CA2313049A1 - Cyclooxygenase-2 inhibition - Google Patents
Cyclooxygenase-2 inhibition Download PDFInfo
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- CA2313049A1 CA2313049A1 CA002313049A CA2313049A CA2313049A1 CA 2313049 A1 CA2313049 A1 CA 2313049A1 CA 002313049 A CA002313049 A CA 002313049A CA 2313049 A CA2313049 A CA 2313049A CA 2313049 A1 CA2313049 A1 CA 2313049A1
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- Prior art keywords
- cyclooxygenase
- phenyl
- methylsulfonyl
- benzenesulfonamide
- pyrazol
- Prior art date
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/655—Azo (—N=N—), diazo (=N2), azoxy (>N—O—N< or N(=O)—N<), azido (—N3) or diazoamino (—N=N—N<) compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- Medicinal Chemistry (AREA)
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- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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
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 WO 99/30721 PCTlUS98/25206 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, 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 (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 WO 99/30721 PCTNS98lZ5206 (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 WO 99/30721 PC'f/US98/25206 (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 (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 (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 (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 ( 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 WO 99/30721 PCT/US98/~5206 ( 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 ( 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 (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 WO 99/30721 PGT/US981Z520b (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 ( 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.
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 WO 99/30721 PCTlUS98/25206 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, 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 (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 WO 99/30721 PCTNS98lZ5206 (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 WO 99/30721 PC'f/US98/25206 (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 (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 (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 (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 ( 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 WO 99/30721 PCT/US98/~5206 ( 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 ( 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 (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 WO 99/30721 PGT/US981Z520b (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 ( 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.
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 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 WO 99/30721 PCT/US98/25206 .
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 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 WO 99/30721 PCT/US98/25206 .
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.
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 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.
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.
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 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.
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.
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.
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 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.
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 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.
Claims (16)
1. 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.
2. The method of Claim 1, wherein the liver disease is an inflammatory liver disorder.
3. The method of Claim 2, wherein the inflammatory liver disorder is selected from the group consisting of chronic viral hepatitis B, chronic viral hepatitis C, alcoholic liver injury, primary biliary cirrhosis, autoimmune hepatitis, nonalcoholic 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)-1H-pyrazol-1-yl]benzenesulfonamide.
5. The method of Claim 3, wherein the selective inhibitor of cyclooxygenase-2 is 4-[5-(4-methylphenyl_-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide.
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 liver 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 liver 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)-1H-pyrazol-1-yl]
benzenesulfonamide.
benzenesulfonamide.
10. The method of Claim 8, wherein the selective inhibitor of cyclooxygenase-2 is 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]
benzenesulfonamide.
benzenesulfonamide.
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 C1-4-alkoxy.
14. The selective inhibitor of Claim 13 which is selected from the group consisting of 4-[5-(4-methyl3-[[(2,3-hydroxy)phenoxy]methyl]-1H-pyrazol-1-yl]benzenesulfonamide and 4-methyl-5-(4-methylsulfonyl)phenyl-2-[(2,3-hydroxyphenoxy)methyl]oxazole 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]methyl]-1H-pyrazol-1-yl]benzenesulfonamide.
