WO2008002246A1 - Composition pharmaceutique comprenant un inhibiteur de la ikk2 et un second ingrédient actif - Google Patents

Composition pharmaceutique comprenant un inhibiteur de la ikk2 et un second ingrédient actif Download PDF

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Publication number
WO2008002246A1
WO2008002246A1 PCT/SE2007/000622 SE2007000622W WO2008002246A1 WO 2008002246 A1 WO2008002246 A1 WO 2008002246A1 SE 2007000622 W SE2007000622 W SE 2007000622W WO 2008002246 A1 WO2008002246 A1 WO 2008002246A1
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alkyl
group
amino
aminocarbonyl
inhibitor
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PCT/SE2007/000622
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English (en)
Inventor
Paul Andersson
Lena BÖRJESSON
Christina Eriksson
Joakim Larsson
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Astrazeneca Ab
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics

Definitions

  • a pharmaceutical composition comprising an IKK2 inhibitor and a second active ingrdient.
  • the present invention relates to combinations of pharmaceutically active substances for use in the treatment of inflammatory disorders, particularly respiratory disorders, especially chronic obstructive pulmonary disease (COPD) and asthma.
  • COPD chronic obstructive pulmonary disease
  • Respiratory diseases include Acute Lung Injury, Acute Respiratory Distress Syndrome (ARDS), occupational lung disease, lung cancer, tuberculosis, fibrosis, pneumoconiosis, pneumonia, emphysema, Chronic Obstructive Pulmonary Disease (COPD) and asthma.
  • ARDS Acute Respiratory Distress Syndrome
  • COPD Chronic Obstructive Pulmonary Disease
  • Asthma is generally defined as an inflammatory disorder of the airways with clinical symptoms arising from intermittent airflow obstruction. It is characterised clinically by paroxysms of wheezing, dyspnea and cough. It is a chronic disabling disorder that appears to be increasing in prevalence and severity. It is estimated that 15% of children and 5% of adults in the population of developed countries suffer from asthma. Therapy should therefore be aimed at controlling symptoms so that normal life is possible and at the same time provide basis for treating the underlying inflammation.
  • COPD is a term which refers to a large group of lung diseases which can interfere with normal breathing.
  • Current clinical guidelines define COPD as a disease state characterized by airflow limitation that is not fully reversible.
  • the airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles and gases.
  • the most important contributory source of such particles and gases is tobacco smoke.
  • COPD patients have a variety of symptoms, including cough, shortness of breath, and excessive production of sputum; such symptoms arise from dysfunction of a number of cellular compartments, including neutrophils, macrophages, and epithelial cells.
  • the two most important conditions covered by COPD are chronic bronchitis and emphysema.
  • Chronic bronchitis is a long-standing inflammation of the bronchi which causes increased production of mucous and other changes. The patients' symptoms are cough and expectoration of sputum. Chronic bronchitis can lead to more frequent and severe respiratory infections, narrowing and plugging of the bronchi, difficult breathing and disability.
  • Emphysema is a chronic lung disease which affects the alveoli and/or the ends of the smallest bronchi.
  • the lung loses its elasticity and therefore these areas of the lungs become enlarged. These enlarged areas trap stale air and do not effectively exchange it with fresh air. This results in difficult breathing and may result in insufficient oxygen being delivered to the blood.
  • the predominant symptom in patients with emphysema is shortness of breath.
  • WO 01/58890, WO 03/010158, WO 03/010163, WO 04/063185 and WO 04/063186 disclose compounds having activity as pharmaceuticals, in particular as inhibitors of IKK2, processes and intermediates used in their preparation, pharmaceutical compositions containing them and their use in therapy.
  • O 02/024679 and WO 02/044153 disclose pyridine derivatives, for example,
  • WO 04/092167 andUS20050239781 disclose beta-carboline derivatives, for example,
  • WO 02/30353, WO 03/02942 and WO 04/053087 disclose thiophene derivatives having IKK2 inhibitory activity.
  • WO 04/022553 discloses indole and benzimidazole derivatives, for example,
  • WO 04/106293 and WO 05/011609 disclose fused tricyclic compounds, for example,
  • IKB kinase 2 (IKK2) is a serine-threonine kinase which is a key regulator of the activity and function of NF- ⁇ B.
  • NF- ⁇ B is a key regulator of inflammatory genes and plays a critical role in the pathogenesis of a number of human disorders, particularly those with an inflammatory component.
  • a large number of the mediators known to be involved in the inflammatory response in COPD are regulated by NF- ⁇ B and in addition Phospho-I ⁇ B ⁇ and activity of NF- ⁇ B is increased in lung tissue of COPD patients compared to non- COPD patients.
  • inflammatory cells for example, neutrophils and monocytes/macrophages
  • inflammatory cells contribute to the pathogenesis of respiratory diseases such as COPD by secretion of proteolytic enzymes, oxidants and pharmacologic mediators.
  • proteolytic enzymes for example, oxidants and pharmacologic mediators.
  • an unexpectedly beneficial therapeutic effect may be observed in the treatment of inflammatory diseases, particularly respiratory diseases, if an IKK2 inhibitor is used in combination with one or more other active agents.
  • the combinations according to the invention are considered to be particularly effective in reducing inflammatory cell influx into the lung.
  • the beneficial effect may be observed when the two or more active substances are administered simultaneously (either in a single pharmaceutical preparation or via separate preparations), or sequentially or separately via separate pharmaceutical preparations. Disclosure of the Invention
  • a pharmaceutical product comprising, in combination,
  • Inhibitors of IKK2 may be detected using a suitable in vitro assay such as the SPA kinase assay disclosed herein.
  • the first active ingredient may be, for example, any of the compounds disclosed in WO 01/58890, WO 03/010158, WO 03/010163, WO 04/063185 and WO 04/063186, the contents of which are incorporated herein in their entirety.
  • the first active ingredient may be any compound previously disclosed in the art as having IKK2 inhibitory activity including, for example, compounds disclosed in WO 02/024679, WO 02/044153, WO 04/092167, US20050239781, WO 02/30353, WO 03/02942, WO 04/053087, WO 04/022553, WO 04/106293 and WO 05/011609.
