WO2002030423A1 - Inhibiteurs du nf-$g(k)b - Google Patents

Inhibiteurs du nf-$g(k)b Download PDF

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WO2002030423A1
WO2002030423A1 PCT/US2001/031865 US0131865W WO0230423A1 WO 2002030423 A1 WO2002030423 A1 WO 2002030423A1 US 0131865 W US0131865 W US 0131865W WO 0230423 A1 WO0230423 A1 WO 0230423A1
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Prior art keywords
alkyl
conh
disease
aryl
heteroaryl
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PCT/US2001/031865
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English (en)
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James F. Callahan
Amy K. Roshak
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Smithkline Beecham Corporation
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Priority to EP01979730A priority Critical patent/EP1328272A1/fr
Priority to US10/399,008 priority patent/US20040006118A1/en
Priority to AU2002211662A priority patent/AU2002211662A1/en
Priority to JP2002533864A priority patent/JP2004532797A/ja
Publication of WO2002030423A1 publication Critical patent/WO2002030423A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • 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
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • 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
    • 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
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • This invention relates in general to a method of inhibiting pathological activation of the transcription factor NF- B (nuclear factor- ⁇ B) using aminoimidazole compounds. Such methods are particularly useful for treating diseases in which activation of NF- B is implicated. More specifically, these methods may be used for inhibiting IKK- ⁇ (I ⁇ B kinase- ⁇ ) phosphorylation of I ⁇ B (inhibitory protein ⁇ B)-which prevents subsequent degradation and activation of NF- KB dimers.
  • Such methods are useful in the treatment of a variety of diseases associated with NF- ⁇ B activation including inflammatory and tissue repair disorders; particularly rheumatoid arthritis, inflammatory bowel disease, asthma and COPD (chronic obstructive pulmonary disease) osteoarthritis; osteoporosis and fibrotic diseases; dermatosis, including psoriasis, atopic dermatitis and ultraviolet radiation (UN)-induced skin damage; autoimmune diseases including systemic lupus eythematosus, multiple sclerosis, psoriatic arthritis, alkylosing spondylitis, tissue and organ rejection, Alzheimer's disease, stroke, atherosclerosis, restenosis, diabetes, glomerulonephritis, cancer, including Hodgkins disease, cachexia, inflammation associated with infection and certain viral infections, including acquired immune deficiency syndrome (AIDS), adult respiratory distress syndrome, Ataxia Telangiestasia.
  • AIDS acquired immune deficiency syndrome
  • AIDS acquired immune deficiency syndrome
  • Nuclear factor KB belongs to a family of closely related dimeric 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- ⁇ Bl (p50/ pl05), NF- ⁇ B2 (p49/ pl00), c-Rel, and 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 dimerization 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 to the nucleus.
  • p65 and cRel possess potent transactivation domains at their C-terminal ends.
  • NF- ⁇ B The activity of NF- ⁇ B is regulated by its interaction with a member of the inhibitor I ⁇ B family of proteins. This interaction effectively blocks the nuclear localization sequence on the NF- ⁇ B proteins, thus preventing migration of the dimer to the nucleus.
  • a wide variety of stimuli activate NF- ⁇ B through what are likely to be multiple signal transduction pathways. Included are bacterial products (LPS), some viruses (HIV-1, HTLV-1), inflammatory cytokines (TNF , IL-1), environmental and oxidative stress and DNA damaging agents. Apparently common to all stimuli however, is the phosphorylation and subsequent degradation of I ⁇ B. I ⁇ B is phosphorylated on two N-terminal serines by the recently identified I ⁇ B kinases (IKK- and IKK- ⁇ ).
  • NF- ⁇ B Site-directed mutagenesis studies indicate that these phosphorylations are critical for the subsequent activation of NF- ⁇ B in that once phosphorylated the protein is flagged for degradation via the ubiquiti ⁇ -proteasome pathway.
  • the active NF- ⁇ B complexes Free from MB, the active NF- ⁇ B complexes are able to translocate to the nucleus where they bind in a selective manner to preferred gene-specific enhancer sequences. Included in the genes regulated by NF- ⁇ B are a number of cytokines and chemokines, cell adhesion molecules, acute phase proteins, immunoregualtory proteins, eicosanoid metabolizing enzymes and anti-apoptotic genes.
  • NF-KB plays a key role in the regulated expression of a large number of pro-inflammatory mediators including cytokines such as TNF, IL- l ⁇ , TL-6 and BL-8, cell adhesion molecules, such as ICAM and NCAM, and inducible nitric oxide synthase (i ⁇ OS).
  • cytokines such as TNF, IL- l ⁇ , TL-6 and BL-8
  • cell adhesion molecules such as ICAM and NCAM
  • i ⁇ OS inducible nitric oxide synthase
  • NF- ⁇ B airway inflammation
  • 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.
