiazolyl, etc.]; unsaturated 5 to 6-membered
heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3
nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g.,
1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.]
etc.; unsaturated condensed heterocyclic group containing 1 to 2
sulfur atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl,
benzothiadiazolyl, etc.] and the like. The term also embraces
radicals where heterocyclic radicals are fused with aryl radicals.
Examples of such fused bicyclic radicals include benzofuran,
benzothiophene, and the like. Preferred heteroaryl radicals include
five to ten membered fused or unfused radicals. More preferred
examples of heteroaryl radicals include benzofuryl,
2,3-dihydrobenzofuryl, benzothienyl, indolyl, dihydroindolyl,
chromanyl, benzopyran, thiochromanyl, benzothiopyran,
benzodioxolyl, benzodioxanyl, pyridyl, thienyl, pyrazolyl,
isoxazolyl, pyrrolyl, thiazolyl, oxazolyl, furyl, and pyrazinyl.
The term "sulfonyl", whether used alone or linked to other terms
such as alkylsulfonyl, denotes respectively divalent radicals
--SO.sub.2--. "Alkylsulfonyl" embraces alkyl radicals attached to a
sulfonyl radical, where alkyl is defined as above. More preferred
alkylsulfonyl radicals are "lower alkylsulfonyl" radicals having
one to six carbon atoms. Examples of such lower alkylsulfonyl
radicals include methylsulfonyl, ethylsulfonyl and propylsulfonyl.
The terms "sulfamyl," "aminosulfonyl" and "sulfonamidyl" denotes a
sulfonyl radical substituted with an amine radical, forming a
sulfonamide (--SO.sub.2NH.sub.2). The terms "carboxy" or
"carboxyl", whether used alone or with other terms, such as
"carboxyalkyl", denotes --CO.sub.2H. The term "alkylthio" embraces
radicals containing a linear or branched alkyl radical, of one to
about ten carbon atoms attached to a divalent sulfur atom. More
preferred alkylthio radicals are "lower alkylthio" radicals having
alkyl radicals of one to six carbon atoms. Examples of such lower
alkylthio radicals are methylthio, ethylthio, propylthio, butylthio
and hexylthio. The term "alkylamino" denotes amino groups which
have been substituted with one or two alkyl radicals forming
N-alkylamino and N,N-dialkylamino radicals, respectively. Preferred
alkylamino radicals are "lower alkylamino" having alkyl portions of
one to six carbon atoms. Examples include N-methylamino,
N-ethylamino, N,N-dimethylamino, N,N-diethylamino and the like.
[0558] The present invention comprises a pharmaceutical composition
for the treatment of inflammation or an inflammation-associated
disorder, such as arthritis, comprising a therapeutically-effective
amount of a compound of Formula I in association with at least one
pharmaceutically-acceptable carrier, adjuvant or diluent.
[0559] The present invention also comprises a therapeutic method of
treating inflammation or an inflammation-associated disorder in a
subject, the method comprising treating a subject having or
susceptible to such inflammation or inflammation-associated
disorder with a therapeutically-effective amount of a compound of
Formula I.
[0560] Also included in the family of compounds of Formula I are
the pharmaceutically-acceptable salts thereof. The term
"pharmaceutically-acceptable salts" embraces salts commonly used to
form alkali metal salts and to form addition salts of free acids or
free bases. The nature of the salt is not critical, provided that
it is pharmaceutically-acceptable. Suitable
pharmaceutically-acceptable acid addition salts of compounds of
Formula I may be prepared from an inorganic acid or from an organic
acid. Examples of such inorganic acids are hydrochloric,
hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric
acid. Appropriate organic acids may be selected from aliphatic,
cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and
sulfonic classes of organic acids, examples of which are formic,
acetic, propionic, succinic, glycolic, gluconic, lactic, malic,
tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic,
aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic,
4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),
methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic,
2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic,
cyclohexylaminosulfonic, stearic, algenic, .beta.-hydroxybutyric,
galactaric and galacturonic acid. Suitable
pharmaceutically-acceptable base addition salts of compounds of
Formula I include metallic salts made from aluminum, calcium,
lithium, magnesium, potassium, sodium and zinc, or organic salts
made from N,N'-dibenzylethylenediamine, chloroprocaine, choline,
diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and
procaine. All of these salts may be prepared by conventional means
from the corresponding compound of Formula I by reacting, for
example, the appropriate acid or base with the compound of Formula
I.
General Synthetic Procedures
[0561] The compounds of the invention can be synthesized according
to the following procedures of Schemes I-XIX, wherein the
R.sup.1-R.sup.14 substituents are as defined for Formulas I-IV,
above, except where further noted. U.S. patent application Ser. No.
08/346,433 is incorporated by reference. 7
[0562] Synthetic Scheme I shows the three step procedure for the
preparation of the prerequisite substituted phenylboronic acids 1
and 2 from commercially available phenyl bromides. In step one,
halogen-metal interchange in THF at -78.degree. C. generates the
corresponding organolithium reagents. In step two, the
organolithium species are reacted with trimethyl borate to give the
corresponding methyl esters. In step three, hydrolysis with aqueous
sodium hydroxide provides the substituted phenylboronic acids 1 and
2, respectively. 8
[0563] Synthetic Scheme II shows an alternative three step
procedure for the preparation of the prerequisite substituted
phenylboronic acids 1 and 2 from commercially available phenyl
bromides. In step one, reaction with magnesium metal in THF at
reflux in the presence of an iodine catalyst generates the
corresponding Grignard reagents. In step two, the Grignard reagents
are reacted with trimethyl borate to give the corresponding methyl
esters. In step three, hydrolysis with aqueous sodium hydroxide
provides the substituted phenylboronic acids 1 and 2, respectively.
9
[0564] Synthetic Scheme III shows the procedure for the preparation
of the substituted 2-bromo-biphenyl intermediates 3 from
commercially available 1,2-dibromobenzenes and the appropriate
substituted phenylboronic acid 1 (prepared in Synthetic Schemes I
and II). Using a coupling procedure similar to the one developed by
Suzuki et al. [Synth. Commun., 11, 513 (1981)], 1,2-dibromobenzenes
are reacted with 1 in toluene/ethanol at reflux in the presence of
a Pd.sup.0 catalyst, e.g.,
tetrakis(triphenylphosphine)palladium(0), and 2M sodium carbonate
to give the corresponding substituted 2-bromo-biphenyl
intermediates 3. 10
[0565] Synthetic Scheme IV shows the procedure for the preparation
of the substituted 2-bromobiphenyl intermediates 4 from
commercially available 1,2-dibromobenzenes and the appropriate
substituted phenylboronic acids 2 (prepared in Synthetic Schemes I
and II). Using a coupling procedure similar to the one developed by
Suzuki et al. (Synthetic Scheme III), 1,2-dibromobenzenes are
reacted with 2 in toluene/ethanol at reflux in the presence of a
Pd.sup.0 catalyst, e.g., tetrakis (triphenylphosphine)palladium(0),
and 2M sodium carbonate to give the corresponding substituted
2-bromobiphenyl intermediates 4. 11
[0566] Synthetic Scheme V shows the procedure for the preparation
of 1,2-diarylbenzene antiinflammatory agents from 2-bromo-biphenyl
intermediates 3 (prepared in Synthetic Scheme III) and the
appropriate substituted phenylboronic acids 2 (prepared in
Synthetic Schemes I and II). Using a coupling procedure similar to
the one developed by Suzuki et al. (Synthetic Scheme III),
intermediates 3 are reacted with 2 in toluene/ethanol at reflux in
the presence of a Pd.sup.0 catalyst, e.g.,
tetrakis(triphenylphosphine)palladium(0), and 2M sodium carbonate
to give the corresponding 1,2-diarylbenzene antiinflammatory agents
5 of this invention. 12
[0567] Synthetic Scheme VI shows the procedure for the preparation
of 1,2-diarylbenzene antiinflammatory agents from 2-bromo-biphenyl
intermediates 4 (prepared in Synthetic Scheme IV) and the
appropriate substituted phenylboronic acids 1 (prepared in
Synthetic Schemes I and II). Using a coupling procedure similar to
the one developed by Suzuki et al. (Synthetic Scheme III),
intermediates 4 are reacted with 1 in toluene/ethanol at reflux in
the presence of a Pd.sup.0 catalyst, e.g., tetrakis
(triphenylphosphine)palladium(0), and 2M sodium carbonate to give
the corresponding 1,2-diarylbenzene antiinflammatory agents 5 of
this invention. 13
[0568] Synthetic Scheme VII shows an alternative one step procedure
for the preparation of 1,2-diarylbenzene antiinflammatory agents 5
from commercially available 1,2-dibromobenzenes and the appropriate
substituted phenylboronic acids 1 and 2 (prepared in Synthetic
Schemes I and II). Using a coupling procedure similar to the one
developed by Suzuki et al. (Synthetic Scheme III), an equimolar
mixture of 1,2-dibromobenzenes, 1 and 2 are reacted in
toluene/ethanol at reflux in the presence of a Pd.sup.0 catalyst,
e.g., tetrakis(triphenylphosphine)pa- lladium(0), and 2M sodium
carbonate to give the corresponding 1,2-diarylbenzene
antiinflammatory agents 5 of this invention. 14
[0569] Synthetic Scheme VIII shows the three step procedure for the
preparation of the 2-aryl-phenylboronic acids 6 and 7 from
corresponding 2-bromobiphenyl intermediates 3 (prepared in
Synthetic Scheme III) and 4 (prepared in Synthetic Scheme IV),
respectively. In step one, halogen-metal interchange in THF at
-78.degree. C. generates the corresponding organolithium reagents.
In step two, the organolithium species are reacted with trimethyl
borate to give the corresponding methyl esters. In step three,
hydrolysis with aqueous sodium hydroxide provides the substituted
phenylboronic acids 6 and 7, respectively. 15
[0570] Synthetic Scheme IX shows the procedure for the preparation
of 1,2-diarylbenzene antiinflammatory agents from commercially
available substituted phenyl bromides and 2-aryl-phenylboronic
acids 6 (prepared in Synthetic Scheme VIII). Using a coupling
procedure similar to the one developed by Suzuki et al. (Synthetic
Scheme III), substituted phenyl bromides are reacted with 6 in
toluene/ethanol at reflux in the presence of a Pd.sup.0 catalyst,
e.g., tetrakis(triphenylphosphine)palladium(0), and 2M sodium
carbonate to give the corresponding 1,2-diarylbenzene
antiinflammatory agents 5 of this invention. 16
[0571] Synthetic Scheme X shows the procedure for the preparation
of 1,2-diarylbenzene antiinflammatory agents 5 from commercially
available substituted phenyl bromides and 2-aryl-phenylboronic
acids 7 (prepared in Synthetic Scheme VIII). Using a coupling
procedure similar to the one developed by Suzuki et al. (Synthetic
Scheme III), substituted phenyl bromides are reacted with 7 in
toluene/ethanol at reflux in the presence of a Pd.sup.0 catalyst,
e.g., tetrakis(triphenylphosphine) palladium(0), and 2M sodium
carbonate to give the corresponding 1,2-diarylbenzene
antiinflammatory agents 5 of this invention. 17
[0572] Synthetic Scheme XI shows the procedure for the preparation
of 3-bromopyridines 9 from commercially available pyridines 8.
Using a procedure similar to the one developed by Reitz et al.
[U.S. Pat. No. 5,155,177], pyridines 8 are reacted with bromine in
the presence of aluminum chloride to give the 3-bromopyridines 9.
18
[0573] Synthetic Scheme XII shows the procedure for the preparation
of pyridyltin intermediates 10 from 3-bromopyridines 9 (prepared in
Synthetic Scheme XI). In step one, halogen-lithium interchange in
THF at -78.degree. C. generates the corresponding organolithium
reagents. In step two, the organolithium species are reacted with
trimethyltin chloride to give the corresponding pyridyltin
intermediates 10. 19
[0574] Synthetic Scheme XIII shows the procedure for the
preparation of 1,2-diarylbenzene antiinflammatory agents 11 from
2-bromo-biphenyl intermediates 3 (prepared in Synthetic Scheme III)
and the appropriate substituted pyridyltin intermediates 10
(prepared in Synthetic Scheme XII). Reaction of 3 with 10 in
toluene at reflux in the presence of a Pd.sup.0 catalyst, e.g.,
tetrakis(triphenylphosphine)palladium (0) gives the corresponding
1,2-diarylbenzene antiinflammatory agents 11 of this invention.
20
[0575] Synthetic Scheme XIV shows the procedure for the preparation
of 1,2-diarylbenzene antiinflammatory agents 13 from
2-aryl-phenylboronic acids 6 (prepared in Synthetic Scheme VIII)
and commercially available bromopyridines 12. Reaction of 6 with 12
in toluene/ethanol at reflux in the presence of a Pd.sup.0
catalyst, e.g., tetrakis(triphenylphosphine)pa- lladium (0) and 2M
sodium carbonate gives the corresponding 1,2-diarylbenzene
antiinflammatory agents 13 of this invention. 21
[0576] Synthetic Scheme XV shows the procedure for the preparation
of 1,2-diarylbenzene antiinflammatory agents 15 from
2-aryl-phenylboronic acids 6 (prepared in Synthetic Scheme VIII)
and commercially available 2-bromofuran 14. Reaction of 6 with 14
in toluene/ethanol at reflux in the presence of a Pd.sup.0
catalyst, e.g., tetrakis(triphenylphosphine)pa- lladium (0) and 2M
sodium carbonate gives the corresponding 1,2-diarylbenzene
antiinflammatory agents 15 of this invention. 22
[0577] Synthetic Scheme XVI shows the procedure for the preparation
of 1,2-diarylbenzene antiinflammatory agents 17 from
2-aryl-phenylboronic acids 6 (prepared in Synthetic Scheme VIII)
and commercially available 3-bromofuran 16. Reaction of 6 with 16
in toluene/ethanol at reflux in the presence of a Pd.sup.0
catalyst, e.g., tetrakis(triphenylphosphine)pa- lladium (0) and 2M
sodium carbonate gives the corresponding 1,2-diarylbenzene
antiinflammatory agents 17 of this invention. 23
[0578] Synthetic Scheme XVII shows the procedure for the
preparation of 1,2-diarylbenzene antiinflammatory agents 19 from
2-aryl-phenylboronic acids 6 (prepared in Synthetic Scheme VIII)
and commercially available 2-bromothiophene 18. Reaction of 6 with
18 in toluene/ethanol at reflux in the presence of a Pd.sup.0
catalyst, e.g., tetrakis(triphenylphosphine- )palladium (0) and 2M
sodium carbonate gives the corresponding 1,2-diarylbenzene
antiinflammatory agents 19 of this invention. 24
[0579] Synthetic Scheme XVIII shows the procedure for the
preparation of 1,2-diarylbenzene antiinflammatory agents 21 from
2-aryl-phenylboronic acids 6 (prepared in Synthetic Scheme VIII)
and commercially available 3-bromothiophene 20. Reaction of 6 with
20 in toluene/ethanol at reflux in the presence of a Pd.sup.0
catalyst, e.g., tetrakis(triphenylphosphine- )palladium (0) and 2M
sodium carbonate gives the corresponding 1,2-diarylbenzene
antiinflammatory agents 21 of this invention. 25
[0580] Synthetic Scheme XIX shows the three step procedure for the
preparation of sulfonamide antiinflammatory agents 23 from their
corresponding methyl sulfones 22. Using a procedure similar to the
one developed by Huang et al. [Tetrahedron Lett., 35, 7201 (1994)],
THF solutions of the methyl sulfones 22 at -78.degree. C. are
treated with base, e.g., n-BuLi, n-C.sub.3H.sub.7MgCl, etc., to
generate the corresponding carbanions. In step two, the anions are
treated with an organoborane, e.g., triethylborane, tributylborane,
etc., at -78.degree. C. and warmed to ambient temperature prior to
stirring at reflux. An alternative to the boron chemistry involves
room temperature alkylation, such as with haloalkyltrialkylsilanes,
followed by treatment with silylalkyl-elimination agents. In step
three, an aqueous solution of sodium acetate and
hydroxyamine-O-sulfonic acid is added to provide the corresponding
sulfonamide antiinflammatory agents 23 (5 where R.sup.12
SO.sub.2NH.sub.2) of this invention.
[0581] The following examples contain detailed descriptions of the
methods of preparation of compounds of Formulas I-IV. These
detailed descriptions fall within the scope, and serve to
exemplify, the above described General Synthetic Procedures which
form part of the invention. These detailed descriptions are
presented for illustrative purposes only and are not intended as a
restriction on the scope of the invention. All parts are by weight
and temperatures are in Degrees centigrade unless otherwise
indicated. HRMS is an abbreviation for High resolution mass
spectrometry. The term "ND" signifies "not determined." All NMR
data are from .sup.1H NMR unless otherwise indicated.
