U.S. patent application number 10/653399 was filed with the patent office on 2005-05-05 for heterocyclo-substituted imidazoles for the treatment of inflammation.
This patent application is currently assigned to G.D. Searle & Co.. Invention is credited to Collins, Paul W., Huff, Renee M., Khanna, Ish K., Koszyk, Francis J., Partis, Richard A., Weier, Richard M., Xu, Xiangdong, Yu, Yi.
Application Number | 20050096368 10/653399 |
Document ID | / |
Family ID | 27379193 |
Filed Date | 2005-05-05 |
United States Patent
Application |
20050096368 |
Kind Code |
A1 |
Khanna, Ish K. ; et
al. |
May 5, 2005 |
Heterocyclo-substituted imidazoles for the treatment of
inflammation
Abstract
A class of imidazolyl compounds is described for use in treating
inflammation. Compounds of particular interest are defined by
formula (V), 1 wherein R.sup.3 is a radical selected from hydrido,
alkyl, haloalkyl, aralkyl, heterocycloalkyl, heteroaralkyl, acyl,
cyano, alkoxy, alkylthio, alkylthioalkyl, alkylsulfonyl,
cycloalkylthio, cycloalkylthioalkyl, cycloalkylsulfonyl,
cycloalkylsulfonylalkyl, haloalkylsulfonyl, arylsulfonyl, halo,
hydroxyalkyl, alkoxyalkyl, alkylcarbonyl, arylcarbonyl,
aralkylcarbonyl, heterocyclocarbonyl, cyanoalkyl, aminoalkyl,
alkylaminoalkyl, N-arylaminoalkyl, N-alkyl-N-arylaminoalkyl,
carboxyalkyl, alkoxycarbonylalkyl, alkoxycarbonyl,
haloalkylcarbonyl, carboxyl, aminocarbonyl, alkylaminocarbonyl,
alkylaminocarbonylalkyl, heteroarylalkoxyalkyl, heteroaryloxyalkyl,
heteroarylthioalkyl, aralkoxy, aralkylthio, heteroaralkoxy,
heteroaralkylthio, heteroarylalkylthioalkyl, heteroaryloxy,
heteroarylthio, arylthioalkyl, aryloxyalkyl, arylthio, aryloxy.
aralkylthioalkyl, aralkoxyalkyl, aryl and heteroaryl; wherein
R.sup.4 is a radical selected from hydrido, alkyl and halo; and
wherein R.sup.13 and R.sup.14 are independently selected from aryl
and heterocyclo, wherein R.sup.13 and R.sup.14 are optionally
substituted at a substitutable position with one or more radicals
independently selected from alkylsulfonyl, aminosulfonyl, halo,
alkylthio, alkyl, cyano, carboxyl, alkoxycarbonyl, haloalkyl,
hydroxyl, alkoxy, hydroxyalkyl, alkoxyalkyl, haloalkoxy, amino,
alkylamino, arylamino and nitro; provided at least one of R.sup.13
and R.sup.14 is aryl substituted with alkylsulfonyl or
aminosulfonyl; or a pharmaceutically-acceptable salt thereof.
Inventors: |
Khanna, Ish K.;
(Libertyville, IL) ; Weier, Richard M.; (Lake
Bluff, IL) ; Collins, Paul W.; (Deerfield, IL)
; Yu, Yi; (Skokie, IL) ; Xu, Xiangdong;
(Evanston, IL) ; Partis, Richard A.; (Evanston,
IL) ; Koszyk, Francis J.; (Prospect Heights, IL)
; Huff, Renee M.; (Park Ridge, IL) |
Correspondence
Address: |
Bradley W. Crawford
McDonnell Boehnen Hulbert & Berghoff
32nd Floor
300 S. Wacker Drive
Chicago
IL
60606
US
|
Assignee: |
G.D. Searle & Co.
|
Family ID: |
27379193 |
Appl. No.: |
10/653399 |
Filed: |
September 2, 2003 |
Related U.S. Patent Documents
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Application
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Filing Date |
Patent Number |
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10653399 |
Sep 2, 2003 |
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10004944 |
Dec 5, 2001 |
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6613789 |
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10004944 |
Dec 5, 2001 |
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09101493 |
Jun 2, 1999 |
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09101493 |
Jun 2, 1999 |
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PCT/US97/00300 |
Jan 24, 1997 |
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10004944 |
Dec 5, 2001 |
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PCT/US95/09506 |
Jul 27, 1995 |
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PCT/US95/09506 |
Jul 27, 1995 |
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08464154 |
Jun 5, 1995 |
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5616601 |
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08464154 |
Jun 5, 1995 |
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08282395 |
Jul 28, 1994 |
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Current U.S.
Class: |
514/397 |
Current CPC
Class: |
C07D 405/04 20130101;
C07D 233/64 20130101; C07D 401/04 20130101; C07D 403/04 20130101;
C07D 419/04 20130101; C07D 233/90 20130101; C07D 409/04 20130101;
C07D 233/32 20130101 |
Class at
Publication: |
514/397 |
International
Class: |
A61K 031/4178 |
Claims
What is claimed is:
1. A compound of Formula I 96wherein R.sup.1 and R.sup.2 are
independently selected from aryl, cycloalkyl, cycloalkenyl and
heterocyclo, wherein R.sup.1 and R.sup.2 are optionally substituted
at a substitutable position with one or more radicals independently
selected from alkylsulfonyl, aminosulfonyl, haloalkylsulfonyl,
halo, alkylthio, alkyl, cyano, carboxyl, alkoxycarbonyl, haloalkyl,
hydroxcyl, alkoxy, hydroxyalkyl, alkoxyalkyl, haloalkoxy, amino,
alkylamino, arylamino and nitro; wherein R.sup.3 is a radical
selected from hydrido, alkyl, haloalkyl, aralkyl, heterocycloalkyl,
acyl, cyano, alkoxy, alkylthio, alkylthioalkyl, alkylsulfonyl,
cycloalkylthio, cycloalkylthioalkyl, cycloalkylsulfonyl,
cycloalkylsulfonylalkyl, cycloalkyloxy, cycloalkyloxyalkyl,
haloalkylsulfonyl, arylsulfonyl, halo, hydroxyalkyl, alkoxyalkyl,
alkylcarbonyl, arylcarbonyl, aralkylcarbonyl,
heterocycloalkylcarbonyl, cyanoalkyl, azidoalkyl, aminoalkyl,
alkylaminoalkyl, N-arylaminoalkyl, N-alkyl-N-arylaminoalkyl,
carboxyalkyl, alkoxycarbonylalkyl, alkoxycarbonyl,
haloalkylcarbonyl, carboxyl, aminocarbonyl, alkylaminocarbonyl,
alkylaminocarbonylalkyl, heteroarylalkoxyalkyl, heteroaryloxyalkyl,
heteroarylthioalkyl, aralkoxy, aralkylthio, heteroaralkoxy,
heteroaralkylthio, heteroarylalkylthioalkyl, heteroaryloxy,
heteroarylthio, arylthioalkyl, aryloxyalkyl, arylthio, aryloxy,
aralkylthioalkyl, aralkoxyalkyl, aryl and heterocyclo; wherein
R.sup.4 is a radical selected from hydrido, alkyl and fluoro;
wherein R.sup.5 is selected from hydroxyl and alkoxy; and wherein
R.sup.6 is hydrido; or wherein R.sup.5 and R.sup.6 together form a
double bond; provided at least one of R.sup.1 and R.sup.2 is aryl
substituted with alkylsulfonyl, haloalkylsulfonyl or aminosulfonyl;
or a pharmaceutically-acceptable salt thereof.
2. Compound of claim 1 wherein R.sup.1 and R.sup.2 are
independently selected from phenyl, naphthyl, biphenyl, lower
cycloalkyl, lower cycloalkenyl and heteroaryl, wherein R.sup.1 and
R.sup.2 are optionally substituted at a substitutable position with
one or more radicals independently selected from lower
alkylsulfonyl, aminosulfonyl, lower haloalkylsulfonyl, halo, lower
alkylthio, lower alkyl, cyano, carboxyl, lower alkoxycarbonyl,
lower haloalkyl, hydroxyl, lower alkoxy, lower hydroxyalkyl, lower
alkoxyalkyl, lower haloalkoxy, amino, lower alkylamino, arylamino
and nitro; wherein R.sup.3 is a radical selected from hydrido,
lower alkyl, lower haloalkyl, lower aralkyl, lower
heterocycloalkyl, acyl, cyano, lower alkoxy, lower alkylthio, lower
alkylsulfonyl, lower cycloalkyloxy, lower cycloalkyloxyalkyl, lower
cycloalkylthio, lower cycloalkylthioalkyl, lower
cycloalkylsulfonyl, lower cycloalkylsulfonylalkyl, phenylsulfonyl,
lower haloalkylsulfonyl, halo, lower hydroxyalkyl, lower
alkoxyalkyl, lower alkylcarbonyl, lower azidoalkyl, lower
haloalkylcarbonyl, phenylcarbonyl, lower aralkylcarbonyl, lower
heterocycloalkylcarbonyl, lower cyanoalkyl, lower aminoalkyl, lower
alkylaminoalkyl, lower N-arylaminoalkyl, lower
N-alkyl-N-arylaminoalkyl, lower carboxyalkyl, lower
alkoxycarbonylalkyl, lower alkoxycarbonyl, lower alkylthioalkyl,
aminocarbonyl, lower alkylaminocarbonyl, lower
alkylaminocarbonylalkyl, lower aralkoxy, lower aralkylthio, lower
heteroaralkoxy, lower heteroaralkylthio, lower
heteroarylalkoxyalkyl, lower heteroarylalkylthioalkyl, lower
heteroaryloxyalkyl, lower heteroarylthioalkyl, lower heteroaryloxy,
lower heteroarylthio, lower arylthioalkyl, lower aryloxyalkyl,
lower arylthio, lower aryloxy, lower aralkylthioalkyl, lower
aralkoxyalkyl, aryl selected from phenyl and naphthyl, and
heteroaryl, wherein the aryl and heteroaryl radicals are optionally
substituted at a substitutable position with one or more radicals
selected from halo, lower alkylthio, lower alkylsulfonyl, lower
alkyl, cyano, lower haloalkyl, hydroxyl, lower alkoxy, lower
hydroxyalkyl and lower haloalkoxy; wherein R.sup.4 is a radical
selected from hydrido, lower alkyl and fluoro; and wherein R.sup.5
is selected from hydroxyl and lower alkoxy; wherein R.sup.6 is
hydrido; or wherein R.sup.5 and R.sup.6 together form a double
bond; or a pharmaceutically-acceptable salt thereof.
3. Compound of claim 2 wherein R.sup.1 and R.sup.2 are
independently selected from phenyl, naphthyl, biphenyl, cyclohexyl,
cyclohexenyl, benzofuryl, benzodioxolyl, furyl, imidazolyl,
thienyl, thiazolyl, pyrrolyl, oxazolyl, isoxazolyl, triazolyl,
pyrimidinyl, isoquinolyl, quinolinyl, benzimidazolyl, indolyl,
pyrazolyl and pyridyl, wherein R.sup.1 and R.sup.2 are optionally
substituted at a substitutable position with one or more radicals
independently selected from methylsulfonyl, aminosulfonyl,
fluoromethylsulfonyl, difluoromethylsulfonyl, fluoro, chloro,
bromo, methylthio, methyl, ethyl, isopropyl, tert-butyl, isobutyl,
pentyl, hexyl, cyano, carboxyl, methoxycarbonyl, ethoxycarbonyl,
isopropoxycarbonyl, tert-butoxycarbonyl, propoxycarbonyl,
butoxycarbonyl, isobutoxycarbonyl, pentoxycarbonyl, fluoromethyl,
difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,
trichloromethyl, pentafluoroethyl, heptafluoropropyl,
difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,
difluoropropyl, dichloroethyl, dichloropropyl, hydroxyl, methoxy,
methylenedioxy, ethoxy, propoxy, n-butoxy, hydroxymethyl,
hydroxyethyl, methoxymethyl, ethoxymethyl, trifluoromethoxy, amino,
methylamnino, N,N-dimethylamino, phenylamino and nitro; wherein
R.sup.3 is a radical selected from hydrido, methyl, ethyl,
isopropyl, tert-butyl, isobutyl, pentyl, hexyl, fluoromethyl,
difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,
trichloromethyl, pentafluoroethyl, heptafluoropropyl,
difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,
difluoropropyl, dichloroethyl, dichloropropyl, benzyl, phenylethyl,
phenylpropyl, furylmethyl, morpholinomethyl, pyrrolidinylmethyl,
piperazinylmethyl, piperidinylmethyl, pyridylmethyl, thienylmethyl,
formyl, cyano, methoxy, ethoxy, propoxy, n-butoxy, methylthio,
ethylthio, isopropylthio, methylsulfonyl, phenylsulfonyl,
trifluoromethylsulfonyl, fluoro, chloro, bromo, hydroxymethyl,
hydroxyethyl, methoxymethyl, ethoxymethyl, methylthiomethyl,
isopropylthiomethyl, cyclohexylthiomethyl, benzyloxy, benzylthio,
methylcarbonyl, ethylcarbonyl, phenylcarbonyl, azidomethyl,
trifluoromethylcarbonyl, difluoromethylcarbonyl,
fluoromethylcarbonyl, benzylcarbonyl, cyanomethyl, cyanobutyl,
aminomethyl, methylaminomethyl, N-phenylaminomethyl,
N-methyl-N-phenylaminomethyl, acetyl, propanoyl, butanoyl,
methoxycarbonylmethyl, ethoxycarbonylethyl, methoxycarbonyl,
ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl,
propoxycarbonyl, isobutoxycarbonyl, carboxymethyl, carboxypropyl,
aminocarbonyl, methylaminocarbonyl, N,N-diethylaminocarbonyl,
N-methylaminocarbonylmethy- l, pyridyloxy, pyridylthio, phenyloxy,
4-chlorophenoxy, furylmethoxy, furylmethylthio,
5-phenylpyridyl-2-methoxy, thienylmethoxy, quinolylmethoxy,
pyridylmethoxy, thienylmethylthio, pyridylmethylthio,
benzylthiomethyl, quinolylmethoxymethyl, furylbutoxyethyl,
pyridyloxymethyl, pyridylmethoxymethyl, thienyloxyhexyl,
thienylthiomethyl, pyridylthiohexyl, furyloxymethyl,
furylmethylthiomethyl, quinolylmethylthioethyl, phenylthiomethyl,
2-chlorophenylthiomethyl, 2,6-dichlorophenylthiomethyl,
4-methylphenylthiomethyl, 2-isopropylphenylthiomethyl,
2-methylphenylthiomethyl, phenyloxymethyl, 4-chlorophenyloxymethyl,
4-methylphenyloxymethyl, benzyloxymethyl, 4-methoxybenzyloxymethyl,
naphthyl, phenyl, thienyl, furyl, pyridyl, wherein the thienyl,
furyl, pyridyl and phenyl radicals are optionally substituted at a
substitutable position with one or more radicals selected from
fluoro, chloro, bromo, methylthio, methylsulfinyl, methyl, ethyl,
isopropyl, tert-butyl, isobutyl, pentyl, hexyl, cyano,
fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,
dichloromethyl, trichloromethyl, pentafluoroethyl,
heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl,
difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl,
hydroxyl, methoxy, methylenedioxy, ethoxy, propoxy, n-butoxy,
hydroxymethyl, hydroxyethyl and trifluoromethoxy; wherein R.sup.4
is a radical selected from hydrido, methyl, ethyl, and fluoro; and
wherein R.sup.5 is selected from hydroxyl, methoxy, ethoxy, propoxy
and n-butoxy; wherein R.sup.6 is hydrido; or wherein R.sup.5 and
R.sup.6 together form a double bond; or a
pharmaceutically-acceptable salt thereof.
4. A compound of Formula V 97wherein R.sup.3 is a radical selected
from hydrido, alkyl, haloalkyl, aralkyl, heterocycloalkyl,
heteroaralkyl, acyl, cyano, alkoxy, alkylthio, alkylthioalkyl,
alkylsulfonyl, cycloalkylthio, cycloalkylthioalkyl,
cycloalkylsulfonyl, cycloalkylsulfonylalkyl, haloalkylsulfonyl,
arylsulfonyl, halo, hydroxyalkyl, alkoxyalkyl, alkylcarbonyl,
arylcarbonyl, aralkylcarbonyl, heterocyclocarbonyl, cyanoalkyl,
aminoalkyl, alkylaminoalkyl, N-arylaminoalkyl,
N-alkyl-N-arylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl,
alkoxycarbonyl, haloalkylcarbonyl, carboxyl, aminocarbonyl,
alkylaminocarbonyl, alkylaminocarbonylalkyl, heteroarylalkoxyalkyl,
heteroaryloxyalkyl, heteroarylthioalkyl, aralkoxy, aralkylthio,
heteroaralkoxy, heteroaralkylthio, heteroarylalkylthioalkyl,
heteroaryloxy, heteroarylthio, arylthioalkyl, aryloxyalkyl,
arylthio, aryloxy, aralkylthioalkyl, aralkoxyalkyl, aryl and
heteroaryl; wherein R.sup.4 is a radical selected from hydrido,
alkyl and halo; and wherein R.sup.13 and R.sup.14 are independently
selected from aryl and heterocyclo, wherein R.sup.13 and R.sup.14
are optionally substituted at a substitutable position with one or
more radicals independently selected from alkylsulfonyl,
aminosulfonyl, halo, alkylthio, alkyl, cyano, carboxyl,
alkoxycarbonyl, haloalkyl, hydroxyl, alkoxy, hydroxyalkyl,
alkoxyalkyl, haloalkoxy, amino, alkylamino, arylamino and nitro;
provided at least one of R.sup.13 and R.sup.14 is aryl substituted
with alkylsulfonyl or aminosulfonyl; or a
pharmaceutically-acceptable salt thereof.
5. Compound of claim 4 wherein R.sup.3 is a radical selected from
hydrido, lower alkyl, lower haloalkyl, lower aralkyl, lower
heterocycloalkyl, lower heteroaralkyl, acyl, cyano, lower alkoxy,
lower alkylthio, lower alkylsulfonyl, phenylsulfonyl, lower
haloalkylsulfonyl, halo, lower hydroxyalkyl, lower alkoxyalkyl,
lower alkylcarbonyl, lower haloalkylcarbonyl, phenylcarbonyl, lower
aralkylcarbonyl, lower cyanoalkyl, lower aminoalkyl, lower
alkylaminoalkyl, lower N-arylaminoalkyl, lower
N-alkyl-N-arylaminoalkyl, lower carboxyalkyl, lower
alkoxycarbonylalkyl, lower alkoxycarbonyl, carboxyl, lower
alkylthioalkyl, aminocarbonyl, lower alkylaminocarbonyl, lower
alkylaminocarbonylalkyl, lower aralkoxy, lower aralkylthio, lower
heteroaralkoxy, lower heteroaralkylthio, lower
heteroarylalkoxyalkyl, lower heteroarylalkylthioalkyl, lower
heteroaryloxyalkyl, lower heteroarylthioalkyl, lower heteroaryloxy,
lower heteroarylthio, lower arylthioalkyl, lower aryloxyalkyl,
lower arylthio, lower aryloxy, lower aralkylthioalkyl, lower
aralkoxyalkyl, aryl selected from phenyl and naphthyl, 5 or 6
membered heteroaryl, wherein the aryl and heteroaryl radicals are
optionally substituted at a substitutable position with one or more
radicals selected from halo, lower alkylthio, lower alkylsulfinyl,
lower alkyl, cyano, lower haloalkyl, hydroxyl, lower alkoxy, lower
hydroxyalkyl and lower haloalkoxy; wherein R.sup.4 is a radical
selected from hydrido, lower alkyl and halo; and wherein R.sup.13
and R.sup.14 are independently selected from phenyl and heteroaryl,
wherein R.sup.13 and R.sup.14 are optionally substituted at a
substitutable position with one or more radicals independently
selected from lower methylsulfonyl, aminosulfonyl, lower alkylthio,
lower alkyl, lower haloalkyl, lower alkoxy, lower hydroxyalkyl,
lower alkoxyalkyl, and lower haloalkoxy; or a
pharmaceutically-acceptable salt thereof.
6. Compound of claim 5 wherein R.sup.3 is a radical selected from
hydrido, methyl, ethyl, isopropyl, tert-butyl, isobutyl, pentyl,
hexyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,
dichloromethyl, trichloromethyl, pentafluoroethyl,
heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl,
difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl,
benzyl, phenylethyl, phenylpropyl, furylmethyl, morpholinomethyl,
pyrrolidinylmethyl, piperazinylmethyl, piperidinylmethyl,
pyridylmethyl, thienylmethyl, formyl, cyano, methoxy, ethoxy,
propoxy, n-butoxy, methylthio, ethylthio, isopropylthio,
methylsulfonyl, phenylsulfonyl, trifluoromethylsulfonyl, fluoro,
chloro, bromo, hydroxymethyl, hydroxyethyl, methoxymethyl,
ethoxymethyl, methylthiomethyl, isopropylthiomethyl,
cyclohexylthiomethyl, benzyloxy, benzylthio, methylcarbonyl,
ethylcarbonyl, phenylcarbonyl, trifluoromethylcarbonyl,
difluoromethylcarbonyl, fluoromethylcarbonyl, benzylcarbonyl,
pyrrolidinylcarbonyl, cyanomethyl, cyanobutyl, aminomethyl,
methylaminomethyl, N-phenylaminomethyl,
N-methyl-N-phenylaminomethyl, acetyl, propanoyl, butanoyl,
methoxycarbonylmethyl, ethoxycarbonylethyl, methoxycarbonyl,
ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl,
propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,
pentoxycarbonyl, carboxyl, carboxymethyl, carboxypropyl,
aminocarbonyl, methylaminocarbonyl, N,N-diethylaminocarbonyl,
N-methoxy-N-methylaminocar- bonyl, methylaminocarbonylmethyl,
pyridyloxy, pyridylthio, phenyloxy, 4-chlorophenoxy, furylmethoxy,
furylmethylthio, thienylmethoxy, quinolylmethoxy, pyridylmethoxy,
5-phenylpyridyl-2-methoxy, thienylmethylthio, pyridylmethylthio,
quinolylmethoxymethyl, furylbutoxyethyl, pyridyloxymethyl,
pyridylmethoxymethyl, thienyloxyhexyl, thienylthiomethyl,
pyridylthiohexyl, furyloxymethyl, furylmethylthiomethyl,
quinolylmethylthioethyl, phenylthiomethyl,
2-chlorophenylthiomethyl, 2,6-dichlorophenylthiomethyl,
4-methylphenylthiomethyl, 2-isopropylphenylthiomethyl,
2-methylphenylthiomethyl, phenyloxymethyl, 4-chlorophenyloxymethyl,
4-methylphenyloxymethyl, benzyloxymethyl, 4-methoxybenzyloxymethyl,
naphthyl, phenyl, thienyl, furyl, pyridyl, wherein the thienyl,
furyl, pyridyl and phenyl radicals are optionally substituted at a
substitutable position with one or more radicals selected from
fluoro, chloro, bromo, methylthio, methylsulfinyl, methyl, ethyl,
isopropyl, tert-butyl, isobutyl, pentyl, hexyl, cyano,
fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,
dichloromethyl, trichloromethyl, pentafluoroethyl,
heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl,
difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl,
hydroxyl, methoxy, methylenedioxy, ethoxy, propoxy, n-butoxy,
hydroxymethyl, hydroxyethyl and trifluoromethoxy; wherein R.sup.4
is a radical selected from hydrido, methyl, ethyl, fluoro, chloro
and bromo; and wherein R.sup.13 and R.sup.14 are independently
selected from phenyl, imidazolyl, thienyl, thiazolyl, pyrrolyl,
oxazolyl, isoxazolyl, triazolyl, pyrazinyl, pyrimidinyl,
isoquinolyl, quinolyl, indolyl, benzimidazolyl, pyrazolyl and
pyridyl, wherein R.sup.13 and R.sup.14 are optionally substituted
at a substitutable position with one or more radicals independently
selected from methylsulfonyl, aminosulfonyl, fluoromethylsulfonyl,
difluoromethylsulfonyl, fluoro, chloro, bromo, methylthio,
methylsulfinyl, methyl, ethyl, isopropyl, tert-butyl, isobutyl,
pentyl, hexyl, cyano, carboxyl, methoxycarbonyl, ethoxycarbonyl,
isopropoxycarbonyl, tert-butoxycarbonyl, propoxycarbonyl,
butoxycarbonyl, isobutoxycarbonyl, pentoxycarbonyl, fluoromethyl,
difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,
trichloromethyl, pentafluoroethyl, heptafluoropropyl,
difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,
difluoropropyl, dichloroethyl, dichloropropyl, hydroxyl, methoxy,
methylenedioxy, ethoxy, propoxy, n-butoxy, hydroxymethyl,
hydroxyethyl, methoxymethyl, ethoxymethyl, trifluoromethoxy, amino,
methylamino, N,N-diethylamino, phenylamino and nitro; or a
pharmaceutically-acceptable salt thereof.
7. Compound of claim 6 wherein R.sup.3 is a radical selected from
hydrido, methyl, ethyl, isopropyl, tert-butyl, isobutyl, pentyl,
hexyl, cyano, fluoromethyl, difluoromethyl, trifluoromethyl,
chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl,
heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl,
difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl and
2-methylphenylthiomethy- l; wherein R.sup.4 is hydrido; wherein
R.sup.13 is phenyl optionally substituted with methylsulfonyl or
aminosulfonyl; and wherein R.sup.14 is selected from imidazolyl,
thienyl, thiazolyl, pyrrolyl, oxazolyl, isoxazolyl, triazolyl,
pyrimidinyl, quinolinyl, isoquinolyl, indolyl, benzimidazolyl,
pyrazolyl and pyridyl, wherein R.sup.14 is optionally substituted
at a substitutable position with one or more radicals independently
selected from methylthio, methyl, ethyl, isopropyl, tert-butyl,
isobutyl, pentyl, hexyl, fluoromethyl, difluoromethyl,
trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,
pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,
dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl,
dichloropropyl, methoxy, methylenedioxy, ethoxy, propoxy, n-butoxy,
hydroxymethyl, hydroxyethyl, methoxymethyl, ethoxymethyl, and
trifluoromethoxy; or a pharmaceutically-acceptable salt
thereof.
8. Compound of claim 4 selected from compounds, and their
pharmaceutically acceptable salts, of the group consisting of
3-[4-[[(methylphenyl)thio]me-
thyl]-1-[4-(methylsulfonyl)phenyl]-1H-imidazol-2-yl]pyridine;
3-[4-methyl-1-[4-(methylsulfonyl)phenyl]-1H-imidazol-2-yl]pyridine;
4-[2-(6-methylpyrindin-2-yl)-4-trifluoromethyl-1H-imidazol-1-yl]benzenesu-
lfonamide;
4-methyl-3-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-i-
midazol-2-yl]pyridine;
4-[2-(2-methylthiazol-4-yl)-4-trifluoromethyl-1H-im-
idazol-1-yl]benzenesulfonamide;
4-[2-(4-methylpyrindin-3-yl)-4-trifluorome-
thyl-1H-imidazol-1-yl]benzenesulfonamide;
3-methyl-2-[1-[4-(methylsulfonyl-
)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine;
1-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]isoqui-
noline;
4-[2-(3-methylpyrindin-2-yl)-4-trifluoromethyl-1H-imidazol-1-yl]be-
nzenesulfonamide;
3-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imi-
dazol-2-yl]quinoline;
4-[2-(2-thienyl)-4-trifluoromethyl-1H-imidazol-1-yl]-
benzenesulfonamide;
3-bromo-5-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromet-
hyl-1H-imidazol-2-yl]pyridine;
1-[4-(methylsulfonyl)phenyl]-2-(3-pyridinyl-
)-1H-imidazole-4-carbonitrile;
2-(2-methyloxazol-4-yl)-1-[4-(methylsulfony-
l)phenyl]-4-trifluoromethyl-1H-imidazole;
4-[2-(5-bromopyrindin-3-yl)-4-tr-
ifluoromethyl-1H-imidazol-1-yl]benzenesulfonamide;
2-(5-methylpyridin-3-yl-
)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole-4-carbonitrile;
3-[4-difluoromethyl-1-[4-(methylsulfonyl)phenyl]-1H-imidazol-2-yl]pyridin-
e;
4-[4-cyano-2-(5-methylpyrindin-3-yl)-1H-imidazol-1-yl]benzenesulfonamid-
e;
4-[2-(2-quinolinyl)-4-trifluoromethyl-1H-imidazol-1-yl]benzenesulfonami-
de;
4-[2-(3-methoxypyridin-5-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benz-
enesulfonamide;
2-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imi-
dazol-2-yl]isoquinoline;
2-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethy-
l)-1H-imidazol-2-yl]pyrazine;
2-methyl-4-[1-[4-(methylsulfonyl)phenyl]-4-(-
trifluoromethyl)-1H-imidazol-2-yl]thiazole;
1-methyl-3-[1-[4-(methylsulfon-
yl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]-1H-indole;
4-[2-(4-methylpyridin-2-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenes-
ulfonamide;
2-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazo-
l-2-yl]thiophene;
3-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-i-
midazol-2-yl]thiophene;
4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-
-imidazol-1-yl]benzenesulfonamide;
2-methyl-3-[1-[4-(methylsulfonyl)phenyl-
]-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine;
4-[2-(2-methylpyridin-3-y-
l)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide;
3-fluoro-5-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol--
2-yl]pyridine;
3-chloro-5-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl-
)-1H-imidazol-2-yl]pyridine;
4-[2-(5-fluoropyridin-3-yl)-4-(trifluoromethy-
l)-1H-imidazol-1-yl]benzenesulfonamide;
4-[2-(5-chloropyridin-3-yl)-4-(tri-
fluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide;
5-methyl-2-[1-[4-(methy-
lsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine;
4-methyl-2-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol--
2-yl]pyridine;
2-methoxy-6-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethy-
l)-1H-imidazo1-2-yl]pyridine;
5-methoxy-2-[1-[4-(methylsulfonyl)phenyl]-4--
(trifluoromethyl)-1H-imidazol-2-yl]pyridine;
4-methoxy-2-[1-[4-(methylsulf-
onyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine;
2-chloro-6-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol--
2-yl]pyridine;
5-chloro-2-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl-
)-1H-imidazol-2-yl]pyridine;
4-chloro-2-[1-[4-(methylsulfonyl)phenyl]-4-(t-
rifluoromethyl)-1H-imidazol-2-yl]pyridine;
2-fluoro-6-[1-[4-(methylsulfony-
l)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine;
4-fluoro-2-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol--
2-yl]pyridine;
4-fluoro-2-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl-
)-1H-imidazol-2-yl]pyridine;
4-[2-(5-methylpyridin-2-yl)-4-(trifluoromethy-
l)-1H-imidazol-1-yl]benzenesulfonamide;
4-[2-(4-methylpyridin-2-yl)-4-(tri-
fluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide;
4-[2-(6-methoxypyridin--
2-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide;
4-[2-(5-methoxypyridin-2-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzene-
sulfonamide;
4-[2-(4-methoxypyridin-2-yl)-4-(trifluoromethyl)-1H-imidazol--
1-yl]benzenesulfonamide;
4-[2-(6-chloropyridin-2-yl)-4-(trifluoromethyl)-1-
H-imidazol-1-yl]benzenesulfonamide;
4-[2-(5-chloropyridin-2-yl)-4-(trifluo-
romethyl)-1H-imidazol-1-yl]benzenesulfonamide;
4-[2-(4-chloropyridin-2-yl)-
-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide;
4-[2-(6-fluoropyridin-2-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenes-
ulfonamide;
4-[2-(5-fluoropyridin-2-yl)-4-(trifluoromethyl)-1H-imidazol-1--
yl]benzenesulfonamide;
4-[2-(4-fluoropyridin-2-yl)-4-(trifluoromethyl)-1H--
imidazol-1-yl]benzenesulfonamide;
3-methoxy-5-[1-[4-(methylsulfonyl)phenyl-
]-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine;
4-methyl-3-[1-[4-(methyls-
ulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine;
3-[4-(4-fluorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazol-2-yl]pyrid-
ine;
2-methylthio-5-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-i-
midazol-2-yl]pyridine;
3-[4-(difluoromethyl)-1-[4-(methylsulfonyl)phenyl]--
1H-imidazol-2-yl]pyridine;
4-[2-(5-methoxypyridin-3-yl)-4-(trifluoromethyl-
)-1H-imidazol-1-yl]benzenesulfonamide;
4-[4-methyl-2-(3-pyridinyl)-1H-imid- azol-1-yl]benzenesulfonamide;
4-[2-(pyridin-3-yl)-4-(trifluoromethyl)-1H-i-
midazol-1-yl]benzenesulfonamide;
4-[4-(4-fluorophenyl)-2-(3-pyridinyl)-1H--
imidazol-1-yl]benzenesulfonamide;
4-[2-[6-(methylthio)pyridin-3-yl]-4-trif-
luoromethyl)-1H-imidazol-1-yl]benzenesulfonamide;
4-[4-(difluoromethyl)-2--
(3-pyridinyl)-1H-imidazol-1-yl]benzenesulfonamide;
3-[1-[4-(methylsulfonyl-
)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine;
2-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]pyri-
dine;
2-methyl-4-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imid-
azol-2-yl]pyridine;
4-[1-(4-(methylsulfonyl)phenyl)-4-(trifluoromethyl)-1H-
-imidazol-2-yl]pyridine;
2-methyl-6-[1-[4-(methylsulfonyl)phenyl]-4-(trifl-
uoromethyl)-1H-imidazol-2-yl]pyridine;
4-[2-(6-methylpyridin-3-yl)-4-(trif-
luoromethyl)-1H-imidazol-1-yl]benzenesulfonamide;
3-methyl-5-[1-[4-(methyl-
sulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine;
2-methoxy-5-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-
-2-yl]pyridine; and
2-[4-[4-fluorophenyl-1-(4-(methylsulfonyl)phenyl]-4-(t-
rifluoromethyl)-1H-imidazol-2-yl]pyridine.
9. Compound of claim 7 selected from compounds, and their
pharmaceutically acceptable salts, of the group consisting of
3-[4-[[(methylphenyl)thio]me-
thyl]-1-[4-(methylsulfonyl)phenyl]-1H-imidazol-2-yl]pyridine;
4-[2-(pyrindin-3-yl)-4-[[(methylphenyl)thio]methyl]-1H-imidazol-1-yl]benz-
enesulfonamide;
3-[4-methyl-1-[4-(methylsulfonyl)phenyl]-1H-imidazol-2-yl]-
pyridine;
4-[2-(6-methylpyrindin-2-yl)-4-trifluoromethyl-1H-imidazol-1-yl]-
benzenesulfonamide;
4-methyl-3-[1-[4-(methylsulfonyl)phenyl]-4-trifluorome-
thyl-1H-imidazol-2-yl]pyridine;
4-[2-(4-methylpyrindin-3-yl)-4-trifluorome-
thyl-1H-imidazol-1-yl]benzenesulfonamide;
3-methyl-2-[1-[4-(methylsulfonyl-
)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine;
1-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]isoqui-
noline;
4-[2-(3-methylpyrindin-2-yl)-4-trifluoromethyl-1H-imidazol-1-yl]be-
nzenesulfonamide;
3-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imi-
dazol-2-yl]quinoline;
4-[2-(2-thienyl)-4-trifluoromethyl-1H-imidazol-1-yl]-
benzenesulfonamide;
3-bromo-5-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromet-
hyl-1H-imidazol-2-yl]pyridine;
1-[4-(methylsulfonyl)phenyl]-2-(3-pyridinyl-
)-1H-imidazole-4-carbonitrile;
2-(2-methyloxazol-4-yl)-1-[4-(methylsulfony-
l)phenyl]-4-trifluoromethyl-1H-imidazole;
4-[2-(5-bromopyrindin-3-yl)-4-tr-
ifluoromethyl-1H-imidazol-1-yl]benzenesulfonamide;
2-(5-methylpyridin-3-yl-
)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole-4-carbonitrile;
3-[4-difluoromethyl-1-[4-(methylsulfonyl)phenyl]-1H-imidazol-2-yl]pyridin-
e;
4-[4-difluoromethyl-2-(pyrindin-3-yl)-1H-imidazol-1-yl]benzenesulfonami-
de;
4-[4-cyano-2-(pyrindin-3-yl)-1H-imidazol-1-yl]benzenesulfonamide;
4-[4-cyano-2-(5-methylpyrindin-3-yl)-1H-imidazol-1-yl]benzenesulfonamide;
4-[2-(2-quinolinyl)-4-trifluoromethyl-1H-imidazol-1-yl]benzenesulfonamide-
;
1-methyl-4-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-
-yl]-1H-pyrazole;
4-[2-(1-methyl-1H-pyrazol-4-yl)-4-trifluoromethyl-1H-imi-
dazol-1-yl]benzenesulfonamide;
2-(1-methyl-1H-imidazol-4-yl)-1-[4-(methyls-
ulfonyl)phenyl]-4-trifluoromethyl-1H-imidazole;
4-[2-(1-methyl-1H-imidazol-
-4-yl)-4-trifluoromethyl-1H-imidazol-1-yl]benzenesulfonamide;
2-(1-methyl-1H-imidazol-5-yl)-1-[4-(methylsulfonyl)phenyl]-4-trifluoromet-
hyl-1H-imidazole;
4-[2-(1-methyl-1H-imidazol-5-yl)-4-trifluoromethyl-1H-im-
idazol-1-yl]benzenesulfonamide;
2-(1-methyl-1H-imidazol-2-yl)-1-[4-(methyl-
sulfonyl)phenyl]-4-trifluoromethyl-1H-imidazole; 4-[2
-(1-methyl-1H-imidazol-2-yl)-4-trifluoromethyl-1H-imidazol-1-yl]benzenesu-
lfonamide;
1-[4-(methylsulfonyl)phenyl]-2-(4-methylthiazol-2-yl)-4-trifluo-
romethyl-1H-imidazole;
4-[2-(4-methylthiazol-2-yl)-4-trifluoromethyl-1H-im-
idazol-1-yl]benzenesulfonamide;
1-[4-(methylsulfonyl)phenyl]-2-(2-methylth-
iazol-5-yl)-4-trifluoromethyl-1H-imidazole;
4-[2-(2-methylthiazol-5-yl)-4--
trifluoromethyl-1H-imidazol-1-yl]benzenesulfonamide;
5-methyl-3-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2--
yl]isoxazole;
4-[2-(5-methylisoxazol-3-yl)-4-trifluoromethyl-1H-imidazol-1-
-yl]benzenesulfonamide;
5-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl--
1H-imidazol-2-yl]pyrimidine;
4-[2-(5-pyrimidinyl)-4-trifluoromethyl-1H-imi-
dazol-1-yl]benzenesulfonamide;
4-[2-(pyrazin-2-yl)-4-(trifluoromethyl)-1H--
imidazol-1-yl]benzenesulfonamide; and
4-[2-(quinol-3-yl)-4-(trifluoromethy-
l)-1H-imidazol-1-yl]benzenesulfonamide.
10. A pharmaceutical composition comprising a
therapeutically-effective amount of a compound, said compound
selected from a family of compounds of claim 1; or a
pharmaceutically-acceptable salt thereof.
11. A pharmaceutical composition comprising a
therapeutically-effective amount of a compound, said compound
selected from a family of compounds of claim 4; or a
pharmaceutically-acceptable salt thereof.
12. A pharmaceutical composition comprising a
therapeutically-effective amount of a compound, said compound
selected from a family of compounds of claim 5; or a
pharmaceutically-acceptable salt thereof.
13. A pharmaceutical composition comprising a
therapeutically-effective amount of a compound, said compound
selected from a family of compounds of claim 6; or a
pharmaceutically-acceptable salt thereof.
14. A pharmaceutical composition comprising a
therapeutically-effective amount of a compound, said compound
selected from a family of compounds of claim 7; or a
pharmaceutically-acceptable salt thereof.
15. A pharmaceutical composition comprising a
therapeutically-effective amount of a compound, said compound
selected from a family of compounds of claim 8; or a
pharmaceutically-acceptable salt thereof.
16. A pharmaceutical composition comprising a
therapeutically-effective amount of a compound, said compound
selected from a family of compounds of claim 9; or a
pharmaceutically-acceptable salt thereof.
17. A method of treating inflammation or an inflammation-associated
disorder in a subject, said method comprising treating the subject
having or susceptible to said disorder with a
therapeutically-effective amount of a compound of claim 1; or a
pharmaceutically-acceptable salt thereof.
18. A method of treating inflammation or an inflammation-associated
disorder in a subject, said method comprising treating the subject
having or susceptible to said disorder with a
therapeutically-effective amount of a compound of claim 4; or a
pharmaceutically-acceptable salt thereof.
19. A method of treating inflammation or an inflammation-associated
disorder in a subject, said method comprising treating the subject
having or susceptible to said disorder with a
therapeutically-effective amount of a compound of claim 5; or a
pharmaceutically-acceptable salt thereof.
20. A method of treating inflammation or an inflammation-associated
disorder in a subject, said method comprising treating the subject
having or susceptible to said disorder with a
therapeutically-effective amount of a compound of claim 6; or a
pharmaceutically-acceptable salt thereof.
21. A method of treating inflammation or an inflammation-associated
disorder in a subject, said method comprising treating the subject
having or susceptible to said disorder with a
therapeutically-effective amount of a compound of claim 7; or a
pharmaceutically-acceptable salt thereof.
22. A method of treating inflammation or an inflammation-associated
disorder in a subject, said method comprising treating the subject
having or susceptible to said disorder with a
therapeutically-effective amount of a compound of claim 8; or a
pharmaceutically-acceptable salt thereof.
23. A method of treating inflammation or an inflammation-associated
disorder in a subject, said method comprising treating the subject
having or susceptible to said disorder with a
therapeutically-effective amount of a compound of claim 9; or a
pharmaceutically-acceptable salt thereof.
24. The method of claim 18 for use in treatment of
inflammation.
25. The method of claim 18 for use in treatment of an
inflammation-associated disorder.
26. The method of claim 25 wherein the inflammation-associated
disorder is arthritis.
27. The method of claim 25 wherein the inflammation-associated
disorder is pain.
28. The method of claim 25 wherein the inflammation-associated
disorder is fever.
29. A process of making a compound of the formula 98or a
pharmaceutically-acceptable salt thereof, wherein R.sup.3 is a
radical selected from hydrido, alkyl, haloalkyl, aralkyl,
heterocycloalkyl, heteroaralkyl, acyl, cyano, alkoxy, alkylthio,
alkylthioalkyl, alkylsulfonyl, cycloalkylthio, cycloalkylthioalkyl,
cycloalkylsulfonyl, cycloalkylsulfonylalkyl, haloalkylsulfonyl,
arylsulfonyl, halo, hydroxyalkyl, alkoxyalkyl, alkylcarbonyl,
arylcarbonyl, aralkylcarbonyl, heterocyclocarbonyl, cyanoalkyl,
aminoalkyl, alkylaminoalkyl, N-arylaminoalkyl,
N-alkyl-N-arylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl,
alkoxycarbonyl, haloalkylcarbonyl, carboxyl, aminocarbonyl,
alkylaminocarbonyl, alkylaminocarbonylalkyl, heteroarylalkoxyalkyl,
heteroaryloxyalkyl, heteroarylthioalkyl, aralkoxy, aralkylthio,
heteroaralkoxy, heteroaralkylthio, heteroarylalkylthioalkyl,
heteroaryloxy, heteroarylthio, arylthioalkyl, aryloxyalkyl,
arylthio, aryloxy, aralkylthioalkyl, aralkoxyalkyl, aryl and
heteroaryl; wherein R.sup.4 is a radical selected from hydrido,
alkyl and halo; and wherein R.sup.14 is selected from aryl and
heterocyclo, wherein R.sup.14 is optionally substituted at a
substitutable position with one or more radicals independently
selected from alkylsulfonyl, aminosulfonyl, halo, alkylthio, alkyl,
cyano, carboxyl, alkoxycarbonyl, haloalkyl, hydroxyl, alkoxy,
hydroxyalkyl, alkoxyalkyl, haloalkoxy, amino, alkylamino, arylamino
and nitro; said method comprising the steps of forming a (protected
sulfonyl)benzenamine, treating said (protected sulfonyl)benzenamine
first with a base and then with a nitrile to form an amidine,
treating said amidine with a haloketone derivative in the presence
of a base to form a hydroxyimidazole, forming a (protected
sulfonylphenyl)imidazole by dehydrating said hydroxyimidazole, and
forming said compounds by deprotecting said (protected
sulfonylphenyl)imidazole.
Description
RELATED CASE
[0001] This is a continuation-in-part of International Application
PCT/US95/09506, with an international filing date of Jul. 27, 1995,
which is a continuation-in-part of patent application Ser. No.
08/464,154, with a filing date of Jun. 5, 1995, which is a
continuation-in-part of patent application Ser. No. 08/282,395,
with a filing date of Jul. 28, 1994.
FIELD OF THE INVENTION
[0002] This invention is in the field of antiinflammatory
pharmaceutical agents and specifically relates to compounds,
compositions and methods for treating inflammation and
inflammation-associated disorders, such as arthritis.
BACKGROUND OF THE INVENTION
[0003] Prostaglandins play a major role in the inflammation process
and the inhibition of prostaglandin production, especially
production of PGG.sub.2, PGH.sub.2 and PGE.sub.2, has been a common
target of antiinflammatory drug discovery. However, common
non-steroidal antiinflammatory drugs (NSAIDs) that are active in
reducing the prostaglandin-induced pain and swelling associated
with the inflammation process are also active in affecting other
prostaglandin-regulated processes not associated with the
inflammation process. Thus, use of high doses of most common NSAIDs
can produce severe side effects, including life threatening ulcers,
that limit their therapeutic potential. An alternative to NSAIDs is
the use of corticosteroids, which have even more drastic side
effects, especially when long term therapy is involved.
[0004] Previous NSAIDs have been found to prevent the production of
prostaglandins by inhibiting enzymes in the human arachidonic
acid/prostaglandin pathway, including the enzyme cyclooxygenase
(COX). The recent discovery of an inducible enzyme associated with
inflammation (named "cyclooxygenase-2 (COX-2)" or "prostaglandin
G/H synthase II") provides a viable target of inhibition which more
effectively reduces inflammation and produces fewer and less
drastic side effects.
[0005] The references below that disclose antiinflammatory
activity, show continuing efforts to find a safe and effective
antiinflammatory agent. The novel imidazoles disclosed herein are
such safe and also effective antiinflammatory agents furthering
such efforts. The invention compounds are found to show usefulness
in vivo as antiinflammatory agents with minimal side effects. The
substituted imidazoles disclosed herein preferably selectively
inhibit cyclooxygenase-2 over cyclooxygenase-1.
[0006] Diaryl oxazoles have been described in WO patent publication
WO94/27980 as having antiinflammatory activity. Substituted
4,5-diarylimidazoles have been described in WO95/00501 and in
copending U.S. application Ser. No. 08/281,903.
[0007] 2-Alkylimidazoles have been described as having angiotensin
II activity. For example, see U.S. Pat. No. 5,185,351 and
WO91/00277.
[0008] U.S. Pat. No. 5,207,820 to Wriede et al. describes
1-arylimidazole carboxylic esters as herbicide safeners.
Specifically, ethyl
[1-[2,6-dinitro-4-(methylsulfonyl)phenyl]-2-methyl-1H-imidazol-3-yl]carbo-
xylate is described.
[0009] WO93/14082, published Jul. 22, 1993, describes
1-pyridyl-2-phenyl-imidazole derivatives for the treatment of
interleukin-1 mediated diseases.
1-(4-Pyridyl)-2-(4-fluorophenyl)-4-methy- limidazole is described.
WO 95/02591, published Jan. 26, 1995, describe tri-substituted
imidazoles for the treatment of cytokine mediated diseases.
[0010] U.S. Pat. No. 3,487,087, to Sarett et al., describes a
method of nitration of imidazoles and specifically
1-methyl-2-[4-(methylsulfonyl)ph- enyl]-5-nitroimidazole.
[0011] U.S. Pat. No. 5,112,532, to Ninomiya et al., describes
imidazoles as an organic non-linear optical material. Specifically,
4-(4-hydroxyphenyl)-2-[2-formyl-4-(methylsulfonyl)phenyl]imidazole
is described.
[0012] U.S. Pat. Nos. 3,682,949 and 3,719,759, to Sarett et al.,
describe 2-aryl-nitroimidazoles as agents for the treatment of
parasites and bacteria. Specifically,
1-(2-hydroxyethyl)-2-(4-sulfonamidophenyl)-5-nitr- oimidazole is
described.
[0013] U.S. Pat. No. 4,822,805, to Takasugi et al., describes
pyridylimidazoles as antiinflammatory agents. Specifically,
2-[2-methoxy-4-(methylsulfonyl)phenyl]-4-methyl-5-(3-pyridyl)imidazole
is described.
[0014] The invention's imidazolyl compounds are found to show
usefulness in vivo as antiinflammatory agents with minimal side
effects.
DESCRIPTION OF THE INVENTION
[0015] A class of substituted imidazolyl compounds useful in
treating inflammation-related disorders is defined by Formula I:
2
[0016] wherein R.sup.1 and R.sup.2 are independently selected from
aryl, cycloalkyl, cycloalkenyl and heterocyclo, wherein R.sup.1 and
R.sup.2 are optionally substituted at a substitutable position with
one or more radicals independently selected from alkylsulfonyl,
aminosulfonyl, haloalkylsulfonyl, halo, alkylthio, alkyl, cyano,
carboxyl, alkoxycarbonyl, haloalkyl, hydroxyl, alkoxy,
hydroxyalkyl, alkoxyalkyl, haloalkoxy, amino, alkylamino, arylamino
and nitro;
[0017] wherein R.sup.3 is a radical selected from hydrido, alkyl,
haloalkyl, aralkyl, heterocycloalkyl, acyl, cyano, alkoxy,
alkylthio, alkylthioalkyl, alkylsulfonyl, cycloalkylthio,
cycloalkylthioalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl,
cycloalkyloxy, cycloalkyloxyalkyl, haloalkylsulfonyl, arylsulfonyl,
halo, hydroxyalkyl, alkoxyalkyl, alkylcarbonyl, arylcarbonyl,
aralkylcarbonyl, heterocycloalkylcarbonyl, cyanoalkyl, azidoalkyl,
aminoalkyl, alkylaminoalkyl, N-arylaminoalkyl,
N-alkyl-N-arylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl,
alkoxycarbonyl, haloalkylcarbonyl, carboxyl, aminocarbonyl,
alkylaminocarbonyl, alkylaminocarbonylalkyl, heteroarylalkoxyalkyl,
heteroaryloxyalkyl, heteroarylthioalkyl, aralkoxy, aralkylthio,
heteroaralkoxy, heteroaralkylthio, heteroarylalkylthioalkyl,
heteroaryloxy, heteroarylthio, arylthioalkyl, aryloxyalkyl,
arylthio, aryloxy, aralkylthioalkyl, aralkoxyalkyl, aryl and
heterocyclo;
[0018] wherein R.sup.4 is a radical selected from hydrido, alkyl
and fluoro; wherein R.sup.5 is selected from hydroxyl and alkoxy;
and wherein R.sup.6 is hydrido; or wherein R.sup.5 and R.sup.6
together form a double bond provided at least one of R.sup.1 and
R.sup.2 is substituted with alkylsulfonyl or aminosulfonyl; or a
pharmaceutically-acceptable salt thereof.
[0019] Compounds of Formula I would be useful for, but not limited
to, the treatment of inflammation in a subject, and for treatment
of other inflammation-associated disorders, such as, as an
analgesic in the treatment of pain and headaches, or as an
antipyretic for the treatment of fever. For example, compounds of
the invention would be useful to treat arthritis, including but not
limited to rheumatoid arthritis, spondyloarthopathies, gouty
arthritis, osteoarthritis, systemic lupus erythematosus and
juvenile arthritis. Such compounds of the invention would be useful
in the treatment of asthma, bronchitis, menstrual cramps,
tendinitis, bursitis, and skin-related conditions such as
psoriasis, eczema, burns and dermatitis. Compounds of the invention
also would be useful to treat gastrointestinal conditions such as
inflammatory bowel disease, Crohn's disease, gastritis, irritable
bowel syndrome and ulcerative colitis, and for the prevention or
treatment of cancer, such as colorectal cancer. Compounds of the
invention would be useful in treating inflammation in such diseases
as vascular diseases, migraine headaches, periarteritis nodosa,
thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma,
rheumatic fever, type I diabetes, neuromuscular junction disease
including myasthenia gravis, white matter disease including
multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet's
syndrome, polymyositis, gingivitis, nephritis, hypersensitivity,
swelling occurring after injury, myocardial ischemia, and the like.
The compounds would also be useful in the treatment of ophthalmic
diseases such as retinitis, retinopathies, uveitis, conjunctivitis,
and of acute injury to the eye tissue. The compounds would also be
useful in the treatment of pulmonary inflammation, such as that
associated with viral infections and cystic fibrosis. The compounds
would also be useful for the treatment of certain central nervous
system disorders such as cortical dementias including Alzheimers
disease. The compounds of the invention are useful as
anti-inflammatory agents, such as for the treatment of arthritis,
with the additional benefit of having significantly less harmful
side effects. These compounds would also be useful in the treatment
of allergic rhinitis, respiratory distress syndrome, endotoxin
shock syndrome, atherosclerosis and central nervous system damage
resulting from stroke, ischemia and trauma.
[0020] Besides being useful for human treatment, these compounds
are also useful for veterinary treatment of mammals, including
companion animals and farm animals, such as, but not limited to,
horses, dogs, cats, cows, sheep and pigs.
[0021] The present compounds may also be used in co-therapies,
partially or completely, in place of other conventional
antiinflammatories, such as together with steroids, NSAIDs,
5-lipoxygenase inhibitors, LTB.sub.4 antagonists and LTA.sub.4
hydrolase inhibitors.
[0022] Suitable LTB.sub.4 inhibitors include, among others,
ebselen, Bayer Bay-x-1005, Ciba Geigy compound CGS-25019C, Leo
Denmark compound ETH-615, Lilly compound LY-2931111, Ono compound
ONO-4057, Terumo compound TMK-688, Lilly compounds LY-213024,
264086 and 292728, ONO compound ONO-LB457, Searle compound
SC-53228, calcitrol, Lilly compounds LY-210073, LY223982, LY233469,
and LY255283, ONO compound ONO-LB-448, Searle compounds SC-41930,
SC-50605 and SC-51146, and SK&F compound SKF-104493.
Preferably, the LTB.sub.4 inhibitors are selected from ebselen,
Bayer Bay-x-1005, Ciba Geigy compound CGS-25019C, Leo Denmark
compound ETH-615, Lilly compound LY-293111, Ono compound ONO-4057,
and Terumo compound TMK-688.
[0023] Suitable 5-LO inhibitors include, among others, masoprocol,
tenidap, zileuton, pranlukast, tepoxalin, rilopirox, flezelastine
hydrochloride, enazadrem phosphate, and bunaprolast.
[0024] The present invention preferably includes compounds which
selectively inhibit cyclooxygenase-2 over cyclooxygenase-1.
Preferably, the compounds have a cyclooxygenase-2 IC.sub.50 equal
to or less than about 0.2 .mu.M, and also have a selectivity ratio
of cyclooxygenase-2 inhibition over cyclooxygenase-1 inhibition of
at least 50, and more preferably of at least 100. Even more
preferably, the compounds have a cyclooxygenase-1 IC.sub.50 of
greater than about 1.0 .mu.M, and more preferably of greater than
10 .mu.M. Such preferred selectivity may indicate an ability to
reduce the incidence of common NSAID-induced side effects.
