WO2008096129A1 - Composés hétrocycliques contenant de l'azote utiles comme modulateurs bifonctionnels de récepteurs m3 et de récepteurs bétâ-2 - Google Patents

Composés hétrocycliques contenant de l'azote utiles comme modulateurs bifonctionnels de récepteurs m3 et de récepteurs bétâ-2 Download PDF

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WO2008096129A1
WO2008096129A1 PCT/GB2008/000407 GB2008000407W WO2008096129A1 WO 2008096129 A1 WO2008096129 A1 WO 2008096129A1 GB 2008000407 W GB2008000407 W GB 2008000407W WO 2008096129 A1 WO2008096129 A1 WO 2008096129A1
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hydroxy
methyl
ethyl
formula
compound
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PCT/GB2008/000407
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English (en)
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Christine Edwards
Nicholas Kindon
Nicholas Charles Ray
Jonathan Mark Sutton
Lilian Alcaraz
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Argenta Discovery Ltd
Astrazeneca Ab
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Priority claimed from GB0702415A external-priority patent/GB0702415D0/en
Priority claimed from GB0702381A external-priority patent/GB0702381D0/en
Application filed by Argenta Discovery Ltd, Astrazeneca Ab filed Critical Argenta Discovery Ltd
Publication of WO2008096129A1 publication Critical patent/WO2008096129A1/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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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 heterocycles, pharmaceutical compositions, methods for their 5 preparation and use in the treatment of diseases where compounds possessing both muscarinic receptor antagonist and ⁇ 2-agonist activity present in the same molecule (bifunctional molecules) are useful (such as in the treatment of asthma or COPD).
  • bifunctional molecules are described in, for example, WO04/074246, WO04/089892, WO05/111004, WO06/023457 and WO06/023460, all of which use different linker radicals for covajently linking an M3 antagonist to a ⁇ 2-agonist.
  • 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.
  • M1 -M5 muscarinic acetylcholine receptors
  • M1 -M5 muscarinic acetylcholine receptors
  • muscarinic receptors M1 , M2 and M3 have been demonstrated to be important and are localized to the trachea, the bronchi, submucosal glands and 35 parasympathetic ganglia (reviewed in Fryer and Jacoby, 1998, Am J Resp Crit Care Med., 158 (5 part 3) S 154 - 160).
  • M3 receptors on airway smooth muscle mediate contraction and therefore bronchoconstriction. Stimulation of M3 receptors localised to submucosal glands results in mucus secretion.
  • vagal tone may either be increased (Gross etal. 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).
  • WO97/30994 describes oxadiazoles and thiadiazoles as muscarinic receptor antagonists.
  • EP0323864 describes oxadiazoles linked to a mono- or bicyclic ring as muscarinic receptor modulators. .
  • ⁇ 2 adrenergic receptor agonists The class of ⁇ 2 adrenergic receptor agonists is well known. Many known ⁇ 2-agonists, in particular, long-acting ⁇ 2-agonists such as salmeterol and formoterol, have a role in the treatment of asthma and COPD. These compounds are also generally administered by inhalation. Compounds currently under evaluation as once-daily ⁇ 2 agonists are described in Expert Opin. Investig. Drugs 14 (7), 775-783 (2005). A well known ⁇ 2- agonist pharmacophore is the moiety:
  • compositions that contain both a muscarinic antagonist and a ⁇ 2-agonist for use in the treatment of respiratory disorders.
  • US2005/0025718 describes a ⁇ 2-agonist in combination with tiotropium, oxotropium, ipratropium or other muscarinic antagonist;
  • WO02/060532 describes a combination of ipratropium with a ⁇ 2-agonist;
  • WO02/060533 describes a combination of oxotropium with a ⁇ 2-agonist.
  • Other M3 antagonist / ⁇ 2-agonist combinations are described in WO04/105759 and WO03/087097.
  • R 1 is H or C 1 -(VaIkVl; and R 3 is lone pair or C r C 6 -alkyl; or
  • R 4 and R 5 are independently selected from the group consisting of aryl, aryl-fused- heterocycloalkyl, heteroaryl, C 1 -CVaIkVl, cycloalkyl;
  • R 6 is -OH, CrCe-alkyl, C r C 6 -alkoxy, hydroxy-CrC 6 -alkyl, nitrile, a group CON(R 12 ) 2 or a hydrogen atom; • • ' . one of W 1 V and A is N. or NR 11 ; another of W, V and A is N, O, S or CR 8 ; and the last one of W, V and A is N or CR 8 X is an C r C 6 alkylene, C 2 -C 6 alkenylene or C 2 -C 6 alkyny!ene group;
  • R 8 , R 11 and R 12 are, independently, hydrogen atom or CrC 6 -alkyl group
  • L a is a divalent linker radical of formula (Ia);
  • L represents a linker comprising a hydrocarbyl chain of up to 14 carbon atoms, wherein up to three carbon atoms of the chain are replaced by groups independently selected from O, NR 45 , S, S(O), S(O) 2 , C(O)O, OC(O), .
