WO2011073662A1 - Association d'une benzoxazinone et d'un autre agent pour le traitement de maladies respiratoires - Google Patents

Association d'une benzoxazinone et d'un autre agent pour le traitement de maladies respiratoires Download PDF

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WO2011073662A1
WO2011073662A1 PCT/GB2010/052103 GB2010052103W WO2011073662A1 WO 2011073662 A1 WO2011073662 A1 WO 2011073662A1 GB 2010052103 W GB2010052103 W GB 2010052103W WO 2011073662 A1 WO2011073662 A1 WO 2011073662A1
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methyl
inhibitor
antagonist
hydroxy
active ingredient
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PCT/GB2010/052103
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Roger Victor Bonnert
Stephen Connolly
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Astrazeneca Ab
Astrazeneca Uk Limited
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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
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K31/439—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 the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system

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) wherein one of the pharmaceutically active substances is N-cyclohexyl-N-(2-(2-(5-hydroxy-3-oxo-3,4-dihydro-2H- benzo[b][l,4]oxazin-8-yl)ethylamino)ethyl)-3-(3-(l-methyl-lH-pyrazol-4- yl)phenethoxy)propanamide or a pharmaceutically acceptable salt thereof.
  • 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
  • glucocorticoids 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
  • 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. Moreover, whilst the use of steroids may lead to therapeutic effects, it is desirable to be able to use steroids in low doses to minimise the occurrence and severity of undesirable side effects that may be associated with regular administration. Recent studies have also highlighted the problem of the acquisition of steroid resistance amongst patients suffering from respiratory diseases.
  • 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
  • Bronchodilators are prescribed mainly for symptomatic relief and they are not considered to alter the natural history of respiratory diseases.
  • 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 N-cyclohexyl-N-(2-(2-(5-hydroxy-3-oxo-
  • chemokine antagonist not CCR1
  • vasodilator a vasodilator
  • an ENAC blocker (Epithelial Sodium-channel blocker).
  • the pharmaceutical product of the present invention comprises a first active ingredient and a second active ingredient, and it may comprise a third active ingredient.
  • the third active ingredient can be chosen from the list of second active ingredients but would normally have a different mechanism of action. So, for example, the second active ingredient might be a muscarinic antagonist and the third active ingredient might be: a non-steroidal glucocorticosteroid receptor agonist, corticosteroid, a CCR1 antagonist or a PDE4 inhibitor.
  • the first active ingredient which is N-cyclohexyl-N-(2-(2-(5-hydroxy-3-oxo-3,4-dihydro- 2H-benzo[b] [ 1 ,4]oxazin-8-yl)ethylamino)ethyl)-3-(3-(l -methyl- lH-pyrazol-4- yl)phenethoxy)propanamide or a salt thereof, may be in the form of a solvate (such as a hydrate).
  • a suitable salt of N-cyclohexyl-N-(2-(2-(5-hydroxy-3- oxo-3,4-dihydro-2H-benzo[b][l,4]oxazin-8-yl)ethylamino)ethyl)-3-(3-(l-methyl-lH- pyrazol-4-yl)phenethoxy)propanamide is, for example, a hydrochloride, hydrobromide, trifluoroacetate, sulphate, sulfonate, phosphate, acetate, fumarate (such as a hemi-fumaric acid salt), maleate, tartrate, lactate, citrate, pyruvate, succinate, oxalate,
  • ethanesulphonate malonate, xinafoate, ascorbate, oleate, nicotinate, saccharinate, adipate, formate, glycolate, L-lactate, D-lactate, aspartate, malate, L-tartrate, D-tartrate, stearate, 2- furoate, 3-furoate, napadisylate (naphthalene- 1, 5 -disulfonate or naphthalene- 1 -(sulfonic acid)-5-sulfonate), edisylate (ethane- 1 ,2-disulfonate or ethane- 1 -(sulfonic acid)-2- sulfonate), isethionate (2-hydroxyethylsulfonate), 2-mesitylenesulphonate, 2- naphthalenesulphonate, 2,5-dichlorobenzenesulphonate, R-mandelate, S-mande
  • the present invention provides a pharmaceutical product wherein the first active ingredient is N-cyclohexyl-N-(2-(2-(5-hydroxy-3-oxo-3,4-dihydro-2H- benzo[b][l,4]oxazin-8-yl)ethylamino)ethyl)-3-(3-(l-methyl-lH-pyrazol-4- yl)phenethoxy)propanamide hemi-fumaric acid salt.
  • the present invention provides a pharmaceutical product comprising, in combination, a first active ingredient which is N-cyclohexyl-N-(2-(2-(5- hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][l,4]oxazin-8-yl)ethylamino)ethyl)-3-(3-(l- methyl-lH-pyrazol-4-yl)phenethoxy)propanamide or a salt thereof, and a second active ingredient selected from a:
  • beta-2 adrenoceptor agonist beta-2 adrenoceptor agonist
  • beta-2 adrenoceptor inverse agonist beta-2 adrenoceptor inverse agonist
  • muscarinic antagonist/beta-2 adrenoceptor agonist muscarinic antagonist/PDE inhibitor
  • a 5HT antagonist is, for example, PRX08066.
  • An adenosine antagonist is, for example, CVT6883 or EPI-12323.
  • An adenosine receptor agonist is, for example, regadenoson (CVT3146) (Adenosine, 2-[4- [(methy lamino)carbony 1] - 1 H-pyrazol- 1 -y 1] -) .
  • An anti-allergic is, for example, tranilast (Benzoic acid, 2-[[3-(3,4-dimethoxyphenyl)-l- oxo-2-propen-l-yl]amino]-).
  • An anti-asthmatic is, for example, VAK694, PF-3893787, PF-3526299 or KPE-06001.
  • An antibiotic is, for example, telithromycin (2H-Oxacyclotetradecino[4,3-d]oxazole- 2,6,8,14(lH,7H,9H)-tetrone, 4-ethyloctahydro-l l-methoxy-3a,7,9,l 1,13, 15-hexamethyl-l- [4-[4-(3-pyridinyl)-lH-imidazol-l-yl]butyl]-10-[[3,4,6-trideoxy-3-(dimethylamino)-.beta.- D-xylo-hexopyranosyl]oxy]-, (3aS,4R,7R,9R,10R,l lR,13R,15R,15aR)-), levofioxacin (7H-Pyrido[ 1 ,2,3-de]- 1 ,4-benzoxazine-6-carboxylic acid, 9-fluor
  • An anti-inflammatory is, for example, PS948115 or PF-3715455.
  • An antioxidant is, for example, niacin (3-Pyridinecarboxylic acid), N-acetylcysteine amide (Propanamide, 2-(acetylamino)-3-mercapto-, (2R)-), N-acetylcysteine, N-acetyl cysteine ethyl ester (L-Cysteine, N-acetyl-, ethyl ester), N-acetyl cysteine choline ester
  • An anti-viral is, for example, pleconaril (1,2,4-Oxadiazole, 3-[3,5-dimethyl-4-[3-(3- methyl-5 -isoxazolyl)propoxy ]phenyl]-5 -(trifluoromethy 1)-) .
  • a beta-2 adrenoceptor agonist is, for example, terbutaline (1,3-Benzenediol, 5-[2-[(l,l- dimethylethyl)amino]-l-hydroxyethyl]-), salmeterol (e.g. as xinafoate) (2- Naphthalenecarboxylic acid, 1 -hydroxy-, compd. with 4-hydroxy-. alpha.1 -[[[6-(4- phenylbutoxy)hexyl]amino]methyl]-l ,3-benzenedimethanol (1 : 1)), salmeterol (1,3- Benzenedimethanol, 4-hydroxy-.
  • GSKl 59802, GSK 642444 (3-(4- ⁇ 6-[2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)- ethylamino]-hexyloxy ⁇ -butyl)-benzenesulfonamide; compound with 3-phenyl-acrylic acid), formoterol (e.g.
  • hydrochloride (Carbamic acid, ⁇ , ⁇ -dimethyl-, 3-[[(dimethylamino)carbonyl]oxy]-5-[2- [(l,l-dimethylethyl)amino]-l-hydroxyethyl]phenyl ester, hydrochloride (1 : 1)), bambuterol (Carbamic acid, ⁇ , ⁇ -dimethyl-, C,C'-[5-[2-[(l,l-dimethylethyl)amino]-l-hydroxyethyl]- 1,3-phenylene] ester), ASF1020, arformoterol (e.g.
  • a beta-2 adrenoceptor inverse agonist is, for example, nadolol (INV002) (2,3- Naphthalenediol, 5-[3-[(l,l-dimethylethyl)amino]-2-hydroxypropoxy]-l,2,3,4-tetrahydro-
  • a C5a antagonist is, for example, MP435 (W54011).
  • a chemokine antagonist is, for example, PS-031291 (Pyrrolidine- 1,2-dicarboxylic acid 2- [(4-chloro-benzyl)-methyl-amide] 1 -[(4-trifluoromethyl-phenyl)-amide]), CCX-354, vicriviroc (Methanone, (4,6-dimethyl-5-pyrimidinyl)[4-[(3S)-4-[(lR)-2-methoxy-l-[4- (trifluoromethyl)phenyl] ethyl] -3 -methyl- 1 -piperazinyl]-4-methyl- 1 -piperidiny), maraviroc (Cyclohexanecarboxamide, 4,4-difluoro-N-[(lS)-3-[(3-exo)-3-[3-methyl-5-(l- methylethyl)-4H-l ,2,4-triazol-4-yl]-8-azabicyclo[3.
  • a COX inhibitor is, for example, piroxicam (2H-l,2-Benzothiazine-3-carboxamide, 4- hydroxy-2-methyl-N-2-pyridinyl-, 1,1 -dioxide), meloxicam (2H-l,2-Benzothiazine-3- carboxamide, 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-, 1,1 -dioxide), indomethacin (lH-Indole-3 -acetic acid, l-(4-chlorobenzoyl)-5-methoxy-2-methyl-), ibuprofen
  • a CSF-1 receptor kinase inhibitor is, for example, JNJ28312141.