EXAMPLE 1
[0582] 26
1-(4-Fluorophenyl)-2-[4-(methylsulfonyl)phenyl]benzene
[0583] Step 1: Preparation of 1-bromo-2-(4-fluorophenyl)benzene
[0584] Under nitrogen, 1.2 g (1.0 mmol) of Pd(PPh.sub.3).sub.4 was
added to a stirred solution of 9.9 g (42 mmol) of
1,2-dibromobenzene (Aldrich) and 3.0 g (21 mmol) of
4-fluorophenylboronic acid in 42 mL of toluene, 42 mL of ethanol
and 42 mL of 2M Na.sub.2CO.sub.3. After vigorous stirring at reflux
for 3 hours, the solvent was removed in vacuo. The residue was
dissolved in ethyl acetate. The resulting solution was washed with
water and dried over MgSO.sub.4. Purification by silica gel
chromatography (Waters Prep-500A) with hexane gave 4.35 g (81%) of
1-bromo-2-(4-fluorophenyl)benzene as a colorless oil: NMR
(CDCl.sub.3) .delta.7.07-7.26 (m, 3H), 7.27-7.44 (m, 4H), 7.67 (d,
J=8 Hz, 1H).
[0585] Step 2: Preparation of 4-methylthiophenylboronic acid Under
nitrogen, 113 mL (181 mmol) of n-BuLi (1.6 M in hexanes) was added
to a stirred solution of 30 g (150 mmol) of 4-bromothioanisole
(Lancaster) in 1,500 mL of anhydrous tetrahydrofuran (THF) at
-78.degree. C. After 30 minutes, 51 mL (450 mmol) of
trimethylborate was added. The reaction was warmed to ambient
temperature and stirred overnight. The resulting solution was
treated with 300 mL of 10% NaOH and stirred vigorously for 1 hour.
The THF was removed in vacuo, the pH adjusted to 4-5 and the solid
collected by filtration. The solid was washed repeatedly with water
and hexane. Drying in vacuo gave 21 g (83%) of
4-methylthiophenylboronic acid as a colorless solid: NMR
(DMSO-d.sub.6) .delta. 2.47 (s, 3H), 7.20 (d, J=8 Hz, 2H), 7.71 (d,
J=8 Hz, 2H), 7.96 (s, 2H).
[0586] Step 3: Preparation of
1-(4-fluorophenyl)-2-[4-(methylthio)phenyl]b- enzene
[0587] Under nitrogen, 200 mg of Pd(PPh.sub.3).sub.4 was added to a
stirred solution of 500 mg (2.0 mmol) of
1-bromo-2-(4-fluorophenyl)benzen- e (Step 1) and 500 mg (3.0 mmol)
of 4-methylthiophenylboronic acid (Step 2) in 7 mL of toluene, 7 mL
of ethanol and 7 mL of 2M Na.sub.2CO.sub.3. After vigorous stirring
at reflux overnight, the solvent was removed in vacuo. The residue
was dissolved in ethyl acetate. The resulting solution was washed
with water and dried over MgSO.sub.4. Purification by silica gel
chromatography (Waters LC-2000) with ethyl acetate/hexane (2:98) as
the eluent gave 550 mg of
1-(4-fluorophenyl)-2-[4-(methylthio)phenyl]benz- ene as a
semi-solid: NMR (CDCl.sub.3) .delta. 2.46 (s, 3H), 6.92 (t, J=8 Hz,
2H), 7.02-7.14 (m, 6H), 7.37-7.47 (m, 4H). MS (EI): m/e (rel
intensity) 294 (100), 279 (39), 277 (56), 246 (74), 227 (40), 190
(43), 190 (38), 140 (44).
[0588] Step 4: Preparation of
1-(4-fluorophenyl)-2-[4-(methylsulfonyl), phenyl]benzene
[0589] To a stirred solution of 550 mg (1.9 mmol) of crude
1-(4-fluoro-phenyl)-2-[4-(methylthio)phenyl]benzene (Step 3) in 10
mL of methylene chloride at ambient temperature was slowly added
1.3 g (4.1 mmol) of 3-chloroperoxybenzoic acid (ca. 55%). Stirring
was continued for 20 minutes prior to the addition of 1 g of
Na.sub.2SO.sub.3. The reaction was allowed to stir for an
additional 10 minutes and the solvent removed in vacuo. The residue
was dissolved in ethyl acetate and the resulting solution washed
twice with saturated NaHCO.sub.3 and dried over MgSO.sub.4.
Recrystallization from ethyl acetate/hexane gave 437 mg (94%) of
1-(4-fluorophenyl)-2-[4-(methylsulfonyl)phenyl]benzene as a
colorless solid: mp 178.0-179.0.degree. C.; NMR (CDCl.sub.3)
.delta. 3.05 (s, 3H), 6.93 (t, J=8 Hz, 2H), 7.03-7.09 (m, 2H), 7.32
(d, J=8 Hz, 2H), 7.38-7.50 (m, 4H), 7.80 (d, J=8 Hz, 2H). MS (FAB):
m/e 333 (M+Li). Anal. Calc'd for C.sub.19H.sub.15FO.sub.2S: C,
69.86; H, 4.60; F, 5.79. Found: C, 69.74; H, 4.72; F, 5.51.
EXAMPLE 2
[0590] 27
4-[2-(4-Fluorophenyl)phenyl]benzenesulfonamide
[0591] Step 1: Preparation of 2-(4-fluorophenyl)phenylboronic
acid
[0592] Following the general procedure outlined in Synthetic Scheme
VIII, 4.35 g (17.3 mmol) of 1-bromo-2-(4-fluorophenyl)benzene
(Example 1, Step 1) was converted to
2-(4-fluorophenyl)phenylboronic acid: NMR (CDCl.sub.3) .delta. 4.27
(s, 2H), 7.09-7.20 (m, 2H), 7.25-7.32 (m, 1H), 7.34-7.53 (m 4H),
7.90 (d, J=8 Hz, 1H).
[0593] Step 2: Preparation of
4-[2-(4-fluorophenyl)phenyl]benzenesulfonami- de
[0594] Following the general procedure outlined in Synthetic Scheme
IX, 1.5 g (6.9 mmol) of 2-(4-fluorophenyl)phenylboronic acid (Step
1) was reacted with 2.5 g (10.4 mmol) of 4-bromobenzenesulfonamide
(Lancaster). Purification by silica gel chromatography (Waters
LC-2000) with ethyl acetate/hexane (3:7) and subsequent
recrystallization from ethyl acetate/hexane gave 1.04 g (46%) of
4-[2-(4-fluorophenyl)phenyl]benzenesu- lfonamide as a colorless
solid: mp 187.3-188.2.degree. C.; NMR (CDCl.sub.3) .delta. 4.83 (s,
2H), 6.92 (t, =9 Hz, 2H), 7.02-7.11 (m, 2H), 7.27 (d, J=9 Hz, 2H),
7.36-7.50 (m, 4H), 7.78 (d, J=8 Hz, 2H). MS (EI): m/e (rel
intensity) 327 (75) 245 (100);
[0595] HRMS Calc'd for C.sub.18H.sub.14FNO.sub.2S: 327.0729. Found:
327.0743. Anal. Calc'd for C.sub.18H.sub.14FNO.sub.2S: C, 66.04; H,
4.31; N, 4.28. Found: C, 65.86; H, 4.51; N, 4.34.
EXAMPLE 3
[0596] 28
4-[2-(4-Chlorophenyl)phenyl]benzenesulfonamide
[0597] Step 1: Preparation of 1-bromo-2-(4-chlorophenyl)benzene
[0598] Following the general procedure outlined in Synthetic Scheme
III, 9.0 g (38 mmol) of 1,2-dibromobenzene was reacted with 3.0 g
(19 mmol) of 4-chlorophenylboronic acid (Lancaster). Purification
by silica gel chromatography (Waters Prep-500A) with hexane gave
4.39 g (84%) of 1-bromo-2-(4-chlorophenyl)benzene as a colorless
oil: NMR (CDCl.sub.3) .delta. 7.18-7.26 (m, 1H), 7.28-7.44 (m, 6H),
7.68 (dd, J=1.5, 8 Hz, 1H).
[0599] Step 2: Preparation of 2-(4-chlorophenyl)phenylboronic
acid
[0600] Following the general procedure outlined in Synthetic Scheme
VIII, 4.39 g (16.4 mmol) of 1-bromo-2-(4-chlorophenyl)benzene (Step
1) was converted to 2-(4-chlorophenyl)phenylboronic acid: NMR
(CDCl.sub.3) .delta. 4.20 (s, 2H), 7.19-7.55 (m, 7H), 7.89 (d, J=8
Hz, 1H).
[0601] Step 3: Preparation of
4-[2-(4-chlorophenyl)phenyl]benzenesulfonami- de
[0602] Following the general procedure outlined in Synthetic Scheme
IX, 1.6 g (6.9 mmol) of 2-(4-chlorophenyl)phenylboronic acid (Step
2) was reacted with 1.8 g (7.6 mmol) of 4-bromobenzenesulfonamide.
Purification by silica gel chromatography (Waters LC-2000) with
ethyl acetate/hexane (3:7) and subsequent recrystallization from
ethyl acetate/hexane gave 1.59 g (67%) of
4-[2-(4-chlorophenyl)phenyl]benzenesulfonamide as a colorless
solid: mp 206.2-207.0.degree. C.; NMR (CDCl.sub.3) .delta. 4.77 (s,
2H), 7.04 (d, J=9 Hz, 2H), 7.16-7.31 (m, 4H), 7.36-7.51 (m, 4H),
7.80 (d, J=9 Hz, 2H). MS (EI): m/e (rel intensity) 343 (100), 308
(13), 262 (21), 228 (82); HRMS Calc'd for
C.sub.18H.sub.14ClNO.sub.2S: 343.0434. Found: 343.0434. Anal.
Calc'd for C.sub.18H.sub.14ClNO.sub.2S: C, 62.88; H, 4.10; N, 4.07.
Found: C, 62.66; H, 4.36; N, 4.09.
EXAMPLE 4
[0603] 29
[0604]
2-Fluoro-1-methoxy-4-[2-[4-(methylsulfonyl)phenyl]phenyl]benzene
[0605] Step 1: Preparation of
1-bromo-2-[4-(methylthio)phenyl]benzene
[0606] Following the general procedure outlined in Synthetic Scheme
IV, 33 g (140 mmol) of 1,2-dibromobenzene was reacted with 12 g (70
mmol) of 4-methylthiophenylboronic acid (Example 1, Step 2).
Purification by silica gel chromatography with hexane gave 17.2 g
(89%) of 1-bromo-2-[4-(methylthio)phenyl]benzene as a colorless
oil: NMR (CDCl.sub.3) .delta. 2.53 (s, 3H), 7.16-7.23 (m, 1H),
7.28-7.39 (m, 6H), 7.66 (d, J=8 Hz, 1H)
[0607] Step 2: Preparation of
1-bromo-2-[4-(methylsulfonyl)phenyl]benzene
[0608] Following the synthetic procedure outlined in Step 4 of
Example 1, 17.1 g (61.3 mmol) of
1-bromo-2-[4-(methylthio)phenyl]benzene (Step 1) was oxidized to
its corresponding sulfone. Purification by silica gel
chromatography (Waters Prep-500A) with ethyl acetate/hexane (3:7)
gave 16.2 g (85%) of 1-bromo-2-[4-(methylsulfonyl)phenyl]benzene as
a colorless solid: mp 168.2-169.5.degree. C.; NMR (CDCl.sub.3)
.delta. 3.12 (s, 3H), 7.23-7.33 (m, 2H), 7.40 (dt, J=1.5, 8 Hz,
1H), 7.61 (d, J=8 Hz, 2H), 7.70 (dd, J=1.5, 8 Hz, 1H), 8.01 (d, J=9
Hz, 2H).
[0609] Step 3: Preparation of 3-fluoro-4-methoxyphenylboronic
acid
[0610] Following the general procedure outlined in Synthetic Scheme
I, 15 g (73 mmol) of 4-bromo-2-fluoroanisole was converted to
3-fluoro-4-methoxyphenylboronic acid: NMR (CDCl.sub.3) .delta. 3.75
(s, 3H), 6.80 (d, J=8 Hz, 1H), 7.36-7.48 (m, 2H).
[0611] Step 4: Preparation of
2-fluoro-1-methoxy-4-[2-[4-(methylsulfonyl)p-
henyl]phenyl]benzene
[0612] Following the general procedure outlined in Synthetic Scheme
VI, 5.0 g (16 mmol) of 1-bromo-2-[4-(methylsulfonyl)phenyl]benzene
(Step 2) was reacted with 4.1 g (24 mmol) of
3-fluoro-4-methoxyphenylboronic acid (Step 3). Purification by
silica gel chromatography (Waters Prep-500A) with ethyl
acetate/hexane (35:65) and subsequent recrystallization from ethyl
acetate/hexane gave 4.82 g (88%) of
2-fluoro-1-methoxy-4-[(2-[4-(me- thylsulfonyl)phenyl[phenyl]benzene
as a colorless solid: mp 136.2-136.6.degree. C.; NMR (CDCl.sub.3)
.delta. 3.06 (s, 3H), 3.87 (s, 3H), 6.72-6.89 (m, 3H), 7.31-7.51
(m, 6H), 7.81 (d, J=9 Hz, 2H). MS (EI): m/e (rel intensity) 356
(100), 262 (28), 246 (22); HRMS Calc'd for
C.sub.20H.sub.17FO.sub.3S: 356.0882. Found: 356.0881. Anal. Calc'd
for C.sub.20H.sub.17FO.sub.3S: C, 67.40; H, 4.81; F, 5.33. Found:
C, 67.24; H, 4.83; F, 5.25.
EXAMPLE 5
[0613] 30
[0614]
2-Chloro-1-methoxy-4-[2-[4-(methylsulfonyl)phenyl]phenyl]benzene
[0615] Step 1: Preparation of 4-bromo-2-chloroanisole
[0616] Under nitrogen, 7.3 mL (77 mmol) of dimethylsulfate was
added to a stirred suspension of 10 g (48 mmol) of
4-bromo-2-chlorophenol and 5.4 g (38 mmol) of powered
K.sub.2CO.sub.3 in 75 mL of fresh acetone. After 2 hours at reflux,
the reaction was cooled to ambient temperature, filtered, and
concentrated in vacuo. The residue was dissolved in ethyl acetate;
the resulting solution was washed with water and dried over
MgSO.sub.4. Concentration in vacuo gave 10.2 g (96%) of
4-bromo-2-chloroanisole as a colorless solid: mp 68.5-70.5.degree.
C.; NMR (CDCl.sub.3) .delta. 3.88 (s, 3H), 6.80 (d, J=9 Hz, 1H),
7.33 (dd, J=2, 9 Hz, 1H), 7.50 (d, J=2 Hz, 1H).
[0617] Step 2: Preparation of 3-chloro-4-methoxyphenylboronic
acid
[0618] Following the general procedure outlined in Synthetic Scheme
I, 10.2 g (46.2 mmol) of 4-bromo-2-chloroanisole (Step 1) was
converted to 3-chloro-4-methoxyphenylboronic acid: NMR (CDCl.sub.3)
.delta. 3.83 (s, 3H), 6.57 (s, 2H), 6.83 (d, J=8 Hz, 1H), 7.64 (dd,
J=1.5, 8 Hz, 1H), 7.77 (d, J=1.5 Hz, 1H).
[0619] Step 3: Preparation of
2-chloro-1-methoxy-4-[2-[4-(methylsulfonyl)p-
henyl]phenyl]benzene
[0620] Following the general procedure outlined in Synthetic Scheme
VI, 4.0 g (13 mmol) of 1-bromo-2-[4-(methylsulfonyl)phenyl]benzene
(Example 4, Step 2) was reacted with 2.86 g (15.4 mmol) of
3-chloro-4-methoxypheny- lboronic acid (Step 2). Purification by
silica gel chromatography (Waters PrepLC 500A) with ethyl
acetate/hexane (35:65) and subsequent recrystallization from ethyl
acetate/hexane gave 3.31 g (69%) of
2-chloro-1-methoxy-4-[2-[4-(methylsulfonyl)phenyl]phenyl]benzene as
a colorless solid: mp 161.5-162.3.degree. C.; NMR (CDCl.sub.3)
.delta. 3.05 (s, 3H), 3.88 (s, 3H), 6.75 (d, J=9 Hz, 1H), 6.87 (dd,
J=1.5, 9 Hz, 1H), 7.17 (d, J=2 Hz, 1H), 7.34 (d, J=9 Hz, 2H),
7.37-7.51 (m, 4H), 7.82 (d, J=8 Hz, 2H). MS (EI): m/e (rel
intensity) 372 (100), 243 (24); HRMS Calc'd for
C.sub.20H.sub.17ClO.sub.3S: 372.0587. Found: 372.0557. Anal. Calc'd
for C.sub.20H.sub.17ClO.sub.3S: C, 64.43; H, 4.60; Cl, 9.51. Found:
C, 64.17; H, 4.56; Cl, 9.63.
