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WO2008104776A1 - Nouvelle combinaison 667 - Google Patents

Nouvelle combinaison 667 Download PDF

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Publication number
WO2008104776A1
WO2008104776A1 PCT/GB2008/000667 GB2008000667W WO2008104776A1 WO 2008104776 A1 WO2008104776 A1 WO 2008104776A1 GB 2008000667 W GB2008000667 W GB 2008000667W WO 2008104776 A1 WO2008104776 A1 WO 2008104776A1
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WO
WIPO (PCT)
Prior art keywords
amino
chloro
oxy
hydroxy
piperidin
Prior art date
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Ceased
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PCT/GB2008/000667
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English (en)
Inventor
Elaine Bridget Cadogan
Stephen Connolly
David John Nicholls
Alan Young
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AstraZeneca UK Ltd
AstraZeneca AB
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AstraZeneca UK Ltd
AstraZeneca AB
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Publication of WO2008104776A1 publication Critical patent/WO2008104776A1/fr
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    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings

Definitions

  • the present invention relates to a combination of two or more pharmaceutically active substances for use in the treatment of respiratory diseases (for example chronic obstructive pulmonary disease (COPD) or asthma).
  • respiratory diseases for example chronic obstructive pulmonary disease (COPD) or 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.
  • Corticosteroids also known as glucocorticosteroids or glucocorticoids
  • glucocorticosteroids are potent antiinflammatory agents. Whilst their exact mechanism of action is not clear, the end result of corticosteroid treatment is a decrease in the number, activity and movement of inflammatory cells into the bronchial submucosa, leading to decreased airway responsiveness. Corticosteroids may also cause reduced shedding of bronchial epithelial lining, vascular permeability, and mucus secretion. Whilst corticosteroid treatment can yield important benefits, the efficacy of these agents is often far from satisfactory, particularly in COPD.
  • steroids may lead to therapeutic effects
  • Recent studies have also highlighted the problem of the acquisition of steroid resistance amongst patients suffering from respiratory diseases. For example, cigarette smokers with asthma have been found to be insensitive to short term inhaled corticosteroid therapy, but the disparity of the response between smokers and non-smokers appears to be reduced with high dose inhaled corticosteroid (Tomlinson et al., Thorax 2005;60:282-287).
  • a further class of therapeutic agent used in the treatment of respiratory diseases are bronchodilators.
  • Bronchodilators may be used to alleviate symptoms of respiratory diseases by relaxing the bronchial smooth muscles, reducing airway obstruction, reducing lung hyperinflation and decreasing shortness of breath.
  • Types of bronchodilators in clinical use include ⁇ 2 adrenoceptor agonists, muscarinic receptor antagonists and methylxanthines. Bronchodilators are prescribed mainly for symptomatic relief and they are not considered to alter the natural history of respiratory diseases.
  • Example 25 in PCT/SE2006/000981 produces what is referred to herein as Polymorphic Form A of the dihydrobromide salt of 7-[(l/?)-2-( ⁇ 2-[(3- ⁇ [2-(2-Chlorophenyl)ethyl]amino ⁇ - propyl)thio]ethyl ⁇ amino)- 1 -hydroxyethyl]-4-hydroxy- 1 ,3-benzothiazol-2(3H)-one.
  • the compound and its salts show at least a 10-fold selectivity of ⁇ 2 adrenoceptor agonism over adrenergic ⁇ lD, adrenergic ⁇ l and dopamine D2 activities.
  • Combination products comprising a ⁇ 2 adrenoceptor agonist and a corticosteroid are available.
  • One such product is a combination of budesonide and formoterol fumarate (marketed by AstraZeneca under the tradename Symbicort ®), which has proven to be effective in controlling asthma and COPD, and improving quality of life in many patients.
  • the present invention provides a pharmaceutical product comprising, in combination, a first active ingredient which is 7-[(l/?)-2-( ⁇ 2-[(3- ⁇ [2-(2-)
  • a second active ingredient selected from: a non-steroidal Glucocorticoid Receptor (GR Receptor) Agonist; an antioxidant; a CCRl antagonist; a chemokine antagonist (not CCRl); a corticosteroid; a CRTh2 antagonist; a DPI antagonist; an ⁇ istone Deacetylase Inducer; an IKK2 inhibitor; a COX inhibitor; a lipoxygenase inhibitor; a leukotriene receptor antagonist; an MPO inhibitor; a muscarinic antagonist which is Aclidinium bromide, Glycopyrrolate (such as R 5 R-, R,S-,
  • S 5 R-, or S,S-glycopyrronium bromide Oxitropium bromide, Pirenzepine, telenzepine or Tiotropium bromide; a p38 inhibitor; a PDE inhibitor; a PPAR ⁇ agonist; a protease inhibitor; a Statin; a thromboxane antagonist; a vasodilator; or, an ENAC blocker (Epithelial Sodium-channel blocker).
  • the first and second active ingredients are in forms suitable for oral administration.
  • a suitable salt of 7-[(17?)-2-( ⁇ 2-[(3- ⁇ [2-(2-Chlorophenyl)ethyl]amino ⁇ propyl)thio]- ethyl ⁇ amino)-l-hydroxyethyl]-4-hydroxy-l,3-benzothiazol-2(3H)-one is, for example, a hydrochloride, hydrobromide (such as dihydrobromide), trifluoroacetate, sulphate, phosphate, acetate, fumarate, maleate, tartrate, lactate, citrate, pyruvate, succinate, oxalate, methanesulphonate, />-toluenesulphonate, bisulphate, benzenesulphonate, ethanesulphonate, malonate, xinafoate, ascorbate, oleate, nic
  • the first and second active ingredients can be administered simultaneously (either in a single pharmaceutical preparation (that is, the active ingredients are in admixture) or via or separate preparations), or sequentially or separately via separate pharmaceutical preparations.
  • a non-steroidal glucocorticoid receptor (GR) agonist is, for example, a compound disclosed in WO 2006/046916.
  • An antioxidant is, for example, Allopurinol, Erdosteine, Mannitol, N-acetyl cysteine choline ester, N-acetyl cysteine ethyl ester, N-Acetylcysteine, N-Acetylcysteine amide or Niacin.
  • a CCRl antagonist is, for example, a compound disclosed in WO2001/062728 or WO2001/098273 such as N-(2 ⁇ (2S)-3[ ⁇ (3R)-l-[(4-chlorophenyl)methyl]-3- pyrrolidiny 1 ⁇ amino]-2-hy droxypropoxy ⁇ -4-fluoropheny l)acetamide, N-(2 ⁇ (2S)-3 [ ⁇ (3 S)- 1 - [(4-chlorophenyl)methyl]-3-pyrrolidinyl ⁇ amino]-2-hydroxypropoxy ⁇ -4- fluoropheny l)acetamide, N-(2- ⁇ (2S)-3 - [ 1 - ⁇ (4-chlorobenzoy l)-4-piperidinyl ⁇ amino]-2- hydroxypropoxy ⁇ -4-hydroxyphenyl)acetamide, (2- ⁇ [(2S)-3- ⁇ [(2R,5S)- 1
  • a chemokine antagonist (other than a CCRl antagonist), for example, 656933 (N-(2- bromophenyl)-N'-(4-cyano-l ⁇ -l,2,3-benzotriazol-7-yl)urea), 766994 (4-( ⁇ [( ⁇ [(2R)-4-(3,4- dichlorobenzyl)morpholin-2-yl]methyl ⁇ amino)carbonyl]-amino ⁇ methyl)benzamide), CCX-282, CCX-915, Cyanovirin N, E-921, INCB-003284, INCB-9471, Maraviroc, MLN- 3701, MLN-3897, T-487 (N- ⁇ l-[3-(4-ethoxyphenyl)-4-oxo-3,4-dihydropyrido[2,3- d]pyrimidin-2-yl]ethyl ⁇ -N-(pyridin-3-ylmethyl)-2-[4-(triflu
  • a corticosteroid is, for example, Alclometasone dipropionate, Amelometasone, Beclomethasone dipropionate, Budesonide, Butixocort propionate, Ciclesonide, Clobetasol propionate, Desisobutyrylciclesonide, Etiprednol dicloacetate, Fluocinolone acetonide, Fluticasone Furoate, Fluticasone propionate, Loteprednol etabonate (topical) or Mometasone furoate.