  • An ENaC Inhibitor is, for example, triamterene (2,4,7-Pteridinetriamine, 6-phenyl-), P- 552-02 (N-(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-N'- ⁇ 4-[4-(2,3-dihydroxy- propoxy)-phenyl]-butyl ⁇ -guanidine), GS9411 (P680), benzamil (2-Pyrazinecarboxamide, 3,5-diamino-6-chloro-N-[imino[(phenylmethyl)amino]methyl]-) or amiloride (2- Pyrazinecarboxamide, 3 ,5 -diamino-N-(aminoiminomethyl)-6-chloro-).
  • a glucocorticoid receptor agonist is, for example, triamcinolone acetonide (Pregna-1,4- diene-3,20-dione, 9-fiuoro-l 1 ,21 -dihydroxy- 16,17-[(l -methylethylidene)bis(oxy)]-, (11. beta., 16.
  • dexamethasone cipecilate Pregna- 1 ,4-diene-3 ,20-dione, 21 -[(cyclohexylcarbonyl)oxy]- 17- [(cyclopropylcarbonyl)oxy]-9-fluoro-l 1 -hydroxy- 16-methyl-, (11. beta., 16. alpha.)-
  • desisobutyryl ciclesonide Pregna- l,4-diene-3,20-dione, 16,17-[[(R)- cyclohexylmethylene]bis(oxy)]-l 1,21-dihydroxy-, (11. beta. ,16.
  • butixocort propionate Pregn-4-ene-3,20-dione, 11 -hydroxy- 17-(1- oxobutoxy)-21-[(l-oxopropyl)thio]-, (1 l .beta.)-), budesonide (Pregna- l,4-diene-3, 20- dione, 16, 17-[butylidenebis(oxy)]-l 1,21-dihydroxy-, (1 l .beta., 16. alpha.)-),
  • beclomethasone dipropionate (Pregna- l,4-diene-3,20-dione, 9-chloro-l 1 -hydroxy- 16- methyl-17,2 l-bis(l -oxopropoxy)-, (1 l .beta., 16.beta.)-), alclometasone dipropionate (Pregna- 1 ,4-diene-3 ,20-dione, 7-chloro- 11 -hydroxy- 16-methyl- 17,21 -bis( 1 -oxopropoxy)-, (7.alpha.,l l .beta.,16.alpha.)-), GSK870086, PF-251802 or PF-4171327.
  • a guanylate cyclase inhibitor is, for example, riociguat (Bay632521) (Carbamic acid, N- [4,6-diamino-2-[l-[(2-fluorophenyl)methyl]-lH-pyrazolo[3,4-b]pyridin-3-yl]-5- pyrimidinyl]-N-methyl-, methyl ester).
  • a histamine/leukotriene antagonist is, for example, azelastine (l(2H)-Phthalazinone, 4-[(4- chlorophenyl)methyl]-2-(hexahydro- 1 -methyl- 1 H-azepin-4-yl)-) .
  • a histone deacetylase inducer is, for example, theophylline (lH-Purine-2,6-dione, 3,9- dihydro-l,3-dimethyl-) or aminophylline (theophylline + 1 ,2-ethandiamine) (1H-Purine- 2,6-dione, 3,9-dihydro-l,3-dimethyl-, compd. with 1 ,2-ethanediamine (2:1)).
  • IKK2 inhibitor is, for example, IMD2560 (N-(3,5-Bis-trifluoromethyl-phenyl)-5- chloro-2-hydroxy-benzamide) or IMD1041.
  • An immunosuppressant is, for example, tacrolimus (15,19-Epoxy-3H-pyrido[2,l- c][l,4]oxaazacyclotricosine-l, 7,20,2 l(4H,23H)-tetrone, 5,6,8,11,12,13, 14,15, 16,17,18,19,24,25,26,26a-hexadecahydro-5,19-dihydroxy-3-[(lE)-2- [(lR,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-l-methylethenyl]-14,16-dimethoxy- 4,10,12,18-tetramethyl-8-(2-propen- 1 -yl)-,
  • An Ion channel modulator is, for example, senicapoc (ICA17043) (Benzeneacetamide, 4- fluoro-.alpha.-(4-fluorophenyl)-.alpha.-phenyl-) or andolast (diazolast; CR2039)
  • a JAK inhibitor is, for example, INCB28050, VX509, R348 or CP-690550 (1- Piperidinepropanenitrile, 4-methyl-3-(methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)- .beta.- ⁇ -, (3R,4R)-).
  • a leukotriene antagonist is, for example, zileuton (Urea, N-(l-benzo[b]thien-2-ylethyl)-N- hydroxy-), zafirlukast (Carbamic acid, N-[3-[[2-methoxy-4-[[[(2- methylphenyl)sulfonyl]amino]carbonyl]phenyl]methyl]-l -methyl- lH-indol-5-yl]-, cyclopentyl ester), pranlukast (Benzamide, N-[4-oxo-2-(2H-tetrazol-5-yl)-4H-l- benzopyran-8-yl]-4-(4-phenylbutoxy)-), montelukast (Cyclopropaneacetic acid, 1-[[[[(1R)-
  • a lipoxygenase inhibitor is, for example, TA270 (4-Hydroxy-l-methyl-3-octyloxy-7- sinapinoylamino-2(lH)-quinolinone), setileuton (MK0633) (2H-l-Benzopyran-2-one, 4- (4-fluorophenyl)-7-[[[5-[(lS)-l-hydroxy-l-(trifluoromethyl)propyl]-l,3,4-oxadiazol-2- yl]amino]methyl]-), PF-4191834, LDP977 (MLN977; PEP03) (Urea, N-[4-[(2S,5S)-5-[(4- fluorophenoxy)methyl]tetrahydro-2-furanyl]-3-butyn- 1 -yl]-N-hydroxy-), clafrinast;
  • a MAP kinase inhibitor is, for example, CEP 1347 (KT7515) (9,12-Epoxy-lH- diindolo[l,2,3-fg:3',2', -kl]pyrrolo[3,4-i][l,6]benzodiazocine-10-carboxylic acid, 5,16- bis[(ethylthio)methyl]-2,3 ,9, 10,11,12-hexahydro- 10-hydroxy-9-methyl- 1 -oxo-, methyl ester, (9S,10R,12R)-) or GLPG0259.
  • CEP 1347 KT7515
  • KT7515 9,12-Epoxy-lH- diindolo[l,2,3-fg:3',2', -kl]pyrrolo[3,4-i][l,6]benzodiazocine-10-carboxylic acid, 5,16- bis[(ethylthio)methyl]-2,
  • a MEK inhibitor is, for example, RDEAl 19 (Cyclopropanesulfonamide, N-[3,4-difluoro- 2-[(2-fluoro-4-iodophenyl)amino]-6-methoxyphenyl]-l-[(2S)-2,3-dihydroxypropyl]-), ARRY300 or ARRY162 (ARRY438162).
  • An MPO inhibitor is, for example, resveratrol (1,3-Benzenediol, 5-[(lE)-2-(4- hydroxyphenyl)ethenyl]-) or piceatannol (1,2-Benzenediol, 4-[(lE)-2-(3,5- dihydroxyphenyl)ethenyl] -) .
  • a mucus clearance promoter is, for example, ambroxol (Cyclohexanol, 4-[[(2-amino-3,5- dibromopheny l)methy 1] amino] - , trans-) .
  • a mucus production inhibitor is, for example, lomucin (MSI 1995; Talniflumate) (3- Pyridinecarboxylic acid, 2-[[3-(trifluoromethyl)phenyl]amino]-, l,3-dihydro-3-oxo-l- isobenzofuranyl ester), BIO 11006 or VR496.
  • a muscarinic antagonist is, for example, trospium chloride (ALKS27) (Spiro[8- azoniabicyclo[3.2.1 ]octane-8, 1 '-pyrrolidinium], 3-[(2-hydroxy-2,2-diphenylacetyl)oxy]-, chloride (1 : 1), (1. alpha. ,3.beta., 5.
  • a muscarinic antagonist is, for example, trospium chloride (ALKS27) (Spiro[8- azoniabicyclo[3.2.1 ]octane-8, 1 '-pyrrolidinium], 3-[(2-hydroxy-2,2-diphenylacetyl)oxy]-, chloride (1 : 1), (1. alpha. ,3.beta., 5.
  • tiotropium bromide (3-Oxa-9- azoniatricyclo[3.3.1.02,4]nonane, 7-[(2-hydroxy-2,2-di-2-thienylacetyl)oxy]-9,9-dimethyl- , bromide (1 : 1), (l .alpha.,2.beta.,4.beta.,5.alpha.,7.beta.)-), QAX028, QAT370, PTOOl, oxitropium bromide (3-Oxa-9-azoniatricyclo[3.3.1.02,4]nonane, 9-ethyl-7-[(2S)-3- hydroxy-l-oxo-2-phenylpropoxy]-9-methyl-, bromide (1 :1),
  • ipratropium bromide 8- Azoniabicyclo[3.2.1 Joctane, 3 -(3 -hydroxy- 1 -oxo-2-phenylpropoxy)-8-methyl-8-(l - methylethyl)-, bromide (1 : 1), (3-endo,8-syn)-), GSK704838, GSK573719 (3-[2-[3-(5- Cyclohexyloxycarbonyl-thiophen-2-yl)-ureido] -3 -(4-hydroxy-phenyl)-propionylamino] - 1 - (3-hydroxy-benzyl)-l-methyl-piperidinium), GSK1160724 (TD4208), glycopyrronium bromide (racemate) (Pyrrolidinium, 3-[(2-cyclopentyl-2-hydroxy-2-phenylpropoxy)-8-methyl-8-(l - methylethyl)-, bromide (1 : 1), (3-
  • a muscarinic antagonist/beta-2 adrenoceptor agonist is, for example, GSK961081
  • a muscarinic antagonist/PDE inhibitor is, for example, UCB 101333-3 (N,2- dicyclopropyl-6-(hexahydro- 1 H-azepin- 1 -yl)-5-methyl-4-pyrimidinamine).
  • a NO donor is, for example, N30-201 (S-nitrosoglutathione).
