U.S. patent application number 09/872463 was filed with the patent office on 2002-01-31 for benzene compounds as antiproliferative and cholesterol lowering agents.
Invention is credited to Clark, David Louis, Flygare, John A., Medina, Julio Cesar, Rosen, Terry J., Shan, Bei.
Application Number | 20020013496 09/872463 |
Document ID | / |
Family ID | 25438246 |
Filed Date | 2002-01-31 |
United States Patent
Application |
20020013496 |
Kind Code |
A1 |
Medina, Julio Cesar ; et
al. |
January 31, 2002 |
Benzene compounds as antiproliferative and cholesterol lowering
agents
Abstract
The invention provides compounds, compositions and methods
relating to novel electrophilic aromatic derivatives and their use
as pharmacologically active agents. The compositions find
particular use as pharmacological agents in the treatment of
disease states, particularly cancer, psoriasis, vascular
restenosis, infections, atherosclerosis and hypercholesterolemia,
or as lead compounds for the development of such agents. The
compositions include compounds of the general Formula I: 1
Inventors: |
Medina, Julio Cesar;
(Belmont, CA) ; Clark, David Louis; (Albany,
CA) ; Flygare, John A.; (Burlingame, CA) ;
Rosen, Terry J.; (Burlingame, CA) ; Shan, Bei;
(Foster City, CA) |
Correspondence
Address: |
TOWNSEND AND TOWNSEND AND CREW
TWO EMBARCADERO CENTER
EIGHTH FLOOR
SAN FRANCISCO
CA
94111-3834
US
|
Family ID: |
25438246 |
Appl. No.: |
09/872463 |
Filed: |
May 31, 2001 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
09872463 |
May 31, 2001 |
|
|
|
08917025 |
Aug 22, 1997 |
|
|
|
Current U.S.
Class: |
564/86 ; 558/413;
558/47; 558/56; 562/430 |
Current CPC
Class: |
A61P 3/06 20180101; A61P
35/00 20180101; C07C 311/21 20130101 |
Class at
Publication: |
564/86 ; 558/413;
562/430; 558/47; 558/56 |
International
Class: |
C07C 313/18 |
Claims
What is claimed is:
1. A compound having the Formula I: 48or a pharmaceutically
acceptable salt thereof, wherein: R.sup.1, R.sup.2, R.sup.4, and
R.sup.5 are independently selected from hydrogen, lower alkyl,
halogen, OCF.sub.3, CF.sub.3, NO.sub.2, CO.sub.2H, CN,
SO.sub.2--N(R.sup.6)(R.sup.7), SO.sub.2--R.sup.8,
CO.sub.2--R.sup.8, and CO--R.sup.8; R.sup.3 is a leaving group; Y
is a single bond, --O--, --N(R.sup.9)--, --N(R.sup.9)--CH.sub.2--,
or --CH(R.sup.9)--; and Ar is an optionally substituted aryl or
heteroaryl group; wherein R.sup.6 and R.sup.7 are independently
chosen from hydrogen, lower alkyl, and lower heteroalkyl; R.sup.8
is selected from lower alkyl or lower heteroalkyl; and R.sup.9 is
selected from: hydrogen, substituted or unsubstituted
(C1-C10)alkyl, substituted or unsubstituted (C1-C10)alkoxy,
substituted or unsubstituted (C3-C6)alkenyl, substituted or
unsubstituted (C2-C6)heteroalkyl, substituted or unsubstituted
(C3-C6)heteroalkenyl, substituted or unsubstituted (C3-C6)alkynyl,
substituted or unsubstituted (C3-C6)cycloalkyl, substituted or
unsubstituted (C5-C7)cycloalkenyl, substituted or unsubstituted
(C5-C7)cycloalkadienyl, substituted or unsubstituted aryl,
substituted or unsubstituted aryloxy, substituted or unsubstituted
aryl-(C3-C8)cycloalkyl, substituted or unsubstituted
aryl-(C5-C7)cycloalkenyl, substituted or unsubstituted
aryloxy-(C3-C8)cycloalkyl, substituted or unsubstituted
aryl-(C1-C4)alkyl, substituted or unsubstituted aryl-(C1-C4)alkoxy,
substituted or unsubstituted aryl-(C1-C4)heteroalkyl, substituted
or unsubstituted aryl-(C3-C6)alkenyl, substituted or unsubstituted
aryloxy-(C1-C4)alkyl, substituted or unsubstituted
aryloxy-(C2-C4)heteroalkyl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted heteroaryloxy, substituted
or unsubstituted heteroaryl-(C1-C4)alkyl, substituted or
unsubstituted heteroaryl-(C1-C4)alkoxy, substituted or
unsubstituted heteroaryl-(C1-C4)heteroalkyl, substituted or
unsubstituted heteroaryl-(C1-C4)alkenyl, substituted or
unsubstituted heteroaryloxy-(C1-C4)alkyl, and substituted or
unsubstituted heteroaryloxy-(C1-C4)heteroalkyl, substituted or
unsubstituted heteroaryl-(C1-C4)alkoxy, substituted or
unsubstituted heteroaryloxy-(C2-C4)heteroalkyl, wherein, if Y is
--N(R.sup.9)--, then R.sup.9 and Ar may be connected by a linking
group E to give a substituent of the Formula 49wherein E represents
a bond, (C1-C4) alkylene, or (C1-C4) heteroalkylene, and the ring
formed by R.sup.9, E, Ar and the nitrogen atom contains no more
than 8 atoms, or preferably R.sup.9 and Ar may be covalently joined
in a moiety that forms a 5- or 6-membered heterocyclic ring with
the nitrogen atom; with the following provisos: At least one of the
R.sup.1, R.sup.2, R.sup.4, and R.sup.5 groups is other than
hydrogen or lower alkyl; When
R.sup.1=R.sup.2=R.sup.3=R.sup.4=R.sup.5=F, then Y is a single bond
or --CH(R.sup.9)--; When
R.sup.1=R.sup.2=R.sup.3=R.sup.4=R.sup.5=Cl, n=2, and Y=--NH--, then
Ar is other than unsubstituted phenyl or unsubstituted p-biphenyl;
When R.sup.1=R.sup.2=R.sup.3=R.sup.4=R.sup.5=Br, n=2, and Y=--NH--,
then Ar is other than unsubstituted phenyl; When R.sup.3=halogen,
n=2, Y=--N(R.sup.9)--, and at least one of R.sup.1, R.sup.2,
R.sup.4 and R.sup.5 is also halogen, then at least one of R.sup.1,
R.sup.2, R.sup.4 and R.sup.5 must be other than hydrogen; When
R.sup.1=H, n=2, and Y=--NH--, then at least one of R.sup.2,
R.sup.3, R.sup.4 and R.sup.5 must be a substituent other than
chloro; When R.sup.1=R.sup.5=H, n=2, and Y=--N(R.sup.9)--, then at
least one of R.sup.2, R.sup.3, and R.sup.4 must be a substituent
other than chloro; When R.sup.1=R.sup.5=halogen, R.sup.2=R.sup.4=H,
n=2, and Y=--N(R.sup.9)--, then R.sup.3 is a substituent other than
chloro or bromo; When R.sup.1=R.sup.2=halogen, R.sup.4=R.sup.5=H,
n=2, and Y=--N(R.sup.8)--, then R.sup.3is a substituent other than
chloro or bromo; When R.sup.1=R.sup.4=halogen, R.sup.2=R.sup.5 H,
and n=2, then R.sup.3 is a substituent other than chloro or bromo;
When R.sup.1=R.sup.5=halogen, R.sup.2=R.sup.4=H, and Y=--O--, then
Ar is a ring system other than quinolinyl; When R.sup.1=F,
R.sup.3=R.sup.4=Cl, and Y=--NH--, then Ar is a ring system other
than 1,3,4-thiadiazolyl; When R.sup.1=R.sup.3=F, R.sup.4=Cl, and
Y=--NH-- or --O--, then Ar is a ring other than unsubstituted
phenyl; When R.sup.1=R.sup.3=R.sup.5=Br, and Y=--NH--, then Ar is a
ring other than phenyl substituted by lower-alkyl; When
R.sup.1=R.sup.3=R.sup.5=Cl, Y=--NH--, and R.sup.9=H or methyl, then
Ar is a phenyl ring substituted by 1-4 groups chosen independently
from halogen, OH, OR', NH.sub.2, NHR', and NR'R"; When
R.sup.2=R.sup.3=R.sup.4=Cl, Y=--NH--, and R.sup.9=propargyl, then
Ar is an unsubstituted ring or a ring substituted by a group other
than a trifluoromethyl or nitro groups; When R.sup.1=R.sup.3=Cl and
Y=--N(R.sup.9)--, then R.sup.2 and R.sup.4 must both be other than
chloro; When R.sup.2=CF.sub.3, R.sup.3=Cl, and Y=--N(R.sup.9)--,
then Ar cannot be either a phenyl ring substituted by
trifluoromethyl, nitro, chloro, or lower-alkyl groups, or a
2-benzothiazolyl ring; When R.sup.2=CO.sub.2H or NO.sub.2,
R.sup.3=Cl, and Y=--N(R.sup.9)--, then Ar is an unsubstituted
phenyl or phenyl substituted by a substituent other than CO.sub.2H
or CO.sub.2--R'; When R.sup.1=NO.sub.2, R.sup.3=Cl, and Y=--NH--,
then Ar is a ring system other than phenyl substituted by either Br
or NO.sub.2; wherein R' and R" are independently chosen from the
group of C1-C8 alkyl groups; and wherein said compound has
pharmacological activity.
2. The compound of claim 1, wherein R.sup.3 is halogen, NO.sub.2,
OCF.sub.3, S(O)--Ar, SO.sub.2--R.sup.8, SO.sub.2--Ar, N.sub.3,
N(R.sup.6)--SO.sub.2--CF.sub.3, N(R.sup.6)--SO.sub.2--(R.sup.8),
N(R.sup.6)--SO.sub.2--Ar, N(R.sup.6)--CO--(R.sup.8),
N(R.sup.6)--CO--Ar, N[CO--R.sup.8].sub.2, N(R.sup.8).sub.3.sup.+,
N(R.sup.8).sub.2(Ar).sup.+, O--SO.sub.2--Ar, O--SO.sub.2--R.sup.8,
O--CO--R.sup.8, O--CO--Ar, O--Ar, O--R.sup.8, or
O--CO--CF.sub.3.
3. The compound of claim 2, wherein n=2.
4. The compound of claim 3, wherein R.sup.1, R.sup.2, R.sup.4 and
R.sup.5 are independently selected from hydrogen, F, Cl, Br,
OCF.sub.3, CF.sub.3, SO.sub.2--R.sup.8, NO.sub.2, CN,
CO.sub.2--R.sup.8, and SO.sub.2--N(R.sup.6)(R.sup.7).
5. The compound of claim 4, wherein R.sup.2 and R.sup.4 are
independently selected from hydrogen, F, Cl, Br, OCF.sub.3,
CF.sub.3, NO.sub.2, CN, and CO.sub.2--R.sup.8.
6. The compound of claim 5, wherein Y is a single bond,
--N(R.sup.9)--, or --CH(R.sup.9)--; and wherein R.sup.6, R.sup.7
and R.sup.9 are independently chosen from hydrogen, lower-alkyl and
lower-heteroalkyl.
7. The compound of claim 6, wherein Y is --N(R.sup.9)--, and there
is no linking group E.
8. The compound of claim 7, wherein R.sup.3 is halogen, OCF.sub.3,
NO.sub.2, N.sub.3, O--SO.sub.2--Ar, O--SO.sub.2--R.sup.8, or
SO.sub.2--Ar.
9. The compound of claim 8, wherein R.sup.3 is F, Cl, Br, or
OCF.sub.3.
10. The compound of claim 9, wherein R.sup.3 is F.
11. The compound of claim 10, wherein R.sup.2 is selected from
NO.sub.2, CN, and CO.sub.2--R.sup.8; and R.sup.4 is selected from
hydrogen, F, Cl, Br, OCF.sub.3, CF.sub.3, NO.sub.2, CN, and
CO.sub.2--R.sup.8.
12. The compound of claim 11, wherein the compound is:
4-Fluoro-1-[(4-methoxyphenyl)aminosulfonyl]-3-nitrobenzene;
4-Fluoro-1-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]-3-nitrobenzene;
4-Fluoro-1-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]-3-nitrobenzene;
4-Fluoro-1-[(3,4-dimethoxyphenyl)aminosulfonyl]-3-nitrobenzene;
4-Fluoro-1-[(4-aminophenyl)aminosulfonyl]-3-nitrobenzene;
2-Fluoro-5-[(4-methoxyphenyl)aminosulfonyl]benzonitrile;
2-Fluoro-5-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzonitrile;
2-Fluoro-5-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzonitrile;
2-Fluoro-5-[(3,4-dimethoxyphenyl)aminosulfonyl]benzonitrile;
5-[(4-Dimethylaminophenyl)aminosulfonyl]-2-fluorobenzonitrile;
4,5-Difluoro-1-[(4-methoxyphenyl)aminosulfonyl]-3-nitrobenzene;
4,5-Difluoro-1-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]-3-nitrobenzene;
4,5-Difluoro-1-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]-3-nitrobenzene;
4,5-Difluoro-1-[(3,4-dimethoxyphenyl)aminosulfonyl]-3-nitrobenzene;
4,5-Difluoro-1-[(4-aminophenyl)aminosulfonyl]-3-nitrobenzene;
2,3,4-Trifluoro-5-[(4-methoxyphenyl)aminosulfonyl]benzoic acid,
ethyl ester;
2,3,4-Trifluoro-5-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzoic
acid, ethyl ester;
2,3,4-Trifluoro-5-[(3-hydroxy-4-methoxyphenyl)aminosul-
fonyl]benzoic acid, ethyl ester;
2,3,4-Trifluoro-5-[(3,4-dimethoxyphenyl)a- minosulfonyl]benzoic
acid, ethyl ester; 2,3,4-Trifluoro-5-[(4-dimethylamin-
ophenyl)aminosulfonyl]benzoic acid, ethyl ester;
2,4,5,6-Tetrafluoro-3-[(4- -methoxyphenyl)aminosulfonyl]benzoic
acid, ethyl ester;
2,4,5,6-Tetrafluoro-3-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzoic
acid, ethyl ester;
2,4,5,6-Tetrafluoro-3-[(3-hydroxy-4-methoxyphenyl)amin-
osulfonyl]benzoic acid, ethyl ester;
2,4,5,6-Tetrafluoro-3-[(3,4-dimethoxy- phenyl)aminosulfonyl]benzoic
acid, ethyl ester; or 2,4,5,6-Tetrafluoro-3-[-
(4-dimethylaminophenyl)aminosulfonyl]benzoic acid, ethyl ester.
13. The compound of claim 12, wherein the compound is:
4-Fluoro-1-[(4-methoxyphenyl)aminosulfonyl]-3-nitrobenzene;
4-Fluoro-1-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]-3-nitrobenzene;
4-Fluoro-1-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]-3-nitrobenzene;
4-Fluoro-1-[(3,4-dimethoxyphenyl)aminosulfonyl]-3-nitrobenzene; or
4-Fluoro-1-[(4-dimethylaminophenyl)aminosulfonyl]-3-nitrobenzene;
14. The compound of claim 12, wherein the compound is:
4,5-Difluoro-1-[(4-methoxyphenyl)aminosulfonyl]-3-nitrobenzene;
4,5-Difluoro-1-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]-3-nitrobenzene;
4,5-Difluoro-1-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]-3-nitrobenzene;
4,5-Difluoro-1-[(3,4-dimethoxyphenyl)aminosulfonyl]-3-nitrobenzene;
4,5-Difluoro-1-[(4-aminophenyl)aminosulfonyl]-3-nitrobenzene;
15. The compound of claim 10, wherein R.sup.2 and R.sup.4 are
independently selected from hydrogen, F, Cl, Br, OCF.sub.3 and
CF.sub.3.
16. The compound of claim 15, wherein the compound is:
1-Bromo-3,4,5,6-tetrafluoro-2-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]b-
enzene;
1-Bromo-3,4,5,6-tetrafluoro-2-[(4-methoxyphenyl)aminosulfonyl)]ben-
zene;
1-Bromo-3,4,5,6-tetrafluoro-2-[(3-fluoro-4-methoxyphenyl)aminosulfon-
yl]benzene;
1-Bromo-2,4,5,6-tetrafluoro-3-[(4-methoxyphenyl)aminosulfonyl)-
]benzene;
1-Bromo-2,4,5,6-tetrafluoro-3-[(3-hydroxy-4-methoxyphenyl)aminos-
ulfonyl]benzene;
1-Bromo-2,4,5,6-tetrafluoro-3-[(3-fluoro-4-methoxyphenyl)-
aminosulfonyl]benzene;
1-Bromo-2,4,5,6-tetrafluoro-3-[(3,4-dimethoxyphenyl-
)aminosulfonyl]benzene;
1-Bromo-2,4,5,6-tetrafluoro-3-[(4-dimethylaminophe-
nyl)aminosulfonyl]benzene;
1,3-Dichloro-2,4,6-trifluoro-5-[(4-methoxypheny-
l)aminosulfonyl]benzene;
1,3-Dichloro-2,4,6-fluoro-5-[(3-fluoro-4-methoxyp-
henyl)aminosulfonyl]benzene;
1,3-Dichloro-2,4,6-trifluoro-5-[(3-hydroxy-4--
methoxyphenyl)aminosulfonyl]benzene;
1-Bromo-4,5,6-trifluoro-2-[(4-methoxy-
phenyl)aminosulfonyl]benzene;
1-Bromo-4,5,6-trifluoro-2-[(3-hydroxy-4-meth-
oxyphenyl)aminosulfonyl]benzene;
1-Bromo-4,5,6-trifluoro-2-[(3-fluoro-4-me-
thoxyphenyl)aminosulfonyl]benzene;
1-Bromo-4,5,6-trifluoro-2-[(3,4-dimetho-
xyphenyl)aminosulfonyl]benzene;
1-Bromo-2,3,4-trifluoro-5-[(3-hydroxy-4-me-
thoxyphenyl)aminosulfonyl]benzene;
1-Bromo-2,3,4-trifluoro-5-[(3-fluoro-4--
methoxyphenyl)aminosulfonyl]benzene;
1-Bromo-2,3,4-trifluoro-5-[(4-methoxy-
phenyl)aminosulfonyl]benzene;
1-Bromo-2,3,4-trifluoro-5-[(3,4-dimethoxyphe-
nyl)aminosulfonyl]benzene;
1-Bromo-3,4,5-trifluoro-2-[(3-hydroxy-4-methoxy-
phenyl)aminosulfonyl]benzene;
1-Bromo-3,4,5-trifluoro-2-[(3-fluoro-4-metho-
xyphenyl)aminosulfonyl]benzene;
1-Bromo-3,4,5-trifluoro-2-[(4-methoxypheny-
l)aminosulfonyl]benzene;
3,4,6-Trifluoro-1-[(4-methoxyphenyl)aminosulfonyl- ]benzene;
3,4,6-Trifluoro-1-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benze-
ne; 3,4,6-Trifluoro-1-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl
]benzene;
2,3,4,6-Tetrafluoro-1-[(4-methoxyphenyl)aminosulfonyl]benzene;
2,3,4,6-Tetrafluoro-1-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzene;
2,3,4,6-Tetrafluoro-1-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzene;
2,3,4,5-Tetrafluoro-1-[(4-methoxyphenyl)aminosulfonyl]benzene;
2,3,4,5-Tetrafluoro-1-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzene;
2,3,4,5-Tetrafluoro-1-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzene;
2,3,4,5-Tetrafluoro-1-[(3,4-dimethoxyphenyl)aminosulfonyl]benzene;
2,3,4,5-Tetrafluoro-1-[(4-dimethylaminophenyl)aminosulfonyl]benzene;
3,4,5-Trifluoro-1-[(4-methoxyphenyl)aminosulfonyl]benzene;
3,4,5-Trifluoro-1-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzene;
3,4,5-Trifluoro-1-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzene;
3,4,5-Trifluoro-1-[(3,4-dimethoxyphenyl)aminosulfonyl]benzene; or
3,4,5-Trifluoro-1-[(4-dimethylaminophenyl)aminosulfonyl]benzene.
17. The compound of claim 16, wherein the compound is:
1-Bromo-3,4,5,6-tetrafluoro-2-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]b-
enzene;
1-Bromo-3,4,5,6-tetrafluoro-2-[(4-methoxyphenyl)aminosulfonyl)]ben-
zene;
1-Bromo-3,4,5,6-tetrafluoro-2-[(3-fluoro-4-methoxyphenyl)aminosulfon-
yl]benzene;
1-Bromo-2,4,5,6-tetrafluoro-3-[(4-methoxyphenyl)aminosulfonyl)-
]benzene ;
1-Bromo-2,4,5,6-tetrafluoro-3-[(3-hydroxy-4-methoxyphenyl)amino-
sulfonyl]benzene;
1-Bromo-2,4,5,6-tetrafluoro-3-[(3-fluoro-4-methoxyphenyl-
)aminosulfonyl]benzene;
1,3-Dichloro-2,4,6-trifluoro-5-[(4-methoxyphenyl)a-
minosulfonyl]benzene;
1,3-Dichloro-2,4,6-trifluoro-5-[(3-fluoro-4-methoxyp- henyl
)aminosulfonyl]benzene;
1,3-Dichloro-2,4,6-trifluoro-5-[(3-hydroxy-4-
-methoxyphenyl)aminosulfonyl]benzene;
1-Bromo-4,5,6-trifluoro-2-[(4-methox-
yphenyl)aminosulfonyl]benzene;
1-Bromo-4,5,6-trifluoro-2-[(3-hydroxy-4-met-
hoxyphenyl)aminosulfonyl]benzene;
1-Bromo-4,5,6-trifluoro-2-[(3-fluoro-4-m-
ethoxyphenyl)aminosulfonyl]benzene;
1-Bromo-3,4,5-trifluoro-2-[(3-hydroxy--
4-methoxyphenyl)aminosulfonyl]benzene;
1-Bromo-3,4,5-trifluoro-2-[(3-fluor-
o-4-methoxyphenyl)aminosulfonyl]benzene;
1-Bromo-3,4,5-trifluoro-2-[(4-met-
hoxyphenyl)aminosulfonyl]benzene;
1-Bromo-2,3,4-trifluoro-5-[(3-hydroxy-4--
methoxyphenyl)aminosulfonyl]benzene;
1-Bromo-2,3,4-trifluoro-5-[(3-fluoro--
4-methoxyphenyl)aminosulfonyl]benzene; or
1-Bromo-2,3,4-trifluoro-5-[(4-me-
thoxyphenyl)aminosulfonyl]benzene.
18. The compound of claim 16, wherein the compound is:
2,3,4,6-Tetrafluoro-1-[(4-methoxyphenyl)aminosulfonyl]benzene;
2,3,4,6-Tetrafluoro-1-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzene;
2,3,4,6-Tetrafluoro-1-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzene;
2,3,4,5-Tetrafluoro-1-[(4-methoxyphenyl)aminosulfonyl]benzene;
2,3,4,5-Tetrafluoro-1-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzene;
2,3,4,5-Tetrafluoro-1-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzene;
2,3,4,5-Tetrafluoro-1-[(3,4-dimethoxyphenyl)aminosulfonyl]benzene;
2,3,4,5-Tetrafluoro-1-[(4-dimethylaminophenyl)aminosulfonyl]benzene;
3,4,5-Trifluoro-1-[(4-methoxyphenyl)aminosulfonyl]benzene;
3,4,5-Trifluoro-1-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzene;
3,4,5-Trifluoro-1-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzene;
3,4,5-Trifluoro-1-[(3,4-dimethoxyphenyl)aminosulfonyl]benzene; or
3,4,5-Trifluoro-1-[(4-dimethylaminophenyl)aminosulfonyl]benzene.
19. The compound of claim 9, wherein R.sup.3 is Cl.
20. The compound of claim 19, wherein R.sup.2 is selected from
NO.sub.2, CN, and CO.sub.2--R.sup.8; and R.sup.4 is selected from
hydrogen, F, Cl, Br, OCF.sub.3, CF.sub.3, NO.sub.2, CN, and
CO.sub.2--R.sup.8.
21. The compound of claim 20, wherein the compound is:
1-Chloro-4-[(4-methoxyphenyl)aminosulfonyl]-2-nitrobenzene;
1-Chloro-4-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]-2-nitrobenzene;
1-Chloro-4-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]-2-nitrobenzene;
1-Chloro-4-[(3,4-dimethoxyphenyl)aminosulfonyl]-2-nitrobenzene;
1-Chloro-4-[(4-dimethylaminophenyl)aminosulfonyl]-2-nitrobenzene;
2-Chloro-5-[(4-methoxyphenyl)aminosulfonyl]benzonitrile;
2-Chloro-5-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzonitrile;
2-Chloro-5-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzonitrile.
2-Chloro-5-[(3,4-dimethoxyphenyl)aminosulfonyl]benzonitrile;
2-Chloro-5-[(4-dimethylaminophenyl)aminosulfonyl]benzonitrile;
2-Chloro-5-[(4-methoxyphenyl)aminosulfonyl]benzoic acid, ethyl
ester; 2-Chloro-5-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzoic
acid, ethyl ester;
2-Chloro-5-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzoic acid,
ethyl ester; 2-Chloro-5-[(3,4-dimethoxyphenyl)aminosulfonyl]benzoic
acid, ethyl ester; or
2-Chloro-5-[(4-dimethylaminophenyl)aminosulfonyl]benzoic acid,
ethyl ester.
22. The compound of claim 19, wherein R.sup.2 and R.sup.4 are
independently selected from hydrogen, F, Cl, Br, OCF.sub.3 and
CF.sub.3.
23. The compound of claim 22, wherein the compound is:
1-Chloro-2,3,5,6-tetrafluoro-4-[(4-methoxyphenyl)aminosulfonyl]benzene;
1-Chloro-2,3,5,6-tetrafluoro-4-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]-
benzene;
1-Chloro-2,3,5,6-tetrafluoro-4-[(3-fluoro-4-methoxyphenyl)aminosu-
lfonyl]benzene;
1-Chloro-2,3,5,6-tetrafluoro-4-[(4-dimethylaminophenyl)ami-
nosulfonyl]benzene;
1-Chloro-2,3,5,6-tetrafluoro-4-[(3,4-dimethoxyphenyl)a-
minosulfonyl]benzene;
1-Chloro-2,3,6-trifluoro-4-[(4-methoxyphenyl)aminosu-
lfonyl]benzene;
1-Chloro-2,3,6-trifluoro-4-[(3-hydroxy-4-methoxyphenyl)ami-
nosulfonyl]benzene;
1-Chloro-2,3,6-trifluoro-4-[(3-fluoro-4-methoxyphenyl)-
aminosulfonyl]benzene;
1-Chloro-2,3,6-trifluoro-4-[(4-dimethylaminophenyl)-
aminosulfonyl]benzene; or
1-Chloro-2,3,6-trifluoro-4-[(3,4-dimethoxyphenyl-
)aminosulfonyl]benzene.
24. The compound of claim 9, wherein R.sup.3is Br.
25. The compound of claim 24, wherein R.sup.2 is selected from
NO.sub.2, CN, and CO.sub.2--R.sup.8; and R.sup.4 is selected from
hydrogen, F, Cl, Br, OCF.sub.3, CF.sub.3, NO.sub.2, CN, and
CO.sub.2--R.sup.8.
26. The compound of claim 25, wherein the compound is:
1-Bromo-4-[(4-methoxyphenyl)aminosulfonyl]-2-nitrobenzene;
1-Bromo-4-[(3-fluoro-4methoxyphenyl)aminosulfonyl]-2-nitrobenzene;
1-Bromo-4-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]-2-nitrobenzene;
1-Bromo-4-[(3,4-dimethoxyphenyl)aminosulfonyl]-2-nitrobenzene;
1-Bromo-4-[(4-dimethylaminophenyl)aminosulfonyl]-2-nitrobenzene;
2-Bromo-5-[(4-methoxyphenyl)aminosulfonyl]benzonitrile;
2-Bromo-5-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzonitrile;
2-Bromo-5-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzonitrile.
2-Bromo-5-[(3,4-dimethoxyphenyl)aminosulfonyl]benzonitrile;
2-Bromo-5-[(4-dimethylaminophenyl)aminosulfonyl]benzonitrile;
2-Bromo-5-[(4-methoxyphenyl)aminosulfonyl]benzoic acid, ethyl
ester; 2-Bromo-5-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzoic
acid, ethyl ester;
2-Bromo-5-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzoic acid,
ethyl ester; 2-Bromo-5-[(3,4-dimethoxyphenyl)aminosulfonyl]benzoic
acid, ethyl ester; or
2-Bromo-5-[(4-dimethylaminophenyl)aminosulfonyl]benzoic acid, ethyl
ester.
27. The compound of claim 24, wherein R.sup.2 and R.sup.4 are
independently selected from hydrogen, F, Cl, Br, OCF.sub.3 and
CF.sub.3.
28. The compound of claim 27, wherein the compound is:
1-Bromo-2,3,5,6-tetrafluoro-4-[(4-methoxyphenyl)aminosulfonyl]benzene;
1-Bromo-2,3,5,6-tetrafluoro-4-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]b-
enzene;
1-Bromo-2,3,5,6-tetrafluoro-4-[(3-fluoro-4-methoxyphenyl)aminosulf-
onyl]benzene;
1-Bromo-2,3,5,6-tetrafluoro-4-[(4-dimethylaminophenyl)aminos-
ulfonyl]benzene;
1-Bromo-2,3,5,6-tetrafluoro-4-[(3,4-dimethoxyphenyl)amino-
sulfonyl]benzene;
1-Bromo-2,3,6-trifluoro-4-[(4-methoxyphenyl)aminosulfony-
l]benzene;
1-Bromo-2,3,6-trifluoro-4-[(3-hydroxy-4-methoxyphenyl)aminosulf-
onyl]benzene;
1-Bromo-2,3,6-trifluoro-4-[(3-fluoro-4-methoxyphenyl)aminosu-
lfonyl]benzene;
1-Bromo-2,3,6-trifluoro-4-[(4-dimethylaminophenyl)aminosul-
fonyl]benzene; or
1-Bromo-2,3,6-trifluoro-4-[(3,4-dimethoxyphenyl)aminosul-
fonyl]benzene.
29. The compound of claim 9, wherein R.sup.3 is OCF.sub.3.
30. The compound of claim 29, wherein R.sup.2 is selected from
NO.sub.2, CN, and CO.sub.2--R.sup.8; and R.sup.4 is selected from
hydrogen, F, Cl, Br, OCF.sub.3, CF.sub.3, NO.sub.2, CN, and
CO.sub.2--R.sup.8.
31. The compound of claim 30, wherein the compound is:
4-Trifluoromethoxy-1-[(4-methoxyphenyl)aminosulfonyl]-3-nitrobenzene;
4-Trifluoromethoxy-1-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]-3-nitroben-
zene;
4-Trifluoromethoxy-1-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]-3-ni-
trobenzene;
4-Trifluoromethoxy-1-[(3,4-dimethoxyphenyl)aminosulfonyl]-3-ni-
trobenzene;
4-Trifluoromethoxy-1-[(4-dimethylaminophenyl)aminosulfonyl]-3--
nitrobenzene;
2-Trifluoromethoxy-5-[(4-methoxyphenyl)aminosulfonyl]benzoni-
trile;
2-Trifluoromethoxy-5-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzo-
nitrile;
2-Trifluoromethoxy-5-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]be-
nzonitrile.
2-Trifluoromethoxy-5-[(3,4-dimethoxyphenyl)aminosulfonyl]benzo-
nitrile;
2-Trifluoromethoxy-5-[(4-dimethylaminophenyl)aminosulfonyl]benzon-
itrile;
2-Trifluoromethoxy-5-[(4-methoxyphenyl)aminosulfonyl]benzoic acid,
ethyl ester;
2-Trifluoromethoxy-5-[(3-fluoro-4-methoxyphenyl)aminosulfony-
l]benzoic acid, ethyl ester;
2-Trifluoromethoxy-5-[(3-hydroxy-4-methoxyphe-
nyl)aminosulfonyl]benzoic acid, ethyl ester;
2-Trifluoromethoxy-5-[(3,4-di- methoxyphenyl)aminosulfonyl]benzoic
acid, ethyl ester; or
2-Trifluoromethoxy-5-[(4-dimethylaminophenyl)aminosulfonyl]benzoic
acid, ethyl ester.
32. The compound of claim 29, wherein R.sup.2 and R.sup.4 are
independently selected from hydrogen, F, Cl, Br, OCF.sub.3 and
CF.sub.3.
33. The compound of claim 32, wherein the compound is:
2,3,5,6-Tetrafluoro-1-trifluoromethoxy-4-[(4-methoxyphenyl)aminosulfonyl]-
benzene;
2,3,5,6-Tetrafluoro-1-trifluoromethoxy-4-[(3-hydroxy-4-methoxyphe-
nyl)aminosulfonyl]benzene;
2,3,5,6-Tetrafluoro-1-trifluoromethoxy-4-[(3-fl-
uoro-4-methoxyphenyl)aminosulfonyl]benzene;
2,3,5,6-Tetrafluoro-1-trifluor-
omethoxy-4-[(4-dimethylaminophenyl)aminosulfonyl]benzene;
2,3,5,6-Tetrafluoro-1-trifluoromethoxy-4-[(3,4-dimethoxyphenyl)aminosulfo-
nyl]benzene;
2,3,6-Trifluoro-1-trifluoromethoxy-4-[(4-methoxyphenyl)aminos-
ulfonyl]benzene;
2,3,6-Trifluoro-1-trifluoromethoxy-4-[(3-hydroxy-4-methox-
yphenyl)aminosulfonyl]benzene;
2,3,6-Trifluoro-1-trifluoromethoxy-4-[(3-fl-
uoro-4-methoxyphenyl)aminosulfonyl]benzene;
2,3,6-Trifluoro-1-trifluoromet-
hoxy-4-[(4-dimethylaminophenyl)aminosulfonyl]benzene; or
2,3,6-Trifluoro-1-trifluoromethoxy-4-[(3,4-dimethoxyphenyl)aminosulfonyl]-
benzene.
34. The compound of claim 8, wherein R.sup.3 is selected from
NO.sub.2, N.sub.3, O--SO.sub.2--Ar, O--SO.sub.2--R.sup.8 and
SO.sub.2--Ar.
35. The compound of claim 34, wherein the compound is:
1-[(4-Methoxyphenyl)aminosulfonyl]-3,4-dinitrobenzene;
1-[(3-Fluoro-4-methoxyphenyl)aminosulfonyl]-3,4-dinitrobenzene;
1-[(3-Hydroxy-4-methoxyphenyl)aminosulfonyl]-3,4-dinitrobenzene;
4-Azido-1-[(3,4-dimethoxyphenyl)aminosulfonyl]-3-nitrobenzene;
4-Azido-1-[(4-aminophenyl)aminosulfonyl]-3-nitrobenzene;
4-Azido-1-[(4-methoxyphenyl)aminosulfonyl]-3-nitrobenzene;
4-Azido-1-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]-3-nitrobenzene;
4-Azido-1-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]-3-nitrobenzene;
2-Azido-5-[(4-methoxyphenyl)aminosulfonyl]benzonitrile;
2-Azido-5-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzonitrile;
2-Azido-5-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzonitrile.
