WO2009154554A1 - Produit pharmaceutique comprenant un antagoniste du récepteur muscarinique et un second principe actif - Google Patents

Produit pharmaceutique comprenant un antagoniste du récepteur muscarinique et un second principe actif Download PDF

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Publication number
WO2009154554A1
WO2009154554A1 PCT/SE2009/050742 SE2009050742W WO2009154554A1 WO 2009154554 A1 WO2009154554 A1 WO 2009154554A1 SE 2009050742 W SE2009050742 W SE 2009050742W WO 2009154554 A1 WO2009154554 A1 WO 2009154554A1
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active ingredient
piperidin
phenyl
antagonist
muscarinic
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PCT/SE2009/050742
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English (en)
Inventor
Antonio Mete
Ian Millichip
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Astrazeneca Ab
Argenta Discovery Ltd.
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Publication of WO2009154554A1 publication Critical patent/WO2009154554A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators

Definitions

  • the present invention relates to combinations of pharmaceutically active substances for use in the treatment of respiratory diseases, especially chronic obstructive pulmonary disease (COPD) and asthma.
  • COPD chronic obstructive pulmonary disease
  • Respiratory diseases include Acute Lung Injury, Acute Respiratory Distress Syndrome (ARDS), occupational lung disease, lung cancer, tuberculosis, fibrosis, pneumoconiosis, pneumonia, emphysema, Chronic Obstructive Pulmonary Disease (COPD) and asthma.
  • ARDS Acute Respiratory Distress Syndrome
  • COPD Chronic Obstructive Pulmonary Disease
  • Asthma is generally defined as an inflammatory disorder of the airways with clinical symptoms arising from intermittent airflow obstruction. It is characterised clinically by paroxysms of wheezing, dyspnea and cough. It is a chronic disabling disorder that appears to be increasing in prevalence and severity. It is estimated that 15% of children and 5% of adults in the population of developed countries suffer from asthma. Therapy should therefore be aimed at controlling symptoms so that normal life is possible and at the same time provide basis for treating the underlying inflammation.
  • COPD is a term which refers to a large group of lung diseases which can interfere with normal breathing.
  • Current clinical guidelines define COPD as a disease state characterized by airflow limitation that is not fully reversible.
  • the airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles and gases.
  • the most important contributory source of such particles and gases is tobacco smoke.
  • COPD patients have a variety of symptoms, including cough, shortness of breath, and excessive production of sputum; such symptoms arise from dysfunction of a number of cellular compartments, including neutrophils, macrophages, and epithelial cells.
  • the two most important conditions covered by COPD are chronic bronchitis and emphysema.
  • Chronic bronchitis is a long-standing inflammation of the bronchi which causes increased production of mucous and other changes. The patients' symptoms are cough and expectoration of sputum. Chronic bronchitis can lead to more frequent and severe respiratory infections, narrowing and plugging of the bronchi, difficult breathing and disability.
  • Emphysema is a chronic lung disease which affects the alveoli and/or the ends of the smallest bronchi.
  • the lung loses its elasticity and therefore these areas of the lungs become enlarged. These enlarged areas trap stale air and do not effectively exchange it with fresh air. This results in difficult breathing and may result in insufficient oxygen being delivered to the blood.
  • the predominant symptom in patients with emphysema is shortness of breath.
  • Muscarinic antagonists are a G-protein coupled receptor (GPCR) family having five family members M 1 , M 2 , M 3 , M 4 and M5. Of the five muscarinic subtypes, three (M 1 , M 2 and M 3 ) are known to exert physiological effects on human lung tissue.
  • GPCR G-protein coupled receptor
  • Parasympathetic nerves are the main pathway for reflex bronchoconstriction in human airways and mediate airway tone by releasing acetylcholine onto muscarinic receptors.
  • Airway tone is increased in patients with respiratory disorders such as asthma and chronic obstructive pulmonary disease (COPD), and for this reason muscarinic receptor antagonists have been developed for use in treating airway diseases.
  • Muscarinic receptor antagonsists often called anticholinergics in clinical practice, have gained widespread acceptance as a first-line therapy for individuals with COPD, and their use has been extensively reviewed in the literature (e.g. Lee et al, Current Opinion in Pharmacology 2001,1, 223-229).
  • the present invention provides a pharmaceutical product comprising, in combination, a first active ingredient which is a muscarinic antagonist selected from: (R)- 1 -[2-(4-Fluoro-phenyl)-ethyl]-3-((5)-2-phenyl-2-piperidin- 1 -yl-propionyloxy)- 1 - azonia-bicyclo[2.2.2]octane X; and (R)- 1 -[3-(2-Methyl-pyridin-4-yl)-propyl]-3-((5)-2-phenyl-2-piperidin- 1 -yl-propionyloxy)- l-azonia-bicyclo[2.2.2]octane X; wherein X represents a pharmaceutically acceptable anion of a mono or polyvalent acid, and a second active ingredient which is selected from i) a phosphodiesterase inhibitor, ii) a modulator of chemokine receptor function, ii
  • a beneficial therapeutic effect may be observed in the treatment of respiratory diseases if a muscarinic antagonist according to the present invention is used in combination with a second active ingredient as specified above.
  • the beneficial effect may be observed when the two active substances are administered simultaneously (either in a single pharmaceutical preparation or via separate preparations), or sequentially or separately via separate pharmaceutical preparations.
  • the pharmaceutical product of the present invention may, for example, be a pharmaceutical composition comprising the first and second active ingredients in admixture.
  • the pharmaceutical product may, for example, be a kit comprising a preparation of the first active ingredient and a preparation of the second active ingredient and, optionally, instructions for the simultaneous, sequential or separate administration of the preparations to a patient in need thereof.
  • the first active ingredient in the combination of the present invention is a muscarinic antagonist selected from:
  • the muscarinic antagonists of the invention are selected members of a novel class of compound described in co-pending application PCT/GB2007/004817 which display high potency to the M3 receptor.
  • the names of the muscarinic antagonists are IUPAC names generated by the Beilstein Autonom 2000 naming package , as supplied by MDL Information Systems Inc., based on the structures depicted in the examples, and stereochemistry assigned according to the Cahn-Ingold-Prelog system.
  • the muscarinic antagonists of the present invention comprise an anion X associated with the positive charge on the quaternary nitrogen atom.
  • the anion X may be any pharmaceutically acceptable anion of a mono or polyvalent (e.g. bivalent) acid.
  • X may be an anion of a mineral acid, for example chloride, bromide, iodide, sulfate, nitrate or phosphate; or an anion of a suitable organic acid, for example toluenesulfonate (tosylate or 4-methylbenzenesulphonate), edisylate (ethane- 1,2- disulfonate), isethionate (2-hydroxyethylsulfonate),lactate, oleic, maleate ((Z)-3-carboxy- acrylate), succinate (3-carboxy-propionate), malate ((5)-3-carboxy -2-hydroxy-propionate), p-acetamidobenzoateacetate
  • the first active ingredient is a muscarinic antagonist which is in the form of a bromide, benzenesulphonate or naphthalene-l,5-disulphonate salt.
