[go: up one dir, main page]

WO1999065495A1 - INHIBITEURS DU FACTEUR DE TRANSCRIPTION NF-λB - Google Patents

INHIBITEURS DU FACTEUR DE TRANSCRIPTION NF-λB Download PDF

Info

Publication number
WO1999065495A1
WO1999065495A1 PCT/US1999/013897 US9913897W WO9965495A1 WO 1999065495 A1 WO1999065495 A1 WO 1999065495A1 US 9913897 W US9913897 W US 9913897W WO 9965495 A1 WO9965495 A1 WO 9965495A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
disease
benzalindanone
compound
6alkyl
Prior art date
Application number
PCT/US1999/013897
Other languages
English (en)
Inventor
James F. Callahan
Marie C. Chabot-Fletcher
Original Assignee
Smithkline Beecham Corporation
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
Priority to HU0102492A priority Critical patent/HUP0102492A2/hu
Application filed by Smithkline Beecham Corporation filed Critical Smithkline Beecham Corporation
Priority to IL14032499A priority patent/IL140324A0/xx
Priority to EP99930459A priority patent/EP1085872A4/fr
Priority to PL99345577A priority patent/PL345577A1/xx
Priority to KR1020007014385A priority patent/KR20010052990A/ko
Priority to CA002335293A priority patent/CA2335293A1/fr
Priority to BR9911151-9A priority patent/BR9911151A/pt
Priority to AU46996/99A priority patent/AU4699699A/en
Priority to JP2000554375A priority patent/JP2002518333A/ja
Publication of WO1999065495A1 publication Critical patent/WO1999065495A1/fr
Priority to NO20006452A priority patent/NO20006452L/no

Links

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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4462—Non condensed piperidines, e.g. piperocaine only substituted in position 3
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • 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
    • 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
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • 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
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • 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
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • 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
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
    • 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