EXAMPLE 6
[0621] 31
4-[2-(3-Fluoro-4-methoxyphenyl)phenyl]benzenesulfonamide
[0622] Step 1: Preparation of
4-[2-(3-fluoro-4-methoxyphenyl)phenyl]benzen- esulfonamide
[0623] Under nitrogen, 5.8 mL (9.2 mmol) of propylmagnesium
chloride (1.6 M in Et.sub.2O) was added to a stirred solution of
3.0 g (8.4 mmol) of
2-fluoro-1-methoxy-4-[2-[4-(methylsulfonyl)phenyl]phenyl]benzene
(the title compound of Example 4, Step 4) in 9.6 mL of anhydrous
tetrahydrofuran at 0.degree. C. The resulting solution was warmed
to ambient temperature and stirred for 30 minutes. The reaction was
cooled to 0.degree. C. prior to the addition of 12.6 mL (12.6 mmol)
of triethylborane (1.0 M in THF). The reaction was warmed to
ambient temperature and stirred for 90 minutes prior to stirring at
reflux for 40 hours. The reaction was cooled to 0.degree. C. and
treated with 6.4 g (78 mmol) of sodium acetate, 3.8 g (34 mmol) of
hydroxylamine-O-sulfonic acid, and 11 mL of water; stirring was
continued as the reaction slowly warmed to ambient temperature. The
reaction mixture was diluted with water and extracted three times
with ethyl acetate. The combined ethyl acetate extractions were
washed with brine and dried over MgSO.sub.4. Purification by silica
gel chromatography (Waters LC-2000) with ethyl acetate/hexane (3:7)
and subsequent recrystallization from ethyl acetate/hexane gave 2.0
g (67%) of 4-[2-(3-fluoro-4-methoxyphenyl)phenyl]-
benzenesulfonamide as a colorless solid: mp 143.5-145.5.degree. C.
(dec); NMR (CDCl.sub.3) .delta.3.96 (s, 3H), 4.90 (s, 2H),
6.74-6.90 (m, 3H), 7.29 (d, J=9 Hz, 2H), 7.35-7.48 (m, 4H), 7.79
(d, J=9 Hz, 2H). MS (FAB): m/e 364 (M+Li); HRMS Calc'd for
C.sub.19H.sub.16FNO.sub.3S: 357.0835. Found: 357.0809. Anal. Calc'd
for C.sub.19H.sub.16FNO.sub.3S (0.20 ethyl acetate &
0.13H.sub.2O)C, 63.04; H, 4.77; N, 3.71. Found: C, 63.03; H, 4.59;
N, 3.52.
EXAMPLE 7
[0624] 32
[0625] Following the general procedure outlined in Synthetic Scheme
XI, 2.5 g (6.7 mmol) of
2-chloro-1-methoxy-4-[2-[4-(methylsulfonyl)phenyl]phe- nyl]benzene
(the title compound of Example 5) was converted to its
corresponding sulfonamide. Purification by silica gel
chromatography (Waters LC-2000) with ethyl acetate/hexane (3:7) and
subsequent recrystallization from ethyl acetate/hexane gave 1.31 g
(52%) of 4-[2-(3-chloro-4-methoxyphenyl)phenyl]benzenesulfonamide
as a colorless solid: mp 179.5-180.2.degree. C.; NMR (CDCl.sub.3)
.delta. 3.87 (s, 3H), 4.76 (s, 2H), 6.75 (d, J=9 Hz, 1H), 6.86 (dd,
J=2, 9 Hz, 1H), 7.20 (d, J=3 Hz, 1H), 7.29 (d, J=9 Hz, 2H),
7.35-7.47 (m, 4H), 7.79 (d, J=8 Hz, 2H). MS (EI): m/e (rel
intensity) 373 (100), 258 (17), 243 (29); HRMS Calc'd for
C.sub.19H.sub.16ClNO.sub.3S: 373.0539. Found: 373.0587. Anal.
Calc'd for C.sub.19H.sub.16ClNO.sub.3S: C, 61.04; H, 4.31; N, 3.75.
Found: C, 60.76; H, 4.28; N, 3.48.
EXAMPLE 8
[0626] 33
[0627] Following the general procedure outlined in Synthetic Scheme
VI, 2.3 g (7.4 mmol) of 1-bromo-2-[4-(methylsulfonyl)phenyl]benzene
(Example 4, Step 2) was reacted with 1.7 g (11 mmol) of
4-chlorophenylboronic acid. Purification by silica gel
chromatography (Waters Prep-500A) with ethyl acetate/hexane (1:3)
and subsequent recrystallization from ethyl acetate/hexane gave
1.90 g (74%) of 1-(4-chlorophenyl)-2-[4-(methylsulfon-
yl)phenyl]benzene as a colorless solid: mp 180.2-180.6.degree. C.;
NMR (CDCl.sub.3) .delta. 3.06 (s, 3H), 7.04 (d, J=8 Hz, 2H), 7.21
(d, J=8 Hz, 2H), 7.33 (d, J=9 Hz, 2H), 7.38-7.51 (m, 4H), 7.81 (d,
J=8 Hz, 2H). MS (EI): m/e (rel intensity) 342 (34), 228 (100); HRMS
Calc'd for C.sub.19H.sub.15ClO.sub.2S: 342.0481. Found: 342.0484.
Anal. Calc'd for C.sub.19H.sub.15ClO.sub.2S: C, 66.56; H, 4.41; Cl,
10.34. Found: C, 66.45; H, 4.48; Cl, 10.63.
EXAMPLE 9
[0628] 34
4-[2-[4-(Trifluoromethyl)phenyl]phenyl]benzenesulfonamide
[0629] Step 1: Preparation of 4-(trifluoromethyl)phenylboronic
acid
[0630] Following the general procedure outlined in Synthetic Scheme
I, 8.9 g (39 mmol) of 4-bromobenzotrifluoride was converted to
4-(trifluoromethyl)phenylboronic acid.
[0631] Step 2: Preparation of
1-[4-(trifluoromethyl)phenyl]-2-[4-(methylsu-
lfonyl)phenyl]benzene
[0632] Following the general procedure outlined in Synthetic Scheme
VI, 4.0 g (13 mmol) of 1-bromo-2-[4-(methylsulfonyl)phenyl]benzene
(Example 4, Step 2) was reacted with 3.8 g (20 mmol) of
4-(trifluoromethyl)phenylb- oronic acid (Step 1). Purification by
silica gel chromatography (Waters Prep-500A) with ethyl
acetate/hexane (1:3) and subsequent recrystallization from ethyl
acetate/hexane gave 3.80 g (77%) of
1-[4-(trifluoromethyl)phenyl]-2-[4-(methylsulfonyl)phenyl]benzene
as a colorless solid: mp 172.8-173.5.degree. C.; NMR (CDCl.sub.3)
.delta. 3.06 (s, 3H), 7.23 (d, J=8 Hz, 2H), 7.33 (d, J=9 Hz, 2H),
7.41-7.46 (m, 2H), 7.48-7.54 (m, 4H), 7.81 (d, J=9 Hz, 2H). MS
(ES): m/e 383 (M+Li); HRMS Calc'd for
C.sub.20H.sub.15F.sub.3O.sub.2S: 376.0745. Found: 376.0766.
[0633] Step 3: Preparation of
4-[2-[4-(trifluoromethyl)phenyl]phenyl]benze- nesulfonamide
[0634] Following the synthetic procedure outlined in Synthetic
Scheme XI, 2.62 g (6.96 mmol) of
1-[4-(trifluoromethyl)phenyl]-2-[4-(methylsulfonyl)- phenyl]benzene
(Step 2) was converted to its corresponding sulfonamide.
Purification by silica gel chromatography (Water Prep-500A) with
ethyl acetate/hexane (3:7) and subsequent recrystallization from
ethyl acetate/hexane gave 1.85 g (70%) of
4-[2-[4-(trifluoromethyl)phenyl]pheny- l]benzenesulfonamide as a
colorless solid: mp 187.5-187.8.degree. C.; NMR (CDCl.sub.3)
.delta. 4.79 (s, 2H), 7.20-7.31 (m, 4H), 7.38-7.54 (m, 6H), 7.80
(d, J=8 Hz, 2H). MS (EI): m/e (rel intensity) 377 (14), 297 (25),
228 (100); HRMS Calc'd for C.sub.19H.sub.14F.sub.3NO.sub.2S:
377.0697. Found: 377.0737. Anal. Calc'd for
C.sub.19H.sub.14F.sub.3NO.sub.2S: C, 60.47; H, 3.74; N, 3.71.
Found: C, 60.43; H, 3.97; N, 3.48.
EXAMPLE 10
[0635] 35
2-Chloro-1-fluoro-4-[2-[4-(methylsulfonyl)phenyl]phenyl]benzene
[0636] Step 1: Preparation of
2-chloro-1-fluoro-4-[2-[4-(methylsulfonyl)ph-
enyl]phenyl]benzene
[0637] Following the general procedure outlined in Synthetic Scheme
VI, 6.43 g (20.6 mmol) of
1-bromo-2-[4-(methylsulfonyl)phenyl]benzene (Example 4, Step 2) was
reacted with 5.37 g (30.9 mmol) of 3-chloro-4-fluorophenylboronic
acid. Purification by silica gel chromatography (Waters Prep-500A)
with ethyl acetate/hexane (1:3) gave 6.64 g (89%) of
2-chloro-1-fluoro-4-[2-[4-(methylsulfonyl)phenyl]phenyl]b- enzene
as a colorless solid: mp 179.5-181.1.degree. C.; NMR (CDCl.sub.3)
.delta. 3.06 (s, 3H), 6.86-6.93 (m, 1H), 6.98 (t, J=8 Hz, 1H), 7.19
(dd, J=2, 7 Hz, 1H), 7.33 (d, J=8 Hz, 2H), 7.38-7.53 (m, 4H), 7.84
(d, J=9 Hz, 2H). MS (FAB): m/e 367 (M+Li); HRMS Calc'd for
C.sub.19H.sub.14ClFO.sub.2- S: 360.0387. Found: 360.0401. Anal.
Calc'd for C.sub.19H.sub.14ClFO.sub.2S- : C, 63.25; H, 3.91; F,
5.27. Found: C, 62.92; H, 4.02; F, 5.19.
EXAMPLE 11
[0638] 36
1,2-Difluoro-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]benzene
[0639] Step 1: Preparation of
1,2-difluoro-4-(4-fluorophenyl)-5-[4-(methyl-
thio)phenyl]benzene
[0640] Under nitrogen, 3 g (2.6 nmol) of Pd(PPh.sub.3).sub.4 was
added to a stirred solution of 5.0 g (18 mmol) of
1,2-dibromo-4,5-difluorobenzene (Aldrich), 4.2 g (25 nmol) of
4-methylthiophenylboronic acid (Example 1, Step 2), and 3.1 g (22
nmol) of 4-fluorophenylboronic acid in 100 mL of toluene, 100 mL of
ethanol, and 100 mL of 2M Na.sub.2CO.sub.3. After vigorous stirring
at reflux overnight, the solvent was removed in vacuo and the
residue dissolved in ethyl acetate. The resulting solution was
washed with water and dried over MgSO.sub.4. Purification by silica
gel chromatography gave
1,2-difluoro-4-(4-fluorophenyl)-5-[4-(methylthio)phen- yl]benzene
as a semi-solid which was used without further purification.
[0641] Step 2: Preparation of
1,2-difluoro-4-(4-fluorophenyl)-5-[4-(methyl-
sulfonyl)phenyl]benzene
[0642] To a stirred solution of 6.34 g (ca. 18 mmol) of the crude
1,2-difluoro-4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]benzene
(Step 1) in 125 mL of methylene chloride at 0.degree. C. was slowly
added 14.6 g (54 mmol) of 3-chloroperoxybenzoic acid (ca 64%);
after stirring for 90 minutes, the reaction was diluted with
additional methylene chloride, washed with 3 times with 5% NaOH,
and dried over MgSO.sub.4. Purification by silica gel
chromatography (Waters Prep-500A) with ethyl acetate/hexane (1:3)
and subsequent recrystallization from ethyl acetate/hexane gave
2.81 g (43%) of
1,2-difluoro-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phen-
yl]benzene as a colorless solid: mp 172.8-173.5.degree. C.; NMR
(CDCl.sub.3) .delta. 3.05 (s, 3H), 6.94 (t, J=8 Hz, 2H), 6.98-7.06
(m, 2H), 7.21-7.31 (m, 4H), 7.81 (d, J=8 Hz, 2H). MS (FAB): m/e 369
(M+Li); HRMS Calc'd for C.sub.19H.sub.13F.sub.3O.sub.2S: 362.0588.
Found: 362.0586. Anal. Calc'd for C.sub.19H.sub.13F.sub.3O.sub.2S:
C, 62.98; H, 3.62; F, 15.73. Found: C, 62.96; H, 3.70; F,
15.76.
EXAMPLE 12
[0643] 37
[0644] Following the general procedure outlined in Synthetic Scheme
XI, 5.0 g (14 mmol) of
2-chloro-1-fluoro-4-[2-[4-(methylsulfonyl)phenyl]pheny- l]benzene
(the title compound of Example 10) was converted to its
corresponding sulfonamide. Purification by silica gel
chromatography (Waters Prep-500A) with ethyl acetate/hexane (28:72)
and subsequent recrystallization from ethyl acetate/hexane gave
1.47 g (29%) of
4-[2-(3-chloro-4-fluorophenyl)phenyl]benzenesulfonamide as a
colorless solid: mp 192.5-193.2.degree. C.; NMR (CDCl.sub.3)
.delta. 6.36 (s, 2H), 6.68-6.76 (m, 1H), 6.81 (t, J=9 Hz, 1H), 7.06
(d, J=8 Hz, 2H), 7.17-7.32 (m, 5H), 7.63 (d, J=8, 2H). MS (FAB):
m/e 368 (M+Li); HRMS Calc'd for C.sub.18H.sub.13ClFNO.sub.2S:
361.0340. Found: 361.0338. Anal. Calc'd for
C.sub.18H.sub.13ClFNO.sub.2S: C, 59.75; H, 3.62; N, 3.87. Found: C,
59.80; H, 3.91; N, 4.05.
EXAMPLE 13
[0645] 38
[0646] Following the general procedure outlined in Synthetic Scheme
XI, 2.65 g (7.32 mmol) of
1,2-difluoro-4-(4-fluorophenyl)-5-[4-(methylsulfony-
l)phenyl]benzene (the title compound of Example 11) was converted
to its corresponding sulfonamide. Purification by silica gel
chromatography (Waters LC-2000) with ethyl acetate/hexane (1:3) and
subsequent recrystallization from ethyl acetate/hexane gave 1.37 g
(52%) of
4-[3,4-difluoro-6-(4-fluorophenyl)phenyl]benzenesulfonamide as a
colorless solid: mp 190.2-191.5.degree. C.; NMR (CDCl.sub.3)
.delta. 4.77 (s, 2H), 6.94 (t, J=8 Hz, 2H), 6.98-7.06 (m, 2H),
7.17-7.28 (m, 4H), 7.79 (d, J=8 Hz, 2H). MS (FAB): m/e 370 (M+Li);
HRMS Calc'd for C.sub.18H.sub.12F.sub.3NO.sub.2S: 363.0541. Found:
363.0576. Anal. Calc'd for C.sub.18H.sub.12F.sub.3NO.sub.2S: C,
59.50; H, 3.33; N, 3.85. Found: C, 59.52; H, 3.57; N, 3.68.
EXAMPLE 14
[0647] 39
[0648] Step 1: Preparation of
1-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-[-
4-(methylthio)phenyl]benzene
[0649] Following the general procedure outlined in Synthetic Scheme
VII, 4.1 g (15 mmol) of 1,2-dibromo-4,5-difluorobenzene, 3.0 g (18
mmol) of 4-methylthiophenylboronic acid (Example 1, Step 2) and 2.9
g (16.5 nmol) of 3-chloro-4-fluorophenylboronic acid were reacted.
Purification by silica gel chromatography gave 3.5 g of
1-(3-chloro-4-fluorophenyl)-4,5-d-
ifluoro-2-[4-(methylthio)phenyl]benzene as a semi-solid which was
used without further purification.
[0650] Step 2: Preparation of
1-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-[-
4-(methylsulfonyl)phenyl]benzene
[0651] Following the synthetic procedure outlined in Step 2 of
Example 11, 3.50 g (ca. 15 mmol) of crude
1-(3-chloro-4-fluorophenyl)-4,5-difluoro-2--
[4-(methylthio)phenyl]benzene (Step 1) was oxidized to its
corresponding sulfonamide. Purification by silica gel
chromatography (Waters Prep-500A) with ethyl acetate/hexane (1:3)
and subsequent recrystallization from ethyl acetate/hexane gave
1.66 g (28%) of 1-(3-chloro-4-fluorophenyl)-4,5-
-difluoro-2-[4-(methylsulfonyl)phenyl]benzene as a colorless solid:
mp 172.2-172.5.degree. C.; NMR (CDCl.sub.3) .delta. 3.05 (s, 3H),
6.82-6.89 (m, 1H), 6.99 (t, J=9 Hz, 1H), 7.14 (dd, J=2, 8 Hz, 1H),
7.20-7.32 (m, 4H), 7.84 (d, J=8 Hz, 2H); MS (EI): m/e (rel
intensity) 396 (22), 317 (12), 282 (100), 262 (25), 243 (10); HRMS
Calc'd for C.sub.19H.sub.12ClF.sub.3O.sub.2S: 396.0199. Found:
396.0203. Anal. Calc'd for C.sub.19H.sub.12ClF.sub.3O.sub.2S: C,
57.51; H, 3.05; F, 14.36. Found: C, 57.31; H, 2.99; F, 14.48.
