WO2008096136A1 - Combinaison inédite - Google Patents

Combinaison inédite Download PDF

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Publication number
WO2008096136A1
WO2008096136A1 PCT/GB2008/000415 GB2008000415W WO2008096136A1 WO 2008096136 A1 WO2008096136 A1 WO 2008096136A1 GB 2008000415 W GB2008000415 W GB 2008000415W WO 2008096136 A1 WO2008096136 A1 WO 2008096136A1
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WO
WIPO (PCT)
Prior art keywords
hydroxy
active ingredient
phenyl
methyl
oxazol
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Application number
PCT/GB2008/000415
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English (en)
Inventor
John Dixon
Tomas Eriksson
John Hansson
Marguerite Mensonides-Harsema
John Mo
Harry Finch
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Argenta Discovery Ltd
Astrazeneca Ab
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Publication of WO2008096136A1 publication Critical patent/WO2008096136A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K31/42—Oxazoles
    • A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
    • 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

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 receptors are a G-protein coupled receptor (GPCR) family having five family members Mi, M 2 , M 3 , M 4 and M 5 . Of the five muscarinic subtypes, three (Mi, 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.
  • COPD chronic obstructive pulmonary disease
  • 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). Whilst treatment with a muscarinic antagonist can yield important benefits, the efficacy of these agents is often far from satisfactory. Moreover, in view of the complexity of respiratory diseases such as asthma and COPD, it is unlikely that any one mediator can satisfactorily treat the disease alone. Hence there is a pressing medical need for new therapies against respiratory diseases such as COPD and asthma, in particular for therapies with disease modifying potential.
  • the present invention provides a pharmaceutical product comprising, in combination, a first active ingredient which is a muscarinic antagonist selected from:
  • 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 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 WO2007/017669 (PCT/GB2006/002956) which display high potency to the M3 receptor.
  • the names of the muscarinic antagonists are IUPAC names generated by the Autonom 2000 plug in for IsisDraw Version 2.5, 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 receptor antagonists of the present invention are ammonium salts.
  • the salt anion may be any pharmaceutically acceptable anion of a mono or polyvalent (e.g. bivalent) acid.
  • the salt anion is selected from chloride, bromide, iodide, sulfate, benzenesulfonate, toluenesulfonate (tosylate), napadisylate (naphthalene- 1,5-disulfonate), edisylate (ethane- 1 ,2-disulfonate), isethionate (2- hydroxyethylsulfonate), phosphate, acetate, citrate, lactate, tartrate, oleic, mesylate (methanesulfonate), maleate ((Z)-3-carboxy-acrylate), fumarate, succinate (3-carboxy- propionate), malate ((S)-3-carboxy -2-hydroxy-propyl
  • the muscarinic receptor antagonist is selected from [2-((S)-Cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-dimethyl-(3-phenoxy- propyl)-ammonium bromide, [2-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-dimethyl-(3-phenoxy- propyl)-ammonium bromide, [2-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-dimethyl-(3-phenoxy- propyl)-ammonium tosylate,
  • the muscarinic receptor antagonist is in the form of a bromide or napadisylate salt.
  • 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.
  • muscarinic antagonists according to this embodiment include [2-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-dimethyl-(3-phenoxy- propyl)-ammonium hemi-naphthalene- 1 ,5-disulfonate,
  • the muscarinic receptor antagonist is in the form of a bromide salt.
  • the second active ingredient of the present invention is selected from
  • a phosphodiesterase inhibitor i) 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. Examples include the compounds
  • 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 CCR 1 receptor antagonist which is a compound of general formula
  • n 0, 1 or 2;
  • R 1 is halogen, C1-C3 haloalkyl or cyano
  • X 1 is -CH 2 - or -C(O)-; n is 0, 1 or 2; p is 0, 1 or 2;
  • R 2 is Ci-C 6 cycloalkyl
  • R 2 forms a bicyclic ring together with the ring it is attached to;
  • R 3 is hydrogen, Ci -C 4 alkyl;
  • R 5 is hydrogen, hydroxyl, -NHC(O)R 6 , -NHS(O) 2 R 6 , -C(O)NR 7 R 8 , -COOR 9 or SO 3 R 9 ;
  • R and R together with the nitrogen atom to which they are attached form a 4- to 7- membered saturated heterocyclic ring that optionally further comprises a ring nitrogen, oxygen or sulphur atom and that is optionally fused to a benzene ring to form a 8- to 11- membered ring system, the heterocyclic ring or ring system being optionally substituted with one or more substituent independently selected from halogen, hydroxyl, amido (-CONH 2 ), Ci-C 6 alkyl, CpC 6 hydroxyalkyl, C 1 -C 6 alkoxy, Ci-C 6 alkoxycarbonyl, Ci-C 6 haloalkyl, Ci-C 6 alkylamino, di-C]-C 6 alkylamino, Ci-C 6 alkylcarbonyl, Cj-C 6 alkylcarbonylamino, C]-C 6 alkylaminocarbonyl, di-C]-C 6 alkylaminocarbonyl, phen
  • R 9 is hydrogen or Ci-C 6 alkyl; q is 0, 1 or 2;
  • R 10 is halogen, hydroxyl, cyano, Ci-C 3 haloalkyl or Ci-C 6 alkoxy; or a pharmaceutically acceptable salt thereof; or, a compound of general formula
  • n 0, 1 or 2;
  • R 1 is halogen, cyano, Ci-C 6 haloalkyl
  • X, Y and Z is a bond, -O-, -NH-, CH 2 - or -C(O)-, provided that only one of X, Y and Z is a bond, and provided that X and Y are not simultaneously -O- or -C(O)-
  • n is 0, 1 or 2;
  • R 2 is Ci-C 6 (cyclo)alkyl; p is 0 or 1 ; R 1 ' is hydrogen, OH or NH 2 ;
  • R 3 is hydrogen or CpQalkyl
  • A is a bond or Ci-C 3 alkyl
  • R 5 is hydrogen, hydroxyl, -NHC(O)R 6 , -NHS(O) 2 R 6 , -C(O)NR 7 R 8 , -COOR 9 or SO 3 R 9
  • R 6 is hydrogen, C 1 -C 3 alkyl, NR 7 R 8 , or OR 9 ;
  • R 7 and R 8 are independently selected from hydrogen or Ci-C 6 alkyl and C 3 -C 7 cycloalkyl; or
  • R 7 and R 8 together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclic ring, which is optionally substituted with on or more hydroxyl groups;
  • R 9 is a hydrogen or C]-C 3 alkyl; and
  • R 10 is halogen, cyano, Cj-C 3 alkoxy or Ci-C 3 haloalkyl, or a pharmaceutically acceptable salt thereof.
  • an alkyl substituent group or an alkyl moiety in a substituent group may be linear or branched.
  • the number and nature of substituents on rings in the compounds of formula (I) and formula (II) will be selected so as to avoid sterically undesirable combinations.
  • the second active ingredient is a compound of formula (I) or (H)
  • m is 1 and R is a halogen atom, particularly a chlorine or fluorine atom.
  • m is 1 and R is chlorine in the 4-position of the benzene ring relative to the carbon
  • X 1 is a -CH 2 - or a -C(O)-. In one embodiment X 1 is -CH 2 -. In a further embodiment, X 1 is -C(O)-.
  • n is 0, 1 or 2. In one embodiment n is 0. In another embodiment n is 1 or
  • 2 i 5 ingredient is a compound of formula (I), n is 2 and R is methyl.
  • R is the group C1-C4 alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl). In one embodiment R is methyl or ethyl.
  • R 11 is hydrogen, hydroxyl or amino group.
  • R 1 1 is hydrogen.
  • R 1 ' is a hydroxyl or aminogroup, particularly a hydroxyl group.
  • X, Y and Z are a bond, -O-, -NH-, CH 2 - or -C(O)-, provided that only one of X, Y and Z is a bond , and provided that X and Y are not simultaneously -O- or -C(O)-.
  • X is -0-
  • Y is a bond and Z is CH 2 .
  • X is a bond
  • Y is -NH-
  • Z is -C(O).
  • X is -CH 2
  • Y is -O- and Z is a bond.
  • R 4 is hydrogen, halogen, hydroxyl or Ci-C 6 hydroxyalkyl, optionally substituted with halogen, cyano, hydroxyl, carboxyl or amido.
  • R 4 is hydrogen.
  • R 4 is halogen such as fluorine.
  • R 4 is hydroxyl.
  • R 4 is -OCH 2 COOH or -OC(CH 3 ) 2 COOH.
  • R 4 is selected from -OCH 2 CF 3 , -OCH 2 CH 2 CF 3 , -OCH 2 CHF 2 or -OCH 2 CN.
  • the integer q is O or 1. In one embodiment, q is O. In yet another embodiment q is 1.
  • R 10 is a halogen, such as chlorine and fluorine. In one embodiment q is 1 and R 10 is chlorine.
  • R 3 is hydrogen or Ci-C 6 alkyl. In one embodiment, R 3 is hydrogen. In another embodiment R 3 is hydrogen or methyl. In one embodiment, R 3 is methyl.
