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WO1999030721A1 - . inhibition de la cyclooxygenase-2 - Google Patents

. inhibition de la cyclooxygenase-2 Download PDF

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Publication number
WO1999030721A1
WO1999030721A1 PCT/US1998/025206 US9825206W WO9930721A1 WO 1999030721 A1 WO1999030721 A1 WO 1999030721A1 US 9825206 W US9825206 W US 9825206W WO 9930721 A1 WO9930721 A1 WO 9930721A1
Authority
WO
WIPO (PCT)
Prior art keywords
cyclooxygenase
phenyl
methylsulfonyl
pyrazol
trifluoromethyl
Prior art date
Application number
PCT/US1998/025206
Other languages
English (en)
Inventor
Andrew J. Dannenberg
Original Assignee
Cornell Research Foundation, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Cornell Research Foundation, Inc. filed Critical Cornell Research Foundation, Inc.
Priority to AU17037/99A priority Critical patent/AU1703799A/en
Priority to US09/554,604 priority patent/US7041694B1/en
Priority to EP98961802A priority patent/EP1039914A4/fr
Priority to CA002313049A priority patent/CA2313049A1/fr
Publication of WO1999030721A1 publication Critical patent/WO1999030721A1/fr

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Classifications

    • 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
    • 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
    • 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
    • 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
    • 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
    • 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

Definitions

  • 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.
  • 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.
  • 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.
  • liver disease was not considered as one of the conditions that was treatable by selective inhibitors of cyclooxygenase-2.
  • One 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 Ehicha ⁇ ne 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.
  • 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.
  • 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.
  • 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.
  • the second embodiment herein 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.
  • the virus-cause liver diseases include, for example, chronic viral hepatitis B and chronic viral hepatitis C.
  • 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.
  • various interferons e.g., recombinant and natural alpha interferons
  • parenteraUy for chronic hepatitis B
  • 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.
  • 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.
  • 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. 5,596,00
  • 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]benzenesulfonamide has the structure
  • 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.
  • 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.
  • 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 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.
  • 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.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

On utilise des inhibiteurs sélectifs de cyclooxygénase-2 pour traiter des hépatopathies et en combinaison avec des médicaments antiviraux afin de traiter des troubles hépatiques d'origine virale. Les inhibiteurs sélectifs de cyclooxygénase-2 inhibant également la synthèse de la cyclooxygénase-2, améliorent l'efficacité d'inhibiteurs sélectifs classiques de cyclooxygénase-2 dans le traitement d'états inflammatoires, de la maladie d'Alzheimer et du cancer.
PCT/US1998/025206 1997-12-17 1998-12-07 . inhibition de la cyclooxygenase-2 WO1999030721A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
AU17037/99A AU1703799A (en) 1997-12-17 1998-12-07 Cyclooxygenase-2 inhibition
US09/554,604 US7041694B1 (en) 1997-12-17 1998-12-07 Cyclooxygenase-2 inhibition
EP98961802A EP1039914A4 (fr) 1997-12-17 1998-12-07 . inhibition de la cyclooxygenase-2
CA002313049A CA2313049A1 (fr) 1997-12-17 1998-12-07 . inhibition de la cyclooxygenase-2

Applications Claiming Priority (2)

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US6995597P 1997-12-17 1997-12-17
US60/069,955 1997-12-17

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WO1999030721A1 true WO1999030721A1 (fr) 1999-06-24

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EP (1) EP1039914A4 (fr)
AU (1) AU1703799A (fr)
CA (1) CA2313049A1 (fr)
WO (1) WO1999030721A1 (fr)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1064940A1 (fr) * 1999-07-02 2001-01-03 Universitair Medisch Centrum Utrecht Thérapie antivirale
WO2001001985A1 (fr) * 1999-07-02 2001-01-11 Universitair Medisch Centrum Utrecht Therapie antivirale
WO2001068086A1 (fr) * 2000-03-17 2001-09-20 Universiteit Utrecht Therapie antivirale
EP1146789A1 (fr) * 1999-01-27 2001-10-24 Cornell Research Foundation, Inc. Traitement de cancers associe a la surexpression de her-2/neu
WO2003059347A1 (fr) * 2002-01-10 2003-07-24 Pharmacia & Upjohn Company Utilisation de cox-2 inhibiteurs en combinaison avec des agents antiviraux pour le traitement d'infections dues au papillomavirus
US6787573B2 (en) 1999-07-02 2004-09-07 Universiteit Utrecht Antiviral therapy
US7320996B2 (en) 2001-08-15 2008-01-22 Sugen, Inc Indolinone protein kinase inhibitors and cyclooxygenase inhibitors for use in combination therapy for the treatment of cancer
US8466159B2 (en) 2011-10-21 2013-06-18 Abbvie Inc. Methods for treating HCV
US8492386B2 (en) 2011-10-21 2013-07-23 Abbvie Inc. Methods for treating HCV
US8809265B2 (en) 2011-10-21 2014-08-19 Abbvie Inc. Methods for treating HCV
US8853176B2 (en) 2011-10-21 2014-10-07 Abbvie Inc. Methods for treating HCV
WO2017189978A1 (fr) 2016-04-28 2017-11-02 Emory University Compositions thérapeutiques à base de nucléotides et nucléosides contenant un alcyne et utilisations associées