  • the first active ingredient is a compound of formula (I)
  • R represents NH2 or R represents a methyl group optionally substituted by one or more groups selected independently from Cj-C 4 alkyl, C 3 -Cg cycloalkyl, halogen, hydroxyl,
  • X represents O or S
  • R represents hydrogen, halogen, cyano, nitro, -NR R , -CONR R , -COOR , -NR 6 COR 7 , -S(O) 1n R 6 , -SO 2 NR 6 R 7 , -NR 6 SO 2 R 7 , Ci-C 2 alkyl, trifluoromethyl, C2-C3 alkenyl, C2-C3 alkynyl, trifluoromethoxy, Cj-C 2 alkoxy or Ci-C 2 alkanoyl;
  • A represents a phenyl ring or a 5- to 7-membered heteroaromatic ring containing one to three heteroatoms selected independently from O, N and S; said phenyl or heteroaromatic ring being optionally substituted by one or more substituents selected independently from halogen, cyano, nitro, -NR 8 R 9 , -CONR 8 R 9 , -COOR 8 , -NR 8 COR 9 , -S(O) 5 R 8 , o Q o q i n 1 1
  • n an integer 1 or 2; and when n represents 2, each R group may be selected independently;
  • R represents a group -W-Y-Z wherein:
  • W represents O, S(O) 1 , NR 13 , CH 2 , -CH 2 -O- or a bond;
  • Y represents a bond or a group -(CH2) p -T-(CH 2 )q- wherein p and q independently
  • 14 15 represent an integer 0, 1 or 2; and T represents O, -CO- or CR R ; 14 15
  • R and R independently represent H, CH3 or F
  • R represents H or CH3 and R represents hydroxyl or OCH3;
  • a 3- to 8-membered saturated or partially unsaturated monocyclic or saturated bicyclic ring system optionally incorporating one or two heteroatoms selected independently from O, N and S, and optionally incorporating a carbonyl group; said ring system being optionally substituted by one or more substituents selected independently from halogen, cyano, -NR 16 R 17 , -CONR 16 R 17 , -COOR 16 , -COR 16 , -NR 16 COR 17 , -S(O) n R 16 , -SO 2 NR 16 R 17 , -NR 16 SO 2 R 17 hydroxyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyl,
  • R is hydrogen or Ci-Cg alkyl; or R and R independently represent Cj-Cg alkoxy;
  • R and R independently represent H or Cj -C4 alkyl; or the group NR R represents a
  • R is hydrogen or C1-C4 alkyl; independently represent H or C1-C2 alkyl;
  • R , R and R independently represent H or Cj-Cg alkyl
  • R represents H or C1-C4 alkyl
  • R and R independently represent H or Ci-Cg alkyl optionally substituted by OH
  • R is hydrogen or Ci-Cg alkyl optionally substituted by OH, C1-C4 alkoxy or one or more fluoro atoms; R and R independently represent H or C 1-C4 alkyl; or the group NR R represents a
  • R is hydrogen or C1-C4 alkyl
  • n, r, s, u and v independently represent an integer 0, 1 or 2;
  • t represents an integer 2, 3 or 4;
  • Certain compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of the compounds of formula (I) and mixtures thereof including racemates. Tautomers and mixtures thereof also form an aspect of the present invention.
  • the invention provides compounds of formula (I) wherein Z represents:
  • Z may also represent hydroxyl, OCH3, CF3, CHF 2 or CH 2 F, provided that the group -Y-Z does not thereby represent — O-(CH 2 ) 2 _4-OCH3; and all other substituents are as defined above.
  • X in formula (I) represents oxygen
  • R in formula (I) represents NH 2 .
  • the group A in formula (I) is a phenyl group or a 5- to 7-membered heteroaromatic ring containing one to three heteroatoms selected independently from O, N and S; said phenyl or heteroaromatic ring being optionally substituted by one or more
  • A represents optionally substituted phenyl. In another embodiment, A represents an optionally substituted pyridyl.
  • the group R in formula (I) represents H, halogen or
  • the group R represents H or methyl.
  • the group R in formula (I) represents H.
  • W in formula (I) represents O, CH2 or a bond.
  • Y in formula (I) represents -CH2— CH2- or a bond.
  • Z in formula (I) represents a 3- to 8-membered saturated or partially unsaturated monocyclic or saturated bicyclic ring system optionally incorporating one or two heteroatoms selected independently from O, N and S, and optionally incorporating a carbonyl group; said ring system being optionally substituted by one or more substituents selected independently from halogen, cyano, -NR R , -CONR R , -COOR 16 , -COR 16 , -NR 16 COR 17 , -S(O) U R 16 , -SO 2 NR 16 R 17 , -NR 16 SO 2 R 17 , hydroxyl,
  • Z in formula (I) represents a phenyl ring or a 5- or 6-membered heteroaromatic ring containing one to three heteroatoms selected independently from O, N and S; said phenyl or heteroaromatic ring being optionally substituted by one or more
  • 16 17 16 17 substit ⁇ ents selected independently from halogen, cyano, -NR R , -CONR R , -COOR 16 , -COR 16 -NR 16 COR 17 , -S(O) 11 R 16 , -SO 2 NR 16 R 17 , -NR 16 SO 2 R 17 , hydroxyl,
  • n has the value 1.
  • the first active ingredient is a compound that is specifically exemplified in WO 03/010158, namely a compound selected from:
  • Ci-Cg alkyl referred to herein denotes a straight or branched chain alkyl group having from 1 to 6 carbon atoms. Examples of such groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl and t-butyl.
  • C1-C2 alkyl and “C1-C4 alkyl” are to be interpreted analogously.
  • C2-C3 alkenyl referred to herein denotes a straight or branched chain alkyl group having 2 or 3 carbon atoms incorporating at least one carbon-carbon double bond. Examples of such groups include ethenyl and propenyl.
  • C2-C6 alkenyl is to be interpreted analogously.
  • C2-C3 alkynyl denotes a straight chain alkyl group having 2 or 3 carbon atoms incorporating one carbon-carbon triple bond. Examples of such groups include ethynyl and propynyl.
  • C2-Cg alkynyl is to be interpreted analogously.
  • C3-C6 cycloalkyl denotes a saturated carbocyclic ring having from 3 to 6 carbon atoms. Examples of such groups include cyclopropyl, cyclopentyl and cyclohexyl.
  • C1-C4 alkoxy referred to herein denotes a straight or branched chain alkoxy group having 1 to 4 carbon atoms. Examples of such groups include methoxy, ethoxy and isopropoxy.
  • C1-C2 alkoxy and “Ci -Cg alkoxy” are to be interpreted analogously,
  • C 1 -C 2 alkanoyl referred to herein denotes a formyl or acetyl group.
  • halogen referred to herein denotes fluoro, chloro, bromo and iodo.
  • Examples of a 5- to 7-membered heteroaromatic ring containing one to three heteroatoms selected independently from O, N and S include furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, triazole, pyridine, pyridazine, pyrimidine and pyrazine.
  • Examples of a 3- to 8-membered saturated or partially unsaturated monocyclic or saturated bicyclic ring system optionally incorporating one or two heteroatoms selected independently from O, N and S, and optionally incorporating a carbonyl group include cyclopropyl, cyclopentyl, cyclohexyl, tetrahydrofuran, tetrahydropyran, pyrrolidine, 3-pyrroline, piperidine, piperazine, 8-oxa-3-azabicyclo[3.2.1]octane, pyrrolidone, 2-oxa-5-azabicyclo[2.2.1 ]heptane, 1 ,4-oxazepane, 2,5-diazabicyclo[2.2.1 ]heptane, piperidone and morpholine.