  • a CRTh2 antagonist is, for example, a compound from WO 2004/106302 or WO 2005/018529.
  • a DPI antagonist is, for example, L888839 or MK0525.
  • An histone deacetylase inducer is, for example, ADC4022, Aminophylline, a Methylxanthine or Theophylline.
  • IKK2 inhibitor is, for example, 2- ⁇ [2-(2-Methylamino-pyrimidin-4-yl)-lH-indole-5- carbonyl]-amino ⁇ -3-(phenyl-pyridin-2-yl-amino)-propionic acid.
  • a COX inhibitor is, for example, Celecoxib, Diclofenac sodium, Etodolac, Ibuprofen, Indomethacin, Meloxicam, Nimesulide, OC 1768, OC2125, OC2184, OC499, OCD9101, I 0 Parecoxib sodium, Piceatannol, Piroxicam, Rofecoxib or Valdecoxib.
  • a lipoxygenase inhibitor is, for example, Ajulemic acid, Darbufelone, Darbufelone mesilate, Dexibuprofen lysine (monohydrate), Etalocib sodium, Licofelone, Linazolast, Lonapalene, Masoprocol, MN-OOl, Tepoxalin, UCB-35440, Veliflapon, ZD-2138, ZD- i 5 4007 or Zileuton (( ⁇ )-l-(l-Benzo[b]thien-2-ylethyl)-l-hydroxyurea).
  • a leukotriene receptor antagonist is, for example, Ablukast, Iralukast (CGP 45715A), Montelukast, Montelukast sodium, Ontazolast, Pranlukast, Pranlukast hydrate (mono Na salt), Verlukast (MK-679) or Zafirlukast. 0
  • An MPO Inhibitor is, for example, a Hydroxamic acid derivative (N-(4-chloro-2-methyl- phenyl)-4-phenyl-4-[[(4-propan-2-ylphenyl)sulfonylamino]methyl]piperidine-l- carboxamide), Piceatannol or Resveratrol.
  • a p38 Inhibitor is, for example, a compound from WO 2005/042502, 681323, 856553, AMG548 (2-[[(2S)-2-amino-3-phenylpropyl]amino]-3-methyl-5-(2-naphthalenyl)-6-(4- pyridinyl)-4(3H)-pyrimidinone), Array-797, AZD6703, Doramapimod, KC-706, PH 797804, Rl 503, SC-80036, SCIO469, 6-chloro-5-[[(25,5/?)-4-[(4-fluorophenyl)methyl]- 2,5-domethyl- 1 -piperazinyl]carbonyl]-iV,N, 1 -trimethyl- ⁇ -oxo- 1 H-indole-3-acetamide,0 VX702 or VX745 (5-(2,6-dichlorophenyl)-2-(phenylthio)
  • a PDE Inhibitor such as a PDE4 inhibitor, for example, 256066, Arofylline (3-(4- chlorophenyl)-3,7-dihydro-l -propyl- lH-Purine-2,6-dione), AWD 12-281 (N-(3,5-dichloro- 4-pyridinyl)-l-[(4-fluorophenyl)methyl]-5-hydroxy- ⁇ -oxo-lH-indole-3-acetamide), BAY19-8004 (Bayer), CDC-801 (Calgene), Celgene compound (( ⁇ R)- ⁇ -(3,4- dimethoxypheny I)- 1 ,3 -dihydro- 1 -oxo-2H-isoindole-2-propanamide), Cilomilast (cis-4- cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]-cyclohexanecarboxylic
  • PDE4 inhibitors include 256066, Arofylline (3-(4-chlorophenyl)-3,7- dihydro-1 -propyl- lH-Purine-2,6-dione), AWD 12-281 (N-(3,5-dichloro-4-pyridinyl)-l-[(4- fluorophenyl)methyl]-5-hydroxy- ⁇ -oxo-lH-indole-3-acetamide), BAYl 9-8004 (Bayer), CDC-801 (Calgene), Celgene compound (( ⁇ R)- ⁇ -(3,4-dimethoxyphenyl)-l,3-dihydro-l- oxo-2H-isoindole-2-propanamide), Cilomilast (cis-4-cyano-4-[3-(cyclopentyloxy)-4- methoxyphenyl]-cyclohexanecarboxylic acid), a compound in WO2006098353 from Ky
  • a PPAR ⁇ agonist is, for example, Pioglitazone, Pioglitazone hydrochloride, Rosiglitazone Maleate, Rosiglitazone Maleate ((-)-enantiomer, free base), Rosiglitazone maleate/Metformin hydrochloride or Tesaglitizar.
  • a Protease Inhibitor is, for example, Alpha 1 -antitrypsin proteinase Inhibitor, EPI-HNE4, UT-77, ZD-0892 or a compound from WO 2006/004532, WO 2005/026123, WO 2002/0744767 or WO 22002/074751; or a TACE Inhibitor (for example DPC-333, Sch- 709156 or Doxycycline).
  • a Statin is, for example, Atorvastatin, Lovastatin, Pravastatin, Rosuvastatin or Simvastatin.
  • a Thromboxane Antagonist is, for example, Ramatroban or Seratrodast.
  • a Vasodilator is, for example, A-306552, Ambrisentan, Avosentan, BMS-248360, BMS- 346567, BMS-465149, BMS-509701, Bosentan, BSF-302146 (Ambrisentan), Calcitonin Gene-related Peptide, Daglutril, Darusentan, Fandosentan potassium, Fasudil, Iloprost, KC-12615 (Daglutril) , KC-12792 2AB (Daglutril) , Liposomal treprostinil, PS-433540, Sitaxsentan sodium, Sodium Ferulate, TBC-11241 (Sitaxsentan), TBC-3214 (N-(2-acetyl- 4,6-dimethylphenyl)-3-[[(4-chloro-3-methyl-5-isoxazolyl)amino]sulfonyl]-2- thiophenecarboxamide), TBC-3711, Trapidil, Tre
  • An ENAC Episomal Sodium-channel blocker
  • Amiloride Benzamil, Triamterene, 552-02, PSA14984, PSA25569, PSA23682 or AER002. All the above active ingredients may be in the form of a solvate, e.g. a hydrate.
  • the present invention provides a pharmaceutical product 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 present invention provides a pharmaceutical product comprising, in combination, a first active ingredient which is 7-[(l/?)-2-( ⁇ 2-[(3- ⁇ [2-(2-)
  • a second active ingredient selected from: a non-steroidal Glucocorticoid Receptor (GR Receptor) Agonist; a CCRl antagonist; a chemokine antagonist (not CCRl); a corticosteroid; an IKK2 inhibitor; a muscarinic antagonist which is Aclidinium bromide, Glycopyrrolate (such as R 5 R-, R,S-, S,R-, or S,S-glycopyrronium bromide), Oxitropium bromide, Pirenzepine, telenzepine or
  • Tiotropium bromide a p38 inhibitor; or, a PDE inhibitor.
  • the present invention provides a pharmaceutical product comprising, in combination, a first active ingredient which is 7-[(l/?)-2-( ⁇ 2-[(3- ⁇ [2-(2- Chlorophenyl)ethyl]amino ⁇ propyl)thio]ethyl ⁇ afnino)- 1 -hydroxyethyl]-4-hydroxy- 1 ,3- benzothiazol-2(3H)-one Dihydrobromide, and a second active ingredient which is a nonsteroidal Glucocorticoid Receptor (GR) Agonist for example, a compound disclosed in WO 2006/046916.
