WO1997032575A1 - Derives mercapto utilises en qualite d'inhibiteurs de cyclo-oxygenases - Google Patents

Derives mercapto utilises en qualite d'inhibiteurs de cyclo-oxygenases Download PDF

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Publication number
WO1997032575A1
WO1997032575A1 PCT/US1997/003279 US9703279W WO9732575A1 WO 1997032575 A1 WO1997032575 A1 WO 1997032575A1 US 9703279 W US9703279 W US 9703279W WO 9732575 A1 WO9732575 A1 WO 9732575A1
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Prior art keywords
group
alkylene
alkenylene
composition
independently
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PCT/US1997/003279
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English (en)
Inventor
Basilia Zingarelli
Andrew Salzman
Csaba Szabo
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Children's Hospital Medical Center
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Application filed by Children's Hospital Medical Center filed Critical Children's Hospital Medical Center
Priority to CA 2247121 priority Critical patent/CA2247121A1/fr
Priority to AU20633/97A priority patent/AU2063397A/en
Priority to JP9531871A priority patent/JP2000506852A/ja
Priority to BR9707953-7A priority patent/BR9707953A/pt
Publication of WO1997032575A1 publication Critical patent/WO1997032575A1/fr

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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
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to the use of mercapto derivatives as inhibitors of cyclooxygenases (COX).
  • Prostaglandins are synthesized from arachidonic acid by a family of enzymes termed cyclooxygenases (COX).
  • COX-1 cyclooxygenases
  • One isoform (COX-1 ) is constitutively present in a variety of tissues and releases PG's in low amounts.
  • the continuous release of PG from COX-1 serves physiological purposes. For instance, prostacyclin, a vasodilatory and anti-aggregatory prostaglandin, reduces the adhesion of platelets to the endothelial surface.
  • the inducible isoform of COX (COX-2) is expressed in
  • endotoxin causes
  • non-steroidal anti-inflammatory drugs are examples of non-steroidal anti-inflammatory drugs.
  • acetylsalicylic acid ibuprofen, etc.
  • COX inhibition examples include 5, 1 55, 1 1 0;
  • This invention is directed to a pharmacologically
  • composition includes a mercapto derivative and a pharmaceutically acceptable carrier, with the mercapto derivative present in the
  • composition in an effective amount to inhibit COX in the mammal.
  • COX inhibitors in that they also inhibit another class of inflammatory enzymes (nitric oxide synthases).
  • the invention also is directed to a method of inhibiting
  • COX in a mammal, which includes the step of administering to the
  • a mercapto derivative in a pure form or in a pharmaceutically acceptable carrier.
  • R T is H, alkyl, alkenyl, phenyl, alkylene, alkenylene, or phenylalkylene or a substituted derivative thereof;
  • R is alkylene or alkenylene
  • R optionally may be
  • R 2 , R 3 , R ' 2 and R ' 3 are independently H, lower alkyl, alkenyl, alkylene, alkenylene, amino, phenyl or phenylalkylene, or a
  • R 2 or R ' 2 is alkylene or alkenylene
  • Z and Z ' are independently alkylene, alkenylene,
  • R 2 , R 3 , R ' 2 or R ' 3 is alkylene or alkenylene
  • R ' 2 or R ' 3 optionally may be joined to the adjacent Z or Z ' to form a
  • alkylene or alkenylene optionally being
  • X is N, NR 4 , O, CR 5 or CR 4 R 5 ;
  • X ' is N, NR ' 4 , O, CR ' 5 or CR ' 4 R ' 5 ; Y is S;
  • R 4 and R ' 4 are independently H, alkyl, alkylene, alkenylene, thioalkylene or thioesteralkylene;
  • R 5 and R ' 5 are independently H, alkyl, alkylene,
  • R 4 or R ' 4 is alkylene, alkenylene, thioalkylene, or thioesteralkylene
  • R 4 or R ' 4 optionally may be joined to R 2 , R 3 , R ' 2 or
  • R ' 3 to form a 5- or 6- membered heterocyclic ring including N, C and
  • R 2 , R 3 , R ' 2 or R ' 3 so joined is alkylene, alkenylene, amino, phenyl,
  • substituted derivative is lower alkyl or halo.
  • Fig. 1 is a graph of the effect of mercaptoeth ⁇ lguanidine
  • Fig. 2 is a graph of the effect of mercaptoethylguanidine
  • Fig. 3 is a graph of the effect of mercaptoethylguanidine
  • This invention is directed to a pharmacologically
  • composition includes a mercapto derivative and a pharmaceutically
  • composition in an effective amount to inhibit COX in the mammal.
  • invention also is directed to a method of inhibiting COX in a mammal
  • R is H, alkyl, alkenyl, phenyl, alkylene, alkenylene, or
  • R is alkylene or alkenylene
  • R optionally may be joined to either of the amidino Ns, to Z or to X of the above formula
  • X is either CR 5 or N;
  • R 2 , R 3 , R ' 2 and R ' 3 are independently H, lower alkyl
  • R 2 or R ' 2 is alkylene or alkenylene
  • Z and Z ' are independently alkylene, alkenylene,
  • R 2 , R 3 , R ' 2 or R ' 3 is alkylene or alkenylene
  • R ' 2 or R ' 3 optionally may be joined to the adjacent Z or Z ' to form a
  • X is N, NR 4 , O, CR 5 or CR 4 R 5 ;