  • This invention relates in general to methods of inhibiting transcription factor NF- KB using ammo-indanones
  • Such compounds are particularly useful for treating diseases in which activation of NF- ⁇ B is implicated More specifically, these compounds inhibit I ⁇ B phosphorylation and subsequent degradation
  • Such compounds are useful in the treatment of a variety of diseases associated with NF- ⁇ B activation including inflammatory disorders, particularly rheumatoid arthritis, inflammatory bowel disease, and asthma, dermatosis, including psoriasis and atopic dermatitis, autoimmune diseases, tissue and organ rejection, Alzheimer's disease, stroke, atherosclerosis, restenosis, cancer, including Hodgkins disease, and certain viral infections, including AIDS osteoarth ⁇ tis. osteoporosis and Ataxia Telangiestasia
  • NF- ⁇ B belongs to a family of closely related dime ⁇ c transcription factor complexes composed of various combinations of the Rel/ NF- ⁇ B family of polypeptides
  • the family consists of five individual gene products in mammals, RelA (p65), NF- ⁇ B l (p507 pl05), NF- ⁇ B2 (p49/ plOO), c-Rel, and RelB, all of which can form hetero- or homodimers
  • RelA p65
  • NF- ⁇ B l p507 pl05
  • NF- ⁇ B2 p49/ plOO
  • c-Rel RelB
  • RelB all of which can form hetero- or homodimers
  • These proteins share a highly homologous 300 amino acid "Rel homology domain" which contains the DNA binding and dime ⁇ zation domains
  • Rel homology domain At the extreme C- terminus of the Rel homology domain is a nuclear translocation sequence important in the transport of NF- ⁇ B from the cytoplasm
  • NF- ⁇ B in inflammatory disorders is further strengthened by studies of airway inflammation including asthma, in which NF- ⁇ B has been shown to be activated This activation may underlie the increased cytokine production and leukocyte infiltration characteristic of these disorders.
  • inhaled steroids are known to reduce airway hyperresponsiveness and suppress the inflammatory response in asthmatic airways.
  • NF- ⁇ B is normally present as an inactive cytoplasmic complex
  • recent immunohistochemical studies have indicated that NF- ⁇ B is present in the nuclei, and hence active, in the cells comprising rheumatoid synovium
  • NF- KB has been shown to be activated in human synovial cells in response to stimulation with TNF-K
  • Such a distribution may be the underlying mechanism for the increased cytokine and eicosanoid production characteristic of this tissue See Roshak, A K , et al , J Biol Chem , 271, 31496-31501 ( 1996)
  • the NF- ⁇ B/Rel and I ⁇ B proteins are also likely to play a key role in neoplastic transformation Family members are associated with cell transformation in vitro and in vivo as a result of overexpression, gene amplification gene rearrangements or translocations In addition, rearrangement and/
  • Amino-indanones are known compounds General preparation of amino-indanone analogs was described by G Maury, E -M Wu N H Cromwell, J. Org. Chem 1968, 33, 1900- 1907 The synthesis of the 3-bromo intermediate was described by B D Pearson, R P Ayer, N H Cromwell, /. Org. Chem 1962 27 3038-3044 The synthesis of 2- ben leoparddanone was desb ⁇ bed by A Hassner N H Cromwell, J. Org. Chem 1958 80 893-900
  • An object of the present invention is to provide a method for treating diseases which may be therapeutically modified by altering the activity of transcription factor NF- KB Accordingly, in the first aspect, this invention provides a pharmaceutical composition comprising a compound according to Formula I and a pharmaceutically acceptable carrier, diluent or excipient
  • this invention provides a method of treating diseases in which the disease pathology may be therapeutically modified by inhibiting NF- ⁇ B
  • this invention provides methods for treating a variety of diseases associated with NF- ⁇ B activation including inflammatory disorders, particularly rheumatoid arthritis, inflammatory bowel disease, and asthma, dermatosis, including pso ⁇ asis and atopic dermatitis, autoimmune diseases, tissue and organ rejection, Alzheimer's disease, stroke, atherosclerosis, restenosis, cancer, including Hodgkins disease, and certain viral infections, including AIDS osteoarth ⁇ tis, osteoporosis, and Ataxia Telangiestasia
  • the present invention provides a method of treatment of diseases associated with NF- ⁇ B activation, comprising administering to an animal, particularly a mammal, most particularly a human in need thereof a compound of Formula I
  • R ] is aryl
  • R2 is selected from the group consisting of H, Cj-6alkyl and aryl,
  • R3 is selected from the group consisting of C ⁇ _6alkyl and C3-8 cycloalkyl
  • R2 and R3 may be joined together to form a heterocychc ring of 5-7 atoms selected from the group consisting of C, N, O and S
  • the present invention particularly provides methods for treating inflammatory disorders, particularly rheumatoid arthritis, inflammatory bowel disease, and asthma, dermatosis.
  • inflammatory disorders particularly rheumatoid arthritis, inflammatory bowel disease, and asthma, dermatosis.
  • pso ⁇ asis and atopic dermatitis autoimmune diseases; tissue and organ rejection; Alzheimer's disease; stroke; atherosclerosis; restenosis; cancer, including Hodgkins disease; and certain viral infections, including AIDS, osteoarthritis; osteoporosis; and Ataxia Telangiestasia.
  • Compounds of Formula I selected from the following group are preferred for use in the methods of the present invention: 3-[(N-Butyl)am ⁇ no]-2-benzalindanone; 3-[(N-cyclohexyl)am ⁇ no]-2-benzal ⁇ ndanone; 3-Morphol ⁇ nyl-2-benzal ⁇ ndanone; and 3-P ⁇ pe ⁇ d ⁇ nyl-2-benzal ⁇ ndanone.
  • the present invention includes the use of all hydrates, solvates. complexes and prodrugs of the compounds of this invention