[0025] A preferred class of compounds consists of those compounds
of Formula I wherein R.sup.1 and R.sup.2 are independently selected
from phenyl, naphthyl, biphenyl, lower cycloalkyl, lower
cycloalkenyl and heteroaryl, wherein R.sup.1 and R.sup.2 are
optionally substituted at a substitutable position with one or more
radicals independently selected from lower alkylsulfonyl,
aminosulfonyl, lower haloalkylsulfonyl, halo, lower alkylthio,
lower alkyl, cyano, carboxyl, lower alkoxycarbonyl, lower
haloalkyl, hydroxyl, lower alkoxy, lower hydroxyalkyl, lower
alkoxyalkyl, lower haloalkoxy, amino, lower alkylamino, arylamino
and nitro; wherein R.sup.3 is a radical selected from hydrido,
lower alkyl, lower haloalkyl, lower aralkyl, lower
heterocycloalkyl, acyl, cyano, lower alkoxy, lower alkylthio, lower
alkylsulfonyl, lower cycloalkyloxy, lower cycloalkyloxyalkyl, lower
cycloalkylthio, lower cycloalkylthioalkyl, lower
cycloalkylsulfonyl, lower cycloalkylsulfonylalkyl, phenylsulfonyl,
lower haloalkylsulfonyl, halo, lower hydroxyalkyl, lower
alkoxyalkyl, lower alkylcarbonyl, lower azidoalkyl, lower
haloalkylcarbonyl, phenylcarbonyl, lower aralkylcarbonyl, lower
heterocycloalkylcarbonyl, lower cyanoalkyl, lower aminoalkyl, lower
alkylaminoalkyl, lower N-arylaminoalkyl, lower
N-alkyl-N-arylaminoalkyl, lower carboxyalkyl, lower
alkoxycarbonylalkyl, lower alkoxycarbonyl, lower alkylthioalkyl,
aminocarbonyl, lower alkylaminocarbonyl, lower
alkylaminocarbonylalkyl, lower aralkoxy, lower aralkylthio, lower
heteroaralkoxy, lower heteroaralkylthio, lower
heteroarylalkoxyalkyl, lower heteroarylalkylthioalkyl, lower
heteroaryloxyalkyl, lower heteroarylthioalkyl, lower heteroaryloxy,
lower heteroarylthio, lower arylthioalkyl, lower aryloxyalkyl,
lower arylthio, lower aryloxy, lower aralkylthioalkyl, lower
aralkoxyalkyl, aryl selected from phenyl and naphthyl, and
heteroaryl, wherein the aryl and heteroaryl radicals are optionally
substituted at a substitutable position with one or more radicals
selected from halo, lower alkylthio, lower alkylsulfinyl, lower
alkyl, cyano, lower haloalkyl, hydroxyl, lower alkoxy, lower
hydroxyalkyl and lower haloalkoxy; wherein R.sup.4 is a radical
selected from hydrido, lower alkyl and fluoro; and wherein R.sup.5
is selected from hydroxyl and lower alkoxy; wherein R.sup.6 is
hydrido; or wherein R.sup.5 and R.sup.6 together form a double
bond; or a pharmaceutically-acceptable salt thereof.
[0026] A class of compounds of particular interest consists of
those compounds of Formula I wherein R.sup.1 and R.sup.2 are
independently selected from phenyl, naphthyl, biphenyl, cyclohexyl,
cyclohexenyl, benzofuryl, benzodioxolyl, furyl, imidazolyl,
thienyl, thiazolyl, pyrrolyl, oxazolyl, isoxazolyl, triazolyl,
pyrimidinyl, quinolinyl, isoquinolinyl, benzimidazolyl, pyrazinyl,
indolyl, pyrazolyl and pyridyl, wherein R.sup.1 and R.sup.2 are
optionally substituted at a substitutable position with one or more
radicals independently selected from methylsulfonyl, aminosulfonyl,
fluoromethylsulfonyl, difluoromethylsulfonyl, fluoro, chloro,
bromo, methylthio, methyl, ethyl, isopropyl, tert-butyl, isobutyl,
pentyl, hexyl, cyano, carboxyl, methoxycarbonyl, ethoxycarbonyl,
isopropoxycarbonyl, tert-butoxycarbonyl, propoxycarbonyl,
butoxycarbonyl, isobutoxycarbonyl, pentoxycarbonyl, fluoromethyl,
difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,
trichloromethyl, pentafluoroethyl, heptafluoropropyl,
difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,
difluoropropyl, dichloroethyl, dichloropropyl, hydroxyl, methoxy,
methylenedioxy, ethoxy, propoxy, n-butoxy, hydroxymethyl,
hydroxyethyl, methoxymethyl, ethoxymethyl, trifluoromethoxy, amino,
methylamino, N,N-dimethylamino, phenylamino and nitro; wherein
R.sup.3 is a radical selected from hydrido, methyl, ethyl,
isopropyl, tert-butyl, isobutyl, pentyl, hexyl, fluoromethyl,
difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,
trichloromethyl, pentafluoroethyl, heptafluoropropyl,
difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,
difluoropropyl, dichloroethyl, dichloropropyl, benzyl, phenylethyl,
phenylpropyl, furylmethyl, morpholinomethyl, pyrrolidinylmethyl,
piperazinylmethyl, piperidinylmethyl, pyridylmethyl, thienylmethyl,
formyl, cyano, methoxy, ethoxy, propoxy, n-butoxy, methylthio,
ethylthio, isopropylthio, methylsulfonyl, phenylsulfonyl,
trifluoromethylsulfonyl, fluoro, chloro, bromo, hydroxymethyl,
hydroxyethyl, methoxymethyl, ethoxymethyl, methylthiomethyl,
isopropylthiomethyl, cyclohexylthiomethyl, benzyloxy, benzylthio,
methylcarbonyl, ethylcarbonyl, phenylcarbonyl, azidomethyl,
trifluoromethylcarbonyl, difluoromethylcarbonyl,
fluoromethylcarbonyl, benzylcarbonyl, cyanomethyl, cyanobutyl,
aminomethyl, methylaminomethyl, N-phenylaminomethyl,
N-methyl-N-phenylaminomethyl, acetyl, propanoyl, butanoyl,
methoxycarbonylmethyl, ethoxycarbonylethyl, methoxycarbonyl,
ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl,
propoxycarbonyl, isobutoxycarbonyl, carboxymethyl, carboxypropyl,
aminocarbonyl, methylaminocarbonyl, N,N-diethylaminocarbonyl,
N-methylaminocarbonylmethy- l, pyridyloxy, pyridylthio, phenyloxy,
4-chlorophenoxy, furylmethoxy, furylmethylthio, thienylmethoxy,
quinolylmethoxy, pyridylmethoxy, 5-phenylpyridyl-2-methoxy,
thienylmethylthio, pyridylmethylthio, benzylthiomethyl,
quinolylmethoxymethyl, furylbutoxyethyl, pyridyloxymethyl,
pyridylmethoxymethyl, thienyloxyhexyl, thienylthiomethyl,
pyridylthiohexyl, furyloxymethyl, furylmethylthiomethyl,
quinolylmethylthioethyl, phenylthiomethyl,
2-chlorophenylthiomethyl, 2,6-dichlorophenylthiomethyl,
4-methylphenylthiomethyl, 2-isopropylphenylthiomethyl,
2-methylphenylthiomethyl, phenyloxymethyl, 4-chlorophenyloxymethyl,
4-methylphenyloxymethyl, benzyloxymethyl, 4-methoxybenzyloxymethyl,
naphthyl, phenyl, thienyl, furyl, pyridyl, wherein the thienyl,
furyl, pyridyl and phenyl radicals are optionally substituted at a
substitutable position with one or more radicals selected from
fluoro, chloro, bromo, methylthio, methylsulfinyl, methyl, ethyl,
isopropyl, tert-butyl, isobutyl, pentyl, hexyl, cyano,
fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,
dichloromethyl, trichloromethyl, pentafluoroethyl,
heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl,
difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl,
hydroxyl, methoxy, methylenedioxy, ethoxy, propoxy, n-butoxy,
hydroxymethyl, hydroxyethyl and trifluoromethoxy; wherein R.sup.4
is a radical selected from hydrido, methyl, ethyl, and fluoro; and
wherein R.sup.5 is selected from hydroxyl, methoxy, ethoxy, propoxy
and n-butoxy; wherein R.sup.6 is hydrido; or wherein R.sup.5 and
R.sup.6 together form a double bond; or a
pharmaceutically-acceptable salt thereof.
[0027] Within Formula I there is a subclass of compounds of high
interest represented by Formula II: 3
[0028] wherein R.sup.3 is a radical selected from hydrido, alkyl,
haloalkyl, aralkyl, heterocycloalkyl, acyl, cyano, alkoxy,
alkylthio, alkylthioalkyl, alkylsulfonyl, cycloalkyloxy,
cycloalkyloxyalkyl, cycloalkylthio, cycloalkylthioalkyl,
cycloalkylsulfonyl, cycloalkylsulfonylalkyl, haloalkylsulfonyl,
arylsulfonyl, halo, hydroxyalkyl, alkoxyalkyl, alkylcarbonyl,
arylcarbonyl, aralkylcarbonyl, heterocycloalkylcarbonyl,
cyanoalkyl, alkylaminoalkyl, N-arylaminoalkyl,
N-alkyl-N-arylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl,
alkoxycarbonyl, haloalkylcarbonyl, aminocarbonyl, azidoalkyl,
alkylaminocarbonylalkyl, heteroarylalkoxyalkyl, heteroaryloxyalkyl,
heteroarylthioalkyl, aralkoxy, aralkylthio, heteroaralkoxy,
heteroaralkylthio, heteroarylalkylthioalkyl, heteroaryloxy,
heteroarylthio, arylthioalkyl, aryloxyalkyl, arylthio, aryloxy,
aralkylthioalkyl, aralkoxyalkyl, aryl and heteroaryl, wherein the
aryl and heteroaryl radicals are optionally substituted at a
substitutable position with one or more radicals selected from
halo, alkylthio, alkylsulfinyl, alkyl, cyano, haloalkyl, hydroxyl,
alkoxy, hydroxyalkyl and haloalkoxy; wherein R.sup.7 is a radical
selected from alkyl, haloalkyl and amino; and wherein R.sup.8 is
one or more radicals selected from hydrido, halo, alkyl, haloalkyl,
alkoxy, amino, haloalkoxy, cyano, carboxyl, hydroxyl, hydroxyalkyl,
alkoxyalkyl, alkylamino, nitro and alkylthio; or a
pharmaceutically-acceptable salt thereof.
[0029] A preferred class of compounds consists of those compounds
of Formula II wherein R.sup.3 is a radical selected from hydrido,
lower alkyl, lower haloalkyl, lower aralkyl, lower
heterocycloalkyl, acyl, cyano, lower alkoxy, lower alkylthio, lower
alkylsulfonyl, phenylsulfonyl, lower haloalkylsulfonyl, lower
cycloalkyloxy, lower cycloalkyloxyalkyl, lower cycloalkylthio,
lower cycloalkylthioalkyl, lower cycloalkylsulfonyl, lower
cycloalkylsulfonylalkyl, halo, lower hydroxyalkyl, lower
alkoxyalkyl, lower alkylcarbonyl, lower haloalkylcarbonyl,
phenylcarbonyl, lower aralkylcarbonyl, lower
heterocycloalkylcarbonyl, lower cyanoalkyl, lower azidoalkyl, lower
alkylaminoalkyl, lower N-arylaminoalkyl, lower
N-alkyl-N-arylaminoalkyl, lower carboxyalkyl, lower
alkoxycarbonylalkyl, lower alkoxycarbonyl, lower alkylthioalkyl,
aminocarbonyl, lower alkylaminocarbonylalkyl, lower aralkoxy, lower
aralkylthio, lower heteroaralkoxy, lower heteroaralkylthio, lower
heteroarylalkoxyalkyl, lower heteroarylalkylthioalkyl, lower
heteroaryloxyalkyl, lower heteroarylthioalkyl, lower heteroaryloxy,
lower heteroarylthio, lower arylthioalkyl, lower aryloxyalkyl,
lower arylthio, lower aryloxy, lower aralkylthioalkyl, lower
aralkoxyalkyl, aryl selected from phenyl and naphthyl, 5 or 6
membered heteroaryl, wherein the aryl and heteroaryl radicals are
optionally substituted at a substitutable position with one or more
radicals selected from halo, lower alkylthio, lower alkylsulfinyl,
lower alkyl, cyano, lower haloalkyl, hydroxyl, lower alkoxy, lower
hydroxyalkyl and lower haloalkoxy; wherein R.sup.7 is a radical
selected from lower alkyl, lower haloalkyl and amino; and wherein
R.sup.8 is a radical selected from hydrido, halo, lower alkyl,
lower haloalkyl, lower alkoxy, amino, lower haloalkoxy, cyano,
carboxyl, hydroxyl, lower hydroxyalkyl, lower alkoxyalkyl, lower
alkylamino, nitro and lower alkylthio; or a
pharmaceutically-acceptable salt thereof.
[0030] A class of compounds of particular interest consists of
those compounds of Formula II wherein R.sup.3 is a radical selected
from hydrido, methyl, ethyl, isopropyl, tert-butyl, isobutyl,
pentyl, hexyl, fluoromethyl, difluoromethyl, trifluoromethyl,
chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl,
heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl,
difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl,
benzyl, phenylethyl, phenylpropyl, furylmethyl, morpholinomethyl,
pyrrolidinylmethyl, piperazinylmethyl, piperidinylmethyl,
pyridylmethyl, thienylmethyl, formyl, cyano, methoxy, ethoxy,
propoxy, n-butoxy, methylthio, ethylthio, isopropylthio,
methylsulfonyl, phenylsulfonyl, trifluoromethylsulfonyl, fluoro,
chloro, bromo, hydroxymethyl, hydroxyethyl, methoxymethyl,
ethoxymethyl, methylthiomethyl, isopropylthiomethyl,
cyclohexylthiomethyl, benzyloxy, benzylthio, methylcarbonyl,
phenylcarbonyl, trifluoromethylcarbonyl, difluoromethylcarbonyl,
fluoromethylcarbonyl, benzylcarbonyl, cyanomethyl, cyanobutyl,
azidomethyl, methylaminomethyl, N-phenylaminomethyl,
N-methyl-N-phenylaminomethyl, acetyl, propanoyl, butanoyl,
methoxycarbonylmethyl, ethoxycarbonylethyl, methoxycarbonyl,
ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl,
propoxycarbonyl, carboxymethyl, carboxypropyl, aminocarbonyl,
N-methylaminocarbonylmethyl, pyridyloxy, pyridylthio, phenyloxy,
4-chlorophenoxy, furylmethoxy, furylmethylthio, thienylmethoxy,
quinolylmethoxy, pyridylmethoxy, 5-phenylpyridyl-2-methoxy,
thienylmethylthio, pyridylmethylthio, benzylthiomethyl,
quinolylmethoxymethyl, furylbutoxyethyl, pyridyloxymethyl,
pyridylmethoxymethyl, thienyloxyhexyl, thienylthiomethyl,
pyridylthiohexyl, furyloxymethyl, furylmethylthiomethyl,
quinolylmethylthioethyl, phenylthiomethyl,
2-chlorophenylthiomethyl, 2,6-dichlorophenylthiomethyl,
4-methylphenylthiomethyl, 2-isopropylphenylthiomethyl,
2-methylphenylthiomethyl, phenyloxymethyl, 4-chlorophenyloxymethyl,
4-methylphenyloxymethyl, benzyloxymethyl, 4-methoxybenzyloxymethyl,
naphthyl, phenyl, thienyl, furyl, pyridyl, wherein the thienyl,
furyl, pyridyl and phenyl radicals are optionally substituted at a
substitutable position with one or more radicals selected from
fluoro, chloro, bromo, methylthio, methylsulfinyl, methyl, ethyl,
isopropyl, tert-butyl, isobutyl, pentyl, hexyl, cyano,
fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,
dichloromethyl, trichloromethyl, pentafluoroethyl,
heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl,
difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl,
hydroxyl, methoxy, methylenedioxy, ethoxy, propoxy, n-butoxy,
hydroxymethyl, hydroxyethyl and trifluoromethoxy; wherein R.sup.7
is methyl or amino; and wherein R.sup.8 is a radical selected from
hydrido, methylsulfonyl, fluoro, chloro, bromo, methylthio, methyl,
ethyl, isopropyl, tert-butyl, isobutyl, pentyl, hexyl, cyano,
carboxyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl,
tert-butoxycarbonyl, propoxycarbonyl, butoxycarbonyl,
isobutoxycarbonyl, pentoxycarbonyl, fluoromethyl, difluoromethyl,
trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,
pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,
dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl,
dichloropropyl, hydroxyl, methoxy, methylenedioxy, ethoxy, propoxy,
n-butoxy, hydroxymethyl, hydroxyethyl, methoxymethyl, ethoxymethyl,
trifluoromethoxy, amino, methylamino, N,N-dimethylamino,
phenylamino and nitro; or a pharmaceutically-acceptabl- e salt
thereof.
[0031] A family of specific compounds of particular interest within
Formula II consists of compounds and pharmaceutically-acceptable
salts thereof as follows:
[0032]
2-(3,4-difluorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromet-
hyl)-1H-imidazole;
[0033]
2-(4-chlorophenyl)-4-[(4-methylphenoxy)methyl]-1-[4-(methylsulfonyl-
)phenyl]-1H-imidazole;
[0034]
2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-[(methylthio)meth-
yl]-1H-imidazole;
[0035]
1,2-bis[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazole;
[0036]
4-[2-(3,4-difluorophenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benz-
enesulfonamide;
[0037]
4-[2-(3-bromo-4-methoxyphenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl-
]benzenesulfonamide;
[0038]
2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole-4-carb-
oxaldehyde;
[0039]
2-(4-chlorophenyl)-4-[[(4-methylphenyl)thiomethyl]-1-[4-(methylsulf-
onyl)phenyl]-1H-imidazole;
[0040]
2-(3-methoxyphenyl)-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl-
)-1H-imidazole;
[0041]
2-(4-chlorophenyl)-4-fluoromethyl)-1-[4-(methylsulfonyl)phenyl]-1H--
imidazole;
[0042]
2-(2-fluorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-
-1H-imidazole;
[0043]
2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-(phenylmethoxymet-
hyl)-1H-imidazole;
[0044]
4-[2-(2-fluorophenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenes-
ulfonamide;
[0045]
N,N-dimethyl-4-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-
-imidazol-2-yl]benzenamine;
[0046]
2-(4-chlorophenyl)-4-[[(1-methylethyl)thio]methyl]-1-[4-(methylsulf-
onyl)phenyl]-1H-imidazole;
[0047]
2-(4-chlorophenyl)-4-[[(cyclohexyl)thio]methyl]-1-(4-(methylsulfony-
l)phenyl-1H-imidazole;
[0048]
1-[4-(methylsulfonyl)phenyl]-2-[3-(trifluoromethyl)phenyl]-4-(trifl-
uoromethyl)-1H-imidazole;
[0049]
2-[3-(methoxymethyl)phenyl]-1-[4-(methylsulfonyl)phenyl]-4-(trifluo-
romethyl)-1H-imidazole;
[0050]
2-fluoro-N,N-dimethyl-4-[1-[4-(methylsulfonyl)phenyl]-4-(trifluorom-
ethyl)-1H-imidazol-2-yl]benzenamine;
[0051]
2-(3-bromophenyl)-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)--
1H-imidazole;
[0052]
4-[4-(trifluoromethyl)-2-[3-(trifluoromethyl)phenyl]-1H-imidazol-1--
yl]benzenesulfonamide;
[0053]
2-(4-chlorophenyl)-4-[[(2-chlorophenyl)thio]methyl]-1-[4-(methylsul-
fonyl)phenyl]-1H-imidazole;
[0054]
1-[4-(methylsulfonyl)phenyl]-2-(3-nitrophenyl)-4-(trifluoromethyl)--
1H-imidazole;
[0055]
2-(4-chlorophenyl)-4-[[(2-methylphenyl)thio]methyl]-1-[4-(methylsul-
fonyl)phenyl]-1H-imidazole;
[0056]
N-methyl-4-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imi-
dazol-2-yl]benzenamine;
[0057]
3-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-y-
l]benzenamine;
[0058]
N,N-dimethyl-3-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-
-imidazol-2-yl]benzenamine;
[0059]
N-methyl-3-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imi-
dazol-2-yl]benzenamine;
[0060]
2-fluoro-N-methyl-4-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethy-
l)-1H-imidazol-2-yl]benzenamine;
[0061]
2-(4-chlorophenyl)-4-[[(2,6-dichlorophenyl)thio]methyl]-1-[4-(methy-
lsulfonyl)phenyl]-1H-imidazole;
[0062]
2-(4-chlorophenyl)-4-[[(2-(1-methylethyl)phenyl]thio]methyl]-1-[4-(-
methylsulfonyl)phenyl]-1H-imidazole;
[0063]
1-[2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazol-4-yl-
]ethanone;
[0064]
1-[4-(methylsulfonyl)phenyl]-2-[3-(methylthio)phenyl]-4-(trifluorom-
ethyl)-1H-imidazole;
[0065]
4-[2-(3-bromophenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesu-
lfonamide;
[0066]
2-(3-chloro-5-methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-(trifluo-
romethyl)-1H-imidazole;
[0067]
4-[2-(3-chloro-5-methylphenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl-
]benzenesulfonamide;
[0068]
2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole-4-acet-
onitrile;
[0069]
2-(3-fluoro-5-methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-(trifluo-
romethyl)-1H-imidazole;
[0070]
2-(3-fluoro-5-methoxyphenyl)-1-[4-(methylsulfonyl)phenyl]-4-(triflu-
oromethyl)-1H-imidazole;
[0071]
4-[2-(3-fluoro-5-methylphenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl-
]benzenesulfonamide;
[0072]
2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole-4-acet-
ic acid;
[0073]
4-[2-(3-fluoro-5-methoxyphenyl)-4-(trifluoromethyl)-1H-imidazol-1-y-
l]benzenesulfonamide;
[0074]
2-(4-chlorophenyl)-4-trifluoromethyl-1-[4-(methylsulfonyl)phenyl]-1-
H-imidazole;
[0075]
2-(4-chlorophenyl)-4-difluoromethyl-1-[4-(methylsulfonyl)phenyl]-1H-
-imidazole;
[0076]
2-(4-chlorophenyl)-4-methyl-1-[4-(methylsulfonyl)phenyl]-1H-imidazo-
le;
[0077]
2-(4-chlorophenyl)-4-ethyl-1-[4-(methylsulfonyl)phenyl]-1H-imidazol-
e;
[0078]
2-(4-chlorophenyl)-4-phenyl-1-[4-(methylsulfonyl)phenyl]-1H-imidazo-
le;
[0079]
2-(4-chlorophenyl)-4-(4-fluorophenyl)-1-[4-(methylsulfonyl)phenyl]--
1H-imidazole;
[0080]
2-(4-chlorophenyl)-4-(4-bromophenyl)-1-[4-(methylsulfonyl)phenyl]-1-
H-imidazole;
[0081]
2-(4-chlorophenyl)-4-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]--
1H-imidazole;
[0082]
2-(4-chlorophenyl)-4-(2-naphthyl)-1-[4-(methylsulfonyl)phenyl]-1H-i-
midazole;
[0083]
2-(4-chlorophenyl)-4-[4-(trifluoromethoxy)phenyl]-1-[4-(methylsulfo-
nyl)phenyl]-1H-imidazole;
[0084]
2-(4-chlorophenyl)-4-(3-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]--
1H-imidazole;
[0085]
2-(4-chlorophenyl)-4-(3-fluorophenyl)-1-[4-(methylsulfonyl)phenyl]--
1H-imidazole;
[0086]
2-(4-chlorophenyl)-4-(4-methoxyphenyl)-1-[4-(methylsulfonyl)phenyl]-
-1H-imidazole;
[0087]
2-(4-chlorophenyl)-4-phenoxymethyl-1-[4-(methylsulfonyl)phenyl]-1H--
imidazole;
[0088]
2-(4-chlorophenyl)-4-(4-chlorophenoxy)methyl-1-[4-(methylsulfonyl)p-
henyl]-1H-imidazole;
[0089]
2-(4-chlorophenyl)-4-(4-fluorophenoxy)methyl-1-[4-(methylsulfonyl)p-
henyl]-1H-imidazole;
[0090]
2-(4-chlorophenyl)-4-phenylthiomethyl-1-[4-(methylsulfonyl)phenyl]--
1H-imidazole;
[0091]
2-(4-chlorophenyl)-4-(N-phenyl-N-methylamino)methyl-1-[4-(methylsul-
fonyl)phenyl]-1H-imidazole;
[0092]
2-(4-chlorophenyl)-4-(2-quinolyl)methoxymethyl-1-[4-(methylsulfonyl-
)phenyl]-1H-imidazole;
[0093]
2-(4-chlorophenyl)-4-methoxymethyl-1-[4-(methylsulfonyl)phenyl]-1H--
imidazole;
[0094]
2-(4-chlorophenyl)-4-(4-methoxybenzyloxy)methyl-1-[4-(methylsulfony-
l)phenyl]-1H-imidazole;
[0095]
2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole-4-meth-
anol;
[0096]
2-(4-chlorophenyl)-4-formyl-1-[4-(methylsulfonyl)phenyl]-1H-imidazo-
le;
[0097]
2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole-4-carb-
onitrile;
[0098]
2-(4-chlorophenyl)-4-benzyl-1-[4-(methylsulfonyl)phenyl]-1H-imidazo-
le;
[0099]
2-(4-chlorophenyl)-4-phenylethyl-1-[4-(methylsulfonyl)phenyl]-1H-im-
idazole;
[0100]
2-(4-chlorophenyl)-4-hexyl-1-[4-(methylsulfonyl)phenyl]-1H-imidazol-
e;
[0101]
2-(4-chlorophenyl)-4-hexylcarbonyl-1-[4-(methylsulfonyl)phenyl]-1H--
imidazole;
[0102]
2-(4-chlorophenyl)-4-phenylcarbonyl-1-[4-(methylsulfonyl)phenyl]-1H-
-imidazole;
[0103]
2-(4-chlorophenyl)-4-benzylcarbonyl-1-[4-(methylsulfonyl)phenyl]-1H-
-imidazole;
[0104]
2-(4-chlorophenyl)-4-(1-hydroxy-1-phenyl-methyl)-1-[4-(methylsulfon-
yl)phenyl]-1H-imidazole;
[0105]
2-(4-chlorophenyl)-4-(1-hexanol)-1-[4-(methylsulfonyl)phenyl]-1H-im-
idazole;
[0106]
2-(4-chlorophenyl)-1-[(methylsulfonyl)phenyl]-1H-imidazole;
[0107]
2-(4-chlorophenyl)-4-octyl-1-[4-(methylsulfonyl)phenyl]-1H-imidazol-
e;
[0108]
2-(4-chlorophenyl)-4-methoxy-1-[4-(methylsulfonyl)phenyl]-1H-imidaz-
ole;
[0109]
2-(4-chlorophenyl)-4-butoxy-1-[4-(methylsulfonyl)phenyl]-1H-imidazo-
le;
[0110]
2-(4-chlorophenyl)-4-methylthio-1-[4-(methylsulfonyl)phenyl]-1H-imi-
dazole;
[0111]
2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethylsu-
lfonyl-1H-imidazole;
[0112]
2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethylca-
rbonyl-1H-imidazole;
[0113]
2-(4-chlorophenyl)-4-(2-thienyl)-1-[4-(methylsulfonyl)phenyl]-1H-im-
idazole;
[0114]
2-(4-chlorophenyl)-4-(3-furyl)-1-[4-(methylsulfonyl)phenyl]-1H-imid-
azole;
[0115]
2-(4-chlorophenyl)-4-(4-pyridyl)-1-[4-(methylsulfonyl)phenyl]-1H-im-
idazole;
[0116]
2-(4-chlorophenyl)-4-chloro-1-[4-(methylsulfonyl)phenyl]-1H-imidazo-
le;
[0117]
2-(4-chlorophenyl)-4-fluoro-1-[4-(methylsulfonyl)phenyl]-1H-imidazo-
le;
[0118]
methyl[2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazol--
4-yl]carboxylate;
[0119]
[2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazol-4-yl]c-
arboxamide;
[0120] methyl
[2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazol-
-4-yl]carboxamide;
[0121]
4-[2-(4-chlorophenyl)-4-trifluoromethyl-1H-imidazol-1-yl]benzenesul-
fonamide;
[0122]
4-[2-(4-chlorophenyl)-4-difluoromethyl-1H-imidazol-1-yl]benzenesulf-
onamide;
[0123]
4-[2-(4-chlorophenyl)-4-methyl-1H-imidazol-1-yl]benzenesulfonamide;
[0124]
4-[2-(4-chlorophenyl)-4-ethyl-1H-imidazol-1-yl]benzenesulfonamide;
[0125]
4-[2-(4-chlorophenyl)-4-phenyl-1H-imidazol-1-yl]benzenesulfonamide;
[0126]
4-[2-(4-chlorophenyl)-4-(4-fluorophenyl)-1H-imidazol-1-yl]benzenesu-
lfonamide;
[0127]
4-[2-(4-chlorophenyl)-4-(4-bromophenyl)-1H-imidazol-1-yl]benzenesul-
fonamide;
[0128]
4-[2-(4-chlorophenyl)-4-(4-chlorophenyl)-1H-imidazol-1-yl]benzenesu-
lfonamide;
[0129]
4-[2-(4-chlorophenyl)-4-(2-naphthyl)-1H-imidazol-1-yl]benzenesulfon-
amide;
[0130]
4-[2-(4-chlorophenyl)-4-[4-(trifluoromethoxy)phenyl]-1H-imidazol-1--
yl]benzenesulfonamide;
[0131]
4-[2-(4-chlorophenyl)-4-(3-chlorophenyl)-1H-imidazol-1-yl]benzenesu-
lfonamide;
[0132]
4-[2-(4-chlorophenyl)-4-(3-fluorophenyl)-1H-imidazol-1-yl]benzenesu-
lfonamide;
[0133]
4-[2-(4-chlorophenyl)-4-(4-methoxyphenyl)-1H-imidazol-1-yl]benzenes-
ulfonamide;
[0134]
4-[2-(4-chlorophenyl)-4-phenoxymethyl-1H-imidazol-1-yl]benzenesulfo-
namide;
[0135]
4-[2-(4-chlorophenyl)-4-(4-chlorophenoxy)methyl-1H-imidazol-1-yl]be-
nzenesulfonamide;
[0136]
4-[2-(4-chlorophenyl)-4-(4-fluorophenoxy)methyl-1H-imidazol-1-yl]be-
nzenesulfonamide;
[0137]
4-[2-(4-chlorophenyl)-4-phenylthiomethyl-1H-imidazol-1-yl]benzenesu-
lfonamide;
[0138]
4-[2-(4-chlorophenyl)-4-(N-phenyl-N-methylamino)methyl-1H-imidazol--
1-yl]benzenesulfonamide;
[0139]
4-[2-(4-chlorophenyl)-4-(2-quinolyl)methoxymethyl-1H-imidazol-1-yl]-
benzenesulfonamide;
[0140]
4-[2-(4-chlorophenyl)-4-methoxymethyl-1H-imidazol-1-yl]benzenesulfo-
namide;
[0141]
4-[2-(4-chlorophenyl)-4-(4-methoxybenzyloxy)methyl-1H-imidazol-1-yl-
]benzenesulfonamide;
[0142]
4-[2-(4-chlorophenyl)-4-hydroxymethyl-1H-imidazol-1-yl]benzenesulfo-
namide;
[0143]
4-[2-(4-chlorophenyl)-4-formyl-1H-imidazol-1-yl]benzenesulfonamide;
[0144]
4-[2-(4-chlorophenyl)-4-cyano-1H-imidazol-1-yl]benzenesulfonamide;
[0145]
4-[2-(4-chlorophenyl)-4-benzyl-1H-imidazol-1-yl]benzenesulfonamide;
[0146]
4-[2-(4-chlorophenyl)-4-phenylethyl-1H-imidazol-1-yl]benzenesulfona-
mide;
[0147]
4-[2-(4-chlorophenyl)-4-hexyl-1H-imidazol-1-yl]benzenesulfonamide;
[0148]
4-[2-(4-chlorophenyl)-4-hexylcarbonyl-1H-imidazol-1-yl]benzenesulfo-
namide;
[0149]
4-[2-(4-chlorophenyl)-4-phenylcarbonyl-1H-imidazol-1-yl]benzenesulf-
onamide;
[0150]
4-[2-(4-chlorophenyl)-4-benzylcarbonyl-1H-imidazol-1-yl]benzenesulf-
onamide;
[0151]
4-[2-(4-chlorophenyl)-4-(1-hydroxy-1-phenyl-methyl)-1H-imidazol-1-y-
l]benzenesulfonamide;
[0152]
4-[2-(4-chlorophenyl)-4-(1-hexanol)-1H-imidazol-1-yl]benzenesulfona-
mide;
[0153]
4-[2-(4-chlorophenyl)-1H-imidazol-1-yl]benzenesulfonamide;
[0154]
4-[2-(4-chlorophenyl)-4-octyl-1H-imidazol-1-yl]benzenesulfonamide;
[0155]
4-[2-(4-chlorophenyl)-4-methoxy-1H-imidazol-1-yl]benzenesulfonamide-
;
[0156]
4-[2-(4-chlorophenyl)-4-butoxy-1H-imidazol-1-yl]benzenesulfonamide;
[0157]
4-[2-(4-chlorophenyl)-4-methylthio-1H-imidazol-1-yl]benzenesulfonam-
ide;
[0158]
4-[2-(4-chlorophenyl)-4-(2-thienyl)-1H-imidazol-1-yl]benzenesulfona-
mide;
[0159]
4-[2-(4-chlorophenyl)-4-(3-furyl)-1H-imidazol-1-yl]benzenesulfonami-
de;
[0160]
4-[2-(4-chlorophenyl)-4-(4-pyridyl)-1H-imidazol-1-yl]benzenesulfona-
mide;
[0161]
4-[2-(4-chlorophenyl)-4-chloro-1H-imidazol-1-yl]benzenesulfonamide;
[0162]
4-[2-(4-chlorophenyl)-4-fluoro-1H-imidazol-1-yl]benzenesulfonamide;
[0163]
[2-(4-chlorophenyl)-1-(4-(aminosulfonyl)phenyl)-1H-imidazol-4-yl]ca-
rboxylic acid;
[0164]
methyl[2-(4-chlorophenyl)-1-[4-(aminosulfonyl)phenyl]-1H-imidazol-4-
-yl]carboxylate;
[0165]
(2-(4-chlorophenyl)-1-[4-(aminosulfonyl)phenyl)-1H-imidazol-4-yl]ca-
rboxamide;
[0166]
methyl[2-(4-chlorophenyl)-1-[4-(aminosulfonyl)phenyl)-1H-imidazol-4-
-yl]carboxamide;
[0167]
2-(3-methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1-
H-imidazole;
[0168]
2-(2-methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1-
H-imidazole;
[0169]
2-(4-fluoro-3-methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-trifluor-
omethyl-1H-imidazole;
[0170]
2-(4-chloro-3-methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-trifluor-
omethyl-1H-imidazole;
[0171]
2-(4-fluoro-3-methoxyphenyl)-1-[4-(methylsulfonyl)phenyl]-4-trifluo-
romethyl-1H-imidazole;
[0172]
2-(4-chloro-3-methoxyphenyl)-1-[4-(methylsulfonyl)phenyl]-4-trifluo-
romethyl-1H-imidazole;
[0173]
2-(3-fluoro-4-methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-trifluor-
omethyl-1H-imidazole;
[0174]
2-(3-chloro-4-methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-trifluor-
omethyl-1H-imidazole;
[0175]
2-(3-fluoro-4-methylthiophenyl)-1-[4-(methylsultonyl)phenyl]-4-trif-
luoromethyl-1H-imidazole;
[0176]
2-(3-chloro-4-methylthiophenyl)-1-[4-(methylsulfonyl)phenyl]-4-trif-
luoromethyl-1H-imidazole;
[0177]
2-(4-fluoro-3-methylthiophenyl)-1-[4-(methylsulfonyl)phenyl]-4-trif-
luoromethyl-1H-imidazole;
[0178]
2-(4-chloro-3-methylthiophenyl)-1-[4-(methylsulfonyl)phenyl]-4-trif-
luoromethyl-1H-imidazole;
[0179]
2-(3,5-dimethyl-4-methoxyphenyl)-1-[4-(methylsulfonyl)phenyl]-4-tri-
fluoromethyl-1H-imidazole;
[0180]
2-(3,5-dichloro-4-methoxyphenyl)-1-[4-(methylsulfonyl)phenyl]-4-tri-
fluoromethyl-1H-imidazole;
[0181]
2-(3,5-difluoro-4-methoxyphenyl)-1-[4-(methylsulfonyl)phenyl]-4-tri-
fluoromethyl-1H-imidazole;
[0182]
2-(3,4-dimethylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-trifluorometh-
yl-1H-imidazole;
[0183]
2-(3,5-dichlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-trifluorometh-
yl-1H-imidazole;
[0184]
4-[2-(3-methylphenyl)-4-trifluoromethyl-1H-imidazol-1-yl]benzenesul-
fonamide;
[0185]
4-[2-(2-methylphenyl)-4-trifluoromethyl-1H-imidazol-1-yl]benzenesul-
fonamide;
[0186]
4-[2-(4-fluoro-3-methylphenyl)-4-trifluoromethyl-1H-imidazol-1-yl]b-
enzenesulfonamide;
[0187]
4-[2-(4-chloro-3-methylphenyl)-4-trifluoromethyl-1H-imidazol-1-yl]b-
enzenesulfonamide;
[0188]
4-[2-(4-fluoro-3-methoxyphenyl)-4-trifluoromethyl-1H-imidazol-1-yl]-
benzenesulfonamide;
[0189]
4-[2-(4-chloro-3-methoxyphenyl)-4-trifluoromethyl-1H-imidazol-1-yl]-
benzenesulfonamide;
[0190]
4-[2-(3-fluoro-4-methylphenyl)-4-trifluoromethyl-1H-imidazol-1-yl]b-
enzenesulfonamide;
[0191]
4-[2-(3-chloro-4-methylthiophenyl)-4-trifluoromethyl-1H-imidazol-1--
yl]benzenesulfonamide;
[0192]
4-[2-(3-fluoro-4-methylthiophenyl)-4-trifluoromethyl-1H-imidazol-1--
yl]benzenesulfonamide;
[0193]
4-[2-(4-fluoro-3-methylthiophenyl)-4-trifluoromethyl-1H-imidazol-1--
yl]benzenesulfonamide;
[0194]
4-[2-(4-chloro-4-methylthiophenyl)-4-trifluoromethyl-1H-imidazol-1--
yl]benzenesulfonamide;
[0195]
4-[2-(3,5-dimethyl-4-methoxyphenyl)-4-trifluoromethyl-1H-imidazol-1-
-yl]benzenesulfonamide;
[0196]
4-[2-(3,5-dichloro-4-methoxyphenyl)-4-trifluoromethyl-1H-imidazol-1-
-yl]benzenesulfonamide;
[0197]
4-[2-(3,5-difluoro-4-methoxyphenyl)-4-trifluoromethyl-1H-imidazol-1-
-yl]benzenesulfonamide;
[0198]
4-[2-(3,4-dimethylphenyl)-4-trifluoromethyl-1H-imidazol-1-yl]benzen-
esulfonamide;
[0199]
4-[2-(3,5-dichlorophenyl)-4-trifluoromethyl-1H-imidazol-1-yl]benzen-
esulfonamide;
[0200] ethyl
[2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazol--
4-yl]carboxylate;
[0201] ethyl
[1-[4-(aminosulfonyl)phenyl]-2-(4-chlorophenyl)-1H-imidazol-4-
-yl]carboxylate;
[0202]
1-[4-(methylsulfonyl)phenyl]-2-(4-methylphenyl)-4-trifluoromethyl-1-
H-imidazole;
[0203]
1-[4-(methylsulfonyl)phenyl]-2-(3-chlorophenyl)-4-trifluoromethyl-1-
H-imidazole;
[0204]
1-[4-(methylsulfonyl)phenyl]-2-(4-methyl-3-chlorophenyl)-4-trifluor-
omethyl-1H-imidazole;
[0205]
5-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]-
-1,3-benzodioxole;
[0206]
1-[4-(methylsulfonyl)phenyl]-2-(4-methoxyphenyl)-4-trifluoromethyl--
1H-imidazole;
[0207]
1-[4-(methylsulfonyl)phenyl]-2-(3-fluorophenyl)-4-trifluoromethyl-1-
H-imidazole;
[0208]
1-[4-(methylsulfonyl)phenyl]-2-(4-fluorophenyl)-4-trifluoromethyl-1-
H-imidazole;
[0209]
1-[4-(methylsulfonyl)phenyl]-2-(4-methoxy-3-fluorophenyl)-4-trifluo-
romethyl-1H-imidazole;
[0210]
1-[4-(methylsulfonyl)phenyl]-2-phenyl-4-trifluoromethyl-1H-imidazol-
e;
[0211]
1-[4-(methylsulfonyl)phenyl]-2-(4-methoxy-3-chlorophenyl)-4-trifluo-
romethyl-1H-imidazole;
[0212]
1-[4-(methylsulfonyl)phenyl]-2-[4-(trifluoromethyl)phenyl]-4-triflu-
oromethyl-1H-imidazole;
[0213]
1-[4-(methylsulfonyl)phenyl]-2-(4-bromophenyl)-4-trifluoromethyl-1H-
-imidazole;
[0214]
1-[4-(methylsulfonyl)phenyl]-2-(2-chlorophenyl)-4-trifluoromethyl-1-
H-imidazole;
[0215]
1-[4-(methylsulfonyl)phenyl]-2-(4-ethylphenyl)-4-trifluoromethyl-1H-
-imidazole,
[0216]
1-[4-(methylsulfonyl)phenyl]-2-(4-butylphenyl)-4-trifluoromethyl-1H-
-imidazole;
[0217]
1-[4-(methylsulfonyl)phenyl]-2-(4-(difluoromethyl)phenyl]-4-trifluo-
romethyl-1H-imidazole;
[0218]
1-[4-(methylsulfonyl)phenyl]-2-(4-butoxyphenyl)-4-trifluoromethyl-1-
H-imidazole;
[0219]
1-[4-(methylsulfonyl)phenyl]-2-[4-(methylthio)phenyl]-4-trifluorome-
thyl-1H-imidazole;
[0220]
1-[4-(methylsulfonyl)phenyl]-2-(4-methoxy-3,5-dichlorophenyl)-4-tri-
fluoromethyl-1H-imidazole;
[0221]
1-[4-(methylsulfonyl)phenyl]-2-(4-methyl-3,5-difluorophenyl)-4-trif-
luoromethyl-1H-imidazole;
[0222]
1-[4-(methylsulfonyl)phenyl]-2-(2,4-dichlorophenyl)-4-trifluorometh-
yl-1H-imidazole;
[0223]
1-[4-(methylsulfonyl)phenyl]-2-(3,4-dichlorophenyl)-4-trifluorometh-
yl-1H-imidazole;
[0224]
1-[4-(methylsulfonyl)phenyl]-2-[4-(trifluoromethyl)phenyl]-4-triflu-
oromethoxy-1H-imidazole;
[0225]
1-[4-(methylsulfonyl)phenyl]-2-(3,5-dimethyl-4-methoxyphenyl)-4-tri-
fluoromethyl-1H-imidazole;
[0226]
1-[4-(methylsulfonyl)phenyl]-2-(3,4-dimethylphenyl)-4-trifluorometh-
yl-1H-imidazole;
[0227]
1-[4-(methylsulfonyl)phenyl]-2-(4-aminophenyl)-4-trifluoromethyl-1H-
-imidazole;
[0228]
4-[2-(4-methylphenyl)-4-trifluoromethyl-1H-imidazol-1-yl]benzenesul-
fonamide;
[0229]
4-[2-(3-chlorophenyl)-4-trifluoromethyl-1H-imidazol-1-yl]benzenesul-
fonamide;
[0230]
4-[2-(4-methyl-3-chlorophenyl)-4-trifluoromethyl-1H-imidazol-1-yl]b-
enzenesulfonamide;
[0231]
5-[1-[4-(aminosulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]--
1,3-benzodioxole;
[0232]
4-[2-(4-methoxyphenyl)-4-trifluoromethyl-1H-imidazol-1-yl]benzenesu-
lfonamide;
[0233]
4-[2-(3-fluorophenyl)-4-trifluoromethyl-1H-imidazol-1-yl]benzenesul-
fonamide;
[0234]
4-[2-(4-fluorophenyl)-4-trifluoromethyl-1H-imidazol-1-yl]benzenesul-
fonamide;
[0235]
4-[2-(4-methoxy-3-fluorophenyl)-4-trifluoromethyl-1H-imidazol-1-yl]-
benzenesulfonamide;
[0236]
4-[2-phenyl-4-trifluoromethyl-1H-imidazol-1-yl]benzenesulfonamide;
[0237]
4-[2-(4-methoxy-3-chlorophenyl)-4-trifluoromethyl-1H-imidazol-1-yl]-
benzenesulfonamide;
[0238]
4-[2-[4-(trifluoromethyl)phenyl]-4-trifluoromethyl-1H-imidazol-1-yl-
]benzenesulfonamide;
[0239]
4-[2-(4-bromophenyl)-4-trifluoromethyl-1H-imidazol-1-yl]benzenesulf-
onamide;
[0240]
4-[2-(2-chlorophenyl)-4-trifluoromethyl-1H-imidazol-1-yl]benzenesul-
fonamide;
[0241]
4-[2-(4-ethylphenyl)-4-trifluoromethyl-1H-imidazol-1-yl]benzenesulf-
onamide;
[0242]
4-[2-(4-butylphenyl)-4-trifluoromethyl-1H-imidazol-1-yl]benzenesulf-
onamide;
[0243]
4-[2-[4-(difluoromethyl)phenyl]-4-trifluoromethyl-1H-imidazol-1-yl]-
benzenesulfonamide;
[0244]
4-[2-(4-butoxyphenyl)-4-trifluoromethyl-1H-imidazol-1-yl]benzenesul-
fonamide;
[0245]
4-[2-[4-(methylthio)phenyl]-4-trifluoromethyl-1H-imidazol-1-yl]benz-
enesulfonamide;
[0246]
4-[2-(4-methoxy-3,5-dichloro-phenyl)-4-trifluoromethyl-1H-imidazol--
1-yl]benzenesulfonamide;
[0247]
4-[2-(4-methyl-3,5-difluorophenyl)-4-trifluoromethyl-1H-imidazol-1--
yl]benzenesulfonamide;
[0248]
4-[2-(2,4-dichlorophenyl)-4-trifluoromethyl-1H-imidazol-1-yl]benzen-
esulfonamide;
[0249]
4-[2-(3,4-dichlorophenyl)-4-trifluoromethyl-1H-imidazol-1-yl]benzen-
esulfonamide;
[0250]
4-[2-[4-(trifluoromethoxy)phenyl]-4-trifluoromethyl-1H-imidazol-1-y-
l]benzenesulfonamide;
[0251]
4-[2-(3,5-dimethyl-4-methoxy-phenyl)-4-trifluoromethyl-1H-imidazol--
1-yl]benzenesulfonamide;
[0252]
4-[2-(3,4-dimethylphenyl)-4-trifluoromethyl-1H-imidazol-1-yl]benzen-
esulfonamide; and
[0253]
4-[2-(4-aminophenyl)-4-trifluoromethyl-1H-imidazol-1-yl]benzenesulf-
onamide.
[0254] Within Formula I there is a second subclass of compounds of
high interest represented by Formula III: 4
[0255] wherein R.sup.3 is a radical selected from hydrido, alkyl,
haloalkyl, aralkyl, heterocycloalkyl, acyl, cyano, alkoxy,
alkylthio, alkylthioalkyl, alkylsulfonyl, cycloalkylthio,
cycloalkylthioalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl,
cycloalkyloxy, cycloalkyloxyalkyl, haloalkylsulfonyl, arylsulfonyl,
halo, hydroxyalkyl, alkoxyalkyl, alkylcarbonyl, arylcarbonyl,
aralkylcarbonyl, heterocycloalkylcarbonyl, cyanoalkyl, azidoalkyl,
alkylaminoalkyl, N-arylaminoalkyl, N-alkyl-N-arylaminoalkyl,
carboxyalkyl, alkoxycarbonylalkyl, alkoxycarbonyl,
haloalkylcarbonyl, aminocarbonyl, N-alkylaminocarbonylalkyl,
heteroarylalkoxyalkyl, heteroaryloxyalkyl, heteroarylthioalkyl,
aralkoxy, aralkylthio, heteroaralkoxy, heteroaralkylthio,
heteroarylalkylthioalkyl, heteroaryloxy, heteroarylthio,
arylthioalkyl, aryloxyalkyl, arylthio, aryloxy, aralkylthioalkyl,
aralkoxyalkyl, aryl and heteroaryl; wherein the aryl and heteroaryl
radicals are optionally substituted at a substitutable position
with one or more radicals selected from halo, alkylthio,
alkylsulfinyl, alkyl, cyano, haloalkyl, hydroxyl, alkoxy,
hydroxyalkyl and haloalkoxy; wherein R.sup.4 is a radical selected
from hydrido, alkyl and fluoro; wherein R.sup.9 is one or more
radicals selected from hydrido, halo, alkyl, haloalkyl, alkoxy,
amino, haloalkoxy, cyano, carboxyl, hydroxyl, hydroxyalkyl,
alkoxyalkyl, alkylamino, nitro and alkylthio; and wherein R.sup.10
is a radical selected from alkyl, haloalkyl and amino; or a
pharmaceutically-acceptable salt thereof.
[0256] A preferred class of compounds consists of those compounds
of Formula III wherein R.sup.3 is a radical selected from hydrido,
lower alkyl, lower haloalkyl, lower aralkyl, lower
heterocycloalkyl, lower heteroaralkyl, acyl, cyano, lower alkoxy,
lower alkylthio, lower alkylsulfonyl, phenylsulfonyl, lower
haloalkylsulfonyl, halo, lower hydroxyalkyl, lower alkoxyalkyl,
lower alkylcarbonyl, lower haloalkylcarbonyl, phenylcarbonyl, lower
aralkylcarbonyl, lower cyanoalkyl, lower azidoalkyl, lower
alkylaminoalkyl, lower N-arylaminoalkyl, lower
N-alkyl-N-arylaminoalkyl, lower carboxyalkyl, lower
alkoxycarbonylalkyl, lower alkoxycarbonyl, lower alkylthioalkyl,
aminocarbonyl, lower alkylaminocarbonylalkyl, lower aralkoxy, lower
aralkylthio, lower heteroaralkoxy, lower heteroaralkylthio, lower
heteroarylalkoxyalkyl, lower heteroarylalkylthioalkyl, lower
heteroaryloxyalkyl, lower heteroarylthioalkyl, lower heteroaryloxy,
lower heteroarylthio, lower arylthioalkyl, lower aryloxyalkyl,
lower arylthio, lower aryloxy, lower aralkylthioalkyl, lower
aralkoxyalkyl, aryl selected from phenyl and naphthyl, 5 or 6
membered heteroaryl, wherein the aryl and heteroaryl radicals are
optionally substituted at a substitutable position with one or more
radicals selected from halo, lower alkylthio, lower alkylsulfinyl,
lower alkyl, cyano, lower haloalkyl, hydroxyl, lower alkoxy, lower
hydroxyalkyl and lower haloalkoxy; wherein R.sup.4 is a radical
selected from hydrido, lower alkyl and fluoro; wherein R.sup.9 is a
radical selected from hydrido, halo, lower alkyl, lower haloalkyl,
lower alkoxy, amino, lower haloalkoxy, cyano, carboxyl, hydroxyl,
lower hydroxyalkyl, lower alkoxyalkyl, lower alkylamino, nitro and
lower alkylthio; and wherein R.sup.10 is a radical selected from
lower alkyl, lower haloalkyl and amino; or a
pharmaceutically-acceptable salt thereof.
[0257] A class of compounds of particular interest consists of
those compounds of Formula III wherein R.sup.3 is a radical
selected from hydrido, methyl, ethyl, isopropyl, tere-butyl,
isobutyl, pentyl, hexyl, fluoromethyl, difluoromethyl,
trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,
pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,
dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl,
dichloropropyl, benzyl, phenylethyl, phenylpropyl, furylmethyl,
morpholinomethyl, pyrrolidinylmethyl, piperazinylmethyl,
piperidinylmethyl, pyridylmethyl, thienylmethyl, formyl, cyano,
methoxy, ethoxy, propoxy, n-butoxy, methylthio, ethylthio,
methylsulfonyl, phenylsulfonyl, trifluoromethylsulfonyl, fluoro,
chloro, bromo, hydroxymethyl, hydroxyethyl, methoxymethyl,
ethoxymethyl, methylthiomethyl, benzyloxy, benzylthio,
methylcarbonyl, phenylcarbonyl, trifluoromethylcarbonyl,
difluoromethylcarbonyl, fluoromethylcarbonyl, benzylcarbonyl,
cyanomethyl, cyanobutyl, azidomethyl, methylaminomethyl,
N-phenylaminomethyl, N-methyl-N-phenylaminomethyl, acetyl,
propanoyl, butanoyl, methoxycarbonylmethyl, ethoxycarbonylethyl,
methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl,
tert-butoxycarbonyl, propoxycarbonyl, aminocarbonyl,
methylaminocarbonylmethyl, pyridyloxy, pyridylthio, phenyloxy,
4-chlorophenoxy, furylmethoxy, furylmethylthio, thienylmethoxy,
quinolylmethoxy, pyridylmethoxy, 5-phenylpyridyl-2-methox- y,
thienylmethylthio, pyridylmethylthio, quinolylmethoxymethyl,
furylbutoxyethyl, pyridyloxymethyl, pyridylmethoxymethyl,
thienyloxyhexyl, thienylthiomethyl, pyridylthiohexyl,
furyloxymethyl, furylmethylthiomethyl, quinolylmethylthioethyl,
phenylthiomethyl, phenyloxymethyl, 4-chlorophenyloxymethyl,
benzyloxymethyl, 4-methoxybenzyloxymethyl, naphthyl, phenyl,
thienyl, furyl, pyridyl, wherein the thienyl, furyl, pyridyl and
phenyl radicals are optionally substituted at a substitutable
position with one or more radicals selected from fluoro, chloro,
bromo, methylthio, methylsulfinyl, methyl, ethyl, isopropyl,
tert-butyl, isobutyl, pentyl, hexyl, cyano, fluoromethyl,
difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,
trichloromethyl, pentafluoroethyl, heptafluoropropyl,
difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,
difluoropropyl, dichloroethyl, dichloropropyl, hydroxyl, methoxy,
methylenedioxy, ethoxy, propoxy, n-butoxy, hydroxymethyl,
hydroxyethyl and trifluoromethoxy; wherein R.sup.4 is a radical
selected from hydrido, methyl, ethyl and fluoro; wherein R.sup.9 is
a radical selected from hydrido, fluoro, chloro, bromo, iodo,
methyl, ethyl, isopropyl, tert-butyl, isobutyl, fluoromethyl,
difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,
trichloromethyl, pentafluoroethyl, heptafluoropropyl,
difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,
difluoropropyl, dichloroethyl, dichloropropyl, methoxy, ethoxy,
isopropoxy, tert-butoxy, propoxy, butoxy, isobutoxy, pentoxy,
methylenedioxy, amino, trifluoromethoxy, cyano, carboxyl, hydroxyl,
nitro, hydroxymethyl, methoxymethyl, ethoxymethyl, methylamino,
methylthio, ethylthio, propylthio and butylthio; and wherein
R.sup.10 is methyl, fluoromethyl or amino, or a
pharmaceutically-acceptable salt thereof.
