Note: Descriptions are shown in the official language in which they were submitted.
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CYCLOOXYGENASE-2 INHIBITION
Technical Field
One invention herein is directed to an expansion of the use of selective
inhibitors of cyclooxygenase-2. A different invention herein is directed to
cyclooxygenase-2 inhibitors with antioxidant properties.
Backeround of the Invention
Substantial research is currently being earned out to develop selecti<~e
inhibitors ofcyclooxygenase-2, i.e., agentswhich selectivelyinhibit
cyclooxygenase-2
in preference to cyciooxygenase-1, so as to obtain the anti-inflammatory
efr'ecf of
cyclooxygenase-2 inhibition without the gastrointestinal side effects, e.g.,
peptic ulcer
disease, that occur when cyclooxygenase-1 is also inhibited. Commonly used
nonsteroidal anti-inflammatory drugs inhibit both cyclooxygenase-2 and
cyclooxygenase- l, and the aforementioned side efr'ects detract from their
usefulness.
The focus of the research has been on synthesis ofnew compounds providing
selective inhibition of cyclooxygenase-2 for use for treating certain
inflammatory
conditions, especially arthritis. The focus has not been on developing new
methods
of treatment, i.e.; on treating conditions not heretofore considered as
appropriately
treatable with cyclooxygenase-2 inhibitors. The focus has not been on
developing
compounds with desirable functions in addition to enzyme inhibition.
Heretofore, it was considered that cyclooaygenase inhibitors could cause liver
injury and for that reason liver disease was not considered as one of the
conditions
that was treatable by selective inhibitors of cycloo~ygenase-2.
Summary of the Invention
One embodiment herein, sometimes referred to hereinafter as the first
embodiment herein, is directed to a method of treating a patient with liver
disease
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comprising administering to said patient a cyclooxygenase-2 inhibiting amount
of a
selective inhibitor of cyclooxygenase-2. Most liver diseases are treated with
mininmal
success. There is no effective treatment for alcoholic liver injury. Although
chronic
hepatitis C affects millions ofiadividuals, interferon therapy is effective in
eradicating
the virus in a relatively small percentage of patients, and in patients where
the virus
is not eradicated, the condition can progress to cirrhosis requiting liver
transplantation. Invention in the method of treatment herein resides inthe
realization
that the anti-inflammatory properties of selective cyclooxygenase-2 inhibitors
will
provide a net benefit in treating liver disease and the only effective
treatment in many
cases. This represents a major advance. Even considering just the ability to
delay the
progression of cirrhosis, the aforedescribed treatment method has enormous
clinical
implications.
A second embodiment herein is directed to a method oftreating a patient with
a virus-caused liver disease comprising administering to said patient a
cyclooxygenase-2 inhibiting amount of a selective inhibitor of cyclooxygenase-
2 and
therapeutic amounts) of anti-viral drugs) where the cyclooxygenase-2 inhibitor
is
an adjunct to anti-viral therapy to increase the effectiveness thereof. In
this
embodiment, the treatment with a selective inhibitor of cyclooxygenase-2 is
considered to cause a decrease in the synthesis of immunosuppressive
eicosanoids,
thereby augmenting anti-viral therapy.
A third embodiment herein is directed to selective inhibitor of
cyclooxygenase-2 which directly inhibits the enzyme cyclooxygenase-2 and which
also inhibits the synthesis ofthe cyclooxygenase-2 protein and which has
antioxidant
properties.
The term "selective inhibitor of cyclooxygenase-2" is used herein to mean
compound which selectively inhibits cyclooxygenase-2 in preference to
cyclooxygenase-1 and particularly compound for which the ratio of the ICso
concentration (concentration inhibiting 50% of activity) for cyclooxygenase-1
to the
ICso concentration for cyclooxygenase-2 is greater than 1. Such ratio is
readily
determined by assaying for cyclooxygenase-2 activity and assaying for
cyclooxygenase-1 activity by the methods set forth at column 39, line 55 -
column 40,
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line 36 of Talley et al. U.S. Patent No. 5,633,272, which is incorporated
herein by
reference, and from the resulting data obtaining a ratio of IC~,s.
Detailed Description
We turn now to the embodiment herein directed to a method of treating a
patient with a liver disease comprising administering to said patient a
cyclooxygenase-2 inhibiting amount of a selective inlu'bitor of cyclooxygenase-
2.
The liver diseases treated herein comprise inflammatory liver disorders and
include, for example, cl>ronic viral hepatitis B, chronic viral hepatitis C,
alcoholic liver
injury, primary biliary cirrhosis, autoimmune hepatitis, nonalcoholic
steatohepatitis,
and liver transplant rejection.
The selective inhibitors of cychooxygenase-2 are preferably those where the
ratio of
the ICso
concentration
for cyclooxygenase-1
to the ICso
concentration
for
cyclooxygenase-2
is 5 or
more, very
preferably
100 or more.