  • A is a bond or Ci-C 3 alkyl.
  • A is a bond.
  • A is Ci-C 3 alkyl (e.g. methyl, ethyl, n-propyl, isopropyl), in particular methyl or ethyl.
  • R 5 is hydrogen, hydroxyl, -NHC(O)R 6 , -NHS(O) 2 R 6 , -C(O)NR 7 R 8 , -COOR 9 or SO 3 R 9 .
  • R 5 is -NHC(O)R 6 , -NHS(O) 2 R 6 , -C(O)NR 7 R 8
  • suitable R 6 , R 7 and R 8 are independently selected from hydrogen or Ci-C 6 alkyl, such as methyl.
  • R 6 is -NR 7 R 8
  • R 7 and R 8 are independently selected from hydrogen or Cj-C 6 alkyl, such as methyl.
  • A is a bond
  • R 6 is - NR 7 R 8
  • R 7 is hydrogen
  • R 8 is Q-C 6 alkyl, such as a methyl.
  • A is a bond
  • R 6 is -NR 7 R 8 and R 7 and R 8 are both C 1 -C 6 alkyl, such as a methyl.
  • R 5 is -NHC(O)R 6 and R 6 is Ci-C 6 alkyl, such as a methyl.
  • R 5 is -C(O)NR 7 R 8 and R 7 and R 8 ar both C]-C 6 alkyl, such as a methyl.
  • A is a bond R 5 is -C(O)NR 7 R 8 and R is a hydrogen and R is C]-C 6 alkyl such as methyl.
  • the second active ingredient is a compound of formula (I)
  • A is a bond
  • R 5 is -NHC(O)R 6
  • R 6 is -NR 7 R 8
  • R 7 and R 8 together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclic ring, which is optionally substituted with one or more hydroxyl groups.
  • R 5 is -C(O)NR 7 R 8 and R 7 and R 8 together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclic ring, which is optionally substituted with one or more hydroxyl groups.
  • heterocyclic groups for R 7 and R 8 and the nitrogen atom to which they are attached include azetininyl, pyrrolidinyl, piperadinyl and pyrrolidinyl.
  • A is methyl or ethyl and R 5 is OH.
  • R 5 is a group -COOR 9 or -SO 3 R 9 , where suitable R 9 substituents are independently selected from hydrogen or Q-C 3 alkyl, such as methyl and ethyl.
  • alkyl includes both straight and branched chain alkyl groups and may be, but are not limited to methyl, ethyl, n-propyl, i- propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, neo-pentyl, n-hexyl or i-hexyl.
  • Ci -4 alkyl having 1 to 4 carbon atoms and may be but are not limited to methyl, ethyl, n-propyl, i-propyl or tert-butyl.
  • alkoxy refers to radicals of the general formula -O-R, wherein R is selected from a hydrocarbon radical.
  • alkoxy may include, but is not limited to methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, isobutoxy, cyclopropylmethoxy, allyloxy or propargyloxy.
  • cycloalkyl refers to an optionally substituted, partially or completely saturated monocyclic, bicyclic or bridged hydrocarbon ring system.
  • the term “Ci_ 6 cycloalkyl” may be, but is not limited to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • the term "3 to 8-membered saturated or unsaturated ring, optionally comprising one or more heteroatom selected from nitrogen, oxygen and sulphur, or the term “4 to 7-membered heterocyclic ring” refers to a ringsystem having, in addition to carbon atoms, zero to three heteroatoms, including the oxidized form of nitrogen and sulfur and any quaternized form of a basic nitrogen, including, but not limited to cyclopropane, oxirane, cyclobutane, azetidine, cyclopentane, cyclohexane, benzyl, furane, thiophene, pyrrolidine, morpholine, piperidine, piperazine, pyrazine, azepane.
  • bicyclic ring refers to a ringsystem in which one (carbo)cycle is fused to another (carbo)cycle.
  • a 8 to 11-membered ring system refers to a hydrocarbon moiety comprising one to three fused rings, optionally having 6, 10 or 14 ⁇ atoms shared in a cyclic array and having, in addition to carbon atoms, zero to five heteroatoms.
  • Fused ringsystems may include, but are not limited to, 8- azabicyclo[3.2.1]octane, 3-azabicyclo[3.2.1]octane, 2-azabicyclo[2.2.2]octane, indole, indoline, benzofuran, benzothiophene, naphtalene, chroman, quinazoline, phenoxazine, azulene, adamantane, anthracene or phenoxazine.
  • haloalkyl means an alkyl group as defined above, which is substituted with halogen as defined above.
  • Q- C 6 haloalkyl may include, but is not limited to fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl or bromopropyl.
  • C]. 3 haloalkylO may include, but is not limited to fluoromethoxy, difluoromethoxy, trifluoromethoxy, fluoroethoxy or difluoroethoxy.
  • halophenyl may include, but is not limited to fluorophenyl, difluorophenyl, trifluorophenyl, chlorophenyl, dichlorophenyl or trichlorophenyl.
  • alkylcarbonyl or “alkoxycarbonyl” may include, but is not limited to an alkyl or alkoxy group as defined above, which is substituted with COOH.
  • alkylcarbonylamino may include, but is not limited to an alkyl group as defined above, which is substituted with NHCOOH.
  • hydroxyalkyl may include, but is not limited to an alkyl group as defined above, which is substituted with one or more hydroxyl groups.
  • alkylsulphonyl may include, but is not limited to an alkyl group as defined above, which is substituted with SO 2 .
  • the second active ingredient is selected from
  • the second active ingredient is selected from
  • the representation of formula (I) and (II) and the examples of the present invention covers both neutral and zwitterionic forms and mixtures thereof in all proportions.
  • the compounds of formula (I) and (II) may be used in the form of a pharmaceutically acceptable salt thereof, conceivably an acid addition salt such as a hydrochloride, hydrobromide, phosphate, sulfphate, acetate, ascorbate, benzoate, 2- fluorobenzoate, 2,6-difluorobenzoate, (hemi)fumarate, furoate, succinate, maleate, tartrate, citrate, oxalate, xinafoate, methanesulphonate orp-toluenesulphonate.
  • an acid addition salt such as a hydrochloride, hydrobromide, phosphate, sulfphate, acetate, ascorbate, benzoate, 2- fluorobenzoate, 2,6-difluorobenzoate, (
  • Pharmaceutically acceptable salts may also be formed together with metals such as calcium, magnesium, sodium, potassium or zinc or bases such as piperazine, 2-aminoethanol, choline, diethylamine or diethanol amine.
  • the compounds of formula (I) and (II) may be used in the form of a pharmaceutically acceptable salt thereof, like an amino acid addition salt such as L-lysine, glycine, L-glutamine, L-asparagine or L-arganine
  • a pharmaceutically acceptable salt also includes internal salt (zwitterionic) forms. Any reference to compounds of formula (I) and (II) or salts thereof also encompasses solvates of such compounds and solvates of such salts (e.g. hydrates).
  • the second active ingredient is a salt of N- ⁇ 2-[((2S)-3- ⁇ [l-(4-chlorobenzyl)piperidin-4-yl]amino ⁇ -2-hydroxy-2-methylpropyl)oxy]-4- hydroxyphenyl ⁇ acetamide or N- ⁇ 5-Chloro-2-[((2S)-3- ⁇ [l-(4-chlorobenzyl)piperidin-4- yl]amino ⁇ -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 p-toluenesulphonate salt.
  • the second active ingredient is a benzoate, furoate or hemifumarate salt of iV- ⁇ 2-[((25)-3- ⁇ [l-(4-chlorobenzyl)piperidin-4-yl]amino ⁇ - 2-hydroxy-2-methylpropyl)oxy]-4-hydroxyphenyl ⁇ acetamide, as described in PCT/SE2006/000920, PCT/SE2006/000921 and PCT/SE2006/000922 (WO2007/015666, WO2007/015667 and WO2007/015668).
  • the second active ingredient is the hemifumarate, furoate, benzoate, 2-fluorobenzoate or 2,6-difluorobenzoate salt of N- ⁇ 5- Chloro-2-[((2S)-3- ⁇ [l-(4-chlorobenzyl)piperidin-4-yl]amino ⁇ -2-hydroxy-2- methylpropyl)oxy]-4-hydroxyphenyl ⁇ acetamide.
