WO2009154555A1 - Produit pharmaceutique comprenant un antagoniste du récepteur muscarinique et un agoniste du béta2-adrénocepteur - Google Patents

Produit pharmaceutique comprenant un antagoniste du récepteur muscarinique et un agoniste du béta2-adrénocepteur Download PDF

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WO2009154555A1
WO2009154555A1 PCT/SE2009/050743 SE2009050743W WO2009154555A1 WO 2009154555 A1 WO2009154555 A1 WO 2009154555A1 SE 2009050743 W SE2009050743 W SE 2009050743W WO 2009154555 A1 WO2009154555 A1 WO 2009154555A1
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ethyl
phenyl
active ingredient
piperidin
hydroxy
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PCT/SE2009/050743
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English (en)
Inventor
Antonio Mete
Ian Millichip
Katherine Wiley
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Astrazeneca Ab
Argenta Discovery Ltd.
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Publication of WO2009154555A1 publication Critical patent/WO2009154555A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • 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
    • 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.
  • Therapeutic agents used in the treatment of respiratory diseases include ⁇ 2 -adrenoceptor agonists. These agents (also known as beta2 ( ⁇ 2 ) - agonists) may be used to alleviate symptoms of respiratory diseases by relaxing the bronchial smooth muscles, reducing airway obstruction, reducing lung hyperinflation and decreasing shortness of breath. Compounds currently under evaluation as once-daily ⁇ 2 agonists are described in Expert Opin. Investig. Drugs 14 (7), 775-783 (2005).
  • a further class of therapeutic agent used in the treatment of respiratory diseases are muscarinic antagonists.
  • Muscarinic receptors are a G-protein coupled receptor (GPCR) family having five family members M 1 , M 2 , M 3 , M 4 and M 5 . Of the five muscarinic subtypes, three (M 1 , M 2 and M 3 ) are known to exert physiological effects on human lung tissue.
  • 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
  • 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 ⁇ 2 - adrenoceptor agonist.
  • 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 (WO2008/075005), 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, toluenesulfonate (tosylate or 4-methylbenzenesulphonate), edisylate (ethane- 1 ,2-disulfonate), isethionate (2-hydroxyethylsulfonate), nitrate or phosphate; or an anion of a suitable organic acid, for example acetate, maleate, fumarate, citrate, lactate, oxalate, oleic, succinate, tartrate, methanesulphonate (mesylate), p- toluenesulphonate, benzenes
  • heminapadisylate maleate ((Z)-3-carboxy-acrylate), succinate (3-carboxy-propionate), malate ((5)-3-carboxy -2-hydroxy-propionate), p-acetamidobenzoate, 2,5- dichlorobenzenesulphonate, l-hydroxy-2-naphthoate (xinafoate) or 1-hydroxynaphthalene- 2-sulphonate.
  • 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. In an embodiment of the invention, 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-((5)-2-phenyl-2-piperidin- 1 -yl-propionyloxy)- 1 - azonia-bicyclo[2.2.2]octane bromide; and (i?)-l-[3-(2-Methyl-pyridin-4-yl)-propyl]-3-((5)-2-phenyl-2-piperidin-l-yl-propionyloxy)- 1 -azonia-bicyclo [2.2.2]octane bromide .
  • the second active ingredient in the combination of the present invention is a ⁇ 2 - adrenoceptor agonist.
  • the ⁇ 2 -adrenoceptor agonist of the present invention may be any compound or substance capable of stimulating the ⁇ 2 -receptors and acting as a bronchodilator.
  • any reference to a ⁇ 2 -adrenoceptor agonist includes active salts, solvates or derivatives that may be formed from said ⁇ 2 -adrenoceptor agonist and any enantiomers and mixtures thereof.
  • Examples of possible salts or derivatives of ⁇ 2 -adrenoceptor agonist are acid addition salts such as the salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, l-hydroxy-2-naphthalenecarboxylic acid, maleic acid, and pharmaceutically acceptable esters (e.g. Ci-C 6 alkyl esters).
  • the ⁇ 2 -agonists may also be in the form of solvates, e.g. hydrates.