Selective inhibitors of cyclooxygenase-2 include the
following compounds:
(1) 4-[5-(4-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazoh-1-
yl]benzenesulfonamide
(2) 4-[5-(4-Bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-
yl]benzenesulfonamide
(3) 4-[5-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-
yl]benzenesulfonamide
(4) 4-[5-(4-Methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-
yl]benzenesulfonamide
(5) 4-[5-(2-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-
yl]benzenesuhfonamide
(6) 4-[5-(4-Trifluorom~hylphenyl~3-(tri$uommetlryl~
1H-pyrazol-1-
yl]benzenesulfonamide
(7) 4-[5-(4-Fluorophenyl)-3-{trifluoromethyl)-1H-pyrazol-1-
yl]benzenesulfonamide
(8) 4-[5-Phenyl-3-(trifluoromethyl)-1H-pyrazol-1-
yl]benzenesulfonamide
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(9) 4-[5-(4-Methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-
yl]benzenesulfonamide
( 10) 4-[5-(4-Trifluoromethoxyphe~nyl~3-(trifluoromethyl~ 1 H-pyrazol-
1-yl]benzenesulfonamide
(11) 4-[5-(2-Methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-
yl]benzenesulfonamide
(12) 4-[5-(4-Chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-1-
yl]benzenesulfonamide
( 13 ) 4-[4-(Aminosulfonyl~henyl]-5-(4-chlorophenyl~ 1 H pyrazol-3-
carboxylate
( 14) 4-[4-(Aminosulfonyl)phenyl]-5-(4-chlorophenyl~ 1 H pyrazol-3-
carboxamide
(15) 4-[5-(4-[Methylthio]phenyl~3-(difluoromethyl)-IH-pyrazol-I-
yl]benzenesulfonamide
( 16) 4-[5-(4-[Methy>su)fonyl]phea~yl}~3-(difluoromethyl~ 1H-pyrazol-1-
yi]benzenesulfonamide
( 17) 4-[5-(2,4-[Difluoro]phenyl.3-(trifluoromethyl)-1H-pyrazol-1-
yl]benzenesulfonamide
(18) 4-[5-(2,6-[Difluoro]phenyl~3-(tritluoromethyl)-1H-pyrazol-1-
yl]benzenesulfonamide
(19) 4-[5-(4-Cyanophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-
yl]benzenesulfonamide
(20) 4-[5-(4-Chlorophenyl~3-(heptafluoropropyl)-1H-pyrazol- I-
yl]benzenesulfonamide
(21) 4-[5-(4-Chlorophenyl~3-(chloro-difluoromethyl~lH-pyrazol-1-
yl]benzenesulfonamide
(22) 4-[5-(4-Chlorophenyl)-3-(pentafluoroethyl)-1H-pyrazol-1-
yl]benzenesulfonamide
(23) 4-[5-(4-Biphenyl)-3-(difluoromethyl)- I H-pyrazol- I-
yl]benzenesulfonamide
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(24) 4-[5-(4-Pyrazinyl)-3-(difluoromethyl)-1H-pyrazol-1-
yl]benzenesulfonamide
(25) 4-[5-(5-Chloro-2-thienyl~3-(difluoromethyl)-1H-pyrazol-1-
yl]benzenesuifonamide
(26) 4-[5-(4-Morpholino)phenyl)-3-(difluoromethylr 1H-pyrazol-1-
yl]benzenesulfonamide
(27) 4-[5-( 1-Cyclohexyl)-3-(difluoromethyl)-1H-pyrazol-1-
yI]benzenesulfonamide
(28) 4-[5-(5-Bromo-2-thienyl)-3-(difluoromethyl)-1H-pyrazol-1-
yl]benzenesulfonamide
(29) 4-[5-(4-Thienyl)-3-(difluoromethyl)-1H-pyrazol-1-
yl]benzenesulfonamide
(30) 4-[5-(4-[Tiifluoromethyl]phenyl~3-(difluoromethyl}-1H pyrazol-
1-yl]benzenesulfonamide
(31) 4-[5-(3,4-Dichlorophenyl~3-(trifluoromethyl)-1H-pyrazol-1-
yl]benzenesulfonamide
(32) 4-[5-(2,4-Dichlorophenyl~3-(trifluoromethyl)-1H-pyrazol-1-
yl]benzenesulfonamide
(33) 4-[5-Phenyl-3-(3-hydroxypropyl)-1 H-pyrazol-1-
yl]benzenesulfonamide
(34) 4-[5-(4-Fluorophenyl)-3-(3-hydroxypropyl)-1H-pyrazol-1-
yl]benzenesulfonamide
(35) 4-[4-(Aminosulfonyl~henyl]-5-(4-~ttorophenyl~lH pyrazole]-3-
propanoic acid
(36) 4,5-Dihydro-4-[3-trifluoromethyl]-1H-benz[g]indazol-1-
yl]benzen.esulfonamide
(37) 4-[5-(4-Chlorophenyl)-4-chloro-1H-pyrazol-1-
yl]benzenesulfonamide
(38) 4-[5-{4-Chiorophenyl~3-(trifluoromethyl}-4-chloro-1H-pyrazoll-
yl]benzenesulfonamide
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(39) 4-[1-(4-Fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-
yl]benzenesulfonamide
(40) 1-(2,4,6-Trichlorobenzoyl~5-me~thoxy-2-methyl 3-indolyl acetic
acid
(41 ) 1-(2,6-dichlombenzoyl~5-methoxy-2-methyl 3-indolyl acetic acid