  • GR Glucocorticoid Receptor
  • the present invention provides a pharmaceutical product comprising, in combination, a first active ingredient which is 7-[(l/?)-2-( ⁇ 2-[(3- ⁇ [2-(2- Chlorophenyl)ethyl]amino ⁇ propyl)thio]ethyl ⁇ amino)-l-hydroxyethyl]-4-hydroxy-l,3- benzothiazol-2(3H)-one Dihydrobromide, and a second active ingredient which is a CCRl antagonist, for example, a compound disclosed in WO2001/062728 or WO2001/098273, or a pharmaceutically acceptable salt thereof (such as a hydrochloride, trifluoroacetate, sulphate, (hemi)fumarate, benzoate, furoate or succinate salt); BX471 ((2R)-l-[[2- [(aminocarbonyl)amino]-4-chlorophenoxy]acetyl]-4-[(4-fluoropheny
  • the present invention provides a pharmaceutical product comprising, in combination, a first active ingredient which is 7-[(l/?)-2-( ⁇ 2-[(3- ⁇ [2-(2- Chlorophenyl)ethyl]amino ⁇ propyl)thio]ethyl ⁇ amino)-l-hydroxyethyl]-4-hydroxy-l,3- benzothiazol-2(3H)-one Dihydrobromide, and a second active ingredient which is a chemokine antagonist (not CCRl), for example, 656933 (N-(2-bromophenyl)-N'-(4-cyano- 1 ⁇ - 1 ,2,3-benzotriazol-7-yl)urea), 766994 (4-( ⁇ [( ⁇ [(2R)-4-(3,4-dichlorobenzyl)morpholin- 2-yl]methyl ⁇ amino)carbonyl]-amino ⁇ methyl)benzamide), CCX-282, CCX-915, Cyclon
  • the present invention provides a pharmaceutical product comprising, in combination, a first active ingredient which is 7-[(l ⁇ )-2-( ⁇ 2-[(3- ⁇ [2-(2- Chlorophenyl)ethyl]amino ⁇ propyl)thio]ethyl ⁇ amino)-l-hydroxyethyl]-4-hydroxy-l,3- benzothiazol-2(3H)-one Dihydrobromide, and a second active ingredient is a corticosteroid, for example, Alclometasone dipropionate, Amelometasone, Beclomethasone dipropionate, Budesonide, Butixocort propionate, Ciclesonide, Clobetasol propionate, Desisobutyrylciclesonide, Etiprednol dicloacetate, Fluocinolone acetonide, Fluticasone Furoate, Fluticasone propionate, Loteprednol etabonate (topical) or Mo
  • the corticosteroid is selected from budesonide, fluticasone propionate, fluticasone fruoate mometasone furoate, beclomethasone dipropionate or butixocort propionate ester.
  • the present invention provides a pharmaceutical product comprising, in combination, a first active ingredient which is 7-[(li?)-2-( ⁇ 2-[(3- ⁇ [2-(2- Chlorophenyl)ethyl]amino ⁇ propyl)thio]ethyl ⁇ amino)-l-hydroxyethyl]-4-hydroxy-l,3- benzothiazol-2(3H)-one Dihydrobromide, and a second active ingredient is a corticosteroid, for example, Budesonide, Fluticasone Furoate or Fluticasone propionate.
  • a corticosteroid for example, Budesonide, Fluticasone Furoate or Fluticasone propionate.
  • the corticosteroid is budesonide.
  • Budesonide and its preparation is described, for example, in Arzneistoff-Forschung (1979), 29 (11), 1687-1690, DE 2,323,215 and US 3,929,768.
  • Presently available formulations of budesonide are marketed under the tradename 'Entocort ®'.
  • the present invention provides a pharmaceutical product comprising, in combination, a first active ingredient which is 7-[(li?)-2-( ⁇ 2-[(3- ⁇ [2-(2- Chlorophenyl)ethyl]amino ⁇ propyl)thio]ethyl ⁇ amino)-l-hydroxyethyl]-4-hydroxy-l,3- benzothiazol-2(3H)-one Dihydrobromide, and a second active ingredient is an IKK2 inhibitor, for example, 2- ⁇ [2-(2-Methylamino-pyrimidin-4-yl)-l ⁇ -indole-5-carbonyl]- amino ⁇ -3-(phenyl-pyridin-2-yl-amino)-propionic acid.
  • a first active ingredient which is 7-[(li?)-2-( ⁇ 2-[(3- ⁇ [2-(2- Chlorophenyl)ethyl]amino ⁇ propyl)thio]ethyl ⁇ amino)-l-
  • the present invention provides a pharmaceutical product comprising, in combination, a first active ingredient which is 7-[(li?)-2-( ⁇ 2-[(3- ⁇ [2-(2- Chlorophenyl)ethyl]amino ⁇ propyl)thio]ethyl ⁇ amino)- 1 -hydroxyethyl]-4-hydroxy- 1 ,3- benzothiazol-2(3H)-one Dihydrobromide, and a second active ingredient is a muscarinic antagonist, for example, Aclidinium bromide, Glyc ⁇ pyrrolate (such as R 5 R-, R,S-, S 5 R-, or S,S-glycopyrronium bromide), Oxitropium bromide, Pirenzepine, telenzepine or Tiotropium bromide.
  • a first active ingredient which is 7-[(li?)-2-( ⁇ 2-[(3- ⁇ [2-(2- Chlorophenyl)ethyl]amino ⁇
  • the muscarinic receptor antagonist is a long acting muscarinic receptor antagonist, i.e. a muscarinic receptor antagonist with activity that persists for more than 12 hours.
  • long acting muscarinic receptor antagonists include tiotropium bromide.
  • the present invention provides a pharmaceutical product comprising, in combination, a first active ingredient which is 7-[(li?)-2-( ⁇ 2-[(3- ⁇ [2-(2-)
  • the present invention provides a pharmaceutical product comprising, in combination, a first active ingredient which is 7-[(l/?)-2-( ⁇ 2-[(3- ⁇ [2-(2- Chlorophenyl)ethyl]amino ⁇ propyl)thio]ethyl ⁇ amino)- 1 -hydroxyethyl]-4-hydroxy- 1 ,3- benzothiazol-2(3H)-one Dihydrobromide, and a second active ingredient is a p38 inhibitor, for example, a compound from WO 2005/042502, 681323, 856553, AMG548 (2-[[(2S)-2- amino-3-phenylpropyl]amino]-3-methyl-5-(2-naphthalenyl)-6-(4-pyridinyl)-4(3 ⁇ )- pyrimidinone), Array-797, AZD6703, Doramapimod, KC-706, PH 797804, Rl 503, SC- 80036, SCIO469
  • the present invention provides a pharmaceutical product comprising, in combination, a first active ingredient which is 7-[(li?)-2-( ⁇ 2-[(3- ⁇ [2-(2- Chlorophenyl)ethyl]amino ⁇ propyl)thio]ethyl ⁇ amino)-l-hydroxyethyl]-4-hydroxy-l,3- benzothiazol-2(3H)-one Dihydrobromide, and a second active ingredient is a PDE Inhibitor: such as a PDE4 inhibitor ⁇ for example, 256066, Arofylline (3-(4-chlorophenyl)- 3,7-dihydro-l-propyl-l ⁇ -Purine-2,6-dione), AWD 12-281 (N-(3,5-dichloro-4-pyridinyl)- 1 -[(4-fluorophenyl)methyl]-5-hydroxy- ⁇ -oxo- 1 H-indole-3-acetamide
  • WO2006098353 from Kyowa Hakko Kogyo Co. Ltd. Japan, 2-(3,5-dichloro-4-pyridinyl)- 1 -(7-methoxyspiro[ 1 ,3-benzodioxole-2, 1 '-cyclopentan]-4-yl)ethanone (CAS number 185406-34-2)), Compound from Pfizer (2-(3,4-difluorophenoxy)-5-fluoro-N-[cis-4-[(2- hydroxy-5-methylbenzoyl)amino]cyclohexyl]-)-3-pyridinecarboxamide), Compound from Pfizer (2-(3,4-difluorophenoxy)-5-fluoro-N-[cis-4-[[2-hydroxy-5- (hydroxymethyl)benzoyl]amino]cyclohexyl]-3-pyridinecarboxamide,), CT2820, GPD- 1116, Ibudilast, IC 485, KF 3133
  • the present invention provides a pharmaceutical product comprising, in combination, a first active ingredient which is 7-[(l/?)-2-( ⁇ 2-[(3- ⁇ [2-(2- Chlorophenyl)ethyl]amino ⁇ propyl)thio]ethyl ⁇ amino)-l-hydroxyethyl]-4-hydroxy-l,3- benzothiazol-2(3H)-one Dihydrobromide, and a second active ingredient is a PDE4 inhibitor, for example, 256066, Arofylline (3-(4-chlorophenyl)-3,7-dihydro-l -propyl- 1 ⁇ - Purine-2,6-dione), AWD 12-281 (N-(3,5-dichloro-4-pyridinyl)-l-[(4- fluorophenyl)methyl]-5-hydroxy- ⁇ -oxo- 1 ⁇ -indole-3-acetamide), BAY 19-8004 (Bayer),
  • the present invention provides a pharmaceutical product comprising, in combination, a first active ingredient which is 7-[(l/?)-2-( ⁇ 2-[(3- ⁇ [2-(2- Chlorophenyl)ethyl]amino ⁇ propyl)thio]ethyl ⁇ amino)-l-hydroxyethyl]-4-hydroxy-l,3- benzothiazol-2(3H)-one Dihydrobromide, and a second active ingredient is a PDE4 5 inhibitor, for example AWD 12-281 (N-(3,5-dichloro-4-pyridinyl)-l-[(4- fluoropheny l)methyl]-5-hydroxy- ⁇ -oxo- 1 ⁇ -indole-3-acetamide) or roflumilast.
