EP0733041A1 - Anthracenespiropyrrolidines utilisees comme immunomodulateurs - Google Patents

Anthracenespiropyrrolidines utilisees comme immunomodulateurs

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Publication number
EP0733041A1
EP0733041A1 EP95903293A EP95903293A EP0733041A1 EP 0733041 A1 EP0733041 A1 EP 0733041A1 EP 95903293 A EP95903293 A EP 95903293A EP 95903293 A EP95903293 A EP 95903293A EP 0733041 A1 EP0733041 A1 EP 0733041A1
Authority
EP
European Patent Office
Prior art keywords
carbon atoms
chain
straight
different
branched alkyl
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP95903293A
Other languages
German (de)
English (en)
Inventor
Eckhard Schwenner
Gaéton LADOUCEUR
Thomas Martin Dr. Aune
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer AG
Original Assignee
Bayer AG
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 Bayer AG filed Critical Bayer AG
Publication of EP0733041A1 publication Critical patent/EP0733041A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/96—Spiro-condensed ring systems
    • 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

Definitions

  • the present invention relates to anthracene spiro-pyrrolidines, processes for their preparation and their use in medicaments.
  • Publication US 48 04-751 A discloses polycyclic dicarboximides with an antipsychotic and anxiolytic effect.
  • T-lymphocytes are cited as initiators of many cellular processes that lead to tissue destruction and symptoms associated with specific autoimmune diseases [Paul, EW 1984, Fundamental Immunology, Ravens Press, New York).
  • Rheumatoid arthritis is an example of such diseases and adjuvant-induced arthritis in the rat is considered a representative animal model for it [Lombardino, JG 1985, Nonsteroidal Antiinflammatory Drugs, John Wiley & Sons, New York].
  • rat adjuvant arthritis model a large number of studies have shown that T cells are involved in the progression of the disease.
  • adjuvant disease rat T cells transmit this disease to healthy animals in the absence of any source of antigen or other inflammatory factors.
  • T cell function should positively influence both the adjuvant arthritis in the rat and the course of the disease of various human autoimmune diseases.
  • a serotonin-type receptor has been identified on Jurkart cells [Aune, T., M. Kelley, UA Ranges, GE Bombera, MP 1990, J. Immunol. 145, 1826] which is believed to regulate T cell function. Therefore been ⁇ is accepted that selective antagonists of this receptor inhibit T-cell proliferation.
  • the present invention relates to anthracene spiropyrrolidines of the general formula (I)
  • a and D are identical or different and represent hydrogen, hydroxyl, halogen, cyano, carboxy, nitro, trifluoromethyl, trifluoromethoxy, or represent straight-chain or branched alkyl or alkoxy each having up to 8 carbon atoms,
  • R 1 and R 2 are identical or different and represent hydrogen, halogen, cyano, formyl, phenyl or hydroxy, or represent straight-chain or branched alkoxy having up to 8 carbon atoms, or represent straight-chain or branched alkyl or alkenyl each having up to 8 Are carbon atoms, optionally up to 2 times the same or different by hydroxy, nitro, phenyl, halogen, by straight chain or branched alkoxy having up to 6 carbon atoms or substituted by a group of the formula -NR 3 R 4 ,
  • R 3 and R 4 are the same or different and are hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms or phenyl,
  • R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are the same or different and are hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, or
  • R 11 denotes aryl having 6 to 10 carbon atoms, which is optionally substituted up to 3 times identically or differently by halogen, hydroxy, nitro, cyano, trifluoromethyl, trifluoromethoxy or by straight-chain or branched alkyl or alkoxy each having up to 8 carbon atoms, or
  • Physiologically acceptable salts are preferred in the context of the present invention.
  • Physiologically acceptable salts of the anthracene spiropyrrolidines can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulfonic acids. Particularly preferred are, for example, salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.
  • Salts in the context of the present invention are also salts of monovalent metals such as alkali metals and the ammonium salts. Sodium, potassium and ammonium salts are preferred.
  • the compounds according to the invention exist in stereoisomeric forms which either behave like images and mirror images (enantiomers) or do not behave like images and mirror images (diastereomers).
