WO2008053199A1 - Thérapie combinée pour traiter des maladies respiratoire - Google Patents

Thérapie combinée pour traiter des maladies respiratoire Download PDF

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WO2008053199A1
WO2008053199A1 PCT/GB2007/004139 GB2007004139W WO2008053199A1 WO 2008053199 A1 WO2008053199 A1 WO 2008053199A1 GB 2007004139 W GB2007004139 W GB 2007004139W WO 2008053199 A1 WO2008053199 A1 WO 2008053199A1
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alkyl
inhibitor
phenyl
alkoxy
substituted
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PCT/GB2007/004139
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English (en)
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Konstantinos Karabelas
Harbans Lal
Peter Sjö
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Astrazeneca Ab
Astrazeneca Uk Limited
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Publication of WO2008053199A1 publication Critical patent/WO2008053199A1/fr

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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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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

  • the present invention relates to combinations of pharmaceutically active substances for 5 use in the treatment of inflammatory diseases or conditions, particularly respiratory diseases or conditions, and especially chronic obstructive pulmonary disease (COPD), asthma and rhinitis.
  • 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, rhinitis, 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
  • COPD is a term that refers to a large group of lung diseases that can interfere with normal 30 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 that 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 that 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.
  • Elastases are possibly the most destructive enzymes in the body, having the ability to degrade virtually all connective tissue components.
  • the uncontrolled proteolytic degradation by elastases has been implicated in a number of pathological conditions.
  • Human neutrophil elastase (hNE) a member of the chymotrypsin superfamily of serine proteases is a 33-KDa enzyme stored in the azurophilic granules of the neutrophils.
  • the main intracellular physiological function of NE is degradation of foreign organic molecules phagocytosed by neutrophils, whereas the main target for extracellular elastase is elastin.
  • NE is unique, as compared to other proteases (for example, proteinase 3) in that it has the ability to degrade almost all extracellular matrix and key plasma proteins. NE is a major common mediator of many pathological changes seen in chronic lung disease including epithelial damage.
  • ⁇ i-Antitrypsin is the most important endogenous inhibitor of human NE.
  • the imbalance between human NE and endogenous antiprotease is believed to cause excess human NE in pulmonary tissues that is considered as a major pathogenic factor in chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • the excessive human NE shows a prominent destructive profile and actively takes part in destroying the normal pulmonary structures, followed by the irreversible enlargement of the respiratory airspaces, as seen mainly in emphysema.
  • Neutrophil-predominant airway inflammation and mucus obstruction of the airways are major pathologic features of COPD, including cystic fibrosis and chronic bronchitis. NE impairs mucin production, leading to mucus obstruction of the airways.
  • NE has been also shown to play a role in the pathogenesis of pulmonary fibrosis.
  • NE ⁇ .protenase inhibitor complex is increased in serum of patients with pulmonary fibrosis, which correlates with the clinical parameters in these patients (Yamanouchi et al., 1998, Eur. Resp. J. 11, 120-125).
  • NE has also been assumed to be involved in the pathogenesis of rheumatoid arthritis (Adeyemi et al., 1986, Rheumatol. Int., 6, 57). The development of collegen induced arthritis in mice is suppressed by a NE inhibitor (Kakimoto et al., 1995, Cellular Immunol. 165, 26-32).
  • human NE is known as one of the most destructive serine proteases and has been implicated in a variety of inflammatory diseases.
  • Inhibitors of human NE are disclosed in, for example, GB 2 392 910, WO 03/053930, WO 2004/020410, WO 2004/020412, WO 2004/024700, WO 2004/024701, WO 2004/043924, WO 2005/021512, WO 2005/021509, WO 2005/026123, WO 2005/026124, WO 2005/082863, WO 2005/082864, WO 2006/082412, WO 2006/098683 and WO 2006/098684-
  • Metalloproteinases are a superfamily of proteinases (enzymes) that includes the matrix metalloproteinases (MMPs) such as the collagenases (MMPl, MMP8, MMP 13), the gelatinases (MMP2, MMP9), the stromelysins (MMP3, MMPlO, MMPl 1), matrilysin (MMP7), metalloelastase (MMP12), enamelysin (MMP19) and the MT-MMPs (MMP14, MMP15, MMP16, MMP17).
  • MMPs matrix metalloproteinases
  • Metalloproteinases have been associated with many diseases or conditions. Inhibition of the activity of one or more metalloproteinases may well be of benefit in these diseases or conditions, for example: various inflammatory and allergic diseases such as, inflammation of the joint (especially rheumatoid arthritis, osteoarthritis and gout), inflammation of the gastro-intestinal tract (especially inflammatory bowel disease, ulcerative colitis and gastritis), inflammation of the skin (especially psoriasis, eczema, dermatitis); in rumour metastasis or invasion; in disease associated with uncontrolled degradation of the extracellular matrix such as osteoarthritis; in bone resorptive disease (such as osteoporosis and Paget' s disease); in diseases associated with aberrant angiogenesis; the enhanced collagen remodelling associated with diabetes, periodontal disease (such as gingivitis), corneal ulceration, ulceration of the skin, post-operative conditions (such as colonic anastomosis) and dermal wound healing; demyelina
  • MMP inhibitors have been reviewed by Whittaker, M. et al (Chemical Reviews, 1999, 99, 2735-2776). Further examples of MMP inhibitors are disclosed in, for example, WO 02/074748, WO 02/074749, WO 02/074751, WO 02/074752, WO 02/074767, WO 03/040098, WO 04/020415, WO 05/095362, WO 06/004532, WO 06/004533, WO 06/065215 and WO 06/065216.
  • the present invention provides a pharmaceutical product comprising, in combination, a first active ingredient which is a neutrophil elastase inhibitor, and a second active ingredient which is selected from the list comprising:
  • a phosphodiesterase inhibitor such as a PDE4 inhibitor, including an inhibitor of the isoform PDE4D, or a PDE5 inhibitor; it) • a selective ⁇ .2 adrenoceptor agonist such as metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, pirbuterol or indacaterol;
  • a muscarinic receptor antagonist for example a Ml, M2 or M3 antagonist, such as a selective M3 antagonist
  • a muscarinic receptor antagonist such as a Ml, M2 or M3 antagonist, such as a selective M3 antagonist
  • ipratropium bromide, tiotropium bromide is oxitropium bromide, pirenzepine or telenzepine
  • a modulator of chemokine receptor function such as a CCRl receptor antagonist
  • a kinase inhibitor such as an inhibitor of p38 or IKK2 function
  • a glucocorticoid such as flunisolide, triamcinolone acetonide, beclomethasone 20 dipropionate, budesonide, fluticasone propionate, ciclesonide or mometasone furoate; and
  • the present invention provides a pharmaceutical product comprising, in 25 combination, a first active ingredient which is a metalloproteinase inhibitor and a second active ingredient which selected from the list comprising:
  • a phosphodiesterase inhibitor such as a PDE4 inhibitor, including an inhibitor of the isoform PDE4D, or a PDE5 inhibitor
  • a selective ⁇ .2 adrenoceptor agonist such as metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, pirbuterol or indacaterol;
  • a muscarinic receptor antagonist for example a Ml , M2 or M3 antagonist, such as a selective M3 antagonist
  • a muscarinic receptor antagonist such as a Ml , M2 or M3 antagonist, such as a selective M3 antagonist
  • Ml , M2 or M3 antagonist such as a selective M3 antagonist
  • a modulator of chemokine receptor function such as a CCRl receptor antagonist
  • a kinase inhibitor such as an inhibitor of p38 or IKK2 function
  • a protease inhibitor • a glucocorticoid, such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide or mometasone furoate; and
  • the present invention provides a pharmaceutical product comprising, in combination, a first active ingredient which is a neutrophil elastase inhibitor, and a second active ingredient which is a metalloproteinase inhibitor.
