WO2008149110A1 - Dérivés de bicyclor [2.2.1] hept-7-ylamine et leur utilisation dans le traitement de maladies et d'états pathologiques dans lesquels est impliquée l'activité des récepteurs muscarinique m3 et bêta-adrénergique - Google Patents

Dérivés de bicyclor [2.2.1] hept-7-ylamine et leur utilisation dans le traitement de maladies et d'états pathologiques dans lesquels est impliquée l'activité des récepteurs muscarinique m3 et bêta-adrénergique Download PDF

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WO2008149110A1
WO2008149110A1 PCT/GB2008/001955 GB2008001955W WO2008149110A1 WO 2008149110 A1 WO2008149110 A1 WO 2008149110A1 GB 2008001955 W GB2008001955 W GB 2008001955W WO 2008149110 A1 WO2008149110 A1 WO 2008149110A1
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hydroxy
alkyl
group
methyl
cycloalkyl
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PCT/GB2008/001955
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English (en)
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Lilian Alcaraz
Nicholas Kindon
Jonathan Mark Sutton
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Argenta Discovery Limited
Astrazeneca Ab
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Priority claimed from GB0711086A external-priority patent/GB0711086D0/en
Priority claimed from GB0711085A external-priority patent/GB0711085D0/en
Application filed by Argenta Discovery Limited, Astrazeneca Ab filed Critical Argenta Discovery Limited
Publication of WO2008149110A1 publication Critical patent/WO2008149110A1/fr

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    • 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
    • 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
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • 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 bicyclo[2.2.1]hept-7-ylamine derivatives, pharmaceutical 5 compositions, methods for their preparation and use in the treatment of M3 muscarinic receptor mediated diseases, for example respiratory diseases.
  • Anticholinergic 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.
  • mAChRs muscarinic acetylcholine receptors
  • M1-M5 muscarinic acetylcholine receptors
  • M3 mAChRs mediate contractile responses (reviewed by Caulfield, 1993, Pharmac. 0 Ther., 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 5 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).
  • M3 mAChR antagonists may be useful as therapeutics in these mAChR-mediated diseases.
  • Tiotropium (Spiriva TM) is a long-acting muscarinic antagonist currently marketed for the treatment of chronic obstructive pulmonary disease, administered by the inhaled route.
  • ipratropium is a muscarinic antagonist marketed for the treatment of COPD.
  • muscarinic receptor modulators have been referred to.
  • US4353922 describes muscarinic modulators based upon a [2.2.1]azabicycloheptane ring system.
  • EP418716 and US005610163 describe various [3.2.1 Jazabicyclooctane ring systems.
  • WO06/017768 describes [3.3.1]azabicyclononane ring systems.
  • [2.2.2]azabicyclooctane systems (quinuclidines) have been previously described, for example in US2005/0209272 and WO06/048225.
  • [3.1.0]azabicyclohexane systems have been described in, for example in WO06/035282.
  • [3.2.1 Jazabicyclooctane systems have been described in for example WO06/035303.
  • ⁇ 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 and other muscarinic antagonists;
  • WO02/060532 describes the combination of ipratropium with ⁇ 2-agonists and
  • WO02/060533 describes the combination of oxotropium with ⁇ 2-agonists.
  • Other M3 antagonist / ⁇ 2-agonist combinations are described in WO04/105759 and WO03/087097.
  • compounds possessing both muscarinic receptor antagonist and ⁇ 2-agonist activity present in the same molecule are described in WO04/105759 and WO03/087097.
  • Such 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 a third active ingredient, for example a steroid.
  • Such 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 the M3 antagonist to the ⁇ 2-agonist.
  • X is OR 4 or NR 5 R 12 ;
  • R 1 is d-Ce-alkyl, (C 3 -C 6 )cycloalkyl or hydrogen; and R 2 is a group-Z-NR 9 R 10 ; and R 3 is a lone pair, or C r C 6 -alkyl, in which cases the nitrogen atom to which it is attached is a quaternary nitrogen and carries a positive charge; or
  • R 1 and R 3 together with the nitrogen to which they are attached form a heterocycloalkyl ring, and R 2 is a group -Z-NR 9 R 10 , in which cases the nitrogen atom to which it is attached is a quaternary nitrogen and carries a positive charge, or
  • R 1 and R 2 together with the nitrogen to which they are attached form a heterocycloalkyl ring, said ring being substituted by a group , -Z-NR 9 R 10 ; and R 3 is a lone pair, or Ci-C 6 -alkyl, in which cases the nitrogen atom to which it is attached is a quaternary nitrogen and carries a positive charge;
  • R 4 is selected from one of the groups of formula (a), (b), (c) or (d):
  • R 5 is selected from one of the groups of formula (a), (b) or (c):
  • R 6 is C r C 6 -alkyl, (C 3 -C 6 )cycloalkyl or a hydrogen atom;
  • R and R are a CrC 6 -alkyl, (C 3 -C 6 )cycloalkyl group or halogen;
  • n and m are independently 0, 1 , 2 or 3;
  • each occurrence of R 8a and R 8b is independently selected from the group consisting of aryl, aryl-fused-heterocycloalkyl, heteroaryl, CVCValkyl, (C 3 -C 6 )cycloalkyl;
  • each occurrence of R 8c is independently selected from -OH, CVCValkyl, (C 3 -
  • R is d-C ⁇ -alkyl, (C 3 -C 6 )cycloalkyl or a hydrogen atom;
  • R is a hydrogen atom, (C 3 -C 6 )cycloalkyl or CrCe-alkyl;
  • R is an aryKCrC ⁇ -alkyl)-, or heteroaryl(CrC 6 -alkyl) group, wherein both CVC 6 -alkyl species are optionally substituted by hydroxy;
  • R is CrC 6 -alkyl, (C 3 -C 6 )cycloalkyl or a hydrogen atom
  • Ar 1 is aryl, heteroaryl or (C 3 -C 6 )cycloalkyl
  • Ar 2 are, independently, aryl, heteroaryl or (C 3 -C 6 )cycloalkyl;
  • Q is an oxygen atom, -CH 2 -, -CH 2 CH 2 - or a bond
  • Z is selected from:
  • L is a hydrocarbyl chain of up to 14 carbon atoms, wherein one, two or 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), NR 46 C(O), C(O)NR 47 , NR 48 S(O) 2 , S(O) 2 NR 49 , NR 50 C(O)NR 51 , NR 52 S(O) 2 NR 53 , OC(O)NR 54 , NR 55 C(O)O, provided that any heteroatoms in the chain are separated by at least 2 carbon atoms; and/or wherein up to four carbon atoms of the chain form part of a mono- or bicyclic
  • 6 cycloalkyl may be optionally substituted by up to three substituents independently selected from halogen, hydroxyl and C 1-6 alkoxy; and the chain may comprise up to three of such rings each selected independently; wherein R 56 , R 65 and R 69 each independently represent C 1-6 alkyl or C 3 . 6 cycloalkyl, wherein C 1 ⁇ alkyl and C 3-6 cycloalkyl may be optionally substituted by up to three substituents independently selected from halogen, hydroxyl, Ci.
  • R 61 , R 62 , R 63 , R 64 , R 66 , R 67 , R 68 , R 70 , R 71 , R 72 and R 73 each independently represent hydrogen, or 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, C 1 ⁇ alkoxy; or any of R 57 and
  • R 58 , R 59 and R 60 , R 61 and R 62 or R 71 and R 72 together with the nitrogen atom to which they are both attached, may form a 4 to 8 membered aliphatic heterocyclic ring, wherein the aliphatic heterocyclic ring may comprise up to three heteroatoms independently selected from N 1 O and S, wherein the ring may be optionally substituted by up to three substituents independently selected from halogen, hydroxyl and C 1-6 alkyl or C 3 .
  • C 1 ⁇ alkyl and C 3-6 cycloalkyl may be optionally substituted by one or more substituents independently selected from halogen and hydroxyl; and wherein the chain may additionally comprise up to three carbon- carbon double bonds; wherein the chain may additionally comprise up to three carbon- carbon triple bonds;
  • L 1 and L 2 each independently represent hydrogen, C 1 ⁇ alkyl or C 3 . 6 cycloalkyl
  • 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
  • L 1 and/or L 3 may be linked to carbon atoms of the hydrocarbyl chain in linker L to form aliphatic rings of up to 6 ring atoms, wherein each ring may comprise up to three heteroatoms independently selected from N, O and S;
  • Z is a linker * -C(L 3 )(L 4 )-L-C(L 1 )(L 2 )- ** ; or a pharmaceutically acceptable salt thereof.
  • the present invention provides a prodrug of a compound of formula (I) as herein defined, or a pharmaceutically acceptable salt thereof.
  • the present invention provides an N-oxide of a compound of formula (I) as herein defined, or a prodrug or pharmaceutically acceptable salt thereof.
  • the present invention provides a solvate (such as a hydrate) of a compound of formula (I) as herein defined, or an N-oxide, prodrug or pharmaceutically acceptable salt thereof.
  • R 1 is d-C 6 -alkyl ;
  • R 2 is a group -Z-NR 9 R 10 and
  • R 3 is a lone pair or C r C 6 -alkyl, in which cases the nitrogen atom to which it is attached is a quaternary nitrogen and carries a positive charge, or:
  • R 1 and R 2 together with the nitrogen to which they are attached represent a heterocycloalkyl ring, said ring being substituted by a group -Z-NR 9 R 10 and R 3 is a lone pair or Ci-C 6 -alkyl, in which cases the nitrogen atom to which it is attached is a quaternary nitrogen and carries a positive charge; or: R 1 and R 3 together with the nitrogen to which they are attached represent a heterocycloalkyl ring, and R 2 is a group -Z-NR 9 R 10 , in which cases the nitrogen atom to which it is attached is a quaternary nitrogen and carries a positive charge;
  • R 4 is selected from one of the groups of formula (a), (b) or (c):
  • R 6 is a hydrogen atom
  • R j7a a _n personallyd_! o R7b are independently a Ci-C 6 -alkyl group or halogen;
  • n and m are independently 0, 1 , 2 or 3;
  • R 8a and R 8b are independently selected from the group consisting of aryl, heteroaryl, CrCe-alkyl, (C 3 -C 6 )cycloalkyl;
  • R is -OH, CVCValkyl, hydroxy-CrC ⁇ -alkyl, or a hydrogen atom;
  • R 9 is a hydrogen atom or CrC 6 -a!kyl; or R 9 is a hydrogen atom;
  • R 10 is a group ArCH(OH)CH 2 - or a group ArCH 2 CH 2 -; or R 10 is a group ArCH(OH)CH 2 -, wherein Ar is a group
  • a 1 , A 2 , A 3 and A 4 are, independently, hydrogen, halogen, trifluoromethyl, cyano, carboxy, hydroxy, nitro, S(O) 2 A 8 , NA 9 S(O) 2 A 10 , C(O)NA 11 A 12 , NA 13 C(O)A 14 , C 1-6 alkyl, C 1-6 alkoxy, C(O)(CL 6 alkyl) or C(O)OC 1-6 alkyl; and A 3 can also be CH 2 OH, NHCHO, NHS(O) 2 NA 15 A 16 or NHSO 2 A 17 ;
  • a 5 , A 6 , A 7 , A 9 , A 11 , A 12 , A 13 , A 14 , A 15 or A 16 are, independently, hydrogen or C 1-6 alkyl;
  • a 8 , A 10 and A 17 are, independently, Cm alkyl.