  • the invention relates to both the antipodes and the racemic forms as well as the diastereomer mixtures. Like the diastereomers, the racemic forms can be separated into the stereoisomerically uniform constituents in a known manner.
  • a and D are identical or different and represent hydrogen, hydroxyl, fluorine, chlorine, bromine, carboxy, nitro, trifluoromethyl, trifluoromethoxy or straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms,
  • R 1 and R 2 are the same or different and represent hydrogen, fluorine, chlorine, bromine, cyano, formyl, phenyl or hydroxy, or represent straight-chain or branched alkoxy having up to 6 carbon atoms, or stand for straight-chain or branched alkyl or alkenyl each having up to 6 carbon atoms, which may optionally be up to 2 times identical or different by hydroxy, nitro, phenyl, fluorine, chlorine, bromine, by straight-chain or branched alkoxy having up to 4 carbon atoms or by a group of the formula -NR 3 R 4 are substituted,
  • R 3 and R 4 are the same or different and are hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms or phenyl,
  • R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are the same or different and are hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, or
  • a represents a number 2, 3, 4, 5, 6 or 7,
  • R 11 is phenyl, which is optionally substituted up to 3 times identically or differently by fluorine, chlorine, bromine, hydroxy, nitro, cyano, trifluoromethyl, trifluoromethoxy or by straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms, or hydrogen , Cyclopentyl, cyclohexyl, cycloheptyl, pyridyl or pyrimidyl, or straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted up to 2 times by the same or different phenyl, which in turn by up to 3 times the same or different Fluorine, chlorine, bromine, hydroxy, nitro, cyano, trifluoromethyl, trifluoromethoxy or by straight-chain or branched alkyl or
  • Alkoxy can each be substituted with up to 6 carbon atoms, and their salts.
  • a and D are the same or different and represent hydrogen, hydroxy, fluorine, chlorine, bromine or straight-chain or branched alkyl having up to 4 carbon atoms,
  • R 1 and R 2 are the same or different and represent hydrogen, fluorine, chlorine, bromine, cyano, formyl, phenyl or hydroxy, or represent straight-chain or branched alkoxy having up to 4 carbon atoms, or represent straight-chain or branched alkyl or alkenyl each have up to 4 carbon atoms, which are optionally substituted up to 2 times identically or differently by hydroxyl, nitro, phenyl, fluorine, chlorine, bromine, by straight-chain or branched alkoxy having up to 3 carbon atoms or by amino or aminomethyl,
  • R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are identical or different and signify hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, or
  • a represents a number 2, 3, 4, 5 or 6,
  • R 11 is phenyl, which is optionally substituted up to three times, identically or differently, by fluorine, chlorine, bromine, hydroxyl, nitro, cyano, trifluoromethyl, trifluoromethoxy or by straight-chain or branched alkyl or alkoxy each having up to 4 carbon atoms, or
  • Hydrogen, cyclopentyl, cyclohexyl, cycloheptyl, pyridyl or pyrimidyl 5 means, or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally up to 2 times the same or different substituted by phenyl, which in turn is up to 3 times the same or different by fluorine, chlorine, bromine, hydroxy, nitro , Cyano, trifluoromethyl, trifluoro or methoxy or can be substituted by straight-chain or branched alkyl or alkoxy each having up to 4 carbon atoms,
  • R 1 , R 2 , R 9 and R 10 represent hydrogen, 0 and their salts.
  • A, D, R 1 , R 2 , R 9 and R 10 have the meaning given above,
  • A, D, R 1 , R 2 , R 9 and R 10 have the meaning given above,
  • S has the meaning of Q given above or represents carboxy or an activated carbonyl radical
  • A, D, a, R 1 , R 2 , R 9 and R 10 have the meaning given above,
  • T includes the scope of Q or S given above,
  • R 11 has the meaning given above
  • R 9 and R 10 have the meaning given above
  • R 9 , R 10 , R 11 and a have the meaning given above,
  • A, D, R 1 and R 2 have the meaning given above,
  • organic solvents that do not change under the reaction conditions are suitable as solvents for the processes.
  • solvents preferably include ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, 1,2-dimethoxyethane or hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or halogenated hydrocarbons such as dichloromethane, trichloro-
  • inorganic or organic bases can be used as bases for the processes according to the invention.
