CYCLOOXYGENASE-2 INHIBITION

Abstract: Selective inhibitors of cyclooxygenase-2 are used to treat liver disease and in combination with anti-viral drugs to treat virus-caused liver disorders. Selective inhibitors of cyclooxygenase-2 which also inhibit the synthesis of cyclooxygenase-2 improve over the efficacy of conventional selective inhibitors of cyclooxygenase-2 in the treatment of inflammatory conditions, Alzheimer's disease and cancer.

Description: 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. Backer ound of the Invention Substantial research is currently being carried out to develop selective inhibitors of cyclooxygenase-2, i.e., agents which selectively inhibit cyclooxygenase-2 in preference to cyclooxygenase-1, so as to obtain the anti-inflammatory effect 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- 1 , and the aforementioned side effects detract from their usefulness. The focus of the research has been on synthesis of new 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 cyclooxygenase 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 cyclooxygenase-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 comprising administering to said patient a cyclooxygenase-2 inhibiting amount of a selective inhibitor of cyclooxygenase-2. Most liver diseases are treated with minimal success. There is no effective treatment for alcoholic liver injury. Although chronic hepatitis C affects millions of individuals, 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 requiring Uver transplantation. Invention in the method of treatment herein resides in the realization that the anti-inflammatory properties of selective cyclooxygenase-2 inhibitors will provide a net benefit in treating Uver 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 impUcations. A second embodiment herein is directed to a method of treating 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 amount(s) of anti-viral drug(s) 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 of the 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 IC 50 concentration (concentration inhibiting 50% of activity) for cyclooxygenase- 1 to the IC 50 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, reference, and from the resulting data obtaining a ratio of IC 50 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 inhibitor of cyclooxygenase-2. The liver diseases treated herein comprise inflammatory Uver disorders and include, for example, chronic viral hepatitis B, chronic viral hepatitis C, alcohoUc Uver injury, primary biliary cirrhosis, autoimmune hepatitis, nonalcohoUc steatohepatitis, and liver transplant rejection. The selective inhibitors of cyclooxygenase-2 are preferably those where the ratio of the IC 50 concentration for cyclooxygenase-1 to the IC 50 concentration for cyclooxygenase-2 is 5 or more, very preferably 100 or more. Selective inhibitors of cyclooxygenase-2 include the foUowing compounds: (1) 4-[5-(4-Chlorophenyl)-3-(trifluoromethyl)- lH-pyrazol- 1- yljbenzenesulfonamide (2) 4-[5-(4-Bromophenyl)-3-(trifluoromethyl)- lH-pyrazol- l- yljbenzenesulfonamide (3) 4-[5-(3-Chlorophenyl)-3-(triffuoromethyl)- lH-pyrazol- l- yljbenzenesulfonamide (4) 4-[5-(4-Methylphenyl)-3-(triffuoromethyl)-lH-pyrazol- 1- yl]benzenesulfonamide (5) 4-[5-(2-Chloroρhenyl)-3-(trifluoromethyl)- lH-pyrazol- l- yljbe zenesulfonamide (6) 4- [5-(4-Trifluoromethylphenyl)-3-(trifluoromethyl)- 1 H-pyrazol- 1 - yljbenzenesulfonamide (7) 4-[5-(4-Fluorophenyl)-3-(trifluoromethyl)- lH-pyrazol- 1- yljbenzenesulfonamide (8) 4- [ 5 - Phenyl- 3 - (trifluo r o methyl)- 1 H- pyra zo l- 1 - yl]benzenesulfonamide (9) 4-[5-(4-Methoxyphenyl)-3-(trifluoromethyl)- 1 H-pyrazol- 1- yl]benzenesulfonamide (10) 