[0258] A family of specific compounds of particular interest within
Formula III consists of compounds and pharmaceutically-acceptable
salts thereof as follows:
[0259]
1-(4-chlorophenyl)-4-trifluoromethyl-2-[4-(methylsulfonyl)phenyl]-1-
H-imidazole;
[0260]
1-(4-chlorophenyl)-4-difluoromethyl-2-[4-(methylsulfonyl)phenyl]-1H-
-imidazole;
[0261]
1-(4-chlorophenyl)-4-methyl-2-[4-(methylsulfonyl)phenyl]-1H-imidazo-
le;
[0262]
1-(4-chlorophenyl)-4-ethyl-2-[4-(methylsulfonyl)phenyl]-1H-imidazol-
e;
[0263]
1-(4-chlorophenyl)-4-phenyl-2-[4-(methylsulfonyl)phenyl]-1H-imidazo-
le;
[0264]
1-(4-chlorophenyl)-4-(4-fluorophenyl)-2-[4-(methylsulfonyl)phenyl]--
1H-imidazole;
[0265]
1-(4-chlorophenyl)-4-(4-bromophenyl)-2-[4-(methylsulfonyl)phenyl]-1-
H-imidazole;
[0266]
1-(4-chlorophenyl)-4-(4-chlorophenyl)-2-[4-(methylsulfonyl)phenyl]--
1H-imidazole;
[0267]
1-(4-chlorophenyl)-4-(2-naphthyl)-2-[4-(methylsulfonyl)phenyl]-1H-i-
midazole;
[0268]
1-(4-chlorophenyl)-4-[4-(trifluoromethoxy)phenyl]-2-[4-(methylsulfo-
nyl)phenyl]-1H-imidazole;
[0269]
1-(4-chlorophenyl)-4-(3-chlorophenyl)-2-[4-(methylsulfonyl)phenyl]--
1H-imidazole;
[0270]
1-(4-chlorophenyl)-4-(3-fluorophenyl)-2-[4-(methylsulfonyl)phenyl]--
1H-imidazole;
[0271]
1-(4-chlorophenyl)-4-(4-methoxyphenyl)-2-[4-(methylsulfonyl)phenyl]-
-1H-imidazole;
[0272]
1-(4-chlorophenyl)-4-phenoxymethyl-2-[4-(methylsulfonyl)phenyl]-1H--
imidazole;
[0273]
1-(4-chlorophenyl)-4-(4-chlorophenoxy)methyl-2-[4-(methylsulfonyl)p-
henyl]-1H-imidazole;
[0274]
1-(4-chlorophenyl)-4-(4-fluorophenoxy)methyl-2-[4-(methylsulfonyl)p-
henyl]-1H-imidazole;
[0275]
1-(4-chlorophenyl)-4-phenylthiomethyl-2-[4-(methylsulfonyl)phenyl]--
1H-imidazole;
[0276]
1-(4-chlorophenyl)-4-(N-phenyl-N-methylamino)methyl-2-[4-(methylsul-
fonyl)phenyl]-1H-imidazole;
[0277]
1-(4-chlorophenyl)-4-(2-quinolyl)methoxymethyl-2-[4-(methylsulfonyl-
)phenyl]-1H-imidazole;
[0278]
1-(4-chlorophenyl)-4-methoxymethyl-2-[4-(methylsulfonyl)phenyl]-1H--
imidazole;
[0279]
1-(4-chlorophenyl)-4-(4-methoxybenzyloxy)methyl-2-[4-(methylsulfony-
l)phenyl]-1H-imidazole;
[0280]
1-(4-chlorophenyl)-4-hydroxymethyl-2-[4-(methylsulfonyl)phenyl]-1H--
imidazole;
[0281]
1-(4-chlorophenyl)-4-formyl-2-[4-(methylsulfonyl)phenyl]-1H-imidazo-
le;
[0282]
1-(4-chlorophenyl)-4-cyano-2-[4-(methylsulfonyl)phenyl]-1H-imidazol-
e;
[0283]
1-(4-chlorophenyl)-4-benzyl-2-[4-(methylsulfonyl)phenyl]-1H-imidazo-
le;
[0284]
1-(4-chlorophenyl)-4-phenylethyl-2-[4-(methylsulfonyl)phenyl]-1H-im-
idazole;
[0285]
1-(4-chlorophenyl)-4-hexyl-2-[4-(methylsulfonyl)phenyl]-1H-imidazol-
e;
[0286]
1-(4-chlorophenyl)-4-hexylcarbonyl-2-[4-(methylsulfonyl)phenyl]-1H--
imidazole;
[0287]
1-(4-chlorophenyl)-4-phenylcarbonyl-2-[4-(methylsulfonyl)phenyl]-1H-
-imidazole;
[0288]
1-(4-chlorophenyl)-4-benzylcarbonyl-2-[4-(methylsulfonyl)phenyl]-1H-
-imidazole;
[0289]
1-(4-chlorophenyl)-4-(1-hydroxy-2-phenyl-methyl)-2-[4-(methylsulfon-
yl)phenyl]-1H-imidazole;
[0290]
1-(4-chlorophenyl)-4-(1-hexanol)-2-[4-(methylsulfonyl)phenyl]-1H-im-
idazole;
[0291]
1-(4-chlorophenyl)-2-[(methylsulfonyl)phenyl]-1H-imidazole;
[0292]
1-(4-chlorophenyl)-4-octyl-2-[4-(methylsulfonyl)phenyl]-1H-imidazol-
e;
[0293]
1-(4-chlorophenyl)-4-methoxy-2-[4-(methylsulfonyl)phenyl]-1H-imidaz-
ole;
[0294]
1-(4-chlorophenyl)-4-butoxy-2-[4-(methylsulfonyl)phenyl]-1H-imidazo-
le;
[0295]
1-(4-chlorophenyl)-4-methylthio-2-[4-(methylsulfonyl)phenyl]-1H-imi-
dazole;
[0296]
1-(4-chlorophenyl)-4-(2-thienyl)-2-[4-(methylsulfonyl)phenyl]-1H-im-
idazole;
[0297]
1-(4-chlorophenyl)-4-(3-furyl)-2-[4-(methylsulfonyl)phenyl]-1H-imid-
azole;
[0298]
1-(4-chlorophenyl)-4-(4-pyridyl)-2-[4-(methylsulfonyl)phenyl]-1H-im-
idazole;
[0299]
1-(4-chlorophenyl)-4-chloro-2-[4-(methylsulfonyl)phenyl]-1H-imidazo-
le;
[0300]
1-(4-chlorophenyl)-4-fluoro-2-[4-(methylsulfonyl)phenyl]-1H-imidazo-
le;
[0301]
[1-(4-chlorophenyl)-2-[4-(methylsulfonyl)phenyl]-1H-imidazol-4-yl]c-
arboxylic acid;
[0302]
methyl[1-(4-chlorophenyl)-2-[4-(methylsulfonyl)phenyl]-1H-imidazol--
4-yl]carboxylate;
[0303]
[1-(4-chlorophenyl)-2-(4-(methylsulfonyl)phenyl)-1H-imidazol-4-yl]c-
arboxamide;
[0304]
methyl[1-(4-chlorophenyl)-2-[4-(methylsulfonyl)phenyl]-1H-imidazol--
4-yl]carboxamide;
[0305]
4-[1-(4-chlorophenyl)-4-trifluoromethyl-1H-imidazol-2-yl]benzenesul-
fonamide;
[0306]
4-[1-(4-chlorophenyl)-4-difluoromethyl-1H-imidazol-2-yl]benzenesulf-
onamide;
[0307]
4-[1-(4-chlorophenyl)-4-methyl-1H-imidazol-2-yl]benzenesulfonamide;
[0308]
4-[1-(4-chlorophenyl)-4-ethyl-1H-imidazol-2-yl]benzenesulfonamide;
[0309]
4-[1-(4-chlorophenyl)-4-phenyl-1H-imidazol-2-yl]benzenesulfonamide;
[0310]
4-[1-(4-chlorophenyl)-4-(4-fluorophenyl)-1H-imidazol-2-yl]benzenesu-
lfonamide;
[0311]
4-[1-(4-chlorophenyl)-4-(4-bromophenyl)-1H-imidazol-2-yl]benzenesul-
fonamide;
[0312]
4-[1-(4-chlorophenyl)-4-(4-chlorophenyl)-1H-imidazol-2-yl]benzenesu-
lfonamide;
[0313]
4-[1-(4-chlorophenyl)-4-(2-naphthyl)-1H-imidazol-2-yl]benzenesulfon-
amide;
[0314]
4-[1-(4-chlorophenyl)-4-[4-(trifluoromethoxy)phenyl]-1H-imidazol-2--
yl]benzenesulfonamide;
[0315]
4-[1-(4-chlorophenyl)-4-(3-chlorophenyl)-1H-imidazol-2-yl]benzenesu-
lfonamide;
[0316]
4-[1-(4-chlorophenyl)-4-(3-fluorophenyl)-1H-imidazol-2-yl]benzenesu-
lfonamide;
[0317]
4-[1-(4-chlorophenyl)-4-(4-methoxyphenyl)-1H-imidazol-2-yl]benzenes-
ulfonamide;
[0318]
4-[1-(4-chlorophenyl)-4-phenoxymethyl-1H-imidazol-2-yl]benzenesulfo-
namide;
[0319]
4-[1-(4-chlorophenyl)-4-(4-chlorophenoxy)methyl-1H-imidazol-2-yl]be-
nzenesulfonamide;
[0320]
4-[1-(4-chlorophenyl)-4-(4-fluorophenoxy)methyl-1H-imidazol-2-yl]be-
nzenesulfonamide;
[0321]
4-[1-(4-chlorophenyl)-4-phenylthiomethyl-1H-imidazol-2-yl]benzenesu-
lfonamide;
[0322]
4-[1-(4-chlorophenyl)-4-(N-phenyl-N-methylamino)methyl-1H-imidazol--
2-yl]benzenesulfonamide;
[0323]
4-[1-(4-chlorophenyl)-4-(2-quinolyl)methoxymethyl-1H-imidazol-2-yl]-
benzenesulfonamide;
[0324]
4-[1-(4-chlorophenyl)-4-methoxymethyl-1H-imidazol-2-yl]benzenesulfo-
namide;
[0325]
4-[1-(4-chlorophenyl)-4-(4-methoxybenzyloxy)methyl-1H-imidazol-2-yl-
]benzenesulfonamide;
[0326]
4-[1-(4-chlorophenyl)-4-hydroxymethyl-1H-imidazol-2-yl]benzenesulfo-
namide;
[0327]
4-[1-(4-chlorophenyl)-4-formyl-1H-imidazol-2-yl]benzenesulfonamide;
[0328]
4-[1-(4-chlorophenyl)-4-cyano-1H-imidazol-2-yl]benzenesulfonamide;
[0329]
4-[1-(4-chlorophenyl)-4-benzyl-1H-imidazol-2-yl]benzenesulfonamide;
[0330]
4-[1-(4-chlorophenyl)-4-phenylethyl-1H-imidazol-2-yl]benzenesulfona-
mide;
[0331]
4-[1-(4-chlorophenyl)-4-hexyl-1H-imidazol-2-yl]benzenesulfonamide;
[0332]
4-[1-(4-chlorophenyl)-4-hexylcarbonyl-1H-imidazol-2-yl]benzenesulfo-
namide;
[0333]
4-[1-(4-chlorophenyl)-4-phenylcarbonyl-1H-imidazol-2-yl]benzenesulf-
onamide;
[0334]
4-[1-(4-chlorophenyl)-4-benzylcarbonyl-1H-imidazol-2-yl]benzenesulf-
onamide;
[0335]
4-[1-(4-chlorophenyl)-4-(1-hydroxy-2-phenyl-methyl)-1H-imidazol-2-y-
l]benzenesulfonamide;
[0336]
4-[1-(4-chlorophenyl)-4-(1-hexanol)-1H-imidazol-2-yl]benzenesulfona-
mide;
[0337]
4-[1-(4-chlorophenyl)-1H-imidazol-2-yl]benzenesulfonamide;
[0338]
4-[1-(4-chlorophenyl)-4-octyl-1H-imidazol-2-yl]benzenesulfonamide;
[0339]
4-[1-(4-chlorophenyl)-4-methoxy-1H-imidazol-2-yl]benzenesulfonamide-
;
[0340]
4-[1-(4-chlorophenyl)-4-butoxy-1H-imidazol-2-yl]benzenesulfonamide;
[0341]
4-[1-(4-chlorophenyl)-4-methylthio-1H-imidazol-2-yl]benzenesulfonam-
ide;
[0342]
4-[1-(4-chlorophenyl)-4-(3-thienyl)-1H-imidazol-2-yl]benzenesulfona-
mide;
[0343]
4-[1-(4-chlorophenyl)-4-(2-furyl)-1H-imidazol-2-yl]benzenesulfonami-
de;
[0344]
4-[1-(4-chlorophenyl)-4-(3-pyridyl)-1H-imidazol-2-yl]benzenesulfona-
mide;
[0345]
4-[1-(4-chlorophenyl)-4-chloro-1H-imidazol-2-yl]benzenesulfonamide;
[0346]
4-[1-(4-chlorophenyl)-4-fluoro-1H-imidazol-2-yl]benzenesulfonamide;
[0347]
[1-(4-chlorophenyl)-2-[4-(aminosulfonyl)phenyl]-1H-imidazol-4-yl]ca-
rboxylic acid;
[0348]
methyl[1-(4-chlorophenyl)-2-[4-(aminosulfonyl)phenyl]-1H-imidazol-4-
-yl]carboxylate;
[0349]
[1-(4-chlorophenyl)-2-[4-(aminosulfonyl)phenyl]-1H-imidazol-4-yl]ca-
rboxamide;
[0350]
methyl[1-(4-chlorophenyl)-2-[4-(aminosulfonyl)phenyl]-1H-imidazol-4-
-yl]carboxamide;
[0351]
2-[4-(methylsulfonyl)phenyl]-1-(4-methylphenyl)-4-trifluoromethyl-1-
H-imidazole;
[0352]
2-[4-(methylsulfonyl)phenyl]-1-(3-chlorophenyl)-4-trifluoromethyl-1-
H-imidazole;
[0353]
2-[4-(methylsulfonyl)phenyl]-2-(4-methyl-3-chlorophenyl)-4-trifluor-
omethyl-1H-imidazole;
[0354]
5-[2-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-1-yl]-
-1,3-benzodioxole;
[0355]
2-[4-(methylsulfonyl)phenyl]-2-(4-methoxyphenyl)-4-trifluoromethyl--
1H-imidazole;
[0356]
2-[4-(methylsulfonyl)phenyl]-1-(3-fluorophenyl)-4-trifluoromethyl-1-
H-imidazole;
[0357]
2-[4-(methylsulfonyl)phenyl]-1-(4-fluorophenyl)-4-trifluoromethyl-1-
H-imidazole;
[0358]
2-[4-(methylsulfonyl)phenyl]-1-(4-methoxy-3-fluorophenyl)-4-trifluo-
romethyl-1H-imidazole;
[0359]
2-[4-(methylsulfonyl)phenyl]-1-phenyl-4-trifluoromethyl-1H-imidazol-
e;
[0360]
2-[4-(methylsulfonyl)phenyl]-1-(4-methoxy-3-chlorophenyl)-4-trifluo-
romethyl-1H-imidazole;
[0361]
2-[4-(methylsulfonyl)phenyl]-1-[4-(trifluoromethyl)phenyl]-4-triflu-
oromethyl-1H-imidazole;
[0362]
2-[4-(methylsulfonyl)phenyl]-1-(4-bromophenyl)-4-trifluoromethyl-1H-
-imidazole;
[0363]
2-[4-(methylsulfonyl)phenyl]-1-(2-chlorophenyl)-4-trifluoromethyl-1-
H-imidazole;
[0364]
2-[4-(methylsulfonyl)phenyl]-1-(4-ethylpheny1)-4-trifluoromethyl-1H-
-imidazole;
[0365]
2-[4-(methylsulfonyl)phenyl]-1-(4-butylphenyl)-4-trifluoromethyl-1H-
-imidazole;
[0366]
2-[4-(methylsulfonyl)phenyl]-1-[4-(difluoromethyl)phenyl]-4-trifluo-
romethyl-1H-imidazole;
[0367]
2-[4-(methylsulfonyl)phenyl]-1-(4-butoxyphenyl)-4-trifluoromethyl-1-
H-imidazole;
[0368]
2-[4-(methylsulfonyl)phenyl]-1-[4-(methylthio)phenyl]-4-trifluorome-
thyl-1H-imidazole;
[0369]
2-[4-(methylsulfonyl)phenyl]-1-(4-methoxy-3,5-dichlorophenyl)-4-tri-
fluoromethyl-1H-imidazole;
[0370]
2-[4-(methylsulfonyl)phenyl]-1-(4-methyl-3,5-difluorophenyl)-4-trif-
luoromethyl-1H-imidazole;
[0371]
2-[4-(methylsulfonyl)phenyl]-1-(2,4-dichlorophenyl)-4-trifluorometh-
yl-1H-imidazole;
[0372]
2-[4-(methylsulfonyl)phenyl]-1-(3,4-dichlorophenyl)-4-trifluorometh-
yl-1H-imidazole;
[0373]
2-[4-(methylsulfonyl)phenyl]-1-[4-(trifluoromethyl)phenyl]-4-triflu-
oromethoxy-1H-imidazole;
[0374]
2-[4-(methylsulfonyl)phenyl]-1-(3,5-dimethyl-4-methoxyphenyl)-4-tri-
fluoromethyl-1H-imidazole;
[0375]
2-[4-(methylsulfonyl)phenyl]-1-(3,4-dimethylphenyl)-4-trifluorometh-
yl-1H-imidazole;
[0376]
2-[4-(methylsulfonyl)phenyl]-1-(4-aminophenyl)-4-trifluoromethyl-1H-
-imidazole;
[0377]
4-[1-(4-methylphenyl)-4-trifluoromethyl-1H-imidazol-2-yl]benzenesul-
fonamide;
[0378]
4-[1-(3-chlorophenyl)-4-trifluoromethyl-1H-imidazol-2-yl]benzenesul-
fonamide;
[0379]
4-[1-(4-methyl-3-chlorophenyl)-4-trifluoromethyl-1H-imidazol-2-yl]b-
enzenesulfonamide;
[0380]
5-[2-[4-(aminosulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-1-yl]--
1,3-benzodioxole;
[0381]
4-[1-(3-fluorophenyl)-4-trifluoromethyl-1H-imidazol-2-yl]benzenesul-
fonamide;
[0382]
4-[1-(4-fluorophenyl)-4-trifluoromethyl-1H-imidazol-2-yl]benzenesul-
fonamide;
[0383]
4-[1-(4-methoxy-3-fluorophenyl)-4-trifluoromethyl-1H-imidazol-2-yl]-
benzenesulfonamide;
[0384]
4-[1-phenyl-4-trifluoromethyl-1H-imidazol-2-yl]benzenesulfonamide;
[0385]
4-[1-(4-methoxy-3-chlorophenyl)-4-trifluoromethyl-1H-imidazol-2-yl]-
benzenesulfonamide;
[0386]
4-[1-[4-(trifluoromethyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl-
]benzenesulfonamide;
[0387]
4-[1-(4-bromophenyl)-4-trifluoromethyl-1H-imidazol-2-yl]benzenesulf-
onamide;
[0388]
4-[1-(2-chlorophenyl)-4-trifluoromethyl-1H-imidazol-2-yl]benzenesul-
fonamide;
[0389]
4-[1-(4-ethylphenyl)-4-trifluoromethyl-1H-imidazol-2-yl]benzenesulf-
onamide;
[0390]
4-[1-(4-butylphenyl)-4-trifluoromethyl-1H-imidazol-2-yl]benzenesulf-
onamide;
[0391]
4-[1-[4-(difluoromethyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]-
benzenesulfonamide;
[0392]
4-[1-(4-butoxyphenyl)-4-trifluoromethyl-1H-imidazol-2-yl]benzenesul-
fonamide;
[0393]
4-[1-[4-(methylthio)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]benz-
enesulfonamide;
[0394]
4-[1-(4-methoxy-3,5-dichloro-phenyl)-4-trifluoromethyl-1H-imidazol--
2-yl]benzenesulfonamide;
[0395]
4-[1-(4-methyl-3,5-difluorophenyl)-4-trifluoromethyl-1H-imidazol-2--
yl]benzenesulfonamide;
[0396]
4-[1-(2,4-dichlorophenyl)-4-trifluoromethyl-1H-imidazol-2-yl]benzen-
esulfonamide;
[0397]
4-[1-(3,4-dichlorophenyl)-4-trifluoromethyl-1H-imidazol-2-yl]benzen-
esulfonamide;
[0398]
4-[1-[4-(trifluoromethoxy)phenyl]-4-trifluoromethyl-1H-imidazol-2-y-
l]benzenesulfonamide;
[0399]
4-[1-(3,5-dimethyl-4-methoxy-phenyl)-4-trifluoromethyl-1H-imidazol--
2-yl]benzenesulfonamide;
[0400]
4-[1-(3,4-dimethylphenyl)-4-trifluoromethyl-1H-imidazol-2-yl]benzen-
esulfonamide; and
[0401]
4-[1-(4-aminophenyl)-4-trifluoromethyl-1H-imidazol-2-yl]benzenesulf-
onamide.
[0402] Within Formula I there is a third subclass of compounds of
high interest represented by Formula IV: 5
[0403] wherein R.sup.3 is selected from alkyl, haloalkyl,
alkylsulfonylalkyl, cycloalkylthioalkyl, alkoxycarbonyl,
aralkoxyalkyl, aryloxyalkyl, arylthioalkyl,
N-aryl-N-alkylaminoalkyl, heteroarylalkoxyalkyl,
heterocyclocarbonyl, heteroaryloxyalkyl,
N-alkoxy-N-alkylaminocarbonyl, heteroaralkylthioalkyl,
heteroarylthioalkyl and aryl optionally substituted at a
substitutable position with halo, alkoxy and haloalkoxy; and
wherein R.sup.11 and R.sup.12 are independently selected from
hydrido, halo, alkyl, haloalkyl, alkoxy, alkylsulfonyl,
haloalkylsulfonyl and sulfamyl; or a pharmaceutically-acceptable
salt thereof.
[0404] A preferred class of compounds consists of those compounds
of Formula IV wherein R.sup.3 is selected from lower alkyl, lower
haloalkyl, lower aralkoxyalkyl, lower aryloxyalkyl, lower
alkoxycarbonyl, lower arylthioalkyl, lower heteroaralkylthioalkyl,
lower heteroarylthioalkyl, lower N-aryl-N-alkylaminoalkyl, lower
heteroarylalkoxyalkyl and aryl selected from naphthyl, phenyl and
biphenyl, wherein the aryl radical is optionally substituted at a
substitutable position with halo, lower alkoxy and lower
haloalkoxy; and wherein R.sup.11 and R.sup.12 are independently
selected from hydrido, halo, lower alkyl, lower haloalkyl, lower
alkoxy, lower alkylsulfonyl, lower haloalkylsulfonyl and sulfamyl;
or a pharmaceutically-acceptable salt thereof.
[0405] A class of compounds of particular interest consists of
those compounds of Formula IV wherein R.sup.3 is selected from
methyl, ethyl, isopropyl, tert-butyl, isobutyl, fluoromethyl,
difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,
trichloromethyl, pentafluoroethyl, heptafluoropropyl,
difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,
difluoropropyl, dichloroethyl, dichloropropyl, ethoxycarbonyl,
methoxycarbonyl, benzyloxymethyl, phenylthiomethyl,
pyridylthiomethyl, pyridylmethylthiomethyl, phenyloxymethyl,
4-chlorophenyloxymethyl, N-phenyl-N-methylaminomethyl,
quinolyloxymethyl and aryl selected from naphthyl and phenyl,
wherein the aryl radical is optionally substituted at a
substitutable position with fluoro, chloro, bromo, iodo, methoxy,
ethoxy, isopropoxy, tert-butoxy, propoxy, butoxy, isobutoxy,
pentoxy, methylenedioxy and trifluoromethoxy; and wherein R.sup.11
and R.sup.12 are independently selected from hydrido, fluoro,
chloro, bromo, iodo, methyl, ethyl, isopropyl, tert-butyl,
isobutyl, fluoromethyl, difluoromethyl, trifluoromethyl,
chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl,
heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl,
difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl,
methoxy, ethoxy, isopropoxy, tert-butoxy, propoxy, butoxy,
isobutoxy, pentoxy, methylenedioxy, methylsulfonyl,
fluoromethylsulfonyl and sulfamyl; or a pharmaceutically-acceptable
salt thereof.
[0406] A family of specific compounds of particular interest within
Formula IV consists of compounds and pharmaceutically-acceptable
salts thereof as follows:
[0407]
2-[4-(dimethylamino)-3-fluorophenyl]-4,5-dihydro-4-hydroxy-1-[4-(me-
thylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazole;
[0408]
2-(4-chlorophenyl)-4-trifluoromethyl-1-[4-(methylsulfonyl)phenyl]-4-
-hydroxy-4,5-dihydro-1H-imidazole;
[0409]
2-(4-chlorophenyl)-4-difluoromethyl-1-[4-(methylsulfonyl)phenyl]-4--
hydroxy-4,5-dihydro-1H-imidazole;
[0410]
2-(4-chlorophenyl)-4-methyl-1-[4-(methylsulfonyl)phenyl]-4-hydroxy--
4,5-dihydro-1H-imidazole;
[0411]
2-(4-chlorophenyl)-4-ethyl-1-[4-(methylsulfonyl)phenyl]-4-hydroxy-4-
,5-dihydro-1H-imidazole;
[0412]
2-(4-chlorophenyl)-4-phenyl-1-[4-(methylsulfonyl)phenyl]-4-hydroxy--
4,5-dihydro-1H-imidazole;
[0413]
2-(4-chlorophenyl)-4-(4-fluorophenyl)-1-[4-(methylsulfonyl)phenyl]--
4-hydroxy-4,5-dihydro-1H-imidazole;
[0414]
2-(4-chlorophenyl)-4-(4-bromophenyl)-1-[4-(methylsulfonyl)phenyl]-4-
-hydroxy-4,5-dihydro-1H-imidazole;
[0415]
2-(4-chlorophenyl)-4-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]--
4-hydroxy-4,5-dihydro-1H-imidazole;
[0416]
2-(4-chlorophenyl)-4-(2-naphthyl)-1-[4-(methylsulfonyl)phenyl]-4-hy-
droxy-4,5-dihydro-1H-imidazole;
[0417]
2-(4-chlorophenyl)-4-[4-(trifluoromethoxy)phenyl]-1-[4-(methylsulfo-
nyl)phenyl]-4-hydroxy-4,5-dihydro-1H-imidazole;
[0418]
2-(4-chlorophenyl)-4-(3-fluorophenyl)-1-[4-(methylsulfonyl)phenyl]--
4-hydroxy-4,5-dihydro-1H-imidazole;
[0419]
2-(4-chlorophenyl)-4-(3-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]--
4-hydroxy-4,5-dihydro-1H-imidazole;
[0420]
2-(4-chlorophenyl)-4-(4-methoxyphenyl)-1-[4-(methylsulfonyl)phenyl]-
-4-hydroxy-4,5-dihydro-1H-imidazole;
[0421]
2-(4-chlorophenyl)-4-phenoxymethyl-1-[4-(methylsulfonyl)phenyl]-4-h-
ydroxy-4,5-dihydro-1H-imidazole;
[0422]
2-(4-chlorophenyl)-4-(4-chlorophenoxy)methyl-1-[4-(methylsulfonyl)p-
henyl]-4-hydroxy-4,5-dihydro-1H-imidazole;
[0423]
2-(4-chlorophenyl)-4-(4-fluorophenoxy)methyl-1-[4-(methylsulfonyl)
phenyl]-4-hydroxy-4,5-dihydro-1H-imidazole;
[0424] 2-(4-chlorophenyl)-4-phenylthiomethyl-1-[4-(methylsulfonyl)
phenyl]-4-hydroxy-4,5-dihydro-1H- imidazole;
[0425]
2-(4-chlorophenyl)-4-(N-phenyl-N-methylamino)methyl-1-[4-(methylsul-
fonyl)phenyl]-4-hydroxy-4,5-dihydro-1H-imidazole;
[0426]
2-(4-chlorophenyl)-4-(2-quinolyl)methoxymethyl-1-[4-(methylsulfonyl-
) phenyl]-4-hydroxy-4,5-dihydro-1H-imidazole;
[0427] 2-(4-chlorophenyl)-4-methoxymethyl-1-[4-(methylsulfonyl)
phenyl]-4-hydroxy-4,5-dihydro-1H-imidazole;
[0428]
2-(4-chlorophenyl)-4-(4-methoxybenzyloxy)methyl-1-[4-(methylsulfony-
l) phenyl]-4-hydroxy-4,5-dihydro-1H-imidazole;
[0429]
2-(4-chlorophenyl)-4-hydroxymethyl-1-[4-(methylsulfonyl)phenyl]-4-h-
ydroxy-4,5-dihydro-1H-imidazole;
[0430]
2-(4-chlorophenyl)-4-formyl-1-[4-(methylsulfonyl)phenyl]-4-hydroxy--
4,5-dihydro-1H-imidazole;
[0431]
2-(4-chlorophenyl)-4-cyano-1-[4-(methylsulfonyl)phenyl]-4-hydroxy-4-
,5-dihydro-1H-imidazole;
[0432]
2-(4-chlorophenyl)-4-benzyl-1-[4-(methylsulfonyl)phenyl]-4-hydroxy--
4,5-dihydro-1H-imidazole;
[0433]
2-(4-chlorophenyl)-4-phenylethyl-1-[4-(methylsulfonyl)phenyl]-4-hyd-
roxy-4,5-dihydro-1H-imidazole;
[0434]
2-(4-chlorophenyl)-4-hexyl-1-[4-(methylsulfonyl)phenyl]-4-hydroxy-4-
,5-dihydro-1H-imidazole;
[0435]
2-(4-chlorophenyl)-4-hexylcarbonyl-1-[4-(methylsulfonyl)phenyl]-4-h-
ydroxy-4,5-dihydro-1H-imidazole;
[0436]
2-(4-chlorophenyl)-4-phenylcarbonyl-1-[4-(methylsulfonyl)phenyl]-4--
hydroxy-4,5-dihydro-1H-imidazole;
[0437]
2-(4-chlorophenyl)-4-benzylcarbonyl-1-[4-(methylsulfonyl)phenyl]-4--
hydroxy-4,5-dihydro-1H-imidazole;
[0438]
2-(4-chlorophenyl)-4-(1-hydroxy-1-phenyl-methyl)-1-[4-(methylsulfon-
yl)phenyl]-4-hydroxy-4,5-dihydro-1H-imidazole;
[0439]
2-(4-chlorophenyl)-4-(1-hexanol)-1-[4-(methylsulfonyl)phenyl]-4-hyd-
roxy-4,5-dihydro-1H-imidazole;
[0440]
2-(4-chlorophenyl)-1-[(methylsulfonyl)phenyl]-4-hydroxy-4,5-dihydro-
-1H-imidazole;
[0441]
2-(4-chlorophenyl)-4-octyl-1-[4-(methylsulfonyl)phenyl]-4-hydroxy-4-
,5-dihydro-1H-imidazole;
[0442]
2-(4-chlorophenyl)-4-methoxy-1-[4-(methylsulfonyl)phenyl]-4-hydroxy-
-4,5-dihydro-1H-imidazole;
[0443]
2-(4-chlorophenyl)-4-butoxy-1-[4-(methylsulfonyl)phenyl]-4-hydroxy--
4,5-dihydro-1H-imidazole;
[0444]
2-(4-chlorophenyl)-4-methylthio-1-[4-(methylsulfonyl)phenyl]-4-hydr-
oxy-4,5-dihydro-1H-imidazole;
[0445]
2-(4-chlorophenyl)-4-(2-thienyl)-1-[4-(methylsulfonyl)phenyl]-4-hyd-
roxy-4,5-dihydro-1H-imidazole;
[0446]
2-(4-chlorophenyl)-4-(2-furyl)-1-[4-(methylsulfonyl)phenyl]-4-hydro-
xy-4,5-dihydro-1H-imidazole;
[0447]
2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-(4-pyridyl)-4-hyd-
roxy-4,5-dihydro-1H-imidazole;
[0448]
2-(4-chlorophenyl)-4-chloro-1-[4-(methylsulfonyl)phenyl]-4-hydroxy--
4,5-dihydro-1H-imidazole;
[0449]
2-(4-chlorophenyl)-4-fluoro-1-[4-(methylsulfonyl)phenyl]-4-hydroxy--
4,5-dihydro-1H-imidazole;
[0450]
[2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-hydroxy-4,5-dihy-
dro-1H-imidazol-4-yl]carboxylic acid;
[0451]
methyl[2-(4-chlorophenyl)-1-(4-(methylsulfonyl)phenyl)-4-hydroxy-4,-
5-dihydro-1H-imidazol-4-yl]carboxylate;
[0452]
[2-(4-chlorophenyl)-1-(4-(methylsulfonyl)phenyl)-4-hydroxy-4,5-dihy-
dro-1H-imidazol-4-yl]carboxamide;
[0453]
methyl[2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-hydroxy-4,-
5-dihydro-1H-imidazol-4-yl]carboxamide;
[0454]
4-[2-(4-chlorophenyl)-4-trifluoromethyl-4-hydroxy-4,5-dihydro-1H-im-
idazol-1-yl]benzenesulfonamide;
[0455]
4-[2-(4-chlorophenyl)-4-difluoromethyl-4-hydroxy-4,5-dihydro-1H-imi-
dazol-1-yl]benzenesulfonamide;
[0456]
4-[2-(4-chlorophenyl)-4-methyl-4-hydroxy-4,5-dihydro-1H-imidazol-1--
yl]benzenesulfonamide;
[0457]
4-[2-(4-chlorophenyl)-4-ethyl-4-hydroxy-4,5-dihydro-1H-imidazol-1-y-
l]benzenesulfonamide;
[0458]
4-[2-(4-chlorophenyl)-4-phenyl-4-hydroxy-4,5-dihydro-1H-imidazol-1--
yl]benzenesulfonamide;
[0459]
4-[2-(4-chlorophenyl)-4-(4-fluorophenyl)-4-hydroxy-4,5-dihydro-1H-i-
midazol-1-yl]benzenesulfonamide;
[0460]
4-[2-(4-chlorophenyl)-4-(4-bromophenyl)-4-hydroxy-4,5-dihydro-1H-im-
idazol-1-yl]benzenesulfonamide;
[0461]
4-[2-(4-chlorophenyl)-4-(4-chlorophenyl)-4-hydroxy-4,5-dihydro-1H-i-
midazol-1-yl]benzenesulfonamide;
[0462]
4-[2-(4-chlorophenyl)-4-(2-naphthyl)-4-hydroxy-4,5-dihydro-1H-imida-
zol-1-yl]benzenesulfonamide;
[0463]
4-[2-(4-chlorophenyl)-4-[4-(trifluoromethoxy)phenyl]-4-hydroxy-4,5--
dihydro-1H-imidazol-1-yl]benzenesulfonamide;
[0464]
4-[2-(4-chlorophenyl)-4-(3-chlorophenyl)-4-hydroxy-4,5-dihydro-1H-i-
midazol-1-yl]benzenesulfonamide;
[0465]
4-[2-(4-chlorophenyl)-4-(3-fluorophenyl)-4-hydroxy-4,5-dihydro-1H-i-
midazol-1-yl]benzenesulfonamide;
[0466]
4-[2-(4-chlorophenyl)-4-(4-methoxyphenyl)-4-hydroxy-4,5-dihydro-1H--
imidazol-1-yl]benzenesulfonamide;
[0467]
4-[2-(4-chlorophenyl)-4-phenoxymethyl-4-hydroxy-4,5-dihydro-1H-imid-
azol-1-yl]benzenesulfonamide;
[0468]
4-[2-(4-chlorophenyl)-4-(4-chlorophenoxy)methyl-4-hydroxy-4,5-dihyd-
ro-1H-imidazol-1-yl]benzenesulfonamide;
[0469]
4-[2-(4-chlorophenyl)-4-(4-fluorophenoxy)methyl-4-hydroxy-4,5-dihyd-
ro-1H-imidazol-1-yl]benzenesulfonamide;
[0470]
4-[2-(4-chlorophenyl)-4-phenylthiomethyl-4-hydroxy-4,5-dihydro-1H-i-
midazol-1-yl]benzenesulfonamide;
[0471]
4-[2-(4-chlorophenyl)-4-(N-phenyl-N-methylamino)methyl-4-hydroxy-4,-
5-dihydro-1H-imidazol-1-yl]benzenesulfonamide;
[0472]
4-[2-(4-chlorophenyl)-4-(2-quinolyl)methoxymethyl-4-hydroxy-4,5-dih-
ydro-1H-imidazol-1-yl]benzenesulfonamide;
[0473] 4-[2-(4-chlorophenyl)-4-methoxymethyl-4-hydroxy-4,5-dihydro
-1H-imidazol -1-yl]benzenesulfonamide;
[0474]
4-[2-(4-chlorophenyl)-4-(4-methoxybenzyloxy)methyl-4-hydroxy-4,5-di-
hydro-1H-imidazol-1-yl]benzenesulfonamide;
[0475]
4-[2-(4-chlorophenyl)-4-hydroxymethyl-4-hydroxy-4,5-dihydro-1H-imid-
azol-1-yl]benzenesulfonamide;
[0476]
4-[2-(4-chlorophenyl)-4-formyl-4-hydroxy-4,5-dihydro-1H-imidazol-1--
yl]benzenesulfonamide;
[0477]
4-[2-(4-chlorophenyl)-4-cyano-4-hydroxy-4,5-dihydro-1H-imidazol-1-y-
l]benzenesulfonamide;
[0478]
4-[2-(4-chlorophenyl)-4-benzyl-4-hydroxy-4,5-dihydro-1H-imidazol-1--
yl]benzenesulfonamide;
[0479]
4-[2-(4-chlorophenyl)-4-phenylethyl-4-hydroxy-4,5-dihydro-1H-imidaz-
ol-1-yl]benzenesulfonamide;
[0480]
4-[2-(4-chlorophenyl)-4-hexyl-4-hydroxy-4,5-dihydro-1H-imidazol-1-y-
l]benzenesulfonamide;
[0481]
4-[2-(4-chlorophenyl)-4-hexylcarbonyl-4-hydroxy-4,5-dihydro-1H-imid-
azol-1-yl]benzenesulfonamide;
[0482]
4-[2-(4-chlorophenyl)-4-phenylcarbonyl-4-hydroxy-4,5-dihydro-1H-imi-
dazol-1-yl]benzenesulfonamide;
[0483]
4-[2-(4-chlorophenyl)-4-benzylcarbonyl-4-hydroxy-4,5-dihydro-1H-imi-
dazol-1-yl]benzenesulfonamide;
[0484]
4-[2-(4-chlorophenyl)-4-(1-hydroxy-1-phenyl-methyl)-4-hydroxy-4,5-d-
ihydro-1H-imidazol-1-yl]benzenesulfonamide;
[0485]
4-[2-(4-chlorophenyl)-4-(1-hexanol)-4-hydroxy-4,5-dihydro-1H-imidaz-
ol-1-yl]benzenesulfonamide;
[0486]
4-[2-(4-chlorophenyl)-4-hydroxy-4,5-dihydro-1H-imidazol-1-yl]benzen-
esulfonamide;
[0487]
4-[2-(4-chlorophenyl)-4-octyl-4-hydroxy-4,5-dihydro-1H-imidazol-1-y-
l]benzenesulfonamide;
[0488]
4-[2-(4-chlorophenyl)-4-methoxy-4-hydroxy-4,5-dihydro-1H-imidazol-1-
-yl]benzenesulfonamide;
[0489]
4-[2-(4-chlorophenyl)-4-butoxy-4-hydroxy-4,5-dihydro-1H-imidazol-1--
yl]benzenesulfonamide;
[0490]
4-[2-(4-chlorophenyl)-4-methylthio-4-hydroxy-4,5-dihydro-1H-imidazo-
l-1-yl]benzenesulfonamide;
[0491]
4-[2-(4-chlorophenyl)-4-(3-thienyl)-4-hydroxy-4,5-dihydro-1H-imidaz-
ol-1-yl]benzenesulfonamide;
[0492]
4-[2-(4-chlorophenyl)-4-(2-furyl)-4-hydroxy-4,5-dihydro-1H-imidazol-
-1-yl]benzenesulfonamide;
[0493]
4-[2-(4-chlorophenyl)-4-(4-pyridyl)-4-hydroxy-4,5-dihydro-1H-imidaz-
ol-1-yl]benzenesulfonamide;
[0494]
4-[2-(4-chlorophenyl)-4-chloro-4-hydroxy-4,5-dihydro-1H-imidazol-1--
yl]benzenesulfonamide;
[0495]
4-[2-(4-chlorophenyl)-4-fluoro-4-hydroxy-4,5-dihydro-1H-imidazol-1--
yl]benzenesulfonamide;
[0496]
[2-(4-chlorophenyl)-1-[4-(aminosulfonyl)phenyl]-4-hydroxy-4,5-dihyd-
ro-1H-imidazol-4-yl]carboxylic acid;
[0497]
methyl[2-(4-chlorophenyl)-1-[4-(aminosulfonyl)phenyl]-4-hydroxy-4,5-
-dihydro-1H-imidazol-4-yl]carboxylate;
[0498]
[2-(4-chlorophenyl)-1-[4-(aminosulfonyl)phenyl]-4-hydroxy-4,5-dihyd-
ro-1H-imidazol-4-yl]carboxamide;
[0499]
methyl[2-(4-chlorophenyl)-1-[4-(aminosulfonyl)phenyl]-4-hydroxy-4,5-
-dihydro-1H-imidazol-4-yl]carboxamide;
[0500]
2-[4-(methylsulfonyl)phenyl]-1-(4-methylphenyl)-4-trifluoromethyl-4-
-hydroxy-4,5-dihydro-1H-imidazole;
[0501]
2-[4-(methylsulfonyl)phenyl]-1-(3-chlorophenyl)-4-trifluoromethyl-4-
-hydroxy-4,5-dihydro-1H-imidazole;
[0502]
1-[4-(methylsulfonyl)phenyl]-2-(4-methyl-3-chlorophenyl)-4-trifluor-
omethyl-4-hydroxy-4,5-dihydro-1H-imidazole;
[0503]
5-[1-[4-(methylsulfonyl)phenyl]-4-hydroxy-4-trifluoromethyl-4,5-dih-
ydro-1H-imidazol-2-yl]-1,3-benzodioxole;
[0504]
1-[4-(methylsulfonyl)phenyl]-2-(4-methoxyphenyl)-4-trifluoromethyl--
4-hydroxy-4,5-dihydro-1H-imidazole;
[0505]
1-[4-(methylsulfonyl)phenyl]-2-(3-fluorophenyl)-4-trifluoromethyl-4-
-hydroxy-4,5-dihydro-1H-imidazole;
[0506]
1-[4-(methylsulfonyl)phenyl]-2-(4-fluorophenyl)-4-trifluoromethyl-4-
-hydroxy-4,5-dihydro-1H-imidazole;
[0507]
1-[4-(methylsulfonyl)phenyl]-2-(4-methoxy-3-fluorophenyl)-4-trifluo-
romethyl-4-hydroxy-4,5-dihydro-1H-imidazole;
[0508]
1-[4-(methylsulfonyl)phenyl]-2-phenyl-4-trifluoromethyl-4-hydroxy-4-
,5-dihydro-1H-imidazole;
[0509]
1-[4-(methylsulfonyl)phenyl]-2-(4-methoxy-3-chlorophenyl)-4-trifluo-
romethyl-4-hydroxy-4,5-dihydro-1H-imidazole;
[0510]
1-[4-(methylsulfonyl)phenyl]-2-[4-(trifluoromethyl)phenyl]-4-triflu-
oromethyl-4-hydroxy-4,5-dihydro-1H-imidazole;
[0511]
1-[4-(methylsulfonyl)phenyl]-2-(4-bromophenyl)-4-trifluoromethyl-4--
hydroxy-4,5-dihydro-1H-imidazole;
[0512]
1-[4-(methylsulfonyl)phenyl]-2-(4-ethylphenyl)-4-trifluoromethyl-4--
hydroxy-4,5-dihydro-1H-imidazole;
[0513]
1-[4-(methylsulfonyl)phenyl]-2-(4-butylphenyl)-4-trifluoromethyl-4--
hydroxy-4,5-dihydro-1H-imidazole;
[0514]
1-[4-(methylsulfonyl)phenyl]-2-[4-(difluoromethyl)phenyl]-4-trifluo-
romethyl-4-hydroxy-4,5-dihydro-1H-imidazole;
[0515]
1-[4-(methylsulfonyl)phenyl]-2-(4-butoxyphenyl)-4-trifluoromethyl-4-
-hydroxy-4,5-dihydro-1H-imidazole;
[0516]
1-[4-(methylsulfonyl)phenyl]-2-[4-(methylthio)phenyl]-4-trifluorome-
thyl-4-hydroxy-4,5-dihydro-1H-imidazole;
[0517]
1-[4-(methylsulfonyl)phenyl]-2-(4-methoxy-3,5-dichloro-phenyl)-4-tr-
ifluoromethyl-4-hydroxy-4,5-dihydro-1H-imidazole;
[0518]
1-[4-(methylsulfonyl)phenyl]-2-(4-methyl-3,5-difluorophenyl)-4-trif-
luoromethyl-4-hydroxy-4,5-dihydro-1H-imidazole;
[0519]
1-[4-(methylsulfonyl)phenyl]-2-(2,4-dichlorophenyl)-4-trifluorometh-
yl-4-hydroxy-4,5-dihydro-1H-imidazole;
[0520]
1-[4-(methylsulfonyl)phenyl]-2-(3,4-dichlorophenyl)-4-trifluorometh-
yl-4-hydroxy-4,5-dihydro-1H-imidazole;
[0521]
1-[4-(methylsulfonyl)phenyl]-2-[4-(trifluoromethyl)phenyl]-4-triflu-
oromethoxy-4-hydroxy-4,5-dihydro-1H-imidazole;
[0522]
2-(3,5-dimethyl-4-methoxy-phenyl)-1-[4-(methylsulfonyl)phenyl]-4-tr-
ifluoromethyl-4-hydroxy-4,5-dihydro-1H-imidazole;
[0523]
2-(3,4-dimethylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-trifluorometh-
yl-4-hydroxy-4,5-dihydro-1H-imidazole;
[0524]
2-(4-aminophenyl)-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-4--
hydroxy-4,5-dihydro-1H-imidazole;
[0525]
4-[2-(4-methylphenyl)-4-trifluoromethyl-4-hydroxy-4,5-dihydro-1H-im-
idazol-1-yl]benzenesulfonamide;
[0526]
4-[2-(3-chlorophenyl)-4-trifluoromethyl-4-hydroxy-4,5-dihydro-1H-im-
idazol-1-yl]benzenesulfonamide;
[0527]
4-[2-(4-methyl-3-chlorophenyl)-4-trifluoromethyl-4-hydroxy-4,5-dihy-
dro-1H-imidazol-1-yl]benzenesulfonamide;
[0528]
5-[1-[4-(aminosulfonyl)phenyl]-4-hydroxy-4-trifluoromethyl-4,5-dihy-
dro-1H-imidazol-2-yl]-1,3-benzodioxole;
[0529]
4-[2-(4-methoxyphenyl)-4-trifluoromethyl-4-hydroxy-4,5-dihydro-1H-i-
midazol-1-yl]benzenesulfonamide;
[0530]
4-[2-(3-fluorophenyl)-4-trifluoromethyl-4-hydroxy-4,5-dihydro-1H-im-
idazol-1-yl]benzenesulfonamide;
[0531]
4-[2-(4-fluorophenyl)-4-trifluoromethyl-4-hydroxy-4,5-dihydro-1H-im-
idazol-1-yl]benzenesulfonamide;
[0532]
4-[2-(4-methoxy-3-fluorophenyl)-4-trifluoromethyl-4-hydroxy-4,5-dih-
ydro-1H-imidazol-1-yl]benzenesulfonamide;
[0533]
4-[2-phenyl-4-trifluoromethyl-4-hydroxy-4,5-dihydro-1H-imidazol-1-y-
l]benzenesulfonamide;
[0534]
4-[2-(4-methoxy-3-chlorophenyl)-4-trifluoromethyl-4-hydroxy-4,5-dih-
ydro-1H-imidazol-1-yl]benzenesulfonamide;
[0535]
4-[2-[4-(trifluoromethyl)phenyl]-4-trifluoromethyl-4-hydroxy-4,5-di-
hydro-1H-imidazol-1-yl]benzenesulfonamide;
[0536]
4-[2-(4-bromophenyl)-4-trifluoromethyl-4-hydroxy-4,5-dihydro-1H-imi-
dazol-1-yl]benzenesulfonamide;
[0537]
4-[2-(2-chlorophenyl)-4-trifluoromethyl-4-hydroxy-4,5-dihydro-1H-im-
idazol-1-yl]benzenesulfonamide;
[0538]
4-[2-(4-ethylphenyl)-4-trifluoromethyl-4-hydroxy-4,5-dihydro-1H-imi-
dazol-1-yl]benzenesulfonamide;
[0539]
4-[2-(4-butylphenyl)-4-trifluoromethyl-4-hydroxy-4,5-dihydro-1H-imi-
dazol-1-yl]benzenesulfonamide;
[0540]
4-[2-[4-(difluoromethyl)phenyl]-4-trifluoromethyl-4-hydroxy-4,5-dih-
ydro-1H-imidazol-1-yl]benzenesulfonamide;
[0541]
4-[2-(4-butoxyphenyl)-4-trifluoromethyl-4-hydroxy-4,5-dihydro-1H-im-
idazol-1-yl]benzenesulfonamide;
[0542]
4-[2-[4-(methylthio)phenyl]-4-trifluoromethyl-4-hydroxy-4,5-dihydro-
-1H-imidazol-1-yl]benzenesulfonamide;
[0543]
4-[2-(4-methoxy-3,5-dichloro-phenyl)-4-trifluoromethyl-4-hydroxy-4,-
5-dihydro-1H-imidazol-1-yl]benzenesulfonamide;
[0544]
4-[2-(4-methyl-3,5-difluorophenyl)-4-trifluoromethyl-4-hydroxy-4,5--
dihydro-1H-imidazol-1-yl]benzenesulfonamide;
[0545]
4-[2-(2,4-dichlorophenyl)-4-trifluoromethyl-4-hydroxy-4,5-dihydro-1-
H-imidazol-1-yl]benzenesulfonamide;
[0546]
4-[2-(3,4-dichlorophenyl)-4-trifluoromethyl-4-hydroxy-4,5-dihydro-1-
H-imidazol-1-yl]benzenesulfonamide;
[0547]
4-[2-[4-(trifluoromethoxy)phenyl]-4-trifluoromethyl-4-hydroxy-4,5-d-
ihydro-1H-imidazol-1-yl]benzenesulfonamide;
[0548]
4-[2-(3,5-dimethyl-4-methoxy-phenyl)-4-trifluoromethyl-4-hydroxy-4,-
5-dihydro-1H-imidazol-1-yl]benzenesulfonamide;
[0549]
4-[2-(3,4-dimethylphenyl)-4-trifluoromethyl-4-hydroxy-4,5-dihydro-1-
H-imidazol-1-yl]benzenesulfonamide;
[0550]
4-[2-(4-aminophenyl)-4-trifluoromethyl-4-hydroxy-4,5-dihydro-1H-imi-
dazol-1-yl]benzenesulfonamide;
[0551]
1-(4-chlorophenyl)-4-trifluoromethyl-2-[4-(methylsulfonyl)phenyl]-4-
-hydroxy-4,5-dihydro-1H-imidazole;
[0552]
1-(4-chlorophenyl)-4-difluoromethyl-2-[4-(methylsulfonyl)phenyl]-4--
hydroxy-4,5-dihydro-1H-imidazole;
[0553]
1-(4-chlorophenyl)-4-methyl-2-[4-(methylsulfonyl)phenyl]-4-hydroxy--
4,5-dihydro-1H-imidazole;
[0554]
1-(4-chlorophenyl)-4-ethyl-2-[4-(methylsulfonyl)phenyl]-4-hydroxy-4-
,5-dihydro-1H-imidazole;
[0555]
1-(4-chlorophenyl)-4-phenyl-2-[4-(methylsulfonyl)phenyl]-4-hydroxy--
4,5-dihydro-1H-imidazole;
[0556]
1-(4-chlorophenyl)-4-(4-fluorophenyl)-2-(4-(methylsulfonyl)phenyl)--
4-hydroxy-4,5-dihydro-1H-imidazole;
[0557]
4-(4-bromophenyl)-1-(4-chlorophenyl)-2-[4-(methylsulfonyl)phenyl]-4-
-hydroxy-4,5-dihydro-1H-imidazole;
[0558]
1-(4-chlorophenyl)-4-(3-chlorophenyl)-2-[4-(methylsulfonyl)phenyl]--
4-hydroxy-4,5-dihydro-1H-imidazole;
[0559]
1-(4-chlorophenyl)-4-(3-fluorophenyl)-2-[4-(methylsulfonyl)phenyl]--
4-hydroxy-4,5-dihydro-1H-imidazole;
[0560]
1-(4-chlorophenyl)-4-(4-methoxyphenyl)-2-[4-(methylsulfonyl)phenyl]-
-4-hydroxy-4,5-dihydro-1H-imidazole;
[0561] 1,4-bis
(4-chlorophenyl)-2-[4-(methylsulfonyl)phenyl]-4-hydroxy-4,5-
-dihydro-1H-imidazole;
[0562]
1-(4-chlorophenyl)-4-(2-naphthyl)-2-[4-(methylsulfonyl)phenyl]-4-hy-
droxy-4,5-dihydro-1H-imidazole;
[0563]
1-(4-chlorophenyl)-4-[4-(trifluoromethoxy)phenyl]-2-[4-(methylsulfo-
nyl)phenyl]-4-hydroxy-4,5-dihydro-1H-imidazole;
[0564]
1-(4-chlorophenyl)-4-phenoxymethyl-2-[4-(methylsulfonyl)phenyl]-4-h-
ydroxy-4,5-dihydro-1H-imidazole;
[0565]
1-(4-chlorophenyl)-4-(4-chlorophenoxy)methyl-2-[4-(methylsulfonyl)p-
henyl]-4-hydroxy-4,5-dihydro-1H-imidazole;
[0566]
1-(4-chlorophenyl)-4-(4-fluorophenoxy)methyl-2-[4-(methylsulfonyl)p-
henyl]-4-hydroxy-4 5-dihydro-1H-imidazole;
[0567]
1-(4-chlorophenyl)-4-phenylthiomethyl-2-[4-(methylsulfonyl)phenyl]--
4-hydroxy-4,5-dihydro-1H-imidazole;
[0568]
1-(4-chlorophenyl)-4-(N-phenyl-N-methylamino)methyl-2-[4-(methylsul-
fonyl)phenyl]-4-hydroxy-4,5-dihydro-1H-imidazole;
[0569]
1-(4-chlorophenyl)-4-(2-quinolyl)methoxymethyl-2-[4-(methylsulfonyl-
)phenyl]-4-hydroxy-4,5-dihydro-1H-imidazole;
[0570]
1-(4-chlorophenyl)-4-methoxymethyl-2-[4-(methylsulfonyl)phenyl]-4-h-
ydroxy-4,5-dihydro-1H-imidazole;
[0571]
1-(4-chlorophenyl)-4-(4-methoxybenzyloxy)methyl-2-[4-(methylsulfony-
l)phenyl]-4-hydroxy-4,5-dihydro-1H-imidazole;
[0572]
1-(4-chlorophenyl)-4-hydroxymethyl-2-[4-(methylsulfonyl)phenyl]-4-h-
ydroxy-4,5-dihydro-1H-imidazole;
[0573]
1-(4-chlorophenyl)-4-formyl-2-[4-(methylsulfonyl)phenyl]-4-hydroxy--
4,5-dihydro-1H-imidazole;
[0574]
1-(4-chlorophenyl)-4-cyano-2-[4-(methylsulfonyl)phenyl]-4-hydroxy-4-
,5-dihydro-1H-imidazole;
[0575]
1-(4-chlorophenyl)-4-benzyl-2-[4-(methylsulfonyl)phenyl]-4-hydroxy--
4,5-dihydro-1H-imidazole;
[0576]
1-(4-chlorophenyl)-4-phenylethyl-2-[4-(methylsulfonyl)phenyl]-4-hyd-
roxy-4,5-dihydro-1H-imidazole;
[0577]
1-(4-chlorophenyl)-4-hexyl-2-[4-(methylsulfonyl)phenyl]-4-hydroxy-4-
,5-dihydro-1H-imidazole;
[0578]
1-(4-chlorophenyl)-4-hexylcarbonyl-2-[4-(methylsulfonyl)phenyl]-4-h-
ydroxy-4,5-dihydro-1H-imidazole;
[0579]
1-(4-chlorophenyl)-4-phenylcarbonyl-2-[4-(methylsulfonyl)phenyl]-4--
hydroxy-4,5-dihydro-1H-imidazole;
[0580]
1-(4-chlorophenyl)-4-benzylcarbonyl-2-[4-(methylsulfonyl)phenyl]-4--
hydroxy-4,5-dihydro-1H-imidazole;
[0581]
1-(4-chlorophenyl)-4-(1-hydroxy-2-phenyl-methyl)-2-[4-(methylsulfon-
yl)phenyl]-4-hydroxy-4,5-dihydro-1H-imidazole;
[0582]
1-(4-chlorophenyl)-4-(1-hexanol)-2-[4-(methylsulfonyl)phenyl]-4-hyd-
roxy-4,5-dihydro-1H-imidazole;
[0583]
1-(4-chlorophenyl)-2-[(methylsulfonyl)phenyl]-4-hydroxy-4,5-dihydro-
-1H-imidazole;
[0584]
1-(4-chlorophenyl)-4-octyl-2-[4-(methylsulfonyl)phenyl]-4-hydroxy-4-
,5-dihydro-1H-imidazole;
[0585]
1-(4-chlorophenyl)-4-methoxy-2-[4-(methylsulfonyl)phenyl]-4-hydroxy-
-4,5-dihydro-1H-imidazole;
[0586]
1-(4-chlorophenyl)-4-butoxy-2-[4-(methylsulfonyl)phenyl]-4-hydroxy--
4,5-dihydro-1H-imidazole;
[0587]
1-(4-chlorophenyl)-4-methylthio-2-[4-(methylsulfonyl)phenyl]-4-hydr-
oxy-4,5-dihydro-1H-imidazole;
[0588]
1-(4-chlorophenyl)-4-(2-thienyl)-2-[4-(methylsulfonyl)phenyl]-4-hyd-
roxy-4,5-dihydro-1H-imidazole;
[0589]
1-(4-chlorophenyl)-4-(2-furyl)-2-[4-(methylsulfonyl)phenyl]-4-hydro-
xy-4,5-dihydro-1H-imidazole;
[0590]
1-(4-chlorophenyl)-4-(4-pyridyl)-2-[4-(methylsulfonyl)phenyl]-4-hyd-
roxy-4,5-dihydro-1H-imidazole;
[0591]
1-(4-chlorophenyl)-4-chloro-2-[4-(methylsulfonyl)phenyl]-4-hydroxy--
4,5-dihydro-1H-imidazole;
[0592]
1-(4-chlorophenyl)-4-fluoro-2-[4-(methylsulfonyl)phenyl]-4-hydroxy--
4,5-dihydro-1H-imidazole;
[0593]
(1-(4-chlorophenyl)-2-[4-(methylsulfonyl)phenyl)-4-hydroxy-4,5-dihy-
dro-1H-imidazol-4-yl]carboxylic acid;
[0594]
methyl[1-(4-chlorophenyl)-2-[4-(methylsulfonyl)phenyl]-4-hydroxy-4,-
5-dihydro-1H-imidazol-4-yl]carboxylate;
[0595]
[1-(4-chlorophenyl)-2-[4-(methylsulfonyl)phenyl]-4-hydroxy-4,5-dihy-
dro-1H-imidazol-4-yl]carboxamide;
[0596]
methyl[1-(4-chlorophenyl)-2-[4-(methylsulfonyl)phenyl]-4-hydroxy-4,-
5-dihydro-1H-imidazol-4-yl]carboxamide;
[0597]
4-[1-(4-chlorophenyl)-4-trifluoromethyl-4-hydroxy-4,5-dihydro-1H-im-
idazol-2-yl]benzenesulfonamide;
[0598]
4-[1-(4-chlorophenyl)-4-difluoromethyl-4-hydroxy-4,5-dihydro-1H-imi-
dazol-2-yl]benzenesulfonamide;
[0599]
4-[1-(4-chlorophenyl)-4-methyl-4-hydroxy-4,5-dihydro-1H-imidazol-2--
yl]benzenesulfonamide;
[0600]
4-[1-(4-chlorophenyl)-4-ethyl-4-hydroxy-4,5-dihydro-1H-imidazol-2-y-
l]benzenesulfonamide;
[0601]
4-[1-(4-chlorophenyl)-4-phenyl-4-hydroxy-4,5-dihydro-1H-imidazol-2--
yl]benzenesulfonamide;
[0602]
4-[1-(4-chlorophenyl)-4-(4-fluorophenyl)-4-hydroxy-4,5-dihydro-1H-i-
midazol-2-yl]benzenesulfonamide;
[0603]
4-[1-(4-chlorophenyl)-4-(4-bromophenyl)-4-hydroxy-4,5-dihydro-1H-im-
idazol-2-yl]benzenesulfonamide;
[0604]
4-[1-(4-chlorophenyl)-4-(4-chlorophenyl)-4-hydroxy-4,5-dihydro-1H-i-
midazol-2-yl]benzenesulfonamide;
[0605]
4-[1-(4-chlorophenyl)-4-(2-naphthyl)-4-hydroxy-4,5-dihydro-1H-imida-
zol-2-yl]benzenesulfonamide;
[0606]
4-[1-(4-chlorophenyl)-4-[4-(trifluoromethoxy)phenyl]-4-hydroxy-4,5--
dihydro-1H-imidazol-2-yl]benzenesulfonamide;
[0607]
4-[1-(4-chlorophenyl)-4-(3-chlorophenyl)-4-hydroxy-4,5-dihydro-1H-i-
midazol-2-yl]benzenesulfonamide;
[0608]
4-[1-(4-chlorophenyl)-4-(3-fluorophenyl)-4-hydroxy-4,5-dihydro-1H-i-
midazol-2-yl]benzenesulfonamide;
[0609]
4-[1-(4-chlorophenyl)-4-(4-methoxyphenyl)-4-hydroxy-4,5-dihydro-1H--
imidazol-2-yl]benzenesulfonamide;
[0610]
4-[1-(4-chlorophenyl)-4-phenoxymethyl-4-hydroxy-4,5-dihydro-1H-imid-
azol-2-yl]benzenesulfonamide;
[0611]
4-[1-(4-chlorophenyl)-4-(4-chlorophenoxy)methyl-4-hydroxy-4,5-dihyd-
ro-1H-imidazol-2-yl]benzenesulfonamide;
[0612]
4-[1-(4-chlorophenyl)-4-(4-fluorophenoxy)methyl-4-hydroxy-4,5-dihyd-
ro-1H-imidazol-2-yl]benzenesulfonamide;
[0613]
4-[1-(4-chlorophenyl)-4-phenylthiomethyl-4-hydroxy-4,5-dihydro-1H-i-
midazol-2-yl]benzenesulfonamide;
[0614]
4-[1-(4-chlorophenyl)-4-(N-phenyl-N-methylamino)methyl-4-hydroxy-4,-
5-dihydro-1H-imidazol-2-yl]benzenesulfonamide;
[0615]
4-[1-(4-chlorophenyl)-4-(2-quinolyl)methoxymethyl-4-hydroxy-4,5-dih-
ydro-1H-imidazol-2-yl]benzenesulfonamide;
[0616]
4-[1-(4-chlorophenyl)-4-methoxymethyl-4-hydroxy-4,5-dihydro-1H-imid-
azol-2-yl]benzenesulfonamide;
[0617]
4-[1-(4-chlorophenyl)-4-(4-methoxybenzyloxy)methyl-4-hydroxy-4,5-di-
hydro-1H-imidazol-2-yl]benzenesulfonamide;
[0618]
4-[1-(4-chlorophenyl)-4-hydroxymethyl-4-hydroxy-4,5-dihydro-1H-imid-
azol-2-yl]benzenesulfonamide;
[0619]
4-[1-(4-chlorophenyl)-4-formyl-4-hydroxy-4,5-dihydro-1H-imidazol-2--
yl]benzenesulfonamide;
[0620]
4-[1-(4-chlorophenyl)-4-cyano-4-hydroxy-4,5-dihydro-1H-imidazol-2-y-
l]benzenesulfonamide;
[0621]
4-[1-(4-chlorophenyl)-4-benzyl-4-hydroxy-4,5-dihydro-1H-imidazol-2--
yl]benzenesulfonamide;
[0622]
4-[1-(4-chlorophenyl)-4-phenylethyl-4-hydroxy-4,5-dihydro-1H-imidaz-
ol-2-yl]benzenesulfonamide;
[0623]
4-[1-(4-chlorophenyl)-4-hexyl-4-hydroxy-4,5-dihydro-1H-imidazol-2-y-
l]benzenesulfonamide;
[0624]
4-[1-(4-chlorophenyl)-4-hexylcarbonyl-4-hydroxy-4,5-dihydro-1H-imid-
azol-2-yl]benzenesulfonamide;
[0625]
4-[1-(4-chlorophenyl)-4-phenylcarbonyl-4-hydroxy-4,5-dihydro-1H-imi-