  • glucocorticoid inhibition of NF- ⁇ B one may speculate that these effects are mediated through an inhibition of NF- ⁇ B. Further evidence for a role of NF- ⁇ B in inflammatory disorders comes from studies of rheumatoid synovium.
  • NF- ⁇ B is normally present as an inactive cytoplasmic complex
  • recent immunohistochemical studies have indicated that NF- KB is present in the nuclei, and hence active, in the cells comprising rheumatoid synovium.
  • NF- ⁇ B has been shown to be activated in human synovial cells in response to stimulation with TNF- ⁇ or EL-l ⁇ . 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).
  • IKK- ⁇ has been shown in synoviocytes of rheumatoid arthritis patients and gene transfer studies have demonstrated the central role of IKK- ⁇ in stimulated inflammatory mediator production in these cells . See Aupperele et al. J. Immunology 1999. 163:427-433 and Aupperle et al. J. Immunology 2001;166:2705-11. More recently, the intra-articular administration of a wild type IKK- ⁇ adenoviral construct was shown to cause paw swelling while intra- articular administration of dominant-negative IKK- ⁇ inhibited adjuvant-induced arthritis in rat. See Tak et al. Arthritis and Rheumatism 2001; 44:1897-1907.
  • NF- ⁇ B/Rel and I ⁇ B proteins are also likely to play a key role in neoplastic transformation and metastasis.
  • Family members are associated with cell transformation in vitro and in vivo as a result of overexpression, gene amplification , gene rearrangements or translocations.
  • rearrangement and/or amplification of the genes encoding these proteins are seen in 20-25% of certain human lymphoid tumors.
  • NF- ⁇ B is activated by oncogenic ras, the most common defect in human tumors and blockade of NF- ⁇ B activation inhibits ras mediated cell transformation.
  • NF- ⁇ B NF- ⁇ B
  • TNF ionizing radiation and DNA damaging agents
  • NF- ⁇ B NF- ⁇ B
  • inhibition of NF- ⁇ B has been shown to enhance apoptotic-killing by these agents in several tumor cell types.
  • inhibitors of NF-kB activation may be useful chemotherapeutic agents as either single agents or adjunct therapy.
  • NF- ⁇ B is an inhibitor of skeletal cell differentiation as well as a regulator of cytokine-induced muscle wasting (Guttridge et al. Science; 2000; 289: 2363-2365.) further supporting the potential of NF-kB inhibitors as novel cancer therapies.
  • NF- ⁇ B inhibitors are described in C. Wahl, et al. J. Clin. Invest.
  • the marine natural product hymenialdisine is known to inhibit NF- ⁇ B. Roshak, A., et al., JPET, 283, 955-961 (1997). Breton, J. J and Chabot-Fletcfter, M. C, 7EEE, 282, 459-466 (1997).
  • German Published Patent Application. DE 2142832 describes the preparation of certain aminoimidazoles. We have now discovered a novel method of inhibiting the activation transcription factor NF- ⁇ B using certain aminoimidazole compounds.
  • the present invention involves novel compounds and methods of using them for inhibiting the activation transcription factor NF- ⁇ B.
  • 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.
  • this invention provides novel compounds and pharmaceutical compositions comprising a compound according to Formula I.
  • this invention provides a method of treating diseases in which the disease pathology may be therapeutically modified by inhibiting phosphorylation and subsequent degradation of I ⁇ B by IKK- ⁇ .
  • this invention provides a method of treating diseases in which the disease pathology may be therapeutically modified by inhibiting pathological activation of NF- ⁇ B.
  • this invention provides methods for treating a variety of diseases associated with NF- ⁇ B activation including inflammatory and tissue repair disorders, particularly rheumatoid arthritis, inflammatory bowel disease, asthma and COPD (chronic obstructive pulmonary disease) osteoaithritis, osteoporosis and fibrotic diseases, dermatosis, including psoriasis, atopic dermatitis and ultraviolet radiation (UN)-induced skin damage; autoimmune diseases including systemic lupus eythematosus, multiple sclerosis, psoriatic arthritis, alkylosing spondylitis, tissue and organ rejection, Alzheimer's disease, stroke, atherosclerosis, restenosis, diabetes, glomerulonephritis, cancer, including Hodgkins disease, cachexia, inflammation associated with infection and certain viral infections, including acquired immune deficiency syndrome (AIDS), adult respiratory distress syndrome and Ataxia Telangiestasia
  • inflammatory and tissue repair disorders particularly rheumatoid arthritis, inflammatory bowel disease
  • Rl is NR4R5
  • R 2 is CONH 2 , or SO 2 NH 2 ;
  • R3 is aryl, or heteroaryl
  • R4 is H, or alkyl
  • R5 is selected from the group consisting of H, CO-Ci- ⁇ alkyl, SO2-C1- ⁇ alkyl, CONH-R 6 , CONH-R7, CSNH-R 6 , CSNH-R7, SO 2 NH-R 7 , and
  • R ⁇ is H or alkyl; except when R2 is CONH2 R4 is H;
  • R7 is H or alkyl; provided that when R2 is CONH2 and R5 is H, R7 is not H;
  • Rg is H, or alkyl and pharmaceutically acceptable salts, hydrates and solvates thereof.