EXAMPLE 15
[0652] 40
[0653] Step 1: Preparation of
1,2,3,4-tetrafluoro-5-(4-fluorophenyl)-6-[4--
(methylthio)phenyl]benzene
[0654] Under nitrogen, 1 g of Pd(PPh.sub.3).sub.4 was added to a
stirred solution of 4.85 g (15.8 mmol) of
1,2-dibromo-3,4,5,6-tetrafluorobenzene (Aldrich), 2.65 g (18.9
mmol) of 4-fluorophenylboronic acid, and 3.17 g (18.9 mmol) of
4-methylthiophenylboronic acid (Example 1, Step 2) in 80 mL of
toluene, 50 mL of ethanol, and 35 mL of 2M Na.sub.2CO.sub.3. After
vigorous stirring at reflux overnight, the solvent was removed in
vacuo. The residue was dissolved in ethyl acetate, washed water,
and dried over Na.sub.2SO.sub.4. Concentration in vacuo gave 7.3 g
of
1,2,3,4-tetrafluoro-5-(4-fluorophenyl)-6-[4-(methylthio)phenyl]benzene
as a yellow oil which was used without further purification.
[0655] Step 2: Preparation of 1, 2, 3,
4-tetrafluoro-5-(4-fluorophenyl)-6--
[4-(methylsulfonyl)phenyl]benzene
[0656] To a stirred solution of 7.3 g of crude
1,2,3,4-tetrafluoro-5-(4-fl-
uorophenyl)-6-[4-(methylthio)phenyl]benzene (Step 1) in 40 mL of
methylene chloride was slowly added 15 g (43.5 mmol) of
3-chloroperoxybenzoic acid (ca. 55%) at -10.degree. C. Purification
by silica gel chromatography (MPLC) with ethyl acetate/hexane (1:5)
followed by reversed phase chromatography (Waters DeltaPrep-3000)
with acetonitrile/water/TFA (48:52:0.05) gave 1.2 g (19% overall
for both steps) of
1,2,3,4-tetrafluoro-5-(4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]benzen-
e as a colorless solid: mp 134.0-135.0.degree. C.; NMR (CDCl.sub.3)
.delta. 3.05 (s, 3H), 6.91-7.03 (m, 4H), 7.26 (d, J=8.5 Hz, 2H),
7.84 (d, J=8.5 Hz, 2H). MS (FAB): m/e 405 (M+Li); HRMS Calc'd for
C.sub.19H.sub.11F.sub.5O.sub.2S: 398.0400, found: 398.0393.
[0657] Step 3: Preparation of
4-[2,3,4,5-tetrafluoro-6-(4-fluorophenyl)phe-
nyl]benzenesulfonamide
[0658] Following the general procedure outlined in Synthetic Scheme
XI, 1.1 g (2.76 nmol) of
1,2,3,4-tetrafluoro-5-(4-fluorophenyl)-6-[4-(methyls-
ulfonyl)phenyl]benzene (Step 2) was converted to its corresponding
sulfonamide. Purification by silica gel chromatography (MPLC) with
ethyl acetate/hexane (1:5) gave 80 mg (7%)
4-[2,3,4,5-tetrafluoro-6-(4-fluoroph-
enyl)phenyl]benzenesulfonamide as a colorless solid: mp
202.0-203.0.degree. C.; NMR (CDCl.sub.3) .delta. 4.78 (br s, 2H),
6.92-7.04 (m, 4H), 7.21 (d, J=8.5 Hz, 2H), 7.82 (d, J=8.5 Hz, 2H).
MS (FAB): m/e 406 (M+Li). Anal. Calc'd for
C.sub.18H.sub.10FSNO.sub.2S-(0.16- H.sub.2O): C, 53.76; H, 2.59; N,
3.48. Found: C, 53.73; H, 2.40; N, 3.44.
EXAMPLE 16
[0659] 41
[0660] Following the general procedure outlined in Synthetic Scheme
XI, 2.00 g (5.04 mmol) of
1-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-[4-(meth-
ylsulfonyl)phenyl]benzene (the title compound of Example 14) was
converted to its corresponding sulfonamide. Purification by reverse
phase chromatography (Waters DeltaPrep-3000) with
acetonitrile/water/TFA (48:52:0.05) and subsequent
recrystallization from ethyl acetate/hexane gave 500 mg (25%) of
4-[2-(3-chloro-4-fluorophenyl)-4,5-difluorophenyl]be-
nzenesulfonamide as a colorless solid: mp 162.5-162.8.degree. C.;
NMR (CDCl.sub.3) .delta. 4.80 (s, 2H), 6.81-6.88 (m, 1H), 6.99 (t,
J=9 Hz, 1H), 7.15-7.28 (m, 5H), 7.83 (d, J=8 Hz, 2H). MS (FAB): m/e
404 (M+Li); HRMS Calc'd for C.sub.18H.sub.11ClF.sub.3NO.sub.2S:
397.0151. Found: 397.0152. Anal. Calc'd for
C.sub.18H.sub.11ClF.sub.3NO.sub.2S: C, 54.35; H, 2.79; N, 3.52.
Found: C, 54.57; H, 3.00; N, 3.42.
EXAMPLE 17
[0661] 42
[0662] Step 1:
5-(4-fluorophenyl)-6-[4-(methylthio)phenyl]-1,3-benzodioxol- e
[0663] Under nitrogen, 1 g of Pd(PPh.sub.3).sub.4 was added to a
stirred solution of 4 g (14.3 mmol) of 5,6-dibromo-1,3-benzodioxole
(Lancaster), 2.4 g (17.2 nmol) of 4-fluorophenylboronic acid, and
2.87 g (17.2 mmol) of 4-methylthiophenylboronic acid (Example 1,
Step 2) in 70 mL of toluene, 40 mL of ethanol, and 30 mL of 2M
Na.sub.2CO.sub.3. After vigorous stirring at reflux overnight, the
solvent was removed in vacuo. The residue was dissolved in ethyl
acetate, washed with water, and dried over Na.sub.2SO.sub.4.
Concentration in vacuo gave 6.9 g of
5-(4-fluorophenyl)-6-[4-(methylthio)phenyl]-1,3-benzodioxole as a
semi-solid which was used without further purification.
[0664] Step 2: Preparation of
5-(4-fluorophenyl)-6-[4-(methylsulfonyl)phen-
yl]-1,3-benzodioxole
[0665] To a stirred solution of 6.9 g of
5-(4-fluorophenyl)-6-[4-(methylth- io)phenyl]-1,3-benzodioxole
(Step 1) in 30 mL of methylene chloride was slowly added 12 g (38.2
mmol) of 3-chloroperoxybenzoic acid (ca. 55%) at -10.degree. C.
Purification by silica gel chromatography (MPLC) with ethyl
acetate/hexane (1:4) followed by reversed phase chromatography
(Waters DeltaPrep-3000) with acetonitrile/water/TFA (45:55:0.05)
gave 200 mg (4% overall for both steps) of
5-(4-fluorophenyl)-6-[4-(methylsulfonyl- )phenyl]-1,3-benzodioxole
as a colorless solid: mp 173.0-174.0.degree. C.; NMR (CDCl.sub.3)
.delta. 3.04 (s, 3H), 6.06 (s, 2H), 6.86-6.92 (m, 4H), 6.96-7.03
(m, 2H), 7.23-7.27 (m, 2H), 7.76 (d, J=8.5 Hz, 2H). MS (FAB): m/e
377 (M+Li); HRMS Calc'd for C.sub.20H.sub.15FO.sub.4S: 370.0675,
found: 370.0680. Anal. Calc'd for C.sub.20H.sub.15FO.sub.4S
(0.25H.sub.2O): C, 64.08; H, 4.17. Found: C, 64.08; H, 4.15.
EXAMPLE 18
[0666] 43
[0667] Step 1: Preparation of
1-bromo-4,5-difluoro-2-F.sub.4-(methylthio)p- henyl]benzene
[0668] Following the general procedure outlined in Synthetic Scheme
IV, 40 g (147 mmol) of 1,2-dibromo-4,5-difluorobenzene was reacted
with 12.3 g (73 mmol) of 4-methylthiophenylboronic acid (Example 1,
Step 2). Purification by silica gel chromatography with hexane gave
40.3 g of 1-bromo-4,5-difluoro-2-[4-(methylthio)phenyl]benzene as a
yellow oil which was used without further purification.
[0669] Step 2: Preparation of
1-bromo-4,5-difluoro-2-[4-(methylsulfonyl)ph- enyl]benzene
[0670] Following the synthetic procedure outlined in Step 4 of
Example 1, 40.3 g (ca. 73 mmol) of
1-bromo-4,5-difluoro-2-[4-(methylthio)phenyl]benz- ene (Step 1) was
oxidized to its corresponding sulfone. Purification by silica gel
chromatography (Waters Prep-500A) with ethyl acetate/hexane (1:3)
gave 17.4 g (68%) of
1-bromo-4,5-difluoro-2-[4-(methylsulfonyl)phen- yl]benzene as a
colorless solid: mp 158.5-159.5.degree. C.; NMR (CDCl.sub.3)
.delta. 3.12 (s, 3H), 7.13-7.21 (m, 1H), 7.50-7.60 (m, 3H), 8.02
(d, J=9 Hz, 2H).
[0671] Step 3: Preparation of
1-(3-chloro-4-methoxyphenyl)-4,5-difluoro-2--
[4-(methylsulfonyl)phenyl]benzene
[0672] Following the general procedure outlined in Synthetic Scheme
VI, 4.4 g (13 mmol) of
1-bromo-4,5-difluoro-2-[4-(methylsulfonyl)phenyl]benze- ne (Step 2)
was reacted with 3.1 g (17 mmol) of 3-chloro-4-methoxy
phenylboronic acid (Example 5, Step 2). Purification by silica gel
chromatography (Waters Prep-500A) with ethyl acetate/hexane (3:7)
and subsequent recrystallization from ethyl acetate/hexane gave
4.47 g (95%) of
1-(3-chloro-4-methoxyphenyl)-4,5-difluoro-2-[4-(methylsulfonyl)phenyl]-
benzene as a colorless solid: mp 147.5-148.5.degree. C.; NMR
(CDCl.sub.3) .delta. 3.05 (s, 3H), 3.88 (s, 3H), 6.75 (d, J=9 Hz,
1H), 6.83 (dd, J=2, 9 Hz, 1H), 7.10 (d, J=2 Hz, 1H), 7.17-7.32 (m,
4H), 7.83 (d, J=9 Hz, 2H). MS (EI): m/e (rel intensity) 408 (33),
314 (15), 294 (52), 279 (63), 251 (100). Anal. Calc'd for
C.sub.20H.sub.15ClF.sub.2O.sub.3S-(0.27 ethyl acetate): C, 58.53;
H, 3.99; F, 8.79. Found: C, 58.75; H, 3.71; F, 8.52.
EXAMPLE 19
[0673] 44
1,2-Difluoro-4-(3-fluoro-4-methoxyphenyl)-5-[4-(methylsulfonyl)phenyl]benz-
ene
[0674] Following the general procedure outlined in Synthetic Scheme
VI, 3.0 g (8.6 mmol) of
1-bromo-4,5-difluoro-2-[4-(methylsulfonyl)phenyl]benz- ene (Example
18, Step 2) was reacted with 1.9 g (11 mmol) of
3-fluoro-4-methoxyphenylboronic acid (Example 4, Step 3).
Purification by silica gel chromatography (Waters Prep-500A) with
ethyl acetate/hexane (1:3) and subsequent recrystallization from
ethyl acetate/hexane gave 3.19 g (94%) of
1,2-difluoro-4-(3-fluoro-4-methoxyphenyl)-5-[4-(methylsul-
fonyl)phenyl]benzene as a colorless solid: mp 159.2-159.7.degree.
C.; NMR (CDCl.sub.3) .delta. 3.05 (s, 3H), 3.87 (s, 3H), 6.63-6.85
(m, 3H), 7.16-7.32 (m, 4H), 7.82 (d, J=8 Hz, 2H). MS (EI): m/e (rel
intensity) 392 (49), 313 (15), 298 (48), 269 (100), 249 (79). Anal.
Calc'd for C.sub.20H.sub.15F.sub.3O.sub.3S (0.26 ethyl acetate): C,
60.85; H, 4-0.15; F, 13.71. Found: C, 61.33; H, 3.90; F, 13.40.
EXAMPLE 20
[0675] 45
[0676] Following the general procedure outlined in Synthetic Scheme
XI, 4.00 g (9.78 mmol) of
1-(3-chloro-4-methoxyphenyl)-4,5-difluoro-2-[4-(met-
hylsulfonyl)phenyl]benzene (the title compound of Example 18) was
converted to its corresponding sulfonamide. Purification by silica
gel chromatography (MPLC) with ethyl acetate/hexane (1:3) and
subsequent recrystallization from ethyl acetate/hexane gave 0.86 g
(21%) of
4-[2-(3-chloro-4-methoxyphenyl)-4,5-difluorophenyl]benzenesulfonamide
as a colorless solid: mp 70.degree. C. (dec); NMR (CDCl.sub.3)
.delta. 3.87 (s, 3H), 4.84 (s, 2H), 6.75 (d, J=9 Hz, 1H), 6.82 (dd,
J=2, 9 Hz, 1H), 7.14 (d, J=2 Hz, 1H), 7.16-7.28 (m, 4H), 7.81 (d,
J=8, 2H). MS (EI): m/e (rel intensity) 409 (22), 294 (15), 279
(28), 251 (100), 231 (20). Anal. Calc'd for
C.sub.19H.sub.14ClF.sub.2NO.sub.3S: C, 55.68; H, 3.44; N, 3.42.
Found: C, 55.42; H, 3.48; N, 3.33.
EXAMPLE 21
[0677] 46
[0678] Following the general procedure outlined in Synthetic Scheme
XI, 2.50 g (6.38 mmol) of
1,2-difluoro-4-(3-fluoro-4-methoxyphenyl)-5-[4-(met-
hyl-sulfonyl)phenyl]benzene (the title compound of Example 19) was
converted to its corresponding sulfonamide. Purification by silica
gel chromatography (MPLC) with ethyl acetate/hexane (1:3) and
subsequent recrystallization from ethyl acetate/hexane gave 0.82 g
(33%) of
4-[4,5-difluoro-2-(3-fluoro-4-methoxyphenyl)phenyl]benzenesulfonamide
as a colorless solid: mp 132.2-132.8.degree. C.; NMR (CDCl.sub.3)
.delta. 3.87 (s, 3H), 4.85 (s, 2H), 6.71-6.85 (m, 3H), 7.15-7.27
(m, 4H), 7.81 (d, J=9 Hz, 2H). MS (EI): m/e (rel intensity) 393
(32), 298 (21), 282 (25), 269 (100), 249 (46). Anal. Calc'd for
C.sub.19H.sub.14F.sub.3NO.sub- .3S: C, 58.01; H, 3.59; N, 3.56.
Found: C, 57.75; H, 3.48; N, 3.48.
EXAMPLE 22
[0679] 47
[0680] Step 1: Preparation of
5-bromo-6-(4-fluorophenyl)-1,3-benzodioxole
[0681] Under nitrogen, 1.1 g of Pd(PPh.sub.3).sub.4 was added to a
stirred solution of 10.4 g (37.2 mol) of
5,6-dibromo-1,3-benzodioxole and 2.6 g (18.6 mmol) of
4-fluorophenylboronic acid in 100 mL of toluene, 60 mL of ethanol,
and 40 mL of 2M Na.sub.2CO.sub.3. After vigorous stirring at reflux
overnight, the solvent was removed in vacuo. The residue was
dissolved in ethyl acetate, washed with water, and dried over
Na.sub.2SO.sub.4. Purification by silica gel chromatography (Waters
Prep-500A) with hexane as the eluent gave 3.9 g (71%) of
5-bromo-6-(4-fluorophenyl)-1,3-benzodioxole as a colorless solid:
mp 86.0-87.5.degree. C.; NMR (CDCl.sub.3) .delta. 6.02 (s, 2H),
6.77 (s, 1H), 7.04-7.13 (m, 3H), 7.28-7.35 (m, 2H).
[0682] Step 2: Preparation of
[6-(4-fluorophenyl)-1,3-benzodioxol-5-yl]bor- onic acid
[0683] Under nitrogen, 6.3 mL (15.8 mmol) of n-BuLi (2.5 M in
hexanes) was added to a stirred solution of 3.9 g (13.2 mmol) of
5-bromo-6-(4-fluorophenyl)-1,3-benzodioxole (Step 1) in 30 mL of
anhydrous THF at -78.degree. C. After 30 minutes, 4.5 mL (39.4
mmol) of trimethylborate was added. The reaction was warmed to
ambient temperature and stirred for 3 hours prior to the addition
of 60 mL of 5% NaOH. The reaction was stirred for an additional 60
minutes, the THF removed in vacuo, and the pH adjusted to ca. 4.