  • 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 pharmaceutical product of the present invention comprises, as an active ingredient, a neutrophil elastase inhibitor.
  • a neutrophil elastase inhibitor is a compound or other substance that is capable of reducing, whether fully or partially, the activity of the enzyme neutrophil elastase, preferably human neutrophil elastase.
  • Methods for assaying for inhibitors of neutrophil elastase are known in the art, for example from WO 2004/043924 which describes a human neutrophil elastase quenched-FRET assay.
  • the pharmaceutical product of the present invention comprises, as an active ingredient, a metalloproteinase inhibitor.
  • a metalloproteinase inhibitor is a compound or other substance that is capable of reducing, whether fully or partially, the activity of the one or more metalloproteinase enzymes.
  • the MMP inhibitor is an inhibitor of MMP12 and/or MMP13 and/or MMP9 and/or MMP8 and/or MMP3; especially an inhibitor of MMP 12 and/or MMP9; most especially an inhibitor of MMP 12.
  • An inhibitor of MMP 12 is a compound or other substance that preferentially inhibits MMP 12, thereby showing a lower IC50 value for MMP 12 than for other metalloproteinases.
  • an inhibitor of MMP 12 and/or MMP9 is a compound or other substance that preferentially inhibits one or other or both of MMP 12 and MMP9 more efficiently than other metalloproteinases.
  • respiratory tract obstructive diseases of the airways including: asthma, including bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including aspirin and NS AID-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; acute respiratory distress syndrome (ARDS); occupational lung disease, 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; acute lung injury; complications of lung transplantation; va
  • osteoarthritides associated with or including osteoarthritis/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 scleroderma; systemic lupus erythematosus, mixed connective
  • 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 such as osteoporosis, Paget'
  • skin psoriasis, atopic dermatitis, contact dermatitis or other eczematous dermatoses, and delayed-type hypersensitivity reactions; eczema; 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; panniculitis;cutaneous lymphomas,
  • eyes 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;
  • gastrointestinal tract glossitis, gingivitis, periodontitis; oesophagitis, including reflux; eosinophilic gastro-enteritis, mastocytosis, Crohn's disease, colitis including ulcerative colitis, microscopic colitis and indeterminant colitis, gastritis, proctitis, pruritis ani; coeliac disease, inflammatory bowel disease, irritable bowel syndrome, irritable bowel disorder, non-inflammatory diarrhea and food-related allergies which may have effects remote from the gut (for example migraine, rhinitis or eczema);
  • abdominal hepatitis, including autoimmune, alcoholic and viral; fibrosis and cirrhosis of the liver; cholecystitis; pancreatitis, both acute and chronic;
  • nephritis including interstitial and glomerulonephritis; nephrotic syndrome; cystitis including acute and chronic (interstitial) cystitis and Hunner's ulcer; acute and chronic urethritis, prostatitis, epididymitis, oophoritis and salpingitis; vulvovaginitis; Peyronie's disease; erectile dysfunction (both male and female); 9. allograft rejection: acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea or following blood transfusion; or chronic graft versus host disease;
  • CNS Alzheimer's disease and other dementing disorders including CJD and nvCJD; amyloidosis; multiple sclerosis and other demyelinating syndromes; cerebral atherosclerosis and vasculitis; temporal arteritis; myasthenia gravis; acute and chronic pain (acute, intermittent or persistent, whether of central or peripheral origin) including visceral pain, headache, migraine, trigeminal neuralgia, atypical facial pain, joint and bone pain, pain arising from cancer and tumor invasion, neuropathic pain syndromes including diabetic, post-herpetic, and HIV-associated neuropathies; neurosarcoidosis; central and peripheral nervous system complications of malignant, infectious or autoimmune processes;
  • cardiovascular atherosclerosis, affecting the coronary and peripheral circulation; restenosis; 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; 14.
  • oncology treatment of common cancers including prostate, breast, lung, ovarian, pancreatic, bowel and colon, stomach, skin and brain tumors 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 are useful for the treatment of inflammatory diseases or conditions such as rheumatoid arthritis, osteoarthritis, osteoporosis, psoriasis, inflammatory bowel diseases, COPD, asthma, allergic rhinitis or cancer or the neurodegenerative diseases such as multiple sclerosis or Alzheimer's disease.
  • inflammatory diseases or conditions such as rheumatoid arthritis, osteoarthritis, osteoporosis, psoriasis, inflammatory bowel diseases, COPD, asthma, allergic rhinitis or cancer or the neurodegenerative diseases such as multiple sclerosis or Alzheimer's disease.
  • the combinations of the present invention are particularly useful for the treatment of respiratory diseases or conditions, and especially chronic obstructive pulmonary disease (COPD), asthma and rhinitis.
  • COPD chronic obstructive pulmonary disease
  • an unexpectedly beneficial therapeutic effect may be observed in the treatment of respiratory diseases if a neutrophil elastase inhibitor is used in combination with a metalloproteinase inhibitor.
  • the beneficial effect may be observed when the two active substances are administered simultaneously (either in a single pharmaceutical preparation or via separate preparations), or sequentially or separately via separate pharmaceutical preparations.
  • the neutrophil elastase inhibitor is a pyridone derivative, preferably a 2-pyridone (2-oxo-l,2-dihydropyridine) derivative. In another embodiment, the neutrophil elastase inhibitor is a 2-oxo-l,2-dihydropyridine-3-carboxamide derivative.
  • the neutrophil elastase inhibitor is a dihydropyridine derivative, a dihydropyridinone derivative, a dihydropyrimidinone derivative or a dihydropyrimidinethione derivative.
  • the MMP inhibitor is a hydantoin (2,4-imidazolidinedione) derivative, preferably a 5-substituted 2,4-imidazolidinedione derivative.
  • the present invention provides a pharmaceutical product comprising, in combination, a first active ingredient which is a 2-pyridone (2-oxo-l,2- dihydropyridine) derivative, and a second active ingredient which is a hydantoin (2,4- imidazolidinedione) derivative.