  • a p38 inhibitor is, for example, TA5493, SCI0323 (2- ⁇ 5-[4-(4-Fluoro-benzyl)-piperidine- 1 -carbonyl]-6-methoxy- 1 -methyl- lH-indol-3-yl ⁇ -N,N-dimethyl-2-oxo-acetamide), PS540446, PH797804 (3-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H- pyridin-l-yl]-4,N-dimethyl-benzamide), losmapimod (GSK856553; GW856553) (3- Pyridinecarboxamide, 6- [5 - [(cyclopropylamino)carbonyl]-3 -fluoro-2-methylphenyl] -N- (2,2-dimethylpropyl)-), KC-706 (2-(5-tert-Butyl-2-m-
  • a PDE inhibitor is, for example, RPL554 (VMX554), tetomilast (OPC6535) (2- Pyridinecarboxylic acid, 6-[2-(3,4-diethoxyphenyl)-4-thiazolyl]-), roflumilast (Benzamide, 3-(cyclopropylmethoxy)-N-(3,5-dichloro-4-pyridinyl)-4-(difluoromethoxy)-), pentoxifylline (1 H-Purine-2,6-dione, 3 ,7-dihydro-3 ,7-dimethyl- 1 -(5-oxohexyl)-), oglemilast (GRC3886) (1-Dibenzofurancarboxamide, N-(3,5-dichloro-4-pyridinyl)-4- (difluoromethoxy)-8-[(methylsulfonyl)amino]-), Ibudilast (KC404) (1-
  • a PDE5 inhibitor is, for example, vardenafil (Imidazo[5,l-f][l ,2,4]triazin-4(lH)-one, 2-[2- ethoxy-5-[(4-ethyl-l-piperazinyl)sulfonyl]phenyl]-5-methyl-7-propyl-), udenafil
  • a CRTh2 antagonist is, for example, SOA002, QAV680, ODC9101 (OC000459) ([5- Fluoro-l-(4-methanesulfonyl-benzenesulfonyl)-2 -methyl- lH-indol-3-yl] -acetic acid), OC499, MLN6095 (SAR398171), AP768, AMG853, AM211, ADC3680 or ACT129968 ([3-(2,3-Dihydro-indole-l-carbonyl)-l,2,3,4-tetrahydro-carbazol-9-yl]-acetic acid).
  • a DPI antagonist is, for example, SAR389644 or laropiprant (L888839; MK-0524) (Cyclopent[b]indole-3-acetic acid, 4-[(4-chlorophenyl)methyl]-7-fluoro-l ,2,3,4-tetrahydro- 5-(methylsulfonyl)-, (3R)-).
  • a phospholipase inhibitor is, for example, giripladib (PLA695) (Benzoic acid, 4-[3-[5- chloro- 1 -(diphenylmethyl)-2-[2-[[[[2-
  • a PI3 kinase inhibitor is, for example, CAL101.
  • a PPARgamma agonist is, for example, rosiglitazone (2,4-Thiazolidinedione, 5-[[4-[2- (methyl-2-pyridinylamino)ethoxy]phenyl]methyl]-), rivoglitazone (2,4-Thiazolidinedione, 5-[[4-[(6-methoxy-l-methyl-lH-benzimidazol-2-yl)methoxy]phenyl]methyl]-), pioglitazone (2,4-Thiazolidinedione, 5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methyl]- ), lobeglitazone (2,4-Thiazolidinedione, 5-[[4-[2-[[6-(4-methoxyphenoxy)-4- pyrimidinyl]methylamino]ethoxy]phenyl]methyl]-) or balaglitazone
  • a protease inhibitor is, for example, JNJ10311795 (RWJ355871) (Phosphonic acid, P-[2- [3-[[methyl[ 1 -(2-naphthalenylcarbonyl)-4-piperidinyl]amino]carbonyl]-2-naphthalenyl]- 1 - (l-naphthalenyl)-2-oxoethyl]-), JNJ18054478, V-85546 (ASH 1793), Ilomastat
  • a RARgamma inhibitor is, for example, palovarotene (R667; Ro667; RO3300067) (Benzoic acid, 4-[(lE)-2-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-(lH-pyrazol-l- ylmethyl)-2-naphthalenyl] ethenyl] -).
  • a selectin inhibitor is, for example, bimosiamose (TBC1269) ([l,l'-Biphenyl]-3-acetic acid, 3',3"'-(l,6-hexanediyl)bis[6'-(. alpha. -D-mannopyranosyloxy)-).
  • a sirtuin activator is, for example, GSK2245840 (SIRT2104).
  • a statin is, for example, simvastatin (Butanoic acid, 2,2-dimethyl-, (lS,3R,7S,8S,8aR)- l,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-[(2R,4R)-tetrahydro-4-hydroxy-6-oxo-2H- pyran-2-yl]ethyl]-l-naphthalenyl ester), rosuvastatin (6-Heptenoic acid, 7-[4-(4- fluorophenyl)-6-( 1 -methylethyl)-2- [methyl(methylsulfonyl)amino] -5 -pyrimidinyl] -3 ,5 - dihydroxy-, (3R,5S,6E)-), pravastatin (1-Naphthaleneheptanoic acid, 1,2,6,7,8,8a- hexahydro-.beta.,
  • lovastatin butanoic acid, 2-methyl-
  • a Syk inhibitor is, for example, tamatinib (R788; R406) (2H-Pyrido[3,2-b]-l,4-oxazin- 3 (4H)-one, 6-[ [5 -fluoro-2- [(3 ,4,5 -trimethoxyphenyl)amino] -4-pyrimidinyl] amino] -2,2- dimethyl-4-[(phosphonooxy)methyl]-) or R343 (2- ⁇ 3-[4-(2,2-Difluoro-3-oxo-3,4-dihydro 2H-benzo[l,4]oxazin-6-ylamino)-5-fluoro-pyrimidin-2-ylamino]-phenoxy ⁇ -N-methyl- acetamide).
  • a Th2 Cytokine Inhibitor is, for example, suplatast tosylate (Sulfonium, [3-[[4-(3-ethoxy- 2-hydroxypropoxy)phenyl]amino]-3-oxopropyl]dimethyl-, 4-methylbenzenesulfonate (1 : 1)) or suplatast (Sulfonium, [3-[[4-(3-ethoxy-2-hydroxypropoxy)phenyl]amino]-3- oxopropy 1] dimethyl-) .
  • a thromboxane antagonist is, for example, seratrodast (Benzeneheptanoic acid, .zeta.- (2,4,5-trimethyl-3,6-dioxo-l,4-cyclohexadien-l-yl)-) or ramatroban (9H-Carbazole-9- propanoic acid, 3-[[(4-fluorophenyl)sulfonyl]amino]-l,2,3,4-tetrahydro-, (3R)-).
  • a TLR agonist is, for example, AVE0675.
  • a vasodilator is, for example, BMS-346567 (PS-433540), LABCGRP, daglutril (lH-1- Benzazepine-1 -acetic acid, 3-[[[l-[(2R)-2-(ethoxycarbonyl)-4- phenylbutyl]cyclopentyl]carbonyl]amino]-2,3,4,5-tetrahydro-2-oxo-, (3S)-), bosentan (Benzenesulfonamide, 4-(l,l-dimethylethyl)-N-[6-(2-hydroxyethoxy)-5-(2- methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]-), sitaxsentan sodium (3-Thiophenesulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[2-(6-methyl-l ,3
  • a VIP agonist is, for example, RG7103 (R7103).
  • 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 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 CCR1 antagonist is, 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-fluorophenyl)methyl]- 2-methylpiperazine monohydrochloride) or CCX634.
  • 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-fluorophenyl)methyl]- 2-methylpiperazine monohydrochloride) or
  • a CCR1 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- pyrrolidinyl ⁇ amino] -2-hydroxypropoxy ⁇ -4-fluorophenyl)acetamide, N-(2 ⁇ (2S)-3 [ ⁇ (3 S)- 1 - [(4-chlorophenyl)methyl] -3 -pyrrolidinyl ⁇ amino] -2-hydroxypropoxy ⁇ -4- fluorophenyl)acetamide, N-(2- ⁇ (2S)-3-[l- ⁇ (4-chlorobenzoyl)-4-piperidinyl ⁇ amino]-2- hydroxypropoxy ⁇ -4-hydroxyphenyl)acetamide, (2- ⁇ [(2S)-3- ⁇ [(2R,5 S)-
  • BX471 ((2R)-l-[[2- [(aminocarbonyl)amino]-4-chlorophenoxy]acetyl]-4-[(4-fluorophenyl)methyl]-2- methylpiperazine monohydrochloride); or CCX634.
  • a CCR1 antagonist is, for example, N- ⁇ 2-[((25)-3- ⁇ [l-(4-chlorobenzyl)piperidin-4- yljamino ⁇ -2-hydroxy-2-methylpropyl)oxy]-4-hydroxyphenyl ⁇ acetamide (see WO
  • a chemokine antagonist (other than a CCR1 antagonist), for example, 656933 (N-(2- bromophenyl)-N * -(4-cyano- 1 H- 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, 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
  • a corticosteroid is, for example, Alclometasone dipropionate, Amelometasone,
  • a CRTh2 antagonist is, for example, a compound from WO 2004/106302 or WO
  • a DPI antagonist is, for example, L888839 or MK0525.
  • An histone deacetylase inducer is, for example, ADC4022, Aminophylline, a
  • An 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, OC1768, OC2125, OC2184, OC499, OCD9101, 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-001 , Tepoxalin, UCB-35440, Veliflapon, ZD-2138, ZD- 4007 or Zileuton (( ⁇ )-l-(l-Benzo[b]thien-2-ylethyl)-l -hydroxyurea)
  • a leukotriene receptor antagonist is, for example, Ablukast, Iralukast (CGP 45715 A), Montelukast, Montelukast sodium, Ontazolast, Pranlukast, Pranlukast hydrate (mono Na salt), Verlukast (MK-679) or Zafirlukast.