  • a first active ingredient which is 7-[(l/?)-2-( ⁇ 2-[(3- ⁇ [2-(2- Chlorophenyl)ethyl]amino ⁇ propyl)thio]e
  • the present invention provides a pharmaceutical product comprising, in combination, a first active ingredient which is 7-[(l ⁇ )-2-( ⁇ 2-[(3- ⁇ [2-(2- i o Chlorophenyl)ethy l]amino ⁇ propyl)thio]ethyl ⁇ amino)- 1 -hydroxyethyl]-4-hydroxy- 1,3- benzothiazol-2(3H)-one Dihydrobromide, and a second active ingredient is roflumilast.
  • the present invention provides a kit comprising a preparation of a first active ingredient which is 7-[(li?)-2-( ⁇ 2-[(3- ⁇ [2-(2- i 5 Chlorophenyl)ethyl]amino ⁇ propyl)thio]ethyl ⁇ amino)-l-hydroxyethyl]-4-hydroxy-l,3- benzothiazol-2(3H)-one or a salt thereof, a preparation of a second active ingredient selected from: a non-steroidal Glucocorticoid Receptor (GR Receptor) Agonist; an antioxidant; 20 a CCRl antagonist; a chemokine antagonist (not CCRl); a corticosteroid; a CRTh2 antagonist; a DPI antagonist; 5 an ⁇ istone Deacetylase Inducer; an IKK2 inhibitor; a COX inhibitor; a lipoxygenase inhibitor; a leukotriene receptor antagonist; 30 an MPO inhibitor; a GR Re
  • Tiotropium bromide Tiotropium bromide; a p38 inhibitor; a PDE inhibitor; a PPAR ⁇ agonist; a protease inhibitor; a Statin; a thromboxane antagonist; a vasodilator; or, an ENAC blocker (Epithelial Sodium-channel blocker), and optionally instructions for the simultaneous, sequential or separate administration of the preparations to a patient in need thereof.
  • ENAC blocker Epitophelial Sodium-channel blocker
  • the first active ingredient and the second active ingredient of the pharmaceutical product of the present invention may be administered simultaneously, sequentially or separately to treat respiratory diseases.
  • simultaneous is meant that the active ingredients are in admixture or they could be in separate chambers of the same inhaler.
  • 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, conveniently less than two hours apart, more conveniently less than 30 minutes apart and most conveniently less than 10 minutes apart, for e.g. less than 10 minutes but not one immediately after the other.
  • 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 be delivered to the lung and/or airways via oral administration in the form of a solution, suspension, aerosol or dry powder formulation.
  • These dosage forms will usually include one or more pharmaceutically acceptable ingredients which may be selected, for example, from an adjuvant, carrier, binder, lubricant, diluent, stabilising agent, buffering agent, emulsifying agent, viscosity- regulating agent, surfactant, preservative, flavouring or colourant.
  • pharmaceutically acceptable ingredients may be selected, for example, from an adjuvant, carrier, binder, lubricant, diluent, stabilising agent, buffering agent, emulsifying agent, viscosity- regulating agent, surfactant, preservative, flavouring or colourant.
  • the first and second active ingredients are administered via a single pharmaceutical composition (that is, they are in admixture). Therefore, the present invention further provides a pharmaceutical composition comprising, in admixture, a first active ingredient which is 7-[(li?)-2-( ⁇ 2-[(3- ⁇ [2-(2-)
  • the pharmaceutical composition further comprises a pharmaceutically acceptable adjuvant, diluent or carrier.
  • compositions of the present invention can 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 the first and second active ingredients 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 first active ingredient is administered via inhalation.
  • the dose of the first active ingredient will generally be 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
  • the second active ingredient is administered by inhalation.
  • the dose of the second active ingredient will generally be 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
  • the present invention provides a pharmaceutical product wherein the molar ratio of first active ingredient to second active ingredient is from 1:1000 to 1000:1, such as from 1 :100 to 100:1, for example from 1:50 to 50:1, for example 1 :20 to 20:1.
  • the present invention provides a pharmaceutical product comprising, in combination, a first active ingredient as defined above, and a second active ingredient as defined above, wherein each active ingredient is formulated for inhaled administration.
  • the pharmaceutical product is in the form of a pharmaceutical composition comprising the first and second active ingredients in admixture, and which composition is formulated for inhaled administration.
  • the active ingredients of the present invention are conveniently delivered via oral administration by inhalation to the lung and/or airways in the form of a solution, suspension, aerosol or dry powder (such as an agglomerated or ordered mixture) formulation.
  • a metered dose inhaler device may be used to administer the first and second active ingredients, dispersed in a suitable propellant and with or without an additional excipient such as ethanol, a surfactant, lubricant or stabilising agent.
  • a suitable propellant is a hydrocarbon, chlorofluorocarbon or hydrofluoroalkane (e.g. heptafluoroalkane) propellant, or mixture of any such propellant, for example in a pressurised metered dose inhaler (pMDI).
  • a preferred propellant is P 134a or P227, each of which may be used alone or in combination with other propellants and/or surfactant and/or other excipients.
  • a nebulised aqueous suspension or, preferably, solution may also be employed, with or without a suitable pH and/or tonicity adjustment, either as a unit-dose or multi-dose formulation.
  • the pharmaceutical product of the present invention can, for example, be administered: via an inhaler having the first and second active ingredients in separate chambers of the inhaler such that on administration the active ingredients mix in either the mouthpiece of the inhaler or the mouth of a patient or both (for simultaneous use); or, where the first and second active ingredients are in separate inhalers, via separate inhalers (for separate or sequential use); or the first and second active ingredients are in admixture in an inhaler when the inhaler is supplied to a patient (for simultaneous use).
  • 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 and a variety of such devices are available.
  • the pharmaceutical product of the present invention may be used to treat diseases of the respiratory tract such as 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 and chronic 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 s infections;
  • the present invention further provides the use of a pharmaceutical product according to the invention in the manufacture of a medicament for the treatment of a respiratory disease, in is 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: (a) a therapeutically effective dose of a first active ingredient as defined above; and,0 (b) a therapeutically effective dose of a second active ingredient as defined above; to a patient in need thereof.
  • the term “therapy” also includes “prophylaxis” unless there are specific indications to the contrary.