dazol-2-yl]benzenesulfonamide;
[0626]
4-[1-(4-chlorophenyl)-4-benzylcarbonyl-4-hydroxy-4,5-dihydro-1H-imi-
dazol-2-yl]benzenesulfonamide;
[0627]
4-[1-(4-chlorophenyl)-4-(1-hydroxy-2-phenyl-methyl)-4-hydroxy-4,5-d-
ihydro-1H-imidazol-2-yl]benzenesulfonamide;
[0628]
4-[1-(4-chlorophenyl)-4-(1-hexanol)-4-hydroxy-4,5-dihydro-1H-imidaz-
ol-2-yl]benzenesulfonamide;
[0629]
4-[1-(4-chlorophenyl)-4-hydroxy-4,5-dihydro-1H-imidazol-2-yl]benzen-
esulfonamide;
[0630]
4-[1-(4-chlorophenyl)-4-octyl-4-hydroxy-4,5-dihydro-1H-imidazol-2-y-
l]benzenesulfonamide;
[0631]
4-[1-(4-chlorophenyl)-4-methoxy-4-hydroxy-4,5-dihydro-1H-imidazol-2-
-yl]benzenesulfonamide;
[0632]
4-[1-(4-chlorophenyl)-4-butoxy-4-hydroxy-4,5-dihydro-1H-imidazol-2--
yl]benzenesulfonamide;
[0633]
4-[1-(4-chlorophenyl)-4-methylthio-4-hydroxy-4,5-dihydro-1H-imidazo-
l-2-yl]benzenesulfonamide;
[0634]
4-[1-(4-chlorophenyl)-4-(2-thienyl)-4-hydroxy-4,5-dihydro-1H-imidaz-
ol-2-yl]benzenesulfonamide;
[0635]
4-[1-(4-chlorophenyl)-4-(2-furyl)-4-hydroxy-4,5-dihydro-1H-imidazol-
-2-yl]benzenesulfonamide;
[0636]
4-[1-(4-chlorophenyl)-4-(3-pyridyl)-4-hydroxy-4,5-dihydro-1H-imidaz-
ol-2-yl]benzenesulfonamide;
[0637]
4-[1-(4-chlorophenyl)-4-chloro-4-hydroxy-4,5-dihydro-1H-imidazol-2--
yl]benzenesulfonamide;
[0638]
4-[1-(4-chlorophenyl)-4-fluoro-4-hydroxy-4,5-dihydro-1H-imidazol-2--
yl]benzenesulfonamide;
[0639]
[1-(4-chlorophenyl)-2-[4-(aminosulfonyl)phenyl]-4-hydroxy-4,5-dihyd-
ro-1H-imidazol-4-yl]carboxylic acid;
[0640]
methyl[1-(4-chlorophenyl)-2-[4-(aminosulfonyl)phenyl]-4-hydroxy-4,5-
-dihydro-1H-imidazol-4-yl]carboxylate;
[0641]
[1-(4-chlorophenyl)-2-[4-(aminosulfonyl)phenyl]-4-hydroxy-4,5-dihyd-
ro-1H-imidazol-4-yl]carboxamide;
[0642]
methyl[1-(4-chlorophenyl)-2-[4-(aminosulfonyl)phenyl]-4-hydroxy-4,5-
-dihydro-1H-imidazol-4-yl]carboxamide;
[0643]
2-[4-(methylsulfonyl)phenyl]-1-(4-methylphenyl)-4-trifluoromethyl-4-
-hydroxy-4,5-dihydro-1H-imidazole;
[0644]
2-[4-(methylsulfonyl)phenyl]-1-(3-chlorophenyl)-4-trifluoromethyl-4-
-hydroxy-4,5-dihydro-1H-imidazole;
[0645]
2-[4-(methylsulfonyl)phenyl]-1-(4-methyl-3-chlorophenyl)-4-trifluor-
omethyl-4-hydroxy-4,5-dihydro-1H-imidazole;
[0646]
5-[2-[4-(methylsulfonyl)phenyl]-4-hydroxy-4-trifluoromethyl-4,5-dih-
ydro-1H-imidazol-1-yl]-1,3-benzodioxole;
[0647]
2-[4-(methylsulfonyl)phenyl]-1-(4-methoxyphenyl)-4-trifluoromethyl--
4-hydroxy-4,5-dihydro-1H-imidazole;
[0648]
2-[4-(methylsulfonyl)phenyl]-1-(3-fluorophenyl)-4-trifluoromethyl-4-
-hydroxy-4,5-dihydro-1H-imidazole;
[0649]
2-[4-(methylsulfonyl)phenyl]-1-(4-fluorophenyl)-4-trifluoromethyl-4-
-hydroxy-4,5-dihydro-1H-imidazole;
[0650]
2-[4-(methylsulfonyl)phenyl]-1-(4-methoxy-3-fluorophenyl)-4-trifluo-
romethyl-4-hydroxy-4,5-dihydro-1H-imidazole;
[0651]
2-[4-(methylsulfonyl)phenyl]-1-phenyl-4-trifluoromethyl-4-hydroxy-4-
,5-dihydro-1H-imidazole;
[0652]
2-[4-(methylsulfonyl)phenyl]-1-(4-methoxy-3-chlorophenyl)-4-trifluo-
romethyl-4-hydroxy-4,5-dihydro-1H-imidazole;
[0653]
2-[4-(methylsulfonyl)phenyl]-1-[4-(trifluoromethyl)phenyl]-4-triflu-
oromethyl-4-hydroxy-4,5-dihydro-1H-imidazole;
[0654]
2-[4-(methylsulfonyl)phenyl]-1-(4-bromophenyl)-4-trifluoromethyl-4--
hydroxy-4,5-dihydro-1H-imidazole;
[0655]
2-[4-(methylsulfonyl)phenyl]-1-(1-chlorophenyl)-4-trifluoromethyl-4-
-hydroxy-4,5-dihydro-1H-imidazole;
[0656]
2-[4-(methylsulfonyl)phenyl]-1-(4-ethylphenyl)-4-trifluoromethyl-4--
hydroxy-4,5-dihydro-1H-imidazole;
[0657]
2-[4-(methylsulfonyl)phenyl]-1-(4-butylphenyl)-4-trifluoromethyl-4--
hydroxy-4,5-dihydro-1H-imidazole;
[0658]
2-[4-(methylsulfonyl)phenyl]-1-[4-(difluoromethyl)phenyl]-4-trifluo-
romethyl-4-hydroxy-4,5-dihydro-1H-imidazole;
[0659]
2-[4-(methylsulfonyl)phenyl]-1-(4-butoxyphenyl)-4-trifluoromethyl-4-
-hydroxy-4,5-dihydro-1H-imidazole;
[0660]
2-[4-(methylsulfonyl)phenyl]-1-[4-(methylthio)phenyl]-4-trifluorome-
thyl-4-hydroxy-4,5-dihydro-1H-imidazole;
[0661]
2-[4-(methylsulfonyl)phenyl]-1-(4-methoxy-3,5-dichloro-phenyl)-4-tr-
ifluoromethyl-4-hydroxy-4,5-dihydro-1H-imidazole;
[0662]
2-[4-(methylsulfonyl)phenyl]-1-(4-methyl-3,5-difluorophenyl)-4-trif-
luoromethyl-4-hydroxy-4,5-dihydro-1H-imidazole;
[0663]
2-[4-(methylsulfonyl)phenyl]-1-(2,4-dichlorophenyl)-4-trifluorometh-
yl-4-hydroxy-4,5-dihydro-1H-imidazole;
[0664]
2-[4-(methylsulfonyl)phenyl]-1-(3,4-dichlorophenyl)-4-trifluorometh-
yl-4-hydroxy-4,5-dihydro-1H-imidazole;
[0665]
2-[4-(methylsulfonyl)phenyl]-1-[4-(trifluoromethyl)phenyl]-4-triflu-
oromethoxy-4-hydroxy-4,5-dihydro-1H-imidazole;
[0666]
2-[4-(methylsulfonyl)phenyl]-1-(3,5-dimethyl-4-methoxyphenyl)-4-tri-
fluoromethyl-4-hydroxy-4,5-dihydro-1H-imidazole;
[0667]
2-[4-(methylsulfonyl)phenyl]-1-(3,4-dimethylphenyl)-4-trifluorometh-
yl-4-hydroxy-4,5-dihydro-1H-imidazole;
[0668]
2-[4-(methylsulfonyl)phenyl]-1-(4-aminophenyl)-4-trifluoromethyl-4--
hydroxy-4,5-dihydro-1H-imidazole;
[0669]
4-[1-(4-methylphenyl)-4-trifluoromethyl-4-hydroxy-4,5-dihydro-1H-im-
idazol-2-yl]benzenesulfonamide;
[0670]
4-[1-(3-chlorophenyl)-4-trifluoromethyl-4-hydroxy-4,5-dihydro-1H-im-
idazol-2-yl]benzenesulfonamide;
[0671]
4-[1-(4-methyl-3-chlorophenyl)-4-trifluoromethyl-4-hydroxy-4,5-dihy-
dro-1H-imidazol-2-yl]benzenesulfonamide;
[0672]
5-[2-[4-(aminosulfonyl)phenyl)]-4-hydroxy-4,5-dihydro-4-trifluorome-
thyl-1H-imidazol-1-yl]-1,3-benzodioxole;
[0673]
4-[1-(3-fluorophenyl)-4-trifluoromethyl-4-hydroxy-4,5-dihydro-1H-im-
idazol-2-yl]benzenesulfonamide;
[0674]
4-[1-(4-fluorophenyl)-4-trifluoromethyl-4-hydroxy-4,5-dihydro-1H-im-
idazol-2-yl]benzenesulfonamide;
[0675]
4-[1-(4-methoxy-3-fluorophenyl)-4-trifluoromethyl-4-hydroxy-4,5-dih-
ydro-1H-imidazol-2-yl]benzenesulfonamide;
[0676]
4-[1-phenyl-4-trifluoromethyl-4-hydroxy-4,5-dihydro-1H-imidazol-2-y-
l]benzenesulfonamide;
[0677]
4-[1-(4-methoxy-3-chlorophenyl)-4-trifluoromethyl-4-hydroxy-4,5-dih-
ydro-1H-imidazol-2-yl]benzenesulfonamide;
[0678]
4-[1-[4-(trifluoromethyl)phenyl]-4-trifluoromethyl-4-hydroxy-4,5-di-
hydro-1H-imidazol-2-yl]benzenesulfonamide;
[0679]
4-[1-(4-bromophenyl)-4-trifluoromethyl-4-hydroxy-4,5-dihydro-1H-imi-
dazol-2-yl]benzenesulfonamide;
[0680]
4-[1-(1-chlorophenyl)-4-trifluoromethyl-4-hydroxy-4,5-dihydro-1H-im-
idazol-2-yl]benzenesulfonamide;
[0681]
4-[1-(4-ethylphenyl)-4-trifluoromethyl-4-hydroxy-4,5-dihydro-1H-imi-
dazol-2-yl]benzenesulfonamide;
[0682]
4-[1-(4-butylphenyl)-4-trifluoromethyl-4-hydroxy-4,5-dihydro-1H-imi-
dazol-2-yl]benzenesulfonamide;
[0683]
4-[1-[4-(difluoromethyl)phenyl]-4-trifluoromethyl-4-hydroxy-4,5-dih-
ydro-1H-imidazol-2-yl]benzenesulfonamide;
[0684]
4-[1-(4-butoxyphenyl)-4-trifluoromethyl-4-hydroxy-4,5-dihydro-1H-im-
idazol-2-yl]benzenesulfonamide;
[0685]
4-[1-[4-(methylthio)phenyl]-4-trifluoromethyl-4-hydroxy-4,5-dihydro-
-1H-imidazol-2-yl]benzenesulfonamide;
[0686]
4-[1-(4-methoxy-3,5-dichloro-phenyl)-4-trifluoromethyl-4-hydroxy-4,-
5-dihydro-1H-imidazol-2-yl]benzenesulfonamide;
[0687]
4-[1-(4-methyl-3,5-difluorophenyl)-4-trifluoromethyl-4-hydroxy-4,5--
dihydro-1H-imidazol-2-yl]benzenesulfonamide;
[0688]
4-[1-(2,4-dichlorophenyl)-4-trifluoromethyl-4-hydroxy-4,5-dihydro-1-
H-imidazol-2-yl]benzenesulfonamide;
[0689]
4-[1-(3,4-dichlorophenyl)-4-trifluoromethyl-4-hydroxy-4,5-dihydro-1-
H-imidazol-2-yl]benzenesulfonamide;
[0690]
4-[1-[4-(trifluoromethoxy)phenyl]-4-trifluoromethyl-4-hydroxy-4,5-d-
ihydro-1H-imidazol-2-yl]benzenesulfonamide;
[0691]
4-[1-(3,5-dimethyl-4-methoxy-phenyl)-4-trifluoromethyl-4-hydroxy-4,-
5-dihydro-1H-imidazol-2-yl]benzenesulfonamide;
[0692]
4-[1-(3,4-dimethylphenyl)-4-trifluoromethyl-4-hydroxy-4,5-dihydro-1-
H-imidazol-2-yl]benzenesulfonamide; and
[0693]
4-[1-(4-aminophenyl)-4-trifluoromethyl-4-hydroxy-4,5-dihydro-1H-imi-
dazol-2-yl]benzenesulfonamide.
[0694] Within Formula I there is a fourth subclass of compounds of
high interest represented by Formula V: 6
[0695] wherein R.sup.3 is a radical selected from hydrido, alkyl,
haloalkyl, aralkyl, heterocycloalkyl, heteroaralkyl, acyl, cyano,
alkoxy, alkylthio, alkylthioalkyl, alkylsulfonyl, cycloalkylthio,
cycloalkylthioalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl,
haloalkylsulfonyl, arylsulfonyl, halo, hydroxyalkyl, alkoxyalkyl,
alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, heterocyclocarbonyl,
cyanoalkyl, aminoalkyl, alkylaminoalkyl, N-arylaminoalkyl,
N-alkyl-N-arylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl,
alkoxycarbonyl, haloalkylcarbonyl, carboxyl, aminocarbonyl,
alkylaminocarbonyl, alkylaminocarbonylalkyl heteroarylalkoxyalkyl,
heteroaryloxyalkyl, heteroarylthioalkyl, aralkoxy, aralkylthio,
heteroaralkoxy, heteroaralkylthio, heteroarylalkylthioalkyl,
heteroaryloxy, heteroarylthio, arylthioalkyl, aryloxyalkyl,
arylthio, aryloxy, aralkylthioalkyl, aralkoxyalkyl, aryl and
heteroaryl; wherein R.sup.4 is a radical selected from hydrido,
alkyl and halo; and wherein R.sup.13 and R.sup.14 are independently
selected from aryl and heterocyclo, wherein R.sup.13 and R.sup.14
are optionally substituted at a substitutable position with one or
more radicals independently selected from alkylsulfonyl,
aminosulfonyl, halo, alkylthio, alkyl, cyano, carboxyl,
alkoxycarbonyl, haloalkyl, hydroxyl, alkoxy, hydroxyalkyl,
alkoxyalkyl, haloalkoxy, amino, alkylamino, arylamino and nitro;
provided at least one of R.sup.13 and R.sup.14 is aryl substituted
with alkylsulfonyl or aminosulfonyl; or a
pharmaceutically-acceptable salt thereof.
[0696] A preferred class of compounds consists of those compounds
of Formula V wherein R.sup.3 is a radical selected from hydrido,
lower alkyl, lower haloalkyl, lower aralkyl, lower
heterocycloalkyl, lower heteroaralkyl, acyl, cyano, lower alkoxy,
lower alkylthio, lower alkylsulfonyl, phenylsulfonyl, lower
haloalkylsulfonyl, halo, lower hydroxyalkyl, lower alkoxyalkyl,
lower alkylcarbonyl, lower haloalkylcarbonyl, phenylcarbonyl, lower
aralkylcarbonyl, lower cyanoalkyl, lower aminoalkyl, lower
alkylaminoalkyl, lower N-arylaminoalkyl, lower
N-alkyl-N-arylaminoalkyl, lower carboxyalkyl, lower
alkoxycarbonylalkyl, lower alkoxycarbonyl, carboxyl, lower
alkylthioalkyl, aminocarbonyl, lower alkylaminocarbonyl, lower
alkylaminocarbonylalkyl, lower aralkoxy, lower aralkylthio, lower
heteroaralkoxy, lower heteroaralkylthio, lower
heteroarylalkoxyalkyl, lower heteroarylalkylthioalkyl, lower
heteroaryloxyalkyl, lower heteroarylthioalkyl, lower heteroaryloxy,
lower heteroarylthio, lower arylthioalkyl, lower aryloxyalkyl,
lower arylthio, lower aryloxy, lower aralkylthioalkyl, lower
aralkoxyalkyl, aryl selected from phenyl and naphthyl, 5 or 6
membered heteroaryl, wherein the aryl and heteroaryl radicals are
optionally substituted at a substitutable position with one or more
radicals selected from halo, lower alkylthio, lower alkylsulfinyl,
lower alkyl, cyano, lower haloalkyl, hydroxyl, lower alkoxy, lower
hydroxyalkyl and lower haloalkoxy; wherein R.sup.4 is a radical
selected from hydrido, lower alkyl and halo; and wherein R.sup.13
and R.sup.14 are independently selected from phenyl and heteroaryl,
wherein R.sup.13 and R.sup.14 are optionally substituted at a
substitutable position with one or more radicals independently
selected from lower methylsulfonyl, aminosulfonyl, lower alkylthio,
lower alkyl, lower haloalkyl, lower alkoxy, lower hydroxyalkyl,
lower alkoxyalkyl, and lower haloalkoxy; or a
pharmaceutically-acceptable salt thereof.
[0697] A class of compounds of particular interest consists of
those compounds of Formula V wherein R.sup.3 is a radical selected
from hydrido, methyl, ethyl, isopropyl, tert-butyl, isobutyl,
pentyl, hexyl, fluoromethyl, difluoromethyl, trifluoromethyl,
chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl,
heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl,
difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl,
benzyl, phenylethyl, phenylpropyl, furylmethyl, morpholinomethyl,
pyrrolidinylmethyl, piperazinylmethyl, piperidinylmethyl,
pyridylmethyl, thienylmethyl, formyl, cyano, methoxy, ethoxy,
propoxy, n-butoxy, methylthio, ethylthio, isopropylthio,
methylsulfonyl, phenylsulfonyl, trifluoromethylsulfonyl, fluoro,
chloro, bromo, hydroxymethyl, hydroxyethyl, methoxymethyl,
ethoxymethyl, methylthiomethyl, isopropylthiomethyl,
cyclohexylthiomethyl, benzyloxy, benzylthio, methylcarbonyl,
ethylcarbonyl, phenylcarbonyl, trifluoromethylcarbonyl,
difluoromethylcarbonyl, fluoromethylcarbonyl, benzylcarbonyl,
pyrrolidinylcarbonyl, cyanomethyl, cyanobutyl, aminomethyl,
methylaminomethyl, N-phenylaminomethyl,
N-methyl-N-phenylaminomethyl, acetyl, propanoyl, butanoyl,
methoxycarbonylmethyl, ethoxycarbonylethyl, methoxycarbonyl,
ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl,
propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,
pentoxycarbonyl, carboxyl, carboxymethyl, carboxypropyl,
aminocarbonyl, methylaminocarbonyl, N,N-diethylaminocarbonyl,
N-methoxy-N-methylaminocar- bonyl, methylaminocarbonylmethyl,
pyridyloxy, pyridylthio, phenyloxy, 4-chlorophenoxy, furylmethoxy,
furylmethylthio, thienylmethoxy, quinolylmethoxy, pyridylmethoxy,
5-phenylpyridyl-2-methoxy, thienylmethylthio, pyridylmethylthio,
quinolylmethoxymethyl, furylbutoxyethyl, pyridyloxymethyl,
pyridylmethoxymethyl, thienyloxyhexyl, thienylthiomethyl,
pyridylthiohexyl, furyloxymethyl, furylmethylthiomethyl,
quinolylmethylthioethyl, phenylthiomethyl,
2-chlorophenylthiomethyl, 2,6-dichlorophenylthiomethyl,
4-methylphenylthiomethyl, 2-isopropylphenylthiomethyl,
2-methylphenylthiomethyl, phenyloxymethyl, 4-chlorophenyloxymethyl,
4-methylphenyloxymethyl, benzyloxymethyl, 4-methoxybenzyloxymethyl,
naphthyl, phenyl, thienyl, furyl, pyridyl, wherein the thienyl,
furyl, pyridyl and phenyl radicals are optionally substituted at a
substitutable position with one or more radicals selected from
fluoro, chloro, bromo, methylthio, methylsulfinyl, methyl, ethyl,
isopropyl, tert-butyl, isobutyl, pentyl, hexyl, cyano,
fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,
dichloromethyl, trichloromethyl, pentafluoroethyl,
heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl,
difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl,
hydroxyl, methoxy, methylenedioxy, ethoxy, propoxy, n-butoxy,
hydroxymethyl, hydroxyethyl and trifluoromethoxy; wherein R.sup.4
is a radical selected from hydrido, methyl, ethyl, fluoro, chloro
and bromo; and wherein R.sup.13 and R.sup.14 are independently
selected from phenyl, imidazolyl, thienyl, thiazolyl, pyrrolyl,
oxazolyl, isoxazolyl, triazolyl, pyrazinyl, pyrimidinyl,
quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, pyrazolyl and
pyridyl, wherein R.sup.13 and R.sup.14 are optionally substituted
at a substitutable position with one or more radicals independently
selected from methylsulfonyl, aminosulfonyl, fluoromethylsulfonyl,
difluoromethylsulfonyl, fluoro, chloro, bromo, methylthio,
methylsulfinyl, methyl, ethyl, isopropyl, tert-butyl, isobutyl,
pentyl, hexyl, cyano, carboxyl, methoxycarbonyl, ethoxycarbonyl,
isopropoxycarbonyl, tert-butoxycarbonyl, propoxycarbonyl,
butoxycarbonyl, isobutoxycarbonyl, pentoxycarbonyl, fluoromethyl,
difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,
trichloromethyl, pentafluoroethyl, heptafluoropropyl,
difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,
difluoropropyl, dichloroethyl, dichloropropyl, hydroxyl, methoxy,
methylenedioxy, ethoxy, propoxy, n-butoxy, hydroxymethyl,
hydroxyethyl, methoxymethyl, ethoxymethyl, trifluoromethoxy, amino,
methylamino, N,N-diethylamino, phenylamino and nitro; or a
pharmaceutically-acceptable salt thereof.
[0698] A class of compounds of even more particular interest
consists of those compounds of Formula V wherein R.sup.3 is a
radical selected from hydrido, cyano, methyl, ethyl, isopropyl,
tert-butyl, isobutyl, pentyl, hexyl, fluoromethyl, difluoromethyl,
trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,
pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,
dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl,
dichloropropyl and 2-methylphenylthiomethy- l; wherein R.sup.4 is
hydrido; wherein R.sup.13 is phenyl substituted-with methylsulfonyl
or aminosulfonyl; and wherein R.sup.14 is selected from imidazolyl,
thienyl, thiazolyl, pyrrolyl, oxazolyl, isoxazolyl, triazolyl,
pyrimidinyl, quinolinyl, indolyl, benzimidazolyl, pyrazolyl and
pyridyl, wherein R.sup.14 is optionally substituted at a
substitutable position with one or more radicals independently
selected from methylthio, methyl, ethyl, isopropyl, tert-butyl,
isobutyl, pentyl, hexyl, fluoromethyl, difluoromethyl,
trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,
pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,
dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl,
dichloropropyl, methoxy, methylenedioxy, ethoxy, propoxy, n-butoxy,
hydroxymethyl, hydroxyethyl, methoxymethyl, ethoxymethyl, and
trifluoromethoxy; or a pharmaceutically-acceptable salt
thereof.
[0699] A family of specific compounds of particular interest within
Formula V consists of compounds and pharmaceutically-acceptable
salts thereof as follows:
[0700]
3-[4-[(methylphenyl)thiolmethyl]-1-[4-(methylsulfonyl)phenyl]-1H-im-
idazol-2-yl]pyridine;
[0701]
4-[2-(pyrindin-3-yl)-4-[[(methylphenyl)thio]methyl]-1H-imidazol-1-y-
l]benzenesulfonamide;
[0702]
3-[4-methyl-1-[4-(methylsulfonyl)phenyl]-1H-imidazol-2-yl]pyridine;
[0703]
4-[2-(6-methylpyrindin-2-yl)-4-trifluoromethyl-1H-imidazol-1-yl]ben-
zenesulfonamide;
[0704]
4-methyl-3-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imida-
zol-2-yl]pyridine;
[0705]
4-[2-(4-methylpyrindin-3-yl)-4-trifluoromethyl-1H-imidazol-1-yl]ben-
zenesulfonamide;
[0706]
3-methyl-2-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imida-
zol-2-yl]pyridine;
[0707]
1-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]-
isoquinoline;
[0708]
4-[2-(3-methylpyrindin-2-yl)-4-trifluoromethyl-1H-imidazol-1-yl]ben-
zenesulfonamide;
[0709]
3-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]-
quinoline;
[0710]
4-[2-(2-thienyl)-4-trifluoromethyl-1H-imidazol-1-yl]benzenesulfonam-
ide;
[0711]
3-bromo-5-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidaz-
ol-2-yl]pyridine;
[0712]
1-[4-(methylsulfonyl)phenyl]-2-(3-pyridinyl)-1H-imidazole-4-carboni-
trile;
[0713]
2-[2-methyloxazol-4-yl)-1-(4-(methylsulfonyl)phenyl]-4-trifluoromet-
hyl-1H-imidazole;
[0714]
4-[2-(5-bromopyrindin-3-yl)-4-trifluoromethyl-1H-imidazol-1-yl]benz-
enesulfonamide;
[0715]
2-(5-methylpyridin-3-yl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole--
4-carbonitrile;
[0716]
3-[4-difluoromethyl-1-[4-(methylsulfonyl)phenyl]-1H-imidazol-2-yl]p-
yridine;
[0717]
4-[4-difluoromethyl-2-(pyrindin-3-yl)-1H-imidazol-1-yl]benzenesulfo-
namide;
[0718]
4-[4-cyano-2-(pyrindin-3-yl)-1H-imidazol-1-yl]benzenesulfonamide;
[0719]
4-[4-cyano-2-(5-methylpyrindin-3-yl)-1H-imidazol-1-yl]benzenesulfon-
amide;
[0720]
4-[2-(2-quinolinyl)-4-trifluoromethyl-1H-imidazol-1-yl]benzenesulto-
namide;
[0721]
1-methyl-4-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imida-
zol-2-yl]-1H-pyrazole;
[0722]
4-[2-(1-methyl-1H-pyrazol-4-yl)-4-trifluoromethyl-1H-imidazol-1-yl]-
benzenesulfonamide;
[0723]
2-[1-methyl-1H-imidazol-4-yl)-1-[4-(methylsulfonyl)phenyl]-4-triflu-
oromethyl-1H-imidazole;
[0724]
4-[2-(1-methyl-1H-imidazol-4-yl)-4-trifluoromethyl-1H-imidazol-1-yl-
]benzenesulfonamide;
[0725]
2-[1-methyl-1H-imidazol-5-yl)-1-[4-(methylsulfonyl)phenyl]-4-triflu-
oromethyl-1H-imidazole;
[0726]
4-[2-(1-methyl-1H-imidazol-5-yl)-4-trifluoromethyl-1H-imidazol-1-yl-
]benzenesulfonamide;
[0727]
2-(1-methyl-1H-imidazol-2-yl)-1-[4-(methylsulfonyl)phenyl]-4-triflu-
oromethyl-1H-imidazole;
[0728]
4-[2-(1-methyl-1H-imidazol-2-yl)-4-trifluoromethyl-1H-imidazol-1-yl-
]benzenesulfonamide;
[0729]
1-[4-(methylsulfonyl)phenyl]-2-(4-methylthiazol-2-yl)-4-trifluorome-
thyl-1H-imidazole;
[0730]
4-[2-(4-methylthiazol-2-yl)-4-trifluoromethyl-1H-imidazol-1-yl]benz-
enesulfonamide;
[0731]
1-[4-(methylsulfonyl)phenyl]-2-(2-methylthiazol-5-yl)-4-trifluorome-
thyl-1H-imidazole;
[0732]
4-[2-(2-methylthiazol-5-yl)-4-trifluoromethyl-1H-imidazo-1-yl]benze-
nesulfonamide;
[0733]
5-methyl-3-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imida-
zol-2-yl]isoxazole;
[0734]
4-[2-(5-methylisoxazol-3-yl)-4-trifluoromethyl-1H-imidazol-1-yl]ben-
zenesulfonamide;
[0735]
5-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]-
pyrimidine;
[0736]
4-[2-(5-pyrimidinyl)-4-trifluoromethyl-1H-imidazol-1-yl]benzenesulf-
onamide;
[0737]
4-[2-(pyrazin-2-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesul-
fonamide;
[0738]
4-[2-(quinol-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulf-
onamide;
[0739]
1-methyl-3-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imida-
zol-2-yl]-1H-indole;
[0740]
4-[2-(1-methylindol-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benz-
enesulfonamide;
[0741]
4-[2-(isoquinol-2-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenes-
ulfonamide;
[0742]
4-[2-(2-methyloxazol-4-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]ben-
zenesulfonamide;
[0743]
4-[2-(2-methylthiazol-4-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]be-
nzenesulfonamide;
[0744]
4-[2-(oxazol-4-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulf-
onamide;
[0745]
4-[2-(1-methylpyrazol-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]be-
nzenesulfonamide;
[0746]
4-[2-(5-methylisoxazol-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]b-
enzenesulfonamide;
[0747]
4-[2-(4-methylpyridin-2-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]be-
nzenesulfonamide;
[0748]
2-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-y-
l]thiophene;
[0749]
3-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-y-
l]thiophene;
[0750]
4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]be-
nzenesulfonamide;
[0751]
2-methyl-3-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imi-
dazol-2-yl]pyridine;
[0752]
4-[2-(2-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]be-
nzenesulfonamide;
[0753]
4-[2-(pyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesul-
fonamide;
[0754]
3-fluoro-5-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imi-
dazol-2-yl]pyridine;
[0755]
3-chloro-5-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imi-
dazol-2-yl]pyridine;
[0756]
4-[2-(5-fluoropyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]be-
nzenesulfonamide;.
[0757]
4-[2-(5-chloropyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]be-
nzenesulfonamide;
[0758]
5-methyl-2-[1-(4-(methylsulfonyl)phenyl)-4-(trifluoromethyl)-1H-imi-
dazol-2-yl]pyridine;
[0759]
4-methyl-2-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imi-
dazol-2-yl]pyridine;
[0760]
2-methoxy-6-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-im-
idazol-2-yl]pyridine;
[0761]
5-methoxy-2-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-im-
idazol-2-yl]pyridine;
[0762]
4-methoxy-2-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-im-
idazol-2-yl]pyridine;
[0763]
2-chloro-6-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imi-
dazol-2-yl]pyridine;
[0764]
5-chloro-2-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imi-
dazol-2-yl]pyridine;
[0765]
4-chloro-2-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imi-
dazol-2-yl]pyridine;
[0766]
2-fluoro-6-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imi-
dazol-2-yl]pyridine;
[0767]
4-fluoro-2-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imi-
dazol-2-yl]pyridine;
[0768]
4-fluoro-2-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imi-
dazol-2-yl]pyridine;
[0769]
4-[2-(5-methylpyridin-2-yl)-4-(trifluoromethyl)-1H-1-midazol-1-yl]b-
enzenesulfonamide;
[0770]
4-[2-(4-methylpyridin-2-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]be-
nzenesulfonamide;
[0771]
4-[2-(6-methoxypyridin-2-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]b-
enzenesulfonamide;
[0772]
4-[2-(5-methoxypyridin-2-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]b-
enzenesulfonamide;
[0773]
4-[2-(4-methoxypyridin-2-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]b-
enzenesulfonamide;
[0774]
4-[2-(6-chloropyridin-2-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]be-
nzenesulfonamide;
[0775]
4-[2-(5-chloropyridin-2-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]be-
nzenesulfonamide;
[0776]
4-[2-(4-chloropyridin-2-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]be-
nzenesulfonamide;
[0777]
4-[2-(6-fluoropyridin-2-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]be-
nzenesulfonamide;
[0778]
4-[2-(5-fluoropyridin-2-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]be-
nzenesulfonamide;
[0779]
4-[2-(4-fluoropyridin-2-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]be-
nzenesulfonamide;
[0780]
3-methoxy-5-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-im-
idazol-2-yl]pyridine;
[0781]
4-methyl-3-[1-[4-(methylsulfonyl)phenyl)-4-(trifluoromethyl)-1H-imi-
dazol-2-yl]pyridine;
[0782]
3-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-y-
l]pyridine-1-oxide;
[0783]
3-[4-(4-fluorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazol-2-yl-
]pyridine;
[0784]
5-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-y-
l]-2-(methylthio)pyridine;
[0785]
3-[4-(difluoromethyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazol-2-yl-
]pyridine;
[0786]
4-[2-(5-methoxypyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]b-
enzenesulfonamide;
[0787]
4-[4-methyl-2-(3-pyridinyl)-1H-imidazol-1-yl]benzenesulfonamide;
[0788]
4-[2-(3-pyridinyl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulf-
onamide-1-oxide;
[0789]
4-[4-(4-fluorophenyl)-2-(3-pyridinyl)-1H-imidazol-1-yl]benzenesulfo-
namide;
[0790]
4-[2-(3-pyridinyl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulf-
onamide-1-oxide;
[0791]
4-[4-(4-fluorophenyl)-2-(3-pyridinyl)-1H-imidazol-1-yl]benzenesulfo-
namide;
[0792]
4-[2-[6-(methylthio)pyridin-3-yl]-4-trifluoromethyl)-1H-imidazol-1--
yl]benzenesulfonamide;
[0793]
4-[4-(difluoromethyl)-2-(3-pyridinyl)-1H-imidazol-1-yl]benzenesulfo-
namide;
[0794]
3-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-y-
l]pyridine;
[0795]
2-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-y-
l]pyridine;
[0796]
2-methyl-4-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imi-
dazol-2-yl]pyridine;
[0797]
4-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-y-
l]pyridine;
[0798]
2-methyl-6-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imi-
dazol-2-yl]pyridine;
[0799]
4-[2-(6-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]be-
nzenesulfonamide;
[0800]
1-methyl-3-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imi-
dazol-2-yl]pyridinium iodide;
[0801]
2-methyl-5-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imi-
dazol-2-yl]pyridine 1-oxide;
[0802]
3-methyl-5-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imi-
dazol-2-yl]pyridine;
[0803]
2-methoxy-5-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-im-
idazol-2-yl]pyridine;
[0804]
2-[4-(4-fluorophenyl-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethy-
l)-1H-imidazol-2-yl]pyridine;
[0805]
3-methyl-5-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imi-
dazol-2-yl]pyridine 1-oxide;
[0806]
3-methoxy-5-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-im-
idazol-2-yl]pyridine;
[0807]
4-[2-(3-methoxypyridin-5-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]b-
enzenesulfonamide;
[0808]
2-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-y-
l]quinoline;
[0809]
2-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-y-
l]pyrazine;
[0810]
2-methyl-4-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imi-
dazol-2-yl]thiazole; and
[0811]
4-[2-(5-methylpyridin-2-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]be-
nzenesulfonamide.
[0812] Compounds of Formula V, especially where R.sup.14 is
pyridyl, may form N-oxides, which may be active forms or prodrugs
which would be converted to compounds of Formula V in vivo.
[0813] Compounds of Formula V would also be capable of inhibiting
cytokines, such as TNF, IL-1, IL-6, and IL-8. As such, the
compounds can be used in the manufacture of a medicament or in a
method for the treatment for the prophylactic or therapeutic
treatment of diseases mediated by cytokines, such as TNF, IL-1,
IL-6, and IL-8.
[0814] The term "hydrido" denotes a single hydrogen atom (H). This
hydrido radical may be attached, for example, to an oxygen atom to
form a hydroxyl radical, or two hydrido radicals may be attached to
a carbon atom to form a methylene (--CH.sub.2--) radical. Where
used, either alone or within other terms such as "haloalkyl",
"alkylsulfonyl", "alkoxyalkyl", and "hydroxyalkyl", the term
"alkyl", embraces linear or branched radicals having one to about
twenty carbon atoms or, preferably, one to about twelve carbon
atoms. More preferred alkyl radicals are "lower alkyl" radicals
having one to about ten carbon atoms. Most preferred are lower
alkyl radicals having one to about six carbon atoms. Examples of
such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl,
isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl and the
like. The term "halo" means halogens such as fluorine, chlorine,
bromine or iodine. The term "haloalkyl" embraces radicals wherein
any one or more of the alkyl carbon atoms is substituted with halo
as defined above. Specifically embraced are monohaloalkyl,
dihaloalkyl and polyhaloalkyl radicals. A monohaloalkyl radical,
for one example, may have either an iodo, bromo, chloro or fluoro
atom within the radical. Dihalo and polyhaloalkyl radicals may have
two or more of the same halo atoms or a combination of different
halo radicals. "Lower haloalkyl" embraces radicals having one to
six carbon atoms. Examples of haloalkyl radicals include
fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,
dichloromethyl, trichloromethyl, trichloromethyl, pentafluoroethyl,
heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl,
difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
The term "hydroxyalkyl" embraces linear or branched alkyl radicals
having one to about ten carbon atoms any one of which may be
substituted with one or more hydroxyl radicals. More preferred
hydroxyalkyl radicals are "lower hydroxyalkyl" radicals having one
to six carbon atoms and one or more hydroxyl radicals. Examples of
such radicals include hydroxymethyl, hydroxyethyl, hydroxypropyl,
hydroxybutyl and hydroxyhexyl. The terms "alkoxy" and "alkoxyalkyl"
embrace linear or branched oxy-containing radicals each having
alkyl portions of one to about ten carbon atoms. More preferred
alkoxy radicals are "lower alkoxy" radicals having one to six
carbon atoms. Examples of such radicals include methoxy, ethoxy,
propoxy, butoxy and tert-butoxy. The term "alkoxyalkyl" embraces
alkyl radicals having one or more alkoxy radicals attached to the
alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkyl
radicals. More preferred alkoxyalkyl radicals are "lower
alkoxyalkyl" radicals having one to six carbon atoms and one or two
alkoxy radicals. Examples of such radicals include methoxymethyl,
methoxyethyl, ethoxyethyl, methoxybutyl and methoxypropyl. The
"alkoxy" or "alkoxyalkyl" radicals may be further substituted with
one or more halo atoms, such as fluoro, chloro or bromo, to provide
"haloalkoxy" or "haloalkoxyalkyl" radicals. More preferred
haloalkoxy radicals are "lower haloalkoxy" radicals having one to
six carbon atoms and one or more halo radicals. Examples of such
radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy,
trifluoroethoxy, fluoroethoxy and fluoropropoxy. The term
"cyanoalkyl", embraces radicals having a cyano or nitrile (--CN)
radical attached to an alkyl radical as described above. More
preferred cyanoalkyl radicals are "lower cyanoalkyl" radicals
having one to six carbon atoms. Examples of such lower cyanoalkyl
radicals include cyanomethyl, cyanopropyl, cyanoethyl and
cyanobutyl. The term "cycloalkyl" embraces saturated carbocyclic
radicals having three to twelve carbon atoms. More preferred
cycloalkyl radicals are "lower cycloalkyl" radicals having three to
about eight carbon atoms. Examples of such radicals include
cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term
"cycloalkenyl" embraces unsaturated cyclic radicals having three to
ten carbon atoms. More preferred cycloalkenyl radicals are "lower
cycloalkenyl" radicals having about five to about eight carbon
atoms. Examples of such radicals include cyclobutenyl,
cyclopentenyl, cyclohexenyl and cycloheptenyl. The term "aryl",
alone or in combination, means a carbocyclic aromatic system
containing one, two or three rings wherein such rings may be
attached together in a pendent manner or may be fused. The term
"aryl" embraces aromatic radicals such as phenyl, naphthyl,
tetrahydronaphthyl, indane and bipheryl. Such aryl radicals may be
substituted at a substitutable position with one or more
substituents selected from halo, alkylthio, alkylsulfinyl, alkyl,
cyano, haloalkyl, hydroxyl, alkoxy, hydroxyalkyl and haloalkoxy.
The terms "heterocyclic" and "heterocyclo" embraces saturated,
partially saturated and unsaturated heteroatom-containing
ring-shaped radicals, where the heteroatoms may be selected from
nitrogen, sulfur and oxygen. Examples of saturated heterocyclo
radicals include saturated 3 to 6-membered heteromonocylic group
containing 1 to 4 nitrogen atoms [e.g. pyrrolidinyl,
imidazolidinyl, piperidino, piperazinyl, etc.]; saturated 3 to
6-membered heteromonocyclic group containing 1 to 2 oxygen atoms
and 1 to 3 nitrogen atoms [e.g. morpholinyl, etc.]; and saturated 3
to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms
and 1 to 3 nitrogen atoms [e.g., thiazolidinyl, etc.]. Examples of
partially saturated heterocyclic radicals include dihydrothiophene,
dihydropyran, dihydrofuran and dihydrothiazole. The term
"heteroaryl" embraces unsaturated heterocyclic radicals. Examples
of "heteroaryl" radicals include unsaturated 3 to 6 membered
heteromonocyclic group containing 1 to 4 nitrogen atoms, for
example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl,
3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl
(e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl,
etc.) tetrazolyl [e.g. 1H-tetrazolyl, 2H-tetrazolyl, etc.], etc.;
unsaturated condensed heterocyclic group containing 1 to 5 nitrogen
atoms, for example, indolyl, isoindolyl, indolizinyl,
benzimidazolyl, quinolyl (quinolinyl), isoquinolyl (isoquinolinyl),
indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g., tetrazolo
[1,5-b]pyridazinyl, etc.], etc.; unsaturated 3 to 6-membered
heteromonocyclic group containing an oxygen atom, for example,
pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 3 to 6-membered
heteromonocyclic group containing a sulfur atom, for example,
2-thienyl, 3-thienyl, etc.; unsaturated 3- to 6-membered
heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3
nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl
(e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl,
etc.) etc.; unsaturated condensed heterocyclic group containing 1
to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. benzoxazolyl,
benzoxadiazolyl, etc.]; unsaturated 3 to 6-membered
heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3
nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g.,
1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.]
etc.; unsaturated condensed heterocyclic group containing 1 to 2
sulfur atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl,
benzothiadiazolyl, etc.] and the like. The term also embraces
radicals where heterocyclic radicals are fused with aryl radicals.
Examples of such fused bicyclic radicals include benzofuran,
benzothiophene, and the like. Said heterocyclo may be substituted
at a substitutable position with one or more substituents selected
from halo, alkylthio, alkylsulfinyl, alkyl, cyano, haloalkyl,
hydroxyl, alkoxy, hydroxyalkyl and haloalkoxy. More preferred
heteroaryl radicals include five to six membered heteroaryl
radicals. The term "heterocycloalkyl" embraces
heterocyclic-substituted alkyl radicals. More preferred
heterocycloalkyl radicals are "lower heterocycloalkyl" radicals
having one to six carbon atoms and a heterocyclic radical. Examples
include such radicals as pyrrolidinylmethyl. The term
"heteroarylalkyl", embraces heteroaryl-substituted alkyl radicals.
More preferred heteroarylalkyl radicals are "lower heteroarylalkyl"
radicals having one to six carbon atoms and a heteroaryl radical.
Examples include such heteroarylalkyl radicals such as
pyridylmethyl and thienylmethyl. The term "alkylthio" embraces
radicals containing a linear or branched alkyl radical, of one to
about ten carbon atoms attached to a divalent sulfur atom. More
preferred alkylthio radicals are "lower alkylthio" radicals having
alkyl radicals of one to six carbon atoms. Examples of such lower
alkylthio radicals are methylthio, ethylthio, propylthio, butylthio
and hexylthio. The term "alkylthioalkyl" embraces alkylthio
radicals attached to an alkyl radical. More preferred
alkylthioalkyl radicals are "lower alkylthioalkyl" radicals having
alkyl radicals of one to six carbon atoms and an alkylthio radical
as described above. Examples of such radicals include
methylthiomethyl. The term "arylthio" embraces radicals containing
an aryl radical, attached to a divalent sulfur atom, such as a
phenylthio radical. The term "arylthioalkyl" embraces arylthio
radicals attached to an alkyl radical. More preferred arylthioalkyl
radicals are "lower arylthioalkyl" radicals having alkyl radicals
of one to six carbon atoms and an arylthio radical as described
above. Examples of such radicals include phenylthiomethyl, where
the phenyl radical may be substituted as described above. The term
"alkylsulfinyl" embraces radicals containing a linear or branched
alkyl radical, of one to ten carbon atoms, attached to a divalent
--S(.dbd.O)-- radical. More preferred alkylsulfinyl radicals are
"lower alkylsulfinyl" radicals having one to six carbon atoms.
Examples of such lower alkylsulfinyl radicals include
methylsulfinyl, ethylsulfinyl, butylsulfinyl and hexylsulfinyl. The
term "sulfonyl", whether used alone or linked to other terms such
as alkylsulfonyl, denotes respectively divalent radicals
--SO.sub.2--. "Alkylsulfonyl" embraces alkyl radicals attached to a
sulfonyl radical, where alkyl is defined as above. More preferred
alkylsulfonyl radicals are "lower alkylsulfonyl" radicals having
one to six carbon atoms. Examples of such lower alkylsulfonyl
radicals include methylsulfonyl, ethylsulfonyl and propylsulfonyl.
The "alkylsulfonyl" radicals may be further substituted with one or
more halo atoms, such as fluoro, chlora or bromo, to provide
"haloalkylsulfonyl" radicals. More preferred haloalkylsulfonyl
radicals are "lower haloalkylsulfonyl" radicals having one or more
halo atoms attached to lower alkylsulfonyl radicals as described
above. Examples of such lower haloalkylsulfonyl radicals include
fluoromethylsulfonyl, trifluoromethylsulfonyl and
chloromethylsulfonyl. The term "arylsulfonyl" embraces aryl
radicals as defined above, attached to a sulfonyl radical. Examples
of such radicals include phenylsulfonyl. The terms "sulfamyl",
"aminosulfonyl" and "sulfonamidyl" denotes NH.sub.2O.sub.2S--. The
term "acyl" denotes a radical provided by the residue after removal
of hydroxyl from an organic acid. Examples of such acyl radicals
include formyl, alkanoyl and aroyl radicals. The alkanoyl radicals
may be substituted or unsubstituted, such as formyl, acetyl,
propanoyl, butanoyl, isobutanoyl, valeryl, isovaleryl, pivaloyl,
hexanoyl or the like. The terms "carboxy" or "carboxyl", whether
used alone or with other terms, such as "carboxyalkyl", denotes
--CO.sub.2H. The term "carbonyl", whether used alone or with other
terms, such as "alkoxycarbonyl", denotes --(C.dbd.O)--. The term
"alkoxycarbonyl" means a radical containing an alkoxy radical, as
defined above, attached via an oxygen atom to a carbonyl radical.