  • Examples of a ⁇ 2 -adrenoceptor agonist that may be used in the pharmaceutical product according to this embodiment include metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol (e.g. as sulphate), formoterol (e.g. as fumarate), salmeterol (e.g. as xinafoate), terbutaline, orciprenaline, bitolterol (e.g. as mesylate), pirbuterol or indacaterol.
  • the ⁇ 2 -adrenoceptor agonist of this embodiment may be a long-acting ⁇ 2 -agonist (i.e.
  • a ⁇ 2 - agonist with activity that persists for more than 24 hours for example salmeterol (e.g. as xinafoate), formoterol (e.g. as fumarate), bambuterol (e.g. as hydrochloride), carmoterol (TA 2005, chemically identified as 2(1H)-Quinolone, 8-hydroxy-5-[l-hydroxy-2-[[2-(4- methoxy-phenyl)-l-methylethyl]-amino]ethyl]-monohydrochloride, [R-(R*, R*)] also identified by Chemical Abstract Service Registry Number 137888-11-0 and disclosed in U.S.
  • salmeterol e.g. as xinafoate
  • formoterol e.g. as fumarate
  • bambuterol e.g. as hydrochloride
  • carmoterol TA 2005, chemically identified as 2(1H)-Quinolone, 8
  • Patent No 4,579,854 indacaterol (CAS no 312753-06-3; QAB-149), formanilide derivatives e.g. 3-(4- ⁇ [6-( ⁇ (2R)-2-[3-(formylamino)-4-hydroxyphenyl]-2- hydroxyethyl ⁇ amino)hexyl]oxy ⁇ -butyl)-benzenesulfonamide as disclosed in WO 2002/76933, benzenesulfonamide derivatives e.g.
  • the ⁇ 2 -adrenoceptor agonist of the present invention is not A/-Cyclohexyl-N 3 -[2-(3- fluorophenyl)ethyl]- ⁇ /-(2- ⁇ [2-(4-hydroxy-2-oxo-2,3-dihydro-l,3-benzothiazol-7- yl)ethyl] amino ⁇ ethyl)- ⁇ -alaninamide or a salt thereof.
  • the ⁇ 2 -adrenoceptor agonist is formoterol.
  • the chemical name for formoterol is 7V-[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- [(I R)-I- hydroxy-2-[[(lR)-2-(4-methoxyphenyl)-l-methylethyl]amino]ethyl]phenyl]-formamide, N- [2-hydroxy-5-[(lS)-l-hydroxy-2-[[(lS)-2-(4-methoxyphenyl)-l- methylethyl]amino]ethyl]phenyl]-formamide and a mixture of such enantiomers, including a racemate.
  • the ⁇ 2 -adrenoceptor agonist is selected from: ⁇ /-[2-(Diethylamino)ethyl]-N-(2- ⁇ [2-(4-hydroxy-2-oxo-2,3-dihydro-l,3-benzothiazol-7- yl)ethyl] amino ⁇ ethyl)-3 -[2-(I -naphthyl)ethoxy]propanamide,
  • the ⁇ 2 -adrenoceptor agonists according to this embodiment may be prepared as described in the experimental preparation section of the present application.
  • the names of the ⁇ 2 -adrenoceptor agonists of this embodiment are IUPAC names generated by the IUPAC NAME, ACD Labs Version 8 naming package.
  • the ⁇ 2 -adrenoceptor agonist is selected from: N-[2-(Diethylamino)ethyl]-N-(2- ⁇ [2-(4-hydroxy-2-oxo-2,3-dihydro-l,3-benzothiazol-7- yl)ethyl] amino ⁇ ethyl)-3 -[2-(I -naphthyl)ethoxy]propanamide dihydrobromide, N-[2-(Diethylamino)ethyl]-N-(2- ⁇ [2-(4-hydroxy-2-oxo-2,3-dihydro-l,3-benzothiazol-7- yl)ethyl] amino ⁇ ethyl)-3 - [2-(3 -chlorophenyl)ethoxy]propanamide dihydrobromide, and 7-[( ⁇ R)-2-( ⁇ 2-[(3- ⁇ [2-(3- ⁇ [2-(3
  • 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 ⁇ 2-adrenoceptor agonist is formoterol (e.g. as fumarate).
  • 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 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, and the ⁇ 2-adrenoceptor agonist is formoterol (e.g. as fumarate).
