WO2009139709A1 - Dérivés de quinuclidine et leur utilisation comme antagonistes des récepteurs muscariniques pour le traitement de l’asthme et de la bronchopneumopathie chronique obstructive (bpco) - Google Patents

Dérivés de quinuclidine et leur utilisation comme antagonistes des récepteurs muscariniques pour le traitement de l’asthme et de la bronchopneumopathie chronique obstructive (bpco) Download PDF

Info

Publication number
WO2009139709A1
WO2009139709A1 PCT/SE2009/050526 SE2009050526W WO2009139709A1 WO 2009139709 A1 WO2009139709 A1 WO 2009139709A1 SE 2009050526 W SE2009050526 W SE 2009050526W WO 2009139709 A1 WO2009139709 A1 WO 2009139709A1
Authority
WO
WIPO (PCT)
Prior art keywords
phenyl
alkyl
bicyclo
azonia
ylmethyl
Prior art date
Application number
PCT/SE2009/050526
Other languages
English (en)
Inventor
Andrew Mather
Antonio Mete
Ian Millichip
Original Assignee
Astrazeneca Ab
Argenta Discovery Ltd.
Ford, Rhonan
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Astrazeneca Ab, Argenta Discovery Ltd., Ford, Rhonan filed Critical Astrazeneca Ab
Publication of WO2009139709A1 publication Critical patent/WO2009139709A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • 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 cycloalkyl-substituted alkyl esters of poly cyclic amino alcohols, a process for their preparation, pharmaceutical compositions containing them, a process for preparing pharmaceutical compositions, their use in therapy and intermediates of use in their preparation.
  • 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.
  • GPCR G-protein coupled receptor
  • Parasympathetic nerves are the main pathway for reflex bronchoconstriction in human airways and mediate airway tone by releasing acetylcholine onto muscarinic receptors.
  • Airway tone is increased in patients with respiratory disorders such as asthma and chronic obstructive pulmonary disease (COPD), and for this reason muscarinic receptor antagonists have been developed for use in treating airway diseases.
  • Muscarinic receptor antagonists often called anticholinergics in clinical practice, have gained widespread acceptance as a first-line therapy for individuals with COPD, and their use has been extensivley reviewed in the literature (e.g. Lee et al, Current Opinion in Pharmacology 2001,1, 223-229).
  • muscarinic receptor antagonists When used to treat respiratory disorders, muscarinic receptor antagonists are typically administered by inhalation. However, when administered by inhalation a significant proportion of the muscarinic receptor antagonist is often absorbed into the systemic circulation resulting in reported side effects such as dry mouth. Additionally, the majority of muscarinic antagonists have a relatively short duration of action requiring that they be administered several times a day. Such a multiple-daily dosing regime is not only inconvenient to the patient but also creates a significant risk of inadequate treatment due to patient non-compliance associated with the frequent repeat dosing schedule.
  • WO 98/04517 describes arylcyclopropane, arylcyclobutane, arylcyclopentane and arylcyclohexane carboxylic esters having antimuscarinic activity on the urinary bladder smooth muscle.
  • R 1 and R 2 together with the carbon atom to which they are both directly attached form a 3 to 8 membered non-aromatic carbocyclic ring which may be optionally substituted by one or more substituents independently selected from halogen, hydroxyl, C 1-6 alkoxy, NH 2 , NH(Ci-O alkyl), N(Ci -6 alkyl) 2 and Ci -6 alkyl, wherein said Ci -6 alkyl may be optionally substituted by one or more substituents independently selected from halogen and hydroxyl;
  • R 3 represents phenyl or a 5 to 6 membered heteroaryl ring, each of which may be optionally substituted by one or more substituents independently selected from halogen, cyano, nitro, hydroxyl, Ci -6 alkoxy, NH 2 , NH(Ci -6 alkyl), N(Ci -6 alkyl) 2 , S(Ci -6 alkyl) and Ci -6 alkyl which Ci -6 alkyl may be optionally substituted by one or more substituents independently selected from halogen and hydroxyl;
  • Y is -CH 2 - or, -CH 2 CH 2 - or -CH 2 CH 2 CH 2 -,
  • n is 1, 2, 3 or 4, and within each grouping CR 4 R 5 , R 4 and R 5 each independently represent hydrogen or a Ci -4 alkyl group;
  • Het 1 represents a 5-membered heteroaryl ring containing 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulphur, said 5-membered heteroaryl ring is substituted by a phenyl group wherein said phenyl group may be optionally substituted by one or more substituents independently selected from cyano, nitro, halogen, hydroxyl, Ci -6 alkoxy, NH 2 , NH(Ci -6 alkyl), N(Ci -6 alkyl) 2 , S(Ci -6 alkyl) and Ci -6 alkyl, wherein said Ci -6 alkyl may be optionally substituted by one or more substituents independently selected from halogen and hydroxyl; or alternatively Het 1 represents a 5,6-fused bicyclic heteroaryl ring containing 2, 3 or 4 hetero
  • X represents a pharmaceutically acceptable anion of a mono or polyvalent acid.
  • the compounds of formula (I) comprise an anion X associated with the positive charge on the quaternary nitrogen atom.
  • the anion X may be any pharmaceutically acceptable anion of a mono or polyvalent (e.g. bivalent) acid.
  • X may be an anion of a mineral acid, for example chloride, bromide, iodide, sulfate, nitrate or phosphate; or an anion of a suitable organic acid, for example acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, methanesulphonate, p-toluenesulphonate, benzenesulphonate, napadisylate (naphthalene-l,5-disulphonate) (e.g. a heminapadisylate), 2,5-dichlorobenzenesulphonate, xinafoate (l-hydroxy-2-naphthoate) or 1- hydroxy
  • Heteroaryl denotes aromatic ring systems comprising at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, and includes monocyclic and bicyclic heteroaromatic rings.
  • 5 to 6 membered heteroaryl rings according to the present invention include thienyl, furanyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, oxazolyl, oxadiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl and triazolyl.
  • bicyclic heteroaromatic rings include fused bicyclic ring systems wherein both rings are aromtaic or, alternatively, one ring is aromatic and the other ring is non-aromatic.
  • heteroaryl groups may be linked through carbon or nitrogen.
  • Examples of 5 to 6 membered heteroaryl rings according to the present invention include thienyl, furanyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, oxazolyl, oxadiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl and triazolyl.
  • Examples of bicyclic heteroaromatic rings include indolyl, indazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl.
  • 'aliphatic carbocyclic ring denotes non-aromatic carbocyclic rings, both monocyclic and bicyclic. Examples of 3 to 8 membered aliphatic carbocyclic rings are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • cycloalkyl denotes saturated monocyclic carbocyclic rings. Cycloalkyl groups are monocyclic, for example cyclopentyl or cyclohexyl. Halogen is for example, fluorine, chlorine or bromine.
  • alkyl groups and moieties may be straight or branched chain and include, for example, methyl, ethyl, n- propyl, iso-propyl or tert-butyl.
  • alkylene denotes bivalent alkyl groups , e.g.
  • alkylene groups may incorporate cycloalkyl rings, e.g. an example of a C 4 alkylene is
  • a group may be optionally substitued with one or more substituents the group may be unsubstituted or substituted; when substituted the group will generally be substitued with one, two or three substituents.
  • a hydroxyl moiety will not be attached to a carbon atom which is adjacent to a nitrogen atom.
  • R 1 and R 2 together with the carbon atom to which they are both directly attached form a 5 to 7 membered non-aromatic carbocyclic ring which may be optionally substituted by one or more substituents independently selected from halogen, hydroxyl, C 1-6 alkoxy, NH 2 , NH(Ci -6 alkyl), N(Ci -6 alkyl) 2 and Ci -6 alkyl, wherein said Ci -6 alkyl may be optionally substituted by one or more substituents independently selected from halogen and hydroxyl.
  • R 1 and R 2 together with the carbon atom to which they are both directly attached form a 6 or 7 membered cycloalkyl ring which may be optionally substituted by one or more substituents independently selected from halogen, hydroxyl, C 1-4 alkoxy, NH 2 , NH(Ci -4 alkyl), N(Ci -4 alkyl) 2 and Ci -4 alkyl, wherein said Ci -4 alkyl may be optionally substituted by one or more substituents independently selected from halogen and hydroxyl.
  • R 1 and R 2 together with the carbon atom to which they are both directly attached form a 7 membered cycloalkyl ring which may be optionally substituted by one or more substituents independently selected from halogen, hydroxyl and Ci -4 alkyl.
  • R 1 and R 2 together with the carbon atom to which they are both directly attached form a group of formula (VIII) wherein q is 0, 1, 2, 3 ,4, 5 or 6; and each R independently represents halogen, hydroxyl, C 1-4 alkoxy, NH 2 , NH(Ci -4 alkyl), N(Ci -4 alkyl) 2 and Ci -4 alkyl, wherein said Ci -4 alkyl may be optionally substituted by one or more substituents independently selected from halogen and hydroxyl.
  • the carbon atoms in the cycloalkyl ring may optionally carry one or two substituents.
  • q is 0, 1 or 2 and each R independently represents halogen, hydroxyl or Ci -4 alkyl.
  • q is 0.
  • R 3 represents phenyl or thienyl, wherein said phenyl or thienyl may be optionally substituted by one or more substituents independently selected from halogen, hydroxyl, Ci -4 alkoxy, NH 2 , NH(Ci -4 alkyl), N(Ci -4 alkyl) 2 , OCF 3 and Ci -4 alkyl, wherein said Ci -4 alkyl may be optionally substituted by one or more substituents independently selected from halogen and hydroxyl.
  • R 3 represents phenyl or thienyl, wherein said phenyl or thienyl may be optionally substituted by one or more substituents independently selected from halogen, hydroxyl, Ci -4 alkyl, OMe, CF 3 and OCF 3 .
  • R 3 represents an unsubstituted phenyl or unsubstituted thienyl.