Preferably, "lower alkoxycarbonyl" embraces alkoxy radicals having
one to six carbon atoms. Examples of such "lower alkoxycarbonyl"
ester radicals include substituted or unsubstituted
methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl
and hexyloxycarbonyl. The term "aralkyl" embraces aryl-substituted
alkyl radicals. Preferable aralkyl radicals are "lower aralkyl"
radicals having aryl radicals attached to alkyl radicals having one
to six carbon atoms. Examples of such phenylalkyl radicals include
benzyl, diphenylmethyl, triphenylmethyl, phenylethyl and
diphenylethyl. The aryl in said aralkyl radicals may be substituted
at a substitutable position with one or more substituents selected
from halo, alkylthio, alkylsulfinyl, alkyl, cyano, haloalkyl,
hydroxyl, alkoxy, hydroxyalkyl and haloalkoxy. The terms benzyl and
phenylmethyl are interchangeable. The terms "alkylcarbonyl",
"arylcarbonyl" and "aralkylcarbonyl" include radicals having alkyl,
aryl and aralkyl radicals, respectively, as defined above, attached
to a carbonyl radical. More preferred alkylcarbonyl radicals are
"lower alkylcarbonyl" radicals having one to six carbon atoms.
Examples of such radicals include methylcarbonyl and ethylcarbonyl.
More preferred aralkylcarbonyl radicals are "lower aralkylcarbonyl"
radicals having aryl radicals attached to alkyl radicals having one
to six carbon atoms. Examples of such aralkylcarbonyl radicals
include benzylcarbonyl. An example of an arylcarbonyl radical is
phenylcarbonyl. The term "alkoxycarbonylalkyl" embraces radicals
having "alkoxycarbonyl", as defined above attached to an alkyl
radical. More preferred alkoxycarbonylalkyl radicals are "lower
alkoxycarbonylalkyl" having lower alkoxycarbonyl radicals as
defined above attached to one to six carbon atoms. Examples of such
lower alkoxycarbonylalkyl radicals include methoxycarbonylmethyl.
The term "haloalkylcarbonyl" embraces radicals having a haloalkyl
radical as described above attached to a carbonyl radical. More
preferred radicals are "lower haloalkylcarbonyl", radicals where
lower haloalkyl radicals, as described above are attached to a
carbonyl radical. The term "carboxyalkyl" embraces radicals having
a carboxy radical as defined above, attached to an alkyl radical.
More preferred carboxyalkyl radicals are "lower carboxyalkyl"
radicals having one or more carboxy radicals attached to an alkyl
radical having one to six carbon atoms. The term "heteroaralkyl"
embraces heteroaryl-substituted alkyl radicals. More preferred
heteroaralkyl radicals are "lower heteroaralkyl" radicals having
five to six membered heteroaryl radicals attached to one to six
carbon atoms. Examples of such radicals include pyridylmethyl,
quinolylmethyl, thienylmethyl, furylethyl and quinolylethyl. The
heteroaryl in said heteroaralkyl may be additionally substituted
with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy. The term
"aryloxy" embraces aryl radicals, as defined above, attached to an
oxygen atom. Examples of such radicals include phenoxy. The term
"heteroaryloxyl" embraces heteroaryl radicals as defined above
attached to an oxygen radical. More preferred heteroaryloxy
radicals are "lower heteroaryloxyl" radicals having five to six
membered heteroaryl radicals. The term "aralkoxy" embraces
oxy-containing aralkyl radicals attached through the oxygen atom to
other radicals. The term "aralkoxyalkyl" embraces alkyl radicals
having one or more aralkoxy radicals attached to the alkyl radical,
that is, to form monoaralkyloxyalkyl and diaralkyloxyalkyl
radicals. The "aralkoxy" or "aralkoxyalkyl", radicals may be
further substituted on the aryl ring portion of the radical. More
preferred aralkoxyalkyl radicals are "lower aralkoxyalkyl" having
an alkoxy attached to one to six carbon atoms. Examples of lower
aralkoxyalkyl radicals include benzyloxymethyl. The term
"cycloalkylthio" embraces radicals containing a cycloalkyl radical,
of three to about ten carbon atoms attached to a divalent sulfur
atom. More preferred cycloalkylthio radicals are "lower
cycloalkylthio" radicals having cycloalkyl radicals of four to six
carbon atoms. Examples of such lower cycloalkylthio radicals are
cyclobutylthio, cyclopentylthio and cyclohexylthio. The term
"cycloalkylthioalkyl", embraces radicals containing a
cycloalkylthio radical, as described above, attached to an alkyl
radical. More preferred cycloalkylthioalkyl radicals are "lower
cycloalkylthioalkyl" radicals having cycloalkyl radicals of four to
six carbon atoms and alkyl radicals of one to six carbons. The term
"cycloalkylsulfonyl" embraces radicals containing a cycloalkyl
radical, of three to about ten carbon atoms attached to a divalent
sulfonyl radical. More preferred cycloalkylsulfonyl radicals are
"lower cycloalkylsulfonyl" radicals having cycloalkyl radicals of
four to six carbon atoms. Examples of such lower cycloalkylsulfonyl
radicals are cyclobutylsulfonyl, cyclopentylsulfonyl and
cyclohexylsulfonyl. The term "cycloalkylsulfonylalkyl" embraces
radicals containing a cycloalkylsulfonyl radical, as described
above, attached to an alkyl radical. More preferred
cycloalkylsulfonylalkyl radicals are "lower
cycloalkylsulfonylalkyl" radicals having cycloalkyl radicals of
four to six carbon atoms and alkyl radicals of one to six carbons.
The term "cycloalkyloxy" embraces radicals containing a cycloalkyl
radical, of three to about ten carbon atoms attached to a divalent
oxygen atom. More preferred cycloalkyloxy radicals are "lower
cycloalkyloxy" radicals having cycloalkyl radicals of four to six
carbon atoms. Examples of such lower cycloalkyloxy radicals are
cyclobutyloxy, cyclopentyloxy and
cyclohexyloxy. The term "cycloalkyloxyalkyl" embraces radicals
containing a cycloalkyloxy radical, as described above, attached to
an alkyl radical. More preferred cycloalkyloxyalkyl radicals are
"lower cycloalkyloxyalkyl" radicals having cycloalkyl radicals of
four to six carbon atoms and alkyl radicals of one to six carbons.
The term "heteroarylthio" embraces radicals having heteroaryl
radicals attached to a sulfur radical. More preferred
heteroarylthio radicals are "lower heteroarylthio" radicals having
five to six membered heteroaryl radicals. Examples of such radicals
include 2-furylthio, 2-thienylthio, 3-thienylthio, 4-pyridylthio
and 3-pyridylthio. The term "heteroarylalkylthio" denotes radicals
having an heteroaryl radical attached to an alkylthio radical. More
preferred heteroarylalkylthio radicals are "lower
heteroarylalkylthio" radicals having heteroaryl radicals attached
to lower alkylthio radicals as described above. Examples of such
radicals include furylmethylthio and quinolylmethylthio. The term
"heteroarylalkylthioalkyl" denotes radicals having an heteroaryl
radical attached to an alkylthic radical further attached through
the sulfur atom to an alkyl radical. More preferred
heteroarylalkylthioalkyl are "lower heteroarylalkylthioalkyl"
radicals having lower heteroarylalkyl radicals as described above.
Examples of such radicals include furylmethylthiomethyl and
quinolylmethylthioethyl. The term "heteroarylthioalkyl" denotes
radicals having an heteroaryl radical attached to a sulfur atom
further attached through the sulfur atom to an alkyl radical. More
preferred heteroarylthioalkyl radicals are "lower
heteroarylthicalkyl" having lower heteroarylthio radicals as
described above. Examples of such radicals include
thienylthiomethyl and pyridylthiohexyl. The term "aralkylthio"
embraces radicals having aralkyl radicals attached to a bridging
sulfur atom. More preferred aralkylthio radicals are "lower
aralkylthio" radicals having the aryl radicals attached to one to
six carbon atoms. Examples of such radicals include benzylthio and
phenylethylthio. The term "aralkylthioalkyl" embraces radicals
having aralkyl radicals attached to alkyl radicals through a
bridging sulfur atom. More preferred aralkylthioalkyl radicals are
"lower aralkylthioalkyl" radicals having the aralkylthio radicals
attached to one to six carbon atoms. Examples of such radicals
include benzylthiomethyl and phenylethylthiomethyl. The term
"heteroaryloxyalkyl" denotes radicals having an heteroaryl radical
attached to an oxygen atom further attached through the oxygen atom
to an alkyl radical. More preferred heteroaryloxyalkyl radicals are
"lower heteroaryloxyalkyl" radicals having five to six membered
heteroaryl radicals. Examples of such radicals include
furyloxyethyl, pyridyloxymethyl and thienyloxyhexyl. The term
"aminoalkyl" embraces alkyl radicals substituted with amino
radicals. More preferred aminoalkyl radicals are "lower aminoalkyl"
having one to six carbon atoms, Examples include aminomethyl,
aminoethyl and aminobutyl. The term "alkylaminoalkyl" embraces
aminoalkyl radicals having the nitrogen atom substituted with at
least one alkyl radical. More preferred alkylaminoalkyl radicals
are "lower alkylaminoalkyl" having one to six carbon atoms attached
to a lower aminoalkyl radical as described above. The term
"alkylamino" denotes amino groups which have been substituted with
one or two alkyl radicals. More preferred alkylamino radicals are
"lower alkylamino" radicals having one or two alkyl radicals of one
to six carbon atoms, attached to a nitrogen atom. Suitable
"alkylamino" may be mono or dialkylamino such as N-methylamino,
N-ethylamino, N,N-dimethylamino, N,N-diethylamino and the like. The
term "aminocarbonyl" denotes an amide group of the formula
--C(.dbd.O)NH.sub.2. The term "alkylaminocarbonyl" embraces
alkylamino radicals, as described above, to a carbonyl radical.
More preferred alkylaminocarbonyl radicals are "lower
alkylaminocarbonyl" having lower alkylamino radicals, as described
above, attached to a carbonyl radical. Examples of such radicals
include N-methylaminocarbonyl and N,N-dimethylaminocarbonyl. The
term "arylamino" denotes amino groups which have been substituted
with one or two aryl radicals, such as N-phenylamino. The
"arylamino" radicals may be further substituted on the aryl ring
portion of the radical. The terms "N-arylaminoalkyl" and
"N-aryl-N-alkylaminoalkyl" denote amino groups which have been
substituted with one aryl radical or one aryl and one alkyl
radical, respectively, and having the amino group attached to an
alkyl radical. More preferred arylaminoalkyl radicals are "lower
arylaminoalkyl" having the arylamino radical attached to one to six
carbon atoms. Examples of such radicals include N-phenylaminomethyl
and N-phenyl-N-methylaminomethy- l. The term
"alkylaminocarbonylalkyl", denotes an alkylaminocarbonyl group
which is attached to an alkyl radical. More preferred are "lower
alkylaminocarbonylalkyl", having lower alkylaminocarbonyl radicals
as described above attached to one to six carbon atoms. The term
"aryloxyalkyl" embraces alkyl radicals having one or more aryloxy
radicals, aryl radicals attached to a divalent oxygen atom,
attached to the alkyl radical, that is, to form monoaryloxyalkyl
and diaryloxyalkyl radicals. The more preferred aryloxyalkyl
radicals are "lower aryloxyalkyl" radicals having aryloxy radicals
attached to one to six carbon atoms. Examples include
phenoxymethyl. The term "heteroarylalkoxy" embraces radicals having
one or more heteroaryl radicals attached to an alkoxy radical. More
preferred heteroarylalkoxy radicals are "lower heteroarylalkoxy"
radicals having five to six membered heteroaryl radicals. Examples
of such radicals include 2-thienylmethoxy, 3-thienylmethoxy,
2-furylmethoxy, 3-furylmethoxy and 2-pyridylmethoxy,
3-pyridylmethoxy, 4-pyridylmethoxy. The term
"heteroarylalkoxyalkyl" embraces alkyl radicals having one or more
heteroaryl radicals attached to an alkoxy radical, further attached
to the alkyl radical. More preferred heteroarylalkoxyalkyl radicals
are "lower heteroarylalkoxyalkyl radicals having five to six
membered heteroaryl radicals. Examples of such radicals include
2-thienylmethoxymethyl. The term "azidoalkyl" denotes alkyl
radicals substituted with azido groups (--N.sub.3). More preferred
azidoalkyl radicals are "lower azidoalkyl" having one to six carbon
atoms. Examples include azidomethyl, azidoethyl and
aminopropyl.
[0815] The present invention comprises a pharmaceutical composition
comprising a therapeutically-effective amount of a compound of
Formula I in association with at least one
pharmaceutically-acceptable carrier, adjuvant or diluent.
[0816] The present invention also comprises a method of treating
inflammation or inflammation-associated disorders in a subject, the
method comprising treating the subject having or susceptible to
such inflammation or disorder with a therapeutically-effective
amount of a compound of Formula I.
[0817] Also included in the family of compounds of Formula I are
the stereoisomers thereof. Compounds of the present invention can
possess one or more asymmetric carbon atoms and are thus capable of
existing in the form of optical isomers as well as in the form of
racemic or nonracemic mixtures thereof. Accordingly, some of the
compounds of this invention may be present in racemic mixtures
which are also included in this invention. The optical isomers can
be obtained by resolution of the racemic mixtures according to
conventional processes, for example by formation of
diastereoisomeric salts by treatment with an optically active acid
or base. Examples of appropriate acids are tartaric,
diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric and
camphorsulfonic acid and then separation of the mixture of
diastereoisomers by crystallization followed by liberation of the
optically active bases from these salts. A different process for
separation of optical isomers involves the use of a chiral
chromatography column optimally chosen to maximize the separation
of the enantiomers. Still another available method involves
synthesis of covalent diastereoisomeric molecules by reacting an
amine functionality of precursors to compounds of Formula I with an
optically pure acid in an activated form or an optically pure
isocyanate. Alternatively, diastereomeric derivatives can be
prepared by reacting a carboxyl functionality of precursors to
compounds of Formula I with an optically pure amine base. The
synthesized diastereoisomers can be separated by conventional means
such as chromatography, distillation, crystallization or
sublimation, and then hydrolyzed to deliver the enantiomerically
pure compound. The optically active compounds of Formula I can
likewise be obtained by utilizing optically active starting
materials. These isomers may be in the form of a free acid, a free
base, an ester or a salt.
[0818] Also included in the family of compounds of Formula I are
the pharmaceutically-acceptable salts thereof. The term
"pharmaceutically-acceptable salts" embraces salts commonly used to
form alkali metal salts and to form addition salts of free acids or
free bases. The nature of the salt is not critical, provided that
it is pharmaceutically-acceptable. Suitable
pharmaceutically-acceptable acid addition salts of compounds of
Formula I may be prepared from an inorganic acid or from an organic
acid. Examples of such inorganic acids are hydrochloric,
hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric
acid. Appropriate organic acids may be selected from aliphatic,
cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and
sulfonic classes of organic acids, example of which are formic,
acetic, propionic, succinic, glycolic, gluconic, lactic, malic,
tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic,
aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic,
p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),
methanesulfonic, ethylsulfonic, benzenesulfonic, pantothenic,
toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, stearic,
cyclohexylaminosulfonic, algenic, 1-hydroxybutyric, salicylic,
galactaric and galacturonic acid Suitable
pharmaceutically-acceptable base addition salts of compounds of
Formula I include metallic salts made from aluminum, calcium,
lithium, magnesium, potassium, sodium and zinc or organic salts
made from N,N'-dibenzylethylenediamine, choline, chloroprocaine,
diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and
procaine. All of these salts may be prepared by conventional means
from the corresponding compound of Formula I by reacting, for
example, the appropriate acid or base with the compound of Formula
I.
[0819] Racemic alcohol containing compounds may be resolved to
their single enantiomers by the following procedure. Treatment of
the racemic alcohols with an acetylating agent, such as vinyl
acetate or isopropenyl acetate, in the presence of an appropriate
enzyme results in the selective acetylation of one of the
constituent enantiomeric alcohols, leading to a crude product
consisting of essentially enantiomerically pure alcohol.
Appropriate enzymes include, but are not limited to, lipases (such
as AMANO Lipase PS30), cholinesterases and proteases. The reaction
may be monitored to complete acetylation of one of the enantiomers
using HPLC. The enantiomerically pure alcohol may be separated from
enantiomerically pure acetate by column chromatography.
Saponification of the acetate using aqueous base provides the other
enantiomerically pure alcohol.
[0820] Alternatively, alcohols can be resolved via procedures
outlined in E. Eliel and S. Wilen, Stereochemistry of Organic
compounds, 337-340 (1994).
GENERAL SYNTHETIC PROCEDURES
[0821] The compounds of the invention can be synthesized according
to the following procedures of Schemes I-XV, wherein the
R.sup.1-R.sup.14 substituents are as defined for Formula I-V,
above, except where further noted. 7
[0822] Scheme I shows the three step preparation of the
4,5-dihydro-imidazoles 5 and substituted imidazoles 6 of the
present invention. In step 1, the reaction of substituted nitrites
(R.sup.2CN) 1 with primary amines (R.sup.1NH.sub.2) 2 in the
presence of alkylaluminum reagents such as trimethylaluminum,
triethylaluminum, dimethylaluminum chloride, diethylaluminum
chloride in the presence of inert solvents such as toluene, benzene
and xylene, gives amidines 3. In step 2, the reaction of amidine 3
with 2-halo-ketones 4 (where X is Br or Cl) in the presence of
bases, such as sodium bicarbonate, potassium carbonate, sodium
carbonate, potassium bicarbonate or hindered tertiary amines such
as N,N'-diisopropylethylamine, gives the 4,5-dihydroimidazoles 5
(where R.sup.5 is hydroxyl and R.sup.6 is hydrido). Some of the
suitable solvents for this reaction are isopropanol, acetone and
dimethylformamide. The reaction may be carried out at temperatures
of about 20.degree. C. to about 90.degree. C. In step 3, the
4,5-dihydroimidazoles 5 may be dehydrated in the presence of an
acid catalyst such as 4-toluenesulfonic acid or mineral acids to
form the 1,2-disubstituted imidazoles 6 of the invention. Suitable
solvents for this dehydration step are e.g., toluene, xylene and
benzene. Trifluoroacetic acid can be used as solvent and catalyst
for this dehydration step.
[0823] In some cases (e.g., where R.sup.3=methyl or phenyl) the
intermediate 5 may not be readily isolable. The reaction, under the
conditions described above, proceeds to give the targeted
imidazoles directly. 8
[0824] Scheme II shows alternative methods of forming amidines 3.
Amidines 3 are also available by the two step conversion of amide 7
(R.sup.2CONHR.sup.1 formed by the conversion of primary amine 2).
In Step 1, the amide is converted to the corresponding imidoyl
chloride by treatment with a halogenating agent such as phosphorus
oxychloride. In step two, treatment of the imidoyl chloride with
ammonia forms the desired amidine 3. In addition, amidines 3 may
also be obtained by conversion of primary amides 8 (e.g.,
R.sup.2CONH.sub.2) or nitrites 1 (R.sup.2CN) to their corresponding
iminothioethers or iminoethers 9 (where X is sulfur and oxygen,
respectively) followed by reaction with amine 2. 9
[0825] Scheme III shows the two step method of preparing certain
2-halo-ketones 12 (compound 4 from Scheme I where X is bromo or
chloro, R.sup.3 is --CH.sub.2YR' [Y is oxygen, sulfur or --NH] and
R.sup.4 is hydrido) which are not commercially available, from
1,2-dihalopropenes 10. In step 1,2,3-dichloro-1-propene 10 is added
to a mixture of alcohol, amine or mercaptan (R'YH) and base, such
as potassium carbonate in acetone, to form the 2-chloropropene 11,
where R' is an alkyl or aryl group and Y is an oxygen, nitrogen or
sulfur atom. In step 2, the 2-chloropropene 11 is converted to
2-haloketones 12 via a method as described by H. E. Morton and M.
R. Leanna (Tet. Letters, 34, 4481 (1993)). 10
[0826] Scheme IV shows a method of forming 2-chloropropenes 14
(compound 11 in Scheme III where Y is oxygen). The
2-chloro-2-propen-1-ol 13 is added to a mixture of an alkyl,
aralkyl or heteroaralkyl halide (XR') and base, such as potassium
carbonate in acetone, to form the 2-chloropropene 14.
[0827] Alternatively, 2-chloropropenes 14 can be formed from the
corresponding 2,3-dichloro-1-propenes 10 (Scheme III) by reaction
with a metal alkoxide in an appropriate solvent. Sodium methoxide
in methanol is an example of one such alkoxide and solvent. 11
[0828] Scheme V shows the three step preparation of
1,2-diarylimidazoles 20 of the present invention. In step l, the
reaction of substituted benzonitriles 15 with substituted anilines
16 in the presence of alkylaluminum reagents such as
trimethylaluminum, triethylaluminum, dimethylaluminum chloride,
diethylaluminum chloride gives amidines 17. In step 2, the reaction
of amidines 17 with haloketones 18 (compound 4 in Scheme I where X
is Br or Cl and R.sup.4 is hydrido) in the presence of bases, such
as sodium bicarbonate, potassium carbonate, sodium carbonate,
potassium bicarbonate or hindered tertiary amines such as
N,N'-diisopropylethylamine, gives the
1,2-diaryl-4,5-dihydro-imidazoles 19. Some of the suitable solvents
for this reaction are isopropanol, acetone and dimethylformamide.
The reaction may be carried out at a temperature between about
20.degree. C. to about 90.degree. C. In step 3, the
1,2-diaryl-4,5-dihydro-imidazoles 19 may be dehydrated in the
presence of an acid catalyst such as 4-toluenesulfonic acid to form
the 1,2-diarylimidazoles 20 of the present invention. Suitable
solvents for this dehydration step are, for example, toluene,
xylene and benzene. Trifluoroacetic acid can be used as solvent and
catalyst for this dehydration step,
[0829] In some cases (e.g,, where R.sup.3 is methyl or phenyl), the
intermediate 19 may not be readily isolable. The reaction, under
the conditions described above, proceeds to give the targeted
imidazoles 20 directly. 12
[0830] Scheme VI shows the formation of 4-hydroxymethyl imidazoles
22 and 4-formyl-imidazoles 23 from benzyloxy-protected imidazoles
21 and from 4-carboalkoxy imidazoles 23. In step 1, the oxidative
deprotection of 4-methoxybenzyl group in 21, such as with ceric
ammonium nitrate, gives the hydroxymethyl imidazoles 22.
Alternatively, the alkoxycarbonyl group of 23 may be reduced to the
hydroxymethyl group. Suitable reducing agents include lithium
borohydride. In step 2, the hydroxymethyl imidazoles 22 are
oxidized, for example, with pyridinium chlorochromate, to give the
4-formyl-imidazoles 24. 13
[0831] Scheme VII shows the formation of
4-difluoromethyl-imidazoles 25 from 4-formyl-imidazoles 24. The
4-formyl-imidazoles 24 are converted to desired
4-difluoromethyl-imidazoles 25 by direct fluorination using the
known reagents such as SF.sub.4 or diethylaminosulfur trifluoride
(DAST). For discussion of the reaction and the representative
procedures, see e.g., Organic Reactions, 34, 319 (1987), Organic
Reactions, 35, 513 (1988), Organic Reactions, 21, 319 (1974) and
Chem. Soc. Reviews, 16, 381 (1987), Alternatively, the imidazoles
25 can be synthesized by reaction of hydrazones of 24 with
N-bromosuccinimide/pyridinium poly(hydrogen fluoride]. This
transformation has been developed by Olah and co-workers [see,
Synlett, 594 (1990)]. 14
[0832] Scheme VIII shows the conversion of the 4-formyl-imidazoles
24 to 4-cyanoimidazoles 26. The 4-formyl-imidazoles 24 are
converted to the target nitrile derivatives 26 by following the
literature procedures [see, e.g., Chem. Letters, 773 (1984),
Synthesis, 510 (1984), Tetrahedron Lett., 1781 (1976), Synthesis,
739 (1981), Synth. Communications, 18, 2179 (1988), Bull. Chem.
Soc. Japan, 54, 1579 (1981), Synthesis, 201 (1985), Synthesis, 190
(1982), Synthesis, 56 (1979), and the references cited therein].
15
[0833] Scheme IX shows other 1,2-diarylimidazoles that can be
synthesized from the 4-formyl-imidazoles 24 in two steps. In step
1, the 4-formyl-imidazoles 24 are converted to carbinol derivatives
(where R is aralkyl or alkyl) by addition of Grignard reagents
(RMgBr). In step 2, the hydroxy derivatives 27 are reduced by
catalytic hydrogenation (using e.g., Pd/C or Pt/C), preferably in
the presence of a small amount of acid (e.g., acetic acid or
aqueous HCl) to form the alkyl or aralkyl derivatives 28.
Alternatively, the ketones 29 are synthesized by oxidation (e.g.,
using pyridinium chlorochromate) of the hydroxy derivatives 27.
16
[0834] Synthetic Scheme X shows the three step procedure used to
prepare sulfonamide antiinflammatory agents 31 and the two step
procedure used to prepare fluoromethyl sulfone antiinflammatory
agents 32 from their corresponding methyl sulfones 30. In step one,
THF solutions of the methyl sulfones 30 at -78.degree. C. are
treated with a base such as alkyllithium reagents, lithioamides and
Grignard reagents. Examples of such bases include n-butyllithium,
methyllithium, lithium diisopropylamide (LDA), butylmagnesium
chloride, phenylmagnesium bromide and methylmagnesium chloride. In
step two, the anions generated in step one are treated with an
organoborane, e.g., triethylborane, tributylborane, etc., at
-78.degree. C. then warmed to ambient temperature prior to stirring
at reflux. An alternative to the boron chemistry involves room
temperature alkylation, such as with haloalkyltrialkylsilanes,
followed by treatment with silylalkyl-elimination agents. Examples
of such haloalkyltrialkylsilanes include
trimethylsilylmethylhalides such as (iodomethyl)trimethylsilane and
(chloromethyl)trimethylsilane. Suitable silylalkyl-elimination
agents include compounds which produce a fluoride ion. Examples of
such compounds include alkylammonium fluorides and cesium fluoride.
Tetrabutylammonium fluoride (1M in THF) is preferred. The
deprotonation of sulfone is conveniently carried out in the
temperature range of about -70.degree. C. to about 25.degree. C.,
preferably at about 0.degree. C. The formation of silylalkylsulfone
is conveniently carried out in the temperature range of about
0.degree. C. to about 35.degree. C., preferably at about 20.degree.
C. In step three, an aqueous solution of sodium acetate and
hydroxylamine-O-sulfonic acid is added to provide the corresponding
sulfonamide antiinflammatory agents 31 of this invention.
Alternatively, the anion solutions generated in step one may be
warmed to 0.degree. C. and treated with
N-fluorodibenzenesulfonamide to provide the corresponding
fluoromethyl sulfone antiinflammatory agents 32 of this invention.
17
[0835] 1-Phenyl-2-heterocycloimidazoles of the current invention 37
are synthesized by following the generic synthesis shown in Scheme
XI. The reaction of a substituted heterocyclonitrile 33 with
substituted anilines 34 (where R.sup.b is as defined above for aryl
and heteroaryl radicals) in the presence of alkylaluminum reagents
such as trimethylaluminum, triethylaluminum, dimethylaluminum
chloride, diethylaluminum chloride gives the amidine 35. The
reaction of amidine 35 with a 2-halo-ketone derivative 18 (X'=Br or
Cl) in the presence of bases such as sodium bicarbonate, potassium
carbonate, sodium carbonate, potassium bicarbonate or
N,N'-diisopropylethylamine gives the alkylated product 36. Some of
the suitable solvents for this reaction are isopropanol, acetone
and dimethylformamide. The reaction may be carried out at 20 to
90.degree. C. The intermediate 36 may be dehydrated in the presence
of an acid catalyst such as 4-toluenesulfonic acid to give the
targeted 1,2-diarylimidazoles 37. Suitable solvents for this
dehydration step are e.g., toluene, xylene and benzene.
Alternatively, trifluoroacetic acid may be used both as solvent and
catalyst in this dehydration step. 18
[0836] Scheme XII shows a two step method of forming sulfonyl
anilines 39 from nitro compounds 38. In step one, the
4-methylthio-nitrobenzene 38 is oxidized to the sulfone with an
oxidizing reagent such as hydrogen peroxide, potassium
peroxymonosulfate (Oxone.RTM.) or 3-chloroperoxybenzoic acid
(MCPBA). In step 2, the 4-methylsulfonyl-nitrobenzene is reduced to
the corresponding aniline 39. 19
[0837] Synthetic Scheme XIII describes an alternative method of
forming 1-aryl-2-pyridyl-imidazoles 44 from 4-alkylthioanilines 40.
The reaction of a substituted cyanopyridine 33 (where R.sup.a is as
defined above for aryl and heteroaryl radicals) with substituted
anilines 40 in the presence of alkylaluminum reagents such as
trimethylaluminum, triethylaluminum, dimethylaluminum chloride,
diethylaluminum chloride gives the amidine 41. Alternatively,
amidine 41 may be synthesized by reaction of aniline 40 first with
a suitable base, and then with nitrile 33. Examples of suitable
bases include sodium hydride, sodium methoxide, n-butyllithium and
lithium diisopropylamide. These reactions may be run in solvents
such as dimethyl sulfoxide, tetrahydrofuran, dimethoxyethane and
methanol or the like. The reaction of amidine 41 with a
2-halo-ketone derivative 18 (X'=Br or Cl) in the presence of bases
such as sodium bicarbonate, potassium carbonate, sodium carbonate,
potassium bicarbonate or N,N'-diisopropylethylamine gives the
alkylated product 42. Some of the suitable solvents for this
reaction are isopropanol, acetone and dimethylformamide. The
reaction may be carried out at 20 to 90.degree. C. The intermediate
42 is dehydrated in the presence of an acid catalyst such as
4-toluenesulfonic acid to give the 1-(4-alkylthio)aryl-2-pyridyli-
midazoles 43. Suitable solvents for this dehydration step are e.g.,
toluene, xylene and benzene. Oxidation of the alkylthio 43, with an
oxidizing reagent such as hydrogen peroxide, Oxone.RTM. or MCPBA,
yields the sulfones 44. 20
[0838] Scheme XIV shows a method of forming sulfones and
sulfonamides 46 from the corresponding 1-phenylimidazoles 45, where
X is a leaving group such as halo. Treatment of 45 with base, such
as butyl lithium, followed by addition of sulfur dioxide and a
substituted alkyl or amine yields the corresponding sulfone or
sulfonamide 46 (where R.sup.a is alkyl or amino). 21
[0839] Synthetic Scheme XV describes an alternative method of
forming 1-aryl-2-pyridyl-imidazoles 53 from
4-nitrobenzenesulfonamide 47. Protection of
4-nitrobenzenesulfonamide 47, such as by reaction with
acetonylacetone with p-toluenesulfonic acid as catalyst in a
solvent such as toluene, forms the protected pyrrolylsulfonyl 48. A
preferred protecting agent is 2,5-lower alkyl pyrrole, and more
preferred is 2,5-dimethyl pyrrole. Reduction of the nitro compound
48, such as by Raney Nickel-catalyzed hydrogenation, yields the
protected benzenamine 49. Amidine 50 is synthesized by reaction of
benzenamine 49 first with a suitable base, and then with nitrile
33. Examples of suitable bases include sodium
bis(trimethylsilyl)amide, sodium hydride, sodium methoxide,
n-butyllithium and lithium diisopropylamide. This reaction may be
run in solvents such as dimethyl sulfoxide, tetrahydrofuran,
dimethoxyethane, methanol, or the like. The reaction of amidine 50
with a 2-halo-ketone derivative 18 (X'=Br or Cl) in the presence of
bases such as sodium bicarbonate, potassium carbonate, sodium
carbonate, potassium bicarbonate or N,N'-diisopropylethylamine
gives the hydroxyimidazole 51. Some of the suitable solvents for
this reaction are isopropanol, acetone and dimethylformamide. The
reaction may be carried out at 20 to 90.degree. C. The intermediate
51 is dehydrated in the presence of an acid catalyst such as
4-toluenesulfonic acid to give the protected
1-(4-sulfonyl)aryl-imidazoles 52. Suitable solvents for this
dehydration step are e.g., toluene, xylene and benzene. Acid
deprotection of 52 such as with aqueous trifluoroacetic acid (TFA)
at reflux temperature produces the sulfonamides 53.
[0840] The following currently pending applications are
incorporated by reference: International Application
PCT/US95/09506, patent application Ser. No. 08/464,154, and patent
application Ser. No. 08/282,395.
[0841] The following examples contain detailed descriptions of the
methods of preparation of compounds of Formula I-V. These detailed
descriptions fall within the scope, and serve to exemplify, the
above described General Synthetic Procedures which form part of the
invention. These detailed descriptions are presented for
illustrative purposes only and are not intended as a restriction on
the scope of the invention. All parts are by weight and
temperatures are in Degrees centigrade unless otherwise indicated.
All compounds showed NMR spectra consistent with their assigned
structures. In some cases, the assigned structures were confirmed
by nuclear Overhauser effect (NOE) experiments.
EXAMPLE 1
[0842] 22
2-(4-Chlorophenyl)-4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-(trifluorometh-
yl)-4,5-dihydro-1H-imidazole
[0843] Step 1: Preparation of
4-chloro-N-[4-(methylsulfonyl)phenyl]benzene- carboximidamide
[0844] To a suspension of 4-(methylsulfonyl)aniline (7 g, 41 mmol)
in toluene (400 mL), trimethylaluminum (2M solution in toluene,
30.5 mL, 61 mmol) was added over 15 minutes. The reaction mixture
was warmed to room temperature and stirred for 2.5 hours. A
solution of 4-chlorobenzonitrile (11.3 g, 82 mmol) in toluene (200
mL) was added over 10 minutes and the reaction mixture was heated
to 80-85.degree. C. After 16 hours, the reaction mixture was cooled
to room temperature and poured over a slurry of silica gel in
chloroform. After filtration, the residue was washed with a mixture
of methylene chloride/methanol. The combined filtrates were
concentrated in vacuo and the resulting yellowish solid was stirred
with a mixture of hexane/ether (2/1, 1000 mL). The intermediate was
filtered and washed with more of hexane/ether (2/1). The pale
yellow solid 4-chloro-N-[4-(methylsulfonyl)phenyl]
benzenecarboximidamide (10.93 g, 86%) was used in the next reaction
without further purification: mp (DSC) 191.degree. C. Anal. Calc'd.
for C.sub.14H.sub.13N.sub.2SO.sub.2Cl: C, 54.46, H, 4.24, N, 9.07.
Found: C, 54.42, H, 4.30, N, 9.07.
[0845] Step 2: Preparation of
2-(4-chlorophenyl)-4-hydroxy-1-[4-(methylsul-
fonyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazole
[0846] To a mixture of
4-chloro-N-[4-(methylsulfonyl)phenyl]benzenecarboxi- midamide from
Step 1 (8 g, 26 mmol) and sodium bicarbonate (4.36 g, 52 mmol) in
isopropanol (240 mL), 3-bromo-1,1,1-trifluoroacetone (5.4 mL, 52
mmol) was added. After heating the reaction mixture at
75-80.degree. C. for 24 hours, the solvent was removed. The residue
was redissolved in methylene chloride and washed with water. The
organic fractions were combined, dried over sodium sulfate,
filtered and concentrated in vacuo. The crude product (16.2 g) was
purified by chromatography (silica gel, hexane/ethyl acetate,
55/45) to give pure 2-(4-chlorophenyl)-4-hydroxy-1--
[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazole
(6.7 g, 62%) as a white solid: Anal. Calc'd. for
C.sub.17H.sub.14N.sub.2S- O.sub.3ClF.sub.3: C, 48.75, H, 3.37, N,
6.69. Found: C, 48.56, H, 3.22, N, 6.51.
EXAMPLE 2
[0847] 23
2-(4-Chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imi-
dazole
[0848] A mixture of
2-(4-chlorophenyl)-4-hydroxy-1-[4-(methylsulfonyl)phen-
yl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazole from Example 1
(6.2 g, 15.4 mmol) and p-toluenesulfonic acid monohydrate (0.9 g,
4.7 mmol) in toluene (300 mL) was heated to reflux for 84 hours.
The reaction mixture was cooled and the solvent removed under
reduced pressure. The crude residue was redissolved in methylene
chloride and washed with water, aqueous sodium bicarbonate and
brine. After drying (Na.sub.2SO.sub.4), filtration and
concentrating in vacuo, the crude mixture was purified by
chromatography on silica gel using hexane/ethyl acetate (1/1) to
give pure
2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)--
1H-imidazole (4.21 g, 71%) as a white solid: mp (DSC) 183.degree.
C. Anal. Calc'd. for C.sub.17H.sub.12N.sub.2SO.sub.2F.sub.3Cl: C,
50.94, H, 3.02, N, 6.99. Found: C, 50.64, H, 3.03, N, 6.85.
EXAMPLE 3
[0849] 24
1-(4-Fluorophenyl)-4-hydroxy-2-[4-(methylsulfonyl)phenyl]-4-(trifluorometh-
yl)-4,5-dihydro-1H-imidazole
[0850] Step 1: Preparation of
4-methylsulfonyl-N-[4-chlorophenyl]benzeneca- rboximidamide
[0851] To a suspension of 4-fluoroaniline (4 mL, 40 mmol) in
toluene (120 mL), trimethylaluminum (2M solution in toluene, 21 mL,
42 mmol) was added over 15 minutes. The reaction mixture was warmed
to room temperature and stirred for 3 hours. A solution of
4-(methylsulfonyl)benzonitrile (7.65 g, 40 mmol) in methylene
chloride (100 mL) was added over 10 minutes and the reaction
mixture was heated to 70-75.degree. C. After 48 hours, the reaction
mixture was cooled to room temperature and poured over a slurry of
silica gel in chloroform. After filtration, the residue was washed
with a mixture of methylene chloride/methanol. The combined
filtrates were concentrated in vacuo and the resulting crude
intermediate (7.7 g) was purified by chromatography [silica gel,
hexane/ethyl acetate, 25/75] to give
4-methylsulfonyl-N-[4-chlorophenyl]benzenecarboximidamide (4.1 g,
35%) as a white solid: mp (DSC) 182" C. Anal. Calc'd. for
C.sub.14H.sub.13N.sub.2SO.sub.2F: C, 57.52, H, 4.48, N, 9.58, S,
10.97. Found: C, 57.37, H, 4.69, N, 9.21, S, 10.69.
[0852] Step 2: Preparation of
1-(4-fluorophenyl)-4-hydroxy-2-[4-(methylsul-
fonyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazole
[0853] To a mixture of
4-methylsulfonyl-N-[4-chlorophenyl]benzenecarboximi- damide from
Step 1 (1 g, 3.42 mmol) and sodium bicarbonate (575 mg, 6.85 mmol)
in isopropanol (30 mL), 3-bromo-1,1,1-trifluoroacetone (5.0 g, 25
mmol) was added. After heating the reaction mixture at
80-90.degree. C. for 24 hours, the solvent was removed. The residue
was redissolved in methylene chloride and washed with water. The
organic fractions were combined, dried over sodium sulfate,
filtered and concentrated in vacuo. The crude product (2.34 g) was
purified by chromatography [silica gel, hexane/ethyl acetate, 1/1]
to give 1-(4-fluorophenyl)-4-hydroxy-2-[4-(met-
hylsulfonyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazole
(650 mg, 47%) as a white solid: mp (DSC) 209.degree. C. Anal.
Calc'd. for C.sub.17H.sub.14N.sub.2SO.sub.3F.sub.4: C, 50.75, H,
3.51, N, 6.96. Found: C, 51.11, H. 3.86, N, 6.57.
EXAMPLE 14
[0854] 25
1-(4-Fluorophenyl)-2-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imi-
dazole
[0855] A mixture of
1-(4-fluorophenyl)-4-hydroxy-2-[4-(methylsulfonyl)phen-
yl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazole (Example 3) (770
mg, 1.9 mmol) and p-toluenesulfonic acid monohydrate (88 mg) in
toluene (80 mL) was heated to reflux for 20 hours. The reaction
mixture was cooled and the solvent removed under reduced pressure.
The crude residue was redissolved in methylene chloride and washed
with water, aqueous sodium bicarbonate and brine. After drying
(Na.sub.2SO.sub.4), filtration and concentration in vacuo, the
crude mixture (520 mg) was purified by chromatography on silica gel
using hexane/ethyl acetate (1/1) to give pure
1-(4-fluorophenyl)-2-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)--
1H-imidazole (328 mg, 44%) as a white solid: mp (DSC) 183.degree.
C. Anal. Calc'd. for C.sub.17H.sub.12N.sub.2SO.sub.2F.sub.4: C,
53.13, H, 3.15, N, 7.29. Found: C, 53.20, H, 3.22, N, 7.18.
EXAMPLE 5
[0856] 26
2-(4-Chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-methyl-1H-imidazole
[0857] To a mixture of
4-chloro-N-[4-(methylsulfonyl)phenyl]benzenecarboxi- midamide
(Example 1, Step 1) (240 mg, 0.78 mmol) and sodium bicarbonate (131
mg, 1.56 mmol) in isopropanol (20 mL), excess chloroacetone (1.5
mL) was added. After heating to reflux, the reaction mixture for 72
hours, the solvent was removed. The residue was redissolved in
methylene chloride and washed with aqueous sodium bicarbonate and
water. The organic fractions were combined, dried over sodium
sulfate, filtered and concentrated in vacuo. The crude product (370
mg) was purified by chromatography (silica gel, hexane/ethyl
acetate, 25/75) to give pure
2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-methyl-1H-imidazole
(160 mg, 67%): mp (DSC) 166.degree. C. Anal Calc'd. for
C.sub.17H.sub.15N.sub.2SO.sub.2Cl C, 58.87, H, 4.36, N, 8.08 Found:
C, 58.78, H, 4.62, N, 7.99.
EXAMPLE 6
[0858] 27
2-(4-Chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-phenyl-1H-imidazole
[0859] To a mixture of
4-chloro-N-[4-(methylsulfonyl)phenyl]benzenecarboxi- midamide
(Example 1, Step 1) (400 mg, 1.29 mmol) and sodium bicarbonate (216
mg, 2.59 mmol) in isopropanol (25 mL), 2-bromoacetophenone (780 mg,
3.87 mmol) was added. After heating the reaction mixture at
55.degree. C. for 20 hours, the solvent was removed. The residue
was redissolved in methylene chloride and washed with aqueous
sodium bicarbonate and water. The organic fractions were combined,
dried over sodium sulfate, filtered and concentrated in vacuo. The
crude product (1.2 g) was purified by chromatography on silica gel
with toluene/ethyl acetate (75/25) to give pure
2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-phenyl-1H-imidazol-
e (300 mg, 57%) as a white solid: mp (DSC) 202.degree. C. Anal.
Calc'd. for C.sub.22H.sub.17N.sub.2SO.sub.2Cl: C, 63.78, H, 4.28,
N, 6.76, S, 7.74. Found: C, 63.69, H, 4.11, N, 6.68, S, 7.65.
EXAMPLE 7
[0860] 28
2-(4-Chlorophenyl)-4-(4-fluorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imid-
azole
[0861] To a mixture of
4-chloro-N-[4-(methylsulfonyl)phenyl]benzenecarboxi- midamide
(Example 1, Step 1) (400 mg, 1.29 mmol) and sodium bicarbonate (216
mg, 2.59 mmol) in isopropanol (25 mL),
2-chloro-4'-fluoroacetophenon- e (670 mg, 3.87 mmol) was added.
After heating the reaction mixture at 80-85.degree. C. for 48
hours, the solvent was removed. The residue was redissolved in
methylene chloride and washed with aqueous sodium bicarbonate and
water. The organic fractions were combined, dried over sodium
sulfate, filtered and concentrated in vacuo. The crude product (800
mg) was purified by chromatography (silica gel, hexane/ethyl
acetate, 1/1) to give
2-(4-chlorophenyl)-4-(4-fluorophenyl)-1-[4-(methyls-
ulfonyl)phenyl]-1H-imidazole (200 mg, 36%) as a pale yellow solid:
mp (DSC) 180.degree. C. Anal. Calc'd. for
C.sub.22H.sub.16N.sub.2SO.sub.2FCl- : C, 61.90, H, 3.78, N, 6.56,
S, 7.51. Found: C, 61.92, H, 3.74, N. 6.43, S, 7.62.
EXAMPLE 8
[0862] 29
4-(4-Bromophenyl)-2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imida-
zole
[0863] To a mixture of
4-chloro-N-[4-(methylsulfonyl)phenyl]benzenecarboxi- midamide
(Example 1, Step 1) (400 mg, 1.29 mmol) and sodium bicarbonate (216
mg, 2.59 mmol) in isopropanol (30 mL), 2,4'-dibromoacetophenone
(720 mg, 2.58 mmol) was added. After heating the reaction mixture
at 80-85.degree. C. for 18 hours, the solvent was removed. The
residue was redissolved in methylene chloride and washed with
aqueous sodium bicarbonate and water. The organic fractions were
combined, dried over sodium sulfate, filtered and concentrated in
vacuo. The crude product (810 mg) was purified by chromatography
(silica gel, hexane/ethyl acetate, 6/4) to give
4-(4-bromophenyl)-2-(4-chlorophenyl)-1-[4-(methylsu-
lfonyl)phenyl]-1H-imidazole (400 mg, 64%) as a pale yellow solid:
mp 145-48.degree. C. Anal. Calc'd. for
C.sub.22H.sub.16N.sub.2SO.sub.2BrCl: C, 54.17, H, 3.31, N, 5.74, S,
6.57. Found: C, 54.41, H, 3.33, N, 5.50, S, 6.52.
EXAMPLE 9
[0864] 30
2-(4-Chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-(2-naphthyl)-1H-imidazol-
e
[0865] To a mixture of
4-chloro-N-[4-(methylsulfonyl)phenyl]benzenecarboxi- midamide
(Example 1, Step 1) (400 mg, 1.29 mmol) and sodium bicarbonate (216
mg, 2.59 mmol) in isopropanol (30 mL), 2-bromo-2'-acetonaphthone
(970 mg, 3.89 mmol) was added. After heating the reaction mixture
at 80-85.degree. C. for 20 hours, the solvent was removed. The
residue was redissolved in methylene chloride and washed with
aqueous sodium bicarbonate and water. The organic fractions were
combined, dried over sodium sulfate, filtered and concentrated in
vacuo. The crude product (1.2 g) was purified by chromatography
(silica gel, hexane/ethyl acetate, 6/4) to give
2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-(2-naphthy-
l)-1H-imidazole (318 mg, 54%) as a pale yellow solid: mp
204-206.degree. C. Anal Calc'd. for
C.sub.26H.sub.19N.sub.2SO.sub.2Cl: C, 68.04, H, 4.17, N, 6.10, S,
6.99. Found: C, 67.65, H, 4.19, N, 5.96, S, 7.10.
EXAMPLE 10
[0866] 31
2-(4-Chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-[4-(trifluoromethoxy)phe-
nyl]-1H-imidazole
[0867] To a mixture of
4-chloro-N-[4-(methylsulfonyl)phenyl]benzenecarboxi- midamide
(Example 1, Step 1) (700 mg, 2.24 mmol) and sodium bicarbonate (376
mg, 4.48 mmol) in isopropanol (25 mL), 4-(trifluoromethoxy)phenyl
bromide (950 mg, 3.36 mmol) was added. After heating the reaction
mixture at 80-85.degree. C. for 22 hours, the solvent was removed.
The residue was redissolved in methylene chloride and washed with
aqueous sodium bicarbonate and water. The organic fractions were
combined, dried over sodium sulfate, filtered and concentrated in
vacuo. The crude product was purified by chromatography (silica
gel, hexane/ethyl acetate, 6/4) to give
2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-[4-(trifluorometho-
xy)phenyl]-1H-imidazole (467 mg, 42%) as a pale yellow solid: mp
95-97.degree. C. Anal. Calc'd. for
C.sub.23H.sub.16N.sub.2SO.sub.3F.sub.3- Cl: C, 56.05, H, 3.27, N,
5.68, S, 6.51. Found: C, 55.90, H, 3.04, N, 5.62, S, 6.74.
EXAMPLE 11
[0868] 32
2,4-Bis(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole
[0869] To a mixture of
4-chloro-N-[4-(methylsulfonyl)phenyl]benzenecarboxi- midamide
(Example 1, Step 1) (700 mg, 2.24 mmol) and sodium bicarbonate (376
mg, 4.48 mmol) in isopropanol (30 mL), 4-chlorophenacyl bromide
(1.05 g, 4.48 mmol) was added. After heating the reaction mixture
at 80-85.degree. C. for 18 hours, the solvent was removed. The
residue was redissolved in methylene chloride and washed with
aqueous sodium bicarbonate and water. The organic fractions were
combined, dried over sodium sulfate, filtered and concentrated in
vacuo. The crude product was purified by chromatography (silica
gel, hexane/ethyl acetate, 6/4) to give
2,4-bis-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole
(545 mg, 55%) as a pale yellow solid: mp 169-171.degree. C. Anal.
Calc'd. for C.sub.22H.sub.16N.sub.2SO.sub.2Cl.sub.2: C, 59.60, H,
3.64, N, 6.32, S, 7.23. Found: C, 59.86, H, 3.80, N, 6.10, S,
7.27.
EXAMPLE 12
[0870] 33
2-(4-Chlorophenyl)-4-(3-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imid-
azole
[0871] To a mixture of
4-chloro-N-[4-(methylsulfonyl)phenyl]benzenecarboxi- midamide
(Example 1, Step 1) (700 mg, 2.24 mmol) and sodium bicarbonate (376
mg, 4.48 mmol) in isopropanol (35 mL), 3-chlorophenacyl bromide
(1.05 g, 4.48 mmol) was added. After heating the reaction mixture
at 80-85.degree. C. for 18 hours, the solvent was removed. The
residue was redissolved in methylene chloride and washed with
aqueous sodium bicarbonate and water. The organic fractions were
combined, dried over sodium sulfate, filtered and concentrated in
vacuo. The crude product was purified by chromatography (silica
gel, hexane/ethyl acetate, 6/4) to give
2-(4-chlorophenyl)-4-(3-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1-
H-imidazole (525 mg, 53%) as a pale yellow solid: mp
156-159.degree. C. Anal Calc'd. for
C.sub.22H.sub.16N.sub.2SO.sub.2Cl.sub.2: C, 59.60, H, 3.69, N,
6.32, S, 7.23. Found: C, 59.43, H, 3.59, N, 6.15, S, 7.16.
EXAMPLE 13
[0872] 34
2-(4-Chlorophenyl)-4-(4-methoxyphenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imi-
dazole
[0873] To a mixture of
4-chloro-N-[4-(methylsulfonyl)phenyl]benzenecarboxi- midamide
(Example 1, Step 1) (700 mg, 2.24 mmol) and sodium bicarbonate (376
mg, 4.48 mmol) in isopropanol (50 mL), 4-methoxyphenacyl bromide
(1.03 g, 4.48 mmol) was added. After heating the reaction mixture
at 75-80.degree. C. for 20 hours, the solvent was removed. The
residue was redissolved in methylene chloride and washed with
aqueous sodium bicarbonate and water. The organic fractions were
combined, dried over sodium sulfate, filtered and concentrated in
vacuo. The crude product was purified by chromatography (silica
gel, hexane/ethyl acetate, 6/4) to give
2-(4-chlorophenyl)-4-(4-methoxyphenyl)-1-[4-(methylsulfonyl)phenyl]--
4-(4-methoxyphenyl)-1H-imidazole (695 mg, 71%) as a white solid: mp
110-113.degree. C. Anal Calc'd. for
C.sub.23H.sub.19N.sub.2SO.sub.3Cl: C, 62.94, H, 4.36, N, 6.38, S,
7.30. Found: C, 62.54, H, 4.43, N, 6.17, S, 7.15.
EXAMPLE 14
[0874] 35
2-(4-Chlorophenyl)-4-(3-fluorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imid-
azole
[0875] To a mixture of
4-chloro-N-[4-(methylsulfonyl)phenyl]benzenecarboxi- midamide
(Example 1, Step 1) (700 mg, 2.24 mmol) and sodium bicarbonate (376
mg, 4.48 mmol) in isopropanol (30 mL), 3-fluorophenacyl bromide
(0.97 g, 4.48 mmol) was added. After heating the reaction mixture
at 75-80.degree. C. for 18 hours, the solvent was removed. The
residue was redissolved in methylene chloride and washed with
aqueous sodium bicarbonate and water. The organic fractions were
combined, dried over sodium sulfate, filtered and concentrated in
vacuo. The crude product was purified by chromatography (silica
gel, hexane/ethyl acetate, 6/4) to give
2-(4-chlorophenyl)-4-(3-fluorophenyl)-1-[4-(methylsulfonyl)phenyl]-1-
H-imidazole (481 mg, 50%) as a white solid: mp 194-196.degree. C.
Anal. Calc'd. for C.sub.22H.sub.16N.sub.2SO.sub.2FCl C, 61.90, H,
3.78, N, 6.56, S, 7.51. Found: C, 61.71, H, 3.59, N, 6.42, S,
7.69.
EXAMPLE 15
[0876] 36
2-(4-Chlorophenyl)-4-[(4-chlorophenoxy)methyl]-1-[4-(methylsulfonyl)phenyl-
]-1H-imidazole
[0877] Step 1: Preparation of
1-(4-chlorophenoxy)-2-chloro-2-propene
[0878] To a mixture of 4-chlorophenol (6.1 g, 47.4 mmol) and
potassium carbonate (13.1 g, 94.7 mmol) in acetone (200 mL),
2,3-dichloropropene (6.6 mL, 71 mmol) was added. After heating to
reflux the reaction mixture for 48 hours, the reaction mixture was
cooled and filtered. The residue was washed with more acetone and
the combined filtrates were concentrated in vacuo. The crude pale
brown liquid (11.5 g) was purified by chromatography (silica gel,
hexane/ethyl acetate, 85/15) to give
1-(4-chlorophenoxy)-2-chloro-2-propene (8.9 g, 98%) as a white
liquid: Anal. Calc'd. for C.sub.9H.sub.8OCl.sub.2: C, 53.23, H,
3.97. Found: C, 53.09, H, 3.95.
[0879] Step 2: Preparation of
1-bromo-3-[(4-chlorophenoxy)phenyl]-2-propan- one
[0880] To a turbid solution of
1-(4-chlorophenoxy)-2-chloro-2-propene from Step 1 (3 g, 15.7 mmol)
in acetonitrile/water (4/1, 100 mL), N-bromosuccinimide (4.84 g,
31.4 mmol) was added in one lot. A catalytic amount of 48% HBr (40
.mu.l) was added to the reaction and the yellowish orange mixture
was stirred at room temperature. After 24 hours, the reaction
mixture was diluted with ether and washed with 5% w/v of sodium
thiosulfate. The organic layer was separated and washed with
saturated sodium bicarbonate and brine. After drying (MgSO.sub.4),
filtration and concentration in vacuo, the crude liquid (4.8 g) was
purified by chromatography (silica gel, hexane/ethyl acetate,
80/20) to give crude
1-bromo-3-[(4-chlorophenoxy)phenyl]-2-propanone (2.3 g, 54%) which
was used in the next step without further purification.
[0881] Step 3: Preparation of
2-(4-chlorophenyl)-4-hydroxy-1-[4-(methylsul-
fonyl)phenyl]-4-[(4-chlorophenoxy)methyl]-4.5-dihydro-1H-imidazole
[0882] To a mixture of
4-chloro-N-[4-(methylsulfonyl)phenyl]benzenecarboxi- midamide
(Example 1, Step 1) (1 g, 3.24 mmol) and sodium bicarbonate (550
mg, 6.5 mmol) in acetone (100 mL),
1-bromo-3-((4-chlorophenoxy)phenyl]-2-- propanone from Step 2 (1.5
g, 5.8 mmol) was added. After heating to reflux for 24 hours, the
reaction mixture was filtered, washed with acetone and concentrated
in vacuo. The crude mixture (2.5 g) was purified by chromatography
(silica gel, toluene/ethyl acetate, 1/1) to give
2-(4-chlorophenyl)-4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-[(4-chlorophe-
noxy)methyl]-4,5-dihydro-1H-imidazole (565 mg, 35%) as a white
solid.