  • Examples of a 5- or 6-membered saturated azacyclic ring optionally containing a further O, S or NR group include pyrrolidine, piperidine, piperazine and morpholine.
  • the second active ingredient in the combination of the present invention may be a non-steroidal anti-inflammatory agent (hereinafter NSAID) including non-selective cyclo- oxygenase COX-I / COX-2 inhibitors whether applied topically or systemically (such as piroxicam, diclofenac, propionic acids such as naproxen, flurbiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac, azapropazone, pyrazolones such as phenylbutazone, salicylates such as aspirin); selective COX-2 inhibitors (such as meloxicam, celecoxib, rofecoxib, valdecoxib, lumarocoxib, parecoxib and etoricoxib); cyclo-oxygenase inhibiting nitric oxide donors (CINODs); glucocor
  • the second active ingredient in the combination of the present invention may alternatively be a cytokine or agonist or antagonist of cytokine function, (including agents which act on cytokine signalling pathways such as modulators of the SOCS system) including alpha-, beta-, and gamma-interferons; insulin-like growth factor type I (IGF-I); interleukins (IL) including ILl to 23, and interleukin antagonists or inhibitors such as anakinra; tumour necrosis factor alpha (TNF- ⁇ ) inhibitors such as anti-TNF monoclonal antibodies (for example infliximab; adalimumab, and CDP-870) and TNF receptor antagonists including immunoglobulin molecules (such as etanercept) and low-molecular-weight agents such as pentoxyfylline.
  • cytokine or agonist or antagonist of cytokine function including agents which act on cytokine signalling pathways such as modulators of the SOCS system
  • the second active ingredient in the combination of the present invention may alternatively be a monoclonal antibody targeting B-Lymphocytes (such as CD20 (rituximab), MRA- aIL16R and T-Lymphocytes, CTLA4-Ig, HuMax 11-15).
  • B-Lymphocytes such as CD20 (rituximab), MRA- aIL16R and T-Lymphocytes, CTLA4-Ig, HuMax 11-15.
  • the second active ingredient in the combination of the present invention may alternatively be a modulator of chemokine receptor function such as an antagonist of CCRl, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCRlO and CCRl 1 (for the C-C family); CXCRl, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-C family) and CX 3 CRl for the C-X 3 -C family.
  • chemokine receptor function such as an antagonist of CCRl, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCRlO and CCRl 1 (for the C-C family); CXCRl, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-C family) and CX 3 CRl for the C-X 3
  • the second active ingredient in the combination of the present invention may alternatively be an inhibitor of matrix metalloprotease (MMPs), i.e., the stromelysins, the collagenases, and the gelatinases, as well as aggrecanase; especially collagenase-1 (MMP-I), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-IO) 3 and stromelysin-3 (MMP-Il) and MMP-9 and MMP- 12, including agents such as doxycycline.
  • MMPs matrix metalloprotease
  • the second active ingredient in the combination of the present invention may alternatively be a leukotriene biosynthesis inhibitor, 5-lipoxygenase (5-LO) inhibitor or 5-lipoxygenase activating protein (FLAP) antagonist such as; zileuton; ABT-761; fenleuton; tepoxalin; Abbott-79175; Abbott-85761; aN-(5-substituted)-thiophene-2-alkylsulfonamide; 2,6-di- tert-butylphenolhydrazones; a methoxytetrahydropyrans such as Zeneca ZD-2138; the compound SB-210661; a pyridinyl-substi ⁇ uted 2-cyanonaphthalene compound such as L- 739,010; a 2-cyanoquinoline compound such as L-746,530; or an indole or quinoline compound such as MK-591, MK-886, and BAY x 1005.
  • the second active ingredient in the combination of the present invention may alternatively be a receptor antagonist for leukotrienes (LT) B4, LTC4, LTD4, and LTE4.
  • LT leukotrienes
  • LTC4, LTD4 leukotrienes
  • LTE4 leukotrienes
  • phenothiazin-3-ls such as L-651,392
  • amidino compounds such as CGS-25019c
  • benzoxalamines such as ontazolast
  • benzenecarboximidamid.es such as BIIL 284/260
  • compounds such as zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP 45715A), and BAY x 7195.
  • the second active ingredient in the combination of the present invention may alternatively be a phosphodiesterase (PDE) inhibitor such as a methylxanthanine including theophylline and aminophylline; a selective PDE isoenzyme inhibitor including a PDE4 inhibitor an inhibitor of the isoform PDE4D, or an inhibitor of PDE5.
  • PDE phosphodiesterase
  • the second active ingredient in the combination of the present invention may alternatively be a histamine type 1 receptor antagonist such as cetirizine, loratadine, desloratadine, fexofenadine, acrivastine, terfenadine, astemizole, azelastine, levocabastine, chlorpheniramine, promethazine, cyclizine, or mizolastine; applied orally, topically or parenterally.
  • a histamine type 1 receptor antagonist such as cetirizine, loratadine, desloratadine, fexofenadine, acrivastine, terfenadine, astemizole, azelastine, levocabastine, chlorpheniramine, promethazine, cyclizine, or mizolastine
  • the second active ingredient in the combination of the present invention may alternatively be a proton pump inhibitor (such as omeprazole) or a gastroprotective histamine type 2 receptor antagonist.
  • the second active ingredient in the combination of the present invention may alternatively be an antagonist of the histamine type 4 receptor.
  • the second active ingredient in the combination of the present invention may alternatively be an alpha- l/alpha-2 adrenoceptor agonist vasoconstrictor sympathomimetic agent, such as propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, tramazoline hydrochloride or ethylnorepinephrine hydrochloride.
  • an alpha- l/alpha-2 adrenoceptor sympathomimetic agent such as propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydroch
  • the second active ingredient in the combination of the present invention may alternatively be an anticholinergic agents including muscarinic receptor (Ml, M2, andM3) antagonist such as atropine, hyoscine, glycopyrrrolate, ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine.
  • Ml, M2, andM3 antagonist such as atropine, hyoscine, glycopyrrrolate, ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine.
  • the second active ingredient in the combination of the present invention may alternatively be a heta-adrenoceptor agonist (including beta receptor subtypes 1-4) such as isoprenaline, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, indacaterol or pirbuterol, or a chiral enantiomer thereof.
  • a heta-adrenoceptor agonist including beta receptor subtypes 1-4
  • the second active ingredient in the combination of the present invention may alternatively be a chromone, such as sodium cromoglycate or nedocromil sodium.
  • the second active ingredient in the combination of the present invention may alternatively be a glucocorticoid, such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, fluticasone furoate, ciclesonide or mometasone furoate.
  • glucocorticoid such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, fluticasone furoate, ciclesonide or mometasone furoate.
  • the second active ingredient in the combination of the present invention may alternatively be an agent that modulates a nuclear hormone receptor such as PPARs.
  • the second active ingredient in the combination of the present invention may alternatively be an immunoglobulin (Ig) or Ig preparation or an antagonist or antibody modulating Ig function such as anti-IgE (for example omalizumab).