  • R 3 represents phenyl which may be optionally substituted by one or more substituents independently selected from halogen, hydroxyl, C 1- 4 alkoxy, NH 2 , NH(Ci -4 alkyl), N(Ci -4 alkyl) 2 , OCF 3 and Ci -4 alkyl, wherein said Ci -4 alkyl may be optionally substituted by one or more substituents independently selected from halogen and hydroxyl.
  • R 3 represents phenyl which may be optionally substituted by one or more substituents independently selected from halogen, hydroxyl, Ci -4 alkyl, OMe, CF 3 and OCF 3 .
  • R 3 represents an unsubstituted phenyl.
  • R 1 and R 2 together with the carbon atom to which they are both directly attached form an unsubstituted 5 to 7-membered cycloalkyl ring, and R 3 represents unsubstituted phenyl or unsubstituted thienyl.
  • R 1 and R 2 together with the carbon atom to which they are both directly attached form an unsubstituted 7-membered cycloalkyl ring, and R 3 represents unsubstituted phenyl or unsubstituted thienyl.
  • R 1 and R 2 together with the carbon atom to which they are both directly attached form an unsubstituted 7-membered cycloalkyl ring, and R 3 represents unsubstituted phenyl.
  • Y is -CH 2 - or -CH 2 CH 2 -. In an embodiment of the invention, Y is -CH 2 CH 2 -.
  • the ring containing Y depicted as a group of formula (III) below, is attached to the remainder of formula (I) by substitution at the 3 or 4 position.
  • the 3 and 4 positions of group (III) are located at the positions depicted in the representation of (III) below; the location of positions 3 and 4 depicted below applies when Y is -CH 2 -, -CH 2 CH 2 - or -CH 2 CH 2 CH 2 -.
  • Y is -CH 2 - or -CH 2 CH 2 - , and the substitution on the ring containing Y is in the 3 position.
  • n is 1, 2 or 3. In an embodiment of the invention n is 1.
  • Het 1 represents a 5-membered heteroaryl ring containing 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulphur, said 5-membered heteroaryl ring is substituted by a phenyl group wherein said phenyl group may be optionally substituted by one or more substituents independently selected from cyano, nitro, halogen, hydroxyl, Ci -4 alkoxy, NH 2 , NH(Ci -4 alkyl), N(Ci -4 alky I) 2 , S(Ci -4 alkyl) and Ci -4 alkyl, wherein said Ci -4 alkyl may be optionally substituted by one or more substituents independently selected from halogen and hydroxyl; or alternatively Het 1 represents a 5,6-fused bicyclic heteroaryl ring containing 2 or 3 heteroatoms independently selected from nitrogen oxygen and sulphur, said 5,
  • Het 1 represents a 5-membered heteroaryl ring containing 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulphur, said 5-membered heteroaryl ring is substituted by a phenyl group wherein said phenyl group may be optionally substituted by one or more substituents independently selected from halogen, hydroxyl, Ci -4 alkoxy, NH 2 , NH(Ci -4 alkyl), N(Ci -4 alkyl) 2 , S(Ci -4 alkyl) and Ci -4 alkyl, wherein said Ci -4 alkyl may be optionally substituted by one or more substituents independently selected from halogen and hydroxyl; or alternatively Het 1 represents a 5,6-fused bicyclic heteroaryl ring containing 2 or 3 heteroatoms independently selected from nitrogen oxygen and sulphur, said 5,6-fused bicyclic heteroaryl ring may be optionally substituted by one or more substituents independently selected from halogen
  • Het 1 represents a 5-membered heteroaryl ring containing 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulphur, said 5-membered heteroaryl ring is substituted by a phenyl group wherein said phenyl group may be optionally substituted by one or more substituents independently selected from halogen, hydroxyl, OMe and Ci -4 alkyl, wherein said Ci -4 alkyl may be optionally substituted by one or more substituents independently selected from halogen and hydroxyl; or alternatively Het 1 represents a 5,6-fused bicyclic heteroaryl ring containing 2 or 3 heteroatoms independently selected from nitrogen oxygen and sulphur, said 5,6-fused bicyclic heteroaryl ring may be optionally substituted by one or more substituents independently selected from halogen, hydroxyl, OMe and Ci -4 alkyl, wherein said Ci -4 alkyl may be optionally substituted by one or more substituents independently selected from halogen, hydroxyl
  • Het 1 represents a 5-membered heteroaryl ring containing 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulphur, said 5-membered heteroaryl ring is substituted by a phenyl group wherein said phenyl group may be optionally substituted by one or more substituents independently selected from halogen, hydroxyl, OMe and Ci -4 alkyl, wherein said Ci -4 alkyl may be optionally substituted by one or more substituents independently selected from halogen and hydroxyl.
  • 5-membered heteroaryl rings examples include thiazole, [l,2,4]oxadiazole, [l,3,4]oxadiazole, isoxazole, [l,2,3]triazole, pyrazole and oxazole.
  • Examples of 5,6-fused bicyclic heteroaryl rings according to the embodiments described herein include benzoxazole and oxazolo[4,5- ⁇ ]pyridine.
  • a further aspect of the present invention provides a compound of formula (IA)
  • R 3 represents phenyl or thienyl, wherein said phenyl or thienyl may be optionally substituted by one or more substituents independently selected from halogen, hydroxyl, C 1-
  • R 6 independently represents halogen, hydroxyl or C 1-
  • J represents N or C; one of D, E and G represents N; another of D, E and G represents N or CH; and the last of D, E and G represents N, CH, O or S; provided that at least two of J, D, E and G independently represent N, O or S; and X represents a pharmaceutically acceptable anion of a mono or polyvalent acid.
  • a further aspect of the present invention provides a compound of formula (IB)
  • R represents phenyl or thienyl, which phenyl or thienyl may be optionally substituted by one or more substituents independently selected from halogen, hydroxyl, Ci -4 alkyl, OMe,
  • each R 8 independently represents halogen, hydroxyl or Ci -4 alkyl
  • s is 0, 1 or 2
  • each R 9 independently represents halogen, hydroxyl, Ci -4 alkyl, OMe, CF 3 or
  • Z represents CH or N
  • Y represents S, O or NR 10 wherein R 10 represents H or Ci -4 alkyl; R 4 , R 5 and n are as defined in formula (I); and X represents a pharmaceutically acceptable anion of a mono or polyvalent acid.
  • the stereochemical configuration at the 3- position of the ring containing Y is (R), as designated by the Cahn-Ingold-Prelog system.
  • the (R) stereoisomer of this embodiment may be present as a mixture with the (S) stereoisomer.
  • the (R) stereoisomer may be present in a racemic (1:1) mixture with the (S) stereoisomer.
  • a further aspect of this embodiment provides an optically pure compound of formula (I) wherein the stereochemical configuration at the 3- position of the ring containing Y is (R).
  • optically pure is defined in terms of enantiomeric excess (e.e.), which is calculated from the ratio of the difference between the amounts of the respective enantiomers present and the sum of these amounts, expressed as a percentage.
  • enantiomeric excess e.e.
  • a preparation containing 95% of one enantiomer and 5% of another enantiomer has an enantiomeric excess (e.e.) of 90% [i.e. (95-5)/(95+5) x 100].
  • An optically pure compound according to the present invention has an e.e. of at least 90%. In an embodiment of the invention, an optically pure compound has an e.e. of at least 95%.
  • an optically pure compound has an e.e. of at least
  • the compound of formula (I) is selected from:
  • octane X wherein X represents a pharmaceutically acceptable anion of a mono or polyvalent acid.
  • Pharmaceutically acceptable anions according to this embodiment include chloride, bromide and iodide.
  • the present invention provides a process for the preparation of compounds of formula (I), which comprises reacting a compound of formula (X) wherein R 1 , R 2 and R 3 are as defined in formula (I), or a Ci_ 6 alkyl ester, acid anhydride or acid halide thereof,
  • R 1 , R 2 and R 3 are as defined in formula (I) and subsequently reacting (XII) with a compound Het 1 (CR 4 R 5 )n-LG, wherein LG is a leaving group (e.g. halogen) and Het 1 , R 4 and R 5 are as defined in formula (I): and optionally
  • reaction of compound (X) may be conveniently conducted in the presence of a suitable solvent such as heptane, tetrahydrofuran, toluene or dichloromethane at a temperature in the range of 0 to 100 0 C.
  • compound (X) may conveniently react via an acid halide (e.g. chloride) as may be prepared by reacting the acid with a suitable reagent (e.g. thionyl chloride or oxalyl chloride) in a suitable solvent such as dichloromethane or toluene, at a temperature in the range of 0 to 100 0 C.
  • a suitable solvent e.g. chloride
  • reaction of compounds (XII) and Het 1 (CR 4 R 5 )n-LG may be conveniently conducted in the presence of a suitable solvent such as chloroform, dichloromethane or acetonitrile at a temperature in the range of 0 to 100 0 C.
  • a suitable solvent such as chloroform, dichloromethane or acetonitrile
  • Alcohol (XVI) may then be converted to an alkyl ether and the alkyl ether subsequently converted to acid (XVII) by treating the alkyl ether with an alkali metal and quenching with CO 2 .
  • the acid (X) may optionally be converted to its Ci ⁇ alkyl ester, acid anhydride or acid halide.
  • reaction of compounds (XIV) and (XV) may be conveniently conducted in the presence of a suitable solvent such as tetrahydrofuran or diethyl ether at a temperature in the range of 0 0 C to 100 0 C.
  • a suitable solvent such as tetrahydrofuran or diethyl ether
  • R 3 Met (XIV) Met may be lithium, sodium, potassium or magnesium halide.
  • Conversion of the alcohol R 1 R 2 R 3 COH (XVI) to its alkyl ether may conveniently be performed by treatment with a compound Ci ⁇ alkyl-LG wherein LG is a leaving group (e.g.
  • a suitable solvent such as dichloromethane, tetrahydrofuran, or acetonitrile with a suitable base such as triethylamine, diisopropylethylamine or sodium hydride at a temperature range of 0 0 C to 90 0 C.
  • a suitable base such as triethylamine, diisopropylethylamine or sodium hydride at a temperature range of 0 0 C to 90 0 C.