  • 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 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 ⁇ 2-adrenoceptor agonist is N-[2-(Diethylamino)ethyl]-7V- (2- ⁇ [2-(4-hydroxy-2-oxo-2,3-dihydro-l,3-benzothiazol-7-yl)ethyl]amino ⁇ ethyl)-3-[2-(l- naphthyl)ethoxy]propanamide or a pharmaceutically acceptable salt thereof (e.g.
  • the muscarinic receptor antagonist is (R)- 1 -[2-(4-Fluoro-phenyl)-ethyl]-3-((5)-2-phenyl-2-piperidin- 1 -yl-propionyloxy)- 1 - 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 4-methylbenzenesulphonate.
  • 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 bromide and the ⁇ 2 -adrenoceptor agonist is N-[2- (Diethylamino)ethyl]-N-(2- ⁇ [2-(4-hydroxy-2-oxo-2,3-dihydro-l,3-benzothiazol-7- yl)ethyl] amino ⁇ ethyl)-3 - [2-( 1 -naphthy l)ethoxy]propanamide dihydrobromide.
  • 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 4-methylbenzene sulphonate and the ⁇ 2 -adrenoceptor agonist is N-[2- (Diethylamino)ethyl]- ⁇ /-(2- ⁇ [2-(4-hydroxy-2-oxo-2,3-dihydro-l,3-benzothiazol-7- yl)ethyl] amino ⁇ ethyl)-3 - [2-( 1 -naphthy l)ethoxy]propanamide dihydrobromide.
  • 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 ⁇ 2-adrenoceptor agonist is N-[2-(Diethylamino)ethyl]-7V- (2- ⁇ [2-(4-hydroxy-2-oxo-2,3-dihydro-l,3-benzothiazol-7-yl)ethyl]amino ⁇ ethyl)-3-[2-(l- naphthyl)ethoxy]propanamide or a pharmaceutically acceptable salt thereof (e.g.
  • the muscarinic receptor antagonist is (R)- 1 -[3-(2-Methyl-pyridin-4-yl)-propyl]-3-((5)-2-phenyl-2-piperidin- 1 -yl-propionyloxy)- 1 -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 ⁇ 2 -adrenoceptor agonist is 7-[(li?)-2-( ⁇ 2-[(3- ⁇ [2-(2- Chlorophenyl)ethyl] amino ⁇ propyl)thio]ethyl ⁇ amino)- 1 -hydroxy ethyl] -4-hydroxy- 1,3- benzothiazol-2(3H)-one or a pharmaceutically acceptable salt thereof (e.g.
  • the muscarinic receptor antagonist is (R)- 1 -[2-(4-Fluoro-phenyl)-ethyl]-3-((5)-2-phenyl-2-piperidin- 1 -yl-propionyloxy)- 1 - 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 ⁇ 2-adrenoceptor agonist is 7-[(li?)-2-( ⁇ 2-[(3- ⁇ [2-(2- Chlorophenyl)ethyl] amino ⁇ propyl)thio]ethyl ⁇ amino)- 1 -hydroxy ethyl] -4-hydroxy- 1,3- benzothiazol-2(3H)-one or a pharmaceutically acceptable salt thereof (e.g.
  • the muscarinic receptor antagonist is (R)- 1 -[3-(2-Methyl-pyridin-4-yl)-propyl]-3-((5)-2-phenyl-2-piperidin- 1 -yl-propionyloxy)- 1 -azonia-bicyclo [2.2.2]octane bromide .
  • 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 ⁇ 2 -adrenoceptor agonist (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 formulations.
  • These dosage forms will usually include one or more pharmaceutically acceptable ingredients which may be selected, for example, from adjuvants, carriers, binders, lubricants, diluents, stabilising agents, buffering agents, emulsifying agents, viscosity- regulating agents, surfactants, preservatives, flavourings and colorants.
  • pharmaceutically acceptable ingredients may be selected, for example, from adjuvants, carriers, binders, lubricants, diluents, stabilising agents, buffering agents, emulsifying agents, viscosity- regulating agents, surfactants, preservatives, flavourings and colorants.
  • the active ingredients are administered via separate pharmaceutical preparations.
  • 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 which is a ⁇ 2 -adrenoceptor agonist, 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, which is a ⁇ 2 -adrenoceptor agonist.