  • human NE inhibitors which may be used in accordance with the present invention include 2-pyridone derivatives having hNE inhibitor properties, as for example described in WO 2004/043924, WO 2005/021512, WO 2005/021509, WO 2005/026123 and WO 2005/026124, the entire contents of which are incorporated herein by reference.
  • human NE inhibitors which may be used in accordance with the present invention include derivatives having hNE inhibitor properties, as for example described in GB 2 392 910, WO 03/053930, WO 2004/020410, WO 2004/020412, WO 2004/024700, WO 2004/024701, WO 2005/082863, WO 2005/082864 and WO 2006/082412, the entire contents of which are incorporated herein by reference.
  • the hNE inhibitor is a 2-pyridone derivative of formula (I)
  • X represents O or S
  • Y represents N or CR ; and when R represents OH, Y may also, in the tautomeric form, represent NR ; 2 3 1 2 2
  • Y represents CR ; and when Y represents CR , then Y may also represent N;
  • R represents H or Cl to 6 alkyl; said alkyl being optionally substituted by one or more
  • R represents H, Cl to 6 alkyl or phenyl; said phenyl being optionally further substituted by halogen, Cl to 6 alkyl and Cl to 6 alkoxy;
  • R represents H, halogen or Cl to 6 alkyl
  • R represents H or F
  • G represents phenyl or a five- or six-membered heteroaromatic ring containing 1 to 3 heteroatoms independently selected from O, S and N; or G represents a five- or six- membered saturated or partially unsaturated cycloalkyl ring; or G represents a five- or six-membered saturated or partially unsaturated heterocyclic ring containing one
  • R 13 13 heteroatom selected from O, S and NR where R represents H or Cl to 6 alkyl;
  • R 5 represents H, halogen, Cl to 6 alkyl, CN, Cl to 6 alkoxy, NO 2 , NR 14 R 15 , Cl to 3 alkyl substituted by one or more F atoms or Cl to 3 alkoxy substituted by one or more F atoms;
  • R and R independently represent H or Cl to 3 alkyl; said alkyl being optionally further substituted by one or more F atoms; n represents an integer 1, 2 or 3 and when n represents 2 or 3, each R group is selected independently;
  • R and R independently represent H or Cl to 6 alkyl; said alkyl being optionally further substituted by OH or Cl to 6 alkoxy;
  • the group -NR L represents a 5 to 7 membered azacyclic ring optionally incorporating one further heteroatom selected from O, S and NR 16 ;
  • 29 L represents a bond, O, NR or Cl to 6 alkyl; said alkyl optionally incorporating a heteroatom selected from O, S and NR ; and said alkyl being optionally further substituted by OH or OMe;
  • G represents a monocyclic ring system selected from: i) phenyl or phenoxy, ii) a 5 or 6 membered heteroaromatic ring containing one to three heteroatoms independently selected from O, S and N, iii) a C3 to 6 saturated or partially unsaturated cycloalkyl, or iv) a C4 to 7 saturated or partially unsaturated heterocyclic ring containing one or two
  • each of the two rings is independently selected from: i) phenyl, ii) a 5 or 6 membered heteroaromatic ring containing one to three heteroatoms independently selected from O, S and N, iii) a C3 to 6 saturated or partially unsaturated cycloalkyl, or iv) a C4 to 7 saturated or partially unsaturated heterocyclic ring containing one or two heteroatoms independently selected from O, S(O)p and NR and optionally further incorporating a carbonyl group; and the two rings are either fused together, or are bonded directly together or are separated by a linker group selected from O, S(O)q or CH 2 , said monocyclic or bicyclic ring system being optionally further substituted by one to three substituents independently selected from CN, OH, Cl to 6 alkyl, Cl to 6 alkoxy, halogen,
  • G may also represent H; m, p, q, s and t independently represent an integer 0, 1 or 2;
  • R and R independently represent H, Cl to 6 alkyl, formyl or C2 to 6 alkanoyl; said alkyl being optionally further substituted by phenyl optionally substituted by halogen, Cl to 6
  • R and R independently represent H, Cl to 6 alkyl, formyl, C2 to 6 alkanoyl, S(O)tR
  • alkyl group being optionally further substituted by halogen, CN, Cl to 4 alkoxy or CONR 4 l R 42 ;
  • R represents H, Cl to 6 alkyl or C3 to 6 cycloalkyl; said alkyl group being optionally further substituted by one or more substituents selected independently from OH, CN,
  • R and R independently represent H, Cl to 6 alkyl, formyl or C2 to 6 alkanoyl;
  • R represents H, Cl to 6 alkyl or C3 to 6 cycloalkyl
  • R represents H, Cl to 6 alkyl or phenyl; said phenyl being optionally further substituted by halogen, Cl to 6 alkyl or Cl to 6 alkoxy;
  • R , R , R , R , R , R , R , R , R and R independently represent H or Cl to 6 alkyl; or a pharmaceutically acceptable salt thereof.
  • 3 1 2 3 1 represents CR ;
  • R represents Cl to 6 alkyl;
  • R and R each represent H;
  • G represents
  • R represents H
  • L represents Cl to 6 alkyl
  • G represents optionally substituted phenyl.
  • G represents phenyl substituted by OSO2R , S(O) 8 R ,
  • Cl to 6 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, t-butyl, pentyl and hexyl.
  • Cl to 3 alkyl and Cl to 4 alkyl are to be interpreted analogously.
  • Cl to 3 alkyl substituted by one or more F atoms include fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl, pentaffuoroethyl and 3,3,3-trifluoropropyl.
  • Cl to 6 alkoxy referred to herein denotes an oxygen substituent bonded to a straight or branched chain alkyl group having from 1 to 6 carbon atoms. Examples of such groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy and s-butoxy.
  • the terms "Cl to 3 alkoxy” and “Cl to 4 alkoxy” are to be interpreted analogously.
  • Cl to 3 alkoxy substituted by one or more F atoms include fiuoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy and 3,3,3-trifluoropropoxy.
  • C2 to 6 alkanoyl denotes a straight or branched chain alkyl group having from 1 to 5 carbon atoms bonded to the molecule via a carbonyl group. Examples of such groups include acetyl, propionyl and pivaloyl.
  • halogen referred to herein denotes fluorine, chlorine, bromine and iodine.
  • Examples of a five or six membered heteroaromatic ring containing 1 to 4 heteroatoms independently selected from O, S and N include furan, thiophene, pyrrole, oxazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, isoxazole, imidazole, pyrazole, thiazole, triazole, thiadiazole, pyridine, pyrimidine, pyrazine and tetrazole.
  • Examples of a five or six membered heteroaromatic ring containing 1 to 3 heteroatoms independently selected from O, S and N include furan, thiophene, pyrrole, oxazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, isoxazole, imidazole, pyrazole, thiazole, triazole, thiadiazole, pyridine, pyrimidine and pyrazine. Such groups are also examples of "heteroaryl" rings.