2-Azido-5-[(3,4-dimethoxyphenyl)aminosulfonyl]benzonitrile;
2-Azido-5-[(4-dimethylaminophenyl)aminosulfonyl]benzonitrile;
5-[(4-Methoxyphenyl)aminosulfonyl]-2-phenylsulfonylbenzonitrile;
5-[(3-Fluoro-4-methoxyphenyl)aminosulfonyl]-2-phenylsulfonylbenzonitrile;
5-[(3-Hydroxy-4-methoxyphenyl)aminosulfonyl]-2-phenylsulfonylbenzonitrile-
.
5-[(3,4-Dimethoxyphenyl)aminosulfonyl]-2-phenylsulfonylbenzonitrile;
5-[(4-Dimethylaminophenyl)aminosulfonyl]-2-phenylsulfonylbenzonitrile;
5-[(4-Methoxyphenyl)aminosulfonyl]-2-phenylsulfonyloxybenzoic acid,
ethyl ester;
5-[(3-Fluoro-4-methoxyphenyl)aminosulfonyl]-2-phenylsulfonyloxyben-
zoic acid, ethyl ester;
5-[(3-Hydroxy-4-methoxyphenyl)aminosulfonyl]-2-phe-
nylsulfonyloxybenzoic acid, ethyl ester;
5-[(3,4-Dimethoxyphenyl)aminosulf- onyl]-2-phenylsulfonyloxybenzoic
acid, ethyl ester;
5-[(4-Dimethylaminophenyl)aminosulfonyl]-2-phenylsulfonyloxybenzoic
acid, ethyl ester.
2,3,5,6-Tetrafluoro-1-[(4-methoxyphenyl)aminosulfonyl]4-nitr-
obenzene;
2,3,5,6-Tetrafluoro-1-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]-
4-nitrobenzene;
2,3,5,6-Tetrafluoro-1-[(3-fluoro-4-methoxyphenyl)aminosulf-
onyl]4-nitrobenzene;
2,3,5,6-Tetrafluoro-1-[(4-dimethylaminophenyl)aminosu-
lfonyl]4-nitrobenzene;
2,3,5,6-Tetrafluoro-1-[(3,4-dimethoxyphenyl)aminosu-
lfonyl]-4-nitrobenzene;
4-Azido-2,3,6-trifluoro-1-[(4-methoxyphenyl)aminos-
ulfonyl]benzene;
4-Azido-2,3,6-trifluoro-1-[(3-hydroxy-4-methoxyphenyl)ami-
nosulfonyl]benzene;
4-Azido-2,3,6-trifluoro-1-[(3-fluoro-4-methoxyphenyl)a-
minosulfonyl]benzene;
4-Azido-2,3,6-trifluoro-1-[(4-dimethylaminophenyl)am-
inosulfonyl]benzene; or
4-Azido-2,3,6-trifluoro-1-[(3,4-dimethoxyphenyl)am-
inosulfonyl]benzene.
36. The compound of claim 7, wherein R.sup.3 is selected from
N(R.sup.6)--SO.sub.2--CF.sub.3, N(R.sup.6)--SO.sub.2--(R.sup.8),
N(R.sup.6)--SO.sub.2--Ar, N(R.sup.6)--CO--(R.sup.8),
N(l.sup.6)--CO--Ar, N[CO--R.sup.8].sub.2, and O--CO--CF.sub.3.
37. The compound of claim 36, wherein the compound is:
4-Trifluoromethylsulfonamido-1-[(4-methoxyphenyl)aminosulfonyl]-3-nitrobe-
nzene;
1-[(3-Fluoro-4-methoxyphenyl)aminosulfonyl]4-trifluoromethylsulfona-
mido-3-nitrobenzene;
4-Trifluoromethylsulfonamido-1-[(3-hydroxy-4-methoxyp-
henyl)aminosulfonyl]-3-nitrobenzene;
2,3,5,6-Tetrafluoro-4-trifluoromethyl-
sulfonamido-1-[(4-methoxyphenyl)aminosulfonyl]benzene;
2,3,5,6-Tetrafluoro-1-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]-4-trifluo-
romethylsulfonamidobenzene;
2,3,5,6-Tetrafluoro-4-trifluoromethylsulfonami-
do-1-[(3-hydroxy-4-methoxyphenyl)-aminosulfonyl]benzene;
4-(Diacetylamino)-2,3-difluoro-1-[(3-fluoro-4-methoxyphenyl)aminosulfonyl-
]-5-nitrobenzene;
4-Trifluoroacetoxy-1-[(4-methoxyphenyl)aminosulfonyl]-3--
nitrobenzene;
4-Trifluoroacetoxy-1-[(3-fluoro-4-methoxyphenyl)aminosulfony-
l]-3-nitrobenzene;
4-Trifluoroacetoxy-1-[(3-hydroxy-4-methoxyphenyl)aminos-
ulfonyl]-3-nitrobenzene;
2,3,5,6-Tetrafluoro-4-trifluoroacetoxy-1-[(4-meth-
oxyphenyl)aminosulfonyl]benzene;
2,3,5,6-Tetrafluoro-4-trifluoroacetoxy-1--
[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzene;
2,3,5,6-Tetrafluoro-4-tr-
ifluoroacetoxy-1-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzene;
1-[(4-Methoxyphenyl)aminosulfonyl]-4-methylsulfonamido-3-nitrobenzene;
1-[(3-Fluoro-4-methoxyphenyl)aminosulfonyl]4-methylsulfonamido-3-nitroben-
zene;
1-[(3-Hydroxy-4-methoxyphenyl)aminosulfonyl]-4-methylsulfonamido-3-n-
itrobenzene;
2,3,5,6-Tetrafluoro-1-[(.sup.4-methoxyphenyl)aminosulfonyl]-4-
-methylsulfonamidobenzene;
2,3,5,6-Tetrafluoro-1-[(.sup.3-fluoro-4-methoxy-
phenyl)aminosulfonyl]-4-methylsulfonamido-benzene;
2,3,5,6-Tetrafluoro-1-[-
(3-hydroxy-4-methoxyphenyl)aminosulfonyl]-4-methylsulfonamido-benzene;
1-[(4-Methoxyphenyl)aminosulfonyl]-3-nitro-4-phenylsulfonamidobenzene;
1-[(3-Fluoro-4methoxyphenyl)aminosulfonyl]-3-nitro-4-phenylsulfonamidoben-
zene;
1-[(3-Hydroxy-4-methoxyphenyl)aminosulfonyl]-3-nitro-4-phenylsulfona-
midobenzene;
2,3,5,6-Tetrafluoro-1-[(4-methoxyphenyl)aminosulfonyl]-4-phen-
ylsulfonamidobenzene;
2,3,5,6-Tetrafluoro-1-[(3-fluoro-4-methoxyphenyl)ami-
nosulfonyl]-4-phenylsulfonamidobenzene; or
2,3,5,6-Tetrafluoro-1-[(3-hydro-
xy-4-methoxyphenyl)aminosulfonyl]-4-phenylsulfonamidobenzene.
38. The compound of claim 6, wherein Y is a single bond or
--CH(R.sup.9)--, and there is no linking group E.
39. The compound of claim 38, wherein R.sup.3 is selected from F,
Cl, Br, and OCF.sub.3.
40. The compound of claim 39, wherein R.sup.2 is selected from
NO.sub.2, CN, and CO.sub.2R.sup.8; and R.sup.4 is selected from
hydrogen, F, Cl, Br, OCF.sub.3, CF.sub.3, NO.sub.2, CN, and
CO.sub.2--R.sup.8.
41. The compound of claim 40, wherein the compound is:
4-Fluoro-1-[(4-methoxyphenyl)methylsulfonyl]-3-nitrobenzene;
4-Fluoro-1-[(3-hydroxy-4-methoxyphenyl)methylsulfonyl]-3-nitrobenzene;
4-Fluoro-1-[(3-fluoro-4-methoxyphenyl)methylsulfonyl]-3-nitrobenzene;
4-Fluoro-1-[(4-methoxyphenyl)sulfonyl]-3-nitrobenzene;
4-Fluoro-1-[(3-hydroxy-4-methoxyphenyl)sulfonyl]-3-nitrobenzene;
4-Fluoro-1-[(3-fluoro-4-methoxyphenyl)sulfonyl]-3-nitrobenzene;
2-Fluoro-5-[(4-methoxyphenyl)sulfonyl]benzonitrile;
2-Fluoro-5-[(3-hydroxy-4-methoxyphenyl)sulfonyl]benzonitrile;
2-Fluoro-5-[(3-fluoro-4-methoxyphenyl)sulfonyl]benzonitrile;
2-Fluoro-5-[(4-methoxyphenyl)methylsulfonyl]benzonitrile;
2-Fluoro-5-[(3-hydroxy-4-methoxyphenyl)methylsulfonyl]benzonitrile;
2-Fluoro-5-[(3-fluoro-4-methoxyphenyl)methylsulfonyl]benzonitrile;
2,3,4-Trifluoro-5-[(4-methoxyphenyl)sulfonyl]benzoic acid, ethyl
ester;
2,3,4-Trifluoro-5-[(3-fluoro-4-methoxyphenyl)sulfonyl]benzoic acid,
ethyl ester;
2,3,4-Trifluoro-5-[(3-hydroxy-4-methoxyphenyl)sulfonyl]benzoic
acid, ethyl ester;
1-Chloro-4-[(4-methoxyphenyl)methylsulfonyl]-2-nitrobe- nzene;
1-Chloro-4-[(4-dimethylaminophenyl)methylsulfonyl]-2-nitrobenzene;
1-Chloro-4-[(4-methoxyphenyl)sulfonyl]-2-nitrobenzene; or
1-Chloro-4-[(4-dimethylaminophenyl)sulfonyl]-2-nitrobenzene.
42. The compound of claim 39, wherein R.sup.2 and R.sup.4 are
independently selected from hydrogen, F, Cl, Br, OCF.sub.3 and
CF.sub.3.
43. The compound of claim 42, wherein the compound is:
1-Bromo-3,4,5,6-tetrafluoro-2-[(3-hydroxy-4-methoxyphenyl)sulfonyl]benzen-
e;
1-Bromo-3,4,5,6-tetrafluoro-2-[(4-methoxyphenyl)sulfonyl)]benzene;
1-Bromo-3,4,5,6-tetrafluoro-2-[(3-fluoro-4-methoxyphenyl)sulfonyl]benzene-
;
1-Bromo-2,4,5,6-tetrafluoro-3-[(4-methoxyphenyl)sulfonyl)]benzene;
1-Bromo-2,4,5,6-tetrafluoro-3-[(3-hydroxy-4-methoxyphenyl)sulfonyl]benzen-
e;
1-Bromo-2,4,5,6-tetrafluoro-3-[(3-fluoro-4-methoxyphenyl)sulfonyl]benze-
ne;
1,3-Dichloro-2,4,6-trifluoro-5-[(4-methoxyphenyl)sulfonyl]benzene;
1,3-Dichloro-2,4,6-trifluoro-5-[(3-fluoro-4-methoxyphenyl)sulfonyl]benzen-
e;
1,3-Dichloro-2,4,6-trifluoro-5-[(3-hydroxy-4-methoxyphenyl)sulfonyl]ben-
zene; 1-Bromo-4,5,6-trifluoro-2-[(4-methoxyphenyl)sulfonyl]benzene;
1-Bromo-4,5,6-trifluoro-2-[(3-hydroxy-4-methoxyphenyl)sulfonyl]benzene;
1-Bromo-4,5,6-trifluoro-2-[(3-fluoro-4-methoxyphenyl)sulfonyl]benzene;
2,3,4,5-Tetrafluoro-1-[(4-methoxyphenyl)sulfonyl]benzene;
2,3,4,5-Tetrafluoro-1-[(3-hydroxy-4-methoxyphenyl)sulfonyl]benzene;
2,3,4,5-Tetrafluoro-1-[(3-fluoro-4-methoxyphenyl)sulfonyl]benzene;
2,3,4,5-Tetrafluoro-1-[(3,4-dimethoxyphenyl)sulfonyl]benzene;
2,3,4,5-Tetrafluoro-1-[(4-dimethylaminophenyl)sulfonyl]benzene;
3,4,5-Trifluoro-1-[(4-methoxyphenyl)sulfonyl]benzene;
3,4,5-Trifluoro-1-[(3-hydroxy-4-methoxyphenyl)sulfonyl]benzene;
3,4,5-Trifluoro-1-[(3-fluoro-4-methoxyphenyl)sulfonyl]benzene;
3,4,5-Trifluoro-1-[(3,4-dimethoxyphenyl)sulfonyl]benzene;
3,4,5-Trifluoro-1-[(4-dimethylaminophenyl)sulfonyl]benzene;
1-Chloro-2,3,5,6-tetrafluoro-4-[(4-methoxyphenyl)sulfonyl]benzene;
1-Chloro-2,3,5,6-tetrafluoro[(3-hydroxy-4-methoxyphenyl)sulfonyl]benzene;
1-Chloro-2,3,5,6-tetrafluoro-4-[(3-fluoro-4-methoxyphenyl)sulfonyl]benzen-
e;
1-Bromo-2,3,5,6-tetrafluoro-4-[(4-methoxyphenyl)sulfonyl]benzene;
1-Bromo-2,3,5,6-tetrafluoro-4-[(3-hydroxy-4-methoxyphenyl)sulfonyl]benzen-
e;
1-Bromo-2,3,5,6-tetrafluoro-4-[(3-fluoro-4-methoxyphenyl)sulfonyl]benze-
ne;
1-Bromo-2,3,5,6-tetrafluoro-4-[(4-dimethylaminophenyl)sulfonyl]benzene-
;
1-Bromo-2,3,5,6-tetrafluoro-4-[(3,4-dimethoxyphenyl)sulfonyl]benzene;
2,3,4,5,6-Pentafluoro-1-[(4-methoxyphenyl)sulfonyl]benzene;
2,3,4,5,6-Pentafluoro-1-[(3-hydroxy-4methoxyphenyl)sulfonyl]benzene;
2,3,4,5,6-Pentafluoro-1-[(3-fluoro-4-methoxyphenyl)sulfonyl]benzene;
2,3,4,5,6-Pentafluoro-1-[(4-dimethylaminophenyl)sulfonyl]benzene;
2,3,4,5,6-Pentafluoro-1-[(3,4-dimethoxyphenyl)sulfonyl]benzene;
2,3,4,5,6-Pentafluoro-1-[(4-methoxyphenyl)methylsulfonyl]benzene;
2,3,4,5,6-Pentafluoro-1-[(3-hydroxy-4-methoxyphenyl)methylsulfonyl
benzene;
2,3,4,5,6-Pentafluoro-1-[(3-fluoro-4-methoxyphenyl)methylsulfony-
l]benzene;
2,3,4,5,6-Pentafluoro-1-[(4-dimethylaminophenyl)methylsulfonyl]-
benzene; or
2,3,4,5,6-Pentafluoro-1-[(3,4-dimethoxyphenyl)methylsulfonyl]b-
enzene.
44. The compound of claim 38, wherein R.sup.3 is selected from
NO.sub.2, S(O)--Ar, SO.sub.2--R.sup.8, SO.sub.2--Ar, N.sub.3,
N(l.sup.6)--SO.sub.2--CF.sub.3, N(R.sup.6)--SO.sub.2--(R.sup.8),
N(R.sup.6)--SO.sub.2--Ar, N(R.sup.6)--CO--(R.sup.8),
N(R.sup.6)--CO--Ar, N[CO--R.sup.8].sub.2, N(R.sup.8).sub.3.sup.+,
N(R.sup.8)2(Ar).sup.+, O--SO.sub.2--Ar, O--SO.sub.2--R.sup.8,
O--CO--R.sup.8, O--CO--Ar, O--Ar, O--R.sup.8 and
O--CO--CF.sub.3.
45. The compound of claim 44, wherein R.sup.2 is selected from
NO.sub.2, CN, and CO.sub.2--R.sup.8; and R.sup.4 is selected from
hydrogen, F, Cl, Br, OCF.sub.3, CF.sub.3, NO.sub.2, CN, and
CO.sub.2--R.sup.8.
46. The compound of claim 45, wherein the compound is:
1-[(4-Methoxyphenyl)sulfonyl]-3,4-dinitrobenzene;
1-[(3-Fluoro-4-methoxyp- henyl)sulfonyl]-3,4-dinitrobenzene;
1-[(3-Hydroxy-4-methoxyphenyl)sulfonyl- ]-3,4-dinitrobenzene;
4-Azido-1-[(3,4-dimethoxyphenyl)sulfonyl]-3-nitroben- zene;
4-Azido-1-[(4-aminophenyl)sulfonyl]-3-nitrobenzene;
4-Azido-1-[(4-methoxyphenyl)sulfonyl]-3-nitrobenzene;
4-Azido-1-[(3-hydroxy-methoxyphenyl)sulfonyl]-3-nitrobenzene;
4-Azido-1-[(3-fluoro-4-methoxyphenyl)sulfonyl]-3-nitrobenzene;
2-Azido-5-[(4-methoxyphenyl)sulfonyl]benzonitrile;
2-Azido-5-[(3-fluoro-4methoxyphenyl)sulfonyl]benzonitrile;
2-Azido-5-[(3-hydroxy-4-methoxyphenyl)sulfonyl]benzonitrile .
5-[(4-Methoxyphenyl)sulfonyl]-2-phenylsulfonyl)benzonitrile;
5-[(3-Fluoro-4-methoxyphenylsulfonyl]-2-phenylsulfonyl)benzonitrile;
5-[(4-Methoxyphenyl)sulfonyl]-2-(phenylsulfonyloxy)benzoic acid,
ethyl ester;
5-[(3-Fluoro-4-methoxyphenyl)sulfonyl]-2-(phenylsulfonyloxy)benzoi-
c acid, ethyl ester;
5-[(3-Hydroxy-4-methoxyphenyl)sulfonyl]-2-(phenylsulf-
onyloxy)benzoic acid, ethyl ester;
4-Trifluoromethylsulfonamido-1-[(4-meth-
oxyphenyl)sulfonyl]-3-nitrobenzene;
4-Trifluoromethylsulfonamido-1-[(3-flu-
oro-4-methoxyphenyl)sulfonyl]-3-nitrobenzene;
4-Trifluoromethylsulfonamido-
-1-[(3-hydroxy-4-methoxyphenyl)sulfonyl]-3-nitrobenzene;
4-Trifluoroacetoxy-1-[(4-methoxyphenyl)sulfonyl]-3-nitrobenzene;
4-Trifluoroacetoxy-1-[(3-fluoro-4-methoxyphenyl)sulfonyl]-3-nitrobenzene;
4-Trifluoroacetoxy-1-[(3-hydroxy-4-methoxyphenyl)sulfonyl]-3-nitrobenzene-
; 1-[(4-Methoxyphenyl)sulfonyl]-4-methylsulfonamido-3-nitrobenzene;
1-[(3-Fluoro-4-methoxyphenyl)sulfonyl]-4-methylsulfonamido-3-nitrobenzene-
;
1-[(3-Hydroxy-4-methoxyphenyl)sulfonyl]-4-methylsulfonamido-3-nitrobenze-
ne;
1-[(4-Methoxyphenyl)sulfonyl]-4-phenylsulfonamido-3-nitrobenzene;
1-[(3-Fluoro-4-methoxyphenyl)sulfonyl]-4-phenylsulfonamido-3-nitrobenzene-
; or
1-[(3-Hydroxy-4-methoxyphenyl)sulfonyl]-4-phenylsulfonamido-3-nitrobe-
nzene.
47. The compound of claim 44, wherein R.sup.2 and R.sup.4 are
independently selected from hydrogen, F, Cl, Br, OCF.sub.3 and
CF.sub.3.
48. The compound of claim 47, wherein the compound is:
2,3,5,6-Tetrafluoro-4-[(4-methoxyphenyl)sulfonyl]-1-nitrobenzene;
2,3,5,6-Tetrafluoro-4-[(3-hydroxy-4-methoxyphenyl)sulfonyl]-1-nitrobenzen-
e;
2,3,5,6-Tetrafluoro-4-[(3-fluoro-4-methoxyphenyl)sulfonyl]-1-nitrobenze-
ne;
2,3,5,6-Tetrafluoro-4-trifluoromethylsulfonamido-1-[(4-methoxyphenyl)s-
ulfonyl]benzene;
2,3,5,6-Tetrafluoro-4-trifluoromethylsulfonamido-1-[(3-fl-
uoro-4-methoxyphenyl)-sulfonyl]benzene;
2,3,5,6-Tetrafluoro-4-trifluoromet-
hylsulfonamido-1-[(3-hydroxy-4-methoxyphenyl)-sulfonyl]benzene;
2,3,5,6-Tetrafluoro-4-trifluoroacetoxy-1-[(4-methoxyphenyl)sulfonyl]benze-
ne;
2,3,5,6-Tetrafluoro-4-trifluoroacetoxy-1-[(3-fluoro-4-methoxyphenyl)su-
lfonyl]benzene;
2,3,5,6-Tetrafluoro-4-trifluoroacetoxy-1-[(3-hydroxy-4-met-
hoxyphenyl)sulfonyl]benzene;
2,3,5,6-Tetrafluoro-1-[(4-methoxyphenyl)sulfo-
nyl]-4-(methylsulfonamido)benzene;
2,3,5,6-Tetrafluoro-1-[(3-fluoro-4-meth-
oxyphenyl)sulfonyl]-4-(methylsulfonamido)benzene;
2,3,5,6-Tetrafluoro-1-[(-
3-hydroxy-4-methoxyphenyl)sulfonyl]-4-(methylsulfonamido)benzene;
2,3,5,6-Tetrafluoro-1-[(4-methoxyphenyl)sulfonyl]-4-(phenylsulfonamido)be-
nzene;
2,3,5,6-Tetrafluoro-1-[(3-fluoro-4-methoxyphenyl)sulfonyl]-4-(pheny-
lsulfonamido)benzene;
2,3,5,6-Tetrafluoro-1-[(3-hydroxy-4-methoxyphenyl)su-
lfonyl]-4-(phenylsulfonamido)benzene;
4-Azido-2,3,5,6-tetrafluoro-1-[(4-me- thoxyphenyl)sulfonyl]benzene;
4-Azido-2,3,5,6-tetrafluoro-1-[(3-hydroxy-4--
methoxyphenyl)sulfonyl]benzene; or
4-Azido-2,3,5,6-tetrafluoro-1-[(3-fluor-
o-4-methoxyphenyl)sulfonyl]benzene.
49. The compound of claim 2, wherein n=1, and there is no linking
group E.
50. The compound of claim 49, wherein the compound is:
1-Bromo-2,4,5,6-tetrafluoro-3-[(4-methoxyphenyl)sulfenyl]benzene;
2,4,5,6-Tetrafluoro-3-[(4-dimethylaminophenyl)sulfenyl]benzoic
acid, ethyl ester;
4-Fluoro-1-[(3-fluoro-4-methoxyphenyl)sulfenyl]-3-nitrobenze- ne;
2-Fluoro-5-[(4-methoxyphenyl)sulfenyl]benzonitrile;
1,3-Dichloro-2,4,6-trifluoro-5-[(3-fluoro-4-methoxyphenyl)sulfenyl]benzen-
e; 2,3,4,5,6-Pentafluoro-1-[(4-methoxyphenyl)sulfenyl]benzene;
2,3,4,5,6-Pentafluoro-1-[(3-hydroxy-methoxyphenyl)sulfenyl]benzene;
2,3,4,5,6-Pentafluoro-1-[(3-fluoro-4-methoxyphenyl)sulfenyl]benzene;
2,3,4,5,6-Pentafluoro-1-[(4-dimethylaminophenyl)sulfenyl]benzene;
or
2,3,4,5,6-Pentafluoro-1-[(3,4-dimethoxyphenyl)sulfenyl]benzene.
51. A pharmaceutical composition comprising a pharmaceutically
acceptable excipient and a compound of Formula I: 50or a
pharmaceutically acceptable salt thereof, wherein: R.sup.1,
R.sup.2, R.sup.4, and R.sup.5 are independently selected from
hydrogen, lower alkyl, halogen, OCF.sub.3, CF.sub.3, NO.sub.2,
CO.sub.2H, CN, SO.sub.2--N(R.sup.6)(R.sup.- 7), SO.sub.2--R.sup.8,
CO.sub.2--R.sup.8, and CO--R.sup.8; R.sup.3 is a leaving group; Y
is a single bond, --O--, --N(R.sup.9)--, --N(R.sup.9)--CH.sub.2--,
or --CH(R.sup.9)--; and Ar is an optionally substituted aryl or
heteroaryl group; wherein R.sup.6 and R.sup.7 are independently
chosen from hydrogen, lower alkyl, and lower heteroalkyl; R.sup.8
is selected from lower alkyl or lower heteroalkyl; and R.sup.9 is
selected from: hydrogen, substituted or unsubstituted
(C1-C10)alkyl, substituted or unsubstituted (C1-C10)alkoxy,
substituted or unsubstituted (C3-C6)alkenyl, substituted or
unsubstituted (C2-C6)heteroalkyl, substituted or unsubstituted
(C3-C6)heteroalkenyl, substituted or unsubstituted (C3-C6)alkynyl,
substituted or unsubstituted (C3-C8)cycloalkyl, substituted or
unsubstituted (C5-C7)cycloalkenyl, substituted or unsubstituted
(C5-C7)cycloalkadienyl, substituted or unsubstituted aryl,
substituted or unsubstituted aryloxy, substituted or unsubstituted
aryl-(C3-C8)cycloalkyl, substituted or unsubstituted
aryl-(C5-C7)cycloalkenyl, substituted or unsubstituted
aryloxy-(C3-C8)cycloalkyl, substituted or unsubstituted
aryl-(C1-C4)alkyl, substituted or unsubstituted aryl-(C1-C4)alkoxy,
substituted or unsubstituted aryl-(C3-C4)heteroalkyl, substituted
or unsubstituted aryl-(C3-C6)alkenyl, substituted or unsubstituted
aryloxy-(C1-C4)alkyl, substituted or unsubstituted
aryloxy-(C2-C4)heteroalkyl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted heteroaryloxy, substituted
or unsubstituted heteroaryl-(C1-C4)alkyl, substituted or
unsubstituted heteroaryl-(C1-C4)alkoxy, substituted or
unsubstituted heteroaryl-(C1-C4)heteroalkyl, substituted or
unsubstituted heteroaryl-(C3-C6)alkenyl, substituted or
unsubstituted heteroaryloxy-(C1-C4)alkyl, and substituted or
unsubstituted heteroaryloxy-(C2-C4)heteroalkyl, wherein, if Y is
--N(R.sup.9)--, then R.sup.9 and Ar may be connected by a linking
group E to give a to substituent of the Formula 51wherein E
represents a bond, (C1-C4) alkylene, or (C1-C4) heteroalkylene, and
the ring formed by R.sup.9, E, Ar and the nitrogen atom contains no
more than 8 atoms, or preferably R.sup.9 and Ar may be covalently
joined in a moiety that forms a 5- or 6-membered heterocyclic ring
with the nitrogen atom; with the following provisos: At least one
of the R.sup.1, R.sup.2, R.sup.4, and R.sup.5 groups is other than
hydrogen or lower alkyl; When
R.sup.1=R.sup.2=R.sup.3=R.sup.4=R.sup.5=F, then Y is a single bond
or --CH(R.sup.9)--; When
R.sup.1=R.sup.2=R.sup.3=R.sup.4=R.sup.5=Cl, n=2, and Y=--NH--, then
Ar is other than unsubstituted phenyl or unsubstituted p-biphenyl;
When R.sup.1=R.sup.2=R.sup.3=R.sup.4=R.sup.5Br, n=2, and Y=--NH--,
then Ar is other than unsubstituted phenyl; When R.sup.3=halogen,
n=2, Y=--N(R.sup.9)--, and at least one of R.sup.1, R.sup.2,
R.sup.4 and R.sup.5 is also halogen, then at least one of R.sup.1,
R.sup.2, R.sup.4 and R.sup.5 must be other than hydrogen; When
R.sup.1=H, n=2, and Y=--NH--, then at least one of R.sup.2,
R.sup.3, R.sup.4 and R.sup.5 must be other than chloro; When
R.sup.1=R.sup.5=H, n=2, and Y=--N(R.sup.9)--, then at least one of
R.sup.2, R.sup.3, and R.sup.4 must be a substituent other than
chloro; When R.sup.1=R.sup.3=R.sup.5=Cl, Y=--NH--, and R.sup.9=H or
methyl, then Ar is a phenyl ring substituted by 1-4 groups chosen
independently from halogen, OH, OR', NH.sub.2, NHR', and NR'R";
When R.sup.1=R.sup.3=Cl and Y=--N(R.sup.9)--, then R.sup.2 and
R.sup.4 must both be other than chloro; and When R.sup.2=CF.sub.3,
R.sup.3=Cl, and Y=--N(R.sup.9)--, then Ar cannot be either a phenyl
ring substituted by trifluoromethyl, nitro, chloro, or lower-alkyl
groups, or a 2-benzothiazolyl ring.; wherein said compound has
pharmacological activity.
52. The composition of claim 51, wherein R.sup.3 is halogen,
NO.sub.2, OCF.sub.3, S(O)--Ar, SO.sub.2--R.sup.8, SO.sub.2--Ar,
N.sub.3, N(.sup.6)--SO.sub.2--CF.sub.3,
N(R.sup.6)--SO.sub.2--R.sup.8, N(R.sup.6)--SO.sub.2--Ar,
N(R.sup.6)--CO--(R.sup.8), N(R.sup.6)--CO--Ar,
N[CO--R.sup.8].sub.2, N(R.sup.8).sub.3.sup.+,
N(R.sup.8).sub.2(Ar).sup.+, O--SO.sub.2--Ar, O--SO.sub.2--R.sup.8,
O--CO--R.sup.8, O--CO--Ar, O--Ar, O--R.sup.8, or
O--CO--CF.sub.3.
53. The composition of claim 52, wherein n=2, there is no linking
group E, and R.sup.1, R.sup.2, R.sup.4 and R.sup.5 are
independently selected from hydrogen, F, Cl, Br, OCF.sub.3,
CF.sub.3,, SO.sub.2--R.sup.8, NO.sub.2, CN, CO.sub.2--R.sup.8, and
SO.sub.2--N(R.sup.6)(R.sup.7).
54. The composition of claim 53, wherein R.sup.2 and R.sup.4 are
independently selected from hydrogen, F, Cl, Br, OCF.sub.3,
CF.sub.3, NO.sub.2, CN, and CO.sub.2--R.sup.8.
55. The composition of claim 54, wherein Y is --N(R.sup.9)--, and
R.sup.6, R.sup.7 and R.sup.9 are independently chosen from
hydrogen, lower alkyl and lower heteroalkyl.
56. The composition of claim 55, wherein R.sup.3 is halogen,
OCF.sub.3, NO.sub.2, N.sub.3, O--SO.sub.2--Ar,
O--SO.sub.2--R.sup.8, or SO.sub.2--Ar.
57. The composition of claim 56, wherein R.sup.3 is F, Cl, Br, or
OCF.sub.3.
58. The composition of claim 57, wherein R.sup.3 is F.
59. The composition of claim 58, wherein R.sup.2 is selected from
NO.sub.2, CN, and CO.sub.2--R.sup.8; and R.sup.4 is selected from
hydrogen, F, Cl, Br, OCF.sub.3, CF.sub.3, NO.sub.2, CN, and
CO.sub.2--R.sup.8.
60. The composition of claim 59, wherein the compound is:
4-Fluoro-1-[(4-methoxyphenyl)aminosulfonyl]-3-nitrobenzene;
4-Fluoro-1-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]-3-nitrobenzene;
4-Fluoro-1-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]-3-nitrobenzene;
4-Fluoro-1-[(3,4-dimethoxyphenyl)aminosulfonyl]-3-nitrobenzene;
4-Fluoro-1-[(4-aminophenyl)aminosulfonyl]-3-nitrobenzene;
2-Fluoro-5-[(4-methoxyphenyl)aminosulfonyl]benzonitrile;
2-Fluoro-5-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzonitrile;
2-Fluoro-5-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzonitrile;
2-Fluoro-5-[(3,4-dimethoxyphenyl)aminosulfonyl]benzonitrile;
2-Fluoro-5-[(4-dimethylaminophenyl)aminosulfonyl]benzonitrile;
4,5-Difluoro-5-[(4-dimethoxyphenyl)aminosulfonyl]-3-nitrobenzene;
4,5-Difluoro-1-[(3-fluoro-methoxyphenyl)aminosulfonyl]-3-nitrobenzene;
4,5-Difluoro-1-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]-3-nitrobenzene;
4,5-Difluoro-1-[(3,4-dimethoxyphenyl)aminosulfonyl]-3-nitrobenzene;
4,5-Difluoro-1-[(4-dimethylaminophenyl)aminosulfonyl]-3-nitrobenzene;
2,3,4-Trifluoro-5-[(4-methoxyphenyl)aminosulfonyl]benzoic acid,
ethyl ester;
2,3,4-Trifluoro-5-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzoic
acid, ethyl ester;
2,3,4-Trifluoro-5-[(3-hydroxy-4-methoxyphenyl)aminosul-
fonyl]benzoic acid, ethyl ester;
2,4,5,6-Tetrafluoro-3-[(4-methoxyphenyl)a- minosulfonyl]benzoic
acid, ethyl ester; 2,4,5,6-Tetrafluoro-3-[(3-fluoro-4-
-methoxyphenyl)aminosulfonyl]benzoic acid, ethyl ester; or
2,4,5,6-Tetrafluoro-3-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzoic
acid, ethyl ester.
61. The composition of claim 60, wherein the compound is:
4-Fluoro-1-[(4-methoxyphenyl)aminosulfonyl]-3-nitrobenzene;
4-Fluoro-1-[(3-hydroxylmethoxyphenyl)aminosulfonyl]-3-nitrobenzene;
4-Fluoro-1-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]-3-nitrobenzene;
4-Fluoro-1-[(3,4-dimethoxyphenyl)aminosulfonyl]-3-nitrobenzene; or
4-Fluoro-1-[(4-dimethylaminophenyl)aminosulfonyl]-3-nitrobenzene;
62. The composition of claim 58, wherein R.sup.2 and R.sup.4 are
independently selected from hydrogen, F, Cl, Br, OCF.sub.3 and
CF.sub.3.