  • the first active ingredient is a muscarinic antagonist which is in the form of a bromide salt.
  • the first active ingredient is a muscarinic antagonist which is in the form of a benzenesulphonate salt.
  • the first active ingredient is a muscarinic antagonist which is in the form of a 4-methylbenzenesulphonate salt.
  • the muscarinic receptor antagonist is selected from: (R)- 1 -[2-(4-Fluoro-phenyl)-ethyl]-3-((S)-2-phenyl-2-piperidin- 1 -yl-propionyloxy)- 1 - azonia-bicyclo[2.2.2]octane bromide; and
  • the second active ingredient of the present invention is selected from i) a phosphodiesterase inhibitor, ii) a modulator of chemokine receptor function, iii) an inhibitor of kinase function, iv) a protease inhibitor, v) a steroidal glucocorticoid receptor agonist, vi) a non-steroidal glucocorticoid receptor agonist, and vii) a purinoceptor antagonist.
  • the second active ingredient is a phosphodiesterase inhibitor.
  • a phosphodiesterase inhibitor that may be used according to this embodiment include a PDE4 inhibitor such as an inhibitor of the isoform PDE4D, a PDE3 inhibitor and a PDE5 inhibitor.
  • PDE4 inhibitor such as an inhibitor of the isoform PDE4D
  • PDE3 inhibitor such as an inhibitor of the isoform PDE4D
  • PDE5 inhibitor examples include the compounds (Z)-3-(3,5-dichloro-4-pyridyl)-2-[4-(2-indanyloxy-5-methoxy-2-pyridyl]propenenitrile,
  • the second active ingredient is a modulator of chemokine receptor function.
  • a modulator of chemokine receptor function that may be used in this embodiment include a CCR3 receptor antagonist, a CCR4 receptor antagonist, a CCR5 receptor antagonist and a CCR8 receptor antagonist.
  • the second active ingredient is a CCRl receptor antagonist.
  • the second active ingredient is a CCRl receptor antagonist selected from: N- ⁇ 2-[((2iS)-3- ⁇ [ 1 -(4-chlorobenzyl)piperidin-4-yl] amino ⁇ -2-hydroxy-2-methylpropyl)oxy]-
  • the second active ingredient is a salt of N- ⁇ 2-[((2iS)-3- ⁇ [ 1 -(4-chlorobenzyl)piperidin-4-yl] amino ⁇ -2-hydroxy-2-methylpropyl)oxy]-4- hydroxyphenyl ⁇ acetamide or N- ⁇ 5-Chloro-2-[((25)-3- ⁇ [l-(4-chlorobenzyl)piperidin-4- yljamino ⁇ -2-hydroxy-2-methylpropyl)oxy]-4-hydroxyphenyl ⁇ acetamide, for example hydrochloride, hydrobromide, phosphate, sulfphate, acetate, ascorbate, benzoate, fumarate, hemifumarate, furoate, succinate, maleate, tartrate, citrate, oxalate, xinafoate, methanesulphonate or/?-toluenesulphonate salt.
  • the second active ingredient is a benzoate, furoate or hemifumarate salt of N- ⁇ 2-[((25)-3- ⁇ [l-(4-chlorobenzyl)piperidin-4-yl]amino ⁇ - 2-hydroxy-2-methylpropyl)oxy]-4-hydroxyphenyl ⁇ acetamide, as described in PCT/SE2006/000920, PCT/SE2006/000921 and PCT/SE2006/000922 (WO2007/015666, WO2007/015667 and WO2007/015668).
  • the second active ingredient is the hemifumarate, furoate, benzoate, 2-fluorobenzoate or 2,6-difluorobenzoate salt of N- ⁇ 5-
  • the second active ingredient is 2- ⁇ 2-chloro-5- ⁇ [(25)-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.
  • 2- ⁇ 2-Chloro-5- ⁇ [(25)-3-(5-chloro-l'H,3H- spiro[l-benzofuran-2,4'-piperidin]-r-yl)-2-hydroxypropyl]oxy ⁇ -4- [(methylamino)carbonyl]phenoxy ⁇ -2-methylpropanoic acid may be prepared by methods according or analogous to those described in PCT/SE2007/000694 (WO2008/010765).
  • the second active ingredient is JV- ⁇ 5-chloro-2- [((2iS)-3- ⁇ [ 1 -(4-chlorobenzyl)piperidin-4-yl] amino ⁇ -2-hydroxy-2-methylpropyl)oxy]-4- hy droxypheny 1 ⁇ acetamide or a pharmaceutically acceptable salt thereof.
  • JV- ⁇ 5-chloro-2- [((2iS)-3- ⁇ [ 1 -(4-chlorobenzyl)piperidin-4-yl] amino ⁇ -2-hydroxy-2-methylpropyl)oxy]-4- hy droxypheny 1 ⁇ acetamide may be prepared by methods according or analogous to those described in WO2007/015664.
  • the muscarinic receptor antagonist is (7?)-l-[2-(4- Fluoro-phenyl)-ethyl]-3-((5)-2-phenyl-2-piperidin- 1 -yl-propionyloxy)- 1 -azonia- bicyclo[2.2.2]octane X, wherein X represents a pharmaceutically acceptable anion of a mono or polyvalent acid, and the second active ingredient is N- ⁇ 2-[((2S)-3- ⁇ [l-(4- chlorobenzyl)piperidin-4-yl] amino ⁇ -2-hydroxy-2-methylpropyl)oxy] -4- hydroxyphenyl ⁇ acetamide or a pharmaceutically acceptable salt thereof (e.g.
  • the muscarinic receptor antagonist is (i?)-l-[2-(4-Fluoro-phenyl)-ethyl]-3-((5)-2-phenyl-2-piperidin-l-yl- propionyloxy)-l-azonia-bicyclo[2.2.2]octane bromide.
  • the muscarinic receptor antagonist is (7?)-l-[3-(2- Methyl-pyridin-4-yl)-propyl]-3-((5)-2-phenyl-2-piperidin- 1 -yl-propionyloxy)- 1 -azonia- bicyclo[2.2.2]octane X, wherein X represents a pharmaceutically acceptable anion of a mono or polyvalent acid, and the second active ingredient is N- ⁇ 2-[((2S)-3- ⁇ [l-(4- chlorobenzyl)piperidin-4-yl] amino ⁇ -2-hydroxy-2-methylpropyl)oxy] -4- hydroxyphenyl ⁇ acetamide or a pharmaceutically acceptable salt thereof (e.g.
  • the muscarinic receptor antagonist is (i?)-l-[3-(2-Methyl-pyridin-4-yl)-propyl]-3-((5)-2-phenyl-2-piperidin-l-yl- propionyloxy)-l-azonia-bicyclo[2.2.2]octane bromide.
  • the muscarinic receptor 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 X, wherein X represents a pharmaceutically acceptable anion of a mono or polyvalent acid, and the second active ingredient is ⁇ /- ⁇ 5-chloro-2-[((25)-3- ⁇ [l- (4-chlorobenzyl)piperidin-4-yl] amino ⁇ -2-hydroxy-2-methylpropyl)oxy] -A- hydroxyphenyl ⁇ acetamide or a pharmaceutically acceptable salt thereof (e.g.