  • the second active ingredient is a hemifumarate salt of N- ⁇ 2-[((25)-3- ⁇ [l-(4-chlorobenzyl)piperidin-4-yl]amino ⁇ -2-hydroxy-2-methylpropyl)oxy]- 4-hydroxyphenyl ⁇ acetamide which exhibits at least the following characteristic X-ray powder diffraction peaks (expressed in degrees 2 ⁇ ):
  • the second active ingredient is a furoate salt of N- ⁇ 2-[((25)-3- ⁇ [ 1 -(4-chlorobenzyl)piperidin-4-yl]amino ⁇ -2-hydroxy-2-methylpropyl)oxy]-4- hydroxyphenyl ⁇ acetamide which exhibits at least the following characteristic X-ray powder diffraction peaks (expressed in degrees 2 ⁇ ): (1) 6.1, 10.7 and 19.3, or (2) 6.1, 12.2 and 14.1, or
  • the second active ingredient is a benzoate salt of N- ⁇ 2-[((2S)-3- ⁇ [ 1 -(4-chlorobenzyl)piperidin-4-yl]amino ⁇ -2-hydroxy-2- methylpropyl)oxy]-4-hydroxyphenyl ⁇ acetamide which exhibits at least the following characteristic X-ray powder diffraction peaks (expressed in degrees 2 ⁇ ):
  • the second active ingredient is a hemifumarate salt of iV- ⁇ 5-chloro-2-[((2S)-3- ⁇ [l-(4-chlorobenzyl)piperidin-4-yl]amino ⁇ -2-hydroxy-2- methylpropyl)oxy]-4-hydroxyphenyl ⁇ acetamide which exhibits at least the following characteristic X-ray powder diffraction peaks (expressed in degrees 2 ⁇ ):
  • the second active ingredient is a furoate salt of N- ⁇ 5-chloro-2-[((25)-3- ⁇ [ 1 -(4-chlorobenzyl)piperidin-4-yl]amino ⁇ -2-hydroxy-2- methylpropyl)oxy]-4-hydroxyphenyl ⁇ acetamide which exhibits at least the following characteristic X-ray powder diffraction peaks (expressed in degrees 2 ⁇ ): (1) 6.7, 17.9 and 20.9 or
  • the second active ingredient is a benzoate salt of N- ⁇ 5-chloro-2-[((25)-3- ⁇ [ 1 -(4-chlorobenzyl)piperidin-4-yl]amino ⁇ -2-hydroxy-2- methylpropyl)oxy]-4-hydroxyphenyl ⁇ acetamide which exhibits at least the following characteristic X-ray powder diffraction peaks (expressed in degrees 2 ⁇ ): (1) 5.6, 10.4 and 14.3 or
  • the second active ingredient is a 2- fluorobenzoate salt of N-f S-chloro ⁇ - ⁇ -S-f [l-(4-chlorobenzyl)piperidin-4-yl]amino ⁇ - 2-hydroxy-2-methylpropyl)oxy]-4-hydroxyphenyl ⁇ acetamide which exhibits at least the following characteristic X-ray powder diffraction peaks (expressed in degrees 2 ⁇ ): (1) 5.6, 9.2 and 11.2, or
  • the second active ingredient is a 2,6- difluorobenzoate salt of N- ⁇ 5-chloro-2-[((25)-3- ⁇ [l-(4-chlorobenzyl)piperidin-4- yl] amino ⁇ -2-hydroxy-2-methylpropyl)oxy]-4-hydroxyphenyl ⁇ acetamide which exhibits at least the following characteristic X-ray powder diffraction peaks (expressed in degrees 2 ⁇ ): (1) 5.6, 9.1 and 11.2, or
  • the second active ingredient is a sulphate salt of N- ⁇ 5-chloro-2-[((25)-3- ⁇ [ 1 -(4-chlorobenzyl)piperidin-4-yl]amino ⁇ -2-hydroxy-2- methylpropyl)oxy]-4-hydroxyphenyl ⁇ acetamide which exhibits at least the following characteristic X-ray powder diffraction peaks (expressed in degrees 2 ⁇ ): (1) 3.3, 9.9 and 19.8, or
  • the compounds of formula (I) may be synthesised using the procedures set out in WO01/98273, WO03/051839 and WO 2005/037814.
  • the compounds of formula (II) may be synthesised using the procedures set out in WO2004/005295, US 60/831,776 and WO 2004/005295.
  • the compounds of formula (I) and (II) or a pharmaceutically acceptable or a pharmaceutically acceptable salt, solvate or solvated salt thereof, as defined above may also be prepared according to the praparation routes described in schemes 1 to 4 below.
  • R 14 and R 15 are hydrogen, Ci -3 alkyl or together with the carbon atom to which they are attaced form a 3-6 membered aliphatic ring.
  • 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 a [2-((R)- Cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-dimethyl-(3-phenoxy-propyl)- ammonium salt
  • the second active ingredient is yV- ⁇ 2-[((25)-3- ⁇ [l-(4- chlorobenzyl)piperidin-4-yl]amino ⁇ -2-hydroxy-2-methylpropyl)oxy]-4- hydroxyphenyl jacetamide or a pharmaceutically acceptable salt thereof (e.g. benzoate, hemifumarate or furoate).
  • the muscarinic receptor antagonist is [2-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-dimethyl- (3-phenoxy-propyl)-ammonium bromide.
  • the muscarinic receptor antagonist is [2-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5- ylmethyl]-dimethyl-(3-phenoxy-propyl)-ammonium napadisylate (e.g. hemi-naphthalene- 1,5-disulfonate).
  • the muscarinic receptor antagonist is a [2-((R)- cyclohexyl-hydroxy-phenyl-methy ⁇ -oxazol-S-ylmethyl]- dimethyl-(2-phenethyloxy- ethyl)-ammonium salt
  • the second active ingredient is N- ⁇ 2-[((2S)-3- ⁇ [l-(4- chlorobenzyl)piperidin-4-yl]amino ⁇ -2-hydroxy-2-methylpropyl)oxy]-4- hydroxyphenyljacetamide or a pharmaceutically acceptable salt thereof (e.g. benzoate, hemifumarate or furoate).
  • the muscarinic receptor antagonist is [2-((R)-cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]- dimethyl- (2-phenethyloxy-ethyl)-ammonium bromide.
  • the muscarinic receptor antagonist is [2-((R)-cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5- ylmethyl]- dimethyl-(2-phenethyloxy-ethyl)-ammonium napadisylate (e.g. hemi- naphthalene- 1 ,5-disulfonate).
  • the muscarinic receptor antagonist is a [[2-((R)- cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]- [3-(3,4-dichloro-phenoxy)- propyl] dimethyl-ammonium salt and the second active ingredient is N- ⁇ 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).
  • a pharmaceutically acceptable salt thereof e.g. benzoate, hemifumarate or furoate.
  • the muscarinic receptor antagonist is [[2-((R)-cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]- [3-(3,4- dichloro-phenoxy)-propyl] dimethyl-ammonium bromide.
  • the muscarinic receptor antagonist is [2-((R)-cyclohexyl-hydroxy-phenyl- methyl)-oxazol-5-ylmethyl]- [3-(3,4-dichloro-phenoxy)-propyl] dimethyl-ammonium napadisylate (e.g. hemi-naphthalene-l,5-disulfonate).
  • the muscarinic receptor antagonist is a [2-((R)- cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-[2-(3,4-dichloro-benzyloxy)- ethyl]- dimethyl-ammonium salt and the second active ingredient is N- ⁇ 2-[((25)-3- ⁇ [ l-(4- chlorobenzyl)piperidin-4-yl]amino ⁇ -2-hydroxy-2-methylpropyl)oxy]-4- hydroxyphenyljacetamide or a pharmaceutically acceptable salt thereof (e.g. benzoate, hemifumarate or furoate).
  • a pharmaceutically acceptable salt thereof e.g. benzoate, hemifumarate or furoate.
  • the muscarinic receptor antagonist is [2-((R)-cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-[2-(3,4- dichloro-benzyloxy)-ethyl]- dimethyl-ammonium bromide.
  • the muscarinic receptor antagonist is [2-((R)-cyclohexyl-hydroxy-phenyl- methyl)-oxazol-5-ylmethyl]-[2-(3,4-dichloro-benzyloxy)-ethyl]- dimethyl-ammonium napadisylate (e.g. hemi-naphthalene-l,5-disulfonate).
  • the muscarinic receptor antagonist is a [2-(4-chloro- benzyloxy)-ethyl]-[2-((R)-cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]- dimethyl-ammonium salt and the second active ingredient is N- ⁇ 2-[((2S)-3- ⁇ [l-(4- chlorobenzyl)piperidin-4-yl]amino ⁇ -2-hydroxy-2-methylpropyl)oxy]-4- hydroxyphenyljacetamide or a pharmaceutically acceptable salt thereof (e.g. benzoate, hemifumarate or furoate).
  • a pharmaceutically acceptable salt thereof e.g. benzoate, hemifumarate or furoate.
  • the muscarinic receptor antagonist is [2-(4-chloro-benzyloxy)-ethyl]-[2-((R)-cyclohexyl-hydroxy-phenyl-methyl)- oxazol-5-ylmethyl]- dimethyl-ammonium bromide.
  • the muscarinic receptor antagonist is [2-(4-chloro-benzyloxy)-ethyl]-[2-((R)-cyclohexyl- hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]- dimethyl-ammonium napadisylate (e.g. hemi-naphthalene- 1 ,5-disulfonate).
  • the muscarinic receptor antagonist is a [2-((R)- Cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-dimethyl-(3-phenoxy-propyl)- ammonium salt
  • the second active ingredient is yV- ⁇ 5-chloro-2-[((2S)-3- ⁇ [l-(4- chlorobenzyl)piperidin-4-yl]amino ⁇ -2-hydroxy-2-methylpropyl)oxy]-4- hydroxyphenyljacetamide or a pharmaceutically acceptable salt thereof (e.g. benzoate, hemifumarate or furoate).