63. The composition of claim 62, wherein the compound is:
1-Bromo-3,4,5,6-tetrafluoro-2-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]b-
enzene;
1-Bromo-3,4,5,6-tetrafluoro-2-[(4-methoxyphenyl)aminosulfonyl)]ben-
zene;
1-Bromo-3,4,5,6-tetrafluoro-2-[(3-fluoro-4-methoxyphenyl)aminosulfon-
yl]benzene;
1-Bromo-2,4,5,6-tetrafluoro-3-[(4-methoxyphenyl)aminosulfonyl)-
]benzene;
1-Bromo-2,4,5,6-tetrafluoro-3-[(3-hydroxy-4-methoxyphenyl)aminos-
ulfonyl]benzene;
1-Bromo-2,4,5,6-tetrafluoro-3-[(3-fluoro-4-methoxyphenyl)-
aminosulfonyl]benzene;
1-Bromo-2,4,5,6-tetrafluoro-3-[(3,4-dimethoxyphenyl-
)aminosulfonyl]benzene;
1-Bromo-2,4,5,6-tetrafluoro-3-[(4-dimethylaminophe-
nyl)aminosulfonyl]benzene;
1,3-Dichloro-2,4,6-trifluoro-5-[(4-methoxypheny-
l)aminosulfonyl]benzene;
1,3-Dichloro-2,4,6-trifluoro-5-[(3-fluoro-4-metho-
xyphenyl)aminosulfonyl]benzene;
1,3-Dichloro-2,4,6-trifluoro-5-[(3-hydroxy-
-4-methoxyphenyl)aminosulfonyl]benzene;
1-Bromo-4,5,6-trifluoro-2-[(4-meth-
oxyphenyl)aminosulfonyl]benzene; 1-Bromo-4,5,6-trifluoro
-2-[(3-hydroxy-4methoxyphenyl)aminosulfonyl]benzene;
1-Bromo-4,5,6-trifluoro-2-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzen-
e;
1-Bromo-4,5,6-trifluoro-2-[(3,4-dimethoxyphenyl)aminosulfonyl]benzene;
1-Bromo-2,3,4-trifluoro-2-[(3-hydroxy-4methoxyphenyl)aminosulfonyl]benzen-
e;
1-Bromo-2,3,4-trifluoro-5-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benz-
ene;
1-Bromo-2,3,4-trifluoro-5-[(4-methoxyphenyl)aminosulfonyl]benzene;
1-Bromo-2,3,4-trifluoro-5-[(3,4-dimethoxyphenyl)aminosulfonyl]benzene;
1-Bromo-3,4,5-trifluoro-2-[(3-hydroxylmethoxyphenyl)aminosulfonyl]benzene-
;
1-Bromo-3,4,5-trifluoro-2-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benze-
ne;
1-Bromo-3,4,5-trifluoro-2-[(4-methoxyphenyl)aminosulfonyl]benzene;
3,4,6-Trifluoro-1-[(4-methoxyphenyl)aminosulfonyl]benzene;
3,4,6-Trifluoro-1-[(3-fluoromethoxyphenyl)aminosulfonyl]benzene;
3,4,6-Trifluoro-1-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzene;
2,3,4,6-Tetrafluoro-1-[(4-methoxyphenyl)aminosulfonyl]benzene;
2,3,4,6-Tetrafluoro-1-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzene;
2,3,4,6-Tetrafluoro-1-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzene;
2,3,4,5-Tetrafluoro-1-[(4-methoxyphenyl)aminosulfonyl]benzene;
2,3,4,5-Tetrafluoro-1-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzene;
2,3,4,5-Tetrafluoro-1-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzene;
2,3,4,5-Tetrafluoro-1-[(3,4-dimethoxyphenyl)aminosulfonyl]benzene;
2,3,4,5-Tetrafluoro-1-[(4-dimethylaminophenyl)aminosulfonyl]benzene;
3,4,5-Trifluoro-1-[(4-methoxyphenyl)aminosulfonyl]benzene;
3,4,5-Trifluoro-1-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzene;
3,4,5-Trifluoro-1-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzene;
3,4,5-Trifluoro-1-[(3,4-dimethoxyphenyl)aminosulfonyl]benzene; or
3,4,5-Trifluoro-1-[(4-dimethylaminophenyl)aminosulfonyl]benzene.
64. The composition of claim 63, wherein the compound is:
1-Bromo-3,4,5,6-tetrafluoro-2-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]b-
enzene;
1-Bromo-3,4,5,6-tetrafluoro-2-[(4-methoxyphenyl)aminosulfonyl)]ben-
zene;
1-Bromo-2,4,5,6-tetrafluoro-3-[(4-methoxyphenyl)aminosulfonyl)]benze-
ne;
1,3-Dichloro-2,4,6-trifluoro-5-[(4-methoxyphenyl)aminosulfonyl]benzene-
;
1,3-Dichloro-2,4,6-trifluoro-5-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl-
]benzene;
1-Bromo-4,5,6-trifluoro-2-[(4-methoxyphenyl)aminosulfonyl]benzen-
e;
1-Bromo-2,3,4-trifluoro-5-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]ben-
zene;
1-Bromo-4,5,6-trifluoro-2-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]-
benzene;
1-Bromo-3,4,5-trifluoro-2-[(3-hydroxy-4-methoxyphenyl)aminosulfon-
yl]benzene; or
1-Bromo-3,4,5-trifluoro-2-[(3-fluoro-4-methoxyphenyl)aminos-
ulfonyl]benzene;
65. The composition of claim 63, wherein the compound is:
2,3,4,6-Tetrafluoro-1-[(4-methoxyphenyl)aminosulfonyl]benzene;
2,3,4,5-Tetrafluoro-1-[(4-methoxyphenyl)aminosulfonyl]benzene;
2,3,4,5-Tetrafluoro-:-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzene;
2,3,4,5-Tetrafluoro-1-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzene;
3,4,5-Trifluoro-1-[(4-methoxyphenyl)aminosulfonyl]benzene;
3,4,5-Trifluoro-1-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzene;
or
3,4,5-Trifluoro-1-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzene;
66. The composition of claim 57, wherein R.sup.3 is Cl; R.sup.2is
selected from NO.sub.2, CN, ad CO.sub.2--R.sup.8; and R.sup.4 is
selected from hydrogen, F, Cl, Br, OCF.sub.3, CF.sub.3, NO.sub.2,
CN, and CO.sub.2--R.sup.8.
67. The composition of claim 66, wherein the compound is:
1-Chloro-4-[(4-methoxyphenyl)aminosulfonyl]-2-nitrobenzene;
1-Chloro-4-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]-2-nitrobenzene;
1-Chloro-4-[(3-hydroxy
4-methoxyphenyl)aminosulfonyl]-2-nitrobenzene;
1-Chloro-4-[(3,4-dimethoxyphenyl)aminosulfonyl]-2-nitrobenzene;
1-Chloro-4-[(4-dimethylaminophenyl)aminosulfonyl]-2-nitrobenzene;
2-Chloro-5-[(4methoxyphenyl)aminosulfonyl]benzonitrile;
2-Chloro-5-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzonitrile;
2-Chloro-5-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzonitrile;
2-Chloro-5-[(3,4-dimethoxyphenyl)aminosulfonyl]benzonitrile; or
2-Chloro-5-[(4-methylaminophenyl)aminosulfonyl]benzonitrile.
68. The composition of claim 57, wherein R.sup.3 is Cl; and R.sup.2
and R.sup.4 are independently selected from hydrogen, F, Cl, Br,
OCF.sub.3 and CF.sub.3.
69. The composition of claim 68, wherein the compound is:
1-Chloro-2,3,5,6-tetrafluoro-4-[(4-methoxyphenyl)aminosulfonyl]benzene;
1-Chloro-2,3,5,6-tetrafluoro-4-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]-
benzene;
1-Chloro-2,3,5,6-tetrafluoro-4-[(3-fluoro-4-methoxyphenyl)aminosu-
lfonyl]benzene;
1-Chloro-2,3,5,6-tetrafluoro-4-[(4-dimethylaminophenyl)ami-
nosulfonyl]benzene;
1-Chloro-2,3,5,6-tetrafluoro-4-[(3,4-dimethoxyphenyl)a-
minosulfonyl]benzene;
1-Chloro-2,3,6-trifluoro-4-[(4-methoxyphenyl)aminosu-
lfonyl]benzene;
1-Chloro-2,3,6-trifluoro-4-[(3-hydroxy-4-methoxyphenyl)ami-
nosulfonyl]benzene;
1-Chloro-2,3,6-trifluoro-4-[(3-fluoro-4-methoxyphenyl)-
aminosulfonyl]benzene;
1-Chloro-2,3,6-trifluoro-4-[(4-dimethylaminophenyl)-
aminosulfonyl]benzene; or
1-Chloro-2,3,6-trifluoro-4-[(3,4-dimethoxyphenyl-
)aminosulfonyl]benzene.
70. The composition of claim 57, wherein R.sup.3 is Br; R.sup.2 is
selected from NO.sub.2, CN, and CO.sub.2--R.sup.8 and R.sup.4 is
selected from hydrogen, F, Cl, Br, OCF.sub.3, CF.sub.3, NO.sub.2,
CN, and CO.sub.2--R.sup.8.
71. The composition of claim 70, wherein the compound is:
1-Bromo-4-[(4-methoxyphenyl)aminosulfonyl]-2-nitrobenzene; 1-Bromo
-4-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]-2-nitrobenzene;
1-Bromo
-4-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]-2-nitrobenzene;
1-Bromo -4-[(3,4-dimethoxyphenyl)aminosulfonyl]-2-nitrobenzene;
1-Bromo -4-[(4-dimethylaminophenyl)aminosulfonyl]-2-nitrobenzene;
2-Bromo -5-[(4-methoxyphenyl)aminosulfonyl]benzonitrile; 2-Bromo
-5-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzonitrile; 2-Bromo
-5-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzonitrile; 2-Bromo
-5-[(3,4-dimethoxyphenyl)aminosulfonyl]benzonitrile; or 2-Bromo
-5-[(4-dimethylaminophenyl)aminosulfonyl]benzonitrile.
72. The composition of claim 57, wherein R.sup.3 is Br; and R.sup.2
and R.sup.4 are independently selected from hydrogen, F, Cl, Br,
OCF.sub.3 and CF.sub.3.
73. The composition of claim 72, wherein the compound is:
1-Bromo-2,3,5,6-tetrafluoro-4-[(4-methoxyphenyl)aminosulfonyl]benzene;
1-Bromo-2,3,5,6-tetrafluoro-4-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]b-
enzene;
1-Bromo-2,3,5,6-tetrafluoro-4-[(3-fluoro-4-methoxyphenyl)aminosulf-
onyl]benzene;
1-Bromo-2,3,5,6-tetrafluoro-4-[(4-dimethylaminophenyl)aminos-
ulfonyl]benzene;
1-Bromo-2,3,5,6-tetrafluoro-4-[(3,4-dimethoxyphenyl)amino-
sulfonyl]benzene; 1-Bromo-2,3,6-trifluoro-4-[(4-methoxy
phenyl)aminosulfonyl]benzene;
1-Bromo-2,3,6-trifluoro-4-[(3-hydroxy-4-met-
hoxyphenyl=)aminosulfonyl]benzene;
1-Bromo-2,3,6-trifluoro-4-[(3-fluoro-4--
methoxyphenyl)aminosulfonyl]benzene;
1-Bromo-2,3,6-trifluoro-4-[(4-dimethy-
laminophenyl)aminosulfonyl]benzene; or
1-Bromo-2,3,6-trifluoro-4-[(3,4-dim-
ethoxyphenyl)aminosulfonyl]benzene.
74. The composition of claim 57, wherein R.sup.3 is OCF.sub.3;
R.sup.2 is selected from NO.sub.2, CN, and CO.sub.2--R.sup.8; and
R.sup.4 is selected from hydrogen, F, Cl, Br, OCF.sub.3, CF.sub.3,
NO.sub.2, CN, and CO.sub.2--R.sup.8.
75. The composition of claim 74, wherein the compound is:
4-Trifluoromethoxy-1-[(4-methoxyphenyl)aminosulfonyl]-3-nitrobenzene;
4-Trifluoromethoxy-1-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]-3-nitroben-
zene;
4-Trifluoromethoxy-1-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]-3-ni-
trobenzene;
4-Trifluoromethoxy-1-[(3,4-dimethoxyphenyl)aminosulfonyl]-3-ni-
trobenzene;
4-Trifluoromethoxy-1-[(4-dimethylaminophenyl)aminosulfonyl]-3--
nitrobenzene;
2-Trifluoromethoxy-5-[(4-methoxyphenyl)aminosulfonyl]benzoni-
trile;
2-Trifluoromethoxy-5-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzo-
nitrile;
2-Trifluoromethoxy-5-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]be-
nzonitrile.
2-Trifluoromethoxy-5-[(3,4-dimethoxyphenyl)aminosulfonyl]benzo-
nitrile;
2-Trifluoromethoxy-5-[(4-dimethylaminophenyl)aminosulfonyl]benzon-
itrile;
2-Trifluoromethoxy-5-[(4-methoxyphenyl)aminosulfonyl]benzoic acid,
ethyl ester;
2-Trifluoromethoxy-5-[(3-fluoro-4-methoxyphenyl)aminosulfony-
l]benzoic acid, ethyl ester;
2-Trifluoromethoxy-5-[(3-hydroxy-4-methoxyphe-
nyl)aminosulfonyl]benzoic acid, ethyl ester;
2-Trifluoromethoxy-5-[(3,4-di- methoxyphenyl)aminosulfonyl]benzoic
acid, ethyl ester; or
2-Trifluoromethoxy-5-[(4-dimethylaminophenyl)aminosulfonyl]benzoic
acid, ethyl ester.
76. The composition of claim 57, wherein R.sup.3 is OCF.sub.3; and
R.sup.2 and R.sup.4 are independently selected from hydrogen, F,
Cl, Br, OCF.sub.3 and CF.sub.3.
77. The composition of claim 76, wherein the compound is:
2,3,5,6-Tetrafluoro-1-trifluoromethoxy-4-[(4-methoxyphenyl)aminosulfonyl]-
benzene;
2,3,5,6-Tetrafluoro-1-trifluoromethoxy-4-[(3-hydroxy-4-methoxyphe-
nyl)aminosulfonyl]benzene;
2,3,5,6-Tetrafluoro-1-trifluoromethoxy-4-[(3-fl-
uoro-4-methoxyphenyl)aminosulfonyl]benzene;
2,3,5,6-Tetrafluoro-1-trifluor-
omethoxy-4-[(4-dimethylaminophenyl)aminosulfonyl]benzene;
2,3,5,6-Tetrafluoro-1-trifluoromethoxy-4-[(3,4-dimethoxyphenyl)aminosulfo-
nyl]benzene;
2,3,6-Trifluoro-1-trifluoromethoxy-4-[(4-methoxyphenyl)aminos-
ulfonyl]benzene;
2,3,6-Trifluoro-1-trifluoromethoxy-4-[(3-hydroxy-4-methox-
yphenyl)aminosulfonyl]benzene; 5
2,3,6-Trifluoro-1-trifluoromethoxy-4-[(3--
fluoro-4-methoxyphenyl)aminosulfonyl]benzene;
2,3,6-Trifluoro-1-trifluorom-
ethoxy-4-[(4-dimethylaminophenyl)aminosulfonyl]benzene; or
2,3,6-Trifluoro-1-trifluoromethoxy-4-[(3,4-dimethoxyphenyl)aminosulfonyl]-
benzene.
78. The composition of claim 56, wherein R.sup.3 is selected from
NO.sub.2, N.sub.3, O--SO.sub.2--Ar, O--SO.sub.2--R.sup.8 and
SO.sub.2--Ar.
79. The composition of claim 78, wherein the compound is:
1-[(4-Methoxyphenyl)aminosulfonyl]-3,4-dinitrobenzene;
1-[(3-Fluoro-4-methoxyphenyl)aminosulfonyl]-3,4-dinitrobenzene;
1-[(3-Hydroxy-4-methoxyphenyl)aminosulfonyl]-3,4-dinitrobenzene;
4-Azido-1-[(3,4-dimethoxyphenyl)aminosulfonyl]-3-nitrobenzene;
4-Azido-1-[(4-aminophenyl)aminosulfonyl]-3-nitrobenzene;
4-Azido-1-[(4-methoxyphenyl)aminosulfonyl]-3-nitrobenzene;
4-Azido-1-[(3-hydroxy.-methoxyphenyl)aminosulfonyl]-3-nitrobenzene;
4-Azido-1-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]-3-nitrobenzene;
2-Azido-5-[(4-methoxyphenyl)aminosulfonyl]benzonitrile;
2-Azido-5-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzonitrile;
2-Azido-5-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzonitrile.
2-Azido-5-[(3,4-dimethoxyphenyl)aminosulfonyl]benzonitrile;
2-Azido-5-[(4-di methylaminophenyl)aminosulfonyl]benzonitrile;
5-[(4-Methoxyphenyl)aminosulfonyl]-2-phenylsulfonylbenzonitrile;
5-[(3-Fluoro-4-methoxyphenyl)aminosulfonyl]-2-phenylsulfonylbenzonitrile;
5-[(3-Hydroxy-4-methoxyphenyl)aminosulfonyl]-2-phenylsulfonylbenzonitrile-
.
5-[(3,4-Dimethoxyphenyl)aminosulfonyl]-2-phenylsulfonylbenzonitrile;
5-[(4-Dimethylaminophenyl)aminosulfonyl]-2-phenylsulfonylbenzonitrile;
5-[(4-Methoxyphenyl)aminosulfonyl]-2-phenylsulfonyloxybenzoic acid,
ethyl ester;
5-[(3-Fluoro-4-methoxyphenyl)aminosulfonyl]-2-phenylsulfonyloxyben-
zoic acid, ethyl ester;
5-[(3-Hydroxy-4methoxyphenyl)aminosulfonyl]-2-phen-
ylsulfonyloxybenzoic acid, ethyl ester;
5-[(3,4-Dimethoxyphenyl)aminosulfo- nyl]-2-phenylsulfonyloxybenzoic
acid, ethyl ester; 5-[(4-Dimethylaminophen-
yl)aminosulfonyl]-2-phenylsulfonyloxybenzoic acid, ethyl ester.
2,3,5,6-Tetrafluoro-1-[(4-methoxyphenyl)aminosulfonyl]4-nitrobenzene;
2,3,5,6-Tetrafluoro-1-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]4-nitrobe-
nzene;
2,3,5,6-Tetrafluoro-1-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]4-ni-
trobenzene;
2,3,5,6-Tetrafluoro-1-[(4-dimethylaminophenyl)aminosulfonyl]4--
nitrobenzene;
2,3,5,6-Tetrafluoro-1-[(3,4-dimethoxyphenyl)aminosulfonyl]ni-
trobenzene;
4-Azido-2,3,6-trifluoro-1-[(4-methoxyphenyl)aminosulfonyl]benz-
ene;
4-Azido-2,3,6-trifluoro-1-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]b-
enzene;
4-Azido-2,3,6-trifluoro-1-[(3-fluoro-4-methoxyphenyl)aminosulfonyl-
]benzene;
4-Azido-2,3,6-trifluoro-1-[(4-dimethylaminophenyl)aminosulfonyl]-
benzene; or
4-Azido-2,3,6-trifluoro-1-[(3,4-dimethoxyphenyl)aminosulfonyl]-
benzene.
80. The composition of claim 55, wherein R.sup.3 is selected from
N(R.sup.6)--SO.sub.2--CF.sub.3, N(R.sup.6)--SO.sub.2--R.sup.8,
N(R.sup.6)--SO.sub.2--Ar, N(R.sup.6)--CO--R.sup.8,
N(R.sup.6)--CO--Ar, N[CO--R.sup.8].sub.2, or O--CO--CF.sub.3.
81. The composition of claim 80, wherein the compound is:
4-Trifluoromethylsulfonamido-1-[(4-methoxyphenyl)aminosulfonyl]-3-nitrobe-
nzene;
1-[(3-Fluoro-4-methoxyphenyl)aminosulfonyl]-4-fluoromethylsulfonami-
do-3-nitrobenzene;
4-Trifluoromethylsulfonamido-1-[(3-hydroxy-4-methoxyphe-
nyl)aminosulfonyl]-3-nitrobenzene;
2,3,5,6-Tetrafluoro-4-trifluoromethylsu-
lfonamido-1-[(4-methoxyphenyl)aminosulfonyl]benzene;
2,3,5,6-Tetrafluoro-1-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]-4-trifluo-
romethylsulfonamidobenzene;
2,3,5,6-Tetrafluoro-4-trifluoromethylsulfonami-
do-1-[(3-hydroxy-4-methoxyphenyl)-aminosulfonyl]benzene;
4-(Diacetylamino)-2,3-difluoro-1-[(3-fluoro-4-methoxyphenyl)aminosulfonyl-
]-5-nitrobenzene; 4-Trifluoroacetoxy-l
-[(4-methoxyphenyl)aminosulfonyl]-3- -nitrobenzene;
4-Trifluoroacetoxy-1-[(3-fluoro-4-methoxyphenyl)aminosulfon-
yl]-3-nitrobenzene;
4-Trifluoroacetoxy-1-[(3-hydroxy-4-methoxyphenyl)amino-
sulfonyl]-3-nitrobenzene;
2,3,5,6-Tetrafluoro-4-trifluoroacetoxy-1-[(4-met-
hoxyphenyl)aminosulfonyl]benzene;
2,3,5,6-Tetrafluoro-4-trifluoroacetoxy-1-
-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzene;
2,3,5,6-Tetrafluoro-4-t-
rifluoroacetoxy-1-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzene;
1-[(4-Methoxyphenyl)aminosulfonyl]4-methylsulfonamido-3-nitrobenzene;
1-[(3-Fluoro-4-methoxyphenyl)aminosulfonyl]4-methylsulfonamido-3-nitroben-
zene;
1-[(3-Hydroxy-4-methoxyphenyl)aminosulfonyl]-4-methylsulfonamido-3-n-
itrobenzene;
2,3,5,6-Tetrafluoro-1-[(4-methoxyphenyl)aminosulfonyl]-4-meth-
ylsulfonamidobenzene;
2,3,5,6-Tetrafluoro-1-[(3-fluoro-4-methoxyphenyl)ami-
nosulfonyl]-4-methylsulfonamido-benzene;
2,3,5,6-Tetrafluoro-1-[(3-hydroxy-
-4-methoxyphenyl)aminosulfonyl]-4-methylsulfonamido-benzene;
1-[(4-Methoxyphenyl)aminosulfonyl]-3-nitro4-phenylsulfonamidobenzene;
1-[(3-Fluoro-4-methoxyphenyl)aminosulfonyl]-3-nitro-4-phenylsulfonamidobe-
nzene;
1-[(3-Hydroxy-4-methoxyphenyl)aminosulfonyl]-3-nitro-4-phenylsulfon-
amidobenzene;
2,3,5,6-Tetrafluoro-1-[(4-methoxyphenyl)aminosulfonyl]-4-phe-
nylsulfonamidobenzene;
2,3,5,6-Tetrafluoro-1-[(3-fluoro-4-methoxyphenyl)am-
inosulfonyl]-4-phenylsulfonamidobenzene; or
2,3,5,6-Tetrafluoro-1-[(3-hydr-
oxy-4-methoxyphenyl)aminosulfonyl]-4-phenylsulfonamido-benzene.
82. The composition of claim 54, wherein Y is a single bond or
--CH(R.sup.9)--.
83. The composition of claim 82, wherein R.sup.3 is selected from
F, Cl, Br, and OCF.sub.3.
84. The composition of claim 83, wherein R.sup.2 is selected from
NO.sub.2, CN, and CO.sub.2--R.sup.8; and R.sup.4 is selected from
hydrogen, F, Cl, Br, OCF.sub.3, CF.sub.3, NO.sub.2, CN, and
CO.sub.2--R.sup.8.
85. The composition of claim 84, wherein the compound is:
4-Fluoro-1-[(4-methoxyphenyl)methylsulfonyl]-3-nitrobenzene;
4-Fluoro-1-[(3-hydroxy-4-methoxyphenyl)methylsulfonyl]-3-nitrobenzene;
4-Fluoro-1-[(3-fluoro-4methoxyphenyl)methylsulfonyl]-3-nitrobenzene;
4-Fluoro-1-[(4-methoxyphenyl)sulfonyl]-3-nitrobenzene;
4-Fluoro-1-[(3-hydroxy-4-methoxyphenyl)sulfonyl]-3-nitrobenzene;
4-Fluoro-1-[(3-fluoro-4-methoxyphenyl)sulfonyl]-3-nitrobenzene;
2-Fluoro-5-[(4-methoxyphenyl)sulfonyl]benzonitrile;
2-Fluoro-5-[(3-hydroxy-4-methoxyphenyl)sulfonyl]benzonitrile;
2-Fluoro-5-[(3-fluoro-4-methoxyphenyl)sulfonyl]benzonitrile;
2-Fluoro-5-[(4-methoxyphenyl)methylsulfonyl]benzonitrile;
2-Fluoro-5-[(3-hydroxy-4-methoxyphenyl)methylsulfonyl]benzonitrile;
2-Fluoro-5-[(3-fluoro-4-methoxyphenyl)methylsulfonyl]benzonitrile;
2,3,4-Trifluoro-5-[(4-methoxyphenyl)sulfonyl]benzoic acid, ethyl
ester;
2,3,4-Trifluoro-5-[(3-fluoro-4-methoxyphenyl)sulfonyl]benzoic acid,
ethyl ester;
2,3,4-Trifluoro-5-[(3-hydroxy-4-methoxyphenyl)sulfonyl]benzoic
acid, ethyl ester;
1-Chloro-4-[(4-methoxyphenyl)methylsulfonyl]-2-nitrobe- nzene;
1-Chloro-4-[(4-dimethylaminophenyl)methylsulfonyl]-2-nitrobenzene;
1-Chloro-4-[(4-methoxyphenyl)sulfonyl]-2-nitrobenzene; or
1-Chloro-4-[(4-dimethylaminophenyl)sulfonyl]-2-nitrobenzene;
86. The composition of claim 83, wherein R.sup.2 and R.sup.4 are
independently selected from hydrogen, F, Cl, Br, OCF.sub.3 and
CF.sub.3.
87. The composition of claim 86, wherein the compound is:
1-Bromo-3,4,5,.sup.6-tetrafluoro-2-[(3-hydroxy-4-methoxyphenyl)sulfonyl]b-
enzene;
1-Bromo-3,4,5,6-tetrafluoro-2-[(4-methoxyphenyl)sulfonyl)]benzene;
1-Bromo-3,4,5,6-tetrafluoro-2-[(3-fluoro-4-methoxyphenyl)sulfonyl]benzene-
;
1-Bromo-2,4,5,6-tetrafluoro-3-[(4-methoxyphenyl)sulfonyl)]benzene;
1-Bromo-2,4,5,6-tetrafluoro-3-[(3-hydroxy-4-methoxyphenyl)sulfonyl]benzen-
e;
1-Bromo-2,4,5,6-tetrafluoro-3-[(3-fluoro-4-methoxyphenyl)sulfonyl]benze-
ne;
1,3-Dichloro-2,4,6-trifluoro-5-[(4-methoxyphenyl)sulfonyl]benzene;
1,3-Dichloro-2,4,6-trifluoro-5-[(3-fluoro-4-methoxyphenyl)sulfonyl]benzen-
e;
1,3-Dichloro-2,4,6-trifluoro-5-[(3-hydroxy-4-methoxyphenyl)sulfonyl]ben-
zene; 1-Bromo-4,5,6-trifluoro-2-[(4-methoxyphenyl)sulfonyl]benzene;
1-Bromo-4,5,6-trifluoro-2-[(3-hydroxy-4-methoxyphenyl)sulfonyl]benzene;
1-Bromo-4,5,6-trifluoro-2-[(3-fluoro-4-methoxyphenyl)sulfonyl]benzene;
2,3,4,5-Tetrafluoro-1-[(4-methoxyphenyl)sulfonyl]benzene;
2,3,4,5-Tetrafluoro-1-[(3-hydroxy-4-methoxyphenyl)sulfonyl]benzene;
2,3,4,5-Tetrafluoro-1-[(3-fluoro-4-methoxyphenyl)sulfonyl]benzene;
2,3,4,5-Tetrafluoro-1-[(3,4-dimethoxyphenyl)sulfonyl]benzene;
2,3,4,5-Tetrafluoro-1-[(4-dimethylaminophenyl)sulfonyl]benzene;
3,4,5-Trifluoro-1-[(4-methoxyphenyl)sulfonyl]benzene;
3,4,5-Trifluoro-1-[(3-hydroxy-4-methoxyphenyl)sulfonyl]benzene;
3,4,5-Trifluoro-1-[(3-fluoro-4-methoxyphenyl)sulfonyl]benzene;
3,4,5-Trifluoro-1-[(3,4-methoxyphenyl)sulfonyl]benzene;
3,4,5-Trifluoro-1-[(4-dimethylaminophenyl)sulfonyl]benzene;
1-Chloro-2,3,5,6-tetrafluoro-4-[(4-methoxyphenyl)sulfonyl]benzene;
1-Chloro-2,3,5,6-tetrafluoro-4-[(3-hydroxy-4-methoxyphenyl)sulfonyl]benze-
ne;
1-Chloro-2,3,5,6-tetrafluoro-4-[(3-fluoro-4-methoxyphenyl)sulfonyl]ben-
zene;
1-Bromo-2,3,5,6-tetrafluoro-4-[(4-methoxyphenyl)sulfonyl]benzene;
1-Bromo-2,3,5,6-tetrafluoro-4-[(3-hydroxy-4-methoxyphenyl)sulfonyl]benzen-
e;
1-Bromo-2,3,5,6-tetrafluoro-4-[(3-fluoro-4-methoxyphenyl)sulfonyl]benze-
ne;
1-Bromo-2,3,5,6tetrafluoro-4-[(4-dimethylaminophenyl)sulfonyl]benzene;
1-Bromo-2,3,5,6-tetrafluoro-4-[(3,4-dimethoxyphenyl)sulfonyl]benzene;
2,3,4,5,6-Pentafluoro-1-[(4-methoxyphenyl)sulfonyl]benzene;
2,3,4,5,6-Pentafluoro-1-[(3-hydroxy-4-methoxyphenyl)sulfonyl]benzene;
2,3,4,5,6-Pentafluoro-1-[(3-fluoro-4-methoxyphenyl)sulfonyl]benzene;
2,3,4,5,6-Pentafluoro-1-[(4-methylaminophenyl)sulfonyl]benzene;
2,3,4,5,6-Pentafluoro-1-[(3,4-dimethoxyphenyl)sulfonyl]benzene;
2,3,4,5,6-Pentafluoro-1-[(4-methoxyphenyl)methylsulfonyl]benzene;
2,3,4,5,6-Pentafluoro-1-[(3-hydroxy-4-methoxyphenyl)methylsulfonyl]benzen-
e;
2,3,4,5,6-Pentafluoro-1-[(3-fluoro-4-methoxyphenyl)methylsulfonyl]benze-
ne;
2,3,4,5,6-Pentafluoro-1-[(4-methylaminophenyl)methylsulfonyl]benzene;
or
2,3,4,5,6-Pentafluoro-1-[(3,4-dimethoxyphenyl)methylsulfonyl]benzene.
88. The composition of claim 82, wherein R.sup.3 is selected from
NO.sub.2, S(O)--Ar, SO.sub.2--R.sup.8, SO.sub.2--Ar, N.sub.3,
N(R.sup.6)--SO.sub.2--CF.sub.3, N(R.sup.6)--SO.sub.2--R.sup.8,
N(R.sup.6)--SO.sub.2--Ar, N(R.sup.6)--CO--R.sup.8,
N(R.sup.6)--CO--Ar, N[CO--R.sup.8].sub.2, N(R.sup.8).sub.3.sup.+,
N(R.sup.8).sub.2(Ar).sup.+, O--SO.sub.2--Ar, O--SO.sub.2--R.sup.8,
O--CO--R.sup.8, O--CO--Ar, O--Ar, O--R.sup.8, and
O--CO--CF.sub.3.
89. The composition of claim 88, wherein R.sup.2 is selected from
NO.sub.2, CN, and CO.sub.2--R.sup.8; and R.sup.4 is selected from
hydrogen, F, Cl, Br, OCF.sub.3, CF.sub.3, NO.sub.2, CN, and
CO.sub.2--R.sup.8.
90. The composition of claim 89, wherein the compound is:
1-[(4-Methoxyphenyl)sulfonyl]-3,4-dinitrobenzene; b
1-[(3-Fluoro-4-methoxyphenyl)sulfonyl]-3,4-dinitrobenzene;
1-[(3-Hydroxy-4-methoxyphenyl)sulfonyl]-3,4-dinitrobenzene;
4-Azido-1-[(3,4-dimethoxyphenyl)sulfonyl]-3-nitrobenzene;
4-Azido-1-[(4-aminophenyl)sulfonyl]-3-nitrobenzene;
4-Azido-1-[(4-methoxyphenyl)sulfonyl]-3-nitrobenzene;
4-Azido-1-[(3-hydroxy-4-methoxyphenyl)sulfonyl]-3-nitrobenzene;
4-Azido-1-[(3-fluoro-4-methoxyphenyl)sulfonyl]-3-nitrobenzene;
2-Azido-5-[(4-methoxyphenyl)sulfonyl]benzonitrile;
2-Azido-5-[(3-fluoro-4-methoxyphenyl)sulfonyl]benzonitrile;
2-Azido-5-[(3-hydroxy-4-methoxyphenyl)sulfonyl]benzonitrile.
5-[(4-Methoxyphenyl)sulfonyl]-2-(phenylsulfonyl)benzonitrile;
5-[(3-Fluoro-4-methoxyphenyl)sulfonyl]-2-(phenylsulfonyl)benzonitrile;
5-[(4-Methoxyphenyl)sulfonyl]-2-(phenylsulfonyloxy)benzoic acid,
ethyl ester;
5-[(3-Fluoro-4-methoxyphenyl)sulfonyl]-2-(phenylsulfonyloxy)benzoi-
c acid, ethyl ester;
5-[(3-Hydroxy-4-methoxyphenyl)sulfonyl]-2-(phenylsulf-
onyloxy)benzoic acid, ethyl ester;
4-Trifluoromethylsulfonamido-1-[(4-meth-
oxyphenyl)sulfonyl]-3-nitrobenzene;
4-Trifluoromethylsulfonamido-1-[(3-flu-
oro-4-methoxyphenyl)sulfonyl]-3-nitrobenzene;
4-Trifluoromethylsulfonamido-
-1-[(3-hydroxy-4-methoxyphenyl)sulfonyl]-3-nitrobenzene;
4-Trifluoroacetoxy-1-[(4-methoxyphenyl)sulfonyl]-3-nitrobenzene;
4-Trifluoroacetoxy-1-[(3-fluoro-4-methoxyphenyl)sulfonyl]-3-nitrobenzene;
4-Trifluoroacetoxy-1-[(3-hydroxy-4-methoxyphenyl)sulfonyl]-3-nitrobenzene-
; 1-[(4-Methoxyphenyl)sulfonyl]-4-methylsulfonamido-3-nitrobenzene;
1-[(3-Fluoro-4-methoxyphenyl)sulfonyl]-4-methylsulfonamido-3-nitrobenzene-
;
1-[(3-Hydroxy-4-methoxyphenyl)sulfonyl]-4-methylsulfonamido-3-nitrobenze-
ne;
1-[(4-Methoxyphenyl)sulfonyl]-4-phenylsulfonamido-3-nitrobenzene;
1-[(3-Fluoro-4-methoxyphenyl)sulfonyl]4-phenylsulfonamido-3-nitrobenzene;
or
1-[(3-Hydroxy-4-methoxyphenyl)sulfonyl]-4-phenylsulfonamido-3-nitroben-
zene.