  • Ig immunoglobulin
  • Ig preparation or an antagonist or antibody modulating Ig function such as anti-IgE (for example omalizumab).
  • anti-IgE for example omalizumab
  • the second active ingredient in the combination of the present invention may alternatively be another systemic or topically-applied anti-inflammatory agent, such as thalidomide or a derivative thereof, a retinoid, dithranol or calcipotriol.
  • another systemic or topically-applied anti-inflammatory agent such as thalidomide or a derivative thereof, a retinoid, dithranol or calcipotriol.
  • the second active ingredient in the combination of the present invention may alternatively be a combination of aminosalicylates and sulfapyridine such as sulfasalazine, mesalazine, balsalazide, and olsalazine; and immunomodulatory agents such as the thiopurines, and corticosteroids such as budesonide.
  • aminosalicylates and sulfapyridine such as sulfasalazine, mesalazine, balsalazide, and olsalazine
  • immunomodulatory agents such as the thiopurines, and corticosteroids such as budesonide.
  • the second active ingredient in the combination of the present invention may alternatively be an antibacterial agent such as a penicillin derivative, a tetracycline, a macrolide, a beta- lactam, a fluoroquinolone, metronidazole, an inhaled aminoglycoside; an antiviral agent including acyclovir, famciclovir, valaciclovir, ganciclovir, cidofovir, amantadine, rimantadine, ribavirin, zanamavir and oseltamavir; a protease inhibitor such as indinavir, nelfinavir, ritonavir, and saquinavir; a nucleoside reverse transcriptase inhibitor such as didanosine, lamivudine, stavudine, zalcitabine or zidovudine; or a non-nucleoside reverse transcriptase inhibitor such as nevirapine or e
  • the second active ingredient in the combination of the present invention may alternatively be a cardiovascular agent such as a calcium channel blocker, a beta-adrenoceptor blocker, an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin-2 receptor antagonist; a lipid lowering agent such as a statin or a fibrate; a modulator of blood cell morphology such as pentoxyfylline; thrombolytic, or an anticoagulant such as a platelet aggregation inhibitor.
  • a cardiovascular agent such as a calcium channel blocker, a beta-adrenoceptor blocker, an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin-2 receptor antagonist
  • ACE angiotensin-converting enzyme
  • angiotensin-2 receptor antagonist an angiotensin-2 receptor antagonist
  • a lipid lowering agent such as a statin or a fibrate
  • a modulator of blood cell morphology such as pentoxyfylline
  • the second active ingredient in the combination of the present invention may alternatively be a CNS agent such as an antidepressant (such as sertraline), an anti-Parkinsonian drug (such as deprenyl, L-dopa, ropinirole, pramipexole, a MAOB inhibitor such as selegine and rasagiline, a comP inhibitor such as tasmar, an A-2 inhibitor, a dopamine reuptake inhibitor, an NMDA antagonist, a nicotine agonist, a dopamine agonist or an inhibitor of neuronal nitric oxide synthase), or an anti- Alzheimer's drug such as donepezil, rivastigmine, tacrine, a COX-2 inhibitor, propentofylline or metrifonate.
  • an antidepressant such as sertraline
  • an anti-Parkinsonian drug such as deprenyl, L-dopa, ropinirole, pramipexole, a MAOB
  • the second active ingredient in the combination of the present invention may alternatively be an agent for the treatment of acute or chronic pain, such as a centrally or peripherally- acting analgesic (for example an opioid or derivative thereof), carbamazepine, phenytoin, sodium valproate, amitryptiline or other anti-depressant agent-s, paracetamol, or a nonsteroidal anti-inflammatory agent.
  • analgesic for example an opioid or derivative thereof
  • carbamazepine for example an opioid or derivative thereof
  • phenytoin for example an opioid or derivative thereof
  • sodium valproate for example an opioid or derivative thereof
  • amitryptiline or other anti-depressant agent-s sodium valproate
  • paracetamol paracetamol
  • nonsteroidal anti-inflammatory agent such as lignocaine or a derivative thereof.
  • the second active ingredient in the combination of the present invention may alternatively be an anti-osteoporosis agent including a hormonal agent such as raloxifene, or a biphosphonate such as alendronate.
  • a hormonal agent such as raloxifene
  • a biphosphonate such as alendronate
  • the second active ingredient in the combination of the present invention may alternatively be a: (i) tryptase inhibitor; (ii) platelet activating factor (PAF) antagonist; (iii) interleukin converting enzyme (ICE) inhibitor; (iv) MPDH inhibitor; (v) adhesion molecule inhibitors including VLA-4 antagonist; (vi) cathepsin; (vii) kinase inhibitor such as an inhibitor of tyrosine kinase (such as Btk, Itk, Jak3 or MAP, for example Gefitinib or Imatinib mesylate), a serine / threonine kinase (such as an inhibitor of a MAP kinase such as p38, JNK, protein kinase A, B or C), or a kinase involved in cell cycle regulation (such as a cylin dependent kinase); (viii) glucose-6 phosphate dehydrogenase inhibitor; (ix
  • -receptor antagonist for example colchicine
  • anti-gout agent for example colchicine
  • xanthine oxidase inhibitor for example allopurinol
  • uricosuric agent for example probenecid, sulfinpyrazone or benzbromarone
  • growth hormone secretagogue for example transforming growth factor (TGF ⁇ );
  • PDGF platelet-derived growth factor
  • fibroblast growth factor for example basic fibroblast growth factor (bFGF);
  • GM-CSF granulocyte macrophage colony stimulating factor
  • capsaicin cream for example tachykinin NK.subl.
  • NKP-608C, SB-233412 (talnetant) or D-4418 receptor antagonist
  • elastase inhibitor such as UT-77 or ZD-0892
  • TACE TNF-alpha converting enzyme inhibitor
  • iNOS induced nitric oxide synthase
  • inhibitor of P38 agent modulating the function of Toll-like receptors (TLR),
  • agent modulating the activity of purinergic receptors such as P2X7; or
  • inhibitor of transcription factor activation such as NFkB, API, or STATS.