4-[5-(4-Trifluoromethoxyphenyl)-3-(trifluoromethyl)- lH-pyrazol- 1 -yljbenzenesulfonamide (11) 4- [5-(2-Methylphenyl)-3-(trifluoromethyl)- l H-pyrazol- 1- yljbenzenesulfonamide (12) 4-[5-(4-Chlorophenyl)-3-(difluoromethyl)- lH-pyrazol- 1- yljbenzenesulfonamide (13) 4-[4-(Aminosulfonyl)phenyl]-5-(4-chlorophenyl)- lH-pyrazol-3- carboxylate ( 14) 4-[4-(Aminosulfonyl)phenyl]-5-(4-chlorophenyl)- lH-pyrazol-3- carboxamide (15) 4-[5-(4-[Methylthio]phenyl)-3-(difluoromethyl)-lH-pyrazol- yljbenzenesulfonamide (16) 4-[5-(4-[ ethylsulfonyl]phenyl)-3-(difluoromethyl)- lH-pyrazol- yl]benzenesulfonamide (17) 4-[5-(2,4-[Difluoro]phenyl)-3-(trifluoromethyl)- lH-pyrazol- yl]benzenesulfonamide (18) 4-[5-(2,6-[Difluoro]ρhenyl)-3-(tιifluoromethyl)- lH-pyrazol- yljbenzenesulfonamide (19) 4-[5-(4-Cyanophenyl)-3-(trifluoromethyl)- lH-pyrazol- yljbenzenesulfonamide (20) 4-[5-(4-Chlorophenyl)-3-(heptafluoropropyl)- lH-pyrazol- yljbenzenesulfonamide (21) 4-[5-(4-Chlorophenyl)-3-(chloro-difluoromethyl)-lH-pyrazol- yl]benzenesulfonamide (22) 4-[5-(4-Chlorophenyl)-3-(pentafluoroethyl)- lH-pyrazol- yl]benzenesulfonamide (23) 4- [5-(4-Biphenyl)-3-(difluoromethyl)- l H-pyrazol- yl]benzenesulfonamide (24) 4-[5-(4-Pyrazinyl)-3-(difluoromethyl)-lH-pyrazol-l- yljbenzenesulfonamide (25) 4-[5-(5-Chloro-2-thienyl)-3-(difluoromethyl)- lH-pyrazol- 1- yljbenzenesulfonamide (26) 4-[5-(4-Morpholino)phenyl)-3-(difluoromethyl)- lH-pyrazol- 1- yljbenzenesulfonamide (27) 4-[5-(l-Cyclohexyl)-3-(difluoromethyl)-lH-pyrazol-l- yljbenzenesulfonamide (28) 4-[5-(5-Bromo-2-thienyl)-3-(difluoromethyl)- lH-pyrazol- 1- yljbenzenesulfonamide (29) 4-[5-(4-Thienyl)-3-(difluoromethyl)- lH-pyrazol- 1- yljbenzenesulfonamide (30) 4-[5-(4-[Trifluoromethyl]phenyl)-3-(difluoromethyl)- lH-pyrazol- l-yl]benzenesulfonamide (31) 4-[5-(3,4-Dichlorophenyl)-3-(trifluoromethyl)-lH-pyrazol- 1- yljbenzenesulfonamide (32) 4- [5-(2,4-Dichlorophenyl)-3-(trifluoromethyl)- 1 H-pyrazol- 1- yl]b enzenesulfona ide (33) 4-[5-Phenyl-3-(3-hydroxypropyl)- 1 H- yrazol- 1- yljbenzenesulfonamide (34) 4-[5-(4-Fluorophenyl)-3-(3-hydroxypropyl)- lH-pyrazol- 1- yljbenzenesulfonamide (35) 4-[4-(Aminosιιlfonyl)phenyl]-5-(4-fluorophenyl)-lH-pyrazole]-3- propanoic acid (36) 4,5-Dihydro-4-[3-trifluoromethyl]- lH-benz[g]indazol- 1- yljbenzenesulfonamide (37) 4- [5-(4-Chlorophenyl)-4-chloro-l H-pyrazol- 1- yljbenzenesulfonamide (38) 4-[5-(4-Chlorophenyl)-3-(tιifluoromethyl>4-chloiO- lH-pyrazol- 1- yljbenzenessulfonamide (39) 4-[ l-(4-Fluorophenyl)-3-(trifluoromethyl)- lH-pyrazol-5- yljbenzenesulfonamide (40) l-(2,4,6-Trichlorobenzoyl)-5-methoxy-2-methyl-3-indolyl acetic acid (41) l-(2,6-dichlorobenzoyl)-5-methoxy-2-methyl-3-indolyl acetic acid (42) 3-(4-(Amino sulfonyl)phenyl)-2-(4-fluorophenyl)- 5-(2-hydroxy-2- propyl)thiophene (43 ) 3-(4-(Aminosulfonyl)phenyl)-2-(4-fluorophenyl)thiophene (44) 3-(4-(Aminosulfonyl)phenyl)-2-(4-fluorophenyl)-5-(2- propyl)thiophene (45 ) 3-(4-(Aminosιιlfonyl)phenyl)-2-cyclohexylthiophene (46) 5-(4-Carboxyphenyl)-4-(4-(methylsulfonyl)phenyl) thiophene-2- carboxyUc acid (47) 4-(4-Fluorophenyl)-2-methyl-5-(4-(methylsulfonyl) phenyl)thiazole (48) 2-(4-Fluorophenyl)-3-(4-methylsulfonyl)phenyl)-2-cyclopenten- 1- one (49) 4-(4-(Methylsulfonyl)phenyl-5-(4-fluorophenyl)-isothiazole (50) 3-(4-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl-2-(5H)-fiιranone (51) 3-(4-Fluorophenyl)-4-(4-(aminosulfonyl)phenyl)-2-(2H)-fiιranone (52) 3-(4-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl)furan (53) 5 , 5-Dimethyl-3 -(4-fluorophenyl)-4-(4-methylsulfonyl-phenyl)-2- (5H)furanone (54) 2-((4-Aminosulfonyl)phenyl)-3-(4-fluorophenyl)thiophene (55) 3-(2,4-Difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)- furanone (56) 