16. The selective inhibitor of cyclooxygenase-2 of Claim 14 which is 4-methyl-5-(4-methylsulfonyl)phenyl-2-[(2,3-hydroxyphenoxy) methyl]oxazole.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US6995597P | 1997-12-17 | 1997-12-17 | |
| US60/069,955 | 1997-12-17 | ||
| PCT/US1998/025206 WO1999030721A1 (en) | 1997-12-17 | 1998-12-07 | Cyclooxygenase-2 inhibition |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2313049A1 true CA2313049A1 (en) | 1999-06-24 |
Family
ID=22092236
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002313049A Abandoned CA2313049A1 (en) | 1997-12-17 | 1998-12-07 | Cyclooxygenase-2 inhibition |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP1039914A4 (en) |
| AU (1) | AU1703799A (en) |
| CA (1) | CA2313049A1 (en) |
| WO (1) | WO1999030721A1 (en) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE60041808D1 (en) * | 1999-01-27 | 2009-04-30 | Cornell Res Foundation Inc | TREATMENT OF CANCER WITH HER-2 / NEU OVEREXPRIMATION |
| JP2003503455A (en) * | 1999-07-02 | 2003-01-28 | ユニベルシテア、メディッシュ、セントラム、ユトレヒト | Antiviral treatment |
| EP1064940A1 (en) * | 1999-07-02 | 2001-01-03 | Universitair Medisch Centrum Utrecht | Antiviral therapy |
| US6787573B2 (en) | 1999-07-02 | 2004-09-07 | Universiteit Utrecht | Antiviral therapy |
| AU4485101A (en) * | 2000-03-17 | 2001-09-24 | Universitair Medisch Centrum Utrecht | Antiviral therapy |
| AU2003201811A1 (en) * | 2002-01-10 | 2003-07-30 | Pharmacia & Upjohn Company | Use of cox-2 inhibitors in combination with antiviral agents for the treatment of papilloma virus infections |
| US8466159B2 (en) | 2011-10-21 | 2013-06-18 | Abbvie Inc. | Methods for treating HCV |
| GB2515942A (en) | 2011-10-21 | 2015-01-07 | Abbvie Inc | Combination treatment (e.g. with ABT-072 or ABT-333) of DAAs for use in treating HCV |
| US8853176B2 (en) | 2011-10-21 | 2014-10-07 | Abbvie Inc. | Methods for treating HCV |
| US8492386B2 (en) | 2011-10-21 | 2013-07-23 | Abbvie Inc. | Methods for treating HCV |
| WO2017189978A1 (en) | 2016-04-28 | 2017-11-02 | Emory University | Alkyne containing nucleotide and nucleoside therapeutic compositions and uses related thereto |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5474995A (en) * | 1993-06-24 | 1995-12-12 | Merck Frosst Canada, Inc. | Phenyl heterocycles as cox-2 inhibitors |
| US5436265A (en) * | 1993-11-12 | 1995-07-25 | Merck Frosst Canada, Inc. | 1-aroyl-3-indolyl alkanoic acids and derivatives thereof useful as anti-inflammatory agents |
| US5466823A (en) | 1993-11-30 | 1995-11-14 | G.D. Searle & Co. | Substituted pyrazolyl benzenesulfonamides |
| US5633272A (en) | 1995-02-13 | 1997-05-27 | Talley; John J. | Substituted isoxazoles for the treatment of inflammation |
| AU6274896A (en) * | 1995-06-06 | 1996-12-24 | Procyte Corporation | Stable copper(i) complexes as active therapeutic substances |
| DK0888127T3 (en) * | 1996-02-13 | 2002-04-08 | Searle & Co | Combinations with immunosuppressive effects containing cyclooxygenase-2 inhibitors and 5-lipooxygenase inhibitors |
| DE69733338T2 (en) * | 1996-02-13 | 2006-03-16 | G.D. Searle & Co., Chicago | PREPARATIONS, CONTAINING A CYCLOOXYGENASE-2 INHIBITOR AND A LEUKOTRIEN B4 RECEPTOR ANTAGONIST |
-
1998
- 1998-12-07 CA CA002313049A patent/CA2313049A1/en not_active Abandoned
- 1998-12-07 WO PCT/US1998/025206 patent/WO1999030721A1/en active Application Filing
- 1998-12-07 EP EP98961802A patent/EP1039914A4/en not_active Withdrawn
- 1998-12-07 AU AU17037/99A patent/AU1703799A/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| WO1999030721A1 (en) | 1999-06-24 |
| AU1703799A (en) | 1999-07-05 |
| EP1039914A1 (en) | 2000-10-04 |
| EP1039914A4 (en) | 2007-06-27 |
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