  • compositions of the present invention may be prepared by mixing the muscarinic antagonist (first active ingredient) with a ⁇ 2 -adrenoceptor agonist (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 ⁇ 2 -adrenoceptor agonist 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 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 1000 ⁇ g, 50 to 100 ⁇ g,
  • the ⁇ 2 -adrenoceptor agonist may conveniently be administered by inhalation.
  • the dose of the ⁇ 2 -agonist 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 present invention provides a pharmaceutical product comprising, in combination, a first active ingredient which is a muscarinic antagonist according to the present invention, and a second active ingredient which is a ⁇ 2 -adrenoceptor agonist, 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 wherein each active ingredient is formulated for oral administration.
  • the pharmaceutical preparations of active ingredients may be administered simultaneously
  • the different pharmaceutical preparations of active ingredients may be administered sequentially. In one embodiment, 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 formulations.
  • Dry powder formulations 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 2 O 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 2 O 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, raffmose, 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.
  • Another possibility is to process the finely divided powder into spheres which break up during the inhalation procedure.
  • 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 treatment of a respiratory disease, in particular chronic obstructive pulmonary disease or asthma.
  • the present invention further provides the use of a pharmaceutical product, kit or pharmaceutical composition according to the invention in the manufacture of a medicament for the treatment of a respiratory disease, in particular chronic obstructive pulmonary disease or asthma.
  • the present invention still further provides a method of treating a respiratory disease which comprises simultaneously, sequentially or separately administering:
  • the term “therapy” also includes “prophylaxis” unless there are specific indications to the contrary.
  • the terms “therapeutic” and “therapeutically” should be construed accordingly. Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the condition or disorder in question. Persons at risk of developing a particular condition or disorder generally include those having a family history of the condition or disorder, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the condition or disorder.
  • the 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.
  • a third active ingredient that may be incorporated into the present invention include
  • Examples of a phosphodiesterase inhibitor that may be used as a third active ingredient according to this embodiment include a PDE4 inhibitor such as an inhibitor of the isoform
  • PDE4D a PDE3 inhibitor
  • PDE5 inhibitor examples include the compounds
  • Examples of a modulator of chemokine receptor function that may be used as a third active ingredient according to this embodiment include a CCR3 receptor antagonist, a CCR4 receptor antagonist, a CCR5 receptor antagonist and a CCR8 receptor antagonist.
  • Examples of an inhibitor of kinase function that may be used as a third active ingredient according to this embodiment include a p38 kinase inhibitor and an IKK inhibitor.
  • protease inhibitor examples include an inhibitor of neutrophil elastase or an inhibitor of MMP 12.
  • Examples of a steroidal glucocorticoid receptor agonist that may be used as a third active ingredient according to 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.
  • Examples of a modulator of a non-steroidal glucocorticoid receptor agonist that may be used as a third active ingredient according to this embodiment include those described in WO2006/046916.
  • Figure 1 X-ray powder diffraction (XRPD) pattern of muscarinic antagonist (7?)-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.
  • Figure 2 X-ray powder diffraction (XRPD) pattern of muscarinic antagonist (i?)-l-[2-(4-
  • Figure 3 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 4-methylbenzene sulphonate.
  • XRPD X-ray powder diffraction
  • Figure 4 Percentage relaxation to indacaterol (1OnM), (i?)-l-[2-(4-Fluoro-phenyl)-ethyl]- 3-((iS)-2-phenyl-2-piperidin- 1 -yl-propionyloxy)- 1 -azonia-bicyclo[2.2.2]octane bromide (InM) and the combination of indacaterol (1OnM) and (i?)-l-[2-(4- Fluoro-phenyl)-ethyl]-3-((5)-2-phenyl-2-piperidin- 1 -yl-propionyloxy)- 1 -azonia- bicyclo[2.2.2]octane bromide (InM) in guinea pig trachea in vitro.
  • 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.
  • 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 G1946D spectrometer or a Hewlett Packard HPl 100 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
  • XRPD X-Ray Powder Diffraction
  • HATU O-(7-Azabenzotriazol-l-yl)- ⁇ /, ⁇ /,N',N'-tetramethyluronium hexafluorophospahte
  • 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.
