WO2010015792A1 - Composés hétérocycliques contenant de l'azote utiles comme modulateurs bifonctionnels des récepteurs m3 et des récepteurs bêta-2 - Google Patents

Composés hétérocycliques contenant de l'azote utiles comme modulateurs bifonctionnels des récepteurs m3 et des récepteurs bêta-2 Download PDF

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WO2010015792A1
WO2010015792A1 PCT/GB2008/002692 GB2008002692W WO2010015792A1 WO 2010015792 A1 WO2010015792 A1 WO 2010015792A1 GB 2008002692 W GB2008002692 W GB 2008002692W WO 2010015792 A1 WO2010015792 A1 WO 2010015792A1
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Prior art keywords
hydroxy
methyl
ethylamino
ethyl
phenyl
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PCT/GB2008/002692
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English (en)
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Jonathan Mark Sutton
Fabien Roussel
Marco Van Den Heuvel
Nicholas Charles Ray
Lilian Alcaraz
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Argenta Discovery Limited
Astrazeneca Ab
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Priority to PCT/GB2008/002692 priority Critical patent/WO2010015792A1/fr
Publication of WO2010015792A1 publication Critical patent/WO2010015792A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • This invention relates to heterocycles, pharmaceutical compositions, methods for their preparation and use in the treatment of diseases where compounds possessing both muscarinic receptor antagonist and ⁇ 2-agonist activity present in the same molecule (bifunctional molecules) are useful (such as in the treatment of asthma or COPD).
  • bifunctional molecules provide bronchodilation through two separate modes of action whilst possessing single molecule pharmacokinetics.
  • Such a molecule might be easier to formulate for therapeutic use as compared to two separate compounds and might be more easily co-formulated with another active ingredient, for example a steroid.
  • Such bifunctional molecules are described in, for example, WO04/074246, WO04/089892, WO05/111004, WO06/023457 and WO06/023460, all of which use different linker radicals for covalently linking an M3 antagonist to a ⁇ 2-agonist.
  • Anti-cholinergic agents prevent the passage of, or effects resulting from the passage of, impulses through the parasympathetic nerves. This is a consequence of the ability of such compounds to inhibit the action of acetylcholine (Ach) by blocking its binding to the muscarinic cholinergic receptors.
  • M1-M5 muscarinic acetylcholine receptors
  • M1-M5 muscarinic acetylcholine receptors
  • M3 mAChRs mediate contractile responses (reviewed by Caulfield, 1993, Pharmac. Then, 58, 319 - 379).
  • muscarinic receptors M1 , M2 and M3 have been demonstrated to be important and are localized to the trachea, the bronchi, submucosal glands and parasympathetic ganglia (reviewed in Fryer and Jacoby, 1998, Am J Resp Crit Care Med., 158 (5 part 3) S 154 - 160).
  • M3 receptors on airway smooth muscle mediate contraction and therefore bronchoconstriction. Stimulation of M3 receptors localised to submucosal glands results in mucus secretion.
  • vagal tone may either be increased (Gross et al. 1989, Chest; 96:984-987) and/or may provoke a higher degree of obstruction for geometric reasons if applied on top of oedematous or mucus-laden airway walls (Gross et al. 1984, Am Rev Respir Dis; 129:856-870).
  • EP0323864 describes oxadiazoles linked to a mono- or bicyclic ring as muscarinic receptor modulators.
  • ⁇ 2 adrenergic receptor agonists The class of ⁇ 2 adrenergic receptor agonists is well known. Many known ⁇ 2- agonists, in particular, long-acting ⁇ 2-agonists such as salmeterol and formoterol, have a role in the treatment of asthma and COPD. These compounds are also generally administered by inhalation. Compounds currently under evaluation as once-daily ⁇ 2 agonists are described in Expert Opin. Investig. Drugs 14 (7), 775-783 (2005). A well known ⁇ 2-agonist pharmacophore is the moiety:
  • compositions that contain both a muscarinic antagonist and a ⁇ 2-agonist for use in the treatment of respiratory disorders.
  • US2005/0025718 describes a ⁇ 2-agonist in combination with tiotropium, oxotropium, ipratropium or other muscarinic antagonist;
  • WO02/060532 describes a combination of ipratropium with a ⁇ 2- agonist;
  • WO02/060533 describes a combination of oxotropium with a ⁇ 2- agonist.
  • Other M3 antagonist / ⁇ 2-agonist combinations are described in WO04/105759 and WO03/087097.
  • R 1 is H or C r C 6 -alkyl; and R 3 is lone pair or CrC 6 -alkyl; or (ii) R 1 and R 3 together with the nitrogen to which they are attached form a heterocycloalkyl ring;
  • R 4 and R 5 are independently selected from the group consisting of aryl, aryl- fused-heterocycloalkyl, heteroaryl, CrC 6 -alkyl, cycloalkyl; R 6 is -OH, CrC 6 -alkyl, CrC 6 -alkoxy, hydroxy-CrC 6 -alkyl, nitrile, a group CON(R 12 ) 2 or a hydrogen atom; one of W, V and A is N or NR 11 ; another of W, V and A is N, O, S or CR 8 ; and the last one of W, V and A is N or CR 8
  • X is an CrC ⁇ alkylene, C 2 -C 6 alkenylene or C 2 -C 6 alkynylene group;
  • R 8 , R 11 and R 12 are, independently, hydrogen atom or CrC 6 -alkyl group;
  • L a is a divalent linker radical of formula (Ia);
  • L represents a linker comprising a hydrocarbyl chain of up to 14 carbon atoms, wherein up to three carbon atoms of the chain are replaced by groups independently selected from O, NR 45 , S, S(O), S(O) 2 , C(O)O, OC(O),
  • Ci- 6 alkyl and C 3-6 cycloalkyl may be optionally substituted by up to three substituents independently selected from halogen, hydroxyl and Ci -6 alkoxy; and the chain may comprise up to three of such rings each selected independently, and; wherein R 56 , R 65 and R 69 each independently represent C 1-6 alkyl or C 3-6 cycloalkyl, wherein C 1-6 alkyl and C 3-6 cycloalkyl may be optionally substituted by up to three substituents independently selected from halogen, hydroxyl, Ci -6 alkoxy; and wherein R 45 , R 46 , R 47 , R 48 , R 49 , R 50 , R 51 , R 52 , R 53 , R 54 , R 55 , R 57 , R 58 , R 59 , R 60 , R 61 , R 62 , R 63 , R 64 , R 66 , R 67 , R 68 , R 70 , R 71 ,
  • L 3 and L 4 each independently represent hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, wherein C 1-6 alkyl and C 3-6 cycloalkyl may be optionally substituted by one or more substituents independently selected from halogen and hydroxyl; and in addition L 1 and/or L 3 may be linked to a carbon atom of the hydrocarbyl chain in linker L to form an aliphatic ring of up to 6 ring atoms, wherein the ring may comprise up to three heteroatoms independently selected from N, O and S; and wherein * denotes the point of attachement of the group of formula (Ia) to the non-aromatic nitrogen bearing R 1 and R 3 , and ** denotes the point of attachment to the group Z 1 ;
  • Z 1 is a moiety having ⁇ 2- adrenoreceptor binding activity; wherein, unless otherwise specified, each occurrence of alkyl, heterocycloalkyl, aryl, aryl-fused-heterocycloalkyl, heteroaryl, cycloalkyl, alkoxy, alkylene, alkenylene, alkynylene or aryl-fused-cycloalkyl may be optionally substituted; and wherein each alkenylene chain contains, where possible, up to 2 carbon- carbon double bonds and each alkynylene chain contains, where possible, up to 2 carbon-carbon triple bonds or a pharmaceutically acceptable salt thereof.