  • 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 muscarinic antagonist is, for example, Aclidinium bromide, Glycopyrrolate (such as R,R-, R,S-, S,R-, or S,S-glycopyrronium bromide), Oxitropium bromide, Pirenzepine, telenzepine, Tiotropium bromide, 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-l-(3- phenoxypropyl)-l-azoniabicyclo[2.2.2]octane bromide (see WO 01/04118), 3(R)-1- phenethyl-3-(9H-xanthene-9-carbonyloxy)-l-azoniabicyclo[2.2.2]octane bromide or (3R)- 3-[(2S)-2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-l-(2-phenoxyethyl)-l- azoniabi
  • a muscarinic antagonist is Aclidinium bromide
  • Glycopyrrolate (such as R,R-, R,S-, S,R-, or S,S-glycopyrronium bromide), Oxitropium bromide, Pirenzepine, telenzepine or Tiotropium bromide.
  • a muscarinic antagonist is Glycopyrrolate (such as R,R-, R,S-, S,R-, or S,S-glycopyrronium bromide) or Tiotropium bromide.
  • a muscarinic antagonist is (i?)-l-[2-(4-Fluoro-phenyl)-ethyl]-3-((5)-2- phenyl-2-piperidin- 1 -yl-propionyloxy)- 1 -azonia-bicyclo[2.2.2]octane (see
  • WO2008/075005 wherein the counter-ion is, for example, chloride, bromide, sulfate, methanesulfonate, benzenesulfonate (besylate), toluenesulfonate (tosylate), napthalene- bissulfonate (napadisylate), phosphate, acetate, citrate, lactate, tartrate, mesylate, maleate, fumarate or succinate).
  • the counter-ion is, for example, chloride, bromide, sulfate, methanesulfonate, benzenesulfonate (besylate), toluenesulfonate (tosylate), napthalene- bissulfonate (napadisylate), phosphate, acetate, citrate, lactate, tartrate, mesylate, maleate, fumarate or succinate).
  • 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, R1503, SC-80036, SCI0469, 6-chloro-5-[[(2 l S,5i?)-4-[(4-fluorophenyl)methyl]- 2,5-domethyl- 1 -piperazinyl]carbonyl]-N,N, 1 -trimethyl-a-oxo- lH-indole-3-acetamide, VX702 or VX745 (5-(2,6-dichlorophenyl)-2-(phenylthio)
  • a PDE Inhibitor such as a PDE4 inhibitor is, for example, 256066, Arofylline (3-(4- chlorophenyl)-3,7-dihydro-l -propyl- 1H-Purine -2, 6-dione), AWD 12-281 (N-(3,5-dichloro- 4-pyridinyl)- 1 -[(4-fluorophenyl)methyl] -5 -hydroxy-a-oxo- 1 H-indole-3 -acetamide), BAY 19-8004 (Bayer), CDC-801 (Calgene), Celgene compound (( ⁇ )- ⁇ -(3,4- dimethoxyphenyl)- 1 ,3-dihydro- 1 -oxo-2H-isoindole-2-propanamide), Cilomilast (cis-4- cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]-cyclohexanecarbox
  • a PDE5 Inhibitor is, for example, Gamma-glutamyl[s-(2-iodobenzyl)cysteinyl]glycine, Tadalafil, Vardenafil, sildenafil, 4-phenyl-methylamino-6-chloro-2-(l-imidazolyl)- quinazoline, 4-phenyl-methylamino-6-chloro-2-(3-pyridyl)-quinazoline, 1 ,3-dimethyl-6-(2- propoxy-5 -methanesulphonylamidophenyl)- 1 ,5 -dihydropyrazolo [3 ,4-d]pyrimidin-4-one or l-cyclopentyl-3-ethyl-6-(3-ethoxy-4-pyridyl)-pyrazolo[3,4-d]pyrimidin-4-one.
  • a PPARy agonist is, for example, Pioglitazone, Pioglitazone hydrochloride, Rosiglitazone Maleate, Rosiglitazone Maleate ((-)-enantiomer, free base), Rosiglitazone
  • 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
  • TACE Inhibitor for example DPC-333, Sch- 709156 or Doxy eye line.
  • 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, Trepro
  • ENAC Episomal Sodium-channel blocker
  • Amiloride Benzamil, Triamterene, 552-02, PSA14984, PSA25569, PSA23682 or AER002.
  • All the above second et seq active ingredients may be in the form of solvates, for example hydrates.
  • 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 N-cyclohexyl-N-(2-(2-(5-hydroxy-3-oxo-
  • Glucocorticoid Receptor GR Receptor Agonist
  • chemokine antagonist not CCR1
  • a p38 inhibitor or, a PDE inhibitor.
  • the present invention provides a pharmaceutical product comprising, in combination, a first active ingredient which is N-cyclohexyl-N-(2-(2-(5-hydroxy-3-oxo- 3,4-dihydro-2H-benzo[b][l,4]oxazin-8-yl)ethylamino)ethyl)-3-(3-(l -methyl- lH-pyrazol-4- yl)phenethoxy)propanamide or a pharmaceutically acceptable salt thereof (such as the hemi-fumaric acid salt), and a second active ingredient which is a non-steroidal
  • Glucocorticoid Receptor (GR) Agonist for example, a compound disclosed in WO
  • the present invention provides a pharmaceutical product comprising, in combination, a first active ingredient which is N-cyclohexyl-N-(2-(2-(5-hydroxy-3-oxo- 3,4-dihydro-2H-benzo[b][l,4]oxazin-8-yl)ethylamino)ethyl)-3-(3-(l -methyl- lH-pyrazol-4- yl)phenethoxy)propanamide or a pharmaceutically acceptable salt thereof (such as the hemi-fumaric acid salt), and a second active ingredient which is a CCR1 antagonist, for example, a compound disclosed in WO2001/062728 or WO2001/098273 [such as N- (2 ⁇ (2S)-3 [ ⁇ (3R)- 1 -[(4-chlorophenyl)methyl]-3-pyrrolidinyl ⁇ amino] -2-hydroxypropoxy ⁇ - 4-fluorophenyl)acetamide, N-
  • a CCR1 antagonist is N- ⁇ 2-[((25)-3- ⁇ [l-(4-chlorobenzyl)piperidin-4- yljamino ⁇ -2-hydroxy-2-methylpropyl)oxy]-4-hydroxyphenyl ⁇ acetamide, or, 2- ⁇ 2-Chloro- 5- ⁇ [(2S)-3-(5-chloro- 1 * H,3H-spiro[ 1 -benzofuran-2,4'-piperidin]- 1 '-yl)-2- hydroxypropyl]oxy ⁇ -4-[(methylamino)carbonyl]phenoxy ⁇ -2-methylpropanoic acid, or a pharmaceutically acceptable salt thereof (for example a hydrochloride, sulphate, (hemi)fumarate, benzoate, furoate or succinate salt).
  • a pharmaceutically acceptable salt thereof for example a hydrochloride, sulphate, (hemi)fumarate, benzoate, furoate or succinate
  • the present invention provides a pharmaceutical product comprising, in combination, a first active ingredient which is N-cyclohexyl-N-(2-(2-(5-hydroxy-3-oxo- 3,4-dihydro-2H-benzo[b][l,4]oxazin-8-yl)ethylamino)ethyl)-3-(3-(l -methyl- lH-pyrazol-4- yl)phenethoxy)propanamide or a pharmaceutically acceptable salt thereof (such as the hemi-fumaric acid salt), and a second active ingredient which is a chemokine antagonist (not CCR1), for example, 656933 (N-(2-bromophenyl)-N'-(4-cyano-lH-l,2,3-benzotriazol- 7-yl)urea), 766994 (4-( ⁇ [( ⁇ [(2R)-4-(3,4-dichlorobenzyl)morpholin-2- yl]methyl
  • the present invention provides a pharmaceutical product comprising, in combination, a first active ingredient which is N-cyclohexyl-N-(2-(2-(5-hydroxy-3-oxo- 3,4-dihydro-2H-benzo[b][l,4]oxazin-8-yl)ethylamino)ethyl)-3-(3-(l -methyl- lH-pyrazol-4- yl)phenethoxy)propanamide or a pharmaceutically acceptable salt thereof (such as the hemi-fumaric acid salt), 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, Flutica
  • 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 N-cyclohexyl-N-(2-(2-(5-hydroxy-3-oxo- 3,4-dihydro-2H-benzo[b][l,4]oxazin-8-yl)ethylamino)ethyl)-3-(3-(l -methyl- lH-pyrazol-4- yl)phenethoxy)propanamide or a pharmaceutically acceptable salt thereof (such as the hemi-fumaric acid salt), 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 N-cyclohexyl-N-(2-(2-(5-hydroxy-3-oxo- 3,4-dihydro-2H-benzo[b][l,4]oxazin-8-yl)ethylamino)ethyl)-3-(3-(l -methyl- lH-pyrazol-4- yl)phenethoxy)propanamide or a pharmaceutically acceptable salt thereof (such as the hemi-fumaric acid salt), and a second active ingredient is an IKK2 inhibitor, for example, 2- ⁇ [2-(2-Methylamino-pyrimidin-4-y 1)- 1 H-indole-5 -carbonyl]-amino ⁇ -3 -(phenyl-pyridin- 2-yl-amino)-propionic acid.
  • a first active ingredient which is N-cyclohexyl-N-(2-(2-(5-
  • the present invention provides a pharmaceutical product comprising, in combination, a first active ingredient which is N-cyclohexyl-N-(2-(2-(5-hydroxy-3-oxo- 3,4-dihydro-2H-benzo[b][l,4]oxazin-8-yl)ethylamino)ethyl)-3-(3-(l -methyl- lH-pyrazol-4- yl)phenethoxy)propanamide or a pharmaceutically acceptable salt thereof (such as the hemi-fumaric acid salt), and a second active ingredient is a muscarinic antagonist, for example, Aclidinium bromide, Glycopyrrolate (such as R,R-, R,S-, S,R-, or S,S- glycopyrronium bromide), Oxitropium bromide, Pirenzepine, telenzepine, Tiotropium bromide, 3(R)-(2-hydroxy-2,2-dithien-2--
  • the present invention provides a pharmaceutical product comprising, in combination, a first active ingredient which is N-cyclohexyl-N-(2-(2-(5-hydroxy-3-oxo- 3,4-dihydro-2H-benzo[b][l,4]oxazin-8-yl)ethylamino)ethyl)-3-(3-(l -methyl- lH-pyrazol-4 yl)phenethoxy)propanamide or a pharmaceutically acceptable salt thereof (such as the hemi-fumaric acid salt), and a second active ingredient is Oxitropium bromide or
  • the muscarinic receptor antagonist is a long acting muscarinic receptor antagonist, that is 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 N-cyclohexyl-N-(2-(2-(5-hydroxy-3-oxo- 3,4-dihydro-2H-benzo[b][l,4]oxazin-8-yl)ethylamino)ethyl)-3-(3-(l -methyl- lH-pyrazol-4 yl)phenethoxy)propanamide or a pharmaceutically acceptable salt thereof (such as the hemi-fumaric acid salt), and a second active ingredient is Tiotropium bromide.