  • the resulting alkyl ether may then be conveniently converted to a structure of formula (X) by treatment with a mixture of sodium and potassium in a solvent such as diethyl ether at a temperature in the range of 0 0 C to -80 0 C and quenching with CO 2 .
  • Ci ⁇ alkyl ester by treatment with a Ci- ⁇ alcohol in a solvent such as Ci_6alcohol (e.g. methanol, ethanol) with an acid catalyst such as toluenesulfonic acid or by treatment of the acid with TMS-diazomethane or diazomethane in a solvent mixture such as tetrahydrofuran / methanol.
  • a solvent such as Ci_6alcohol (e.g. methanol, ethanol) with an acid catalyst such as toluenesulfonic acid or by treatment of the acid with TMS-diazomethane or diazomethane in a solvent mixture such as tetrahydrofuran / methanol.
  • Further elaboration of the acid may be performed to furnish an acid anhydride or acid halide by treatment with oxalyl chloride or sulfonyl chloride in a solvent such as dichloromethane at a temperature in the range of -20 0
  • Compounds of formula (X) may alternatively be prepared by reaction of a group of formula R 3 CH 2 COOH (or Ci ⁇ alkyl ester thereof) with a base followed by treatment with a group of formula H 2 CCH(CH 2 )2LG wherein LG is a leaving group (e.g. halogen). Multiple repetition of this process is required to ensure full conversion to a compound of formula R 3 (H 2 CCH(CH 2 ) 2 ) 2 CCOOH (XVII) or Ci -6 alkyl ester thereof. Treatment of (XVII) with metathesis catalyst such as Grubbs catalyst (2 nd Generation) to afford the cyclised alkene of formula (XVIII)
  • reaction of compounds of formula R 3 CH 2 COOH (or Ci ⁇ alkyl ester thereof) and a compound of formula H 2 CCH(CH 2 ) 2 LG may be conveniently conducted in a solvent such as tetrahydrofuran or diethyl ether with a base such as lithium dizs ⁇ propylamide or lithium ⁇ zs(trimethylsilyl)amide in the temperature range of -78°C to room temperature.
  • a solvent such as tetrahydrofuran or diethyl ether
  • a base such as lithium dizs ⁇ propylamide or lithium ⁇ zs(trimethylsilyl)amide in the temperature range of -78°C to room temperature.
  • reaction of a compound of formula R 3 (H 2 CCH(CH 2 ) 2 ) 2 CCOOH (XVII) or Ci -6 alkyl ester thereof to a compound of formula (XVIII) or Ci ⁇ alkyl ester thereof may be conveniently conducted in a solvent such as toluene, xylene or dichloromethane with a catalyst such as Grubbs Catalyst (2 nd Generation) in the temperature range of 30 0 C to 150 0 C.
  • a solvent such as toluene, xylene or dichloromethane
  • a catalyst such as Grubbs Catalyst (2 nd Generation
  • the hydrogenation reaction of a compound of formula (XVIII) may be conveniently conducted with a catalyst such as palladium on carbon or tm(triphenylphosphine)rhodium(I) chloride in a solvent such as methanol or ethanol in the temperature range of 20 0 C to 100 0 C.
  • a catalyst such as palladium on carbon or tm(triphenylphosphine)rhodium(I) chloride in a solvent such as methanol or ethanol in the temperature range of 20 0 C to 100 0 C.
  • a catalyst such as palladium on carbon or tm(triphenylphosphine)rhodium(I) chloride
  • solvent such as methanol or ethanol in the temperature range of 20 0 C to 100 0 C.
  • Compounds of formula (XI) are either commercially available or may be made by methods according or analogous to those described in the literature; see for example EP 188255, Leonard et. al. J. Or
  • the compounds of the invention have activity as pharmaceuticals, in particular as anticholinergic agents including muscarinic receptor (Ml, M2, and M3) antagonists, in particular M3 antagonists.
  • Diseases and conditions which may be treated with the compounds include:
  • respiratory tract obstructive diseases of the airways including: asthma, including bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including aspirin and NS AID-induced) and dust- induced asthma, both intermittent and persistent and of all severities, and other causes of airway hyper-responsiveness; chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; farmer's lung and related diseases; hypersensitivity pneumonitis; lung fibrosis, including cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonias, fibrosis complicating anti-neoplastic therapy and chronic infection, including tuberculosis and aspergillosis and other fungal infections; complications of lung transplantation; vasculitic and thrombotic disorders of the lung vascul
  • osteoarthritides associated with or including osteoarthritis/osteoarthrosis both primary and secondary to, for example, congenital hip dysplasia; cervical and lumbar spondylitis, and low back and neck pain; rheumatoid arthritis and Still's disease; seronegative spondyloarthropathies including ankylosing spondylitis, psoriatic arthritis, reactive arthritis and undifferentiated spondarthropathy; septic arthritis and other infection- related arthopathies and bone disorders such as tuberculosis, including Potts' disease and Poncet's syndrome; acute and chronic crystal-induced synovitis including urate gout, calcium pyrophosphate deposition disease, and calcium apatite related tendon, bursal and synovial inflammation; Behcet's disease; primary and secondary Sjogren's syndrome; systemic sclerosis and limited scleroderma; systemic lupus erythematosus, mixed connective tissue
  • arthitides for example rheumatoid arthritis, osteoarthritis, gout or crystal arthropathy
  • other joint disease such as intervertebral disc degeneration or temporomandibular joint degeneration
  • bone remodelling disease such as osteoporosis, Paget's disease or osteonecrosis
  • polychondritits such as osteoporosis, Paget'
  • skin psoriasis, atopic dermatitis, contact dermatitis or other eczematous dermatoses, and delayed-type hypersensitivity reactions; phyto- and photodermatitis; seborrhoeic dermatitis, dermatitis herpetiformis, lichen planus, lichen sclerosus et atrophica, pyoderma gangrenosum, skin sarcoid, discoid lupus erythematosus, pemphigus, pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitides, toxic erythemas, cutaneous eosinophilias, alopecia areata, male-pattern baldness, Sweet's syndrome, Weber-Christian syndrome, erythema multiforme; cellulitis, both infective and non-infective; panniculitis; cutaneous lymphomas, non-melanoma
  • eyes blepharitis; conjunctivitis, including perennial and vernal allergic conjunctivitis; ulceris; anterior and posterior uveitis; choroiditis; autoimmune; degenerative or inflammatory disorders affecting the retina; ophthalmitis including sympathetic ophthalmitis; sarcoidosis; infections including viral , fungal, and bacterial;
  • gastrointestinal tract glossitis, gingivitis, periodontitis; oesophagitis, including reflux; eosinophilic gastro-enteritis, mastocytosis, Crohn's disease, colitis including ulcerative colitis, proctitis, pruritis ani; coeliac disease, irritable bowel syndrome, and food-related allergies which may have effects remote from the gut (for example migraine, rhinitis or eczema);
  • abdominal hepatitis, including autoimmune, alcoholic and viral; fibrosis and cirrhosis of the liver; cholecystitis; pancreatitis, both acute and chronic; 8. genitourinary: nephritis including interstitial and glomerulonephritis; nephrotic syndrome; cystitis including acute and chronic (interstitial) cystitis and Hunner's ulcer; acute and chronic urethritis, prostatitis, epididymitis, oophoritis and salpingitis; vulvovaginitis; Peyronie's disease; erectile dysfunction (both male and female);
  • allograft rejection acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea or following blood transfusion; or chronic graft versus host disease;
  • CNS Alzheimer's disease and other dementing disorders including CJD and nvCJD; amyloidosis; multiple sclerosis and other demyelinating syndromes; cerebral atherosclerosis and vasculitis; temporal arteritis; myasthenia gravis; acute and chronic pain (acute, intermittent or persistent, whether of central or peripheral origin) including visceral pain, headache, migraine, trigeminal neuralgia, atypical facial pain, joint and bone pain, pain arising from cancer and tumor invasion, neuropathic pain syndromes including diabetic, post-herpetic, and HIV-associated neuropathies; neurosarcoidosis; central and peripheral nervous system complications of malignant, infectious or autoimmune processes; 11.
  • cardiovascular atherosclerosis, affecting the coronary and peripheral circulation; pericarditis; myocarditis , inflammatory and auto-immune cardiomyopathies including myocardial sarcoid; ischaemic reperfusion injuries; endocarditis, valvulitis, and aortitis including infective (for example syphilitic); vasculitides; disorders of the proximal and peripheral veins including phlebitis and thrombosis, including deep vein thrombosis and complications of varicose veins;
  • oncology treatment of common cancers including prostate, breast, lung, ovarian, pancreatic, bowel and colon, stomach, skin and brain tumors and malignancies affecting the bone marrow (including the leukaemias) and lymphoproliferative systems, such as Hodgkin's and non-Hodgkin's lymphoma; including the prevention and treatment of metastatic disease and tumour recurrences, and paraneoplastic syndromes; and, 15.
  • gastrointestinal tract Coeliac disease, proctitis, eosinopilic gastro-enteritis, mastocytosis, Crohn's disease, ulcerative colitis, microscopic colitis, indeterminant colitis, irritable bowel disorder, irritable bowel syndrome, non-inflammatory diarrhea, food- related allergies which have effects remote from the gut, e.g., migraine, rhinitis and eczema.
  • the present invention further provides a compound of formula (I), as hereinbefore defined for use in therapy.
  • the invention provides the use of a compound of formula (I), as hereinbefore defined, in the manufacture of a medicament for use in therapy.
  • the term “therapy” also includes “prophylaxis” unless there are specific indications to the contrary.
  • the terms “therapeutic” and “therapeutically” should be construed accordingly.
  • a further aspect of the invention provides a method of treating a disease state in a mammal suffering from, or at risk of, said disease, which comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula (I) as hereinbefore defined.