  • Prodrugs are any covalently bonded compounds which release the active parent drug according to Formula I in v vo If a chiral center or another form of an isomenc center is present in a compound of the present invention, all forms of such isomer or isomers, including enantiomers and diastereomers, are intended to be covered herein.
  • C]_6alkyl as applied herein is meant to include substituted and unsubstituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl, pentyl, n-pentyl, isopentyl, neopentyl and hexyl and the simple aliphatic isomers thereof.
  • Any C ⁇ _6alkyl group may be optionally substituted independently by one or two halogens, SR', OR', N(R")2 > C(0)N(R')2, carbamyl or C ⁇ _4alkyl, where R' is C ⁇ _6alkyl.
  • C3-8 cycloalkyl as applied herein is meant to include substituted and unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl and the simple aliphatic isomers thereof Any C3-8 cycloalkyl group may be optionally substituted independently by one or two halogens, SR', OR', N(R")2, C(0)N(R')2, carbamyl or C ⁇ _4alkyl, where R' IS C i-6alkyl
  • Halogen means F. Cl, Br, and I
  • Ar or aryl means phenyl or naphthyl, optionally independently substituted by one or more of Ph-Co -O alkyl, Het-C ⁇ -galkyl, Cj.galkyl, Cj.galkoxy, Ph-Co_galkoxy, Het- C Q . ⁇ alkoxy, OH. CN, CO2R', or halogen.
  • Cgalkyl means that no alkyl group is present in the moiety
  • Ar-C Q alkyl is equivalent to Ar
  • Two C i .galkyl groups may be combined to form a 5-7 membered ring, saturated or unsaturated, fused onto the Ar ring Ph may be optionally substituted with one or more of C j.galkyl, C j . ⁇ alkoxy, OH, CO2R', or halogen
  • Het or "heterocychc” represents a stable 5- to 7-membered monocychc ring, which is either saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quatermzed, and including any bicychc group in which any of the above-defined heterocychc rings is fused to a benzene ring.
  • the heterocychc ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure, and may optionally be substituted with one or two moieties selected from the group consisting of Ph-Co-6 lkyl, Het-C .
  • Acid addition salts of the compounds of Formula I are prepared in a standard manner in a suitable solvent from the parent compound and an excess of an acid, such as hydrochloric, hydrobromic, hydrofluoric, sulfu ⁇ c, phosphoric, acetic, t ⁇ fluoroacetic, maleic, succinic or methanesulfonic Certain of the compounds form inner salts or zwitte ⁇ ons which may be acceptable
  • Catiomc salts are prepared by treating the parent compound with an excess of an alkaline reagent, such as a hydroxide, carbonate or alkoxide, containing the appropriate cation, or with an appropriate organic amine Cations such as L ⁇ + , Na + , K + , Ca ++ , Mg ++ and NH4 + are specific examples of cations present in pharmaceutically acceptable salts Hahdes, sulfate, phosphate, alkanoates (such as acetate and t ⁇ fluoro
  • compositions which comprises a compound according to Formula I and a pharmaceutically acceptable carrier, diluent or excipient
  • the compounds of Formula I may be used in the manufacture of a medicament
  • Pharmaceutical compositions of the compounds of Formula I prepared as hereinbefore described may be formulated as solutions or lyophihzed powders for parenteral administration Powders may be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use
  • the liquid formulation may be a buffered, lsotonic.
  • aqueous solution examples include normal isotonic saline solution, standard 5% dextrose in water or buffered sodium or ammonium acetate solution
  • suitable diluents are normal isotonic saline solution, standard 5% dextrose in water or buffered sodium or ammonium acetate solution
  • excipients such as polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, manmtol, sodium chloride or sodium citrate
  • these compounds may be encapsulated, tableted or prepared in an emulsion or syrup for oral administration
  • Pharmaceutically acceptable solid or liquid carriers may be added to enhance or stabilize the composition, or to facilitate preparation of the composition
  • Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stea ⁇ c acid, talc, pectin, acacia, agar or gelatin Liquid
  • the compounds of Formula I may also be combined with excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols and molded into a suppository
  • topical administration is meant non-systemic administration, including the application of a compound of the invention externally to the epidermis, to the buccal cavity and instillation of such a compound into the ear, eye and nose, wherein the compound does not significantly enter the blood stream.
  • systemic administration is meant oral, intravenous, intraperitoneal and intramuscular administration
  • active ingredient a compound of Formula I (hereinafter referred to as the active ingredient) required for therapeutic or prophylactic effect upon topical administration will, of course, vary with the compound chosen, the nature and severity of the condition being treated and the animal undergoing treatment, and is ultimately at the discretion of the physician
  • the active ingredient may comprise, for topical administration, from 0.01 to 5 0 wt% of the formulation.
  • topical formulations of the present invention both for veterinary and for human medical use. comprise an active ingredient together with one or more acceptable carriers therefor, and optionally any other therapeutic ingredients
  • the earner must be
  • Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of where treatment is required such as liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose
  • Drops according to the present invention may comprise sterile aqueous or oily solutions or suspensions and may be prepared by dissolving the active ingredient in a suitable aqueous solution of a bactencidal and/or fungicidal agent and/or any other suitable preservative, and preferably including a surface active agent