  • the muscarinic receptor antagonist is [2-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-dimethyl- (3-phenoxy-propyl)-ammonium bromide.
  • the muscarinic receptor antagonist is [2-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5- ylmethyl]-dimethyl-(3-phenoxy-propyl)-ammonium napadisylate (e.g. hemi-naphthalene- 1,5-disulfonate).
  • the muscarinic receptor antagonist is a [2-((R)- cyclohexyl-hydroxy-phenyl-methyty-oxazol-S-ylmethyl]- dimethyl-(2-phenethyloxy- ethyl)-ammonium salt
  • the second active ingredient is ⁇ f- ⁇ 5-chloro-2-[((2S)-3- ⁇ [l-(4- chlorobenzyl)piperidin-4-yl] amino ⁇ -2-hydroxy-2-methylpropyl)oxy] -A- hydroxyphenyljacetamide or a pharmaceutically acceptable salt thereof (e.g. benzoate, hemifumarate or furoate).
  • the muscarinic receptor antagonist is [2-((R)-cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]- dimethyl- (2-phenethyloxy-ethyl)-ammonium bromide.
  • the muscarinic receptor antagonist is [2-((R)-cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5- ylmethyl]- dimethyl-(2-phenethyloxy-ethyl)-ammonium napadisylate (e.g. hemi- naphthalene- 1 ,5-disulfonate).
  • the muscarinic receptor antagonist is a [[2-((R)- cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]- [3-(3,4-dichloro-phenoxy)- propyl] dimethyl-ammonium salt 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. benzoate, hemifumarate or furoate).
  • a pharmaceutically acceptable salt thereof e.g. benzoate, hemifumarate or furoate.
  • the muscarinic receptor antagonist is [[2-((R)-cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]- [3-(3,4- dichloro-phenoxy)-propyl] dimethyl-ammonium bromide.
  • the muscarinic receptor antagonist is [2-((R)-cyclohexyl-hydroxy-phenyl- methyl)-oxazol-5-ylmethyl]- [3-(3,4-dichloro-phenoxy)-propyl] dimethyl-ammonium napadisylate (e.g. hemi-naphthalene-l,5-disulfonate).
  • the muscarinic receptor antagonist is a [2-((R)- cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-[2-(3,4-dichloro-benzyloxy)- ethyl]- dimethyl-ammonium salt and the second active ingredient is yV- ⁇ 5-chloro-2-[((25)- 3- ⁇ [ 1 -(4-chlorobenzyl)piperidin-4-yl]amino ⁇ -2-hydroxy-2-methylpropyl)oxy]-4- hydroxyphenyljacetamide or a pharmaceutically acceptable salt thereof (e.g. benzoate, hemifumarate or furoate).
  • a pharmaceutically acceptable salt thereof e.g. benzoate, hemifumarate or furoate.
  • the muscarinic receptor antagonist is [2-((R)-cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-[2-(3,4- dichloro-benzyloxy)-ethyl]- dimethyl-ammonium bromide.
  • the muscarinic receptor antagonist is [2-((R)-cyclohexyl-hydroxy-phenyl- methyl)-oxazol-5-ylmethyl]-[2-(3,4-dichloro-benzyloxy)-ethyl]- dimethyl-ammonium napadisylate (e.g. hemi-naphthalene-l,5-disulfonate).
  • the muscarinic receptor antagonist is a [2-(4-chloro- benzyloxy)-ethyl]-[2-((R)-cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]- dimethyl-ammonium salt and the second active ingredient is N- ⁇ 5-chloro-2-[((25)-3- ⁇ [1- (4-chlorobenzyl)piperidin-4-yl]amino ⁇ -2-hydroxy-2-methylpropyl)oxy]-4- hydroxyphenyljacetamide or a pharmaceutically acceptable salt thereof (e.g. benzoate, hemifumarate or furoate).
  • a pharmaceutically acceptable salt thereof e.g. benzoate, hemifumarate or furoate.
  • the muscarinic receptor antagonist is [2-(4-chloro-benzyloxy)-ethyl]-[2-((R)-cyclohexyl-hydroxy-phenyl-methyl)- oxazol-5-ylmethyl]- dimethyl-ammonium bromide.
  • the muscarinic receptor antagonist is [2-(4-chloro-benzyloxy)-ethyl]-[2-((R)-cyclohexyl- hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]- dimethyl-ammonium napadisylate (e.g. hemi -naphthalene- 1 ,5-disulfonate).
  • the muscarinic receptor antagonist is a [2-((R)- Cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-dimethyl-(3-phenoxy-propyl)- ammonium salt
  • 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-
  • the muscarinic receptor antagonist is [2-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-dimethyl- (3-phenoxy-propyl)-ammonium bromide.
  • the muscarinic receptor antagonist is [2-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5- ylmethyl]-dimethyl-(3-phenoxy-propyl)-ammonium napadisylate (e.g. hemi-naphthalene- 1,5-disulfonate).
  • the muscarinic receptor antagonist is a [2-((R)- cyclohexyl-hydroxy-phenyl-methy ⁇ -oxazol-S-ylmethyl]- dimethyl-(2-phenethyloxy- ethyl)-ammonium salt
  • 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 [2-((R)-cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]- dimethyl- (2-phenethyloxy-ethyl)-ammonium bromide.
  • the muscarinic receptor antagonist is [2-((R)-cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5- ylmethyl]- dimethyl-(2-phenethyloxy-ethyl)-ammonium napadisylate (e.g. hemi- naphthalene- 1 ,5-disulfonate).
  • the muscarinic receptor antagonist is a [[2-((R)- cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]- [3-(3,4-dichloro-phenoxy)- propyl] dimethyl-ammonium salt and the second active ingredient is 2- ⁇ 2-Chloro-5- ⁇ [(2S)- 3-(5-chloro- 1 'H,3H-spiro[ 1 -benzofuran-2,4'-piperidin]- 1 '-yl)-2-hydroxypropyl]oxy ⁇ -A- [(methylamino)carbonyl]phenoxy ⁇ -2-methylpropanoic acid or a pharmaceutically acceptable salt thereof.
  • the muscarinic receptor antagonist is [[2-((R)-cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]- [3-(3,4- dichloro-phenoxy)-propyl] dimethyl-ammonium bromide.
  • the muscarinic receptor antagonist is [2-((R)-cyclohexyl-hydroxy-phenyl- methyl)-oxazol-5-ylmethyl]- [3-(3,4-dichloro-phenoxy)-propyl] dimethyl-ammonium napadisylate (e.g. hemi-naphthalene-l,5-disulfonate).
  • the muscarinic receptor antagonist is a [2-((R)- cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-[2-(3,4-dichloro-benzyloxy)- ethyl]- dimethyl-ammonium salt 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 [2-((R)-cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-[2-(3,4- dichloro-benzyloxy)-ethyl]- dimethyl-ammonium bromide.
  • the muscarinic receptor antagonist is [2-((R)-cyclohexyl-hydroxy-phenyl- methyl)-oxazol-5-ylmethyl]-[2-(3,4-dichloro-benzyloxy)-ethyl]- dimethyl-ammonium napadisylate (e.g. hemi-naphthalene-l,5-disulfonate).
  • the muscarinic receptor antagonist is a [2-(4-chloro- benzyloxy)-ethyl]-[2-((R)-cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]- dimethyl-ammonium salt 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 [2-(4-chloro-benzyloxy)-ethyl]-[2-((R)-cyclohexyl-hydroxy-phenyl-methyl)- oxazol-5-ylmethyl]- dimethyl-ammonium bromide.
  • the muscarinic receptor antagonist is [2-(4-chloro-benzyloxy)-ethyl]-[2-((R)-cyclohexyl- hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]- dimethyl-ammonium napadisylate (e.g. hemi-naphthalene- 1 ,5-disulfonate).
  • 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.
  • the muscarinic receptor antagonist is a [2-((R)- cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-dimethyl-(3-phenoxy-propyl)- ammonium salt, and the second active ingredient is budesonide.
  • the muscarinic receptor antagonist is [2-((R)-cyclohexyl-hydroxy-phenyl- methyl)-oxazol-5-ylmethyl]-dimethyl-(3-phenoxy-propyl)-ammonium bromide.
  • the muscarinic receptor antagonist is [2-((R)-cyclohexyl- hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-dimethyl-(3-phenoxy-propyl)-ammonium napadisylate (e.g. hemi-naphthalene-l,5-disulfonate).
  • the muscarinic receptor antagonist is a [2-((R)- cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]- dimethyl-(2-phenethyloxy- ethyl)-ammonium salt, and the second active ingredient is budesonide.
  • the muscarinic receptor antagonist is [2-((R)-cyclohexyl-hydroxy- phenyl-methyl)-oxazol-5-ylmethyl]- dimethyl-(2-phenethyloxy-ethyl)-ammonium bromide.
  • the muscarinic receptor antagonist is [2- ((R)-cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]- dimethyl-(2-phenethyloxy- ethyl)-ammonium napadisylate (e.g. hemi-naphthalene-l,5-disulfonate).