  • the present invention provides compounds falling within the scope of, but not specifically disclosed in, our co-pending application PCT/GB2008/000407 referred to above.
  • the present invention provides a compound selected from the group consisting of: 8-[2-(2- ⁇ 4-[( ⁇ 2-[2-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-yl]-ethyl ⁇ - methyl-amino)-methyl]-phenyl ⁇ -ethylamino)-1-hydroxy-ethyl]-5-hydroxy-4H- benzo[1 ,4]oxazin-3-one;
  • the present invention provides a prodrug of a compound as listed above, or a pharmaceutically acceptable salt thereof.
  • the present invention provides an N-oxide of a compound as listed above, or a prodrug or pharmaceutically acceptable salt thereof.
  • the present invention provides a solvate (such as a hydrate) of a compound as listed above or an N-oxide, prodrug or pharmaceutically acceptable salt thereof.
  • both enantiomers of the invention generally exhibit affinity at the M 3 receptor, although one enantiomer is generally favoured on criteria of potency at the M 3 receptor and/or selectivity against the M 2 receptor.
  • the absolute stereochemistry of the favoured enantiomer is known.
  • Compounds of the invention may be useful in the treatment or prevention of diseases in which activation of muscarinic receptors are implicated, for example the present compounds are useful for treating a variety of indications, including but not limited to respiratory-tract disorders such as chronic obstructive lung disease (also known as chronic obstructive pulmonary disease or 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, pneumoconiosis (for example aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, taba
  • a compound of the present invention is useful in the treatment or prevention of respiratory-tract disorders such as chronic obstructive lung disease (also known 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).
  • chronic obstructive lung disease also known as chronic obstructive pulmonary disease, COPD
  • the duration of action of quaternary ammonium salts of the invention administered by inhalation is may be more than 12, or more than 24 hours for a typical dose.
  • administration by the parenteral route usually the oral route may be preferred.
  • Another aspect of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier, diluent or excipient.
  • Another aspect of the invention is the use of a compound of the invention for the manufacture of a medicament for the treatment or prevention of a disease or condition in which muscarinic M3 receptor activity and ⁇ 2-adrenergic activity are implicated.
  • Diseases or conditions in which muscarinic M3 receptor activity and ⁇ 2-adrenergic activity are implicated include respiratory- tract disorders, gastrointestinal-tract disorders and cardiovascular disorders. Specific examples of such diseases and conditions include those listed above.
  • Another aspect of the invention provides a compound of the invention for the treatment or prevention of a disease or condition in which muscarinic M3 receptor activity and ⁇ 2-adrenergic activity are implicated.
  • Diseases or conditions in which muscarinic M3 receptor activity and ⁇ 2-adrenergic activity are implicated include respiratory-tract disorders, gastrointestinal-tract disorders and cardiovascular disorders. Specific examples of such diseases and conditions include those listed above.
  • Another aspect of the invention provides a method of treatment of a disease or condition in which M3 muscarinic receptor activity and ⁇ 2-adrenergic activity are implicated comprising administration to a subject in need thereof a therapeutically effective amount of a compound of the invention.
  • Diseases or conditions in which muscarinic M3 receptor activity and ⁇ 2-adrenergic activity are implicated include respiratory-tract disorders, gastrointestinal-tract disorders and cardiovascular disorders. Specific examples of such diseases and conditions include those listed above.
  • Another aspect of the invention provides a compound of the invention for use in therapy.
  • “Pharmaceutically acceptable salt” means a physiologically or toxicologically tolerable salt and includes, when appropriate, pharmaceutically acceptable base addition salts, pharmaceutically acceptable acid addition salts, and pharmaceutically acceptable quaternary ammonium salts.
  • pharmaceutically acceptable base addition salts that may be formed include sodium, potassium, calcium, magnesium and ammonium salts, or salts with organic amines, such as, diethylamine, ⁇ /-methyl-glucamine, diethanolamine or amino acids (e.g.
  • a compound of the invention contains a basic group, such as an amino group
  • pharmaceutically acceptable acid addition salts that may be formed include hydrochlorides, hydrobromides, sulfates, phosphates, acetates, citrates, lactates, tartrates, mesylates, napadisylate (naphthalene- 1 ,5-disulfonate or naphthalene-1 -(sulfonic acid)-5-sulfonate), edisylate (ethane-1 ,2-disulfonate or ethane-1 -(sulfonic acid)-2-sulfonate), maleates, fumarates, succinates, isethionates (2-hydroxyethyl-1 -sulfonates) and the like.
  • the present invention covers all permissible ratios of cationic ammonium species to counter-ion, for example hemi-napadisylate and napadisylate.
  • Prodrug refers to a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis, reduction or oxidation) to a compound of the invention. Suitable groups for forming pro-drugs are described in 'The
  • references to the compounds of the invention are meant to also include the prodrug forms.
  • Compounds of the invention may exist in one or more geometrical, optical, enantiomeric, diastereomeric and tautomeric forms, including but not limited to cis- and frans-forms, E- and Z-forms, R-, S- and meso-forms, keto-, and enol-forms. Unless otherwise stated a reference to a particular compound includes all such isomeric forms, including racemic and other mixtures thereof. Where appropriate such isomers can be separated from their mixtures by the application or adaptation of known methods (e.g. chromatographic techniques and recrystallisation techniques). Where appropriate such isomers may be prepared by the application of adaptation of known methods (e.g. asymmetric synthesis).
  • Compounds of the invention are ⁇ 2-adrenergic binding compounds. Such compounds may be antagonists, partial agonists or full agonists. Compounds that are antagonists are useful tools, for example, for the generation of structure-activity relationships and as radioligands. Compounds that are partial or full agonists may be useful as pharmacological compounds for the treatment of the diseases described above.