91. The composition of claim 88, wherein R.sup.2 and R.sup.4 are
independently selected from hydrogen, F, Cl, Br, OCF.sub.3 and
CF.sub.3.
92. The composition of claim 91, wherein the compound is:
2,3,5,6-Tetrafluoro-4-[(4-methoxyphenyl)sulfonyl]-p 1-nitrobenzene;
2,3,5,6-Tetrafluoro-4-[(3-hydroxy-4-methoxyphenyl)sulfonyl]-3-nitrobenzen-
e;
2,3,5,6-Tetrafluoro-4-[(3-fluoro-4-methoxyphenyl)sulfonyl]-1-nitrobenze-
ne;
2,3,5,6-Tetrafluoro-4-trifluoromethylsulfonamido-1-[(.sup.4-methoxyphe-
nyl)sulfonyl]benzene;
2,3,5,6-Tetrafluoro-4-trifluoromethylsulfonamido-1-[-
(3-fluoro-4-methoxyphenyl)-sulfonyl]benzene;
2,3,5,6-Tetrafluoro-4-trifluo-
romethylsulfonamido-1-[(3-hydroxy-4-methoxyphenyl)-sulfonyl]benzene;
2,3,5,6-Tetrafluoro-4-trifluoroacetoxy-1-[(4-methoxyphenyl)sulfonyl]benze-
ne;
2,3,5,6-Tetrafluoro-4-trifluoroacetoxy-1-[(3-fluoro-4-methoxyphenyl)su-
lfonyl]benzene;
2,3,5,6-Tetrafluoro-4-trifluoroacetoxy-1-[(3-hydroxy-4-met-
hoxyphenyl)sulfonyl]benzene;
2,3,5,6-Tetrafluoro-1-[(4-methoxyphenyl)sulfo-
nyl]-4-(methylsulfonamido)benzene;
2,3,5,6-Tetrafluoro-1-[(3-fluoro-4-meth-
oxyphenyl)sulfonyl]-4-(methylsulfonamido)benzene;
2,3,5,6-Tetrafluoro-1-[(-
3-hydroxy-4-methoxyphenyl)sulfonyl]-4-(methylsulfonamido)benzene;
2,3,5,6-Tetrafluoro-1-[(4-methoxyphenyl)sulfonyl]-4-(phenylsulfonamido)be-
nzene;
2,3,5,6-Tetrafluoro-1-[(3-fluoro-4-methoxyphenyl)sulfonyl]-4-(pheny-
lsulfonamido)benzene;
2,3,5,6-Tetrafluoro-1-[(3-hydroxy-4-methoxyphenyl)su-
lfonyl]-4-(phenylsulfonamido)benzene;
4-Azido-2,3,5,6-tetrafluoro-1-[(4-me- thoxyphenyl)sulfonyl]benzene;
4-Azido-2,3,5,6-tetrafluoro-1-[(3-hydroxy-4--
methoxyphenyl)sulfonyl]benzene; or
4-Azido-2,3,5,6-tetrafluoro-1-[(3-fluor-
o-4-methoxyphenyl)sulfonyl]benzene.
93. The composition of claim 52, wherein n=1 and there is no
linking group E.
94. The composition of claim 93, wherein the compound is:
3-Bromo-2,4,5,6-tetrafluoro-1-[(4-methoxyphenyl)sulfenyl]benzene;
2,4,5,6-Tetrafluoro-3-[(4-dimethylaminophenyl)sulfenyl]benzoic
acid, ethyl ester;
4-Fluoro-1-[(3-fluoro-4-methoxyphenyl)sulfenyl]-3-nitrobenze- ne;
2-Fluoro-5-[(4-methoxyphenyl)sulfenyl]benzonitrile;
1,3-Dichloro-2,4,6-trifluoro-5-[(3-fluoro-4-methoxyphenyl)sulfenyl]benzen-
e; 2,3,4,5,6-Pentafluoro-1-[(4-methoxyphenyl)sulfenyl]benzene;
2,3,4,5,6-Pentafluoro-1-[(3-hydroxy-4-methoxyphenyl)sulfenyl]benzene;
2,3,4,5,6-Pentafluoro-1-[(3-fluoro-.sup.4-methoxyphenyl)sulfenyl]benzene;
2,3,4,5,6-Pentafluoro-1-[(4-dimethylaminophenyl)sulfenyl]benzene;
or
2,3,4,5,6-Pentafluoro-1-[(3,4-dimethoxyphenyl)sulfenyl]benzene.
95. A method of treating or preventing a disease state
characterized by abnormally high levels of low density lipoprotein
particles or cholesterol in the blood, or by an abnormally high
level of cell proliferation, which method comprises administering
to a mammalian subject in need thereof a therapeutically effective
amount of a composition containing a compound of formula I: 52or a
pharmaceutically acceptable salt thereof, wherein: R.sup.1,
R.sup.2, R.sup.4, and R.sup.5 are independently selected from
hydrogen, lower alkyl, halogen, OCF.sub.3, CF.sub.3, NO.sub.2,
CO.sub.2H, CN, SO.sub.2--N(R.sup.6)(R.sup.- 7), SO.sub.2--R.sup.8,
CO.sub.2--R.sup.8, and CO--R.sup.8; R.sup.3 is a leaving group; Y
is a single bond, --O--, --N(R.sup.9)--, --N(R.sup.9)--CH.sub.2--,
or --CH(R.sup.9)--; and Ar is an optionally substituted aryl or
heteroaryl group; wherein R.sup.6 and R.sup.7 are independently
chosen from hydrogen, lower alkyl, and lower heteroalkyl; R.sup.8
is selected from lower alkyl or lower heteroalkyl; and R.sup.9 is
selected from: hydrogen, substituted or unsubstituted
(C1-C10)alkyl, substituted or unsubstituted (C1-C10)alkoxy,
substituted or unsubstituted (C3-C6)alkenyl, substituted or
unsubstituted (C2-C6)heteroalkyl, substituted or unsubstituted
(C3-C6)heteroalkenyl, substituted or unsubstituted (C3-C6)alkynyl,
substituted or unsubstituted (C3-C8)cycloalkyl, substituted or
unsubstituted (C5-C7)cycloalkenyl, substituted or unsubstituted
(C5-C7)cycloalkadienyl, substituted or unsubstituted aryl,
substituted or unsubstituted aryloxy, substituted or unsubstituted
aryl-(C3-C8)cycloalkyl, substituted or unsubstituted
aryl-(C5-C7)cycloalkenyl, substituted or unsubstituted
aryloxy-(C3-C8)cycloalkyl, substituted or unsubstituted
aryl-(C1-C4)alkyl, substituted or unsubstituted aryl-(C1-C4)alkoxy,
substituted or unsubstituted aryl-(C1-C4)heteroalkyl, substituted
or unsubstituted aryl-(C3-C6)alkenyl, substituted or unsubstituted
aryloxy-(C1-C4)alkyl, substituted or unsubstituted
aryloxy-(C2-C4)heteroalkyl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted heteroaryloxy, substituted
or unsubstituted heteroaryl-(C1-C4)alkyl, substituted or
unsubstituted heteroaryl-(C1-C4)alkoxy, substituted or
unsubstituted heteroaryl-(C1-C4)heteroalkyl, substituted or
unsubstituted heteroaryl-(C3-C6)alkenyl, substituted or
unsubstituted heteroaryloxy-(C1-C4)alkyl, and substituted or
unsubstituted heteroaryloxy-(C2-C4)heteroalkyl, wherein, if Y is
--N(R.sup.9)--, then R.sup.9 and Ar may be connected by a linking
group E to give a substituent of the Formula 53wherein E represents
a bond, (C1-C4) alkylene, or (C1-C4) heteroalkylene, and the ring
formed by R.sup.9, E, Ar and the nitrogen atom contains no more
than 8 atoms, or preferably R.sup.9 and Ar may be covalently joined
in a moiety that forms a 5- or 6-membered heterocyclic ring with
the nitrogen atom.
96. The method of claim 95, wherein R.sup.3 is halogen, NO.sub.2,
OCF.sub.3, S(O)--Ar, SO.sub.2--R.sup.8, SO.sub.2--Ar, N.sub.3,
N(R.sup.6)--SO.sub.2--CF.sub.3, N(R.sup.6)--SO.sub.2--R.sup.8,
N(R.sup.6)--SO.sub.2--Ar, N(R.sup.6)--CO--(R.sup.8),
N(R.sup.6)--CO--Ar, N[CO--R.sup.8].sub.2, N(R.sup.8).sub.3.sup.+,
N(.sup.8).sub.2(Ar).sup.+, O--SO.sub.2--Ar, O--SO.sub.2--R.sup.8,
O--CO--R.sup.8, O--CO--Ar, O--Ar, O--R.sup.8, or
O--CO--CF.sub.3.
97. The method of claim 96, wherein n=2, there is no linking group
E, and R.sup.1, R.sup.2, R.sup.4 and R.sup.5 are independently
selected from hydrogen, F, Cl, Br, OCF.sub.3, CF.sub.3,
SO.sub.2--R.sup.8, NO.sub.2, CN, CO.sub.2--R.sup.8, and
SO.sub.2--N(R.sup.6)(R.sup.7).
98. The method of claim 97, wherein Y is --N(R.sup.9)--, and
wherein R.sup.6, R.sup.7 and R.sup.9 are independently chosen from
hydrogen, lower-alkyl and lower-heteroalkyl.
99. The method of claim 98, wherein R.sup.3 is halogen or
OCF.sub.3.
100. The method of claim 99, wherein the compound is:
4-Fluoro-1-[(4-methoxyphenyl)aminosulfonyl]-3-nitrobenzene;
4-Fluoro-1-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]-3-nitrobenzene;
20
4-Fluoro-1-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]-3-nitrobenzene;
4-Fluoro-1-[(3,4-dimethoxyphenyl)aminosulfonyl]-3-nitrobenzene;
4-Fluoro-1-[(4-aminophenyl)aminosulfonyl]-3-nitrobenzene;
2-Fluoro-5-[(4-methoxyphenyl)aminosulfonyl]benzonitrile;
2-Fluoro-5-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzonitrile;
2-Fluoro-5-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzonitrile;
2-Fluoro-5-[(3,4-dimethoxyphenyl)aminosulfonyl]benzonitrile;
5-[(4-Dimethylaminophenyl)aminosulfonyl]-2-fluorobenzonitrile;
4,5-Difluoro-1-[(4-methoxyphenyl)aminosulfonyl]-3-nitrobenzene;
4,5-Difluoro-1-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]-3-nitrobenzene;
4,5-Difluoro-1-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]-3-nitrobenzene;
4,5-Difluoro-1-[(3,4-dimethoxyphenyl)aminosulfonyl]-3-nitrobenzene;
4,5-Difluoro--[(4-aminophenyl)aminosulfonyl]-3-nitrobenzene;
2,3,4-Trifluoro-5-[(4-methoxyphenyl)aminosulfonyl]benzoic acid,
ethyl ester;
2,3,4-Trifluoro-5-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzoic
acid, ethyl ester;
2,3,4-Trifluoro-5-[(3-hydroxy-4-methoxyphenyl)aminosul-
fonyl]benzoic acid, ethyl ester;
2,3,4-Trifluoro-5-[(3,4-dimethoxyphenyl)a- minosulfonyl]benzoic
acid, ethyl ester; 2,3,4-Trifluoro-5-[(4-dimethylamin-
ophenyl)aminosulfonyl]benzoic acid, ethyl ester;
2,4,5,6-Tetrafluoro-3-[(4- -methoxyphenyl)aminosulfonyl]benzoic
acid, ethyl ester;
2,4,5,6-Tetrafluoro-3-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzoic
acid, ethyl ester;
2,4,5,6-Tetrafluoro-3-[(3-hydroxy-4-methoxyphenyl)amin-
osulfonyl]benzoic acid, ethyl ester;
2,4,5,6-Tetrafluoro-3-[(3,4-dimethoxy- phenyl)aminosulfonyl]benzoic
acid, ethyl ester; 2,4,5,6-Tetrafluoro-3-[(4--
dimethylaminophenyl)aminosulfonyl]benzoic acid, ethyl ester;
1-Bromo-3,4,5,6-tetrafluoro-2-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]b-
enzene;
1-Bromo-3,4,5,6-tetrafluoro-2-[(4-methoxyphenyl)aminosulfonyl)]ben-
zene;
1-Bromo-3,4,5,6tetrafluoro-2-[(3-fluoro-4-methoxyphenyl)aminosulfony-
l]benzene;
1-Bromo-2,4,5,6-tetrafluoro-3-[(4-methoxyphenyl)aminosulfonyl)]-
benzene;
1-Bromo-2,4,5,6-tetrafluoro-3-[(3-hydroxy-4-methoxyphenyl)aminosu-
lfonyl]benzene;
1-Bromo-2,4,5,6-tetrafluoro-3-[(3-fluoro-4-methoxyphenyl)a-
minosulfonyl]benzene;
1-Bromo-2,4,5,6-tetrafluoro-3-[(3,4-dimethoxyphenyl)-
aminosulfonyl]benzene;
1-Bromo-2,4,5,6-tetrafluoro-3-[(4-dimethylaminophen-
yl)aminosulfonyl]benzene;
1,3-Dichloro-2,4,6trifluoro-5-[(4-methoxyphenyl)-
aminosulfonyl]benzene;
1,3-Dichloro-2,4,6-trifluoro-5-[(3-fluoro-4-methoxy-
phenyl)aminosulfonyl]benzene;
1,3-Dichloro-2,4,6-trifluoro-5-[(3-hydroxy-4-
-methoxyphenyl)aminosulfonyl]benzene;
1-Bromo-4,5,6-trifluoro-2-[(4-methox-
yphenyl)aminosulfonyl]benzene;
1-Bromo-4,5,6-trifluoro-2-[(3-hydroxy-4-met-
hoxyphenyl)aminosulfonyl]benzene;
1-Bromo-4,5,6-trifluoro-2-[(3-fluoro-4-m-
ethoxyphenyl)aminosulfonyl]benzene;
1-Bromo-4,5,6-trifluoro-2-[(3,4-dimeth-
oxyphenyl)aminosulfonyl]benzene;
1-Bromo-2,3,4-trifluoro-5-[(3-hydroxy-4-m-
ethoxyphenyl)aminosulfonyl]benzene;
1-Bromo-2,3,4-trifluoro-5-[(3-fluoro-4-
-methoxyphenyl)aminosulfonyl]benzene;
1-Bromo-2,3,4-trifluoro-5-[(4-methox-
yphenyl)aminosulfonyl]benzene;
1-Bromo-2,3,4-trifluoro-5-[(3,4-dimethoxyph-
enyl)aminosulfonyl]benzene;
1-Bromo-3,4,5-trifluoro-2-[(3-hydroxy-4-methox-
yphenyl)aminosulfonyl]benzene;
1-Bromo-3,4,5-trifluoro-2-[(3-fluoro-4-meth-
oxyphenyl)aminosulfonyl]benzene;
1-Bromo-3,4,5-trifluoro-2-[(4-methoxyphen-
yl)aminosulfonyl]benzene;
3,4,6-Trifluoro-1-[(4-methoxyphenyl)aminosulfony- l]benzene;
3,4,6-Trifluoro-1-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benz-
ene;
3,4,6-Trifluoro-1-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzene;
2,3,4,6-Tetrafluoro-1-[(4-methoxyphenyl)aminosulfonyl]benzene;
2,3,4,6-Tetrafluoro-1-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzene;
2,3,4,6-Tetrafluoro-1-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzene;
2,3,4,5-Tetrafluoro-1-[(4-methoxyphenyl)aminosulfonyl]benzene;
2,3,4,5-Tetrafluoro-1-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzene;
2,3,4,5-Tetrafluoro-1-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzene;
2,3,4,5-Tetrafluoro-1-[(3,4-dimethoxyphenyl)aminosulfonyl]benzene;
2,3,4,5-Tetrafluoro-1-[(4-dimethylaminophenyl)aminosulfonyl]benzene;
3,4,5-Trifluoro-1-[(4-methoxyphenyl)aminosulfonyl]benzene;
3,4,5-Trifluoro-1-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzene;
3,4,5-Trifluoro-1-[(3-fluoro-4-methoxyphenyl)aminosulfonyl=benzene;
3,4,5-Trifluoro-1-[(3,4-dimethoxyphenyl)aminosulfonyl]benzene;
3,4,5-Trifluoro-1-[(4-dimethylaminophenyl)aminosulfonyl]benzene;
1-Chloro-4-1-[4-methoxyphenyl)aminosulfonyl]-2-nitrobenzene;
1-Chloro-4-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]-2-nitrobenzene;
1-Chloro-4-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]-2-nitrobenzene;
1-Chloro-4-[(3,4-dimethoxyphenyl)aminosulfonyl]-2-nitrobenzene;
1-Chloro-4-[(4-dimethylaminophenyl)aminosulfonyl]-2-nitrobenzene;
2-Chloro-5-[(4-methoxyphenyl)aminosulfonyl]benzonitrile;
2-Chloro-5-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzonitrile;
2-Chloro-5-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzonitrile.
2-Chloro-5-[(3,4-dimethoxyphenyl)aminosulfonyl]benzonitrile;
2-Chloro-5-[(4-dimethylaminophenyl)aminosulfonyl]benzonitrile;
2-Chloro-5-[(4-methoxyphenyl)aminosulfonyl]benzoic acid, ethyl
ester; 2-Chloro-5-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzoic
acid, ethyl ester;
2-Chloro-5-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzoic acid,
ethyl ester; 2-Chloro-5-[(3,4-dimethoxyphenyl)aminosulfonyl]benzoic
acid, ethyl ester;
2-Chloro-5-[(4-dimethylaminophenyl)aminosulfonyl]benzoic acid,
ethyl ester;
1-Chloro-2,3,5,6-tetrafluoro-4-[(4-methoxyphenyl)amino-
sulfonyl]benzene;
1-Chloro-2,3,5,6-tetrafluoro-4-[(3-hydroxy-4-methoxyphen-
yl)aminosulfonyl]benzene;
1-Chloro-2,3,5,6-tetrafluoro-4-[(3-fluoro-4-meth-
oxyphenyl)aminosulfonyl]benzene;
1-Chloro-2,3,5,6-tetrafluoro-4-[(4-dimeth-
ylaminophenyl)aminosulfonyl]benzene;
1-Chloro-2,3,5,6-tetrafluoro-4-[(3,4--
dimethoxyphenyl)aminosulfonyl]benzene;
1-Chloro-2,3,6-trifluoro-4-[(4-meth-
oxyphenyl)aminosulfonyl]benzene ;
1-Chloro-2,3,6-trifluoro-4-[(3-hydroxy-4-
-methoxyphenyl)aminosulfonyl]benzene;
1-Chloro-2,3,6-trifluoro-4-[(3-fluor-
o-4-methoxyphenyl)aminosulfonyl]benzene;
1-Chloro-2,3,6-trifluoro-4-[(4-di-
methylaminophenyl)aminosulfonyl]benzene;
1-Chloro-2,3,6-trifluoro-4-[(3,4-- dimethoxyphenyl)
aminosulfonyl]benzene; 1-Bromo-4-[(4-methoxyphenyl)aminos-
ulfonyl]-2-nitrobenzene;
1-Bromo-4-[(3-fluoro-4-methoxyphenyl)aminosulfony-
l]-2-nitrobenzene;
1-Bromo-4-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]-2--
nitrobenzene;
1-Bromo-4-[(3,4-dimethoxyphenyl)aminosulfonyl]-2-nitrobenzen- e;
1-Bromo-4-[(4-dimethylaminophenyl)aminosulfonyl]-2-nitrobenzene;
2-Bromo-5-[(4-methoxyphenyl)aminosulfonyl]benzonitrile;
2-Bromo-5-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzonitrile;
2-Bromo-5-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzonitrile.
2-Bromo-5-[(3,4-dimethoxyphenyl)aminosulfonyl]benzonitrile;
2-Bromo-5-[(4-dimethylaminophenyl)aminosulfonyl]benzonitrile;
2-Bromo-5-[(4-methoxyphenyl)aminosulfonyl]benzoic acid, ethyl
ester; 2-Bromo-5-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzoic
acid, ethyl ester;
2-Bromo-5-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzoic acid,
ethyl ester; 2-Bromo-5-[(3,4-dimethoxyphenyl)aminosulfonyl]benzoic
acid, ethyl ester;
2-Bromo-5-[(4-dimethylaminophenyl)aminosulfonyl]benzoic acid, ethyl
ester; 1-Bromo-2,3,5,6-tetrafluoro-4-[(4-methoxyphenyl)aminos-
ulfonyl]benzene;
1-Bromo-2,3,5,6-tetrafluoro-4-[(3-hydroxy-4-methoxyphenyl-
)aminosulfonyl]benzene;
1-Bromo-2,3,5,6-tetrafluoro-4-[(3-fluoro-4-methoxy-
phenyl)aminosulfonyl]benzene;
1-Bromo-2,3,5,6-tetrafluoro-4-[(4-dimethylam-
inophenyl)aminosulfonyl]benzene;
1-Bromo-2,3,5,6-tetrafluoro-4-[(3,4-dimet-
hoxyphenyl)aminosulfonyl]benzene;
1-Bromo-2,3,6-trifluoro-4-[(4-methoxyphe-
nyl)aminosulfonyl]benzene;
1-Bromo-2,3,6-trifluoro-4-[(3-hydroxy-4methoxyp-
henyl)aminosulfonyl]benzene;
1-Bromo-2,3,6-trifluoro-4-[(3-fluoro-4methoxy-
phenyl)aminosulfonyl]benzene;
1-Bromo-2,3,6-trifluoro-4-[(4-dimethylaminop-
henyl)aminosulfonyl]benzene;
1-Bromo-2,3,6-trifluoro-4-[(3,4-dimethoxyphen-
yl)aminosulfonyl]benzene;
4-Trifluoromethoxy-1-[(4-methoxyphenyl)aminosulf-
onyl]-3-nitrobenzene;
4-Trifluoromethoxy-1-[(3-fluoro-4-methoxyphenyl)amin-
osulfonyl]-3-nitrobenzene;
4-Trifluoromethoxy-1-[(3-hydroxy-4-methoxypheny-
l)aminosulfonyl]-3-nitrobenzene;
4-Trifluoromethoxy-1-[(3,4-dimethoxypheny-
l)aminosulfonyl]-3-nitrobenzene;
4-Trifluoromethoxy-1-[(4-dimethylaminophe-
nyl)aminosulfonyl]-3-nitrobenzene;
2-Trifluoromethoxy-5-[(4-methoxyphenyl)-
aminosulfonyl]benzonitrile;
2-Trifluoromethoxy-5-[(3-fluoro-methoxyphenyl)-
aminosulfonyl]benzonitrile;
2-Trifluoromethoxy-5-[(3-hydroxy-4-methoxyphen-
yl)aminosulfonyl]benzonitrile.
2-Trifluoromethoxy-5-[(3,4-dimethoxyphenyl)-
aminosulfonyl]benzonitrile;
2-Trifluoromethoxy-5-[(4-dimethylaminophenyl)a-
minosulfonyl]benzonitrile;
2-Trifluoromethoxy-5-[(4-methoxyphenyl)aminosul- fonyl]benzoic
acid, ethyl ester; 2-Trifluoromethoxy-5-[(3-fluoro-4-methoxy-
phenyl)aminosulfonyl]benzoic acid, ethyl ester;
2-Trifluoromethoxy-5-[(3-h-
ydroxy-4-methoxyphenyl)aminosulfonyl]benzoic acid, ethyl ester;
2-Trifluoromethoxy-5-[(3,4-dimethoxyphenyl)aminosulfonyl]benzoic
acid, ethyl ester;
2-Trifluoromethoxy-5-[(4-methylaminophenyl)aminosulfonyl]ben- zoic
acid, ethyl ester;
2,3,5,6-Tetrafluoro-1-trifluoromethoxy-4-[(4methox-
yphenyl)aminosulfonyl]benzene;
2,3,5,6-Tetrafluoro-1-trifluoromethoxy-4-[(-
3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzene;
2,3,5,6-Tetrafluoro-1-tri-
fluoromethoxy-4-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzene;
2,3,5,6-Tetrafluoro-1-trifluoromethoxy-4-[(4-dimethylaminophenyl)aminosul-
fonyl]benzene;
2,3,5,6-Tetrafluoro-1-trifluoromethoxy-4-[(3,4-dimethoxyphe-
nyl)aminosulfonyl]benzene;
2,3,6-Trifluoro-1-trifluoromethoxy-4-[(4-methox-
yphenyl)aminosulfonyl]benzene;
2,3,6-Trifluoro-1-trifluoromethoxy-4-[(3-hy-
droxy-4-methoxyphenyl)aminosulfonyl]benzene;
2,3,6-Trifluoro-1-trifluorome-
thoxy-4-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzene;
2,3,6-Trifluoro-1-trifluoromethoxy-4-[(4-dimethylaminophenyl)aminosulfony-
l]benzene; or
2,3,6-Trifluoro-1-trifluoromethoxy-4-[(3,4-dimethoxyphenyl)a-
minosulfonyl]benzene.
101. The method of claim 98, wherein R.sup.3is selected from
NO.sub.2, N.sub.3, O--SO.sub.2--Ar, O--SO.sub.2--R.sup.8and
SO.sub.2--Ar.
102. The method of claim 1 01, wherein the compound is:
1-[(4-Methoxyphenyl)aminosulfonyl]-3,4-dinitrobenzene;
1-[(3-Fluoro-4-methoxyphenyl)aminosulfonyl]-3,4-dinitrobenzene;
1-[(3-Hydroxy-4-methoxyphenyl)aminosulfonyl]-3,4-dinitrobenzene;
4-Azido-1-[(3,4-dimethoxyphenyl)aminosulfonyl]-3-nitrobenzene;
4-Azido-1-[(4aminophenyl)aminosulfonyl]-3-nitrobenzene;
4-Azido-1-[(4-methoxyphenyl)aminosulfonyl]-3-nitrobenzene;
4-Azido-1-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]-3-nitrobenzene;
4-Azido-1-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]-3-nitrobenzene;
2-Azido-5-[(4-methoxyphenyl)aminosulfonyl]benzonitrile;
2-Azido-5-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzonitrile;
2-Azido-5-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzonitrile.
2-Azido-5-[(3,4-dimethoxyphenyl)aminosulfonyl]benzonitrile;
2-Azido-5-[(4-dimethylaminophenyl)aminosulfonyl]benzonitrile;
5-[(4-Methoxyphenyl)aminosulfonyl]-2-phenylsulfonylbenzonitrile;
5-[(3-Fluoro-4-methoxyphenyl)aminosulfonyl]-2-phenylsulfonylbenzonitrile;
5-[(3-Hydroxy-4-methoxyphenyl)aminosulfonyl]-2-phenylsulfonylbenzonitrile-
.
5-[(3,4-Dimethoxyphenyl)aminosulfonyl]-2-phenylsulfonylbenzonitrile;
5-[(4-Dimethylaminophenyl)aminosulfonyl]-2-phenylsulfonylbenzonitrile;
5-[(4-Methoxyphenyl)aminosulfonyl]-2-phenylsulfonyloxybenzoic acid,
ethyl ester;
5-[(3-Fluoro-4-methoxyphenyl)aminosulfonyl]-2-phenylsulfonyloxyben-
zoic acid, ethyl ester;
5-[(3-Hydroxy-4-methoxyphenyl)aminosulfonyl]-2-phe-
nylsulfonyloxybenzoic acid, ethyl ester;
5-[(3,4-Dimethoxyphenyl)aminosulf- onyl]-2-phenylsulfonyloxybenzoic
acid, ethyl ester;
5-[(4-Dimethylaminophenyl)aminosulfonyl]-2-phenylsulfonyloxybenzoic
acid, ethyl ester.
2,3,5,6-Tetrafluoro-1-[(4-methoxyphenyl)aminosulfonyl]4-nitr-
obenzene;
2,3,5,6-Tetrafluoro-1-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]-
4-nitrobenzene;
2,3,5,6-Tetrafluoro-1-[(3-fluoro-4-methoxyphenyl)aminosulf-
onyl]-4-nitrobenzene;
2,3,5,6-Tetrafluoro-1-[(4-dimethylaminophenyl)aminos-
ulfonyl]-4-nitrobenzene;
2,3,5,6-Tetrafluoro-1-[(3,4-dimethoxyphenyl)amino-
sulfonyl]-4-nitrobenzene;
4-Azido-2,3,6-trifluoro-1-[(4-methoxyphenyl)amin-
osulfonyl]benzene;
4-Azido-2,3,6-trifluoro-1-[(3-hydroxy-4-methoxyphenyl)a-
minosulfonyl]benzene;
4-Azido-2,3,6-trifluoro-1-[(3-fluoro-4-methoxyphenyl-
)aminosulfonyl]benzene;
4-Azido-2,3,6-trifluoro-1-[(4-dimethylaminophenyl)-
aminosulfonyl]benzene; or
4-Azido-2,3,6-trifluoro-1-[(3,4-dimethoxyphenyl)-
aminosulfonyl]benzene.
103. The method of claim 98, wherein R.sup.3 is selected from
N(R.sup.6)--SO.sub.2--CF.sub.3, N(R.sup.6)--SO.sub.2--R.sup.8,
N(R.sup.6)--SO.sub.2--Ar, N(.sup.6)--CO--R.sup.8,
N(R.sup.6)--CO--Ar, N[CO--R.sup.8].sub.2, and O--CO--CF.sub.3.
104. The method of claim 103, wherein the compound is:
4-Trifluoromethylsulfonamido-1-[(4-methoxyphenyl)aminosulfonyl]-3-nitrobe-
nzene;
1-[(3-Fluoro-4-methoxyphenyl)aminosulfonyl]-4-trifluoromethylsulfon-
amido-3-nitrobenzene;
4-Trifluoromethylsulfonamido-1-[(3-hydroxy-4-methoxy-
phenyl)aminosulfonyl]-3-nitrobenzene;
2,3,5,6-Tetrafluoro-4-trifluoromethy-
lsulfonamido-1-[(4-methoxyphenyl)aminosulfonyl]benzene;
2,3,5,6-Tetrafluoro-1-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]-4-trifluo-
romethylsulfonamidobenzene;
2,3,5,6-Tetrafluoro-4-trifluoromethylsulfonami-
do-1-[(3-hydroxy-4-methoxyphenyl)-aminosulfonyl]benzene;
4-(Diacetylamino)-2,3-difluoro-1-[(3-fluoro-4-methoxyphenyl)aminosulfonyl-
]-5-nitrobenzene:
4-Trifluoroacetoxy-1-[(4-methoxyphenyl)aminosulfonyl]-3--
nitrobenzene;
4-Trifluoroacetoxy-1-[(3-fluoro-4-methoxyphenyl)aminosulfony-
l]-3-nitrobenzene;
4-Trifluoroacetoxy-1-[(3-hydroxy-4-methoxyphenyl)aminos-
ulfonyl]-3-nitrobenzene;
2,3,5,6-Tetrafluoro-4-trifluoroacetoxy-1-[(4-meth-
oxyphenyl)aminosulfonyl]benzene;
2,3,5,6-Tetrafluoro-4-trifluoroacetoxy-1--
[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzene;
2,3,5,6-Tetrafluoro-4-tr-
ifluoroacetoxy-1-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzene;
1-[(4-Methoxyphenyl)aminosulfonyl]-4-methylsulfonamido-3-nitrobenzene;
1-[(3-Fluoro-4-methoxyphenyl)aminosulfonyl]-4-methylsulfonamido-3-nitrobe-
nzene;
1-[(3-Hydroxy-4-methoxyphenyl)aminosulfonyl]-4-methylsulfonamido-3--
nitrobenzene;
2,3,5,6-Tetrafluoro-1-[(4-methoxyphenyl)aminosulfonyl]-4-met-
hylsulfonamidobenzene;
2,3,5,6-Tetrafluoro-1-[(3-fluoro-4-methoxyphenyl)am-
inosulfonyl]-4-methylsulfonamido-benzene;
2,3,5,6-Tetrafluoro-1-[(3-hydrox-
y-4-methoxyphenyl)aminosulfonyl]-4-methylsulfonamido-benzene;
1-[(4-Methoxyphenyl)aminosulfonyl]-3-nitro-4-phenylsulfonamidobenzene;
1-[(3-Fluoro-4-methoxyphenyl)aminosulfonyl]-3-nitro-4-phenylsulfonamidobe-
nzene;
1-[(3-Hydroxy-4-methoxyphenyl)aminosulfonyl]-3-nitro-4-phenylsulfon-
amidobenzene;
2,3,5,6-Tetrafluoro-1-[(4-methoxyphenyl)aminosulfonyl]-4-phe-
nylsulfonamidobenzene;
2,3,5,6-Tetrafluoro-1-[(3-fluoro-4-methoxyphenyl)am-
inosulfonyl]4-phenylsulfonamidobenzene; or
2,3,5,6-Tetrafluoro-1-[(3-hydro-
xy-4-methoxyphenyl)aminosulfonyl]-4-phenylsulfonamidobenzene.
105. The method of claim 97, wherein Y is a single bond or
--CH(R.sup.9)--; and R.sup.3 is halogen, OCF.sub.3, NO.sub.2,
N.sub.3, O--SO.sub.2--Ar, O--SO.sub.2--R.sup.8, or
SO.sub.2--Ar.