  • the muscarinic receptor antagonist is a [[2-((R)- cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]- [3-(3,4-dichloro-phenoxy)- propyl] dimethyl-ammonium salt and the second active ingredient is budesonide.
  • the muscarinic receptor antagonist is [[2-((R)-cyclohexyl- hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]- [3-(3,4-dichloro-phenoxy)-propyl] dimethyl- ammonium bromide.
  • the muscarinic receptor antagonist is [2-((R)-cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]- [3-(3,4- dichloro-phenoxy)-propyl] dimethyl-ammonium napadisylate (e.g. hemi-naphthalene-1,5- disulfonate).
  • the muscarinic receptor antagonist is a [2-((R)- cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-[2-(3,4-dichloro-benzyloxy)- ethyl]- dimethyl-ammonium salt and the second active ingredient is budesonide.
  • the muscarinic receptor antagonist is [2-((R)-cyclohexyl- hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-[2-(3,4-dichloro-benzyloxy)-ethyl]- dimethyl- ammonium bromide.
  • the muscarinic receptor antagonist is [2-((R)-cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-[2-(3,4- dichloro-benzyloxy)-ethyl]- dimethyl-ammonium napadisylate (e.g. hemi-naphthalene-1,5- disulfonate).
  • the muscarinic receptor antagonist is a [2-(4-chloro- benzyloxy)-ethyl]-[2-((R)-cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]- dimethyl-ammonium salt and the second active ingredient is budesonide.
  • the muscarinic receptor antagonist is [2-(4-chloro-benzyloxy)-ethyl]-[2- ((R)-cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]- dimethyl-ammonium bromide.
  • the muscarinic receptor antagonist is [2-(4- chloro-benzyloxy)-ethyl]-[2-((R)-cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]- dimethyl-ammonium napadisylate (e.g. hemi-naphthalene-l,5-disulfonate).
  • 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. It will be understood that the therapeutic dose of each active ingredient administered in accordance with the present invention will vary depending upon the particular active ingredient employed, the mode by which the active ingredient is to be administered, and the condition or disorder to be treated.
  • the muscarinic antagonist (first active ingredient) according to the present invention is administered via inhalation.
  • the dose of the muscarinic antagonist according to the present invention will generally be in the range of from 0.1 microgram ( ⁇ g) to 5000 ⁇ g, 0.1 to 1000 ⁇ g, 0.1 to 500 ⁇ g, 0.1 to 100 ⁇ g, 0.1 to 50 ⁇ g, 0.1 to 5 ⁇ g, 5 to 5000 ⁇ g, 5 to 1000 ⁇ g, 5 to 500 ⁇ g, 5 to 100 ⁇ g, 5 to 50 ⁇ g, 5 to 10 ⁇ g, 10 to 5000 ⁇ g, 10 to 1000 ⁇ g, 10 to 500 ⁇ g, 10 to 100 ⁇ g, 10 to 50 ⁇ g, 20 to 5000 ⁇ g, 20 to 1000 ⁇ g, 20 to 500 ⁇ g, 20 to 100 ⁇ g, 20 to 50 ⁇ g, 50 to 5000 ⁇ g, 50 to 1000 ⁇ g, 50 to 500 ⁇ g, 50 to 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.
  • compositions of active ingredients may be administered simultaneously.
  • the different pharmaceutical preparations of active ingredients may be administered sequentially. In an 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.
  • 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 C 8 - 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 C 8 - 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, 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.
  • 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 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.
  • the term “agent” and " active ingredient” means the compounds comprised in the combination of the present invention, e.g. a muscarine antagonist or a CCRl antagonist.
  • the pharmaceutical product, kit or composition of the present invention may optionally comprise a third active ingredient which third active ingredient is a substance suitable for use in the treatment of respiratory diseases.
  • third active ingredients examples include those listed herein above as second active ingredients (i.e. a phosphodiesterase inhibitor, a modulator of chemokine receptor function, an inhibitor of kinase function, a protease inhibitor, a steroidal glucocorticoid receptor agonist, a non-steroidal glucocorticoid receptor agonist or a purinoceptor antagonist) it being recognised that they may be utilised as third active ingredients in embodiments where they have not been utilised as the second active ingredient .
  • second active ingredients i.e. a phosphodiesterase inhibitor, a modulator of chemokine receptor function, an inhibitor of kinase function, a protease inhibitor, a steroidal glucocorticoid receptor agonist, a non-steroidal glucocorticoid receptor agonist or a purinoceptor antagonist
  • the third active ingredient is a ⁇ 2 -adrenoceptor agonist.
  • the ⁇ 2 -adrenoceptor agonist may be any compound or substance capable of stimulating the ⁇ 2 -receptors and acting as a bronchodilator.
  • Examples of ⁇ 2 -adrenoceptor agonists that may be employed in the present invention include formoterol.
  • the chemical name for formoterol is ⁇ f-[2-hydroxy-5-[(l)-l-hydroxy-2-[[(l)-2-(4-methoxyphenyl)-l- methylethyl]amino]ethyl]phenyl]-formarnide.
  • 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 N-[2-hydroxy-5-[(lR)-l-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 pharmaceutical product, kit or pharmaceutical composition does not contain a ⁇ 2 -adrenoceptor agonist.
  • the invention is illustrated by the following non-limiting Examples. In the Examples the following Figures are presented:
  • FIG 1 X-ray powder diffraction pattern of Muscarinic Antagonist 2 (MA2) [2-((R)- Cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-dimethyl-(3-phenoxy- propyl)-ammonium bromide: Crystalline Form
  • Figure 2 X-ray powder diffraction pattern of Muscarinic Antagonist 7 (MA7) [2-((R)-
  • FIG. 5 X-ray powder diffraction pattern of Muscarinic Antagonist 11 (MAl 1 ⁇ [2-(4- chloro-benzyloxy)-ethyl]-[2-((R)-cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5- ylmethyl]-dimethyl-ammonium hemi -naphthalene- 1 ,5-disulfonate: Crystalline Form
  • Figure 6 X-ray powder diffraction pattern of the hemifumarate salt of N- ⁇ 5-chloro-2-
  • Figure 7 X-ray powder diffraction pattern of the sulphate salt of N- ⁇ 5-chloro-2-[((25)-3- ⁇ [ 1 -(4-chlorobenzyl)piperidin-4-yl]amino ⁇ -2-hydroxy-2-methylpropyl)oxy]-4- hydroxyphenyl ⁇ acetamide (CCRl anatgonist)
  • 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 obtained on a Varian Unity Inova 400 spectrometer with a 5 mm inverse detection triple resonance probe operating at 400 MHz or on a Bruker Avance DRX 400 spectrometer with a 5 mm inverse detection triple resonance TXI probe operating at 400 MHz or on a Bruker Avance DPX 300 spectrometer with a standard 5 mm dual frequency probe operating at 300 MHz. Shifts are given in ppm relative to tetramethylsilane.
  • 'flash silica' refers to silica gel for chromatography, 0.035 to 0.070 mm (220 to 440 mesh) (e.g. Fluka silica gel 60), and an applied pressure of nitrogen up to 10 p.s.i accelerated column elution.
  • thin layer chromatography TLC
  • it refers to silica gel TLC using plates, typically 3 x 6 cm silica gel on aluminium foil plates with a fluorescent indicator (254 nm), (e.g. Fluka 60778). All solvents and commercial reagents were used as received.
  • MS ionisation method Electrospray (positive and negative ion) LC-MS method 3
  • MS ionisation method Electrospray (positive and negative ion)
  • MS ionisation method Electrospray (positive ion) X-Ray Powder Diffraction (XRPD) patterns were collected, on a high resolution Philips X- Pert MPD machine in reflection mode and ⁇ - 2 ⁇ configuration, over the scan range 2° to 40° 2 ⁇ with 100-second exposure per 0.03° increment.
  • the X-rays were generated by a copper tube operated at 45kV and 4OmA.
  • the wavelengths of the direct beam X-rays was 1.5406A (K ⁇ i ) as a monochromator was used.
  • the data was collected on zero background holders on which ⁇ 2mg of the compound was placed.
  • the holder (provided by PANalytical) was made from a single crystal of silicon, which had been cut along a non- diffracting plane in the 2° to 40° 2 ⁇ range and then polished on an optically flat finish.
  • the X-rays incident upon this surface were negated by Bragg extinction.
  • Raw data were stored electronically and evaluation was performed on raw or smoothed diffraction patterns. XRPD were recorded at ambient temperature and relative humidity.
  • DSC Differential scanning calorimetry
  • Thermogravimetric analysis (TGA) thermograms were measured using a TA Q500 Thermogravimetric Analyser, with platinum pans. The sample weights varied between 1 and 5mg. The procedure was carried out under a flow of nitrogen gas (60ml/min) and the temperature studied from 25 to 200 0 C at a constant rate of temperature increase of 10 0 C per minute.