  • the second active ingredient in the combination of the present invention may alternatively be an existing therapeutic agent for the treatment of cancer, for example suitable agents include:
  • an antiproliferative/antineoplastic drug or a combination thereof, as used in medical oncology such as an alkylating agent (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan or a nitrosourea); an antimetabolite (for example an antifolate such as a fluoropyrimidine like 5-fluorouracil or tegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea, gemcitabine or paclitaxel); an antitumour antibiotic (for example an anthracycline such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycm or mithramycin); an antimitotic agent (for example a vinca alkaloid such as
  • an agent which inhibits cancer cell invasion for example a metalloproteinase inhibitor like marimastat or an inhibitor of urokinase plasminogen activator receptor function
  • an inhibitor of growth factor function for example: a growth factor antibody (for example the anti-erbb2 antibody trastuzumab, or the anti-erbbl antibody cetuximab
  • a farnesyl transferase inhibitor for example an EGFR family tyrosine kinase inhibitor such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3- morpholrnopropoxy)qumazolin-4-amine (gei ⁇ tinib, AZD 1839), N-(3-ethynylphenyl)-6,7- bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) or 6-acrylamido-N-(3- chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine (CI 1033)), an inhibitor of the platelet-derived growth factor family, or an inhibitor of the hepatocyte growth
  • an inhibitor of the epidermal growth factor family for example an EGFR family tyrosine kinase inhibitor such as N-(3-chloro-4-fluorophen
  • an antiangiogenic agent such as one which inhibits the effects of vascular endothelial growth factor (for example the anti-vascular endothelial cell growth factor antibody bevacizumab, a compound disclosed in WO 97/22596, WO 97/30035, WO 97/32856 or WO 98/13354), or a compound that works by another mechanism (for example linomide, an inhibitor of integrin ⁇ v ⁇ 3 function or an angiostatin);
  • vascular endothelial growth factor for example the anti-vascular endothelial cell growth factor antibody bevacizumab, a compound disclosed in WO 97/22596, WO 97/30035, WO 97/32856 or WO 98/13354
  • a compound that works by another mechanism for example linomide, an inhibitor of integrin ⁇ v ⁇ 3 function or an angiostatin
  • vascular damaging agent such as combretastatin A4, or a compound disclosed in WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 or WO 02/08213;
  • an agent used in antisense therapy for example one directed to one of the targets listed above, such as ISIS 2503, an anti-ras antisense;
  • an agent used in a gene therapy approach for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; or (ix) an agent used in an immunotherapeutic approach, for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies.
  • GDEPT gene-directed enzyme pro-drug therapy
  • the second active ingredient in the combination of the present invention is selected from: a) a PDE4 inhibitor including an inhibitor of the isoform PDE4D; b) a ⁇ -adrenoceptor agonist such as metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, pirbuterol or indacaterol; c) a muscarinic receptor antagonist (for example a Ml, M2 or M3 antagonist, such as a selective M3 antagonist) such as ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine; d) a modulator of chemokine receptor function (such as a CCRl or CCR8 receptor antagonist); e) an inhibitor of p38 kina
  • any reference to a second active ingredient includes all active salts, solvates or derivatives thereof.
  • the pharmaceutical product of the present invention may, for example, be a pharmaceutical composition comprising the first and second active ingredients in admixture.
  • the pharmaceutical product may, for example, be a kit comprising a preparation of the first active ingredient and a preparation of the second active ingredient and, optionally, instructions for the simultaneous, sequential or separate administration of the preparations to a patient in need thereof.
  • the combinations of the present invention can be used in the treatment of inflammatory conditions.
  • obstructive diseases of the airways including: asthma, including bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including aspirin and NSAID-induced) and dust-induced asthma, both intermittent and persistent and of all severities, and other causes of airway hyper-responsiveness; chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; farmer's lung and related diseases; hypersensitivity pneumonitis; lung fibrosis, including cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonias, fibrosis complicating anti-neoplastic therapy and chronic infection, including tuberculosis and aspergillosis and other fungal infections; complications of lung transplantation; vascul
  • the combinations of the present invention can also be used in the treatment of diseases of bone and joints such as arthritides associated with or including steoarthritis/osteoarthrosis, both primary and secondary to, for example, congenital hip dysplasia; cervical and lumbar spondylitis, and low back and neck pain; rheumatoid arthritis and Still's disease; seronegative spondyloarthropathies including ankylosing spondylitis, psoriatic arthritis, reactive arthritis and undifferentiated spondarthropathy; septic arthritis and other infection- related arthopathies and bone disorders such as tuberculosis, including Potts' disease and Poncet's syndrome; acute and chronic crystal-induced synovitis including urate gout, calcium pyrophosphate deposition disease, and calcium apatite related tendon, bursal and synovial inflammation; Behcet's disease; primary and secondary Sjogren's syndrome; systemic sclerosis and limited sclero
  • the combinations of the present invention can also be used in the treatment of pain and connective tissue remodelling of musculoskeletal disorders due to injury [for example, sports injury] or disease: arthitides (for example rheumatoid arthritis, osteoarthritis, gout or crystal arthropathy), other joint disease (such as intervertebral disc degeneration or temporomandibular joint degeneration), bone remodelling disease (such as osteoporosis, Paget's disease or osteonecrosis), polychondritits, scleroderma, mixed connective tissue disorder, spondyloarthropathies or periodontal disease (such as periodontitis).
  • arthitides for example rheumatoid arthritis, osteoarthritis, gout or crystal arthropathy
  • other joint disease such as intervertebral disc degeneration or temporomandibular joint degeneration
  • bone remodelling disease such as osteoporosis, Paget's disease or osteonecrosis
  • the combinations of the present invention can also be used in the treatment of diseases of skin such as psoriasis, atopic dermatitis, contact dermatitis or other eczematous dermatoses, and delayed-type hypersensitivity reactions; phyto- and photodermatitis; seborrhoeic dermatitis, dermatitis herpetiformis, lichen planus, lichen sclerosus et atrophica, pyoderma gangrenosum, skin sarcoid, discoid lupus erythematosus, pemphigus, pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitides, toxic erythemas, cutaneous eosinophilias, alopecia areata, male-pattern baldness, Sweet's syndrome, Weber- Christian syndrome, erythema multiforme; cellulitis, both infective and non-infective
  • the combinations of the present invention can also be used in the treatment of diseases of the eye such as blepharitis; conjunctivitis, including perennial and vernal allergic conjunctivitis; ulceris; anterior and posterior uveitis; choroiditis; autoimmune; degenerative or inflammatory disorders affecting the retina; ophthalmitis including sympathetic ophthalmitis; sarcoidosis; infections including viral , fungal, and bacterial.
  • diseases of the eye such as blepharitis; conjunctivitis, including perennial and vernal allergic conjunctivitis; ulceris; anterior and posterior uveitis; choroiditis; autoimmune; degenerative or inflammatory disorders affecting the retina; ophthalmitis including sympathetic ophthalmitis; sarcoidosis; infections including viral , fungal, and bacterial.
  • the combinations of the present invention can also be used in the treatment of diseases of the gastrointestinal tract such as glossitis, gingivitis, periodontitis; oesophagitis, including reflux; eosinophilic gastro-enteritis, mastocytosis, Crohn's disease, colitis including ulcerative colitis, proctitis, pruritis ani; coeliac disease, irritable bowel syndrome, non- inflammatory diarrhoea, and food-related allergies which may have effects remote from the gut (for example, migraine, rhinitis or eczema).