  • 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 Form A (R)-l-[2-(4-Fluoro-phenyl)-ethyl]-3-((S)-2-phenyl-2- piperidin-l-yl-propionyloxyj-l-azonia-bicyclo [2.2.2] octane bromide (Form A)
  • XRPD PANalytical X'Pert or Cubix system
  • GVS GVS
  • DSC 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 Form C (R)-l-[2-(4-Fluoro-phenyl)-ethyl]-3-((S)-2-phenyl-2- piperidin-l-yl-propionyloxyj-l-azonia-bicyclo [2.2.2] octane bromide (Form C)
  • XRPD PANalytical X'Pert or Cubix system
  • GVS GVS
  • DSC DSC and TGA.
  • 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
  • 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;
  • Example 57 the measured human plasma protein binding figure using the procedure described above was 98% bound. Methacholine Induced Bronchoconstriction in vivo
  • 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.
  • 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.
  • ⁇ 2 -adrenoceptor agonists that may be employed in the combination of the present invention may be prepared as follows.
  • ⁇ 2 -adrenoceptor agonists and the intermediates used in their preparation are herein named, based upon the structures depicted, using the IUPAC NAME, ACD Labs Version 8 naming package.
  • the aqueous layer was subsequently acidified (using IM hydrochloric acid) and extracted with ether (2 x 30 mL). The combined organics were washed with brine (20 mL), dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to give the sub-titled compound (5.66 g) as a clear oil.
  • Oxalyl chloride (0.33 g) was added dropwise to a solution of 3 -[2-(I - naphthyl)ethoxy]propanoic acid (0.53 g) in dichloromethane (10 mL), dimethylformamide (1 drop) was added and stirring continued at room temperature for 1 hour. The mixture was subsequently concentrated, re-dissolved in dichloromethane (10 mL) and added dropwise to a solution of 2-(2-diethylaminoethylamino)ethanol (0.35 g) and diisopropylethylamine (0.56 g) in dichloromethane (10 mL).
  • Triethylamine (0.29 g) was added and the reaction allowed to warm to room temperature over 1 hour, the mixture was subsequently diluted (dichloromethane 30 mL), the organics washed with sodium bicarbonate (20 mL), brine (20 mL), dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to give the sub-titled compound (0.21 g).
  • Oxalyl chloride (151 mL) was added dropwise over 45 minutes to a solution of 3-[2-(l- naphthyl)ethoxy]propanoic acid (389 g) (Example 7 step b)) in dichloromethane (2.1 L) and DMF (0.5 mL). The reaction mixture was stirred for a further 16 hours. The mixture was subsequently concentrated, redissolved in DCM (1.7 L) and added dropwise over 1.75 hours at O 0 C to a solution of ⁇ /'-(2,2-dimethoxyethyl)-N, ⁇ /-diethylethane-l,2-diamine (325 g) and isopropyldiethylamine (551 mL) in DCM (1.7 L).
  • Aluminium hydride was prepared by the drop-wise addition of a solution of sulphuric acid (8.40 mL) in dry THF (60 mL) to a stirred solution of 1.0M lithium aluminium hydride in THF (314 mL), at 0-10 0 C, under a nitrogen atmosphere. After stirring at 5 0 C for 30 minutes, a solution of l-chloro-2-[(£)-2-nitrovinyl]benzene (12.83 g) in dry THF (160 mL) was added dropwise maintaining the internal temperature between O 0 C and 1O 0 C. When the addition was complete the reaction was heated at reflux for 5 minutes.
  • the reaction mixture was diluted with ethyl acetate, washed with water, then IN HCl, then saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered and the solvents removed in vacuo.
  • the material was purified by silica column chromatography eluting with 20% ethyl acetate in isohexane to give the desired material (12.43 g).
  • H292 cells were grown in 225cm2 flasks incubator at 37 0 C, 5% CO 2 in RPMI medium containing, 10% (v/v) FBS (foetal bovine serum) and 2 mM L-glutamine.
  • Adherent H292 cells were removed from tissue culture flasks by treatment with AccutaseTM cell detachment solution for 15 minutes. Flasks were incubated for 15 minutes in a humidified incubator at 37 0 C, 5% CO 2 . Detached cells were re-suspended in RPMI media (containing 10% (v/v) FBS and 2 mM L-glutamine) at 0.05 x 10 6 cells per mL. 5000 cells in 100 ⁇ L were added to each well of a tissue-culture-treated 96-well plate and the cells incubated overnight in a humidified incubator at 37 0 C, 5% CO 2 .