  • Preferred compounds of the present invention include those wherein
  • R4 is H
  • R5 is selected from the group consisting of CO-Ci_6alkyl, SO2-Ci_6 lkyl,
  • More preferred compounds are those wherein R 5 is CONH-R 6 , or SO 2 NH-R 8 .
  • the present invention also involves an embodiment of formula (I) wherein R ⁇ is NR4R5;
  • R 2 is SO 2 NH 2 ;
  • R3 is aryl, or heteroaryl;
  • R4 is H, or alkyl
  • R5 is selected from the group consisting of H, CO-Ci-6alkyl, SO2-C1-.
  • R6 is H, or alkyl
  • R7 is aryl, or heteroaryl
  • R 8 is H, or alkyl. Another embodiment of the present invention involves a compound according to formula (I) wherein: Ri is NR4R5;
  • R 2 is CONH 2
  • R3 is aryl, or heteroaryl
  • R4 is alkyl
  • R5 is selected from the group consisting of H, CO-Ci- ⁇ alkyl, SO2-C1-. 6alkyl, CONH-R 6 , CONH-R7, CSNH-R 6 , CSNH-R7, SO 2 NH-R 7 , and
  • R5 is H, or alkyl
  • R7 is aryl, or heteroaryl
  • R is H, or alkyl.
  • Ri is NR4R5;
  • R 2 is CONH 2;
  • R3 is aryl, or heteroaryl;
  • R4 is H;
  • R5 is selected from the group consisting of CONH-Rg, CONH-R7, CSNH-
  • R6 is alkyl
  • R7 is aryl, and heteroaryl.
  • Rl is NR4R5
  • R 2 is CONH ;
  • R3 is aryl, or heteroaryl;
  • R4 is H, or alkyl
  • R5 is SO 2 -Ci-6alkyl, SO 2 NH-R 7 , or SO 2 NH-R 8 ;
  • R7 is aryl, or heteroaryl
  • R is H, or alkyl.
  • the present invention further provides a preferred method of treatment of diseases associated with NF-kB activation, comprising administering to an animal, particularly a mammal, most particularly a human in need thereof one or more compounds selected from the group consisting of: 5-Amino-2-phenyl-lH-imidazole-4-carboxylic acid amide;
  • This invention provides methods for treating a variety of diseases associated with NF-KB activation including inflammatory and tissue repair disorders; particularly rheumatoid arthritis, inflammatory bowel disease, asthma and COPD (chronic obstructive pulmonary disease) and fibrotic diseases; dermatosis, including psoriasis, atopic dermatitis and ultraviolet radiation (UN)-induced skin damage; autoimmune diseases including multiple sclerosis; tissue and organ rejection; Alzheimer's disease; stroke; atherosclerosis; restenosis; cancer, including Hodgkins disease; inflammation associated with infection and certain viral infections, including aquired immune deficiency syndrome (AIDS); osteoarthritis; osteoporosis; and Ataxia Telangiestasia, using the compounds of Formula I, especially the preferred and most preferred compounds listed above.
  • diseases associated with NF-KB activation including inflammatory and tissue repair disorders; particularly rheumatoid arthritis, inflammatory bowel disease, asthma and COPD (chronic obstructive pulmonary disease) and fibro
  • the present invention includes 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 Formulas I and II in vivo. If a chiral center or another form of an isomeric 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.
  • Inventive compounds containing a chiral center may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well-known techniques and an individual enantiomer may be used alone.
  • alkyl refers to an optionally substituted hydrocarbon group joined by single carbon-carbon bonds and having 1-6 carbon atoms joined together.
  • the alkyl hydrocarbon group may be linear, branched or cyclic, saturated or unsaturated.
  • Substituents on optionally substituted alkyl are selected from the group consisting of aryl, OH, O-alkyl, CO, halogen, CF3, and OCF3.
  • aryl refers to an optionally substituted aromatic group with at least one ring having a conjugated pi-electron system, containing up to two conjugated or fused ring systems.
  • Aryl includes carbocyclic aryl, and biaryl groups, all of which may be optionally substituted. Substituents are selected from the group consisting of halogen, C1.4 alkyl, NH2, OCF3 5 CF 3j O-alkyl, S-alkyl, CN, CHO, SO2-alkyl and NO2.