  • diseases of the gastrointestinal tract such as glossitis, gingivitis, periodontitis; oesophagitis, including reflux; eosinophilic gastro-enteritis, mastocytosis, Crohn's disease, colitis including ulcerative colitis, proctitis, pruritis ani; coeliac disease, irritable bowel syndrome, non- inflammatory diarrhoea, and food-related
  • the combinations of the present invention can also be used in the treatment of diseases of the cardiovascular system such as atherosclerosis, affecting the coronary and peripheral circulation; pericarditis; myocarditis, inflammatory and auto-immune cardiomyopathies including myocardial sarcoid; ischaemic reperfusion injuries; endocarditis, valvulitis, and aortitis including infective (for example syphilitic); vasculitides; disorders of the proximal and peripheral veins including phlebitis and thrombosis, including deep vein thrombosis and complications of varicose veins.
  • diseases of the cardiovascular system such as atherosclerosis, affecting the coronary and peripheral circulation; pericarditis; myocarditis, inflammatory and auto-immune cardiomyopathies including myocardial sarcoid; ischaemic reperfusion injuries; endocarditis, valvulitis, and aortitis including infective (for example
  • the combinations of the present invention can also be used in oncology such as in the treatment of common cancers including prostate, breast, lung, ovarian, pancreatic, bowel and colon, stomach, skin and brain tumours and malignancies affecting the bone marrow (including the leukaemias) and lymphoproliferative systems, such as Hodgkin's and non- Hodgkin's lymphoma; including the prevention and treatment of metastatic disease and tumour recurrences, and paraneoplastic syndromes.
  • oncology such as in the treatment of common cancers including prostate, breast, lung, ovarian, pancreatic, bowel and colon, stomach, skin and brain tumours and malignancies affecting the bone marrow (including the leukaemias) and lymphoproliferative systems, such as Hodgkin's and non- Hodgkin's lymphoma; including the prevention and treatment of metastatic disease and tumour recurrences, and paraneoplastic syndromes.
  • the combinations of the present invention may be used in the treatment of adult respiratory distress syndrome (ARDS), cystic fibrosis, pulmonary emphysema, bronchitis, bronchiectasis, chronic obstructive pulmonary disease (COPD), pulmonary hypertension, asthma, rhinitis, ischemia-reperiusion injury, rheumatoid arthritis, osteoarthritis, cancer, atherosclerosis and gastric mucosal injury.
  • ARDS adult respiratory distress syndrome
  • cystic fibrosis pulmonary emphysema
  • bronchitis bronchiectasis
  • COPD chronic obstructive pulmonary disease
  • the combinations of the present invention may be used in the treatment of chronic obstructive pulmonary disease (COPD), asthma and rhinitis.
  • COPD chronic obstructive pulmonary disease
  • COPD chronic obstructive pulmonary disease
  • the combinations of the present invention may demonstrate anti-inflammatory activity at dose levels where either component alone does not significantly affect inflammation.
  • the combinations of the present invention may exhibit an anti-inflammatory activity that is greater than that expected from the additive effect of the two ingredients.
  • Such a synergistic effect observed when combining the ingredients could be used, for example, to lower the therapeutic dose of one active ingredient, or at the same dose, to achieve an enhanced efficacy on inflammation in comparison to the use of the single active ingredient alone.
  • the pharmaceutical product of the present invention may further optionally comprise a third active ingredient.
  • the third active ingredient may be chosen from the same list as for the second active ingredient.
  • the inhibitor of IKK2 (first active ingredient), second active ingredient and optionally third active ingredient of the present invention may be administered simultaneously, sequentially or separately to treat respiratory diseases.
  • sequential it is meant that the active ingredients are administered, in any order, one immediately after the other. They still have the desired effect if they are administered separately, but when administered in this manner they are generally administered less than 4 hours apart, more conveniently less than two hours apart, more conveniently less than 30 minutes apart and most conveniently less than 10 minutes apart.
  • the active ingredients of the present invention may be administered by oral or parenteral (e.g. intravenous, subcutaneous, intramuscular or intraarticular) administration using conventional systemic dosage forms, such as tablets, capsules, pills, powders, aqueous or oily solutions or suspensions, emulsions and sterile injectable aqueous or oily solutions or suspensions.
  • the active ingredients may also be administered topically (to the lung and/or airways) in the form of solutions, suspensions, aerosols and dry powder formulations.
  • These dosage forms will usually include one or more pharmaceutically acceptable ingredients which may be selected, for example, from adjuvants, carriers, binders, lubricants, diluents, stabilising agents, buffering agents, emulsifying agents, viscosity- regulating agents, surfactants, preservatives, flavourings and colorants.
  • pharmaceutically acceptable ingredients may be selected, for example, from adjuvants, carriers, binders, lubricants, diluents, stabilising agents, buffering agents, emulsifying agents, viscosity- regulating agents, surfactants, preservatives, flavourings and colorants.
  • the active ingredients are administered via separate pharmaceutical preparations.
  • the present invention provides a kit comprising a preparation of a first active ingredient which is an inhibitor of IKK2 or a pharmaceutically acceptable salt thereof, and a preparation of a second active ingredient, and optionally instructions for the simultaneous, sequential or separate administration of the preparations to a patient in need thereof.
  • the kit may further optionally comprise a preparation of a third active ingredient.
  • the active ingredients may be administered via a single pharmaceutical composition. Therefore, the present invention further provides a pharmaceutical composition comprising, in admixture, a first active ingredient which is an inhibitor of IKK2 or pharmaceutically acceptable salt thereof, and a second active ingredient.
  • the pharmaceutical composition may further optionally comprise a third active ingredient.
  • the present invention also provides a process for the preparation of a pharmaceutical composition which comprises mixing the first active ingredient with the second active ingredient and optionally with the third active ingredient.
  • compositions of the present invention may be prepared by mixing the first active ingredient and the second active ingredient with a pharmaceutically acceptable adjuvant, diluent or carrier, and, optionally, the third active ingredient. Therefore, in a further aspect of the present invention there is provided a process for the preparation of a pharmaceutical composition, which comprises mixing an inhibitor of IKK2 or a pharmaceutically acceptable salt thereof, with a second active ingredient, and a pharmaceutically acceptable adjuvant, diluent or carrier, and, optionally, a third active ingredient.
  • each active ingredient administered in accordance with the present invention will vary depending upon the particular active ingredient employed, the mode by which the active ingredient is to be administered, and the condition or disorder to be treated.
  • the first, second (and when present, the third) active ingredients of the present invention are each administered by inhalation.
  • the active ingredients are inhaled simultaneously, sequentially or separately.
  • the amount of the active ingredients used relate to inhaled unit doses unless explicitly defined differently.