  • the culture media was removed and cells were washed twice with 100 ⁇ L assay buffer and replaced with 50 ⁇ L assay buffer (HBSS solution containing 1OmM HEPES pH7.4 and 5 mM glucose). Cells were rested at room temperature for 20 minutes after which time 25 ⁇ L of rolipram (1.2 mM made up in assay buffer containing 2.4% (v/v) dimethylsulphoxide) was added. Cells were incubated with rolipram for 10 minutes after which time Compound A was added and the cells were incubated for 60 minutes at room temperature. The final rolipram concentration in the assay was 300 ⁇ M and final vehicle concentration was 1.6% (v/v) dimethylsulphoxide. The reaction was stopped by removing supernatants, washing once with 100 ⁇ L assay buffer and replacing with 50 ⁇ L lysis buffer. The cell monolayer was frozen at -80 0 C for 30 minutes (or overnight).
  • AlphaScreenTM cAMP detection The concentration of cAMP (cyclic adenosine monophosphate) in the cell lysate was determined using AlphaScreenTM methodology. The frozen cell plate was thawed for 20 minutes on a plate shaker then 10 ⁇ L of the cell lysate was transferred to a 96-well white plate. 40 ⁇ L of mixed AlphaScreenTM detection beads pre-incubated with biotinylated cAMP, was added to each well and the plate incubated at room temperature for 10 hours in the dark. The AlphaScreenTM signal was measured using an En Vision spectrophotometer (Perkin-Elmer Inc.) with the recommended manufacturer's settings.
  • En Vision spectrophotometer Perkin-Elmer Inc.
  • cAMP concentrations were determined by reference to a calibration curve determined in the same experiment using standard cAMP concentrations.
  • a concentration response curve for Compound A was constructed and data was fitted to a four parameter logistic equation to determine both the PEC50 and Intrinsic Activity.
  • Intrinsic Activity was expressed as a fraction relative to the maximum activity determined for formoterol in each experiment. Result are in Table 1.
  • Membranes were prepared from human embryonic kidney 293 (HEK293) cells expressing recombinant human ⁇ lo receptor. These were diluted in Assay Buffer (5OmM HEPES, ImM EDTA, 0.1% gelatin, pH 7.4) to provide a final concentration of membranes that gave a clear window between maximum and minimum specific binding.
  • Assay Buffer 5OmM HEPES, ImM EDTA, 0.1% gelatin, pH 7.4
  • the plates were incubated for 2 hours at room temperature and then filtered onto PEI coated GF/B filter plates, pre-soaked for 1 hour in Assay Buffer, using a 96-well plate Tomtec cell harvester. Five washes with 250 ⁇ L wash buffer (5OmM HEPES, ImM EDTA, pH 7.4) were performed at 4°C to remove unbound radioactivity. The plates were dried then sealed from underneath using Packard plate sealers and MicroScint-0 (50 ⁇ L) was added to each well. The plates were sealed (TopSeal A) and filter-bound radioactivity was measured with a scintillation counter (TopCount, Packard BioScience) using a 3-minute counting protocol.
  • wash buffer 250 ⁇ L wash buffer
  • MicroScint-0 50 ⁇ L
  • Membrane Preparation Membranes containing recombinant human adrenergic beta 1 receptors were obtained from Euroscreen. These were diluted in Assay Buffer (5OmM HEPES, ImM EDTA, 12OmM NaCl, 0.1% gelatin, pH 7.4) to provide a final concentration of membranes that gave a clear window between maximum and minimum specific binding.
  • Assay Buffer 5OmM HEPES, ImM EDTA, 12OmM NaCl, 0.1% gelatin, pH 7.4
  • the plates were incubated for 2 hours at room temperature and then filtered onto PEI coated GF/B filter plates, pre-soaked for 1 hour in Assay Buffer, using a 96-well plate Tomtec cell harvester. Five washes with 250 ⁇ L wash buffer (5OmM HEPES, ImM EDTA, 12OmM NaCl, pH 7.4) were performed at 4°C to remove unbound radioactivity. The plates were dried then sealed from underneath using Packard plate sealers and MicroScint-0 (50 ⁇ L) was added to each well. The plates were sealed (TopSeal A) and filter-bound radioactivity was measured with a scintillation counter (TopCount, Packard BioScience) using a 3-minute counting protocol.