  • heteroaryl refers to an optionally substituted aromatic group with at least one ring having a conjugated pi-electron system, containing up to two conjugated or fused ring systems and 1-3 heteroatoms selected from O, S and N.
  • Heteroaryl includes carbocyclic heteroarylaryl, aryl-heteroaryl and biheteroarylaryl groups, all of which may be optionally substituted.
  • Preferred aryl include phenyl and naphthyl. More preferred aryl include phenyl.
  • Preferred substituents are selected from the group consisting of halogen, Cj_4 alkyl, NH2, OCF3 ; CF3 ?
  • heteroaryl rings included pyrrole, furan, thiophene, indole, isoindole, benzofuran, isobenzofuran, benzothiphene, pyridine, quinoline, isoquinoline, quinolizine, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, pyridazine, pyrimidine, and pyrazine.
  • halogen refers to include F, Cl, Br, and I.
  • the compounds of the present invention may be conveniently prepared by the methods set forth in Schemes 1-6 below.
  • a general solution preparation of aminoimidazole carboxamides is disclosed in DE. Patent Application No. 2142832, of J. Heyes, et al. incorporated herein by reference, and is described below and in Scheme 1.
  • a method for the general preparation for the corresponding sulfonamides is outlined in Scheme 2.
  • a method for the general preparation of the imidazole urea carboxamide analogs is described in Scheme 3 and methods for. the general. preparation of the imidazole urea sulfonamide analogs is described in Scheme 4.
  • 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, sulfuric, phosphoric, acetic, trifluoroacetic, maleic, succinic or methanesulfonic. Certain of the compounds form inner salts or zwitterions which may be acceptable.
  • Cationic 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 Li 4 ", ⁇ a"*", K + , Ca 4* "*", Mg ++ and ⁇ H4 * are specific examples of cations present in pharmaceutically acceptable salts.
  • Halides, sulfate, phosphate, alkanoates (such as acetate and trifluoroacetate), benzoates, and sulfonates (such as mesylate) are examples of anions present in pharmaceutically acceptable salts.
  • This invention provides a pharmaceutical composition which comprises a compound according to Formula I and a pharmaceutically acceptable carrier, diluent or excipient. Accordingly, the compounds of Formula I may be used in the manufacture of a medicament.
  • compositions of the compounds of Formula I prepared as hereinbefore described may be formulated as solutions or lyophilized 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, isotonic, aqueous solution.
  • suitable diluents are normal isotonic saline solution, standard 5% dextrose in water or buffered sodium or ammonium acetate solution.
  • Such formulation is especially suitable for parenteral administration, but may also be used for oral administration or contained in a metered dose inhaler or nebulizer for insufflation. It may be desirable to add excipients such as polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, 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 stearic acid, talc, pectin, acacia, agar or gelatin.
  • Liquid carriers include syrup, peanut oil, olive oil, saline and water.
  • the carrier may also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax.
  • the amount of solid carrier varies but, preferably, will be between about 20 mg to about 1 g per dosage unit.
  • the pharmaceutical preparations are made following the conventional techniques of pharmacy involving milling, mixing, granulating, and compressing, when necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms.
  • a liquid carrier When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension.
  • Such a liquid formulation may be administered directly p.o. or filled into a soft gelatin capsule.
  • the compounds of this invention may also be combined with excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols and molded into a suppository.
  • excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols and molded into a suppository.
  • the methods of the present invention include topical administration of the compounds of Formula I.
  • 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.
  • the amount of a compound of the invention (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.
  • an active ingredient While it is possible for an active ingredient to be administered alone as the raw chemical, it is preferable to present it as a pharmaceutical formulation.
  • 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 carrier must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • 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 bactericidal 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.
  • 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 phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%).
  • Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol and propylene glycol.
  • 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 bactericide 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 comprise 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 derivatives, or a fatty acid such as stearic 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, cellulose derivatives or in organic materials such as silicaceous silicas, and other ingredients such as lanolin, may also be included.
  • the compounds of Formula I are useful as inhibitors of the IKK-beta kinase phosphorylation of MB and as such are inhibitors of NF- ⁇ B activation.
  • the present method utilizes compositions and formulations of said compounds, including pharmaceutical compositions and formulations of said compounds.
  • the present invention particularly provides methods of treatment of diseases associated with inappropriate NF- ⁇ B activation, which methods comprise administering to an animal, particularly a mammal, most particularly a human in need thereof one or more compounds of Formula I.