  • the present invention also provides a compound of formula (I) as hereinbefore defined, for treating chronic obstructive pulmonary disease (COPD) (such as irreversible COPD).
  • COPD chronic obstructive pulmonary disease
  • the present invention also provides a compound of formula (I) as hereinbefore defined, for treating asthma.
  • the present invention also provides the use of a compound of formula (I) as hereinbefore defined, in the treatment of chronic obstructive pulmonary disease (COPD) (such as irreversible COPD).
  • COPD chronic obstructive pulmonary disease
  • the present invention also provides the use of a compound of formula (I) as hereinbefore defined, in the treatment of asthma.
  • the present invention also provides the use of a compound of formula (I) as hereinbefore defined, in the manufacture of a medicament for use in the treatment of chronic obstructive pulmonary disease (COPD) (such as irreversible COPD).
  • COPD chronic obstructive pulmonary disease
  • the present invention also provides the use of a compound of formula (I) as hereinbefore defined, in the manufacture of a medicament for use in the treatment of asthma.
  • the present invention further provides a method of treating chronic obstructive pulmonary disease (COPD) (such as irreversible COPD), in a warm-blooded animal, such as man, which comprises administering to a mammal in need of such treatment an effective amount of a compound of formula (I) as hereinbefore defined.
  • COPD chronic obstructive pulmonary disease
  • the present invention further provides a method of treating asthma in a warm-blooded animal, such as man, which comprises administering to a mammal in need of such treatment an effective amount of a compound of formula (I) as hereinbefore defined.
  • a compound of the invention for the therapeutic treatment of a warmblooded animal, such as man, said ingredient is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
  • the present invention provides a pharmaceutical composition that comprises a compound of the invention as hereinbefore defined and a pharmaceutically acceptable adjuvant, diluent or carrier.
  • a process for the preparation of said composition which comprises mixing active ingredient with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the pharmaceutical composition will, for example, comprise from 0.05 to 99%w (per cent by weight), such as from 0.05 to 80%w, for example from 0.10 to 70%w, such as from 0.10 to 50%w, of active ingredient, all percentages by weight being based on total composition.
  • the pharmaceutical compositions of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by topical (such as to the lung and/or airways or to the skin), oral, rectal or parenteral administration.
  • the compounds of this invention may be formulated by means known in the art into the form of, for example, aerosols, dry powder formulations, tablets, capsules, syrups, powders, granules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible powders, suppositories, ointments, creams, drops and sterile injectable aqueous or oily solutions or suspensions.
  • aerosols dry powder formulations, tablets, capsules, syrups, powders, granules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible powders, suppositories, ointments, creams, drops and sterile injectable aqueous or oily solutions or suspensions.
  • a suitable pharmaceutical composition of this invention is one suitable for oral administration in unit dosage form, for example a tablet or capsule, which contains between 0.1 mg and Ig of active ingredient.
  • a pharmaceutical composition of the invention is one suitable for intravenous, subcutaneous or intramuscular injection.
  • Each patient may receive, for example, an intravenous, subcutaneous or intramuscular dose of O.Olmgkg "1 to lOOmgkg "1 of the compound, for example in the range of O.lmgkg "1 to 20mgkg ⁇ 1 of this invention, the composition being administered 1 to 4 times per day.
  • the intravenous, subcutaneous and intramuscular dose may be given by means of a bolus injection.
  • the intravenous dose may be given by continuous infusion over a period of time.
  • each patient will receive a daily oral dose, which is approximately equivalent to the daily parenteral dose, the composition being administered 1 to 4 times per day
  • Another suitable pharmaceutical composition of this invention is one suitable for inhaled administration, inhalation being a particularly useful method for administering the compounds of the invention when treating respiratory diseases such as chronic obstructive pulmonary disease (COPD) or asthma.
  • COPD chronic obstructive pulmonary disease
  • the compounds of formula (I) may be used effectively at doses in the ⁇ g range, for example 0.1 to 500 ⁇ g, 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 of active ingredient.
  • a pharmaceutical composition comprising a compound of the invention as hereinbefore defined, in association with a pharmaceutically acceptable adjuvant, diluent or carrier,
  • metered dose inhaler devices When administered by inhalation, metered dose inhaler devices may be used to administer the active ingredient, dispersed in a suitable propellant and with or without additional excipients such as ethanol, surfactants, lubricants or stabilising agents.
  • Suitable propellants include hydrocarbon, chlorofiuorocarbon and hydrofiuoroalkane (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 inhalers may be used to administer the active ingredient, 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 invention further relates to combination therapies wherein a compound of the invention or a pharmaceutical composition or formulation comprising a compound of the invention, is administered concurrently or sequentially or as a combined preparation with another therapeutic agent or agents, for the treatment of one or more of the conditions listed.
  • the compounds of the invention may be combined with agents listed below.
  • Non-steroidal anti-inflammatory agents including non-selective cyclo-oxygenase COX-I / COX-2 inhibitors whether applied topically or systemically
  • piroxicam such as piroxicam, diclofenac, propionic acids such as naproxen, flurbiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac, azapropazone, pyrazolones such as phenylbutazone, salicylates such as aspirin); selective COX-2 inhibitors (such as meloxicam, celecoxib, rofecoxib, valdecoxib, lumarocoxib, parecoxib and etoricoxib); cyclo-oxygenase inhibiting nitric oxide donors (CINODs); glucocorticosteroids (whether administered by topical, oral, intramuscular, intravenous, or intra-articular routes); methotrexate; leflunomide; hydroxychloroquine; d-penicillamine; auranofin or other
  • the present invention still further relates to the combination of a compound of the invention together with a cytokine or agonist or antagonist of cytokine function, (including agents which act on cytokine signalling pathways such as modulators of the SOCS system) including alpha-, beta-, and gamma- interferons; insulin-like growth factor type I (IGF-I); interleukins (IL) including ILl to 17, and interleukin antagonists or inhibitors such as anakinra; tumour necrosis factor alpha (TNF- ⁇ ) inhibitors such as anti-TNF monoclonal antibodies (for example infliximab; adalimumab, and CDP-870) and TNF receptor antagonists including immunoglobulin molecules (such as etanercept) and low-molecular- weight agents such as pentoxyfylline.
  • a cytokine or agonist or antagonist of cytokine function including agents which act on cytokine signalling pathways such as modulators of the SOCS
  • the invention relates to a combination of a compound of the invention with a monoclonal antibody targeting B-Lymphocytes (such as CD20 (rituximab), MRA-aIL16R and T-Lymphocytes, CTLA4-Ig, HuMax 11-15).
  • B-Lymphocytes such as CD20 (rituximab), MRA-aIL16R and T-Lymphocytes, CTLA4-Ig, HuMax 11-15.
  • the present invention still further relates to the combination of a compound of the invention with a modulator of chemokine receptor function such as an antagonist of CCRl, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCRlO and CCRl 1 (for the C-C family); CXCRl, CXCR2, CXCR3, CXCR4 and CXCR5
  • a modulator of chemokine receptor function such as an antagonist of CCRl, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCRlO and CCRl 1 (for the C-C family); CXCRl, CXCR2, CXCR3, CXCR4 and CXCR5
  • the present invention further relates to the combination of a compound of the invention with an inhibitor of matrix metalloprotease (MMPs), i.e., the stromelysins, the collagenases, and the gelatinases, as well as aggrecanase; especially collagenase-1 (MMP- 1), collagenase-2 (MMP-8), collagenase-3 (MMP- 13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-IO), and stromelysin-3 (MMP-11) and MMP-9 and MMP- 12, including agents such as doxycycline.
  • MMPs matrix metalloprotease
  • the present invention still further relates to the combination of a compound of the invention and a leukotriene biosynthesis inhibitor, 5 -lipoxygenase (5-LO) inhibitor or 5- lipoxygenase activating protein (FLAP) antagonist such as; zileuton; ABT-761; fenleuton; tepoxalin; Abbott-79175; Abbott-85761; a N-(5-substituted)-thiophene-2- alkylsulfonamide; 2,6-di-tert-butylphenolhydrazones; a methoxytetrahydropyrans such as Zeneca ZD-2138; the compound SB-210661; a pyridinyl-substituted 2-cyanonaphthalene compound such as L-739,010; a 2-cyanoquinoline compound such as L-746,530; or an indole or quinoline compound such as MK-591, MK-886, and BAY x 1005.
  • the present invention further relates to the combination of a compound of the invention and a receptor antagonist for leukotrienes (LT) B4, LTC4, LTD4, and LTE4 selected from the group consisting of the phenothiazin-3-ls such as L-651,392; amidino compounds such as CGS-25019c; benzoxalamines such as ontazolast; benzenecarboximidamides such as BIIL 284/260; and compounds such as zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP 45715A), and BAY x 7195.
  • LT leukotrienes
  • the present invention still further relates to the combination of a compound of the invention and a phosphodiesterase (PDE) inhibitor such as a methylxanthanine including theophylline and aminophylline; a selective PDE isoenzyme inhibitor including a PDE4 inhibitor an inhibitor of the isoform PDE4D, or an inhibitor of PDE5.