  • the terms “therapeutic” and 5 "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 by0 genetic testing or screening to be particularly susceptible to developing the condition or disorder.
  • Figure 1 Shows the onset times for roflumilast (l ⁇ M), Compound A (0.InM) and Compound A (0.InM) in the presence of roflumilast (l ⁇ M) in guinea pig trachea in vitro.
  • Aluminium hydride was prepared by the drop- wise addition of a solution of sulphuric acid (8.40 mL) in dry THF (60 mL) to a stirred solution of 1.0M lithium aluminium hydride in THF (314 mL), at 0-10 0 C, under a nitrogen atmosphere. After stirring at 5 0 C for 30 minutes, a solution of l-chloro-2-[(£)-2-nitrovinyl]benzene (12.83 g) in dry THF (160 mL) was added dropwise maintaining the internal temperature between O 0 C and 1O 0 C. When the addition was complete the reaction was heated at reflux for 5 minutes.
  • tert-Butyl allyl[2-(2-chlorophenyl)ethyl]carbamate (31.0 g) was mixed with 2-mercaptoethanol (7.37 mL), and AIBN (1.15 g), and stirred at 65 0 C for 45 minutes. The mixture was cooled and more mercaptoethanol (1 mL) and AIBN (200 mg) added. The mixture was then heated at 65 0 C for a further 30 minutes. The material was purified by 0 silica column chromatography, loading the material in 20% ethyl acetate in isohexane, then eluting with 20% ethyl acetate in isohexane, changing to 50%, to give the desired material (31.94 g).
  • the reaction mixture was diluted with ethyl acetate, washed with water, then IN HCl, then saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered and the solvents removed in vacuo.
  • the material was purified by silica column chromatography eluting with 20% ethyl acetate in isohexane to give the desired material (12.43 g).
  • Type A material (Example 2) was placed into a vial, to which was added water (ImI). The mixture was left to stir at room temperature in a capped vial for one week. The resulting suspension was then centrifuged and the solid collected and left to dry overnight in a fume hood.
  • Fumaric acid 120.39 mg was added to a suspension of 7-[(li?)-2-( ⁇ 2-[(3- ⁇ [2-(2- chlorophenyl)ethyl]amino ⁇ propyl)thio]ethyl ⁇ -amino)- 1 -hydroxyethyl]-4-hydroxy- 1 ,3- benzothiazol-2(3H)-one (0.5 g) in methanol (5 mL). The mixture was then stirred at room temperature for 2 h. The solvent was removed in vacuo and the residue was suspended in ethyl acetate (20 mL) and stirred at room temperature for 48 h. The title compound was isolated by filtration, washed with ethyl acetate (5 mL) and dried in vacuo to leave a noncrystalline product (0.59 g).
  • Citric acid (199.27 mg) was added to a suspension of 7-[(l/?)-2-( ⁇ 2-[(3- ⁇ [2-(2- chlorophenyl)ethyl]amino ⁇ propyl)thio]ethyl ⁇ -amino)-l-hydroxyethyl]-4-hydroxy-l,3- benzothiazol-2(3H)-one (0.5 g) in methanol (5 mL). The mixture was sonicated then stirred at room temperature for 2 h. The solvent was removed in vacuo and the residue was suspended in diethyl ether (20 mL) and stirred at room temperature for 1 h. The title compound was isolated by filtration, washed with diethyl ether (5 mL) and dried in vacuo to leave a non-crystalline product.
  • Phosphoric acid (119.58 mg) was added to a suspension of 7-[(U?)-2-( ⁇ 2-[(3- ⁇ [2-(2- chlorophenyl)ethyl]amino ⁇ propyl)thio]ethy 1 ⁇ -amino)- 1 -hydroxy ethy l]-4-hydroxy- 1,3- benzothiazol-2(3H)-one (0.5 g) in methanol (5 mL). The mixture was then stirred at room temperature for 1 h. The solvent was removed in vacuo and the residue was suspended in diethyl ether (20 mL) and stirred at room temperature for 16 h. The solvent had evaporated so the residue was treated with more diethyl ether (5 mL). The title compound was isolated by filtration, washed with diethyl ether (5 mL) and dried in vacuo to leave a non-crystalline product (0.47g).
  • H292 cells were grown in 225cm2 flasks incubator at 37°C, 5% CO 2 in RPMI medium containing, 10% (v/v) FBS (foetal bovine serum) and 2 mM L-glutamine.
  • the culture media was removed and cells were washed twice with 100 ⁇ L assay buffer and replaced with 50 ⁇ L assay buffer (HBSS solution containing 1OmM HEPES pH7.4 and 5 mM glucose). Cells were rested at room temperature for 20 minutes after which time 25 ⁇ L of rolipram (1.2 mM made up in assay buffer containing 2.4% (v/v) dimethylsulphoxide) was added. Cells were incubated with rolipram for 10 minutes after which time Compound A was added and the cells were incubated for 60 minutes at room temperature. The final rolipram concentration in the assay was 300 ⁇ M and final vehicle concentration was 1.6% (v/v) dimethylsulphoxide. The reaction was stopped by removing supernatants, washing once with 100 ⁇ L assay buffer and replacing with 50 ⁇ L lysis buffer. The cell monolayer was frozen at -80°C for 30 minutes (or overnight). AlphaScreenTM cAMP detection
  • the concentration of cAMP (cyclic adenosine monophosphate) in the cell lysate was determined using AlphaScreenTM methodology. The frozen cell plate was thawed for 20 minutes on a plate shaker then 10 ⁇ L of the cell lysate was transferred to a 96- well white 5 plate. 40 ⁇ L of mixed AlphaScreenTM detection beads pre-incubated with biotinylated cAMP, was added to each well and the plate incubated at room temperature for 10 hours in the dark. The AlphaScreenTM signal was measured using an EnVision spectrophotometer (Perkin-Elmer Inc.) with the recommended manufacturer's settings. cAMP concentrations were determined by reference to a calibration curve determined in the same experiment
  • Membranes were prepared from human embryonic kidney 293 (HEK293) cells expressing recombinant human ⁇ lo receptor. These were diluted in Assay Buffer (5OmM HEPES, ImM EDTA, 0.1% gelatin, pH 7.4) to provide a final concentration of membranes that gave a clear window between maximum and minimum specific binding. 5
  • Assay Buffer 5OmM HEPES, ImM EDTA, 0.1% gelatin, pH 7.4
  • the plates were incubated for 2 hours at room temperature and then filtered onto PEI coated GF/B filter plates, pre-soaked for 1 hour in Assay Buffer, using a 96-well plate Tomtec cell harvester. Five washes with 250 ⁇ L wash buffer (5OmM HEPES, ImM EDTA, pH 7.4) were performed at 4°C to remove unbound radioactivity. The plates were dried then sealed from underneath using Packard plate sealers and MicroScint-0 (50 ⁇ L) was added to each well. The plates were sealed (TopSeal A) and filter-bound radioactivity was measured with a scintillation counter (TopCount, Packard BioScience) using a 3-minute counting protocol.
  • wash buffer 250 ⁇ L wash buffer
  • MicroScint-0 50 ⁇ L
  • Membranes containing recombinant human adrenergic beta 1 receptors were obtained from Euroscreen. These were diluted in Assay Buffer (5OmM HEPES, ImM EDTA, 12OmM NaCl, 0.1% gelatin, pH 7.4) to provide a final concentration of membranes that gave a clear window between maximum and minimum specific binding.
  • Assay Buffer 5OmM HEPES, ImM EDTA, 12OmM NaCl, 0.1% gelatin, pH 7.4
  • the plates were incubated for 2 hours at room temperature and then filtered onto PEI coated GF/B filter plates, pre-soaked for 1 hour in Assay Buffer, using a 96-well plate Tomtec cell harvester. Five washes with 250 ⁇ L wash buffer (5OmM HEPES, ImM EDTA, 12OmM NaCl, pH 7.4) were performed at 4°C to remove unbound radioactivity. The plates were dried then sealed from underneath using Packard plate sealers and MicroScint-0 (50 ⁇ L) was added to each well. The plates were sealed (TopSeal A) and filter-bound radioactivity was measured with a scintillation counter (TopCount, Packard BioScience) using a 3-minute counting protocol.