  • C3 to 6 saturated or partially unsaturated cycloalkyl referred to herein denotes a 3 to 6 membered non-aromatic carbocyclic ring optionally incorporating one or more double bonds. Examples include cyclopropyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl.
  • the term "five- or six-membered saturated or partially unsaturated cycloalkyl ring” is to be interpreted analogously.
  • NR and optionally further incorporating a carbonyl group denotes a 4 to 7 membered non-aromatic heterocyclic ring optionally incorporating one or more double bonds and optionally incorporating a carbonyl group.
  • Examples include tetrahydrofuran, thiolane 1,1 -dioxide, tetrahydropyran, 4-oxo-4H-pyran, pyrrolidine, pyrroline, imidazolidine, 1,3-dioxolane, piperidine, piperazine, morpholine, perhydroazepine, pyrrolidone and piperidone.
  • heterocycloalkyl five- or six-membered saturated or partially unsaturated heterocyclic ring containing one heteroatom selected from O, S and NR " is to be interpreted analogously. Such groups may alternatively be referred to as "heterocycloalkyl”.
  • Examples of a “5 to 7 membered azacyclic ring optionally incorporating one further 5 heteroatom selected from O, S and NR " include pyrrolidine, piperidine, morpholine, thiomorpholine and piperazine.
  • Cl to 6 alkyl; said alkyl optionally incorporating a heteroatom selected from O, S and NR embraces a straight or branched chain arrangement of 1 to 6 io carbon atoms in which any two carbon atoms are optionally separated by O, S or NR .
  • the definition thus includes, for example, methylene, ethylene, propylene, hexamethylene, ethylethylene, -CH 2 CH 2 O-CH 2 - -CH 2 CH 2 O-CH 2 -CH 2 - -CH 2 CH 2 S- and
  • Such groups may also be referred to as "(Cl-6)heteroalkyl” or “(Cl- 6)heteroalkylene”
  • bicyclic ring systems in which the two rings are either fused together, or are bonded directly together or are separated by a linker group selected from O, S(O)q or CH 2 include biphenyl, thienylphenyl, pyrazolylphenyl, phenoxyphenyl, naphthyl, indanyl, quinolyl, tetrahydroquinolyl, benzofuranyl, indolyl, isoindolyl, indolinyl, benzofuranyl, 20 benzothienyl, indazolyl, benzimidazolyl, benzthiazolyl, purinyl, isoquinolyl, chromanyl, indenyl, quinazolyl, quinoxalyl, chromanyl, isocromanyl, 3H-indolyl, lH-indazolyl, quinuclidyl, tetrahydronaphthyl, dihydrobenz
  • bicyclic ring systems in which the two rings are separated by a linker group S(0) q include 4-(piperazin-l-ylsulfonyl)phenyl, 4-(morpholin-4-ylsulfonyl)phenyl,
  • the hNE inhibitor is a 2-pyridone derivative of formula (II)
  • Y represents CR or N
  • R represents H or Cl to 6 alkyl
  • R represents phenyl or a five- or six-membered heteroaromatic ring containing 1 to 4 heteroatoms independently selected from O, S and N; said aromatic ring being optionally substituted by 1 to 3 substituents selected independently from OH, halogen, Cl to 6 alkyl, Cl to 6 alkoxy, NR 58 COR 50 , COOR 51 , COR 52 , CONR 53 R 54 and NR 47 R 48 ; said alkyl
  • R and R independently represent H, Cl to 6 alkyl or C2 to 6 alkanoyl
  • R represents H or F
  • G represents phenyl or a five- or six-membered heteroaromatic ring containing 1 to 3 heteroatoms independently selected from O, S and N;
  • R 5 represents H, halogen, Cl to 6 alkyl, CN, Cl to 6 alkoxy, NO 2 , NR 14 R 15 , Cl to 3 alkyl substituted by one or more F atoms or Cl to 3 alkoxy substituted by one or more F atoms;
  • R and R independently represent H or Cl to 3 alkyl; said alkyl being optionally further substituted by one or more F atoms; n represents an integer 1, 2 or 3 and when n represents 2 or 3, each R group is selected independently;
  • R represents H or Cl to 6 alkyl; said alkyl being optionally further substituted by OH or
  • group -NR L represents a 5 to 7 membered azacyclic ring optionally incorporating one further heteroatom selected from O, S and
  • 29 L represents a bond, O, S(O)p, NR or Cl to 6 alkyl; said alkyl optionally incorporating a heteroatom selected from O, S and NR ; and said alkyl being optionally further substituted by OH or OMe;
  • 2 G represents a monocyclic ring system selected from: i) phenyl or phenoxy, ii) a 5 or 6 membered heteroaromatic ring containing one to three heteroatoms independently selected from O, S and N, iii) a C3 to 6 saturated or partially unsaturated cycloalkyl, or iv) a C4 to 7 saturated or partially unsaturated heterocyclic ring containing one or two
  • each of the two rings is independently selected from: i) phenyl, ii) a 5 or 6 membered heteroaromatic ring containing one to three heteroatoms independently selected from O, S and N, iii) a C3 to 6 saturated or partially unsaturated cycloalkyl, or iv) a C4 to 7 saturated or partially unsaturated heterocyclic ring containing one or two
  • G may also represent H
  • p, q, s and t independently represent an integer 0, 1 or 2;
  • R and R independently represent H, Cl to 6 alkyl, formyl, C2 to 6 alkanoyl, S(O)tR
  • alkyl group being optionally further substituted by halogen, CN, Cl
  • R represents H, Cl to 6 alkyl or C3 to 6 cycloalkyl; said alkyl group being optionally further substituted by one or more substituents selected independently from OH, CN,Q CONR 35 R 36 , CO 2 R 37 , OCOR 40 , C3 to 6 cycloalkyl, a C4 to 7 saturated heterocyclic ring
  • R represents H, Cl to 6 alkyl or C3 to 6 cycloalkyl; R 16 , R 17 , R 20 , R 21 , R 22 , R 23 , R 24 , R 26 , R 27 , R 2 ', R 31 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 ,
  • R 4 ', R 50 , R 51 , R 52 , R 53 , R 54 , R 55 , R 56 , R 57 and R independently represent H or Cl to 6 alkyl;
  • R represents methyl;
  • R represents an optionally substituted five-membered heteroaromatic ring containing 2 or 3 heteroatoms selected independently from O, S and N;
  • G represents phenyl; R represents Cl, CH3, CN or CF3; R represents H; L represents Cl
  • G represents phenyl substituted by OSO 2 R , S(O) 3 R , SO 2 NR R ,
  • the hNE inhibitor is a 2- ⁇ yridone derivative of formula (III)
  • R represents hydrogen or Cj-Cg alkyl
  • W represents S(0) m wherein m represents an integer 0, 1 or 2;
  • 25 Z represents a single bond, -CH 2 - or -NR -; 14