  • RT room or ambient temperature, i.e. a temperature of from 16 to 25 0 C,
  • NMS N-methyl scopolamine
  • Muscarinic antagonists, and the intermediates used in their preparation, described herein have been given IUPAC names generated by the Autonom 2000 plug in for IsisDraw version 2.5, as supplied by MDL Information Systems. Inc. Intermediates used in Preparation of Muscarinic Antagonists
  • Oxalyl chloride (6.1 g, 48 mmol) was added to a solution of phenylglyoxylic acid (6.0 g, 40 mmol) and 3 drops of DMF in dry DCM (50 mL). The reaction mixture was stirred at RT for 3 h then the solvent was removed. The residue was taken up in dry DCM (50 mL) and the solution was cooled to 0 0 C. A mixture of propargyl amine (2.2 g, 40 mmol) and triethylamine (4.05 g, 40 mmol) was added cautiously over a period of 10 min then the mixture was allowed to warm to RT. Stirring was continued for 2.5 h then water (10 mL) was added.
  • Methane sulfonic acid (1O g, 104 mmol) was added drop wise to a solution of 2-oxo-2- phenyl-./V-prop-2-ynyl-acetamide (Intermediate 1) (2.4 g, 12.83 mmol) in 1,4-dioxane (20 mL).
  • the resultant solution was heated at 90 0 C for 66 h.
  • the reaction mixture was cooled and the solvent was removed.
  • the dark residue was partitioned between DCM and water.
  • the DCM fraction was washed with 1 M HCl (2x), satd. sodium hydrogencarbonate solution (aq., 2x), then brine.
  • the solution was dried (Na 2 SO 4 ) and the solvent was removed to give the crude product.
  • Muscarinic Antagonist 1 [2-((S)-CvcIohexyI-hydroxy-phenyl-methvI)-oxazoI- 5-ylmethv ⁇ -dimethvI-(3-phenoxy-propyI)-ammonium bromide
  • Muscarinic Antagonist 2 (MA2); r2-((R)-Cvclohexyl-hvdroxy-phenyl-methyl)-oxazoI- 5-vImethvIl-dimethyl-(3-phenoxy-propyl)-amnionium bromide
  • MA2 Muscarinic Antagonist 2
  • MA2 Muscarinic Antagonist 2
  • MA2 Crystalline Form A General Experimental conditions for the preparation of MA2 Crystalline Form A are the same as those described herein below in Preparation [2] of MA 11.
  • the reaction mixture was dosed to a mixture of 23.1 w/w% NH 4 Cl (3.97 L/kg) and water (3.97 L/kg). The phases were separated and the aqueous layer extracted with ethyl acetate (7 L/kg). The combined organic layers were washed with water (5.25 L/kg), and 70% of the volume removed by distillation (p > 130 mbar, 50 0 C). To the distillation residue acetonitrile (7.82 L/kg) was added and the suspension heated until complete dissolution was attained (70 0 C). The reaction was then cooled to 0 0 C over 7 h and stirred at O 0 C for at least Ih.
  • reaction product ( ⁇ )- cyclohexyl-(5-dimethylaminomethyl-oxazol-2-yl)-phenyl-methanol was then collected by filtration and washed three times with cold acetonitrile (1.65 L/kg). Yields achieved with this procedure ranged between 60-70% and the purities achieved were > 97% peak area (HPLC) and > 97% w/w (NMR).
  • the resulting suspension was cooled to 0 0 C and stirred for 3 h at this temperature.
  • the product was collected by filtration, using iso-propanol (2.14 L/kg) to aid transfer from vessel to filter.
  • the filter cake was washed with iso-propanol ( 1 L/kg) and dried on a rotary evaporator over night.
  • the crude product was obtained as a white solid in 86% yield.
  • the solution was filtered through a heated in line filter into a stirring vessel.
  • the reactor and the filter lines were rinsed with warm (55°C) iso-propanol (1.11 L/kg).
  • the content of the stirring vessel was transferred back into the reactor and rinsed with iso-propanol (1.1 lL/kg).
  • Iso-propanol (5.5517kg) was distilled off at a temperature of 47°C-50°C and a pressure of 200 mbar.
  • the residue was cooled to 52 0 C.
  • TBME (10 L/kg) was added over 35 min.
  • the resulting solution was stirred for 2 h at 50 0 C.
  • Seed crystals (1.18 %w/w (with respect to input (R)-cyclohexyl-(5-dimethylaminomethyl- oxazol-2-yl)-phenyl-methanol)) were added and the mixture was stirred for additional 2 h at 50 0 C.
  • the suspension formed was cooled to 0 0 C over 3 h and stirred at that temperature for 13 h.
  • the filter cake was pre-dried for 4.5hr in a stream of nitrogen and afterwards it was further dried on a rotary evaporator at 45°C and >12mmbar to yield the product as a crystalline white solid. Yield obtained by this process on a 2.7kg scale was 90.5% and the purity 98.3% peak area (HPLC) and 98.9% w/w (NMR). Loss on drying was 0.23% w/w (gravimetric).
  • the melting temperature of Form A as determined by DSC was found to be 15O 0 C (onset) ( ⁇ 2 0 C). Weight loss observed prior to melting by TGA was negligible, near 0.0%. GVS determination gave a 0.8 % weight increase (%w/w) at 80% RH ( ⁇ 0.2%).
  • An XRPD spectrum of Muscarinic Antagonist 2 (MA2) Crystalline Form A is presented in Figure 1.
  • Muscarinic Antagonist 3 [2-((R)-Cvclohexyl-hvdroxy-phenyl-methvI)-oxazol- 5-ylmethvH -dimethyl-(2-phenethvIoxy-ethyl)-ammoniuni bromide
  • Muscarinic Antagonist 4 (MA4): r2-((R)-CyclohexyI-hvdroxy-phenyl-methyl)-oxazol- 5-ylmethvIH3-(3,4-dichloro-phenoxy)-propyll-dimethvI-ammonium bromide
  • Muscarinic Antagonist 5 MA5: r2-((R)-Cvclohexyl-hvdroxy-phenyI-methyl)-oxazol- 5-ylmethvn-r2-(3,4-dichIoro-benz ⁇ loxy)-ethyIl-dimethyl-ammonium bromide
  • Muscarinic Antagonist 6 MA6: r2-(4-chIoro-benzvIox ⁇ )-ethvI1-[2-((R)-cyclohexyl- hvdroxy-phenyl-meth ⁇ I)-oxazol-5-vImethyll-dimethyl-ammonium bromide
  • Muscarinic Antagonist 7 (MA7): r2-((R)-CvcIohexyI-hvdroxy-phenvI-methvI)-oxazoI-
  • MA7 Amorphous form (as prepared herein above) was heated in toluene with stirring at 60° for 48hours and allowed to cool to RT while stirring to afford the product as small platelets.
  • the product was collected by filtration and dried under vacuum at 50 0 C for 3 h.
  • the melting temperature of Form 1 was determined by DSC, during which testing Form 1 underwent dehydration and subsequently the dehydrated Form 1, totally or partially converted into an anhydrous form, melted at 225 0 C ⁇ 2°C (onset).
  • Water content as determined by TGA was 0.7 % ( ⁇ 0.2%).
  • GVS determination gave a 3.1 % weight increase (%w/w) at 80 % RH ( ⁇ 0.5%).
  • Form 1 Further quantities of Form 1 were prepared as follows: MA7 Amorphous form was crystallised from refluxing acetonitrile using a hot filtration of the solution and allowed to cool to RT while stirring to afford the product as small platelets. The product was collected by filtration and stirred in toluene at 60 0 C for 19 h. The solids were collected by decanting the solvent and dried under vacuum at 50 0 C for 3h. XRPD and DSC analysis were consistent with Form 1.
  • MA7 Amorphous form was heated in anisole at 154 0 C for 3hrs then left to stand at RT for 48hrs. The solids were collected by decanting the solvent and dried under vacuum at 45 0 C. The melting temperature of Form 2 as determined by DSC was found to be 227 0 C ⁇ 2°C (onset). Water content as determined by TGA was 0.0 %. GVS determination gave a 0.7 % weight increase (%w/w) at 80 % RH ( ⁇ 0.-2%).
  • Form 2 Further quantities of Form 2 were prepared as follows: MA7 Amorphous form was crystallised from refluxing chlorobenzene and allowed to slowly cool to RT to afford the product as fine needles. The product was collected by filtration and dried under vacuum at RT overnight. XRPD and DSC analysis were consistent with Form 2. Further quantities of Form 2 were prepared as follows: MA7 Amorphous form was stirred in toluene at 80 0 C over for at least 60 hours. The solids were collected by decanting the solvent and dried under vacuum at 45 0 C. XRPD and DSC analysis were consistent with Form 2.
  • MA7 Amorphous form was crystallised from refluxing acetone/water mixture using a hot filtration of the solution and allowed to cool to RT while stirring to afford the product as a white powder. The product was collected by filtration and dried under vacuum at RT overnight.
  • the melting temperature of Form 3 was determined by DSC, during which testing Form 3 underwent dehydration and subsequently the dehydrated Form 3, totally or partially converted into an anhydrous form, melted at 224 0 C ⁇ 2°C (onset). Water content as determined by TGA was 2.1 % ( ⁇ 0.2%). GVS determination gave a 3.0 % weight increase (%w/w) at 80 % RH ( ⁇ 0.2%).