  • a scintillation counter TopCount, Packard BioScience
  • B 0 Total specific binding was determined by subtracting the mean NSB from the mean maximum binding. NSB values were also subtracted from values from all other wells. These data were expressed as percent of B 0 .
  • Compound concentration-effect curves (inhibition of [ 125 I]-Iodocyanopindolol binding) were determined using serial dilutions typically in the range 0.1 nM to 10 ⁇ M. Data was fitted to a four parameter logistic equation to determine the compound potency, which was expressed as pIC 5 o (negative log molar concentration inducing 50% inhibition of [ 125 I]-Iodocyanopindolol binding). A result is shown in Table 1 below.
  • Membranes containing recombinant human Dopamine Subtype D2s receptors were obtained from Perkin Elmer. These were diluted in Assay Buffer (5OmM HEPES, ImM EDTA, 12OmM NaCl, 0.1% gelatin, pH 7.4) to provide a final concentration of membranes that gave a clear window between maximum and minimum specific binding.
  • Assay Buffer 5OmM HEPES, ImM EDTA, 12OmM NaCl, 0.1% gelatin, pH 7.4
  • the plates were incubated for 2 hours at room temperature and then filtered onto PEI coated GF/B filter plates, pre-soaked for 1 hour in Assay Buffer, using a 96-well plate Tomtec cell harvester. Five washes with 250 ⁇ L wash buffer (5OmM HEPES, ImM EDTA, 12OmM NaCl, pH 7.4) were performed at 4°C to remove unbound radioactivity. The plates were dried then sealed from underneath using Packard plate sealers and MicroScint-0 (50 ⁇ L) was added to each well. The plates were sealed (TopSeal A) and filter-bound radioactivity was measured with a scintillation counter (TopCount, Packard BioScience) using a 3-minute counting protocol.
  • a scintillation counter TopCount, Packard BioScience
  • Example 1 The present invention will now be further explained by reference to the following illustrative Examples.
  • Example 1 The present invention will now be further explained by reference to the following illustrative Examples.
  • LPS lippopolvsaccharride
  • CRL:CD rats LPS challenge in CRL:CD rats causes an influx of inflammatory cells into the lungs.
  • Rats are challenged either with an aerosol of 0.9% w/v saline or O.lmg/mL LPS in 0.9% saline for 30 min or an intratracheal dose of 0.1-1 O ⁇ g/kg. This is repeated up to 8 times according to the experimental protocol. Rats are dosed with vehicle, standard compound or test compound by the appropriate route and frequency at various time points before and after challenge depending upon the experimental protocol.
  • Test compound groups could either be the same compound at different doses or single doses of different compounds or a combination of the two.
  • Test compounds are given by intraperitoneal, intravenous or subcutaneous injection or by inhalation or intratracheal administration.
  • the rats are euthanized at various time points after challenge depending upon the nature of the study, but typically 4hr after LPS challenge with ImL pentobarbitone sodium.
  • a tracheotomy is performed and a cannula inserted.
  • the airway is then lavaged using 3 mL sterile PBS at room temperature.
  • the PBS is left in the airway for 10 seconds before being removed.
  • the PBS containing cells is placed into a 15 mL centrifuge tube on ice. This process is repeated three times.
  • Cytospin slides are prepared by adding a 100 ⁇ l aliquot of BAL fluid into cytospin funnels in a Shandon Cytospin3 operated at 700 rpm for 5 min. Slides are stained on the Hema-Tek-2000 automatic slide stainer, using Wright-Giemsa stain and typically, 200 cells are counted under a microscope. Cells are classified as eosinophils, neutrophils and mononuclear cells (mononuclear cells included monocytes, macrophages and lymphocytes) and are expressed as a percentage of the total count.
  • Example 2 Evaluation of compound activity on intra-alveolar neutrophil migration after aerosol challenge with lippopolysaccharride (LPS) in the guinea-pig.
  • Male Dunkin-Hartley guinea-pigs 300-60Og are placed into open fronted guinea-pig holding cones attached at random around a cylindrical aerosol chamber. Guinea-pigs are held in the challenge cones and exposed to an aerosol of vehicle, or LPS at concentrations of 0.1-30 ⁇ g/ml in 0.9%saline per group Aerosols are generated using 2 jet nebulisers per column with a flow rate of 12 L/m. 10ml of the challenge agent is placed into each nebuliser. Alternatively animals receive an intratracheal dose of 0.1-10 ⁇ g/kg. This is repeated up to 8 times according to the experimental protocol.
  • LPS lippopolysaccharride
  • Guinea-pigs are dosed with vehicle, standard compound or test compound by the appropriate route and frequency at various time points before and after challenge depending upon the experimental protocol.
  • Test compound groups could either be the same compound at different doses or single doses of different compounds or a combination of the two.
  • Test compounds are given by intraperitoneal, intravenous or subcutaneous injection or by inhalation or intratracheal administration.
  • Challenged guinea-pigs are killed by anaesthesia overdose (0.5ml Euthetal i.p.) at 4h-24h post challenge. The lungs are then lavaged.
  • HBSS Hanks Buffered Salt Solution
  • EDTA EDTA -free
  • the lavaging is performed with gentle massaging of the chest to ensure appropriate agitation of the fluid in the lungs.
  • the washes are harvested into a 15ml conical, polypropylene centrifuge tube, an aliquot of BAL fluid is removed and counted on Sysmex (Sysmex UK, Milton Keynes).
  • Cytospin slides are prepared by adding a 100 ⁇ l aliquot of BAL fluid into cytospin funnels in a Shandon Cytospin3 operated at 700 rpm for 5 min. Slides are stained on the Hema-Tek-2000 automatic slide stainer, using Wright-Giemsa stain and typically, 200 cells are counted under a microscope. Cells are classified as eosinophils, neutrophils and mononuclear cells (mononuclear cells included monocytes, macrophages and lymphocytes) and are expressed as a percentage of the total count.
  • Example 3 Evaluation of compound activity on intra-alveolar neutrophil migration after aerosol challenge with lippopolysaccharride (LPS) in the mouse.
  • Male C57BL/6/J or BALB/C mice (20-35g) are placed in Perspex exposure boxes in groups of up to 20 and exposed to an aerosol of either 0.3 mg/ml LPS or 0.9% w/v saline.
  • the LPS (Sigma, E.Coli, Ref L-3755, Serotype 026:B6, Lot no. 11 lk4078) is made up in 0.9% w/v saline.
  • An aerosol is generated using two jet nebulisers operated at a flow rate of 12 L/min (6L/min for each nebuliser) for 15 min.
  • animals receive an intratracheal dose of 0.1-1 O ⁇ g/kg. This may be repeated up to 8 times.
  • mice are dosed with vehicle, standard compound or test compound by the appropriate route and frequency at various time points before and after challenge depending upon the experimental protocol.
  • Test compound groups could either be the same compound at different doses or single doses of different compounds or a combination of the two.
  • Test compounds are given by intraperitoneal, intravenous or subcutaneous injection or by inhalation or intratracheal administration.
  • mice are killed with an overdose of Euthatal i.p 30 minutes, l-24hr after LPS challenge.
  • the trachea is cannulated (Portex intravenous cannula) and the airways lavaged with 3 x 0.3ml of Isoton II (Beckman Coulter Ref. 8448011 Lot no.25775).
  • Isoton II Beckman Coulter Ref. 8448011 Lot no.25775
  • lOO ⁇ l of the BALF is added to a cytospin funnel and spun, using a ThermoShandon Cytospin model 3 or 4, at 700 rpm for 5 min.
  • Cells on the slide are stained on the Hema-Tek-2000 automatic slide stainer, using Wright-Giemsa stain and differential cell counts carried out to differentiate eosinophils, neutrophils and lymphomononuclear cells (including monocytes, macrophages and lymphocytes). Typically, 200 cells are counted per slide and each cell type expressed as a percentage of the total count. BALF total white cell count is measured using a Sysmex (Sysmex UK, Milton Keynes).