  • Ar is selected from wherein
  • a 1 , A 2 , and A 4 are, independently, hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy; and A 3 can also be CH 2 OH, NHCHO, NHS(O) 2 NA 15 A 16 or NHSO 2 A 17 ;
  • a or A are independently selected from hydrogen or C 1-6 alkyl
  • a 1 ' is C 1-6 alkyl
  • C 1-6 alkyl examples include C 1-4 alkyl and C 1-2 alkyl.
  • C 1-6 alkoxy examples include C 1-4 alkoxy and C 1-2 alkoxy.
  • Ar is selected from:
  • X is OR 4 or NR 5 R 12 ;
  • R 1 is d-C ⁇ -alkyl ;
  • R 2 is a group -Z-NR 9 R 10 and R 3 is a lone pair or C r C 6 -alkyl, in which cases the nitrogen atom to which it is attached is a quaternary nitrogen and carries a positive charge, or: R 1 and R 2 together with the nitrogen to which they are attached represent a heterocycloalkyl ring, said ring being substituted by a group -Z-NR 9 R 10 and R 3 is a lone pair or Ci-C 6 -alkyl, in which cases the nitrogen atom to which it is attached is a quaternary nitrogen and carries a positive charge; or: R 1 and R 3 together with the nitrogen to which they are attached represent a heterocycloalkyl ring, and R 2 is a group -Z-NR 9 R 10 , in which cases the nitrogen atom to which it is attached is a quaternary nitrogen and carries a positive charge; or alternatively:
  • R 1 is H;
  • R 2 is -Z-NR 9 R 10 & R 3 is a lone pair;
  • R 4 and R 5 are independently selected from one of the groups of formula (a), (b) or (c):
  • Ar 1 is a phenyl group
  • R 6 is a hydrogen atom
  • n and m are 0;
  • R 8a and R >8 8 b b are both a phenyl group; or, R and R are both a thienyl group, or R' is a phenyl group and R is a cycloalkyl group, such as cyclopentyl or cyclohexyl;
  • R is -OH or CrC 6 -alkyl (especially methyl or ethyl); In a further embodiment, R is -OH;
  • Ar 2 is a phenyl ring
  • R 8c is hydrogen, C 1-6 alkyl (especially methyl) or -OH
  • R 9 is a hydrogen atom or CrCg-alkyl
  • R 10 is an aryl(C r C 6 -alkyl)-, or heteroaryKd-Ce-alkyl) group, selected from the group
  • X is OR 4 and the radical MD(L 1 )(L 2 J-L-C(L 3 )(L 4 )-
  • X is NR 5 R 12 and the radical MD(L 1 )(L 2 J-L-
  • the compounds of the invention be predominantly in the anti-endo configuration.
  • Compounds of the invention can also exist as optical isomers since substituted bicyclic ring systems can lack a plane of symmetry.
  • the absolute configuration of the molecule can be defined using Cahn-lngold-Prelog rules to assign the R or S designation to each position. To avoid confusion the ring numbering used below is employed.
  • compounds of the invention include racemates, single enantiomers and mixtures of the enantiomers in any ratio, since all such forms have muscarinic M3 receptor modulating activity to varying extents.
  • R 4 is selected from one of the groups of formula (a), (b), (c) or (d):
  • R 5 is selected from one of the groups of formula (a), (b) or (c):
  • R 6 may be C r C 6 -alkyl such as methyl or ethyl or a hydrogen atom
  • Ar 1 may be an aryl group such as phenyl, a heteroaryl group such as thienyl, especially 2-thienyl, or a cycloalkyl group such as cyclohexyl, cyclopentyl, cyclopropyl, or cyclobutyl
  • ring substituents R 7a and R 7b may be independently a d- C 6 -alkyl group, such as methyl, ethyl, n- or isopropyl, n-, sec- or tertbutyl, or halogen such as fluoro, chloro or bromo
  • m and n may be independently 0, 1 , 2 or 3.
  • R 8a and R 8b may be independently selected from any of those aryl, aryl-fused-heterocycloalkyl, aryl-fused-cycloalkyl, heteroaryl, Ci-C 6 -alkyl, or cycloalkyl groups specifically mentioned in the discussion of R 5 above. Additionally, R 8b may also be a hydrogen atom. R 8c may be -OH, a hydrogen atom, CrC 6 -alkyl such as methyl or ethyl, or hydroxy-CrCValkyl such as hydroxymethyl,. Presently preferred is the case where R 8c is -OH.
  • R 8a and R 8b are preferred combinations wherein (i) each of R 8a and R 8b is optionally substituted monocyclic heteroaryl of 5 or 6 ring atoms such as pyridyl, oxazolyl, thiazolyl, furyl and especially thienyl such a 2-thienyl; (ii) R 8a and R 8b are both optionally substituted phenyl; (iii) one of R 8a and R 8b is optionally substituted phenyl and the other is cycloalkyl such as cyclopropyl, cyclobutyl, cycloheptyl, cyclooctyl or especially cyclopentyl or cyclohexyl; and (iv) one of R 8a and R 8b is optionally substituted monocyclic heteroaryl of 5 or 6 ring atoms such as pyridyl, thienyl, ox
  • R 8c may be -OH, a hydrogen atom, CrC 6 -alkyl such as methyl or ethyl, or hydroxy-CrC 6 -alkyl such as hydroxymethyl.
  • R 8c is -OH.
  • Each Ar 2 is an aryl, heteroaryl or cycloalkyl ring and may be, for example, any of those aryl, heteroaryl, C r C 6 -alkyl, or cycloalkyl rings specifically mentioned in the discussion of R 5 above.
  • Preferred Ar 2 rings include phenyl.
  • the bridge -Q between the two Ar 2 rings is -O-, -CH 2 -, -CH 2 CH 2 - or a bond.
  • R 4 be a group (a) or (b) or (c).
  • R 1 is H
  • R 2 is -Z-NR 9 R 10 & R 3 is a lone pair, wherein R 9 and R 10 are as previously defined.
  • One embodiment of the present invention provides compounds of formula (I) wherein the nitrogen attached to R 1 and R 3 is a quaternary nitrogen and carries a positive charge.
  • One embodiment of the present invention provides compounds of formula (I) wherein X is NR 5 R 12 and Z is a CrC ⁇ -alkylene, C 2 -C 16 -alkenylene or C 2 -C 16 -alkynylene group.
  • One embodiment of the present invention provides compounds of formula (I) wherein X is NR 5 R 12 and Z is a linker * -C(L 3 )(L 4 )-L-C(L 1 )(L 2 )- ** , wherein L, L 1 , L 2 , L 3 and L 4 are as previously defined.
  • One embodiment of the present invention proviides compounds of formula (I) wherein X is OR 4 .
  • R 1 is CrCValkyl or hydrogen; and R 2 is a group-Z-NR 9 R 10 ; and R 3 is a lone pair, or Ci-C 6 -alkyl, in which cases the nitrogen atom to which it is attached is a quaternary nitrogen and carries a positive charge; or (ii) R 1 and R 3 together with the nitrogen to which they are attached form a heterocycloalkyl ring, and R 2 is a group -Z-NR 9 R 10 , in which cases the nitrogen atom to which it is attached is a quaternary nitrogen and carries a positive charge, or
  • R 1 and R 2 together with the nitrogen to which they are attached form a heterocycloalkyl ring, said ring being substituted by a group , -Z-NR 9 R 10 ; and R 3 is a lone pair or CrC 6 -alkyl, in which cases the nitrogen atom to which it is attached is a quaternary nitrogen and carries a positive charge.
  • One embodiment of the present invention consists of compounds of formula (I) wherein R 6 is C r C 6 -alkyl or a hydrogen atom.
  • One embodiment of the present invention consists of compounds of formula (I) wherein R 7a and R 7b are a C 1 -CVaIkVl group or halogen.
  • One embodiment of the present invention consists of compounds of formula (I) wherein R 8c is -OH, CVCe-alkyl, hydroxy-C r C 6 -alkyl, nitrile, a group CONR 8d 2 or a hydrogen atom.
  • One embodiment of the present invention consists of compounds of formula (I) wherein R 8d is CrC 6 -alkyl or a hydrogen atom.
  • One embodiment of the present invention consists of compounds of formula (I) wherein R 9 is a hydrogen atom or C r C 6 -alkyl.
  • One embodiment of the present invention consists of compounds of formula (I) wherein R 9 is a hydrogen atom.
  • One embodiment of the present invention consists of compounds of formula (I) wherein R 10 is a group ArCH(OH)CH 2 -.
  • One embodiment of the present invention consists of compounds of formula (I) wherein R 10 is selected from the group:
  • One embodiment of the present invention consists of compounds of formula (I) wherein R 12 is CrC 6 -alkyl or a hydrogen atom.
  • One embodiment of the present invention consists of a compound of formula (I) selected from:
  • 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 diseases described hereinafter. Compounds that are antagonists may be represented by those wherein R 10 is a group ArCH 2 CH 2 -, whilst those that are partial or full agonists may be represented by those wherein R 10 is a group ArCH(OH)CH 2 -.
  • 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, 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, tabacosis and byssinosis); gastrointestinal-tract
  • quaternary ammonium salts of the invention administered by inhalation is may be more than 12, or more than 24 hours for a typical dose.
  • 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 or excipient.
  • Another aspect of the invention is the use of a compound of the invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in the treatment of prevention of a disease or condition in which M3 muscarinic receptor activity and ⁇ -adrenergic receptor activity are implicated.
  • Another aspect of the invention is a method of treatment of a disease or condition in which M3 muscarinic receptor activity and ⁇ -adrenergic receptor activity are implicated comprising administration to a subject in need thereof of an effective amount of a compound of the invention.
  • 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 is implicated.