  • the present invention is also concerned with pharmaceutical formulations comprising, as an active ingredient, a compound of the invention.
  • Other compounds may be combined with compounds of this invention for the prevention and treatment of inflammatory diseases of the lung.
  • the present invention is also concerned with pharmaceutical compositions for preventing and treating respiratory-tract disorders such as chronic obstructive lung disease, chronic bronchitis, asthma, chronic respiratory obstruction, pulmonary fibrosis, pulmonary emphysema, and allergic rhinitis comprising a therapeutically effective amount of a compound of the invention and one or more other therapeutic agents.
  • Other compounds may be combined with compounds of this invention for the prevention and treatment of inflammatory diseases of the lung.
  • the invention includes a combination of an agent of the invention as hereinbefore described with one or more anti-inflammatory, bronchodilator, antihistamine, decongestant or anti-tussive agents, said agents of the invention hereinbefore described and said combination agents existing in the same or different pharmaceutical compositions, administered separately or simultaneously.
  • Preferred combinations would have two or three different pharmaceutical compositions.
  • Suitable therapeutic agents for a combination therapy with compounds of the invention include:
  • One or more other bronchodilators such as PDE3 inhibitors;
  • Methyl xanthines such as theophylline
  • a corticosteroid for example fluticasone propionate, ciclesonide, mometasone furoate or budesonide, or steroids described in WO02/88167, WO02/12266, WO02/100879, WO02/00679, WO03/35668, WO03/48181 , WO03/62259, WO03/64445, WO03/72592, WO04/39827 and WO04/66920;
  • a non-steroidal glucocorticoid receptor agonist for example fluticasone propionate, ciclesonide, mometasone furoate or budesonide, or steroids described in WO02/88167, WO02/12266, WO02/100879, WO02/00679, WO03/35668, WO03/48181 , WO03/62259, WO03/64445, WO03/72592, WO04/39827 and WO04/66920;
  • a leukotriene modulator for example montelukast, zafirlukast or pranlukast
  • protease inhibitors such as inhibitors of matrix metalloprotease for example MMP12 and TACE inhibitors such as marimastat, DPC-333, GW-3333
  • MMP12 matrix metalloprotease
  • TACE inhibitors such as marimastat, DPC-333, GW-3333
  • Human neutrophil elastase inhibitors such as sivelestat and those described in WO04/043942, WO05/021509, WO05/021512, W 005/026123, WO05/026124, WO04/024700, WO04/024701 , WO04/020410, WO04/020412, WO05/080372, WO05/082863, WO05/082864, WO03/053930;
  • Phosphodiesterase-4 (PDE4) inhibitors for example roflumilast, arofylline, cilomilast, ONO-6126 or IC-485;
  • An antitussive agent such as codeine or dextramorphan
  • Kinase inhibitors particularly P38 MAPKinase inhibitors
  • P2X7 anatgonists iNOS inhibitors
  • iNOS inhibitors iNOS inhibitors
  • NSAID non-steroidal anti-inflammatory agent
  • a dopamine receptor antagonist A dopamine receptor antagonist
  • TNF- ⁇ inhibitors for example anti-TNF monoclonal antibodies, such as Remicade and CDP-870 and TNF receptor immunoglobulin molecules, such as Enbrel;
  • A2a agonists such as those described in EP1052264 and EP1241176;
  • A2b antagonists such as those described in WO2002/42298;
  • Modulators of chemokine receptor function for example antagonists of CCR 1 , CCR2, CCR3, CXCR2, CXCR3, CX3CR1 and CCR8, such as SB-332235,
  • PGD 2 (DP1 or CRTH2), or a thromboxane A 2 antagonist eg ramatrobant;
  • Compounds which modulate Th1 or Th2 function for example, PPAR agonists; lnterleukin 1 receptor antagonists, such as Kineret; lnterleukin 10 agonists, such as llodecakin;
  • HMG-CoA reductase inhibitors for example rosuvastatin, mevastatin, lovastatin, simvastatin, pravastatin and fluvastatin;
  • Mucus regulators such as INS-37217, diquafosol, sibenadet, CS-003, talnetant, DNK-333, MSI-1956, gefitinib;
  • Antiinfective agents antibiotic or antiviral
  • antiallergic drugs including, but not limited to, anti-histamines.
  • the present invention provides a combination comprising a compound of the invention and an inhaled corticosteroid (for example fluticasone propionate, ciclesonide, mometasone furoate or budesonide), or an inhaled PDE 4 inhibitor (for example roflumilast, cilomilast, Tofimilast).
  • an inhaled corticosteroid for example fluticasone propionate, ciclesonide, mometasone furoate or budesonide
  • an inhaled PDE 4 inhibitor for example roflumilast, cilomilast, Tofimilast.
  • any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dosage of a compound of the present invention.
  • the active compound may be administered by any convenient, suitable or effective route.
  • Suitable routes of administration are known to those skilled in the art, and include oral, intravenous, rectal, parenteral, topical, ocular, nasal, buccal and pulmonary.
  • prophylactic or therapeutic dose of a compound of the invention will, of course, vary depending upon a range of factors, including the activity of the specific compound that is used, the age, body weight, diet, general health and sex of the patient, time of administration, the route of administration, the rate of excretion, the use of any other drugs, and the severity of the disease undergoing treatment.
  • the daily dose range for inhalation will lie within the range of from about 0.1 ⁇ g to about 10 mg per kg body weight of a human, preferably 0.1 ⁇ g to about 0.5 mg per kg, and more preferably 0.1 ⁇ g to 50 ⁇ g per kg, in single or divided doses. On the other hand, it may be necessary to use dosages outside these limits in some cases.
  • compositions suitable for administration by inhalation are known, and may include carriers and/or diluents that are known for use in such compositions.
  • the composition may contain 0.01-99% by weight of active compound.
  • a unit dose comprises the active compound in an amount of 1 ⁇ g to 10 mg.
  • suitable doses are 10 ⁇ g per kg to 100mg per kg, preferably 40 ⁇ g per kg to 4 mg per kg.
  • compositions which comprise a compound of the invention and a pharmaceutically acceptable carrier.
  • composition is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) (pharmaceutically acceptable excipients) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
  • the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the invention, additional active ingredient(s), and pharmaceutically acceptable excipients.
  • compositions of the present invention comprise a compound of the invention as an active ingredient or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic bases or acids and organic bases or acids, and salts of quaternary ammonium compounds with pharmaceutically acceptable counter-ions.
  • the active compound is preferably in the form of microparticles. They may be prepared by a variety of techniques, including spray-drying, freeze-drying and micronisation.
  • a composition of the invention may be prepared as a suspension for delivery from a nebuliser or as an aerosol in a liquid propellant, for example for use in a pressurised metered dose inhaler (PMDI).