  • Muscarinic Antagonist 8 [2-((R)-CvcIohexyl-hvdroxy-phenyl-methyl)-oxazol-5- vImethv ⁇ -dimethyl-(2-phenethyloxy-ethyl)-ammonium hemi-naphthalene-l,5-disulfonate
  • Muscarinic Antagonist 9 (MA9): r2-((R)-CycIohexyl-hvdroxy-phenyl-inethyl)-oxazol-
  • Muscarinic Antagonist 10 [2-((R)-CycIohexyl-hvdroxy-phenyI-methvI)- oxazol-5-vIniethyl1-r2-(3,4-dichIoro-benzvioxy)-ethvn-dimethyl-ammonium hemi- naphthalene- 1,5-disulfonate
  • Muscarinic Antagonist 11 (MAIl): f2-(4-chloro-benzyloxy)-ethyll-[2-((R)-cvcIohexyl- hvdroxy-phenyl-methyI)-oxazoI-5-vImethyll-dimethyl-ammonium hemi-naphthalene- 1,5-disulfonate
  • MAl 1 may be prepared according to the method used in MA7, but using [2-(4-chloro- benzyloxy)-ethyl]-[2-((R)-cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]- dimethyl-ammonium bromide (MA6) instead of [2-((R)-cyclohexyl-hydroxy-phenyl- methyl)-oxazol-5-ylmethyl]-dimethyl-(3-phenoxy-propyl)-ammonium bromide.
  • MA6 dimethyl-ammonium bromide
  • NMR spectra were obtained on a Bruker AVANCE400 spectrometer: Frequency: 400 MHz; 2-Channel; z-Gradient. Temp Range: 0-120 0 C.
  • the melting temperature of Form A as determined by DSC was found to be 233 0 C (onset) ( ⁇ 3 0 C). Weight loss observed prior to melting by TGA was very low (0.0% - 0.5 %) GVS determination gave weight increase of less than 0.5(%w/w) at 80% RH ( ⁇ 0.3%).
  • 'Salt Form A' was Micronised in a 50 mm jet mill, with ejector pressure 5 bar and milling pressure 1.5-2 bar, giving (90% yield). Particle size of the micronised material as determined by Malvern Laser Diffraction with dry powder feeder was d(0,l) 0,77 ⁇ m: d(0,5), 1,45 ⁇ : d(0,9): 2,65 ⁇ m. An investigational evaluation of the deaggregation properties of micronised 'Salt Form A' showed excellent Fine Particle Fraction (FPF >60%) across a range of relative humidity (0-75% RH).
  • 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.
  • the rate at which [ 3 H]-QNB is detected binding to the muscarinic receptors is related to the rate at which the antagonist dissociates from the receptor, i.e. to the half life of the antagonists on the receptors.
  • Method A Instrument Agilent 1100; Column: Kromasil C18 100 x 3 mm, 5 ⁇ particle size, Solvent A: 0.1 %TFA/water, Solvent B: 0.08%TFA/acetonitrile Flow: 1 ml/min, Gradient 10-100% B 20 min, 100% B 1 min. Absorption was measured at 220, 254 and 280 nm.
  • Method B Instrument Agilent 1100; Column: XTerra C8, 100 x 3 mm, 5 ⁇ particle size, Solvent A: 15 mM NH 3 /water, Solvent B: acetonitrile Flow: 1 ml/min, Gradient 10-100% B 20 min, 100% B 1 min.
  • X-ray powder diffraction (XRPD) analyses may be performed on samples prepared according to standard methods (see for example Giacovazzo et aL, eds., Fundamentals of Crystallography, Oxford University Press (1992); Jenkins & Snyder, eds., Introduction to X-Ray Powder Diffractometry, John Wiley & Sons, New York (1996); Bunn, ed., Chemical Crystallography, Clarendon Press, London (1948); and Klug & Alexander eds., X-ray Diffraction Procedures, John Wiley & Sons, New York (1974)).
  • X-ray powder diffraction patterns of the Forms A salt described in Examples 1 and 2 were obtained as described below:
  • a Bragg-Brentano parafocusing powder X-ray diffractometer using monochromatic CuKa radiation (45 kV and 40 mA) was used for the analyses.
  • the primary optics contained soller slits and an automatic divergence slit.
  • Flat samples were prepared on zero background plates that were rotated during the meausurements.
  • the secondary optics contained soller slits, an automatic anti scatter slit, a receiving slit and a monochromator.
  • the diffracted signal was detected with a proportional xenon-filled detector.
  • Diffraction patterns were collected between 2° ⁇ 2 ⁇ (theta) ⁇ 40° in a continous scan mode with a step size of 0.016° 2 ⁇ at a rate of 4° 2 ⁇ per minute.
  • Raw data were stored electronically. Evaluation was performed on raw or smoothed diffraction patterns.
  • a Panalytical X 'pert PRO MPD ⁇ - ⁇ diffractometer in reflection mode was used for the above-mentioned measurements.
  • a person skilled in the art can set up instrumental parameters for a powder X-ray diffractometer so that diffraction data comparable to the data presented can be collected.
  • N- ⁇ 5-chloro-2-[((2S)-3- ⁇ [ 1 -(4-chlorobenzyl)piperidin-4-yl]amino ⁇ -2-hydroxy-2- methylpropyl)oxy]-4-hydroxyphenyl ⁇ acetamide (55 mg) is dissolved in 2-butanol (4 mL) and, under stirring, heated to 55 0 C. To this a IM H 2 SO 4 in 2-butanol solution (0.11 mL), that is kept at room temperature, is added in one portion. The mixture is warmed to 70 0 C, additional 2-butanol is added (16 mL) and the suspension stirred for 12h.
  • CCRl Antagonist 2 Methyl 3-(2- ⁇ [(25)-3- ⁇ [l-(4-chlorobenzyl)piperidin-4-yI]amino ⁇ -2- hydroxypropyl]oxy ⁇ -4-fluorophenyl)propanoate
  • Step I Methyl 3-(4-fluoro-2-f(2 1 $')-oxiran-2-ylmethoxylphenyUpropanoate
  • Step I (4-Fluoro-2- ⁇ r(2S)-2-methyloxiran-2-yllmethoxy)phenyl)methanol
  • a mixture of 5-fluoro-2-(hydroxymethyl)phenol (284 mg), [(2S)-2-methyloxiran-2- yl]methyl 3-nitrobenzenesulfonate (546 mg), and Cs 2 CO 3 (986 mg) in DMF (5 ml) was stirred at room temperature for 18h. The mixture then was diluted with ethyl acetate (100 ml), and washed with water (2 x 50 ml). The organic layer was dried with sodium sulphate. The solvent was removed in vacuo to afford subtitle compound, 452 mg, which was used in the next step without further purification.
  • Step II fert-Butyl ri-(4-chlorobenzyl)piperidin-4-yll((2.S')-3-r5-fluoro-2-
  • Step HI rert-Butyl ri-(4-chlorobenzyl)piperidin-4-yll((25)-3-r2-(chloromethyl)-5- fluorophenoxy1-2-hydroxy-2-methylpropyl ) carbamate
  • Step IV (2-f f(2S)-3-l ri-(4-chlorobenzyl)piperidin-4-yllamino)-2-hvdroxy-2-o methylpropylloxy ) -4-fluorophen vDmethanesulfonic acid
  • Step HI Ethyl 5-chloro-2-hvdroxy-4-[Y4-methoxybenzyl)oxylbenzoate
  • aceton 50 mL
  • 4-methoxybenzylchloride 1.42 g
  • K 2 CO 3 1.25 g
  • the reaction was heated to reflux for 18 h, afterwhich the solvent was removed in vacuo.
  • the residue was redissolved in EtOAc and washed with water.
  • the organic solvent was removed in vacuo and the residue recrystallized from methanol and subsequently from ethanol, yielding 1.38 g of the subtitled compound as a white solid.
  • Step IV 5-Chloro-2hvdroxy-4-r(4-methoxybenzyl)oxy1benzoic acid
  • ethanol 15 mL
  • 1 M NaOH aq 15 mL
  • the reaction was heated to reflux for Ih, diluted with water (100 mL) and the pH adjusted with 1 M HCl aq (15 mL) to acidic.
  • the precipitate was filtered, washed with water and dried in a vacuum oven yielding 1.09 g of the subtitled compound as a white solid.
  • Step VA 5-Chloro-6-r(4-methoxybenzyl)oxyl- 1 ,3-benzoxazol-2(3H)-one
  • a solution of 5-chloro-2-hydroxy-4-[(4-methoxybenyl)oxy]benzoyl azide (30 mg) in toluene (2 mL) was stirred at 100 0 C for 18 h.
  • the precipitate was colected, yielding 19 mg of the subtitled compound.