  • R represents a hydrogen atom or OH or a group selected from Q -Cg alkyl and a saturated or unsaturated 3- to 10-membered ring system optionally comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur; each group being optionally substituted with at least one substituent selected from phenyl, Ci-Cg alkoxycarbonyl, halogen, C1-C4 alkyl, C1-C4 alkoxy, CN, OH, NO2, C1-C3 alkyl substituted by one or more F atoms, Ci -C3 alkoxy substituted by one or more F atoms, NR R , G ⁇ CR ,
  • R and R independently represent H, CJ-CO alkyl, formyl or C 2 -Cg alkanoyl; or the
  • group -NR R together represents a 5 to 7 membered azacyclic ring optionally incorporating one further heteroatom selected from O, S and NR ;
  • R represents H, C1-C3 alkyl, Si(CH3)3 or phenyl
  • R and R independently represent H or C1-C3 alkyl; said alkyl being optionally substituted by one or more F atoms;
  • R represents H or F;
  • R represents phenyl or a five- or six-membered heteroaromatic ring containing 1 to 3 heteroatoms independently selected from O, S and N; said ring being optionally substituted with at least one substituent selected from halogen, Ct-Cg alkyl, cyano, Ci -CO alkoxy, nitro, methylcarbonyl, NR R , C1-C3 alkyl substituted by one or more F atoms or C1-C3 alkoxy substituted by one or more F atoms;
  • R and R independently represent H or C1-C3 alkyl; said alkyl being optionally further substituted by one or more F atoms;
  • R represents hydrogen or Ci-Cg alkyl optionally substituted with at least one substituent
  • 24 X represents a single bond, O, NR or a group -Ci-Cg alkylene-Y-, wherein Y represents
  • alkylene 24 a single bond, oxygen atom, NR or S(0) w ; and said alkylene being optionally further 17 18 19 40 41 substituted by OH, halogen, CN, NR R , C 1 -C 3 alkoxy, CONR R SO 2 R and
  • R and X are joined together such that the group -NR X together represents a 5 to 7 membered azacyclic ring optionally incorporating one further heteroatom selected from O,
  • a 5- or 6-membered heteroaromatic ring comprising at least one ring heteroatom selected from nitrogen, oxygen and sulphur, iv)a saturated or partially unsaturated C 3 -Cg hydrocarbyl ring, or v) a saturated or partially unsaturated 4- to 7-membered heterocyclic ring comprising
  • ring heteroatom selected from oxygen, S(O) 1 - and NR , wherein at least one of the ring carbon atoms may be optionally replaced by a carbonyl group,
  • R represents a bicyclic ring system in which the two rings are independently selected from the monocyclic ring systems defined in ii), iii), iv) and v) above, wherein the two rings are either fused together, bonded directly to one another or are separated from one another by a linker group selected from oxygen, S(O)t or C 1 -CO alkylene optionally comprising one or more internal or terminal heteroatoms selected from oxygen, sulphur
  • NR 55 C( NH)NH 2 , S(O) V R 21 , SO 2 NR 56 R 57 , C 1 -C 3 alkoxy substituted by one or more F 58 atoms and Ci-C 3 alkyl substituted by SO2R or by one or more F atoms; said C1-C6 alkyl being optionally further substituted with at least one substituent selected from cyano, hydroxyl, Ci-C 6 alkoxy, Ci-C 6 alkylthio and -C(O)NR 22 R 23 ; or R may also represent H; R represents hydrogen, Q-C 6 alkyl, Ci-C 6 alkylcarbonyl or Ci-C 6 alkoxycarbonyl;
  • R represents hydrogen, Ci-C 6 alkyl or C 3 -Cs cycloalkyl; said alkyl or cycloalkyl group being optionally further substituted by one or more substituents selected independently from OH, CN 5 C1-C3 alkoxy and CONR 59 R 60 ;
  • R and R independently represent H, Ci-C 6 alkyl, formyl or C2-C 6 alkanoyl; R and R independently represent H, Ci-C 6 alkyl, formyl, C2-C 6 alkanoyl, S(O)qR
  • alkyl group being optionally further substituted by halogen, CN, Ci-C 4 alkoxy or CONR 64 R 65 ;
  • R and R independently represent H, Ci-C 6 alkyl or C 3 -C 6 cycloalkyl; p is O, 1 or 2; q is O, 1 or 2; r is 0, 1 or 2; t is 0, 1 or 2; w is 0, 1 or 2; v is 0, 1 or 2; R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 31 , R 32 , R 3 ', R 40 , R 42 , R 43 , R 44 , R 45 , R 46 , R 49 , R 50 , R 51 , R 52 , R 53 , R 54 , R 55 , R 56 , R 57 , R 58 , R 59 , R 60 , R 62 , R 63 , R M and R 65 each independently represent hydrogen or Ci-C 6 alkyl; or a pharmaceutically acceptable salt thereof.
  • R represents methyl
  • W represents
  • Z represents a single bond
  • R represents H
  • R represents a phenyl group substituted with a trifluoromethyl substituent
  • R represents hydrogen; X represents methylene; and R represents phenyl or pyridinyl
  • R represents methyl
  • W represents
  • Z represents a single bond
  • R represents phenyl optionally substituted by one or two substituents independently selected from cyano, F, Cl, Br, CF3, NO2 and -C ⁇ CH;
  • R represents a phenyl group substituted with a trifluoromethyl substituent
  • R represents hydrogen
  • X represents a linear or branched C1-C4 alkylene optionally substituted by OH, F, CN or OCH 3
  • R 5 represents H.
  • 2-Pyridone derivatives of formulae (I), (II) and (III) may be prepared according to known chemistry, for example by methods according to or analogous to those described in WO 2004/043924, WO 2005/026123 and WO 2006/098684.
  • the 2-pyridone derivatives of formulae (I), (II) and (III) may exist in enantiomeric forms. It is to be understood that all enantiomers, diastereomers, racemates and mixtures thereof are included within the scope of the invention.
  • the hNE inhibitor is:
  • 3-carboxylic acid 4-methanesulfonyl-benzylamide; 6-methyl-5-(5-methyl-4H-[l,2,4]triazol-3-yl)-2-oxo-l-(3-trifluorometliyl ⁇ henyl)-l,2- dihydro-pyridine-3 -carboxylic acid 4-methylsulfonyl-benzylamide;
  • an active ingredient in the combination of the present invention is an MMP inhibitor.
  • MMP inhibitors which may be used in accordance with the present invention include hydantoin derivatives having MMP inhibitor properties, as for example described in WO 02/074748, WO 02/074749, WO 02/074751 , WO 02/074752, WO 02/074767 and WO 04/020415, WO 05/095362, WO 06/004532, WO 06/004533, WO 06/065215 and WO 06/065216, the entire contents of which are incorporated herein by reference.