(42) 3-(4-(Aminosulfonyl~henyl}.2-(4-fluorophenyl~5-(2-hydroxy-2-
propyl~hiophene
(43) 3-(4-(Aminosulfonyl~henyl}-2-(4-fluorophenyl)thiophene
(44) 3-(4-(Aminosulfonyl)phenyl)-2-(4-fluorophenyl)-5-(2-
propyl~hiophene
(45) 3-(4-(Aminosulfonyl~henyl~2-cyclohexylthiophene
(46) 5-(4-Carboxyphenyl~4-(4-(methylsulfonyl~henyl) thiophene-2-
carboxylic acid
(47) 4-(4-Fluorophe~nyl}-2-methyl-5-(4-(methylsulfonyl) phenyl)thiazole
(48) 2-(4-Fluorophenyl}-3-(4-methylsulfonyl~henyl~2-cyclopenten-1-
one
(49) 4-(4-(Methylsulfonyl~henyl5-(4-fluorophenyl~isothiazole
(50) 3-{4-Fluorophenyl~4-(4-(methyls~ulfonyl~henyl2-(SHrfuranone
(51) 3-(4-Fluorophenyl~4-(4-(aminosulfonyi~henyl~2-(2H~furanone
(52) 3-(4-Fluorophenyl~4-(4-(methylsulfonyl~henyl)furan
(53) 5,5-Dimethyl-3-(4-fluorophenyl)-4-(4-methylsulfonyl phenyl~2-
(SH)furanone
(54) 2-((4-Aminosulfonyl)phenyl~3-(4-fluorophenyl~hiophene
(55) 3-(2,4-Difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(SH)-
furanone
(56) 3-(3,4-Difluorophenyl)-4-(4-{methylsulfonyl)phenyl)-2-(SH)-
furanone
(57) 3-(2,6-Difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(SH)-
furanone
(58) 3-(2,5-Difluorophenyl~4-(4-(methylsulfonyl)phenyl)-2-(SH)-
furanone
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(59) 3-(3,5-Difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(SH)-
furanone
(60) 3-(4-Bromophenyl)-4-(4-(m~hylsulfonyl~henyl~2-(SH)-furanone
(61) 3-(4-Chlorophyl}.4-(4-(methylsulfonyl~henyl~2-(SH~furanone
(62) 3-(4-Methoxyphenyl)-4-(4-(methylsulfonyl)phenyl~2-(SH)-
furanone
(63) 3-(Phenyl~4-(4-(methylsulfonyl)phenyl)-2-(SH}-furanone
(64) 3-(2-Chioroph~yl}-4-(4-(methylsulfonyl~henyl~2-(SH}~furanone
(65) 3-(2-Bromo-4-fluorophenyl~4-(4-(methylsulfonyl~henyl~2-(SH)-
furanone
(66) 3-(2-Bromo-4-Chlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-
(SHrfuranone
(67) 3-(4-Chloro-2-fluorophenyl~4-(4-(methylsulfonyl) phenyl)-2-
(SH~furanone
(68) 3-(3-Bromo-4-fluorophenyl)-4-(4-(methylsvlfonyl) phenyl~2-
(SH~furanone
(69) 3-(3-Chlorophenyl)-4-(4-(methylsulfonyl) phenyl~2-(SH)-
furanone
(70) 3-(2-Chloro-4-fluorophenyl~4-{4-(methylsulfonyl) phenyl~2-
(SH~fiuanone
(71) 3-(2,4-Dichlorophenyl~4-(4-(methylsulfonyl)phenyl~2-(SH)-
furanone
{72) 3-(3,4-Dichlorophenylr4-(4-(methylsulfonyl)phenyl)-2-(SH)-
fiuanone
(73) 3-(2,6-Dichlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(SH)-
furanone
(74) 3-(3-Chloro-4-fluorophenyl~4-(4-(methylsulfonyl) phenylr2-
(SH~furanone
(75) 3-(4-Trifluoromethylphenyl~4-(4-(methylsulfonyl) phenyl)-2-
(SHrfuranone
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(76) 3-(3-Fluoro-4-methoxyphenyl~4-(4-(methylsulfonyl) phenyl~2-
(SH)-furanone
(77) 3-(3-Chloro-4-methoxyphenyl~4-(4-(methylsulfonyl) phenyl~2-
( SH~furanone
(78) 3-(3-Bromo-4-methoxyphenyl)-4-(4-(methylsulfonyl) phenyl)-2-
(SH~furanone
(79) 3-(2-Fluorophenyl~4-(4-(methylsulfonyl~h~yl~2-(SH~furanone
(80) 3-(4-Methylthiophenyl~4-(4-(methylsulfonyl~henyl)-2-(SHE
furanone
(81) 3-(3-Fluorophenyl~4-(4-(methylsulfonyl~henyl~2-(5H)-furanone
(82) 3-(2-Chloro-6-fluorophenyl~4-(4-(methylsulfonyl) phenyl~2-
(SH)-furanone
(83) 3-(3-Bromo-4-methylphenyl}-4-(4-(methylsulfonyl) phenyl~2-
( SH~furanone
(84) 3-(4-Bromo-2-fluorophenyl)-4-(4-(methylsulfonyl) phenyl~2-
(SHrfuranone
(85) 3-(3,4-Dibromophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(SH)-
furanone
(86) 3-(4-Chloro-3-fluorophenyl~4-(4-(methylsulfonyl) phenyl~2-
(SH~fiuanone
(87) 3-(4-Bromo-3-fluorophe~nyl}~4-(4-(methylsulfonyl)phenyl~2-(SHE
furanone
(88) 3-(4-Bromo-2-chlorophenyl~4-(4-(methylsulfonyl) phenyl~2-
(SH~furanone
(89) 3-(2-Naphthyl~4-(4-(methylsulfonyl)phenyl~2-(SH~furanone
(90) 3-(7-Quinolinyl~-4-(4-(methylsulfonyl)phenyl)-2-(SH)-furanone
(91) 3-(3,4-Dichlorophenyl)-4-(4-(aminosulfonyl)phenyl)-2-(2H)-
furanone