  • Another aspect of the invention is the use of a compound of formula (Ia):
  • R 1 is C 1 -CVaIkVl or a hydrogen atom
  • R 2 is a hydrogen atom or a group -R 5 , or a group, -Z-Y-R 5 , or a group -Z-NR 9 R 10 , or a group -Z-N(R 9 )C(O)R 11
  • R 3 is a lone pair, or d-C ⁇ -alkyl in which case the nitrogen atom to which it is attached is a quaternary nitrogen and carries a positive charge
  • R 4 is selected from one of the groups of formula (a), (b), (c) or (d);
  • Z is a CVC 16 -alkylene, C 2 -C 16 -aIkenylene or C 2 -C 16 -alkynylene group;
  • Y is a bond or oxygen atom
  • R 5 is an C r C 6 -alkyl, aryl, arylalkyl; aryl-fused-cycloalkyl, aryl-fused-heterocycloalkyl, heteroaryl, ary ⁇ d-Ce-alkyl)-, heteroary ⁇ d-Cs-alkyl)-, cycloalkyl or heterocycloalkyl group;
  • R 6 is CrC 6 -alkyl or a hydrogen atom
  • R 7a and R 7b are a C ⁇ Ce-alkyl group or halogen
  • n and m are independently 0, 1 , 2 or 3;
  • R 8a and R 8b are independently selected from the group consisting of aryl, aryl-fused- heterocycloalkyl, heteroaryl, Ci-C 6 -alkyl, cycloalkyl and hydrogen;
  • R 8c is -OH, Ci-C 6 -alkyl, hydroxy-CrC 6 -alkyl, or a hydrogen atom;
  • R 9 and R 10 are independently a hydrogen atom, CVC 6 -alkyl, aryl, aryl-fused- heterocycloalkyl, aryl-fused-cycloalkyl, heteroaryl, aryl(C r C 6 -alkyl)-, or heteroaryl(C r C 6 -alkyl)- group; or R 9 and R 10 together with the nitrogen atom to which they are attached form a heterocyclic ring of 4-8 atoms, optionally containing a further nitrogen or oxygen atom;
  • R 11 is CrCe-alkyl or a hydrogen atom
  • Ar 1 is aryl, heteroaryl or cycloalkyl
  • Ar 2 are independently aryl, heteroaryl or cycloalkyl
  • Q is an oxygen atom, -CH 2 -, -CH 2 CH 2 - or a bond
  • Another aspect of the invention is a method of treatment of a disease or condition in which M3 muscarinic receptor activity and ⁇ -adrenergic receptor activity is implicated comprising administration to a subject in need thereof of an effective amount of a compound of formula (Ia), as defined above.
  • acyl means a -CO-alkyl group in which the alkyl group is as described herein.
  • exemplary acyl groups include -COCH 3 and -COCH(CH 3 ) 2 .
  • Acylamino means a -NR-acyl group in which R and acyl are as described herein.
  • exemplary acylamino groups include -NHCOCH 3 and -N(CH 3 )COCH 3 .
  • Alkoxy and “alkyloxy” means an -O-alkyl group in which alkyl is as described below.
  • Exemplary alkoxy groups include methoxy (-OCH 3 ) and ethoxy (-OC 2 H 5 ).
  • Alkoxycarbonyl means a -COO-alkyl group in which alkyl is as defined below.
  • exemplary alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl.
  • Alkyl as a group or part of a group refers to a straight or branched chain saturated hydrocarbon group having from 1 to 12, preferably 1 to 6, carbon atoms, in the chain.
  • exemplary alkyl groups include methyl, ethyl, 1 -propyl and 2-propyl.
  • alkenyl as a group or part of a group refers to a straight or branched chain hydrocarbon group having from 2 to 12, preferably 2 to 6, carbon atoms and one carbon-carbon double bond in the chain.
  • alkenyl groups include ethenyl, 1-propenyl, and 2-propenyl.
  • Alkynyl as a group or part of a group refers to a straight or branched chain hydrocarbon group having from 2 to 12, preferably 2 to 6, carbon atoms and one carbon-carbon triple bond in the chain.
  • exemplary alkenyl groups include ethynyl, 1- propynyl, and 2-propynyl.
  • Alkylamino means a -NH-alkyl group in which alkyl is as defined above.
  • exemplary alkylamino groups include methylamino and ethylamino.
  • Alkylene means an -alkyl- group in which alkyl is as defined previously.
  • exemplary alkylene groups include -CH 2 -, -(CH 2 ) 2 - and -C(CH 3 )HCH 2 -.
  • alkenylene means an -alkenyl- group in which alkenyl is as defined previously.
  • Alkynylene means an -alkynyl- group in which alkynyl is as defined previously.
  • exemplary alkenylene groups include -CC-, -CCCH 2 -, and -CH 2 CC-.
  • Alkylsulfinyl means a -SO-alkyl group in which alkyl is as defined above.
  • alkylsulfinyl groups include methylsulfinyl and ethylsulfinyl.
  • Alkylsulfonyl means a -SO 2 -alkyl group in which alkyl is as defined above.
  • exemplary alkylsulfonyl groups include methylsulfonyl and ethylsulfonyl.
  • Alkylthio means a -S-alkyl group in which alkyl is as defined above.
  • exemplary alkylthio groups include methylthio and ethylthio.
  • aminoacyl means a -CO-NRR group in which R is as herein described.
  • exemplary aminoacyl groups include -CONH 2 and -CONHCH 3 .
  • Aminoalkyl means an alkyl-NH 2 group in which alkyl is as previously described.
  • Exemplary aminoalkyl groups include -CH 2 NH 2 .
  • aminosulfonyl means a -SO 2 -NRR group in which R is as herein described.
  • exemplary aminosulfonyl groups include -SO 2 NH 2 and -SO 2 NHCH 3 .
  • Aryl as a group or part of a group denotes an optionally substituted monocyclic or multicyclic aromatic carbocyclic moiety of from 6 to 14 carbon atoms, preferably from 6 to 10 carbon atoms, such as phenyl or naphthyl. The aryl group may be substituted by one or more substituent groups.
  • Arylalkyl means an aryl-alkyl- group in which the aryl and alkyl moieties are as previously described. Preferred arylalkyl groups contain a C 1 4 alkyl moiety.
  • Exemplary arylalkyl groups include benzyl, phenethyl and naphthlenemethyl. The aryl part thereof may be substituted by one or more substituent groups.
  • Arylalkyloxy means an aryl-alkyloxy- group in which the aryl and alkyloxy moieties are as previously described. Preferred arylalkyloxy groups contain a C alkyl moiety. Exemplary arylalkyl groups include benzyloxy. The aryl part thereof may be substituted by one or more substituent groups.
  • Aryl-fused-heterocycloalkyl means a monocyclic aryl ring, such as phenyl, fused to a heterocycloalkyl group, in which the aryl and heterocycloalkyl are as described herein.
  • Exemplary aryl-fused-heterocycloalkyl groups include tetrahydroquinolinyl, indolinyl, benzodioxinyl, benzodioxolyl, dihydrobenzofuranyl and isoindolonyl.
  • the aryl and heterocycloalkyl rings may each be substituted by one or more substituent groups.
  • the aryl-fused-heterocycloalkyl group may be attached to the remainder of the compound by any available carbon or nitrogen atom.
  • Aryloxy means an -O-aryl group in which aryl is described above.
  • Exemplary aryloxy groups include phenoxy. The aryl part thereof may be substituted by one or more substituent groups.
  • Cyclic amine is a special case of "Heterocycloalkyl” or “heterocyclic” and means an optionally substituted 3 to 8 membered monocyclic cycloalkyl ring system where one of the ring carbon atoms is replaced by nitrogen, and which may optionally contain an additional heteroatom selected from O, S or NR (where R is as described herein).
  • Exemplary cyclic amines include pyrrolidine, piperidine, morpholine, piperazine and ⁇ /-methylpiperazine.
  • the cyclic amine group may be substituted by one or more substituent groups.
  • Cycloalkyl means an optionally substituted saturated monocyclic or bicyclic ring system of from 3 to 12 carbon atoms, preferably from 3 to 8 carbon atoms, and more preferably from 3 to 6 carbon atoms.
  • Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • the cycloalkyl group may be substituted by one or more substituent groups.
  • Dialkylamino means a -N(alkyl)2 group in which alkyl is as defined above.
  • dialkylamino groups include dimethylamino and diethylamino.
  • Halo or “halogen” means fluoro, chloro, bromo, or iodo. Preferred are fluoro or chloro.
  • Haloalkoxy means an -O-alkyl group in which the alkyl is substituted by one or more halogen atoms.
  • exemplary haloalkyl groups include trifluoromethoxy and difluoromethoxy.
  • Haloalkyl means an alkyl group which is substituted by one or more halo atoms.
  • Exemplary haloalkyl groups include trifluoromethyl.
  • Heteroaryl as a group or part of a group denotes an optionally substituted aromatic monocyclic or multicyclic organic moiety of from 5 to 14 ring atoms, preferably from 5 to 10 ring atoms, in which one or more of the ring atoms is/are element(s) other than carbon, for example nitrogen, oxygen or sulfur.
  • Examples of such groups include benzimidazolyl, benzoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, furyl, imidazolyl, indolyl, indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl, oxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, tetrazolyl, 1 ,3,4-thiadiazolyl, thiazolyl, thienyl and triazolyl groups.
  • the heteroaryl group may be may be substituted by one or more substituent groups.
  • the heteroaryl group may be attached to the remainder of the compound of the invention by any available carbon or nitrogen atom.
  • Heteroarylalkyl means a heteroaryl-alkyl- group in which the heteroaryl and alkyl moieties are as previously described. Preferred heteroarylalkyl groups contain a lower alkyl moiety. Exemplary heteroarylalkyl groups include pyridylmethyl. The heteroaryl part thereof may be substituted by one or more substituent groups.
  • Heteroarylalkyloxy means a heteroaryl-alkyloxy- group in which the heteroaryl and alkyloxy moieties are as previously described. Preferred heteroarylalkyloxy groups contain a lower alkyl moiety. Exemplary heteroarylalkyloxy groups include pyridylmethyloxy. The hetroaryl part thereof may be substituted by one or more substituent groups.
  • Heteroaryloxy means a heteroaryloxy- group in which the heteroaryl is as previously described. Exemplary heteroaryloxy groups include pyridyloxy. The heteroaryl part thereof may be substituted by one or more substituent groups.
  • Heterocycloalkyl or “heterocyclic” means: (i) an optionally substituted cycloalkyl group of from 4 to 8 ring members which contains one or more heteroatoms selected from O, S or NR; (ii) a cycloalkyl group of from 4 to 8 ring members which contains CONR and CONRCO (examples of such groups include succinimidyl and 2-oxopyrrolidinyl).
  • the heterocycloalkyl group may be be substituted by one or more substituents groups.
  • the heterocycloalkyl group may be attached to the remainder of the compound by any available carbon or nitrogen atom.
  • “Lower alkyl” as a group means unless otherwise specified, an aliphatic hydrocarbon group which may be straight or branched having 1 to 4 carbon atoms in the chain, i.e. methyl, ethyl, propyl (propyl or /so-propyl) or butyl (butyl, /so-butyl or tert- butyl).