[0883] Step 4: Preparation of
2-(4-chlorophenyl)-1-[4-(methylsulfonyl
phenyl]-4-[(4-chlorophenoxy)methyl]-1H-imidazole
[0884] A mixture of
2-(4-chlorophenyl)-4-hydroxy-1-[4-(methylsulfonyl)phen-
yl]-4-[(4-chlorophenoxy)methyl]-4,5-dihydro-1H-imidazole from Step
3 (750 mg, 1.5 mmol) and p-toluenesulfonic acid monohydrate (135
mg) in toluene (100 mL) was heated to reflux for 48 hours. The
reaction mixture was cooled and the solvent removed under reduced
pressure. The crude residue was redissolved in methylene chloride
and washed with water, aqueous sodium bicarbonate and brine. After
drying (Na.sub.2SO.sub.4), filtration and concentration in vacuo,
the crude mixture was purified by chromatography on silica gel
using hexane/ethyl acetate (1/1) to give
2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-[(4-chlorophenoxy)methy-
l]-1H-imidazole as a white solid: mp (DSC) 173.degree. C. Anal.
Calc'd for C.sub.23H.sub.18N.sub.2Cl.sub.2SO.sub.3.multidot.0.25
H.sub.2O: C, 57.81; H, 3.90; N, 5.86; Cl, 14.84. Found: C, 57.67;
H, 3.83; N, 5.52; Cl, 15.17.
EXAMPLE 16
[0885] 37
2-(3-Chloro-4-methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethy-
l)-1H-imidazole
[0886] Step 1: Preparation of
3-chloro-4-methyl-N-[4-(methylsulfonyl)pheny-
l]benzenecarboximidamide
[0887] To a suspension of 4-(methylsulfonyl)aniline (2.82 g, 16.5
mmol) in toluene (150 mL), trimethylaluminum (2M solution in
toluene, 12.5 mL, 24.7 mmol) was added over 15 minutes. The
reaction mixture was warmed to room temperature and stirred for 2.5
hours. A solution of 3-chloro-4-methylbenzonitrile (5 g, 33 mmol)
in toluene (100 mL) was added over 10 minutes and the reaction
mixture was heated to 90-95.degree. C. After 20 hours, the reaction
mixture was cooled to room temperature and poured over a slurry of
silica gel in chloroform. After filtration, the residue was washed
with a mixture of methylene chloride/methanol (2/1). The combined
filtrates were concentrated in vacuo and the resulting yellowish
solid was stirred with a mixture of hexane/ether (2/1, 700 mL). The
intermediate was filtered and washed with more of hexane/ether
(2/1). The pale yellow solid 3-chloro-4-methyl-N-[4--
(methylsulfonyl)phenyl]benzenecarboximidamide (4.7 g, 88%) was used
in the next reaction without further purification: mp (DSC)
179.degree. C. Anal. Calc'd. for C.sub.15H.sub.15N.sub.2SO.sub.2Cl:
C, 55.81, H, 4.68, N, 8.68. Found: C, 55.65, H. 4.63, N, 8.59.
[0888] Step 2: Preparation of
2-(3-chloro-4-methylpenyl)-4-hydroxy-1-[4-(m-
ethylsulfonyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazole
[0889] To a mixture of
3-chloro-4-methyl-N-[4-(methylsulfonyl)phenyl]benze-
necarboximidamide from step 1 (2.35 g, 7.3 mmol) and sodium
bicarbonate (1.23 g, 14.6 mmol) in isopropanol (100 mL),
3-bromo-1,1,1-trifluoroaceto- ne (5.4 mL, 52 mmol) was added. After
heating to reflux the reaction mixture for 24 hours, the solvent
was removed. The residue was redissolved in methylene chloride and
washed with water. The organic fractions were combined, dried over
sodium sulfate, filtered and concentrated in vacuo. The crude
mixture (7.3 g) was purified by chromatography (silica gel,
toluene/ethyl acetate, 1/1) to give
2-(3-chloro-4-methylphenyl)-4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-(tri-
fluoromethyl)-4,5-dihydro-1H-imidazole (0.79 g, 25%) as a white
solid: mp 201.degree. C. Anal. Calc'd. for
C.sub.18H.sub.16N.sub.2SO.sub.3F.sub.3Cl- .multidot.0.5 PhCH.sub.3:
C, 53.92, H, 4.21, N, 5.81. Found: C, 54.20, H, 4.19, N, 5.67.
[0890] Step 3: Preparation of
2-3(3-chloro-4-methylphenyl)-1-[4-methylsulf-
onyl)phenyl]-4-(trifluoromethyl)-1H-imidazole
[0891] A mixture of
2-(3-chloro-4-methylphenyl)-4-hydroxy-1-[4-(methylsulf-
onyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazole from Step
2 (725 mg, 1.7 mmol) and p-toluenesulfonic acid monohydrate (150
mg) in toluene (40 mL) was heated to reflux for 48 hours. The
reaction mixture was cooled and the solvent removed under reduced
pressure. The crude residue was redissolved in methylene chloride
and washed with water, aqueous sodium bicarbonate and brine. After
drying (Na.sub.2SO.sub.4), filtration and concentration in vacuo,
the crude mixture (860 mg) was purified by chromatography on silica
gel using toluene/ethyl acetate 1/1 to give pure
2-(3-chloro-4-methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-(trifluorometh-
yl)-1H-imidazole (660 mg, 95%) as a white solid: mp(DSC)
206.degree. C. Anal. Calc'd. for
C.sub.18H.sub.14N.sub.2SO.sub.2F.sub.3Cl: C, 52.12, H, 3.40, N,
6.75, S, 7.73. Found: C, 52.24, H, 3.45, N, 6.64, S, 7.83.
EXAMPLE 17
[0892] 38
5-[1-[4-(Methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]-1,3--
benzodioxole
[0893] Step 1: Preparation of
3,4-methylenedioxy-N-[4-(methylsulfonyl)phen-
yl]benzenecarboximidamide
[0894] To a suspension of (4-methylsulfonyl)aniline (2.82 g, 16.5
mmol) in toluene (150 mL), trimethylaluminum (2M solution in
toluene, 12.5 mL, 24.7 mmol) was added over 15 minutes. The
reaction mixture was warmed to room temperature and stirred for 2.5
hours. A solution of piperonylonitrile (4.85 g, 33 mmol) in toluene
(100 mL) was added over 10 minutes and the reaction mixture was
heated to 90-95.degree. C. After 20 hours, the reaction mixture was
cooled to room temperature and poured over a slurry of silica gel
in chloroform. After filtration, the residue was washed with a
mixture of methylene chloride/methanol (2/1). The combined
filtrates were concentrated in vacuo and the resulting yellowish
solid was stirred with a mixture of hexane/ether (2/1, 1000 mL).
The product was filtered and washed with more of hexane/ether
(2/1). The pale yellow solid
3,4-methylenedioxy-N-[4-(methylsulfonyl)phenyl]
benzenecarboximidamide (4.8 g, 91%) was used in the next reaction
without further purification: mp (DSC) 214.degree. C. Anal. Calc'd.
for C.sub.15H.sub.14N.sub.2SO.sub.4: C, 56.59, H, 4.43, N, 8.80.
Found: C, 56.33, H, 4.28, N, 8.66.
[0895] Step 2: Preparation of
5-[1-[4-(methylsulfonyl)phenyl]-4-hydroxy-4--
(trifluoromethyl)-4,5-dihydro-1H-imidazol-2-yl]-1,3-benzodioxole
[0896] To a mixture of
3,4-methylenedioxy-N-[4-(methylsulfonyl)phenyl]benz-
enecarboximidamide from Step 1 (2.32 g, 7.3 mmol) and sodium
bicarbonate (1.23 g, 14.6 mmol) in isopropanol (100 mL),
3-bromo-1,1,1-trifluoroaceto- ne (5.4 mL, 52 mmol) was added. After
heating the reaction mixture to reflux for 24 hours, the solvent
was removed. The residue was redissolved in methylene chloride and
washed with water. The organic fractions were combined, dried over
sodium sulfate, filtered and concentrated in vacuo. The crude
mixture (7.1 g) was purified by chromatography (silica gel,
toluene/ethyl acetate, 1/1) to give
5-[1-[4-(methylsulfonyl)phenyl]-4-hyd-
roxy-4-(trifluoromethyl)-4,5-dihydro-1H-imidazol-2-yl]-1,3-benzodioxole
(1.46 g, 47%) as a white solid: mp 200-202.degree. C. Anal. Calc'd.
for C.sub.18H.sub.15N.sub.2SO.sub.5F.sub.3.multidot.0.25
PhCH.sub.3: C, 52.55, H, 3.80, N, 6.21. Found: C, 52.73, H, 3.78,
N, 6.01.
[0897] Step 3: Preparation of
5-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoro-
methyl)-1H-imidazol-2-yl]-1,3-benzodioxole
[0898] A mixture of
5-[1-[4-(methylsulfonyl)phenyl]-4-hydroxy-4-(trifluoro-
methyl)-4,5-dihydro-1H-imidazol-2-yl]-1,3-benzodioxole from Step 2
(1.26 g, 2.9 mmol) and p-toluenesulfonic acid monohydrate (200 mg)
in toluene (50 mL) was heated to reflux for 72 hours. The reaction
mixture was cooled and the solvent removed under reduced pressure.
The crude residue was redissolved in methylene chloride and washed
with water, aqueous sodium bicarbonate and brine. After drying
(Na.sub.2SO.sub.4), filtration and concentration in vacuo, the
crude mixture (1.34 g) was purified by chromatography on silica gel
using toluene/ethyl acetate 1/1 to give pure
5-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]-1,3-
-benzodioxole (940 mg, 80%) as a white solid: mp (DSC) 165.degree.
C. Anal Calc'd. for C.sub.18H.sub.13N.sub.2SO.sub.4F.sub.3: C,
52.68, H, 3.19, N, 6.83. Found: C, 53.05, H, 3.19, N, 6.65.
EXAMPLE 18
[0899] 39
2-(3-Fluoro-4-methoxyphenyl)-1-[4-(methylsulfonyl)phenyl]-4-(trifluorometh-
yl)-1H-imidazole
[0900] Step 1: Preparation of
3-fluoro-4-methoxy-N-[4-(methylsulfonyl)phen-
yl]benzenecarboximidamide
[0901] To a suspension of 4-(methylsulfonyl)aniline (2.82 g, 16.5
mmol) in toluene (150 mL), trimethylaluminum (2M solution in
toluene, 12.5 mL, 24.7 mmol) was added over 15 minutes. The
reaction mixture was warmed to room temperature and stirred for 2.5
hours. A solution of 3-fluoro-4-methoxybenzonitrile (5 g, 33 mmol)
in toluene (100 mL) was added over 10 minutes and the reaction
mixture was heated to 80-85.degree. C. After 20 hours, the reaction
mixture was cooled to room temperature and poured over a slurry of
silica gel in chloroform. After filtration, the residue was washed
with a mixture of methylene chloride/methanol (2/1). The combined
filtrates were concentrated in vacuo and the resulting yellowish
solid was stirred with a mixture of hexane/ether (2/1, 1000 mL).
The intermediate was filtered and washed with more hexane/ether
(2/1). The pale yellow solid
3-fluoro-4-methoxy-N-[4-(methylsulfonyl)phenyl]
benzenecarboximidamide (3.95 g, 74%) was used in the next reaction
without further purification: mp (DSC) 195.degree. C. Anal. Calc'd.
for C.sub.15H.sub.15N.sub.2SO.sub.3- F: C, 55.89, H, 4.69, N, 8.69.
Found: C, 55.92, H, 4.74, N, 8.53.
[0902] Step 2: Preparation of
2-(3-fluoro-4-methoxyphenyl)-4-hydroxy-1-[4--
(methylsulfonyl)phenyl]-4-(trifluoromethyl)-4.5-dihydro-1H-imidazole
[0903] To a mixture of
3-fluoro-4-methoxy-N-[4-(methylsulfonyl)phenyl]benz-
enecarboximidamide from Step 1 (4.15 g, 12.9 mmol) and sodium
bicarbonate (2.16 g, 25.8 mmol) in isopropanol (150 mL),
3-bromo-1,1,1-trifluoroaceto- ne (4.8 mL, 45 mmol) was added. After
heating the reaction mixture at 70-75.degree. C. for 20 hours, the
solvent was removed. The residue was redissolved in methylene
chloride and washed with water. The organic fractions were
combined, dried over sodium sulfate, filtered and concentrated in
vacuo. The crude mixture (7.8 g) was purified by chromatography
(silica gel, toluene/ethyl acetate, 7/3) to give
2-(3-fluoro-4-methoxyphenyl)-4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-(tr-
ifluoromethyl)-4,5-dihydro-1H-imidazole (3.54 g, 64%) as a white
solid: mp (DSC) 210.degree. C. Anal. Calc'd. for
C.sub.18H.sub.16N.sub.2SO.sub.4F.s- ub.4.multidot.0.1PhCH.sub.3: C,
50.86, H, 3.83, N, 6.34. Found: C, 50.61, H. 3.64, N, 6.16.
[0904] Step 3: Preparation of
2-(3-fluoro-4-methoxyphenyl)-1-[4-(methylsul-
fonyl)phenyl]-4-(trifluoromethyl)-1H-imidazole
[0905] A mixture of
2-(3-fluoro-4-methoxyphenyl)-4-hydroxy-1-[4-(methylsul-
fonyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazole from
Step 2 (3.4 g, 7.9 mmol) and p-toluenesulfonic acid monohydrate
(700 mg) in toluene (200 mL) was heated to reflux for 72 hours. The
reaction mixture was cooled and the solvent removed under reduced
pressure. The crude residue was redissolved in methylene chloride
and washed with water, aqueous sodium bicarbonate and brine. After
drying (Na.sub.2SO.sub.4), filtration and concentration in vacuo,
the crude mixture (3.6 g) was purified by chromatography on silica
gel using toluene/ethyl acetate (8/2) to give pure
2-(3-fluoro-4-methoxyphenyl)-1[-4-(methylsulfonyl)phen-
yl]-4-(trifluoromethyl)-1H-imidazole (2.12 g, 65%) as a white
solid: mp (DSC) 182.degree. C. Anal. Calc'd. for
C.sub.18H.sub.14N.sub.2SO.sub.3F.s- ub.4: C, 52.17, H, 3.41, N,
6.76, S, 7.74. Found: C, 52.56, H, 3.65, N, 6.53, S, 8.01.
EXAMPLE 19
[0906] 40
2-(4-Chlorophenyl)-4-[(phenylthio)methyl]-1-[4-(methylsulfonyl)phenyl]-1H--
imidazole
[0907] Step 1: Preparation of 1-bromo-3-phenylthio-2-propanone
[0908] 1-Bromo-3-phenylthio-2-propanone is synthesized by reaction
of thiophenol with 2,3-dichloropropene followed by treatment of the
resulting product with aqueous NBS as described for Example 15.
[0909] Step 2: Preparation of
2-(4-chlorophenyl)-4-hydroxy-1-[4-(methylsul-
fonyl)phenyl]-4-[(phenylthio)methyl]-4,5-dihydro-1H-imidazole
[0910] To a mixture of
4-chloro-N-[4-(methylsulfonyl)phenyl]benzenecarboxi- midamide
(Example 1, Step 1) (1 mmol) and sodium bicarbonate (2 mmol) in
acetone (20 mL), 1-bromo-3-phenylthio-2-propanone (1.5 mmol) is
added. After heating to reflux for 24 hours, the reaction mixture
is filtered, washed with acetone and concentrated in vacuo. The
crude product is purified by chromatography (silica gel,
toluene/ethyl acetate) to give
2-(4-chlorophenyl)-4-hydroxy-1-[4-(methylsulfonyl)
phenyl]-4-[(phenylthio)methyl]-4,5-dihydro-1H-imidazole.
[0911] Step 3: Preparation of
2-(4-chlorophenyl)-4-[phenylthio)methyl]-1-[-
4-(methylsulfonyl)phenyl]-1H-imidazole
[0912] A mixture of
2-(4-chlorophenyl)-4-hydroxy-1-[4-(methylsulfonyl)phen-
yl]-4-[(phenylthio)methyl]-4,5-dihydro-1H-imidazole (1 mmol) and
p-toluenesulfonic acid monohydrate (100 mg) in toluene (70 mL) is
heated to reflux for 48 hours. The reaction mixture is cooled and
the solvent removed under reduced pressure. The crude residue is
redissolved in methylene chloride and washed with water, aqueous
sodium bicarbonate and brine. After drying (Na.sub.2SO.sub.4),
filtration and concentration in vacuo, the crude mixture is
purified by chromatography on silica gel using hexane/ethyl acetate
to give 2-(4-chlorophenyl)-4-[(phenylthio)
methyl]-1-[4-(methylsulfonyl)phenyl]-1H-imidazole.
EXAMPLE 20
[0913] 41
2-(4-Chlorophenyl)-4-[(N-methyl-N-phenylamino)methyl]-1-[4-(methylsulfonyl-
)phenyl]-1H-imidazole
[0914] Step 1: Preparation of
1-bromo-3-(N-methyl-N-phenylamine)-2-propano- ne
[0915] 1-Bromo-3-(N-methyl-N-phenylamine)-2-propanone is
synthesized by reaction of N-methylaniline with 2,3-dichloropropene
followed by treatment of the resulting product with aqueous NBS as
described for Example 15.
[0916] Step 2: Preparation of
2-(4-chlorophenyl)-4-hydroxy-4-[(N-methyl-N--
phenylamino)methyl]-1-[4-(methylsulfonyl)phenyl]-4,5-dihydro-1H-imidazole
[0917] To a mixture of
4-chloro-N-[4-(methylsulfonyl)phenyl]benzenecarboxi- midamide
(Example 1, Step 1) (1 mmol) and sodium bicarbonate (2 mmol) in
acetone (20 mL), 1-bromo-3-(N-methyl-N-phenylamine)-2-propanone
from Step 1 (1.5 mmol) is added. After heating to reflux for 24
hours, the reaction mixture is filtered, washed with acetone and
concentrated in vacuo. The crude product is purified by
chromatography (silica gel, toluene/ethyl acetate) to give
2-(4-chlorophenyl)-4-hydroxy-4-[(N-methyl-N-phenylamine)-
methyl]-1-[4-(methylsulfonyl)phenyl]-4,5-dihydro-1H-imidazole.
[0918] Step 3: Preparation of
2-(4-chlorophenyl)-4-[(N-methyl-N-phenylamin-
o)methyl]-1-[4-(methylsulfonyl)phenyl]-1H-imidazole
[0919] A mixture of
2-(4-chlorophenyl)-4-hydroxy-4-[(N-methyl-N-phenylamin-
e)methyl]-1-[4-(methylsulfonyl)phenyl]-4,5-dihydro-1H-imidazole (1
mmol) and p-toluenesulfonic acid monohydrate (100 mg) in toluene
(70 mL) is heated to reflux for 48 hours. The reaction mixture is
cooled and the solvent removed under reduced pressure. The crude
residue is redissolved in methylene chloride and washed with water,
aqueous sodium bicarbonate and brine. After drying
(Na.sub.2SO.sub.4), filtration and concentration in vacuo, the
crude mixture is purified by chromatography on silica gel using
hexane/ethyl acetate to give
2-(4-chlorophenyl)-4-[(N-methyl-N-phen-
ylamine)methyl]-1-[4-(methylsulfonyl)phenyl]-1H-imidazole.
EXAMPLE 21
[0920] 42
2-(4-Chlorophenyl)-4-[2-quinolyl)methoxymethyl]-1-[4-(methylsulfonyl)pheny-
l]-1H-imidazole
[0921] Step 1: Preparation of
1-bromo-3-(2-quinolylmethoxy)-2-propanone
[0922] The compound 1-bromo-3-(2-quinolylmethoxy)-2-propanone is
synthesized by reaction of 2-chloromethylquinoline with
2-chloro-2-propen-1-ol followed by treatment of the resulting
quinolylether with aqueous NBS.
[0923] Step 2: Preparation of
2-(4-chlorophenyl)-4-hydroxy-1-[4-(methylsul-
fonyl)phenyl]-4-[(2-quinolylmethoxy)methyl]-4,5-dihydro-1H-imidazole
[0924] To a mixture of
4-chloro-N-[4-(methylsulfonyl)phenyl]benzenecarboxi- midamide
(Example 1, Step 1) (1 mmol) and sodium bicarbonate (2 mmol) in
acetone (20 mL), 1-bromo-3-(2-quinolylmethoxy)-2-propanone from
Step 1 (1.5 mmol) is added. After heating to reflux for 24 hours,
the reaction mixture is filtered, washed with acetone and
concentrated in vacuo. The crude product is purified by
chromatography (silica gel, toluene/ethyl acetate) to give
2-(4-chlorophenyl)-4-hydroxy-1-[4-(methylsulfonyl)phenyl-
]-4-[(2-quinolylmethoxy)methyl]-4,5-dihydro-1H-imidazole.
[0925] Step 3: Preparation of
2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phen-
yl]-4-[(2-quinolylmethoxy)methyl]-1H-imidazole
[0926] A mixture of
2-(4-chlorophenyl)-4-hydroxy-1-[4-(methylsulfonyl)phen-
yl]-4-[(2-quinolylmethoxy)methyl]-4,5-dihydro-1H-imidazole (1 mmol)
and p-toluenesulfonic acid monohydrate (100 mg) in toluene (70 mL)
is heated to reflux for 48 hours. The reaction mixture is cooled
and the solvent removed under reduced pressure. The crude residue
is redissolved in methylene chloride and washed with water, aqueous
sodium bicarbonate and brine. After drying (Na.sub.2SO.sub.4),
filtration and concentration in vacuo, the crude mixture is
purified by chromatography on silica gel using hexane/ethyl acetate
to give 2-(4-chlorophenyl)-1-(4-(methylsulfony-
l)phenyl]-4-[(2-quinolylmethoxy)methyl]-1H-imidazole.
EXAMPLE 22
[0927] 43
2-(4-Fluorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imida-
zole
[0928] Step 1: Preparation of
4-fluoro-N-[4-(methylsulfonyl)phenyl]benzene- carboximidamide
[0929] To a suspension of 4-(methylsulfonyl)aniline (3.53 g, 20.2
mmol) in toluene (100 mL), trimethylaluminum (15.2 ml, 2M solution
in toluene, 30.2 mmol) was added over 15 minutes. The reaction
mixture was warmed to room temperature and stirred for 2.5 hours. A
solution of 4-fluorobenzonitrile (5 g, 40.3 mmol) in toluene (100
mL) was added over 10 minutes and the reaction mixture heated to
80-85.degree. C. After 20 hours, the reaction mixture was cooled to
room temperature and poured over a slurry of silica gel in
chloroform. After filtration, the residue was washed with a mixture
of methylene chloride/methanol (2/1). The combined filtrates were
concentrated in vacuo and the resulting yellowish solid stirred
with a mixture of hexane/ether (2/1, 1000 mL). The intermediate was
filtered and concentrated. The pale yellow solid
4-fluoro-N-[4-(methylsulfonyl)phenyl] benzenecarboximidamide (5.25
g, 87%) was used in the next reaction without further purification:
mp (DSC) 206.2.degree. C. Anal. Calc'd for
C.sub.14H.sub.13N.sub.2FSO.sub.3.multid- ot.1.25 H.sub.2O: C,
53,41; H, 4.91; N, 8.90. Found: C, 53.08; H, 4,50; N, 8.61.
[0930] Step 2: Preparation of
2-(4-fluorophenyl)-4-hydroxy-1-[4-(methylsul-
fonyl)phenyl]-4-trifluoromethyl-4,5-dihydro-1H-imidazole
[0931] To a mixture of
4-fluoro-N-[4-(methylsulfonyl)phenyl]benzenecarboxi- midamide (Step
1) (4.5 g. 15.4 mmol) and sodium bicarbonate (2.59 g, 30.8 mmol) in
isopropanol (200 mL), 3-bromo-1,1,1-trifluoroacetone (3.2 mL) was
added. After heating the reaction mixture at 75-80.degree. C. for
22 hours, the solvent was removed. The residue was redissolved in
methylene chloride and washed with water. The organic fractions
were combined, dried over sodium sulfate, filtered and concentrated
in vacuo. The crude mixture (7.2 g) was purified by chromatography
(silica gel, toluene/ethyl acetate, 1/1) to give
2-(4-fluorophenyl)-4-hydroxy-1-[4-(methylsulfonyl)p-
henyl]-4-trifluoromethyl-4,5-dihydro-1H-imidazole (3.28 g, 53%) as
a white solid: mp (DSC) 203.degree. C. Anal. Calc'd for
C.sub.17H.sub.14N.sub.2F.- sub.4SO.sub.3: C, 50.75; H, 3.51; N,
6.96. Found: C, 51.16; H, 3.69; N, 6.54.
[0932] Step 3: Preparation of
2-(4-fluorophenyl)-1-[4-(methylsulfonyl)phen-
yl]-4-trifluoromethyl-1H-imidazole
[0933] A mixture of
2-(4-fluorophenyl)-4-hydroxy-1-[4-(methylsulfonyl)phen-
yl]-4-trifluoromethyl-4,5-dihydro-1H-imidazole (Step 2) (2.8 g, 7
mmol) and p-toluenesulfonic acid monohydrate (300 mg) in toluene
(200 mL) was heated to reflux for 72 hours. The reaction mixture
was cooled and the solvent removed under reduced pressure. The
crude residue was redissolved in methylene chloride and washed with
water, aqueous sodium bicarbonate and brine. After drying
(Na.sub.2SO.sub.4), filtration and concentration in vacuo, the
crude mixture (3.2 g) was purified by chromatography on silica gel
using toluene/ethyl acetate (1/1) to give pure
2-(4-fluorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imid-
azole (1.38 g, 52%) as a white solid: mp (DSC) 205.5.degree. C.
Anal. Calc'd for C.sub.17H.sub.12N.sub.2F.sub.4SO.sub.2: C, 53.13;
H, 3.15; N, 7.29; S, 8.34. Found: C, 53.18; H, 3.17; N, 7.26; S,
8.57.
EXAMPLE 23
[0934] 44
1-[4-(Methylsulfonyl)phenyl]-2-phenyl-4-trifluoromethyl-1H-imidazole
[0935] Step 1: Preparation of
N-[4-(methylsulfonyl)phenyl]benzenecarboximi- damide
[0936] To a suspension of 4-(methylsulfonyl)aniline (12 g, 70 mmol)
in toluene (400 mL) , trimethylaluminum (52.5 ml, 2M solution in
toluene, 0.1 mol) was added over 15 minutes. The reaction mixture
was warmed to room temperature and stirred for 3.5 hours. A
solution of benzonitrile (14.5 g, 0.14 mol) in toluene (300 mL) was
added over 10 minutes and the reaction mixture heated to
70-75.degree. C. After 17 hours, the reaction mixture was cooled to
room temperature and poured over a slurry of silica gel in
chloroform. After filtration, the residue is washed with a mixture
of methylene chloride/methanol (2/1). The combined filtrates are
concentrated in vacuo and the resulting yellowish solid is stirred
with a mixture of hexane/ether (2/1, 1000 mL). The intermediate is
filtered and washed with more of hexane/ether (2/1). The yellowish
solid N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide (16.7 g,
87%) was used in the next reaction without further
purification.
[0937] Step 2: Preparation of
4-hydroxy-1-[4-(methylsulfonyl)-phenyl]-2-ph-
enyl-4-trifluoromethyl-4,5-dihydro-1H-imidazole
[0938] To a mixture of N-[4-(methylsulfonyl)phenyl]
benzenecarboximidamide (Step 1) (16.5 g, 60.1 mmol) and sodium
bicarbonate (10.1 g, 0.12 mol) in isopropanol (900 mL),
3-bromo-1,1,1-trifluoroacetone (8.7 ml, 84 mmol) was added. After
heating the reaction mixture at 75 -80.degree. C. for 20 hours, the
solvent was removed. The residue was redissolved in methylene
chloride and washed with water. The organic fractions were
combined, dried over sodium sulfate, filtered and concentrated in
vacuo. The crude mixture was purified by chromatography (silica
gel, hexane/ethyl acetate, 45/55) to give
4-hydroxy-1-[4-(methylsulfonyl)phenyl]-2-phenyl-4-trifluor-
omethyl-4,5-dihydro-1H-imidazole (13.6 g, 59%) as a white solid: mp
189-190.degree. C. Anal. Calc'd for
C.sub.17H.sub.15N.sub.2F.sub.3SO.sub.- 3: C, 53.12; H, 3.93; N,
7.29; S, 8.34. Found: C, 53.05; H, 3.90; N, 7.14; S, 8.38.
[0939] Step 3: Preparation of
1-[4-(methylsulfonyl)phenyl]-2-phenyl-4-trif-
luoromethyl-1H-imidazole
[0940] A mixture of
4-hydroxy-1-[4-(methylsulfonyl)phenyl]-2-phenyl-4-trif-
luoromethyl-4,5-dihydro-1H-imidazole (Step 2) (5.43 g, 14.1 mmol)
and p-toluenesulfonic acid monohydrate (1.63 g) in toluene (500 mL)
was heated to reflux for 96 hours. The reaction mixture was cooled
and the solvent removed under reduced pressure. The crude residue
was redissolved in methylene chloride and washed with water,
aqueous sodium bicarbonate and brine. After drying
(Na.sub.2SO.sub.4), filtration and concentration in vacuo, the
crude mixture was purified by chromatography on silica gel using
hexane/ethyl acetate (65/35) to give pure
1-[4-(methylsulfonyl)phen-
yl]-2-phenyl-4-trifluoromethyl-1H-imidazole (3.12 g, 60%) as a
white solid: mp (DSC) 233.degree. C. Anal. Calc'd for
C.sub.17H.sub.13N.sub.2F.- sub.3SO.sub.2: C, 55.73; H, 3.58; N,
7.65; S, 8.75. Found: C, 55.49; H, 3.47; N,7.46; S,8.95.
EXAMPLE 24
[0941] 45
2-(4-Methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imida-
zole
[0942] Step 1: Preparation of
4-methyl-N-[4-(methylsulfonyl)phenyl]benzene- carboximidamide
[0943] To a suspension of 4-(methylsulfonyl)aniline (3.57 g, 20.9
mmol) in toluene (150 mL), trimethylaluminum (15.6 ml, 2M solution
in toluene, 31.4 mmol) was added over 15 minutes. The reaction
mixture was warmed to room temperature and stirred for 2.5 hours. A
solution of 4-methylbenzonitrile (5 ml, 41.8 mmol) in toluene (100
mL) was added over 10 minutes and the reaction mixture heated to
80-85.degree. C. After 20 hours, the reaction mixture was cooled to
room temperature and poured over a slurry of silica gel in
chloroform. After filtration, the residue was washed with a mixture
of methylene chloride/methanol (2/1). The combined filtrates are
concentrated in vacuo and the resulting yellowish solid was stirred
with a mixture of hexane/ether (2/1, 600 mL). The intermediate was
filtered and washed with more of hexane/ether (2/1). The pale
yellow solid
4-methyl-N-[4-(methylsulfonyl)phenyl]benzenecarboximida- mide (5.3
g, 88%) was used in the next reaction without further purification:
mp (DSC) 213.degree. C. Anal. Calc'd for
C.sub.15H.sub.16N.sub.2SO.sub.2: C, 62.48; H, 5.59; N, 9.71. Found:
C, 62.00, H, 5.52; N,9.60.
[0944] Step 2: Preparation of
2-(4-methylphenyl)-4-hydroxy-1-[4-(methylsul-
fonyl)phenyl]-4-trifluoromethyl-4,5-dihydro-1H-imidazole
[0945] To a mixture of
4-methyl-N-[4-(methylsulfonyl)phenyl]benzenecarboxi- midamide (Step
1) (5 g, 17.4 mmol) and sodium bicarbonate (2.9 g, 34.7 mmol) in
isopropanol (200 mL), 3-bromo-1,1,1-trifluoroacetone (3.6 ml, 34.7
mmol) was added. After heating the reaction mixture at
75-80.degree. C. for 20 hours, the solvent was removed. The residue
was redissolved in methylene chloride and washed with water. The
organic fractions were combined, dried over sodium sulfate,
filtered and concentrated in vacuo. The crude mixture (8.9 g) was
purified by chromatography (silica gel, toluene/ethyl acetate 6/4)
to give 2-(4-methylphenyl)-4-hydroxy-1-[4-(met-
hylsulfonyl)phenyl]-4-trifluoromethyl-4,5-dihydro-1H-imidazole
(3.28 g, 47%) as a white solid: mp 198-199.degree. C. Anal. Calc'd
for C.sub.18H.sub.17N.sub.2F.sub.3SO.sub.3.multidot.0.3 PhMe C,
56.67; H, 4.59; N. 6.58. Found: C, 56.95; H, 4.68; N, 6.13.
[0946] Step 3: Preparation of
2-(4-methylphenyl)-1-[4-(methylsulfonyl)phen-
yl]-4-trifluoromethyl-1H-imidazole
[0947] A mixture of
2-(4-methylphenyl)-4-hydroxy-1-[4-(methylsulfonyl)phen-
yl]-4-trifluoromethyl-4,5-dihydro-1H-imidazole (Step 2) (0.9 g, 2.3
mmol) and p-toluenesulfonic acid monohydrate (150 mg) in toluene
(100 mL) was heated to reflux for 72 hours. The reaction mixture
was cooled and the solvent removed under reduced pressure. The
crude residue was redissolved in methylene chloride and washed with
water, aqueous sodium bicarbonate and brine. After drying
(Na.sub.2SO.sub.4), filtration and concentration in vacuo, the
crude mixture was purified by chromatography on silica gel using
toluene/ethyl acetate (1/1) to give pure
2-(4-methylphenyl)-1-[4-(m-
ethylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazole (462 mg, 54%)
as a white solid: mp (DSC) 190.degree. C. Anal. Calc'd for
C.sub.18H.sub.15N.sub.2F.sub.3SO.sub.2: C, 56.84; H, 3.97; N, 7.36;
S, 8.43. Found: C, 56.66; H, 3.82; N, 7.23; S, 8.45.
EXAMPLE 25
[0948] 46
1-[4-(Methylsulfonyl)phenyl]-2-(4-trifluoromethylphenyl)-4-trifluoromethyl-
-1H-imidazole
[0949] Step 1: Preparation of
4-(trifluoromethyl)-N-[4-(methylsulfonyl)phe-
nyl]benzenecarboximidamide
[0950] To a suspension of 4-(methylsulfonyl)aniline (10 mmol) in
toluene (100 mL), trimethylaluminum (2M solution in toluene, 15
mmol) is added over 15 minutes. The reaction mixture is warmed to
room temperature and stirred for 2.5 hours. A solution of
4-trifluoromethylbenzonitrile (20 mmol) in toluene (50 mL) is added
over 10 minutes and the reaction mixture is heated to 80-85.degree.
C. After 20 hours, the reaction mixture is cooled to room
temperature and poured over a slurry of silica gel in chloroform.
After filtration, the residue is washed with a mixture of methylene
chloride/methanol (2/1). The combined filtrates are concentrated in
vacuo and the resulting yellowish solid is stirred with a mixture
of hexane/ether (2/1, 1000 mL). The intermediate is filtered and
washed with more of hexane/ether (2/1). The pale yellow solid
4-(trifluoromethyl)-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide
is used in the next reaction without further purification. Step 2:
Preparation of
4-hydroxy-1-[4-(methylsulfonyl)phenyl]-2-(4-trifluoromethy-
lphenyl)-4-trifluoromethyl-4,5-dihydro-1H-imidazole
[0951] To a mixture of
4-(trifluoromethyl)-N-[4-(methylsulfonyl)phenyl]ben-
zenecarboximidamide (10 mmol) and sodium bicarbonate (20 mmol) in
isopropanol (100 mL), 3-bromo-1,1,1-trifluoroacetone (20 mmol) is
added. After heating the reaction mixture at 70-75.degree. C. for
20 hours, the solvent is removed. The residue is redissolved in
methylene chloride and washed with water. The organic fractions are
combined, dried over sodium sulfate, filtered and concentrated in
vacuo. The crude product is purified by chromatography (silica gel,
toluene/ethyl acetate, 7/3) to give
4-hydroxy-1-[4-(methylsulfonyl)phenyl]-2-(4-trifluoromethylphenyl)-4-
-trifluoromethyl-4,5-dihydro-1H-imidazole.
[0952] Step 3: Preparation of
1-[4-(methylsulfonyl)phenyl]-2-(4-trifluorom-
ethyl-phenyl)-4-trifluoromethyl-1H-imidazole
[0953] A mixture of
4-hydroxy-1-[4-(methylsulfonyl)phenyl]-2-(4-trifluorom-
ethylphenyl)-4-trifluoromethyl-4,5-dihydro-1H-imidazole (10 mmol)
and p-toluenesulfonic acid monohydrate (1 mmol) in toluene (100 mL)
is heated to reflux for 72 hours. The reaction mixture is cooled
and the solvent removed under reduced pressure. The crude residue
is redissolved in methylene chloride and washed with water, aqueous
sodium bicarbonate and brine. After drying (Na.sub.2SO.sub.4),
filtration and concentration in vacuo, the crude mixture is
purified by chromatography on silica gel using toluene/ethyl
acetate to give pure 1-[4-(methylsulfonyl)phenyl]-2-(-
4-trifluoromethylphenyl)-4-trifluoromethyl-1H-imidazole.
EXAMPLE 26
[0954] 47
4-[2-(4-Chlorophenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonam-
ide
[0955] To a clear solution of
2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phen-
yl]-4-(trifluoromethyl)-1H-imidazole from Example 2 (400 mg, 1
mmol) in tetrahydrofuran (THF) (8 mL) at 0.degree. C., n-BuMgCl (2M
solution in THF, 2 mL, 4 mmol) was added over 10 minutes. After
stirring for additional 10 minutes, ice bath was removed and
solution stirred for 1 hour. The reaction mixture was re-cooled to
0.degree. C. and triethylborane (1M solution in THF, 5 mL, 5 mmol)
was added. After stirring for 2 hours, the reaction was heated to
reflux for 48 hours. The reaction mixture was cooled to room
temperature and treated with aqueous sodium acetate (1 g in 4 mL
water). After stirring for 5 minutes, solid
hydroxylamine-O-sulfonic acid (1 g) was added and the mixture
stirred for 20 hours. The reaction mixture was diluted with water
and extracted with ether (2.times.250).The ethereal layer was dried
over sodium sulfate, filtered and concentrated in vacuo. The crude
solid (568 mg) was purified by chromatography [silica gel, ethyl
acetate/toluene (3/7)] to give
4-[2-(4-chlorophenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfona-
mide (260 mg, 65%): mp (DSC) 225.degree. C. Anal. Calc'd. for
C.sub.16H.sub.11N.sub.3SO.sub.2F.sub.3Cl: C, 47.83, H, 2.76 N,
10.46, S, 7.98. Found: C, 48.00, H, 2.83, N, 10.14, S, 7.94.
EXAMPLE 27
[0956] 48
4-[2-(3-Chloro-4-methylphenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzen-
esulfonamide
[0957] To a clear solution of
2-(3-chloro-4-methylphenyl)-1-[4-(methylsulf-
onyl)phenyl]-4-(trifluoromethyl)-1H-imidazole (Example 16) (500 mg,
1.2 mmol) in tetrahydrofuran (10 mL) at 0.degree. C., n-BuMgCl (2M
solution in THF, 2.4 mL, 4.8 mmol) was added over 10 minutes. After
stirring for additional 10 minutes ice bath was removed and
solution stirred for 1 hour. The reaction mixture was re-cooled to
0.degree. C. and triethylborane (1M solution in THF, 6 mL, 6 mmol)
was added. After stirring for 2 hours, the reaction was heated to
reflux for 72 hours. The reaction mixture was cooled to room
temperature and treated with aqueous sodium acetate (1 g in 4 mL
water). After stirring for 5 minutes, solid
hydroxylamine-O-sulfonic acid (1 g) was added and the mixture
stirred for 20 hours. The reaction mixture was diluted with water
and extracted with ether (2.times.250).The ethereal layer was dried
over sodium sulfate, filtered and concentrated in vacuo. The crude
product (710 mg) was purified by chromatography (silica gel, ethyl
acetate/toluene 3/7) to give pure
4-[2-(3-chloro-4-methylphenyl)-4-(trifluoromethyl)-1H-imidazol--
1-yl]benzenesulfonamide (180 mg, 36%) as a white solid: mp (DSC)
222.degree. C. Anal. Calc'd. for
C.sub.17H.sub.13N.sub.3SO.sub.2F.sub.3Cl- : C, 49.10, H, 3.15, N,
10.11. Found: C, 49.42, H, 3.19, N, 9.75.
EXAMPLE 28
[0958] 49
3-[1-[4-(Methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridin-
e
[0959] Step 1: Preparation of
N-[4-(methylsulfonyl)phenyl]-3-pyridinecarbo- ximidamide
[0960] To a suspension of 4-(methylsulfonyl)aniline hydrochloride
(6 g, 28.8 mmol) in toluene (150 ml) at 0.degree. C.,
trimethylaluminum (2M solution in toluene, 21.6 ml, 43.2 mmol) was
added over 15 minutes. The reaction mixture was warmed to room
temperature and stirred for 2.5 hours. A solution of
3-cyanopyridine (6 g, 57.6 mmol) in toluene (150 ml) was added over
10 minutes and the reaction mixture was heated to 90-95.degree. C.
After 24 hours, the reaction mixture was cooled to room temperature
and poured over a slurry of silica gel in chloroform. After
filtration, the residue was washed with a mixture of methylene
chloride/methanol and later methanol. The combined filtrates were
concentrated and the resulting yellowish solid was stirred with
ethyl acetate (1000 ml) and filtered. The pale yellow amidine (4.5
g, 34%) was used in the next reaction without further purification:
mp (DSC) 265.degree. C. Anal Calc'd. for
C.sub.13H.sub.14N.sub.3SO.sub.2Cl.multido- t.0.5 H.sub.2O: C,
48.67, H, 4.71, N, 13.10. Found: C, 48.34, H, 4.26, N, 12.77.
[0961] Step 2: Preparation of
3-[4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4--
(trifluoromethyl)-4,5-dihydro-1H-imidazol-2-yl]pyridine
[0962] To a mixture of the amidine of Step 1 (4.4 g, 16 mmol) and
sodium bicarbonate (2.68 g, 32 mmol) in isopropanol (400 ml),
3-bromo-1,1,1-trifluoroacetone (2.5 ml, 24 mmol) was added. After
heating at 60-65.degree. C. for 36 hours, the reaction mixture was
cooled and filtered. The residue was washed with methylene chloride
and the combined organic fractions were dried over sodium sulfate,
filtered and concentrated. The crude mixture (16.2 g) was purified
by chromatography [silica gel, ethyl acetate/acetone (98:2)] to
give the compound (3.7 g, 60%) as a white solid. Anal Calc'd. for
C.sub.16H.sub.14N.sub.3SO.sub.3F.- sub.3.multidot.0.5 H.sub.2O: C,
48.18, H, 3.92, N, 10.53. Found: C, 48.52, H, 3.61, N, 9.79.
[0963] Step 3: Preparation of
3-[1-[4-(methylsulfonyl)phenyl]-4-trifluorom-
ethyl-1H-imidazol-2-yl]pyridine
[0964] A mixture of the compound of step 2 (3.6 g, 9.35 mmol) and
p-toluenesulfonic acid monohydrate (0.52 g, 2.7 mmol) in toluene
(280 ml) was heated to reflux for 24 hours. The reaction mixture
was cooled and the solvent removed under reduced pressure. The
crude mixture was purified by chromatography on silica gel using
ethyl acetate/acetone (98/2) to give pure
3-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H--
imidazol-2-yl]pyridine (790 mg, 23%) as a white solid: mp (DSC)
193.degree. C. Anal Calc'd. for
C.sub.16H.sub.12N.sub.3SO.sub.2F.sub.3: C, 52.30, H, 3.29, N,
11.44, S, 8.73. Found: C, 52.38, H, 3.26, N, 11.30, S, 8.76.
EXAMPLE 29
[0965] 50
2-[1-[4-(Methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridin-
e
[0966] Step 1: Preparation of
N-[4-(methylsulfonyl)phenyl]-2-pyridinecarbo- ximidamide
[0967] To a suspension of 4-(methylsulfonyl)aniline hydrochloride
(6 g, 28.8 mmol) in toluene (150 ml) at 0.degree. C.,
trimethylaluminum (2M solution in toluene, 21.6 ml, 43.2 mmol) was
added over 15 minutes. The reaction mixture was warmed to room
temperature and stirred for 2.5 hours. A solution of
2-cyanopyridine (6 g, 57.6 mmol) in toluene (150 ml) was added over
10 minutes and the reaction mixture was heated to 85-90.degree. C.
After 24 hours, the reaction mixture was cooled to room temperature
and poured over a slurry of silica gel in chloroform. After
filtration, the residue was washed with a mixture of methylene
chloride/methanol and later methanol. The combined filtrates were
concentrated and the resulting yellowish solid was stirred with
ethyl acetate (1500 ml) and filtered. The pale yellow solid (5.2 g,
66%) was used in the next reaction without further
purification.
[0968] Step 2: Preparation of
2-[4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4--
(trifluoromethyl)-4,5-dihydro-1H-imidazol-2-yl]pyridine
[0969] To a mixture of the amidine of step 1 (4.4 g, 16 mmol) and
sodium bicarbonate (2.7 g, 32 mmol) in isopropanol (400 ml),
3-bromo-1,1,1-trifluoroacetone (2.5 ml, 24 mmol) was added. After
heating at 75-80.degree. C. for 24 hours, the reaction mixture was
cooled and filtered. The residue was washed with methylene chloride
and the combined organic fractions were dried over sodium sulfate,
filtered and concentrated. The crude product (16.2 g) was purified
by chromatography (silica gel, ethyl acetate/toluene 1/1) to give
2-[4-hydroxy-1-[4-(methyl-
sulfonyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazol-2-yl]pyridine
(1.1 g, 18%) as a white solid: mp 195-198.degree. C. Anal. Calc'd.
for C.sub.16H.sub.14N.sub.3SO.sub.3F.sub.3: C, 49.87, H, 3.66, N.
10.90. Found: C, 50.13 , H, 3.66, N, 10.30.
[0970] Step 3: Preparation of
2-[1-[4-(methylsulfonyl)phenyl]-4-trifluorom-
ethyl-1H-imidazol-2-yl]pyridine
[0971] A mixture of
2-[4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-(trifluoro-
methyl)-4,5-dihydro-1H-imidazol-2-yl]pyridine from step 2 (1.0 g,
2.6 mmol) and p-toluenesulfonic acid monohydrate (0.2 g, 2.7 mmol)
in toluene (100 ml) was heated to reflux for 24 hours. The reaction
mixture was cooled and the solvent removed under reduced pressure.
The crude mixture (1.2 g) was purified by chromatography on silica
gel using ethyl acetate/toluene (1/1) to give pure
2-[1-[4-(methylsulfonyl)phenyl]-4-trif-
luoromethyl-1H-imidazol-2-yl]pyridine (620 mg, 65%) as a white
solid: mp (DSC) 184.degree. C. Anal. Calc'd. for
C.sub.16H.sub.12N.sub.3SO.sub.2F.s- ub.3: C, 52.30, H, 3.29, N,
11.44. Found: C, 52.23, H, 3.23, N, 11.19.
EXAMPLE 30
[0972] 51
4-[1-[4-(Methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridin-
e
[0973] Step 1: Preparation of
N-[4-(methylsulfonyl)phenyl]-4-pyridinecarbo- ximidamide
[0974] To a suspension of 4-(methylsulfonyl)aniline hydrochloride
(10 g, 48.1 mmol) in toluene (250 ml) at 0.degree. C.,
trimethylaluminum (2M solution in toluene, 36.1 ml, 72.2 mmol) was
added over 10 minutes. The reaction mixture was warmed to room
temperature and stirred for 2.5 hours. A solution of
4-cyanopyridine (10 g, 96.2 mmol) in toluene (250 ml) was added
over 10 minutes and the mixture was heated to 70.degree. C. After
24 hours, the reaction mixture was cooled to room temperature and
poured over a slurry of silica gel in chloroform. After filtration,
the residue was washed with a mixture of methylene
chloride/methanol and later with methanol. The combined filtrates
were concentrated and the resulting yellowish solid was stirred
with ethyl acetate and filtered. The pale yellow solid (4.8 g, 36%)
was used in the next reaction without further purification. Anal.
Calc'd. for C.sub.13H.sub.14N.sub.3SClO.sub.2 H.sub.2O: C, 47.34,
H, 4.89, N, 12.74, S, 9.72. Found : C, 47.69, H, 4.35, N, 12.77, S,
9.74.
[0975] Step 2: Preparation of
4-[4-hydroxy-1-[4-(methylsulfonyl]phenyl)-4--
(trifluoromethyl)-4,5-dihydro-1H-imidazol-2-yl]pyridine
[0976] To a mixture of the amidine of step 1 (4.75 g, 16 mmol) and
sodium bicarbonate (2.86 g, 34.4 mmol) in isopropanol (400 ml),
3-bromo-1,1,1-trifluoroacetone (2.7 ml, 26 mmol) was added. After
heating at 75-80.degree. C. for 24 hours, the reaction mixture was
cooled and filtered. The residue was washed with methylene chloride
and the combined organic fractions were dried over sodium sulfate,
filtered and concentrated. The crude product (16.2 g) was purified
by chromatography (silica gel, ethyl acetate/isopropanol (95/5)) to
give
4-[4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-
-1H-imidazol-2-yl]pyridine (1.55 g. 23%) as a white solid: mp
219.degree. C., Anal. Calc'd. for
C.sub.16H.sub.14N.sub.3SO.sub.3F.sub.3 C, 49.87, H, 3.66, N, 10.90,
S, 8.32. Found: C, 49.93, H, 3.51, N, 10.79, S, 8.66.
[0977] Step 3: Preparation of
4-[1-[4-(methylsulfonyl)phenyl]-4-trifluorom-
ethyl-1H-imidazol-2-yl]pyridine
[0978] A mixture of the 4,5-dihydro-imidazole of step 2 (0.85 g,
2.2 mmol) and p-toluenesulfonic acid monohydrate (0.12 g) in
toluene (150 ml) was heated to reflux for 24 hours. The reaction
mixture was cooled and the solvent removed under reduced pressure.
The crude mixture was purified by chromatography on silica gel
using ethyl acetate/acetone (96/4) to give pure
4-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]p-
yridine (330 mg, 41%) as a white solid: mp (DSC) 197.degree. C.
Anal. Calc'd. for C.sub.16H.sub.12N.sub.3SO.sub.2F.sub.3: C, 52.30,
H, 3.29, N, 11.44, S, 8.73. Found: C, 52.19, H. 3.26, N, 11.25, S,
8.99.
EXAMPLE 31
[0979] 52
2-Methyl-5-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-y-
l]pyridine
[0980] Step 1: Preparation of
2-methyl-N-[4-(methylsulfonyl)phenyl]-5-pyri-
dinecarboximidamide
[0981] To a suspension of 4-(methylsulfonyl)aniline hydrochloride
(8.8 g, 42.3 mmol) in toluene (150 ml) at 0.degree. C.,
trimethylaluminum (2M solution in toluene, 42.3 ml, 84.6 mmol) was
added over 10 minutes. The reaction mixture was warmed to room
temperature and stirred for 2.5 hours. A solution of
6-methyl-4-cyanopyridine (10 g, 84.6 mmol) in toluene (150 ml) was
added over 10 minutes and the mixture was heated to 80-85.degree.
C. After 24 hours, the reaction mixture was cooled to room
temperature and poured over a slurry of silica gel in chloroform.
After filtration, the residue was washed with a mixture of
methylene chloride/methanol and later with methanol. The combined
filtrates were concentrated and the resulting yellowish solid was
stirred with ethyl acetate and filtered. The pale yellow solid (9.8
g, 80%) was used in the next reaction without further purification.
Anal Calc'd. for C.sub.14H.sub.15N.sub.3SO.sub.2.multidot.H.sub.2O:
C, 54.71, H, 5.57, N, 13.67. Found: C, 54.62, H, 5.24, N,
13.67.
[0982] Step 2: Preparation of
2-methyl-5-[4-hydroxy-1-[4-(methylsulfonyl)p-
henyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazol-2-yl]pyridine
[0983] To a mixture of the amidine of Step 1 (9.8 g, 33.9 mmol) and
sodium bicarbonate (5.7 g, 67.8 mmol) in isopropanol (700 ml),
3-bromo-1,1,1-trifluoroacetone (5.3 ml, 50.8 mmol) was added. After
heating at 80-85.degree. C. for 24 hours, the reaction mixture was
cooled and filtered. The residue was washed with methylene chloride
and the combined organic fractions were dried over sodium sulfate,
filtered and concentrated. The crude material (25.7 g) was purified
by chromatography (silica gel, ethyl acetate/acetone, 98/2) to give
2-methyl-5-[4-hydroxy-1-
-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazol-2--
yl]pyridine (6.3 g, 46%) as a white solid: Anal. Calc'd. for
C.sub.17H.sub.16N.sub.3SO.sub.3F.sub.3: C, 50.55, H, 4.12, N,
10.40. Found: C, 50.51, H, 3.91, N, 10.25.
[0984] Step 3: Preparation of
2-methyl-5-(1-[4-(methylsulfonyl)phenyl-4-tr-
ifluoromethyl-1H-imidazol-2-yl]pyridine
[0985] A mixture of the 4,5-dihydro-imidazole of step 2 (6.2 g,
15.5 mmol) and p-toluenesulfonic acid monohydrate (1.6 g, 8.4 mmol)
in toluene (550 ml) was heated to reflux for 24 hours. The reaction
mixture was cooled and the solvent removed under reduced pressure.
The crude mixture (8.2 g) was purified by chromatography on silica
gel using ethyl acetate/acetone (98/2) to give pure
2-methyl-5-[1-[4-(methylsulfonyl)phenyl]-4-trifluorom-
ethyl-1H-imidazol-2-yl]pyridine (3.9 g, 66%) as a white solid: mp
(DSC) 163.degree. C. Anal Calc'd. for
C.sub.17H.sub.14N.sub.3SO.sub.2F.sub.3: C, 53.54, H. 3.70, N,
11.02, S, 8.41. Found: C, 53.12, H, 3.56, N, 11.00, S, 8.50.
EXAMPLE 32
[0986] 53
2-Methyl-6-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-y-
l]pyridine
[0987] Step 1: Preparation of
2-methyl-N-[4-(methylsulfonyl)phenyl]-6-pyri-
dinecarboximidamide
[0988] To a suspension of 4-(methylsulfonyl)aniline hydrochloride
(4.2 g, 20.3 mmol) in toluene (100 ml) at 0.degree. C., was added
trimethylaluminum (2M solution in toluene, 12 ml, 24 mmol) over 10
minutes. The reaction mixture was warmed to room temperature and
stirred for 2 hours. A solution of 6-methyl-2-cyanopyridine (3.6 g,
30.5 mmol) in toluene (100 ml) was added over 10 minutes and the
mixture was heated to 85-90.degree. C. After 24 hours, the reaction
mixture was cooled to room temperature and poured over a slurry of
silica gel in chloroform. After filtration, the residue was washed
with a mixture of methylene chloride/methanol and later with
methanol. The combined filtrates were concentrated and the
resulting yellowish solid was stirred with hexane and ethyl acetate
(1000 ml) and filtered. The white solid (5.1 g, 87%) was used in
the next reaction without further purification. Anal. Calc'd. for
C.sub.14H.sub.16N.sub.3SClO.sub.2 0.2H.sub.2O: C, 51.05, H, 5.02,
N, 12.76. Found: C, 50.97, H, 4.78, N, 12.80.
[0989] Step 2: Preparation of
2-methyl-6-[4-hydroxy-1-[4-(methylsulfonyl)p-
henyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazol-2-yl]pyridine
[0990] To a mixture of the amidine of Step 1 (4.9 g, 16.95 mmol)
and sodium bicarbonate (2.85 g, 33.9 mmol) in isopropanol (300 ml),
3-bromo-1,1,1-trifluoroacetone (2.65 ml, 25.4 mmol) was added.