  • bases preferably include alkali metal hydroxides or such as sodium hydroxide, potassium hydroxide or Lithium hydroxide, barium hydroxide, alkali or alkaline earth carbonates such as sodium carbonate, potassium carbonate, calcium carbonate or cesium carbonate, or alkali or alkaline earth alcoholates such as sodium or potassium methoxide or potassium tert-butoxide, or lithium diisopropylamide (LDA), or organic amines (trialkyl (C 1 -C 6 ) amines) such as triethylamine, or heterocycles such as 1,4-diazabicyclo [2.2.2] octane (DABCO), l, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), pyridine, diaminopyridine , Methylpiperidine or morpholine. It is also possible to use alkali metals such
  • the base is used in an amount of 0.05 mol to 10 mol, preferably 1 mol to 2 mol, in each case based on 1 mol of the compounds of the general formulas (III), (V) and (VII ) on.
  • Lewis acids such as zinc chloride, titanium tetrachloride, boron tribromide, aluminum chloride or lithium perchlorate or thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide or are suitable as auxiliaries for activating the carboxylic acid function in the compounds of the general formula (V) and for the Diels-Alder reaction Oxalyl chloride.
  • carbonyl compounds such as carbonyldiimidazole or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-l, 2-oxazolium-3-sulfonate or propanephosphoric anhydride or isobutylchloroformate or benzotriazolyloxy-tris (dimethylamino) phosphonium hexylfluorophiphenate or phosphonamide acid or phosphonate are suitable Methanesulfonic acid chloride, optionally in the presence of bases such as triethylamine or N-ethylmorpholine or N-methylpiperidine or dicyclohexylcarbodiimide and N-hydroxysuccinimide.
  • bases such as triethylamine or N-ethylmorpholine or N-methylpiperidine or dicyclohexylcarbodiimide and N-hydroxysuccinimide.
  • the processes according to the invention are generally carried out in a temperature range from 0 ° C. to + 180 ° C., preferably from + 20 ° C. to + 150 ° C.
  • the process according to the invention is generally carried out at normal pressure. However, it is also possible to carry out the process under overpressure or under underpressure (for example in a range from 0.5 to 5 bar).
  • the reduction of carbonyl functions is generally carried out with complex hydrides, such as lithium aluminum hydride or sodium borohydride, preferably with lithium aluminum hydride in inert solvents such as ethers or hydrocarbons or mixtures thereof, preferably in ethers such as, for example, diethyl ether, tetrahydrofuran or dioxane, in a temperature range from 0 ° C. up to + 150 ° C, preferably from + 20 ° C to + 100 ° C, at normal pressure.
  • complex hydrides such as lithium aluminum hydride or sodium borohydride
  • inert solvents such as ethers or hydrocarbons or mixtures thereof, preferably in ethers such as, for example, diethyl ether, tetrahydrofuran or dioxane
  • R 9 , R 10 and R 11 are generally carried out by methods known from the literature, examples being the reduction of aldehydes or alkoxycarbonyl compounds to alcohols (a), the reduction of double bonds (b) and the alkylation (c) with the following:
  • hydrides such as lithium aluminum hydride or sodium borohydride, preferably in the case of the alkoxycarbonyl compounds using lithium aluminum hydride and, in the case of the aldehydes, preferably using sodium borohydride in inert solvents such as ethers, hydrocarbons or alcohols or mixtures thereof , preferably in ethers such as diethyl ether, tetrahydrofuran or dioxane, or alcohols such as ethanol, in the case of the aldehydes preferably with sodium borohydride in ethanol, in a temperature range from 0 ° C. to + 150 ° C., preferably from + 20 ° C. to + 100 ° C, at normal pressure.
  • the reduction of a double bond is generally carried out by hydrogenation with hydrogen in the presence of a catalyst such as platinum or platinum oxides, rhodium, ruthenium, chlorotris (triphenylphosphine) rhodium, or palladium on charcoal, preferably with palladium on animal charcoal in a temperature range from 0 ° C to + 150 ° C, preferably from + 25 ° C to + 100 ° C.
  • a catalyst such as platinum or platinum oxides, rhodium, ruthenium, chlorotris (triphenylphosphine) rhodium, or palladium on charcoal, preferably with palladium on animal charcoal in a temperature range from 0 ° C to + 150 ° C, preferably from + 25 ° C to + 100 ° C.
  • Protic solvents such as methanol, ethanol and / or aprotic solvents such as, for example, tetrahydrofuran, toluene, dimethylformamide, methylene chloride, are suitable as solvents for the hydrogenation.
  • the hydrogenation is carried out at a pressure of 1 to 300 atm, preferably at 1 to 20 atm.