  • the MMP inhibitor is a hydantoin derivative of s formula (IV)
  • each of Gl and G2 is a monocyclic ring structure comprising each of up to 6 ring atoms independently selected from (C3-6)cycloalkyl, phenyl, heterocycloalkyl or heteroaryl, with each ring structure being independently optionally substituted by one or two substituents independently selected from halogen, hydroxy, halo-(Cl-6)alkoxy, acetamido, cyano, (Cl-
  • B is selected from a direct bond, O, (Cl-6)alkyl, (Cl-6)heteroalkyl, CO, NHCO, CONH,
  • R2 is selected from H, (Cl-6)alkyl, alkoxyalkyl, aminoalkyl, (N-alkylamino)alkyl, (N,N- dialkylamino)alkyl and amidoalkyl, or R2 is a group of formula (V)
  • (V) D and E are independently selected from a direct bond, H, (Cl-C ⁇ )alkyl and (Cl-
  • G3 is a monocyclic ring structure comprising up to 6 ring atoms independently selected from phenyl, heterocycloalkyl and heteroaryl, optionally substituted by one or two substituents independently selected from halogen, aminocarbonyl and (Cl-6)alkyl;
  • R3 is selected from H or (Cl-3)alkyl and R4 is H;
  • R2 and R3 may join to form a ring comprising up to 7 ring atoms, or R3 and R4 may join to form a ring comprising up to 7 ring atoms; or a pharmaceutically acceptable salt thereof.
  • the MMP inhibitor is a compound of formula (VI)
  • Gl is a monocyclic ring structure comprising each of up to 7 ring atoms independently selected from (C3-7)cycloalkyl, phenyl, heterocycloalkyl or heteroaryl, with each ring structure being independently optionally substituted by one or two substituents independently selected from halogen, hydroxy, halo-(Cl-6)alkoxy, acetamido, cyano, (Cl- 6)alkyl, (Cl- ⁇ )alkoxy and alkylsulfonyl, wherein any alkyl radical within any substituent may itself be optionally substituted with one or more groups selected from halogen, hydroxy and (Cl- ⁇ )alkoxy;
  • G2 is optionally substituted piperidine or piperazine
  • B is selected from a direct bond, O, CO, S and (C2-6)alkynyl;
  • R2 is selected from H, (Cl- ⁇ )alkyl, alkoxyalkyl, aminoalkyl, (N-alkylamino)alkyl, (N 5 N- dialkylamino)alkyl and amidoalkyl or R2 is a group of formula (VII)
  • D and E are independently selected from a direct bond, H, (Cl-C ⁇ )alkyl and (Cl-
  • G3 is a monocyclic ring structure comprising up to 7 ring atoms independently selected from phenyl, heterocycloalkyl and heteroaryl, optionally substituted by one or two substituents independently selected from halogen, aminocarbonyl and (Cl- ⁇ )alkyl;
  • R3 is selected from H or (Cl-3)alkyl and R4 is H;
  • R2 and R3 may join to form a ring comprising up to 7 ring atoms, or R3 and R4 may join to form a ring comprising up to 7 ring atoms; or a pharmaceutically acceptable salt thereof.
  • the MMP inhibitor is a hydantoin derivative of formula (IV)
  • each of Gl and G2 is a monocyclic ring structure comprising each of up to 6 ring atoms independently selected from cycloalkyl, phenyl, heterocycloalkyl or heteroaryl, with each ring structure being independently optionally substituted by one or two substituents independently selected from halogen, cyano, Cj -C ⁇ alkyl and Ci-Cg alkoxy, wherein any alkyl radical within any substituent may itself be optionally substituted with one or more groups selected from halogen;
  • Z is SO 2 N(Ro);
  • B is selected from a direct bond, O and Cl-6alkylene;
  • R2 is selected from H, Cl-6alkyl and phenyl;
  • R3 and R4 are independently selected from H or Cl-3alkyl;
  • R6 is H or R6 is Cl-3alkyl optionally substituted by phenyl, heteroaryl or heterocycloalkyl;
  • R2 and R6 may join to form a ring comprising up to 6 ring atoms or R3 and R6 may join to form a ring comprising up to 6 ring atoms; or a pharmaceutically acceptable salt thereof.
  • Gl and G2 are independently selected from phenyl and heteroaryl and R3 and R6 are joined so as to form a 5- or 6-membered ring.
  • the MMP inhibitor is a compound of formula (VIII)
  • R represents Cl to 2 alkyl, cyclopropyl, OCH3, SCH3 or OCF3; said alkyl or cyclopropyl group being optionally further substituted by one or more fluoro atoms;
  • R represents Cl to 3 alkyl; or a pharmaceutically acceptable salt thereof.
  • the MMP inhibitor is a compound of formula (IX)
  • R represents cyclobutyl or cyclopropyl; said cyclopropyl group being optionally further substituted by CH3, CN or one or two fluoro atoms;
  • R represents Cl to 3 alkyl or cyclopropyl
  • A, A and B independently represent CH or N; or a pharmaceutically acceptable salts thereof.
  • Hydantoin derivatives of formulae (IV), (VI), (VIII) and (IX) may be prepared according to known chemistry, for example by methods according to or analogous to those described in WO 02/074751, WO 02/074767, WO 06/004532 and WO 06/065215.
  • hydantoin derivatives of formulae (IV), (VI), (VIII) and (IX) may exist in enantiomeric forms. It is to be understood that all enantiomers, diastereomers, racemates and mixtures thereof are included within the scope of the invention.
  • the MMP inhibitor is: (5iS)-5-[( ⁇ 4-[(5-bromopyridin-2-yl)oxy]piperidin-l-yl ⁇ sulfonyl)methyl]-5- methylimidazolidme-2,4-dione; (5JS)-5- [4-(3 ,4-dichloro-phenoxy)-piperidine- 1 -sulfonylmethyl]-5 -methyl-imidazolidine-
  • the present invention includes compounds of formulae (I), (II), (III), (IV), (VI), (VIII) and (IX) in the form of salts, in particular acid addition salts.
  • Suitable salts include those formed with both organic and inorganic acids. Such acid addition salts will normally be pharmaceutically acceptable although salts of non-pharmaceutically acceptable acids may be of utility in the preparation and purification of the compound in question.
  • preferred salts include those formed from hydrochloric, hydrobromic, sulphuric, phosphoric, citric, tartaric, lactic, pyruvic, acetic, succinic, fumaric, maleic, methanesulphonic and benzenesulphonic acids.
  • the first active ingredient and the second 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 administerted 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 most appropriate method of administering the active ingredients is dependent on a number of factors.
  • the active ingredients are administered via separate pharmaceutical preparations.
  • each pharmaceutical preparation may be independently adapted for oral, parenteral or topical administration.
  • the different pharmaceutical preparations of active ingredients may be administered simultaneously, sequentially or separately.
  • the present invention provides a kit comprising a preparation of a first active ingredient which is a hNE inhibitor, 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 present invention provides a kit comprising a preparation of a first active ingredient which is a MMP inhibitor, 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 present invention provides a kit comprising a preparation of a first active ingredient which is a hNE inhibitor, and a preparation of a second active ingredient which is a MMP inhibitor, and optionally instructions for the simultaneous, sequential or separate administration of the preparations to a patient in need thereof.
