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WO2009139707A1 - Produit pharmaceutique comprenant un antagoniste du récepteur muscarinique et un deuxième principe actif - Google Patents

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

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Publication number
WO2009139707A1
WO2009139707A1 PCT/SE2009/050524 SE2009050524W WO2009139707A1 WO 2009139707 A1 WO2009139707 A1 WO 2009139707A1 SE 2009050524 W SE2009050524 W SE 2009050524W WO 2009139707 A1 WO2009139707 A1 WO 2009139707A1
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WIPO (PCT)
Prior art keywords
phenyl
active ingredient
bicyclo
cycloheptanecarbonyloxy
azonia
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Inventor
Richard Bull
Rhonan Ford
Andrew Mather
Antonio Mete
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Argenta Discovery Ltd
AstraZeneca AB
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Argenta Discovery Ltd
AstraZeneca AB
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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
    • 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 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:
  • 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, 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.
  • a second active ingredient which 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
  • 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/GB2007/004350 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), edisylate (ethane- 1 ,2-disulfonate), isethionate (2- hydroxyethylsulfonate),lactate, oleic, maleate ((Z)-3-carboxy-acrylate), succinate (3- carboxy-propionate), malate ((S)-3-carboxy -2-hydroxy-propionate), p- acetamidobenzoateacetate, maleate, fum
  • the muscarinic receptor antagonist is in the form of a bromide or napadisylate salt.
  • the muscarinic receptor antagonist is selected from
  • the muscarinic receptor antagonist is in the form of a napadisylate salt.
  • the cation/anion ratio may vary, and for example may be 1 : 1 or 2: 1 , or a value between 1 : 1 and 2:1.
  • the muscarinic antagonist is in the form of a napadisylate salt wherein the napadisylate salt cation/anion ratio is 2:1. i.e. a hemi- napadisylate.
  • Examples of muscarinic antagonists according to this embodiment include: (R)-3 -(I -Phenyl-cycloheptanecarbonyloxy)- 1 -(pyrazin-2-ylcarbamoylmethyl)-l -azonia- bicyclo[2.2.2]octane hemi-naphthalene-l,5-disulfonate; and (i?)-3 -(I -Phenyl-cycloheptanecarbonyloxy)- 1 -(pyridin-2-ylcarbamoylmethyl)-l -azonia- bicyclo[2.2.2]octane hemi-naphthalene- 1 ,5-disulfonate.
  • the muscarinic receptor antagonist is in the form of a 2,5-dichlorobenzene sulphonate or l-hydroxynaphthalene-2-sulphonate salt.
  • muscarinic antagonists according to this embodiment include:
  • the muscarinic receptor antagonist is in the form of a bromide salt.
  • 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-[((25)-3- ⁇ [ 1 -(4-chlorobenzyl)piperidin-4-yl] amino ⁇ -2-hydroxy-2-methylpropyl)oxy]-
  • the second active ingredient is a salt of N- ⁇ 2-[((25)-3- ⁇ [ 1 -(4-chlorobenzyl)piperidin-4-yl] amino ⁇ -2-hydroxy-2-methylpropyl)oxy]-4- hydroxyphenyl ⁇ acetamide or TV- ⁇ 5-Chloro-2-[((25)-3- ⁇ [ 1 -(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 ⁇ /- ⁇ 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-difiuorobenzoate salt of N- ⁇ 5- Chloro-2-[((25)-3- ⁇ [l-(4-chlorobenzyl)piperidin-4-yl]amino ⁇ -2-hydroxy-2- methylpropyl)oxy]-4-hydroxyphenyl ⁇ acetamide.
  • the second active ingredient is 2- ⁇ 2-chloro-5- ⁇ [(2S)-3-(5-chloro-l ⁇ ,3H-spiro[l-benzofuran-2,4'-piperidin]-r-yl)-2- hydroxypropyl]oxy ⁇ -4-[(methylamino)carbonyl]phenoxy ⁇ -2-methylpropanoic acid or a pharmaceutically acceptable salt thereof.
  • [(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 7V- ⁇ 5-chloro-2- [((25)-3- ⁇ [ 1 -(4-chlorobenzyl)piperidin-4-yl] amino ⁇ -2-hydroxy-2-methylpropyl)oxy]-4- hydroxyphenyl ⁇ acetamide or a pharmaceutically acceptable salt thereof.
  • 7V- ⁇ 5-chloro-2- [((25)-3- ⁇ [ 1 -(4-chlorobenzyl)piperidin-4-yl] amino ⁇ -2-hydroxy-2-methylpropyl)oxy]-4- hydroxyphenyl ⁇ acetamide may be prepared by methods according or analogous to those described in WO2007/015664.
  • the muscarinic receptor antagonist is (i?)-3-(l-Phenyl- cycloheptanecarbonyloxy)- 1 -(pyrazin-2-ylcarbamoylmethyl)- 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- ⁇ [ ⁇ -(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?)-3-(l-Phenyl-cycloheptanecarbonyloxy)-l-(pyrazin-2- ylcarbamoylmethyl)-l-azonia-bicyclo[2.2.2]octane bromide.