3-(3,4-Difluorophenyl)-4-(4-(methylsulfonyl)ρhenyl)-2-(5H)- fiiranone (57) 3-(2,6-Difluorophenyl)-4-(4-(methylsulfonyl)ρhenyl)-2-(5H)- fiiranone (58) 3-(2,5-Difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)- furanone (59) 3-(3,5-Difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)- furanone (60) 3-(4-Bromophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone (61) 3-(4-Chlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone (62) 3-(4-Methoxyphenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)- furanone (63 ) 3-(Phenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone (64) 3-(2-Chlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone (65) 3-(2-Bromo-4-f orophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)- fiiranone (66) 3-(2-Bromo-4-Chlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2- (5H)-furanone (67) 3-(4-Chloro-2-fluorophenyl)-4-(4-(methylsulfonyl) phenyl)-2- (5H)-furanone (68) 3-(3-Bromo-4-fluorophenyl)-4-(4-(methylsulfonyl) phenyl)-2- (5H)-furanone (69) 3-(3-Chlorophenyl)-4-(4-(methylsulfonyl) phenyl)-2-(5H)- furanone (70) 3-(2-Chloro-4-fluoiOphenyl)-4-(4-(methylsulfonyl) phenyl)-2- (5H)-furanone (71) 3-(2,4-Dichloroρhenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)- fiiranone (72) 3-(3,4-Dichlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)- furanone (73) 3-(2,6-Dichloroρhenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)- fiiranone (74) 3-(3-Chloro-4-fluorophenyl)-4-(4-(methylsulfonyl) phenyl)-2- (5H)-fiuanone (75) 3-(4-Trifluoromethylphenyl)-4-(4-(methylsulfonyl) phenyl)-2- (5H)-furanone (76) 3-(3-Fluoro-4-methoxyphenyl)-4-(4-(methylsulfonyl) phenyl)-2- (5H)-furanone (77) 3-(3-Chloro-4-methoxyphenyl)-4-(4-(methylsulfonyl) phenyl)-2- (5H)-furanone (78) 3-(3-Bromo-4-methoxyphenyl)-4-(4-(methylsulfonyl) phenyl)-2- (5H)-furanone (79) 3-(2-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone (80) 3-(4-Methylthiophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)- furanone (81) 3-(3-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone (82) 3-(2-Chloro-6-fluorophenyl)-4-(4-(methylsulfonyl) phenyl)-2- (5H)-fiιranone (83) 3-(3-Bromo-4-methylphenyl)-4-(4-(methylsu_fonyl) phenyl)-2- (5H)-fiιranone (84) 3-(4-Bromo-2-fluorophenyl)-4-(4-(methylsulfonyl) phenyl)-2- (5H)-furanone (85) 3-(3,4-Dibromophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)- furanone (86) 3-(4-Chloro-3-fluorophenyl)-4-(4-(methylsulfonyl) phenyl)-2- (5H)-fiιranone (87) 3-(4-Bromo-3-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)- furanone (88) 3-(4-Bromo-2-chlorophenyl)-4-(4-(methylsulfonyl) ρhenyl)-2- (5H)-furanone (89) 3-(2-Naphthyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone (90) 3-(7-Quinolinyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone (91) 3-(3,4-Dichlorophenyl)-4-(4-(aminosulfonyl)phenyl)-2-(2H)- furanone (92) 3-(3,4-Dichloroρhenyl)-4-(4-(anώιosulfonyl)phenyl)-2-(2H)- furanone (93) 3-(3,4-Dichlorophenyl)-4-(4-(aminosulfonyl)phenyl)-2-(2H)- furanone (94) 3-(3-Bromo-4-methoxyphenyl)-4-(4-(aminosulfonyl) phenyl)-2- (2H)-furanone (95 ) 3-(4-(Methylsulfonyl)phenyl)-2-phenylbenzo[b]furan (96) 3-(4-Methylsulfonyl)phenyl)-2-phenylbenzo[b]thiophene (97) 3-(4-Methylsulfonyl)phenyl-2-phenylinden- 1-one (98) 2-(4-Fluorophenyl)-3-(4-(methylsulfonyl)phenyl)indole (99) 3-(4-Fluorophenyl)-2-(4-(methylsulfonyl)phenyl)indole ( 100) 2-(4-Fluorophenyl)-3-(4-(methylsulfonyl)phenyl)-4H-thieno[2,3- c]-furan-6-one (101) 2-(3,4-Difluorophenyl)-3-(4-(methylsulfonyl)ρhenyl)-4H- thieno[2,3-c]-furan-6-one ( 102) 2-(4-Huorophenyl 3-(4-(aminosulfonyl)phenyl 4H-thieno[2,3-c]- furan-6-one (103) 2-(3,4-Difluorophenyl)-3-(4-(aminosulfonyl)phenyl)-4H- thieno[2,3-c]-furan-6-one (104) 3-(4-(Methylsulfonyl)phenyl)-2-ρhenyl)-4,7-dihydrothieno[2,3- c]pyran-5-one (105) 2-(4-(Methylsulfonyl)phenyl)-3-phenyl)-4H-thieno[2,3-c]furan-6- one (106) 5-(4-(Methylsulfonyl)phenyl)-6-phenylimidazo[2,l-b] thiazole (107) 2-Methyl-5-(4-(methylsulfonyl)phenyl)-6-phenylimidazo [2,1- bjthiazole (108) 3-Methyl-5-(4-(methylsulfonyl)phenyl)-6-phenyUmidazo [2,1- bjthiazole (109) 2-Bromo-5-(4-(methylsulfonyl)phenyl)-6-phenyUmidazo [2,1- bjthiazole (110) 3 -Trifluoromethyl- 5-(4-(methylsulfonyl)phenyl)- 6- phenyliιι_idazo[2, l-b]tbiazole (111) 2,3-E)ime yl-5-(4-(methylsulfonyl)phenyl)-6-phenyl-imidazo[2, 1- b]thiazole (112) 5-(4-(Methylsulfonyl)phenyl)-6-(4-fluorophenyl) imidazo[2, l- bjthiazole (113) 5-Phenyl)-6-(4-(methylsulfonyl)phenyl)-imidazo[2, l-b]tbiazole (114) 2-Chloro-5-(4-(methylsulfonyl)phenyl)-6-(4-chlorophen- yl)imidazo[2, l-b]thiazole (115) 2 , 2-Dichloro- 5 - (4-( methylsulfonyl)ph enyl)- 6- ( 4- chlorophenyl)imidazo[2, l-b]thiazole ( 116) 5-(4-(Methylsulfonyl)phenyl)-6-(imidazo[2, 1-b]- 1,3,4-thiadiazole (117) 5-Phenyl-6-(4-(methylsulfonyl)ρhenyl)-imidazo[2, 1-b]- 1,3,4- thiadiazole (118) 2-Methyl-5-(4-(methylsulfonyl)phenyl)-6-phenyl-imidazo[2, 1-b]- 1,3,4-thiadiazole (119) 2-Methyl-5-phenyl-6-(4-methylsulfonyl)phenyl)-imidazo[2, 1-b]- 1,3,4-thiadiazole (120) 5-(4-(Methylsulfonyl)phenyl)-6-(4-fluoiOphenyl)-_midazo[2, 1-b]- 1,3,4-thiadiazole (121) 5-(4-(Methylsulfonyl)phenyl)-6-phenyl- lH-imidazo[2,l-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)phenyl)-6-phenyUmidazo[2, 1- bjthiazole ( 124) 2- [(4-Methylthio)phenyl]- 1 -biphenyl (125) l-Cyclohexene-2-(4'-methylsulfonylphenyl)benzene ( 126) 3-(4'-Methylsulfonylphenyl)-4-phenylphenol (127) 1 - [2-(4-Methylsulfonylphenyl)phenyl]pip eridine (128) l-[2-(4'-Methylsulfonylphenyl)phenyl]pyιτole (129) l-Phenoxy-2-(4'-methylsulfonylphenyl)benzene 130) 5-(4-Fluorophenyl)-2-methoxy-4-[4-(methylsulfonyl)phenyl]-6- (trifluoromethyl)pyridine 131) 2-Ethoxy-5-(4-fluorophenyι)-4-[4-(methylsulfonyl)phenyl]-6- (trifluoromethyl)pyridine ;i32) 5-(4-Fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-2-(2- propynyloxy)-6-(trifluoromethyl)pyridine ' 133) 2-Bromo-5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-6- (trifluoromethyl)pyridine ' 134) 3-[ l-(p-Bromobenzyl)-5-methoxy-2-methy]indol-3-yl]propanoic acid 135) 3-[l-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]butanoic acid, sodium salt 136) 2-Ben3zyl-3-[l-(p-bromobenzyl)-5-methoxy-2-methyUndol-3-yl- propanoic acid ;i37) 3-[l-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]-2,2- dimethylpropanoic acid 138) 3-[l-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]-4,4,4- trifluorobutanoic acid, sodium salt ^139) trans- 2-[l-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]-cyclo- propanecarboxyhc acid, sodium salt 140) 3-[l-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]-hydroxy-2- methyl propanoic acid, sodium salt 141) [l-( l-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]- cyclopropylacetic acid, sodium salt 142) trans-(+)-2-[l-(p-Bromobenzyl)-5-methoxy-2-methylindol-3- yl]cyclopropanecarboxyUc acid, sodium salt ;i43) 3-[l-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]-2- methylpropanoic acid and sodium salt 144) 3-[l-(p-Chlorobenzyl)-5-methoxy-2-methyUndol-3-yl]-4,4,4- trifluorobutanoic acid and sodium salt 145) syn-3-[l-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]-2- methylbutanoic acid 146) anti-3-[l-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]-2- methylbutanoic acid and sodium salt 147) 3-[5-(Bromo- l-(p-bromobenzyl)-2-methyUndol-3-yl]butanoic acid and sodium salt 148) (— )-3-[l-(p-Bromobenzyl)-5-methoxy-2-methylmdol-3-yl]- butanoic acid and sodium salt 149) (+)-3-[ l-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]- butanoic