WO1999042464A1 - ANTAGONISTES DU RECEPTEUR DE L'INTERLEUKINE-8 A BASE D'IMIDAZO[1,2-a;3,4-a']DIQUINOLINYLIUM SUBSTITUE - Google Patents

ANTAGONISTES DU RECEPTEUR DE L'INTERLEUKINE-8 A BASE D'IMIDAZO[1,2-a;3,4-a']DIQUINOLINYLIUM SUBSTITUE Download PDF

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Publication number
WO1999042464A1
WO1999042464A1 PCT/US1998/026706 US9826706W WO9942464A1 WO 1999042464 A1 WO1999042464 A1 WO 1999042464A1 US 9826706 W US9826706 W US 9826706W WO 9942464 A1 WO9942464 A1 WO 9942464A1
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Prior art keywords
imidazo
diquinolin
ylium
alkyl
butyl
Prior art date
Application number
PCT/US1998/026706
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English (en)
Inventor
Joseph Edwin Low
Bharat Kalidas Trivedi
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Warner-Lambert Company
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 Warner-Lambert Company filed Critical Warner-Lambert Company
Priority to AU19181/99A priority Critical patent/AU1918199A/en
Publication of WO1999042464A1 publication Critical patent/WO1999042464A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems

Definitions

  • the present invention relates to novel substituted imidazo[l,2-a; 3,4-a']diquinolinylium compounds useful as pharmaceutical agents, to methods for their production, to pharmaceutical compositions which include these compounds and a pharmaceutical carrier, and to pharmaceutical methods of treatment.
  • the compounds of the present invention are Interleukin-8 (IL-8) receptor antagonists. More particularly, the compounds of the present invention are useful in the treatment of a chemokine-mediated disease wherein the chemokine binds to an IL-8a (CXCR1) or b (CXCR2) receptor such as, for example, a chemokine-mediated disease selected from psoriasis or atopic dermatitis, disease associated with pathological angiogenesis (i.e.
  • asthma chronic obstructive pulmonary disease
  • adult respiratory distress syndrome arthritis
  • inflammatory bowel disease Crohn's disease
  • ulcerative colitis gastric ulcer
  • septic shock endotoxic shock
  • gram negative sepsis toxic shock syndrome
  • stroke cardiac and renal reperfusion injury
  • glomerulo-nephritis or thrombosis
  • Alzheimer's disease graft versus host reaction, or allograft rejections.
  • IL-8 is a 72 amino acid protein, which is a member of the superfamily of leukocyte chemoattractant proteins, which have been referred to as intercrines,
  • C-X-C or C-C cytokines or, more recently as chemokines (Oppenheim J.J., Zachariae J.J. et al., "Properties of the novel proinflammatory supergene "intercrine” cytokine family," Annu. Rev. Immunol, 1991;9:617-648).
  • Many members of the chemokine family appear to be involved in the inflammatory process and in the trafficking of leukocytes.
  • the chemokine superfamily is composed of two branches: the ⁇ -chemokines and the ⁇ -chemokines.
  • the ⁇ -chemokine branch includes IL-8, neutrophil activating peptide-2 (NAP-2), melanoma growth stimulatory activity (MGSA/gro or GRO ⁇ ), and ENA-78, all ot -2- which have attracting and activating effects predominantly on neutrophils.
  • This branch also includes PF4, ⁇ -thromboglobulin, and CTAPIII, which do not affect neutrophils.
  • IL-8 was originally identified by its ability to both attract and activate polymorphonuclear leukocytes (neutrophils) and has now been shown to be rapidly induced in a wide variety of cell and tissue types in response to proinflammatory cytokines such as IL-l ⁇ or TNF ⁇ . Additionally, there is data demonstrating high systemic levels of IL-8 in certain neutrophil-mediated inflammatory diseases, suggesting that IL-8 and closely related factors may be the principal endogenous mediators of neutrophil activation.
  • IL-8 inhibits neutrophil influx in a rabbit model of endotoxin-induced pleurisy," J. Immunol, 1994;152(6):2960-2967).
  • IL-8 neutralizing antibodies in animal models of dermatitis, joint arthritis, and glomerulonephritis.
  • knockout mice have been generated in which the apparent mouse homologue of the IL-8R (closer to
  • IL-8RB was deleted by homologous recombination (Cacalano G., Lee J. et al., "Neutrophil and B cell expansion in mice that lack the murine IL-8 receptor -3- homolog," Science, 1994;265(5172):682-684 Issn: 0036-8075). Although these mice appear healthy, their neutrophils are greatly impaired, as compared to wild- type mice, in their ability to migrate to the peritoneum in response to intraperitoneal thioglycollate injection.
  • IL-8 is an important mediator of neutrophil migration and activity in some inflammatory settings, and that a small molecule antagonist to the receptors for IL-8 should prove to be an effective treatment for some inflammatory pathologies and has the potential to be a broadly useful anti-inflammatory agent. Also, there have been reports that IL-8 is an important cytokine involved in tumor growth and angiogenesis in a variety of malignancies (Hebert et al., Cancer Invest.,
  • the present invention is a method of treating a chemokine- mediated disease state, wherein the chemokine binds to a IL-8a (CXCR1) or b (CXCR2) receptor in a mammal, which comprises administering to said mammal an effective amount of a compound of Formula I or Formula II -4-
  • R 1 is alkyl
  • R 4 is alkyl, cycloalkyl, aryl, or aralkyl, or