  • 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 a hNE inhibitor, and a second active ingredient.
  • the present invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising, in admixture, a first active ingredient, which is a MMP inhibitor, and a second active ingredient.
  • the present invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising, in admixture, a first active ingredient, which is a hNE inhibitor, and a second active ingredient, which is a MMP inhibitor.
  • compositions of the present invention may be prepared by mixing the first active ingredient with the second active ingredient and a pharmaceutically acceptable adjuvant, diluent or carrier. Therefore, in a further aspect of the present invention there is provided a process for the preparation of a pharmaceutical composition, which comprises mixing a hNE inhibitor with a second active ingredient and a pharmaceutically acceptable adjuvant, diluent or carrier.
  • a process for the preparation of a pharmaceutical composition which comprises mixing a MMP inhibitor with a second active ingredient and a pharmaceutically acceptable adjuvant, diluent or carrier.
  • a process for the preparation of a pharmaceutical composition which comprises mixing a hNE inhibitor with a MMP inhibitor and a pharmaceutically acceptable adjuvant, diluent or carrier.
  • 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 active ingredient is dosed in the range of from 0.1 microgram ( ⁇ g) to 5000 ⁇ g, 0.1 to 1000 ⁇ g, 0.1 to 500 ⁇ g, 0.1 to 100 ⁇ g, 0.1 to 50 ⁇ g, 0.1 to 5 ⁇ g, 5 to 5000 ⁇ g, 5 to 1000 ⁇ g, 5 to 500 ⁇ g, 5 to 100 ⁇ g, 5 to 50 ⁇ g, 5 to 10 ⁇ g, 10 to 5000 ⁇ g, 10 to 1000 ⁇ g, 10 to 500 ⁇ g, 10 to 100 ⁇ g, 10 to 50 ⁇ g, 20 to 5000 ⁇ g, 20 to 1000 ⁇ g, 20 to 500 ⁇ g, 20 to 100 ⁇ g, 20 to 50 ⁇ g, 50 to 5000 ⁇ g, 50 to 1000 ⁇ g, 50 to 500 ⁇ g, 50 to 100 ⁇ g, 100 to 5000 ⁇ g, 100 to 1000 ⁇ g or 100 to 500 ⁇ g.
  • the dose will generally be administered from 1 to
  • the active ingredient is dosed in the range of from 5 to 1000 milligram (mg), 5 to 800 mg, 5 to 600 mg, 5 to 500 mg, 5 to 400 mg, 5 to 300 mg, 5 to 200 mg, 5 to 100 mg, 5 to 50 mg, 20 to 1000 mg, 20 to 800 mg, 20 to 600 mg, 20 to 500 mg, 20 to 400 mg, 20 to 300 mg, 20 to 200 mg, 20 to 100 mg, 20 to 50 mg, 50 to 1000 mg, 50 to 800 mg, 50 to 600 mg, 50 to 500 mg, 50 to 400 mg, 50 to 300 mg, 50 to 200 mg, 50 to 100 mg, 100 to 1000 mg, 100 to 800 mg, 100 to 600 mg, 100 to 500 mg, 100 to 400 mg, 100 to 300 mg, or 100 to 200 mg.
  • the dose 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 hNE inhibitor, and a second active ingredient, wherein each active ingredient is formulated for oral administration.
  • the present invention provides a pharmaceutical product comprising, in combination, a first active ingredient which is a MMP inhibitor, and a second active ingredient, wherein each active ingredient is formulated for oral administration.
  • the present invention provides a pharmaceutical product comprising, in combination, a first active ingredient which is a hNE inhibitor, and a second active ingredient which is a MMP inhibitor, wherein each active ingredient is formulated for oral administration.
  • the present invention provides a pharmaceutical product comprising, in combination, a first active ingredient which is a hNE inhibitor, and a second active ingredient, wherein each active ingredient is formulated for inhaled administration.
  • the present invention provides a pharmaceutical product comprising, in combination, a first active ingredient which is a MMP inhibitor, and a second active ingredient, wherein each active ingredient is formulated for inhaled administration.
  • the present invention provides a pharmaceutical product comprising, in combination, a first active ingredient which is a hNE inhibitor, and a second active ingredient which is a MMP inhibitor, wherein each active ingredient is formulated for inhaled administration.
  • the active ingredients of the present invention 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.
  • 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, surfactants, lubricants or stabilising agents.
  • suitable propellants include hydrocarbon, chlorofluorocarbon and hydrofluoroalkane (e.g. heptafluoroalkane) propellants, or mixtures of any such propellants.
  • Preferred propellants are P 134a 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.
  • Metered dose inhaler, nebuliser and dry powder inhaler devices are well known in the art and a variety of such devices are available.
  • 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:
  • the present invention still further provides a method of treating a respiratory disease which comprises simultaneously, sequentially or separately administering:
  • the present invention still further provides a method of treating a respiratory disease which comprises simultaneously, sequentially or separately administering:
  • the term “therapy” also includes “prophylaxis” unless there are specific indications to the contrary.
  • the terms “therapeutic” and “therapeutically” should be construed accordingly. Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the condition or disorder in question. Persons at risk of developing a particular condition or disorder generally include those having a family history of the condition or disorder, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the condition or disorder.
  • the invention further relates to triple combination therapies for the treatment of inflammatory diseases or conditions such as rheumatoid arthritis, osteoarthritis, osteoporosis, psoriasis, inflammatory bowel diseases, COPD, asthma, allergic rhinitis or cancer or the neurodegenerative diseases such as multiple sclerosis or Alzheimer's disease, wherein:
  • a first active ingredient being a neutrophil elastase inhibitor is used in combination with two further active ingredients;
  • a first active ingredient being a MMP inhibitor is used in combination with two further active ingredients;
  • a first active ingredient being a neutrophil elastase inhibitor and a second active ingredient being a MMP inhibitor is used in combination with one further active ingredient.
  • the further active ingredient or ingredients may be chosen from:
  • a non-steroidal anti-inflammatory agent 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); glucocorticosteroids (whether administered by topical, oral, intramuscular
  • a monoclonal antibody targeting B-Lymphocytes such as CD20 (rituximab), MRA-aIL16R and T-Lymphocytes, CTLA4-Ig, HuMax 11-15).
  • 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.
  • 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; a N-(5-substituted)-thiophene-2- alkylsulfonamide; 2,6-di-tert-butylphenolhydrazones; a methoxytetrahydropyrans such as Zeneca ZD-2138; the compound SB-210661; a pyridinyl-substituted 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.
  • 5-LO 5-lipoxygenase
  • FLAP 5- lipoxygenase
  • a receptor antagonist for leukotrienes (LT) B4, LTC4, LTD4, and LTE4. selected from the group consisting of the phenothiazin-3-ls such as L-651,392; amidino compounds such as CGS-25019c; benzoxalamines such as ontazolast; benzenecarboximidamides such as BIIL 284/260; and compounds such as zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP 45715A), and BAY x 7195.