  • X ' is N, NR ' 4 , O, CR ' 5 or CR ' 4 R ' 5 ;
  • Y is S; R 4 and R ' 4 are independently H, alkyl, alkylene,
  • R 5 and R ' 5 are independently H, alkyl, alkylene, alkenylene, thioalkylene, thioesteralkylene, amino or carboxyl;
  • R 4 or R ' 4 is alkylene, alkenylene, thioalkylene, or
  • R 4 or R ' 4 optionally may be joined to R 2 , R 3 , R ' 2 or
  • R ' 3 to form a 5- or 6- membered heterocyclic ring including N, C and not more than one atom of O or S, with the proviso that R 2 , R 3 , R ' 2 or
  • R ' 3 is alkylene, alkenylene, amino, phenyl, phenylalkylene, or a
  • salt refers to any addition salt
  • acids examples include hydrochloric, h ⁇ drobromic, sulfuric,
  • any alkyl or alkylene may be any alkyl or alkylene.
  • halo includes bromine
  • R is H, alkyl, alkenyl, phenyl,
  • alkylene alkenylene or phenylalkylene, or a substituted derivative
  • this R, derivative may be substituted with one or
  • R 2 , R 3 , R' 2 and R' 3 are independently H, lower alkyl, alkenyl, alkylene, alkenylene, amino, phenyl or phenylalkylene, or a substituted derivative thereof. If desired, the R 2 , R 3 , R' 2 and R' 3
  • the thioalkylene preferably has a formula [-(CH 2 ) n -SH] where n is
  • R 4 , R 5 , R' 4 or R' 6 is thioesteralkylene
  • thioesteralkylene preferably has the formula HCH 2 ) n -S-R 6 ] where R 6 is
  • n is independently 1 to 4.
  • the substituent may include an alkoxy, halo, hydroxy,
  • a preferred subgroup of the mercapto derivative includes
  • R is H or lower alkyl
  • R 2 is H
  • R 3 is H
  • nonlimiting examples include mercaptoethylguanidine,
  • R 2 is H; R 3 is H; R' 2 is H; R' 3 is H; X is NR 4 ; X' is NR' 4 ; R 4 is H; R' 4 is
  • H; and Z and Z' are independently a C, ⁇ alkylene.
  • Nonlimiting examples include mercaptoethylguanidine, mercaptopropylguanidine, and guanidinoethyldisulfide.
  • the mercapto derivative in pure form or in a
  • the mercapto derivative may be any suitable cyclooxygenase enzymes.
  • the mercapto derivative may be any suitable cyclooxygenase enzymes.
  • the mercapto derivative may be any suitable cyclooxygenase enzymes.
  • the mercapto derivative may be any suitable cyclooxygenase enzymes.
  • the mercapto derivative may be any suitable cyclooxygenase enzymes.
  • a circulatory shock including its various aspects such as vascular and myocardial dysfunction, metabolic failure including the
  • Circulatory shock may be a result of gram-negative and gram positive sepsis, trauma, hemorrhage, burn
  • cytokines such as TNF, IL-1 and IL-2 or therapy with cytokine-inducing agents
  • mercapto derivatives may be useful to inhibit PG
  • COX-2 activity contributes to the pathophysiology of the condition
  • autoimmune and/or inflammatory conditions such as arthritis, rheumatoid arthritis and systemic lupus erythematosus (SLE) and in insulin-dependent diabetes mellitus, and, therefore,
  • mercapto derivatives may prove helpful in treating these conditions.
  • disorders include: inflammatory bowel diseases such as ileitis and
  • corneal dystrophy including corneal dystrophy, trachoma, onchocerciasis, uveitis,
  • disorders of the joints including arthritis and osteoarthritis, tuberculosis,
  • sclerodermatitis including sclerodermatitis, psoriasis and eczema; inflammatory diseases
  • dementia such as multiple sclerosis, dementia including AIDS-related
  • autoimmune diseases including immune-
  • the heart including ischemic heart disease and cardiomyopathy.
  • derivatives include adrenal insufficiency; hypercholesterolemia;
  • Atherosclerosis bone disease associated with increased bone resorption, e.g., osteoporosis, pre-eclampsia, eclampsia, uremic complications; chronic liver failure, noninflammatory diseases of the
  • central nervous system including stroke and cerebral ischemia; and various forms of cancer.
  • buccai and sub-lingual vaginal or parenteral (including intramuscular, sub-cutaneous and intravenous) administration, or for administration by
  • formulations may, where appropriate, be
  • compositions suitable for oral administration are provided.
  • capsules as capsules, cachets or tablets, each containing a predetermined
  • the active ingredient may
  • Tablets and capsules for oral administration may
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in
  • a powder or granules optionally mixed with a binder, lubricant, inert
  • Oral fluid may be coated according to methods well known in the art.
  • Oral fluid may be coated according to methods well known in the art.
  • preparations may be in the form of, for example, aqueous or oily
  • suspensions solutions, emulsions, syrups or elixirs, or may be
  • Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous solvents, and the like.
  • Formulations for parenteral administration include:
  • aqueous and non-aqueous sterile injection solutions which may contain
  • aqueous and non-aqueous sterile suspensions which may include
  • the formulations may be any suitable suspending agents and thickening agents.
  • the formulations may be any suitable suspending agents and thickening agents.