  • Sulfonyl means a -SO 2 -alkyl group in which alkyl is as described herein.
  • exemplary sulfonyl groups include methanesulfonyl.
  • “Sulfonylamino” means a -NR-sulfonyl group in which R and sulfonyl are as described herein. Exemplary sulfonylamino groups include -NHSO 2 CH 3 .
  • R means alkyl, aryl, or heteroaryl as described herein.
  • “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.
  • a compound of the invention contains one or more acidic groups, for example carboxy groups
  • 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, napadisylates (naphthalene-1 ,5-disulfonates or naphthalene-1 -(sulfonic acid)-5-sulfonates), edisylates (ethane-1 ,2-disulfonates or ethane-1 -(sulfonic acid)-2-sulfonates), maleates, fumarates, succinates and the like; (iii) when R 3 is not a lone pair the compound of formula (I) has a quaternary ammonium group for which the counter-ion may be, for example, chloride, bromide, sulfate
  • 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.
  • metabolic means e.g. by hydrolysis, reduction or oxidation
  • an ester prodrug of a compound of the invention containing a hydroxy group may be convertible by hydrolysis in vivo to the parent molecule.
  • Suitable esters of compounds of the invention containing a hydroxy group are for example acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis- ⁇ -hydroxynaphthoates, gentisates, isothionates, di-p-toluoyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates and quinates.
  • ester prodrug of a compound of the invention containing a carboxy group may be convertible by hydrolysis in vivo to the parent molecule.
  • ester prodrugs are those described by F. J. Leinweber, Drug Metab. Res., 1987, 18, 379. It will be understood that, as used in herein, references to the compounds of the invention are meant to also include the prodrug forms.
  • “Saturated” pertains to compounds and/or groups which do not have any carbon-carbon double bonds or carbon-carbon triple bonds.
  • Optionally substituted means optionally substituted with up to four susbtituents.
  • Optional substituent groups include acyl (e.g. -COCH 3 ), alkoxy (e.g., -
  • alkoxycarbonyl e.g. -COOCHJ 3
  • alkylamino e.g. -NHCHJ 3
  • alkylsulfinyl e.g.
  • alkylsulfonyl e.g. -SO 2 CH 3
  • alkylthio e.g. -SCH 3
  • -NH 2 aminoacyl
  • aminoacyl e.g. - CON(CH 3 R aminoalkyl (e.g. -CH 2 NH 2 ), arylalkyl (e.g. -CH 2 Ph or -CH 2 -CH 2 -Ph), cyano, dialkylamino (e.g. -N(CH 3 J 2 ), halo, haloalkoxy (e.g. -OCF 3 or -OCHF 2 ), haloalkyl (e.g. -CF 3J, alkyl (e.g.
  • aryl optionally substituted with alkoxy, haloalkoxy, halogen, alkyl or haloalkyl
  • heteroaryl optionally substituted with alkoxy, haloalkoxy, halogen, alkyl or haloalkyl
  • heterocycloalkyl aminoacyl (e.g. -CONH 2 , -CONHCH 3 ), aminosulfonyl (e.g. -SO 2 NH 2 , -SO 2 NHCH 3 ), acylamino (e.g. -NHCOCH 3 ), sulfonylamino (e.g.
  • heteroarylalkyl cyclic amine (e.g. morpholine), aryloxy, heteroaryloxy, arylalkyloxy (e.g. benzyloxy) and heteroarylalkyloxy.
  • Alkyl, alkylene, alkenylene or alkynylene radicals may be optionally substituted.
  • Optional substituent groups in the foregoing radicals include alkoxy (e.g., -OCHJ 3 , alkylamino (e.g. -NHCHJ 3 , alkylsulfinyl (e.g. -SOCH 3J, alkylsulfonyl (e.g. - SO 2 CH 3J, alkylthio (e.g. -SCH 3J, -NH 2 , aminoalkyl (e.g. -CH c 0 .NHJ - ⁇ , arylalkyl (e.g.
  • -CH Ph or -CH -CH -Ph
  • cyano dialkylamino (e.g. -N(CHJJ, halo, haloalkoxy (e.g. -OCF 3 or -OCHF 2 ), haloalkyl (e.g. -CF 3 ), alkyl (e.g. -CH 3 or -CH 2 CH 3 ), -OH, and -NO 2 .
  • Compounds of the invention may exist in one or more geometrical, optical, enantiomeric, diastereomeric and tautomeric forms, including but not limited to cis- and trans-iorms, 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).
  • 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.
  • 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,
  • 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, WO05/026123, WO05/026124,
  • Phosphodiesterase-4 (PDE4) inhibitors for example roflumilast, arofylline, cilomilast,
  • An antitussive agent such as codeine or dextramorphan
  • P2X7 anatgonists P2X7 anatgonists; iNOS inhibitors; A non-steroidal anti-inflammatory agent (NSAID), for example ibuprofen or ketoprofen;
  • 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 CCR1 , CCR2,
  • DP1 or CRTH2 a thromboxane A 2 antagonist eg ramatroban
  • Th1 or Th2 function 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 (statins); 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 weight ratio of the first and second active ingredients may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used.
  • 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
  • Propellents 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
  • 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.
  • an example is: Compound of the invention 24 mg / canister Lecithin, NF Liq. Cone. 1.2 mg / canister
  • 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.
  • Volumatic® Volumatic®
  • Automatic devices emitting a puffer spray for metered aerosols
  • a number of technical solutions are available (e.g. Diskhaler®, Rotadisk®, Turbohaler® or the inhalers for example as described EP-A-0505321).
  • compounds of the invention may be delivered in multi-chamber devices thus allowing for delivery of combination agents.
  • the invention further provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above.
  • L, L 1 , L 2 , L 3 , L 4 and R 1 are as defined in formula (I) above.
  • Ar is as defined in R 10 above.
  • X is as defined in formula (I) above, or may be optionally suitably protected (for example such that R 4 or R 12 does not equal hydrogen).
  • the process comprises;
  • LG 1 represents a leaving group such as chloride, bromide, iodide, methanesulfonate or para-toluenesulfonate, with a compound of formula (III) or (Ilia), or a suitable salt thereof such as a hydrobromide, acetate or hydrochloride salt
  • P 1 is hydrogen or a protective group such as tert-butyldimethyl silyl in the presence of a base such as potassium carbonate, triethylamine or diisopropylethylamine, followed by removal of the protective group (e.g. using a hydrofluoric acid-pyridine complex); or
  • LG 1 represents a leaving group such as chloride, bromide, iodide, methanesulfonate or para-toluenesulfonate
  • P 2 represents a protective group (e.g. tert-butylcarbonyl) with a compound of formula (III) or (Ilia), or a suitable salt thereof
  • a base e.g. potassium carbonate, triethylamine or diisopropylethylamine
  • removal of the protective group e.g. treatment with hydrochloric or trifluoroacetic acid
  • P 3 represents hydrogen or an activating group (e.g. 3-nitrophenylsulfonyl) with a compound of formula (VIII) or (Villa), or a suitable salt thereof,
  • LG 2 represents a leaving group (e.g. chloride, bromide, iodide, methanesulfonate or para-toluenesulfonate) and P 1 is as defined in compound of formula (III) in the presence of a base (e.g. when P 3 is hydrogen, potassium carbonate, triethylamine, diisopropylethylamine and, when P 3 is 3-nitrophenylsulfonyl, sodium hydride or lithium di-/so-propylamide), followed by removal of the protective groups (e.g. using hydrofluoric acid-pyridine complex, thiophenol, thioacetic acid); or with a compound of formula (IX), or a suitable salt thereof,
  • a base e.g. when P 3 is hydrogen, potassium carbonate, triethylamine, diisopropylethylamine and, when P 3 is 3-nitrophenylsulfonyl, sodium hydride or lithium di-/so-
  • Ar is as defined in formula (I) in the presence of a base (e.g. when P 3 is hydrogen, potassium carbonate, triethylamine, diisopropylethylamine and, when P 3 is 3-nitrophenylsulfonyl, sodium hydride or lithium di-Zsopropylamide), followed by removal of the protective groups (e.g. trifluoroacetic acid, thiophenol, thioacetic acid); or with a compound of formula (X), or a suitable salt thereof,
  • a base e.g. when P 3 is hydrogen, potassium carbonate, triethylamine, diisopropylethylamine and, when P 3 is 3-nitrophenylsulfonyl, sodium hydride or lithium di-Zsopropylamide
  • the protective groups e.g. trifluoroacetic acid, thiophenol, thioacetic acid
  • LG 2 represents a leaving group (e.g. chloride, bromide, iodide, methanesulfonate or para-toluenesulfonate) in the presence of a base (e.g. when P 3 is hydrogen, potassium carbonate, triethylamine, diisopropylethylamine and, when P 3 is 3-nitrophenylsulfonyl, sodium hydride or lithium di-/so-propylamide), followed by reduction of the ketone (e.g. using sodium borohydride or a borane/chiral catalyst complex), followed by removal of the protective groups (e.g. trifluoroacetic acid, thiophenol, thioacetic acid); or (f) When R 1 represents hydrogen, reacting a compound of formula (Xl)
  • a base e.g. when P 3 is hydrogen, potassium carbonate, triethylamine, diisopropylethylamine and, when P 3 is 3-nitrophenyls
  • P 2 represents a protective group (e.g. tert-butylcarbonyl)
  • P 3 represents hydrogen or an activating group (e.g. 3-nitrophenylsulfonyl), with a compound of formula (VIII), (IX) or (X), or a suitable salt thereof, in the presence of a base (e.g. when P 3 is hydrogen, potassium carbonate, triethylamine, diisopropylethylamine and when P 3 is 3-nitrophenylsulfonyl, sodium hydride or lithium di-/so-propylamide), followed by removal of the protective groups (e.g. using trifluoroacetic acid, thiophenol, thioacetic acid); or
  • Ar, L 1 L 1 , and L 2 are as defined in formula (I), P 1 is as defined in compound of formula (III), P 3 represents a protective group (e.g. tert-butylcarbonyl or 3- nitrophenylsulfonoyl), LG 3 represents a leaving group (e.g. chloride, bromide, iodide, methanesulfonate or para-toluenesulfonate), with a compound of formula (XIII) or a suitable salt thereof, in the presence of a base (e.g. potassium carbonate, triethylamine, diisopropylethylamine), followed by removal of the protective groups (e.g. trifluoroacetic acid, thiophenol, thioacetic acid); or
  • a base e.g. potassium carbonate, triethylamine, diisopropylethylamine
  • P 1 is as defined in formula (III) with a suitable reducing agent (e.g. borane tetrahydrofuran complex), followed by removal of the protective group (e.g. using hydrofluoric acid-pyridine complex); or,
  • a suitable reducing agent e.g. borane tetrahydrofuran complex
  • removal of the protective group e.g. using hydrofluoric acid-pyridine complex
  • P 2 is as defined in compound of formula (Xl) with a suitable reducing agent (e.g. borane tetrahydrofuran complex), followed by removal of the protective group (e.g. using hydrofluoric acid-pyridine complex); and optionally after (a), (b), (c), (d), (e), (f), (g), (h), (i) or (j) carrying out one or more of the following:
  • a suitable reducing agent e.g. borane tetrahydrofuran complex
  • the protective group e.g. using hydrofluoric acid-pyridine complex
  • the reaction may conveniently be carried out in an organic solvent such as ⁇ /, ⁇ /-dimethylformamide, ethanol, n-butanol or dimethyl sulfoxide, at a temperature, for example, in the range from 50 to 140°C.