  • PDE phosphodiesterase
  • the present invention further relates to the combination of a compound of the invention and a histamine type 1 receptor antagonist such as cetirizine, loratadine, desloratadine, fexofenadine, acrivastine, terfenadine, astemizole, azelastine, levocabastine, chlorpheniramine, promethazine, cyclizine, or mizolastine; applied orally, topically or parenterally.
  • a histamine type 1 receptor antagonist such as cetirizine, loratadine, desloratadine, fexofenadine, acrivastine, terfenadine, astemizole, azelastine, levocabastine, chlorpheniramine, promethazine, cyclizine, or mizolastine
  • the present invention still further relates to the combination of a compound of the invention and a proton pump inhibitor (such as omeprazole) or a gastroprotective histamine type 2 receptor antagonist.
  • a proton pump inhibitor such as omeprazole
  • a gastroprotective histamine type 2 receptor antagonist such as a gastroprotective histamine type 2 receptor antagonist.
  • the present invention further relates to the combination of a compound of the invention and an antagonist of the histamine type 4 receptor.
  • the present invention still further relates to the combination of a compound of the invention and an alpha- l/alpha-2 adrenoceptor agonist vasoconstrictor sympathomimetic agent, such as propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, tramazoline hydrochloride or ethylnorepinephrine hydrochloride.
  • an alpha- l/alpha-2 adrenoceptor agonist vasoconstrictor sympathomimetic agent such as propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochlor
  • the present invention still further relates to the combination of a compound of the invention and a beta-adrenoceptor agonist (including beta receptor subtypes 1-4) such as isoprenaline, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, pirbuterol, or indacaterol or a chiral enantiomer thereof.
  • a beta-adrenoceptor agonist including beta receptor subtypes 1-4
  • the present invention further relates to the combination of a compound of the invention and a chromone, such as sodium cromoglycate or nedocromil sodium.
  • a chromone such as sodium cromoglycate or nedocromil sodium.
  • the present invention still further relates to the combination of a compound of the invention with a glucocorticoid, such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide or mometasone furoate.
  • a glucocorticoid such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide or mometasone furoate.
  • a compound of the invention with an agent that modulates a nuclear hormone receptor such as PPARs.
  • the present invention still further relates to the combination of a compound of the invention together with an immunoglobulin (Ig) or Ig preparation or an antagonist or antibody modulating Ig function such as anti-IgE (for example omalizumab).
  • Ig immunoglobulin
  • Ig preparation or an antagonist or antibody modulating Ig function such as anti-IgE (for example omalizumab).
  • anti-IgE for example omalizumab
  • the present invention further relates to the combination of a compound of the invention and another systemic or topically-applied anti-inflammatory agent, such as thalidomide or a derivative thereof, a retinoid, dithranol or calcipotriol.
  • a compound of the invention and another systemic or topically-applied anti-inflammatory agent, such as thalidomide or a derivative thereof, a retinoid, dithranol or calcipotriol.
  • the present invention still further relates to the combination of a compound of the invention and combinations of aminosalicylates and sulfapyridine such as sulfasalazine, mesalazine, balsalazide, and olsalazine; and immunomodulatory agents such as the thiopurines, and corticosteroids such as budesonide.
  • aminosalicylates and sulfapyridine such as sulfasalazine, mesalazine, balsalazide, and olsalazine
  • immunomodulatory agents such as the thiopurines, and corticosteroids such as budesonide.
  • the present invention further relates to the combination of a compound of the invention together with an antibacterial agent such as a penicillin derivative, a tetracycline, a macrolide, a beta-lactam, a fluoroquinolone, metronidazole, an inhaled aminoglycoside; an antiviral agent including acyclovir, famciclovir, valaciclovir, ganciclovir, cidofovir, amantadine, rimantadine, ribavirin, zanamavir and oseltamavir; a protease inhibitor such as indinavir, nelfinavir, ritonavir, and saquinavir; a nucleoside reverse transcriptase inhibitor such as didanosine, lamivudine, stavudine, zalcitabine or zidovudine; or a non-nucleoside reverse transcriptase inhibitor such as nevirapine
  • the present invention still further relates to the combination of a compound of the invention and a cardiovascular agent such as a calcium channel blocker, a beta- adrenoceptor blocker, an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin-2 receptor antagonist; a lipid lowering agent such as a statin or a fibrate; a modulator of blood cell morphology such as pentoxyfylline; thrombolytic, or an anticoagulant such as a platelet aggregation inhibitor.
  • a cardiovascular agent such as a calcium channel blocker, a beta- adrenoceptor blocker, an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin-2 receptor antagonist
  • ACE angiotensin-converting enzyme
  • angiotensin-2 receptor antagonist angiotensin-2 receptor antagonist
  • a lipid lowering agent such as a statin or a fibrate
  • a modulator of blood cell morphology such as pentoxyfylline
  • the present invention further relates to the combination of a compound of the invention and a CNS agent such as an antidepressant (such as sertraline), an anti-Parkinsonian drug (such as deprenyl, L-dopa, ropinirole, pramipexole, a MAOB inhibitor such as selegine and rasagiline, a comP inhibitor such as tasmar, an A-2 inhibitor, a dopamine reuptake inhibitor, an NMDA antagonist, a nicotine agonist, a dopamine agonist or an inhibitor of neuronal nitric oxide synthase), or an anti- Alzheimer's drug such as donepezil, rivastigmine, tacrine, a COX-2 inhibitor, propentofylline or metrifonate.
  • a CNS agent such as an antidepressant (such as sertraline), an anti-Parkinsonian drug (such as deprenyl, L-dopa, ropinirole, pr
  • the present invention still further relates to the combination of a compound of the invention and an agent for the treatment of acute or chronic pain, such as a centrally or peripherally-acting analgesic (for example an opioid or derivative thereof), carbamazepine, phenytoin, sodium valproate, amitryptiline or other anti-depressant agent-s, paracetamol, or a non-steroidal anti-inflammatory agent.
  • analgesic for example an opioid or derivative thereof
  • carbamazepine for example an opioid or derivative thereof
  • phenytoin for example an opioid or derivative thereof
  • sodium valproate for example an opioid or derivative thereof
  • amitryptiline or other anti-depressant agent-s for example an opioid or derivative thereof
  • paracetamol for example an opioid or derivative thereof
  • non-steroidal anti-inflammatory agent for example an opioid or derivative thereof
  • the present invention further relates to the combination of a compound of the invention together with a parenterally or topically-applied (including inhaled) local anaesthetic agent such as lignocaine or a derivative thereof.
  • a parenterally or topically-applied (including inhaled) local anaesthetic agent such as lignocaine or a derivative thereof.
  • a compound of the present invention can also be used in combination with an anti- osteoporosis agent including a hormonal agent such as raloxifene, or a biphosphonate such as alendronate.
  • a hormonal agent such as raloxifene
  • a biphosphonate such as alendronate.
  • the present invention still further relates to the combination of a compound of the invention together with a: (i) tryptase inhibitor; (ii) platelet activating factor (PAF) antagonist; (iii) interleukin converting enzyme (ICE) inhibitor; (iv) IMPDH inhibitor; (v) adhesion molecule inhibitors including VLA-4 antagonist; (vi) cathepsin; (vii) kinase inhibitor such as an inhibitor of tyrosine kinase (such as Btk, Itk, Jak3 or MAP, for example Gefitinib or Imatinib mesylate), a serine / threonine kinase (such as an inhibitor of a MAP kinase such as p38, JNK, protein kinase A, B or C, or IKK), or a kinase involved in cell cycle regulation (such as a cylin dependent kinase); (viii) glucose-6 phosphate de
  • -receptor antagonist for example colchicine
  • anti-gout agent for example colchicine
  • xanthine oxidase inhibitor for example allopurinol
  • uricosuric agent for example probenecid, sulfinpyrazone or benzbromarone
  • growth hormone secretagogue for example transforming growth factor (TGF ⁇ );
  • PDGF platelet-derived growth factor
  • fibroblast growth factor for example basic fibroblast growth factor (bFGF);
  • GM-CSF granulocyte macrophage colony stimulating factor
  • capsaicin cream for example tachykinin NKl or NK3 receptor antagonist such as NKP-608C, SB-233412 (talnetant) or D-4418;
  • elastase inhibitor such as UT-77 or ZD-0892
  • TNF-alpha-1 for example colchicine
  • xanthine oxidase inhibitor for example allopurinol
  • uricosuric agent for example
  • a compound of the invention can also be used in combination with an existing therapeutic agent for the treatment of cancer, for example suitable agents include: (i) an antiproliferative/antineoplastic drug or a combination thereof, as used in medical oncology, such as an alkylating agent (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan or a nitrosourea); an antimetabolite (for example an antifolate such as a fluoropyrimidine like 5-fluorouracil or tegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea, gemcitabine or paclitaxel); an antitumour antibiotic (for example an anthracycline such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dact