106. The method of claim 105, wherein the compound is:
4-Fluoro-1-[(4-methoxyphenyl)methylsulfonyl]-3-nitrobenzene;
4-Fluoro-1-[(3-hydroxy-4-methoxyphenyl)methylsulfonyl]-3-nitrobenzene;
4-Fluoro-1-[(3-fluoro-4-methoxyphenyl)methylsulfonyl]-3-nitrobenzene;
4-Fluoro-1-[(4-methoxyphenyl)sulfonyl]-3-nitrobenzene;
4-Fluoro-1-[(3-hydroxy-4-methoxyphenyl)sulfonyl]-3-nitrobenzene;
4-Fluoro-1-[(3-fluoro-4-methoxyphenyl)sulfonyl]-3-nitrobenzene;
2-Fluoro-5-[(4-methoxyphenyl)sulfonyl]benzonitrile;
2-Fluoro-5-[(3-hydroxy-4-methoxyphenyl)sulfonyl]benzonitrile;
2-Fluoro-5-[(3-fluoro-4-methoxyphenyl)sulfonyl]benzonitrile;
2-Fluoro-5-[(4-methoxyphenyl)methylsulfonyl]benzonitrile;
2-Fluoro-5-[(3-hydroxy-4-methoxyphenyl)methylsulfonyl]benzonitrile;
2-Fluoro-5-[(3-fluoro-4-methoxyphenyl)methylsulfonyl]benzonitrile;
2,3,4-Trifluoro-5-[(4-methoxyphenyl)sulfonyl]benzoic acid, ethyl
ester;
2,3,4-Trifluoro-5-[(3-fluoro-4-methoxyphenyl)sulfonyl]benzoic acid,
ethyl ester;
2,3,4-Trifluoro-5-[(3-hydroxy-4-methoxyphenyl)sulfonyl]benzoic
acid, ethyl ester;
1-Chloro-4-[(4-methoxyphenyl)methylsulfonyl]-2-nitrobe- nzene;
1-Chloro-4-[(4-methylaminophenyl)methylsulfonyl]-2-nitrobenzene;
1-Chloro-4-[(4-methoxyphenyl)sulfonyl]-2-nitrobenzene;
1-Chloro-4-[(4-methylaminophenyl)sulfonyl]-2-nitrobenzene;
1-Bromo-3,4,5,6-tetrafluoro-2-[(3-hydroxy-4-methoxyphenyl)sulfonyl]benzen-
e;
1-Bromo-3,4,5,6-tetrafluoro-2-[(4-methoxyphenyl)sulfonyl)]benzene;
1-Bromo-3,4,5,6-tetrafluoro-2-[(3-fluoro-4-methoxyphenyl)sulfonyl]benzene-
; 1-Bromo-2,4,5,6-tetrafluoro-3-[(4methoxyphenyl)sulfonyl)]benzene;
1-Bromo-2,4,5,6-tetrafluoro-3-[(3-hydroxy-4-methoxyphenyl)sulfonyl]benzen-
e;
1-Bromo-2,4,5,6-tetrafluoro-3-[(3-fluoro-4-methoxyphenyl)sulfonyl]benze-
ne;
1,3-Dichloro-2,4,6-trifluoro-5-[(4-methoxyphenyl)sulfonyl]benzene;
1,3-Dichloro-2,4,6-trifluoro-5-[(3-fluoro-4-methoxyphenyl)sulfonyl]benzen-
e;
1,3-Dichloro-2,4,6-trifluoro-5-[(3-hydroxy-4-methoxyphenyl)sulfonyl]ben-
zene; 1-Bromo-4,5,6-trifluoro-2-[(4-methoxyphenyl)sulfonyl]benzene;
1-Bromo-4,5,6-trifluoro-2-[(3-hydroxy-4-methoxyphenyl)sulfonyl]benzene;
1-Bromo-4,5,6-trifluoro-2-[(3-fluoro-4methoxyphenyl)sulfonyl]benzene;
2,3,4,5-Tetrafluoro-1-[(4-methoxyphenyl)sulfonyl]benzene;
2,3,4,5-Tetrafluoro-1-[(3-hydroxy-4-methoxyphenyl)sulfonyl]benzene;
2,3,4,5-Tetrafluoro-1-[(3-fluoro-4-methoxyphenyl)sulfonyl]benzene;
2,3,4,5-Tetrafluoro-1-[(3,4-dimethoxyphenyl)sulfonyl]benzene;
2,3,4,5-Tetrafluoro-1-[(4-dimethylaminophenyl)sulfonyl]benzene;
3,4,5-Trifluoro-1-[(4-methoxyphenyl )sulfonyl]benzene;
3,4,5-Trifluoro-1-[(3-hydroxy-4-methoxyphenyl)sulfonyl]benzene;
3,4,5-Trifluoro-1-[(3-fluoro-4-methoxy phenyl)sulfonyl]benzene;
3,4,5-Trifluoro-1-[(3,4-dimethoxyphenyl)sulfonyl]benzene;
3,4,5-Trifluoro-1-[(4-dimethylaminophenyl)sulfonyl]benzene;
1-Chloro-2,3,5,6-tetrafluoro-4-[(4-methoxyphenyl)sulfonyl]benzene;
1-Chloro-2,3,5,6-tetrafluoro-4-[(3-hydroxy-4-methoxyphenyl)sulfonyl]benze-
ne;
1-Chloro-2,3,5,6-tetrafluoro-4-[(3-fluoro-4-methoxyphenyl)sulfonyl]ben-
zene;
1-Bromo-2,3,5,6-tetrafluoro-[(4-methoxyphenyl)sulfonyl]benzene;
1-Bromo-2,3,5,6-tetrafluoro-4-[(3-hydroxy-4-methoxyphenyl)sulfonyl]benzen-
e;
1-Bromo-2,3,5,6-tetrafluoro-4-[(3-fluoro-4-methoxyphenyl)sulfonyl]benze-
ne;
1-Bromo-2,3,5,6-tetrafluoro-4-[(4-dimethylaminophenyl)sulfonyl]benzene-
;
1-Bromo-2,3,5,6-tetrafluoro-4-[(3,4-dimethoxyphenyl)sulfonyl]benzene;
2,3,4,5,6-Pentafluoro-1-[(4-methoxyphenyl)sulfonyl]benzene;
2,3,4,5,6-Pentafluoro-1-[(3-hydroxy-4-methoxyphenyl)sulfonyl]benzene;
2,3,4,5,6-Pentafluoro-1-[(3-fluoro-4-methoxyphenyl)sulfonyl]benzene;
2,3,4,5,6-Pentafluoro-1-[(4-dimethylaminophenyl)sulfonyl]benzene;
2,3,4,5,6-Pentafluoro-1-[(3,4-dimethoxyphenyl)sulfonyl]benzene;
2,3,4,5,6-Pentafluoro-1-[(4-methoxyphenyl)methylsulfonyl]benzene;
2,3,4,5,6-Pentafluoro-1-[(3-hydroxy-4-methoxyphenyl)methylsulfonyl]benzen-
e;
2,3,4,5,6-Pentafluoro-1-[(3-fluoro-4-methoxyphenyl)methylsulfonyl]benze-
ne;
2,3,4,5,6-Pentafluoro-1-[(4-methylaminophenyl)methylsulfonyl]benzene;
2,3,4,5,6-Pentafluoro-1-[(3,4-dimethoxyphenyl)methylsulfonyl]benzene;
1-[(4-Methoxyphenyl)sulfonyl)-3,4-dinitrobenzene;
1-[(3-Fluoro-4-methoxyp- henyl)sulfonyl]-3,4-dinitrobenzene;
1-[(3-Hydroxy-4-methoxyphenyl)sulfonyl- ]-3,4-dinitrobenzene;
4-Azido-1-[(3,4-dimethoxyphenyl)sulfonyl]-3-nitroben- zene;
4-Azido-1-[(4-aminophenyl)sulfonyl]-3-nitrobenzene;
4-Azido-1-[(4-methoxyphenyl)sulfonyl]-3-nitrobenzene;
4-Azido-1-[(3-hydroxy-4-methoxyphenyl)sulfonyl]-3-nitrobenzene;
4-Azido-1-[(3-fluoro-4-methoxyphenyl)sulfonyl]-3-nitrobenzene;
2-Azido-5-[(4-methoxyphenyl)sulfonyl]benzonitrile;
2-Azido-5-[(3-fluoro-4-methoxyphenyl)sulfonyl]benzonitrile;
2-Azido-5-[(3-hydroxy-4-methoxyphenyl)sulfonyl]benzonitrile.
5-[(4-Methoxyphenyl)sulfonyl]-2-(phenylsulfonyl)benzonitrile;
5-[(3-Fluoro-4-methoxyphenyl)sulfonyl]-2-(phenylsulfonyl)benzonitrile;
5-[(4Methoxyphenyl)sulfonyl]-2-(phenylsulfonyloxy)benzoic acid,
ethyl ester;
5-[(3-Fluoro-4-methoxyphenyl)sulfonyl]-2-(phenylsulfonyloxy)benzoi-
c acid, ethyl ester;
5-[(3-Hydroxy-4-methoxyphenyl)sulfonyl]-2-(phenylsulf-
onyloxy)benzoic acid, ethyl ester;
4-Trifluoromethylsulfonamido-1-[(4-meth-
oxyphenyl)sulfonyl]-3-nitrobenzene;
4-Trifluoromethylsulfonamido-1-[(3-flu-
oro-4-methoxyphenyl)sulfonyl]-3-nitrobenzene;
4-Trifluoromethylsulfonamido-
-1-[(3-hydroxy-4-methoxyphenyl)sulfonyl]-3-nitrobenzene;
4-Trifluoroacetoxy-1-[(4-methoxyphenyl)sulfonyl]-3-nitrobenzene;
4-Trifluoroacetoxy-1-[(3-fluoro-4-methoxyphenyl)sulfonyl]-3-nitrobenzene;
4-Trifluoroacetoxy-1-[(3-hydroxy-4-methoxyphenyl)sulfonyl]-3-nitrobenzene-
; 1-[(4-Methoxyphenyl)sulfonyl]4-methylsulfonamido -3-nitrobenzene;
1-[(3-Fluoro-4-methoxyphenyl)sulfonyl]-4-methylsulfonamido-3-nitrobenzene-
;
1-[(3-Hydroxy-4-methoxyphenyl)sulfonyl]-4-methylsulfonamido-3-nitrobenze-
ne;
1-[(4-Methoxyphenyl)sulfonyl]-4-phenylsulfonamido-3-nitrobenzene;
1-[(3-Fluoro-4-methoxyphenyl)sulfonyl]-4-phenylsulfonamido-3-nitrobenzene-
;
1-[(3-Hydroxy-4-methoxyphenyl)sulfonyl]4-phenylsulfonamido-3-nitrobenzen-
e;
2,3,5,6-Tetrafluoro-4-[(4-methoxyphenyl)sulfonyl]-1-nitrobenzene;
2,3,5,6-Tetrafluoro-4-[(3-hydroxy-4-methoxyphenyl)sulfonyl]-1-nitrobenzen-
e;
2,3,5,6-Tetrafluoro-4-[(3-fluoro-4-methoxyphenyl)sulfonyl]-1-nitrobenze-
ne;
2,3,5,6-Tetrafluoro-4-trifluoromethylsulfonamido-1-[(4-methoxyphenyl)s-
ulfonyl]benzene;
2,3,5,6-Tetrafluoro-4-trifluoromethylsulfonamido-1-[(3-fl-
uoro-4-methoxyphenyl) sulfonyl]benzene;
2,3,5,6-Tetrafluoro-4-trifluoromet-
hylsulfonamido-1-[(3-hydroxy-4-methoxyphenyl)-sulfonyl]benzene;
2,3,5,6-Tetrafluoro-4-trifluoroacetoxy-1-[(4-methoxyphenyl)sulfonyl]benze-
ne;
2,3,5,6-Tetrafluoro-4-trifluoroacetoxy-1-[(3-fluoro-4-methoxyphenyl)su-
lfonyl]benzene;
2,3,5,6-Tetrafluoro-4-trifluoroacetoxy-1-[(3-hydroxy-4-met-
hoxyphenyl)sulfonyl]benzene;
2,3,5,6-Tetrafluoro-1-[(4-methoxyphenyl)sulfo-
nyl]-4-(methylsulfonamido)benzene;
2,3,5,6-Tetrafluoro-1-[(3-fluoro-4-meth-
oxyphenyl)sulfonyl]-4-(methylsulfonamido)benzene;
2,3,5,6-Tetrafluoro-1-[(-
3-hydroxy-4-methoxyphenyl)sulfonyl]-4-(methylsulfonamido)benzene;
2,3,5,6-Tetrafluoro-1-[(4-methoxyphenyl)sulfonyl]-4-(phenylsulfonamido)be-
nzene;
2,3,5,6-Tetrafluoro-1-[(3-fluoro-4-methoxyphenyl)sulfonyl]-4-(pheny-
lsulfonamido)benzene;
2,3,5,6-Tetrafluoro-1-[(3-hydroxy-4-methoxyphenyl)su-
lfonyl]-4-(phenylsulfonamido)benzene;
4-Azido-2,3,5,6-tetrafluoro-1-[(4-me- thoxyphenyl)sulfonyl]benzene;
4-Azido-2,3,5,6-tetrafluoro-1-[(3-hydroxy-4--
methoxyphenyl)sulfonyl]benzene; or
4-Azido-2,3,5,6-tetrafluoro-1-[(3-fluor-
o-4-methoxyphenyl)sulfonyl]benzene.
107. The method of claim 97, wherein Y is a single bond or
--CH(R.sup.9)--; and R.sup.3 is selected from S(O)--Ar,
SO.sub.2--R.sup.8, N(R.sup.6)--SO.sub.2--CF.sub.3,
N(R.sup.6)--SO.sub.2--R.sup.8, N(R.sup.6)--SO.sub.2--Ar,
N(R.sup.6)--CO--R.sup.8, N(R.sup.6)--CO--Ar, N[CO--R.sup.8].sub.2,
N(R.sup.8).sub.3.sup.+, N(R.sup.8).sub.2(Ar).sup.+, O--CO--R.sup.8,
O--CO--Ar, O--Ar, O--R.sup.8, and O--CO--CF.sub.3.
108. The method of claim 107, wherein the compound is:
1-[(4-Methoxyphenyl)sulfonyl]-3,4-dinitrobenzene;
1-[(3-Fluoro-4-methoxyp- henyl)sulfonyl]-3,4-dinitrobenzene;
1-[(3-Hydroxy-4-methoxyphenyl)sulfonyl- ]-3,4-dinitrobenzene;
4-Azido-1-[(3,4-dimethoxyphenyl)sulfonyl]-3-nitroben- zene;
4-Azido-1-[(4-aminophenyl)sulfonyl]-3-nitrobenzene;
4-Azido-1-[(4-methoxyphenyl)sulfonyl]-3-nitrobenzene;
4-Azido-1-[(3-hydroxy-4-methoxyphenyl)sulfonyl]-3-nitrobenzene;
4-Azido-1-[(3-fluoro-4-methoxyphenyl)sulfonyl]-3-nitrobenzene;
2-Azido-5-[(4-methoxyphenyl)sulfonyl]benzonitrile;
2-Azido-5-[(3-fluoro-4-methoxyphenyl)sulfonyl]benzonitrile;
2-Azido-5-[(3-hydroxy-4-methoxyphenyl)sulfonyl]benzonitrile.
5-[(4-Methoxyphenyl)sulfonyl]-2-(phenylsulfonyl)benzonitrile;
5-[(3-Fluoro-4-methoxyphenyl)sulfonyl]-2-(phenylsulfonyl)benzonitrile;
5-[(4-Methoxyphenyl)sulfonyl]-2-(phenylsulfonyloxy)benzoic acid,
ethyl ester;
5-[(3-Fluoro-4-methoxyphenyl)sulfonyl]-2-(phenylsulfonyloxy)benzoi-
c acid, ethyl ester;
5-[(3-Hydroxy-4-methoxyphenyl)sulfonyl]-2-(phenylsulf-
onyloxy)benzoic acid, ethyl ester; 5
4-Trifluoromethylsulfonamido-1-[(4-me-
thoxyphenyl)sulfonyl]-3-nitrobenzene;
4-Trifluoromethylsulfonamido--[(3-fl-
uoro-4-methoxyphenyl)sulfonyl]-3-nitrobenzene;
4-Trifluoromethylsulfonamid-
o-1-[(3-hydroxy-4-methoxyphenyl)sulfonyl]-3-nitrobenzene;
4-Trifluoroacetoxy-1-[(4-methoxyphenyl)sulfonyl]-3-nitrobenzene;
4-Trifluoroacetoxy-1-[(3-fluoro-4-methoxyphenyl)sulfonyl]-3-nitrobenzene;
4-Trifluoroacetoxy-1-[(3-hydroxy-4-methoxyphenyl)sulfonyl]-3-nitrobenzene-
; 1-[(4-Methoxyphenyl)sulfonyl]-4-methylsulfonamido-3-nitrobenzene;
1-[(3-Fluoro-4-methoxyphenyl)sulfonyl]-4-methylsulfonamido-3-nitrobenzene-
;
1-[(3-Hydroxy-4-methoxyphenyl)sulfonyl]-4-methylsulfonamido-3-nitrobenze-
ne;
1-[(4-Methoxyphenyl)sulfonyl]-4-phenylsulfonamido-3-nitrobenzene;
1-[(3-Fluoro-4-methoxyphenyl)sulfonyl]-4phenylsulfonamido-3-nitrobenzene;
1-[(3-Hydroxy-4-methoxyphenyl)sulfonyl]4-phenylsulfonamido-3-nitrobenzene-
; 2,3,5,6-Tetrafluoro-4-[(4-methoxyphenyl)sulfonyl]-1-nitrobenzene;
2,3,5,6-Tetrafluoro-4-[(3-hydroxy-4-methoxyphenyl)sulfonyl]-1-nitrobenzen-
e;
2,3,5,6-Tetrafluoro-4-[(3-fluoro-4-methoxyphenyl)sulfonyl]-1-nitrobenze-
ne;
2,3,5,6-Tetrafluoro-4-trifluoromethylsulfonamido-1-[(4-methoxyphenyl)s-
ulfonyl]benzene;
2,3,5,6-Tetrafluoro-4-trifluoromethylsulfonamido-1-[(3-fl-
uoro-4-methoxyphenyl)-sulfonyl]benzene;
2,3,5,6-Tetrafluoro-4-trifluoromet-
hylsulfonamido-1-[(3-hydroxy-4-methoxyphenyl)-sulfonyl]benzene;
2,3,5,6-Tetrafluoro-4-trifluoroacetoxy-1-[(4-methoxyphenyl)sulfonyl]benze-
ne;
2,3,5,6-Tetrafluoro-4-trifluoroacetoxy-1-[(3-fluoro-4-methoxyphenyl)su-
lfonyl]benzene;
2,3,5,6-Tetrafluoro-4-trifluoroacetoxy-1-[(3-hydroxy-4-met-
hoxyphenyl)sulfonyl]benzene;
2,3,5,6-Tetrafluoro-1-[(4-methoxyphenyl)sulfo-
nyl]-4-(methylsulfonamido)benzene;
2,3,5,6-Tetrafluoro-1-[(3-fluoro-4-meth-
oxyphenyl)sulfonyl]-4-(methylsulfonamido)benzene;
2,3,5,6-Tetrafluoro-1-[(-
3-hydroxy-4-methoxyphenyl)sulfonyl]4-(methylsulfonamido)benzene;
2,3,5,6-Tetrafluoro-1-[(4-methoxyphenyl)sulfonyl]4-(phenylsulfonamido)ben-
zene;
2,3,5,6-Tetrafluoro-1-[(3-fluoro-4-methoxyphenyl)sulfonyl]-4-(phenyl-
sulfonamido)benzene;
2,3,5,6-Tetrafluoro-1-[(3-hydroxy-4-methoxyphenyl)sul-
fonyl]-4-(phenylsulfonamido)benzene;
4-Azido-2,3,5,6-tetrafluoro-1-[(4-met- hoxyphenyl)sulfonyl]benzene;
4-Azido-2,3,5,6-tetrafluoro-1-[(3-hydroxy-4-m-
ethoxyphenyl)sulfonyl]benzene; or
4-Azido-2,3,5,6-tetrafluoro-1-[(3-fluoro-
-4-methoxyphenyl)sulfonyl]benzene.
109. The method of claim 96, wherein n=1, and R.sup.1, R.sup.2,
R.sup.4 and R.sup.5 are independently selected from hydrogen, F,
Cl, Br, OCF.sub.3, CF.sub.3, SO.sub.2--R.sup.8, NO.sub.2, CN,
CO.sub.2--R.sup.8, and SO.sub.2--N(R.sup.6)(R.sup.7).
110. The method of claim 109, wherein the compound is:
1-Bromo-2,4,5,6-tetrafluoro-3-[(4-methoxyphenyl)sulfenyl]benzene;
2,4,5,6-Tetrafluoro-3-[(4-dimethylaminophenyl)sulfenyl]benzoic
acid, ethyl ester;
4-Fluoro-1-[(3-fluoro-4-methoxyphenyl)sulfenyl]-3-nitrobenze- ne;
2-Fluoro-5-[(4-methoxyphenyl)sulfenyl]benzonitrile;
1,3-Dichloro-2,4,6-trifluoro-5-[(3-fluoro-4-methoxyphenyl)sulfenyl]benzen-
e; 2,3,4,5,6-Pentafluoro-1-[(4-methoxyphenyl)sulfenyl]benzene;
2,3,4,5,6-Pentafluoro-1-[(3-hydroxy-4-methoxyphenyl)sulfenyl]benzene;
2,3,4,5,6-Pentafluoro-1-[(3-fluoro-4-methoxyphenyl)sulfenyl]benzene;
2,3,4,5,6-Pentafluoro-1-[(4-dimethylaminophenyl)sulfenyl]benzene;
or
2,3,4,5,6-Pentafluoro-1-[(3,4-dimethoxyphenyl)sulfenyl]benzene.
111. The method of claim 95, wherein the composition is
administered in combination with a therapeutically effective amount
of a hypolipidemic agent or a hypocholesterolemic agent that is not
represented by Formula I.
112. The method of claim 95, wherein the composition is
administered in combination with a therapeutically effective amount
of an antineoproliferative, chemotherapeutic, or cytotoxic agent
that is not represented by formula I.
113. The method of claim 95, wherein the compound is administered
as a prodrug.
114. The method of claim 95, wherein the compound is conjugated to
a targeting molecule which preferentially directs the compound to a
targeted cell.
115. The method of claim 95, wherein the disease state is cancer or
a cancerous condition.
116. The method of claim 95, wherein the proliferative disease
state is infection by a microorganism.
117. The method of claim 95, wherein the proliferative disease
state is psoriasis.
118. The method of claim 95, wherein the proliferative disease
state is vascular restenosis.
119. The method of claim 95, wherein the disease state is
hypercholesterolemia or another disease state associate with
abnormally high blood levels of cholesterol or lipoproteins.
120. The method of claim 95, wherein the composition is
administered orally.
121. The method of claim 95, wherein the composition is
administered intravenously or intramuscularly.
Description
FIELD OF THE INVENTION
[0001] The field of the invention is a particular class of
substituted benzene derivatives and analogs and their use as
pharmacologically active agents capable of lowering plasma
cholesterol levels and inhibiting abnormal cell proliferation.
BACKGROUND
[0002] Atherosclerosis is a leading cause of death in the United
States. The disease results from excess cholesterol accumulation in
the arterial walls, which forms plaques that inhibit blood flow and
promote clot formation, ultimately causing heart attacks, stroke
and claudication. A principal source of these cholesterol deposits
is the low-density lipoprotein (LDL) particles that are present in
the blood. There is a direct correlation between LDL concentration
and plaque formation in the arteries. LDL concentration is itself
largely regulated by the supply of active LDL cell surface
receptors, which bind LDL particles and translocate them from the
blood into the cell's interior. Accordingly, the upregulation of
LDL receptor expression provides an important therapeutic
target.
[0003] Lipoprotein disorders have been previously called the
hyperlipoproteinemias and defined as the elevation of a lipoprotein
level above normal. The hyperlipoproteinemias result in elevations
of cholesterol, triglycerides or both, and are clinically important
because of their contribution to atherosclerotic diseases and
pancreatitis.
[0004] Lipoproteins are spherical macromolecular complexes of lipid
and protein. The lipid constituents of lipoproteins are esterified
and unesterified (free) cholesterol, triglycerides, and
phospholipids. Lipoproteins transport cholesterol and triglycerides
from sites of absorption and synthesis to sites of utilization.
Cholesteryl esters and triglycerides are nonpolar and constitute
the hydrophobic core of lipoproteins in varying proportions. The
lipoprotein surface coat contains the polar constituents--free
cholesterol, phospholipids, and apolipoproteins--that permit these
particles to be miscible in plasma.
[0005] Cholesterol is used for the synthesis of bile acids in the
liver, the manufacture and repair of cell membranes, and the
synthesis of steroid hormones. There are both exogenous and
endogenous sources of cholesterol. The average American consumes
about 450 mg of cholesterol each day and produces an additional 500
to 1,000 mg in the liver and other tissues. Another source is the
500 to 1,000 mg of biliary cholesterol that is secreted into the
intestine daily; about 50 percent is reabsorbed (enterohepatic
circulation). The rate-limiting enzyme in endogenous cholesterol
synthesis is 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)
reductase. Triglycerides, which are nonpolar lipids consisting of a
glycerol backbone and three fatty acids of varying length and
degrees of saturation, are used for storage in adipose tissue and
for energy.
[0006] Lipoproteins are classified into groups based upon size,
density, electrophoretic mobility, and lipid and protein
composition. Very low density lipoproteins (VLDL) are large,
triglyceride-rich lipoproteins that are synthesized and secreted by
hepatocytes. VLDL interacts with lipoprotein lipase in capillary
endothelium, and the core triglycerides are hydrolyzed to provide
fatty acids to adipose and muscle tissue. About half of the
catabolized VLDL particles are taken up by hepatic LDL receptors
and the other half remain in plasma, becoming intermediate-density
lipoprotein (IDL). IDL is enriched in cholesteryl esters relative
to triglycerides and is gradually converted by hepatic triglyceride
lipase to the smaller, denser, cholesterol ester-rich LDL. As IDL
is converted to LDL, apolipoprotein E becomes detached, and only
one apolipoprotein remains, apo B-100.
[0007] LDL normally carries about 75 percent of the circulating
cholesterol. Cellular LDL uptake is mediated by a glycoprotein
receptor molecule that binds to apo B-100. Approximately 70 percent
of LDL is cleared by receptor uptake, and the remainder is removed
by a scavenger cell pathway using nonreceptor mechanisms. The LDL
receptors span the thickness of the cell's plasma membrane and are
clustered in specialized regions where the cell membrane is
indented to form craters called coated pits. These pits invaginate
to form coated vesicles, where LDL is separated from the receptor
and delivered to a lysosome so that digestive enzymes can expose
the cholesteryl ester and cleave the ester bond to form free
cholesterol. The receptor is recycled to the cell surface.
[0008] As free cholesterol liberated from LDL accumulates within
cells, there are three important metabolic consequences. First,
there is a decrease in the synthesis of HMG-CoA reductase, the
enzyme that controls the rate of de novo cholesterol biosynthesis
by the cell. Second, there is activation of the enzyme acyl
cholesterol acyltransferase (ACAT), which esterifies free
cholesterol into cholesterol ester, the cell's storage form of
cholesterol. Third, accumulation of cholesterol suppresses the
cell's synthesis of new LDL receptors. This feedback mechanism
reduces the cell's uptake of LDL from the circulation.
[0009] Lipoproteins play a central role in atherosclerosis. This
association with the most common cause of death in the developed
world defines the principal clinical importance of the
hyperlipoproteinemias. Individuals with an elevated cholesterol
level are at higher risk for atherosclerosis. Multiple lines of
evidence, including epidemiological, autopsy, animal studies and
clinical trials, have established that LDL is atherosclerogenic and
that the higher the LDL level, the greater the risk of
atherosclerosis and its clinical manifestations. A certain degree
of LDL elevation appears to be a necessary factor in the
development of atherosclerosis, although the process is modified by
many other factors (e.g., blood pressure, tobacco use, blood
glucose level, antioxidant level, and clotting factors). Acute
pancreatitis is another major clinical manifestation of
dyslipoproteinemia. It is associated with chylomicronemia and
elevated VLDL levels. Most patients with acute pancreatitis have
triglyceride levels above 2,000 mg/dL, but a 1983 NIH consensus
development conference recommended that prophylactic treatment of
hypertriglyceridemnia should begin when fasting levels exceed 500
mg/dL. The mechanism by which chylomicronemia and elevated VLDL
levels cause pancreatitis is unclear. Pancreatic lipase may act on
triglycerides in pancreatic capillaries, resulting in the formation
of toxic fatty acids that cause inflammation.
[0010] Abundant evidence indicates that treatment of
hyperlipoproteinemia will diminish or prevent atherosclerotic
complications. In addition to a diet that maintains a normal body
weight and minimizes concentrations of lipids in plasma,
therapeutic agents that lower plasma concentrations of
lipoproteins, either by diminishing the production of lipoproteins
or by enhancing the efficiency of their removal from plasma, are
clinically important. The most promising class of drugs currently
available for the treatment of hyperlipoproteinemia or
hypercholesterolemia acts by inhibiting HMG-CoA reductase, the
rate-limiting enzyme in endogenous cholesterol synthesis. Drugs of
this class competitively inhibit the activity of the enzyme.
Eventually, this inhibition leads to a decrease in the endogenous
synthesis of cholesterol and by normal homeostatic mechanisms,
plasma cholesterol is taken up by LDL receptors to restore the
intracellular cholesterol balance.
[0011] Through both the release of precursors of LDL and
receptor-mediated LDL uptake from the serum, liver cells play a
critical role in maintaining serum cholesterol homeostasis. In both
man and animal models, an inverse correlation appears to exist
between liver LDL receptor expression levels and LDL-associated
serum cholesterol levels. In general, higher hepatocyte LDL
receptor numbers result in lower LDL-associated serum cholesterol
levels. Cholesterol released into hepatocytes can be stored as
cholesteryl esters, converted into bile acids and released into the
bile duct, or it can enter into an oxycholesterol pool. It is this
oxycholesterol pool that is believed to be involved in end product
repression of both the genes of the LDL receptor and enzymes
involved in the cholesterol synthetic pathway.
[0012] Transcription of the LDL receptor gene is known to be
repressed when cells have an excess supply of cholesterol, probably
in the form of oxycholesterol. A DNA sequence in the LDL receptor
promoter region, known as the sterol response element (SRE),
appears to confer this sterol end product repression. This element
has been extensively investigated (Brown, Goldstein and Russell,
U.S. Pat. Nos. 4,745,060 and 4,935,363). The SRE can be inserted
into genes that normally do not respond to cholesterol, conferring
sterol end product repression of the chimeric gene. The exact
mechanism of the repression is not understood. Brown and Goldstein
have disclosed methods for employing the SRE in a screen for drugs
capable of stimulating cells to synthesize LDL receptors (U.S. Pat.
No. 4,935,363). It would be most desirable if the synthesis of LDL
receptors could be upregulated at the level of gene expression. The
upregulation of LDL receptor synthesis at this level offers the
promise of resetting the level of serum cholesterol at a lower, and
clinically more desirable, level. Presently, however, there are no
cholesterol lowering drugs that are known to operate at the level
of gene expression. The present invention describes methods and
compounds that act to inhibit directly or indirectly the repression
of the LDL receptor gene, resulting in induction of the LDL
receptor on the surface of liver cells, facilitating LDL uptake,
bile acid synthesis and secretion to remove cholesterol metabolites
and hence the lowering of LDL-associated serum cholesterol
levels.
[0013] A number of human diseases stem from processes of
uncontrolled or abnormal cellular proliferation. Most prevalent
among these is cancer, a generic name for a wide range of cellular
malignancies characterized by unregulated growth, lack of
differentiation, and the ability to invade local tissues and
metastasize. These neoplastic malignancies affect, with various
degrees of prevalence, every tissue and organ in the body. A
multitude of therapeutic agents have been developed over the past
few decades for the treatment of various types of cancer. The most
commonly used types of anticancer agents include: DNA-alkylating
agents (e.g., cyclophosphamide, ifosfamide), antimetabolites (e.g.,
methotrexate, a folate antagonist, and 5-fluorouracil, a pyrimidine
antagonist), microtubule disruptors (e.g., vincristine,
vinblastine, paclitaxel), DNA intercalators (e.g., doxorubicin,
daunomycin, cisplatin), and hormone therapy (e.g., tamoxifen,
flutamide). The ideal antineoplastic drug would kill cancer cells
selectively, with a wide therapeutic index relative to its toxicity
towards non-malignant cells. It would also retain its efficacy
against malignant cells even after prolonged exposure to the drug.
Unfortunately, none of the current chemotherapies possess an ideal
profile. Most possess very narrow therapeutic indexes, and in
practically every instance cancerous cells exposed to slightly
sublethal concentrations of a chemotherapeutic agent will develop
resistance to such an agent, and quite often cross-resistance to
several other antineoplastic agents.
[0014] Psoriasis, a common chronic skin disease characterized by
the presence of dry scales and plaques, is generally thought to be
the result of abnormal cell proliferation. The disease results from
hyperproliferation of the epidermis and incomplete differentiation
of keratinocytes. Psoriasis often involves the scalp, elbows,
knees, back, buttocks, nails, eyebrows, and genital regions, and
may range in severity from mild to extremely debilitating,
resulting in psoriatic arthritis, pustular psoriasis, and
exfoliative psoriatic dermatitis. No therapeutic cure exists for
psoriasis. Milder cases are often treated with topical
corticosteroids, but more severe cases may be treated with
antiproliferative agents, such as the antimetabolite methotrexate,
the DNA synthesis inhibitor hydroxyurea, and the microtubule
disrupter colchicine.
[0015] Other diseases associated with an abnormally high level of
cellular proliferation include restenosis, where vascular smooth
muscle cells are involved, inflammatory disease states, where
endothelial cells, inflammatory cells and glomerular cells are
involved, myocardial infarction, where heart muscle cells are
involved, glomerular nephritis, where kidney cells are involved,
transplant rejection, where endothelial cells are involved,
infectious diseases such as HIV infection and malaria, where
certain immune cells and/or other infected cells are involved, and
the like. Infectious and parasitic agents per se (e.g. bacteria,
trypanosomes, fungi, etc) are also subject to selective
proliferative control using the subject compositions and
compounds.
[0016] Accordingly, it is one object of the present invention to
provide compounds which directly or indirectly upregulate LDL
receptor synthesis at the level of gene expression and are useful
in the treatment of hypercholesterolemia or
hyperlipoproteinemia
[0017] A further object of the present invention is to provide
therapeutic compositions for treating said conditions.
[0018] A further object of the invention is to provide therapeutic
compositions for treating pancreatitis.
[0019] Still further objects are to provide methods for
upregulating LDL receptor synthesis, for lowering serum LDL
cholesterol levels, and for preventing and treating
atherosclerosis.
[0020] A further object of the present invention is to provide
compounds which directly or indirectly are toxic to actively
dividing cells and are useful in the treatment of cancer, viral and
bacterial infections, vascular restenosis, inflammatory diseases,
autoimmune diseases, and psoriasis.
[0021] A further object of the present invention is to provide
therapeutic compositions for treating said conditions.
[0022] Still further objects are to provide methods for killing
actively proliferating cells, such as cancerous, bacterial, or
epithelial cells, and treating all types of cancers, infections,
inflammatory, and generally proliferative conditions. A further
object is to provide methods for treating other medical conditions
characterized by the presence of rapidly proliferating cells, such
as psoriasis and other skin disorders.
[0023] Other objects, features and advantages will become apparent
to those skilled in the art from the following description and
claims.