  • R3 and R 4 are taken together to form a 4- to 7-membered ring optionally containing an oxygen atom or N-R-> wherein R ⁇ is hydrogen, alkyl, or aryl or a sulfur atom and wherein optionally the carbon atoms of the ring may be substituted by alkyl or alkoxy, or R3 and R 4 are taken together to form a bicyclic ring containing up to
  • R4 alkyl, -5- cycloalkyl, and halogen with the proviso that when R ⁇ is -N-R ⁇ wherein R3 and
  • R4 R4 are as defined above, R ⁇ is hydrogen or alkyl; and X is a pharmaceutically acceptable anion; or a pharmaceutically acceptable salt thereof.
  • the compounds of Formula I or Formula II can be used as agents for treating psoriasis or atopic dermatitis, disease associated with pathological angiogenesis (i.e.
  • asthma chronic obstructive pulmonary disease
  • adult respiratory distress syndrome arthritis
  • inflammatory bowel disease Crohn's disease
  • ulcerative colitis gastric ulcer
  • septic shock endotoxic shock
  • gram negative sepsis toxic shock syndrome
  • stroke cardiac and renal reperfusion injury
  • glomerulo-nephritis or thrombosis
  • Alzheimer's disease graft versus host reaction, or allograft rejections.
  • a still further embodiment of the present invention is a pharmaceutical composition for administering an effective amount of a compound of Formula I or Formula II in unit dosage form in the treatment methods mentioned above.
  • the present invention is directed to methods for production of compounds of Formula I or Formula II.
  • alkyl means a straight or branched hydrocarbon radical having from 1 to 10 carbon atoms and includes, for example, methyl, ethyl, H-propyl, isopropyl, H-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, «-hexyl, ⁇ -heptyl, «-octyl, w-nonyl, n-decyl, and the like.
  • Alkoxy and thioalkoxy are O-alkyl or S-alkyl of from 1 to 10 carbon atoms as defined above for “alkyl”.
  • cycloalkyl means a saturated hydrocarbon ring having 3 to 8 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
  • aryl means an aromatic radical which is a phenyl group, a phenyl group substituted by 1 to 4 substituents selected from alkyl as defined above, alkoxy as defined above, thioalkoxy as defined above, hydroxy, halogen, trifluoromethyl, amino, alkylamino as defined above for alkyl, dialkylamino as
  • aralkyl or "arylalkyl” means an aromatic radical attached to an alkyl radical wherein “aryl” and “alkyl” are as defined above, for example, benzyl, fluorenylmethyl, and the like.
  • aryl and “alkyl” are as defined above, for example, benzyl, fluorenylmethyl, and the like.
  • N-R5" includes, for example, azetidine, pyrrolidine, pyrrazolidine, imidazolidine, oxazolidine, piperidine, piperazine, morpholine, homopiperidine, and the like.
  • the carbon atoms of the above 4- to 7-membered ring may be substituted independently by alkyl, amino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, carboxy, carboxyalkyl, alkylcarboxyalkyl, thio, thioalkyl, alkylthioalkyl, hydroxy, hydroxyalkyl, alkoxy, or alkoxyalkyl.
  • bicyclic ring containing up to 9 members optionally containing
  • N-R5" includes, for example, 3-azabicyclo[3JJ]norane, 2- azabicyclo[2JJ]heptane, 2,5-diazabicyclo[2JJ]octane, 1,4- diazabicyclo[3JJ]octane, 2,5-diazabicyclo[2JJ]heptane, and the like.
  • the carbon atoms of the above bicyclic rings may be substituted independently by alkyl, amino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, carboxy, -7- carboxyalkyl, alkylcarboxyalkyl, thio, thioalkyl, alkylthioalkyl, hydroxy, hydroxyalkyl, alkoxy, or alkoxyalkyl.
  • Halogen is fluorine, chlorine, bromine, or iodine.
  • pharmaceutically acceptable anion means a counterion, such as, for example, chloride, bromide, iodide, fluoride, acetate, an arylsulfonate as defined above for “aryl”, an alkylsulfonate as defined above for “alkyl”, and the like.
  • Pharmaceutically acceptable acid addition salts of the compounds of Formula I or Formula II include salts derived from nontoxic inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, hydrofluoric, phosphorous, and the like, as well as the salts derived from nontoxic organic acids, such as aliphatic mono- and dicarboxyhc acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc.
  • nontoxic inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, hydrofluoric, phosphorous, and the like
  • nontoxic organic acids such as aliphatic mono- and dicarboxyhc acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedio
  • Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like.
  • salts of amino acids such as arginate and the like and gluconate, galacturonate (see, for example, Berge S.M. et al., "Pharmaceutical Salts,” J. ofPharma. Sci., 1977;66:1).
  • the acid addition salts of said basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner.
  • the free base form may be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner.
  • the free base forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free base for purposes of the present invention.
  • -8- Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine,
  • the base addition salts of said acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner.
  • the free acid form may be regenerated by contacting the salt form with an acid and isolating the free acid in the conventional manner.
  • the free acid forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free acid for purposes of the present invention.