  • the present invention particularly provides methods for treating inflammatory and tissue repair disorders, particularly rheumatoid arthritis, inflammatory bowel disease, asthma and COPD (chronic obstructive pulmonary disease) osteoarthritis, osteoporosis and fibrotic diseases; dermatosis, including psoriasis, atopic dermatitis and ultraviolet radiation (UV)-induced skin damage, autoimmune diseases including systemic lupus eythematosus, multiple sclerosis, psoriatic arthritis, alkylosing spondylitis, tissue and organ rejection, Alzheimer's disease, stroke, atherosclerosis, restenosis, diabetes, glornerulonephritis, cancer, including Hodgkins disease, cachexia, inflammation associated with infection and certain viral infections, including aquired immune
  • parenteral administration of one or more compounds of Formula I is useful.
  • the parenteral dose will be about 0.01 to about 50 mg/kg; preferably between 0.1 and 20 mg/kg, in a manner to maintain the concentration of drug in the plasma at a concentration effective to inhibit IKK-beta and therefore activation of NF- B.
  • the compounds are;. administered one to four times daily at a level to achieve a total daily dose of about 0.4 to about 80 mg/kg/day.
  • 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.
  • the oral dose would be about 0.5 to about 20 mg/kg.
  • the compounds of Formulas I may also be administered topically to the patient, in a manner such that the concentration of drug is sufficient to inhibit IKK- beta and therefore activation of NF-kB 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 TNF, IL-l ⁇ , 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 TNF, IL-l ⁇ , IL-6 and IL-8
  • ICAM and VCAM Marui et al., 1993; Kawai et al, 1995; Ledebur and Parks, 1995
  • iNOS inducible nitric oxide synth
  • 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. Evidence for an important role of NF- ⁇ B in inflammatory disorders is obtained in studies of asthmatic patients.
  • Bronchial biopsies taken from mild atopic asthmatics show significant increases in the number of cells in the submucosa staining for activated NF- ⁇ B, total NF- ⁇ B, and NF- ⁇ B -regulated cytokines such as GM-CSF and TNF ⁇ compared to biopsies from normal non-atopic controls (Wilson et al., 1998). Furthermore, the percentage of vessels expressing NF- ⁇ B immunoreactivity is increased as is IL-8 immunoreactivity in the epithelium of the biopsy specimens (Wilson et al., 1998). As such, inhibition of IL-8 production through the inhibition of NF- ⁇ B, as has been demonstrated by these compounds would be predicted be beneficial in airway inflammation.
  • 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 uninflamed 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., 1998).
  • corticosteroid treatment strongly inhibits intestinal NF- ⁇ B activation and reduces colonic inflammation (Ardite et al., 1998; Schreiber et al., 1998). Again, inhibition of IL-8 production through the inhibition of NF- ⁇ B, as has been demonstrated by these compounds would be predicted be beneficial in inflammatory bowel disease.
  • NF- B a key regulator of colonic inflammation.
  • Increased NF- ⁇ B activity is observed in the lamina limbal macrophages in 2,4,6,-trinitrobenzene sulfonic acid (TNBS)-induced colitis in mice with p65 being a major component of the activated complexes (Neurath et al., 1996; Neurath and Pettersson, 1997).
  • TNBS 2,4,6,-trinitrobenzene sulfonic acid
  • 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- KB would be useful in the treatment of D3D.
  • NF- ⁇ B is normally present as an inactive cytoplasmic complex
  • recent immunohistochemical studies have indicated that NF- KB 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 endothelium (Marok et al., 1996).
  • NF- ⁇ B 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-l ⁇ or TNF ⁇ (Roshak et al., 1996; Fujisawa et al., 1996; Roshak et al, 1997).
  • the activation of NF- ⁇ B may underlie the increased cytokine production and leukocyte infiltration characteristic of inflamed synovium.
  • pro-inflammatory mediators e.g. cytokines and prostanoids
  • 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.
  • 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 6 /mL. The cells are harvested by centrifugation, washed in PBS without Ca + and Mg 2+ and resuspended in PBS with Ca 2+ and Mg 2+ at lxlO 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- ⁇ (5.0 ng/mL) for an additional 15 min.
  • DMSO drug or vehicle
  • TNF- ⁇ 5.0 ng/mL
  • Cellular and nuclear extracts are prepared follows. Briefly, at the end of the incubation period the cells (1x10 cells) are washed 2x in PBS without Ca 2+ and Mg 2+ .
  • the resulting cell pellets are resuspended in 20 uL of Buffer A (10 mM Hepes (pH 7.9), 10 mM KCl, 1.5 mM MgCl 2 , 0.5 mM dithiothreitol (DTT) and 0.1% NP-40) and incubated on ice for 10 min.
  • Buffer A 10 mM Hepes (pH 7.9), 10 mM KCl, 1.5 mM MgCl 2 , 0.5 mM dithiothreitol (DTT) and 0.1% NP-40
  • the resulting supernatant was collected as the cellular extract and the nuclear pellet was resuspended in 15 uL Buffer C (20 mM Hepes (pH 7.9), 0.42 M NaCl, 1.5mM MgCl 2 , 25% glycerol, 0.2 mM EDTA, 0.5 mM DTT, and 0.5 mM phenylmethylsulphonyl fluoride (PMSF)).