  • mice Male Dunkin-Hartley guinea-pigs (300-60Og) are weighed and dosed with either vehicle or compound in an appropriate vehicle according to the experimental protocol via the intratracheal route under recoverable gaseous anaesthesia (5% halothane in oxygen). Following dosing, the animals are administered supplemental oxygen and monitored until full recovery. Typically a dose volume of 0.5 mL/kg is used for the intratracheal route. In a dose response study, animals are dosed with compound or vehicle two hours prior to the administration of histamine. Test compound groups could either be the same compound at different doses or single doses of different compounds or a combination of the two.
  • the guinea-pigs are anaesthetised with pentobarbitone (1 mL/kg of 60 mg/mL solution intraperitoneally) approximately 30 minutes prior to the first bronchoconstrictor administration.
  • the trachea is cannulated (Portex intravenous cannula, 200/300/070 (orange) or 200/300/060 (yellow)) and the animal ventilated using a constant volume respiratory pump (Harvard Rodent Ventilator model 683) at a rate of 60 breath/min and a tidal volume of 5 ml/kg.
  • a jugular vein is cannulated (Portex intravenous catheter 200/300/010 (green)) for the administration of histamine or maintenance anaesthetic (0.1 mL of pentobarbitone solution, 60 mg/mL, as required).
  • the animals are then transferred to a Flexivent System (SCIREQ, Montreal, Canada) in order to measure airway resistance.
  • the animals are ventilated (quasi-sinusoidal ventilation pattern) at 60 breaths/min at a tidal volume of 5 mL/kg.
  • a positive end expiratory pressure of 2-3 CmH 2 O is applied.
  • Respiratory resistance is measured using the Flexivent "snapshot" facility (1 second duration, 1 Hz frequency).
  • the animals are given histamine dihydrochloride or methacholine in ascending doses (Histamine; 0.5, 1, 2, 3 and 5 ⁇ g/kg, i.v., methacholine; 3, 10 and 30 ⁇ g/kg, i.v.) at approximately 4-minute intervals via the jugular catheter. After each administration of histamine the peak resistance value is recorded. Guinea pigs are euthanised with approximately 1.OmL pentobarbitone sodium (Euthatal) intravenously after the completion of the lung function measurements.
  • Percentage bronchoprotection produced by a compound is calculated at each dose of histamine as follows:
  • % change R veh is the mean of the maximum percentage change in airway resistance in the vehicle treated group.
  • Rats are dosed via the appropriate route with vehicle, standard compound or test compound at various time points before and after challenge depending upon the experimental protocol. Rats are euthanised with 0.5 mL pentobarbitone sodium (Euthatal) intraperitoneally at various times after challenge. A tracheotomy is performed and the trachea cannulated. The airway is then lavaged using 3 mL sterile PBS at room temperature. The PBS is left in the airway for 10 seconds before being removed. The PBS containing cells is placed into a 15 mL centrifuge tube on ice. This process is repeated three times. The final volume recovered is recorded. An aliquot of BAL fluid is removed and counted using a Sysmex (Sysmex UK, Milton Keynes).
  • Cytospin slides are prepared by adding a 100 ⁇ l aliquot of BAL fluid into cytospin funnels in a Shandon Cytospin 3 operated at 700 rpm for 5 min. Slides are stained on the Hema- Tek-2000 automatic slide stainer, using Wright-Giemsa stain and typically, 200 cells are counted under a microscope. Cells are classified as eosinophils, neutrophils and mononuclear cells. Mononuclear cells included monocytes, macrophages and lymphocytes.
  • mice 20-25g male BALB/c mice are sensitized to ovalbumin by i.p administration of 100 ⁇ g of grade V ovalbumin (Sigma) adsorbed onto lmg of aluminium hydroxide gel mixture (Fisher Scientific UK) in 0.3 ml saline. Groups of mice are pre-dosed with compound if required, a minimum of two weeks after sensitization. They are then dosed daily for 1-8 days as study protocol specified, with test compound or 0.25 ml vehicle.
  • mice are placed in perspex chambers (20x11x1 lcm, 10 mice max./chamber) and administered an aerosol challenge of 20mg ml '1 ovalbumin for 36 min (8 ml for 18 min followed by another 8 ml for 18 min). Aerosol delivery is achieved using a DeVilbiss jet nebulizer with a flow rate of 61 min "1 . 24h after the last dose the mice are killed with euthatal 0.2 ml i.p.
  • trachea is cannulated using a pink luer mount Portex cannula cut to lcm and the lungs are lavaged using 3 washes of ImI of Isoton IL.
  • lOO ⁇ l of the BALF is added to a cytospin funnel and spun, using a ThermoShandon Cytospin model 3 or 4, at 700 rpm for 5 min.
  • Cells on the slide are stained on the Hema-Tek-2000 automatic slide stainer, using Wright-Giemsa stain and differential cell counts carried out to differentiate eosinophils, neutrophils and lymphomononuclear cells (including monocytes, macrophages and lymphocytes). Typically, 200 cells are counted per slide and each cell type expressed as a percentage of the total count. BALF total white cell count is measured using a Sysmex (Sysmex UK, Milton Keynes).
  • mice undergo whole body exposure to main stream smoke (50 min/12 cigarettes) and fresh air once or twice a day for 1-9 days.
  • Mice are dosed via the appropriate route with vehicle, standard compound or test compound at various time points before and after challenge depending upon the experimental protocol.
  • mice are either killed with euthatal 0.2 ml i.p. and broncho-aveolar lavage fluid obtained for analysis of white blood cell infiltration (as described above) or lung function is assessed using a Flexivent System (SCIREQ, Montreal, Canada).
  • SCIREQ Flexivent System
  • EMMS forced manoeuvres system
  • Mice are anaesthetised with pentobarbitone (1/lOdilution at a dose volume of 1 mL/kg intraperitoneally).
  • the trachea is cannulated and the animal transferred to the Flexivent System where they are ventilated (quasi-sinusoidal ventilation pattern) at a rate of 150 breath/min and a tidal volume of 10 ml/kg in order to measure airways resistance, Respiratory resistance is measured using the Flexivent "snapshot" facility (1 second duration, 1 Hz frequency).
  • Mice are euthanised with approximately 0.5mL pentobarbitone sodium (Euthatal) intravenously after the completion of the lung function measurements.
  • Example 8 Evaluation of bronchodilator activity in the guinea pig isolated tracheal ring preparation: onset measurements.
  • Guinea pigs (300-50Og) were killed by cervical dislocation and the trachea was isolated.
  • the trachea was cut into segments 2-3 cartilage rings in width and suspended in 10ml organ baths in modified Krebs' solution (mM; NaCl, 90; NaHCO 3 , 45; KCl, 5; MgSO 4 JH 2 O, 0.5; Na 2 HPO 4 .2H 2 O, 1 ; CaCl 2 , 2.25; glucose, 10; pH 7.4 gassed with 5% CO 2 , 95% O 2 at 37°C).
  • the tracheal rings were attached to an isometric force transducer for the measurement of isometric tension.
  • the tissues were washed and a force of Ig was applied to each tissue.
  • the rings were contracted with methacholine (1 ⁇ M). Once the contraction had reached a plateau, vehicle (0.01% DMSO in distilled H 2 O), compound A (0.1 nM), roflumilast ( 1 ⁇ M) or a combination of compound A (0.1 nM) and roflumilast (l ⁇ M) was added and the tissue left until the response had reached a plateau. Data were collected using the Chart 4 software (ADInstruments, Charlgrove, UK). The time to 90% of the maximum effect of compound A (onset time) was measured for each tissue and expressed in min (mean ⁇ s.e.mean).