  • the formulations may be any suitable suspending agents and thickening agents.
  • ampoules and vials may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline, water-for-injection, immediately prior to use.
  • sterile liquid carrier for example, saline, water-for-injection
  • formulations may be presented for continuous infusion.
  • Extemporaneous injection solutions and suspensions may be
  • Formulations for rectal administration may be presented as a suppository with the usual carriers such as cocoa butter or
  • a flavored base such as sucrose and acacia or tragacanth
  • pastilles comprising the active ingredient in
  • a base such as gelatin and glycerin or sucrose and acacia.
  • Drops may be formulated with an aqueous or non-aqueous base also comprising
  • Liquid sprays are conveniently delivered from pressurized
  • Pressurized packs may comprise a suitable propellant such as
  • dichlorodifluoromethane trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the compounds according to the invention may take the form of a dry powder composition, for example a powder mix of the
  • powder composition may be presented in unit dosage form, in for
  • capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator for example, capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.
  • compositions according to the invention may also be administrados in any other organoethyl alcohols.
  • the pharmaceutical compositions according to the invention may also be referred to be administrados in any other organoethyl alcohols.
  • the pharmaceutical compositions according to the invention may also be referred to be administrados in any other organoethyl alcohols.
  • the compounds of the invention may also be used in any combination.
  • inflammatory agents particularly nitric oxide synthase inhibitors
  • agents including cisplatin, NO donors or NO inhalation therapy, or PAF
  • formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example, those suitable for oral
  • administration may include flavoring agents.
  • Preferred unit dosage formulations are those containing an
  • the pharmaceutical composition preferably is administered
  • administration may vary depending upon the condition and its severity.
  • FIG. 1 illustrates the effect of mercaptoethyguanidine on arachidonic acid or immunostimulation- induced 6-keto prostaglandin F1 alpha formation in J774.2 macrophages.
  • J774 macrophage cell lines were obtained from the
  • DMEM Dulbecco's Modified Eagle Medium
  • fetal bovine serum 10% fetal bovine serum, glutamine, penicillin (10,000 U/l) and streptomycin (10,000 U/l).
  • Cells were grown in 96-well plates for measure of the production of prostaglandin metabolites and cell viability. All the experiments were carried out without fetal calf serum in order to avoid interference with radioimmunoassay.
  • Concentration of 6-keto prostaglandin 1 alpha the stable metabolite product of prostacyclin in the culture medium, was determined by radioimmunoassay.
  • Supernatant or reaction samples were diluted 1 :5 in a buffer containing 0.1 % polyvinylpyrolidine, 0.9%
  • 6-keto-PGF1 alpha was determined by radioimmunoassay as described (Wise WC, Cook JA, Haluskha PV. "Arachidonic Acid Metabolism in
  • Inhibitors were given as a 30-minute pretreatment. Cells were then stimulated with arachidonic acid (16 ⁇ M) in order to activate the constitutive cyclooxygenase (COX-1 ). Cells were then incubated for a further period of 30 minutes and the supernatant was collected for the measurement of arachidonic acid metabolism evaluation by radioimmunoassay.
  • Inhibitors were given as a 30-minute pretreatment. Cells were then stimulated with endotoxin of E.co/H LPS, 10 ⁇ g/mL) and interferon
  • MTT mitochondrial-dependent reduction of MTT [3- (4,5 - dimethylthiazol-2-yl) - 2,5 - diphenyltetrazolium bromide] to formazan.
  • Cells in 96-well plates were incubated (37 ⁇ C) with MTT (0.2 mg/ml for
  • FIG. 2 illustrates the effect of mercaptoethylguanidine on arachidonic acid or immunostimulation- induced thromboxane B2 formation in J774.2 macrophages.
  • J774 macrophage cell lines were cultured and treated as described in example 1 .
  • Concentration of thromboxane B2, the stable metabolite of thromboxane A2 was determined by radioimmunoassay.
  • Supernatant or reaction samples were diluted 1 :5 in a buffer containing 0.1 % polyvinylpyrolidine, 0.9% NaCI, 50mM Tris base, 1.7 mM MgSo 4
  • PG mercaptoethylguanidine
  • FIG. 3 illustrates the effect of mercaptoethylguanidine on 6-keto prostaglandin F1 alpha formation by purified COX-1 I (A) and COX-2 (B) isoenzymes.
  • 6-keto-PGF1 a was determined by radioimmunoassay as described (Wise WC, Cook JA, Haluskha PV, "Arachidonic Acid Metabolism in Endotoxin Tolerance", Adv. Shock, Vol. 10, pp. 131-142, 1983).
  • EXAMPLE 4 This Example illustrates a method for synthesizing mercaptoethylguanidine sulphate.
  • Mercaptoethylamine hydrochtoride (2g) was dissolved in methanol (5 ml) and cooled in a salt/ice bath.