  • PMDI pressurised metered dose inhaler
  • Propellants suitable for use in a PMDI are known to the skilled person, and include CFC- 12, HFA-134a, HFA-227, HCFC-22 (CCI 2 F 2 ) and HFA-152 (C 2 H 4 F 2 ) and isobutane.
  • a composition of the invention is in dry powder form, for delivery using a dry powder inhaler (DPI).
  • DPI dry powder inhaler
  • Many types of DPI are known.
  • Microparticles for delivery by administration may be formulated with excipients that aid delivery and release.
  • microparticles may be formulated with large carrier particles that aid flow from the DPI into the lung.
  • Suitable carrier particles are known, and include lactose particles; they may have a mass median aerodynamic diameter of greater than 90 ⁇ m.
  • the active compounds may be dosed as described depending on the inhaler system used.
  • the administration forms may additionally contain excipients, such as, for example, propellants (e.g. Frigen in the case of metered aerosols), surface-active substances, emulsifiers, stabilizers, preservatives, flavorings, fillers (e.g. lactose in the case of powder inhalers) or, if appropriate, further active compounds.
  • the compounds of the invention of the present invention can be prepared according to the procedures of the following examples, using appropriate materials, and are further exemplified by the following specific examples. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.
  • the compounds of the invention may be isolated in the form of their pharmaceutically acceptable salts, such as those described previously herein above. It may be necessary to protect reactive functional groups (e.g. hydroxy, amino, thio or carboxy) in intermediates used in the preparation of compounds of the invention to avoid their unwanted participation in a reaction leading to the formation of the compounds.
  • reactive functional groups e.g. hydroxy, amino, thio or carboxy
  • Conventional protecting groups for example those described by T. W. Greene and P. G. M. Wuts in "Protective groups in organic chemistry” John Wiley and Sons, 1999, may be used.
  • the compounds of the invention have activity as pharmaceuticals, in particular as dual adrenergic ⁇ 2 receptor agonists and anticholinergic agents including muscarinic receptor (M1 , M2, and M3) antagonists, in particular M3 antagonists.
  • Diseases and conditions which may be treated with the compounds of the invention and their pharmaceutically acceptable salts include:
  • respiratory tract obstructive diseases of the airways including: asthma, including bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced
  • 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 vasculature, and pulmonary hypertension; antitussive activity including treatment of chronic cough associated with inflammatory and secretory conditions of the airways, and iatrogenic cough; acute
  • 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; osteoporosis; 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 erythemat
  • 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's
  • 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; vulvo-vaginitis; 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;
  • 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; 14.
  • 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,
  • gastrointestinal tract Coeliac disease, proctitis, eosinopilic gastroenteritis, 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 provides a compound of the invention or a pharmaceutically-acceptable salt thereof as hereinbefore defined for use in therapy.
  • the present invention provides the use of a compound of the invention or a pharmaceutically acceptable salt thereof 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.
  • 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 disease or condition in question.
  • Persons at risk of developing a particular disease or condition generally include those having a family history of the disease or condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the disease or condition.
  • the invention still further provides a method of treating, or reducing the risk of, an inflammatory disease or condition (including a reversible obstructive airways disease or condition) which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof as hereinbefore defined.
  • an inflammatory disease or condition including a reversible obstructive airways disease or condition
  • the compounds of this invention may be used in the treatment of adult respiratory distress syndrome (ARDS), pulmonary emphysema, bronchitis, bronchiectasis, chronic obstructive pulmonary disease (COPD), asthma and rhinitis.
  • ARDS adult respiratory distress syndrome
  • COPD chronic obstructive pulmonary disease
  • the daily dosage of the compound of the invention if inhaled, may be in the range from 0.05 micrograms per kilogram body weight ( ⁇ g/kg) to 100 micrograms per kilogram body weight ( ⁇ g/kg).
  • the daily dosage of the compound of the invention may be in the range from 0.01 micrograms per kilogram body weight ( ⁇ g/kg) to 100 milligrams per kilogram body weight (mg/kg).
  • the compounds of the invention and pharmaceutically acceptable salts thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the invention compound/salt (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • a pharmaceutically acceptable adjuvant diluent or carrier.
  • Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, "Pharmaceuticals - The Science of Dosage Form Designs", M. E. Aulton, Churchill Livingstone, 1988.
  • the pharmaceutical composition will preferably comprise from 0.05 to 99 %w (per cent by weight), more preferably from 0.05 to 80 %w, still more preferably from 0.10 to 70 %w, and even more preferably from 0.10 to 50 %w, of active ingredient, all percentages by weight being based on total composition.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt thereof as hereinbefore defined, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of the invention or a pharmaceutically acceptable salt thereof as hereinbefore defined with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • compositions may be administered topically (e.g. to the skin or to the lung and/or airways) in the form, e.g., of creams, solutions, suspensions, heptafluoroalkane (HFA) aerosols and dry powder formulations, for example, formulations in the inhaler device known as the Turbuhaler ® ; or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules; or by parenteral administration in the form of solutions or suspensions; or by subcutaneous administration; or by rectal administration in the form of suppositories; or transdermally.
  • HFA heptafluoroalkane
  • Dry powder formulations and pressurized HFA aerosols of the compounds of the invention 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 2O 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 2O 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.
  • the compounds of the invention may also be administered by means of a dry powder inhaler.
  • the inhaler may be a single or a multi dose inhaler, and may be a breath actuated dry powder inhaler.
  • 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 compound of the invention may be admixed with an adjuvant or a carrier, for example, lactose, saccharose, sorbitol, mannitol; a starch, for example, potato starch, corn starch or amylopectin; a cellulose derivative; a binder, for example, gelatine or polyvinylpyrrolidone; and/or a lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax, paraffin, and the like, and then compressed into tablets.
  • an adjuvant or a carrier for example, lactose, saccharose, sorbitol, mannitol
  • a starch for example, potato starch, corn starch or amylopectin
  • a cellulose derivative for example, gelatine or polyvinylpyrrolidone
  • a lubricant for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax
  • the cores may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide.
  • a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide.
  • the tablet may be coated with a suitable polymer dissolved in a readily volatile organic solvent.
  • the compound of the invention may be admixed with, for example, a vegetable oil or polyethylene glycol.
  • Hard gelatine capsules may contain granules of the compound using either the above-mentioned excipients for tablets.
  • liquid or semisolid formulations of the compound of the invention may be filled into hard gelatine capsules.
  • Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing the compound of the invention, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol.
  • Such liquid preparations may contain colouring agents, flavouring agents, saccharine and/or carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art.
  • the compounds of the invention may also be administered in conjunction with other compounds used for the treatment of the above conditions.