  • a cytostatic agent such as an antioestrogen (for example tamoxifen, toremifene, raloxifene, droloxifene or iodoxyfene), an oestrogen receptor down regulator (for example fulvestrant), an antiandrogen (for example bicalutamide, flutamide, nilutamide or cyproterone acetate), a LHRH antagonist or LHRH agonist (for example goserelin, leuprorelin or buserelin), a progestogen (for example megestrol acetate), an aromatase inhibitor (for example as anastrozole, letrozole, vorazole or exemestane) or an inhibitor of 5 ⁇ -reductase such as finasteride;
  • an antioestrogen for example tamoxifen, toremifene, raloxifene, droloxifene or iodoxyfene
  • an agent which inhibits cancer cell invasion for example a metalloproteinase inhibitor like marimastat or an inhibitor of urokinase plasminogen activator receptor function
  • an inhibitor of growth factor function for example: a growth factor antibody (for example the anti-erbb2 antibody trastuzumab, or the anti-erbbl antibody cetuximab [C225]), a farnesyl transferase inhibitor, a tyrosine kinase inhibitor or a serine/threonine kinase inhibitor, an inhibitor of the epidermal growth factor family (for example an EGFR family tyrosine kinase inhibitor such as N-(3-chloro-4-fiuorophenyl)-7-methoxy-6-(3- morpholinopropoxy)quinazolin-4-amine (gefitinib, AZD 1839), N-(3-ethynylphenyl)-6,7
  • a growth factor antibody for example
  • the present invention provides a pharmaceutical product comprising, in combination, a first active ingredient which is a compound of formula (I) as hereinbefore described, and at least one further active ingredient selected from:-
  • the pharmaceutical product according to this embodiment may, for example, be a pharmaceutical composition comprising the first and further active ingredients in admixture.
  • the pharmaceutical product may, for example, comprise the first and further active ingredients in separate pharmaceutical preparations suitable for simultaneous, sequential or separate administration to a patient in need thereof.
  • the pharmaceutical product of this embodiment is of particular use in treating respiratory diseases such as asthma, COPD or rhinitis.
  • Examples of a phosphodiesterase inhibitor that may be used in the pharmaceutical product 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
  • 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 -agonists, for example salmeterol (e.g.
  • Examples of a modulator of chemokine receptor function that may be used in the pharmaceutical product according to this embodiment include a CCRl receptor antagonist.
  • Examples of an inhibitor of kinase function that may be used in the pharmaceutical product 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 in the pharmaceutical product 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 in the pharmaceutical product according to this embodiment include those described in WO2006/046916.
  • the NMR spectra were measured on a Varian Unity Inova spectrometer at a proton frequency of either 300 or 400 or 500 MHz, or on a Bruker DRX spectrometer at a proton frequency of 400 or 500 MHz, or on a Bruker Avance spectrometer with a proton frequency of 600 MHz or or on a Bruker Avance DPX 300 spectrometer with a proton frequency of 300 MHz.
  • the MS spectra were measured on either an Agilent 1100 MSD G1946D spectrometer or a Hewlett Packard HPl 100 MSD G1946A spectrometer. Names were generated using the Autonom.
  • HPLC High Pressure/Performance Liquid Chromatography
  • TLC Thin Layer Chromatography
  • THF tetrahydrofuran
  • Example Ia 1-Phenylcycloheptanol (Example Ia) (7.6 g) was dissolved in tetrahydrofuran (100 mL) and sodium hydride (60% in oil, 2.0 g) added. The reaction was stirred at 60 0 C for 5 minutes and iodomethane (7.1 g) added. The mixture was maintained at 60 0 C overnight and then further quantities of sodium hydride (60% in oil, 2.0 g) and iodomethane (7.1 g) were added and the reaction was refluxed for 70 hours. The reaction mixture was partitioned between water (100 mL) and z ' s ⁇ hexane (100 mL) and the organic layer separated, dried (MgSO 4 ) and evaporated to afford the sub-titled compound (11.31 g).
  • Example Ic 1-Phenyl-cycloheptanecarboxylic acid (Example Ic) (4.15 g) was refluxed in methanol (150 mL) and concentrated hydrochloric acid (5 mL) for 24 hours. The solvent was evaporated and the residue was dissolved in ether (100 mL) which was washed with water (100 mL), saturated sodium bicarbonate (50 mL) and water (100 mL), dried (MgSO 4 ) and evaporated to afford the sub-titled compound (3.5 g) as an oil.
  • Methyl l-phenylcycloheptanecarboxylate (1.0 g) and (i?)-quinuclidin-3-ol (0.39 g) were refluxed in heptane (50 mL) containing sodium ( ⁇ 5 mg) in a Dean and Stark apparatus for 24 hours. Heptane (20 mL) was replaced with toluene (20 mL) and the reflux was continued for 3 days. The reaction was partitioned between water (50 mL) and ether (50 mL) and the ether layer was separated, dried (MgSO 4 ) and evaporated. The crude product was purified by column chromatography on silica eluting with ethyl acetate / triethylamine (99/1) to afford the titled compound (0.83 g) as an oil.
  • Example 2b l-Thiophen-2-yl-cyclohept-4-enecarboxylic acid ethyl ester (2.86 g) was dissolved in ethanol (30 mL) and tris(triphenylphosphine)rhodium(I) chloride (0.100 g) was added. The reaction was stirred rapidly under 5 atmospheres of hydrogen overnight. Further tris(triphenylphosphine)rhodium(I) chloride (0.050 g) was added and the reaction was stirred under 5 atmospheres of hydrogen for 3 days.
  • Example 2c l-Thiophen-2-yl-cycloheptanecarboxylic acid ethyl ester (Example 2c) (2.5 g) and (R)- quinuclidin-3-ol (2.08 g) were dissolved in toluene (350 mL) and sodium hydride (0.100 g) added under nitrogen. The mixture was heated to reflux for 20 h after which the majority of the toluene was carefully distilled off to leave -100 mL which was cooled and washed with water (100 mL), dried with MgSO 4 and evaporated. The crude product was purified by column chromatography on silica eluting with ethyl acetate / triethylamine (99/1) to afford the sub-titled compound (2.84 g).
  • Benzamide (200 mg) and l,3-dichloro-propan-2-one (210 mg) in ethanol (3 mL) were heated at 80 0 C for 8 h. The mixture was allowed to cool and the resulting solid filtered off and washed with ethanol. The compound was purified by chromatography eluting with dichloromethane to yield a the sub-titled compound as a colourless oil which solidified (165 mg).
  • the titled compound was prepared by a procedure analogous to the method of Example 17a, using 1-phenyl-cyclohexanecarboxylic acid methyl ester and (i?)-quinuclidin-3-ol.
  • the affinity (pICso) of compounds to the M 3 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 with serial dilutions of the compounds of the invention, [ 3 H]NMS at 0.2nM, half Kd (experimentally determined dissociation constant) and assay buffer (20 mM HEPES pH 7.4 containing 5 mM MgCl 2 ). The assay was conducted in a final volume of 200 ⁇ L, in the presence of 1% (v/v) dimethyl sulphoxide (DMSO). Total binding of [ 3 H]NMS was determined in the absence of competing compound and non-specific binding of [ 3 H]NMS was determined in the presence of 1 ⁇ M atropine.
  • DMSO dimethyl sulphoxide
  • the plates were incubated for 16 hours at room temperature and then read on Wallac Microbeta TM using a normalised 3 H protocol.
  • the PIC 50 defined as the negative logarithm of the concentration of compound required for 50% reduction in specific [ 3 H]-NMS binding, was determined. Table 1 shows the pICso figures for some representative Examples.
  • Table 2 gives IC50 strengths for the compounds of the examples.
  • the extent of plasma protein binding was determined via equilibrium dialysis of a compound between human plasma and aqueous buffer at 37°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°C. These cells were then rotated for a minimum of 4 hours to equilibrate. After equilibration 500 ⁇ l of the buffer samples were removed and added to HPLC vials along with 100 ⁇ l of plasma (sample in 6-fold diluted plasma), and 100 ⁇ l of the plasma samples were removed and added to HPLC vials along with 500 ⁇ l of dialysis buffer (sample in 6-fold diluted plasma).
  • 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;
  • Dunkin-Hartley guinea-pigs 300 - 60Og were supplied by a designated breeding establishment. Animals were dosed with test compound or vehicle either by inhalation in conscious guinea-pigs or by intratracheal instillation (0.5ml/kg) under recoverable gaseous anaesthesia (5% halothane). Animals were allowed to recover from the anaesthesia prior to the measurement of bronchoconstriction. Up to 48 hours post-dosing guinea-pigs were terminally anaesthetized with sodium pentobarbitone (60 mg/kg), the trachea cannulated for artificial ventilation and the jugular vein was cannulated for intravenous administration of methacholine.
  • the guinea-pigs were ventilated using a constant volume respiratory pump (Harvard Rodent Ventilator model 683) at a rate of 60 breath/min and a tidal volume of 5 ml/kg during surgical preparation.
  • Lung function (lung resistance and compliance) was measured in anaesthetised and ventilated guinea-pigs using a pulmonary measurement Flexivent system (SCIREQ, Montreal, Canada) connected to the tracheal cannulae.
  • SCIREQ pulmonary measurement Flexivent system
  • the animals were ventilated (quasi-sinusoidal ventilation pattern) at 60 breaths/min at a tidal volume of 5 ml/kg.
  • a positive end expiratory pressure of 2-3 CmH 2 O was applied.
  • Respiratory resistance was measured using the Flexivent "snapshot" facility (1 second duration, 1 Hz frequency). Lung resistance and compliance was measured before and after intravenous administration of methacholine (3, 10 and 30 ug/kg). The peak increase in resistance following methacholine challenge was calculated and the effect of the test compound on methacholine-induced lung function changes was calculated. Percentage inhibition of bronchoconstriction was calculated at each dose of methacholine as follows:
  • 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 H20, 1.5g/kg).
  • Inhibition of saliva produced by the compound could be calculated by using the following equation: (l-(Test-baseline)/(Veh-baseline))*100.