  • a first active ingredient which is N-cyclohexyl-N-(2-(2-(5-hydroxy-3-oxo- 3,4-dihydro-2H-benzo[b][l,4]oxazin-8-yl)ethylamino)ethyl)-3-(3-(l -methyl- lH-pyrazol-4 yl)
  • the present invention provides a pharmaceutical product comprising, in combination, a first active ingredient which is N-cyclohexyl-N-(2-(2-(5-hydroxy-3-oxo- 3,4-dihydro-2H-benzo[b][l,4]oxazin-8-yl)ethylamino)ethyl)-3-(3-(l -methyl- lH-pyrazol-4 yl)phenethoxy)propanamide or a pharmaceutically acceptable salt thereof (such as the hemi-fumaric acid salt), and a second active ingredient is Tiotropium bromide.
  • a first active ingredient which is N-cyclohexyl-N-(2-(2-(5-hydroxy-3-oxo- 3,4-dihydro-2H-benzo[b][l,4]oxazin-8-yl)ethylamino)ethyl)-3-(3-(l -methyl- lH-pyrazol-4 yl)
  • the present invention provides a pharmaceutical product comprising, in combination, a first active ingredient which is N-cyclohexyl-N-(2-(2-(5-hydroxy-3-oxo- 3,4-dihydro-2H-benzo[b][l,4]oxazin-8-yl)ethylamino)ethyl)-3-(3-(l -methyl- lH-pyrazol-4 yl)phenethoxy)propanamide or a pharmaceutically acceptable salt thereof (such as the hemi-fumaric acid salt), and a second active ingredient is Glycopyrrolate (such as R,R-, R,S-, S,R-, or S,S-glycopyrronium bromide).
  • a first active ingredient which is N-cyclohexyl-N-(2-(2-(5-hydroxy-3-oxo- 3,4-dihydro-2H-benzo[b][l,4]oxazin-8-yl)ethyla
  • the present invention provides a pharmaceutical product comprising, in combination, a first active ingredient which is N-cyclohexyl-N-(2-(2-(5-hydroxy-3-oxo- 3,4-dihydro-2H-benzo[b][l,4]oxazin-8-yl)ethylamino)ethyl)-3-(3-(l -methyl- lH-pyrazol-4- yl)phenethoxy)propanamide or a pharmaceutically acceptable salt thereof (such as the hemi-fumaric acid salt), and a second active ingredient is (i?)-l-[2-(4-Fluoro-phenyl)- ethyl]-3-((5)-2-phenyl-2-piperidin-l-yl-propionyloxy)-l-azonia-bicyclo[2.2.2]octane; wherein the counter-ion is, for example, chloride, bromide, sulfate, methan
  • the present invention provides a pharmaceutical product comprising, in combination, a first active ingredient which is N-cyclohexyl-N-(2-(2-(5-hydroxy-3-oxo- 3,4-dihydro-2H-benzo[b][l,4]oxazin-8-yl)ethylamino)ethyl)-3-(3-(l -methyl- lH-pyrazol-4- yl)phenethoxy)propanamide or a pharmaceutically acceptable salt thereof (such as the hemi-fumaric acid salt), 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(3H)-pyrimidinone), Array-797, AZD
  • the present invention provides a pharmaceutical product comprising, in combination, a first active ingredient which is N-cyclohexyl-N-(2-(2-(5-hydroxy-3-oxo- 3,4-dihydro-2H-benzo[b][l,4]oxazin-8-yl)ethylamino)ethyl)-3-(3-(l -methyl- lH-pyrazol-4- yl)phenethoxy)propanamide or a pharmaceutically acceptable salt thereof (such as the hemi-fumaric acid salt), 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-lH- Purine-2,6-dione), A WD 12-281 (N-(3,5-dichloro-4-pyridinyl)-l-[(4-)-
  • the present invention provides a pharmaceutical product comprising, in combination, a first active ingredient which is N-cyclohexyl-N-(2-(2-(5-hydroxy-3-oxo- 3,4-dihydro-2H-benzo[b][l,4]oxazin-8-yl)ethylamino)ethyl)-3-(3-(l -methyl- lH-pyrazol-4- yl)phenethoxy)propanamide or a pharmaceutically acceptable salt thereof (such as the hemi-fumaric acid salt), and a second active ingredient is 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)- 1 - [(4-fluorophenyl
  • Cilomilast cis-4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]-cyclohexanecarboxylic acid
  • WO2006098353 from Kyowa Hakko Kogyo Co. Ltd.
  • PD189659/PD 168787 (Parke-Davis), Pentoxifylline (3,7-dihydro-3,7-dimethyl-l-(5- oxohexyl)-)-lH-purine-2,6-dione), Pfizer compound (5-fluoro-N-[4-[(2-hydroxy-4-methyl- benzoyl)amino]cyclohexyl]-2-(thian-4-yloxy)pyridine-3-carboxamide), Pfizer UK
  • the present invention provides a pharmaceutical product comprising, in combination, a first active ingredient which is N-cyclohexyl-N-(2-(2-(5-hydroxy-3-oxo- 3,4-dihydro-2H-benzo[b][l,4]oxazin-8-yl)ethylamino)ethyl)-3-(3-(l -methyl- lH-pyrazol-4- yl)phenethoxy)propanamide or a pharmaceutically acceptable salt thereof (such as the hemi-fumaric acid salt), and a second active ingredient is a PDE4 inhibitor, for example AWD 12-281 (N-(3,5-dichloro-4-pyridinyl)-l-[(4-fluorophenyl)methyl]-5-hydroxy-a-oxo- lH-indole-3-acetamide) or roflumilast.
  • a first active ingredient which is N-cyclohexyl-N-(2-(2-
  • the present invention provides a pharmaceutical product comprising, in combination, a first active ingredient which is N-cyclohexyl-N-(2-(2-(5-hydroxy-3-oxo- 3,4-dihydro-2H-benzo[b][l,4]oxazin-8-yl)ethylamino)ethyl)-3-(3-(l -methyl- lH-pyrazol-4- yl)phenethoxy)propanamide or a pharmaceutically acceptable salt thereof (such as the hemi-fumaric acid salt), and a second active ingredient is roflumilast.
  • a first active ingredient which is N-cyclohexyl-N-(2-(2-(5-hydroxy-3-oxo- 3,4-dihydro-2H-benzo[b][l,4]oxazin-8-yl)ethylamino)ethyl)-3-(3-(l -methyl- lH-pyrazol-4- yl
  • 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.
  • simultaneously 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 example 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 colorant.
  • the most appropriate method of administering the active ingredients is dependent on a number of factors.
  • the first and second active ingredients are administered via a single pharmaceutical composition (that is, the first and second active ingredients are in admixture). Therefore, the present invention further provides a pharmaceutical
  • composition comprising, in admixture, a first active ingredient which is N-cyclohexyl-N- (2-(2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][l,4]oxazin-8-yl)ethylamino)ethyl)-3-(3- (1 -methyl- lH-pyrazol-4-yl)phenethoxy)propanamide or a pharmaceutically acceptable salt thereof (such as the hemi-fumaric acid salt), and a second active ingredient as defined above.
  • the pharmaceutical composition optionally 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 (that is N-cyclohexyl-N-(2-(2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][l,4]oxazin-8- yl)ethylamino)ethyl)-3 -(3 -( 1 -methyl- 1 H-pyrazol-4-yl)phenethoxy)propanamide in: salt form, solvate form, or, solvate of salt form) will generally be in the range of from 0.1 microgram fog) 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 ⁇
  • 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 fog) 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 100 ⁇ g, 100 to 5000 ⁇ g, 100 to 1000 ⁇ g or 100 to 500 .
  • 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 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 includes a hydrocarbon, chlorofluorocarbon or a hydrofluoroalkane (e.g.
  • heptafluoroalkane heptafluoroalkane propellant, or a mixture of any such propellants, for example in a pressurised metered dose inhaler (pMDI).
  • Preferred propellants are PI 34a and P227, each of which may be used alone or in combination with other another propellant and/or surfactant and/or other excipient.
  • 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.
  • a suitable device for delivering a dry powder is Turbuhaler®.
  • 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).
  • a dry powder inhaler may be used to administer the active ingredients, alone or in combination with a pharmaceutically acceptable carrier (such as lactose), in the later case either as a finely divided powder or as an ordered mixture.
  • a pharmaceutically acceptable carrier such as lactose
  • 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 is available.
  • the combination 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; emphysema;
  • COPD chronic obstructive pulmonary disease
  • lung fibrosis including cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonias, fibrosis complicating anti-neoplastic therapy and chronic infection, including tuberculosis and aspergillosis and other fungal infections; complications of lung transplantation; vasculitic and thrombotic disorders of the lung vasculature, and pulmonary hypertension; antitussive activity including treatment of chronic cough associated with inflammatory and secretory conditions of the airways, and iatrogenic cough; acute and chronic rhinitis including rhinitis medicamentosa, and vasomotor rhinitis; perennial and seasonal allergic rhinitis including rhinitis nervosa (hay fever); nasal polyposis; acute viral infection including the common cold, and infection due to respiratory syncytial virus, influenza, coronavirus (including SARS) and adenovirus.
  • SARS coronavirus
  • the present invention further provides a pharmaceutical product according to the invention for simultaneous, sequential or separate use in therapy.