  • the muscarinic receptor antagonist is (i?)-3-(l-Phenyl- cycloheptanecarbonyloxy)- 1 -(pyrazin-2-ylcarbamoylmethyl)- 1 -azonia- bicyclo[2.2.2]octane hemi-naphthalene-l,5-disulfonate.
  • the muscarinic receptor antagonist is (i?)-3-(l-Phenyl- cycloheptanecarbonyloxy)- 1 -(pyrazin-2-ylcarbamoylmethyl)- 1 -azonia- bicyclo[2.2.2]octane chloride.
  • the muscarinic receptor antagonist is (i?)-3-(l-Phenyl-cycloheptanecarbonyloxy)-l-(pyrazin-2- ylcarbamoylmethyl)-l-azonia-bicyclo[2.2.2]octane 2,5-dichlorobenzenesulfonate.
  • the muscarinic receptor antagonist is (i?)-3-(l-Phenyl- cycloheptanecarbonyloxy)- 1 -(pyrazin-2-ylcarbamoylmethyl)- 1 -azonia- bicyclo[2.2.2]octane 1 -hydroxy-naphthalene-2-sulfonate.
  • the muscarinic receptor antagonist is (i?)-3-(l-Phenyl- cycloheptanecarbonyloxy)-l-(pyridin-2-ylcarbamoylmethyl)-l-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-[((25)-3- ⁇ [l-(4-chlorobenzyl)piperidin-4- yljamino ⁇ -2-hydroxy-2-methylpropyl)oxy]-4-hydroxyphenyl ⁇ acetamide or a pharmaceutically acceptable salt thereof (e.g.
  • the muscarinic receptor antagonist is (i?)-3-(l-Phenyl- cycloheptanecarbonyloxy)-l-(pyridin-2-ylcarbamoylmethyl)-l-azonia-bicyclo[2.2.2]octane bromide.
  • the muscarinic receptor antagonist is (R)- 3 -( 1 -Phenyl-cycloheptanecarbonyloxy)- 1 -(pyridin-2-ylcarbamoylmethyl)- 1 -azonia- bicyclo[2.2.2]octane chloride.
  • the muscarinic receptor antagonist is (i?)-3 -(I -Phenyl-cycloheptanecarbonyloxy)- l-(pyridin-2- ylcarbamoylmethyl)-l-azonia-bicyclo[2.2.2]octane hemi-naphthalene-l,5-disulfonate.
  • the muscarinic receptor antagonist is (i?)-l-[(5-Fluoro- pyridin-2-ylcarbamoyl)-methyl] -3 -( 1 -phenyl-cycloheptanecarbonyloxy)- 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- ⁇ [ ⁇ -(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-[(5-Fluoro-pyridin-2-ylcarbamoyl)-methyl]-3-(l-phenyl- cycloheptanecarbonyloxy)- 1 -azonia-bicyclo[2.2.2]octane chloride.
  • the muscarinic receptor antagonist is (i?)-3-[l-(3- Fluoro-phenyl)-cycloheptanecarbonyloxy]-l-(isoxazol-3-ylcarbamoylmethyl)-l-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?)-3-[l-(3-Fluoro-phenyl)-cycloheptanecarbonyloxy]-l-(isoxazol-3- ylcarbamoylmethyl)-l-azonia-bicyclo[2.2.2]octane bromide.
  • the muscarinic receptor antagonist is (i?)-3 -(I -Phenyl- cycloheptanecarbonyloxy)- 1 -(pyrazin-2-ylcarbamoylmethyl)- 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- ⁇ 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 (R)-3 -(I -Phenyl-cycloheptanecarbonyloxy)- l-(pyrazin-2- ylcarbamoylmethyl)-l-azonia-bicyclo[2.2.2]octane bromide.
  • the muscarinic receptor antagonist is (i?)-3 -(I -Phenyl- cycloheptanecarbonyloxy)- 1 -(pyrazin-2-ylcarbamoylmethyl)- 1 -azonia- bicyclo[2.2.2]octane hemi-naphthalene-l,5-disulfonate.
  • the muscarinic receptor antagonist is (i?)-3-(l-Phenyl- cycloheptanecarbonyloxy)- 1 -(pyrazin-2-ylcarbamoylmethyl)- 1 -azonia- bicyclo[2.2.2]octane chloride.
  • the muscarinic receptor antagonist is (i?)-3 -(I -Phenyl-cycloheptanecarbonyloxy)- l-(pyrazin-2- ylcarbamoylmethyl)-l-azonia-bicyclo[2.2.2]octane 2,5-dichlorobenzenesulfonate. (R)-3- ( 1 -Phenyl-cycloheptanecarbonyloxy)- 1 -(pyrazin-2-ylcarbamoylmethyl)- 1 -azonia- bicyclo[2.2.2]octane 1 -hydroxy-naphthalene-2-sulfonate.
  • the muscarinic receptor antagonist is (R)-3 -(I -Phenyl- cycloheptanecarbonyloxy)-! -(pyridin-2-ylcarbamoylmethyl)-l-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]-4-hydroxyphenyl ⁇ acetamide or a pharmaceutically acceptable salt thereof (e.g.
  • the muscarinic receptor antagonist is (i?)-3 -(I -Phenyl- cycloheptanecarbonyloxy)-! -(pyridin-2-ylcarbamoylmethyl)-l-azonia-bicyclo[2.2.2]octane bromide.