(92) 3-(3,4-Dichlorophenyl~4-(4-(aminosulfonyl)phenyl)-2-(2H)-
furanone
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(93) 3-(3,4-Dichlorophenyl)-4-(4-(aminosulfonyl)phenyl)-2-(2H)-
fiuanone
(94) 3-(3-Bromo-4-methoxyphenyl~4-(4-(aminosulfonyl) phenyl)-2-
(2H~furanone
(95) 3-(4-(Methylsulfonyl~henyl)-2-phenylbenzo[b]furan
(96) 3-(4-Methylsulfonyl~henyl~2-phenylbenzo[b]thiophene
(97) 3-(4-Methylsulfonyl~henyl2-phenylinden-1-one
(98) 2-(4-Fluorophenylr3-(4-(methylsulfonyl)phenyl)indole
(99) 3-(4-Fluorophenyl~2-(4-(methylsulfonyl~henyl)indole
( 100) 2-(4-Fluorophenyl)-3-(4-(methylsulfonyl~henyl~4H-thieno[2,3-
c]-fiuan-6-one
(101) 2-(3,4-Difluorophenyl)-3-(4-(methylsulfonyl)phenyl)-4H-
thieno[2,3-c]-furan-6-one
(102) 2-(4-Fluorophenyl~3-(4-(aminosulfonyl~henyl~4H thieno[2,3-c]-
furan-6-one
(103) 2-(3,4-Difluorophenyl)-3-(4-(aminosulfonyl)phenyl)-4H-
thieno[2,3-c]-fiuan-6-one
( 104) 3-(4-(Methylsulfonyl)phenyl~2-pheny1~4,7-dihydrothieno[2,3-
c]pyran-5-one
(105) 2-(4-(Methylsulfonyl)phenyl~3-phenyl~4H-thieno[2,3-c]fiuan-6-
one
(106) 5-(4-(Methylsulfonyl)phenyl~6-phenylimidazo[2,1-b] thiazole
( 107) 2-Methyl-5-(4-(methyIsulfonyl~henyl)-6-phenylimidazo [2,1-
b]thiazole
( 108) 3-Methyl-5-(4-(methyisulfonyl~henyl)~6-phenylimidazo [2,1-
b]thiazole
( 109) 2-Bromo-5-(4-(methylsulfonyl~henyl~6-phenylimidazo [2,1-
b]thiazole
(110) 3-Trifluorometliyl-5-(4-(methylsulfonyl)phenyl)-6-
phenylimidazo[2,1-b]thiazole
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( 111 ) 2,3-Dimethyl-5-{4-(methylsulfonyl~henyl)-6-phenyl-imidazo[2,1-
b]thiazole
( 112) 5-(4-(Methylsulfonyl~henyl~6-(4-fluorophenyl) imidazo[2,1-
b]thiazole
( 113 ) 5-Phenyl)-6-(4-(methylsulfonyl)phenyl)-imidazo[2,1-b]thiazole
(114) 2-Chloro-5-(4-(methylsulfonyl)phenyl)-6-(4-chlorophen-
yl)imidazo[2,1-b]thiazole
(115) 2,2-Dichloro-5-(4-(methylsulfonyl)phenyl)-6-(4-
chlorophenyl~midazo[2,1-b]thiazole
( 116) 5-(4-(Methylsulfonyl~henyLr6-(imidazo[2,1-b]-1,3,4-thiadiazole
(117) 5-Phenyl-6-(4-(methylsulfonyl)phenyl)-imidazo[2,1-b]-1,3,4-
thiadiazole
( 118) 2-Methyl-5-(4-(methylsulfonyl~henylr6-phenyl-imidazo[2,1-b]-
1,3,4-thiadiazole
( 119) 2-Methyl-5-phenyl-6-(4-methylsulfonyl~henylrimidazoj2,1-b]-
1,3,4-thiadiazole
( 120) 5-(4-(Methylsulfonyl~henyl~6-(4-fluorophenyl~imidazo[2,1-b]-
1,3,4-thiadiazole
(121) 5-(4-(Methylsulfonyl)phenyl)-6-phenyl-1H-imidazo[2,1-b]-s-
triazole
(122) 5-Phenyl-6-(4-(methylsulfonyl)phenyl)thiazolo(3,2-b]-1,3,4-
triazole
(123) 2,3-Dihydro-5-(4-(methylsulfonyl~henyl~6-phenylimidazo[2,1-
b]thiazole
( 124) 2-[(4-Methylthio)phenyl]-1-biphenyl
( 125 ) 1-Cyclohexene-2-(4'-methylsulfonylphenyl)benzene
( 126) 3-(4'-Methylsulfonylphenyl~4-phenylphenol
( 127) 1-[2-(4-Methylsulfonylphenyl)phenyl]piperidine
( 128) 1-[2-(4'-Methylsulfonylphenyl)phenyl]pyrrole
( 129) 1-Phenoxy-2-(4'-methylsulfonylphenyi)benzene
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( 130) 5-(4-Fluorophenyl~2-methoxy 4-[4-(methylsulfonyl)phenylJ-6-
(trifluoromethyl)pyridine
( 131 ) 2-Ethoxy-5-(4-fluorophenylr4-[4-(methylsulfonyl)phenyl]-6-
. (trifluoromethyl~yridine
(132) 5-{4-Fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-2-(2-
propynyloxy~6-(trifluoromethyl~yridine
(133) 2-Bromo-5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-6-
(trifluoromethyl~yridine
(134) 3-[1-(p-Bromobenzyl~5-methoxy-2-methylindol-3-yl]propanoic
acid
(135) 3-[1-(p-Bromobenzyl~5-methoxy-2-methylindol-3-yl]butanoic
acid, sodium salt
(136) 2-Benzyl-3-[1-(p-bromobenzylr5-methoxy-2-methylindol-3-yl-
propanoic acid
(137) 3-[1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]-2,2-
dimethylpropanoic acid
( 138) 3-[ 1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl}-4,4,4-
trifluorobutanoic acid, sodium salt
( 139) traps-2-[ 1-(p-Bromobenzyl}-5-methox~2-methylimdol 3-yl]-cyclo-