  • the phenothiazin-3-ls such as L-651,392
  • amidino compounds such as CGS-25019c
  • benzoxalamines such as ontazolast
  • benzenecarboximidamides such as BIIL 284/260
  • compounds such as
  • 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
  • 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 proton pump inhibitor such as omeprazole or a gastroprotective histamine type 2 receptor antagonist.
  • 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 anticholinergic agent including muscarinic receptor (Ml, M2, and M3) antagonist such as atropine, hyoscine, glycopyrrrolate, ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine.
  • Ml, M2, and M3 antagonist such as atropine, hyoscine, glycopyrrrolate, ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine.
  • a beta-adrenoceptor agonist such as isoprenaline, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, or pirbuterol, or a chiral enantiomer thereof
  • a chromone such as sodium cromoglycate or nedocromil sodium
  • a glucocorticoid such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide or mometasone furoate; or a non-steroidal glucocorticoid receptor agonist.
  • 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 efavirenz.
  • an antiviral agent including acycl
  • 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.
  • ACE angiotensin-converting enzyme
  • an angiotensin-2 receptor antagonist such as a statin or a fibrate
  • a modulator of blood cell morphology such as pentoxyfylline
  • thrombolytic thrombolytic
  • an anticoagulant such as a platelet aggregation inhibitor.
  • 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 inhibitor such as selegine and rasagiline
  • 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 non-steroidal anti-inflammatory agent.
  • a parenterally or topically-applied (including inhaled) local anaesthetic agent such as lignocaine or a derivative thereof.
  • An anti-osteoporosis agent including a hormonal agent such as raloxifene, or a biphosphonate such as alendronate.
  • a tryptase inhibitor a platelet activating factor (PAF) antagonist; an interleukin converting enzyme (ICE) inhibitor; an IMPDH inhibitor; an adhesion molecule inhibitors including VLA-4 antagonist; cathepsin; a kinase inhibitor such as an inhibitor of tyrosine kinase (such as Btk, Itk, Jak3 or MAP, for example, Gef ⁇ tinib 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 IBCK), or a kinase involved in cell cycle regulation (such as a cylin dependent kinase); a glucose-6 phosphate dehydrogenase inhibitor; a kinin-B.subl.
  • PAF platelet activating factor
  • ICE interleukin converting enzyme
  • -receptor antagonist an anti-gout agent, for example colchicine; a xanthine oxidase inhibitor, for example allopurinol; a uricosuric agent, for example probenecid, sulfinpyrazone or benzbromarone; a growth ho ⁇ none secretagogue; a transforming growth factor (TGF ⁇ ); a platelet-derived growth factor (PDGF); a fibroblast growth factor for example basic fibroblast growth factor (bFGF); a granulocyte macrophage colony stimulating factor (GM-CSF); capsaicin cream; a tachykinin NK.subl. or NK.sub3.
  • TGF ⁇ transforming growth factor
  • PDGF platelet-derived growth factor
  • bFGF fibroblast growth factor for example basic fibroblast growth factor
  • GM-CSF granulocyte macrophage colony stimulating factor
  • capsaicin cream a tachykinin NK.subl. or NK.
  • TNF-alpha converting enzyme inhibitor TACE
  • iNOS induced nitric oxide synthase
  • TLR Toll-like receptors
  • i-p-X pentobarbitone sodium
  • i-p-X pentobarbitone sodium
  • BALF bronchoalveolar lavage fluid
  • test compounds were prepared as suspensions in hydroxypropylmethylcellulose (HPMC) 0.5%: water 99.5% on the day of the experiment.
  • HPMC hydroxypropylmethylcellulose
  • the formulation of the liNE inhibitor, 6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-l-[3- (trifluoromethyl)phenyl]-l,2-dihydropyridine-3-carboxamide, hereinafter Compound A was prepared as a 1 or 2 mg/ml suspension.
  • mice were given oral administration of a combination of Compound A (5 ml/kg of a 2 mg/ml formulation giving a total dose of 10 mg/ml, p.o.) and Compound B (5 ml/kg of a 2 mg/ml formulation giving a total dose of 10 mg/ml, p.o.) twice in a day (1 st dose 30 min prior to the start of acrolein exposure; 2 nd dose immediately after the acrolein exposure; and 3 rd dose on day 2 in the morning).
  • the group of control animals received an equal volume of vehicle (10 ml/kg animal weight, p.o.).
  • the formulations of Compound A and Compound B were administered separately one after another keeping the total volume of administration to 10 ml/kg at each dosing time.
  • treatment with either Compound A (10 mg/kg) or Compound B (10 mg/kg) alone in this study did not produce any significant effect on neutrophils or TIMP-I levels (Table 1).

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  • Health & Medical Sciences (AREA)
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  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Pulmonology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention porte sur un produit pharmaceutique, une trousse ou une composition comprenant un premier principe actif qui est un inhibiteur du hNE ou un inhibiteur du MMP et un deuxième principe actif, s'utilisant dans le traitement de maladies respiratoires comme l'obstruction pulmonaire chronique et l'asthme.
PCT/GB2007/004139 2006-10-30 2007-10-29 Thérapie combinée pour traiter des maladies respiratoire WO2008053199A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11130740B2 (en) 2017-04-25 2021-09-28 Arbutus Biopharma Corporation Substituted 2,3-dihydro-1H-indene analogs and methods using same

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002074767A1 (fr) * 2001-03-15 2002-09-26 Astrazeneca Ab Inhibiteurs des metalloproteinases
WO2004043924A1 (fr) * 2002-11-12 2004-05-27 Astrazeneca Ab Derives de 2-pyridone en tant qu'inhibiteurs de l'elastase de neutrophile
US20050201951A1 (en) * 2004-03-09 2005-09-15 Barr Philip J. Treatment of chronic obstructive pulmonary disease by low dose inhalation of protease inhibitor
US20060009494A1 (en) * 1999-05-20 2006-01-12 Voorhees John J Compositions and methods for use against acne-induced inflammation and dermal matrix-degrading enzymes

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060009494A1 (en) * 1999-05-20 2006-01-12 Voorhees John J Compositions and methods for use against acne-induced inflammation and dermal matrix-degrading enzymes
WO2002074767A1 (fr) * 2001-03-15 2002-09-26 Astrazeneca Ab Inhibiteurs des metalloproteinases
WO2004043924A1 (fr) * 2002-11-12 2004-05-27 Astrazeneca Ab Derives de 2-pyridone en tant qu'inhibiteurs de l'elastase de neutrophile
US20050201951A1 (en) * 2004-03-09 2005-09-15 Barr Philip J. Treatment of chronic obstructive pulmonary disease by low dose inhalation of protease inhibitor

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11130740B2 (en) 2017-04-25 2021-09-28 Arbutus Biopharma Corporation Substituted 2,3-dihydro-1H-indene analogs and methods using same

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