  • Solvents with alkylating agents such as (C 1 -C 8 ) alkyl halides, sulfonic acid esters or substituted or unsubstituted (Cj-Cg) dialkyl or (C 1 -C 8 ) diaryl sulfates, preferably methyl iodide, p-toluenesulfonic acid ester or Dimethyl sulfate.
  • alkylating agents such as (C 1 -C 8 ) alkyl halides, sulfonic acid esters or substituted or unsubstituted (Cj-Cg) dialkyl or (C 1 -C 8 ) diaryl sulfates, preferably methyl iodide, p-toluenesulfonic acid ester or Dimethyl sulfate.
  • the compounds of the general formula (II) are known or can then be prepared, for example, by reacting anthracene or its substituted derivatives with itaconic anhydride or its substituted derivatives in an aprotic solvent, such as methylene chloride, in the presence of one of the Lewis acids listed above.
  • Acids for example aluminum chloride, in a temperature range from 0 ° C to 80 ° C, preferably at room temperature to + 40 ° C.
  • the compounds of the general formula (VI) are new and can be prepared, for example, as described above.
  • the compounds of the general formula (I) according to the invention surprisingly show an immunomodulating effect.
  • FA Freund's adjuvant
  • Mycobacterium butyricum which has been killed in the heat, in extra-heavy mineral oil.
  • Lewis rats receive a 0.1 ml injection of FA (1 mg / animal) subcutaneously into the right hind paw.
  • Swelling areas in the treated paw on day 5 are followed by an increase in swelling (chronic inflammatory reaction) between days 10 and 12 and the appearance of swelling in the opposite untreated paw (secondary immune response).
  • the cell infiltration of chronic inflammation and the second immune response are predominantly mononuclear, indicating the presence of cell-directed immunization.
  • the animals are observed daily and the swelling is measured on days 12 and 16 in millimeters with a micrometer that can be adjusted by hand.
  • the swelling peaks on the 16th day, when the animals are killed and tissue samples are taken for histological evaluation.
  • the extent of the swelling is determined by calculating the greatest difference between the 16th and the 0th day of the ankle diameter.
  • the animals receive the compounds according to the invention in a suspension of 5% polyethylene glycol and 0.5% Tween 80 in phosphate buffer solution p.o. or i.p. on days 0, 1, 2, 5, 7, 9, 12 and 14 [cf. see L. Sokoloff, 1984, Int. Rev. Exp. Pathol. 26, 107; M.E.J. Bittingham et al., 1989, J. Exp. Med. 171, 339; K.M. Connolly et al., 1989, Agents and Actions 27, 328].
  • the in vitro activity of the compounds according to the invention results from their ability to inhibit T cell proliferation, which is previously stimulated by serotonin.
  • PBMC Peripheral mononuclear blood cells
  • T cells or purified T cells (depleted of monocytes) with 5 x 10 5 / ml, 100 ⁇ l / well are in RPMI-1640 medium with 10% fetal calf serum (GIBCO) and L-glutamine in 96-well Microculture plates (Becton-Dickinson) cultured under a 5% CO 2 atmosphere at 37 ° C for 7 days.
  • the cultures are mixed with 1 ⁇ Ci 3 H-thymidine for 6 h on the 7th day, collected on filter paper, and the incorporated radioactivity is determined by means of liquid scintillation counting.
  • test substances are dissolved in 10 mM HC1 in order to reach a final concentration of 1 mM each.
  • the connections are made 3 times with medium as standard added to obtain a final concentration between 33 ⁇ M - 0.1 ⁇ M.
  • PWM 1: 200, poke weed mitogen
  • 5-HT 100 ⁇ M, serotonin
  • the positive control is obtained from cultures with T cells, PWM and 5-HT.
  • the negative control minimal proliferation
  • the inhibitory activity of the test substances is expressed as IC 50 in ⁇ M.
  • the new active compounds can be converted in a known manner into the customary formulations, such as tablets, dragées, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable excipients or solvents.
  • the therapeutically active compound should in each case be present in a concentration of about 0.5 to 90% by weight of the total mixture, i.e. in amounts sufficient to achieve the dosage range indicated.
  • the formulations are prepared, for example, by stretching the active ingredients with solvents and / or carriers, optionally using emulsifiers and / or dispersants, e.g. if water is used as the diluent, organic solvents can optionally be used as auxiliary solvents.
  • the application is carried out in the usual way, preferably orally or parenterally, in particular perlingually or intravenously.
  • solutions of the active ingredient can be used using suitable liquid carrier materials.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Immunology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Indole Compounds (AREA)