[0991] After heating at 80-85.degree. C. for 24 hours, the reaction
mixture was cooled and filtered. The residue was washed with
methylene chloride and the combined organic fractions were dried
over sodium sulfate, filtered and concentrated. The crude mixture
(9 g) was purified by chromatography (silica gel, ethyl
acetate/isopropanol/ammonium hydroxide 95/5/0.5) to give
2-methyl-6-[4-hydroxy-1-[4-(methylsulfonyl)ph-
enyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazol-2-yl]pyridine
(1.4 g, 21%) as a white solid: Anal. Calc'd. for
C.sub.17H.sub.16N.sub.3SO.sub.3F- .sub.3: C, 51.12, H, 4.02, N,
10.52. Found: C, 51.43, H, 3.96, N, 10.06.
[0992] Step 3: Preparation of
2-methyl-6-[1-[4-(methylsulfonyl)phenyl]-4-t-
rifluoromethyl-1H-imidazol-2-yl]pyridine
[0993] A mixture of the 4,5-dihydro-imidazole of step 2 (1.3 g,
3.26 mmol) and p-toluenesulfonic acid monohydrate (0.26 g, 1.36
mmol) in toluene (200 ml) was heated to reflux for 24 hours. The
reaction mixture was cooled and the solvent removed under reduced
pressure. The crude mixture (1.56 g) was purified by chromatography
on silica gel using ethyl acetate/acetone (98/2) to give pure
2-methyl-6-[1-[4-(methylsulfonyl)phen-
yl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine (0.48 g, 38%) as a
white solid: mp (DSC) 205.degree. C. Anal. Calc'd. for
C.sub.17H.sub.14N.sub.3S- O.sub.2F.sub.3 0.25H.sub.2O: C, 52.91, H,
3.79, N, 10.89, S, 8.31. Found: C, 52.67, H, 3.55, N, 10.64, S,
8.68.
EXAMPLE 33
[0994] 54
5-Methyl-2-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-y-
l]pyridine
[0995] Step 1: Preparation of 5-methyl-2-cyanopyridine
[0996] To a solution of 2-fluoro-5-methylpyridine (39 g; 351.5
mmol) in 141 ml of dimethylsulfoxide was added 17.23 g of sodium
cyanide ( 351.5 mmol). After stirring for 3 days at 150.degree. C.,
an additional 3 g of sodium cyanide was added and heating was
continued for 5 hours. The reaction mixture was cooled to
25.degree. C. then poured into 525 ml of ice water. The solution
was filtered through a coarse fritted funnel and a dark brown solid
was collected. The solid was 20 air dried to give 17 g of the
desired cyanopyridine: Anal Calc'd. for C.sub.7H.sub.6N.sub.2: C,
71.17; H, 5.12; N, 23.71. Found: C, 69.91; H, 5.24; N, 23.26.
[0997] Step 2: Preparation of
5-methyl-N-[4-(methylthio)phenyl]-2-pyridine- carboximidamide
[0998] To a solution of 4-thiomethylaniline (8.25 g; 59 mmol) in
1,2-dichloroethane (164 ml) at 0.degree. C., triethylaluminum (1.9M
solution in toluene, 31.2 ml, 59 mmol) was added over 10 minutes.
The reaction mixture was warmed to room temperature and stirred for
1.5 hours. A solution of 5-methyl-2-cyanopyridine (Step 1) (59
mmol) in 1,2-dichloroethane (62 ml) was added over 10 minutes and
the mixture was heated to reflux. After 12 hours, the reaction
mixture was cooled to room temperature and 50 g of silica gel were
added. The suspension was stirred for 1-2 hours at 25.degree. C.
and 12 ml of methanol was added and stirred at 25.degree. C. After
filtration through Celite.RTM., the residue was washed with a
mixture of methylene chloride/methanol and later with methanol. The
combined filtrates were concentrated and the resulting solid
stirred with hexane/ethyl acetate (1000 ml) and filtered. The solid
obtained (7 g) was used in the next reaction without further
purification: Anal Calc'd. for C.sub.14H.sub.15N.sub.3.multidot.0.3
H.sub.2O: C, 63.99; H, 5.98; N, 15.99. Found: C, 64.05; H, 6.06; N,
16.11.
[0999] Step 3: Preparation of
5-methyl-2-[4-hydroxy-1-[4-(methylthio)pheny-
l]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazol-2-yl]pyridine
[1000] To a mixture of the amidine of step 2 (10 g, 52.41 mmol) and
sodium bicarbonate (8.6 g, 103 mmol) in isopropanol (1200 ml),
3-bromo-1,1,1-trifluoroacetone (10 g, 52 mmol) was added. After
heating at reflux for 22 hours, the reaction mixture was cooled and
filtered. The residue was dissolved in methylene chloride and
washed water than brine. The organic extracts were dried
(MgSO.sub.4), filtered and concentrated. The crude mixture was
purified by chromatography (silica gel, 100% ethyl acetate) to give
the desired dihydro-imidazole (5.1 g): Anal Calc'd. for
C.sub.17H.sub.16N.sub.3SOF.sub.3: C, 55.58; H, 4.39; N, 11.44.
Found: C, 55.54; H, 4.35; N, 11.20.
[1001] Step 4: Preparation of
5-methyl-2-[1-[4-(methylthio)phenyl]-4-trifl-
uoromethyl-1H-imidazol-2-yl]pyridine
[1002] A mixture of the dihydro-imidazole of step 3 (3.95 g, 13.9
mmol) and p-toluenesulfonic acid monohydrate (785 mg, 4 mmol) in
toluene (500 ml) was heated to reflux for 4-5 hours. The reaction
mixture was cooled and 10 ml of triethylamine was added and the
solvent removed under reduced pressure. The crude mixture was
purified by chromatography on silica gel using ethyl acetate to
give the desired product which was used in the next reaction
without further purification.
[1003] Step 5: Preparation of
5-methyl-2-[1-[4-(methylsulfonyl)phenyl]-4-t-
rifluoromethyl-1H-imidazol-2-yl]pyridine
[1004] To solution of the methylthio compound from step 4 (3.95 g,
11.5 mmol) in 45 ml of methanol was added an aqueous solution of
Oxone.RTM. (6.94 g dissolved in 28 ml of water). After stirring at
25.degree. C. for 4-5 hours, the solvent was removed under reduced
pressure, redissolved in 50 ml of methylene chloride and extracted
with 50 ml of an aqueous solution of sodium bicarbonate. The
organic extracts were dried (MgSO.sub.4), filtered and
concentrated. The crude material was purified by chromatography
(silica gel; 50% ethyl acetate/toluene) to provide 1.6 g of the
desired product: mp 196.degree. C. Anal calc'd. for
C.sub.17H.sub.14N.sub.3SO.sub.2F.sub.3: C, 53.54; H, 3.70; N,
11.02; S, 8.41. Found: C, 53.09; H, 3.43; N, 10.75; S, 8.69.
EXAMPLE 34
[1005] 55
4-Methyl-2-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-y-
l]pyridine
[1006] Step 1: Preparation of 2-cyano-4-methylpyridine
[1007] To a suspension of 4-picoline N-oxide (13.64 g, 0.124 mole)
in 82 ml of THF, under an inert atmosphere, was added
trimethylsilyl cyanide (20.1 ml, 0.15 mole) followed by
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (4.4 ml, 0.028 mole).
After stirring at 25.degree. C. for 12 hours, the reaction mixture
was heated to reflux. After 4.5 hours, the solvent was removed
under reduced pressure and the crude sample was eluted with
methylene chloride through a pad of Florisil.RTM.. The solvent was
removed under reduced pressure to provide (8.7 g, 60%) of
2-cyano-4-methyl pyridine, a white crystalline solid: mp
88-89.degree. C. Anal. Calc'd. for C.sub.7H.sub.6N.sub.2: C, 71.17;
H, 5.12; N, 23.71. Found: C, 70.17; H, 5.12; N, 23,44.
[1008] Step 2: Preparation of
4-methyl-N-[4-(methylsulfonyl)phenyl]-2-pyri-
dinecarboximidamide
[1009] To a solution of 4-methylsulfonyl aniline (7.62 g, 44.5
mmol) in 40 ml of 1,2-dichloroethane, was added 23.4 ml of a 1.9 M
solution of triethylaluminum in toluene. After stirring for 1.5
hours at 0.degree. C., 2-cyano-4-methyl-pyridine from step 1 (5.26
g, 44.5 mmol) was added. The reaction mixture was heated to reflux
for 20 hours and poured onto a pad of silica gel, in a fritted
filter funnel, pre-wetted and washed with 50% methanol/methylene
chloride. The filtrates were evaporated under reduced pressure to
provide 11.05 g (85%) of the desired amidine as a light brown
solid: mp 180-184.degree. C. Anal. Calc'd. for
C.sub.14H.sub.15N.sub.3O.sub.2S: C, 58.11; H, 5.23; N, 14.52.
Found: C, 57.56; H, 5.15; N, 14.35.
[1010] Step 3. Preparation of
4-methyl-2-[4-hydroxy-1-[4-(methylsulfonyl)p-
henyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazol-2-yl]pyridine
[1011] To the amidine of step 2 (12.9 g, 44.67 mmol) and sodium
bicarbonate (7.15 g, 85.1 mmol) in 1 L of isopropanol,
3-bromo-1,1,1-trifluoro-acetone (12.3 g, 64.4 mmol) was added. The
mixture was heated to reflux. After 24 hours, the solvent was
removed under reduced pressure and the resulting residue was
partitioned between methylene chloride and brine. The organic
extracts were dried (MgSO.sub.4), filtered and the solvent was
removed under reduced pressure to provide a dark brown oil which
was purified by flash chromatography (SiO.sub.2, 5%
isopropanol/methylene chloride) to provide 3.81 g (24%) of the
4,5-dihydro-imidazole as a brown solid.
[1012] Step 4: Preparation of
4-methyl-2-[1-[4-(methylsulfonyl)phenyl]-4-t-
rifluoromethyl-1H-imidazol-2-yl]pyridine
[1013] To a suspension of the 4,5-dihydro-imidazole of step 3 (3.82
g, 10.78 mmol) in 700 ml of toluene was added 0.62 g of
p-toluenesulfonic acid. After heating at reflux for 12 hours, an
additional 0.3 g of p-toluenesulfonic acid was added. After 12
hours, 2.7 ml of triethylamine was added and the solvent was
removed under reduced pressure to provide 5.17 g of crude compound.
Crude compound was purified by chromatography twice (SiO.sub.2; 30%
heptane/ethyl acetate) by HPLC to provide 263 mg of the targeted
compound. Impure fractions containing the desired product were
recombined and repurified by chromatography using HPLC (SiO.sub.2;
50% ethyl acetate/toluene) to provide an additional 639.5 mg of the
desired compound: mp (DSC) 195.degree. C. Anal. Calc'd. for
C.sub.17H.sub.14F.sub.3N.sub.3O.sub.2S: C, 53.54; H. 3.70; N,
11.02; S, 8.41. Found: C, 53.21; H, 3.71; N, 10.77; S, 8.63.
EXAMPLE 35
[1014] 56
2-Methoxy-5-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2--
yl]pyridine
[1015] Step 1: Preparation of
2-methoxy-N-[4-(methylsulfonyl)phenyl]-5-pyr-
idinecarboximidamide
[1016] To a suspension of 4-(methylsulfonyl)aniline hydrochloride
(1.8 g, 8.7 mmol) in toluene (50 ml) at 0.degree. C.,
trimethylaluminum (2M solution in toluene, 5.2 ml, 10.4 mmol) was
added over 10 minutes. The reaction mixture was warmed to room
temperature and stirred for 2 hours. A solution of
6-methoxy-3-cyanopyridine (1.75 g, 13 mmol) in toluene (100 ml) was
added over 10 minutes and the mixture was heated to 85-90.degree.
C. After 24 hours, the reaction mixture was cooled to room
temperature and poured over a slurry of silica gel in chloroform.
After filtration, the residue was washed with a mixture of
methylene chloride and methanol and later with methanol. The
combined filtrates were concentrated and the resulting yellowish
solid was stirred with ethyl acetate (1000 ml) and filtered. The
white solid (2 g, 75%) was used in the next reaction without
further purification. Anal. Calc'd. for C.sub.14H.sub.16N.sub.3SC-
lO.sub.3.multidot.0.5 H.sub.2O: C, 47.93, H, 4.88, N, 11.98. Found:
C, 48.01, H, 4.82, N, 11.32.
[1017] Step 2: Preparation of
2-methoxy-5-[4-hydroxy-1-[4-(methylsulfonyl)-
phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazol-2-yl]pyridine
[1018] To a mixture of the amidine of step 1 (1.9 g, 6.23 mmol) and
sodium bicarbonate (1.05 g, 12.46 mmol) in isopropanol (150 ml),
3-bromo-1,1,1-trifluoroacetone (0.97 ml, 9.34 mmol) was added.
[1019] After heating at 85-90.degree. C. for 48 hours, the reaction
mixture was cooled and filtered. The residue was washed with
methylene chloride and the combined organic fractions were dried
over sodium sulfate, filtered and concentrated. The crude mixture
(4.25 g) was purified by chromatography (silica gel, methylene
chloride/methanol/ammon- ium hydroxide, 95/5/0.5) to give the
4,5-dihydro-imidazole (1.1 g, 42%) as a white solid: Anal. Calc'd.
for C.sub.17H.sub.16N.sub.3SO.sub.4F.sub.3.m- ultidot.0.5 EtOAc: C,
49.67, H, 4.39, N, 9.15. Found: C, 49.80, H, 4.06, N, 9.33.
[1020] Step 3: Preparation of
2-methoxy-5-[1-[4-(methylsulfonyl)phenyl]-4--
trifluoromethyl-1H-imidazol-2-yl]pyridine
[1021] A mixture of the 4,5-dihydro-imidazole of step 2 (0.8 g,
1.93 mmol) and p-toluenesulfonic acid monohydrate (0.2 g, 1.04
mmol) in toluene (150 ml) was heated to reflux for 24 hours. The
reaction mixture was cooled and the solvent removed under reduced
pressure. The crude mixture (1.1 g) was purified by chromatography
on silica gel using ethyl acetate/toluene (1/1) to give pure
2-methoxy-5-[1-[4-(methylsulfonyl)phenyl]-4-trifluorom-
ethyl-1H-imidazol-2-yl]pyridine (0.38 g, 49%) as a white solid: mp
(DSC) 166.degree. C. Anal. Calc'd. for
C.sub.17H.sub.14N.sub.3SO.sub.3F.sub.3: C, 51.38, H, 3.55, N,
10.57. Found: C, 51.38, H, 3.25, N, 10.41.
EXAMPLE 36
[1022] 57
4-[2-(6-Methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesu-
lfonamide
[1023] To a clear solution of Example 31 (2.4 g, 6.3 mmol) in
tetrahydrofuran (60 ml) at 0.degree. C., n-BuMgCl (2M solution in
THF, 15.7 ml, 31.5 mmol) was added over 10 minutes. After stirring
for additional 20 minutes, the ice bath was removed and the
solution was stirred for 2 hours. The reaction mixture was recooled
to 0.degree. C. and triethylborane (1M solution in THF, 38 ml, 38
mmol) was added. After stirring for 1 hour, the reaction was heated
to reflux for 72 hours. The reaction mixture was cooled to room
temperature and treated with aqueous sodium acetate (5.5 g in 22 ml
water). After stirring for 5 minutes, solid
hydroxylamine-O-sulfonic acid (5.5 g) was added and the mixture
stirred for 24 hours. The reaction mixture was diluted with water
and extracted with ether. The ethereal layer was dried over sodium
sulfate, filtered and concentrated. The crude solid (13.3 g) was
purified by chromatography (silica gel, hexane/isopropanol, 7/3) to
give
4-[2-(6-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenes-
ulfonamide (298 mg, 12%): mp (DSC) 203.degree. C. Anal. Calc'd. for
C.sub.16H.sub.13N.sub.4SO.sub.2F.sub.3.multidot.0.25 H.sub.2O: C,
49.68, H, 3.52 N, 14.48, S, 8.29. Found: C, 49.88, H, 3.39, N,
13.94, S, 8.47.
EXAMPLE 37
[1024] 58
4-[2-(6-Methylpyridin-2-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesu-
lfonamide
[1025] To a clear solution of Example 32 (10 mmol) in
tetrahydrofuran (60 ml) at 0.degree. C., n-BuMgCl (2M solution in
THF, 25 ml, 50 mmol) is added over 10 minutes. After stirring for
an additional 20 minutes, the ice bath is removed and the solution
is stirred for 2 hours. The reaction mixture is recooled to
0.degree. C. and triethylborane (1M solution in THF, 60 ml, 60
mmol) is added. After stirring for 1 hour, the reaction is heated
to reflux for 72 hours. The reaction mixture is cooled to room
temperature and treated with aqueous sodium acetate 5.5 g in 22 ml
water). After stirring for 5 minutes, solid
hydroxylamine-O-sulfonic acid (5.5 g) is added and the mixture
stirred for 24 hours. The reaction mixture is diluted with water
and extracted with ether. The ethereal layer is dried over sodium
sulfate, filtered and concentrated. The crude solid is purified by
chromatography on silica gel using mixtures of hexane and
isopropanol to give the desired product.
EXAMPLE 38
[1026] 59
2-[4-(4-Fluorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazol-2-yl]pyridi-
ne
[1027] Step 1: Preparation of
N-[4-(methylsulfonyl)phenyl]-2-pyridinecarbo- ximidamide
[1028] To a suspension of 5.00 g (24.0 mmol) of
4-methylsulfonylaniline hydrochloride in 150 ml of toluene stirring
in an ice bath under nitrogen, was added dropwise 18.0 ml
(containing 36.0 mmol) of a 2M solution of trimethylaluminum in
toluene. After stirring for 30 minutes, a solution of 3.75 g (36.0
mmol) of 2-cyanopyridine in 20 ml of toluene. The resulting
solution was stirred overnight at room temperature, and then at
85.degree. for four hours. After cooling, the toluene was decanted
and evaporated. The residue was taken up in 150 ml of methylene
chloride and added back to the reaction flask. Methanol (150 ml)
was cautiously added, and the mixture was filtered through a bed of
silica gel using 50-50 methanol/methylene chloride as eluent.
Evaporation of the solvent gave the amidine (6.85 g) as a yellow
solid, which was used in the next reaction without further
purification.
[1029] Step 2: Preparation of
2-[4-(4-fluorophenyl)-1-[4-(methylsulfonyl)p-
henyl]-1H-imidazol-2-yl]pyridine
[1030] A mixture of the amidine of Step 1 (2.00 g, 7.27 mmol),
2-bromo-4'-fluoroacetophenone (3.16 g, 14.5 mmol) and sodium
bicarbonate (1.22 g, 14.5 mmol) in isopropanol (70 ml) was stirred
at reflux for two days. After cooling, the solvent was evaporated.
The residue was partitioned between methylene chloride and aqueous
sodium chloride, and the aqueous layer further extracted with
methylene chloride. The combined organic extracts were dried over
sodium sulfate, filtered, and evaporated. Chromatography of the
residue over silica gel using 40% ethyl acetate/toluene followed by
a second chromatography over silica gel using 40% ethyl
acetate/methylene chloride as eluant gave
2-[4-(4-fluorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazol-2-yl]pyrid-
ine (190 mg) as a light tan solid: m.p. 88-91.degree. C. Anal.
Calc'd for C.sub.21H.sub.16FN.sub.3O.sub.2S (M.W. 393.44): C,
64.11;, H, 4.10, N, 10.68. Found: C, 63.80; H, 4.16, N, 10.23.
EXAMPLE 39
[1031] 60
3-Methyl-5-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-
-yl]pyridine
[1032] Step 1: Preparation of 5-methylnicotinic acid:
[1033] The 5-methylnicotinic acid was prepared by the method of E.
P. Kyba et al., J. Org. Chem., 53, 3513-3521 (1988)]. To a solution
of KMnO.sub.4 in water (1.1 L) was added lutidine (25.0 g, 0.233
mol) and the mixture was stirred mechanically at 45.degree. C.
overnight. The reaction mixture was cooled and filtered through
Celite.RTM. to remove MnO.sub.2. The filtrate was concentrated to
about 150 mL and acidified with a 2N HCl solution. White solid
precipitated and was removed by filtration and washed with water
(2.times.50 mL). The filtrate and washings were evaporated to
dryness. The residue was boiled with ethanol (200 mL) and filtered
repeatedly. The combined filtrate was concentrated to give of
5-methylnicotinic acid as a white solid (14.8 g, 46%): mp
213-215.degree. C.
[1034] Step 2: Preparation of 5-methylpyridinylcarboxamide
[1035] A solution of 5-methylnicotinic acid from step 1 (14.5 g,
0.106 mol) in 125 mL of thionyl chloride was heated to reflux for 5
hours. Excess thionyl chloride was removed by distillation and the
residue was suspended in 75 mL of dichloroethane. Ammonia was
bubbled into the mixture at -30.degree. C. for half hour and the
mixture was stirred at room temperature overnight. Solvent was
evaporated and the residue was treated with methanol and filtered.
The filtrate was concentrated and the residue was extracted with
boiling hot ethyl acetate (3.times.150 mL) to separate product from
ammonium chloride. The extracts were filtered and concentrated to
afford 10.6 g of 5-methylpyridinylcarboxamide as a brown solid
(73%): mp 160-163.degree. C.
[1036] Step 3: Preparation of 3-cyano-5-methylpyridine
[1037] To a suspension of 5-methylpyridinylcarboxamide from step 2
(10.5 g, 0.077 mol) in triethylamine (23.3 g, 0.23 mol) and 400 mL
of methylene chloride was added trifluoroacetic anhydride (21.0 g,
0.100 mol) rapidly at 0.degree. C. The reaction was completed after
a few minutes. Water was added and the aqueous layer was extracted
with methylene chloride. The combined organic layers were washed
with water, brine and dried over magnesium sulfate. After
filtration, the filtrate was concentrated to give 9.18 g of
3-cyano-5-methylpyridine crude, which was used in the next step
without purification.
[1038] Step 4: Preparation of
3-methyl-5-[4-hydroxy-1-[4-(methylsulfonyl)p-
henyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazol-2-yl]pyridine
[1039] To a suspension of 4-(methylsulfonyl)aniline hydrochloride
(10.5 g, 0.051 mol) in toluene (500 mL) was added trimethylaluminum
(2M solution in toluene, 75.0 mL, 0.150 mol) over 15 minutes at
0.degree. C. The reaction mixture was warmed up to room temperature
and stirred for 2 hours. A solution of 3-cyano-5-methylpyridine
from step 3 in 90 mL of toluene was added over 10 minutes and the
mixture was stirred at 85-90.degree. C. for 16 hours. The reaction
mixture was cooled to room temperature and filtered through a
slurry of silica gel. After filtration, the residue was washed with
methanol (800 mL). The combined filtrate was concentrated under
reduced pressure and the residue was treated with a mixture of
ether and hexane (2/1, 1000 mL). The brownish solid was filtered
and washed with more ether and hexane to give 11.8 g of
N-[4-(methylsulfonyl)phenyl]-5-methylnicotinamidine (80%). To a
mixture of the above crude amidine (11.3 g, 0.039 mol) and sodium
bicarbonate (9.83 g, 0.12 mol) in isopropanol (400 mL) was added
3-bromo-1,1,1-trifluoroacetone (11.2 g, 0.059 mol) quickly at room
temperature. After heating the reaction mixture at 75-80.degree. C.
for 16 hours, the solvent was removed and the residue was
partitioned between water and methylene chloride. The organic
layers were washed with brine, dried over anhydrous magnesium
sulfate, filtered and concentrated under reduced pressure. The
crude was purified by chromatography on silica gel (ethyl
acetate/acetone, 98:2) to give pure 3-methyl-5-[4-hydroxy-1-[4-(me-
thylsulfonyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazol-2-yl]pyri-
dine as a yellow solid (3.85 g, 25%): mp (DSC) 237-239.degree. C.;
Anal. Calc'd. for C.sub.17H.sub.16F.sub.3N.sub.3O.sub.3S: C, 51.12,
H, 4.04, N, 10.52, S, 8.03. Found: C, 51.02, H, 3.94, N, 10.19, S,
8.11.
[1040] Step 5: Preparation of
3-methyl-5-[1-[4-(methylsulfonyl)phenyl]-4-(-
trifluoromethyl)-1H-imidazol-2-yl]pyridine
[1041] A mixture of
3-methyl-5-[4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-(-
trifluoromethyl)-4,5-dihydro-1H-imidazol-2-yl]pyridine from step 4
(3.8 g, 9.5 mmol) and p-toluenesulfonic acid monohydrate (0.91 g,
4.8 mmol) in 150 mL of toluene was heated to reflux for 24 hours.
The reaction mixture was cooled and the solvent was removed under
reduced pressure. The residue was partitioned between water and
methylene chloride. The organic layer was washed with water,
saturated sodium bicarbonate solution and brine, dried over
magnesium sulfate and filtered. The filtrate was evaporated in
vacuo and the crude product was purified by flash chromatography on
silica gel (ethyl acetate/acetone, 98:2) to give
3-methyl-5-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol--
2-yl]pyridine as a yellow solid (1.7 g, 47%): mp (DSC)
196-198.degree. C.; Anal. Calc'd. for
C.sub.17H.sub.14F.sub.3N.sub.3O.sub.2S: C, 53.54, H, 3.70, N,
11.02, S, 8.41. Found: C, 53.50, H, 3.65, N, 10.82, S, 8.55.
EXAMPLE 40
[1042] 61
4-[2-(4-Methylpyridin-2-yl)-4-(trifluoromethyl)-1H-imidazol1-yl]benzenesul-
fonamide
[1043] To a stirred solution of the product of Example 34 (294.5
mg, 0.77 mmol) in 11 ml of freshly distilled THF at 0.degree. C.
was added 1.54 ml of butyl magnesium chloride (2.0 M solution in
THF) over a period of 6 minutes.
[1044] After stirring at 25.degree. C. for 2.5 hours, the reaction
was cooled to 0.degree. C. and 3.85 ml of triethylborane (1.0 M
solution in THF) was added over 30 minutes. The reaction mixture
was stirred at 25.degree. C. for 1.5 hours and heated to reflux.
After 72 hours, the reaction mixture was diluted with 50 ml of
ethyl acetate and washed with aqueous sodium bicarbonate
(2.times.50 ml). The organic extracts were dried (MgSO.sub.4),
filtered and the solvent removed under reduced pressure to provide
359 of an orange solid, which was purified by chromatography
(SiO.sub.2; 40% toluene/ethyl acetate) to provide 68.1 mg of a
light yellow solid. Preparative thin layer chromatography
(SiO.sub.2; 50% ethyl acetate/toluene) of 22 mg of this material
yielded 14 mg of
4-[2-(4-methylpyridin-2-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl-
]benzenesulfonamide: mp (DSC) 283.degree. C. Anal. Calc'd. for
C.sub.16H.sub.13F.sub.3N.sub.4O.sub.2S: C, 50.26; H, 3.43; N,
14.65; S, 8.50. Found: C, 50.41; H, 3.37; N, 14.18; S, 8.51.
EXAMPLE 41
[1045] 62
2-[1-[4-(Methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]thiop-
hene
[1046] Step 1: Preparation of
N-[4-(methylsulfonyl)phenyl]-2-thiophenecarb- oximidamide
[1047] To a suspension of 4-(methylsulfonyl)aniline (10.4 g, 61.1
mmol) in toluene (400 ml) at 0.degree. C., trimethylaluminum (2M
solution in toluene, 46.8 ml, 91.6 mmol) was added over 15 minutes.
The reaction mixture was warmed to room temperature and stirred for
2 hours. A solution of 2-thiophenecarbonitrile (10.0 g, 91.6 mmol)
in toluene (200 ml) was added over 10 minutes and the mixture was
heated to 80-85.degree. C. After 16 hours, the reaction mixture was
cooled to room temperature and poured over a slurry of silica gel
in chloroform. After filtration, the residue was washed with a
mixture of methylene chloride/methanol and later with methanol. The
combined filtrates were concentrated and the resulting yellow solid
was stirred with ethyl acetate and filtered. The pale yellow solid
(9.8 g, 57%) was used in the next reaction without further
purification: m.p. (DSC) 182.degree. C. Anal. Calc'd. for
C.sub.12H.sub.12N.sub.2S.sub.2O.sub.2: C, 51.41, H, 4.31, N, 9.99,
S, 22.87. Found: C, 51.02, H, 4.37, N, 9.80, S, 22.93.
[1048] Step 2: Preparation of
2-[4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4--
(trifluoromethyl)-4,5-dihydro-1H-imidazol-2-yl]thiophene
[1049] To a mixture of the amidine of step 1 (2.0 g, 7.1 mmol) and
sodium bicarbonate (1.2 g, 14.3 mmol) in isopropanol (200 ml),
3-bromo-1,1,1-trifluoroacetone 1.1 ml, 10.7 mmol) was added. After
heating at 80-85.degree. C. for 16 hours, the reaction mixture was
cooled and filtered. The residue was washed with methylene chloride
and the combined organic fractions were dried over sodium sulfate,
filtered and concentrated. The crude mixture (25.7 g) was purified
by chromatography (silica gel, ethyl acetate/hexane 55/45) to give
the 4,5-dihydro-imidazole (1.1 g, 38%) as a white solid: mp (DSC)
214.degree. C. Anal. Calc'd. for
C.sub.15H.sub.13N.sub.2S.sub.2O.sub.3F.sub.3: C, 46.15, H, 3.36, N,
7.18, S, 16.43. Found: C, 46.09, H, 3.26, N, 7.07, S, 16.71.
[1050] Step 3: Preparation of 2-[1-[4-(methylsulfonyl)
phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]thiophene
[1051] A mixture of the 4,5-dihydro-imidazole of step 2 (0.60 g,
1.54 mmol) and p-toluenesulfonic acid monohydrate (0.12 g, 0.63
mmol) in toluene (100 ml) was heated to reflux for 4.5 hours. The
reaction mixture was cooled and the solvent removed under reduced
pressure. The crude mixture (1.2 g) was purified by chromatography
on silica gel using ethyl acetate/hexane 50/50 to give pure
2-[1-[4-(methylsulfonyl)phenyl]-4-(trif-
luoromethyl)-1H-imidazol-2-yl]thiophene (0.47 g, 82%) as a white
solid: mp (DSC) 182.degree. C. Anal. Calc'd. for
C.sub.15H.sub.11N.sub.2S.sub.2O.su- b.2F.sub.3 C, 48.38, H, 2.98,
N, 7.52, S, 17.22. Found: C, 48.36, H, 3.02, N, 7.42, S, 17.47.
EXAMPLE 42
[1052] 63
3-[1-[4-(Methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]thiop-
hene
[1053] Step 1: Preparation of
N-[4-(methylsulfonyl)phenyl]-2-thiophenecarb- oximidamide
[1054] To a suspension of 4-(methylsulfonyl)aniline (3.3 g, 19.5
mmol) in toluene (200 ml) at 0.degree. C., trimethylaluminum (2M
solution in toluene, 14.7 ml, 29.3 mmol) was added over 15 minutes.
The reaction mixture was warmed to room temperature and stirred for
2 hours. A solution of 3-thiophenecarbonitrile (3.2 g, 29.3 mmol)
in toluene (50 ml) was added over 10 minutes and the mixture was
heated to 80-85.degree. C. After 16 hours, the reaction mixture was
cooled to room temperature and poured over a slurry of silica gel
in chloroform. After filtration, the residue was washed with a
mixture of methylene chloride/methanol and later with methanol. The
combined filtrates were concentrated and the resulting yellow solid
was stirred with ethyl acetate and filtered. The pale yellow solid
(2.7 g, 49%) was used in the next reaction without further
purification: mp (DSC) 213.degree. C., Anal. Calc'd. for
C.sub.12H.sub.12N.sub.2S.sub.2O.sub.2: C, 51.41, H, 4.31, N, 9.99,
S, 22.87. Found: C, 51.28, H, 4.06, N, 9.86, S, 23.14.
[1055] Step 2: Preparation of
3-[4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4--
(trifluoromethyl)-4,5-dihydro-1H-imidazol-2-yl]thiophene
[1056] To a mixture of the amidine of step 1 (3.5 g, 12.5 mmol) and
sodium bicarbonate (2.1 g, 25.0 mmol) in isopropanol (200 ml),
3-bromo-1,1,1-trifluoroacetone (1.96 ml, 18.7 mmol) was added.
After heating at 80-85.degree. C. for 16 hours, the reaction
mixture was cooled and filtered. The residue was washed with
methylene chloride and the combined organic fractions were dried
over sodium sulfate, filtered and concentrated. The crude material
was purified by chromatography (silica gel, ethyl acetate/toluene
(6/4)) to give 3-[4-hydroxy-1-[4-(methylsulfon-
yl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazol-2-yl]thiophene
(1.7 g, 35%) as a white solid: mp (DSC) 226.degree. C. Anal.
Calc'd. for C.sub.15H.sub.13N.sub.2S.sub.2O.sub.3F.sub.3: C, 46.15,
H. 3.36, N, 7.18, S, 16.43. Found: C, 46.56, H. 3.39, N, 7.01, S,
16.88.
[1057] Step 3: Preparation of
3-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoro-
methyl)-1H-imidazol-2-yl]thiophene
[1058] A mixture of the 4,5-dihydro-imidazole of step 2 (1.5 g, 3.8
mmol) and p-toluenesulfonic acid monohydrate (0.30 g, 1.5 mmol) in
toluene (250 ml) was heated to reflux for 40 hours. An additional
p-toluenesulfonic acid monohydrate (0.15 g, 0.78 mmol) was added.
The reaction mixture was heated to reflux for 18 hours. The
reaction mixture was cooled and the solvent removed under reduced
pressure. The crude mixture (3.5 g) was purified by chromatography
on silica gel using ethyl acetate/toluene (55/45) to give pure
3-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)--
1H-imidazol-2-yl]thiophene (0.90 g, 64%) as a white solid: mp
194-197.degree. C. Anal. Calc'd. for
C.sub.15H.sub.11N.sub.2S.sub.2O.sub.- 2F.sub.3: C, 48.38, H, 2.98,
N. 7.52, S, 17.22. Found: C, 48.74, H, 2.98, N, 7.56, S, 17.45
EXAMPLE 43
[1059] 64
4-[2-(5-Methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesu-
lfonamide
[1060] To a solution of
3-methyl-5-[1-[4-(methylsulfonyl)phenyl]-4-(triflu-
oromethyl)-1H-imidazol-2-yl]pyridine (Example 39) (1.9 mmol) in 25
mL of dry THF was added n-BuMgCl (3.8 mL of 2.0 M THF solution, 7.5
mmol) slowly at 0.degree. C. After stirring for additional 15
minutes, the solution was stirred at room temperature for 2 hours.
The reaction mixture was re-cooled to 0.degree. C. and
triethylborane (9.5 mL of 1.0 M THF solution, 9.5 mmol) was added.
After stirring at for 2 hours, the mixture was heated to reflux for
72 hours. The reaction mixture was cooled to room temperature and
treated with a solution of sodium acetate (2.3 g) in 10 mL of
water. After stirring for 5 minutes, hydroxylamine-O-sulfonic acid
(2.3 g) was added and the mixture was stirred for 20 hours. The
reaction mixture was extracted with ether (2.times.100 mL). The
ethereal layer was dried over MgSO.sub.4, filtered and concentrated
in vacuo. The crude product was purified by chromatography on
silica gel (isopropanol/toluene, 5:95) to give 0.07 g of
4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benze-
nesulfonamide as a colorless solid (8%): mp 242-243.degree. C.
Anal. Calc'd. For C.sub.16H.sub.13F.sub.3N.sub.4O.sub.2S: C, 50.26,
H, 3.43, N, 14.65, S, 8.39. Found: C, 50.02, H, 3.63, N, 14.26, S,
8.41.
EXAMPLE 44
[1061] 65
2-Methyl-3-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-
-yl]pyridine
[1062] Step 1: Preparation of 2-methylnicotinamide:
[1063] To a stirred mixture of 2-methylnicotinic acid (15.0 g,
0.111 mol) and 1,1'-carbonyldiimidazole (36.0 g, 0.222 mol) was
added 300 mL of methylene chloride dropwise. The reaction mixture
was stirred at room temperature overnight. Ammonia gas was
distilled into the reaction mixture for 30 minutes using a dry ice
condenser and the mixture was stirred at room temperature for an
additional hour. Solvent was removed under vacuum and the residue
was dissolved with 500 mL of acetonitrile. The solution was
concentrated to half volume at low temperature and the product
precipitated out as white solid. The crude mixture was
recrystallized from ethanol/ether to give 11.5 g of
2-methylnicotinamide as a colorless crystal (76%): mp
160-163.degree. C. Anal. Calc'd. For C.sub.7H.sub.8N.sub.2O: C,
61.75, H, 5.92, N, 20.57. Found: C, 61.44, H, 6.14, N, 20.66.
[1064] Step 2: Preparation of 3-cyano-2-methylpyridine:
[1065] To a suspension of 2-methylnicotinamide from step 1 (11.1 g,
0.081 mol) in triethylamine (24.8 g, 0.243 mol) and 400 mL of
methylene chloride was added trifluoroacetic anhydride (21.0 g,
0.100 mol) rapidly at 0.degree. C. The reaction was complete after
a few minutes at this temperature. Water was added and the aqueous
layer was extracted with methylene chloride. The combined organic
layers were washed with water, brine and dried over magnesium
sulfate. After filtration, the filtrate was concentrated and the
residue was purified by chromatography on silica gel (ethyl
acetate/hexane, 1:1) to give 7.2 g of 3-cyano-2-methylpyridine as a
pale yellow solid (75%): mp(DSC) 56-58.degree. C.
[1066] Step 3: Preparation of
2-methyl-3-[4-hydroxy-1-[4-(methylsulfonyl)p-
henyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazol-2-yl]pyridine:
[1067] To a suspension of 4-(methylsulfonyl)aniline hydrochloride
(6.85 g, 0.040 mol) in dichloroethane (400 mL) was added
triethylaluminum (1.9M solution in toluene, 32.0 mL, 60 mmol) over
15 minutes at 0.degree. C. The reaction mixture was warmed to room
temperature and stirred for 2 hours. A solution of
3-cyano-2-methylpyridine, from step 2, in 70 mL of dichloroethane
was added over 10 minutes and the mixture was stirred at 75.degree.
C. for 16 hours. The reaction mixture was cooled to room
temperature and treated with 50 g of silica gel. The mixture was
stirred for 30 minutes and filtered. The filtrate and washings were
concentrated under reduced pressure and the residue was washed with
ether to give 7.3 g of crude
2-methyl-N-[4-(methylsulfonyl)phenyl]-3-pyridinecarboximidamid- e
(60%). To a mixture of the above crude amidine (7.0 g, 0.024 mol)
and sodium bicarbonate (4.0 g, 0.048 mol) in isopropanol (350 mL)
was added 3-bromo-1,1,1-trifluoroacetone (6.9 g, 0.036 mol) rapidly
at room temperature. After heating the reaction mixture at
75-80.degree. C. for 16 hours, the solvent was removed and the
residue was partitioned between water and methylene chloride. The
organic layers were washed with brine, dried over anhydrous
magnesium sulfate, filtered and concentrated under reduced
pressure. The crude was purified by chromatography on silica gel
(ethyl acetate/acetone, 98:2) to give 4.02 g of pure
2-methyl-3-[4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-4,-
5-dihydro-1H-imidazol-2-yl]pyridine as a yellow solid (25%): mp
(DSC) 237-239.degree. C. Anal. Calc'd. for
C.sub.17H.sub.16F.sub.3N.sub.3O.sub.- 3S: C, 51.12, H, 4.04, N,
10.52, S, 8.03. Found: C, 50.92, H, 4.12, N, 10.04, S, 7.83.
[1068] Step 4: Preparation of
2-methyl-3-[1H-[4-(methylsulfonyl)phenyl]-4--
(trifluoromethyl)-1H-imidazol-2-yl]pyridine:
[1069] A mixture of
2-methyl-3-[4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-(-
trifluoromethyl)-4,5-dihydro-1H-imidazol-2-yl]pyridine from step 3
(3.97 g, 0.01 mol) and p-toluenesulfonic acid monohydrate (0.60 g,
0.0032 mol) in 250 mL of toluene was heated to reflux for 24 hours.
The reaction mixture was cooled and the solvent was removed under
reduced pressure. The residue was partitioned between water and
methylene chloride. The organic layer was washed with water,
saturated sodium bicarbonate solution and brine, dried over
magnesium sulfate and filtered. The filtrate was evaporated in
vacuo and the crude product was purified by recrystallization from
ethyl acetate/hexane to give 2.8 g of
2-methyl-3-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol--
2-yl]pyridine (73%): mp 160-161.degree. C. Anal. Calc'd. for
C.sub.17H.sub.14F.sub.3N.sub.3O.sub.2S: C, 53.54, H, 3.70, N,
11.02, S, 8.41. Found: C, 53.58, H, 3.88, N, 11.02, S, 8.51.
EXAMPLE 45
[1070] 66
4-[2-(2-Methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesu-
lfonamide
[1071] Step 1: Preparation of
2-methyl-3-[1-[4-[[2-(trimethylsilyl)ethyl]s-
ulfonyl]phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine
[1072] To a solution of diisopropylamine (0.7 mL, 0.005 mol) in 9
mL of dry THF was added butyllithium (BuLi) (2.83 mL of 1.62M
solution in hexane, 4.6 mmol) at 0.degree. C. The solution was
stirred at this temperature for 5 minutes and cooled to -78.degree.
C. with a dry ice/isopropanol bath. A solution of
2-methyl-3-[1-[4-(methylsulfonyl)phen-
yl]-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine (Example 44)
(1.46 g, 3.8 mmol) in 12 mL of dry THF was added over 10 minutes
and the reaction mixture was stirred at -78.degree. C. for 1 hour.
(Iodomethyl)trimethylsi- lane (1.23 g, 57 mmol) was added dropwise
and the reaction mixture was warmed to room temperature and was
stirred overnight. The reaction was quenched with 50 mL of 1 N HCl
and the aqueous phase was extracted with ethyl acetate (3.times.60
mL). The combined organic layers were washed with brine, dried over
MgSO.sub.4, filtered and concentrated. The crude mixture was
purified by chromatography on silica gel (ethyl acetate/hexane,
65:35) to give 1.30 g of 2-methyl-3-[1-[4-[[2-(trimethyls-
ilyl)ethyl]sulfonyl]phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine
as a white solid (74%): mp(DSC) 155-157.degree. C. Anal. Calc'd.
for C.sub.21H.sub.24F.sub.3N.sub.3O.sub.2SSi: C, 53.94; H, 5.17; N,
8.99; S, 6.86. Found: C, 53.77; H, 4.94; N, 8.75; S, 6.98.
[1073] Step 2: Preparation of
4-[2-(2-methylpyridin-3-yl)-4-(trifluorometh-
yl)-1H-imidazol-1-yl]benzenesulfonamide:
[1074] To a solution of
2-methyl-3-[1-[4-[[2-(trimethylsilyl)ethyl]sulfony-
l]phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine from Step 1
(0.234 g, 0.5 mmol) in 1.5 mL of dry THF was added n-Bu.sub.4NF
(1.5 mL of 1.0M THF solution, 1.5 mmol). The mixture was heated to
reflux for 1 hour and cooled to room temperature. A solution of
sodium acetate (0.19 g, 2.3 mmol) in 3 mL of water and
hydroxylamine-O-sulfonic acid (0.28 g, 2.5 mmol) were added
sequentially and the mixture was stirred for 1 hour. Water (7 mL)
and ethyl acetate (7 mL) were added. The organic phase was
separated and washed with sat. NaHCO.sub.3 solution, water, and
brine, dried over MgSO.sub.4 and filtered. The filtrate was
concentrated and the residue was purified by chromatography on
silica gel (ethyl acetate/acetone, 95:5) to give 0.16 g of
4-[2-(2-methylpyridin-3-yl)-4-(t-
rifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide as a colorless
solid (84%): mp 235-237.degree. C. Anal. Calc'd. for
C.sub.16H.sub.13F.sub.3N.s- ub.4O.sub.2S: C, 50.26; H, 3.43; N,
14.65; S, 8.39. Found: C, 50.06; H, 3.29; N, 14.44; S, 8.52.
EXAMPLE 46
[1075] 67
4-[2-(Pyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamid-
e
[1076]
3-[1-[4-[[2-(Trimethylsilyl)ethyl]sulfonyl]phenyl]-4-(trifluorometh-
yl)-1H-imidazol-2-yl]pyridine was prepared with the product of
Example 28 with a method similar to that described in Example 45,
Step 1. To a solution of
3-[1-[4-[[2-(trimethylsilyl)ethyl]sulfonyl]phenyl]-4-(trifluo-
romethyl)-1H-imidazol-2-yl]pyridine (0.200 g, 0.46 mmol) in 1.0 mL
of dry THF was added n-Bu.sub.4NF (1.38 mL of 1.0 M THF solution,
1.38 mmol). The mixture was heated to reflux for 1 hour and cooled
to room temperature. A solution of sodium acetate (0.17 g, 2.1
mmol) in 3 mL of water and hydroxylamine-O-sulfonic acid (0.26 g,
2.3 mmol) were added sequentially and the mixture was stirred for 1
hour. Water (7 mL) and ethyl acetate (7 mL) were added. The organic
phase was separated and washed with saturated NaHCO.sub.3 solution,
water, brine, dried over MgSO.sub.4 and filtered. The filtrate was
concentrated and the residue was purified by chromatography on
silica gel (ethyl acetate/acetone, 95:5) to give 0.147 g of
4-[2-(pyridin-3-yl)-4-(trifluoromethyl)-1H-imida-
zol-1-yl]benzenesulfonamide as a colorless solid (87%): mp(DSC)
213-215.degree. C. Anal. Calc'd. for
C.sub.15H.sub.11F.sub.3N.sub.4O.sub.- 2S: C, 48.91; H, 3.01; N,
15.21; S, 8.71. Found: C, 48.58; H, 2.99; N, 14.87; S, 8.85.
[1077] The following imidazole derivatives could be prepared by the
procedure described in Example 26 or 45:
[1078] Example 47:
4-[2-(4-chlorophenyl)-4-methyl-1H-imidazol-1-yl]benzene-
sulfonamide;
[1079] Example 48:
4-[2-(4-chlorophenyl)-4-phenyl-1H-imidazol-1-yl]benzene-
sulfonamide;
[1080] Example 49:
4-[2-(4-chlorophenyl)-4-(4-fluorophenyl)-1H-imidazol-1--
yl]benzenesulfonamide;
[1081] Example 50:
4-[2-(4-chlorophenyl)-4-(4-bromophenyl)-1H-imidazol-1-y-
l]benzenesulfonamide;
[1082] Example 51:
4-[2-(4-chlorophenyl)-4-1,2-naphthyl)-1H-imidazol-1-yl]-
benzenesulfonamide;
[1083] Example 52:
4-[2-(4-chlorophenyl)-4-[4-(trifluoromethoxy)phenyl]-1H-
-imidazol-1-yl]benzenesulfonamide;
[1084] Example 53:
4-[2,4-bis(4-chlorophenyl)-1H-imidazol-1-yl]benzenesulf-
onamide;
[1085] Example 54:
4-[2-(4-chlorophenyl)-4-(3-chlorophenyl)-1H-imidazol-1--
yl]benzenesulfonamide;
[1086] Example 55:
4-[2-(4-chlorophenyl)-4-[4-(methoxy)phenyl]-1H-imidazol-
-1-yl]benzenesulfonamide;
[1087] Example 56:
4-[2-(4-chlorophenyl)-4-(3-fluorophenyl)-1H-imidazol-1--
yl]benzenesulfonamide;
[1088] Example 57:
4-[2-(4-chlorophenyl)-4-[(4-chlorophenoxy)methyl]-1H-im-
idazol-1-yl]benzenesulfonamide;
[1089] Example 58:
4-[2-(3,4-methylenedioxyphenyl)-4-(trifluoromethyl)-1H--
imidazol-1-yl]benzenesulfonamide;
[1090] Example 59:
4-[2-(3-fluoro-4-methoxyphenyl)-4-(trifluoromethyl)-1H--
imidazol-1-yl]benzenesulfonamide;
[1091] Example 60:
4-[2-(4-chlorophenyl)-4-[(phenylthio)methyl]-1H-imidazo-
l-1-yl]benzenesulfonamide;
[1092] Example 61:
4-[2-(4-chlorophenyl)-4-[(N-methyl-N-phenylamine)methyl-
]-1H-imidazol-1-yl]benzenesulfonamide;
[1093] Example 62:
4-[2-(4-chlorophenyl)-4-[(2-quinolylmethoxy)methyl]-1H--
imidazol-1-yl]benzenesulfonamide;
[1094] Example 63:
4-[2-(4-chlorophenyl)-4-methoxymethyl-1H-imidazol-1-yl]-
benzenesulfonamide;
[1095] Example 64:
4-[2-(4-fluorophenyl)-4-(trifluoromethyl)-1H-imidazol-1-
-yl]benzenesulfonamide;
[1096] Example 65:
4-[2-phenyl-4-(trifluoromethyl)-1H-imidazol-1-yl]benzen-
esulfonamide; and
[1097] Example 66:
4-[2-(4-trifluoromethylphenyl)-4-(trifluoromethyl)-1H-i-
midazol-1-yl]benzenesulfonamide.
[1098] The following imidazole derivative was prepared by the
procedure described in Example 28:
[1099] Example 67:
1-methyl-3-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromet-
hyl-1H-imidazol-2-yl]-1H-indole.
[1100] The following imidazole derivatives in Tables I-IV were
obtained according to procedures of Schemes I-XV. Many of these
were synthesized by using the experimental conditions given in
Examples 1-5, and 44. The sulfonamide derivatives were synthesized
from the corresponding sulfones using experimental procedure given
for Examples 26-27, and 45 and from protected nitrobenzenes as in
Example 179.