  • the dose of the first active ingredient will generally be in the range of from 0.1 ⁇ g to 10000 ⁇ g, 0.1 to 5000 ⁇ g, 0.1 to 1000 ⁇ g, 0.1 to 500 ⁇ g, 0.1 to 200 ⁇ g, 0.1 to 200 ⁇ g, 0.1 to 100 ⁇ g, 0.1 to 50 ⁇ g, 5 ⁇ g to 5000 ⁇ g, 5 to 1000 ⁇ g, 5 to 500 ⁇ g, 5 to 200 ⁇ g, 5 to 100 ⁇ g, 5 to 50 ⁇ g, 10 to 5000 ⁇ g, 10 to 1000 ⁇ g, 10 to 500 ⁇ g, 10 to 200 ⁇ g, 10 to 100 ⁇ g, 10 to 50 ⁇ g, 20 to 5000 ⁇ g, 20 to 1000 ⁇ g, 20 to 500 ⁇ g, 20 to 200 ⁇ g, 20 to 100 ⁇ g, 20 to 50 ⁇ g, 50 to 5000 ⁇ g, 50 to 1000 ⁇ g, 50 to 1000 ⁇ g, 50 to 1000 ⁇ g, 50 to 1000 ⁇ g, 20 to
  • the dose of the second active ingredient will generally be in the range of from 0.1 microgram ( ⁇ g) to 1000 ⁇ g, 0.1 to 500 ⁇ g, 0.1 to 200 ⁇ g, 0.1 to 100 ⁇ g, 0.1 to 50 ⁇ g, 0.1 to 5 ⁇ g, 5 to 1000 ⁇ g, 5 to 500 ⁇ g, 5 to 200 ⁇ g, 5 to 50 ⁇ g, 5 to 10 ⁇ g, 10 to 1000 ⁇ g, 10 to 500 ⁇ g, 10 to 200 ⁇ g, 10 to 100 ⁇ g, 10 to 50 ⁇ g, 20 to 1000 ⁇ g, 20 to 500 ⁇ g, 20 to 200 ⁇ g, 20 to 100 ⁇ g, 20 to 50 ⁇ g, 50 to 1000 ⁇ g, 50 to 500 ⁇ g, 50 to 200 ⁇ g, 50 to 100 ⁇ g, 100 to 1000 ⁇ g, or 100 to 500 ⁇ g.
  • the amount of the first active agent used is in the range 1 ⁇ g to 200 ⁇ g, and that of the second agent in the range 1 ⁇ g to 200 ⁇ g.
  • the molar ratio of the second active ingredient to the first active ingredient in a dose may typically be in the range of 1 : 10 to 10:1.
  • the ratio is in the range 1 : 1 to 10: 1 , and preferably still, in the range 5:1 to 20:1.
  • the third active ingredient may conveniently be administered by inhalation at a dose generally in the range of from 0.1 to 100 ⁇ g, 0.1 to 50 ⁇ g, 0.1 to 40 ⁇ g, 0.1 to 30 ⁇ g, 0.1 to 20 ⁇ g, 0.1 to 10 ⁇ g; 5 to 100 ⁇ g, 5 to 50 ⁇ g, 5 to 40 ⁇ g, 5 to 30 ⁇ g, 5 to 20 ⁇ g, 5 to 10 ⁇ g, 10 to 100 ⁇ g, 10 to 50 ⁇ g, 10 to 40 ⁇ g, 10 to 30 ⁇ g, or 10 to 20 ⁇ g.
  • the dose of the third active ingredient is in the range 1 to 30 ⁇ g.
  • the doses of the first and second (and where present the third) active ingredients will generally be administered from 1 to 4 times a day, conveniently once or twice a day, and most conveniently once a day.
  • the present invention provides a pharmaceutical product comprising, in combination, a first active ingredient which is a an inhibitor of IKX2 or a pharmaceutically acceptable salt thereof, and a second active ingredient, and optionally a third active ingredient, wherein each active ingredient is formulated for inhaled administration.
  • the active ingredients are conveniently administered via inhalation (e.g. topically to the lung and/or airways) in the form of solutions, suspensions, aerosols and dry powder formulations. Administration may be by inhalation orally or intranasally.
  • the active ingredients are preferably adapted to be administered, either together or individually, from a dry powder inhaler, pressurised metered dose inhaler, or a nebuliser.
  • the active ingredients may be used in admixture with one or more pharmaceutically acceptable additives, diluents or carriers.
  • suitable diluents or carriers include lactose (e.g. the monohydrate), dextran, mannitrol or glucose.
  • Metered dose inhaler devices may be used to administer the active ingredients, dispersed in a suitable propellant and with or without additional excipients such as ethanol, a surfactants, a lubricant, an anti-oxidant or a stabilising agent.
  • suitable propellants include hydrocarbon, chlorofluorocarbon and hydrofluoroalkane (e.g. heptafluoroalkane) propellants, or mixtures of any such propellants.
  • Preferred propellants are P134a and P227, each of which may be used alone or in combination with other propellants and/or surfactant and/or other excipients.
  • Nebulised aqueous suspensions or, preferably, solutions may also be employed, with or without a suitable pH and/or tonicity adjustment, either as a unit-dose or multi-dose formulations.
  • Dry powder inhalers may be used to administer the active ingredients, alone or in combination with a pharmaceutically acceptable carrier, in the later case either as a finely divided powder or as an ordered mixture.
  • the dry powder inhaler may be single dose or multi-dose and may utilise a dry powder or a powder-containing capsule.
  • the active ingredients When the active ingredients are adapted to be administered, either together or individually, via a nebuliser they may be in the form of a nebulised aqueous suspension or solution, with or without a suitable pH or tonicity adjustment, either as a single dose or multidose device.
  • Metered dose inhaler, nebuliser and dry powder inhaler devices are well known and a variety of such devices are available.
  • the inhibitor of IKK2 or pharmaceutically salt thereof may be administered orally and the other active ingredient(s) administered by inhalation.
  • the present invention further provides a pharmaceutical product, kit or pharmaceutical composition according to the invention for simultaneous, sequential or separate use in therapy.
  • the present invention further provides the use of a pharmaceutical product, kit or pharmaceutical composition according to the invention in the manufacture of a medicament for the treatment of a respiratory disease, in particular chronic obstructive pulmonary disease or asthma.
  • the present invention still further provides a method of treating a respiratory disease which comprises simultaneously, sequentially or separately administering:
  • SPA Scintillation Proximityo Assay
  • the test compounds were dissolved to 10 mM in dimethylsulphoxide (DMSO). The compounds were then serial diluted 1 to 5 with DMSO. One ⁇ L of diluted test compounds was added to wells of 96-well assay plates (Corning #3604; white, flat with clear bottom). Duplicates were added on separate assay plates. Controls were added to assay plate columns 1 and 12. As 0% control 1 ⁇ L DMSO was used and as 100 % control 1 ⁇ L 400 ⁇ M AZl 1705240 was used (around 1000*IC 50 as final concentration in the assay).
  • DMSO dimethylsulphoxide
  • P]ATP (Amersham #AH9960) diluted in Assay Buffer.
  • the final concentration during phosphorylation of biotin-DRHDSGLDSMKD-NH 2 was 3 ⁇ M and 0.5 ⁇ M of ATP (around Km, 0.045 ⁇ Ci [ ⁇ - 33 P]ATP).