  • the muscarinic receptor antagonist is (i?)-l-[2-(4-Fluoro-phenyl)-ethyl]-3-((5)-2-phenyl-2-piperidin-l-yl- propionyloxy)-l-azonia-bicyclo[2.2.2]octane bromide.
  • the muscarinic receptor antagonist is (i?)-l-[3-(2- Methyl-pyridin-4-yl)-propyl]-3-((5)-2-phenyl-2-piperidin- 1 -yl-propionyloxy)- 1 -azonia- bicyclo[2.2.2]octane X, wherein X represents a pharmaceutically acceptable anion of a mono or polyvalent acid, and the second active ingredient is 7V- ⁇ 5-chloro-2-[((25)-3- ⁇ [l- (4-chlorobenzyl)piperidin-4-yl] amino ⁇ -2-hydroxy-2-methylpropyl)oxy] -4- hydroxyphenyl ⁇ acetamide or a pharmaceutically acceptable salt thereof (e.g.
  • the muscarinic receptor antagonist is (i?)-l-[3-(2-Methyl-pyridin-4-yl)-propyl]-3-((5)-2-phenyl-2-piperidin-l-yl- propionyloxy)-l-azonia-bicyclo[2.2.2]octane bromide.
  • the muscarinic receptor antagonist (i?)-l-[2-(4-Fluoro- phenyl)-ethyl]-3-((5)-2-phenyl-2-piperidin- 1 -yl-propionyloxy)- 1 -azonia- bicyclo[2.2.2]octane X , wherein X represents a pharmaceutically acceptable anion of a mono or polyvalent acid, and the second active ingredient is 2- ⁇ 2-Chloro-5- ⁇ [(25)-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.
  • the muscarinic receptor antagonist is (i?)-l-[2-(4-Fluoro-phenyl)-ethyl]-3-((5)-2-phenyl-2-piperidin-l -yl- propionyloxy)-! -azonia-bicyclo[2.2.2]octane bromide.
  • the muscarinic receptor antagonist (7?)-l-[3-(2-Methyl- pyridin-4-yl)-propyl]-3-((5)-2-phenyl-2-piperidin- 1 -yl-propionyloxy)- 1 -azonia- bicyclo[2.2.2]octane X wherein X represents a pharmaceutically acceptable anion of a mono or polyvalent acid, and the second active ingredient is 2- ⁇ 2-Chloro-5- ⁇ [(25)-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.
  • the muscarinic receptor antagonist is (i?)-l-[3-(2-Methyl-pyridin-4-yl)-propyl]-3-((5)-2-phenyl-2-piperidin-l-yl- propionyloxy)-l-azonia-bicyclo[2.2.2]octane bromide.
  • the second active ingredient is an inhibitor of kinase function.
  • an inhibitor of kinase function that may be used in this embodiment include a p38 kinase inhibitor and an IKK inhibitor.
  • the second active ingredient is a protease inhibitor.
  • a protease inhibitor that may be used in this embodiment include an inhibitor of neutrophil elastase or an inhibitor of MMP 12.
  • the second active ingredient is a steroidal glucocorticoid receptor agonist.
  • a steroidal glucocorticoid receptor agonist that may be used in this embodiment include budesonide, fluticasone (e.g. as propionate ester), mometasone (e.g. as furoate ester), beclomethasone (e.g. as 17-propionate or 17,21- dipropionate esters), ciclesonide, loteprednol (as e.g.
  • etabonate etiprednol (as e.g. dicloacetate), triamcinolone (e.g. as acetonide), flunisolide, zoticasone, flumoxonide, rofleponide, butixocort (e.g. as propionate ester), prednisolone, prednisone, tipredane, steroid esters e.g.
  • the muscarinic receptor antagonist (i?)-l-[2-(4-Fluoro- phenyl)-ethyl]-3-((iS)-2-phenyl-2-piperidin- 1 -yl-propionyloxy)- 1 -azonia- bicyclo[2.2.2]octane X , wherein X represents a pharmaceutically acceptable anion of a mono or polyvalent acid, and the second active ingredient is budesonide
  • the muscarinic receptor antagonist (i?)-l-[2-(4-Fluoro-phenyl)-ethyl]-3- ((5)-2-phenyl-2-piperidin- 1 -yl-propionyloxy)- 1 -azonia-bicyclo[2.2.2]octane bromide.
  • the second active ingredient is a non-steroidal glucocorticoid receptor agonist.
  • a modulator of a non-steroidal glucocorticoid receptor agonist that may be used in this embodiment include selective non-steroidal glucocorticoid receptor agonists.
  • Non-steroidal glucocorticoid receptor agonists are described for example in WO2006/046916 and US6323199.
  • the second active ingredient is a purinoceptor antagonist, for example a P2X 7 receptor antagonist.
  • P2X 7 receptor antagonists are described in WO00/61569, WO01/44170, WO01/94338, WO03/041707, WO03/080579, WO04/106305, WO05/009968, WO06/025784 and WO06/059945.
  • the combination of the present invention may provide a beneficial therapeutic effect in the treatment of respiratory diseases.
  • beneficial therapeutic effect include improvements in one or more of the following parameters: reducing inflammatory cell influx into the lung, mild and severe exacerbations, FEVi (forced expiratory volume in one second), vital capacity (VC), peak expiratory flow (PEF), symptom scores and Quality of Life.
  • FEVi force expiratory volume in one second
  • VC vital capacity
  • PEF peak expiratory flow
  • symptom scores Quality of Life.
  • the muscarinic antagonist (first active ingredient) and second active ingredient of the present invention may be administered simultaneously, sequentially or separately to treat respiratory diseases.
  • sequential it is meant that the active ingredients are administered, in any order, one immediately after the other. They may still have the desired effect if they are administered separately, but when administered in this manner they will generally be administered less than 4 hours apart, more conveniently less than two hours apart, more conveniently less than 30 minutes apart and most conveniently less than 10 minutes apart.
  • the active ingredients of the present invention may be administered by oral or parenteral (e.g. intravenous, subcutaneous, intramuscular or intraarticular) administration using conventional systemic dosage forms, such as tablets, capsules, pills, powders, aqueous or oily solutions or suspensions, emulsions and sterile injectable aqueous or oily solutions or suspensions.
  • the active ingredients may also be administered topically (to the lung and/or airways) in the form of solutions, suspensions, aerosols and dry powder .
  • These dosage forms will usually include one or more pharmaceutically acceptable ingredients which may be selected, for example, from adjuvants, carriers, binders, lubricants, diluents, stabilising agents, buffering agents, emulsifying agents, viscosity-regulating agents, surfactants, preservatives, flavourings and colorants.
  • pharmaceutically acceptable ingredients may be selected, for example, from adjuvants, carriers, binders, lubricants, diluents, stabilising agents, buffering agents, emulsifying agents, viscosity-regulating agents, surfactants, preservatives, flavourings and colorants.
  • the most appropriate method of administering the active ingredients is dependent on a number of factors.