SUMMARY OF THE INVENTION
[0024] The invention provides methods and compositions relating to
novel substituted benzene derivatives and analogs and their use as
pharmacologically active agents. The compositions find particular
use as pharmacological agents in the treatment of disease states,
particularly hypercholesterolemia, atherosclerosis, cancer,
bacterial infections, and psoriasis, or as lead compounds for the
development of such agents. The invention provides novel methods
for treating pathology such as hypercholesterolemia,
atherosclerosis, pancreatitis, and hyperlipoproteinemia, including
administering to a patient an effective formulation of one or more
of the subject compositions.
[0025] In one embodiment, the invention provides compounds of
general Formula I: 2
[0026] or a pharmaceutically acceptable salt thereof, wherein:
[0027] R.sup.1, R.sup.2, R.sup.4, and R.sup.5 are independently
selected from hydrogen, lower alkyl, halogen, OCF.sub.3, CF.sub.3,
NO.sub.2, CO.sub.2H, CN, SO.sub.2--N(R.sup.6)(R.sup.7),
SO.sub.2--R.sup.8, CO.sub.2--R.sup.8, and CO--R.sup.8;
[0028] R.sup.3 is a leaving group, such as halogen, NO.sub.2,
OCF.sub.3, S(O)--Ar, SO.sub.2--R.sup.8, SO.sub.2--Ar, N.sub.3,
N(R.sup.6)--SO.sub.2--CF.sub.3, N(R.sup.6--SO.sub.2--R.sup.8,
N(R.sup.6)--SO.sub.2--Ar, N(R.sup.6)--CO--R.sup.8,
N(R.sup.6)--CO--Ar, N[CO--R.sup.8].sub.2, N(R.sup.8).sub.3.sup.+,
N(R.sup.8).sub.2(Ar).sup.+, O--SO.sub.2--Ar, O--SO.sub.2R.sup.8,
O--SO.sub.2--CF.sub.3, O--CO-(R.sup.8), O--CO--Ar, O--Ar,
O--R.sup.8, and O--CO--CF.sub.3;
[0029] Y is a single bond, --O--, --N(R.sup.9)--,
--N(R.sup.9)--CH.sub.2--- , or --CH(R.sup.9)--;
[0030] and Ar is an optionally substituted aryl or heteroaryl
group;
[0031] wherein R.sup.6 and R.sup.7 are independently chosen from
hydrogen, lower alkyl, and lower heteroalkyl;
[0032] R.sup.8 is selected from lower alkyl or lower heteroalkyl;
and R.sup.9 is selected from:
[0033] hydrogen,
[0034] substituted or unsubstituted (C1-C10)alkyl,
[0035] substituted or unsubstituted (C1-C10)alkoxy,
[0036] substituted or unsubstituted (C3-C6)alkenyl,
[0037] substituted or unsubstituted (C2-C6)heteroalkyl,
[0038] substituted or unsubstituted (C3-C6)heteroalkenyl,
[0039] substituted or unsubstituted (C3-C6)alkynyl,
[0040] substituted or unsubstituted (C3-C8)cycloalkyl,
[0041] substituted or unsubstituted (C5-C7)cycloalkenyl,
[0042] substituted or unsubstituted (C5-C7)cycloalkadienyl,
[0043] substituted or unsubstituted aryl,
[0044] substituted or unsubstituted aryloxy,
[0045] substituted or unsubstituted aryl-(C3-C8)cycloalkyl,
[0046] substituted or unsubstituted aryl-(C5-C7)cycloalkenyl,
[0047] substituted or unsubstituted aryloxy-(C3-C8)cycloalkyl,
[0048] substituted or unsubstituted aryl-(C1-C4)alkyl,
[0049] substituted or unsubstituted aryl-(C1-C4)alkoxy,
[0050] substituted or unsubstituted aryl-(C1-C4)heteroalkyl,
[0051] substituted or unsubstituted aryl-(C3-C6)alkenyl,
[0052] substituted or unsubstituted aryloxy-(C5-C4)alkyl,
[0053] substituted or unsubstituted aryloxy-(C2-C4)heteroalkyl,
[0054] substituted or unsubstituted heteroaryl,
[0055] substituted or unsubstituted heteroaryloxy,
[0056] substituted or unsubstituted heteroaryl-(C1-C4)alkyl,
[0057] substituted or unsubstituted heteroaryl-(C1-C4)alkoxy,
[0058] substituted or unsubstituted
heteroaryl-(C1-C4)heteroalkyl,
[0059] substituted or unsubstituted heteroaryl-(C3-C6)alkenyl,
[0060] substituted or unsubstituted heteroaryloxy-(C1-C4)alkyl,
and.
[0061] substituted or unsubstituted
heteroaryloxy-(C2-C4)heteroalkyl,
[0062] wherein, if Y is --N(R.sup.9)--, then R.sup.9 and Ar may be
connected by a linking group E to give a substituent of the Formula
3
[0063] wherein E represents a bond, (C1-C4) alkylene, or (C1-C4)
heteroalkylene, and the ring formed by R.sup.9, E, Ar and the
nitrogen atom contains no more than 8 atoms, or preferably R.sup.9
and Ar may be covalently joined in a moiety that forms a 5- or
6-membered heterocyclic ring with the nitrogen atom;
[0064] with the following provisos:
[0065] At least one of the R.sup.1, R.sup.2, R.sup.4, and R.sup.5
groups is other than hydrogen or lower alkyl;
[0066] When R.sup.1=R.sup.2=R.sup.3=R.sup.4=R.sup.5=F, then Y is a
single bond or --CH(R.sup.9)--;
[0067] When R.sup.1=R.sup.2=R.sup.3=R.sup.4 =R.sup.5=Cl, n=2, and
Y=--NH--, then Ar is other than unsubstituted phenyl or
unsubstituted p-biphenyl;
[0068] When R.sup.1=R.sup.2=R.sup.3=R.sup.4=R.sup.5=Br, n=2, and
Y=--NH--, then Ar is other than unsubstituted phenyl;
[0069] When R.sup.3=halogen, n=2, Y =--NH-- or --N(R.sup.9)--, and
at least one of R.sup.1, R.sup.2, R.sup.4 and R.sup.5 is also
halogen, then at least one of R.sup.1, R.sup.2, R.sup.4 and R.sup.5
must be other than hydrogen;
[0070] When R.sup.1=H, n=2, and Y=--NH--, then at least one of
R.sup.2, R.sup.3, R.sup.4 and R.sup.5 must be a substituent other
than chloro;
[0071] When R.sup.1=R.sup.5=H, n=2, and Y=--N(R.sup.9)--, then at
least one of R.sup.2, R.sup.3, and R.sup.4 must be a substituent
other than chloro;
[0072] When R.sup.1=R.sup.5=halogen, R.sup.2=R.sup.4=H, n=2, and
Y=--N(R.sup.9)--, then R.sup.3 is a substituent other than chloro
or bromo;
[0073] When R.sup.1=R.sup.2=halogen, R.sup.4=R.sup.5=H, n=2, and
Y=--N(R.sup.9)--, then R.sup.3 is a substituent other than chloro
or bromo;
[0074] When R.sup.1=R.sup.4=halogen, R.sup.2=R.sup.5=H, and n=2,
then R.sup.3is a substituent other than chloro or bromo;
[0075] When R.sup.1=R.sup.5 halogen, R.sup.2=R.sup.4=H, and
Y=--O--, then Ar is a ring system other than quinolinyl;
[0076] When R.sup.1=F, R.sup.3=R.sup.4=Cl, and Y=--NH--, then Ar is
a ring system other than 1,3,4-thiadiazolyl;
[0077] When R.sup.1=R.sup.3=F, R.sup.4=Cl, and Y=--NH-- or --O--,
then Ar is a ring other than unsubstituted phenyl;
[0078] When R.sup.1=R.sup.3=R.sup.5=Br, and Y=--NH--, then Ar is a
ring other than phenyl substituted by lower-alkyl;
[0079] When R.sup.1=R.sup.3=R.sup.5=Cl, Y=--NH--, and R.sup.9=H or
methyl, then Ar is a phenyl ring substituted by 14 groups chosen
independently from halogen, OH, OR', NH.sub.2, NHR', and NR'R",
wherein R' and R" are as defined below;
[0080] When R.sup.2=R.sup.3=R.sup.4=Cl, Y=--NH--, and
R.sup.9=propargyl, then Ar is an unsubstituted ring or a ring
substituted by a group other than trifluoromethyl or nitro;
[0081] When R.sup.1=R.sup.3=Cl, and Y=--N(R.sup.9)--, then R.sup.2
and R.sup.4 must both be other than chloro;
[0082] When R.sup.2=CF.sub.3, R.sup.3=Cl, and Y=--N(R.sup.9)--,
then Ar cannot be either a phenyl ring substituted by
trifluoromethyl, nitro, chloro, or lower-alkyl groups, or a
2-benzothiazolyl ring;
[0083] When R.sup.2=CO.sub.2H or NO.sub.2, R.sup.3=Cl, and
Y=--N(R.sup.9)--, then Ar is an unsubstituted phenyl or phenyl
substituted by a substituent other than CO.sub.2H or
CO.sub.2R';
[0084] When R.sup.1=NO.sub.2, R.sup.3=Cl, and Y=--NH--, then Ar is
a ring system other than phenyl substituted by either Br or
NO.sub.2.
[0085] Substituents for the alkyl, alkoxy, alkenyl, heteroalkyl,
heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl,
and cycloalkadienyl radicals are selected independently from
[0086] --H
[0087] --OH
[0088] --O--(C1-C10)alkyl
[0089] .dbd.O
[0090] --NH.sub.2
[0091] --NH--(C1-C10)alkyl
[0092] --N[(C1-C10)alkyl].sub.2
[0093] --SH
[0094] --S--(C1-C10)alkyl
[0095] -halo
[0096] --Si[(C1-C10)alkyl].sub.3
[0097] in a number ranging from zero to (2N+1), where N is the
total number of carbon atoms in such radical.
[0098] Substituents for the aryl and heteroaryl groups are selected
independently from
[0099] -halo
[0100] --OH
[0101] --O--R'
[0102] --O--C(O)R'
[0103] --NH.sub.2
[0104] --NHR'
[0105] --NR'R"
[0106] --SH
[0107] --SR'
[0108] R'
[0109] --CN
[0110] --NO.sub.2
[0111] --CO.sub.2H
[0112] --CO.sub.2--R'
[0113] --CONH.sub.2
[0114] --CONH--R'
[0115] --CONR'R"
[0116] --O--C(O)--NH--R'
[0117] --O--C(O)--NR'R"
[0118] --NH--C(O)--R'
[0119] --NR"--C(O)--R'
[0120] --NH--C(O)--OR'
[0121] --NR"--C(O)--R'
[0122] --NH--C(NH.sub.2).dbd.NH
[0123] --NR'--C(NH.sub.2).dbd.NH
[0124] --NH--C(NH.sub.2).dbd.NR'
[0125] --S(O)--R'
[0126] --S(O).sub.2--R'
[0127] --S(O).sub.2--NH--R'
[0128] --S(O).sub.2--NR'R"
[0129] --N.sub.3
[0130] --CH(Ph).sub.2
[0131] substituted or unsubstituted aryloxy
[0132] substituted or unsubstituted arylamino
[0133] substituted or unsubstituted heteroarylamino
[0134] substituted or unsubstituted heteroaryloxy
[0135] substituted or unsubstituted aryl-(C1-C4)alkoxy,
[0136] substituted or unsubstituted heteroaryl-(C1-C4)alkoxy,
[0137] perfluoro(C1-C4)alkoxy, and
[0138] perfluoro(C1-C4)alkyl,
[0139] in a number ranging from zero to the total number of open
valences on the aromatic ring system;
[0140] and where R' and R" are independently selected from:
[0141] substituted or unsubstituted (C1-C8)alkyl, substituted or
unsubstituted (C1-C10)heteroalkyl,
[0142] substituted or unsubstituted (C2-C6)alkenyl,
[0143] substituted or unsubstituted (C2-C6)heteroalkenyl,
[0144] substituted or unsubstituted (C2-C6)alkynyl,
[0145] substituted or unsubstituted (C3-C8)cycloalkyl,
[0146] substituted or unsubstituted (C3-C8)heterocycloalkyl,
[0147] substituted or unsubstituted (C5-C6) cycloalkyl,
[0148] substituted or unsubstituted (C5-C6)cycloalkadienyl,
[0149] substituted or unsubstituted aryl,
[0150] substituted or unsubstituted aryl-(1-C4)alkyl,
[0151] substituted or unsubstituted aryl-(C1-C4)heteroalkyl,
[0152] substituted or unsubstituted aryl-(C1-C4)alkenyl,
[0153] substituted or unsubstituted aryl-(C2-C6)alkyl,
[0154] substituted or unsubstituted aryloxy-(C1-C4)heteroalkyl,
[0155] substituted or unsubstituted heteroaryl,
[0156] substituted or unsubstituted heteroaryl-(C1-C4)alkyl,
[0157] substituted or unsubstituted
heteroaryl-(C1-C4)heteroalkyl,
[0158] substituted or unsubstituted heteroaryl-(C2-C6)alkenyl,
[0159] substituted or unsubstituted heteroaryloxy-(C1-C4)alkyl,
and
[0160] substituted or unsubstituted
heteroaryloxy-(C1-C4)heteroalkyl .
[0161] Two of the substituents on adjacent atoms of the aryl or
heteroaryl ring may optionally be replaced with a substituent of
the Formula --T--C(O)--(CH.sub.2).sub.n--U--, wherein T and U are
independently selected from N, O, and C, and n=0-2. Alternatively,
two of the substituents on adjacent atoms of the aryl or heteroaryl
ring may optionally be replaced with a substituent of the Formula
--A--(CH.sub.2)p--B--, wherein A and B are independently selected
from C, O, N, S, SO, SO.sub.2, and SO.sub.2NR', and p=1-3. One of
the single bonds of the new ring so formed may optionally be
replaced with a double bond. Alternatively, two of the substituents
on adjacent atoms of the aryl or heteroaryl ring may optionally be
replaced with a substituent of the Formula
--(CH.sub.2).sub.q--X--(CH.sub.2).sub.r--, where q and r are
independently selected from 1-3, and X is selected from O, N, S,
SO, SO.sub.2 and SO.sub.2NR'. The substituent R' in SO.sub.2NR' is
selected from hydrogen or (C1-C6)alkyl.
[0162] In another embodiment, the invention provides for the
pharmaceutical use of compounds of the general Formula I and for
pharmaceutically acceptable compositions of compounds of
[0163] Formula I: 4
[0164] or a pharmaceutically acceptable salt thereof, wherein:
[0165] R.sup.1, R.sup.2, R.sup.4, and R.sup.5 are independently
selected from hydrogen, lower alkyl, halogen, OCF.sub.3, CF.sub.3,
NO.sub.2, CO.sub.2H, CN, SO.sub.2--N(.sup.6)(R.sup.7),
SO.sub.2--R.sup.8, CO.sub.2--R.sup.8, and CO--R.sup.8;
[0166] R.sup.3 is a leaving group, such as halogen, NO.sub.2,
OCF.sub.3, S(O)--Ar, SO.sub.2--R.sup.8, SO.sub.2--Ar, N.sub.3,
N(R.sup.6)--SO.sub.2--CF.sub.3, N(R.sup.6)--SO.sub.2--R.sup.8,
N(R.sup.6)--SO.sub.2--Ar, N(R.sup.6)--CO--R.sup.8,
N(R.sup.6)--CO--Ar, N[CO--R.sup.8].sub.2, N(R.sup.8).sub.3.sup.+,
N(R.sup.8).sub.2(Ar).sup.+, O--SO.sub.2--Ar, O--SO.sub.2--R.sup.8,
O--SO.sub.2--CF.sub.3, O--CO- .sup.8), O--CO--Ar, O--Ar,
O--R.sup.8, and O--CO--CF.sub.3;
[0167] Y is a single bond, --O--, --N(R.sup.9)--,
--N(R.sup.9)--CH.sub.2--- , or --CH(R.sup.9)--;
[0168] and Ar is an optionally substituted aryl or heteroaryl
group;
[0169] wherein R.sup.6 and R.sup.7 are independently chosen from
hydrogen, lower alkyl, and lower heteroalkyl;
[0170] R.sup.8 is selected from lower alkyl or lower heteroalkyl;
and R.sup.9 is selected from:
[0171] hydrogen,
[0172] substituted or unsubstituted (C1-C10)alkyl,
[0173] substituted or unsubstituted (C1-C10)alkoxy,
[0174] substituted or unsubstituted (C3-C6)alkenyl,
[0175] substituted or unsubstituted (C2-C6)heteroalkyl,
[0176] substituted or unsubstituted (C3-C6)heteroalkenyl,
[0177] substituted or unsubstituted (C3-C6)alkynyl,
[0178] substituted or unsubstituted (C3-C8)cycloalkyl,
[0179] substituted or unsubstituted (C5-C7)cycloalkenyl,
[0180] substituted or unsubstituted (C5-C7)cycloalkadienyl,
[0181] substituted or unsubstituted aryl,
[0182] substituted or unsubstituted aryloxy,
[0183] substituted or unsubstituted aryl-(C3-C8)cycloalkyl,
[0184] substituted or unsubstituted aryl-(C5-C7)cycloalkenyl,
[0185] substituted or unsubstituted aryloxy-(C3-C8)cycloalkyl,
[0186] substituted or unsubstituted aryl-(C1-C4)alkyl,
[0187] substituted or unsubstituted aryl-(C1-C4)alkoxy,
[0188] substituted or unsubstituted aryl-(C3-C4)heteroalkyl,
[0189] substituted or unsubstituted aryl-(C3-C6)alkenyl,
[0190] substituted or unsubstituted aryloxy-(C1-C4)alkyl,
[0191] substituted or unsubstituted aryloxy-(C2-C4)heteroalkyl,
[0192] substituted or unsubstituted heteroaryl,
[0193] substituted or unsubstituted heteroaryloxy,
[0194] substituted or unsubstituted heteroaryl-(C1-C4)alkyl,
[0195] substituted or unsubstituted heteroaryl-(C1-C4)alkoxy,
[0196] substituted or unsubstituted heteroaryl-(C1-C4
)heteroalkyl,
[0197] substituted or unsubstituted heteroaryl-(C3-C6)alkenyl,
[0198] substituted or unsubstituted heteroaryloxy-(C1-C4)alkyl,
and
[0199] substituted or unsubstituted
heteroaryloxy-(C2-C4)heteroalkyl,
[0200] wherein, if Y is --N(R.sup.9)--, then R.sup.9 and Ar may be
connected by a linking group E to give a substituent of the Formula
5
[0201] wherein E represents a bond, (C1-C4) alkylene, or (C1-C4)
heteroalkylene, and the ring formed by R.sup.9, E, Ar and the
nitrogen atom contains no more than 8 atoms, or preferably R.sup.9
and Ar may be covalently joined in a moiety that forms a 5- or
6-membered heterocyclic ring with the nitrogen atom;
[0202] with the following provisos:
[0203] At least one of the R.sup.1, R.sup.2, R.sup.4, and R.sup.5
groups is other than hydrogen or lower alkyl;
[0204] When R.sup.1=R.sup.2=R.sup.3=R.sup.4=R.sup.5=F, then Y is a
single bond or --CH(R.sup.9)--;
[0205] When R.sup.1=R.sup.2=R.sup.3=R.sup.4=R.sup.5=Cl, n=2, and
Y=--NH--, then Ar is other than unsubstituted phenyl or
unsubstituted p-biphenyl;
[0206] When R.sup.1=R.sup.2=R.sup.3=R.sup.4=R.sup.5=Br, n=2, and
Y=--NH--, then Ar is other than unsubstituted phenyl;
[0207] When R.sup.3=halogen, n=2, Y=--NH-- or --N(R.sup.9)--, and
at least one of R.sup.1, R.sup.2, R.sup.4 and R.sup.5 is also
halogen, then at least one of R.sup.1, R.sup.2, R.sup.4 and R.sup.5
must be other than hydrogen;
[0208] When R.sup.1=H, n=2, and Y=--NH--, then at least one of
R.sup.2, R.sup.3, R.sup.4 and R.sup.5 must be other than
chloro;
[0209] When R.sup.1=R.sup.5=H, n=2, and Y=--N(R.sup.9)--, then at
least one of R.sup.2, R.sup.3, and R.sup.4 must be a substituent
other than chloro;
[0210] When R.sup.1=R.sup.3=R.sup.5=Cl, Y=--NH--, and R.sup.9=H or
methyl, then Ar is a phenyl ring substituted by 14 groups chosen
independently from halogen, OH, OR', NH.sub.2, NHR', and NR'R",
wherein R' and R" are as defined above;
[0211] When R.sup.1=R.sup.3=Cl and Y=--N(R.sup.9)--, then R.sup.2
and R.sup.4 must both be other than chloro; and
[0212] When R.sup.2=CF.sub.3, R.sup.3=Cl, and Y=--N(R.sup.9)--,
then Ar cannot be either a phenyl ring substituted by
trifluoromethyl, nitro, chloro, or lower-alkyl groups, or a
2-benzothiazolyl ring.
[0213] In yet another embodiment, the present invention provides
novel methods for the use of the subject pharmaceutical
compositions for treating pathology such as cancer, bacterial
infections, psoriasis, hypercholesterolemia, atherosclerosis,
pancreatitis, and hyperlipoproteinemia, including administering to
a patient an effective formulation of one or more of the subject
compositions.
DETAILED DESCRIPTION OF PARTICULAR EMBODIMENTS OF THE INVENTION
[0214] The term "alkyl" by itself or as part of another substituent
means, unless otherwise stated, a straight or branched chain
hydrocarbon radical, including di- and multi-radicals, having the
number of carbon atoms designated (i.e. C1-C10 means one to ten
carbons) and includes straight or branched chain groups such as
methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl,
sec-butyl, homologs and isomers of n-pentyl, n-hexyl,
2-methylpentyl, 1,5-dimethylhexyl, 1-methyl-4-isopropylhexyl and
the like. The term "alkylene" by itself or as part of another
substituent means a divalent radical derived from an alkane, as
exemplified by --CH.sub.2CH.sub.2CH.sub.2CH.sub.2--. A "lower
alkyl" is a shorter chain alkyl, generally having six or fewer
carbon atoms.
[0215] The term "heteroalkyl" by itself or in combination with
another term means, unless otherwise stated, a stable straight or
branched chain radical consisting of the stated number of carbon
atoms and one or two heteroatoms selected from the group consisting
of O, N, and S, and wherein the nitrogen and sulfur atoms may
optionally be oxidized and the nitrogen heteroatom may optionally
be quaternized. The heteroatom(s) may be placed at any position of
the heteroalkyl group, including between the rest of the
heteroalkyl group and the fragment to which it is attached, as well
as attached to the most distal carbon atom in the heteroalkyl
group. Examples include --O--CH.sub.2--CH.sub.2--CH.sub.3,
--CH.sub.2--CH.sub.2--O--CH.sub.3,
--CH.sub.2--CH.sub.2--CH.sub.2--OH,
--CH.sub.2--CH.sub.2--NH--CH.sub.3,
--CH.sub.2--CH.sub.2--N(CH.sub.3)--CH- .sub.3,
--CH.sub.2--S--CH.sub.2--CH.sub.3, --CH.sub.2--CH.sub.2--S(O)--CH.-
sub.3, --O--CH.sub.2--CH.sub.2--CH.sub.2--NH--CH.sub.3, and
--CH.sub.2--CH.sub.2--S(O).sub.2--CH.sub.3. Up to two heteroatoms
may be consecutive, such as, for example,
--CH.sub.2--NH--OCH.sub.3. The term "heteroalkylene" by itself or
as part of another substituent means a divalent radical derived
from heteroalkyl, as exemplified by
--CH.sub.2--CH.sub.2--S--CH.sub.2--CH.sub.2-- and
--CH.sub.2--S--CH.sub.2- --CH.sub.2--NH--.
[0216] The terms "cycloalkyl" and "heterocycloalkyl", by themselves
or in combination with other terms represent, unless otherwise
stated, cyclic versions of "alkyl" and "heteroalkyl", respectively.
Examples of cycloalkyl include cyclopentyl, cyclohexyl,
cycloheptyl, and the like. Examples of heterocycloalkyl include
1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl,
3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl,
tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl,
2-piperazinyl, and the like.
[0217] The term "alkenyl" employed alone or in combination with
other terms means, unless otherwise stated, a stable straight chain
or branched monounsaturated or diunsaturated hydrocarbon group
having the stated number of carbon atoms. Examples include vinyl,
propenyl (allyl), crotyl, isopentenyl, butadienyl, 1,3-pentadienyl,
1,4-pentadienyl, and the higher homologs and isomers. A divalent
radical derived from an alkene is exemplified by
--CH=CH--CH.sub.2--.
[0218] The term "heteroalkenyl" by itself or in combination with
another term means, unless otherwise stated, a stable straight or
branched chain monounsaturated or diunsaturated hydrocarbon radical
consisting of the stated number of carbon atoms and one or two
heteroatoms selected from the group consisting of O, N, and S, and
wherein the nitrogen and sulfur atoms may optionally be oxidized
and the nitrogen heteroatom may optionally be quarternized. Up to
two heteroatoms may be placed consecutively. Examples include
--CH.dbd.CH--O--CH.sub.3, --CH.dbd.CH--CH.sub.2--OH,
--CH.sub.2--CH.dbd.N--OCH.sub.3,
--CH.dbd.CH--N(CH.sub.3)--CH.sub.3, and
--CH.sub.2--CH.dbd.CH--CH.sub.2--- SH.
[0219] The term "alkynyl" employed alone or in combination with
other terms means, unless otherwise stated, a stable straight chain
or branched hydrocarbon group having the stated number of carbon
atoms, and containing one or two carbon-carbon triple bonds, such
as ethynyl, 1- and 3-propynyl, 4-but-1-ynyl, and the higher
homologs and isomers.
[0220] The term "alkoxy" employed alone or in combination with
other terms means, unless otherwise stated, an alkyl group, as
defined above, connected to the rest of the molecule via an oxygen
atom, such as, for example, methoxy, ethoxy, 1-propoxy, 2-propoxy
and the higher homologs and isomers.
[0221] The terms "halo" or "halogen" by themselves or as part of
another substituent mean, unless otherwise stated, a fluorine,
chlorine, bromine, or iodine atom.
[0222] The term "aryl" employed alone or in combination with other
terms means, unless otherwise stated, a phenyl, 1-naphthyl, or
2-naphthyl group. The maximal number of substituents allowed on
each one of these ring systems is five, seven, and seven,
respectively. Substituents are selected from the group of
acceptable substituents listed above.
[0223] The term "heteroaryl" by itself or as part of another
substituent means, unless otherwise stated, an unsubstituted or
substituted, stable, mono- or bicyclic heterocyclic aromatic ring
system which consists of from four to ten carbon atoms and from one
to four heteroatoms selected from the group consisting of N, O, and
S, and wherein the nitrogen and sulfur atoms may optionally be
oxidized, and the nitrogen atom(s) may optionally be quaternized.
The heterocyclic system may be attached, unless otherwise stated,
at any heteroatom or carbon atom which affords a chemically stable
structure. The heterocyclic system may be substituted or
unsubstituted with one to four substituents independently selected
from the list of acceptable aromatic substituents listed above.
Examples of such heterocycles include 1-pyrrolyl, 2-pyrrolyl,
3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl,
2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl,
5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl,
3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,
2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl,
2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl,
2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6quinolyl.
[0224] The term "lower" used alone or in combination with another
term indicates that a radical or substituent group contains a total
number of heavy atoms (carbon, oxygen, nitrogen, etc) between one
and ten.
[0225] A "leaving group" as used herein is a substituent on an
aromatic ring that can be displaced by a heteroatom nucleophile in
an aromatic substitution or "S.sub.NAr" reaction, particularly by a
sulfhydryl group under physiological conditions, i.e. within the
range of intracellular pH, ionic strength and temperature
tolerances. Reactions of the S.sub.NAr type proceed in solution
through a .sigma.-complex (Meisenheimer complex) which may be an
intermediate or a transition state; see, Advanced Organic
Chemistry, by Jerry March, 2nd Edition, McGraw-Hill, New York:
1997, pages 594595, and references in footnote 2 of Chapter 13. A
wide variety of such leaving groups find use in the subject
invention. Exemplary suitable leaving groups include: fluoro,
chloro, bromo, iodo, nitro, trifluoromethoxy, Ph-S(O), azido,
CF.sub.3SO.sub.2NH--, PhSO.sub.2NH--, trimethylammonium,
PhOSO.sub.2--, and trifluoroacetate. Preferred leaving groups are
at least as thiolate reactive as the para-fluorine substituent of
the corresponding 2,3,4-trifluorobenezene moiety containing
compound of the invention. Thiolate nucleophile S.sub.NAr
reactivity is readily determined empirically with the assays
described below or as a calculated free energy barrier; see, e.g.
Zheng and Omnstein (J. Am. Chem. Soc., 1997, 119,648-655). Briefly,
ab initio quantum mechanical calculations including gas phase
geometry optimization in the reaction intermediates and complexes
are performed, e.g. at the HF/6-31+G** level of theory using
GAUSSLAN 94 (Gausssian Inc., Pittburg Pa.). The solvation free
energy is then calculated from the ab initio results using a
solvent-effect modeling program (e.g. PS-GVB), and the overall free
energy for the S.sub.NAr reaction is obtained by adding the gas
phase and solution free energy profiles.
[0226] Pharmaceutically acceptable salts of the compounds of
Formula I include salts of these compounds with relatively nontoxic
acids or bases, depending on the particular substituents found on
specific compounds of Formula I. When compounds of Formula I
contain relatively acidic functionalities, base addition salts can
be obtained by contacting the neutral form of compound I with a
sufficient amount of the desired base, either neat or in a suitable
inert solvent Examples of pharmaceutically acceptable base addition
salts include sodium, potassium, calcium; ammonium, organic amino,
or magnesium salt, or a similar salt. When compounds of Formula I
contain relatively basic functionalities, acid addition salts can
be obtained by contacting the neutral form of compound I with a
sufficient amount of the desired acid, either neat or in a suitable
inert solvent Examples of pharmaceutically acceptable acid addition
salts include those derived from inorganic acids like hydrochloric,
hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,
monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,
monohydrogensulfuric, hydriodic, or phosphorous acids and the like,
as well as the salts derived from relatively nontoxic organic acids
like acetic, propionic, isobutyric, oxalic, maleic, malonic,
benzoic, succinic, suberic, fumnaric, mandelic, phthalic,
benzenesulfonic, p-tolylsulfonic, citric, tartaric,
methanesulfonic, and the like. Also included are salts of amino
acids such as arginate and the like, and salts of organic acids
like gluconic or galactunoric acids and the like (see, for example,
Berge, S. M., et al, "Pharmaceutical Salts", Journal of
Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds
of Formula I contain both basic and acidic functionalities that
allow the compounds to be converted into either base or acid
addition salts.
[0227] The neutral forms of the compounds may be regenerated by
contacting the salt with a base or acid and isolating the parent
compound in the conventional manner. The parent form of the
compound differs from the various salt forms in certain physical
properties, such as solubility in polar solvents, but otherwise the
salts are equivalent to the parent form of the compound for the
purposes of the present invention.
[0228] Certain compounds of the present invention can exist in
unsolvated forms as well as solvated forms, including hydrated
forms. In general, the solvated forms are equivalent to unsolvated
forms and are intended to be encompassed within the scope of the
present invention.
[0229] Certain compounds of the present invention possess
asymmetric carbon atoms (optical centers); the racemates,
diastereomers, and individual isomers are all intended to be
encompassed within the scope of the present invention.
[0230] The compounds of the present invention may also contain
unnatural proportions of atomic isotopes at one or more of the
atoms that constitute such compounds. For example, the compounds
may be radiolabeled with radioactive isotopes, such as for example
tritium (.sup.3H) or carbon-14 (.sup.14C). All isotopic variations
of the compounds of the present invention, whether radioactive or
not, are intended to be encompassed within the scope of the present
invention.