  • the muscarinic receptor antagonist is (R)- 3 -( 1 -Phenyl-cycloheptanecarbonyloxy)- 1 -(pyridin-2-ylcarbamoylmethyl)- 1 -azonia- bicyclo[2.2.2]octane chloride.
  • the muscarinic receptor antagonist is (R)-3 -(I -Phenyl-cycloheptanecarbonyloxy)- l-(pyridin-2- ylcarbamoylmethyl)-l-azonia-bicyclo[2.2.2]octane hemi-naphthalene-l,5-disulfonate.
  • the muscarinic receptor antagonist is (i?)-l-[(5-Fluoro- pyridin-2-ylcarbamoyl)-methyl]-3-(l -phenyl-cycloheptanecarbonyloxy)-!
  • X represents a pharmaceutically acceptable anion of a mono or polyvalent acid
  • the second active ingredient is N- ⁇ 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. benzoate, hemifumarate or furoate).
  • the muscarinic receptor antagonist is (R)-I -[(5 -Fluoro-pyridin-2-ylcarbamoyl)-methyl] -3 -(I -phenyl- cycloheptanecarbonyloxy)- 1 -azonia-bicyclo[2.2.2]octane chloride.
  • the muscarinic receptor antagonist is (i?)-3-[l-(3- Fluoro-phenyl)-cycloheptanecarbonyloxy]-l-(isoxazol-3-ylcarbamoylmethyl)-l-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- ⁇ 5-c ⁇ oro-2-[((2S)-3- ⁇ [ ⁇ - (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?)-3-[l-(3-Fluoro-phenyl)-cycloheptanecarbonyloxy]-l-(isoxazol-3- ylcarbamoylmethyl)-l-azonia-bicyclo[2.2.2]octane bromide.
  • the muscarinic receptor antagonist (i?)-3-(l-Phenyl- cycloheptanecarbonyloxy)- 1 -(pyrazin-2-ylcarbamoylmethyl)- 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- ⁇ [(2S)-3-(5- chloro- 1 ⁇ ,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?)-3-(l-Phenyl-cycloheptanecarbonyloxy)-l-(pyrazin-2- ylcarbamoylmethyl)-l-azonia-bicyclo[2.2.2]octane bromide.
  • the muscarinic receptor antagonist is (i?)-3-(l-Phenyl- cycloheptanecarbonyloxy)- 1 -(pyrazin-2-ylcarbamoylmethyl)- 1 -azonia- bicyclo[2.2.2]octane hemi-naphthalene-l,5-disulfonate.
  • the muscarinic receptor antagonist is (i?)-3-(l-Phenyl- cycloheptanecarbonyloxy)- 1 -(pyrazin-2-ylcarbamoylmethyl)- 1 -azonia- bicyclo[2.2.2]octane chloride.
  • the muscarinic receptor antagonist is (i?)-3-(l-Phenyl-cycloheptanecarbonyloxy)-l-(pyrazin-2- ylcarbamoylmethyl)-l-azonia-bicyclo[2.2.2]octane 2,5-dichlorobenzenesulfonate.
  • the muscarinic receptor antagonist is (i?)-3-(l-Phenyl- cycloheptanecarbonyloxy)-l-(pyridin-2-ylcarbamoylmethyl)-l-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- ⁇ [(2S)-3-(5-chloro-l'H,3H-spiro[l- benzofuran-2,4'-piperidin]- 1 '-yl)-2-hydroxypropyl]oxy ⁇ -4-
  • the muscarinic receptor antagonist is (i?)-3-(l-Phenyl-cycloheptanecarbonyloxy)-l-(pyridin-2-ylcarbamoylmethyl)- l-azonia-bicyclo[2.2.2]octane bromide.
  • the muscarinic receptor antagonist is (i?)-3 -(I -Phenyl-cycloheptanecarbonyloxy)- l-(pyridin-2- ylcarbamoylmethyl)-l-azonia-bicyclo[2.2.2]octane chloride.
  • the muscarinic receptor antagonist is (i?)-3-(l-Phenyl- cycloheptanecarbonyloxy)-l-(pyridin-2-ylcarbamoylmethyl)-l-azonia-bicyclo[2.2.2]octane hemi-naphthalene-l,5-disulfonate.
  • the muscarinic receptor antagonist is (i?)-l-[(5-Fluoro- pyridin-2-ylcarbamoyl)-methyl] -3 -( 1 -phenyl-cycloheptanecarbonyloxy)- 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- ⁇ [(2S)-3-(5- chloro- 1 ⁇ ,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 (R)-I -[(5 -Fluoro-pyridin-2-ylcarbamoyl)-methyl] -3 -(I -phenyl- cycloheptanecarbonyloxy)- 1 -azonia-bicyclo[2.2.2]octane chloride.
  • the muscarinic receptor antagonist is (i?)-3-[l-(3- Fluoro-phenyl)-cycloheptanecarbonyloxy]-l-(isoxazol-3-ylcarbamoylmethyl)-l-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- ⁇ [(2S)-3-(5- chloro- 1 ⁇ ,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?)-3-[l-(3-Fluoro-phenyl)-cycloheptanecarbonyloxy]-l-(isoxazol-3- ylcarbamoylmethyl)-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.