acid and sodium salt 150) trans-( — )-2-[l-(p-Bromobenzyl)-5-methoxy-2-methylindol-3- yl]cyclopropanecarboxyUc acid and sodium salt 151) 3- [ l-(p-Bromobenzyl)-2,5-dimethylindol-3-yl]propanoic acid 152) 3-[5-(Bromo- l-(p-bromobenzyl)-2-methylindol-3-yl]propanoic acid 153) 3-[l-(p-Bromobenzyl)-5-clιloro-2-methyUndol-3-yl)propanoic acid 154) 3-[l-(p-Chlorobenzyl)-5-methoxy-2-methylindol-3-yl)-2- methylpropanoic acid 155) Methyl 3-[l-(p-bromobenzyl)-5-methoxy-2-methylindol- 3-yl)propanoate 156) 3-[l-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl)-3- methylbutanoic acid 157) 5-Methanesulfonamido-6-(2,4-difluorophenylthio)- 1-indanone 158) 5-Methanesulfonamido-6-(2,4-dichlorophenoxy)- 1-indanone 159) 2-(4-Chlorophenyl)-4-hydroxy- l-[4-(methylsulfonyl)phenyl]-4- (trifluoromethyl)-4,5-dihydro-lH-imidazole 160) 2-(4-Chlorophenyl)- l - [4-(methylsulfonyl)phenyl]-4- (trifluoromethyl)- lH-imidazole 161) 1 -(4-Fluorophenyl)-4-hydroxy-2- [4-(methylsulfonyl)phenyl]-4- (trifluoromethyl)-4,5-dihydiO-lH-imidazole (162) l -(4-Fluorophenyl)-2-[4-(methylsulfonyl)phenyl] -4- (trifluoromethyl)- lH-imidazole (163) 2-(4-Chlorophenyl)- l-[4-methylsulfonyl)phenyl]-4-methyl- 1 H- imidazole ( 164) 2-(4- Chlorophenyl)- 1 - [4-methylsulfonyl)phenyl]-4-phenyl- 1 H- imidazole (165) 2-(4-Chlorophenyl)-4-(4-fluorophenyl)- l- [4-(methyl- sulfonyl)phenyl]- lH-imidazole (166) 4-(4-Bromophenyl)-2-(4-chlorophenyl)- l-[4-(methylsulfo- nyl)phenyl]- lH-imidazole (167) 2-(4-Chlorophenyl)- 1 - [4-(methylsulfonyl)phenyl]-4-(2-naphthyl)- lH-imidazole (168) 2-(4-Chlorophenyi)- l-[4-(methylsulfonyl)phenyl]-4- [4- (trifluoromethoxy)phenyl]-lH-imidazole (169) 2, 4-Bis(4- chlorophenyl)- l-[4-(methylsulfonyl)phenyl]- 1H- imidazole (170) 2-(4-Chlorophenyl)-4-(3-chlorophenyl)- l-[4-(methyl- sulfonyl)phenyl]- lH-imidazole (171) 2-(4-Chlorophenyl)-4-(4-methoxyρhenyl)- l- [4-(methyl- sulfonyl)phenyl]- lH-imidazole (172) 2-(4-Chlorophenyl)-4-(3-fluorophenyl)- l-[4-(methyl- sulfonyl)phenyl]- lH-imidazole (173) 2-(4-Chlorophenyl)-4-[(4-chlorophenoxy)methyl]- 1 - [4- (methylsulfonyl)phenyl]- 1 H-imidazole (174) 2-(3-Chloro-4-methylphenyl)- l-[4-(methylsulfonyl)phenyl]-4- (trifluoromethyl)- lH-imidazole (175) 5-[l-[4-(Methylsulfonyl)ρhenyl)-4-(trifluoromethyl)- lH-imidazole- 2-yl]- 1 ,3-benzodioxole (176) 2-(3-Fluoro-4-methoxyphenyl)- l-[4-(methylsulfonyl)-phenyl-4- (trifluoromethyl)- lH-imidazole (177) 2-(4-Chlorophenyl)-4-[(phenylthio)methyl]-l-[4- (methylsulfonyl)phenyl]- 1 H-imidazole (178) 2-(4-Chlorophenyl)-4-[(N-methyl-N-phenylamino)methyl]- 1-[4- (methylsulfonyl)phenyl]- 1 H-imidazole (179) 2-(4-Chlorophenyl)-4-[2-quinolyl)methoxymethyl]- 1-[4- (methylsulfonyl)phenyl]- 1 H-imidazole (180) 2-(4-Chlorophenyl)-4-methoxymethyl-l-[4- (methylsulfonyl)phenyl]- 1 H-imidazole (181) 2-(4-Fluorophenyl)- l-[4-(methylsulfonyl)phenyl]-4- trifluoromethyl- 1 H-imidazole (182) l-[4-(Methylsutfonyl)phenyl]-2-phenyl-4-trifluoromethyl- 1H- imidazole (183) 2-(3-Chloro-4-methoxyphenyl)- l-[4-(methylsulfonyl)phenyl]-4- trifluoromethyl- lH-imidazole (184) 2-(4-Methylphenyl)- l-[4-(methylsulfonyl)ρhenyl]-4- trifluoromethyl- 1 H-imidazole (185) l-[4-(Methylsulfonyl)phenyl]-2-(4-trifluoromethyl-phenyl)-4- trifluomethyl- lH-imidazole (186) 4-[2-(4-Chlorophenyl)-4-(trifluoromethyl)-lH-imidazol-l- yl]benzenesulfonamide ( 187) 4-[2-(3-Chloro-4-methylphenyl)-4-(tιifluoromethyl)- lH-imidazol- l-yl]benzenesulfonamide (188) 3-[ l-(4-Methylsulfonyl)phenyl]-4-trifluoromethyl- lH-imidazol-2- yl]pyridine (189) 2- [ l-(4-Methylsulfonyl)phenyl]-4-trifluoromethyl- lH-imidazol-2- yljpyridine (190) 4-[l-[4-(Methylsuffonyl)phenyl]-4-trifhιoromethyl-lH-imidazol-2- yljpyridine (191) 2-Methyl-5-[l-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl- 