  • the invention therefore further relates to combination therapies wherein a compound of the invention, or a pharmaceutically acceptable salt thereof, 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.
  • NSAIDs non-steroidal anti-inflammatory agents
  • COX-1 / COX-2 inhibitors whether applied topically or systemically (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 mel
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, 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-1); interleukins (IL) including IL1 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
  • the invention relates to a combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with a monoclonal antibody targeting B-Lymphocytes (such as CD20 (rituximab), MRA-alLI6R) or T-Lymphocytes (CTLA4-lg, HuMax 11-15).
  • B-Lymphocytes such as CD20 (rituximab), MRA-alLI6R
  • T-Lymphocytes CLA4-lg, HuMax 11-15.
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with a modulator of chemokine receptor function such as an antagonist of CCR1 , CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for the C-C family); CXCR1 , CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-C family) and CX 3 CRI for the C-X 3 -C family.
  • a modulator of chemokine receptor function such as an antagonist of CCR1 , CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for the C-C family); CXCR1 , CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, 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-10), 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, or a pharmaceutically acceptable salt thereof, 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-( ⁇ -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
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a receptor antagonist for leukotrienes (LT) B4, LTC4, LTD4, and LTE4.
  • a receptor antagonist for leukotrienes (LT) B4, LTC4, LTD4, and LTE4 selected from the group consisting of the phenothiazin-3-1s 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.
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, 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, or a pharmaceutically acceptable salt thereof, 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, or a pharmaceutically acceptable salt thereof, 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, or a pharmaceutically acceptable salt thereof, and an antagonist of the histamine type 4 receptor.
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an alpha-1/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.
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a chromone, such as sodium cromoglycate
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, 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.
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, 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, or a pharmaceutically acceptable salt thereof, together with an immunoglobulin (Ig) or Ig preparation or an antagonist or antibody modulating Ig function such as anti-lgE (for example omalizumab).
  • Ig immunoglobulin
  • Ig preparation or an antagonist or antibody modulating Ig function
  • anti-lgE for example omalizumab
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, 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, or a pharmaceutically acceptable salt thereof, 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.
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, 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 transcripta
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, 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
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, 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
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, 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 antidepressant agent-s, paracetamol, or a non-steroidal anti-inflammatory agent.
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with a parenterally or topically-applied (including inhaled) local anaesthetic agent such as lignocaine or a derivative thereof.
  • a compound of the present invention, or a pharmaceutically acceptable salt thereof can also be used in combination with an anti-osteoporosis agent including a hormonal agent such as raloxifene, or a biphosphonate such as alendronate.
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, 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 lmatinib mesylate), a serine / threonine kinase (such as an inhibitor of
  • -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 NK.subL or NK.sub3.
  • NKP-608C, SB-233412 (talnetant) or D-4418 elastase inhibitor such as UT-77 or ZD-0892
  • elastase inhibitor such as UT-77 or ZD-0892
  • TACE TNF-alpha converting enzyme inhibitor
  • iNOS induced nitric oxide synthase
  • chemoattractant receptor-homologous molecule expressed on TH2 cells such as a CRTH2 antagonist
  • inhibitor of P38 agent modulating the function of Toll-like receptors (TLR),
  • agent modulating the activity of purinergic receptors such as P2X7
  • inhibitor of transcription factor activation such as NFkB, API or STATS
  • a glucocorticoid receptor GR-receptor
  • the present invention provides a combination (for example for the treatment of COPD, asthma or allergic rhinitis) of a compound of the invention and one or more agents selected from the list comprising: o a non-steroidal glucocorticoid receptor (GR-receptor) agonist; o a PDE4 inhibitor including an inhibitor of the isoform PDE4D; o a modulator of chemokine receptor function (such as a CCR 1 receptor antagonist); o a steroid (such as budesonide); and o an inhibitor of p38 kinase function.
  • GR-receptor non-steroidal glucocorticoid receptor
  • PDE4 inhibitor including an inhibitor of the isoform PDE4D
  • o a modulator of chemokine receptor function such as a CCR 1 receptor antagonist
  • o a steroid such as budesonide
  • an inhibitor of p38 kinase function for example for the treatment of COPD, asthma or allergic
  • a compound of the invention, or a pharmaceutically acceptable salt thereof, can also be used in combination with an existing therapeutic agent for the treatment of cancer
  • 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,
  • 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-erbb1 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-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4- amine (gefitinib, AZD1839), N-(3-ethynylphenyl)-6,7-bis(2- methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) or 6-acrylamido-N-(3- chloro-4-fluorophenyl)
  • vascular damaging agent such as combretastatin A4, or a compound disclosed in WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 or WO 02/08213;
  • an agent used in antisense therapy for example one directed to one of the targets listed above, such as ISIS 2503, an anti-ras antisense;
  • an agent used in a gene therapy approach for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; or (ix) an agent used in an immunotherapeutic approach, for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies.
  • GDEPT gene-directed enzyme pro-drug therapy
  • Silica used for medium pressure column chromatography is 0.035 to 0.070 mm (220 to 440 mesh) (e.g. Fluka silica 60), and an applied pressure up to 10 psi accelerated column elution.
  • TLC thin layer chromatography
  • it refers to silica TLC using plates, typically 3 x 6 cm silica on aluminium foil plates with a fluorescent indicator (254 nm) (e.g. Fluka 60778). All solvents and commercial reagents were used as received.
  • Purification by pre-packed SCX-2 cartridge refers to Isolute ® SCX-2, a strong cation exchange sorbent (Argonaut/IST).
  • MS, ELS, UV 100 ⁇ L split to MS with in-line UV detector.
  • MS ionisation method Electrospray (positive and negative ion).
  • MS, ELS, UV 100 ⁇ L split to MS with in-line UV detector.
  • MS ionisation method Electrospray (positive and negative ion).
  • MS ionisation method Electrospray (positive and negative ion).
  • MS MS, ELS, UV (200 ⁇ L/min split to ESI source).
  • MS ionisation method Electrospray (positive ion).
  • DCM dichloromethane
  • DIPEA diisopropylethylamine
  • DMF ⁇ /,/V-dimethylformamide
  • EtOAc ethyl acetate
  • h hour(s)
  • HATU (>(7-azabenzotriazol-1-yl)-N, ⁇ /, ⁇ /' ⁇ /-tetramethyluronium- hexafluorophosphate
  • HPLC high performance liquid chromatography
  • NBS ⁇ /-bromosuccinimide
  • TBDPS te/t-butyldiphenylsilyl
  • TFA trifluoroacetic acid
  • Dess-Martin periodinane (154 mg, 0.36 mmol) was added to a solution of 2- ⁇ 4-[( ⁇ 2-[2-((R)-cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-yl]-ethyl ⁇ - methyl-amino)-methyl]-phenyl ⁇ -ethanol (65 mg, 0.14 mmol) and TFA (11.2 ⁇ l_, 0.14 mmol) in DCM (5.2 ml_).