  • acetonide fiunisolide
  • zoticasone flumoxonide
  • rofleponide butixocort (e.g. as propionate ester)
  • prednisolone prednisone
  • tipredane steroid esters e.g.
  • the muscarinic receptor antagonist (i?)-3-(l-Phenyl- cycloheptanecarbonyloxy)- 1 -(pyrazin-2-ylcarbamoylmethyl)- 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 is (i?)-3 -(I -Phenyl-cycloheptanecarbonyloxy)- l-(pyrazin-2- ylcarbamoylmethyl)-l-azonia-bicyclo[2.2.2]octane hemi-naphthalene-l,5-disulfonate.
  • the muscarinic receptor antagonist is (i?)-3-(l-Phenyl- cycloheptanecarbonyloxy)- 1 -(pyrazin-2-ylcarbamoylmethyl)- 1 -azonia- bicyclo[2.2.2]octane chloride.
  • the muscarinic receptor antagonist is (i?)-3 -(I -Phenyl-cycloheptanecarbonyloxy)- l-(pyrazin-2- ylcarbamoylmethyl)-l-azonia-bicyclo[2.2.2]octane 2,5-dichlorobenzenesulfonate. (R)-3- (1 -Phenyl-cycloheptanecarbonyloxy)- 1 -(pyrazin-2-ylcarbamoylmethyl)- 1 -azonia- bicyclo[2.2.2]octane 1 -hydroxy-naphthalene-2-sulfonate.
  • the muscarinic receptor antagonist is (R)-3 -(I -Phenyl- cycloheptanecarbonyloxy)-! -(pyridin-2-ylcarbamoylmethyl)-l-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 is (i?)-3 -(I -Phenyl-cycloheptanecarbonyloxy)- l-(pyridin-2- ylcarbamoylmethyl)-l-azonia-bicyclo[2.2.2]octane bromide.
  • the muscarinic receptor antagonist is (i?)-3-(l-Phenyl- cycloheptanecarbonyloxy)-! -(pyridin-2-ylcarbamoylmethyl)-l-azonia-bicyclo[2.2.2]octane chloride.
  • the muscarinic receptor antagonist is (R)- 3 -( 1 -Phenyl-cycloheptanecarbonyloxy)- 1 -(pyridin-2-ylcarbamoylmethyl)- 1 -azonia- bicyclo[2.2.2]octane hemi-naphthalene- 1 ,5-disulfonate.
  • the muscarinic receptor antagonist is (i?)-l-[(5-Fluoro- pyridin-2-ylcarbamoyl)-methyl] -3 -( 1 -phenyl-cycloheptanecarbonyloxy)- 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 is (i?)-l-[(5-Fluoro-pyridin-2- ylcarbamoyl)-methyl]-3-(l -phenyl-cycloheptanecarbonyloxy)- 1 -azonia- bicyclo[2.2.2]octane chloride.
  • the muscarinic receptor antagonist is (i?)-3-[l-(3- Fluoro-phenyl)-cycloheptanecarbonyloxy]-l-(isoxazol-3-ylcarbamoylmethyl)-l-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 is (i?)-3-[l-(3-Fluoro-phenyl)- cycloheptanecarbonyloxy]-l-(isoxazol-3-ylcarbamoylmethyl)-l-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.
  • 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 to 500 ⁇ g, 50 to to 100
  • 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.
  • satisfactory results will generally be obtained when 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 200mg, 5 to lOOmg, 5 to 50mg, 20 to 1000 mg, 20 to 800mg, 20 to 600mg, 20 to 500mg, 20 to 400mg, 20 to 300mg, 20 to 200mg, 20 to lOOmg, 20 to 50mg, 50 to 1000 mg, 50 to 800mg, 50 to 600mg, 50 to 500mg, 50 to 400mg, 50 to 300mg, 50 to 200mg, 50 to lOOmg, 100 to 1000 mg, 100 to 800mg,
  • 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) 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.
  • the pharmaceutical preparations of active ingredients may be administered simultaneously. In an embodiment 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- C 20 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- C 20 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, raffinose, 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: (a) a (therapeutically effective) dose of a first active ingredient which is a muscarinic antagonist according to the present invention; and
  • 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 that may be incorporated into the present invention 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
  • 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 N-[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 7V-[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 pattern of muscarinic antagonist (i?)-3-(l-Phenyl- cycloheptanecarbonyloxy)- 1 -(pyrazin-2-ylcarbamoylmethyl)- 1 -azonia- bicyclo[2.2.2]octane bromide Crystalline Form A (Example 1).
  • Figure 2 X-ray powder diffraction pattern of muscarinic antagonist (i?)-3-(l-Phenyl- cycloheptanecarbonyloxy)- 1 -(pyrazin-2-ylcarbamoylmethyl)- 1 -azonia- bicyclo[2.2.2]octane chloride Crystalline Form A (Example 2).
  • Figure 3 X-ray powder diffraction pattern of muscarinic antagonist (i?)-3-(l-Phenyl- cycloheptanecarbonyloxy)- 1 -(pyridin-2-ylcarbamoylmethyl)- 1 -azonia- bicyclo[2.2.2]octane chloride Crystalline Form A (Example 3).