1H- imidazol- 2-yl]pyridine (192) 2-Methyl-6-[l-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl- 1H- imidazol-2-yl]pyridine (193) 5-Methyl-2-[l-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl- 1H- imidazol-2-yl]pyrid__αe ( 194) 4-Methyl-2- [ 1- [4-(methylsulfonyl)ρhenyl]-4-trifluoromethyl- 1 H- imidazol-2-yl]pyridine (195) 2-Methoxy-5-[l-[4-(me ylsulfonyl)phenyl]-4-trifluoromethyl- 1H- imidazol-2-yl]pyridine (196) 4-[2-(6-Methylpyridin-3-yl)-4-(trifluoromethyl)- lH-imidazol- 1- yljbenzenesulfonamide (197) 4-[2-(6-Methylpyridin-2-yl)-4-(trifluoiOmethyl)- lH-iroidazol- 1- yljbenzenesulfonamide (198) 3-Methyl-5-[l-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)- 1H- imidazol-2-yl]pyridine ( 199) 4-[2-(4-Methylρyridin-2-yl)-4-(trifluoromethyl)- lH-imidazol- 1- yljbenzenesulfonamide (200) 2-[l-[4-(Methylsulfonyl)phenyl]-4-(trifluoromethyl)- lH-imidazol- 2-yl]thiophene (201 ) 3-[ l-[4-(Methylsulfonyl)phenyl]-4-(trifluoiOmethyl)- lH-imidazol- 2-yl]thiophene (202) 4-[2-(5-Methylpyridin-3-yl)-4-(trifluoromethyl)- lH-imidazol- 1- yljbenzenesulfonamide (203) 2-Methyl-3-[l-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)- 1H- imidazol-2-yl]thiophene (204) 4-[2-(2-Methylpyridin-3-yl)-4-(trifluoromethyl)- lH-imidazol- 1- yl]benzenesulfonamide (205) 4-[2-Pyridin-3-yl)-4-(trifluoromethyl)- lH-imidazol- l - yl]benzenesulfonamide The synthesis of compounds 1-39 is disclosed in TaUey et al. U.S. Patent 66,823. The synthesis of compounds 40 and 41 is disclosed in Black et al. U.S. Patent No. 5,436,265. The synthesis of compounds 42-94 is disclosed in Ehichaπne et al. U.S. Patent No. 5,474,995. The synthesis of compounds 95-105 is disclosed in Prasit et al. U.S. Patent No. 5,521,213. The synthesis of compounds 106-123 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 Khartna et al. U.S. Patent No. 5,616,601. Other selective inhibitors of cyclooxygenase-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 of which is incorp orated herein by reference. StiU other selective inhibitors of cyclooxygenase-2 and their synthesis are taught in Examples 1-13 including Examples la-lp and 4a-4h of TaUey et aL U.S. Patent No. 5,633,272, the disclosure of which is incorporated herein by reference. StiU 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. StiU other selective inhibitors of cyclooxygenase-2 are taught in Examples 1-6 of TaUey et al. U.S. Patent No. 5,643,933, the disclosure of which is incorporated herein by reference. StiU 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-pyrazol- 1 -yljbenzenesulfonamide which is compound (1) set forth above and 4-[5-(4-methylphenyl)-3-(trifluoromethyl)- lH- pyrazol-1-yl] benzenesulfonamide which is compound (4) set forth above; it is beUeved the latter compound is ceUcoxib (Trade name Celebrex). Another preferred 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 therapeuticaUy effective amount. In general, the dosage for the first embodiment herein ranges from 0.1 to 30 mg/kg. 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 cyclooxygenase-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 Uver disease with a cyclooxygenase-2 inhibiting amount of a selective inhibitor of cyclooxygenase-2 and a therapeutic amount of an anti-viral drug where the cyclooxygenase-2 inhibitor 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 conventionaUy 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 parenteraUy 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 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 inhibitors of cyclooxygenase-2 which directly inhibit 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,_ 4 -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: TaUey et al. U.S. Patent No. 5,643,933; TaUey et al. U.S. Patent No. 5,633,272; Khanna et aL U.S. Patent 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]-lH-pyrazol-l-yl]benzenesulfonamide and 4-methyl-5-(4-methylsulfonyl)phenyl-2-[(2,3-hydroxyphenoxy)methyl]oxazole and the corresponding compounds where methoxy or ethoxy replaces hydroxy. 