The residue was dissolved in ethyl acetate; the resulting solution
was dried over Na.sub.2SO.sub.4 and concentrated in vacuo to give
1.7 g (50%) of [6-(4-fluorophenyl)-1,3-benz- odioxol-5-yl]boronic
acid as a pale yellow solid: NMR (CDCl.sub.3) .delta. 4.00 (br s,
2H), 6.06 (s, 2H), 6.75 (s, 1H), 7.08-7.17 (m, 2H), 7.26 (s, 1H),
7.31-7.39 (m, 2H).
[0684] Step 3: Preparation of
4-[6-(4-fluorophenyl)-1,3-benzodioxol-5-yl]b- enzenesulfonamide
[0685] Under nitrogen, 500 mg of Pd(PPh.sub.3).sub.4 was added to a
stirred solution of 1.55 g (6.0 nmol) of
[6-(4-fluorophenyl)-1,3-benzodio- xol-5-yl]boronic acid (Step 2)
and 1.09 g (4.62 mmol) of 4-bromobenzenesulfonamide (Lancaster) in
30 mL of toluene, 20 mL of ethanol, and 15 mL of 2M
Na.sub.2CO.sub.3. After vigorous stirring at reflux for 6 hours,
the solvent was removed in vacuo and the residue dissolved in ethyl
acetate. The resulting solution was washed with water and dried
over Na.sub.2SO.sub.4. Purification by silica gel chromatography
(MPLC) with ethyl acetate/hexane (3:7) gave 1.3 g (76%) of
4-[6-(4-fluorophenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide as a
colorless solid: mp 191.0-192.5.degree. C.; NMR (CDCl.sub.3)
.delta. 4.80 (s, 2H), 6.06 (s, 2H), 6.83-6.92 (m, 4H), 6.97-7.06
(m, 2H), 7.20 (d, J=8.5 Hz, 2H), 7.74 (d, J=8.5 Hz, 2H). MS (FAB):
m/e 372 (M+H). Anal. Calc'd for C.sub.19H.sub.14FNO.sub.4S: C,
61.45; H, 3.80; N, 3.77. Found: C, 61.48; H, 3.92; N, 3.68.
EXAMPLE 23
[0686] 48
[0687] Following the general procedure outlined in Synthetic Scheme
VI, 2.56 g (7.37 mmol) of
1-bromo-4,5-difluoro-2-[(4-methylsulfonyl)phenyl]be- nzene (Example
18, Step 2) was reacted with 1.35 g (9.93 mmol) of
4-methylphenylboronic acid. Purification by silica gel
chromatography (MPLC) with ethyl acetate/hexane (3:7) gave 2.55 g
(97%) of
1,2-difluoro-4-(4-methylphenyl)-5-[4-(methylsulfonyl)phenyl]benzene
as a colorless solid: mp 147.0-148.0.degree. C.; NMR (CDCl.sub.3)
.delta. 2.32 (s, 3H), 3.05 (s, 3H), 6.92 (d, J=8 Hz, 2H), 7.03 (d,
J=8 Hz, 2H), 7.17-7.32 (m, 4H), 7.79 (d, J=8 Hz, 2H). MS (FAB): m/e
365 (M+Li). Anal. Calc'd for C.sub.20H.sub.16F.sub.2O.sub.2S: C,
67.03; H, 4.50. Found: C, 67.18; H, 4.48.
EXAMPLE 24
[0688] 49
5-[4,5-Difluoro-2-[4-(methylsulfonyl)phenyl]phenyl]-1,3-benzodioxole
[0689] Step 1: Preparation of (1,3-benzodioxol-5-yl)boronic
acid
[0690] Following the synthetic procedure outlined in Step 2 of
Example 1, 15.2 g (75.6 mmole) of 5-bromo-1,3-benzodioxole
(Aldrich) was converted to (1,3-benzodioxol-5-yl)boronic acid as a
colorless solid: NMR (CDCl.sub.3) .delta. 5.98 (s, 2H), 6.88 (t,
J=8 Hz, 1H), 7.26-7.41 (m, 2H), 7.80 (br s, 2H).
[0691] Step 2: Preparation of
5-[4,5-difluoro-2-[4-(methylsulfonyl)phenyl]-
phenyl]-1,3-benzodioxole
[0692] Following the general procedure outlined in Synthetic Scheme
I, 2.24 g (6.45 mmol) of
1-bromo-4,5-difluoro-2-[4-(methylsulfonyl)phenyl]be- nzene (Example
18, Step 2) was reacted with 1.39 g (8.38 mmol) of
(1,3-benzodioxol-5-yl)boronic acid (Step 1). Purification by silica
gel chromatography (MPLC) with ethyl acetate/hexane (1:4) gave 2.47
g (99%) of
5-[4,5-difluoro-2-[4-(methylsulfonyl)phenyl]phenyl]-1,3-benzodioxole
as a colorless solid: mp 110.0-111.0.degree. C.; NMR (CDCl.sub.3)
.delta. 3.05 (s, 3H), 5.95 (s, 2H), 6.47-6.52 (m, 2H), 6.67 (d,
J=8.5 Hz, 1H), 7.16-7.24 (m, 2H), 7.32 (d, J=8.5 Hz, 2H), 7.82 (d,
J=8.5 Hz, 2H). MS (FAB): m/e 395 (M+Li). Anal. Calc'd for
C.sub.20H.sub.14F.sub.2O.sub.4S: C, 61.85; H, 3.63. Found: C,
61.92; H, 3.66.
EXAMPLE 25
[0693] 50
[0694] Following the general procedure outlined in Synthetic Scheme
XI, 2.43 g (6.78 mmol) of
1,2-difluoro-4-(4-methylphenyl)-5-[4-(methylsulfony-
l)phenyl]benzene (the title compound of Example 23) was converted
to its corresponding sulfonamide. Purification by silica gel
chromatography (MPLC) with ethyl acetate/hexane (1:5) gave 1.90 g
(78%) of
4-[4,5-difluoro-2-(4-methylphenyl)phenyl]benzenesulfonamide as a
colorless solid: mp 103.0-104.0.degree. C.; NMR (CDCl.sub.3)
.delta. 2.32 (s, 3H), 4.81 (s, 2H), 6.93 (d, J=8 Hz, 2H), 7.04 (d,
J=8 Hz, 2H), 7.16-7.29 (m, 4H), 7.78 (d, J=8.5 Hz, 2H). MS (EI):
m/e 359 (26), 279 (33), 278 (41), 264 (100), 251 (36), 119 (62), 80
(70), 64 (56). Anal. Calc'd for C.sub.19H.sub.15F.sub.2NO.sub.2S:
C, 63.50; H, 4.21; N, 3.90. Found: C, 63.55; H, 4.24; N, 3.80.
EXAMPLE 26
[0695] 51
[0696] Following the general procedure outlined in Synthetic Scheme
XI, 2.34 g (6.02 mmol) of
5-[4,5-difluoro-2-[4-(methylsulfonyl)phenyl]phenyl]-
-1,3-benzodioxole (the title compound of Example 24) was converted
to its corresponding sulfonamide. Purification by silica gel
chromatography (MPLC) with ethyl acetate/hexane (3:7) gave 1.84 g
(78%) of
4-[2-(1,3-benzodioxol-5-yl)-4,5-difluorophenyl]benzenesulfonamide
as a colorless solid: mp 142.0-143.0.degree. C.; NMR (CDCl.sub.3)
.delta. 4.83 (s, 2H), 5.95 (s, 2H), 6.49-6.54 (m, 2H), 6.69 (d, J=8
Hz, 1H), 7.15-7.30 (m, 4H), 7.81 (d, J=8 Hz, 2H). MS (EI): m/e 389
(18), 308 (14), 251 (100), 231 (43). Anal. Calc'd for
C.sub.19H.sub.13F.sub.2NO.sub.4S-(0.19H- .sub.2O): C, 58.09; H,
3.43; N, 3.57. Found: C, 58.11; H, 3.51; N, 3.48.
EXAMPLE 27
[0697] 52
[0698]
1-(3-Chloro-4-methylphenyl)-4,5-difluoro-2-[4-(methylsulfonyl)pheny-
l]benzene
[0699] Step 1: Preparation of 3-chloro-4-methylphenylboronic
acid
[0700] Following the general procedure outlined in Synthetic Scheme
I, 11.1 g (54 mmol) of 4-bromo-2-chlorotoluene was converted to
3-chloro-4-methylphenylboronic acid as a colorless solid: NMR
(CDCl.sub.3) .delta. 2.47 (s, 3H), 7.37 (d, J=8 Hz, 1H), 7.98 (d,
J=8 Hz, 1H), 8.08 (s, 1H).
[0701] Step 2: Preparation of
1-(3-chloro-4-methylphenyl)-4,5-difluoro-2-[-
4-(methylsulfonyl)phenyl]benzene
[0702] Following the general procedure outlined in Synthetic Scheme
VI, 2.49 g (7.17 mmol) of
1-bromo-4,5-difluoro-2-[4-(methylsulfonyl)phenyl]be- nzene (Example
18, Step 2) was reacted with 1.59 g (9.33 mmol) of
3-chloro-4-methylphenylboronic acid (Step 1). Purification by
silica gel chromatography (MPLC) with ethyl acetate/hexane (1:5)
gave 2.65 g (94%) of
1-(3-chloro-4-methylphenyl)-4,5-difluoro-2-[4-(methylsulfonyl)phenyl]b-
enzene as a colorless solid: mp 138.0-139.0.degree. C.; NMR
(CDCl.sub.3) .delta. 2.34 (s, 3H), 3.05 (s, 3H), 6.75 (dd, J=2, 8
Hz, 1H), 7.03-7.10 (m, 2H), 7.18-7.26 (m, 2H), 7.29 (d, J=8 Hz,
2H), 7.83 (d, J=8 Hz, 2H). MS (FAB): m/e 399 (M+Li). Anal. Calc'd
for C.sub.20H.sub.15ClF.sub.2O.sub- .2S: C; 61.15; H, 3.85. Found:
C, 61.12; H, 3.82.
EXAMPLE 28
[0703] 53
[0704] Step 1: Preparation of
4-bromo-2-chloro-N,N-dimethylaniline
[0705] Under nitrogen, 11.6 mL (186 mmol) of iodomethane was added
to a stirred solution of 12.8 g (62 mmol) of
4-bromo-2-chloroaniline and 42.8 g (310 mmol) of powdered
K.sub.2CO.sub.3 in 200 mL of DMF. Purification by silica gel
chromatography (Waters Prep-500A) with ethyl acetate/hexane (5:95)
gave 11.3 g (78%) of 4-bromo-2-chloro-N,N-dimethylaniline as a
colorless liquid: NMR (CDCl.sub.3) .delta. 2.79 (s, 6H), 6.92 (d,
J=9 Hz, 1H), 7.25-7.34 (m, 1H), 7.49 (d, J=2 Hz, 1H).
[0706] Step 2: Preparation of
3-chloro-4-(N,N-dimethylamino)phenylboronic acid
[0707] Following the general procedure outlined in Synthetic Scheme
I, 11.3 g (48.2 mmol) of 4-bromo-2-chloro-N,N-dimethylaniline (Step
1) was converted to 3-chloro-4-(N,N-dimethylamino)phenylboronic
acid as a colorless solid: NMR (CDCl.sub.3) .delta. 2.93 (s, 6H),
7.12 (d, J=8 Hz, 1H), 8.01 (d, J=8 Hz, 1H), 8.12 (s, 1H).
[0708] Step 3: Preparation of
2-chloro-4-[4,5-difluoro-2-[4-(methylsulfony-
l)phenyl]phenyl]-N,N-dimethylbenzenamine
[0709] Following the general procedure outlined in Synthetic Scheme
VI, 2.25 g (6.48 mmol) of
1-bromo-4,5-difluoro-2-[4-(methylsulfonyl)phenyl]be- nzene (Example
18, Step 2) was reacted with 1.68 g (8.42 mmol) of
3-chloro-4-(N,N-dimethylamino)phenylboronic acid (Step 2).
Purification by silica gel chromatography (MPLC) with ethyl
acetate/hexane (3:7) gave 2.65 g (97%) of
2-chloro-4-[4,5-difluoro-2-[4-(methylsulfonyl)phenyl]phen-
yl]-N,N-dimethylbenzenamine as a colorless solid: mp
129.0-130.0.degree. C.; NMR (CDCl.sub.3) .delta. 2.81 (s, 6H), 3.05
(s, 3H), 6.76-6.91 (m, 2H), 7.08 (d, J=2 Hz, 1H), 7.17-7.26 (m,
2H), 7.31 (d, J=8.5 Hz, 2H), 7.83 (d, J=8.5 Hz, 2H). MS (FAB): m/e
428 (M+Li). Anal. Calc'd for C.sub.21H.sub.18ClF.sub.2NO.sub.2S: C,
59.79; H, 4.30; N, 3.32. Found: C, 59.40; H, 4.29; N, 3.24.
EXAMPLE 29
[0710] 54
[0711] Following the general procedure outlined in Synthetic Scheme
XI, 2.54 g (6.47 mmol) of
1-(3-chloro-4-methylphenyl)-4,5-difluoro-2-[4-(meth-
yl-sulfonyl)phenyl]benzene (the title compound of Example 27) was
converted to its corresponding sulfonamide. Purification by silica
gel chromatography (MPLC) with ethyl acetate/hexane (1:5) gave 1.80
g (71%) of
4-[2-(3-chloro-4-methylphenyl)-4,5-difluorophenyl]benzenesulfonamide
as a colorless solid: mp 139.0-140.0.degree. C.; NMR (CDCl.sub.3)
.delta. 2.33 (s, 3H), 4.81 (s, 2H), 6.74 (dd, J=2, 8 Hz, 1H), 7.04
(d, J=8 Hz, 1H), 7.12 (d, J=2 Hz, 1H), 7.17-7.25 (m, 4H), 7.80 (d,
J=8 Hz, 2H). MS (FAB): m/e 400 (M+Li). Anal. Calc'd for
C.sub.19H.sub.14F.sub.2ClNO.sub.2- S: C, 57.95; H, 3.58; N, 3.56.
Found: C, 57.91; H, 3.55; N, 3.54.
EXAMPLE 30
[0712] 55
[0713] Following the general procedure outlined in Synthetic Scheme
XI, 2.50 g (5.93 mmol) of
2-chloro-4-[4,5-difluoro-2-[4-(methylsulfonyl)pheny-
l]phenyl]-N,N-dimethylbenzenamine (the title compound of Example
28) was converted to its corresponding sulfonamide. Purification by
silica gel chromatography (MPLC) with ethyl acetate/hexane (3:7)
gave 1.75 g (70%) of
4-[2-[3-chloro-4-(N,N-dimethylamino)phenyl]-4,5-difluorophenyl]benzene-
sulfonamide as a colorless solid: mp 193.0-194.0.degree. C.; NMR
(CDCl.sub.3) .delta. 2.83 (s, 6H), 4.80 (s, 2H), 6.79 (dd, J=2, 9
Hz, 1H), 6.87-6.95 (m, 1H), 7.13 (d, J=2 Hz, 1H), 7.17-7.29 (m,
4H), 7.82 (d, J=8 Hz, 2H). MS (FAB): m/e 429 (M+Li). Anal. Calc'd
for C.sub.20H.sub.17ClF.sub.2N.sub.2O.sub.2S (0.27H.sub.2O): C,
56.16; H, 4.13; N, 6.55. Found: C, 56.16; H, 4.02; N, 6.39.
EXAMPLE 31
[0714] 56
[0715] Step 1: Preparation of 4-fluoro-3-methylphenylboronic
acid
[0716] Following the general procedure outlined in Synthetic Scheme
1,5'-bromo-2-fluorotoluene was converted to
4-fluoro-3-methylphenylboroni- c acid: NMR (CDCl.sub.3) .delta.
2.39 (d, J=2 Hz, 3H), 7.13 (t, J=9 Hz, 1H), 7.99-8.08 (m, 2H)
[0717] Step 2: Preparation of
1,2-difluoro-4-(4-fluoro-3-methylphenyl)-5-[-
4(methylsulfonyl)phenyl]benzene
[0718] Following the general procedure outlined in Synthetic Scheme
VI, 1-bromo-4,5-difluoro-2-[4-(methylsulfonyl)phenyl]benzene
(Example 18, Step 2) was reacted with
4-fluoro-3-methylphenylboronic acid (Step 1) to give
1,2-difluoro-4-(4-fluoro-3-methylphenyl)-5-[4-(methylsulfonyl)phenyl-
]benzene as a colorless solid: mp 167.2-167.5.degree. C.; NMR
(CDCl.sub.3) .delta. 2.19 (d, J=2 Hz, 3H), 3.04 (s, 3H), 6.71-6.78
(m, 1H), 6.84 (t, J=9 Hz, 1H), 6.92 (dd, J=2, 8 Hz, 1H), 7.18-7.32
(m, 4H), 7.81 (d, J=8 Hz, 2H); MS (FAB) m/z 383 (M+Li).sup.+; HRMS
calc'd for M+376.0745, found 376.0752. Anal. Calc'd for
C.sub.20HlsF.sub.3O.sub.2S: C, 63.82; H, 4.02; F, 15.14. Found: C,
64.00; H, 3.95; F, 14.96.