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US5466823A (en) 1993-11-30 1995-11-14 G.D. Searle & Co. Substituted pyrazolyl benzenesulfonamides
US5474995A (en) 1993-06-24 1995-12-12 Merck Frosst Canada, Inc. Phenyl heterocycles as cox-2 inhibitors
WO1996039144A1 (fr) * 1995-06-06 1996-12-12 Procyte Corporation Complexes cuivreux stables utilises comme substances a activite therapeutique
US5633272A (en) 1995-02-13 1997-05-27 Talley; John J. Substituted isoxazoles for the treatment of inflammation

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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
DK0888127T3 (da) * 1996-02-13 2002-04-08 Searle & Co Kombinationer med immunoundertrykkende virkninger indeholdende cyclooxygenase-2-inhibitorer og 5-lipooxygenaseinhibitortorer
PT880362E (pt) * 1996-02-13 2005-10-31 Searle & Co Composicoes compreendendo um inibidor do cicloxigenase tipo 2 e um antagonista do receptor do leucotrieno b4

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US5474995A (en) 1993-06-24 1995-12-12 Merck Frosst Canada, Inc. Phenyl heterocycles as cox-2 inhibitors
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
WO1996039144A1 (fr) * 1995-06-06 1996-12-12 Procyte Corporation Complexes cuivreux stables utilises comme substances a activite therapeutique

Non-Patent Citations (5)

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Title
DATABASE WPIDS ON STN, DERWENT INFORMATION LTD., AN 97-042830; & WO 9639144 A1 (BRANCA A. et al.). *
DINCHUK J.E. et al., "Renal Abnormalities and an Altered Inflammatory Response in Mice Lacking Cyclooxygenase II", NATURE, November 1995, Vol. 378, pages 406-409. *
NANJI ET AL., GASTROENTEROLOGY, vol. 112, 1997, pages 943 - 951
NANJI ET AL., HEPATOLOGY, vol. 26, no. 6, 1997, pages 1538 - 1545
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Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1146789A1 (fr) * 1999-01-27 2001-10-24 Cornell Research Foundation, Inc. Traitement de cancers associe a la surexpression de her-2/neu
EP1146789A4 (fr) * 1999-01-27 2007-02-14 Cornell Res Foundation Inc Traitement de cancers associe a la surexpression de her-2/neu
EP1064940A1 (fr) * 1999-07-02 2001-01-03 Universitair Medisch Centrum Utrecht Thérapie antivirale
WO2001001985A1 (fr) * 1999-07-02 2001-01-11 Universitair Medisch Centrum Utrecht Therapie antivirale
US6787573B2 (en) 1999-07-02 2004-09-07 Universiteit Utrecht Antiviral therapy
WO2001068086A1 (fr) * 2000-03-17 2001-09-20 Universiteit Utrecht Therapie antivirale
US7320996B2 (en) 2001-08-15 2008-01-22 Sugen, Inc Indolinone protein kinase inhibitors and cyclooxygenase inhibitors for use in combination therapy for the treatment of cancer
WO2003059347A1 (fr) * 2002-01-10 2003-07-24 Pharmacia & Upjohn Company Utilisation de cox-2 inhibiteurs en combinaison avec des agents antiviraux pour le traitement d'infections dues au papillomavirus
US8466159B2 (en) 2011-10-21 2013-06-18 Abbvie Inc. Methods for treating HCV
US8492386B2 (en) 2011-10-21 2013-07-23 Abbvie Inc. Methods for treating HCV
US8680106B2 (en) 2011-10-21 2014-03-25 AbbVic Inc. Methods for treating HCV
US8685984B2 (en) 2011-10-21 2014-04-01 Abbvie Inc. Methods for treating HCV
US8809265B2 (en) 2011-10-21 2014-08-19 Abbvie Inc. Methods for treating HCV
US8853176B2 (en) 2011-10-21 2014-10-07 Abbvie Inc. Methods for treating HCV
US8969357B2 (en) 2011-10-21 2015-03-03 Abbvie Inc. Methods for treating HCV
US8993578B2 (en) 2011-10-21 2015-03-31 Abbvie Inc. Methods for treating HCV
US9452194B2 (en) 2011-10-21 2016-09-27 Abbvie Inc. Methods for treating HCV
WO2017189978A1 (fr) 2016-04-28 2017-11-02 Emory University Compositions thérapeutiques à base de nucléotides et nucléosides contenant un alcyne et utilisations associées
US11192914B2 (en) 2016-04-28 2021-12-07 Emory University Alkyne containing nucleotide and nucleoside therapeutic compositions and uses related thereto

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EP1039914A1 (fr) 2000-10-04
EP1039914A4 (fr) 2007-06-27
AU1703799A (en) 1999-07-05
CA2313049A1 (fr) 1999-06-24

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