  • 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 particular chronic obstructive pulmonary disease, asthma, rhinitis, emphysema or bronchitis (such as chronic obstructive pulmonary disease or asthma; for example chronic obstructive pulmonary disease).
  • a respiratory disease in particular chronic obstructive pulmonary disease, asthma, rhinitis, emphysema or bronchitis (such as chronic obstructive pulmonary disease or asthma; for example chronic obstructive pulmonary disease).
  • the present invention still further provides a method of treating a respiratory disease which comprises simultaneously, sequentially or separately administering:
  • the present invention provides the use of a pharmaceutical product, kit or composition as hereinbefore described for the treatment of a respiratory disease, in particular chronic obstructive pulmonary disease, asthma, rhinitis, emphysema or bronchitis (such as chronic obstructive pulmonary disease or asthma; for example chronic obstructive pulmonary disease).
  • a respiratory disease in particular chronic obstructive pulmonary disease, asthma, rhinitis, emphysema or bronchitis (such as chronic obstructive pulmonary disease or asthma; for example chronic obstructive pulmonary disease).
  • 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 dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated.
  • the daily dosage of a combination of the invention, as hereinbefore defined, when inhaled may be in the range from 0.05 micrograms per kilogram body weight ⁇ g/kg) to 100 micrograms per kilogram body weight ⁇ g/kg).
  • a combination of the invention, as hereinbefore defined, may be used on its own but will generally be administered in the form of a pharmaceutical composition in which a combination of the invention, as hereinbefore defined, is in association with a
  • the pharmaceutical composition will for example comprise from 0.05 to 99 %w (per cent by weight), such as from 0.05 to 80 %w, for example from 0.10 to 70 %w, and such as from 0.10 to 50 %w, of active ingredients, all percentages by weight being based on total composition.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a combination as hereinbefore defined, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • TLC Thin Layer Chromatography
  • Analytical HPLC was carried out using either a Waters XBridgeTM C8 3.5 ⁇ column eluting with a gradient of acetonitrile in either 0.1% aqueous trifluoroacetic acid, 0.1% aqueous formic acid, 0.1% aqueous ammonium acetate or 0.1% aqueous ammonia; a Waters XBridgeTM CI 8 3.5 ⁇ column with a gradient of acetonitrile in 0.1% aqueous ammonia; a Waters SymmetryTM C18 3.5 ⁇ column with a gradient of acetonitrile in 0.1%) aqueous trifluoroacetic acid; a Waters SunfireTM C8 3.5 ⁇ column with a gradient of acetonitrile in 0.1% aqueous trifluoroacetic acid; or a Phenomenex GeminiTM CI 8 3 ⁇ column with a gradient of acetonitrile in 0.1% aqueous trifluoroacetic acid
  • Preparative HPLC was carried out using either a Phenomenex GeminiTM CI 8 5 ⁇ column, a Waters SunfireTM CI 8 5 ⁇ column, a Waters XBridgeTM C8 5 ⁇ column or a Waters XTerraTM 5 ⁇ , unless otherwise detailed, using either acetonitrile in aqueous 0.1- 0.2% trifluoroacetic acid, acetonitrile in aqueous 0.1-0.2% ammonium acetate, or acetonitrile in an aqueous 0.1-0.2% ammonia solution as eluent, as detailed. Fractions were collected following detection by UV spectroscopy at a wavelength such as 220 or 254 nm. Fraction purity was determined by either TLC or analytical HPLC.
  • XRPD was carried out on PANalytical CubiX PRO machine in 0 - 0 configuration over the scan range 2° to 40° 20 with 100-second exposure per 0.02° increment.
  • the X-rays were generated by a copper long-fine focus tube operated at 45kV and 40mA.
  • the wavelength of the copper X-rays was 1.5418 A .
  • the Data was collected on zero background holders on which ⁇ 2mg of the compound was placed.
  • the holder was made from a single crystal of silicon, which had been cut along a non-diffracting plane and then polished on an optically flat finish.
  • the X-rays incident upon this surface were negated by Bragg extinction.
  • DSC thermograms were measured using a TA Q1000 Differential Scanning Calorimeter, with aluminium pans and pierced lids. The sample weights varied between 0.3 to 5mg. The procedure was carried out under a flow of nitrogen gas (50ml/min) and the temperature studied from 25 to 300°C at a constant rate of temperature increase of 10°C per minute.
  • the aqueous phase may added to an identical quantity of preheated (50°C) 3 M aqueous hydrogen chloride. On cooling to 20°C the suspension may be filtered to yield the sub-titled compound.
  • 2-Nitro-l,3-dihydroxybenzene (10 g) was slurried in methanesulfonic acid (41 mL). After stirring for 25minutes, acetic acid anhydride (9 mL) was charged over 30 minutes. The reaction was stirred for 25.5 hours then diluted with acetic acid (10 mL) and then charged dropwise to pre-heated (50°C) water (200 mL). The reaction was rinsed through with acetic acid (12 mL). Further acetic acid (9 mL) was charged. The temperature was adjusted to 60°C and then set to cool to 35°C over 42 minutes. Water (10 mL) was charged and the mixture reheated to 55°C then set to cool to 0°C over 200 minutes.
  • Lithium tert-butoxide (4.06 g) was added to a stirred solution of l-(2,4-dihydroxy-3- nitrophenyl)ethanone (10 g) in DMF (100 mL), under nitrogen, whilst maintaining the internal temperature below 30°C. After stirring for a further 10 min at ambient temperature, benzyl bromide (6.03 mL) was added and the mixture stirred for a further 20 h. Further benzyl bromide (3 mL) was added and the mixture stirred for 24 h.
  • the reaction was quenched with water (300 mL), 1M aqueous sodium hydroxide (50 mL) was added and the mixture was washed with ether (2 x 300 mL), filtering through Celite to aid separation.
  • the basic solution was cooled in ice/water, acidified with ice cold 2M hydrochloric acid (200 mL) and the resulting precipitate filtered off, washed with water and dried to afford a light brown solid.
  • the solid was slurried with ethanol (100 mL) for 1 h and the solid filtered off, washed with cold ethanol (20 mL), and dried under vacuum at 40°C to afford the subtitled compound as a light brown solid (6.8 g).
  • Acetonitrile 700 mL was added to the product of Intermediate 1 (Procedure B) (100 g) and sodium bicarbonate (49.0 g). The mixture was heated to 60°C and benzyl bromide (75.62 mL) added. The mixture was heated to reflux. After 6.5 h the mixture was cooled to 60°C and water (450 mL) added. The mixture was cooled to below 45°C and methyl tert- butyl ether (450 mL) added. The mixture was cooled to 20°C and stirred for at least 1.5 hours. The suspension was filtered and washed with water (250 mL) then ethanol (250 mL) to yield the title compound as a damp solid, 155.65 g. Alternatively the material can be dried under vacuum.
  • Zinc dust (5.5 g) was added portionwise to a suspension of l-(4-(benzyloxy)-2-hydroxy-3- nitrophenyl)ethanone (5.5 g) in acetic acid (55 mL) over 15 min, whilst maintaining the internal temperature below 40 °C with an ice bath. The mixture was allowed to attain ambient temperature and stirred for a further 2 h. The mixture was filtered through Celite (caution gets hot, do not allow to dry), washed with acetic acid, and the filtrate poured onto ice/water (500 mL). The resulting precipitate was filtered off, washed with water, and dried under vacuum at 40°C to afford the subtitled compound as a light brown solid (4.8 g).
  • Tetrahydrofuran (1000 mL) and triethylamine (9.70 mL) were added to the product of Intermediate 2 (Procedure B) (100 g) and platinum on carbon (1%; Johnson-Matthey Type 18MA) (6 g).
  • the mixture was hydrogenated at 50°C and 4 barg until complete then cooled to 20°C and filtered.
  • the mixture was concentrated under vacuum to approximately half the initial volume then methyl isobutyl ketone (500 mL) was charged.
  • the mixture was concentrated under vacuum to half the initial volume then methyl isobutyl ketone (500 mL) was charged.
  • the resulting mixture can be directly used in the next step or evaporated to dryness to afford the sub-titled compound as a brown solid.
  • Benzyltrimethylammonium dichloroiodate 14.17 g was added to a stirred solution of 8- acetyl-5-(benzyloxy)-2H-benzo[b][l,4]oxazin-3(4H)-one (5.5 g) in a mixture of dichloromethane (100 mL), acetic acid (33 mL) and water (5.5 mL) and the reaction mixture stirred at 65°C for 20 h. The reaction was cooled to ambient temperature, treated with aqueous sodium bisulphite (5.78 g in 100 mL) and stirred for a further 30 min.
  • Acetic acid (45 mL), concentrated hydrochloric acid (10.2 mL) and water (45 mL) were added to a hydrogenation vessel containing 8-(2-azidoacetyl)-5-(benzyloxy)-2H- benzo[b][l,4]oxazin-3(4H)-one (5 g) and 10%> palladium on carbon (2.5 g) to give a slurry.
  • the mixture was hydrogenated at 4.7 bar and 25°C for 2h 20min to give a partial solution.
  • the solution was then warmed to 40°C and hydrogenated at 4.7 bar for 68 h.
  • the mixture was filtered through GF/F filter paper and the filtrate evaporated to 50 mL.
  • N-Cyclohexyl-N-(2,2-dimethoxyethyl)-3-(3-(l -methyl- lH-pyrazol-4- yl)phenethoxy)propanamide (0.5 g) was stirred in DCM (10 mL) followed by the addition of p-toluenesulfonic acid monohydrate (0.43 g). The mixture was stirred for 1 h. Ethyl acetate was added followed by sodium hydrogen carbonate solution. The aqueous phase was removed and the remaining organic phase washed once with water, once with brine, dried over sodium sulphate, filtered and the solvent removed to afford the desired material as an oil (0.48 g). This material was used directly as prepared.
  • the reaction was stirred overnight before the addition of sodium hydrogen carbonate solution, which was extracted three times with DCM.
  • the solvents were removed under vacuum from the pooled organics followed by the addition of ethyl acetate (100 mL), water (50 mL), sodium bicarbonate followed by BOC anhydride.