  • Certain of the compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms, are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.
  • Certain of the compounds of the present invention possess one or more chiral centers and each center may exist in the R(D) or S(L) configuration.
  • the present invention includes all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Additionally, the compounds of the present invention may exist as geometric isomers.
  • the present invention includes all cis, trans, syn, anti,
  • E
  • Z
  • isomers as well as the appropriate mixtures thereof.
  • a preferred compound of Formula I or Formula II is one wherein
  • R1 is alkyl or
  • R ⁇ is hydrogen or alkyl
  • R 4 is alkyl, cycloalkyl, aryl, or -9- aralkyl, or
  • R and R are taken together to form a 4- to 7-membered ring optionally containing an oxygen atom or N-R ⁇ wherein R ⁇ is hydrogen, alkyl, or aryl or a sulfur atom and wherein optionally the carbon atoms of the ring may be substituted by alkyl or alkoxy, or
  • R3 and R4 are taken together to form a bicyclic ring containing up to
  • R4 alkyl, or cycloalkyl is one wherein lkyl or
  • R ⁇ is hydrogen or alkyl
  • R4 R 4 is alkyl, cycloalkyl, aryl, or aralkyl, or 3 and R4 are taken together to form a 4- to 7-membered ring optionally containing an oxygen atom or N-R ⁇ wherein R ⁇ is hydrogen, alkyl, or aryl or a sulfur atom and wherein optionally the carbon atoms of the ring may be substituted by alkyl or alkoxy, or
  • R3 and R are taken together to form a bicyclic ring containing up to
  • Particularly valuable compounds of Formula I or Formula II containing a pharmaceutically acceptable anion used in the method of the present invention are selected from the group consisting of:
  • Most particularly valuable compounds of Formula I or Formula II containing a pharmaceutically acceptable anion used in the method of the present invention are selected from the group consisting of:
  • the compounds of Formula I or Formula II are valuable receptor antagonists of IL-8.
  • the IL-8 chemokine inhibitory effects of compounds of the present invention were determined by the following procedures: -13- Chemotaxis Assay
  • chemotaxis buffer which is made of one part of RPMI 1640 medium, one part of
  • the compounds of Formula I and Formula II are prepared by applying synthetic methodology known in the art such as, for example, as disclosed in United States Patent No. 4,207,320 which is herein incorporated by reference. Thus, the compounds of Formula I and Formula II may be prepared as described in Scheme 1 wherein R and R ⁇ are as defined above.
  • the compounds of the present invention can be prepared and administered in a wide variety of oral and parenteral dosage forms.
  • the compounds of the present invention can be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally.
  • the compounds of the present invention can be administered by inhalation, for example, intranasally.
  • the compounds of the present invention can be administered transdermally.
  • the following dosage forms may comprise as the active component, either a compound of Formula I or Formula II, or a corresponding pharmaceutically acceptable salt of a compound of Formula I or
  • pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • a solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier is a finely divided solid which is in a mixture with the finely divided active component.
  • the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain from five or ten to about seventy percent of the active compound.
  • Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
  • the term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component, with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included.
  • Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter
  • the active component is dispersed homogeneously therein, as by stirring.
  • the molten homogenous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
  • Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water propylene glycol solutions.
  • liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
  • Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.
  • viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration.
  • liquid forms include solutions, suspensions, and emulsions.
  • These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • the pharmaceutical preparation is preferably in unit dosage form.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • the quantity of active component in a unit dose preparation may be varied or adjusted from 1 mg to 1000 mg, preferably 10 mg to 100 mg according to the particular application and the potency of the active component.
  • the composition can, if desired, also contain other compatible therapeutic agents.
  • the compounds utilized in the pharmaceutical method of this invention can be administered at the initial dosage of about 1 mg to about 100 mg per kilogram daily.
  • a daily dose range of about 25 mg to about 75 mg per kilogram is preferred.
  • the dosages may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstance is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.
  • An intravenous preparation of the titled compound can be formulated in a solution containing 2% ethanol, 4% polyethylene glycol 400 (PEG 400), 0.9% lecithin in pH 4.85 acetate buffer at 0.24 mg/mL concentration.
  • PEG 400 polyethylene glycol 400