[0231] Illustrative examples of compounds and pharmaceutical
compositions of the subject pharmaceutical methods include:
[0232]
4-Fluoro-1-[(4-methoxyphenyl)aminosulfonyl]-3-nitrobenzene;
[0233]
4-Fluoro-1-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]-3-nitrobenzen-
e;
[0234]
4-Fluoro-1-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]-3-nitrobenzene-
;
[0235]
1-Bromo-3,4,5,6-tetrafluoro-2-[(3-hydroxy-4-methoxyphenyl)aminosulf-
onyl]benzene;
[0236]
1-Bromo-3,4,5,6-tetrafluoro-2-[(4-methoxyphenyl)aminosulfonyl)]benz-
ene;
[0237]
1-Bromo-2,4,5,6-tetrafluoro-3-[(4-methoxyphenyl)aminosulfonyl)]benz-
ene;
[0238]
1-Bromo-2,3,5,6-tetrafluoro-4-[(4-methoxyphenyl)aminosulfonyl]benze-
ne;
[0239]
1-Chloro-2,3,5,6-tetrafluoro4-[(4-methoxyphenyl)aminosulfonyl]benze-
ne;
[0240]
1,3-Dichloro-2,4,6-trifluoro-5-[(4-methoxyphenyl)aminosulfonyl]benz-
ene;
[0241]
1,3-Dichloro-2,4,6-trifluoro-5-[(3-hydroxy4-methoxyphenyl)aminosulf-
onyl]benzene;
[0242]
1-Bromo4,5,6-trifluoro-2-[(4-methoxyphenyl)aminosulfonyl]benzene;
[0243]
1-Bromo4,5,6-trifluoro-3-[(3-hydroxy4-methoxyphenyl)aminosulfonyl]b-
enzene;
[0244]
1-Bromo4,5,6-trifluoro-2-[(3-hydroxy4-methoxyphenyl)aminosulfonyl]b-
enzene;
[0245]
1-Bromo-3,4,5-trifluoro-2-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl-
]benzene;
[0246]
1-Bromo-3,4,5-trifluoro-2-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]-
benzene;
[0247]
2,3,4-Trifluoro-1-[(4-methoxyphenyl)aminosulfonyl]benzene;
[0248]
1-Bromo-3,4,5-trifluoro-2-[(4-methoxyphenyl)aminosulfonyl]benzene;
[0249] 2,3,4-Trifluoro-1-[(3-fluoro4-
methoxyphenyl)aminosulfonyl]benzene;
[0250]
1-[(3-Chloro4-methoxyphenyl)aminosulfonyl]-2,3,4-trifluorobenzene;
[0251]
2,3,4-Trifluoro-1-[(3-hydroxy4-methoxyphenyl)aminosulfonyl]benzene;
[0252]
3,4,6-Trifluoro-1-[(4-methoxyphenyl)aminosulfonyl]benzene;
[0253]
2,3,4,6-Tetrafluoro-1-[(4-methoxyphenyl)aminosulfonyl]benzene;
[0254]
2,3,4,5-Tetrafluoro-1-[(4-methoxyphenyl)aminosulfonyl]benzene;
[0255]
2,3,4,5-Tetrafluoro-1-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]ben-
zene;
[0256]
2,3,4,5-Tetrafluoro-1-[(3-fluoro4-methoxyphenyl)aminosulfonyl]benze-
ne;
[0257]
3,4,5-Trifluoro-1-[(4-methoxyphenyl)aminosulfonyl]benzene;
[0258]
3,4,5-Trifluoro-1-[(3-hydroxy4-methoxyphenyl)aminosulfonyl]benzene;
[0259]
3,4,5-Trifluoro-1-[(3-fluoro4-methoxyphenyl)aminosulfonyl]benzene;
[0260]
1-Bromo-3,4,5,6-tetrafluoro-2-[(3-fluoro-4-methoxyphenyl)aminosulfo-
nyl]benzene;
[0261]
1-Bromo-2,4,5,6-tetrafluoro-3-[(3-hydroxy-4-methoxyphenyl)aminosulf-
onyl]benzene;
[0262]
1-Bromo-2,3,5,6-tetrafluoro-4-[(3-hydroxy-4-methoxyphenyl)aminosulf-
onyl]benzene;
[0263]
1-Bromo-2,4,5,6-tetrafluoro-3-[(3-fluoro-4-methoxyphenyl)aminosulfo-
nyl]benzene;
[0264]
1-Bromo-2,3,5,6-tetrafluoro-4-[(3-fluoro-4-methoxyphenyl)aminosulfo-
nyl]benzene;
[0265]
1-Chloro-2,3,5,6-tetrafluoro-4-[(3-hydroxy-4-methoxyphenyl)aminosul-
fonyl]benzene;
[0266]
1-Chloro-2,3,5,6-tetrafluoro-4-[(3-fluoro-4-methoxyphenyl)aminosulf-
onyl]benzene;
[0267]
1,3-Dichloro-2,4,6-trifluoro-5-[(3-fluoro-4-methoxyphenyl)aminosulf-
onyl]benzene;
[0268]
1-Bromo-4,5,6-trifluoro-3-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]-
benzene;
[0269]
4-Fluoro-1-[(4-methoxyphenyl)methylsulfonyl]-3-nitrobenzene;
[0270] 2-Fluoro-5-[(4-methoxyphenyl)aminosulfonyl]benzonitrile;
[0271]
2-Fluoro5-[(3-fluoro4-methoxyphenyl)aminosulfonyl]benzonitrile;
[0272]
2-Fluoro-5-[(3-hydroxy4-methoxyphenyl)aminosulfonyl]benzonitrile;
[0273] 4,5-Difluoro-1-[(4-
methoxyphenyl)aminosulfonyl]-3-nitrobenzene;
[0274]
4,5-Difluoro-1-[(3-fluoro4-methoxyphenyl)aminosulfonyl]-3-nitrobenz-
ene;
[0275]
4,5-Difluoro-1-[(3-hydroxy4methoxyphenyl)aminosulfonyl]-3-nitrobenz-
ene;
[0276]
4-Trifluoromethylsulfonamido-1-[(4-methoxyphenyl)aminosulfonyl]-3-n-
itrobenzene;
[0277]
4-Trifluoromethylsulfonamido-1-[(3-fluoro-4-methoxyphenyl)aminosulf-
onyl]-3-nitrobenzene;
[0278]
4-Trifluoromethylsulfonamido-1-[(3-hydroxy4-methoxyphenyl)aminosulf-
onyl]-3-nitrobenzene;
[0279]
4(Diacetylamino)-2,3-difluoro-1-[(3-fluoro-4-methoxyphenyl)aminosul-
fonyl]-5-nitrobenzene;
[0280] 2,3,4-Trifluoro-5-[(4-methoxyphenyl)aminosulfonyl]benzoic
acid, ethyl ester;
[0281]
2,3,4-Trifluoro-5-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzoic
acid, ethyl ester;
[0282]
2,3,4-Trifluoro-5-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzoic
acid, ethyl ester;
[0283]
2,4,5,6-Tetrafluoro-3-[(4-methoxyphenyl)aminosulfonyl]benzoic acid,
ethyl ester;
[0284]
2,4,5,6-Tetrafluoro-3-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benz-
oic acid, ethyl ester;
[0285]
2,4,5,6-Tetrafluoro-3-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]ben-
zoic acid, ethyl ester;
[0286]
1-Chloro-4-[(4-methoxyphenyl)aminosulfonyl]-2-nitrobenzene;
[0287]
1-Chloro-4-[(3-fluoro4-methoxyphenyl)aminosulfonyl]-2-nitrobenzene;
[0288]
1-Chloro-4-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]-2-nitrobenzen-
e;
[0289]
4-Fluoro-1-[(3-hydroxy4-methoxyphenyl)methylsulfonyl]-3-nitrobenzen-
e;
[0290] 4-Fluoro-1-[(4-methoxyphenyl)sulfonyl]-3-nitrobenzene;
[0291]
4-Fluoro-1-[(3-hydroxy-4-methoxyphenyl)sulfonyl]-3-nitrobenzene;
[0292]
1-Bromo-3,4,5,6-tetrafluoro-2-[(3-hydroxy-4-methoxyphenyl)methylsul-
fonyl]benzene;
[0293]
1-Bromo-2,3,5,6-tetrafluoro4-[(3-fluoro4-methoxyphenyl)sulfonyl]ben-
zene;
[0294]
1-Bromo-2,4,5,6-tetrafluoro-3-[(4-methoxyphenyl)sulphenyl]benzene;
[0295]
1,3-Dichloro-2,4,6-trifluoro-5-[(3-fluoro-4-methoxyphenyl)methylsul-
fonyl]benzene;
[0296]
2,3,4,5-Tetrafluoro-1-[(4-methoxyphenyl)sulfonyl]benzene;
[0297]
2,3,4,6-Tetrafluoro-1-[(3-hydroxy4-methoxyphenyl)methylsulfonyl]ben-
zene;
[0298] 2-Fluoro-5-[(4-methoxyphenyl)sulfonyl]benzonitrile;
[0299]
2-Fluoro-5-[(3,4-dimethoxyphenyl)methylsulfonyl]benzonitrile;
[0300] 2,3,4-Trifluoro-5-[(4-dimethylaminophenyl)sulfonyl]benzoic
acid, ethyl ester;
[0301]
2,4,5,6-Tetrafluoro-3-[(4-dimethylaminophenyl)sulfenyl]benzoic
acid, ethyl ester;
[0302]
1-Chloro4-[(4-methoxyphenyl)methylsulfonyl]-2-nitrobenzene;
[0303]
1-Chloro-4-[(4-dimethylaminophenyl)sulfonyl]-2-nitrobenzene;
[0304] 2-Chloro-5-[(4-methoxyphenyl)aminosulfonyl]benzonitrile;
[0305]
2-Chloro-5-[(3-fluoro4-methoxyphenyl)aminosulfonyl]benzonitrile;
[0306]
2-Chloro-5-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzonitrile;
[0307]
4-Fluoro-5-[(3,4-dimethoxyphenyl)aminosulfonyl]-3-nitrobenzene;
[0308] 4-Fluoro-
-[(4-dimethylaminophenyl)aminosulfonyl]-3-nitrobenzene;
[0309]
4,5-Difluoro-1-[(3,4-dimethoxyphenyl)aminosulfonyl]-3-nitrobenzene;
and
[0310]
4,5-Difluoro-1-[(4-dimethylaminophenyl)aminosulfonyl]-3-nitrobenzen-
e;
[0311] Compounds of general Formula I, or a pharmaceutically
acceptable salt thereof, are preferred in which:
[0312] R.sup.1, R.sup.2, R.sup.4, and R.sup.5 are independently
selected from hydrogen, F, Cl, Br, OCF.sub.3, CF.sub.3,
SO.sub.2--(lower-alkyl), NO.sub.2, CN, and
SO.sub.2--N(.sup.6)(R.sup.7);
[0313] R.sup.3 is halogen or OCF.sub.3;
[0314] n=2;
[0315] Y is a single bond, --N(R.sup.9)--, or --CH(R.sup.9)--;
[0316] Ar is an optionally substituted aryl or heteroaryl
group;
[0317] and R.sup.6, R.sup.7 and R.sup.9 are independently chosen
from hydrogen, lower alkyl, and lower heteroalkyl.
[0318] Also preferred are compounds of Formula I in which there is
no linking group E between R.sup.9 and Ar.
[0319] Most preferred are compounds of Formula I in which:
[0320] R.sup.1, R.sup.2, R.sup.4, and R.sup.5 are independently
selected from hydrogen, F, Cl, Br, OCF.sub.3, CF.sub.3, NO.sub.2,
and CN;
[0321] R.sup.3 is halogen or OCF.sub.3;
[0322] Y is --NH--;
[0323] n=2;
[0324] Ar is an optionally substituted aryl group;
[0325] R.sup.6 and R.sup.7 are independently selected from
lower-alkyl; R.sup.9 is hydrogen;
[0326] and there is no linking group E between R.sup.9 and Ar.
[0327] Preferred compounds and compositions of this embodiment of
the invention have specific pharmacological properties. Examples of
most preferred compounds and compositions of this embodiment of the
invention include:
[0328]
4-Fluoro-1-[(4-methoxyphenyl)aminosulfonyl]-3-nitrobenzene;
[0329]
4-Fluoro-1-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]-3-nitrobenzen-
e;
[0330]
4-Fluoro-1-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]-3-nitrobenzene-
;
[0331]
4-Fluoro-1-[(3,4-dimethoxyphenyl)aminosulfonyl]-3-nitrobenzene;
[0332]
4-Fluoro-1-[(4-aminophenyl)aminosulfonyl]-3-nitrobenzene;
[0333] 2-Fluoro-5-[(4-methoxyphenyl)aminosulfonyl]benzonitrile;
[0334]
2-Fluoro-5-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzonitrile;
[0335]
2-Fluoro-5-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzonitrile;
[0336]
2-Fluoro-5-[(3,4-dimethoxyphenyl)aminosulfonyl]benzonitrile;
[0337]
5-[(4-Dimethylaminophenyl)aminosulfonyl]-2-fluorobenzonitrile;
[0338]
4,5-Difluoro-1-[(4-methoxyphenyl)aminosulfonyl]-3-nitrobenzene;
[0339]
4,5-Difluoro-1-[(3-fluoro-4methoxyphenyl)aminosulfonyl]-3-nitrobenz-
ene;
[0340]
4,5-Difluoro-1-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]-3-nitrobe-
nzene;
[0341]
4,5-Difluoro-1-[(3,4-dimethoxyphenyl)aminosulfonyl]-3-nitrobenzene;
[0342]
4,5-Difluoro-1-[(4-aminophenyl)aminosulfonyl]-3-nitrobenzene;
[0343] 2,3,4-Trifluoro-5-[(4-methoxyphenyl)aminosulfonyl]benzoic
acid, ethyl ester;
[0344]
2,3,4-Trifluoro-5-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzoic
acid, ethyl ester;
[0345]
2,3,4-Trifluoro-5-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzoic
acid, ethyl ester;
[0346]
2,3,4-Trifluoro-5-[(3,4-dimethoxyphenyl)aminosulfonyl]benzoic acid,
ethyl ester;
[0347]
2,3,4-Trifluoro-5-[(4-dimethylaminophenyl)aminosulfonyl]benzoic
acid, ethyl ester;
[0348] 2,4-Trifluoro-3-[(4-methoxyphenyl)aminosulfonyl]benzoic
acid, ethyl ester;
[0349]
2,4,5,6-Tetrafluoro-3-[(4-methoxyphenyl)aminosulfonyl]benzoic acid,
ethyl ester;
[0350]
2,4,5,6-Tetrafluoro-3-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]ben-
zoic acid, ethyl ester;
[0351]
2,4,5,6-Tetrafluoro-3-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]ben-
zoic acid, ethyl ester;
[0352]
2,4,5,6-Tetrafluoro-3-[(3,4-dimethoxyphenyl)aminosulfonyl]benzoic
acid, ethyl ester;
[0353]
2,4,5,6-Tetrafluoro-3-[((4-dimethylaminophenyl)aminosulfonyl]benzoi-
c acid, ethyl ester;:
[0354]
1-Bromo-3,4,5,6-tetrafluoro-2-[(3-hydroxy-4-methoxyphenyl)aminosulf-
onyl)]benzene;
[0355]
1-Bromo-3,4,5,6-tetrafluoro-2-[(4-methoxyphenyl)aminosulfonyl)]benz-
ene;
[0356]
1-Bromo-3,4,5,6-tetrafluoro-2-[(3-fluoro-4-methoxyphenyl)aminosulfo-
nyl]benzene;
[0357] 1
Bromo-2,4,5,6-tetrafluoro-3-[(4-methoxyphenyl)aminosulfonyl)]benz-
ene;
[0358]
1-Bromo-2,4,5,6-tetrafluoro-3-[(3-hydroxy-4-methoxyphenyl)aminosulf-
onyl]benzene;
[0359]
1-Bromo-2,4,5,6-tetrafluoro-3-[(3,4-dimethoxyphenyl)aminosulfonyl]b-
enzene;
[0360]
1-Bromo-2,4,5,6-tetrafluoro-3-[(4-dimethoxyphenyl)aminosulfonyl]ben-
zene;
[0361]
1,3-Bromo-2,4,5,6-tetrafluoro-3-[(4-methoxyphenyl)aminosulfonyl]ben-
zene;
[0362]
1,3-Dichloro-2,4,6-trifluoro-5-[(3-hydro-4-methoxyphenyl)aminosulfo-
nyl]benzene;
[0363]
1,3-Dichloro-2,4,6-trifluoro-5-[(3-fluoro-4-methoxyphenyl)aminosulf-
onyl]benzene;
[0364]
1,3-Dichloro-2,4,6-trifluoro-5-[(3-hydroxy-4-methoxyphenyl)aminosul-
fonyl]benzene;
[0365]
1-Bromo-4,5,6-trifluoro-2-[(4-methoxyphenyl)aminosulfonyl]benzene;
[0366]
1-Bromo-4,5,6-trifluoro-2-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl-
]benzene;
[0367]
1-Bromo-4,5,6-trifluoro-2-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]-
benzene;
[0368]
1-Bromo-4,5,6-trifluoro-2-[(3,4-methoxyphenyl)aminosulfonyl]benzene-
;
[0369]
1-Bromo-2,3,4-trifluoro-5-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl-
]benzene;
[0370]
1-Bromo-2,3,4-trifluoro-5-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]-
benzene;
[0371]
1-Bromo-2,3,4-trifluoro-5-[(4-methoxyphenyl)aminosulfonyl]benzene;
[0372]
1-Bromo-2,3,4-trifluoro-5-[(3,4-dimethoxyphenyl)aminosulfonyl]benze-
ne;
[0373]
1-Bromo-3,4,5-trifluoro-2-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl-
]benzene;
[0374]
1-Bromo-3,4,5-trifluoro-2-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]-
benzene;
[0375]
1-Bromo-3,4,5-trifluoro-2-[(4-methoxyphenyl)aminosulfonyl]benzene;
[0376]
2,3,4,5-Tetrafluoro-1-[(4-methoxyphenyl)aminosulfonyl]benzene;
[0377]
2,3,4,5-Tetrafluoro-1-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]ben-
zene;
[0378]
2,3,4,5-Tetrafluoro-1-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benz-
ene;
[0379]
2,3,4,5-Tetrafluoro-1-[(3,4-dimethoxyphenyl)aminosulfonyl]benzene;
[0380]
2,3,4,5-Tetrafluoro-1-[(4-dimethylaminophenyl)aminosulfonyl]benzene-
;
[0381]
3,4,5-Trifluoro-1-[(4-methoxyphenyl)aminosulfonyl]benzene;
[0382]
3,4,5-Trifluoro-1-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzene-
;
[0383]
3,4,5-Trifluoro-1-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzene;
[0384]
3,4,5-Trifluoro-1-[(3,4-dimethoxyphenyl)aminosulfonyl]benzene;
or
[0385]
3,4,5-Trifluoro-1-[(4-dimethylaminophenyl)aminosulfonyl]benzene.
[0386]
1-Chloro-4-[(4-methoxyphenyl)aminosulfonyl]-2-nitrobenzene;
[0387]
1-Chloro-4-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]-2-nitrobenzene-
;
[0388] 1-Chloro-[(3-hydroxy-4-methoxyphenyl
)aminosulfonyl]-2-nitrobenzene ;
[0389]
1-Chloro-4-[(3,4-dimethoxyphenyl)aminosulfonyl]-2-nitrobenzene;
[0390]
1-Chloro-4-[(4-dimethylaminophenyl)aminosulfonyl]-2-nitrobenzene;
[0391] 2-Chloro-5-[(4-methoxyphenyl)aminosulfonyl]benzonitrile;
[0392]
2-Chloro-5-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzonitrile;
[0393]
2-Chloro-5-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzonitrile.
[0394]
2-Chloro-5-[(3,4-dimethoxyphenyl)aminosulfonyl]benzonitrile;
[0395]
2-Chloro-5-[(4-dimethylaminophenyl)aminosulfonyl]benzonitrile;
[0396] 2-Chloro-5-[(4-methoxyphenyl)aminosulfonyl]benzoic acid,
ethyl ester;
[0397] 2-Chloro-5-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzoic
acid, ethyl ester;
[0398] 2-Chloro-5-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzoic
acid, ethyl ester;
[0399] 2-Chloro-5-[(3,4-dimethoxyphenyl)aminosulfonyl]benzoic acid,
ethyl ester;
[0400] 2-Chloro-5-[(4-dimethylaminophenyl)aminosulfonyl]benzoic
acid, ethyl ester;
[0401]
1-Chloro-2,3,5,6-tetrafluoro-4-[(4-methoxyphenyl)aminosulfonyl]benz-
ene;
[0402]
1-Chloro-2,3,5,6-tetrafluoro-4-[(3-hydroxy-4-methoxyphenyl)aminosul-
fonyl]benzene;
[0403]
1-Chloro-2,3,5,6-tetrafluoro-4-[(3-fluoro-4-methoxyphenyl)aminosulf-
onyl]benzene;
[0404]
1-Chloro-2,3,5,6-tetrafluoro-4-[(4-dimethylaminophenyl)aminosulfony-
l]benzene;
[0405]
1-Chloro-2,3,5,6-tetrafluoro-4-[(3,4-dimethoxyphenyl)aminosulfonyl]-
benzene;
[0406]
1-Chloro-2,3,6-trifluoro-[(4-methoxyphenyl)aminosulfonyl]benzene;
[0407]
1-Chloro-2,3,6-trifluoro-4-[(3-hydroxy-4-methoxyphenyl)aminosulfony-
l]benzene;
[0408]
1-Chloro-2,3,6-trifluoro-4-[(3-fluoro-4-methoxyphenyl)aminosulfonyl-
]benzene;
[0409]
1-Chloro-2,3,6-trifluoro-4-[(4-dimethylaminophenyl)aminosulfonyl]be-
nzene;
[0410]
1-Chloro-2,3,6-trifluoro-4-[(3,4-dimethoxyphenyl)aminosulfonyl]benz-
ene;
[0411]
1-Bromo-4-[(4-methoxyphenyl)aminosulfonyl]-2-nitrobenzene;
[0412]
1-Bromo-4-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]-2-nitrobenzene;
[0413]
1-Bromo-4-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]-2-nitrobenzene-
;
[0414]
1-Bromo-4-[(3,4-dimethoxyphenyl)aminosulfonyl]-2-nitrobenzene;
[0415]
1-Bromo-4-[(4-dimethylaminophenyl)aminosulfonyl]-2-nitrobenzene;
[0416] 2-Bromo-5-[(4-methoxyphenyl)aminosulfonyl]benzonitrile;
[0417]
2-Bromo-5-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzonitrile;
[0418]
2-Bromo-5-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzonitrile.
[0419]
2-Bromo-5-[(3,4-dimethoxyphenyl)aminosulfonyl]benzonitrile;
[0420]
2-Bromo-5-[(4-dimethylaminophenyl)aminosulfonyl]benzonitrile;
[0421] 2-Bromo-5-[(4-methoxyphenyl)aminosulfonyl]benzoic acid,
ethyl ester;
[0422] 2-Bromo-5-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzoic
acid, ethyl ester;
[0423] 2-Bromo-5-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzoic
acid, ethyl ester;
[0424] 2-Bromo-5-[(3,4-dimethoxyphenyl)aminosulfonyl]benzoic acid,
ethyl ester;
[0425] 2-Bromo-5-[(4-dimethylaminophenyl)aminosulfonyl]benzoic
acid, ethyl ester;
[0426]
1-Bromo-2,3,5,6-tetrafluoro-4-[(4-methoxyphenyl)aminosulfonyl]benze-
ne;
[0427]
1-Bromo-2,3,5,6-tetrafluoro-4-[(3-hydroxy-4-methoxyphenyl)aminosulf-
onyl]benzene;
[0428]
1-Bromo-2,3,5,6-tetrafluoro-4-[(3-fluoro-4-methoxyphenyl)aminosulfo-
nyl]benzene;
[0429]
1-Bromo-2,3,5,6-tetrafluoro-4-[(4-dimethylaminophenyl)aminosulfonyl-
]benzene;
[0430]
1-Bromo-2,3,5,6-tetrafluoro-4-[(3,4-dimethoxyphenyl)aminosulfonyl]b-
enzene;
[0431]
1-Bromo-2,3,6-trifluoro-4-[(4-methoxyphenyl)aminosulfonyl]benzene;
[0432]
1-Bromo-2,3,6-trifluoro-4-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl-
]benzene;
[0433]
1-Bromo-2,3,6-trifluoro-4-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]-
benzene;
[0434]
1-Bromo-2,3,6-trifluoro-4-[(4-dimethylaminophenyl)aminosulfonyl]ben-
zene;
[0435]
1-Bromo-2,3,6-trifluoro-4-[(3,4-dimethoxyphenyl)aminosulfonyl]benze-
ne;
[0436]
4-Trifluoromethoxy-1-[(4-methoxyphenyl)aminosulfonyl]-3-nitrobenzen-
e;
[0437]
4-Trifluoromethoxy-1-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]-3-ni-
trobenzene;
[0438]
4-Trifluoromethoxy-1-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]
-3-nitrobenzene;
[0439]
4-Trifluoromethoxy-1-[(3,4-dimethoxyphenyl)aminosulfonyl]-3-nitrobe-
nzene;
[0440]
4-Trifluoromethoxy-1-[(4-dimethylaminophenyl)aminosulfonyl]-3-nitro-
benzene;
[0441]
2-Trifluoromethoxy-5-[(4-methoxyphenyl)aminosulfonyl]benzonitrile;
[0442]
2-Trifluoromethoxy-5-[(3-fluoro-methoxyphenyl)aminosulfonyl]benzoni-
trile;
[0443]
2-Trifluoromethoxy-5-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benz-
onitrile.
[0444]
2-Trifluoromethoxy-5-[(3,4-dimethoxyphenyl)aminosulfonyl]benzonitri-
le;
[0445]
2-Trifluoromethoxy-5-[(4-dimethylaminophenyl)aminosulfonyl]benzonit-
rile;
[0446] 2-Trifluoromethoxy-5-[(4-methoxyphenyl)aminosulfonyl]benzoic
acid, ethyl ester;
[0447]
2-Trifluoromethoxy-5-[(3-fluoro-4-methoxyphenyl)aminosulfonyl]benzo-
ic acid, ethyl ester;
[0448]
2-Trifluoromethoxy-5-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benz-
oic acid, ethyl ester;
[0449]
2-Trifluoromethoxy-5-[(3,4-dimethoxyphenyl)aminosulfonyl]benzoic
acid, ethyl ester;
[0450]
2,3,5,6-Tetrafluoro-1-trifluoromethoxy-4-[(4-methoxyphenyl)aminosul-
fonyl]benzene;
[0451]
2,3,5,6-Tetrafluoro-1-trifluoromethoxy-4-[(3-hydroxy-4-methoxypheny-
l)aminosulfonyl]benzene;
[0452]
2,3,5,6Tetrafluoro-1-trifluoromethoxy-4-[(3-fluoro-4-methoxyphenyl)-
aminosulfonyl]benzene;
[0453]
2,3,5,6-Tetrafluoro-1-trifluoromethoxy-4-[(4-dimethylaminophenyl)am-
inosulfonyl]benzene;
[0454]
2,3,5,6-Tetrafluoro-1-trifluoromethoxy-4-[(3,4-dimethoxyphenyl)amin-
osulfonyl]benzene;
[0455]
2,3,6-Trifluoro-1-trifluoromethoxy-4-[(4-methoxyphenyl)aminosulfony-
l]benzene;
[0456] 2,3,6-Trifluoro-1-trifluoromethoxy
[(3-hydroxy-4-methoxyphenyl)amin- osulfonyl]benzene;
[0457]
2,3,6-Trifluoro-1-trifluoromethoxy-4-[(3-fluoro-4-methoxyphenyl)ami-
nosulfonyl]benzene;
[0458]
2,3,6-Trifluoro-1-trifluoromethoxy-4-[(4-dimethylaminophenyl)aminos-
ulfonyl]benzene; or
[0459]
2,3,6-Trifluoro-1-trifluoromethoxy-4-[(3,4-dimethoxyphenyl)aminosul-
fonyl]benzene.
[0460] Synthesis
[0461] The invention provides methods of making the subject
compounds and compositions. In one general embodiment, the methods
involve combining an appropriate sulfonyl chloride (iii) with an
appropriate aniline (iv), as outlined in Scheme 1, to yield a
sulfonamide (v). The necessary sulfonyl chlorides (iii) can be
prepared by sulfonation of the appropriately substituted aromatic
compounds (i) with fuming sulfuric acid, followed by treatment with
a chlorinating agent, such as PCl.sub.5, POCl.sub.3 and the like,
to afford the corresponding sulfonyl chlorides (iii), (Scheme 1).
When the sulfonamides contain certain groups, such as chloro or
bromo, these groups can be catalytically reduced to produce yet
other analogous sulfonamides (vi). 6
[0462] An alternative way of preparing the desired sulfonyl
chlorides (iii) is by heating the starting aromatic compounds (i)
with chlorosulfonic acid as shown in Scheme 2. 7
[0463] Alternatively, the desired sulfonyl chlorides (iii) are
prepared from their corresponding anilines (vii) by dissolving the
aniline in an acidic aqueous solution, such as HCl and the like,
followed by addition of an aqueous solution of sodium nitrite at a
temperature below ambient temperature, typically between -20 and
+5.degree. C. The resulting mixture, containing the desired
diazonium salt, is then added to a saturated solution of sulfur
dioxide in glacial acetic acid containing cuprous chloride, at a
temperature between -10 and +10.degree. C., to yield the
corresponding sulfonyl chloride (iii) (see Scheme 3). 8
[0464] The desired sulfonyl chlorides (iii) can also be prepared by
oxidation of the respective thiophenols (ix) with chlorine and
hydrogen peroxide in acetic acid as shown in Scheme 4. 9
[0465] The sulphinamides described in this patent can be
synthesized by reaction of the desired sulfinyl chlorides (xiii)
with the appropriate amine (iv), as shown in Scheme 5. The
necessary sulfinyl chlorides (xiii) are prepared by metal-halogen
exchange reaction on the appropriate aryl bromides (x), chlorides
or iodides, with an alkyllithium reagent such as butyl-lithium, or
with magnesium metal, followed by treatment of the resulting aryl
organometallic compounds (xi) with sulfa dioxide affords the
lithium sulfinates (xii) that can be further reacted with thionyl
chloride to afford the desired sulfinyl chlorides (xiii). 10
[0466] The sulfoxides (xviii) and sulfones (xix) described in this
patent can be prepared by reaction of the desired substituted
thiophenols (xv) with the derivatized benzylic halides (xvi) to
yield the corresponding sulfides (xvii), which can be oxidized to
the corresponding sulfoxides (xviii) or sulfones (xix) according to
Scheme 6. The necessary thiophenols (xv) can be prepared from the
starting substituted anilines (vii) by diazotization, followed by
treatment with sodium sulfide (Scheme 6).
[0467] Alternatively, the thiophenols (xv) can be prepared by
treatment of the diazonium salts (viii) with potassium ethyl
xanthate, followed by saponification of the resulting xanthates
(xx), as shown in Scheme 7. Other alternate methods for the
synthesis of the desired substituted thiophenols (xv) are described
in the chemical literature and are well known to individuals versed
in the art of organic synthesis. 11 12
[0468] Sulfoxides (xxiv) and sulfones (xxv) wherein both aromatic
rings are directly attached to S can be prepared as shown in Scheme
8. The reaction of fluorobenzene derivatives (xxi) with substituted
thiophenols (xxii) provides the diaryl sulfides (xxiii). Oxidation
of these sulfides provides the desired sulfoxides (xxiv) or
sulfones (xxv). 13
[0469] In cases where the desired compounds of Formula I contain
one or more bromine, chlorine, or iodide atoms, these can be
hydrogenated in the presence of a catalyst, such as palladium on
carbon, to give the corresponding dehalogenated compounds. This
process is outlined in Scheme 1. The compounds used as initial
starting materials in this invention may be purchased from
commercial sources or alternatively are readily synthesized by
standard procedures which are well know to those of ordinary skill
in the art.
[0470] Some of the compounds of Formula I may exist as
stereoisomers, and the invention includes all active stereoisomeric
forms of these compounds. In the case of optically active isomers,
such compounds may be obtained from corresponding optically active
precursors using the procedures described above or by resolving
racemic mixtures. The resolution may be carried out using various
techniques such as chromatography, repeated recrystallization of
derived asymmetric salts, or derivatization, which techniques are
well known to those of ordinary skill in the art.
[0471] The compounds of the invention may be labeled in a variety
of ways. For example, the compounds may contain radioactive
isotopes such as, for example, .sup.3H (tritium) and .sup.14C
(carbon-14). Similarly, the compounds may be advantageously joined,
covalently or noncovalently, directly or through a linker molecule,
to a wide variety of other compounds, which may provide pro-drugs
or function as carriers, labels, adjuvents, coactivators,
stabilizers, etc. Such labeled and joined compounds are
contemplated within the present invention.
[0472] Analysis of Compounds
[0473] The subject compounds and compositions were demonstrated to
have pharmacological activity in in vitro and in vivo assays, e.g.,
they are capable of specifically modulating a cellular physiology
to reduce an associated pathology or provide or enhance a
prophylaxis.
[0474] Compounds and compositions of a particular embodiment of the
invention are capable of specifically regulating LDL receptor gene
expression. Compounds may be evaluated in vitro for their ability
to increase LDL receptor expression using western-blot analysis,
for example, as described by Tam et al. (J. Biol. Chem. 1991, 266,
16764). Preferred such compounds and compositions provide
EC.sub.max of less than about 50 .mu.M, preferably less than about
5 .mu.M, more preferably less than about 0.5 .mu.M, more preferably
less than about 0.05 .mu.M, and most preferably less than about
0.005 .mu.M in this assay (see, e.g. Example 28 herein).
Established animal models to evaluate hypocholesterolemic effects
of compounds are known in the art. For example, compounds disclosed
herein are shown to lower cholesterol levels in hamsters fed a
high-cholesterol diet, using a protocol similar to that described
by Spady et al. (J. Clin. Invest. 1988, 81, 300), Evans et al. (J.
Lipid Res. 1994, 35, 1634), and Lin et al (J. Med. Chem. 1995,
38,277).
[0475] Compounds and compositions of a particular embodiment of the
invention display specific toxicity to various types of cells,
preferably exerting their cytotoxic effects by interacting with
cellular tubulin, preferably covalently and irreversibly. Compounds
and compositions may be evaluated in vitro for their ability to
inhibit cell growth, for example, as described by Ahmed et al. (J.
Immunol. Methods 1994, 170, 211). Preferred such compounds and
compositions provide IC.sub.50 of less than about 50 .mu.M,
preferably less than about 5 .mu.M, more preferably less than about
0.5 .mu.M, more preferably less than about 0.05 .mu.M, and most
preferably less than about 0.005 .mu.M in this assay (see, e.g.
Example 28 herein). Established animal models to evaluate
antiproliferative effects of compounds are known in the art. For
example, compounds can be evaluated for their ability to inhibit
the growth of human tumors grafted into immunodeficient mice using
methodology similar to that described by Rygaard and Povlsen (Acta
Pathol. Microbiol. Scand. 1969, 77,758) and Giovanella and Fogh
(Adv. Cancer Res. 1985, 44, 69).
[0476] Formulation and Administration of Compounds and
Pharmaceutical Compositions
[0477] The invention provides methods of using the subject
compounds and compositions to treat disease or provide medicinal
prophylaxis, to upregulate LDL receptor gene expression in a cell,
to reduce blood cholesterol concentration in a host, to slow down
and/or reduce the growth of tumors, etc. These methods generally
involve contacting the cell with or administering to the host an
effective amount of the subject compounds or pharmaceutically
acceptable compositions.
[0478] The compositions and compounds of the invention and the
pharmaceutically acceptable salts thereof can be administered in
any effective way such as via oral, parenteral or topical routes.
Generally, the compounds are administered in dosages ranging from
about 2 mg up to about 2,000 mg per day, although variations will
necessarily occur depending on the disease target, the patient, and
the route of administration. Preferred dosages are administered
orally in the range of about 0.05 mg/kg to about 20 mg/kg, more
preferably in the range of about 0.05 mg/kg to about 2 mg/kg, most
preferably in the range of about 0.05 mg/kg to about 0.2 mg per kg
of body weight per day.
[0479] In one embodiment, the invention provides the subject
compounds combined with a pharmaceutically acceptable excipient
such as sterile saline or other medium, water, gelatin, an oil,
etc. to form pharmaceutically acceptable compositions. The
compositions and/or compounds may be administered alone or in
combination with any convenient carrier, diluent, etc. and such
administration may be provided in single or multiple dosages.
Useful carriers include solid, semi-solid or liquid media including
water and non-toxic organic solvents. In another embodiment, the
invention provides the subject compounds in the form of a pro-drug,
which can be metabolically converted to the subject compound by the
recipient host. A wide variety of pro-drug formulations are known
in the art.
[0480] The compositions may be provided in any convenient form
including tablets, capsules, lozenges, troches, hard candies,
powders, sprays, creams, suppositories, etc. As such the
compositions, in pharmaceutically acceptable dosage units or in
bulk, may be incorporated into a wide variety of containers. For
example, dosage units may be included in a variety of containers
including capsules, pills, etc.
[0481] The compositions may be advantageously combined and/or used
in combination with other hypocholesterolemic or antiproliferative
therapeutic or prophylactic agents, different from the subject
compounds. In many instances, administration in conjunction with
the subject compositions enhances the efficacy of such agents.
Exemplary antiproliferative agents include cyclophosphamide,
methotrexate, adriamycin, cisplatin, daunomycin, vincristine,
vinblastine, vinarelbine, paclitaxel, docetaxel, tamoxifen,
flutamide, hydroxyurea, and mixtures thereof. Exemplary
hypocholesterolemic and/or hypolipemic agents include: bile acid
sequestrants such as quaternary amines (e.g. cholestyramine and
colestipol); nicotinic acid and its derivatives; HMG-CoA reductase
inhibitors such as mevastatin, pravastatin, and simvastatin;
gemfibrozil and other fibric acids, such as gemfibrozil,
clofibrate, fenofibrate, benzafibrate and cipofibrate; probucol;
raloxifene and its derivatives; and mixtures thereof.