  • the active ingredients are administered via separate pharmaceutical preparations. Therefore, in one aspect, the present invention provides a kit comprising a preparation of a first active ingredient which is a muscarinic antagonist according to the present invention, and a preparation of a second active ingredient, and optionally instructions for the simultaneous, sequential or separate administration of the preparations to a patient in need thereof.
  • the active ingredients may be administered via a single pharmaceutical composition. Therefore, the present invention further provides a pharmaceutical composition comprising, in admixture, a first active ingredient, which is a muscarinic antagonist according to the present invention, and a second active ingredient, as defined above.
  • compositions of the present invention may be prepared by mixing the muscarinic antagonist (first active ingredient) with the second active ingredient and a pharmaceutically acceptable adjuvant, diluent or carrier. Therefore, in a further aspect of the present invention there is provided a process for the preparation of a pharmaceutical composition, which comprises mixing a muscarinic antagonist according to the present invention with a second active ingredient according to the present invention and a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the therapeutic dose of 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 muscarinic antagonist (first active ingredient) according to the present invention is administered via inhalation.
  • the dose of the muscarinic antagonist according to the present invention will generally be in the range of from 0.1 microgram ( ⁇ g) to 5000 ⁇ g, 0.1 to 1000 ⁇ g, 0.1 to 500 ⁇ g, 0.1 to 100 ⁇ g, 0.1 to 50 ⁇ g, 0.1 to 5 ⁇ g, 5 to 5000 ⁇ g, 5 to 1000 ⁇ g, 5 to 500 ⁇ g, 5 to 100 ⁇ g, 5 to 50 ⁇ g, 5 to 10 ⁇ g, 10 to 5000 ⁇ g, 10 to 1000 ⁇ g, 10 to 500 ⁇ g, 10 to 100 ⁇ g, 10 to 50 ⁇ g, 20 to 5000 ⁇ g, 20 to 1000 ⁇ g, 20 to 500 ⁇ g, 20 to 100 ⁇ g, 20 to 50 ⁇ g, 50 to 5000 ⁇ g, 50 to 1000 ⁇ g, 50 to 500 ⁇ g, 50 to 100 ⁇ g, 100 to 5000 ⁇ g, 100 to 1000 ⁇ g or 100 to 500 ⁇ g.
  • the dose will generally be
  • the second active ingredient of the present invention may conveniently be administered by inhalation.
  • the dose of the second active ingredient will generally be in the range of from 0.1 to 50 ⁇ g, 0.1 to 40 ⁇ g, 0.1 to 30 ⁇ g, 0.1 to 20 ⁇ g, 0.1 to 10 ⁇ g, 5 to 10 ⁇ g, 5 to 50 ⁇ g, 5 to 40 ⁇ g, 5 to 30 ⁇ g, 5 to 20 ⁇ g, 5 to 10 ⁇ g, 10 to 50 ⁇ g, 10 to 40 ⁇ g 10 to 30 ⁇ g, or 10 to 20 ⁇ g.
  • the dose will generally be administered from 1 to 4 times a day, conveniently once or twice a day, and most conveniently once a day.
  • the second active ingredient is administered orally.
  • Oral administration of the second active ingredient may for example be used in a pharmaceutical product or kit wherein the other active ingredient(s) are administered by inhalation.
  • the dose of the second active ingedient is in the range of from 5 to 1000 milligram (mg), 5 to 800mg, 5 to 600mg, 5 to 500mg, 5 to 400mg, 5 to 300mg, 5 to
  • the present invention provides a pharmaceutical product comprising, in combination, a first active ingredient which is a muscarinic antagonist, and a second active ingredient, as defined herein above, wherein each active ingredient is formulated for inhaled administration.
  • the first active ingredient which is a muscarinic antagonist
  • the second active ingredient(s), as defined herein above may be formulated for inhaled administration.
  • the first active ingredient which is a muscarinic antagonist
  • the second active ingredient(s), as defined herein above may be formulated for oral administration.
  • the first active ingredient which is a muscarinic antagonist
  • the second active ingredient(s), as defined herein above wherein each active ingredient is formulated for oral administration.
  • compositions of active ingredients may be administered simultaneously.
  • the different pharmaceutical preparations of active ingredients may be administered sequentially.
  • the different pharmaceutical preparations of active ingredients may be administered separately.
  • the active ingredients of the present invention are conveniently administered via inhalation (e.g. topically to the lung and/or airways) in the form of solutions, suspensions, aerosols and dry powder formulations.
  • metered dose inhaler devices may be used to administer the active ingredients, dispersed in a suitable propellant and with or without additional excipients such as ethanol, surfactants, lubricants or stabilising agents.
  • suitable propellants include hydrocarbon, chlorofluorocarbon and hydrofluoroalkane (e.g. heptafluoroalkane) propellants, or mixtures of any such propellants.
  • Preferred propellants are P 134a and P227, each of which may be used alone or in combination with other propellants and/or surfactant and/or other excipients.
  • Nebulised aqueous suspensions or, preferably, solutions may also be employed, with or without a suitable pH and/or tonicity adjustment, either as a unit-dose or multi-dose.
  • Dry powders and pressurized HFA aerosols of the active ingredients may be administered by oral or nasal inhalation.
  • the compound is desirably finely divided.
  • the finely divided compound preferably has a mass median diameter of less than 10 ⁇ m, and may be suspended in a propellant mixture with the assistance of a dispersant, such as a Cs- C20 fatty acid or salt thereof, (for example, oleic acid), a bile salt, a phospholipid, an alkyl saccharide, a perfluorinated or polyethoxylated surfactant, or other pharmaceutically acceptable dispersant.
  • a dispersant such as a Cs- C20 fatty acid or salt thereof, (for example, oleic acid), a bile salt, a phospholipid, an alkyl saccharide, a perfluorinated or polyethoxylated surfactant, or other pharmaceutically acceptable dispersant.
  • a carrier substance for example, a mono-, di- or polysaccharide, a sugar alcohol, or another polyol.
  • Suitable carriers are sugars, for example, lactose, glucose, raff ⁇ nose, melezitose, lactitol, maltitol, trehalose, sucrose, mannitol; and starch.
  • the finely divided compound may be coated by another substance.
  • the powder mixture may also be dispensed into hard gelatine capsules, each containing the desired dose of the active compound.
  • This spheronized powder may be filled into the drug reservoir of a multidose inhaler, for example, that known as the Turbuhaler ® in which a dosing unit meters the desired dose which is then inhaled by the patient.
  • a multidose inhaler for example, that known as the Turbuhaler ® in which a dosing unit meters the desired dose which is then inhaled by the patient.
  • the active ingredient with or without a carrier substance, is delivered to the patient.
  • the combination of the present invention is useful in the treatment or prevention of respiratory-tract disorders such as chronic obstructive pulmonary disease (COPD), chronic bronchitis of all types (including dyspnoea associated therewith), asthma (allergic and non- allergic; 'whez-infant syndrome'), adult/acute respiratory distress syndrome (ARDS), chronic respiratory obstruction, bronchial hyperactivity, pulmonary fibrosis, pulmonary emphysema, and allergic rhinitis, exacerbation of airway hyperreactivity consequent to other drug therapy, particularly other inhaled drug therapy or pneumoconiosis (for example aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis).