Abstract

On prépare des anthracènespiropyrrolidines de formule générale (I) en faisant réagir des anthracènespirofurannes ou des anthracènespiropyrrolidines non substituées avec des amines substituées de manière appropriée ou en faisant réagir des dérivés non substitués de l'anthracène avec des méthylènepyrrolidines substituées de manière appropriée. Ces substances peuvent être employées comme substances actives dans des médicaments, en particulier pour la préparation de médicaments immunomodulateurs.
EP95903293A 1993-12-09 1994-11-28 Anthracenespiropyrrolidines utilisees comme immunomodulateurs Withdrawn EP0733041A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US08/164,511 US5461054A (en) 1993-12-09 1993-12-09 Anthracene-spiro-pyrrolindines
US164511 1993-12-09
PCT/EP1994/003933 WO1995015947A1 (fr) 1993-12-09 1994-11-28 Anthracenespiropyrrolidines utilisees comme immunomodulateurs

Publications (1)

Publication Number Publication Date
EP0733041A1 true EP0733041A1 (fr) 1996-09-25

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Application Number Title Priority Date Filing Date
EP95903293A Withdrawn EP0733041A1 (fr) 1993-12-09 1994-11-28 Anthracenespiropyrrolidines utilisees comme immunomodulateurs

Country Status (5)

Country Link
US (1) US5461054A (fr)
EP (1) EP0733041A1 (fr)
JP (1) JPH09506355A (fr)
AU (1) AU1241095A (fr)
WO (1) WO1995015947A1 (fr)

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JP4365984B2 (ja) * 1999-05-14 2009-11-18 キヤノン株式会社 再生プラスチック材料の製造方法
WO2004009017A2 (fr) 2002-07-18 2004-01-29 Bristol-Myers Squibb Company Modulateurs de recepteurs de glucocorticoides et procede associe
US7253283B2 (en) 2004-01-16 2007-08-07 Bristol-Myers Squibb Company Tricyclic modulators of the glucocorticoid receptor, AP-1, and/or NF-κB activity and use thereof
US7625921B2 (en) 2004-01-16 2009-12-01 Bristol-Myers Squibb Company Modulators of the glucocorticoid receptor, AP-1, and/or NF-κB activity and use thereof
US7273881B2 (en) 2004-01-16 2007-09-25 Bristol-Myers Squibb Company Modulators of glucocorticoid receptor, AP-1, and/or NF-κB activity and use thereof
US7605264B2 (en) 2004-01-16 2009-10-20 Bristol-Myers Squibb Company Heterocyclic modulators of the glucocorticoid receptor, AP-1, and/or NF-κB activity and use thereof
US7326728B2 (en) 2004-01-16 2008-02-05 Bristol-Myers Squibb Company Modulators of glucocorticoid receptor, AP-1, and/or NF-κβ activity and use thereof
US7569689B2 (en) 2004-01-16 2009-08-04 Bristol-Myers Squibb Company Modulators of the glucocorticoid receptor, AP-1, and/or NF-κB activity and use thereof
WO2006115509A2 (fr) 2004-06-24 2006-11-02 Novartis Vaccines And Diagnostics Inc. Immuno-potentialisateurs a petites molecules et analyses visant a detecter leur presence
US7317024B2 (en) 2005-01-13 2008-01-08 Bristol-Myers Squibb Co. Heterocyclic modulators of the glucocorticoid receptor, AP-1, and/or NF-κB activity and use thereof
US7411071B2 (en) 2005-01-13 2008-08-12 Bristol-Myers Squibb Company Modulators of the glucocorticoid receptor, AP-1, and/or NF-κB activity and use thereof
US7642273B2 (en) 2005-01-13 2010-01-05 Bristol-Myers Squibb Company Modulators of the glucocorticoid receptor, AP-1, and/or NF-κB activity and use thereof
US7361654B2 (en) 2005-01-13 2008-04-22 Bristol-Myers Squibb Co. Substituted heteroaryl amide modulators of glucocorticoid receptor, AP-1, and/or NF-κB activity and use thereof

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Also Published As

Publication number Publication date
JPH09506355A (ja) 1997-06-24
US5461054A (en) 1995-10-24
AU1241095A (en) 1995-06-27
WO1995015947A1 (fr) 1995-06-15

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