propanecarboxylic acid, sodium salt
(140) 3-[1-(p-Bromobenzyl)-5-methoxy 2-methylindol 3-ylJ-hydroxy 2-
methyl propanoic acid, sodium salt
(141) [1-(1-{p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]-
cyclopropyiacetic acid, sodium salt
( 142) traps-(+~2-[ 1-(p-Bromobenzyl~5-methoxy-2-methylindol-3-
ylJcyclopropanecarboxylic acid, sodium salt
(143) 3-[1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]-2-
methylpropanoic acid and sodium salt
(144) 3-[1-(p-Chlorobenzyl)-5-methoxy-2-methylindol-3-yl]-4,4,4-
trifluorobutanoic acid and sodium salt
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( 145) syn-3-[ 1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]-2-
methylbutanoic acid
( 146) anti-3-[ 1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]-2-
methylbutanoic acid and sodium salt
( 147) 3-[5-(Bromo- 1-(p-bromobenzyl)-2-methylindol-3-yl]butanoic acid
and sodium salt
( 148) (-)-3-[ I-(p-Bromobenzyl~5-methoxy-2-methylindol-3-yI]-
butanoic acid and sodium salt
(149) ~ (+)-3-(1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]-
butanoic acid and sodium salt
(150) traps-(-)-2-[1-(p-Bromobenzyl)-S-methoxy-2-methylindol-3-
yl]cyclopropanecarboxylic acid and sodium salt
(151) 3-[1-(p-Bromobenzyl)-2,5-dimethylindol-3-yl]propanoic acid
( 152) 3-[5-(Bromo-1-(p-bromobenzyl)-2-methylindol-3-yl]propanoic
acid
( 153 ) 3-[ 1-(p-Bromobenzyl)-5-chloro-2-methylindol-3-yl~ropanoic acid
(154) 3-[1-(p-Chlorobenzyl)-5-methoxy-2-methylindol-3-yl)-2
methylpropanoic acid
( 155) Methyl 3-[ 1-(p-bromobenzyl)-5-methoxy-2-methylindol-
3-yl~ropanoate
(156) 3-[I-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl)-3-
methylbutanoic acid
(157) 5-Methanesulfonamido-6-(2,4-diffuorophenylthio)-I-indanone
(158) 5-Methanesulfonamido-6-(2,4-dichlorophenoxy)-1-indanone
{I59) 2-(4-Chlorophenyl)-4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-
(trifluoromethy1~4,5-dihydro- lH-imidazole
(160) 2-{4-Chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-
(triffuoromethyl}-1 H-imidazole
(161) 1-(4-Fluorophenyl)-4-hydroxy-2-[4-(methylsulfonyl)phenyl]-4-
(trifluor omethyl)-4.5-dihydro-1 H-imidazole
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(162) 1-(4-Fluorophenyl)-2-[4-(methyisulfonyl)phenyl]-4-
(trifluoromethyl~ 1 H-imidazole
( 163) 2-(4-Chlorophenyl)- I-[4-methylsulfonyl~henyl]-4-methyl-1 H-
imidazole
( 164) 2-(4-Chlorophenyi)-1-[4-methylsulfonyl)phenyl]-4-phenyl-1 H-
imidazole
(165) 2-(4-Chlorophenyl)-4-(4-fluorophenyl)-1-[4-(methyl-
sulfonyl)phenyl]-1 H-imidazole
(166) 4-(4-Bromophenyl)-2-(4-chlorophenyl)-1-[4-(methylsulfo-
nyl~henyl]-1 H-imidazole
( 167) 2-(4-Chlorophenyl~ 1-[4-(methylsulfonyl~henyl]-4-(2-naphthyl}-
1H-imidazole
(168) 2-(4-Chiorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-[4-
(trifluoromethoxy~henyl]-1 H imidazole
( 169) 2,4-Bis(4-chlorophenyl)-1-[4-(methylsulfonyl)phenylJ-1 H-
imidazole
(170) 2-(4-Chlorophenyl)-4-(3-chlorophenyi)-1-[4-(methyl-
sulfonyl~henyl]-1 H-imidazole
(171) 2-(4-Chlorophenyl)-4-(4-methoxyphenyl)-1-[4-(methyl-
sulfonyl~henyl]-1H-imidazole
(172) 2-(4-Chlorophenyl)-4-(3-fluorophenyl)-1-[4-(methyl-
sulfonyl~henyl]-1 H-imidazoie
(173) 2-(4-Chlorophenyl)-4-[(4-chlorophenoxy)methylJ-1-[4-
(methylsulfonyl~henyl]-1H-imidazole
( 174) 2-(3-Chloro-4-methylphenyi)-1-[4-(methylsulfonyl)phenyiJ-4-
(trifluoromethyl~ 1H-imidazole
( 175 ) 5-[ 1-[4-(Methylsulfonyl~henyl)-4-(triffuoromethyl)-1 H imidazole-
2-yl]-1,3-benzodioxole
( 176) 2-(3-Fluoro-4-metho?.yphenyl)-1-[4-(methylsulfonyl~phenyl-4-
(trifluoromethyl)-1H-imidazole
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(177) 2-(4-Chlorophenyl)-4-[(phenylthio)methyl]-I-[4-
(methylsulfonyl)phenyl]-1 H imidazole
(178) 2-(4-Chlorophenyl}-4-[(N-methyl-N-phenylamino)methyl]-1-[4-