1TABLE I Characterization of Compounds 68 Elemental Analysis mp
Calc'd Found Example X DSC (.degree. C.) C H N S C H N S 68
4-CH.sub.3 263 53.54 3.70 11.02 8.41 53.91 3.62 10.71 8.57 69
3-CH.sub.3 222.9 53.54 3.70 11.02 8.41 53.81 3.56 10.89 8.54 70
3-Cl 204.1 47.82 2.76 10.46 7.98 48.09 2.50 10.09 8.16 71 3, 5-diF,
4-OCH.sub.3 245.1 57.27 3.85 10.02 7.64 56.94 3.77 9.78 7.50 72 H
234-235 52.31 3.29 11.44 8.71 52.40 3.27 11.06 8.44 73 3,4-diF
215.9 47.65 2.50 10.42 7.95 47.68 2.44 10.25 8.07 74 3-Cl,
4-OCH.sub.3 212.0 47.29 3.03 9.73 7.43 47.41 2.76 9.49 7.48 75 3-F
204-205 49.74 3.13 10.88 8.30 49.99 2.95 10.49 8.45 76 4-Cl,
5-OCH.sub.3 208-209 47.29 3.03 9.73 7.43 47.21 2.95 9.62 7.73 77
3-F, 5-OCH.sub.3 208.8 49.16 3.15 10.12 7.72 49.31 2.95 9.84 7.88
78 3-Br, 4-OCH.sub.3 208-210 41.69 2.98 8.58 6.55 41.52 2.9 7.81
6.14 79 2-F 169-171 49.87 2.88 10.9 8.32 49.5 2.83 10.34 8.61 80
3-Br 203-205 43.07 2.48 9.42 7.19 42.71 2.44 8.94 6.68 81 3-Cl,
4-SCH.sub.3 205-207 45.59 2.93 9.38 14.32 46.00 3.11 8.96 14.29 82
3-Cl, S-CH.sub.3 219-221 49.1 3.15 10.11 7.71 49.44 3.11 9.7 7.89
83 3-F, 5-CH.sub.3 230-231 51.13 3.28 10.52 8.03 51.49 3.51 10.00
8.15 84 3-CF.sub.3 208.8 46.90 2.55 9.65 7.37 47.30 2.54 9.47
7.49
[1101]
2TABLE II Characterization of Compounds 69 Elemental Analysis mp
Calc'd Found Example X DSC (.degree. C.) C H N S C H N S 85 3,4-diF
159.5 50.75 2.76 6.96 8.80 50.66 2.82 6.87 8.30 86 3-CH.sub.3 169.8
56.84 3.97 7.36 8.43 56.88 3.76 7.26 8.81 87 3-Cl 175.4 50.94 3.02
6.99 8.00 51.06 3.06 6.93 8.13 88 3-F 189.3 53.13 3.15 7.29 8.34
53.50 3.16 7.22 8.46 89 4-F, 3-CH.sub.3 166.9 54.27 3.54 7.03 8.05
54.47 3.40 6.88 8.31 90 3-CF.sub.3 168.2 49.77 2.78 6.45 7.38 49.91
2.60 6.34 7.68 91 3,5-diF, 4-OCH.sub.3 174.7 50.00 3.03 6.48 7.42
50.00 3.03 6.33 7.44 92 3-CH.sub.2OCH.sub.3 101.9 55.60 4.18 6.83
7.81 55.50 4.14 6.72 8.06 93 3-Cl, 4-OCH.sub.3 193.3 50.18 3.28
6.50 7.44 49.78 3.32 6.39 7.42 94 3,4-diCH.sub.3 187-188 57.86 4.34
7.10 8.13 57.59 4.23 7.20 8.05 95 4-OCH.sub.3 167.5 54.54 3.81 7.07
8.09 54.32 3.88 6.90 8.24 96 3-OCH.sub.3 143.2 54.54 3.81 7.07 8.09
54.27 3.82 6.91 8.31 97 4-Cl, 5-OCH.sub.3 215.3 50.18 3.28 6.50
7.44 50.20 3.20 6.23 7.76 98 3-F, 5-OCH.sub.3 178-179 52.17 3.41
6.76 7.74 52.07 3.29 6.66 7.87 99 4-SCH.sub.3 193-195 52.42 3.67
6.79 15.55 52.19 3.63 6.61 15.55 100 4-SO.sub.2CH.sub.3 215-216
48.64 3.4 6.3 14.43 48.87 3.47 6.24 14.36 101 3,5-CH.sub.3,
4-OCH.sub.3 167-169 56.6 4.51 6.6 7.55 56.04 4.61 6.44 7.72 102
2,5-CH.sub.3, 4-OCH.sub.3 193-194 56.6 4.51 6.6 7.55 56.63 4.65
6.47 7.99 103 2-F 192-192 53.13 3.15 7.29 8.34 53.55 3.55 6.89 8.55
104 2-Cl 201-203 50.94 3.02 6.99 8.00 50.86 3.06 6.88 7.83 105
4-N(CH.sub.3).sub.2 219-221 55.74 4.43 10.26 7.83 55.19 4.00 10.06
7.81 106 3-F, 4-N(CH.sub.3).sub.2 163-164 53.59 4.01 9.83 7.5 53.48
3.79 9.73 7.67 107 3-Br 163-165 45.86 3.73 6.29 7.2 45.84 2.59 6.16
7.37 108 3-NO.sub.2 207-209 49.64 2.94 10.21 7.79 49.48 3.01 10.07
7.81 109 4-NH(CH.sub.3) 200-202 54.68 4.08 10.63 8.11 54.74 3.98
10.42 7.96 110 3-NH.sub.2 218-200 53.54 3.71 1.02 8.41 52.92 3.58
10.67 8.6 111 3-NH(CH.sub.3) 90-92 54.68 4.08 10.63 8.11 54.56 4.12
10.28 8.09 112 3-F, 4-NH(CH.sub.3) 205-206 52.3 3.66 10.16 7.76
51.74 3.51 9.96 7.99 113 3-SCH.sub.3 135-137 52.42 3.67 6.79 15.55
52.29 3.57 6.74 15.22 114 3-Cl, 5-CH.sub.3 171-173 52.12 3.4 6.75
7.73 51.95 3.22 6.69 7.9 115 3,5-Cl, 4-OCH.sub.3 198-202 46.47 2.82
6.02 15.24 46.49 2.77 5.81 4.73 116 3-F, 4-CH.sub.3 173-176 54.27
3.54 7.03 8.05 54.65 3.64 6.74 8.14 117 3-F, 5-CH.sub.3 178-181
54.27 3.54 7.03 8.05 53.85 3.29 6.81 8.3 118 4-Cl, 3-CH.sub.3
182-184 52.12 3.4 6.25 7.73 52.36 3.49 6.78 7.95 119 3-Cl,
4-N(CH.sub.3).sub.2 178-179 51.41 3.86 9.47 7.22 51.44 3.65 9.34
7.28 120 3-Cl, 4-SCH.sub.3 281-184 48.38 3.16 6.27 14.35 47.9 3.05
5.97 13.84 121 2-CH.sub.3 132-134 56.84 3.97 7.36 8.43 56.75 3.82
7.28 8.59 122 3-N(CH.sub.3).sub.2 170-171 55.74 4.43 10.26 7.83
55.66 4.66 9.95 7.7
[1102]
3TABLE III Characterization of Compounds 70 Elemental Analysis mp
Calc'd Found Example X DSC (.degree. C.) C H N S C H N S 123 3-Cl,
4-OCH.sub.3 222.1 48.17 3.59 6.24 7.14 48.11 3.83 5.80 7.21 124
3-CH.sub.3, 4-OCH.sub.3 173.7 54.85 4.70 6.73 7.71 54.65 4.45 6.58
8.30 125 4-OCH.sub.3 168.5 52.17 4.13 6.76 7.74 52.32 4.20 6.52
7.84 126 3-OCH.sub.3 176.4 52.17 4.13 6.76 7.74 51.80 4.12 6.55
8.02 127 4-Cl, S-OCH.sub.3 137-138 46.85 3.80 6.07 6.95 46.45 3.72
5.84 7.25 128 3-F, 5-OCH.sub.3 185-186 50.00 3.73 6.48 7.42 50.12
3.78 6.36 7.70 129 4-SCH.sub.3 187-190 50.22 3.98 6.51 14.9 49.99
3.88 6.32 14.95 130 3-F, 4-N(CH.sub.3).sub.2 212-214 51.23 4.3 9.43
7.2 50.58 4.38 9.09 7.23
[1103]
4TABLE IV Characterization of Compounds Elemental Analysis mp
Calc'd Found Ex. R Y Z DSC (.degree. C.) C H N S C H N S 131
NH.sub.2 CF.sub.3 3-methoxy-5-pyridyl 262-264 48.24 3.29 14.06 8.05
48.49 3.34 13.55 8.01 132 CH.sub.3 CF.sub.3 3-methoxy-5-pyridyl
207-208 51.38 3.55 10.57 8.07 50.98 3.31 10.38 8.15 133 CH.sub.3
CF.sub.3 2-isoquinolyl 264.5 57.55 3.38 10.07 7.68 57.52 3.36 9.98
7.60 134 CH.sub.3 CF.sub.3 2-pyrazinyl 200.6 48.91 3.01 15.21 48.79
2.84 15.00 135 CH.sub.3 CF.sub.3 2-methyl-4-thiazolyl 197.2 46.51
3.12 10.85 16.35 46.53 3.28 10.62 16.67 136 NH.sub.2 H
5-methyl-2-pyridyl 216 50.26 3.43 14.65 50.58 3.49 14.50 137
CH.sub.3 CH.sub.3 3-pyridyl 130-131 57.99 4.56 12.68 57.84 4.83
12.49 138 NH.sub.2 CF.sub.3 6-methyl-2-pyridyl 260 50.26 3.43 14.65
50.33 3.60 14.39 139 CH.sub.3 CF.sub.3 4-methyl-3-pyridyl 192-193
53.54 3.70 11.02 8.41 53.40 3.62 10.68 8.60 140 NH.sub.2 CF.sub.3
2-methyl-4-thiazolyl 250.8 43.30 2.85 14.43 16.51 43.28 2.79 14.14
16.48 141 NH.sub.2 CF.sub.3 4-methyl-3-pyridyl 224-227 50.26 3.43
14.65 8.39 49.94 3.49 14.44 8.58 142 CH.sub.3 CF.sub.3
3-methyl-2-pyridyl 178 53.54 3.70 11.02 53.44 3.49 10.92 143
CH.sub.3 CF.sub.3 1-isoquinolyl 200-201 57.55 3.38 10.07 57.58 3.38
10.03 144 NH.sub.2 CF.sub.3 3-methyl-2-pyridyl 235 50.26 3.43 14.65
49.92 3.34 14.43 145 CH.sub.3 CF.sub.3 3-quinolyl 221 57.26 3.47
9.66 57.16 3.39 9.59 146 NH.sub.2 CF.sub.3 2-thienyl 225.5-226.5
45.04 2.70 11.25 17.18 44.92 2.62 11.09 17.48 147 CH.sub.3 CF.sub.3
5-bromo-3-pyridyl 235-237 43.07 2.48 9.42 7.19 42.64 2.34 9.22 7.69
148 CH.sub.3 CF.sub.3 2-methyl-4-oxazolyl 234.9 48.52 3.26 11.32
8.63 48.51 3.19 11.22 8.89 149 NH.sub.2 CF.sub.3 5-bromo-3-pyridyl
266-268 40.28 2.25 12.53 7.17 40.16 2.26 12.35 7.20 150 NH.sub.2
CF.sub.3 2-quinolyl 245 54.54 3.13 13.39 54.35 2.92 13.38 151
CH.sub.3 CF.sub.2H 3-pyridyl 212-213.5 55.01 3.75 12.03 54.86 3.87
11.78 152 CH.sub.3 CN 3-pyridyl 193.9 58.44 3.68 17.04 58.37 3.55
16.78 153 CH.sub.3 CN 5-methyl-3-pyridyl 184.3 60.34 4.17 16.56
60.08 4.22 16.23 154 NH.sub.2 CN 5-methyl-3-pyridyl 280-283 54.46
3.71 19.85 54.84 3.83 19.50 155 CH.sub.3 71 3-pyridyl ND 62.14 4.76
9.45 62.11 4.70 9.25
EXAMPLE 156
[1104] 72
Ethyl
[2-(4-chlorophenyl)-4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4.5-dihyd-
ro-1H-imidazol-4-yl] carboxylate
[1105] A mixture of 4-chloro-N-[4-(methylsulfonyl)phenyl]
benzenecarboximidamide (Example 1, step 1) (1.00 g, 3.34 mmol),
sodium bicarbonate (544 mg, 6.47 mmol), and ethyl bromopyruvate
(1.40 g, 7.19 mmol) in 50 ml of isopropanol was stirred at reflux
for 7 hours. After cooling, the mixture was evaporated. The residue
was partitioned between dichloromethane and water, and the aqueous
layer further extracted with dichloromethane. The combined organic
extracts were dried over sodium sulfate, filtered, and evaporated.
Chromatography of the residue over silica gel using mixtures of
ethyl acetate and toluene as eluents gave the title compound as a
pale yellow solid: mp (DSC) 162.degree. C. Anal. Calc'd. for
C.sub.19H.sub.19ClN.sub.2O.sub.5S (MW 422.89): C, 53.96; H, 4.53;
N, 6.62. Found: C, 53.99; H, 4.49; N, 6.42.
EXAMPLE 157
[1106] 73
Ethyl
[2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazol-4-yl]
carboxylate
[1107] A mixture of 4-chloro-N-[4-(methylsulfonyl)phenyl]
benzenecarboximidamide (Example 1, step 1) (12.1 g, 39.2 mmol),
sodium bicarbonate (6.58 g, 78.3 mmol), and 90% ethyl bromopyruvate
(16.9 g) in 480 ml of 2-propanol was stirred at reflux overnight.
After cooling, the mixture was concentrated. The residue was
partitioned between dichloromethane and water and the aqueous layer
further extracted with dichloromethane. The combined organic
extracts were dried over sodium sulfate, filtered, and evaporated.
Trituration of the residue with ethyl acetate gave the title
compound as a pale beige, crystalline solid (6.61 g): mp (DSC)
218.degree. C. Anal. Calc'd. for C.sub.19H.sub.17ClN.sub.2O.-
sub.4S (MW 404.87): C, 56.37; H, 4.23; N, 6.92. Found: C, 56.28; H,
4.13; N, 6.80.
EXAMPLE 158
[1108] 74
2-(4-Chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole-4-methanol
[1109] To a solution of 4.00 g (9.88 mmol) of Example 157 in 125 ml
of dichloromethane stirring in a dry ice/isopropanol bath was added
24.7 ml of 1M diisobutylaluminum hydride in toluene (containing
24.7 mmol). The mixture was warmed to room temperature overnight.
Excess reagent was quenched with methanol, and the resulting
mixture was washed with 15% aqueous acetic acid. The aqueous layer
was further extracted with dichloromethane, and the combined
organic extracts were dried over sodium sulfate. After filtration
and evaporation, the residue was triturated with 50% ethyl
acetate/hexane, and the alcohol was obtained as a white solid: m.p.
205-208.degree. C. Anal. Calc'd. for C.sub.17H.sub.15ClN.sub.-
2O.sub.3S.multidot.1/2 H.sub.2O (MW 371.84): C, 54.91; H, 4.07: N,
7.53. Found: C, 54.75; H, 3.96; N, 7.17.
EXAMPLE 159
[1110] 75
2-(4-Chlorophenyl)-4-[(4-methylphenoxy)methyl]-1-[4-(methylsulfonyl)phenyl-
]-1H-imidazole
[1111] Step 1: Preparation of
4-chloromethyl-2-(4-chlorophenyl)-1-[4-(meth-
ylsulfonyl)phenyl]-1H-imidazole
[1112] A suspension of the title product of Example 158 (1.82 g,
4.96 mmol) in 10 ml of chloroform was treated with thionyl chloride
(1.18 g, 9.92 mmol), and the resulting mixture was stirred at
reflux for 1 hour. Another 1.18 g of thionyl chloride was added,
and reflux continued for 1 hour. After cooling, the mixture was
evaporated and the residue was chromatographed over silica gel
using 50% ethyl acetate/hexane as eluent to give the chloromethyl
compound as a very pale yellow crystalline solid (1.26 g): m.p.
166-169.degree. C.
[1113] Step 2: Preparation of
2-(4-Chlorophenyl)-4-[(4-methylphenoxy)methy-
l]-1-[4-(methylsulfonyl)phenyl]-1H-imidazole
[1114] A mixture of 122 mg (0.32 mmole) of
4-chloromethyl-2-[4-chloropheny-
l)-1-(4-(methylsulfonyl)phenyl]-1H-imidazole (Step 1), p-cresol (69
mg, 0.64 mmole), and potassium carbonate (110 mg, 0.8 mmole) in 5
ml of dimethylformamide was stirred at 85-90 .degree. C. for 6
hours. After cooling, the mixture was partitioned between ethyl
acetate and aqueous sodium chloride, and the aqueous layer was
extracted with ethyl acetate. The combined organic extracts were
washed with brine, dried over sodium sulfate, filtered, and
evaporated. Chromatography of the residue over silica gel using
mixtures of ethyl acetate and hexane gave
2-(4-chlorophenyl)-4-[(4-methylphenoxy)methyl]-1-[4-(methylsulfonyl)pheny-
l]-1H-imidazole as a pure white solid (118 mg): m.p. (DSC)
193.degree. C. Anal. Calc'd. for C.sub.24H.sub.21ClN.sub.2O.sub.3S
(MW 452.96): C, 63.64; H, 4.67; N, 6.18. Found: C, 63.42; H, 4.64;
N, 5.79.
EXAMPLE 160
[1115] 76
2-(4-Chlorophenyl)-4-[[(4-methylphenoxy)thio]methyl]-1-[4-(methylsulfonyl)-
phenyl]-1H-imidazole
[1116] To a solution of
4-chloromethyl-2-(4-chlorophenyl)-1-[4-(methylsulf-
onyl)phenyl]-1H-imidazole (Example 159, Step 1) in 5 ml of
dimethylformamide was added p-thiocresol (98 mg, 0.79 mmole) and
anhydrous potassium carbonate (136 mg, 0.985 mmole), and the
mixture was stirred rapidly overnight. The mixture was partitioned
between ethyl acetate and water, and the aqueous layer was
extracted with ethyl acetate The combined organic extracts were
dried over sodium sulfate, filtered and evaporated. Chromatography
of the residue over silica gel using mixtures of ethyl acetate and
hexane as eluent gave the title compound as a glassy solid: m.p.
(DSC) 51.degree. C. Anal. Calc'd. for
C.sub.24H.sub.21ClN.sub.2O.sub.2S.sub.2 (MW 469.03): C, 61.46; H,
4.51; N, 5.97. Found: C, 61.38; H, 4.68; N. 5.81.
EXAMPLE 161
[1117] 77
2-(4-Chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-[(4-methylthio)methyl]-1-
H-imidazole
[1118] To a solution of
4-chloromethyl-2-(4-chlorophenyl)-1-[4-(methylsulf-
onyl)phenyl]-1H-imidazole (Example 159, Step 1) (150 mg, 0.394
mmole) in 5 ml of dimethylformamide was added sodium thiomethoxide
(55 mg, 0.79 mmole) and the mixture was stirred for three days. The
mixture was partitioned between ethyl acetate and water, and the
aqueous layer was extracted with ethyl acetate. The combined
organic extracts were washed with brine, dried over sodium sulfate,
filtered, and evaporated. Chromatography of the residue over silica
gel using mixtures of ethyl acetate and hexane as eluents gave the
title compound as a pale yellow oil (64 mg): Anal. Calc'd. for
C.sub.18H.sub.17ClN.sub.2O.sub.2S.sub.2.mu- ltidot.1/2 H.sub.2O (MW
401.93): C, 53.79; H, 4.26; N, 6.97. Found: C, 53.97; H, 4.43; N,
6.84.
EXAMPLE 162
[1119] 78
2-(4-Chlorophenyl)-4-(4-methoxymethyl)-1-[4-(methylsulfonyl)phenyl]-1H-imi-
dazole
[1120] To a solution of 46 mg (2.0 mmol) of sodium metal in 2 ml of
methanol was added a solution of
4-chloromethyl-2-(4-chlorophenyl)-1-[4-(-
methylsulfonyl)phenyl]-1H-imidazole (Example 159, Step 1) (167 mg,
0.438 mmole) and the mixture was stirred overnight. The mixture was
partitioned between ethyl acetate and water, and the aqueous layer
was extracted with ethyl acetate. The combined organic extracts
were washed with brine, dried over sodium sulfate, filtered, and
evaporated. Chromatography of the residue over silica gel using
ethyl acetate as the eluent gave the title compound as a white
crystalline solid (72%): mp 171-172.degree. C. Anal. Calc'd. for
C.sub.18H.sub.17ClN.sub.2O.sub.3S (MW 376.86): C, 57.37; H, 4.55;
N, 7.43. Found: C, 57.29; H, 4.42; N, 7.33.
EXAMPLE 163
[1121] 79
2-(4-Chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole-4-carboxaldeh-
yde
[1122] To 8 ml of a 1:1 mixture of dimethyl sulfoxide and
dichloromethane stirring in a dry ice/isopropanol bath under
nitrogen was added dropwise oxalyl chloride (321 .mu.l, 3.69 mmol).
After stirring for 10 minutes, a solution of
2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole--
4-methanol (Example 158) (670 mg, 1.85 mmol) in 25 ml of a 1:1
mixture of dimethyl sulfoxide and dichloromethane. Stirring was
continued while warming to 0.degree. C., where it was maintained
for 15 minutes. Triethylamine (1.87 g, 18.5 mmol) was added, and
the mixture was stirred overnight while warming to room
temperature. The mixture was partitioned between dichloromethane
and water, the organic layer was washed with water and then brine,
dried over sodium sulfate, filtered, and evaporated. Chromatography
of the residue over silica gel using mixtures of ethyl acetate and
hexane gave the title compound as an off-white solid (330 mg): mp
(DSC) 203.degree. C. Anal. Calc'd. for
C.sub.17H.sub.13ClN.sub.2O.sub.3S (MW 360.82): C, 56.59; H. 3.63;
N, 7.76. Found: C, 56.24; H, 3.62; N, 7.50.
EXAMPLE 164
[1123] 80
2-(4-Chlorophenyl)-4-fluoromethyl-1-[4-(methylsulfonyl)phenyl]-1H-imidazol-
e
[1124] To a suspension of
2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]--
1H-imidazole-4-methanol (Example 158) (250 mg, 0.689 mmole) in 5 ml
of dichloromethane was added dropwise a solution of diethylamino
sulfur trifluoride (DAST) (166 mg, 1.03 mmole) in 1 ml of
dichloromethane. As the addition proceeded, the mixture became
homogeneous. After stirring for two hours, water was added, the
layers separated and the aqueous layer was extracted with
dichloromethane. The combined organic extracts were dried over
sodium sulfate, filtered and evaporated. Chromatography of the
residue over silica gel using 60% ethyl acetate in hexane gave the
title compound as a very slightly yellow solid (106 mg): mp (DSC)
165.degree. C. Anal. Calc'd. for
C.sub.17H.sub.14ClFN.sub.2O.sub.2S.multi- dot.1/4 H.sub.2O (MW
369.33): C, 55.29; H, 3.82; N, 7.59. Found: C, 55.15; H, 3.82; N,
7.42.
EXAMPLE 165
[1125] 81
4-Azidomethyl-2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole
[1126] A mixture of
4-chloromethyl-2-(4-chlorophenyl)-1-[4-(methylsulfonyl-
)phenyl]-1H-imidazole (Example 159, Step 1) (500 mg, 1.31 mmol) and
sodium azide (256 mg, 3.94 mmol) in 5 ml of dimethylformamide was
stirred overnight at room temperature. The mixture was warmed to
80.degree. C. for one hour and then cooled. The mixture was
partitioned between ethyl acetate and water, and the aqueous layer
was extracted with ethyl acetate. The combined organic extracts
were washed with brine, dried over sodium sulfate, filtered, and
evaporated. Chromatography of the residue over silica gel using 50%
ethyl acetate in hexane as the eluent gave the title compound as a
pure white crystalline solid (496 mg): mp (DSC) 186.degree. C.
Anal. Calc'd. for C.sub.17H.sub.14ClN.sub.5O.sub.2S (MW 387.85): C,
52.64; H, 3.64; N, 18.06. Found: C, 52.46; H, 3.77; N, 17.84.
EXAMPLE 166
[1127] 82
2-(4-Chlorophenyl)-4-difluoromethyl-1-[4-(methylsulfonyl)phenyl]-1H-imidaz-
ole
[1128] To a suspension of
2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]--
1H-imidazole-4-carboxaldehyde (Example 163) (150 mg, 0.416 mmole)
in 5 ml of dichloromethane was added dropwise a solution of DAST
(201 mg, 1.25 mmol) of in 1 ml of dichloromethane, producing a
homogeneous solution. After stirring at room temperature for 30
minutes, the mixture was partitioned between dichloromethane and
water, and the aqueous layer was extracted with dichloromethane.
The combined organic extracts were dried over sodium sulfate,
filtered, and evaporated. Chromatography of the residue over silica
gel using 50% ethyl acetate in hexane as the eluent, followed by
crystallization from ethyl acetate and hexane gave the title
compound as very small pale beige plates (21 mg): m.p.
179-180.degree. C. Anal. Calc'd. for
C.sub.17H.sub.13ClF.sub.2N.sub.2O.sub.2S (MW 382.82): C, 53.34; H,
3.42; N, 7.32. Found: C, 53.42; H, 3.26; N, 7.08.
EXAMPLE 167
[1129] 83
2-(4-Chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-[[(4-phenylmethyl)thio]m-
ethyl]-1H-imidazole
[1130] To a solution of benzyl mercaptan (195 mg, 1.6 mmol) in 5 ml
of dimethylformamide was added 63 mg of a 60% dispersion of sodium
hydride in mineral oil. After gas evolution ceased,
4-chloromethyl-2-(4-chlorophe-
nyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole (Example 159, Step
1) (300 mg, 0.787 mmole) was added as a solid and stirring
continued overnight. The mixture was partitioned between ethyl
acetate and water, and the aqueous layer was extracted with ethyl
acetate. The combined organic extracts were washed with brine,
dried over sodium sulfate, filtered, and evaporated. Radial
chromatography of the residue over a 2 mm layer of silica gel using
50% ethyl acetate in hexane as the eluent gave the title compound
as a pale yellow solid (343 mg): mp(DSC) 41.degree. C. Anal.
Calc'd. for C.sub.24H.sub.21ClN.sub.2O.sub.2S.sub.2 (MW 469.03): C,
61.46; H, 4.51; N, 5.97. Found: C, 61.06; H, 4.34; N, 5.80.
EXAMPLE 168
[1131] 84
2-(4-Chlorophenyl)-4-[[(1-methylethyl)thio]methyl]-1-[4-(methylsulfonyl)ph-
enyl]-1H-imidazole
[1132] The title compound was prepared as a white solid by the
method of Example 167 except that 2-mercaptopropane was used in
place of benzyl mercaptan: mp (DSC) 118.degree. C. Anal. Calc'd.
for C.sub.20H.sub.21ClN.sub.2O.sub.2S.sub.2 (MW 420.98): C, 57.06;
H, 5.03; N, 6.65. Found: C, 56.72; H. 4.89; N, 6.42.
EXAMPLE 169
[1133] 85
2-(4-Chlorophenyl)-4-[[(cyclohexyl)thio]methyl]-1-[4-(methylsulfonyl)pheny-
l]-1H-imidazole
[1134] The title compound was prepared as a white solid by the
method of Example 167 except that cyclohexyl mercaptan was used in
place of benzyl mercaptan, and that 40% ethyl acetate in hexane was
used as the chromatography eluent: mp (DSC) 48.degree. C. Anal.
Calc'd. for C.sub.23H.sub.25ClN.sub.2O.sub.2S.sub.2 (MW 461.05): C,
59.92; H, 5.47; N, 6.08. Found: C, 59.63; H, 5 5.52; N, 5.96.
EXAMPLE 170
[1135] 86
2-(4-Chlorophenyl)-4-[[(2-chlorophenyl)thio]methyl]-1-[4-(methylsulfonyl)p-
henyl]-1H-imidazole
[1136] To a solution of
4-chloromethyl-2-(4-chlorophenyl)-1-[4-(methylsulf-
onyl)phenyl]-1H-imidazole (Example 159, Step 1) (250 mg, 0.656
mmol) and 2-chlorothiophenol (190 mg, 1.31 mmol) in 5 ml of
dimethylformamide was added potassium carbonate (226 mg, 1.64
mmol). The mixture was stirred rapidly overnight at room
temperature and partitioned between ethyl acetate and water. The
aqueous layer was extracted with ethyl acetate, the combined
organic extracts were washed with brine, and dried over sodium
sulfate. The solution was filtered and then concentrated.
Chromatography of the residue over silica gel using 50% ethyl
acetate in hexane as the eluent followed by crystallization gave
the title compound as a pure white crystalline solid (147 mg): mp
(DSC) 153.degree. C. Anal. Calc'd. for
C.sub.23H.sub.18Cl.sub.2N.sub.2O.sub.2S.sub.2 (MW 489.44): C,
56.44; H, 3.71; N, 5.72. Found: C, 56.51; H, 3.54; N, 5.57.
EXAMPLE 171
[1137] 87
2-(4-Chlorophenyl)-4-[[(2-methylphenyl)thio]methyl]-1-[4-(methylsulfonyl)p-
henyl]-1H-imidazole
[1138] To a solution of
4-chloromethyl-2-(4-chlorophenyl)-1-[4-(methylsulf-
onyl)phenyl]-1H-imidazole (Example 159, Step 1) (250 mg, 0.656
mmol) and o-thiocresol (163 mg, 1.31 mmol) in 5 ml of dry
dimethylformamide was added anhydrous potassium carbonate (226 mg,
1.64 mmol). The mixture was stirred rapidly overnight at room
temperature. The mixture was then partitioned between ethyl acetate
and water. The aqueous layer was further extracted with ethyl
acetate, the combined organic extracts washed with brine, and dried
over sodium sulfate. The solution was filtered and concentrated.
Chromatography of the residue over silica gel using 40% ethyl
acetate in hexane gave the title compound as a very pale yellow
solid (210 mg): mp (DSC) 51.degree. C. Anal. Calc'd. for
C.sub.24H.sub.21ClN.sub.2O.sub.2S.sub.2 (MW 469.03): C, 61.46; H,
4.51; N, 5.97. Found: C, 61.16; H, 4.50; N, 5.86.
EXAMPLE 172
[1139] 88
2-(4-Chlorophenyl)-4-[[(2,6-dichlorophenyl)thio]methyl]-1-[4-(methylsulfon-
yl)phenyl]-1H-imidazole
[1140] To a solution of
4-chloromethyl-2-(4-chlorophenyl)-1-[4-(methylsulf-
onyl)phenyl]-1H-imidazole (Example 159, Step 1) (250 mg, 0.656
mmole) and 2,6-dichlorothiophenol in 5 ml of dimethylformamide (235
mg, 1.31 mmol) was added 226 mg (1.64 mmol) of potassium carbonate.
The resulting mixture was stirred rapidly at room temperature for
two days. The mixture was partitioned between ethyl acetate and
water and the aqueous layer was further extracted with ethyl
acetate. The combined organic extracts were washed with brine,
dried over sodium sulfate, filtered, and evaporated. Chromatography
of the residue over silica gel using 50% ethyl acetate in hexane
gave the title compound, 282 mg, as a pure white solid: mp (DSC)
202.degree. C. Anal. Calc'd. for
C.sub.23H.sub.17Cl.sub.3N.sub.2O.sub.2S.- sub.2 (MW 523.89): C,
52.73; H, 3.27; N, 5.35. Found: C, 52.55; H, 2.98; N, 5.19.
EXAMPLE 173
[1141] 89
2-(4-Chlorophenyl)-4-[[[2-(1-methylethyl)phenyl]thio]methyl]-1-[4-(methyls-
ulfonyl)phenyl]-1H-imidazole
[1142] The title compound was prepared as a white solid by the
method of Example 172 except that 2-isopropylthiophenol was used in
place of 2,6-dichlorothiophenol and that 40% ethyl acetate in
hexane was used as chromatography eluent: m.p. 68-70.degree. C.
Anal. Calc'd. for
C.sub.26H.sub.25ClN.sub.2O.sub.2S.sub.2.multidot.1/4H.sub.2O (MW
501.58): C, 62.26; H, 5.02; N, 5.59. Found: C, 62.36; H, 5.11; N,
5.45.
EXAMPLE 174
[1143] 90
2-(4-Chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole-4-carbonitril-
e
[1144] A solution of 82 mg (0.23 mmole) of
2-(4-chlorophenyl)-1-[4-(methyl-
sulfonyl)phenyl]-1H-imidazole-4-carboxaldehyde (Example 163) and 51
mg (0.45 mmole) of hydroxylamine O-sulfonic acid in 10 ml of
absolute ethanol and 1 ml of pyridine was stirred at reflux
overnight. After cooling, the mixture was evaporated, and the
residue was taken up in dichloromethane. The solution was washed
with aqueous sodium bicarbonate, dried over sodium sulfate,
filtered, and evaporated. Chromatography of the residue over silica
gel using 50% ethyl acetate in hexane as the eluent gave the title
compound, 71 mg, as a pure white crystalline solid: mp (DSC)
205.degree. C. Anal. Calc'd. for C.sub.17H.sub.12ClN.sub.3O.sub.-
2S.multidot.1/4 H.sub.2O (MW 362.32): C, 56.36; H, 3.34; N, 11.60.
Found: C, 56.49; H, 3.27; N, 11.45.
EXAMPLE 175
[1145] 91
2-(4-Chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole-4-acetonitril-
e
[1146] A mixture of 250 mg (0.656 mmole) of
4-chloromethyl-2-[4-chlorophen-
yl)-1-(4-(methylsulfonyl)phenyl]-1H-imidazole (Example 159, Step 1)
and 86 mg (1.3 mmol) of potassium cyanide in 4 ml of
dimethylformamide was stirred at 85.degree. C. for 24 hours. An
additional 86 mg of potassium cyanide was added, and stirring
continued for 8 hours. After cooling, the mixture was partitioned
between dichloromethane and water and the aqueous layer further
extracted with dichloromethane. The combined organic extracts were
washed with brine, dried over sodium sulfate, filtered, and
evaporated chromatography of the residue over silica gel using 60%
ethyl acetate in toluene, followed by trituration with ethyl
acetate gave the title compound, 59 mg, as a very pale yellow
crystalline solid: mp (DSC) 197.degree. C. Anal. Calc'd. for
C.sub.18H.sub.14ClN.sub.3O.sub.2S (MW 371.85): C, 58.14; H, 3.80;
N, 11.30. Found: C, 57.92; H, 3.57; N, 11.01.
EXAMPLE 176
[1147] 92
2-(4-Chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole-4-acetic
acid
[1148] A mixture of 50 mg (0.13 mmole) of the title product of
Example 175 and 5 ml of concentrated hydrochloric acid was stirred
at reflux for one hour. After cooling, the mixture was evaporated
and the residue taken up in water. The mixture was basified with
aqueous sodium bicarbonate solution, and the pH then adjusted to 4
with acetic acid. The mixture was extracted with dichloromethane
and the combined organic extracts dried over sodium sulfate. After
filtration, the solution was evaporated and the residue
azeotropically distilled with toluene. Trituration of the residue
with ethyl acetate gave the title compound, 31 mg, as a white
solid: m.p. 263-264.degree. C. Anal. Calc'd. for
C.sub.18H.sub.15ClN.sub.- 2O.sub.4S.multidot.1/4H.sub.2O (MW
395.35): C, 54.69; H, 3.82; N, 7.09. Found: C, 54.39; H, 3.88; N,
6.72.
EXAMPLE 177
[1149] 93
1-[2-(4-Chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole-4-yl]-1-et-
hanone
[1150] Step 1-Preparation of
2-(4-chlorophenyl)-1-[4-(methylsulfonyl)pheny-
l]-1H-imidazole-4-carboxylic acid
[1151] A suspension of ethyl
[2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phen-
yl]-1H-imidazol-4-yl] carboxylate (Example 159) (929 mg, 2.29 mmol)
in 16 ml of methanol and 16 ml of 1N aqueous sodium hydroxide was
stirred at reflux for one hour. After cooling, the mixture was
concentrated, water was added, and the resulting mixture was
acidified with acetic acid. The mixture was extracted with
dichloromethane, and the combined organic extracts were dried over
sodium sulfate, filtered, and evaporated. Acetic acid was removed
by azeotropic distillation with toluene to give the title compound,
520 mg, as a white crystalline solid: mp (DSC) 121.degree. C. Anal.
Calc'd. for C.sub.17H.sub.13ClN.sub.2O.sub.4S.multid- ot.H.sub.2O
(MW 394.83): C, 51.71; H, 3.32; N, 7.10. Found: C, 51.89; H, 3.29;
N, 6.97.
[1152] Step 2 -Preparation of
2-(4-chlorophenyl)-N-methoxy-N-methyl-1-[4-(-
methylsulfonyl)phenyl]-1H-imidazole-4-carboxamide
[1153] Oxalyl chloride (0.34 g, 2.65 mmole) in 5 ml acetonitrile
was added to 16 ml acetonitrile containing dimethylformamide (0.25
g, 3.46 mmole) cooled to 0.degree. C. After 15 minutes,
2-(4-chlorophenyl)-1-[4-(methyls-
ulfonyl)phenyl]-1H-imidazole-4-carboxylic acid from step 1 (1.0 g,
2.65 mmole) was added with 20 ml acetonitrile. After warming to
room temperature N,O-dimethylhydroxylamine HCl (0.28 g, 2.92 mmole)
and pyridine (0.42 g, 5.31 mmole) were added and the mixture was
stirred at room temperature for three days. The reaction mixture
was concentrated to give an oily solid. The amide was purified by
silica gel chromatography: Anal. Calc'd.
C.sub.19H.sub.18N.sub.3O.sub.4SCl (419.89); C, 54.35; H, 4.32; N,
10.01. Found: C, 53.96; H, 4.30; N, 9.68.
[1154] Step 3--Preparation of
1-[2-(4-chlorophenyl)-1-[4-(methylsulfonyl)p-
henyl]-1H-imidazol-4-yl]-1-ethanone
[1155] Methyl lithium-LiBr complex (1.5 M in ethyl ether) (0.47 ml,
0.7 mmol) was added by syringe to a cold (-70.degree. C.) solution
of
2-(4-chlorophenyl)-N-methoxy-N-methyl-1-[4-(methylsulfonyl)phenyl]-1H-imi-
dazole-4-carboxamide from step 2 (250 mg, 0.6 mmol) in 50 ml
tetrahydrofuran. The reaction was warmed to 0.degree. C. and
re-cooled to -60.degree. C. before additional methyl lithium (0.47
ml) was added. The reaction was warmed to room temperature. After
stirring for two days, 50 ml of 10% acetic acid was added and the
mixture was concentrated to a gum. The gum was dissolved in 50 ml
ethyl acetate, washed with water (2.times.50 ml), dried over
Na.sub.2SO.sub.4, filtered and concentrated. The product was
purified by silica gel chromatography: Anal. Calc'd.
C.sub.18H.sub.15N.sub.2O.sub.3SCl.multidot.1/4 H.sub.2O: C, 56.99;
H, 4.12; N, 7.38. Found: C, 56.88; H, 4.05; N, 7.6838
EXAMPLE 178
[1156] 94
2-(4-Chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-(phenylmethoxymethyl)-1H-
-imidazole
[1157] To a suspension of 58 mg of 60% sodium hydride in mineral
oil (containing 35 mg, 1.4 mmol) in 2 ml of dimethylformamide was
added a solution of 142 mg (1.31 mmol) of benzyl alcohol in 0.5 ml
of dimethyl formamide. The mixture was stirred while heating to
40.degree. C. After 15 minutes, 250 mg (0.656 mmole) of the title
product of Example 158 was added as a solid and stirred while
heating to 85.degree. C. The temperature was maintained for 6 hours
and then the mixture was cooled. The mixture was partitioned
between ethyl acetate and water and the aqueous layer further
extracted with ethyl acetate. The combined organic extracts were
washed with brine, dried over sodium sulfate, filtered, and
evaporated. Chromatography of the residue over silica gel using 50%
ethyl acetate in hexane as the eluent gave the title compound, 60
mg, as pure white crystalline solid, m.p. 64-65.degree. C. Anal.
Calc'd. for C.sub.24H.sub.21ClN.sub.2O.sub.3S.multidot.1/4H.sub.2O
(MW 457.56): C, 63.01; H, 4.63; N, 6.12. Found: C, 62.76; H, 4.43;
N, 6.20.
EXAMPLE 179
[1158] 95
4-[2-(2-Methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesu-
lfonamide
[1159] Step 1: Preparation of
4-[(2,5-dimethyl-1H-pyrrole-1-yl)sulfonyl]ni- trobenzene
[1160] A mixture of 4-nitrobenzenesulfonamide (30.3 g, 0.15 mol),
acetonylacetone (34.2 g, 0.30 mol) and 4-toluenesulfonic acid (3.0
g, catalyst) in 200 mL of toluene was heated at reflux under
nitrogen using a Dean-Stark trap for 18 hours. The reaction was
cooled and filtered through silica gel (700 g), eluting with
mixtures of ethyl acetate and hexane. Removal of solvent in vacuo
gave a crude brown solid. The crude product in ethyl acetate was
treated with activated charcoal, and recrystallized from ethyl
acetate and hexane to afford
4-[(2,5-dimethyl-1H-pyrrol-1-yl)sulfonyl]nitrobenzene (32.5 g, 77%)
as a light yellow solid: mp (DSC) : 101-103.degree. C. Anal.
Calc'd. for C.sub.12H.sub.12N.sub.2O.sub.4S: C, 51.42; H, 4.32; N,
9.99; S, 11.44. Found: C, 51.62; H, 4.18; N, 9.96; S, 11.31.
[1161] Step 2: Preparation of
4-[(2.5-dimethyl-1H-pyrrol-1-yl)sulfonyl]ben- zenamine
[1162] A mixture of
4-[(2,5-dimethyl-1H-pyrrol-1-yl)sulfonyl]nitrobenzene (Step 1) (7.3
g, 26 mmol) and Raney Nickel (0.7 g) in 70 mL of methanol was
hydrogenated in a Parr apparatus at a pressure of 50 psi. After 3
hours, the catalyst was filtered and the filtrate was concentrated
to give 4-[(2,5-dimethyl-1H-pyrrol-1-yl)sulfonyl]benzenamine (6.4
g) as a pale yellow solid: mp (DSC): 110-111.degree. C. Anal.
Calc'd. for C.sub.12H.sub.14N.sub.2O.sub.2S: C, 57.58; H, 5.64; N,
11.16; S, 12.81. Found: C, 57.44; H, 5.78; N, 11.11; S, 12.30.
[1163] Step 3: Preparation of
1-[4-[(2,5-dimethyl-1H-pyrrol-1-yl)sulfonyl]-
phenyl]-4,5-dihydro-2-(2-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidaz-
ol-4-ol
[1164] To a solution of sodium bis(trimethylsilyl)amide (120 mL of
1.0 M in tetrahydrofuran, 0.12 mol) was added dropwise a solution
of 4-[(2,5-dimethyl-1H-pyrrol-1-yl)sulfonyl]benzenamine (Step 2)
(28.43 g, 0.114 mol) in 35 mL of tetrahydrofuran at room
temperature. The dark solution was stirred for 10 minutes. A
solution of 3-cyano-2-methylpyridine in 20 mL of tetrahydrofuran
was added rapidly. The reaction mixture was stirred for 16 hours,
poured into 1 L of water and extracted with ethyl acetate (500 mL).
The organic layer was washed with brine, dried over magnesium
sulfate and filtered. The filtrate was concentrated to give 22.0 g
of crude amidine as a pale yellow solid which was used in next step
without purification. To a suspension of the crude amidine (21.9 g,
0.065 mol) and sodium bicarbonate (8.20 g, 0.098 mol) in 600 mL of
isopropanol at 50.degree. C., was added a solution of
3-bromo-1,1,1-trifluoroacetone (18.6 g, 0.098 mol) in 30 mL of
isopropanol over 30 minutes. The mixture was stirred at 80.degree.
C. for 4 hours, cooled and filtered. The filtrate was concentrated
and the residue was treated with ethyl acetate/hexane to give 28.6
g of
1-[4-[(2,5-dimethyl-1H-pyrrol-1-yl)sulfonyl]phenyl]-4,5-dihydro-2-(2-meth-
ylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-4-ol as a yellowish
solid (53%): mp (DSC) 213-216.degree. C. Anal. Calc'd. for
C.sub.22H.sub.19F.sub.3N.sub.4O.sub.3S: C, 55.46, H, 4.02, N,
11.76, S, 6.73. Found: C, 54.71, H, 4.40, N, 11.21, S, 6.78.
[1165] Step 4: Preparation of
3-[1-[4-[(2,5-dimethyl-1H-pyrrol-1-yl)sulfon-
yl]phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]-2-methylpyridine
[1166] A mixture of
1-[4-[(2,5-dimethyl-1H-pyrrol-1-yl)sulfonyl]phenyl]-4,-
5-dihydro-2-(2-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-4-ol
(Step 3) (18.0 g, 38 mmol) and p-toluenesulfonic acid (1.8 g) in
400 mL of toluene was heated at reflux with a Dean-Stark trap under
a nitrogen atmosphere for 36 hours. The mixture was cooled to room
temperature and filtered. The filtrate was basified with ammonium
hydroxide and extracted with ethyl acetate (400 mL). The organic
layer was washed with brine, dried over magnesium sulfate and
filtered. The filtrate was concentrated and purified by
chromatography on silica gel (ethyl acetate/hexane, 95:5) to give
3-[1-[4-[2,5-dimethyl-1H-pyrrol-1-yl)sulfonyl]phenyl]-4-(trifluor-
omethyl)-1H-imidazol-2-yl]-2-methylpyridine as a white solid (11.86
g, 72%): mp (DSC): 141-143.degree. C. Anal. Calc'd. for
C.sub.22H.sub.19F.sub.3N.sub.4O.sub.2S: C, 57.64; H, 3.74; N,
12.22; S, 6.99. Found: C, 57.27; H, 4.03; N, 11.79; S, 7.05.
[1167] Step 5: Preparation of
4-[2-(2-methylpyridin-3-yl)-4-(trifluorometh-
yl)-1H-imidazol-1-yl]benzenesulfonamide
[1168] A mixture of
3-[1-[4-[(2,5-dimethyl-1H-pyrrol-1-yl)sulfonyl]phenyl]-
-4,5-dihydro-4-(trifluoromethyl)-1H-imidazol-2-yl]-2-methylpyridine
(Step 4) (4.6 g, 0.01 mol) in 75 mL of TFA and 25 mL of water was
heated at reflux for 2 hours. The solution was cooled, treated with
400 mL of water and basified with sodium bicarbonate to pH 8. The
aqueous phase was extracted with ethyl acetate (400 mL). The
organic layer was washed with brine, dried over magnesium sulfate
and filtered. The filtrate was concentrated and the crude was
purified by chromatography on silica gel (ethyl acetate/acetone,
95:5) to afford 4-[2-(2-methylpyridin-3-yl)-4-(tr-
ifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide as a white solid
(3.0 g, 78%): mp (DSC): 235-237.degree. C. Anal. Calc'd. for
C.sub.16H.sub.13F.sub.3N.sub.3O.sub.2S: C, 50.26; H, 3.43; N,
14.65; S, 8.39. Found: C, 50.06; H,3.29; N, 14.4; S, 8.52.
BIOLOGICAL EVALUATION
[1169] Rat Carrageenan Foot Pad Edema Test
[1170] The carrageenan foot edema test was performed with
materials, reagents and procedures essentially as described by
Winter, et al., (Proc. Soc. Exp. Biol. Ned., 111, 544 (1962)). Male
Sprague-Dawley rats were selected in each group so that the average
body weight was as close as possible. Rats were fasted with free
access to water for over sixteen hours prior to the test. The rats
were dosed orally (1 ml) with compounds suspended in vehicle
containing 0.5% methylcellulose and 0.025% surfactant, or with
vehicle alone. One hour later a subplantar injection of 0.1 ml of
1% solution of carrageenan/sterile 0.9% saline was administered and
the volume of the injected foot was measured with a displacement
plethysmometer connected to a pressure transducer with a digital
indicator. Three hours after the injection of the carrageenan, the
volume of the foot was again measured. The average toot swelling in
a group of drug-treated animals was compared with that of a group
of placebo-treated animals and the percentage inhibition of edema
was determined (Otterness and Bliven, Laboratory Models for Testing
NSAIDs, in Non-steroidal Anti-Inflammatory Drugs, (J. Lombardino,
ed. 1985)). The % inhibition shows the % decrease from control paw
volume determined in this procedure and the data for selected
compounds in this invention are summarized in Table V.
[1171] Rat Carrageenan-induced Analgesia Test
[1172] The rat carrageenan analgesia test was performed with
materials, reagents and procedures essentially as described by
Hargreaves, et al., (Pain, 32, 77 (1988)). Male Sprague-Dawley rats
were treated as previously described for the Carrageenan Foot Pad
Edema test. Three hours after the injection of the carrageenan, the
rats were placed in a special plexiglass container with a
transparent floor having a high intensity lamp as a radiant heat
source, positionable under the floor. After an initial twenty
minute period, thermal stimulation was begun on either the injected
foot or on the contralateral uninjected foot. A photoelectric cell
turned off the lamp and timer when light was interrupted by paw
withdrawal. The time until the rat withdraws its foot was then
measured. The withdrawal latency in seconds was determined for the
control and drug-treated groups, and percent inhibition of the
hyperalgesic foot withdrawal determined. Results are shown in Table
V.
5TABLE V RAT PAW EDEMA ANALGESIA % Inhibition % Inhibition Example
@ 30 mg/kg body weight @ 10 mg/kg body weight 2 9 5 21 6 23.5 7 27
18 36 13 23 38 25 24 24 19 26 51 47 27 40 21 28 57 51 29 37 31 28
36 32 30 36 68 40 42 43 45* 18 45 49 47 59 34 27 69 43 32 70 34* 35
72 55 28 74 48 83 25 84a 36 8 86 36 7 87 28* 5 91 16 93 16 4 117 51
*10 mg/kg
[1173] Evaluation of COX-1 and COX-2 activity in vitro
[1174] The compounds of this invention exhibited inhibition in
vitro of COX-2. The COX-2 inhibition activity of the compounds of
this invention illustrated in the Examples was determined by the
following methods.
[1175] a. Preparation of Recombinant COX Baculoviruses
[1176] Recombinant COX-1 and COX-2 were prepared as described by
Gierse et al, [J. Biochem., 305, 479-84 (1995)]. A 2.0 kb fragment
containing the coding region of either human or murine COX-1 or
human or murine COX-2 was cloned into a BamHl site of the
baculovirus transfer vector pVL1393 (Invitrogen) to generate the
baculovirus transfer vectors for COX-1 and COX-2 in a manner
similar to the method of D. R. O'Reilly et al (Baculovirus
Expression Vectors: A Laboratory Manual (1992)). Recombinant
baculoviruses were isolated by transfecting 4 .mu.g of baculovirus
transfer vector DNA into SF9 insect cells (2.times.10.sup.8) along
with 200 ng of linearized baculovirus plasmid DNA by the calcium
phosphate method. See M. D. Summers and G. E. Smith, A Manual of
Methods for Baculovirus Vectors and Insect Cell Culture Procedures,
Texas Agric. Exp. Station Bull. 1555 (1987). Recombinant viruses
were purified by three rounds of plaque purification and high titer
(10.sup.7-10.sup.8 pfu/ml) stocks of virus were prepared. For large
scale production, SF9 insect cells were infected in 10 liter
fermentors (0.5.times.10.sup.6/ml) with the recombinant baculovirus
stock such that the multiplicity of infection was 0.1. After 72
hours the cells were centrifuged and the cell pellet homogenized in
Tris/Sucrose (50 mM: 25%, pH 8.0) containing 1%
3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS).
The homogenate was centrifuged at 10,000.times.G for 30 minutes,
and the resultant supernatant was stored at -80.degree. C. before
being assayed for COX activity.
[1177] b. Assay for COX-1 and COX-2 Activity
[1178] COX activity was assayed as PGE.sub.2 formed/.mu.g
protein/time using an ELISA to detect the prostaglandin released.
CHAPS-solubilized insect cell membranes containing the appropriate
COX enzyme were incubated in a potassium phosphate buffer (50 mM,
pH 8.0) containing epinephrine, phenol, and heme with the addition
of arachidonic acid (10 .mu.M). Compounds were pre-incubated with
the enzyme for 10-20 minutes prior to the addition of arachidonic
acid. Any reaction between the arachidonic acid and the enzyme was
stopped after ten minutes at 37.degree. C./room temperature by
transferring 40 .mu.l of reaction mix into 160 .mu.l ELISA buffer
and 25 .mu.M indomethacin. The PGE.sub.2 formed was measured by
standard ELISA technology (Cayman Chemical). Results are shown in
Table VI.
6TABLE VI Human COX-2 Human COX-1 Example ID.sub.50 .mu.M ID.sub.50
.mu.M 1 4 >100 2 0.1 23 3 40 >100 4 4.7 >100 5 0.2 >100
6 0.3 >100 7 0.1 >100 9 0.3 >100 10 0.5 >100 12 0.2
>100 13 1.6 >100 14 0.2 >100 16 <0.1 >100 17 0.2 1.0
18 0.2 49 23 0.1 >100 24 0.2 26 26 <0.1 1.6 27 <0.1 0.6 28
1.8 >100 29 1.5 >100 30 >100 >100 31 1.8 >100 32 2.9
>100 34 0.5 >100 35 1.2 49 36 0.3 88.5 40 0.4 >100 41 0.5
>100 43 0.5 >100 45 9.6 >100 56 0.1 3.6 57 <0.1 0.9 59
<0.1 3.6 67 1.1 >100 68 0.2 4.6 69 <0.1 2.8 70 <0.1 6.2
72 <0.1 19.3 73 <0.1 29.8 74 <0.1 5.8 75 <0.1 67.7 76
<0.1 8.6 78 <0.1 2.7 79 0.1 31.2 80 <0.1 7.0 81 <0.1
3.6 82 <0.1 >100 83 <0.1 82.0 85 0.1 >100 86 <0.1
78.1 87 <0.1 >100 88 <0.1 >100 89 0.2 24.1 90 0.2
>100 91 0.2 >100 93 0.1 >100 94 0.2 29.9 95 0.6 3.0 96 0.4
>100 97 0.3 >100 98 1.0 >100 99 0.2 2.1 101 0.7 >100
103 0.5 >100 104 0.9 >100 105 0.8 4.5 106 0.3 17.1 107
<0.1 >100 108 0.6 >100 109 1.48 53.5 112 0.7 >100 113
0.3 >100 114 <0.1 >100 115 0.1 >100 116 0.1 >100 117
0.1 >100 118 <0.1 7.9 119 0.3 1.6 120 <0.1 >100 122 3.0
42.2 129 9.7 >100 130 49.4 >100 132 37.6 >100 133 1.2 32
135 1.0 >100 136 0.7 >100 137 79 >100 138 0.4 >100 139
54 >100 140 0.5 >100 141 51 >100 142 5.8 >100 143 1.71
>100 144 1.5 >100 145 0.6 82 146 <0.1 47 147 1.0 >100
149 <0.3 >100 151 33 >100 152 24.4 >100 153 45 >100
155 10.7 >100 161 <0.1 >100 162 <0.1 >100 163 0.6
>100 165 1.6 >100 166 0.4 >100 168 0.6 >100 169 0.1
>100 170 0.6 >100 171 0.1 >100 172 <0.1 >100 173
<0.1 >100 174 <0.1 13.7 175 <0.1 >100 176 0.3
>100 177 1.5 >100 180 0.5 100
[1179] Biological paradigms for testing the cytokine-inhibiting
activity of these compounds are found in WO95/13067, published 18
May 1995.
[1180] Also embraced within this invention is a class of
pharmaceutical compositions comprising the active compounds of this
combination therapy in association with one or more non-toxic,
pharmaceutically-acceptable carriers and/or diluents and/or
adjuvants (collectively referred to herein as "carrier" materials)
and, if desired, other active ingredients. The active compounds of
the present invention may be administered by any suitable route,
preferably in the form of a pharmaceutical composition adapted to
such a route, and in a dose effective for the treatment intended.
The active compounds and composition may, for example, be
administered orally, intravascularly, intraperitoneally,
subcutaneously, intramuscularly or topically.
[1181] For oral administration, the pharmaceutical composition may
be in the form of, for example, a tablet, capsule, suspension or
liquid. The pharmaceutical composition is preferably made in the
form of a dosage unit containing a particular amount of the active
ingredient. Examples of such dosage units are tablets or capsules.
The active ingredient may also be administered by injection as a
composition wherein, for example, saline, dextrose or water may be
used as a suitable carrier.
[1182] The amount of therapeutically active compounds that are
administered and the dosage regimen for treating a disease
condition with the compounds and/or compositions of this invention
depends on a variety of factors, including the age, weight, sex and
medical condition of the subject, the severity of the disease, the
route and frequency of administration, and the particular compound
employed, and thus may vary widely. The pharmaceutical compositions
may contain active ingredients in the range of about 0.1 to 2000
mg, preferably in the range of about 0.5 to 500 mg and most
preferably between about 1 and 100 mg. A daily dose of about 0.01
to 100 mg/kg body weight, preferably between about 0.5 and about 20
mg/kg body weight and most preferably between about 0.1 to 10 mg/kg
body weight, may be appropriate. The daily dose can be administered
in one to four doses per day.
[1183] In the case of psoriasis and other skin conditions, it may
be preferable to apply a topical preparation of compounds of this
invention to the affected area two to four times a day.
[1184] For inflammations of the eye or other external tissues,
e.g., mouth and skin, the formulations are preferably applied as a
topical ointment or cream, or as a suppository, containing the
active ingredients in a total amount of, for example, 0.075 to 30%
w/w, preferably 0.2 to 20% w/w and most preferably 0.4 to 15% w/w.
When formulated in an ointment, the active ingredients may be
employed with either paraffinic or a water-miscible ointment base.
Alternatively, the active ingredients may be formulated in a cream
with an oil-in-water cream base. If desired, the aqueous phase of
the cream base may include, for example at least 30% w/w of a
polyhydric alcohol such as propylene glycol, butane-1,3-diol,
mannitol, sorbitol, glycerol, polyethylene glycol and mixtures
thereof. The topical formulation may desirably include a compound
which enhances absorption or penetration of the active ingredient
through the skin or other affected areas. Examples of such dermal
penetration enhancers include dimethylsulfoxide and related
analogs. The compounds of this invention can also be administered
by a transdermal device. Preferably topical administration will be
accomplished using a patch either of the reservoir and porous
membrane type or of a solid matrix variety. In either case, the
active agent is delivered continuously from the reservoir or
microcapsules through a membrane into the active agent permeable
adhesive, which is in contact with the skin or mucosa of the
recipient. If the active agent is absorbed through the skin, a
controlled and predetermined flow of the active agent is
administered to the recipient. In the case of microcapsules, the
encapsulating agent may also function as the membrane.
[1185] The oily phase of the emulsions of this invention may be
constituted from known ingredients in a known manner. While the
phase may comprise merely an emulsifier, it may comprise a mixture
of at least one emulsifier with a fat or an oil or with both a fat
and an oil. Preferably, a hydrophilic emulsifier is included
together with a lipophilic emulsifier which acts as a stabilizer.
It is also preferred to include both an oil and a fat. Together,
the emulsifier(s) with or without stabilizer(s) make-up the
so-called emulsifying wax, and the wax together with the oil and
fat make up the so-called emulsifying ointment base which forms the
oily dispersed phase of the cream formulations. Emulsifiers and
emulsion stabilizers suitable for use in the formulation of the
present invention include Tween 60, Span 80, cetostearyl alcohol,
myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate,
among others.
[1186] The choice of suitable oils or fats for the formulation is
based on achieving the desired cosmetic properties, since the
solubility of the active compound in most oils likely to be used in
pharmaceutical emulsion formulations is very low. Thus, the cream
should preferably be a non-greasy, non-staining and washable
product with suitable consistency to avoid leakage from tubes or
other containers. Straight or branched chain, mono-or dibasic alkyl
esters such as di-isoadipate, isocetyl stearate, propylene glycol
diester of coconut fatty acids, isopropyl myristate, decyl oleate,
isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a
blend of branched chain esters may be used. These may be used alone
or in combination depending on the properties required.
Alternatively, high melting point lipids such as white soft
paraffin and/or liquid paraffin or other mineral oils can be
used.
[1187] Formulations suitable for topical administration to the eye
also include eye drops wherein the active ingredients are dissolved
or suspended in suitable carrier, especially an aqueous solvent for
the active ingredients. The antiinflammatory active ingredients are
preferably present in such formulations in a concentration of 0.5
to 20%, advantageously 0.5 to 10% and particularly about 1.5%
w/w.
[1188] For therapeutic purposes, the active compounds of this
combination invention are ordinarily combined with one or more
adjuvants appropriate to the indicated route of administration. If
administered per os, the compounds may be admixed with lactose,
sucrose, starch powder, cellulose esters of alkanoic acids,
cellulose alkyl esters, talc, stearic acid, magnesium stearate,
magnesium oxide, sodium and calcium salts of phosphoric and
sulfuric acids, gelatin, acacia gum, sodium alginate,
polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted
or encapsulated for convenient administration. Such capsules or
tablets may contain a controlled-release formulation as may be
provided in a dispersion of active compound in hydroxypropylmethyl
cellulose. Formulations for parenteral administration may be in the
form of aqueous or non-aqueous isotonic sterile injection solutions
or suspensions. These solutions and suspensions may be prepared
from sterile powders or granules having one or more of the carriers
or diluents mentioned for use in the formulations for oral
administration. The compounds may be dissolved in water,
polyethylene glycol, propylene glycol, ethanol, corn oil,
cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium
chloride, and/or various buffers other adjuvants and modes of
administration are well and widely known in the pharmaceutical
art.
[1189] Although this invention has been described with respect to
specific embodiments, the details of these embodiments are not to
be construed as limitations.
* * * * *