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention se rapporte à des composés de quinoxaline, ainsi qu'à des procédés de préparation de ces composés et à des compositions pharmaceutiques contenant ces composés, qui servent comme antagonistes du récepteur de l'interleukine-8 (IL-8) et qui peuvent être utilisés dans le traitement des maladies induites par la chémokine, dans lesquelles la chémokine se fixe à un récepteur d'IL-8a (CXCR1) ou b (CXCR2), telles que des maladies induites par la chémokine choisies parmi le psoriasis ou la dermatite atopique, les maladies associées à une angiogenèse pathologique (par exemple le cancer), l'asthme, les broncho-pneumopathies chroniques obstructives, le syndrome de détresse respiratoire chez l'adulte, l'arthrite, les infections intestinales inflammatoires, la maladie de Crohn, la colite ulcéreuse, l'ulcère gastrique, le choc septique, le choc endotoxique, les septicémies à germes Gram négatif, le syndrome du choc toxique staphylococcique, les attaques, les lésions de reperfusion cardiaque et rénale, la glomérulonéphrite ou les thromboses, la maladie d'Alzheimer, les réactions du greffon contre l'hôte ou les rejets d'allogreffes.
PCT/US1998/026706 1998-02-23 1998-12-15 ANTAGONISTES DU RECEPTEUR DE L'INTERLEUKINE-8 A BASE D'IMIDAZO[1,2-a;3,4-a']DIQUINOLINYLIUM SUBSTITUE WO1999042464A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU19181/99A AU1918199A (en) 1998-02-23 1998-12-15 Substituted imidazo(1,2-a;3,4-a')diquinolinylium interleukin-8 receptor antagonists