  • Benzyltrimethylammonium dichloroiodate (9.27 g, 26.6 mmol) was added to a stirred solution of 8-acetyl-5-benzyloxy-4/-/-benzo[1 ,4]oxazin-3-one (3.60 g, 12.1 mmol) in a mixture of DCM (65 ml_), acetic acid (22 ml_), and water (3.6 mL) that was heated at 65 0 C and protected from light, for 18 h. The reaction mixture was cooled to RT and a solution of sodium bisulphite (3.78 g) in water (65 mL) was added and mixed vigorously to form a suspension.
  • Manganese(IV) oxide 250 mg, 2.70 mmol was added to a stirred solution of 3-( ⁇ 2-[2-((R)-cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-yl]-ethyl ⁇ - methyl-amino)- ⁇ /-(4-hydroxymethyl-phenyl)-propionamide (137 mg, 0.27 mmol) in DCM (3 mL) and the resulting mixture heated to reflux for 1 h. The mixture was filtered through a pad of Celite, the pad washed with DCM and the filtrate concentrated in vacuo to afford the crude aldehyde, used without further purification.
  • HATU (439 mg, 0.77 mmol) was added to a stirred solution of 3- (benzyl- ⁇ 2-[2-((R)-cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-yl]-ethyl ⁇ - amino)-propionic acid (356 mg, 0.77 mmol), (4-amino-phenyl)-methanol (142 mg, 1.15 mmol) and DIPEA (370 ⁇ L, 2.11 mmol) in DCM (25 ml_). After 20 h the reaction mixture was filtered and then concentrated in vacuo.
  • the title compound was prepared from ⁇ 2-[2-((R)-cyclohexyl-hydroxy- phenyl-methyl)-oxazol-5-yl]-ethyl ⁇ -[2-(4-hydroxymethyl-phenylcarbamoyl)- ethyl]-carbamic acid te/t-butyl ester by similar methods to those employed for Intermediate 21.
  • the title compound was prepared from ⁇ 2-[2-((R)-cyclohexyl-hydroxy- phenyl-methyl)-oxazol-5-yl]-ethyl ⁇ -[2-(4-formyl-phenylcarbamoyl)-ethyl]- carbamic acid tert-butyl ester and 7-((R)-2-amino-1-hydroxy-ethyl)-4-hydroxy- 3H-benzothiazol-2-one hydrochloride (prepared according to WO2007/027133) by a similar method to that employed for Intermediate 22.
  • the title compound was prepared from ⁇ 2-[2-((R)-cyclohexyl-hydroxy- phenyl-methyl)-oxazol-5-yl]-ethyl ⁇ -[2-(4-formyl-phenylcarbamoyl)-ethyl]- carbamic acid te/t-butyl ester and 5-[(f?)-2-amino-1-(te/t-butyl-dimethyl- silanyloxy)-ethyl]-8-(4-methoxy-benzyloxy)-1 /-/-quinolin-2-one by a similar method to that employed for Intermediate 22.
  • 2,6-Lutidine (3.4 mL, 29 mmol) was added to a solution of 5-benzyloxy-8-(2- chloro-1-hydroxy-ethyl)-4/-/-benzo[1 ,4]oxazin-3-one (first eluting enantiomer) (4.76 g, 14.3 mmol) in dry DMF (30 mL) at 0 0 C under a nitrogen atmosphere, followed by slow addition of TBDMS trifluoromethanesulfonate (6.4 mL, 28 mmol). Fumes were formed and the reaction mixture was stirred below 10 °C for 5 min, after which the reaction mixture was allowed to warm to RT.
  • the title compound was prepared from ⁇ 5-[( ⁇ 3-[4-(2-bromo-ethyl)- phenoxy]-propyl ⁇ -methyl-amino)-methyl]-isoxazol-3-yl ⁇ -diphenyl-methanol and 5-[(/?)-2-amino-1-(t ⁇ At-butyl-dimethyl-silanyloxy)-ethyl]-8-(4-methoxy- benzyloxy)-1 H-quinolin-2-one using a similar method to that employed for 37.
  • the title compound was prepared from ⁇ 3-[4-(2-bromo-ethyl)-phenoxy]- propyl ⁇ -[3-(hydroxy-diphenyl-methyl)-isoxazol-5-ylmethyl]-carbamic acid tert- butyl ester (Intermediate 41 ) and (R)-2-amino-1 -(2,2-dimethyl-4/-/- benzo[1 ,3]dioxin-6-yl)-ethanol (Prepared according to WO 2005/044787) using a similar method to that employed for Intermediate 37.
  • a crystal of iodine was added to a stirred suspension of magnesium (2.35 g, 95.8 mmol) in dry THF (50 ml_) under a nitrogen atmosphere. After stirring at RT for 5 min the iodine colour was still present. Cyclobutyl bromide (12.10 g, 86.0 mmol) was added dropwise to the mixture and after about 2 ml_ was added the colour disappeared and heat was evolved. The addition was continued to maintain a steady exotherm. Dry THF (50 ml_) was added simultaneously. After the addition, the reaction mixture was heated at 65 0 C for 0.5 h (only a small portion of magnesium remaining in clear brown solution), allowed to cool to RT and then cooled on ice to afford a suspension.
  • Re-analysis of EnantiomeM and 2 Chromatin A, KCl
  • the title compound was prepared from (5-aminomethyl-oxazol-2-yl)- diphenyl-methanol using similar methods to those employed for Intermediates 45 and 36, respectively.
  • the title compound was prepared from [2-(4- ⁇ [(R)-2-(te/ ⁇ -butyl-dimethyl- silanyloxy)-2-(8-hydroxy-2-oxo-1 ,2-dihydro-quinolin-5-yl)-ethylamino]-methyl ⁇ - phenylcarbamoyl)-ethyl]- ⁇ 2-[2-((R)-cyclohexyl-hydroxy-phenyl-methyl)-oxazol- 5-yl]-ethyl ⁇ -carbamic acid te/f-butyl ester (Intermediate 28) by similar methods to those employed for Examples 3 and 2, respectively.
  • the crude product was purified by HPLC to afford the desired product as a formic acid salt.
  • the title compound was prepared from [2-(4- ⁇ [2-(te/?-butyl-dimethyl- silanyloxy)-2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1 ,4]oxazin-8-yl)- ethylamino]-methyl ⁇ -phenylcarbamoyl)-ethyl]- ⁇ 2-[2-((R)-cyclohexyl-hydroxy- phenyl-methyl)-oxazol-5-yl]-ethyl ⁇ -carbamic acid tert-butyl (Intermediate 33) by similar methods to those employed for Examples 3 and 2, respectively.