  • Figure 4 X-ray powder diffraction pattern of muscarinic antagonist (i?)-3-(l-Phenyl- cycloheptanecarbonyloxy)- 1 -(pyridin-2-ylcarbamoylmethyl)- 1 -azonia- bicyclo[2.2.2]octane bromide Crystalline Form A (Example 4).
  • Figure 5 X-ray powder diffraction pattern of muscarinic antagonist (i?)-3-(l-Phenyl- cycloheptanecarbonyloxy)- 1 -(pyrazin-2-ylcarbamoylmethyl)- 1 -azonia- bicyclo[2.2.2]octane l-hydroxy-naphthalene-2-sulfonate Crystalline Form A (Example 5).
  • Figure 6 X-ray powder diffraction pattern of muscarinic antagonist (i?)-3-(l-Phenyl- cycloheptanecarbonyloxy)- 1 -(pyrazin-2-ylcarbamoylmethyl)- 1 -azonia- bicyclo[2.2.2]octane 2,5-dichloro-benzenesulfonate Crystalline Form A (Example 6).
  • Figure 7 X-ray powder diffraction pattern of muscarinic antagonist (i?)-3-(l-Phenyl- cycloheptanecarbonyloxy)- 1 -(pyrazin-2-ylcarbamoylmethyl)- 1 -azonia- bicyclo[2.2.2]octane hemi-naphthalene- 1 ,5-disulfonate Crystalline Form A
  • Figure 8 X-ray powder diffraction pattern of muscarinic antagonist (i?)-3-(l-Phenyl- cycloheptanecarbonyloxy)- 1 -(pyridin-2-ylcarbamoylmethyl)- 1 -azonia- bicyclo[2.2.2]octane hemi-naphthalene- 1, 5 -disulfonate Crystalline Form A (Example 14)
  • 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.
  • the NMR spectra were measured on a Varian Unity Inova spectrometer at a proton frequency of either 300 or 400 or 500 MHz, or on a Bruker DRX spectrometer at a proton frequency of 400 or 500 MHz, or on a Bruker Avance spectrometer with a proton frequency of 600 MHz or or on a Bruker Avance DPX 300 spectrometer with a proton frequency of 300 MHz.
  • the MS spectra were measured on either an Agilent 1100 MSD G1946D spectrometer or a Hewlett Packard HPl 100 MSD G1946A spectrometer or a Waters Micromass ZQ2000 spectrometer. Names were generated using the Autonom 2000 (version 4.01.305) software supplied by MDL.
  • XRPD data were collected using either a PANalytical CubiX PRO machine or a PANalytical X-Pert machine.
  • Data was collected with a PANalytical CubiX PRO machine in ⁇ - ⁇ configuration over the scan range 2° to 40° 2 ⁇ with 100-second exposure per 0.02° increment.
  • 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 ⁇ 2 mg 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.
  • Data was collected using a PANalytical X-Pert machine in 2 ⁇ - # configuration over the scan range 2° to 40° 2 ⁇ with 100-second exposure per 0.02° increment.
  • the X-rays were generated by a copper long-fine focus tube operated at 45kV and 4OmA.
  • the wavelengths of the copper X-rays was 1.5418 A .
  • the Data was collected on zero background holders on which ⁇ 2 mg 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
  • thermograms were measured using a TA Instruments Q500 TGA Thermogravimetric Analyser, with platinum pans. The sample weights varied between 1 and 5 mg. The procedure was carried out under a flow of nitrogen gas (60 mL/min) and the temperature studied from 25 up to 200-300 0 C at a constant rate of temperature increase of 10 0 C per minute.
  • DSC Differential Scanning Calorimeter
  • GVS Gravimetric vapour sorption
  • HATU O-(7-Azabenzotriazol-l-yl)- ⁇ /, ⁇ /,N',N'-tetramethyluronium hexafluorophospahte MeCN - Acetonitrile
  • Example Ia 1-Phenyl-cycloheptanol (Example Ia) (7.6 g) was dissolved in tetrahydrofuran (100 mL) and sodium hydride (60% in oil, 2.0 g) added. The reaction was stirred at 60 0 C for 5 minutes and iodomethane (7.1 g) added. The mixture was maintained at 60 0 C overnight and then further quantities of sodium hydride (60% in oil, 2.0 g) and iodomethane (7.1 g) were added and the reaction was refluxed for 70 hours. The reaction mixture was partitioned between water (100 mL) and z ' s ⁇ hexane (100 mL) and the organic layer separated, dried (MgSO 4 ) and evaporated to afford the sub-titled compound (11.31 g).
  • Example Ic 1-Phenyl-cycloheptanecarboxylic acid (Example Ic) (4.15 g) was refluxed in methanol (150 mL) and concentrated hydrochloric acid (5 mL) for 24 hours. The solvent was evaporated and the residue was dissolved in ether (100 mL) which was washed with water (100 mL), saturated sodium bicarbonate (50 mL) and water (100 mL), dried (MgSO 4 ) and evaporated to afford the sub-titled compound (3.5 g) as an oil.