  • the reaction was stirred overnight before the layers were separated and the aqueous layer extracted once more with ethyl acetate.
  • the pooled organics were washed once with water, once with brine, dried over sodium sulphate, filtered and the solvent removed to afford crude product, which was purified on silica twice using ethyl acetate.
  • the solvent was removed to afford 200 mg of a mixture of mono-protected and di-protected material.
  • the vial was sealed and heated at 110 °C within a Discover microwave for 40 min with stirring.
  • the reaction was cooled followed by the addition of ethyl acetate, which was washed once with water, once with brine, dried over sodium sulphate and the solvent removed.
  • the residue was purified on silica using neat ethyl acetate to afford the protected product (250 mg).
  • This material was taken up in DCM followed by the addition of 4M hydrochloric acid in dioxane and stirred overnight.
  • the solvent was removed under vacuum to afford of crude material (330 mg). This was basified with sodium hydrogen carbonate solution, which was extracted three times with DCM.
  • the pooled organics were acidified with 0.5 mL of TFA and the solvent removed to afford the titled compound as a TFA salt.
  • the solution was partially evaporated under vacuum to give a solution measuring 490mL and split into 2 portions. Firstly half of the solution was cooled to 20°C and added to dibutyl ether (400 mL) at 20°C to give a precipitate which was stirred at 20°C for 2 h. The suspension was filtered, washed with dibutyl ether (100 mL) and dried at 50°C under vacuum to afford the sub-titled compound (34.1 g). The second half of the solution was added to dibutyl ether (400 mL) at 65°C to give a precipitate which was maintained at 65°C for 10 min then cooled to 15°C and stirred for 1 h. The suspension was filtered, washed with dibutyl ether (100 mL) and dried at 50°C under vacuum to afford the subtitled compound as a white solid (30.5 g).
  • a line wash of tetrahydrofuran (50.3 mL) was then added and the solution stirred at ambient temperature for 1 h before being added to a solution of sodium hydroxide (19.6 g) and sodium chloride (100.6 g) in water (502.9 mL) at ⁇ 5°C.
  • a line wash of tetrahydrofuran (25.1 mL) was then added and the solution warmed to 20°C.
  • 1- Butanol (100.6 mL) was added and the layers separated. The separated organic layer can be evaporated to dryness to afford the sub-titled compound as an orange/brown oil or the solution used directly in the next Step.
  • the oil was dissolved in methanol (10 mL) and acetonitrile (10 mL) and charged to tert-butyl methyl ether (20 mL) to yield an oil and the retained decanted organic solvent recharged. After 3 days the solvent was allowed to evaporate. After 6 further days ethyl acetate (50 mL) was charged to the concentrate. After 2 further days additional ethyl acetate (40 mL) was charged. After 14 days the solid was filtered and washed with ethyl acetate (25 mL) and dried to a weight of 2.305g.
  • the oil was dissolved in methanol (10 mL) and acetonitrile (10 mL) and charged to tert-butyl methyl ether (20 mL) to yield an oil and the retained decanted organic solvent recharged. After 3 days the solvent was allowed to evaporate. After 6 further days ethyl acetate (50 mL) was charged to the concentrate. After 16 days the solid was filtered and washed with ethyl acetate (25 mL) and dried to a weight of 2.546g.
  • the mixture of enantiomers was separated by chiral HPLC using a chiracel OJ-H column using an isocratic system of 80% z ' sohexane / ethanol to afford the two enantiomers, which were defined as Isomer 1 and Isomer 2 in order of elution.
  • the diffraction raw data were processed within the Denzo-SMN program package (Otwinowski & Minor, 1998) converting the information from the digital image frame to a file containing h, k, 1 indices, background and Lp corrected intensities of the diffraction spots, along with estimate of errors.
  • the melting temperature of Preparation 4 bromide Form C as determined by DSC was found to be 184°C (onset) ( ⁇ 2°C). Weight loss observed prior to melting by TGA was 4%. GVS determination gave 4% weight increase (%w/w) at 80% RH ( ⁇ 0.2%).
  • (+/-)-2-Phenylpropionic acid (20.5g) was dissolved in methanol (62mL) in a reaction vessel. Sulfuric acid (98%, 0.82mL) was then charged followed by methanol (20.5mL) as a line rinse. The reaction was then heated to 63°C ( ⁇ 3°C) and stirred at this temperature for up to 4hrs. The reaction was monitored by HPLC analyzing the methyl 2- phenylpropanoate: (+/-)-2-phenylpropionic acid ratio (specification >97:3). Upon completion the reaction mixture was cooled to 23°C ( ⁇ 3°C).
  • Cyclohexane (102mL) was added followed by Na 2 C0 3 (aq) (3.7% wt/wt, 61.5mL). Layers were allowed to separate and the lower aqueous phase discarded. Water (61.5mL) was then charged and the mixture stirred for lOmins before the layers were separated discarding the lower aqueous phase. Cyclohexane (205mL) was then charged to the organic phase. The reaction mixture was then distilled under reduced pressure at 45°C, 150-240mbar removing 180mL solvent. The reaction mixture was then cooled to 23°C ( ⁇ 3°C) yielding methyl 2-phenylpropanoate in a solution in cyclohexane.
  • Methyl 2-phenylpropanoate in a solution in cyclohexane (Intermediate 1) (22.42g; based on 100% yield from step a) was charged to a reaction vessel. Hydrobromic acid (48%, 0.62mL) was then charged followed by cyclohexane (22.4mL) as a line wash. Dibenzoyl peroxide (75%, 2.2 lg) and N-bromosuccinimide (31.61g) were then charged to the vessel and the reaction heated to 50°C ( ⁇ 3°C) and stirred at this temperature for at least 4hrs.
  • the reaction was monitored by GC analyzing the methyl 2-bromo-2-phenylpropanoate : methyl 2-phenylpropanoate ratio (specification >96:4). Upon completion the reaction mixture was cooled to 20°C ( ⁇ 3°C). The reaction mixture was filtered to remove the solid succinimide by-product, washing the filter cake twice with cyclohexane (22.4mL). The solid byproduct was discarded. NaHS0 3 (aq) (10%w/w, 81.9mLl) was then charged and stirred for 15mins before allowing the phases to separate discarding the lower aqueous phase. Water (81.9mL,) was then charged and stirred for 15mins before allowing the phases to separate discarding the lower aqueous phase.
  • 3-Pentanone (201.9mL) was then charged and the mixture was distilled at 45°C, 150-280mbar removing 210mL of solvent. The reaction mixture was cooled to 23°C ( ⁇ 3°C). 3-Pentanone (lOlmL) was then charged and the solvent composition analyzed by GC (specification ⁇ 30% cyclohexane) to yield methyl 2- bromo-2-phenylpropanoate in a solution of 3-pentanone.
  • the two aqueous phases were then combined, sampled and analyzed by GC to ensure all impurities were ⁇ 0.5 % with the exception of methyl 2-phenyl-3-(piperidin-l-yl)propanoate impurity).
  • the aqueqous phase was then charged to a mixture of Na 2 C0 3 (32.29g), water (232mL) and methyl 'butyl ether
  • the organic phase was sampled and analyzed by GC to ensure methyl 2-phenyl-3-(piperidin-l-yl)propanoate impurity was less than 0.5%.
  • the mixture was then distilled at 45°C, 80-220mbar removing 265mLsolvent.
  • Methanol (332mL) was then charged to the vessel and the mixture again distilled at 45°C, 80-220mbar removing 332mL solvent.
  • the reaction mixture was cooled to 23°C ( ⁇ 3°C) to yield methyl 2-phenyl-2-piperidin-l-ylpropanoate in a solution of methanol.
  • the product was then analyzed by NMR assay and HPLC for purity. 23.8g (at 100w/w%) 70.5% yield, >99.5% HPLC purity.
  • Racemic methyl 2-phenyl-2-piperidin-l-ylpropanoate (Intermediate 3) was purified by Simulated Moving Bed (SMB) chromatography to yield methyl (S)-2-phenyl-2-piperidin- 1-ylpropanoate.
  • SMB Simulated Moving Bed
  • (5)-methyl 2-phenyl-2-(piperidin-l-yl)propanoate was isolated as a 40w/w% solution in toluene.
  • Typical conditions for the SMB purification were as follows
  • the reaction mixture was stirred at 60°C ( ⁇ 5°C) for at least 2hrs and monitored by HPLC analyzing the methyl (5)-methyl 2-phenyl-2-(piperidin-l-yl)propanoate : (S)-((R)- quinuclidin-3-yl) 2-phenyl-2-(piperidin-l-yl)propanoate ratio (specification >95 :5) followed by toluene (8.8 mL) as a line rinse.
  • the reaction mixture was cooled to 20°C ( ⁇ 5°C). Butanenitrile (88mL) and water (88mL) were charged and the mixture stirred for 20mins before allowing the phases to separate discarding the lower aqueous phase.
  • reaction was then weighed and analysed by; NMR assay (w/w% of product) and GC (solvent composition) to determine the amount of product in solution and the solvent composition, toluene (18.5mL, 1.05vol) and butanenitrile (52.5mL, 3vol) was then added to the mixture to yield (S)-((R)- quinuclidin-3-yl) 2-phenyl-2-(piperidin-l-yl)propanoate (19.67g, 81% yield) in a 7:3 butanenitrile :toluene solvent composition at 140mg/mL concentration.
  • reaction was monitored by HPLC analyzing the (5)-((i?)-quinuclidin-3-yl) 2-phenyl-2-(piperidin-l- yl)propanoate : product ratio (specification >96:4).
  • the reaction mixture was cooled to 40°C over at least 40mins (0.5°C/min) and then cooled to -5°C over at least 6hrs
  • the white foam was dissolved in hot acetoniltrile ( ⁇ 5 mL) and allowed to cool to RT with stirring for 3 days. A white solid formed which was collected by filtration, washed with cold acetonitrile ( ⁇ 2 mL) and dried in vacuo at 60°C for 2 days to yield the product (0.490 g).
  • the lower aqueous phase was removed and discarded.
  • the hot organic phase was filtered into a clean vessel.
  • the original vessel was washed with butanenitrile (30 mL) and this solvent was added to the filtrate via the filter into the clean vessel.