  • the resulting solution may then be clarified by filtration, transferred to a suitable container which is then sealed and sterilized by autoclaving or maintaining at 90- 100 C for half an hour Alternatively, the solution may be sterilized by filtration and transferred to the container by an aseptic technique
  • bactericidal and fungicidal agents suitable for inclusion in the drops are examples of bactericidal and fungicidal agents suitable for inclusion in the drops.
  • Lotions according to the present invention include those suitable for application to the skin or eye
  • An eye lotion may comprise a sterile aqueous solution optionally containing a bacte ⁇ cide and may be prepared by methods similar to those for the preparation of drops
  • Lotions or liniments for application to the skin may also include an agent to hasten drying and to cool the skin, such as an alcohol or acetone, and/or a moisturizer such as glycerol or an oil such as castor oil or arachis oil
  • Creams, ointments or pastes according to the present invention are semi-solid formulations of the active ingredient for external application They may be made by mixing the active ingredient in finely-divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous fluid, with the aid of suitable machinery, with a greasy or non-greasy basis
  • the basis may comp ⁇ se hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap, a mucilage, an oil of natural origin such as almond, corn, arachis, castor or olive oil, wool fat or its de ⁇ vatives, or a fatty acid such as stea ⁇ c or oleic acid together with an alcohol such as propylene glycol or macrogols
  • the formulation may incorporate any suitable surface active agent such as an anionic, cationic or non-ionic surface active agent such as sorbitan esters or polyoxyethylene derivatives thereof Suspending agents such as natural gums,
  • the compounds of Formula I are useful as inhibitors of NF- ⁇ B
  • the present invention provides useful compositions and formulations of said compounds, including pharmaceutical compositions and formulations of said compounds
  • the present invention also provides methods of treatment of diseases associated with NF- ⁇ B activation, which methods comprise administering to an animal, particularly a mammal, most particularly a human in need thereof a compound of Formula I
  • the present invention particularly provides methods for treating lnflammatorv disorders, particularly rheumatoid arthritis inflammatorv bowel disease, and asthma dermatosis, including psoriasis and atopic dermatitis autoimmune diseases, tissue and organ rejection, Alzheimer's disease, stroke, atherosclerosis restenosis, cancer, including Hodgkins disease, and certain viral infections, including AIDS osteoarth ⁇ tis osteoporosis and Ataxia Telangiestasia
  • parenteral administration of a compound of Formula I is preferred
  • An intravenous infusion of the compound in 57c dextrose in water or normal saline, or a similar formulation with suitable excipients, is most effective, although an intramuscular bolus injection is also useful
  • the parenteral dose will be about 0 01
  • the compounds of Formula I may also be administered orally to the patient, in a manner such that the concentration of drug is sufficient to inhibit NF- ⁇ B or to achieve any other therapeutic indication as disclosed herein
  • a pharmaceutical composition containing the compound is administered at an oral dose of between about 0 1 to about 50 mg/kg in a manner consistent with the condition of the patient Preferably the oral dose would be about 0 5 to about 20 mg/kg
  • the compounds of Formula I may also be administered topically to the patient, in a manner such that the concentration of drug is sufficient to inhibit NF- ⁇ B or to achieve any other therapeutic indication as disclosed herein
  • a pharmaceutical composition containing the compound is administered in a topical formulation of between about 0 01 % to about 5% w/w
  • NF- ⁇ B plays a key role in the regulated expression of a large number of pro- inflammatory mediators including cytokines such as IL-6 and IL-8 (Mukaida et al., 1990; Liberman and Baltimore, 1990; Matsusaka et al., 1993), cell adhesion molecules, such as ICAM and VCAM (Marui et al., 1993; Kawai et al., 1995; Ledebur and Parks, 1995), and inducible nitric oxide synthase (iNOS) (Xie et al., 1994; Adcock et al., 1994). (Full reference citations are at the end of this section).
  • cytokines such as IL-6 and IL-8
  • cell adhesion molecules such as ICAM and VCAM (Marui et al., 1993; Kawai et al., 1995; Ledebur and Parks, 1995)
  • iNOS inducible nitric oxide synthase
  • Such mediators are known to play a role in the recruitment of leukocytes at sites of inflammation and in the case of iNOS, may lead to organ destruction in some inflammatory and autoimmune diseases (McCartney-Francis et al , 1993, Kleemann et al , 1993)
  • the compounds described herein inhibit IL-8 synthesis and the production of nitnc oxide, a product of iNOS activity ⁇ see Table 2)
  • NF- ⁇ B may also play a critical role in the pathogenesis of inflammatory bowel disease (IBD)
  • IBD inflammatory bowel disease
  • Activated NF- ⁇ B is seen in colonic biopsy specimens from Chron's disease and ulcerative colitis patients (Ardite et al , 1998, Rogler et al , 1998, Schreiber et al , 1998) Activation is evident in the inflamed mucosa but not in umnflamed mucosa (Ardite et al , 1998, Rogler et al , 1998) and is associated with increased IL-8 mRNA expression in the same sites (Ardite et al .
  • NF- ⁇ B a kev regulator of colonic inflammation
  • Increased NF- ⁇ B activity is observed in the lamina prop ⁇ a macrophages in 2.4,6,-t ⁇ n ⁇ trobenzene sulfonic acid (TNBS)- ⁇ nduced colitis in mice with p65 being a major component of the activated complexes (Neurath et al , 1996, Neurath and Pettersson, 1997)
  • Local administration of p65 antisense abrogates the signs of established colitis in the treated animals with no signs of toxicity (Neurath et al , 1996 Neurath and Pettersson, 1997)