  • a scintillation counter TopCount, Packard BioScience
  • Total specific binding (B 0 ) was determined by subtracting the mean NSB from the mean maximum binding. NSB values were also subtracted from values from all other wells. These data were expressed as percent of Bo.
  • Compound concentration-effect curves (inhibition of [ 125 I]-Iodocyanopindolol binding) were determined using serial dilutions typically in the range 0.1 nM to 10 ⁇ M. Data was fitted to a four parameter logistic equation to determine the compound potency, which was expressed as pICso (negative log molar concentration inducing 50% inhibition of [ 125 I] -Iodocyanopindolol binding). Results are shown in Table 1 below.
  • Membranes containing recombinant human Dopamine Subtype D2s receptors were obtained from Perkin Elmer. These were diluted in Assay Buffer (5OmM HEPES, ImM EDTA, 12OmM NaCl, 0.1% gelatin, pH 7.4) to provide a final concentration of membranes that gave a clear window between maximum and minimum specific binding.
  • Assay Buffer 5OmM HEPES, ImM EDTA, 12OmM NaCl, 0.1% gelatin, pH 7.4
  • Assays were performed in U-bottomed 96-well polypropylene plates. 30 ⁇ L [ H]- spiperone (0.16 nM final concentration) and 30 ⁇ L of Compound A (10x final concentration) were added to each test well. For each assay plate 8 replicates were obtained for [ 3 H] -spiperone binding in the presence of 30 ⁇ L vehicle (10% (v/v) DMSO in Assay Buffer; defining maximum binding) or 30 ⁇ L Haloperidol (10 ⁇ M final concentration; defining non-specific binding (NSB)). Membranes were then added to achieve a final volume of 300 ⁇ L.
  • the plates were incubated for 2 hours at room temperature and then filtered onto PEI coated GF/B filter plates, pre-soaked for 1 hour in Assay Buffer, using a 96-well plate Tomtec cell harvester. Five washes with 250 ⁇ L wash buffer (5OmM HEPES, ImM EDTA, 12OmM NaCl, pH 7.4) were performed at 4°C to remove unbound radioactivity. The plates were dried then sealed from underneath using Packard plate sealers and MicroScint-0 (50 ⁇ L) was added to each well. The plates were sealed (TopSeal A) and filter-bound radioactivity was measured with a scintillation counter (TopCount, Packard BioScience) using a 3-minute counting protocol.
  • a scintillation counter TopCount, Packard BioScience
  • Guinea pigs (300-50Og) were killed by cervical dislocation and the trachea was isolated.
  • the trachea was cut into segments 2-3 cartilage rings in width and suspended in 10ml organ baths in modified Krebs' solution (mM; NaCl, 90; NaHCO 3 , 45; KCl, 5; MgSO 4 JH 2 O, 0.5; Na 2 HPO 4 .2H 2 O, 1; CaCl 2 , 2.25; glucose, 10; pH 7.4 gassed with 5% CO 2 , 95% O 2 at 37°C).
  • the tracheal rings were attached to an isometric force transducer for the measurement of isometric tension.
  • the tissues were washed and a force of 1 g was applied to each tissue.
  • Muscarinic antagonist (i?)-l-[2-(4-Fluoro-phenyl)-ethyl]-3-((5)-2-phenyl-2-piperidin-l-yl- propionyloxy)-l-azonia-bicyclo[2.2.2]octane bromide was prepared as in Example 1 (Form A) described herein above.
  • ⁇ 2 -Adrenoceptor agonist ⁇ /-[2-(Diethylamino)ethyl]-iV-(2- ⁇ [2- (4-hydroxy-2-oxo-2,3-dihydro-l,3-benzothiazol-7-yl)ethyl]amino ⁇ ethyl)-3-[2-(l- naphthyl)ethoxy]propanamide dihydrobromide was prepared as in preparation (BAl) described herein above.
  • the following protocol is a prophetic description of an experimental model that might be used to evaluate the effects of muscarinic receptor antagonists according to the present invention in combination with ⁇ 2 -adrenoceptor agonists.