  • the reaction may conveniently be carried out in an organic solvent such as methanol, ethanol, dichloromethane, acetic acid N- methylpyrolidinone, or ⁇ /, ⁇ /-dimethylformamide containing up to 10%w of water and acetic acid.
  • reaction may conveniently be carried out in an organic solvent such as tetrahydrofuran, at a temperature, for example, in the range from 0 to 80 0 C.
  • organic solvent such as tetrahydrofuran
  • L 2 is as defined in formula (II) and Mt represents a metal such as lithium or magnesium, or aluminium or boron (e.g. methyllithium, methylmagnesium bromide, lithium aluminium hydride, sodium borohydride) in an organic solvent, for example, tetrahydrofuran or ether, at a temperature, for example in the range from 0 to 6O 0 C, followed by conversion of the resulting hydroxyl group into a suitable leaving group (e.g. chloride, bromide, iodide, methanesulfonate or para-toluenesulfonate).
  • a suitable leaving group e.g. chloride, bromide, iodide, methanesulfonate or para-toluenesulfonate.
  • Compounds of formula (IV) may be prepared by reacting a compound of formula (XVII) with a compound of formula (XVIII) in an organic solvent, for example, tetrahydrofuran or ether, at a temperature, for example in the range from 0 to 6O 0 C, followed by oxidation of the resulting hydroxyl group with a suitable oxidising agent (e.g. Swern reagent, Dess-Martin reagent or pyridiniumchlorochromate) in an organic solvent such as dichloromethane, ⁇ /, ⁇ /-dimethylformamide or dimethylsulfoxide at a temperature, for example in the range from -78 to 60 0 C.
  • a suitable oxidising agent e.g. Swern reagent, Dess-Martin reagent or pyridiniumchlorochromate
  • an organic solvent such as dichloromethane, ⁇ /, ⁇ /-dimethylformamide or dimethylsulfoxide at a temperature,
  • P 2 , L, L 3 , L 4 , and X are as defined in formula (V), with a compound of formula (XVIII) in an organic solvent, for example, tetrahydrofuran or ether, at a temperature, for example in the range from 0 to 6O 0 C, followed by conversion of the resulting hydroxyl group into a suitable leaving group (e.g. chloride, bromide, iodide, methanesulfonate or para-toluenesulfonate).
  • an organic solvent for example, tetrahydrofuran or ether
  • Compounds of formula (Vl) may be prepared by reacting a compound of formula (XVIII) with a compound of formula (XIX), followed by oxidation of the resulting hydroxyl group with a suitable oxidating agent (e.g. Swern reagent, Dess-Martin reagent or pyridiniumchlorochromate) in an organic solvent such as dichloromethane, ⁇ /, ⁇ /-dimethylformamide or dimethylsulfoxide at a temperature, for example in the range from -78 to 6O 0 C.
  • a suitable oxidating agent e.g. Swern reagent, Dess-Martin reagent or pyridiniumchlorochromate
  • an organic solvent such as dichloromethane, ⁇ /, ⁇ /-dimethylformamide or dimethylsulfoxide at a temperature, for example in the range from -78 to 6O 0 C.
  • Compounds of formula (VII) in which L 1 represents hydrogen and L, L 2 , L 3 , L 4 , and R 4 are as defined in formula (VII) may be prepared by (a) reacting a compound of formula (II) with sodium azide, in an organic solvent for example, tetrahydrofuran, ⁇ /, ⁇ /-dimethylformamide or dimethylsulfoxide at a temperature, for example in the range from 25 to 85 0 C, followed by reduction of the resulting azido compound using a suitable reducing agent (e.g. triphenylphosphine) in an organic solvent for example, tetrahydrofuran and water, and eventually followed by protection of the resulting amine (e.g. treatment with 3-nitrophenylsulfonyl chloride in the presence of a base such as pyridine); or,
  • a suitable reducing agent e.g. triphenylphosphine
  • a compound of formula (IV) with an amine (e.g. benzylamine, ⁇ -methyl benzylamine, 4-methoxybenzylamine or 2,4-methoxybenzylamine) followed by reduction of the resulting imine using a suitable reducing agent (e.g. sodium cyanoborohydride or sodium triacetoxyborohydride) in an organic solvent such as methanol, ethanol, dichloromethane, acetic acid, ⁇ /-methylpyrolidinone or N, N- dimethylformamide containing up to 10%w of water and acetic acid, followed by removal of the resulting benzyl protective group using the appropriate reagent (e.g.
  • an amine e.g. benzylamine, ⁇ -methyl benzylamine, 4-methoxybenzylamine or 2,4-methoxybenzylamine
  • a suitable reducing agent e.g. sodium cyanoborohydride or sodium triacetoxyborohydride
  • organic solvent such as methanol
  • a suitable catalyst Palladium on carbon or palladium hydroxide
  • DDQ 2,3- dichloro-5,6-dicyanobenzoquinone
  • CAN ammonium cerium nitrate
  • an organic solvent for example, ethanol, methanol, tetrahydrofuran, dichloromethane, acetonitrile, water, or a mixture thereof, at a temperature ranging from 25 to 80 0 C, and eventually followed by protection of the resulting amine (e.g. treatment with 3- nitrophenylsulfonyl chloride in the presence of a base such as pyridine);
  • LG 4 is a leaving group (e.g. hydroxyl or chloride), with reagents such as, when LG 4 is hydroxyl, diphenylphosphonic azide, in a presence of an amine (e.g. triethylamine), in an organic solvent, for example, tert-butanol, tetrahydrofuran, dichloromethane, water, or a mixture thereof, at a temperature ranging from 25 to 100 0 C, or when LG 4 is chloride, sodium azide, in an organic solvent, for example, ether, te/t-butanol, tetrahydrofuran, water, or a mixture thereof, at a temperature ranging from 25 to 100°C (Angewandte Chemie, 2005, 54, 5188), eventually followed by protection of the resulting amine (e.g. treatment with 3-nitrophenylsulfonyl chloride in the presence of a base such as pyridine).
  • a base such as pyridine
  • Compounds of formula (Xl) in which L 1 represents hydrogen may be prepared by (a) reacting a compound of formula (V) with sodium azide in an organic solvent, for example, tetrahydrofuran, ⁇ /, ⁇ /-dimethylformamide or dimethylsulfoxide at a temperature, for example in the range from 25 to 85 0 C, followed by reduction of the resulting azido compound using a suitable reducing agent (e.g. triphenylphosphine or hydrogen) in an organic solvent for example, tetrahydrofuran and water, eventually followed by protection of the resulting amine (e.g.
  • a suitable reducing agent e.g. triphenylphosphine or hydrogen
  • a compound of formula (Vl) with an amine (e.g. benzylamine, a- methyl benzylamine, 4-methoxybenzyl amine or 2,4-methoxybenzyl amine), followed by reduction of the resulting imine using a suitable reducing agent (e.g.
  • a suitable catalyst Palladium on carbon or palladium hydroxide
  • DDQ 2,3- dichloro-5,6-dicyanobenzoquinone
  • CAN ammonium cerium nitrate
  • an organic solvent for example, ethanol, methanol, tetrahydrofuran, dichloromethane, acetonitrile, water, or a mixture thereof, at a temperature ranging from 25 to 80°C, eventually followed by protection of the resulting amine (e.g. treatment with 3- nitrophenylsulfonyl chloride in the presence of a base such as pyridine).
  • LG 4 is a leaving group (e.g. hydroxyl or chloride), L, L 1 , L 2 , L 3 , L 4 , X and P 2 are as defined in formula (Xl), with reagents such as, when LG 4 is hydroxyl, diphenylphosphonic azide, in a presence of an amine (e.g.
  • triethylamine in an organic solvent, for example, terf-butanol, tetrahydrofuran, dichloromethane, water, or a mixture thereof, at a temperature ranging from 25 to 100 0 C, or when LG 4 is chloride, sodium azide, in an organic solvent, for example, ether, terf-butanol, tetrahydrofuran, water, or a mixture thereof, at a temperature ranging from 25 to 100 0 C (Angewandte Chemie, 2005, 54, 5188), eventually followed by protection of the resulting amine (e.g. treatment with 3-nitrophenylsulfonyl chloride in the presence of a base such as pyridine).
  • a base such as pyridine
  • Compounds of formula (XII) or (XIIa) can be prepared by (a) reacting a compound of formula (XXII) wherein P 5 is hydrogen or a protective group (e.g. tert-butyldimethylsilyl, tetrahydropyran) and L, L 1 and L 2 are as defined in formula (XII), with a compound of formula (VIII), (Villa), (IX) or (X), or a suitable salt thereof, in the presence of a base (e.g.
  • potassium carbonate triethylamine or diisopropylethylamine when P 3 is hydrogen and sodium hydride or lithium di-/so-propylamide when P 3 is 3- nitrophenylsulfonyl) in an organic solvent such as ⁇ /, ⁇ /-dimethylformamide, N- methylpyrolidinone, tetrahydrofuran, ethanol, n-butanol or dimethyl sulfoxide, at a temperature, for example, in the range from 50 to 140°C.
  • an organic solvent such as ⁇ /, ⁇ /-dimethylformamide, N- methylpyrolidinone, tetrahydrofuran, ethanol, n-butanol or dimethyl sulfoxide, at a temperature, for example, in the range from 50 to 140°C.
  • ketone e.g. using sodium borohydride or a borane/chiral catalyst complex.
  • Appropriate selective removal of the protective group e.g.
  • P 6 and P 7 represent an acyclic or cyclic carbonyl protective group (e.g. dimetoxy or diethoxy acetal, 1 ,3-dioxolane or 1 ,3-dioxane) and L, L 1 , L 2 , and P 3 are as defined in formula (XII), with a compound of formula (VIII), (Villa), (IX) or (X), or a suitable salt thereof, in the presence of a base (e.g.
  • a base e.g.
  • P 5 is hydrogen or a protective group (e.g. tert-butyldimethylsilyl, tetrahydropyran) and, L and L 2 are as defined in formula (XII), with a compound of formula (III) or (Ilia), or a suitable salt thereof, in the presence of a suitable reducing agent (e.g.