  • the wet organic solution was distilled in order to azeodry it (120-150mbar - vessel jacket at 80°C). After ca. 60 mL of solvent had been distilled a precipitate was observed; contents were at 48°C. In total, 1 10 mL of solvent (10 mL water: 100 mL butanenitrile) was collected. At this point the vacuum was released and the vessel contents warmed to 75°C.
  • Acetonitrile (45 mL) was added and the vessel contents re -heated to 75°C (not all material dissolved). More acetonitrile (45 mL) was added and the vessel contents re-heated to 75°C (all material dissolved). The solution was cooled to 5°C over 120 minutes (precipitation started at 65°C). With the vessel contents at 5°C the product was collected by filtration, washed with cold (5°C) butanenitrile (30 mL) and pulled as dry as possible on the filter to give 15.27 g of solid.
  • X-Ray Powder Diffraction - PANalytical X'Pert machine in 20 - 0 configuration or a PANalytical Cubix machine in 0 - 0 configuration over the scan range 2° to 40° 20 with 100-second exposure per 0.02° increment.
  • the X-rays were generated by a copper long-fine focus tube operated at 45kV and 40mA. The wavelength of the copper X-rays was 1.5418 A.
  • the Data was collected on zero background holders on which ⁇ 2mg of the compound was placed. The holder was made from a single crystal of silicon, which had been cut along a non-diffracting plane and then polished on an optically flat finish. The X- rays incident upon this surface were negated by Bragg extinction.
  • DSC Differential Scanning Calorimetry
  • TA Q1000 Differential Scanning Calorimeter
  • the sample weights varied between 0.5 to 5mg.
  • the procedure was carried out under a flow of nitrogen gas (50mL/min) and the temperature studied from 30 to 230°C at a constant rate of temperature increase of 10°C per minute.
  • Gravimetric Vapour Sorption (GVS) profiles were measured using a Surface
  • H292 cells were grown in 225cm2 flasks incubator at 37°C, 5% C0 2 in RPMI medium containing, 10% (v/v) FBS (foetal bovine serum) and 2 mM L-glutamine.
  • Adherent H292 cells were removed from tissue culture flasks by treatment with
  • the culture media was removed and cells were washed twice with 100 assay buffer and replaced with 50 assay buffer (HBSS solution containing lOmM HEPES pH7.4 and 5 mM glucose). Cells were rested at room temperature for 20 min after which time 25 ⁇ ⁇ 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 min after which time test compounds were added and the cells were incubated for 60 min at room temperature. The final rolipram concentration in the assay was 300 ⁇ and final vehicle concentration was 1.6% (v/v) dimethylsulphoxide. The reaction was stopped by removing supernatants, washing once with 100 ⁇ assay buffer and replacing with 50 ⁇ ⁇ lysis buffer. The cell monolayer was frozen at -80°C for 30 min (or overnight).
  • the concentration of cAMP (cyclic adenosine monophosphate) in the cell lysate was determined using AlphaScreenTM methodology. The frozen cell plate was thawed for 20 min on a plate shaker then 10 ⁇ of the cell lysate was transferred to a 96-well white plate. 40 [iL of mixed AlphaScreenTM detection beads pre-incubated with biotinylated cAMP, was added to each well and the plate incubated at room temperature for 10 h in the dark. The AlphaScreenTM signal was measured using an En Vision 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 using standard cAMP concentrations.
  • Membranes were prepared from human embryonic kidney 293 (HEK293) cells expressing recombinant human lo receptor. These were diluted in Assay Buffer (50mM HEPES, lmM EDTA, pH 7.4) to provide a final concentration of membranes that gave a clear window between maximum and minimum specific binding.
  • Assay Buffer 50mM HEPES, lmM EDTA, pH 7.4
  • Assays were performed in U-bottomed 96-well polypropylene plates. 10 ⁇ , [ 3 H]-prazosin (0.3 nM final concentration) and 10 ⁇ of test compound (lOx final concentration) were added to each test well. For each assay plate 8 replicates were obtained for [ 3 H]-prazosin binding in the presence of 10 vehicle (10% (v/v) DMSO in Assay Buffer; defining maximum binding) or ⁇ ⁇ BMY7378 (10 ⁇ final concentration; defining non-specific binding (NSB)). Membranes were then added to achieve a final volume of 100 ⁇ .
  • the plates were incubated for 2 h at room temperature and then filtered onto PEI coated GF/B filter plates, pre-soaked for 1 h in Assay Buffer, using a 96-well plate Tomtec cell harvester. Five washes with 250 ⁇ wash buffer (50mM HEPES, lmM 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 ⁇ ) 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.
  • 250 ⁇ wash buffer 50mM HEPES, lmM EDTA, pH 7.4
  • MicroScint-0 50 ⁇
  • Membranes containing recombinant human adrenergic beta 1 receptors were obtained from Euroscreen. These were diluted in Assay Buffer (50mM HEPES, ImM EDTA, 120mM 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 50mM HEPES, ImM EDTA, 120mM NaCl, 0.1% gelatin, pH 7.4
  • Assays were performed in U-bottomed 96-well polypropylene plates. 10 ⁇ , [ 125 I]- Iodocyanopindolol (0.036 nM final concentration) and 10 of test compound (lOx final concentration) were added to each test well. For each assay plate 8 replicates were obtained for [ 125 I]-Iodocyanopindolol binding in the presence of 10 vehicle (10%> (v/v) DMSO in Assay Buffer; defining maximum binding) or 10 ⁇ Propranolol (10 ⁇ final concentration; defining non-specific binding (NSB)). Membranes were then added to achieve a final volume of 100 ⁇ .
  • the plates were incubated for 2 h at room temperature and then filtered onto PEI coated GF/B filter plates, pre-soaked for 1 h in Assay Buffer, using a 96-well plate Tomtec cell harvester. Five washes with 250 ⁇ ⁇ wash buffer (50mM HEPES, ImM EDTA, 120mM 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 Micro Scint-0 (50 ⁇ ) was added to each well. The plates were sealed
  • Membranes containing recombinant human Dopamine Subtype D2s receptors were obtained from Perkin Elmer. These were diluted in Assay Buffer (50mM HEPES, ImM EDTA, 120mM 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 50mM HEPES, ImM EDTA, 120mM NaCl, 0.1% gelatin, pH 7.4
  • 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 [ 3 H] -spiperone binding) were determined using serial dilutions typically in the range 0.1 nM to 10 ⁇ . 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 [ 3 H] -spiperone binding).
  • 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 0.1-10 ⁇ 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 lmL 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 ⁇ 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.
  • mice Male Dunkin-Hartley guinea-pigs (300-600g) 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.
  • 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 ⁇ 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.
  • mice 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
  • 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 0.1-10 ⁇ 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
  • cytospins ⁇ 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.
  • BALF total white cell count is measured using a Sysmex (Sysmex UK, Milton Keynes).
  • mice 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/rnL 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 0 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 recoreded. Guinea pigs are euthanised with approximately l .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)
  • a tracheotomy is performed and the trachea cannulated.
  • the airway is then lavaged using 3 mL sterile PBS at room
  • Cytospin slides are prepared by adding a 100 ⁇ 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 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 (20x1 lxl 1cm, 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 1cm and the lungs are lavaged using 3 washes of 1ml of Isoton II..
  • cytospins ⁇ 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.
  • 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.
  • Guinea pigs (300-500g) are killed by cervical dislocation and the trachea is isolated.
  • the trachea is cut into segments 2-3 cartilage rings in width and suspended in 10ml organ baths in modified Krebs' solution (mM; NaCl, 90; NaHC0 3 , 45; KC1, 5; MgS0 4 .7H 2 0, 0.5; Na 2 HP0 4 .2H 2 0, 1; CaCl 2 , 2.25; glucose, 10; pH 7.4 gassed with 5% C0 2 , 95% 0 2 at 37°C).
  • the tracheal rings are attached to an isometric force transducer for the

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Abstract

L'invention porte sur un produit pharmaceutique, une trousse pharmaceutique ou une composition pharmaceutique comprenant un premier principe actif qui est le N-cyclohexyl-N-(2-(2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)éthylamino)éthyl)-3-(3-(1-méthyl-1H-pyrazol-4-yl)phénéthoxy)propanamide ou un sel pharmaceutiquement acceptable de celui-ci et un second principe actif choisi parmi : un agoniste du récepteur de glucocorticoïdes (récepteur GR) non stéroïdien; un antioxydant; un antagoniste de CCR1; un antagoniste de chimiokine (qui n'est pas CCR1); un corticostéroïde; un antagoniste de CRTh2; un antagoniste de DP1; un inducteur d'histone désacétylase; un inhibiteur d'IKK2; un inhibiteur de COX; un inhibiteur de lipoxygénase; un antagoniste de récepteur de leucotriènes; un inhibiteur de MPO; un antagoniste muscarinique; un inhibiteur de p38; un inhibiteur de PDE; un agoniste de PPARγ; un inhibiteur de protéase; une statine; un antagoniste de thromboxane; un vasodilatateur; ou un bloqueur d'ENAC (bloqueur de canaux sodiques épithéliaux); et sur son utilisation dans le traitement d'une maladie respiratoire (par exemple, la broncho-pneumopathie chronique obstructive (BPCO) ou l'asthme).
PCT/GB2010/052103 2009-12-17 2010-12-16 Association d'une benzoxazinone et d'un autre agent pour le traitement de maladies respiratoires WO2011073662A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102993116A (zh) * 2012-12-04 2013-03-27 常州大学 一种苯并噁嗪类激动剂的制备方法
WO2021185746A1 (fr) * 2020-03-16 2021-09-23 Aarhus Universitet Composés destinés à être utilisés dans le traitement d'une maladie respiratoire
WO2021263281A3 (fr) * 2020-06-26 2022-03-10 Ann And Robert H. Lurie Children's Hospital Of Chicago Procédés et compositions pour le traitement de la covid-19 ainsi que de la détresse respiratoire et du syndrome de défaillance multiviscérale associés, de la septicémie, du syndrome de détresse respiratoire aiguë et de maladies cardiovasculaires

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