  • Example Id 1-Phenyl-cycloheptanecarboxylic acid methyl ester (Example Id) (1.0 g) and (R)- quinuclidin-3-ol (0.39 g) were refluxed in heptane (50 mL) containing sodium ( ⁇ 5 mg) in a Dean and Stark apparatus for 24 hours. Heptane (20 mL) was replaced with toluene (20 mL) and the reflux was continued for 3 days. The reaction was partitioned between water (50 mL) and ether (50 mL) and the ether layer was separated, dried (MgSO 4 ) and evaporated. The crude product was purified by column chromatography on silica eluting with ethyl acetate / triethylamine (99/1) to afford the titled compound as an oil (0.83 g).
  • Example 1 (if)-3-(l-Phenyl-cycloheptanecarbonyloxy)-l-(pyrazin-2- ylcarbamoylmethyl)-l-azonia-bicyclo[2.2.2]octane bromide Crystalline Form A
  • Example 1 (if)-3-(l-Phenyl-cycloheptanecarbonyloxy)-l-(pyrazin-2- ylcarbamoylmethyl)-l-azonia-bicyclo[2.2.2]octane bromide Crystalline Form A
  • Example 1 Crystalline Form A obtained by the procedure described above was analysed by XRPD (PANalytical X'Pert or CubiX system), DSC and TGA.
  • Example 1 bromide Form A as determined by DSC was found to be 202 0 C (onset) ( ⁇ 2°C). Weight loss observed prior to melting by TGA was 2.7%. GVS determination gave a 3% weight increase (%w/w) at 80% RH ( ⁇ 0.2%).
  • Example 2 (R)-3-(l-Phenyl-cycloheptanecarbonyloxy)-l-(pyrazin-2- ylcarbamoylmethyl)-l-azonia-bicyclo[2.2.2] octane chloride
  • Example 2 (if)-3-(l-Phenyl-cycloheptanecarbonyloxy)-l-(pyrazin-2- ylcarbamoylmethyl)-l-azonia-bicyclo[2.2.2]octane chloride Crystalline Form A
  • Example 2 (if)-3-(l-Phenyl-cycloheptanecarbonyloxy)-l-(pyrazin-2- ylcarbamoylmethyl)-l-azonia-bicyclo[2.2.2]octane chloride Crystalline Form A
  • Example 2 Crystalline Form A obtained by the procedure described above was analysed by XRPD (PANalytical X'Pert or CubiX system), DSC and TGA.
  • Example 2 chloride Form A as determined by DSC was found to be 215°C (onset) ( ⁇ 2°C). GVS determination gave a 9% weight increase (%w/w) at 80% RH ( ⁇ 0.2%).
  • Phenylmagnesium bromide (3.0M solution in diethyl ether) (271 mL), was added dropwise to a stirred (overhead stirrer) solution of cycloheptanecarbonitrile (50 g) in 229 mL diethyl ether under nitrogen at such a rate as to maintain gentle reflux. The reaction mixture was then heated at reflux for 3 hours. TLC indicated no starting material present in the reaction mixture. The reaction mixture was allowed to cool to room temperature and stood under nitrogen overnight. The reaction mixture was cooled to 0 0 C and treated dropwise with 102 mL 4N HCl(aq) keeping the temperature below 20 0 C.
  • Example 3 (if)-3-(l-Phenyl-cycloheptanecarbonyloxy)-l-(pyridin-2- ylcarbamoylmethyl)-l-azonia-bicyclo[2.2.2]octane chloride Crystalline Form A
  • Example 3 Crystalline Form A obtained by the procedure described above was analysed by XRPD (PANalytical X'Pert system), DSC and TGA.
  • Example 3 chloride Form A as determined by DSC was found to be 239°C (onset) ( ⁇ 2°C). Weight loss observed prior to melting by TGA was negligible. GVS determination gave a neglible weight increase (%w/w) at 80% RH ( ⁇ 0.2%).
  • Example 4 (R)-3-(l-Phenyl-cycloheptanecarbonyloxy)-l-(pyridin-2- ylcarbamoylmethyl)-l-azonia-bicyclo[2.2.2] octane bromide
  • Example 4 (if)-3-(l-Phenyl-cycloheptanecarbonyloxy)-l-(pyridin-2- ylcarbamoylmethyl)-l-azonia-bicyclo[2.2.2]octane bromide Crystalline Form A
  • Example 4 Crystalline Form A obtained by the procedure described above was analysed by XRPD (PANalytical X'Pert system), DSC and TGA.
  • Example 4 bromide Form A as determined by DSC was found to be 230 0 C (onset) ( ⁇ 2°C). Weight loss observed prior to melting by TGA was negligible. GVS determination gave a neglible weight increase (%w/w) at 80% RH ( ⁇ 0.2%).
  • Example 5 (if)-3-(l-Phenyl-cycloheptanecarbonyloxy)-l-(pyrazin-2- ylcarbamoylmethyl)-l-azonia-bicyclo[2.2.2]octane l-hydroxy-naphthalene-2- sulfonate Crystalline Form A
  • Example 5 (if)-3-(l-Phenyl-cycloheptanecarbonyloxy)-l-(pyrazin-2- ylcarbamoylmethyl)-l-azonia-bicyclo[2.2.2]octane l-hydroxy-naphthalene-2- sulfonate Crystalline Form A
  • Example 5 Crystalline Form A obtained by the procedure described above was analysed by XRPD (PANalytical X'Pert or CubiX system) and DSC.