Landscapes

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

Abstract

L'invention concerne des composés de formule (I) dans laquelle R1, R2, R3, R4, R5, Het1, n, Y et X sont tels que définis dans la description, un procédé pour leur préparation, des compositions pharmaceutiques les contenant, un procédé pour la préparation de compositions pharmaceutiques, leur utilisation en thérapie et des intermédiaires utiles dans leur fabrication.
PCT/SE2009/050526 2008-05-13 2009-05-12 Dérivés de quinuclidine et leur utilisation comme antagonistes des récepteurs muscariniques pour le traitement de l’asthme et de la bronchopneumopathie chronique obstructive (bpco) WO2009139709A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0808708.2 2008-05-13
GBGB0808708.2A GB0808708D0 (en) 2008-05-13 2008-05-13 New compounds 274

Publications (1)

Publication Number Publication Date
WO2009139709A1 true WO2009139709A1 (fr) 2009-11-19

Family

ID=39571294

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/SE2009/050526 WO2009139709A1 (fr) 2008-05-13 2009-05-12 Dérivés de quinuclidine et leur utilisation comme antagonistes des récepteurs muscariniques pour le traitement de l’asthme et de la bronchopneumopathie chronique obstructive (bpco)

Country Status (2)

Country Link
GB (1) GB0808708D0 (fr)
WO (1) WO2009139709A1 (fr)

Cited By (10)