  • P 6 and P 7 represent an acyclic or cyclic carbonyl protective group (e.g. dimethoxy or diethoxy acetal, 1 ,3-dioxolane or 1 ,3-dioxane) and, L and L 2 are as defined in formula (XII), with a compound of formula (III) or (Ilia), or a suitable salt thereof, in the presence of a suitable reducing agent (e.g.
  • an organic solvent such as methanol, ethanol, dichloromethane, acetic acid, ⁇ /-methypyrolidinone or ⁇ /, ⁇ /-dimethylformamide containing up to 10%w of water and acetic acid, followed by removal of the protective group (e.g. diluted hydrochloric acid or amberlyst-15 resin in methanol).
  • Compounds of formula (XIV) or (XIVa) can be prepared by converting compound of formula (XII) or (XIIa), or a precursor to compound of formula (XII) or (XIIa) as decribed above, chosing an appropriate sequence of reactions such as, for example, reduction of an aldehyde to an alcohol (e.g. sodium borohydride), appropriate selective removal of the protective group (e.g. hydrofluoric acid-pyridine complex, tetrabutylamonium fluoride, diluted hydrochloric acid or amberlyst-15 resin in methanol) and conversion of an alcohol into a suitable leaving group (e.g. halogen, mesylate, tosylate); or,
  • an alcohol e.g. sodium borohydride
  • the protective group e.g. hydrofluoric acid-pyridine complex, tetrabutylamonium fluoride, diluted hydrochloric acid or amberlyst-15 resin in methanol
  • L, L 3 , L 4 , and X are as defined in formula (XV)
  • P 8 represents either R 1 as defined in compound of formula (XV) or P 2 as defined in compound of formula (XVI) and LG 6 represent hydroxyl or a leaving group (e.g. chloride) with a compound of formula (III) or (Ilia), or a suitable salt thereof.
  • LG 6 represent hydroxyl or a leaving group (e.g. chloride) with a compound of formula (III) or (Ilia), or a suitable salt thereof.
  • the reaction is conveniently carried out in the presence of an activating reagent, for example, carbonyldiimidazole or O-(7- azabenzotriazol-1 -yl)- ⁇ /, ⁇ /, ⁇ /', ⁇ /-tetramethyluroniumhexafluorophosphate (HATU), in an organic solvent, for example, ⁇ /, ⁇ /-dimethylformamide or dichloromethane, at a temperature, for example in the range from 0 to 60 0 C
  • an activating reagent for example, carbonyldiimidazole or O-(7- azabenzotriazol-1 -yl)- ⁇ /, ⁇ /, ⁇ /', ⁇ /-tetramethyluroniumhexafluorophosphate (HATU)
  • an organic solvent for example, ⁇ /, ⁇ /-dimethylformamide or dichloromethane
  • LG 6 represents chloride
  • the reaction is conveniently carried out in the presence of a base, for example, triethy
  • Suitable solvents are dichloromethane or more suitably water, dioxane and tetrahydrofuran mixtures.
  • R 8a , R 8b , and R 8c are as defined in formula (b) and LG is a leaving group, for example, an O-alkyl, halogen or 1-imidazolyl group.
  • the reaction is conducted in the presence of a strong base such as NaH or NaOMe in a solvent such as toluene, THF or dichloromethane at a range of temperatures, preferably between O 0 C and the reflux temperature of the solvent.
  • P 12 is a protecting group such as benzyl, 4-methoxybenyl or 3,4- dimethoxybenzyl and R 1 is as defined in formula (I), by reaction with hydrogen in the presence of a catalyst, preferably palladium hydroxide on carbon, in a polar solvent such as MeOH or EtOAc in the presence of di-tert butyl dicarbonate.
  • a catalyst preferably palladium hydroxide on carbon
  • a polar solvent such as MeOH or EtOAc
  • reaction by reaction with a tin reagent, preferably Bu 3 SnH and a radical initiator, preferably AIBN.
  • a tin reagent preferably Bu 3 SnH and a radical initiator, preferably AIBN.
  • the reaction can be performed in a range of solvents, preferably toluene, at a range of temperatures, preferably between room temperature and the reflux temperature of the solvent.
  • reaction by reaction with benzyl alcohol.
  • the reaction is performed in the presence of a strong base such as NaH in a range of solvents, preferably THF or DMF at a range of temperatures, preferably between -78 0 C and ambient temperature.
  • a strong base such as NaH in a range of solvents, preferably THF or DMF at a range of temperatures, preferably between -78 0 C and ambient temperature.
  • R 4 may be a hydrogen atom or a suitable protecting group
  • P 9 and P 10 represent the corresponding nitrogen substituents in compounds of formulas (II), (IV), (V), (Vl), (VII), (Xl), (XV), (XVI), (XVII), (XIX), (XX), (XXI) and (XXVI).;
  • Ar 2 and R 8c are as defined for formula (I) and LG 8 is a leaving group, for example, an O-alkyl, halogen or 1-imidazolyl group.
  • the reaction is conducted in the presence of a strong base such as NaH in a solvent such as toluene, THF or dichloromethane at a range of temperatures, preferably between 0 0 C and the reflux temperature of the solvent, followed by deprotection using similar conditions as described for the preparation of compounds of formula (XIII) from compounds of formula (XXVII).
  • reaction is conducted in the presence of a strong base such as NaH in a solvent such as toluene, THF, preferably DMSO at a range of temperatures, preferably between 0 0 C and the reflux temperature of the solvent, , followed by deprotection using similar conditions as described for the preparation of compounds of formula (XIII) from compounds of formula (XXVII).
  • a strong base such as NaH
  • a solvent such as toluene, THF, preferably DMSO
  • R 6 and R 6 is H and R 12 is as defined above for formula (I) may be prepared from compounds of formula (XXVIII-b), wherein R 1 and R 12 are as defined in formula (I):
  • Suitable methods for the preparation of compounds of formula (XXVIII-b), include reaction of compounds of formula (XXXI-b), wherein R 1 and R 12 are as defined in formula (I):
  • Compounds of formula (XXXI-b) can be prepared from compounds of formula (XXXII-e) wherein R 1 and R 12 are as defined in formula (I), or R 12 is a suitable protecting group, by reaction with di-tert-butyl dicarbonate in the presence of a suitable base such as diisopropylethylamine and suitable solvents such as THF or dichloromethane:
  • reaction can be performed in a range of solvents such as 1 ,2-dichloroethane, chloroform, dichloromethane, alcohols, optionally in the presence of an acid such as acetic acid, at a temperature from 0 0 C to the reflux temperature of the solvent, preferably from 0 0 C to ambient temperature of the solvent.
  • solvents such as 1 ,2-dichloroethane, chloroform, dichloromethane, alcohols
  • an acid such as acetic acid
  • Compounds of Formula (XXXII-d) may be prepared from compounds of formula (XXXI l-c) wherein R 12 is as defined in formula (I) or is a suitable protecting group, by reduction of the oxime with a suitable reducing agent, such as a borohydride reagent, specifically NaBHVNiCI 2 in a suitable solvent such as methanol at a suitable temperature, such as 20° C. ⁇ (0H (XXXII-C)
  • Compounds of formula (XXXII-c) may be prepared from compounds of formula (XXXII-b) wherein R 12 is as defined in formula (I) or is a suitable protecting group, by treatment with hydroxylamine or a salt thereof in the presence of a suitable solvent such as methanol, optionally in the presence of a base such as sodium acetate, at a temperature between 0° C and the reflux temperature of the solvent, preferably at ambient temperature.
  • a suitable solvent such as methanol
  • a base such as sodium acetate
  • Compounds of formula (XXXII-b) may be prepared from compounds of formula (XXXIV-b) wherein R 12 is as defined above by reaction with a tin reagent, preferably Bu 3 SnH and a radical initiator, preferably AIBN.
  • a tin reagent preferably Bu 3 SnH and a radical initiator, preferably AIBN.
  • the reaction can be performed in a range of solvents, preferably toluene, at a range of temperatures, preferably between ambient temperature and the reflux temperature of the solvent.
  • R 12 NHBn (XLII)
  • the reaction may be performed in a range of solvents, preferably THF/dichloromethane at a range of temperatures, preferably between 0 and 100 0 C.
  • solvents preferably THF/dichloromethane
  • XLII Compounds of formula (XLII) are well known in the art and can be prepared by known methods, or are commercially available.
  • the compounds of formula I 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 formula (I) and their pharmaceutically acceptable salts include:
  • respiratory tract obstructive diseases of the airways including: asthma, including bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including aspirin and NSAID-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 vasculature
  • 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 erythemato
  • 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 skin
  • 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;
  • 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; 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 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 provides a compound of formula (I) or a pharmaceutically-acceptable salt thereof as hereinbefore defined for use in therapy.
  • the present invention provides the use of a compound of formula (I) 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 formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined.
  • 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 dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated.
  • 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 formula (I) 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 formula (I) 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 formula (I) 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 formula (I) 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 2 O fatty acid or salt thereof, (for example, oleic acid), a bile salt, a phospholipid, an alkyl saccharide, a perfluorinated or polyethoxylated surfactant, or other pharmaceutically acceptable dispersant.
  • a dispersant such as a C 8 -C 2 O fatty acid or salt thereof, (for example, oleic acid), a bile salt, a phospholipid, an alkyl saccharide, a perfluorinated or polyethoxylated surfactant, or other pharmaceutically acceptable dispersant.
  • 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.
  • 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 JO dioxide.
  • a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium JO 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. Also 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 nonsteroidal anti-inflammatory agents
  • COX-1 / COX-2 inhibitors whether applied topically or systemically
  • 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
  • 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-(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 , M
  • 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.
  • an alpha-1/alpha-2 adrenoceptor agonist vasoconstrictor sympathomimetic agent such as propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine, naphazoline hydrochloride, oxy
  • 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 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, 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).
  • 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.
  • 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, 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 such as
  • 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 anti-depressant agent-s, paracetamol, or a nonsteroidal 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 sodium valproate
  • paracetamol paracetamol
  • nonsteroidal anti-inflammatory agent for example an opioid or derivative thereof
  • 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 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.
  • 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 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
  • - or B.sub2. -receptor antagonist for example colchicine;
  • xi xanthine oxidase inhibitor, for example allopurinol;
  • uricosuric agent for example probenecid, sulfinpyrazone or benzbromarone;
  • xiii growth hormone secretagogue;
  • PDGF platelet-derived growth factor;
  • PDGF platelet-derived growth factor
  • fibroblast growth factor for example basic fibroblast growth factor (bFGF);
  • GM-CSF granulocyte macrophage colony stimulating factor (GM-CSF);
  • GM-CSF granulocyte macrophage colony stimulating factor
  • capsaicin cream for example tachykinin NK.subi .
  • NKP-608C SB-233412 (talnetant) or D-4418
  • 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 formula (I) 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.