  • the suspensions are mixed gently for 20 min at 4 °C then microcentrifuged at 14,000 rpm for 10 min at 4 °C.
  • the supernatant is collected and diluted to 60 uL with Buffer D (20mM Hepes (pH 7.9), 50 mM KCl, 20% glycerol, 0.2 mM EDTA, 0.5 mM DTT, and 0.5 mM PMSF). All samples are stored at -80 °C until analyzed. The protein concentration of the extracts is determined according to the method of Bradford (Bradford, 1976) with BioRad reagents.
  • EMS A electrophoretic mobility shift assay
  • The- binding mixtures (10 ug nuclear extract protein) are incubated for 20 min at room temperature with 0.5 ng of 32 P-labelled oligonucleotide (50,000-100,000 cpm) in the presence or absence of unlabeled competitor after which the mixture is loaded on a 4% polyacrylamide gel prepared in IX Tris borate/EDTA and electrophoresed at 200 V for 2 h. Following electrophoresis the gels are dried and exposed to film for detection of the binding reaction. The effect of compounds on the phosphorylation of I ⁇ B may be monitored in a Western blot.
  • Cellular extracts are subjected to sodium dodecyl sulfate- polyacrylamide gel electrophoresis (SDS-PAGE) on 10% gels (BioRad, Hercules, CA) and the proteins transferred to nitrocellulose sheets (Hybond tm -ECL, Amersham Corp., Arlington Heights, IL).
  • Immunoblot assays are performed using a polyclonal rabbit antibody directed against I ⁇ B ⁇ or I ⁇ B ⁇ followed with a peroxidase- conjugated donkey anti-rabbit secondary antibody (Amersham Corp., Arlington Heights, IL). hnmunoreactive bands are detected using the Enchanced Chemiluminescence (ECL) assay system (Amersham Corp., Arlington Heights, IL).
  • IKK- ⁇ was expressed as a hexa-histidine tagged protein in baculovirus-infected insect cells and purified over a Ni-NTA affinity column.
  • Kinase activity was assayed using 50 ng of purified protein in assay buffer (20 mM Hepes, pH 7.7, 2 mM MgCl2, 1 mM MnCl2, 10 mM ⁇ -glycerophosphate, 10 mM NaF, 10 mM PNPP, 0.3 mM Na3VO4, 1 mM benzamidine, 2 ⁇ M PMSF, 10 ⁇ g/ml aprotinin, 1 ug/mL leupeptin, 1 ug/mL pepstatin, lmM DTT) containing various concentrations of compound or DMSO vehicle and ATP as indicated (Pharmacia Biotech Inc., Piscataway, NJ).
  • the reaction was started by the addition of 200 ng IKB-GST (Santa Cruz Biotechnology, Inc., Santa Cruz, CA), in a total volume of 50 uL. The reaction was allowed to proceed for 1 h. at 30 °C after which the reaction was terminated by the addition of EDTA to a final concentration of 20 mM.
  • Kinase activity was determined by dissociation-enhanced lanthanide fluorescence immunoassay (Wallac Oy, Turku, Finland) using a phospho-I ⁇ B- ⁇ (Ser32) antibody (New England Biolabs, Inc., Beverly, MA) and an Eu ⁇ +Tabelled anti-rabbit IgG (Wallac Oy, Turku, Finland).
  • the plates were read in a VICTOR 1420 Multilabel Counter (Wallac), using a standard europium protocol (excitation 340 nm, emission 615 nm; fluorescence measured for 400 ⁇ s after a 400 usec delay). Data are expressed as fluorescence (cps) units.
  • IKK- ⁇ was expressed as a GST-tagged protein, and its activity was assessed in a 96-well scintillation proximity assay (SPA). Briefly, IKK- ⁇ was diluted in assay buffer as described above (20 nM final), with various concentrations of compound or DMSO vehicle, 240 nM ATP and 200 nCi [ ⁇ - 33 P]-ATP (10 mCi/mL, 2000 Ci/mmol; NEN Life Science Products, Boston, MA). The reaction was started with the addition of a biotinylated peptide comprising amino acids 15 - 46 of I ⁇ B- ⁇ (American Peptide) to a final concentration of 2.4 ⁇ M, in a total volume of 50 uL.