  • Example 5 l-hydroxy-naphthalene-2-sulfonate Form A as determined by DSC was found to be 193°C (onset) ( ⁇ 2°C). GVS determination gave a neglible weight increase, near 0.3% (%w/w) at 80% RH ( ⁇ 0.2%).
  • An XRPD spectrum of Example 5 l-hydroxy-naphthalene-2-sulfonate Form A is presented in Figure 5.
  • Example 6 (if)-3-(l-Phenyl-cycloheptanecarbonyloxy)-l-(pyrazin-2- ylcarbamoylmethyrj-l-azonia-bicyclo ⁇ ] octane 2,5-dichloro-benzenesulfonate Crystalline Form A
  • Example 6 (if)-3-(l-Phenyl-cycloheptanecarbonyloxy)-l-(pyrazin-2- ylcarbamoylmethyl)-l-azonia-bicyclo[2.2.2] octane 2,5-dichloro-benzenesulfonate Crystalline Form A
  • XRPD PANalytical X'Pert system
  • DSC DSC
  • Example 6 2,5-dichloro-benzenesulfonate Form A as determined by DSC was found to be 158°C (onset) ( ⁇ 2°C). GVS determination gave a neglible weight increase, near 0.2% (%w/w) at 80% RH ( ⁇ 0.2%).
  • Example 7 (if)-3-(l-Phenyl-cycloheptanecarbonyloxy)-l-(pyrazin-2- ylcarbamoylmethyO-l-azonia-bicyclo ⁇ .l.l] octane hemi-naphthalene-l,5-disulfonate Crystalline Form A
  • Example 7 (if)-3-(l-Phenyl-cycloheptanecarbonyloxy)-l-(pyrazin-2- ylcarbamoylmethyO-l-azonia-bicyclo ⁇ .l.l] octane hemi-naphthalene-l,5-disulfonate Crystalline Form A
  • Example 7 Crystalline Form A obtained by the procedure described above was analysed by XRPD (PANalytical X'Pert or CubiX system) and DSC.
  • Example 7 hemi-naphthalene-l,5-disulfonate Form A as determined by DSC was found to be 222°C (onset) ( ⁇ 2°C). GVS determination gave a 1.6% weight increase (%w/w) at 80% RH ( ⁇ 0.2%).
  • Example 8a To 2-but-3-enyl-2-(3-fluoro-phenyl)-hex-5-enoic acid methyl ester (Example 8a) (5.0 g) in dichloromethane (100 mL) was added Grubbs Catalyst (2nd Generation, Sigma- Aldrich Company Ltd) (0.05 g). The mixture was warmed to reflux under nitrogen. After 20 hours the reaction was cooled to room temperature, evaporated to an oil and purified by column chromatography on silica eluting with ethyl acetate / z ' s ⁇ hexane (5 / 95) to yield an oil. Analysis of the product showed that significant amounts of starting material was present in the mixture so the mixture was subjected to a repetition of the reaction conditions and purification as above to afford the subtitled compound as a coloured oil (3.60 g).
  • Example 8c H l-(3-Fluoro-phenyl)-cycloheptanecarboxylic acid methyl ester (0.280 g) was dissolved in toluene (100 mL) and (i?)-quinuclidin-3-ol (0.320 g) was added. Toluene (10 mL) was distilled off in a Dean and Stark apparatus and after cooling sodium hydride (10 mg) was added. The reaction was refluxed in a Dean and Stark apparatus for 4 hours after which time an extra amount of sodium hydride (10 mg) was added and the reaction was refluxed for a further for 4 hours.
  • Example 14 (R)-3-(l-Phenyl-cycloheptanecarbonyloxy)-l-(pyridin-2- ylcarbamoylmethyO-l-azonia-bicyclo ⁇ .l.l] octane hemi-naphthalene-l,5-disulfonate Crystalline Form A
  • Example 14 (R)-3-(l-Phenyl-cycloheptanecarbonyloxy)-l-(pyridin-2- ylcarbamoylmethyl)-l-azonia-bicyclo[2.2.2] octane hemi-naphthalene-l,5-disulfonate Crystalline Form A
  • Example 14 Crystalline Form A obtained by the procedure described above was analysed by XRPD (PANalytical X'Pert or CubiX system) and DSC.
  • Example 14 hemi-naphthalene-l,5-disulfonate Form A as determined by DSC was found to be 198°C (onset) ( ⁇ 2°C). GVS determination gave a 1% weight increase (%w/w) at 80% RH ( ⁇ 0.3%).
  • Cycloheptanecarboxylic acid (3.75kg) and methanol (37.50 L) were charged to a reaction vessel and the resultant mixture stirred.
  • Sulfuric Acid (100%, 51.73 g) was charged, the temperature raised to 60 0 C and stirring continued for 18 hours.
  • Methanol was removed by distillation under reduced pressure to leave a total volume of 11.25L.
  • Toluene (37.50 L) was charged and a further 15L of solvent removed by distillation under reduced pressure. Analysis by 1 H NMR spectroscopy was carried out to confirm that methanol was no longer present in the solution.