  • 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, for example suitable agents include:
  • 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, dactinomycin or mithramycin); an antimitotic agent (for example a vinca alkaloid such as vincri
  • 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 £J-(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-hJ-(3-chloro-4-fluorophen
  • 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
  • Silica gel used for medium pressure column chromatography is 0.035 to 0.070 mm (220 to 440 mesh) (e.g. Fluka silica gel 60), and an applied pressure up to 10 psi accelerated column elution.
  • TLC thin layer chromatography
  • it refers to silica gel TLC using plates, typically 3 x 6 cm silica gel on aluminium foil plates with a fluorescent indicator (254 nm) (e.g. Fluka 60778). All solvents and commercial reagents were used as received.
  • Purification by pre-packed SCX-2 cartridge refers to Isolute ® SCX-2, a strong cation exchange sorbent (Argonaut/I ST).
  • Micromass Platform LCT with a C18 reversed-phase column (100 x 3.0 mm i.d., Higgins Clipeus, 5 ⁇ m particle size), elution using linear gradients of mixtures of solvent A (water with 0.1% formic acid) and solvent B (acetonitrile with 0.1% formic acid) at a flow rate of 1 mL/min. Gradient:
  • MS, ELS, UV 100 ⁇ l_ split to MS with in-line UV detector).
  • MS ionization method Electrospray (positive ion).
  • MS, ELS, UV 100 ⁇ L split to MS with in-line UV detector.
  • MS ionisation method Electrospray (positive and negative ion).
  • MS MS, ELS, UV (100 ⁇ l_ split to MS with in-line UV detector).
  • MS ionisation method Electrospray (positive and negative ion).
  • MS Detection MS, ELS, UV (200 ⁇ L/min split to MS with in-line Waters 996 DAD detection).
  • MS ionisation method Electrospray (positive and negative ion).
  • MS ionisation method APCI (positive ion and negative ions).
  • MS ionisation method APCI (positive ion and negative ions).
  • MS ionisation method Electrospray (positive ion).
  • AIBN (2,2'-azobis(2-methylproprionitrile)
  • CDI 1 ,1'-carbonyldiimidazole
  • DIPEA diisopropylethylamine
  • DMF ⁇ /, ⁇ /-dimethylformamide
  • EtOAc ethyl acetate
  • HATU 0-(7-azabenzotriazol-1 -yl)- ⁇ /, ⁇ /,/V'/V -tetramethyluroniumhexafluoro- phosphate
  • NaHCO 3 sodium hydrogen carbonate
  • TFA trifluoroacetic acid
  • THF tetrahydrofuran
  • the reaction was quenched with 10% aqueous citric acid solution and the organic extracts washed with water and brine, dried over MgSO 4 and concentrated in vacuo.
  • the crude product was purified by chromatography over silica gel on a Teledyne ISCO CombiFlash using 0-15% diethyl ether/cyclohexane as eluent to give the title compound as a colourless syrup.
  • the title compound was prepared from 7-(2-amino-ethyl)-4-hydroxy-3H- benzothiazol-2-one hydrochloride and (4-nitro-phenyl)-acetaldehyde by similar methods to those employed for intermediates 7-9, respectively.
  • Dess-Martin periodinane (1.22 g, 2.88 mmol) was added to ⁇ /-(2,2-dimethoxy- ethyl)-4-(2-hydroxy-ethyl)-benzamide (0.55 g, 2.17 mmol) in DCM (15 mL). After 1 h saturated aqueous NaHCO 3 (25 mL), sodium thiosulphate (25 mL) and EtOAc (80 mL) were added. The mixture was shaken vigorously for 1 min and then separated.
  • HATU (8.30 g, 21.83 mmol) was added portion-wise over 10 min to a cooled 0 0 C stirred solution of 4-(hydroxymethyl)benzoic acid (2.60 g, 17.09 mmol), 2,2- dimethoxyethanamine (3.00 g, 28.53 mmol) and triethylamine (8.00 g, 79.06 mmol) in DMF (40 mL). After 1 h the reaction mixture was quenched with water (200 mL) and extracted with EtOAc (6 x 350 mL). The organic extracts were combined, dried ol
  • Manganese(IV) oxide (3.38 mL, 195.54 mmol) was added to stirred solution of ⁇ /-(2,2-dimethoxy-ethyl)-4-hydroxymethyl-benzamide (4.00 g, 16.72 mmol) in DCM (200 mL) at RT. After 2 h the mixture was filtered through a pad of Celite, washed with DCM, and the solution evaporated in vacuo to afford the crude aldehyde, which was used directly without characterization.
  • the title compound was prepared from ⁇ /-(2,2-dimethoxy-ethyl)-4-formyl- benzamide and 7-(2-amino-ethyl)-4-hydroxy-3/-/-benzothiazol-2-one hydrochloride by similar methods to those employed for intermediates 14 (reductive amination and Boc-protection stages) and 15, and was used directly without characterization.
  • Lithium hydroxide monohydrate (2.66 mL, 95.62 mmol) was added to
  • the title compound was prepared from carbonic acid 7-(2- ⁇ tert- butoxycarbonyl-[2-(3-hydroxymethyl-phenyl)-ethyl]-amino ⁇ -ethyl)-2-oxo-2,3-dihydro- benzothiazol-4-yl ester tert-butyl ester by a similar method to that employed for intermediate 17.
  • the title compound was prepared from ⁇ 4-[2-(terf-butyl-dimethyl-silanyloxy)- ethyl]-phenyl ⁇ -acetaldehyde and 7-(2-amino-ethyl)-4-hydroxy-3H-benzothiazol-2-one hydrochloride by similar methods to the reductive amination and Boc-protection steps for Intermediate 7.
  • a solution of the intermediate amino TBDMS ether in MeOH (20 ml_) was converted to the amino alcohol by addition of concentrated aqueous HCI (2 ml_). After 20 min the mixture was concentrated in vacuo to afford the crude de-silylated intermediate, which was taken on to react with Boc anhydride to afford the title compound.
  • the title compound was prepared from carbonic acid 7-[2-(te ⁇ i- butoxycarbonyl- ⁇ 2-[4-(2-hydroxy-ethyl)-phenyl]-ethyl ⁇ -amino)-ethyl]-2-oxo-2,3- dihydro-benzothiazol-4-yl ester te/t-butyl ester by a similar Dess-Martin oxidation method used in the synthesis of Intermediate 14, and was used directly without characterization.
  • the title compound was prepared from [3-(3-bromo-propoxy)-phenyl]- acetaldehyde and 7-(2-amino-ethyl)-4-hydroxy-3/-/-benzothiazol-2-one hydrochloride by similar methods to those used for intermediate 7.
  • the crude product was purified by HPLC (System 1) to afford the desired product as a white solid.
  • the title compound was prepared from ⁇ 5-[2-(tert-butyl-dimethyl-silanyloxy)- ethyl]-furan-2-yl ⁇ -acetic acid and 7-(2-aminoethyl)-4-hydroxybenzo[d]thiazol-2(3/ ⁇ )- one hydrobromide by similar methods to those employed for Intermediates 16, 23 and 25, respectively.
  • the title compound was prepared from 9-hydroxy-9/-/-xanthene-9-carboxylic acid (1S,2S,4R,7R)-2- ⁇ [3-(4-formyl-phenoxy)-propyl]-methyl-amino ⁇ - bicyclo[2.2.1]hept-7-yl ester and 4-(3-bromo-propoxy)-benzaldehyde by a similar method to that employed for Intermediate 41.
  • the title compound was prepared from 9-hydroxy-9H-xanthene-9-carboxylic acid (1S,2S,4R,7R)-2-methylamino-bicyclo[2.2.1]hept-7-yl ester and 5-[(R)-2-amino- 1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-8-hydroxy-1 H-quinolin-2-one by a similar method to that employed for Intermediate 42.
  • the title compound was prepared from hydroxy-di-thiophen-2-yl-acetic acid (1 S,2R,4S,7S)-7- ⁇ [2-(4-formyl-phenylcarbamoyl)-ethyl]-methyl-amino ⁇ - bicyclo[2.2.1]hept-2-yl ester and 5-[(R)-2-amino-1-(tert-butyl-dimethyl-silanyloxy)- ethyl]-8-hydroxy-1 H-quinolin-2-one by a similar method to that employed for Intermediate 52.
  • 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_), which was heated at 65 0 C, 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.
  • the title compound was prepared from hydroxy-di-thiophen-2-yl-acetic acid (1 S,2S,4R,7R)-2- ⁇ [3-(4-formyl-phenoxy)-propyl]-methyl-amino ⁇ -bicyclo[2.2.1]hept-7-yl ester (Intermediate 41) and 7-((R)-2-amino-1-hydroxy-ethyl)-4-hydroxy-3H- benzothiazol-2-one hydrochloride (prepared according to WO2007/027133) by a similar a method to that employed in intermediate 42.
  • the crude product was purified by preparative reversed-phase HPLC (System 1), eluting with 10-30% MeCN/water (0.1% formic acid) over 20 min. The pure fractions were combined and lyophilized to afford the title product as white solid.
  • the title compound was prepared from 9-hydroxy-9H-xanthene-9-carboxylic acid (1S,2S,4R,7R)-2- ⁇ [3-(4- ⁇ [(R)-2-(terf-butyl-dimethyl-silanyloxy)-2-(8-hydroxy-2- oxo-1 ,2-dihydro-quinolin-5-yl)-ethylamino]-methyl ⁇ -phenoxy)-propyl]-methyl-amino ⁇ - bicyclo[2.2.1]hept-7-yl ester (Intermediate 45) by a similar a method to that employed for Example 2.
  • the crude product was purified by preparative reversed-phase HPLC (System 1), eluting with 10-30% MeCN/water (0.1% formic acid) over 20 min. The pure fractions were combined and lyophilized to afford the title product as white solid.
  • reaction mixture was treated with a mixture of aqueous saturated NaHCO 3 and sodium thiosulphate solution, followed by EtOAc and was then stirred vigorously for 10 min.
  • the organic layer was separated and washed with saturated aqueous NaHCO 3 , brine, dried over Na 2 SO 4 , filtered, and concentrated in vacuo.
  • the residue was re-dissolved in MeOH (1 mL) and 7-((R)-2-amino-1-hydroxy-ethyl)-4-hydroxy-3/-/-benzothiazol-2-one hydrochloride (101 mg, 0.38 mmol) and acetic acid (20 ⁇ l_, 0.35 mmol) were added.
  • the title compound was prepared from hydroxy-di-thiophen-2-yl-acetic acid (1S,2S,4R,7R)-2- ⁇ [2-(3-formyl-benzoylamino)-ethyl]-methyl-amino ⁇ -bicyclo[2.2.1]hept- 7-yl ester (Intermediate 51) and 7-((R)-2-amino-1-hydroxy-ethyl)-4-hydroxy-3H- benzothiazol-2-one hydrochloride by a similar method to that employed for Intermediate 52.