  • SPA 96-well scintillation proximity assay
  • IKK- ⁇ inhibitors The effect of IKK- ⁇ inhibitors on primary synovial fibroblast mediator production was assesses as follows: Primary cultures of human RSF were obtained by enzymatic digestion of synovium obtained from adult patients with rheumatoid arthritis as previously described (Roshak et al., 1996b). Cells were cultured in Earl's Minimal Essential Medium (EMEM) which contained 10% fetal bovine serum (FBS), 100 units/ml penicillin and 100 ⁇ g/ml streptomycin (GIBCO, Grand Island, NY), at 37°C and 5% CO2. Cultures were used at passages 4 through 9 in order to obtain a more uniform type B fibroblast population. For some studies, fibroblasts were plated at 5 x 10 ⁇ cells/mL in 16 mm (diameter) 24 well plates (Costar,
  • Isolated monocyte enriched PBMCs were then adhered to 24 well culture plates at 2 x 10 6 cells/mL in RPMI 1640 10% FBS (Hyclone, Logan, Utah) for 2 h. to further enrich the monocyte population. The media was then removed, cells washed once with RPMI 1640, and 1 mL RPMI 1640 10% FBS was added to the wells. Test compounds are added to the wells with a final vehicle concentration of 0.05% DMSO. Monocytes were activated by the addition of 200 ng/mL endotoxin (LPS; E. coli serotype 026:B6)(Sigma, St. Louis, MO.) and incubated for 24 hrs.
  • LPS endotoxin
  • ELIS A for TNF- ⁇ (EIA developed at SB), PGE2 (Cayman Chemical, Ann Arbor, MI), and IL-8 and IL-6 Biosource International, Camarillo, CA). Viability of the cells was determined by trypan blue exclusion. Effect of IKK- ⁇ inhibitors on phorbol ester-induced inflammation was assessed as follows: The inflammatory response induced by the cutaneous application of phorbol ester (PMA) to the external pinnae of Balb/c mice has proven to be a useful model to examine multifactorial inflammatory cell infiltration and inflammatory alteration of epidermis.
  • PMA phorbol ester
  • the intense inflammatory lesion is dominated by neutrophil infiltration, which can be easily quantified by measurement tissue concentration myeloperoxidase, an azuriphilic granular enzyme present in neutrophils.
  • the overall intensity of the inflammatory response can be measured by determination of ear thickness.
  • Nuclear magnetic resonance spectra were recorded at either 250, 300 or 400 MHz using, respectively, a Bruker AM 250, Bruker ARX 300 or Bruker AC 400 spectrometer.
  • CDCI3 is deuteriochloroform
  • DMSO-d6 is hexadeuteriodimethylsulf oxide
  • CD3OD is tetradeuteriomethanol. Chemical shifts are reported in parts per million (d) downfield from the internal standard tetramethylsilane.

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Abstract

La présente invention concerne de nouveaux composés et de nouveaux procédés d'utilisation desdits composés permettant de traiter des maladies au moyen d'inhibiteurs aminoimidazole de la phosphorylation IKK-β de IλB.
PCT/US2001/031865 2000-10-12 2001-10-12 Inhibiteurs du nf-$g(k)b WO2002030423A1 (fr)

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AU2002211662A AU2002211662A1 (en) 2000-10-12 2001-10-12 Nf-kappab inhibitors
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WO2003041640A2 (fr) * 2001-11-09 2003-05-22 The General Hospital Corporation Methodes de traitement d'une lesion d'ischemie-reperfusion au moyen d'inhibiteurs de l'i$g(k)b kinase-$g(b)
US6846834B2 (en) 2000-10-26 2005-01-25 Amgen Inc. Antiinflammation agents
EP1534686A2 (fr) * 2002-05-31 2005-06-01 Michigan State University Inhibiteurs de nf-kb et utilisations de ces inhibiteurs
EP1583528A1 (fr) * 2003-01-17 2005-10-12 Michigan State University Inhibiteurs de nf-kb et leurs utilisations
WO2007005534A2 (fr) 2005-06-30 2007-01-11 Smithkline Beecham Corporation Composes chimiques
US7176314B2 (en) 2001-12-05 2007-02-13 Amgen, Inc. Inflammation modulators
US7199119B2 (en) 2002-10-31 2007-04-03 Amgen Inc. Antiinflammation agents
WO2008118724A1 (fr) 2007-03-23 2008-10-02 Smithkline Beecham Corporation Indole carboxamides en tant qu'inhibiteurs d'ikk2
WO2009132050A2 (fr) 2008-04-21 2009-10-29 Otonomy, Inc. Préparations auriculaires de traitement de maladies et états otiques