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US7555398P 1998-02-23 1998-02-23
US60/075,553 1998-02-23

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WO1999042464A1 true WO1999042464A1 (fr) 1999-08-26

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001079209A2 (fr) * 2000-04-13 2001-10-25 Millennium Pharmaceuticals, Inc. Antagonistes des recepteurs d'il-8 a base de diazafluorenone
WO2002045702A2 (fr) * 2000-12-05 2002-06-13 Chemokine Therapeutics Corporation Traitement des maladies induites par les chimiokines
WO2002094270A2 (fr) * 2001-05-18 2002-11-28 Chemokine Therapeutics Corporation Medicaments a base de ligands de recepteurs mip-1 alpha destines aux maladies auto-immunes et a mediation par cellules t
US6706767B2 (en) 2000-12-05 2004-03-16 Chemokine Therapeutics Corporation Therapeutics for chemokine mediated diseases
WO2005103711A2 (fr) * 2004-04-20 2005-11-03 Bayer Healthcare Ag Agents diagnostiques et therapeutiques pour des maladies associees au recepteur 1 des chimiokines cxc (cxcr1)
US7084156B2 (en) 2001-11-27 2006-08-01 Merck & Co., Inc. 2-Aminoquinoline compounds
EP2066335A1 (fr) * 2006-09-26 2009-06-10 Case Western Reserve University Signalisation de cytokine
US11291641B2 (en) * 2016-10-03 2022-04-05 The Children's Medical Center Corporation Prevention and treatment of diabetic nephropathy

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4207320A (en) * 1978-08-28 1980-06-10 Warner-Lambert Company Amino-substituted imidazo[1,2-a:3,4-a']diquinolin-15-ium salts compositions and method of use
EP0411754A2 (fr) * 1989-06-13 1991-02-06 Smithkline Beecham Corporation Médicament pour l'inhibition de la production de l'interleucine-1 ou du facteur de nécrose tumorale par des monocytes et/ou macrophages

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4207320A (en) * 1978-08-28 1980-06-10 Warner-Lambert Company Amino-substituted imidazo[1,2-a:3,4-a']diquinolin-15-ium salts compositions and method of use
EP0411754A2 (fr) * 1989-06-13 1991-02-06 Smithkline Beecham Corporation Médicament pour l'inhibition de la production de l'interleucine-1 ou du facteur de nécrose tumorale par des monocytes et/ou macrophages

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001079209A3 (fr) * 2000-04-13 2002-05-16 Warner Lambert Co Antagonistes des recepteurs d'il-8 a base de diazafluorenone
WO2001079209A2 (fr) * 2000-04-13 2001-10-25 Millennium Pharmaceuticals, Inc. Antagonistes des recepteurs d'il-8 a base de diazafluorenone
US6706767B2 (en) 2000-12-05 2004-03-16 Chemokine Therapeutics Corporation Therapeutics for chemokine mediated diseases
WO2002045702A2 (fr) * 2000-12-05 2002-06-13 Chemokine Therapeutics Corporation Traitement des maladies induites par les chimiokines
WO2002045702A3 (fr) * 2000-12-05 2003-01-03 Chemokine Therapeutics Corp Traitement des maladies induites par les chimiokines
WO2002094270A2 (fr) * 2001-05-18 2002-11-28 Chemokine Therapeutics Corporation Medicaments a base de ligands de recepteurs mip-1 alpha destines aux maladies auto-immunes et a mediation par cellules t
WO2002094270A3 (fr) * 2001-05-18 2003-04-03 Chemokine Therapeutics Corp Medicaments a base de ligands de recepteurs mip-1 alpha destines aux maladies auto-immunes et a mediation par cellules t
US7084156B2 (en) 2001-11-27 2006-08-01 Merck & Co., Inc. 2-Aminoquinoline compounds
WO2005103711A2 (fr) * 2004-04-20 2005-11-03 Bayer Healthcare Ag Agents diagnostiques et therapeutiques pour des maladies associees au recepteur 1 des chimiokines cxc (cxcr1)
WO2005103711A3 (fr) * 2004-04-20 2006-03-23 Bayer Healthcare Ag Agents diagnostiques et therapeutiques pour des maladies associees au recepteur 1 des chimiokines cxc (cxcr1)
EP2066335A1 (fr) * 2006-09-26 2009-06-10 Case Western Reserve University Signalisation de cytokine
EP2066335A4 (fr) * 2006-09-26 2010-01-20 Univ Case Western Reserve Signalisation de cytokine
JP2010504996A (ja) * 2006-09-26 2010-02-18 ケース ウエスタン リザーブ ユニバーシティ サイトカインシグナリング
US11291641B2 (en) * 2016-10-03 2022-04-05 The Children's Medical Center Corporation Prevention and treatment of diabetic nephropathy

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ZA991411B (en) 1999-08-23

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