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Abstract

Cette invention concerne une composition acceptable sur le plan pharmacologique, laquelle composition permet d'inhiber la cyclo-oxygénase chez les mammifères et comprend un dérivé mercapto ainsi qu'un véhicule acceptable sur le plan pharmaceutique. Cette invention concerne également un procédé d'inhibition de cyclo-oxygénase et de traitement de divers états où l'on a intérêt a inhiber la biosynthèse de prostaglandine. Ce procédé consiste à administrer à un mammifère un dérivé mercapto sous sa forme pure ou dans un véhicule acceptable sur le plan pharmaceutique.
PCT/US1997/003279 1996-03-05 1997-03-03 Derives mercapto utilises en qualite d'inhibiteurs de cyclo-oxygenases WO1997032575A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
CA 2247121 CA2247121A1 (fr) 1996-03-05 1997-03-03 Derives mercapto utilises en qualite d'inhibiteurs de cyclo-oxygenases
AU20633/97A AU2063397A (en) 1996-03-05 1997-03-03 Mercapto derivatives as inhibitors of cyclooxygenases
JP9531871A JP2000506852A (ja) 1996-03-05 1997-03-03 シクロオキシゲナーゼの阻害剤としてのメルカプト誘導体
BR9707953-7A BR9707953A (pt) 1996-03-05 1997-03-03 Derivados de mercapto como inibidores de ciclooxigenases

Applications Claiming Priority (2)

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US61109796A 1996-03-05 1996-03-05
US08/611,097 1996-03-05

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WO1997032575A1 true WO1997032575A1 (fr) 1997-09-12

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CN (1) CN1212620A (fr)
AU (1) AU2063397A (fr)
BR (1) BR9707953A (fr)
TR (1) TR199801731T2 (fr)
WO (1) WO1997032575A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1024696A1 (fr) * 1997-10-22 2000-08-09 Merck & Co., Inc. Therapie d'association permettant de reduire les risques lies aux maladies cardio-vasculaires et cerebro-vasculaires
CH700523A1 (de) * 2009-03-09 2010-09-15 Markus Luethy Neue Hautaufheller.
US10093725B2 (en) 2010-08-19 2018-10-09 Zoetis Belgium S.A. Anti-NGF antibodies and their use

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101178947B1 (ko) * 2011-04-29 2012-09-03 한국생명공학연구원 올레아놀린산 아세테이트를 유효성분으로 포함하는 ｔｌｒ 및 ｉｌ-6 매개성 질환 예방 또는 치료용 약학적 조성물

Citations (3)

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EP1024696A1 (fr) * 1997-10-22 2000-08-09 Merck & Co., Inc. Therapie d'association permettant de reduire les risques lies aux maladies cardio-vasculaires et cerebro-vasculaires
EP1024696A4 (fr) * 1997-10-22 2004-07-14 Merck & Co Inc Therapie d'association permettant de reduire les risques lies aux maladies cardio-vasculaires et cerebro-vasculaires
CH700523A1 (de) * 2009-03-09 2010-09-15 Markus Luethy Neue Hautaufheller.
US10093725B2 (en) 2010-08-19 2018-10-09 Zoetis Belgium S.A. Anti-NGF antibodies and their use

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AU2063397A (en) 1997-09-22
CN1212620A (zh) 1999-03-31
JP2000506852A (ja) 2000-06-06
BR9707953A (pt) 2000-10-24

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