* 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
US9233108B2 (en) 2011-11-11 2016-01-12 Almirall, S.A. Cyclohexylamine derivatives having β2 adrenergic agonist and M3 muscarinic antagonist activities
WO2016046390A1 (fr) * 2014-09-26 2016-03-31 Almirall, S.A. Nouveaux dérivés bicycliques présentant une activité agoniste du récepteur bêta-2 adrénergique et une activité antagoniste du récepteur muscarinique m3
US9315463B2 (en) 2010-05-13 2016-04-19 Almirall, S.A. Cyclohexylamine derivatives having β2 adrenergic agonist and M3 muscarinic antagonist activities
US9518050B2 (en) 2012-12-18 2016-12-13 Almirall, S.A. Cyclohexyl and quinuclidinyl carbamate derivatives having β2 adrenergic agonist and M3 muscarinic antagonist activity
US9562039B2 (en) 2013-02-27 2017-02-07 Almirall, S.A. Salts of 2-amino-1-hydroxyethyl-8-hydroxyquinolin-2(1H)-one derivatives having both β2 adrenergic receptor agonist and M3 muscarinic receptor antagonist activities
US9579316B2 (en) 2013-07-25 2017-02-28 Almirall, S.A. Salts of 2-amino-1-hydroxyethyl-8-hydroxyquinolin-2(1H)-one derivatives having both muscarinic receptor antagonist and β2 adrenergic receptor agonist activities
US9643961B2 (en) 2010-05-13 2017-05-09 Almirall, S.A. Cyclohexylamine derivatives having β2 adrenergic antagonist and M3 muscarinic antagonist activities
US10456390B2 (en) 2013-07-25 2019-10-29 Almirall, S.A. Combinations comprising MABA compounds and corticosteroids

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002053564A2 (fr) * 2000-12-28 2002-07-11 Almirall Prodesfarma Ag Nouveaux derives de quinuclidine et compositions medicinales contenant ces derniers
US20020169208A1 (en) * 2001-04-03 2002-11-14 Pascal Druzgala Novel anticholinergic compounds and methods of use
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
EP1785421A1 (fr) * 2004-08-30 2007-05-16 Ono Pharmaceutical Co., Ltd. Dérivé du tropane
EP1894568A1 (fr) * 2006-08-31 2008-03-05 Novartis AG Composées pharmaceutiques destinées au traitement des maladies inflammatoires ou obstructives des bronches
WO2008059245A1 (fr) * 2006-11-14 2008-05-22 Astrazeneca Ab Dérivés de quiniclidine d'acide (hétéro)arylcycloheptane carboxylique en tant qu'antagonistes du récepteur muscarinique
WO2008059239A1 (fr) * 2006-11-14 2008-05-22 Astrazeneca Ab Nouveaux composés 514

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002053564A2 (fr) * 2000-12-28 2002-07-11 Almirall Prodesfarma Ag Nouveaux derives de quinuclidine et compositions medicinales contenant ces derniers
US20020169208A1 (en) * 2001-04-03 2002-11-14 Pascal Druzgala Novel anticholinergic compounds and methods of use
EP1785421A1 (fr) * 2004-08-30 2007-05-16 Ono Pharmaceutical Co., Ltd. Dérivé du tropane
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
EP1894568A1 (fr) * 2006-08-31 2008-03-05 Novartis AG Composées pharmaceutiques destinées au traitement des maladies inflammatoires ou obstructives des bronches
WO2008059245A1 (fr) * 2006-11-14 2008-05-22 Astrazeneca Ab Dérivés de quiniclidine d'acide (hétéro)arylcycloheptane carboxylique en tant qu'antagonistes du récepteur muscarinique
WO2008059239A1 (fr) * 2006-11-14 2008-05-22 Astrazeneca Ab Nouveaux composés 514

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
US8329729B2 (en) 2008-05-13 2012-12-11 Astrazeneca Ab Quinuclidine derivatives as muscarinic M3 receptor antagonists
US9315463B2 (en) 2010-05-13 2016-04-19 Almirall, S.A. Cyclohexylamine derivatives having β2 adrenergic agonist and M3 muscarinic antagonist activities
US9643961B2 (en) 2010-05-13 2017-05-09 Almirall, S.A. Cyclohexylamine derivatives having β2 adrenergic antagonist and M3 muscarinic antagonist activities
US9757383B2 (en) 2011-11-11 2017-09-12 Almirall, S.A. Cyclohexylamine derivatives having β2 adrenergic agonist and M3 muscarinic antagonist activities
US9233108B2 (en) 2011-11-11 2016-01-12 Almirall, S.A. Cyclohexylamine derivatives having β2 adrenergic agonist and M3 muscarinic antagonist activities
US10300072B2 (en) 2011-11-11 2019-05-28 Almirall, S.A. Cyclohexylamine derivatives having β2 adrenergic agonist and M3 muscarinic antagonist activities
US9549934B2 (en) 2011-11-11 2017-01-24 Almirall, S.A. Cyclohexylamine derivatives having β2 adrenergic agonist and M3 muscarinic antagonist activities
US9518050B2 (en) 2012-12-18 2016-12-13 Almirall, S.A. Cyclohexyl and quinuclidinyl carbamate derivatives having β2 adrenergic agonist and M3 muscarinic antagonist activity
US9562039B2 (en) 2013-02-27 2017-02-07 Almirall, S.A. Salts of 2-amino-1-hydroxyethyl-8-hydroxyquinolin-2(1H)-one derivatives having both β2 adrenergic receptor agonist and M3 muscarinic receptor antagonist activities
US9579316B2 (en) 2013-07-25 2017-02-28 Almirall, S.A. Salts of 2-amino-1-hydroxyethyl-8-hydroxyquinolin-2(1H)-one derivatives having both muscarinic receptor antagonist and β2 adrenergic receptor agonist activities
US10456390B2 (en) 2013-07-25 2019-10-29 Almirall, S.A. Combinations comprising MABA compounds and corticosteroids
CN106715414A (zh) * 2014-09-26 2017-05-24 阿尔米雷尔有限公司 具有β2肾上腺素激动剂和M3毒蕈碱拮抗剂活性的新的双环衍生物
JP2017529372A (ja) * 2014-09-26 2017-10-05 アルミラル・ソシエダッド・アノニマＡｌｍｉｒａｌｌ， Ｓ．Ａ． ベータ２アドレナリンアゴニスト活性およびｍ３ムスカリンアンタゴニスト活性を有する新規の二環式誘導体
US10005771B2 (en) 2014-09-26 2018-06-26 Almirall, S.A. Bicyclic derivatives having β2 adrenergic agonist and M3 muscarinic antagonist activities
WO2016046390A1 (fr) * 2014-09-26 2016-03-31 Almirall, S.A. Nouveaux dérivés bicycliques présentant une activité agoniste du récepteur bêta-2 adrénergique et une activité antagoniste du récepteur muscarinique m3
CN106715414B (zh) * 2014-09-26 2019-08-30 阿尔米雷尔有限公司 具有β2肾上腺素激动剂和M3毒蕈碱拮抗剂活性的新的双环衍生物

Also Published As

Publication number Publication date
GB0808708D0 (en) 2008-06-18

Similar Documents

Publication Publication Date Title
EP2094694B1 (fr) Dérivés de quiniclidine d'acide (hétéro) arylcycloheptane carboxylique en tant qu'antagonistes du récepteur muscarinique
EP2121137B1 (fr) Dérivés quinuclidinol utilisés en tant qu'antagonistes du récepteur muscarinique
WO2009139709A1 (fr) Dérivés de quinuclidine et leur utilisation comme antagonistes des récepteurs muscariniques pour le traitement de l’asthme et de la bronchopneumopathie chronique obstructive (bpco)
US20130030001A1 (en) Quinuclidine derivatives as muscarinic m3 receptor antagonists
US20090233965A1 (en) Alkyl Esters Of Cyclic Amino Alcohols With Muscarinic M3 Receptor Antagonist Activity, Useful For Treating E.G. Chronic Bronchial Obstruction, Asthma And Overactive Bladder
WO2010067102A1 (fr) Dérivés de diazaspiro[5.5]undécane et composés associés utilisés comme antagonistes des récepteurs muscariniques et agonistes des récepteurs bêta adrénergiques dans le traitement des affections pulmonaires
US20090042942A1 (en) Muscarinic Receptor Antagonists
WO2009139710A1 (fr) Dérivés de quinuclidine et leur utilisation comme antagonistes des récepteurs muscariniques
WO2008059239A1 (fr) Nouveaux composés 514
WO2008075006A1 (fr) Composés de piperldinum pour le traitement de maladies pulmonaires obstructives
WO2009153536A1 (fr) Dérivés de 1-aza-bicyclo [2.2.2] octane utiles en tant qu’antagonistes des récepteurs muscariniques
WO2010018352A1 (fr) Composés hétérocycliques utilisés dans le traitement de maladies impliquant l’activation améliorée du récepteur m3
ES2357988T3 (es) Derivados de quiniclidina de ácido(hetero)arilcicloheptanocarboxílico como antagonistas del receptor muscarínico.

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 09746869

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 09746869

Country of ref document: EP

Kind code of ref document: A1