  • small molecule inhibitors of NF- ⁇ B would be useful in the treatment of IBD
  • NF- ⁇ B is normally present as an inactive cytoplasmic complex
  • recent immunohistochemical studies have indicated that NF- ⁇ B is present in the nuclei, and hence active, in the cells comprising human rheumatoid synovium (Handel et al , 1995, Marok et al , 1996, Sioud et al 1998) and in animal models of the disease (Tsao et al , 1997)
  • the staining is associated with type A synoviocytes and vascular endothe um (Marok et al , 1996)
  • constitutive activation of NF- ⁇ B is seen in cultured synoviocytes (Roshak et al , 1996, Miyazawa et al , 1998) and in synovial cell cultures stimulated with IL- 1 ⁇ or TNF ⁇ (Roshak et al , 1996 Fuji
  • Vascular cell adhesion molecule- 1 (VCAM- 1 ) gene transcription and expression are regulated through an antioxidant-sensitive mechanism in human vascular endothehal cells J Cltn Invest 92 1866- 1874 Kawai M, Nishikomo ⁇ R Jung E Y, Tai G, Yamanak C, Mayumi M, Heike T ( 1995) Pyrrohdine dithiocarbamate inhibits intercellular adhesion molecule- 1 biosynthesis induced by cytokines in human fibroblasts J Immunol 154 2333-2341 Ledebur HC, Parks TP ( 1995) Transc ⁇ ptional regulation of the intracellular adhesion molecule- 1 gene by inflammatory cytokines in human endothehal cells J Biol Chem
  • the compounds of this invention may be tested in one of several biological assays to determine the concentration of compound which is required to have a given pharmacological effect
  • Assays of NF- ⁇ B activity are conducted using a cell based luciferase reporter assay as described in Breton, J J and Chabot-Fletcher, M C , JPET, 282, 459-466 ( 1997) Briefly, U937 human histiocytic lymphoma cell line permanently transfected with the NF- KB reporter plasmids (see below) are cultured in the above medium with the addition of 250 ⁇ g/ml Geneticin (G418 sulfate, Life Technologies, Grand Island, NY) The luciferase reporter assay is conducted in the transfected U937 clones These are twice centnfuged at 300 xg for 5 min and resuspended in RPMI 1640 with 10% FBS to a density of 1 x 10' cells/ml One ml
  • the luminometer dispenses 100 ⁇ l luciferase assay reagent (Promega Corporation, Madison, WI) into each well and the integrated light output is recorded for 20 sec Light output is measured in relative light units (RLUs)
  • NF- ⁇ B activity may also be measured in an electrophoretic mobility shift assay (EMSA) to assess the presence of NF- ⁇ B protein in the nucleus
  • ESA electrophoretic mobility shift assay
  • the cells of interest are cultured to a density of lxlO" /ml
  • the cells are harvested by cent ⁇ fugation, washed in PBS without Ca and Mg + and resuspended in PBS with Ca * and Mg + at lx lO 7 cells/ml
  • Ca * and Mg + at lx lO 7 cells/ml
  • the cell suspensions are treated with various concentrations of drug or vehicle (DMSO, 0 1 %) for 30 min at 37°C prior to stimulation with TNF ⁇ (5 Ong/ml) for an additional 15 min
  • DMSO drug or vehicle
  • TNF ⁇ 5 Ong/ml
  • Cellular and nuclear extracts are prepared follows Briefly, at the end of the incubation period the cells ( lxlO 7 cells) are washed 2x in PBS without Ca and Mg " The resulting cell pellets are resuspended in 20 ⁇ l of Buffer A ( lOmM Hepes (pH 7 9), lOmM KCl, 1 5mM MgCl,, 0 5mM dithiothreitol (DTT) and 0 1 % NP-40) and incubated on ice for 10 min The nuclei are pelleted by microcent ⁇ fugation at 3500 rpm for 10 min at 4°C The resulting supernatant was collected as the cellular extract and the nuclear
  • the binding mixture (25 ⁇ l) contains lOmM Hepes-NaOH (pH 7 9), 4mM Tns- HC1 (pH 7 9), 60mM KCl, ImM EDTA, ImM dithiothreitol, 107c glycerol, 0 3 mg/ml bovine serum albumin, and 1 ⁇ g poly(dI-dC)»poly(dI-dC)
  • the binding mixtures (10 ⁇ g nuclear extract protein) are incubated for 20 min at room temperature with 0 5 ng of 32 P- labelled ohgonucleotide (50,000-100,000 cpm) in the presence or absence of unlabeled competitor after which the mixture is loaded on a 47c polyacrylamide gel prepared in IX T ⁇ s borate/EDTA and electrophoresed at 200 V for
  • Anti-inflammatory activity in vivo is assessed using the phorbol ester-induced ear inflammation model in mice Phorbol my ⁇ state acetate (PMA) (4 ⁇ g/20 ⁇ l acetone) is applied to the inner and outer surfaces of the left ear of Male Balb/c mice (6/group) (Charles River Breeding Laboratones, Wilmington, MA) Four hours later, compound dissolved in 25 ⁇ l acetone is applied to the same ear The thickness of both ears is measured with a dial micrometer (Mitutoyo, Japan) after 20 hours and a second topical dose of compound is applied Twenty-four hours later, ear thickness measurements are taken and the data expressed as the change in thickness (x 10 ' ⁇ cm) between treated and untreated ears The inflamed left ears are then removed and stored at -70°unt ⁇ l assayed for myeloperoxidase (MPO) activity, a measure of inflammatory cell infiltration Inflammatory cell infiltration is assessed through the measurement of myeloperoxidase activity present in
  • Nuclear magnetic resonance spectra were recorded at either 250. 300 or 400 MHz using, respectively, a Bruker AM 250, Bruker, Bruker ARX 300 or Bruker AC 400 spectrometer
  • CDCI3 is deute ⁇ ochloroform
  • DMSO-d6 is hexadeute ⁇ odimethylsulfoxide
  • CD3OD is tetradeute ⁇ omethanol
  • Chemical shifts are reported in parts per million (d) downfield from the internal standard tetramethylsilane
  • Mass spectra were taken on either VG 70 FE, PE Syx API III, or VG ZAB HF instruments, using fast atom bombardment (FAB) or electrospray (ES) lonization techniques Elemental analyses were obtained using a Perkin-Elmer 240C elemental analyzer Melting points were taken on a Thomas-Hoover melting point apparatus and are uncorrected All temperatures are reported in degrees Celsius