  • COPD chronic obstructive pulmonary disease
  • chronic bronchitis of all types including dyspnoea associated therewith
  • asthma allergic and non-
  • Dry powder inhalers may be used to administer the active ingredients, alone or in combination with a pharmaceutically acceptable carrier, in the later case either as a finely divided powder or as an ordered mixture.
  • the dry powder inhaler may be single dose or multi-dose and may utilise a dry powder or a powder-containing capsule.
  • Metered dose inhaler, nebuliser and dry powder inhaler devices are well known and a variety of such devices are available.
  • the present invention further provides a pharmaceutical product, kit or pharmaceutical composition according to the invention for simultaneous, sequential or separate use in therapy.
  • the present invention further provides the use of a pharmaceutical product, kit or pharmaceutical composition according to the invention in the manufacture of a medicament for the treatment of a respiratory disease, in particular chronic obstructive pulmonary disease or asthma.
  • the present invention further provides a pharmaceutical product, kit or pharmaceutical composition according to the invention for use in the treatment of a respiratory disease, in particular chronic obstructive pulmonary disease or asthma.
  • the present invention still further provides a method of treating a respiratory disease which comprises simultaneously, sequentially or separately administering:
  • the term “therapy” also includes “prophylaxis” unless there are specific indications to the contrary.
  • the terms “therapeutic” and “therapeutically” should be construed accordingly. Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the condition or disorder in question. Persons at risk of developing a particular condition or disorder generally include those having a family history of the condition or disorder, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the condition or disorder.
  • agent and "active ingredient” means the compounds comprised in the combination of the present invention, e.g. a muscarine antagonist or a CCRl antagonist.
  • the pharmaceutical product, kit or composition of the present invention may optionally comprise a third active ingredient which third active ingredient is a substance suitable for use in the treatment of respiratory diseases.
  • third active ingredients examples include those listed herein above as second active ingredients (i.e. a phosphodiesterase inhibitor, a modulator of chemokine receptor function, an inhibitor of kinase function, a protease inhibitor, a steroidal glucocorticoid receptor agonist, a non-steroidal glucocorticoid receptor agonist or a purinoceptor antagonist) it being recognised that they may be utilised as third active ingredients in embodiments where they have not been utilised as the second active ingredient .
  • second active ingredients i.e. a phosphodiesterase inhibitor, a modulator of chemokine receptor function, an inhibitor of kinase function, a protease inhibitor, a steroidal glucocorticoid receptor agonist, a non-steroidal glucocorticoid receptor agonist or a purinoceptor antagonist
  • the third active ingredient is a ⁇ 2 -adrenoceptor agonist.
  • the ⁇ 2 -adrenoceptor agonist may be any compound or substance capable of stimulating the ⁇ 2 -receptors and acting as a bronchodilator.
  • Examples of ⁇ 2 -adrenoceptor agonists that may be employed in the present invention include formoterol.
  • the chemical name for formoterol is ⁇ /-[2-hydroxy-5-[(l)-l-hydroxy-2-[[(l)-2-(4-methoxyphenyl)-l- methylethyl]amino]ethyl]phenyl]-formamide.
  • the preparation of formoterol is described, for example, in WO 92/05147.
  • the ⁇ 2 -adrenoceptor agonist is formoterol fumarate. It will be understood that the invention encompasses the use of all optical isomers of formoterol and mixtures thereof including racemates.
  • the term formoterol encompasses JV-[2-hydroxy-5-[(lR)-l-hydroxy-2-[[(lR)-2- (4-methoxyphenyl)-l-methylethyl]amino]ethyl]phenyl]-formamide, 7V-[2-hydroxy-5-[(lS)- 1 -hydroxy-2-[[(l S)-2-(4-methoxyphenyl)- 1 -methylethyl]amino]ethyl]phenyl]-formamide and a mixture of such enantiomers, including a racemate.
  • the pharmaceutical product, kit or pharmaceutical composition does not contain a ⁇ 2 -adrenoceptor agonist.
  • Figure 1 X-ray powder diffraction (XRPD) pattern of muscarinic antagonist (i?)-l-[2-(4- Fluoro-phenyl)-ethyl]-3-((5)-2-phenyl-2-piperidin- 1 -yl-propionyloxy)- 1 -azonia- bicyclo[2.2.2]octane bromide Form A.
  • XRPD X-ray powder diffraction
  • Figure 2 X-ray powder diffraction (XRPD) pattern of muscarinic antagonist (i?)-l-[2-(4- Fluoro-phenyl)-ethyl]-3-((5)-2-phenyl-2-piperidin- 1 -yl-propionyloxy)- 1 -azonia- bicyclo[2.2.2]octane bromide Form C.
  • XRPD X-ray powder diffraction
  • Figure 3 X-ray powder diffraction pattern (XRPD) of (R)- 1 -(4-fluorophenethyl)-3 -(( ⁇ S)-2- phenyl-2-(piperidin-l-yl)propanoyloxy)-l-azoniabicyclo[2.2.2]octane A- methylbenzenesulphonate.
  • XRPD X-ray powder diffraction pattern
  • Muscarinic antagonists according to the present invention may be prepared as follows. Alternative salts to those described herein may be prepared by conventional chemistry using methods analogous to those described. General Experimental Details for Preparation of Muscarinic Antagonists
  • NMR spectra were measured on a Varian Unity Inova spectrometer at a proton frequency of either 300, 400 or 500 MHz.
  • the MS spectra were measured on either an Agilent 1100 MSD G 1946D spectrometer or a Hewlett Packard HP 1100 MSD G 1946 A spectrometer.
  • Preparative HPLC separations were performed using a Waters Symmetry ® or Xterra ® column using 0.1% aqueous trifluoroacetic acid: acetonitrile, 0.1% aqueous ammonia: acetonitrile or 0.1% ammonium acetate: acetonitrile as the eluent.
  • Absolute configuration at the 2' position of Example 2 is assigned on the basis of the (5)-2-Phenyl-2-piperidin-l-yl- propionic acid methyl ester intermediate (Intermediate A - Isomer 1) used in its preparation.
  • the absolute configuration of Intermediate A - Isomer 1 is assigned on the basis of the absolute configuration of Example 1, which was assigned by single crystal X- ray diffraction.
  • the preparation of Intermediate A - Isomer 1 , its use in the preparation of Example 1, and the assignment of the absolute configuration of Example 1 by single crystal X-ray diffraction is described below.
  • GVS Gravimetric vapour sorption
  • HATU O-(7-Azabenzotriazol-l-yl)- ⁇ /, ⁇ /,N',N'-tetramethyluronium hexafluorophospahte MeCN - Acetonitrile
  • XRPD X-Ray Powder Diffraction
  • the X-rays were generated by a copper long-fine focus tube operated at 45kV and 4OmA.
  • 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.
  • thermograms were measured using a TA QlOOO Differential Scanning Calorimeter, with aluminium pans and pierced lids.
  • 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 0 C at a constant rate of temperature increase of 10 0 C per minute.