  • the crude product was purified by HPLC to afford the desired product as a formic acid salt.
  • the title compound was prepared from 5-[(R)-1 -(te/?-butyl-dimethyl- silanyloxy)-2-(2- ⁇ 3-[3-( ⁇ 2-[2-((R)-cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5- yl]-ethyl ⁇ -methyl-amino)-propoxy]-phenyl ⁇ -ethylamino)-ethyl]-8-hydroxy-1 H- quinolin-2-one (Intermediate 37) by a similar method to that employed for Example 2. The crude product was purified by HPLC to afford the desired product as a formic acid salt.
  • the title compound was prepared from 5-((R)-1-(tert-butyl-dimethyl- silanyloxy)-2- ⁇ 2-[4-(3- ⁇ [3-(hydroxy-diphenyl-methyl)-isoxazol-5-ylmethyl]- methyl-amino ⁇ -propoxy)-phenyl]-ethylamino ⁇ -ethyl)-8-hydroxy-1 H-quinolin-2- one (Intermediate 39) by a similar method to that employed for Example 2. The crude product was purified by HPLC to afford the desired product as a formic acid salt.
  • the title compound was prepared from 5-((R)-1-(terf-butyl-dimethyl- silanyloxy)-2- ⁇ 2-[4-(3- ⁇ [3-(hydroxy-diphenyl-methyl)-isoxazol-5-ylmethyl]- amino ⁇ -propoxy)-phenyl]-ethylamino ⁇ -ethyl)-8-hydroxy-1 /-/-quinolin-2-one trifluoroacetate salt (Intermediate 42) by a similar method to that employed for Example 2. The crude product was purified by HPLC to the desired product as a formic acid salt.
  • the title compound was prepared from ⁇ 3-[4-(2-bromo-ethyl)-phenoxy]- propyl ⁇ -[3-(hydroxy-diphenyl-methyl)-isoxazol-5-ylmethyl]-carbamic acid tert- butyl ester (Intermediate 41) and 8-[2-amino-1-(terf-butyl-dimethyl-silanyloxy)- ethyl]-5-hydroxy-4/-/-benzo[1 ,4]oxazin-3-one (Intermediate 32) by similar methods to those employed for Intermediate 42 and Example 2.
  • the crude product was purified by HPLC to afford the desired product as a formic acid salt.
  • the title compound was prepared from ⁇ 3-[4-(2-bromo-ethyl)-phenoxy]- propyl ⁇ -[3-(hydroxy-diphenyl-methyl)-isoxazol-5-ylmethyl]-carbamic acid tert- butyl ester (Intermediate 41 ) and ⁇ /- ⁇ 5-[(R)-2-amino-1 -(tert-butyl-dimethyl- silanyloxy)-ethyl]-2-hydroxy-phenyl ⁇ -formamide (Prepared according to US 2007/0249675) by similar methods to those employed for Intermediate 42 and Example 2. The crude product was purified by HPLC to afford the desired product as a formic acid salt.
  • the title compound was prepared from (R)-[5-(2- ⁇ [5-(2-bromo-ethyl)- thiophen ⁇ -ylmethylj-methyl-aminoJ-ethyO-oxazol ⁇ -ylj-cyclohexyl-phenyl- methanol (Intermediate 44) and 7-((R)-2-amino-1-hydroxy-ethyl)-4-hydroxy- 3H-benzothiazol-2-one hydrochloride (prepared according to WO2007/027133) by similar a method to that employed for Intermediate 37. The crude product was purified by HPLC to afford the desired product as a formic acid salt.
  • the title compound was prepared from (R)-[5-(2- ⁇ [5-(2-bromo-ethyl)- thiophen-2-ylmethyl]-methyl-amino ⁇ -ethyl)-oxazol-2-yl]-cyclohexyl-phenyl- methanol (Intermediate 44) and 8-[2-amino-1-(te/?-butyl-dimethyl-silanyloxy)- ethyl]-5-hydroxy-4/-/-benzo[1 ,4]oxazin-3-one (Intermediate 32) by similar methods to those employed for Intermediate 37 and Example 2, respectively.
  • the crude product was purified by HPLC to afford the desired product as a formic acid salt.
  • the title compound was prepared from [5-(2-bromo-ethyl)-thiophen-2- ylmethyl]- ⁇ 2-[2-((R)-cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-yl]-ethyl ⁇ - carbamic acid terf-butyl ester (Intermediate 47) and 5-[(/?)-2-amino-1-(terf- butyl-dimethyl-silanyloxy)-ethyl]-8-(4-methoxy-benzyloxy)-1 /-/-quinolin-2-one by similar methods to those employed for Intermediate 42 and Example 2, respectively.
  • the crude product was purified by HPLC to afford the desired product as a formic acid salt.
  • Examples 16-29 shown in the table below, with the exception of the benzothiazolone containing compounds, were prepared using similar methods to those described for Example 15.
  • the benzothiazolone containing examples were prepared from 7-((R)-2-amino-1-hydroxy-ethyl)-4-hydroxy-3H- benzothiazol-2-one by similar methods to those employed for Intermediate 42. All compounds were purified by HPLC to afford the desired compounds as formic acid salts.
  • the title compound was prepared from [5-(2-bromo-ethyl)-thiophen-2- ylmethyl]- ⁇ 2-[2-(hydroxy-diphenyl-methyl)-oxazol-5-yl]-ethyl ⁇ -carbamic acid tert-butyl ester (Intermediate 46) and (R)-2-amino-1-(2,2-dimethyl-4H- benzo[1 ,3]dioxin-6-yl)-ethanol (Prepared according to WO 2005/044787) by similar methods to those employed for Intermediate 37 and Example 11 , respectively.
  • the crude product was purified by HPLC to afford the desired product as a formic acid salt.
  • the inhibitory effects of compounds of the present invention at the M 3 muscarinic receptor and the ⁇ 2 adrenergic receptor may be determined by the following binding assays:
  • H292 cells are grown in RPMI (Roswell Park Memorial Institute) medium containing, 10% (v/v) FBS (foetal bovine serum) and 2 mM L- glutamine. Cells are grown in 225cm2 flasks containing 25 mL media in a humidified incubator at 37°C, 5% CO 2 . Cells are harvested from the flask and passaged at a 1 in 10 dilution once per week.
  • the media from flasks containing H292 cells is removed, rinsed with 10 mL PBS (phosphate buffered saline) and replaced with 10 ml_ AccutaseTM cell detachment solution. Flasks are incubated for 15 minutes in a humidified incubator at 37°C, 5% CO 2 . The cell suspension is counted and the cells re- suspended in RPMI media (containing 10% (v/v) FBS and 2 mM L-glutamine) at 0.05 x 10 6 cells per mL. 5000 cells in 100 ⁇ L are added to each well of a tissue-culture-treated 96-well plate and the cells incubated overnight in a humidified incubator at 37°C, 5% CO 2 .