(methylsulfonyl)phenyl]-1H imidazole
(179) 2-(4-Chlorophenyi)-4-[2-quinolyl)methoxymethyl]-1-[4-
(methylsulfonyl}phenyl]-1 H-imidazole
(180) 2-(4-Chlorophenyl)-4-methoxymethyl-1-[4-
(methylsulfonyl)phenyl]-1H-imidazole
(181) 2-(4-Fluorophenyl)-I-[4-(methylsulfonyl)phenyl]-4-
trifluoromethyl-1 H imidazole
( 182) 1-[4-(Methylsulfonyl)phenyl]-2-phenyl-4-triffuoromethyl-1H-
imidazole
(183) 2-(3-Chloro-4-methoxyphenyl)-1-[4-(methylsulfonyl~henyl]-4-
trifluoromethyl-IH-imidazole
(184) 2-(4-Methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-
trifluoromethyl-1 H-imidazole
(185} 1-[4-(Methylsulfonyl)phenyl]-2-(4-trifluoromethyl-phenyl)-4-
trifluomethyl 1H imidazole
(186) 4-[2-(4-Chlorophenyl)-4-(trifluoromethyl)-1H-imidazol-1-
yl]benzenesuIfonamide
( 187) 4-[2-(3-Chloro-4-methylphenyl~4-(trifluoromethyl~ 1H imidazol
1-yl]benzenesulfonamide
(188) 3-[I-(4-Methylsulfonyl)phenyl]-4-trifluoromethyl-1H imidazol-2-
yl]pyridine
(189) 2-[1-(4-Methylsulfonyl)phenyl]-4-trifluoromethyl-1H imidazol-2-
yl]pyridine
( 190) 4-[1-[4-(Methylsulfonyl)phenyl]-4-trifluoromethyl 1H imidazol-2-
yl]pyridine
(191) 2-Methyl-5-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-
imidazol-2-yl]pyridine
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( 192) 2-Methyl-6-[ 1-[4-(methylsulfonyl~henyl]-4-triffuoromethyl-1 H-
imidazol-2-yl]pyridine
( 193) 5-Methyl 2-[ 1-[4-(methylsulfonyl~henyl]-4-triffuoromethyl-1H-
imidazol-2-yl]pyridine
( 194) 4-Methyl-2-[ 1-[4-(methylsulfonyl~henyl]-4-trifluoromethyl-1 H-
imidazol-2-yl]pyridine
( 195 ) 2-Methoxy-5-[ 1-[4-(methylsulfonyl)ph~yl]-4-trifluoromethyl-1 H-
imidazol-2-yl]pyridine
( 196) 4-[2-(6-Methylpyridin-3-y1~4-(trifluoromethyl)-1 H-imidazol-1-
yl]benzenesulfonamide
(197) 4-[2-{6-Methylpyridin-2-yl)-4-(trifluoromethyl~lH-imidazol-1-
yl]benzenesulfonamide
(198) 3-Methyl-5-[1-[4-(me~thylsulfonyl~henyl]-4-(trifluoromethyl)-1H-
imidazol-2-yl]pyridine
( 199) 4-[2-(4-Methylpyridin-2-y1~4-(trifluoromethyl~ 1H-imidazol-1-
yl]benzenesulfonamide
(200) 2-[1-[4-(Me~hylsulfonyl~henyl]-4-(tritluoromethyl~lH imidazol-
2-yl]thiophene
(201 ) 3-[ 1-[4-(Methylsulfonyl~henyl]-4-(trifluoromethyl~ 1H imidazol-
2-yl]thiophene
(202) 4-[2-(5-Methylpyridin-3-y1~4-(triffuoromethyl~ 1H-imidazol 1-
yl]benzenesulfonamide
(203) 2-Methyl-3-[1-[4-(methylsulfonyl~he~nyl]-4-(trifluoromethyl~ 1H-
imidazol-2-yl]thiophene
(204) 4-[2-(2-Methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-
yl]benzenesulfonamide
(205) 4-[2-Pyridin-3-yl)-4-(trifluoromethyl)-1 H-imidazol-1-
yl]benzenesulfonamide
The synthesis of compounds 1-39 is disclosed in Talley et al. U. S. Patent
No. 5,466,823. The synthesis of compounds 40 and 41 is disclosed in Black et
al.
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16
U. S. Patent No. 5,436,265. The synthesis of compounds 42-94 is disclosed in
Ducharme et al. U. S. Patent No. 5,474,995. 'Ihe synthesis of compounds 95-105
is
disclosed in Prasit et al. U.S. Patent No. 5,521,213. The synthesis of
compounds
106-I23 is disclosed in Gauthier et al. U.S. Patent No. 5,552,422. The
synthesis of
compounds 124-129 is disclosed in Batt U.S. Patent No. 5,593,994. The
synthesis
of compounds 130-133 is disclosed in Lee U. S. Patent No. 5,596,008. The
synthesis
of compounds 134-156 is disclosed in Lau et al. U.S. Patent No. 5,604,253. The
synthesis of compounds 157 and 158 is disclosed in Guay et al. U.S. Patent No.
5,604,260. The synthesis of compounds 159-205 is disclosed in Khanna et al.
U.S.
Patent No. 5,616,601.
Other selective inhibitors of cyclooxygeuase-2 and their synthesis are taught
in Examples 2-108, 110-129, 131-150, 152, 301-312, and 401-413 ofBatt et al.
U.S.
Patent No. 5,593,994, the disclosure of which is incorporated herein by
reference.