EXAMPLE 32
[0719] 57
[0720] Step 1: Preparation of 4-chloro-3-methylphenylboronic
acid
[0721] Following the general procedure outlined in Synthetic Scheme
1,5-bromo-2-chlorotoluene was converted to
4-chloro-3-methylphenylboronic acid: NMR (DMSO-d.sub.6) .delta.
2.31 (s, 3H), 7.35 (d, J=8 Hz, 1H), 7.59 (d, J=8 Hz, 1H), 7.71 (s,
1H), 8.10 (br s, 2H).
[0722] Step 2: Preparation of
4-(4-chloro-3-methylphenyl)-1.2-difluoro-5-[-
4-(methylsulfonyl)phenyl]benzene
[0723] Following the general procedure outlined in Synthetic Scheme
VI, 1-bromo-4,5-difluoro-2-[4-(methylsulfonyl)phenyl]benzene
(Example 18, Step 2) was reacted with
4-chloro-3-methylphenylboronic acid (Step 1) to give
4-(4-chloro-3-methylphenyl)-1,2-difluoro-5-[4-(methylsulfonyl)phenyl-
]benzene as a colorless solid: mp 151.5-152.2.degree. C.; NMR
(CDCl.sub.3) .delta. 2.29 (s, 3H), 3.05 (s, 3H), 6.73 (dd, J=2, 8
Hz, 1H), 6.98 (d, J=2 Hz, 2H), 7.16 (d, J=9 Hz, 1H), 7.19-7.32 (m,
4H), 7.82 (d, J=9 Hz, 2H); MS (FAB) m/z 399 (M+Li).sup.+; HRMS
calc'd for M+392.0449, found 392.0437. Anal. Calc'd for
C.sub.20H.sub.15ClF.sub.2O.sub.2S: C, 61.15; H, 3.85; F, 9.67.
Found: C, 61.04; H, 3.79; F, 9.55.
EXAMPLE 33
[0724] 58
[0725] Step 1: Preparation of 3,4-dimethylphenylboronic acid
[0726] Following the general procedure outlined in Synthetic Scheme
1,4-bromo-.alpha.-xylene was converted to 3,4-dimethylphenylboronic
acid: NMR (CDCl.sub.3) .delta. 2.19 (s, 6H), 7.07 (d, J=8 Hz, 1H),
7.45-7.54 (m, 2H), 7.84 (br s, 2H).
[0727] Step 2: Preparation of
1,2-difluoro-4-(3,4-dimethylphenyl)-5-[4-(me-
thylsulfonyl)phenyl]benzene
[0728] Following the general procedure outlined in Synthetic Scheme
VI, 1-bromo-4,5-difluoro-2-(4-(methylsulfonyl)phenyl]benzene
(Example 18, Step 2) was reacted with 3,4-dimethylphenylboronic
acid (Step 1) to give
1,2-difluoro-4-(3,4-dimethylphenyl)-5-[4-(methylsulfonyl)phenyl]benzene
as a colorless solid: mp 125.1-125.8.degree. C.; NMR (CDCl.sub.3)
.delta. 2.16 (s, 3H), 2.23 (s, 3H), 3.04 (s, 3H), 6.69 (dd, J=2, 8
Hz, 1H), 6.86 (s, 1H), 6.95 (d, J=8 Hz, 1H), 7.16-7.26 (m, 3H),
7.29 (d, J=9 Hz, 1H), 7.79 (d, J=9 Hz, 2H); MS (FAB) m/z 379
(M+Li).sup.+; HRMS calc'd for M+372.0996, found 372.0978. Anal.
Calc'd for C.sub.20H.sub.18F.sub.2O.sub- .2S: C, 67.73; H, 4.87; F,
10.20. Found: C, 67.93; H, 4.92; F, 9.82.
EXAMPLE 34
[0729] 59
[0730] Following the general procedure outlined in Synthetic Scheme
XI,
1,2-difluoro-4-(4-fluoro-3-methylphenyl)-5-[4-(methylsulfonyl)phenyl]benz-
ene (Example 31) was converted to
4-[4,5-difluoro-2-(4-fluoro-3-methylphen-
yl)phenyl]benzenesulfonamide as a colorless solid: mp
151.5-152.0.degree. C.; NMR (CDCl.sub.3) .delta. 2.18 (d, J=9 Hz,
1H), 6.94 (dd, J=2, 8 Hz, 1H), 7.15-7.29 (m, 4H), 7.79 (d, J=8 Hz,
2H); MS (FAB) 384 (M+Li).sup.+; HRMS calc'd for M+377.0697, found
377.0720. Anal. Calc'd for C.sub.19H.sub.14NF.sub.3O.sub.2S: C,
60.47; H, 3.74; N, 3.71. Found: C, 60.07; H, 3.84; N, 3.62.
EXAMPLE 35
[0731] 60
[0732] Step 1: Preparation of 4-bromo-2-methylanisole Under
nitrogen, to a stirred suspension of 38.9 g (208 mmol) of
4-bromo-2-methylphenol and 43.1 g (312 mmol) of K.sub.2CO.sub.3
powder in 300 mL of THF was added 39 mL (624 mmol) of iodomethane.
The mixture was heated to reflux overnight, and cooled to ambient
temperature. The inorganic salts were removed by filtration, and
the organic solvent was removed in vacuo. The residue was dissolved
in ethyl acetate, washed with water and brine, and dried over
MgSO.sub.4. Purification by silica gel plug with ethyl
acetate/hexane (5:95) gave 28 g (67%) of 4-bromo-2-methylanisole as
a colorless solid: mp 65.0-66.0.degree. C.; NMR (CDCl.sub.3)
.delta. 2.18 (s, 3H), 3.80 (s, 3H), 6.67 (d, J=9 Hz, 1H), 7.22-7.28
(m, 2H).
[0733] Step 2: Preparation of 4-methoxy-3-methylphenylboronic
acid
[0734] Following the general procedure outlined in Synthetic Scheme
1,4-bromo-2-methylanisole was converted to
3-methyl-4-methoxyphenylboroni- c acid: NMR (CDCl.sub.3) .delta.
2.33 (s, 3H), 3.92 (s, 3H), 6.96 (d, J=8 Hz, 1H), 7.98 (s, 1H),
8.03 (d, J=8 Hz, 1H).
[0735] Step 3: Preparation of
1,2-difluoro-4-(4-methoxy-3-methylphenyl)-5--
[4-(methylsulfonyl)phenyl]benzene
[0736] Following the general procedure outlined in Synthetic Scheme
VI, 1-bromo-4,5-difluoro-2-[4-(methylsulfonyl)phenyl]benzene
(Example 18, Step 2) was reacted with
3-methyl-4-methoxyphenylboronic acid (Step 2) to give
1,2-difluoro-4-(4-methoxy-3-methylpheny)-5-[4-(methylsulfonyl)phenyl-
]benzene as a colorless solid: mp 160.5-161.5.degree. C.; NMR
(CDCl.sub.3) .delta. 2.11 (s, 3H), 3.04 (s, 3H), 3.79 (s, 3H), 6.63
(d, J=9 Hz, 1H), 6.74 (dd, J=2, 9 Hz, 1H), 6.85 (d, J=2 Hz, 1H),
7.15-7.27 (m, 3H), 7.30 (d, J=8 Hz, 1H), 7.80 (d, J=8 Hz, 2H); MS
(FAB) m/z 395 (M+Li).sup.+; HRMS calc'd for M+388.0945, found
388.0940. Anal. for C.sub.21H.sub.18F.sub.2O.sub.3S: C, 64.94; H,
4.67; F, 9.78. Found: C, 64.59; H, 4.84; F, 9.52.
EXAMPLE 36
[0737] 61
[0738] Following the general procedure outlined in Synthetic Scheme
XI,
4-(4-chloro-3-methylphenyl)-1,2-difluoro-5-[4-(methylsulfonyl)phenyl]benz-
ene (Example 32) was converted to
4-[2-(4-chloro-3-methylphenyl)-4,5-diflu-
orophenyl]benzenesulfonamide as a colorless solid: mp
141.5-142.8.degree. C.; NMR (CDCl.sub.3) .delta. 2.29 (s, 3H), 4.89
(s, 2H), 6.73 (dd, J=2, 8 Hz, 1H), 7.00 (d, J=8 Hz, 1H), 7.17-7.27
(m, 5H), 7.80 (d, J=9 Hz, 1H); MS (FAB) m/z 400 (M+Li).sup.+; HRMS
for M+393.0402, found 393.0416. Anal. Calc'd for
C.sub.19H.sub.14NF.sub.2ClO.sub.2S: C, 57.95; H, 3.58; N, 3.56.
Found: C, 57.73; H, 3.55; N, 3.48.
EXAMPLE 37
[0739] 62
[0740] Following the general procedure outlined in Synthetic Scheme
XI,
1,2-difluoro-4-(3,4-dimethylphenyl)-5-[4-(methylsulfonyl)phenyl]benzene
(Example 33) was converted to
4-[4,5-difluoro-2-(3,4-dimethylphenyl)pheny- l]benzenesulfonamide
as a colorless solid: mp 132.8-133.9.degree. C.; NMR (CDCl.sub.3)
.delta. 2.16 (s, 3H), 2.22 (s, 3H), 4.83 (s, 2H), 6.68 (dd, 2, 8
Hz, 1H), 6.88 (s, 1H), 6.94.degree. (d, 8 Hz, 1H), 7.15-7.28 (m,
4H), 7.77 (d, J=8 Hz, 2H); MS (FAB) m/z 380 (M+Li).sup.+; HRMS for
M+373.0948, found 373.0972. Anal. Calc'd for
C.sub.20H.sub.17NF.sub.2O.su- b.2S: C, 64.33; H, 4.59; N, 3.75.
Found: C, 64.20; H, 4.58; N, 3.72.
EXAMPLE 38
[0741] 63
4-[2-(3,5-Dichloro-4-methoxyphenyl)-4,5-difluorophenyl]benzenesulfonamide
[0742] Step 1: Preparation of 4-bromo-2,6-dichloroanisole
[0743] Following the methylation procedure described in Step 1 of
Example 35, 4-bromo-2,6-dichlorophenol was methylated to give
4-bromo-2,6-dichloroanisole as a colorless solid: mp
67.0-68.0.degree. C.; NMR (CDCl.sub.3) .delta. 3.88 (s, 3H), 7.45
(s, 2H).
[0744] Step 2: Preparation of 3,5-dichloro-4-methoxyphenylboronic
acid
[0745] Following the general procedure outlined in Synthetic Scheme
1,4-bromo-2,6-dichloroanisole was converted to
3,5-dichloro-4-methoxyphen- yl boronic acid: NMR (CDCl.sub.3)
.delta. 3.83 (s, 3H), 7.73 (s, 2H).
[0746] Step 3: Preparation of
4-(2-bromo-4,5-difluorophenyl]benzenesulfona- mide
[0747] Following the general procedure outlined in Synthetic Scheme
XI, 1-bromo-4,5-difluoro-2-[4-(methylsulfonyl)phenyl]benzene
(Example 18, Step 2) was converted to
4-[2-bromo-4,5-difluorophenyl]benzenesulfonamide as a colorless
solid: NMR (CDCl.sub.3) .delta. 4.87 (s, 2H), 7.12-7.21 (m, 1H),
7.49-7.58 (m, 3H), 8.00 (d, J=9 Hz, 2H).
[0748] Step 4: Preparation of
4-[2-(3,5-dichloro-4-methoxyphenyl)-4,5-difl-
uorophenyl]benzenesulfonamide
[0749] Following the general procedure outlined in Synthetic Scheme
VI, 3,5-dichloro-4-methoxyphenylboronic acid (Step 2) was reacted
with 4-[2-bromo-4,5-difluorophenyl]benzenesulfonamide (Step 3) to
give
4-[2-(3,5-dichloro-4-methoxyphenyl)-4,5-difluorophenyl]benzenesulfonamide
as a colorless solid: mp 145.5-146.0.degree. C.; NMR (CDCl.sub.3)
.delta. 3.89 (s, 3H), 4.78 (s, 2H), 6.98 (s, 2H), 7.18-7.29 (m,
4H), 7.85 (d, J=8 Hz, 2H); MS (FAB) m/z 450 (M+Li).sup.+; HRMS
calc'd for (M+H)+444.0039, found 444.0052. Anal. Calc'd for
C.sub.19H.sub.13NCl.sub.2F.sub.2O.sub.3S- : C, 51.37; H, 2.95; N,
3.15. Found: C, 51.59; H, 3.03; N, 3.15.
EXAMPLE 39
[0750] 64
4-[4,5-Difluoro-2-(4-methoxy-3-methylphenyl)phenyl]benzenesulfonamide
[0751] Following the general procedure outlined in Synthetic Scheme
XI,
1,2-difluoro-4-(4-methoxy-3-methylpheny)-5-[4-(methylsulfonyl)phenyl]benz-
ene (Example 35) was converted to
4-[4,5-difluoro-2-(4-methoxy-3-methylphe-
nyl)phenyl]benzenesulfonamide as a colorless solid: mp
120.0-121.8.degree. C.; NMR (CDCl.sub.3) .delta. 2.11 (s, 3H), 3.79
(s, 3H), 4.84 (s, 2H), 6.63 (d, J=9 Hz, 1H), 6.74 (dd, J=2, 9 Hz,
1H), 6.88 (d, J=2 Hz, 1H), 7.13-7.28 (m, 4H), 7.78 (d, J=8 Hz, 2H);
MS (FAB) m/z 396 (M+Li).sup.+; HRMS calc'd for M+389.0897, found
389.0921. Anal. Calc'd for C.sub.20H.sub.17NF.sub.2O.sub.3S: C,
61.69; H, 4.40; N, 3.60. Found: C, 61.79; H, 4.37; N, 3.67.
EXAMPLE 40
[0752] 65
1,2-Difluoro-4-(3,4-dimethoxypheny)-5-[4-(methylsulfonyl)phenyl]benzene
[0753] Step 1: Preparation of 3,4-dimethoxyphenyboronic acid
[0754] Following the general procedure outlined in Synthetic Scheme
1,1-bromo-3,4-dimethoxybenzene was converted to
3,4-dimethoxyphenyboronic acid: NMR (CDCl.sub.3) .delta. 3.98 (s,
3H), 4.02 (s, 3H), 7.02 (d, J=9 Hz, 1H), 7.69 (s, 1H), 7.86 (d, J=9
Hz, 1H).
[0755] Step 2: Preparation of
1,2-difluoro-4-(3,4-dimethoxypheny)-5-[4-(me-
thylsulfonyl)phenyl]benzene
[0756] Following the general procedure outlined in Synthetic Scheme
VI, 1-bromo-4,5-difluoro-2-[4-(methylsulfonyl)phenyl]benzene
(Example 18, Step 2) was reacted with 3,4-dimethoxyphenyboronic
acid (Step 1) to give
1,2-difluoro-4-(3,4-dimethoxypheny)-5-[4-(methylsulfonyl)phenyl]benzene
as a colorless solid: mp 140.0-141.0.degree. C.; NMR (CDCl.sub.3)
.delta. 3.04 (s, 3H), 3.61 (s, 3H), 3.86 (s, 3H), 6.48 (d, J=2 Hz,
1H), 6.65 (dd, J=2, 8 Hz, 1H), 6.75 (d, J=8 Hz, 1H), 7.17-7.29 (m,
2H), 7.31 (d, J=8 Hz, 2H), 7.81 (d, J=8 Hz, 2H); MS (FAB) m/z 411
(M+Li).sup.+; HRMS calc'd for M+404.0894, found 404.0893. Anal.
Calc'd for C.sub.21H.sub.18F.sub.2O.sub- .4S (0.24H.sub.2O): C,
61.70; H, 4.51. Found: C, 61.69; H, 4.56.
EXAMPLE 41
[0757] 66
6-[4,5-Difluoro-2-[4-(methylsulfonyl)phenyl]-2,3-dihydro-1,4-benzodioxin
[0758] Step 1: Preparation of 2,3-dihydro-1,4-benzodioxin-6-boronic
acid
[0759] Following the general procedure outlined in Synthetic Scheme
1,3,4-ethylenedioxylbromobenzene was converted to
2,3-dihydro-1,4-benzodi- oxin-6-boronic acid: NMR (CDCl.sub.3)
.delta. 4.27-4.36 (m, 4H), 6.97 (d, J=9 Hz, 1H), 7.67-7.72 (m,
2H).
[0760] Step 2: Preparation of
6-[4,5-difluoro-2-[4-(methylsulfonyl)phenyl]-
-2,3-dihydro-1,4-benzodioxin
[0761] Following the general procedure outlined in Synthetic Scheme
VI, 1-bromo-4,5-difluoro-2-[4-(methylsulfonyl)phenyl]benzene
(Example 18, Step 2) was reacted with
2,3-dihydro-1,4-benzodioxin-6-boronic acid (Step 1) to give
6-[4,5-difluoro-2-[4-(methylsulfonyl)phenyl]-2,3-dihydro-1,4-b-
enzodioxin as a colorless solid: mp 82.0-83.0.degree. C.; NMR
(CDCl.sub.3) .delta. 3.05 (s, 3H), 4.21-4.26 (m, 4H), 6.43 (dd,
J=2, 8 Hz, 1H), 6.61 (d, J=2 Hz, 1H), 6.68 (d, J=8 Hz, 1H),
7.14-7.24 (m, 2H), 7.31 (d, J=8 Hz, 2H), 7.81 (d, J=8 Hz, 2H); MS
(FAB) m/z 409 (M+Li).sup.+; HRMS calc'd for M+402.0737, found
402.0749. Anal. Calc'd for C.sub.21H.sub.16F.sub.2O- .sub.4S (0.17
hexane): C, 63.41; H, 4.44. Found: C, 63.50; H, 4.28.