  • mice Male Dunkin-Hartley guinea pigs (300-60Og) are weighed and dosed with vehicle (0.05M phosphate, 0.1% Tween 80, 0.6% saline, pH 6) or compound via the intratracheal route under recoverable gaseous anaesthesia (5% halothane in oxygen). Animals are dosed with compound or vehicle two hours prior to the administration of methacholine. Guinea pigs are anaesthetised with pentobarbitone (1 mL/kg of 60 mg/mL solution i.p.) approximately 30 minutes prior to the first bronchoconstrictor administration.
  • the trachea is cannulated and the animal ventilated using a constant volume respiratory pump (Harvard Rodent Ventilator model 683) at a rate of 60 breath/min and a tidal volume of 5 mL/kg.
  • a jugular vein is cannulated for the administration of methacholine or maintenance anaesthetic (0.1 mL of pentobarbitone solution, 60 mg/mL, as required).
  • the animals are transferred to a Flexivent System (SCIREQ, Montreal, Canada) in order to measure airway resistance.
  • the animals are ventilated (quasi-sinusoidal ventilation pattern) at 60 breaths/min at a tidal volume of 5 mL/kg.
  • a positive end expiratory pressure of 2-3 cm H 2 O was applied.
  • Respiratory resistance is measured using the Flexivent "snapshot" facility (1 second duration, 1 Hz frequency).
  • the animals are given methacholine in ascending doses (0.5, 1, 2, 3 and 5 ⁇ g/kg, i.v) at approximately 4-minute intervals via the jugular catheter. After each administration of bronchoconstrictor the peak resistance value is recorded.
  • Guinea pigs are euthanised with approximately 1.OmL pentobarbitone sodium (Euthatal) intravenously after the completion of the lung function measurements. Percentage bronchoprotection produced by the compound is calculated at each dose of brochoconstrictor as follows:
  • % change R veh is the mean of the maximum percentage change in airway resistance in the vehicle treated group.

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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 qui est un agoniste du β2-adrénocepteur, utiles pour traiter des maladies respiratoires, notamment la bronchopneumopathie chronique obstructive et l'asthme.
PCT/SE2009/050743 2008-06-17 2009-06-16 Produit pharmaceutique comprenant un antagoniste du récepteur muscarinique et un agoniste du béta2-adrénocepteur WO2009154555A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
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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WO2004096800A2 (fr) * 2003-05-02 2004-11-11 Novartis Ag Composes organiques
WO2005115463A1 (fr) * 2004-05-31 2005-12-08 Almirall Prodesfarma S.A. Combinaisons d'agents antimuscariniques et d'agonistes beta-adrenergique
WO2006048225A1 (fr) * 2004-11-02 2006-05-11 Novartis Ag Derives de la quinuclidine et leur utilisation en tant qu'antagonistes du recepteur m3 muscarinique
WO2007018461A1 (fr) * 2005-08-09 2007-02-15 Astrazeneca Ab Dérivés innovants de benzothiazolone
WO2008075005A1 (fr) * 2006-12-19 2008-06-26 Astrazeneca Ab Dérivés quinuclidinol utilisés 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
WO2005115463A1 (fr) * 2004-05-31 2005-12-08 Almirall Prodesfarma S.A. Combinaisons d'agents antimuscariniques et d'agonistes beta-adrenergique
WO2006048225A1 (fr) * 2004-11-02 2006-05-11 Novartis Ag Derives de la quinuclidine et leur utilisation en tant qu'antagonistes du recepteur m3 muscarinique
WO2007018461A1 (fr) * 2005-08-09 2007-02-15 Astrazeneca Ab Dérivés innovants de benzothiazolone
WO2008075005A1 (fr) * 2006-12-19 2008-06-26 Astrazeneca Ab Dérivés quinuclidinol utilisés en tant qu'antagonistes du récepteur muscarinique

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Title
CAZZOLA M. ET AL: "Ultra long-acting beta2-agonists in development for asthma and chronic obstructive pulmonary disease", EXPERT OPINION ON INVESTIGATIONAL DRUGS, vol. 14, no. 7, 2005, pages 775 - 783, XP003026042 *

Cited By (3)

* 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
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

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