  • Step VI N-15-Chloro-4-f(4-methoxybenzyl)oxyl-2-r(2S)-oxiran-2-ylmethoxylphenyl-N'- cyclopropyl urea 5
  • a solution of 5-chloro-6-[(4-methoxybenzyl)oxy]-l,3-benzoxazol-2(3H)-one (1.62 g) in cyclopropylamine (10 mL) was stirred at room temperature for 2h and at 50 0 C for 2 h.
  • Step I N-ethyl- ⁇ r-(2-r(2S)-oxiran-2ylmethoxylphenylurea
  • Two stocksolutions of 0.2 M N-ethyl-W-(2-hydroxyphenyl)urea in DMF and 0.2 M [(2S)- 2methyloxiran-2-yl] methyl 3-nitrobenzenesulfonate in DMF were combined (total volume 100 ⁇ L).
  • cesium carbonate (0.03 mmol) was added and the reaction was stirred at room temperature for 18h.
  • the mixture was partitioned between water and DCM and the organic layer washed with water.
  • the organic solvent was removed and the compound used without further purification in stepll, example 6 APCI-MS: m/z 251 (MH + ).
  • CCRl Antagonist 7 (2S)-l-(2-ethyIphenoxy)-3[(l-[4-chlorobenzyl]4-piperidinyl)amino]propan-2-ol Prepared following procedure as described for CCRl Antagonist 6.
  • Step I N-cvclopropyl-2-fluoro-6-hydroxy benzamide
  • Step II N-cvclopropyl-2-fluoro-6-r(2S)-oxiran-2ylmethoxy1benzamide
  • N-cyclopropyl-2-fluoro-6-hydroxy benzamide 100 mg
  • S)-glycidyl nosylate 110 mg
  • cesium carbonate 250 mg
  • the suspension was stirred at room temperature for 18 h.
  • the mixture was partitioned between EtOAc and water and the organic layer washed four times with water, dried over sodium sulphate and removed in vacuo yielding 89 mg of the subtitled compound.
  • the material was used without further purification in step III of example 10.
  • Step ⁇ i Prepared following procedure as described for CCRl Antagonist 6, step II.
  • 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 ADInstruments 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
  • LPS Lipopolyaccharide
  • 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.
  • mice 4 hours after the LPS challenge, 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.
  • pentobarbital 60 mg/ml, Apoteksbolaget, Sweden
  • PBS 1: 1 for 1 - 2 min.
  • Bronchoa.lv eolar 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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  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
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Abstract

La présente invention a trait à un produit, une trousse ou une composition pharmaceutique comprenant un premier principe actif, qui est un antagoniste d'un récepteur muscarinique sélectionné, et un second principe actif, qui est choisi parmi un inhibiteur de la phosphodiestérase, un modulateur de l'action du récepteur des chimiokines, un inhibiteur de l'activité kinase, un inhibiteur des protéases, un agoniste stéroïdien du récepteur des glucocorticoïdes, un agoniste non stéroïdien du récepteur des glucocorticoïdes et un antagoniste du purinocepteur, utilisable dans le cadre du traitement de maladies respiratoires comme la bronchopneumopathie chronique obstructive et l'asthme.
PCT/GB2008/000415 2007-02-07 2008-02-06 Combinaison inédite WO2008096136A1 (fr)

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Cited By (7)

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EP2125728A1 (fr) * 2007-02-23 2009-12-02 AstraZeneca AB Nouvelle combinaison de composés utilisés dans le traitement des maladies des voies aériennes, en particulier la bronchopneumopathie chronique obstructive (copd) et l'asthme
WO2009154554A1 (fr) * 2008-06-17 2009-12-23 Astrazeneca Ab Produit pharmaceutique comprenant un antagoniste du récepteur muscarinique et un second principe actif
WO2010019097A1 (fr) * 2008-08-12 2010-02-18 Astrazeneca Ab Produit pharmaceutique constitué d’un antagoniste du récepteur muscarinique et d’un second principe actif
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
EP3061821A1 (fr) 2009-07-22 2016-08-31 Puretech Ventures Procédés et compositions pour le traitement de troubles améliorés par l'activation du récepteur muscarinique
US10925832B2 (en) 2018-09-28 2021-02-23 Karuna Therapeutics, Inc. Compositions and methods for treatment of disorders ameliorated by muscarinic receptor activation

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EP0307141A2 (fr) * 1987-09-10 1989-03-15 MERCK SHARP & DOHME LTD. Oxazoles et thiazoles pour le traitement de la démence sénile
WO1997030994A1 (fr) * 1996-02-22 1997-08-28 Pfizer Research And Development Company, N.V./S.A. Oxa- et thia-diazoles utilises comme antagonistes des recepteurs muscariniques
US20020052312A1 (en) * 2000-05-30 2002-05-02 Reiss Theodore F. Combination therapy of chronic obstructive pulmonary disease using muscarinic receptor antagonists
WO2006112778A1 (fr) * 2005-04-20 2006-10-26 Astrazeneca Ab Nouveaux antagonistes des recepteurs muscariniques
WO2007017669A1 (fr) * 2005-08-08 2007-02-15 Argenta Discovery Ltd. Derives d'azole et de thiazole et utilisation de ceux-ci
WO2008017827A2 (fr) * 2006-08-08 2008-02-14 Argenta Discovery Limited Composés chimiques

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EP0307141A2 (fr) * 1987-09-10 1989-03-15 MERCK SHARP & DOHME LTD. Oxazoles et thiazoles pour le traitement de la démence sénile
WO1997030994A1 (fr) * 1996-02-22 1997-08-28 Pfizer Research And Development Company, N.V./S.A. Oxa- et thia-diazoles utilises comme antagonistes des recepteurs muscariniques
US20020052312A1 (en) * 2000-05-30 2002-05-02 Reiss Theodore F. Combination therapy of chronic obstructive pulmonary disease using muscarinic receptor antagonists
WO2006112778A1 (fr) * 2005-04-20 2006-10-26 Astrazeneca Ab Nouveaux antagonistes des recepteurs muscariniques
WO2007017669A1 (fr) * 2005-08-08 2007-02-15 Argenta Discovery Ltd. Derives d'azole et de thiazole et utilisation de ceux-ci
WO2008017827A2 (fr) * 2006-08-08 2008-02-14 Argenta Discovery Limited Composés chimiques

Cited By (17)

* 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
EP2125728A1 (fr) * 2007-02-23 2009-12-02 AstraZeneca AB Nouvelle combinaison de composés utilisés dans le traitement des maladies des voies aériennes, en particulier la bronchopneumopathie chronique obstructive (copd) et l'asthme
EP2125728A4 (fr) * 2007-02-23 2011-06-22 Astrazeneca Ab Nouvelle combinaison de composés utilisés dans le traitement des maladies des voies aériennes, en particulier la bronchopneumopathie chronique obstructive (copd) et l'asthme
US8329729B2 (en) 2008-05-13 2012-12-11 Astrazeneca Ab Quinuclidine derivatives as muscarinic M3 receptor antagonists
WO2009154554A1 (fr) * 2008-06-17 2009-12-23 Astrazeneca Ab Produit pharmaceutique comprenant un antagoniste du récepteur muscarinique et un second principe actif
WO2010019097A1 (fr) * 2008-08-12 2010-02-18 Astrazeneca Ab Produit pharmaceutique constitué d’un antagoniste du récepteur muscarinique et d’un second principe actif
US10369143B2 (en) 2009-07-22 2019-08-06 PureTech Health LLC Methods and compositions for treatment of disorders ameliorated by muscarinic receptor activation
US10238643B2 (en) 2009-07-22 2019-03-26 PureTech Health LLC Methods and compositions for treatment of disorders ameliorated by muscarinic receptor activation
EP3061821A1 (fr) 2009-07-22 2016-08-31 Puretech Ventures Procédés et compositions pour le traitement de troubles améliorés par l'activation du récepteur muscarinique
US10369144B2 (en) 2009-07-22 2019-08-06 PureTech Health LLC Methods and compositions for treatment of disorders ameliorated by muscarinic receptor activation
EP3646870A1 (fr) 2009-07-22 2020-05-06 Puretech Health LLC Procédés et compositions pour le traitement de troubles améliorés par l'activation du récepteur muscarinique
US10695339B2 (en) 2009-07-22 2020-06-30 PureTech Health LLC Methods and compositions for treatment of disorders ameliorated by muscarinic receptor activation
US10925832B2 (en) 2018-09-28 2021-02-23 Karuna Therapeutics, Inc. Compositions and methods for treatment of disorders ameliorated by muscarinic receptor activation
US10933020B2 (en) 2018-09-28 2021-03-02 Karuna Therapeutics, Inc. Compositions and methods for treating disorders ameliorated by muscarinic receptor activation
US11452692B2 (en) 2018-09-28 2022-09-27 Karuna Therapeutics, Inc. Compositions and methods for treating disorders ameliorated by muscarinic receptor activation
US11471413B2 (en) 2018-09-28 2022-10-18 Karuna Therapeutics, Inc. Compositions and methods for treating disorders ameliorated by muscarinic receptor activation
US11890378B2 (en) 2018-09-28 2024-02-06 Karuna Therapeutics, Inc. Compositions and methods for treating disorders ameliorated by muscarinic receptor activation

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