  • RPMI media containing 10% (v/v) FBS and 2 mM L-glutamine
  • the culture media is removed, washed twice with 100 ⁇ L assay buffer and replaced with 50 ⁇ L assay buffer.
  • Cells are rested at room temperature for 20 minutes after which time 25 ⁇ L of rolipram (1.2 mM made up in assay buffer containing 2.4% (v/v) dimethylsulphoxide) is added.
  • Cells are incubated with rolipram for 10 minutes after which time test compounds (made up as x4 concentrated stocks in assay buffer containing 4% (v/v) dimethylsulphoxide) are added and the cells are incubated for 10 minutes at room temperature.
  • Final rolipram concentration in the assay is 300 ⁇ M and final vehicle concentration is 1.6% (v/v) dimethylsulphoxide.
  • the reaction is stopped by removing supematants, washing once with 100 ⁇ L assay buffer and replacing with 50 ⁇ L lysis buffer.
  • the cell monolayer is frozen at -80 0 C for 30 minutes (or overnight).
  • the concentration of cAMP (cyclic adenosine monophosphate) in the cell lysate is determined using the AlphaScreenTM methodology.
  • the frozen cell plate is thawed for 20 minutes on a plate shaker then 10 ⁇ L of the cell lysate is transferred to a 96-well white plate.
  • 40 ⁇ L of mixed AlphaScreenTM detection beads containing equal volumes of donor beads (pre-incubated with biotinylated cAMP in the dark for 30 minutes) and acceptor beads, is added to each well and the plate incubated at room temperature for 10 hours in the dark.
  • the AlphaScreenTM signal is measured using an EnVision spectrophotometer (Perkin-Elmer Inc.) with the recommended manufacturer's settings.
  • cAMP concentrations are determined by reference to a calibration curve determined in the same experiment using standard cAMP concentrations (made up in lysis buffer in a 96-well tissure-culture-treated plate and frozen/thawed alongside the test samples) and detected using the same protocol.
  • Concentration response curves for agonists are constructed to determine both the pEC 50 and Intrinsic Activity. Intrinsic Activity is expressed as a fraction relative to the maximum activity determined for formoterol in each experiment.
  • H292 cells are grown in 225cm2 flasks incubator at 37°C, 5% CO 2 in RPMI medium containing10% (v/v) FBS (foetal bovine serum) and 2 mM L- glutamine.
  • Experimental Method Adherent H292 cells re removed from tissue culture flasks by treatment with AccutaseTM cell detachment solution for 15 minutes. Flasks are incubated for 15 minutes in a humidified incubator at 37°C, 5% CO 2 . Detached cells are re-suspended in RPMI media (containing 10% (v/v) FBS and 2 mM L-glutamine) at 0.05 x 10 6 cells per ml_.
  • 5000 cells in 100 ⁇ l_ are added to each well of a tissue-culture-treated 96-well plate and the cells incubated overnight in a humidified incubator at 37°C, 5% CO 2 .
  • the culture media is removed and cells are washed twice with 100 ⁇ l_ assay buffer and replaced with 50 ⁇ l_ assay buffer (HBSS solution containing 1OmM HEPES pH7.4 and 5 mM glucose).
  • Cells are rested at room temperature for 20 minutes after which time 25 ⁇ l_ of rolipram (1.2 mM made up in assay buffer containing 2.4% (v/v) dimethylsulphoxide) is added.
  • the concentration of cAMP (cyclic adenosine monophosphate) in the cell lysate is determined using AlphaScreenTM methodology.
  • the frozen cell plate is thawed for 20 minutes on a plate shaker then 10 ⁇ l_ of the cell lysate is transferred to a 96-well white plate.
  • 40 ⁇ L of mixed AlphaScreenTM detection beads pre-incubated with biotinylated cAMP, is added to each well and the plate incubated at room temperature for 10 hours in the dark.
  • the AlphaScreenTM signal is measured using an EnVision spectrophotometer (Perkin-Elmer Inc.) or a Fusion ⁇ HT (Packard) with the recommended manufacturer's settings.
  • cAMP concentrations are determined by reference to a calibration curve determined in the same experiment using standard cAMP concentrations.
  • Concentration response curves for agonists are constructed and data is fitted to a four parameter logistic equation to determine both the pEC-50 and Intrinsic Activity.
  • Intrinsic Activity is expressed as a fraction relative to the maximum activity determined for formoterol in each experiment.
  • Compounds of the invention tested in this assay had a pEC 50 of ⁇ 1 ⁇ M and an intrinsic activity of > 0.6.
  • the affinity (plC 50 ) of compounds to the M 3 receptor is determined by competition binding of [ 3 H]N-methyl scopolamine (NMS) to CHO-K1 (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 are precoated with membranes and then incubated at 2mg of beads per well with serial dilutions of 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 MgCI 2 ). The assay is conducted in a final volume of 200 ⁇ L, in the presence of 1 % (v/v) dimethyl sulphoxide (DMSO). Total binding of [ 3 H]NMS is determined in the absence of competing compound and non-specific binding of [ 3 H]NMS is determined in the presence of 1 ⁇ M atropine.
  • DMSO dimethyl sulphoxide
  • the plates are incubated for 16 hours at room temperature and then read on Wallac Microbeta TM using a normalised 3 H protocol.
  • the plC 50 defined as the negative logarithm of the concentration of compound required for 50% reduction in specific [ 3 H]-NMS binding, is determined.

Abstract

La présente invention porte sur les composés cités représentés par la formule (I) ayant à la fois une activité d'antagoniste des récepteurs M3 et une activité d'agoniste des récepteurs β2 ; sur des compositions comprenant de tels composés ; sur l'utilisation de tels composés en thérapie (telle que pour des troubles des voies respiratoires) ; et sur une méthode de traitement d'un patient avec de tels composés.
PCT/GB2008/002692 2008-08-06 2008-08-06 Composés hétérocycliques contenant de l'azote utiles comme modulateurs bifonctionnels des récepteurs m3 et des récepteurs bêta-2 WO2010015792A1 (fr)

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US8329729B2 (en) 2008-05-13 2012-12-11 Astrazeneca Ab Quinuclidine derivatives as muscarinic M3 receptor antagonists
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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
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WO2022268740A1 (fr) 2021-06-21 2022-12-29 Genmab A/S Régime posologique combiné d'agents de liaison cd137 et pd-l1
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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
JP2013526520A (ja) * 2010-05-10 2013-06-24 ギリアード サイエンシーズ， インコーポレイテッド 二機能キノリン誘導体
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
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