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
US7858796B2 (en) 2004-09-21 2010-12-28 Glaxo Group Limited Chemical compounds
US8063071B2 (en) 2007-10-31 2011-11-22 GlaxoSmithKline, LLC Chemical compounds
US8354539B2 (en) 2009-03-10 2013-01-15 Glaxo Group Limited Indole derivatives as IKK2 inhibitors
US8501780B2 (en) 2004-06-24 2013-08-06 Glaxosmithkline Llc Indazole carboxamides and their use
US8552206B2 (en) 2002-05-31 2013-10-08 Board Of Trustees Of Michigan State University NF-κB inhibitors and uses thereof
US10821185B2 (en) 2016-06-29 2020-11-03 Otonomy Inc. Triglyceride otic formulations and uses thereof
US11969501B2 (en) 2008-04-21 2024-04-30 Dompé Farmaceutici S.P.A. Auris formulations for treating otic diseases and conditions

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Cited By (31)

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US6846834B2 (en) 2000-10-26 2005-01-25 Amgen Inc. Antiinflammation agents
US7186841B2 (en) 2000-10-26 2007-03-06 Amgen Inc. Antiinflammation agents
WO2003041640A3 (fr) * 2001-11-09 2003-12-31 Gen Hospital Corp Methodes de traitement d'une lesion d'ischemie-reperfusion au moyen d'inhibiteurs de l'i$g(k)b kinase-$g(b)
WO2003041640A2 (fr) * 2001-11-09 2003-05-22 The General Hospital Corporation Methodes de traitement d'une lesion d'ischemie-reperfusion au moyen d'inhibiteurs de l'i$g(k)b kinase-$g(b)
US7176314B2 (en) 2001-12-05 2007-02-13 Amgen, Inc. Inflammation modulators
EP1534686B1 (fr) * 2002-05-31 2009-05-20 Michigan State University Inhibiteurs de nf-kb et utilisations de ces inhibiteurs
EP1534686A2 (fr) * 2002-05-31 2005-06-01 Michigan State University Inhibiteurs de nf-kb et utilisations de ces inhibiteurs
US8552206B2 (en) 2002-05-31 2013-10-08 Board Of Trustees Of Michigan State University NF-κB inhibitors and uses thereof
US7635695B2 (en) 2002-10-31 2009-12-22 Amgen Inc. Antiinflammation agents
US7199119B2 (en) 2002-10-31 2007-04-03 Amgen Inc. Antiinflammation agents
EP1583528A1 (fr) * 2003-01-17 2005-10-12 Michigan State University Inhibiteurs de nf-kb et leurs utilisations
EP1583528A4 (fr) * 2003-01-17 2009-10-21 Univ Michigan State Inhibiteurs de nf-kb et leurs utilisations
US8501780B2 (en) 2004-06-24 2013-08-06 Glaxosmithkline Llc Indazole carboxamides and their use
US7858796B2 (en) 2004-09-21 2010-12-28 Glaxo Group Limited Chemical compounds
WO2007005534A2 (fr) 2005-06-30 2007-01-11 Smithkline Beecham Corporation Composes chimiques
US8354406B2 (en) 2005-06-30 2013-01-15 Glaxosmithkline Llc Chemical compounds
US8372875B2 (en) 2007-03-23 2013-02-12 GlaxoSmithKline, LLC Indole carboxamides as IKK2 inhibitors
US8071584B2 (en) 2007-03-23 2011-12-06 Glaxosmithkline Llc Indole carboxamides as IKK2 inhibitors
WO2008118724A1 (fr) 2007-03-23 2008-10-02 Smithkline Beecham Corporation Indole carboxamides en tant qu'inhibiteurs d'ikk2
US8063071B2 (en) 2007-10-31 2011-11-22 GlaxoSmithKline, LLC Chemical compounds
WO2009132050A2 (fr) 2008-04-21 2009-10-29 Otonomy, Inc. Préparations auriculaires de traitement de maladies et états otiques
US9132087B2 (en) 2008-04-21 2015-09-15 Otonomy, Inc. Auris formulations for treating otic diseases and conditions
US10272034B2 (en) 2008-04-21 2019-04-30 Otonomy, Inc. Auris formulations for treating otic diseases and conditions
US10751281B2 (en) 2008-04-21 2020-08-25 Otonomy, Inc. Auris formulations for treating otic diseases and conditions
US11123285B2 (en) 2008-04-21 2021-09-21 Otonomy, Inc. Auris formulations for treating OTIC diseases and conditions
US11123286B2 (en) 2008-04-21 2021-09-21 Otonomy, Inc. Auris formulations for treating otic diseases and conditions
US11969501B2 (en) 2008-04-21 2024-04-30 Dompé Farmaceutici S.P.A. Auris formulations for treating otic diseases and conditions
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
US8299055B2 (en) 2008-10-02 2012-10-30 Asahi Kasei Pharma Corporation 8-substituted isoquinoline derivative and the use thereof
US8354539B2 (en) 2009-03-10 2013-01-15 Glaxo Group Limited Indole derivatives as IKK2 inhibitors
US10821185B2 (en) 2016-06-29 2020-11-03 Otonomy Inc. Triglyceride otic formulations and uses thereof

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