EXAMPLE 42
[0762] 67
4-[4,5-Difluoro-2-(3,4-dimethoxyphenyl)phenyl]benzenesulfonamide
[0763] Following the general procedure outlined in Synthetic Scheme
XI,
1,2-difluoro-4-(3,4-dimethoxypheny)-5-[4-(methylsulfonyl)phenyl]benzene
(Example 40) was converted to
4-[4,5-difluoro-2-(3,4-dimethoxyphenyl)phen- yl]benzenesulfonamide
as a colorless solid: mp 157.0-158.0.degree. C.; NMR (CDCl.sub.3)
.delta. 3.61 (s, 3H), 3.86 (s, 3H), 4.77 (s, 2H), 6.46 (d, J=2 Hz,
1H), 6.65 (dd, J=2, 8 Hz, 1H), 6.75 (d, J=8 Hz, 1H), 7.16-7.30 (m,
4H), 7.79 (d, J=8 Hz, 2H); MS (FAB) m/z 412 (M+Li).sup.+; HRMS
calc'd for M+405.0846, found 405.0870. Anal. Calc'd for
C.sub.20H.sub.17NF.sub.2- O.sub.4S (0.35H.sub.2O): C, 58.33; H,
4.33; N, 3.40. Found: C, 58.34; H, 4.23; N, 3.31.
EXAMPLE 43
[0764] 68
4-[2-(2,3-Dihydro-1,4-benzodioxin-6-yl)-4,5-difluorophenyl]benzenesulfonam-
ide
[0765] Following the general procedure outlined in Synthetic Scheme
XI,
6-(4,5-difluoro-2-[4-(methylsulfonyl)phenyl]-2,3-dihydro-1,4-benzodioxin
(Example 41) was converted to
4-[2-(2,3-dihydro-1,4-benzodioxin-6-yl)-4,5-
-difluorophenyl]benzenesulfonamide as a colorless solid: mp
107.0-108.0.degree. C.; NMR (CDCl.sub.3) .delta. 4.22-4.26 (m, 4H),
4.75 (s, 2H), 6.43 (dd, J=2, 8 Hz, 1H), 6.62 (d, J=2 Hz, 1H), 6.68
(d, J=8 Hz, 1H), 7.13-7.30 (m, 4H), 7.80 (d, J=8 Hz, 2H); MS (FAB)
m/z 410 (M+Li).sup.+; HRMS calc'd for M+403.0690, found 403.0697.
Anal. Calc'd for C.sub.20H.sub.15NO.sub.4F.sub.2S: C, 59.55; H,
3.75; N, 3.47. Found: C, 59.89; H, 3.99; N, 3.20.
EXAMPLE 44
[0766] 69
[0767] Step 1: Preparation of benzyltrimethylammonium
tetrachloroiodate
[0768] Following Kajigaeshi's procedure (Tetrahedron Lett., 29,
7201-7204, (1988)], 18.6 g (100 mmol) of benzyltrimethylammonium
chloride was added to a stirred solution of 23.3 g (100 mmol) of
IC.sub.13 in 300 mL of CH.sub.2Cl.sub.2. The product was collected
and dried in vacuo to give 38.4 g (92%) of benzyltrimethylammonium
tetrachloroiodate as a bright yellow solid: mp 105.5-127.5.degree.
C.
[0769] Step 2: Preparation of 1,2-dichloro-4,5-dimethoxybenzene
[0770] Following Kajigaeshi's procedure [Chem. Lett., 415-418,
(1989)], 38 g (91 mmol) of benzyltrimethylammonium
tetrachloroiodate (Step 1) was added to a stirred solution of 6.3 g
(45.5 mmol) of 1,2-dimethoxybenzene in 100 mL of HOAc, and the
reaction was stirred for 2 hours at ambient temperature.
Concentration in vacuo gave a residue, which was dissolved in
toluene. The resulting solution was washed with aqueous
Na.sub.2SO.sub.3 and dried over MgSO.sub.4. Recrystallization from
hexane gave 6.0 g (64%) of 1,2-dichloro-4,5-dimethoxybenzene as a
colorless solid: mp 81.0-82.5.degree. C.; NMR (CDCl.sub.3) .delta.
3.86 (s, 6H), 6.91 (s, 2H).
[0771] Step 3: Preparation of 1,2-dichlorocatechol Under nitrogen,
83.4 mL (83.4 mmol) of BBr.sub.3 (1.0 M in CH.sub.2Cl.sub.2) was
added at 0.degree. C. to a stirred solution of 5.75 g (27.8 mmol)
of 1,2-dichloro-4,5-dimethoxybenzene (Step 2) in 200 mL of
CH.sub.2Cl.sub.2, and the reaction was stirred for 2 hours at
ambient temperature. Concentration in vacuo gave a residue, which
was dissolved in ethyl acetate. The resulting solution was washed
with brine and dried over Na.sub.2SO.sub.4. Recrystallization from
ethyl acetate/hexane (5:95) gave 5.0 g (96%) of
1,2-dichlorocatechol as a gray solid: mp 113.0-114.5.degree. C.;
NMR (CDCl.sub.3) .delta. 5.18 (s, 2H), 6.98 (s, 2H).
[0772] Step 4: Preparation of
1,2-dichloro-4,5-bis(trifluoromethanesulfony- l)benzene
[0773] Under nitrogen, 8.4 mL (104 mmol) of pyridine and 9.0 mL
(53.5 mmol) of triflic anhydride at 0.degree. C. was added to a
stirred solution of 3.72 g (20.8 mmol) of 1,2-dichlorocatechol
(Step 3) in 40 mL of CH.sub.2Cl.sub.2, and the reaction was stirred
for 7 days at ambient temperature. The mixture was poured into
ice-water, extracted with CH.sub.2Cl.sub.2, and the combined
extracts were dried over Na.sub.2SO.sub.4. Purification by silica
gel plug with ethyl acetate/hexane (5:95) gave 7.9 g (86%) of
1,2-dichloro-4,5-bis(trifluorom- ethanesulfonyl)benzene as a yellow
oil: NMR (CDCl.sub.3) .delta. 7.62 (s, 2H).
[0774] Step 5: Preparation of
1,2-dichloro-4-[4-(methylthio)phenyl]-5-(tri-
fluoromethanesulfonyl)benzene
[0775] Under nitrogen, 5 g (4.3 mmol) of Pd(PPh.sub.3).sub.4 was
added to a stirred solution of 7.9 g (17.8 mmol) of
1,2-dichloro-4,5-bis(trifluoro- methanesulfonyl)benzene (Step 4),
3.0 g (18 mmol) of 4-methylthiophenylboronic acid (Example 1, Step
2) and 7.4 g (54 mmol) of anhydrous K.sub.2CO.sub.3 powder in 90 mL
of toluene. The reaction was stirred at reflux for 48 hours, and
diluted with CH.sub.2Cl.sub.2. The resulting solution was washed
with water and brine, and dried over MgSO.sub.4. Purification by
silica gel plug with ethyl acetate/hexane (5:95 to 30:70) gave 4.8
g (56%) of 1,2-dichloro-4-[4-(methylthio)phenyl]-
-5-(trifluoromethanesulfonyl)benzene as a colorless solid: NMR
(CDCl.sub.3) .delta. 2.54 (s, 3H), 7.33 (s, 4H), 7.50 (s, 1H), 7.56
(s, 1H).
[0776] Step 6: Preparation of
1,2-dichloro-4-(4-fluorophenyl)-5-[4-(methyl-
sulfonyl)phenyl]benzene
[0777] Under nitrogen, 480 mg (0.42 mmol) of Pd(PPh.sub.3).sub.4
was added to a stirred solution of 1.64 g (3.93 mmol) of
1,2-dichloro-4-[4-(methylt-
hio)phenyl]-5-(trifluoromethanesulfonyl)benzene (Step 5), 1.1 g
(7.9 mmol) of 4-fluorophenylboronic acid and 1.6 g (11.6 mmol) of
anhydrous K.sub.2CO.sub.3 powder in 20 mL of toluene. The reaction
was vigorously stirred at reflux for 7 days, and cooled to ambient
temperature. The reaction mixture was diluted with ethyl acetate.
The resulting solution was washed with water, and dried over
MgSO.sub.4. Purification by silica gel plug with ethyl
acetate/hexane (5:95) gave an oil residue which was subsequently
dissolved in 15 mL of CH.sub.2Cl.sub.2. The resulting solution was
treated with 1.4 g (11.8 mmol) of 3-chloroperbenzoic acid (MCPBA)
(70%) at 0.degree. C.; and the reaction was stirred overnight at
ambient temperature. Excess MCPBA was quenched by the addition of
Na.sub.2SO.sub.3 at 0.degree. C., and stirred for 30 minutes at
ambient temperature. The mixture was diluted with CH.sub.2Cl.sub.2,
the resulting solution was washed with water and brine, and dried
over Na.sub.2SO.sub.4. Purification by silica gel chromatography
(MPLC) with ethyl acetate/hexane (3:7) gave 505 mg (33%) of
1,2-dichloro-4-(4-fluorop-
henyl)-5-[4-(methylsulfonyl)phenyl]benzene as a colorless solid: mp
143.5-144.5.degree. C.; NMR (CDCl.sub.3) .delta. 3.05 (s, 3H), 6.95
(d, J=9 Hz, 2H), 6.99-7.07 (m, 2H), 7.30 (d, J=9 Hz, 2H), 7.52 (d,
J=9 Hz, 2H), 7.83 (d, J=9 Hz, 2H); MS (CI) m/z 395 (M+H).sup.+;
HRMS calc'd for (M+Li)+401.0157, found 401.0142. Anal. Calc'd for
C.sub.19H.sub.13O.sub.2- SFCl.sub.2: C, 57.73; H, 3.31; F, 4.81;
Cl, 17.94. Found: C, 57.89; H, 3.45; F, 4.81; Cl, 17.56.
EXAMPLE 45
[0778] 70
2-[4,5-Difluoro-4'-(methylsulfonyl)-(1,1'-biphenyl)-2-yl]-5-methylpyridine
[0779] Step 1: Preparation of
4,5-difluoro-2-[(4-methylthio)phenyl]phenylb- oronic acid
[0780] Under nitrogen, 1 mL of dibromoethane was added to a mixture
of 3.87 g (12.3 mmol) of
1-bromo-4,5-difluoro-2-[4-(methylthio)phenyl]benzen- e (Example 18,
Step 1) and 300 mg (12.3 mmol) of magnesium turnings in 12 mL of
anhydrous THF. The reaction was heated to reflux for 5 hours,
cooled to 0.degree. C., treated with 2.8 mL (24.6 mmol) of
trimethylborate, and stirred overnight. After 10 mL of 10% NaOH was
added, the solution was stirred for 3 hours, acidified to pH 4, and
extracted with ethyl acetate three times. The combined extracts
were dried over MgSO.sub.4 and concentrated in vacuo to give 2.7 g
(78%) of 4,5-difluoro-2-[(4-methylthio)phenyl]phenylboronic acid as
a pale yellow semi-solid.
[0781] Step 2: Preparation of
2-[4,5-difluoro-4'-(methylsulfonyl)-(1,1'-bi-
phenyl)-2-yl]-5-methylpyridine
[0782] Under nitrogen, 1 g (0.86 mmol) of Pd(PPh.sub.3).sub.4 was
added to a stirred solution of 2.7 g (9.6 mmol) of
4,5-difluoro-2-[(4-methylthio)p- henyl]phenylboronic acid (Step 1)
and 1.7 g (9.8 mmol) of 2-bromo-5-methylpyridine in a mixed solvent
of 25 mL of toluene, 25 mL of ethanol and 25 mL of 0.2M
Na.sub.2CO.sub.3. The reaction was stirred at reflux for 48 hours,
and the solvent was removed in vacuo. The residue was dissolved in
ethyl acetate, and the resulting solution was washed with water and
brine, and dried over Na.sub.2SO.sub.4. Purification by silica gel
plug with ethyl acetate/hexane (15:85) gave a semi-solid residue
which was then dissolved in a mixed solvent of 15 mL of THF and 15
mL of CH.sub.3OH. A solution of 3.5 g (5.7 mmol) of potassium
peroxymonosulfate (OXONE.RTM.) in 15 mL of H.sub.2O was slowly
added, and the stirring was continued for 3 hours at ambient
temperature. Excess OXONE.RTM. was destroyed by the addition of 2 g
of Na.sub.2SO.sub.3. Concentrated in vacuo gave a residue which was
dissolved in ethyl acetate; and the resulting solution was washed
with brine, and dried over Na.sub.2SO.sub.4. Purification by silica
gel chromatography (MPLC) with ethyl acetate/hexane (45:55) gave
1.0 g (29%) of 2-[4,5-difluoro-4'-(meth-
ylsulfonyl)-(1,1'-biphenyl)-2-yl]-5-methylpyridine as a colorless
foam: NMR (CDCl.sub.3) .delta. 2.32 (s, 3H), 3.05 (s, 3H), 6.76 (d,
J=8 Hz, 1H), 7.17-7.36 (m, 4H), 7.53 (t, J=9 Hz, 1H), 7.82 (d, J=9
Hz, 2H), 8.42 (s, 1H); MS (FAB) m/z 360 (M+H).sup.+;
[0783] HRMS calc'd for (M+H)+360.0870, found 360.0885. Anal. Calc'd
for C.sub.19H.sub.15NO.sub.2SF.sub.2: C, 63.50; H, 4.21; N, 3.90;
F, 10.57. Found: C, 63.28; H, 4.30; N, 3.65; F, 10.24.
EXAMPLE 46
[0784] 71
4-[4,5-Difluoro-2-(5-methylpyridin-2-yl)phenyl]benzenesulfonamide
[0785] Following the general procedure outlined in Synthetic Scheme
XI,
2-[4,5-difluoro-4'-(methylsulfonyl)-(1,1'-biphenyl)-2-yl]-5-methylpyridin-
e (Example 45) was converted to
4-[4,5-difluoro-2-(5-methylpyridin-2-yl)ph- enyl]benzenesulfonamide
as a colorless foam: NMR (CDCl.sub.3) .delta. 2.55 (s, 3H), 4.91
(s, 2H), 6.81 (d, J=8 Hz, 1H), 7.18-7.31 (m, 3H), 7.35 (d, J=8 Hz,
1H), 7.50-7.59 (m, 1H), 7.82 (d, J=9 Hz, 2H), 8.47 (s, 1H); MS
(FAB) m/z 361 (M+H).sup.+; HRMS calc'd for (M+Li)+367.0904, found
367.0904. Anal. Calc'd for C.sub.18H.sub.14N.sub.2O.sub.2SF.sub.2
(0.13 hexane): C, 60.73; H, 4.30; N, 7.13. Found: C, 60.47; H,
4.54; N, 7.13.
EXAMPLE 47
[0786] 72
5-[4,5-Difluoro-4'-(methylsulfonyl)-(1,1'-biphenyl)-2-yl]-2-methylpyridine
[0787] Step 1: Preparation of 5-bromo-2-methylpyridine
[0788] Following Reitz's procedure [U.S. Pat. No. 5,155,177], under
nitrogen, 12.3 mL (238 mmol) of bromine was slowly added at
100.degree. C. to a stirred suspension of 76.6 g (576 mmol) of
AlCl.sub.3 in 23.7 mL (240 mmol) of 2-methylpyridine. The reaction
was heated at 100.degree. C. overnight, cooled to ambient
temperature, and slowly poured into ice water. Aqueous
Na.sub.2SO.sub.3 was added to destroy excess bromine, followed by
50% aqueous NaOH to dissolved the aluminum salts. The mixture was
extracted with ethyl ether (3 X) and dried over MgSO.sub.4.
Purification by silica gel chromatography (Waters PrepLC 500A) with
ethyl acetate/hexane (15:85) gave 8.6 g (21%) of
5-bromo-2-methylpyridine as a pale brown oil: NMR (CDCl.sub.3)
.delta. 2.48 (s, 3H), 7.02 (d, J=9 Hz, 1H), 7.65 (dd, J=2, 9 Hz,
1H), 8.52 (d, J=2 Hz, 1H).
[0789] Step 2: Preparation of 2-methyl-5-(trimethyltin)pyridine
[0790] Under nitrogen, 14 mL (35 mmol) of .alpha.-butylithium (2.5
M in hexanes) was added to a stirred solution of 5.2 g (30 mmol) of
5-bromo-2-methylpyridine (Step 1) in 300 mL of anhydrous THF at
-78.degree. C. After 10 minutes, a solution of 7.2 g (36 mmol) of
trimethyltin chloride in 5 mL of anhydrous THF was added. The
reaction was warmed to ambient temperature, and stirred overnight.