  • the mixture of enantiomers was separated by chiral hplc using a chiracel OJ-H column using an isocratic system of 80% ⁇ ohexane / ethanol to afford the two enantiomers, which were defined as Isomer 1 and Isomer 2 in order of elution.
  • Example 1 Single crystal X-ray diffraction data obtained for Example 1 proved the structure to be (R)- l-[2-(4-Fluoro-phenyl)-ethyl]-3-((5)-2-phenyl-2-piperidin- 1 -yl-propionyloxy)- 1 -azonia- bicyclo[2.2.2]octane bromide.
  • the data set was collected at RT with graphite monochromatized MoK(a) radiation on a KappaCCD Single-Crystal X-Ray diffractometer equipped with an k-axis goniometer and a CCD area detector (Nonius, 1998).
  • 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.
  • Example 1 bromide Form A obtained by the procedure described above was analysed by XRPD (PANalytical X'Pert or Cubix system), GVS, DSC and TGA.
  • Example 1 bromide Form A as determined by DSC gave found a double endothermic events occurring at 17PC (1 st onset) and 183 0 C (2 nd onset) ( ⁇ 2°C). Weight loss observed prior to melting by TGA was negligible. GVS determination gave 0.1% weight increase (%w/w) at 80% RH ( ⁇ 0.2%).
  • Example 1 Crystalline Form C obtained by the procedure described above was analysed by XRPD (PANalytical X'Pert or Cubix system), GVS, DSC and TGA.
  • the melting temperature of Example 1 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%).
  • Example 2a 4-(3-Bromo-propyl)-2-methyl-pyridine hydrobromide (Example 2a) ( ⁇ 200mg wet) was treated with 10% sodium hydroxide solution (2 mL) and then extracted with diethyl ether (x3). The organic layer was washed with brine, dried (MgSO 4 ) and the solvent was evaporated to yield a colourless oil.
  • 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 0 C for 2 days to yield the product (0.490 g).
  • Step a) was monitored by HPLC using an Ace phenyl column with standard aqueous/acetonitrile/TFA mobile phase on a gradient, with UV detection at 230 nm.
  • Steps b), c) and d) were monitored by GC using DB-5 capilllary column with FID detection and standard oven gradient from 4O 0 C to 300 0 C, with split injection.
  • Steps e), f), g) and h) are monitored by HPLC using Cl 8 phase with standard aqueous/acetonitrile/TFA mobile phase on a gradient, with UV detection at 220 nm.
  • Step e) solvent composition was monitored by GC using a DB-624 capillary column with FID detection and oven gradient from 4O 0 C to 25O 0 C, with split injection.
  • Step e) was monitored for levels of quinuclidinol by GC using an HP-I capillary column with FID detection and oven gradient from 4O 0 C to 300 0 C, with split injection.
  • (+/-)-2-Phenylpropionic acid (20.5 g) 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 CO 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 18OmL 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 (prepared in step a) (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%, 2.2Ig) and JV-bromosuccinimide (31.6Ig) were then charged to the vessel and the reaction heated to 50 0 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 0 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 by-product was discarded. NaHSO 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.
  • reaction mixture was then cooled to 23°C ( ⁇ 3°C) and then filtered to remove the piperidine hydrobromide salt by-product, and the filter cake washed with methyl 'butyl ether (66.4mL). The filter cake was discarded.
  • Methyl 'butyl ether (133mL) and hydrogen chloride (2.74M, 172.6mL) were then added and the reaction mixture stirred for 15mins before taking a pH reading to ensure pH ⁇ 4.
  • the layers were then allowed to separate retaining the lower aqueous phase.
  • Hydrogen chloride (2.74M, 60.4mL) was then added to the organic phase and the mixture stirred for at least 15mins before allowing the phases to separate retaining the lower aqueous phase.
  • 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 CO 3 (32.29g), water (232mL) and methyl 'butyl ether (332mL). The mixture was stirred for at least 15mins before taking a pH reading to ensure pH >6. The layers were then allowed to separate discarding the lower aqueous phase. Water (66.4mL) was then charged and stirred for 15mins before allowing the phases to separate discarding the lower aqueous phase.
  • Citric acid (0.8wt%, 66.4mL) was then charged to the organic phase and the mixture stirred for 15mins before allowing the phases to separate discarding the lower aqueous phase.
  • a second charge of citric acid (0.8wt%, 66.4mL) was then added to the organic phase and the mixture stirred for 15mins before allowing the phases to separate discarding the lower aqueous phase.
  • 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.
  • the reaction was then heated to 60 0 C ( ⁇ 5°C) and potassium tert-pentoxide (25w/w%, 43.12g) was added.
  • the reaction mixture was stirred at 60 0 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 0 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.
  • Water (88mL) was charged and the mixture stirred for 20mins before allowing the phases to separate discarding the lower aqueous phase.
  • the organic phase was analysed by GC to ensure residual (7?)-(-)-3-quinuclidinol levels were below 0.5%.
  • the organic phase was distilled at 60 0 C, 100-430mbar removing 142mL of solvent.
  • 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.
  • the 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 0 C over at least 40mins (0.5°C/min) and then cooled to -5°C over at least 6hrs (0.125°C/min). During the cool no crystallisation had occurred when at 20 0 C.
  • reaction was seeded with a sample of (i?)-l-(4-fluorophenethyl)-3-((5)-2-phenyl-2- (piperidin-l-yl)propanoyloxy)-l-azoniabicyclo[2.2.2]octane bromide (25mg - obtainable by methods described in WO 2008/075005 - Form A). After the reaction mixture reached - 5°C toluene (39.3mL) was added and the slurry stirred at -5°C for at least lhr.
  • a solution of sodium p-toluenesulfonate (26.97 g) in water (300 mL; 16.65 moles) was prepared.
  • a 500 mL jacketed vessel was charged with (i?)-l-(4-fluorophenethyl)-3-((5)-2- phenyl-2-(piperidin-l-yl)propanoyloxy)-l-azoniabicyclo[2.2.2]octane bromide (15.00 g).
  • Butanenitrile (225 mL) and half of the sodium tosylate solution were added to the reaction vessel.
  • the vessel was then stirred and heated to 35°C. When the vessel contents reached 35°C and were adequately mixed the stirring was stopped and the phases allowed to settle.
  • the lower aqueous phase was removed and discarded.
  • the second half of the sodium tosylate solution was added and the vessel contents heated to 35°C with stirring. When the vessel contents reached 35°C and were adequately mixed the stirring was stopped and the phases allowed to settle. The lower aqueous phase was removed and discarded. Water (75 mL) was added and the mixture heated to 70 0 C. When the vessel contents reached 70 0 C and were adequately mixed the stirring was stopped and the phases allowed to settle. 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 0 C). After ca. 60 mL of solvent had been distilled a precipitate was observed; contents were at 48°C. In total, 110 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 affinity (pICso) of compounds to the M3 receptor was determined by competition binding of [ 3 H]N-methyl scopolamine (NMS) to CHO-Kl (Chinese Hamster Ovary) cell membranes expressing the human muscarinic acetylcholine M 3 receptor (M 3 -ACh) in a scintillation proximity assay (SPA) format.