Still other selective inhibitors of cyclooxygenase-2 and their synthesis are
taught in
Examples 1-11, 13-16, and 18-25 of Guay et aL U. S. Patent No. 5,604,260, the
disclosure ofwhich is incorporated herein by reference. Still other selective
inhibitors
of cyclooxygenase-2 and their synthesis are taught in Examples 1-13 including
Examples la-lp and 4a-4h of Talley et aL U. S. Patent No. 5,633,272, the
disclosure
of which is incorporated herein by reference. Still other selective inhibitors
of
cyclooxygenase-2 are taught in Examples 1-131 of Lau et al. U. S. Patent
No. 5,639,780, the disclosure of which is incorporated herein by reference.
Still
other selective inhibitors of cyclooxygenase-2 are taught in Examples 1-6 of
Talley
et aL U.S. Patent No. 5,643,933, the disclosure ofwhich is incorporated herein
by
reference. Still other selective inhibitors of cyclooxygenase-2 are taught in
Examples
1-4 of Lau et al. U. S. Patent No. 5, 510,368, the disclosure of which is
incorporated
herein: by reference.
Preferred inhibitors of cyclooxygenase-2 for use herein are 4-[5-(4-
chlorophenyl~3-(trifluoromethyl~ 1 H-pyrazot-1-yl]benzenesulfonamide which is
compound ( 1) set forth above and 4-[5-(4-methylphenyl~3-(trifluoromethyl~ 1H-
pyrazol-1-yl] benzenesulfonamide which is compound (4) set forth above; it is
believed the latter compound is celicoxib (Trade name Celebrex). Another
preferred
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selective inhibitor of cyclooxygenase-2 is vioxx which is MK 0966. Other
preferred
inhibitors of cyclooxygenase-2 for use in this embodiment are those described
hereinafter in connection with the third embodiment herein.
The dosage of inhibitor of cyclooxygenase-2 for the method of the first
embodiment herein is a cyclooxygenase-2 inhibiting amount which is a
therapeutically
effective amount. In g~eral, the dosage for the first embodiment herein ranges
from
0.1 to 30 mglkg. The dosages for any particular agent will vary within said
range.
For compound (1) referred to above, the dosage preferably ranges from 3 to 12
mg/kg. The administration is preferably chronic treatment, i.e., carried out
indefinitely.
The route of administration for the inhibitors of cyclooxygenaso-2 for the
first
embodiment herein is preferably oral but other routes of administration, e.g.,
parenteral such as intravenous, are also useful.
We turn now to the second embodiment herein, which is a method of treating
a patient with a virus-caused liver disease with a cyclooxygenase-2
inlu'biting amount
of a selective inhibitor of cyclooxygenase-2 and a therapeutic amount of an
anti-viral
drug where the cyclooxygenase-2 inhl'bitor is an adjunct to the anti-viral
therapy to
increase the effectiveness thereof.
For the second embodiment herein, the virus-cause liver diseases include, for
example, chronic viral hepatitis B and chronic viral hepatitis C.
For the second embodiment herein, the inhibitors of cyclooxygenase-2 that
are useful are the same as those for the first embodiment herein and the
dosage
regimen and routes of administration are the same as for the first embodiment.
The anti-viral drugs are the same as those used conventionally for the
disorder
treated, and the dosages and routes of administration are those conventional
for the
disorder treated. For example, for chronic hepatitis B, various interferons,
e.g.,
recombinant and natural alpha interferons, are administered parenterally and
for
chronic hepatitis C, interferon alpha-2b is administered subcutaneously (3MU
three
times a week for six months). Other anti-viral compounds for use in the second
embodiment herein include, for example, acyclovir, adenine arabinoside, and
ribavirin,
used, for example in conventional dosages. Combinations of agents, e.g., a
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combination of interferon and ribavirin., may be used with the selective
inhibitor of
cyclooxygenase-2.
We turn now to the third embodiment herein which is directed to selective
inli'bitors of cyclooxygenase-2 which directly nnli'bit the enzyme
cyclooxygenase-2
and which also inhibit the synthesis of cyclooxygenase-2 protein and which
have
antioxidant properties.
The cyclooxygenase-2 inhibitors for this third embodiment preferably contain
phenyl group with two or more substituents selected from the group consisting
of
hydroxy and C,~-alkoxy (e.g., methoxy) on the phenyl Such compounds are
embraced by generic description in various patents but no species of selective
cyclooxygenase-2 inhibitor containing phenyl group with two or more hydroxy or
alkoxy substituents is disclosed in any of said patents. The patents referred
to are:
Talley .et al. U.S. Patent No. 5,643,933; Talley et al. U.S. Patent No.
5,633,272:
Khanna et aL U.S. Pateat No. 5,616,601; Lee U.S. Patent No. 5,596,008; Batt et
al.
U.S. Patent No. 5,593,994; and Adams et aL U.S. Patent No. 5,593,992.
Specific compounds for the third embodiment herein include, for example, 4-
[5-methyl-3-[[(2,3-hydroxy)phenoxy]methyl]-1H pyrazol-1-yl]benzenesulfonamide
and 4-methyl-5-(4-methyLsulfonyl~henyl 2-[(2,3-hydroxyphenoxy~ethyl]oxazole
and the corresponding compounds where methoxy or ethoxy replaces hydroxy. 4-[5-
Methyl-3-[[(2,3-hydroxy~henoxy]methyl]-1H pyrazo~l yl]benzenesulfonamidehas
the structure
Ra
~s ~to.
0
N~ D.