Concentration in vacuo gave a residue, which was dissolved in ethyl
acetate. The resulting solution was washed with brine and dried
over Na.sub.2SO.sub.4. Purification by silica gel chromatography
(Waters PrepLC 500A) with ethyl acetate/hexane (1:3) gave 2.0 g
(29%) of 2-methyl-5-(trimethyltin)pyridin- e as a yellow oil: NMR
(CDCl.sub.3) .delta. 0.31 (s, 9H), 2.52 (s, 3H), 7.11 (d, J=8 Hz,
1H), 7.65 (dd, J=2, 8 Hz, 1H), 8.49 (s, 1H).
[0791] Step 3: Preparation of
5-[4,5-difluoro-4'-(methylsulfonyl)-(1,1'-bi-
phenyl)-2-yl]-2-methylpyridine
[0792] Under nitrogen, 100 mg (0.1 mmol) of Pd(PPh.sub.3).sub.4 was
added to a stirred solution of 200 mg (0.6 mmol) of
1-bromo-4,5-difluoro-2-[(4-- methyl-sulfonyl)phenyl]benzene
(Example 18, Step 2) and 300 mg (1.2 mmol) of
2-methyl-5-(trimethyltin)pyridine (Step 2) in 5 mL of toluene. The
reaction was stirred at reflux for 16 hours, and cooled to ambient
temperature. Concentration in vacuo gave a residue which was
dissolved in ethyl acetate. The resulting solution was washed with
water and brine, and dried over Na.sub.2SO.sub.4. Purification by
silica gel chromatography (MPLC) with ethyl acetate/hexane (1:1)
gave 70 mg (32%) of
5-[4,5-difluoro-4'-(methylsulfonyl)-(1,1'-biphenyl)-2-yl]-2-methylpyridin-
e as a pale brown solid: mp 141.0-142.5.degree. C.; NMR
(CDCl.sub.3) .delta. 2.52 (s, 3H), 3.04 (s, 3H), 7.02 (d, J=8 Hz,
1H), 7.19-7.32 (m, 5H), 7.82 (d, J=8 Hz, 2H), 8.24 (S, 1H); MS
(FAB) m/z 360 (M+H).sup.+; HRMS calc'd for (M+H)+360.0870, found
360.0862. Anal. Calc'd for C.sub.19H.sub.15NO.sub.2SF.sub.2
(0.33H.sub.2O): C, 62.45; H, 4.24; N, 3.84. Found: C, 62.46; H,
4.32; N, 3.83.
EXAMPLE 48
[0793] 73
4-[4,5-Difluoro-2-(6-methylpyridin-3-yl)phenyl]benzenesulfonamide
[0794] Under nitrogen, 150 mg of Pd(PPh.sub.3).sub.4 was added to a
stirred solution of 800 mg (2.3 mmol) of
4-(2-bromo-4,5-difluorophenyl]be- nzenesulfonamide (Example 38,
Step 3) and 1.0 g (4.6 mmol) of 2-methyl-5-(trimethyltin)pyridine
(Example 47, Step 2) in 20 mL of toluene. The reaction was stirred
at reflux for 16 hours, and the solvent was removed in vacuo. The
residue was dissolved in ethyl acetate; and the resulting solution
was washed with water and brine, and dried over MgSO.sub.4.
Purification by silica gel chromatography (MPLC) with ethyl
acetate/hexane (1:1) followed by reverse phase chromatography
(Waters Delta Prep) gave 540 mg (65%) of
4-[4,5-difluoro-2-(6-methylpyridin-3-yl)- phenyl]benzenesulfonamide
as a colorless solid: mp>96.degree. C. (dec); NMR (CDCl.sub.3)
.delta. 2.55 (s, 3H), 5.10 (s, 2H), 7.09 (d, J=8 Hz, 1H), 7.20-7.28
(m, 4H), 7.32 (dd, J=2, 9 Hz, 1H), 7.81 (d, J=9 Hz, 2H), 8.21 (d,
J=2 Hz, 1H); MS (FAB) m/z 361 (M+H).sup.+; HRMS calc'd for
(M+H)+361.0822, found 361.0823. Anal. Calc'd for
C.sub.18H.sub.14N.sub.2O- .sub.2SF.sub.2: C, 59.99; H, 3.92; N,
7.77; F, 10.54. Found: C, 59.72; H, 4.05; N, 7.64; F, 10.46.
Biological Evaluation
[0795] Rat Carrageenan Foot Pad Edema Test
[0796] The carrageenan foot edema test was performed with
materials, reagents and procedures essentially as described by
Winter, et al., (Proc. Soc. Exp. Biol. Med., 111, 544 (1962)). Male
Sprague-Dawley rats were selected in each group so that the average
body weight was as close as possible. Rats were fasted with free
access to water for over sixteen hours prior to the test. The rats
were dosed orally (1 mL) with compounds suspended in vehicle
containing 0.5% methylcellulose and 0.025% surfactant, or with
vehicle alone. One hour later a subplantar injection of 0.1 mL of
1% solution of carrageenan/sterile 0.9% saline was administered and
the volume of the injected foot was measured with a displacement
plethysmometer connected to a pressure transducer with a digital
indicator. Three hours after the injection of the carrageenan, the
volume of the foot was again measured. The average foot swelling in
a group of drug-treated animals was compared with that of a group
of placebo-treated animals and the percentage inhibition of edema
was determined (Otterness and Bliven, Laboratory Models for Testing
NSAIDs, in Non-steroidal Anti-Inflammatory Drugs, (J. Lombardino,
ed. 1985)). The % inhibition shows the % decrease from control paw
volume determined in this procedure and the data for selected
compounds in this invention are summarized in Table I.
[0797] Rat Carrageenan-induced Analgesia Test
[0798] The analgesia test using rat carrageenan was performed with
materials, reagents and procedures essentially as described by
Hargreaves, et al., (Pain, 32, 77 (1988)). Male Sprague-Dawley rats
were treated as previously described for the Carrageenan Foot Pad
Edema test. Three hours after the injection of the carrageenan, the
rats were placed in a special plexiglass container with a
transparent floor having a high intensity lamp as a radiant heat
source, positionable under the floor. After an initial twenty
minute period, thermal stimulation was begun on either the injected
foot or on the contralateral uninjected foot. A photoelectric cell
turned off the lamp and timer when light was interrupted by paw
withdrawal. The time until the rat withdraws its foot was then
measured. The withdrawal latency in seconds was determined for the
control and drug-treated groups, and percent inhibition of the
hyperalgesic foot withdrawal determined. Results are shown in Table
I.
1TABLE I RAT PAW EDEMA ANALGESIA % Inhibition % Inhibition @ 10
mg/kg @30 mg/kg Examples body weight body weight 1 26 ND 2 6 28 3
14 1 20 19 22* *Assay performed at 50 mg/kg body weight
[0799] Evaluation of COX I and COX II Activity In Vitro
[0800] The compounds of this invention exhibited inhibition in
vitro of COX II. The COX II inhibition activity of the compounds of
this invention illustrated in the Examples was determined by the
following methods.
[0801] a. Preparation of Recombinant COX Baculoviruses
[0802] A 2.0 kb fragment containing the coding region of either
human or murine COX-1 or human or murine COX-2 was cloned into a
BamHI site of the baculovirus transfer vector pVL1393 (Invitrogen)
to generate the baculovirus transfer vectors for COX-1 and COX-2 in
a manner similar to the method of D. R. O'Reilly et al (Baculovirus
Expression Vectors: A Laboratory Manual (1992)). Recombinant
baculoviruses were isolated by transfecting 4 .mu.g of baculovirus
transfer vector DNA into SF.sub.9 insect cells (2.times.10.sup.8)
along with 200 ng of linearized baculovirus plasmid DNA by the
calcium phosphate method. See M. D. Summers and G. E. Smith, A
Manual of Methods for Baculovirus Vectors and Insect Cell Culture
Procedures, Texas Agric. Exp. Station Bull. 1555 (1987).
Recombinant viruses were purified by three rounds of plaque
purification and high titer (10.sup.7-10.sup.8 pfu/ml) stocks of
virus were prepared. For large scale production, SF.sub.9 insect
cells were infected in 10 liter fermentors (0.5.times.10.sup.6/ml)
with the recombinant baculovirus stock such that the multiplicity
of infection was 0.1. After 72 hours the cells were centrifuged and
the cell pellet homogenized in Tris/Sucrose (50 mM: 25%, pH 8.0)
containing 1%
3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS).
The homogenate was centrifuged at 10,000.times.G for 30 minutes,
and the resultant supernatant was stored at -80.degree. C. before
being assayed for COX activity.
[0803] b. Assay for COX-1 and COX-2 Activity:
[0804] COX activity was assayed as PGE.sub.2 formed/.mu.g
protein/time using an ELISA to detect the prostaglandin released.
CHAPS-solubilized insect cell membranes containing the appropriate
COX enzyme were incubated in a potassium phosphate buffer (50 mM,
pH 8.0) containing epinephrine, phenol, and heme with the addition
of arachidonic acid (10 .mu.M). Compounds were pre-incubated with
the enzyme for 10-20 minutes prior to the addition of arachidonic
acid. Any reaction between the arachidonic acid and the enzyme was
stopped after ten minutes at 37.degree. C./room temperature by
transferring 40 .mu.l of reaction mix into 160 .mu.l ELISA buffer
and 25 .mu.M indomethacin. The PGE.sub.2 formed was measured by
standard ELISA technology (Cayman Chemical). Results are shown in
Table II.
2TABLE II Human COX-2 Human COX-1 Example ID.sub.50 .mu.M ID.sub.50
.mu.M 1 0.3 >100 2 <0.1 19 3 <0.1 3.9 4 2.6 >100 5 11.4
>100 6 <0.1 13.1 7 <0.1 8.2 8 0.1 >100 9 2.8 32.6 10
0.4 >100 11 <0.1 >100 12 <0.1 9.2 13 <0.1 5.7 14
<0.1 >100 15 7.2 >100 16 <0.1 5.5 17 <0.1 >100 18
<0.1 >100 19 <0.1 >100 20 <0.1 18.9 21 <0.1 22.5
22 <0.1 5.3 23 <0.1 >100 24 <0.1 >100 25 <0.1
17.0 26 <0.1 1.7 27 <0.1 >100 28 <0.1 >100 29
<0.1 16.5 30 <0.1 0.6 31 <0.1 >100 32 <0.1 >100
33 <0.1 >100 34 <0.1 3.7 35 <0.1 >100 36 <0.1 3.9
37 <0.1 14.6 38 <0.1 >100 39 <0.1 10.9 40 0.3 >100
42 <0.1 >100 43 <0.1 17.9 45 52.3 >100 46 0.3 >100
47 0.2 >100 48 <0.1 >100
[0805] Also embraced within this invention is a class of
pharmaceutical compositions comprising the active compounds of this
combination therapy in association with one or more non-toxic,
pharmaceutically-aceptable carriers and/or diluents and/or
adjuvants (collectively referred to herein as "carrier" materials)
and, if desired, other active ingredients. The active compounds of
the present invention may be administered by any suitable route,
preferably in the form of a pharmaceutical composition adapted to
such a route, and in a dose effective for the treatment intended.
The active compounds and composition may, for example, be
administered orally, intravascularly, intraperitoneally,
subcutaneously, intramuscularly or topically.
[0806] For oral administration, the pharmaceutical composition may
be in the form of, for example, a tablet, capsule, suspension or
liquid. The pharmaceutical composition is preferably made in the
form of a dosage unit containing a particular amount of the active
ingredient. Examples of such dosage units are tablets or capsules.
The active ingredient may also be administered by injection as a
composition wherein, for example, saline, dextrose or water may be
used as a suitable carrier.
[0807] The amount of therapeutically active compounds that are
administered and the dosage regimen for treating a disease
condition with the compounds and/or compositions of this invention
depends on a variety of factors, including the age, weight, sex and
medical condition of the subject, the severity of the disease, the
route and frequency of administration, and the particular compound
employed, and thus may vary widely. The pharmaceutical compositions
may contain active ingredients in the range of about 0.1 to 2000
mg, preferably in the range of about 0.5 to 500 mg and most
preferably between about 1 and 100 mg. A daily dose of about 0.01
to 100 mg/kg body weight, preferably between about 0.5 and about 20
mg/kg body weight and most preferably between about 0.1 to 10 mg/kg
body weight, may be appropriate. The daily dose can be administered
in one to four doses per day.
[0808] In the case of psoriasis and other skin conditions, it may
be preferable to apply a topical preparation of compounds of this
invention to the affected area two to four times a day.
[0809] For inflammations of the eye or other external tissues,
e.g., mouth and skin, the formulations are preferably applied as a
topical ointment or cream, or as a suppository, containing the
active ingredients in a total amount of, for example, 0.075 to 30%
w/w, preferably 0.2 to 20% w/w and most preferably 0.4 to 15% w/w.
When formulated in an ointment, the active ingredients may be
employed with either paraffinic or a water-miscible ointment base.
Alternatively, the active ingredients may be formulated in a cream
with an oil-in-water cream base. If desired, the aqueous phase of
the cream base may include, for example at least 30% w/w of a
polyhydric alcohol such as propylene glycol, butane-1,3-diol,
mannitol, sorbitol, glycerol, polyethylene glycol and mixtures
thereof. The topical formulation may desirably include a compound
which enhances absorption or penetration of the active ingredient
through the skin or other affected areas. Examples of such dermal
penetration enhancers include dimethylsulfoxide and related
analogs. The compounds of this invention can also be administered
by a transdermal device. Preferably topical administration will be
accomplished using a patch either of the reservoir and porous
membrane type or of a solid matrix variety. In either case, the
active agent is delivered continuously from the reservoir or
microcapsules through a membrane into the active agent permeable
adhesive, which is in contact with the skin or mucosa of the
recipient. If the active agent is absorbed through the skin, a
controlled and predetermined flow of the active agent is
administered to the recipient. In the case of microcapsules, the
encapsulating agent may also function as the membrane.
[0810] The oily phase of the emulsions of this invention may be
constituted from known ingredients in a known manner. While the
phase may comprise merely an emulsifier, it may comprise a mixture
of at least one emulsifier with a fat or an oil or with both a fat
and an oil. Preferably, a hydrophilic emulsifier is included
together with a lipophilic emulsifier which acts as a stabilizer.
It is also preferred to include both an oil and a fat. Together,
the emulsifier(s) with or without stabilizer(s) make-up the
so-called emulsifying wax, and the wax together with the oil and
fat make up the so-called emulsifying ointment base which forms the
oily dispersed phase of the cream formulations. Emulsifiers and
emulsion stabilizers suitable for use in the formulation of the
present invention include Tween 60, Span 80, cetostearyl alcohol,
myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate,
among others.
[0811] The choice of suitable oils or fats for the formulation is
based on achieving the desired cosmetic properties, since the
solubility of the active compound in most oils likely to be used in
pharmaceutical emulsion formulations is very low. Thus, the cream
should preferably be a non-greasy, non-staining and washable
product with suitable consistency to avoid leakage from tubes or
other containers. Straight or branched chain, mono- or dibasic
alkyl esters such as di-isoadipate, isocetyl stearate, propylene
glycol diester of coconut fatty acids, isopropyl myristate, decyl
oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate
or a blend of branched chain esters may be used. These may be used
alone or in combination depending on the properties required.
Alternatively, high melting point lipids such as white soft
paraffin and/or liquid paraffin or other mineral oils can be
used.
[0812] Formulations suitable for topical administration to the eye
also include eye drops wherein the active ingredients are dissolved
or suspended in suitable carrier especially an aqueous solvent for
the active ingredients. The antiinflammatory active ingredients are
preferably present in such formulations in a concentration of 0.5
to 20%, advantageously 0.5 to 10% and particularly about 1.5%
w/w.
[0813] For therapeutic purposes, the active compounds of this
combination invention are ordinarily combined with one or more
adjuvants appropriate to the indicated route of administration. If
administered per os, the compounds may be admixed with lactose,
sucrose, starch powder, cellulose esters of alkanoic acids,
cellulose alkyl esters, talc, stearic acid, magnesium stearate,
magnesium oxide, sodium and calcium salts of phosphoric and
sulfuric acids, gelatin, acacia gum, sodium alginate,
polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted
or encapsulated for convenient administration. Such capsules or
tablets may contain a controlled-release formulation as may be
provided in a dispersion of active compound in hydroxypropylmethyl
cellulose. Formulations for parenteral administration may be in the
form of aqueous or non-aqueous isotonic sterile injection solutions
or suspensions. These solutions and suspensions may be prepared
from sterile powders or granules having one or more of the carriers
or diluents mentioned for use in the formulations for oral
administration. The compounds may be dissolved in water,
polyethylene glycol, propylene glycol, ethanol, corn oil,
cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium
chloride, and/or various buffers. Other adjuvants and modes of
administration are well and widely known in the pharmaceutical
art.
[0814] Although this invention has been described with respect to
specific embodiments, the details of these embodiments are not to
be construed as limitations.
* * * * *