  • SPA beads were precoated with membranes and then incubated at 2mg of beads per well with serial dilutions of the compounds of the invention, [ 3 H]NMS at 0.2nM, half Kd (experimentally determined dissociation constant) and assay buffer (20 mM HEPES pH 7.4 containing 5 mM MgCl 2 ). The assay was conducted in a final volume of 200 ⁇ L, in the presence of 1% (v/v) dimethyl sulphoxide (DMSO). Total binding of [ 3 H]NMS was determined in the absence of competing compound and non-specific binding of [ 3 H]NMS was determined in the presence of 1 ⁇ M atropine.
  • DMSO dimethyl sulphoxide
  • the plates were incubated for 16 hours at room temperature and then read on Wallac Microbeta TM using a normalised 3 H protocol.
  • the PIC50 defined as the negative logarithm of the concentration of compound required for 50% reduction in specific [ 3 H]-NMS binding, was determined. Using the procedure given above pICso values determined for Examples 1, and 2, were 9.9 and 9.9 respectively.
  • the standard deviation of the M 3 receptor assay described above is between 0.2 and 0.3 log units.
  • the pIC50 values quoted above are means of replicate determinations which were within 2 x SD (95% confidence) of each other.
  • the extent of plasma protein binding was determined via equilibrium dialysis of a compound between human plasma and aqueous buffer at 37 0 C and determination of the concentration of compound in the plasma and buffer by HPLC-MS/MS.
  • Dialysis cells (molecular weight cut-off 5000) were prepared by rinsing with water followed by soaking in the dialysis buffer for a minimum of 1 hour.
  • the dialysis buffer was isotonic buffered saline pH 7.4.
  • Stock solutions of compound in dimethylsulphoxide were prepared at a concentration of 0.5mM. Frozen pooled Human plasma was obtained from volunteers.
  • the stock DMSO solution of a compound was added to the plasma at a ratio of 10 ⁇ l of DMSO to each ml of plasma. This gave a 1% DMSO in plasma solution with each compound at a concentration of 5 ⁇ M.
  • Dialysis cells were then prepared and one half of the cell filled with 750 ⁇ l of dialysis buffer and the other half of the cell with 750 ⁇ l of plasma solution of compound. Once prepared the cells were sealed and placed in an incubator box at 37 0 C. These cells were then rotated for a minimum of 4 hours to equilibrate.
  • the concentration of compound in the samples were determined using MassLynx version 4.1 software (produced by Waters/Micromass) that automatically calculated a calibration curve and the concentration of compound in the cells.
  • Plasma protein binding was determined from the calibration curve as the percentage of compound bound in human plasma (% bound) using the following equation; buffer peak area '
  • /buffer injection volume % bound 100 - 100 / plasma peak area . plasma injection volume.
  • Example 57 the measured human plasma protein binding figure using the procedure described above was 98% bound.
  • Dunkin-Hartley guinea-pigs 300 - 60Og were supplied by a designated breeding establishment. Animals were dosed with test compound or vehicle either by inhalation in conscious guinea-pigs or by intratracheal instillation (0.5ml/kg) under recoverable gaseous anaesthesia (5% halothane). Animals were allowed to recover from the anaesthesia prior to the measurement of bronchoconstriction. Up to 48 hours post-dosing guinea-pigs were terminally anaesthetized with sodium pentobarbitone (60 mg/kg), the trachea cannulated for artificial ventilation and the jugular vein was cannulated for intravenous administration of methacholine.
  • the guinea-pigs were 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 during surgical preparation.
  • Lung function (lung resistance and compliance) was measured in anaesthetised and ventilated guinea-pigs using a pulmonary measurement Flexivent system (SCIREQ, Montreal, Canada) connected to the tracheal cannulae.
  • SCIREQ pulmonary measurement Flexivent system
  • the animals were ventilated (quasi-sinusoidal ventilation pattern) at 60 breaths/min at a tidal volume of 5 ml/kg.
  • a positive end expiratory pressure of 2-3 CmH 2 O was applied.
  • Respiratory resistance was measured using the Flexivent "snapshot" facility (1 second duration, 1 Hz frequency). Lung resistance and compliance was measured before and after intravenous administration of methacholine (3, 10 and 30 ug/kg). The peak increase in resistance following methacholine challenge was calculated and the effect of the test compound on methacholine -induced lung function changes was calculated.
  • Percentage inhibition of bronchoconstriction was calculated at each dose of methacholine as follows: [Change in resistance in vehicle treated group - Change in resistance in compound treated group! x 100 [Change in resistance in vehicle treated group]
  • Guinea pigs (450-55Og) supplied by Harlan UK or David Hall, Staffs UK and acclimatised to the in-house facilities for a minimum of three days before use. Guinea pigs were randomly assigned into treatment groups and weighed. Each animal was lightly anaesthetised (4% Halothane) and administered compound or vehicle intranasally (0.5ml/kg) at up to 24 hours before challenge with pilocarpine. At the test time point, guinea pigs were terminally anaesthetised with urethane (25% solution in H 2 O, 1.5g/kg).
  • Saliva production was calculated by subtracting the pre-weighed weight of the pad from each 5 minute period post weighed pad and these numbers added together to produce an accumulation of saliva over 15 minutes. Each 5 minute period could be analysed in addition to the whole 15 minute recording period. Baseline production of saliva was assumed to be constant and multiplied by three to produce a reading for baseline saliva production over 15 minutes.
  • Inhibition of saliva produced by the compound could be calculated by using the following equation: (l-(Test-baseline)/(Veh-baseline))* 100.
  • indomethacin to prevent development of smooth muscle tone due to the synthesis of cyclooxygenase products
  • corticosterone to inhibit the uptake 2 process
  • ascorbate to prevent catecholamine oxidation
  • CGP20712A and phentolamine to avoid any complicating effects of ⁇ l- and ⁇ -adrenoceptor activation respectively.
  • the tracheal rings are suspended between two stainless steel hooks, one attached to an isometric force transducer and the other to a stationary support in the organ bath. Changes in isometric force are recorded.
  • Acetyl- ⁇ -methylcholine chloride (Methacholine), Indomethacin, Corticosterone-21 -acetate, Phentolamine hydrochloride, Ascorbic acid, and CGP20712A methanesulphate may be obtained from the Sigma chemical company. Indomethacin may be dissolved in 10% w/v Na 2 CO 3 , corticosterone 21 -acetate in ethanol and other compounds in DMSO. Muscarinic antagonists and Budesonide may be diluted in Krebs prior to adding to tissues and the level of DMSO in the bath ⁇ 0.1 %.
  • Data may be collected using the AD Instruments Chart5 for windows software, the tension generated may be measured before addition of methacholine and after its response reaches a plateau.
  • the response to the muscarinic antagonist and/or Budesonide may be measured at 10 minute intervals following their addition. All responses may be expressed as percentage inhibition of the methacholine -induced contraction.
  • the following protocol is a prophetic description of an experimental protocol that may be used to evaluate the effects of muscarinic M3 receptor antagonists according to the present invention, in combination with CCRl anatgonists.
  • BAL broncholalveolar lavage
  • Rats are anaesthetized with Efrane and put in a supine position, head up, on a board tilted at 30°.