  • the kinase reaction was stopped after 60 minutes (linear phosphorylation) incubation at room temperature by adding 200 ⁇ L SPA stop solution, consisting of 1 mg streptavidin-coated SPA beads/200 ⁇ L (Amersham #RPNQ0007) in 50 mM Tris (pH 7.4), 0.01% Triton X-100 and 40 mM EDTA.
  • the assay plates were sealed with plastic foil and left for 60 minutes to allow the substrate to bind to the SPA beads. After centrifugation at 2500 rpm for 5 minutes on a Hettig Rotanta 460 R centrifuge, the assay plates were analyzed on a plate-based liquid scintillation counter (Wallac Microbeta 1450 Trilux).
  • BAL broncholalveolar lavage
  • LPS Lipopolyaccharide
  • LPS instillation Rats were anaesthetized with Efrane and put in a supine position, head up, on a board tilted at 30°. LPS (Lipopolysaccharide B.E.coli 026:B6) (2.5 ⁇ g/ml) dissolved in saline (0.9% NaCl), or saline alone (negative control) in a volume of 200 ⁇ l was administered intratracheally using a modified metal cannula.
  • LPS Lipopolysaccharide B.E.coli 026:B6
  • saline alone negative control
  • the first and second active ingredients are separately dissolved in appropriate vehicles (for example, ethanol) and then mixed with 3.66 mM citric acid 1- hydrate and 15.85 mM sodium hydrogen phosphate, pH: 6.5 solution to give a suitable final concentration depending on the activity of the particular compound. Combination formulations were prepared similarly.
  • appropriate vehicles for example, ethanol
  • 3.66 mM citric acid 1- hydrate and 15.85 mM sodium hydrogen phosphate, pH: 6.5 solution to give a suitable final concentration depending on the activity of the particular compound.
  • Combination formulations were prepared similarly.
  • Treatments Animals were intratracheally instilled with solutions (1 ml/kg) of the combination, or of the first active ingredient alone, or of the second active ingredient alone, or with saline (negative and positive control animals). The treatments were carried out under light anaesthesia (Efrane) to secure that the solution reached the lungs. The drugs were administrated 30min before the LPS instillation.
  • NFKB nuclear factor kappa B activation in cells
  • IL-8 Interleukin-8
  • NHBE Normal Human Bronchial Epithelial
  • TNF ⁇ tumour necrosis factor alpha
  • Primary NHBE cells (Clonetics, San-Diego, CA, USA) were obtained from In Vitro Sweden AB (Stockholm, Sweden). The cells were cultured in Bronchial Epithelial cell Growth Medium (BEGM) according to the manufacturer's instructions (Clonetics, catalogue # CC-3170).
  • BEGM consisted of basal medium (BEBM) supplemented with bovine pituitary extract (52 mg/mL), hydrocortisone (0.5 mg/mL), HEGF (0.5 ng/mL), epinephrine (0.5 mg/mL), transferrin (10 mg/mL), insulin (5 mg/mL), retinoic acid (0.1 ng/mL) and triiodothyronine (6.5 ng/mL), all supplied by Clonetics. Cultures were maintained at 37 °C in a humidified atmosphere of 5% CO2 in air. Cells were sub-cultured using the methods and reagents provided by Clonetics (catalogue # CC-5034). AU experiments were performed on cells at passages 2, 3, 4 and 5.
  • -BEGM medium incomplete BEGM medium, lacking hydrocortisone, retinoic acid and epinephrine, hereafter referred to as -BEGM medium.
  • Cells were seeded in non-coated 24-well plates (Costar, Cambridge, MA, USA) and grown in BEGM until ⁇ 60% confluency.
  • Experiments were started by starving the cells in -BEGM medium for 24 h, where after 10 ⁇ g/mL human recombinant TNF ⁇ (R&D Systems, Minneapolis, MN, USA) was added in the presence or absence of the IKK2 inhibitor and/or the second active agent.
  • Test compounds were dissolved in DMSO to 10 mM and diluted 1 : 10 in DMSO to obtain the correct "stock” dilutions. These "stock” dilutions contained a 1000 times higher concentration than the final concentration in the cells, since 1 ⁇ l of each "stock” dilution in DMSO was added to the wells containing cells in 1 ml medium. DMSO concentrations up to 0.3% have been tested and shown to not interfere with the read-out. Cells were treated for 24 h and the experiment was ended by centrifuging the plates for 10 minutes at 1000 rpm, 4 °C. Each exposure was performed in duplicate and supernatants stored at -70 0 C until use. DNA content was measured to correct for the number of cells present in each well.
  • IL-8 levels were detected by enzyme- linked immunosorbent assay (ELISA), using human IL-8 Quantikine ELISA kit (R&D Systems, Minneapolis, MN, USA, catalogue # D8000C). The ELISA was performed as described by the manufacturer. The amount of IL-8 in each sample was calculated from the standard curve, determined in pg/mL culture medium, and related to the DNA content in the corresponding well. All samples were analysed in duplicate. The absorbance at 450 nm was measured by spectrophotometry.

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Abstract

La présente invention concerne des compositions pharmaceutiques comprenant un inhibiteur de la IKK2 et un second ingrédient actif, et leur utilisation en thérapie.
PCT/SE2007/000622 2006-06-28 2007-06-26 Composition pharmaceutique comprenant un inhibiteur de la ikk2 et un second ingrédient actif WO2008002246A1 (fr)

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WO2007005941A2 (fr) * 2005-07-05 2007-01-11 President And Fellows Of Harvard College Conjugues cibles sur le foie
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US7858666B2 (en) 2007-06-08 2010-12-28 Mannkind Corporation IRE-1α inhibitors
US8614253B2 (en) 2007-06-08 2013-12-24 Mannkind Corporation IRE-1α inhibitors
US9241942B2 (en) 2007-06-08 2016-01-26 Mannkind Corporation IRE-1α inhibitors
US9546149B2 (en) 2007-06-08 2017-01-17 Mannkind Corporation IRE-1α inhibitors
US9981901B2 (en) 2007-06-08 2018-05-29 Fosun Orinove Pharmatech, Inc. IRE-1α inhibitors
WO2009130475A1 (fr) * 2008-04-26 2009-10-29 Chroma Therapeutics Ltd., Thiophènecarboxamides substitués en tant qu’inhibiteurs de sérine-thréonine protéine kinase ikk-bêta
CN102036980A (zh) * 2008-04-26 2011-04-27 色品疗法有限公司 作为IKK-β丝氨酸苏氨酸蛋白激酶抑制剂的取代噻吩羧酰胺
WO2012046793A1 (fr) * 2010-10-07 2012-04-12 参天製薬株式会社 Nouvel inhibiteur de jak3 contenant, à titre de principe actif, un dérivé de thiophène portant un groupe uréido et un groupe aminocarbonyle à titre de substituants
WO2012142704A1 (fr) 2011-04-20 2012-10-26 Sulvaris Inc. Conversion de gaz acide en engrais à base de sulfate ou de phosphate

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