R
where R' is methyl and R2 is NHz. 4-(Methyl~5-(4-methylsulfonyl)phenyl-2-[(2,3-
hydroxyphenoxy)methyl]oxazole has the struchue
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off
HO
N
i~/,/ ~
O
s
O
O
These compounds are embraced by broad disclosure in Talley et al. U. S. Patent
No. 5,643,933 but are not specifically disclosed therein. These compounds can
be
made analogously to Scheme XXII in U.S. Patent No. 5,643,933 by reacting 2,3-
dl'hydroxybenzyl bromide, where the hydroxy groups are protected by
conventional
techniques (for example, as descn'bed in E. Haslam, "Protection of Phenols and
Catechols", pages 145-182 in Protective Groups in Organic Chemistry, McOmie,
J. F. W., editor, Plenum Press, London (1973), with alcohol corresponding to
the
product sought, in the presence of base, and deprotecting, and in the case of
the
methoxy or ethoxy compounds with alkoxy substituents in phenyl moiety,
replacing
the hydroxy substituents with alkoxy. Alternatively, these compounds can be
made
by reacting said alcohol with mesyl chloride to yield the unstable mesylate
and then
reacting with appropriate tn'hydroxyphenol. These compounds directly inhibit
the
cyclooxygenase-2 enzyme and also inhibit the synthesis of cyclooxygenase-2.
The selective inhibitors of cyclooxygenase-2 for the third embodiment herein
have utility as broad spectrum anti-inflammatory agents for treating
inflammation and
inflammation-associated disorders mediated by cyclooxygenase-2 such as
arthritis,
inflammatorybowel disease, diabetes, Alzheimer's disease, pancreatitis,
inflammatory
vascular and ocular disorders, and liver disease (as described in conjunction
with the
first embodiment herein). They also have utility in preventing or treating
cancer. The
dosages are generally those set forth for selective inhibitors of
cyclooxygenase-2 in
the first embodim~t herein. The route of administration is preferably oral
although
other routes of administration, e. g., parenteral, such as intravenous, may
also be used.
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The selective inhibitors of cyclooxyg~ase-2 of the third embodiment herein
have improved anti-inflammatory e~cacy compared to selective inhibitors of
cyclooxygenase-2 which do not inhibit the synthesis of cyclooxygenase-2
protein.
The three embodiments described above are illustrated in the following
examples.
EXAMPLE I
A patient with alcoholic hepatitis is admitted to a hospital complaining of
nausea and upper abdominal pain. Liver function test results are total
bilirubin of 4.0
mg/dl, direct bilirubin of 3.1 mg/dl, ALT of 100 IU/L, AST of 120 IL1/L and
prothrombin time of 15.1 seconds.
Treatment is carried out by administration of 4-[5-(4-chlorophenyl)-3-
(trifluorom~hyl~ 1H pyrazol-1-yl]benzenesulfonamide at a dosage of6 mg/kg by
oral
route of administration, daily.
At the end of three weeks, the nausea and upper abdominal pain have
resolved. Each of the blood tests has improved.
The same result is obtained when the drug administered is 4-[5-(4-
methylphenyl~3-(triffuoromethyl~ 1H-pyrazol-1-yl]benzenesulfonamide at a
dosage
of 6 mg/kg by oral route of administration daily.
EXAMPLE II
The patient is a 45-year old female with new onset nausea, loss of appetite .
and right upper quadrant tenderness. She is noted to have elevated liver
chemistries.
Serologic workup is notable for positive antinuclear and antismooth muscle
anh'bodies. She is considered to have autoimmune hepatitis. Liver biopsy is
consistent with this diagnosis. Treatments with 6 mg/kg oral 4-[5-{4-
chlorophenyl~
3-(trifluoromethylr 1H pyrazol-1-yl]benzene-sulfonamide for two months,
results in
resolution of symptoms. The patient is subsequently maintained on an oral dose
of
6 mg/kg of the same drug.
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The same result is obtained when the drug administered is 4-[5-(4-
methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-ylJbenzenesulfonamide at an
oral
dose of 6 mg/kg.
EXAMPLE Bi
A patient having symptoms of malaise, anorexia and fatigue, has persistently
elevated liver function tests. A blood test confirms the diagnosis of chronic
viral
hepatitis C.
The patient is treated by oral administration of 4-[5-(4-chlorophenyl~3-
(trifluoromethyl)-1H-pyrazol-1-yl]benzene-sulfonamide at a dose of 6 mg/kg,
daily
for 12 months and also with subcutaneous interferon alpha-2b at a dose of 3MU
three
times a week for six months, resulting in sustained normalization of liver
enzymes.
The same result is obtained when the cyclooxygenase-2 inhibitor is 4-[5-(4-
methylphenyl~3-(triffuoromethyi~lH-pyrazol-1-yl]benzenesulfonamide at an oral
dose of 6 mg/kg and the anti-viral drug is subcutaneous interferon alpha-2b at
a dose
of 3 Mu three times a week for six months.
EXAMPLE IV
R~
S /
O~I
O
OH
Rt
where R' is methyl and R2 is NHz is reacted with 2,3-dl'hydroxybenzylbromide
where
the hydroxyls are protected, under basic conditions (K,rC03), and then
deprotecting
iscarriedouttoproduce4-[5-methyl-3-[(2,3-hydroxy~henoxy]methyl]-1H pyrazo~
1-ylJbenzenesulfonamide. The product has the structure
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W
I
O
where R' is methyl and R2 is NH2. The starting material is made by the
reaction to
produce compound 78 in Scheme XVII depicted in Talley et al. U. S. Patent No.
5,643,933.
Many variations ofthe above will be obvious to those skilled in the art. Thus,
the invention is defined by the claims.