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Rheumatology (AREA)
  • Dermatology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Pulmonology (AREA)
  • Virology (AREA)
  • Neurosurgery (AREA)
  • Psychiatry (AREA)
  • Molecular Biology (AREA)
  • Communicable Diseases (AREA)
  • Vascular Medicine (AREA)
  • Oncology (AREA)
  • Pain & Pain Management (AREA)
  • Urology & Nephrology (AREA)
  • Hospice & Palliative Care (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • AIDS & HIV (AREA)
  • Toxicology (AREA)
  • Transplantation (AREA)

Abstract

La présente invention concerne des inhibiteurs amino-indanone du facteur de transcription NF-λB, des sels, des hydrates et des solvates pharmaceutiquement acceptables de ces inhibiteurs, des compositions pharmaceutiques à base de ces composés, ainsi que des méthodes de traitement des maladies impliquant une activation de NF-λB. En particulier, la présente invention concerne des méthodes de traitement d'un ensemble de maladies associées à l'activation de NF-λB, notamment les troubles inflammatoires; en particulier la polyarthrite rhumatoïde, les affections intestinales inflammatoires, et l'asthme; les dermopathies, y compris le psoriasis et la dermatose aiguë; les maladies auto-immunes; les rejets de tissus et d'organes; la maladie d'Alzheimer; les accidents cérébrovasculaires; l'athérosclérose; la resténose, le cancer, notamment la maladie de Hodgkin; certaines infections virales, comme le SIDA; l'arthrose; l'ostéoporose; et le syndrome de Louis-Bar par administration d'un composé de la présente invention au patient qui en a besoin.
PCT/US1999/013897 1998-06-19 1999-06-18 INHIBITEURS DU FACTEUR DE TRANSCRIPTION NF-λB WO1999065495A1 (fr)

Priority Applications (10)

Application Number Priority Date Filing Date Title
HU0102492A HUP0102492A2 (hu) 1998-06-19 1998-06-18 Amino-indanon származékok alkalmazása NF-kB transzkripciós faktor inhibitor hatású gyógyszerkészítmények előállítására
IL14032499A IL140324A0 (en) 1998-06-19 1999-06-18 Inhibition of transcription factor nf-kb
EP99930459A EP1085872A4 (fr) 1998-06-19 1999-06-18 INHIBITEURS DU FACTEUR DE TRANSCRIPTION NF-$g(k)B
PL99345577A PL345577A1 (en) 1998-06-19 1999-06-18 Inhibitors of transcription factor nf-κb
KR1020007014385A KR20010052990A (ko) 1998-06-19 1999-06-18 전사 인자 ＮＦ-κＢ의 저해제
CA002335293A CA2335293A1 (fr) 1998-06-19 1999-06-18 Inhibiteurs du facteur de transcription nf-.kappa.b
BR9911151-9A BR9911151A (pt) 1998-06-19 1999-06-18 Inibidores do fator de transcrição nf-kb
AU46996/99A AU4699699A (en) 1998-06-19 1999-06-18 Inhibitors of transcription factor NF-KappaB
JP2000554375A JP2002518333A (ja) 1998-06-19 1999-06-18 転写因子ＮＦ−κＢの阻害剤
NO20006452A NO20006452L (no) 1998-06-19 2000-12-18 Inhibitorer av transkripsjonsfaktor NF-kB

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US9001698P 1998-06-19 1998-06-19
US60/090,016 1998-06-19

Publications (1)

Publication Number Publication Date
WO1999065495A1 true WO1999065495A1 (fr) 1999-12-23

Family

ID=22220761

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1999/013897 WO1999065495A1 (fr) 1998-06-19 1999-06-18 INHIBITEURS DU FACTEUR DE TRANSCRIPTION NF-λB

Country Status (17)

Country Link
EP (1) EP1085872A4 (fr)
JP (1) JP2002518333A (fr)
KR (1) KR20010052990A (fr)
CN (1) CN1306428A (fr)
AR (1) AR019871A1 (fr)
AU (1) AU4699699A (fr)
BR (1) BR9911151A (fr)
CA (1) CA2335293A1 (fr)
CO (1) CO5080752A1 (fr)
CZ (1) CZ20004760A3 (fr)
HU (1) HUP0102492A2 (fr)
IL (1) IL140324A0 (fr)
NO (1) NO20006452L (fr)
PL (1) PL345577A1 (fr)
TR (1) TR200003779T2 (fr)
WO (1) WO1999065495A1 (fr)
ZA (1) ZA200007448B (fr)