4- [5- Methyl-3-[[(2,3-hydroxy)phenoxy]methyl]-lH-pyrazol-l-yl]benzenesulfonamidehas the structure where R 1 is methyl and R 2 is NH 2 . 4-(Methyl)-5-(4-methylsulfonyl)phenyl-2-[(2,3- hydroxyphenoxy)methyl]oxazole has the structure These compounds are embraced by broad disclosure in TaUey et al. U.S. Patent No. 5,643,933 but are not specificaUy disclosed therein. These compounds can be made analogously to Scheme XXII in U.S. Patent No. 5,643,933 by reacting 2,3- dihydroxybenzyl bromide, where the hydroxy groups are protected by conventional techniques (for example, as described 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 trihydroxyphenol. 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, inflammatory bowel 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 generaUy those set forth for selective inhibitors of cyclooxygenase-2 in the first embodiment herein. The route of administration is preferably oral although other routes of administration, e.g., parenteral, such as intravenous, may also beused. The selective inhibitors of cyclooxygenase-2 of the third embodiment herein have improved anti-inflammatory eflScacy compared to selective inhibitors of cyclooxygenase-2 which do not inhibit the synthesis of cyclooxygenase-2 protein. The three embodiments described above are Ulustrated in the foUowing examples. EXAMPLE I A patient with alcohoUc 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 IU/L and prothrombin time of 15.1 seconds. Treatment is carried out by administration of 4-[5-(4-chlorophenyl)-3- (trifluoromethyl)- lH-pyrazol- 1 -yljbenzenesulfonamide at a dosage of 6 mg/kg by oral route of administration, daUy. 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-(trifluoromethyl)- lH-pyrazol- l-yl]benzenesulfonamide at a dosage of 6 mg/kg by oral route of administration daUy. 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 Uver chemistries. Serologic workup is notable for positive antinuclear and antismooth muscle antibodies. 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-(trifluoromethyl)- lH-pyrazol- l-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. The same result is obtained when the drug administered is 4-[5-(4- methylphenyl)-3-(trifIuoromethyl)-lH-pyrazol-l-ylJbenzenesulfonamide at an oral dose of 6 mg/kg. EXAMPLE III A patient having symptoms of malaise, anorexia and fatigue, has persistently elevated Uver 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)-lH-pyrazol-l-yl]benzene-sulfonamide at a dose of 6 mg/kg, daUy 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 Uver enzymes. The same result is obtained when the cyclooxygenase-2 inhibitor is 4-[5-(4- methylphenyl)-3-(trifluoromethyl)-l H-pyrazol- 1 -yljbenzenesulfonamide 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 where R 1 is methyl and R 2 is NH 2 is reacted with 2.3-dihydroxybenzylbromide where the hydroxyls are protected, under basic conditions (K 2 CO 3 ), and then deprotecting is carried outto produce 4-[5-methyl-3-[(2,3-hydroxy)phenoxy]methylJ- lH-pyrazol- 1 -yljbenzenesulfonamide. The product has the structure where R 1 is methyl and R 2 is NH 2 . The starting material is made by the reaction to produce compound 78 in Scheme XNII depicted in TaUey et al. U.S. Patent No. 5,643,933. Many variations of the above will be obvious to those skiUed in the art. Thus, the invention is defined by the claims.