[0482] The compounds and compositions also find use in a variety of
in vitro and in vivo assays, including diagnostic assays. For
example, various allotypic LDL receptor gene expression processes
may be distinguished in sensitivity assays with the subject
compounds and compositions, or panels thereof In certain assays and
in in vivo distribution studies, it is desirable to used labeled
versions of the subject compounds and compositions, e.g.
radioligand displacement assays. Accordingly, the invention
provides the subject compounds and compositions comprising a
detectable label, which may be spectroscopic (e.g. fluorescent),
radioactive, etc.
[0483] The following examples are offered by way of illustration
and not by way of limitation.
EXAMPLES
[0484] .sup.1H-NMR spectra were recorded on a Varian Gemini 400 MHz
NMR spectrometer. Significant peaks are tabulated in the order:
number of protons, multiplicity (s, singlet; d, doublet; t,
triplet; q, quartet; m, multiplet; br s, broad singlet) and
coupling constant(s) in Hertz. Electron Ionization (EI) mass
spectra were recorded on a Hewlett Packard 5989A mass spectrometer.
Mass spectrometry results are reported as the ratio of mass over
charge, followed by the relative abundance of each ion (in
parentheses).
[0485] Preparation of Synthetic Intermediates
[0486] Starting materials for the synthesis of the examples of the
present invention are available from commercial sources, known in
the art, e.g. Organic Syntheses, Coll. Vol. VII; 1990, Jeremiah P.
Freeman, ed., John Wiley & Sons, 508-511; Robson, P., Smith, T.
A., Stephens, R., Tatlow, J., J. Chem. Soc., 1963, 3692-3703; and
Synthesis of Fluoroorganic Compounds; 1985, Knunyants, I. and
Yakobson, G., eds., Springer-Verlag, 190, and/or exemplified
below:
Example A
[0487] 14
[0488] 4-Fluoro-3-nitrophenylsulfonyl chloride.
[0489] 2-Fluoronitrobenzene (10.0 g, 70.9 mmol) was added to
chlorosulfonic acid (10.0 ml, 150 mmol) at 65.degree. C. After
stirring at 85.degree. C. for 18 h, the reaction mixture was cooled
to room temperature and poured onto ice chips and extracted with
CH.sub.2Cl.sub.2 (2.times.250 ml). The combined organic extracts
were washed with saturated NaHCO.sub.3 solution and dried
(MgSO.sub.4). Concentration at room temperature and then at
100.degree. C. under high vacuum produced 2.40 g (14%) of the title
compound as a yellow oil. .sup.1H-NMR (CDCl.sub.3): .delta. 8.76
(1H, dd, J=2.4, 6.5 Hz), 8.33 (1H, ddd, J=2.4, 3.8, 9.2 Hz), 7.61
(1H, t, J=9.2 Hz). MS (EI): 239 (15, M.sup.+), 204 (100).
Example B
[0490] 15
[0491] 3,5-Dichloro-2,4,6-trifluorophenylsulfonyl chloride.
[0492] 1,3-Dichloro-2,4,6-trifluorobenzene (5.0 g, 25 mmol) and
chlorosulfonic acid (10.0 ml, 150 mmol) were mixed at ambient
temperature under a nitrogen atmosphere and the reaction was heated
at 80.degree. C. for 24 h. The mixture was then allowed to cool to
ambient temperature and was poured onto 12 g of crushed ice. The
product was extracted with diethyl ether, dried over MgSO.sub.4,
and evaporated to produce 4.9 g of the title compound, which was
used without further purification. MS (EI): 300 (30, M.sup.+), 298
(28), 263 (100), 199 (80).
Example C
[0493] 16
[0494] 2,4,6-Trifluorophenylsulfonyl chloride.
[0495] The title compound was synthesized from
1,3,5-trifluorobenzene by a method similar to that used in Example
B. MS (El): 230 (20, M.sup.+), 195 (80), 131 (50), 81 (100).
Examples D and E
[0496] 17
[0497] 5-Bromo-2,3,4trifluorophenylsulfonyl chloride (Example D)
and 2-Bromo-3,4,5-trifluorophenylsulfonyl chloride (Example E). The
title compounds were obtained as a mixture from
1-bromo-2,3,4trifluorobenzene by a method similar to that used in
Example B.
Example F
[0498] 18
[0499] 2-Bromo-3,4,5,6-tetrafluorophenylsulfonyl chloride.
[0500] 1-Bromo-2,3,4,5-tetrafluorobenzene (5.0 g, 21.8 mmol) was
mixed at ambient temperature with 20% fuming sulfuric acid (20 ml).
The mixture was heated at 40.degree. C. for 3 h and at 110.degree.
C. for 2 h. The reaction mixture was allowed to cool to ambient
temperature and poured onto 12 g of crushed ice. The mixture was
acidified dropwise with concentrated HCl (2 ml) until a solid,
consisting mostly of 2-bromo-3,4,5,6-tetrafluorophenylsulfonic acid
was formed. The solid was filtered, washed with 12N HCl, and dried
under high vacuum to afford 5.3 g of
2-bromo-3,4,5,6-tetrafluorophenylsulfonic acid as a white
hygroscopic solid that was used without further purification. To
the sulfonic acid (3.0 g, 9.7 mmol) was then added phosphorous
pentachloride (8.0 g, 38.4 mmol) in small portions, at ambient
temperature (Caution: exothermic reaction with significant
evolution of HCl). The reaction was allowed to stir for 20 minutes
after the final addition of phosphorous pentachloride. The reaction
mixture was then poured onto crushed ice and the white solid that
formed was filtered and dried to afford 2.8 g of the title
compound, which was used without further purification. MS (EI): 328
(30, M.sup.+), 293 (70), 229 (30), 148 (100).
Example G
[0501] 19
[0502] 3-Bromo-2,4,5,6-tetrafluorophenylsulfonyl chloride.
[0503] The title compound was synthesized from
1-bromo-2,3,4,6-tetrafluoro- benzene by a method similar to that
used in Example F. MS (El): 328 (20, M.sup.+), 293 (70), 229 (50),
148 (100).
Example H
[0504] 20
[0505] 4-Bromo-2,3,5,6-tetrafluorophenylsulfonyl chloride.
[0506] The title compound was synthesized from
1-bromo-2,3,5,6-tetrafluoro- benzene by a method similar to that
used in Example F. MS (El): 328 (20, M.sup.+), 293 (70), 229 (50),
148 (100).
Example 1
[0507] 21
[0508]
4-Fluoro-1-[(4-methoxyphenyl)aminosulfonyl]-3-nitrobenzene.
[0509] p-Anisidine (760 mg, 6.18 mmol) was added to a solution of
4-fluoro-3-nitrophenylsulfonyl chloride (740 mg, 3.09 mmol; Example
A) in MeOH (10 ml) at ambient temperature. After stirring at room
temperature for 15 min, the reaction mixture was concentrated under
reduced pressure and the residue was taken up in ethyl acetate and
filtered through a pad of silica gel. Concentration of the
filtrate, followed by chromatography, provided 603 mg (60% yield)
of the title compound. .sup.1H-NMR (CDCl.sub.3): .delta. 8.42 (1H,
dd, J=2.3, 6.8 Hz), 7.88 (1H, ddd, J=2.4, 4.0, 8.8 Hz), 7.33 (1H,
dd, J=8.8, 9.9 Hz), 6.98 (2H, m), 6.81 (2H, m), 6.45 (1H, s), 3.77
(3H, s). MS (EI): 326 (11, M.sup.+), 122 (100). Anal. Calcd. for
C.sub.13H.sub.11FN.sub.2O.sub.5S: C, 47.85; H, 3.40; N, 8.59; S,
9.83. Found: C, 47.68; H, 3.44; N, 8.54; S, 9.88.
Example 2
[0510] 22
[0511]
4-Fluoro-1-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]-3-nitrobenzen-
e.
[0512] The title compound was prepared in a manner similar to that
described in Example 1, by replacing p-anisidine with
3-hydroxy-4-methoxyaniline. .sup.1H-NMR (CDCl.sub.3): .delta. 8.41
(1H, dd, J=2.4, 6.7 Hz), 7.92 (1H, m), 7.14 (1H, ddd, J=2.4, 4.0,
9.0 Hz), 7.35 (1H, dd, J=9.6, 9.0 Hz), 6.72 (1H, d, J=8.5 Hz), 6.62
(1H, d, J=2.5 Hz), 6.58 (1H, dd, J=2.5, 8.5 Hz), 6.44 (1H, s), 5.64
(1H, s), 3.85 (3H, s). Anal. Calcd. for
C.sub.13H.sub.11FN.sub.2O.sub.6S: C, 45.62; H, 3.24; N, 8.18; S,
9.37. Found: C, 45.71; H, 3.25; N, 8.17; S, 9.29.
Example 3
[0513] 23
[0514]
1-Bromo-3,4,5,6-tetrafluoro-2-[(3-hydroxy-4-methoxyphenyl)aminosulf-
onyl]benzene.
[0515] The title compound was prepared in a manner similar to that
described in Example 1 by replacing p-anisidine with
3-hydroxy-4-methoxyaniline and replacing
4-fluoro-3-nitrophenylsulfonyl chloride with
2-bromo-3,4,5,6-tetrafluorophenylsulfonyl chloride (Example F).
.sup.1H-NMR (CDCl.sub.3): .delta. 7.28 (br s, 1H), 6.69 (m, 3H),
5.72 (s, 1H), 3.82 (s, 3H). MS (EI): 431 (20), 429 (20), 138 (100).
Anal. Calcd. for C.sub.13H.sub.8BrF.sub.4NO.sub.4S: C, 36.30; H,
1.87; N, 3.26; S, 7.45.
[0516] Found: C, 36.20; H, 1.90; N, 3.31; S, 7.39.
Example 4
[0517] 24
[0518]
1-Bromo-3,4,5,6-tetrafluoro-2-[(4-methoxyphenyl)aminosulfonyl]benze-
ne.
[0519] The title compound was prepared in a manner similar to that
described in Example 1 by replacing 4-fluoro-3-nitrophenylsulfonyl
chloride with 2-bromo-3,4,5,6-tetrafluorophenylsulfonyl chloride
(Example F). .sup.1H-NMR (CDCl.sub.3): .delta. 7.23 (1H, br s),
7.07 (2H, dd, J=9.0 and 2.0 Hz), 6.78 (2H, dd, J=9.0 and 2.0 Hz),
3.75 (3H, s). MS (El): 415/413 (10, M.sup.+), 122 (100). Anal.
Calcd. for C.sub.13H.sub.8BrF4NO.sub.3S: C, 37.70; H, 1.95; N,
3.38; S, 7.74. Found: C, 37.60; H, 1.92; N, 3.30; S, 7.71.
Example 5
[0520] 25
[0521]
1-Bromo-2,4,5,6-tetrafluoro-3-[(4-methoxyphenyl)aminosulfonyl)]benz-
ene.
[0522] The title compound was prepared in a manner similar to that
described in Example 1 by replacing 4-fluoro-3-nitrophenylsulfonyl
chloride with 3-bromo-2,4,5,6-tetrafluorophenylsulfonyl chloride
(Example G). .sup.1H-NMR (CDCl.sub.3): .delta. 7.10 (2H, dd, J=9.0
and 2.0 Hz), 7.07 (1H, br s), 6.82 (2H, dd, J=9.0 and 2.0 Hz), 3.77
(3H, s). MS(EI): 415/413 (10, M.sup.+), 122 (100). Anal. Calcd. for
C.sub.13H.sub.8BrF.sub.4NO.sub.3S: C, 37.70; H, 1.95; N, 3.38; S,
7.74. Found: C, 37.66; H, 1.94; N, 3.33; S, 7.67.
Example 6
[0523] 26
[0524]
1-Bromo-2,3,5,6-tetrafluoro-4-[(4-methoxyphenyl)aminosulfonyl]benze-
ne.
[0525] The title compound was prepared in a manner similar to that
described in Example 1 by replacing 4-fluoro-3-nitrophenylsulfonyl
chloride with 4-bromo-2,3,5,6-tetrafluorophenylsulfonyl chloride
(Example H). .sup.1H-NMR (CDCl.sub.3): .delta. 7.16 (1H, br s),
7.11 (2H, dd, J=9.0 and 2.0 Hz), 6.82 (2H, dd, J=9.0 and 2.0 Hz),
3.77 (3H, s). MS(EI): 415/413 (10, M.sup.+), 122 (100). Anal.
Calcd. for C1.sub.3H.sub.8BrF.sub.4NO.sub.3S: C, 37.70; H, 1.95; N,
3.38; S, 7.74. Found: C, 37.62; H, 1.95; N, 3.34; S, 7.66.
Example 7
[0526] 27
[0527]
1-Chloro-2,3,5,6-tetrafluoro-4-[(4-methoxyphenyl)aminosulfonyl]benz-
ene.
[0528] The title compound was prepared in a manner similar to that
described in Example 1 by replacing 4-fluoro-3-nitrophenylsulfonyl
chloride with 4-chloro-2,3,5,6-tetrafluorophenylsulfonyl chloride.
.sup.1H-NMR (CDCl.sub.3): .delta. 7.12 (2H, d, J=9.0 Hz), 6.90 (1H,
br s), 6.83 (2H, J=9.0 Hz), 3.78 (3H, s). MS(EI): 369 (20,
M.sup.+), 122 (100).
Example 8
[0529] 28
[0530]
1,3-Dichloro-2,4,6-trifluoro-5-[(4-methoxyphenyl)aminosulfonyl]benz-
ene.
[0531] The title compound was prepared in a manner similar to that
described in Example 1 by replacing 4-fluoro-3-nitrophenylsulfonyl
chloride with 3,5-dichloro-2,4,6-trifluorophenylsulfonyl chloride
(Example B). .sup.1H-NMR (CDCl.sub.3): .delta. 7.09 (2H, d, J=9.0
Hz), 6.85 (1H, br s), 6.82 (2H, d, J=9.0 Hz), 3.77 (3H, s). MS
(EI): 386 (15, M.sup.+), 385 (20), 122 (100). Anal. Calcd. for
C.sub.13H.sub.8Cl.sub.2F.- sub.3NO.sub.3S: C, 40.43; H, 2.09; N,
3.63; S, 8.30. Found: C, 40.34; H, 2.06; N, 3.70; S, 8.22.
Example 9
[0532] 29
[0533]
1,3-Dichloro-2,4,6-trifluoro-5-[(3-hydroxy-4-methoxyphenyl)aminosul-
fonyl]benzene.
[0534] The title compound was prepared in a manner similar to that
described in Example 1 by replacing p-anisidine with
3-hydroxy-4-methoxyaniline and replacing
4-fluoro-3-nitrophenylsulfonyl chloride with
3,5-dichloro-2,4,6-trifluorophenylsulfonyl chloride (Example B).
.sup.1H-NMR (CDCl.sub.3): .delta. 6.88 (1H, br s), 6.7-6.8 (3H, m),
5.66 (1H, s), 3.85 (3H, s). MS(EI):
[0535] 402 (15, M.sup.+), 401 (20), 138 (100). Anal. Calcd. for
C.sub.13H.sub.8Cl.sub.2F.sub.3NO.sub.4S: C, 38.83; H, 2.00; N,
3.48; S, 7.97. Found: C, 38.66; H, 1.97; N, 3.39; S, 7.86.
Example 10
[0536] 30
[0537]
1-Bromo-2,3,4-trifluoro-5-1(4-methoxyphenyl)aminosulfonyl]benzene.
[0538]
1-Bromo-2,3,4-trifluoro-5-[(4-methoxyphenyl)aminosulfonyl~benzene
(Example 10) and
1-Bromo-4,5,6-trifluoro-2-[(4-methoxyphenyl)aminosulfony- l]benzene
(Example 11) were prepared in a manner similar to that described in
Example 1 by replacing 4-fluoro-3-nitrophenylsulfonyl chloride with
a mixture of 5-bromo-2,3,4-trifluorophenylsulfonyl chloride
(Example D) and 2-bromo-3,4,5-trifluorophenylsulfonyl chloride
(Example E). The two isomeric compounds were separated by column
chromatography (silica gel; ethyl acetate:hexanes, 1:4).
.sup.1H-NMR (CDCl.sub.3): .delta. 7.76 (1H, m), 7.04 (2 H; d, J=9.0
Hz), 6.82 (1H, br s), 6.80 (2H, d, J=9.0 Hz), 3.75 (3H, s). MS(EI):
397/395 (20, M.sup.+), 122 (100). Anal. Calcd. for
C.sub.13H.sub.9BrF.sub.3NO.sub.3S: C, 39.41; H, 2.29; N, 3.54; S,
8.08. Found: C, 39.34; H, 2.23; N, 3.47; S, 7.99.
Example 11
[0539] 31
[0540]
1-Bromo-4,5,6-trifluoro-2-[(4-methoxyphenyl)aminosulfonyl]benzene.
[0541] .sup.1H-NMR (CDCl.sub.3): .delta. 7.69 (1H, m), 7.08 (1H, br
s); 7.03 (2H, dd, J=9.0 and 2.0 Hz), 6.76 (2H, dd, J=9.0 and 2.0
Hz), 3.75 (3H, s). MS(EI): 397/395 (20, M.sup.+), 122 (100). Anal.
Calcd. for C.sub.13H.sub.9BrF.sub.3NO.sub.3S: C, 39.41; H, 2.29; N,
3.54; S, 8.08. Found: C, 39.32; H, 2.31; N, 3.44; S, 7.99.
Example 12
[0542] 32
[0543]
1-Bromo-2,3,4-trifluoro-5-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl-
]benzene.
[0544]
1-Bromo-2,3,4-trifluoro-5-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl-
]benzene (Example 12) and
1-Bromo-4,5,6-trifluoro-2-[(3-hydroxy-4methoxyph-
enyl)aminosulfonyl]benzene (Example 13) were prepared in a manner
similar to that described in Example 1 by replacing
4-fluoro-3-nitrophenylsulfony- l chloride with a mixture of
5-bromo-2,3,4-trifluorophenylsulfonyl chloride (Example D) and
2-bromo-3,4,5-trifluorophenylsulfonyl chloride (Example E) and
replacing p-anisidine with 3-hydroxy-4-methoxyaniline. The two
isomeric compounds were separated by column chromatography (silica
gel; ethyl acetate:hexanes, 1:4). .sup.1H-NMR (CDCl.sub.3): .delta.
7.79 (1H, m), 6.72-6.62 (4H, m), 5.65 (1H, s), 3.85 (3H, s).
Example 13
[0545] 33
[0546]
1-Bromo-4,5,6-trifluoro-2-1(3-hydroxy-4-methoxyphenyl)aminosulfonyl-
]benzene.
[0547] .sup.1H-NMR (CDCl.sub.3): .delta. 7.73 (1H, m), 6.94 (1H, br
s), 6.72-6.62 (3H, m), 5.63 (1 H, s),3.83 (3H, s).
Example 14
[0548] 34
[0549]
2,3,4-Trifluoro-1-[(4-methoxyphenyl)aminosulfonyl]benzene.
[0550] The title compound was prepared in a manner similar to that
described in Example 1 by replacing 4-fluoro-3-nitrophenylsulfonyl
chloride with 2,3,4-trifluorophenylsulfonyl chloride. .sup.1H-NMR
(CDCl.sub.3): .delta. 7.51 (1H, m), 7.02 (3H, m), 6.78 (2H, dd,
J=9.0 and 2.0 Hz), 6.65 (1H, br s), 3.76 (3H, s). MS(EI): 317 (20,
M.sup.+), 122 (100). Anal. Calcd. for
C.sub.13H.sub.10F.sub.3NO.sub.3S: C, 49.21; H, 3.18; N, 4.41; S,
10.10. Found: C, 49.10; H, 3.14; N, 4.32; S, 9.99.
Example 15
[0551] 35
[0552]
2,3,4-Trifluoro-1-[(3-Fluoro-4-methoxyphenyl)aminosulfonyl]ybenzene-
.
[0553] The title compound was prepared in a manner similar to that
described in Example 1, by replacing 4-fluoro-3-nitrophenylsulfonyl
chloride with 2,3,4-trifluorophenylsulfonyl chloride and replacing
p-anisidine with 3-fluoro-4-methoxyaniline. .sup.1H-NMR
(CDCl.sub.3): .delta. 7.52 (1H, m), 7.00 (1H, m), 6.93 (1H, m),
6.80 (2H, m), 6.70 (1H, br s), 3.80 (3H, s).
Example 16
[0554] 36
[0555]
1-[(3-Chloro-4-methoxyphenyl)aminosulfonyl]-2,3,4-trifluorobenzene.
[0556] The title compound was prepared in a manner similar to that
described in Example 1 by 20 replacing
4-fluoro-3-nitrophenylsulfonyl chloride with
2,3,4-trifluorophenylsulfonyl chloride and replacing p-anisidine
with 3-chloro-4-methoxyaniline. .sup.1H-NMR (CDCl.sub.3): .delta.
7.56 (1H, m), 7.17 (1H, d, J=2.0 Hz), 7.02 (1H, m), 6.98 (1H, dd,
J=9.0 and 2.0 Hz), 6.78 (1H, d, J=9.0 Hz), 6.72 (1H, br s), 3.83
(3H, s). MS(EI): 352 (7, M.sup.+), 351 (20), 156 (100). Anal.
Calcd. for C.sub.13H.sub.9ClF.sub.3NO.sub.3S: C, 44.39; H, 2.58; N,
3.98; S, 9.11. Found: C, 44.31; H, 2.58; N, 3.96; S, 9.08.
Example 17
[0557] 37
[0558]
1-[(3-Hydroxy-4-methoxyphenyl)aminosulfonyl]-2,3,4-trifluorobenzene-
.
[0559] The title compound was prepared in a manner similar to that
described in Example 1 by replacing 4-fluoro-3-nitrophenylsulfonyl
chloride with 2,3,4-trifluorophenylsulfonyl chloride and replacing
p-anisidine with 3-hydroxy-4-methoxyaniline. .sup.1H-NMR
(CDCl.sub.3): .delta. 7.55 (1H, m), 7.00 (1H, m), 6.70 (2H, m),
6.60 (2H, m), 5.61 (1H, s), 3.83 (3H, s). Anal. Calcd. for
C.sub.13H.sub.10F.sub.3NO.sub.4S: C, 46.85; H, 3.02; N, 4.20; S,
9.62. Found: C, 46.79; H, 3.03; N, 4.24; S, 9.53.
Example 18
[0560] 38
[0561]
2,4,6-Trifluoro-1-[(4-methoxyphenyl)aminosulfonyl]benzene.
[0562] The title compound was prepared in a manner similar to that
described in Example 1 by replacing 4-fluoro-3-nitrophenylsulfonyl
chloride with 2,4,6-trifluorophenylsulfonyl chloride (Example C).
.sup.1H-NMR (CDCl.sub.3): .delta. 7.08 (2H, dd, J=9.0 and 2.0 Hz),
6.8-6.7 (5H, m), 3.75 (3H, s). Anal. Calcd. for
C.sub.13H.sub.10F.sub.3NO- .sub.3S: C, 49.21; H, 3.18; N, 4.41; S,
10.10. Found: C, 49.13; H, 3.20; N, 4.39; S, 10.01.
Example 19
[0563] 39
[0564] 2,3,4,6Tetrafluoro-1-[(4-methoxyphenyl)aminosulfonyl]
benzene.
[0565]
1-Bromo-2,4,5,6-tetrafluoro-3-[(4-methoxyphenyl)aminosulfonyl]benze-
ne (250 mg, 0.6 mmol) (Example 5) was dissolved in methanol (25 ml)
and placed in a closed vessel. A catalytic amount of 10%
Pd/charcoal (25 mg) was added and the mixture was hydrogenated at
60 psi H.sub.2 for 4 h. The mixture was filtered through celite,
the solvent was evaporated and the residue was purified by
chromatography (silica; EtOAc/Hexane, 1:4) to yield 82 mg of the
title compound. .sup.1H-NMR (CDCl.sub.3): .delta. 7.10 (2H, dd,
J=9.0 and 2.0 Hz), 6.94 (1H, br s), 6.85 (1H, m), 6.79 (2H, dd,
J=9.0 and 2.0 Hz), 3.75 (3H, s). MS(El): 335 (20, M.sup.+), 122
(100). Anal. Calcd. for C.sub.13H.sub.9F.sub.4NO.sub.3S: C, 46.57;
H, 2.71; N, 4.18; S, 9.56. Found: C, 46.46; H, 2.67; N, 4.17; S,
9.52.
Example 20
[0566] 40
[0567]
2,3,4,5-Tetrafluoro-1-[(4-methoxyphenyl)aminosulfonyl]benzene.
[0568] The title compound was prepared in a manner similar to that
described in Example 19 by replacing
1-bromo-2,4,5,6-tetrafluoro-3-[(4-me-
thoxyphenyl)aminosulfonyl]benzene with
1-bromo-3,4,5,6-tetrafluoro-2-[(4-m-
ethoxyphenyl)aminosulfonyl]benzene (Example 4). .sup.1H-NMR
(CDCl.sub.3): .delta. 7.40 (1H, m), 7.05 (2H, dd, J=9.0 and 2.0
Hz), 6.80 (2H, dd, J=9.0 and 2.0 Hz), 3.76 (3H, s). MS(EI): 335
(20, M.sup.+), 122 (100). Anal. Calcd. for
C.sub.13H.sub.9F.sub.4NO.sub.3S: C, 46.57; H, 2.71; N, 4.18; S,
9.56. Found: C, 46.44; H, 2.67; N, 4.13; S, 9.47.
Example 21
[0569] 41
[0570]
2,3,4,5Tetrafluoro-1-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benz-
ene.
[0571] The title compound was prepared in a manner similar to that
described in Example 19 by replacing
1-bromo-2,4,5,6-tetrafluoro-3-[(4-me-
thoxyphenyl)aminosulfonyl]benzene with
1-bromo-3,4,5,6-tetrafluoro-2-[(3-h-
ydroxy-4-methoxyphenyl)aminosulfonyl]benzene (Example 3).
.sup.1H-NMR (CDCl.sub.3): .delta. 7.43 (1H, m), 6.80 (1H, br s),
6.73-6.60 (3H, m), 5.67 (1H, s), 3.84 (3H, s). MS(EI): 351 (20,
M.sup.+), 138 (100). Anal. Calcd. for
C.sub.13H.sub.9F.sub.4NO.sub.4S: C, 44.45; H, 2.58; N, 3.99; S,
9.13. Found: C, 44.39; H, 2.59; N, 3.94; S, 9.24.
Example 22
[0572] 42
[0573]
3,4,5-Trifluoro-1-[(4-methoxyphenyl)aminosulfonyl]benzene.
[0574] The title compound was prepared in a manner similar to that
described in Example 19 by replacing
1-bromo-2,4,5,6-tetrafluoro-3-[(4-me-
thoxyphenyl)aminosulfonyl]benzene with
1-bromo-4,5,6-trifluoro-2-[(4-metho- xyphenyl)aminosulfonyl]benzene
(Example 11). .sup.1H-NMR (CDCl.sub.3): .delta. 7.35 (2H, t, J=6.0
Hz), 7.00 (2H, d, J=9.0 Hz), 6.81 (2H, d, J=9.0 Hz), 3.78 (3H, s).
MS(EI) : 317 (20, M.sup.+), 122 (100). Anal. Calcd. for
C.sub.13H.sub.10F.sub.3NO.sub.3S: C, 49.21; H, 3.18; N, 4.41; S,
10.10. Found: C, 49.09; H, 3.15; N, 4.37; S, 10.03.
Example 23
[0575] 43
[0576]
3,4,5-Trifluoro-1-[(3-hydroxy-4-methoxyphenyl)aminosulfonyl]benzene-
.
[0577] The title compound was prepared in a manner similar to that
described in Example 19 by replacing
1-bromo-2,4,5,6-tetrafluoro-3-[(4-me-
thoxyphenyl)aminosulfonyl]benzene with
1-bromo-4,5,6-trifluoro-2-[(3-hydro-
xy-4-methoxyphenyl)aminosulfonyl]benzene (Example 13). .sup.1H-NMR
(CDCl.sub.3): .delta. 7.38 (2H, t, J=6.0 Hz), 6.74 (1H, d, J=9.0
Hz), 6.64 (1H, d, J=2.0 Hz), 6.58 (1H, dd, J=9.0 and 2.0 Hz), 5.64
(1H, s), 3.88 (3H, s). Anal. Calcd. for
C.sub.13H.sub.10F.sub.3NO.sub.4S: C, 46.85; H, 3.02; N, 4.20; S,
9.62. Found: C, 46.75; H, 3.01; N, 4.20; S, 9.56.
Example 24
[0578] 44
[0579] 4-Methoxybenzyl pentafluorophenyl sulfone. To a solution of
4-methoxybenzylbromide (2.00 g, 9.95 mmol) in DMF (20 ml) at room
temperature was added potassium carbonate (2.07 g, 15.0 mmol)
followed by pentafluorothiophenol (1.33 ml, 9.97 mmol). After
stirring at room temperature for 1 h, the reaction mixture was
poured onto water and extracted with diethyl ether. The combined
organic extracts were washed with 1M NaOH, dried and concentrated
to give a white solid which was used directly in the next step. The
sulfide (1.11 g, 3.47 mmol) was dissolved in dichloromethane (20
ml) and cooled to 0.degree. C. m-chloroperbenzoic acid, MCPBA,
(1.20 g, 6.95 mmol) was added and the resulting mixture stirred at
room temperature for 2 h. The reaction mixture was poured onto 1M
NaOH (50 ml) and extracted with dichloromethane (3.times.25 ml).
The combined organic extracts were washed with brine, dried (Mg
SO.sub.4),concentrated and flash chromatographed (25:25:1,
20:20:3/hexanes:dichloromethane:ethyl acetate) to provide 413 mg
(34%) of the title compound as a white solid. .sup.1H NMR
(CDCl.sub.3): d 7.18-7.22 (2H, m), 6.85-6.80 (2H, m), 4.48 (2H, s),
3.78 (3H, s). MS (El): m/z 352 (2, M.sup.+), 121 (100). Anal.
Calcd. for C.sub.14H.sub.9F.sub.5O.sub.3S: C, 47.73; H, 2.58; S,
9.10. Found: C, 47.88; H, 2.66; S, 8.97.
Example 25
[0580] 45
[0581]
1-[(3,4-Dimethoxyphenyl)aminosulfonyl]-3-fluoro-5-nitro-4-trifluoro-
methoxy-benzene.
[0582] 3,4-Dimethoxyaniline (1.53 g, 10 mmol) is added to a
solution of 3-fluoro-5-nitro4-trifluoromethoxyphenylsulfonyl
chloride (2.87 g, 12 mmol) in MeOH (20 ml) at ambient temperature.
After stirring at room temperature for 15 min, the reaction mixture
is concentrated under reduced pressure and the residue is taken up
in ethyl acetate and filtered through a pad of silica gel.
Concentration of the filtrate, followed by chromatography, provides
the title compound.
Example 26
[0583] 46
[0584]
4-Azido-1-[(4-dimethylamino-3-methoxyphenyl)aminosulfonyl]-2,3,5,6--
tetrafluoro-benzene.
[0585] 4-Dimethylamino-3-methoxyaniline (1.66 g, 10 mmol) is added
to a solution of 4-azido-2,3,5,6-tetrafluorophenylsulfonyl chloride
(3.47 g, 12 mmol) in MeOH (20 ml) at ambient temperature. After
stirring at room temperature for 15 min, the reaction mixture is
concentrated under reduced pressure and the residue is taken up in
ethyl acetate and filtered through a pad of silica gel.
Concentration of the filtrate, followed by chromatography, provides
the title compound.
Example 27
[0586] 47
[0587]
3,5-dinitro-1-[(3,4-methylenedioxyphenyl)aminosulfonyl]-4-(trifluom-
ethylsulfonamido)benzene
[0588] 3,4-Methylenedioxyaniline (1.37 g, 10 mmol) is added to a
solution of
3,5-dinitro-4-(trifluoromethylsulfonamido)phenylsulfonyl chloride
(4.96 g, 12 mmol) in MeOH (20 ml) at ambient temperature. After
stirring at room temperature for 15 min, the reaction mixture is
concentrated under reduced pressure and the residue is taken up in
ethyl acetate and filtered through a pad of silica gel.
Concentration of the filtrate, followed by chromatography, provides
the title compound.
Example 28
[0589] Assessment of Biological Activity.
[0590] Compounds were evaluated for their ability to inhibit in
vitro the growth of HeLa cells, an immortal cell line derived from
a human cervical carcinoma commonly used to evaluate the
cytotoxicity of potential therapeutic agents. The following data
reflect the cytotoxicity of selected examples of the present
invention. The values given represent the concentration of test
compound required to inhibit by 50% the uptake of Alamar Blue
(Biosource International, Camarillo, Calif.) by HeLA cell cultures,
which correlates directly with the overall levels of cellular
metabolism in the culture, and is generally accepted as an
appropriate marker of cell growth. The test was conducted according
to the method of Ahmed et al. (J. Immunol. Methods 1994, 170, 211).
The following selected examples display potent cytotoxic activity
in this assay, with IC.sub.50 values ranging from 0.05 .mu.M to 5.0
.mu.M.
1 Compound IC50 (.mu.M) Example 2 0.15 Example 3 0.05 Example 4
0.15 Example 5 0.15 Example 6 5.0 Example 7 1.5 Example 8 0.15
Example 9 0.05 Example 10 0.5 Example 11 0.5 Example 17 1.5 Example
19 5.0 Example 20 0.5 Example 21 0.15 Example 22 5.0 Example 23 1.5
Example 24 5.0
[0591] Certain compounds were evaluated for their ability to
increase LDL receptor expression in HepG2 cells using western-blot
analysis as described by Tam et al., (J. Biol. Chem., 1991, 266,
16764). The data presented (ECU) reflect the minimum concentration
at which a maximal induction of LDL receptor levels was observed
for each compound. In all cases, the level of induction was greater
than that observed under lipid-free conditions (activated system)
in the absence of the test compounds.
2 Compound EC.sub.max (.mu.m) Example 1 5 Example 2 1.5 Example 3
0.15 Example 4 0.5 Example 5 0.5 Example 6 50 Example 7 50 Example
8 0.5 Example 9 0.15 Example 10 1.5 Example 11 1.5 Example 19 15
Example 20 1.5 Example 21 0.5 Example 22 5 Example 24 1.5
[0592] All publications and patent applications cited in this
specification are herein incorporated by reference as if each
individual publication or patent application were specifically and
individually indicated to be incorporated by reference. Although
the foregoing invention has been described in some detail by way of
illustration and example for purposes of clarity of understanding,
it will be readily apparent to those of ordinary skill in the art
in light of the teachings of this invention that certain changes
and modifications may be made thereto without departing from the
spirit or scope of the appended claims.
* * * * *