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  • Life Sciences & Earth Sciences (AREA)
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Abstract

L'invention porte sur un produit pharmaceutique, un coffret ou une composition comprenant un premier ingrédient actif qui est la 7-[(1R)-2-({2-[(3-{[2-(2-chlorophényl)éthyl]amino}propyl)-thio]éthyl}amino)-1-hydroxyéthyl]-4-hydroxy-1,3-benzothiazol-2(3H)-one ou un sel de celui-ci, et un second ingrédient actif choisi parmi un agoniste du récepteur glucocorticoïde non stéroïdien (récepteur GR) ; un anti-oxydant ; un antagoniste de CCR1 ; un antagoniste de la chimiokine (non CCR1) ; un corticostéroïde ; un antagoniste de CRTh2 ; un antagoniste de DP1 ; un inducteur de l'histone désacétylase ; un inhibiteur d'IKK2 ; un inhibiteur de la COX ; un inhibiteur de la lipoxygénase ; un antagoniste du récepteur des leucotriènes ; un inhibiteur de MPO ; un antagoniste muscarinique qui est le bromure d'aclidinium, le glycopyrrolate, le bromure d'oxitropium, la pirenzépine, le télenzépine ou le bromure de tiotropium ; un inhibiteur de la p38 ; un inhibiteur de PDE ; un agoniste de PPARγ ; un inhibiteur de protéase ; une statine ; un antagoniste de thromboxane ; un vasodilatateur ; ou un bloquant d'ENAC (bloquant des canaux sodiques épithéliaux). L'invention porte également sur l'utilisation de ce produit pharmaceutique dans le traitement d'une maladie respiratoire.
PCT/GB2008/000667 2007-03-01 2008-02-29 Nouvelle combinaison 667 Ceased WO2008104776A1 (fr)

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7700782B2 (en) 2006-12-20 2010-04-20 Astrazeneca Ab Compounds 569
US7709511B2 (en) 2005-08-09 2010-05-04 Astrazeneca Ab Benzothiazolone derivatives
WO2011012897A1 (fr) * 2009-07-31 2011-02-03 Astrazeneca Ab Nouvelle combinaison pour le traitement de l'asthme
WO2011061527A1 (fr) 2009-11-17 2011-05-26 Astrazeneca Ab Combinaisons qui comprennent un modulateur du récepteur glucocorticoïde, destinées au traitement de maladies respiratoires
US7951954B2 (en) 2006-03-14 2011-05-31 Astrazeneca Ab Bezothiazol derivatives as Beta2 adrenoreceptor agonists
US8017602B2 (en) 2008-06-18 2011-09-13 Astrazeneca Ab N-(2-(2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)ethylamino)ethyl)-3-(phenethoxy)propanamide derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy
US8058294B2 (en) 2007-02-08 2011-11-15 Astrazeneca Ab Pharmaceutical salts of N-[2-(diethylamino)ethyl]-N-(2-{[2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino}ethyl)-3-[2-(1-napthyl)ethoxy]propanamide
WO2012046050A1 (fr) 2010-10-07 2012-04-12 Astrazeneca Ab Nouvelles combinaisons
MD4369C1 (ro) * 2011-03-04 2016-04-30 Sosei R&D Ltd Utilizarea glicopirolatului pentru tratarea tahicardiei, doză unică, dispozitiv de administrare, metodă de tratament şi profilaxie a tahicardiei
EP3061821A1 (fr) 2009-07-22 2016-08-31 Puretech Ventures Procédés et compositions pour le traitement de troubles améliorés par l'activation du récepteur muscarinique
US10265311B2 (en) 2009-07-22 2019-04-23 PureTech Health LLC Methods and compositions for treatment of disorders ameliorated by muscarinic receptor activation
US10925832B2 (en) 2018-09-28 2021-02-23 Karuna Therapeutics, Inc. Compositions and methods for treatment of disorders ameliorated by muscarinic receptor activation

Citations (1)

* Cited by examiner, † Cited by third party
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WO2007027134A1 (fr) * 2005-08-29 2007-03-08 Astrazeneca Ab Derives de 7-(2-amino-1-hydroxy-ethyl)-4-hydroxybenzothiazol-2(3h)-one comme agonistes de l'adrenocepteur $g(b)2

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007027134A1 (fr) * 2005-08-29 2007-03-08 Astrazeneca Ab Derives de 7-(2-amino-1-hydroxy-ethyl)-4-hydroxybenzothiazol-2(3h)-one comme agonistes de l'adrenocepteur $g(b)2

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7709511B2 (en) 2005-08-09 2010-05-04 Astrazeneca Ab Benzothiazolone derivatives
US7951954B2 (en) 2006-03-14 2011-05-31 Astrazeneca Ab Bezothiazol derivatives as Beta2 adrenoreceptor agonists
US7700782B2 (en) 2006-12-20 2010-04-20 Astrazeneca Ab Compounds 569
US8058294B2 (en) 2007-02-08 2011-11-15 Astrazeneca Ab Pharmaceutical salts of N-[2-(diethylamino)ethyl]-N-(2-{[2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino}ethyl)-3-[2-(1-napthyl)ethoxy]propanamide
US8017602B2 (en) 2008-06-18 2011-09-13 Astrazeneca Ab N-(2-(2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)ethylamino)ethyl)-3-(phenethoxy)propanamide derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy
US10238643B2 (en) 2009-07-22 2019-03-26 PureTech Health LLC Methods and compositions for treatment of disorders ameliorated by muscarinic receptor activation
US10369143B2 (en) 2009-07-22 2019-08-06 PureTech Health LLC Methods and compositions for treatment of disorders ameliorated by muscarinic receptor activation
US10695339B2 (en) 2009-07-22 2020-06-30 PureTech Health LLC Methods and compositions for treatment of disorders ameliorated by muscarinic receptor activation
EP3646870A1 (fr) 2009-07-22 2020-05-06 Puretech Health LLC Procédés et compositions pour le traitement de troubles améliorés par l'activation du récepteur muscarinique
EP3061821A1 (fr) 2009-07-22 2016-08-31 Puretech Ventures Procédés et compositions pour le traitement de troubles améliorés par l'activation du récepteur muscarinique
US10369144B2 (en) 2009-07-22 2019-08-06 PureTech Health LLC Methods and compositions for treatment of disorders ameliorated by muscarinic receptor activation
US10265311B2 (en) 2009-07-22 2019-04-23 PureTech Health LLC Methods and compositions for treatment of disorders ameliorated by muscarinic receptor activation
WO2011012897A1 (fr) * 2009-07-31 2011-02-03 Astrazeneca Ab Nouvelle combinaison pour le traitement de l'asthme
WO2011061527A1 (fr) 2009-11-17 2011-05-26 Astrazeneca Ab Combinaisons qui comprennent un modulateur du récepteur glucocorticoïde, destinées au traitement de maladies respiratoires
WO2012046050A1 (fr) 2010-10-07 2012-04-12 Astrazeneca Ab Nouvelles combinaisons
MD4369C1 (ro) * 2011-03-04 2016-04-30 Sosei R&D Ltd Utilizarea glicopirolatului pentru tratarea tahicardiei, doză unică, dispozitiv de administrare, metodă de tratament şi profilaxie a tahicardiei
US10925832B2 (en) 2018-09-28 2021-02-23 Karuna Therapeutics, Inc. Compositions and methods for treatment of disorders ameliorated by muscarinic receptor activation
US10933020B2 (en) 2018-09-28 2021-03-02 Karuna Therapeutics, Inc. Compositions and methods for treating disorders ameliorated by muscarinic receptor activation
US11452692B2 (en) 2018-09-28 2022-09-27 Karuna Therapeutics, Inc. Compositions and methods for treating disorders ameliorated by muscarinic receptor activation
US11471413B2 (en) 2018-09-28 2022-10-18 Karuna Therapeutics, Inc. Compositions and methods for treating disorders ameliorated by muscarinic receptor activation
US11890378B2 (en) 2018-09-28 2024-02-06 Karuna Therapeutics, Inc. Compositions and methods for treating disorders ameliorated by muscarinic receptor activation

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