  • the crude product was purified by preparative reversed-phase HPLC (System 1), eluting with 10-25% MeCN/water (0.1% formic acid) over 15 min. The pure fractions were combined and lyophilized to afford the title product as white fluffy solid.
  • the title compound was prepared from hydroxy-di-thiophen-2-yl-acetic acid (1 S,2R,4S,7S)-7- ⁇ [2-(4-formyl-phenylcarbamoyl)-ethyl]-methyl-amino ⁇ - bicyclo[2.2.1]hept-2-yl ester (Intermediate 54) and 7-((R)-2-amino-1-hydroxy-ethyl)-4- hydroxy-3H-benzothiazol-2-one hydrochloride by a similar method to that employed for Intermediate 52.
  • the crude product was purified by preparative reversed-phase HPLC (System 1), eluting with 10-25% MeCN/water (0.1% formic acid) over 20 min. The pure fractions were combined and lyophilized to afford the title product as white fluffy solid.
  • the title compound was prepared from hydroxy-di-thiophen-2-yl-acetic acid (1S,2S,4R,7R)-2-( ⁇ 2-[3-(2-hydroxy-ethyl)-benzoylamino]-ethyl ⁇ -methyl-amino)- bicyclo[2.2.1]hept-7-yl ester (Intermediate 59) by a similar method to that employed for Example 8.
  • the crude product was purified by preparative reversed-phase HPLC (System 1), eluting with 10-25% MeCN/water (0.1% formic acid) over 15 min. The pure fractions were combined and lyophilized to afford the title product as white fluffy solid.
  • 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:
  • the activity of compounds at the M 3 receptor is determined by competition binding of [ 3 H] ⁇ /-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.
  • NMS [ 3 H] ⁇ /-methyl scopolamine
  • CHO-K1 Choinese 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 2 mg of beads per well with compounds of the invention, [ 3 H]NMS at 0.2 nM, 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) 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. The plates are incubated for 16 h at RT and then read on Wallac Microbeta TM using a normalised 3 H protocol.
  • plC 50 determinations the assay is conducted using serial dilutions of compounds of the invention.
  • the plC 50 is defined as the negative logarithm of the concentration of compound required for 50% reduction in specific [ 3 H]-NMS binding.
  • spot test activity determinations compounds of the invention are incubated at a single 10 nM concentration using the protocol described above. The percentage inhibition of specific [ 3 H]NMS binding is reported.

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Abstract

La présente invention concerne des composés de formule (I) qui exercent une activité modulante vis à vis des récepteurs muscarinique M3 et β-adrénergique; R1, R2, R3 et X sont tels que définis ici.
PCT/GB2008/001955 2007-06-08 2008-06-06 Dérivés de bicyclor [2.2.1] hept-7-ylamine et leur utilisation dans le traitement de maladies et d'états pathologiques dans lesquels est impliquée l'activité des récepteurs muscarinique m3 et bêta-adrénergique WO2008149110A1 (fr)

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GB0711086A GB0711086D0 (en) 2007-06-08 2007-06-08 New chemical compounds
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Cited By (16)

* Cited by examiner, † Cited by third party
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WO2011081937A1 (fr) 2009-12-15 2011-07-07 Gilead Sciences, Inc. Composés de type corticostéroïde-bêta-agoniste-antagoniste muscarinique pour applications thérapeutiques
EP2386555A1 (fr) 2010-05-13 2011-11-16 Almirall, S.A. Nouveaux dérivés de cyclohéxylamine dotés d'activités agoniste bêta 2 adrénergique et antagoniste muscarinique m3
WO2011154678A1 (fr) 2010-06-11 2011-12-15 Astrazeneca Ab Composés
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
WO2013068554A1 (fr) 2011-11-11 2013-05-16 Almirall, S.A. Nouveaux dérivés de cyclohexilamine ayant des activités d'agoniste des récepteurs β2-adrénergique et d'antagoniste des récepteurs muscariniques m3
WO2013068552A1 (fr) 2011-11-11 2013-05-16 Almirall, S.A. Nouveaux dérivés de cyclohexilamine ayant des activités d'agoniste des récepteurs β2-adrénergique et d'antagoniste des récepteurs muscariniques m3
WO2014095920A1 (fr) 2012-12-18 2014-06-26 Almirall, S.A. Nouveaux dérivés de cyclohexyl et quinuclidinyl carbamate ayant une activité d'agoniste adrénergique beta2 et une activité d'antagoniste muscarinique m3
US9315463B2 (en) 2010-05-13 2016-04-19 Almirall, S.A. Cyclohexylamine derivatives having β2 adrenergic agonist and M3 muscarinic antagonist activities
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
WO2018108089A1 (fr) 2016-12-14 2018-06-21 北京硕佰医药科技有限责任公司 Classe de composés bifonctionnels de structure de sel d'ammonium quaternaire
US10005771B2 (en) 2014-09-26 2018-06-26 Almirall, S.A. Bicyclic derivatives having β2 adrenergic agonist and M3 muscarinic antagonist activities
US10456390B2 (en) 2013-07-25 2019-10-29 Almirall, S.A. Combinations comprising MABA compounds and corticosteroids
WO2020244452A1 (fr) * 2019-06-06 2020-12-10 中国医药研究开发中心有限公司 DÉRIVÉ HÉTÉROCYCLIQUE AYANT UNE ACTIVITÉ D'ACTIVATION DU RÉCEPTEUR β2 ET UNE ACTIVITÉ ANTAGONISTE DU RÉCEPTEUR M ET UTILISATION MÉDICALE ASSOCIÉE
CN115536517A (zh) * 2022-11-09 2022-12-30 苏州昊帆生物股份有限公司 4-羟甲基苯乙酸的制备方法

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WO2007017669A1 (fr) * 2005-08-08 2007-02-15 Argenta Discovery Ltd. Derives d'azole et de thiazole et utilisation de ceux-ci
WO2008017824A1 (fr) * 2006-08-08 2008-02-14 Argenta Discovery Limited Dérivés bicyclo[2.2.1]hept-7-ylamine et leur utilisation
WO2008096127A2 (fr) * 2007-02-07 2008-08-14 Argenta Discovery Ltd Composés chimiques inédits

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WO2005111004A1 (fr) * 2004-05-14 2005-11-24 Boehringer Ingelheim International Gmbh Nouveaux bronchodilatateurs pour le traitement de maladies respiratoires
WO2007017670A1 (fr) * 2005-08-08 2007-02-15 Argenta Discovery Ltd. Dérivés bicyclo[2,2]hept-7-ylamine et leurs utilisations
WO2007017669A1 (fr) * 2005-08-08 2007-02-15 Argenta Discovery Ltd. Derives d'azole et de thiazole et utilisation de ceux-ci
WO2008017824A1 (fr) * 2006-08-08 2008-02-14 Argenta Discovery Limited Dérivés bicyclo[2.2.1]hept-7-ylamine et leur utilisation
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Cited By (25)

* 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
WO2011081937A1 (fr) 2009-12-15 2011-07-07 Gilead Sciences, Inc. Composés de type corticostéroïde-bêta-agoniste-antagoniste muscarinique pour applications thérapeutiques
US9315463B2 (en) 2010-05-13 2016-04-19 Almirall, S.A. Cyclohexylamine derivatives having β2 adrenergic agonist and M3 muscarinic antagonist activities
EP2386555A1 (fr) 2010-05-13 2011-11-16 Almirall, S.A. Nouveaux dérivés de cyclohéxylamine dotés d'activités agoniste bêta 2 adrénergique et antagoniste muscarinique m3
WO2011141180A1 (fr) 2010-05-13 2011-11-17 Almirall, S.A. Nouveaux dérivés de cyclohexylamine ayant des activités d'agoniste des récepteurs β2-adrénergiques et d'antagoniste des récepteurs muscariniques m3
US9643961B2 (en) 2010-05-13 2017-05-09 Almirall, S.A. Cyclohexylamine derivatives having β2 adrenergic antagonist and M3 muscarinic antagonist activities
JP2013526494A (ja) * 2010-05-13 2013-06-24 アルミラル・ソシエダッド・アノニマ β２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シクロヘキシルアミン誘導体
WO2011154678A1 (fr) 2010-06-11 2011-12-15 Astrazeneca Ab Composés
WO2013068554A1 (fr) 2011-11-11 2013-05-16 Almirall, S.A. Nouveaux dérivés de cyclohexilamine ayant des activités d'agoniste des récepteurs β2-adrénergique et d'antagoniste des récepteurs muscariniques m3
US10300072B2 (en) 2011-11-11 2019-05-28 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
US9549934B2 (en) 2011-11-11 2017-01-24 Almirall, S.A. Cyclohexylamine derivatives having β2 adrenergic agonist and M3 muscarinic antagonist activities
JP2014532748A (ja) * 2011-11-11 2014-12-08 アルミラル・ソシエダッド・アノニマＡｌｍｉｒａｌｌ， Ｓ．Ａ． β２アドレナリン受容体アゴニストおよびＭ３ムスカリン受容体アンタゴニスト活性を有する新規シクロヘキシルアミン誘導体
WO2013068552A1 (fr) 2011-11-11 2013-05-16 Almirall, S.A. Nouveaux dérivés de cyclohexilamine ayant des activités d'agoniste des récepteurs β2-adrénergique et d'antagoniste des récepteurs muscariniques m3
US9757383B2 (en) 2011-11-11 2017-09-12 Almirall, S.A. Cyclohexylamine derivatives having β2 adrenergic agonist and M3 muscarinic antagonist activities
WO2014095920A1 (fr) 2012-12-18 2014-06-26 Almirall, S.A. Nouveaux dérivés de cyclohexyl et quinuclidinyl carbamate ayant une activité d'agoniste adrénergique beta2 et une activité d'antagoniste muscarinique m3
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
US10005771B2 (en) 2014-09-26 2018-06-26 Almirall, S.A. Bicyclic derivatives having β2 adrenergic agonist and M3 muscarinic antagonist activities
WO2018108089A1 (fr) 2016-12-14 2018-06-21 北京硕佰医药科技有限责任公司 Classe de composés bifonctionnels de structure de sel d'ammonium quaternaire
WO2020244452A1 (fr) * 2019-06-06 2020-12-10 中国医药研究开发中心有限公司 DÉRIVÉ HÉTÉROCYCLIQUE AYANT UNE ACTIVITÉ D'ACTIVATION DU RÉCEPTEUR β2 ET UNE ACTIVITÉ ANTAGONISTE DU RÉCEPTEUR M ET UTILISATION MÉDICALE ASSOCIÉE
CN115536517A (zh) * 2022-11-09 2022-12-30 苏州昊帆生物股份有限公司 4-羟甲基苯乙酸的制备方法

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