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001052892A3 (fr) * 2000-01-24 2002-01-24 Genzyme Corp Inhibiteurs du trajet de jak/stat et leurs utilisations
US6649164B2 (en) 1996-12-23 2003-11-18 Immunex Corporation Method for enhancing the functional capacity of dendritic cells
US7097834B1 (en) 1997-04-16 2006-08-29 Amgen Inc. Osteoprotegerin binding proteins
EP1355642A4 (fr) * 2000-11-17 2007-04-04 Res Dev Foundation INHIBITION DE NF-(k)B PAR COMPOSITIONS DE TRITERPENE
WO2007097981A2 (fr) 2006-02-16 2007-08-30 Millennium Pharmaceuticals, Inc. Alpha carbolines et leurs utilisations
US7364736B2 (en) 2001-06-26 2008-04-29 Amgen Inc. Antibodies to OPGL
US7425580B2 (en) 2004-05-19 2008-09-16 Wyeth (Diaryl-methyl)-malononitriles and their use as estrogen receptor ligands
WO2010038465A1 (fr) 2008-10-02 2010-04-08 旭化成ファーマ株式会社 Dérivé d'isoquinoléine substitué en position 8 et son utilisation
US7790684B2 (en) 1996-12-23 2010-09-07 Immunex Corporation Method of inhibiting osteoclast activity
WO2010108058A3 (fr) * 2009-03-20 2011-03-17 University Of Pittsburgh-Of The Commonwealth System Of Higher Education Inhibiteurs de dusp6 à petite molécule et utilisations de ceux-ci
US20120129775A1 (en) * 2009-07-31 2012-05-24 Enrique Zudaire Antiangiogenic small molecules and methods of use
US9670236B2 (en) 2012-10-31 2017-06-06 University of Pittsburgh—of the Commonwealth System of Higher Education Class of HDAC inhibitors expands the renal progenitor cells population and improves the rate of recovery from acute kidney injury
US10160705B2 (en) 2011-02-10 2018-12-25 University of Pittsburgh—of the Commonwealth System of Higher Education Class of HDAC inhibitors expands the renal progenitor cells population and improves the rate of recovery from acute kidney injury

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DATABASE HCAPLUS ON STN, AMERICAN CHEMICAL SOCIETY, AN 1969:106237, MAURY G. et al., "Mobile Keto Allyl Systems. VIII. Properties of 2-(.alpha.-Aminobenzyl)-1-indenones"; & J. ORG. CHEM., 1969, 34(3), pages 596-601. *
DATABASE HCAPLUS ON STN, AMERICAN CHEMICAL SOCIETY, AN 1981:514971, GUPTA R.C. et al., "N-Substituted .alpha.-Aminoalkylacrylophenones and Some Related Compounds: A New Class of Spermicidal Agents"; & INDIAN J. CHEM., 1981, 20(B), pages 303-307. *
See also references of EP1085872A4 *

Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7932375B2 (en) 1996-12-23 2011-04-26 Immunex Corporation Kits for detecting rank nucleic acids
US6649164B2 (en) 1996-12-23 2003-11-18 Immunex Corporation Method for enhancing the functional capacity of dendritic cells
US7262274B2 (en) 1996-12-23 2007-08-28 Immunex Corporation Kits containing rank polypeptides
US8569456B2 (en) 1996-12-23 2013-10-29 Immunex Corporation Receptor activator of NF-kappaB
US7411050B2 (en) 1996-12-23 2008-08-12 Immunex Corporation Monoclonal blocking antibody to human RANKL
US8333963B2 (en) 1996-12-23 2012-12-18 Immunex Corporation Method of inhibiting osteoclast activity
US8153775B2 (en) 1996-12-23 2012-04-10 Immunex Corporation Kits for detecting rank
US7790684B2 (en) 1996-12-23 2010-09-07 Immunex Corporation Method of inhibiting osteoclast activity
US7097834B1 (en) 1997-04-16 2006-08-29 Amgen Inc. Osteoprotegerin binding proteins
WO2001052892A3 (fr) * 2000-01-24 2002-01-24 Genzyme Corp Inhibiteurs du trajet de jak/stat et leurs utilisations
EP1355642A4 (fr) * 2000-11-17 2007-04-04 Res Dev Foundation INHIBITION DE NF-(k)B PAR COMPOSITIONS DE TRITERPENE
US7364736B2 (en) 2001-06-26 2008-04-29 Amgen Inc. Antibodies to OPGL
US7425580B2 (en) 2004-05-19 2008-09-16 Wyeth (Diaryl-methyl)-malononitriles and their use as estrogen receptor ligands
WO2007097981A2 (fr) 2006-02-16 2007-08-30 Millennium Pharmaceuticals, Inc. Alpha carbolines et leurs utilisations
WO2010038465A1 (fr) 2008-10-02 2010-04-08 旭化成ファーマ株式会社 Dérivé d'isoquinoléine substitué en position 8 et son utilisation
US9127016B2 (en) 2009-03-20 2015-09-08 University of Pittsburgh—of the Commonwealth System of Higher Education Small molecule inhibitors of Dusp6 and uses therefor
WO2010108058A3 (fr) * 2009-03-20 2011-03-17 University Of Pittsburgh-Of The Commonwealth System Of Higher Education Inhibiteurs de dusp6 à petite molécule et utilisations de ceux-ci
US9439877B2 (en) 2009-03-20 2016-09-13 University of Pittsburgh—of the Commonwealth System of Higher Education Small molecule inhibitors of Dusp6 and uses therefor
US9682919B2 (en) 2009-03-20 2017-06-20 University of Pittsburgh—of the Commonwealth System of Higher Education Small molecule inhibitors of Dusp6 and uses therefor
EP2461806A4 (fr) * 2009-07-31 2012-12-26 Us Health Petites molécules anti-angiogéniques et procédés d utilisation
US20120129775A1 (en) * 2009-07-31 2012-05-24 Enrique Zudaire Antiangiogenic small molecules and methods of use
US9186365B2 (en) * 2009-07-31 2015-11-17 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Antiangiogenic small molecules and methods of use
US9504729B2 (en) 2009-07-31 2016-11-29 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Antiangiogenic small molecules and methods of use
US10160705B2 (en) 2011-02-10 2018-12-25 University of Pittsburgh—of the Commonwealth System of Higher Education Class of HDAC inhibitors expands the renal progenitor cells population and improves the rate of recovery from acute kidney injury
US10626071B2 (en) 2011-02-10 2020-04-21 University of Pittsburgh—of the Commonwealth System of Higher Education Class of HDAC inhibitors expands the renal progenitor cells population and improves the rate of recovery from acute kidney injury
US9670236B2 (en) 2012-10-31 2017-06-06 University of Pittsburgh—of the Commonwealth System of Higher Education Class of HDAC inhibitors expands the renal progenitor cells population and improves the rate of recovery from acute kidney injury
US10233201B2 (en) 2012-10-31 2019-03-19 University of Pittsburg—Of the Commonwealth System of Higher Education Class of HDAC inhibitors expands the renal progenitor cells population and improves the rate of recovery from acute kidney injury