  • the mixture was allowed to cool to ambient temperature and diluted with toluene (7.50 L). Saturated aqueous sodium bicarbonate (18.75L) was charged.
  • reaction mixture was stirred for 15 min, then stirring stopped and the layers allowed to separate.
  • the lower aqueous layer was removed to waste.
  • Saturated aqueous sodium chloride (18.75 L) was charged.
  • the reaction mixture was stirred for 15 min, then stirring stopped and the layers allowed to separate.
  • the lower aqueous layer was removed to waste.
  • the crude product solution was dried by azeotropic distillation under reduced pressure to remove 7.5L of toluene, giving 28.3kg of a 14.08% w/w toluene solution of cycloheptanecarboxylic acid methyl ester.
  • Diisopropylamine (3.44 kg) and toluene (16.52 kg) were charged to a first reaction vessel and cooled to 0 0 C with stirring.
  • N-Hexyllithium (8.81 kg, 33%w/w) was added, maintaining a temperature of 5 0 C ⁇ 5°C.
  • the mixture was stirred for 20min at this temperature.
  • Cycloheptanecarboxylic acid methyl ester (14.08% w/w in toluene; 26.93 kg) was first concentrated by removal of 11.37L of toluene by distillation under reduced pressure, then charged to the first reaction vessel, maintaining a temperature of 5 0 C ⁇ 5°C.
  • the crude product was collected by filtration and washed with water (31.60 L), then dispersed in methanol (37.41 L) and water (9.35 L). The mixture was heated with stirring to 62 0 C at a rate of 1 °C/min then cooled to 5 0 C at a rate of 0.3 °C/min and held at 5 0 C overnight. The product was collected by filtration, washed with water (2 x 12.64 L) and dried in a vacuum oven at 40 0 C for 72 hours to give 1- Phenyl-cycloheptanecarboxylic acid (5.60 kg).
  • the inhibitory effects of compounds of the muscarinic antagonists were determined by a Muscarinic Receptor Radioligand Binding Assay.
  • Radioligand binding studies utilising [ 3 H]-N-methyl scopolamine ([ 3 H]-NMS) and commercially available cell membranes expressing the human muscarinic receptors (M2 or M3) were used to assess the affinity of muscarinic antagonists for M2 and M3 receptors.
  • Membranes in TRIS buffer were incubated in 96-well plates with [ 3 H]-NMS and M3 antagonist at various concentrations for 3 hours. Membranes and bound radioligand were then harvested by filtration and allowed to dry overnight. Scintillation fluid was then added and the bound radioligand counted using a Canberra Packard Topcount scintillation counter
  • the half-life of antagonists at each muscarinic receptor was measured using the alternative radioligand [ 3 H]-QNB and an adaptation of the above affinity assay. Antagonists were incubated for 3 hours at a concentration 10-fold higher than their Ki, as determined with the [ 3 H]-QNB ligand, with membranes expressing the human muscarinic receptors. At the end of this time, [ 3 H]-QNB was added to a concentration 25 -fold higher than its Kd for the receptor being studied and the incubation continued for various time periods from 15 minutes up to 180 minutes. Membranes and bound radioligand were then harvested by filtration and allowed to dry overnight.
  • Table 2 gives IC50 strengths for the compounds of the examples.
  • the following protocol may be used to evaluate the effects of muscarinic M3 receptor antagonists according to the present invention in combination with budesonide.
  • 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 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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Abstract

L'invention concerne un produit pharmaceutique, un kit ou une composition comprenant un premier principe actif qui est un antagoniste du récepteur muscarinique sélectionné, et un deuxième principe actif qui est sélectionné parmi un inhibiteur de phosphodiestérase, un modulateur de la fonction du récepteur des chimiokines, un inhibiteur de la fonction kinase, un inhibiteur de protéase, un antagoniste stéroïdien du récepteur des glucocorticoïdes, un agoniste non-stéroïdien du récepteur des glucocorticoïdes et un antagoniste de purinocepteur, à utiliser dans le traitement de maladies respiratoires de type maladie pulmonaire obstructive chronique ou asthme.
PCT/SE2009/050524 2008-05-13 2009-05-12 Produit pharmaceutique comprenant un antagoniste du récepteur muscarinique et un deuxième principe actif Ceased WO2009139707A1 (fr)

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Cited By (2)

* 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

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004096800A2 (fr) * 2003-05-02 2004-11-11 Novartis Ag Composes organiques
WO2007015664A1 (fr) * 2005-08-01 2007-02-08 Astrazeneca Ab Nouveaux dérivés de pipéridine en tant que modulateurs de récepteur de chimiokine utiles pour le traitement des affections respiratoires
WO2007015667A1 (fr) * 2005-08-02 2007-02-08 Astrazeneca Ab Nouveau sel ii
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

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004096800A2 (fr) * 2003-05-02 2004-11-11 Novartis Ag Composes organiques
WO2007015664A1 (fr) * 2005-08-01 2007-02-08 Astrazeneca Ab Nouveaux dérivés de pipéridine en tant que modulateurs de récepteur de chimiokine utiles pour le traitement des affections respiratoires
WO2007015667A1 (fr) * 2005-08-02 2007-02-08 Astrazeneca Ab Nouveau sel ii
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

Cited By (2)

* 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

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