  • LPS Lipopolysaccharide B.E.coli 026:B6
  • saline 0.9% NaCl
  • saline alone negative control
  • CCRl anatgonists are dissolved in 0.9% NaCl solution to a final concentration of 0.001 to 0.100 mg.
  • Muscarinic antagonists are dissolved in 0.9% NaCl solution to an appropriate final concentration of 0.001 to 1.0 mg/ml.
  • CCRl antagonist, Muscarinic antagonist or mixed s are made by dissolving CCRl antagonist in Muscarinic antagonist suspensions, giving a final concentration of 001 to 0.100 CCRl antagonist /ml and 001 to 1.0 mg Muscarinic antagonist /ml.
  • Treatments Animals were intratracheally instilled with solutions (1 ml/kg) of Muscarinic antagonist / CCRl antagonist (0.002/ 001 to 0.100 mg/kg), or of Muscarinic antagonist (001 to 1.0 mg/kg) alone, or CCRl antagonist (001 to 0.100 mg/kg) alone, or with saline (negative and positive control animals). The treatments were carried out under light anaesthesia (Efrane) to secure that the solution reached the lungs. The drugs were administrated 30 min before the LPS instillation.
  • rats are intraperitoneally injected with the mixture (0.3 ml) of pentobarbital (60 mg/ml, Apoteksbolaget, Sweden) and PBS (1 :1) for 1 - 2 min.
  • Bronchoalveolar lavage After termination, BAL is performed twice with PBS. The BAL fluid is centrifuged and the cell pellet was resuspended in PBS. The total numbers of BAL cells is counted in a SYSMEX cell counter.

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

Abstract

L'invention concerne un produit pharmaceutique, une trousse ou une composition comprenant un premier principe actif qui est un antagoniste sélectionné du récepteur muscarinique et un second principe actif, utiles pour traiter des maladies respiratoires, notamment la bronchopneumopathie chronique obstructive et l'asthme. Le second principe actif est sélectionné parmi: un inhibiteur de phosphodiestérase, un modulateur de la fonction du récepteur de chimiokine, un inhibiteur de la fonction kinase, un inhibiteur de protéase, un agoniste du récepteur des glucocorticoïdes stéroïdiens, un agoniste du récepteur des glucocorticoïdes non stéroïdiens, et un antagoniste de purinocepteur.
PCT/SE2009/050742 2008-06-17 2009-06-16 Produit pharmaceutique comprenant un antagoniste du récepteur muscarinique et un second principe actif WO2009154554A1 (fr)

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GBGB0811099.1A GB0811099D0 (en) 2008-06-17 2008-06-17 New combination 376
GB0811099.1 2008-06-17

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WO2009154554A1 true WO2009154554A1 (fr) 2009-12-23

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010094964A1 (fr) 2009-02-20 2010-08-26 Astrazeneca Ab Sel de tosylate d'un dérivé de 5-pyrazolyl-2-pyridone, utile dans le traitement de la broncho-pneumopathie chronique obstructive
WO2010144043A1 (fr) * 2009-06-12 2010-12-16 Astrazeneca Ab Nouveau sel 4-méthylbenzènesulphonate et procédé de préparation d'une composition pharmaceutique comprenant le sel
WO2011160920A1 (fr) * 2010-06-22 2011-12-29 Chiesi Farmaceutici S.P.A. Formulation de poudre sèche comprenant un médicament antimuscarinique
US8207193B2 (en) 2006-11-14 2012-06-26 Astrazeneca Ab Quiniclidine derivatives of (hetero) arylcycloheptanecarboxylic acid as muscarinic receptor antagonists
US8329729B2 (en) 2008-05-13 2012-12-11 Astrazeneca Ab Quinuclidine derivatives as muscarinic M3 receptor antagonists

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WO2007024182A1 (fr) * 2005-08-26 2007-03-01 Astrazeneca Ab Combinaison de composés pouvant être employée dans le traitement de maladies respiratoires, en particulier de broncho-pneumopathie chronique obstructive (bpco) et d'asthme
WO2008010765A1 (fr) * 2006-07-19 2008-01-24 Astrazeneca Ab Nouveaux composés
WO2008059245A1 (fr) * 2006-11-14 2008-05-22 Astrazeneca Ab Dérivés de quiniclidine d'acide (hétéro)arylcycloheptane carboxylique en tant qu'antagonistes du récepteur muscarinique
WO2008075005A1 (fr) * 2006-12-19 2008-06-26 Astrazeneca Ab Dérivés quinuclidinol utilisés en tant qu'antagonistes du récepteur muscarinique
WO2008096136A1 (fr) * 2007-02-07 2008-08-14 Argenta Discovery Ltd Combinaison inédite

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Publication number Priority date Publication date Assignee Title
WO2007024182A1 (fr) * 2005-08-26 2007-03-01 Astrazeneca Ab Combinaison de composés pouvant être employée dans le traitement de maladies respiratoires, en particulier de broncho-pneumopathie chronique obstructive (bpco) et d'asthme
WO2008010765A1 (fr) * 2006-07-19 2008-01-24 Astrazeneca Ab Nouveaux composés
WO2008059245A1 (fr) * 2006-11-14 2008-05-22 Astrazeneca Ab Dérivés de quiniclidine d'acide (hétéro)arylcycloheptane carboxylique en tant qu'antagonistes du récepteur muscarinique
WO2008075005A1 (fr) * 2006-12-19 2008-06-26 Astrazeneca Ab Dérivés quinuclidinol utilisés en tant qu'antagonistes du récepteur muscarinique
WO2008096136A1 (fr) * 2007-02-07 2008-08-14 Argenta Discovery Ltd Combinaison inédite

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Title
FITZGERALD M.F. ET AL: "Emerging trends in the therapy of COPD: bronchodilators as mono- and combination therapies", DRUG DISCOVERY TODAY, vol. 12, no. 11/12, June 2007 (2007-06-01), pages 472 - 478, XP022095610 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8207193B2 (en) 2006-11-14 2012-06-26 Astrazeneca Ab Quiniclidine derivatives of (hetero) arylcycloheptanecarboxylic acid as muscarinic receptor antagonists
US8329729B2 (en) 2008-05-13 2012-12-11 Astrazeneca Ab Quinuclidine derivatives as muscarinic M3 receptor antagonists
WO2010094964A1 (fr) 2009-02-20 2010-08-26 Astrazeneca Ab Sel de tosylate d'un dérivé de 5-pyrazolyl-2-pyridone, utile dans le traitement de la broncho-pneumopathie chronique obstructive
WO2010144043A1 (fr) * 2009-06-12 2010-12-16 Astrazeneca Ab Nouveau sel 4-méthylbenzènesulphonate et procédé de préparation d'une composition pharmaceutique comprenant le sel
WO2011160920A1 (fr) * 2010-06-22 2011-12-29 Chiesi Farmaceutici S.P.A. Formulation de poudre sèche comprenant un médicament antimuscarinique
CN102946868A (zh) * 2010-06-22 2013-02-27 奇斯药制品公司 包含抗毒蕈碱药的干粉制剂

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