Also Published As

Publication number Publication date
BR9911151A (pt) 2001-03-06
PL345577A1 (en) 2001-12-17
ZA200007448B (en) 2001-12-12
EP1085872A4 (fr) 2003-04-16
HUP0102492A2 (hu) 2001-11-28
AR019871A1 (es) 2002-03-20
AU4699699A (en) 2000-01-05
CA2335293A1 (fr) 1999-12-23
CO5080752A1 (es) 2001-09-25
IL140324A0 (en) 2002-02-10
KR20010052990A (ko) 2001-06-25
CN1306428A (zh) 2001-08-01
CZ20004760A3 (cs) 2001-08-15
EP1085872A1 (fr) 2001-03-28
NO20006452D0 (no) 2000-12-18
NO20006452L (no) 2001-02-16
TR200003779T2 (tr) 2001-06-21
JP2002518333A (ja) 2002-06-25

Similar Documents

Publication Publication Date Title
US6492425B1 (en) Inhibitors of transcription factor-NF-κB
WO2002030353A2 (fr) INHIBITEURS DU NF-λB
US20040192943A1 (en) Nf-kappab inhibitors
JPWO2007020888A1 (ja) 脳・神経細胞保護剤および睡眠障害治療薬
JP2006510676A (ja) ＮＦ−κＢ阻害剤
EP1085872A1 (fr) INHIBITEURS DU FACTEUR DE TRANSCRIPTION NF-$g(k)B
JP2010502618A (ja) セロトニン５−ｈｔ２ａ受容体のモジュレータとしてのベンゾフラン誘導体
WO2009051909A1 (fr) Composés présentant une activité de correction du traitement cellulaire cftr mutante, et utilisations de ceux-ci
EP1328272A1 (fr) Inhibiteurs du nf-kappa-b
US7183311B2 (en) NF-κB inhibitors
US7300952B2 (en) NF-κb inhibitors
US20040024047A1 (en) Nf-kb inhibitors
MXPA00012499A (en) INHIBITORS OF TRANSCRIPTION FACTOR NF-&kgr;B
MXPA00012498A (en) INHIBITORS OF TRANSCRIPTION FACTOR NF-&kgr;B
US20040006118A1 (en) Nf-kb inhibitors
CN101547902B (zh) 治疗与胰岛素抵抗或高血糖症相关的代谢障碍的吡啶衍生物

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 99807572.8

Country of ref document: CN

AK Designated states

Kind code of ref document: A1

Designated state(s): AE AL AU BA BB BG BR CA CN CZ EE GE GH GM HR HU ID IL IN IS JP KP KR LC LK LR LT LV MG MK MN MX NO NZ PL RO SG SI SK SL TR TT UA US UZ VN YU ZA

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SL SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
WWE Wipo information: entry into national phase

Ref document number: 508803

Country of ref document: NZ

WWE Wipo information: entry into national phase

Ref document number: 1999930459

Country of ref document: EP

Ref document number: 2000/07448

Country of ref document: ZA

Ref document number: 46996/99

Country of ref document: AU

Ref document number: 200007448

Country of ref document: ZA

WWE Wipo information: entry into national phase

Ref document number: PA/a/2000/012499

Country of ref document: MX

Ref document number: 140324

Country of ref document: IL

Ref document number: IN/PCT/2000/00733/MU

Country of ref document: IN

ENP Entry into the national phase

Ref document number: 2335293

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: PV2000-4760

Country of ref document: CZ

Ref document number: 1020007014385

Country of ref document: KR

ENP Entry into the national phase

Ref document number: 2000 554375

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 09720008

Country of ref document: US

Ref document number: 2000/03779

Country of ref document: TR

WWP Wipo information: published in national office

Ref document number: 1999930459

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1020007014385

Country of ref document: KR

WWP Wipo information: published in national office

Ref document number: PV2000-4760

Country of ref document: CZ

WWR Wipo information: refused in national office

Ref document number: PV2000-4760

Country of ref document: CZ

WWW Wipo information: withdrawn in national office

Ref document number: 1999930459

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1020007014385

Country of ref document: KR