Claims: WHAT IS CLAIMED IS: 1. A method of treating a patient with Uver disease comprising administering to said patient a cyclooxygenase-2 inhibiting amount of a selective inhibitor of cyclooxygenase-2. 2. The method of Claim 1 , wherein the Uver disease is an inflammatory Uver disorder. 3. The method of Claim 2, wherein the inflammatory Uver disorder is selected from the group consisting of chronic viral he atitis B , chronic viral hep atitis C, alcohoUc Uver injury, primary biUary cirrhosis, autoimmune hep atitis, nonalcohohc steatohepatitis, and liver transplant rejection. 4. The method of Claim 3, wherein the selective inhibitor of cyclooxygenase-2 is 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)- lH-pyrazol- 1- yljbenzenesulfonamide. 5. The method of Claim 3, wherein the selective inhibitor of cyclooxygenase-2 is 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-lH-pyrazol- 1- yljbenzenesulfonamide. 6. The method of Claim 3, wherein the selective inhibitor of cyclooxygenase-2 directly inhibits the enzyme cyclooxygenase-2 and also inhibits the synthesis of cyclooxygenase-2 protein. 7. A method of treating a patient with a virus-caused Uver disease comprising administering to said patient a cyclooxygenase-2 inhibiting amount of selective inhibitor of cyclooxygenase-2 and therapeutic amount(s) of anti-viral drug(s). 8. The method of Claim 7, wherein the Uver disease is selected from the group consisting of chronic viral hepatitis B and chronic viral hepatitis C. 9. The method of Claim 8, wherein the selective inhibitor of cyclooxygenase-2 is 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)- lH-pyrazol- 1- yljbenzenesulfonamide. 10. The method of Claim 8, wherein the selective inhibitor of cyclooxygenase-2 is 4-[5-(4-methylphenyl)-3-(trifluoromethyl)- lH-pyrazol- 1- yljbenzenesulfonamide. 11. The method of Claim 8, wherein the selective inhibitor of cyclooxygenase-2 directly inhibits the enzyme cyclooxygenase-2 and also inhibits the synthesis of cyclooxygenase- protein. 12. A selective inhibitor of cyclooxygenase-2 which directly inhibits the enzyme cyclooxygenase-2 and which also inhibits the synthesis of cyclooxygenase-2 protein. 13. The selective inhibitor of cyclooxygenase-2 of Claim 12 which contains phenyl group with two or more substituents on the phenyl group selected from the group consisting of hydroxy and C 1 . 4 -alkoxy. 14. The selective inhibitor of Claim 13 which is selected from the group consisting of 4-[5-(4-methyl-3-[[(2,3-hydroxy)phenoxy]methylJ- lH-pyrazol- 1- yljbenzenesulfonamide and 4-methyl-5-(4-methylsulfonyl)phenyl-2-[(2,3- hydroxyphenoxy)methylJoxazole and the corresponding compounds where methoxy or ethoxy replace hydroxy. 15. The selective inhibitor of cyclooxygenase-2 of Claim 14 which is 4- [5- methyl-3-[[(2,3-hydroxy)phenoxy]methylJ-lH-pyrazol-l-yl]benzenesulfonamide. 16. The selective inhibitor of cyclooxygenase-2 of Claim 14 which is 4- methyl-5-(4-methylsulfonyl)phenyl-2-[(2,3-hydroxyphenoxy) methylJoxazole.

Inventors: DANNENBERG ANDREW J, DANNENBERG, ANDREW, J.
Applicants: CORNELL RES FOUNDATION INC, DANNENBERG ANDREW J, CORNELL RESEARCH FOUNDATION, INC., DANNENBERG, ANDREW, J.
Application year: 1998
Main classification: A61K31
IPC codes: A61K31, C07D231, C07D263