  • any heteroatoms in the chain are separated by at least 2 carbon atoms; and/or up to four carbon atoms of the chain form part of a mono- or bicyclic aliphatic, heteroaliphatic, aromatic or heteroaromatic ring having up to four heteroatoms independently selected from N, O or S, said ring comprising up to
  • C 1-6 alkyl and C 3-6 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, and;
  • R 56 , ' R 65 and R 69 each independently represent C 1-6 alkyl or C 3-6 cycloalkyl, wherein C 1-6 alkyl and C 3-6 cycloalkyl may be optionally substituted by up to three substituents independently selected from halogen, hydroxyl, C 1-6 alkoxy; and
  • R 45 , R 46 , R 47 , R 48 , R 49 , R 50 , R 51 , R 52 , R 53 , R 54 , R 55 , R 57 , R 58 , R 59 , R 60 , R 61 , R 62 , R 63 , R 64 , R 66 , R 67 , R 68 , R 70 , R 71 , R 72 and R 73 each independently represent hydrogen, Ci- 6 alkyl or C 3-6 cycloalkyl, wherein Ci -6 alkyl and C 3 .
  • 6 cycloaikyl may be optionally substituted by up to three substituents independently selected from halogen, hydroxyl, C 1-6 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, O and S, wherein the ring may be optionally substituted by up to three substituents independently selected from halogen, hydroxyl and Ci -6 alkyl or C 3-6 cycloalkyl, wherein Ci -6 alkyl and C 3-6 cycloalkyl may be optionally substituted by one or more substituents independently selected from halogen and hydroxyl; and
  • chain may additionally comprise up to. three carbon-carbon double bonds;
  • chain may additionally comprise up to three carbon-carbon triple bonds
  • L 1 and L 2 each independently represent. hydrogen, Ci -6 alkyl pr
  • L 3 and L 4 each independently represent hydrogen, Ci -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 a carbon atom of the hydrocarbyl chain in linker L to form an aliphatic ring of up to 6 ring atoms, wherein the ring may comprise up to three heteroatoms independently selected from N, O and
  • Z 1 is a moiety having ⁇ 2- adrenoreceptor binding activity
  • rocycloalkyl, aryl, aryl-fused-heterocycloalkyl, heteroaryl, cycloalkyl, alkoxy, alkylene, alkenylene, alkynylene or aryl-fused-cycloalkyl may be optionally substituted; and wherein each alkenylene chain contains, where possible, up to 2 carbon-carbon double bonds and each alkynylene chain contains, where possible, up to 2 carbon- carbon triple bonds or a pharmaceutically acceptable salt thereof.
  • the present invention provides a prodrug of a compound of formula (1) 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.
  • the present invention provides compounds of formula (I), as defined above, wherein, unless otherwise specified, each occurrence of alkyl may be optionally substituted with one or more substituent groups chosen from C 1 -C 6 - haloalkyl, C 1 -C ⁇ aIkOXy, CrC 6 -haloalkoxy, CN and halo; and each occurrence of heterocycloalkyl, aryl, aryl-fused-heterocycloalkyl, heteroaryl, cycloalkyl, alkoxy, alkylene, alkenylene, alkynylene or aryl-fused-cycloalkyl may be optionally substituted with one or more substituent groups chosen from C r C 6 -alkyl, CrCe-haloalkyl, C 1 -C 6 - haloalkoxy, C r C 6 -alkoxy, CN and halo.
  • the present invention provides compounds of formula (I), as defined above, wherein, unless otherwise specified, each occurrence of alkyl, heterocycloalkyl, aryl, aryl-fused-heterocycloalkyl, heteroaryl, cycloalkyl,. alkoxy, . alkylene, alkenylene, alkynylene or aryl-fused-cycloalkyl is not substituted.
  • the present invention also provides compounds of formula (I), PROVIDED THAT . when A is an oxygen or sulfur atom and W is a nitrogen atom, then V is not a group CR 8 .
  • the present invention provides a compound of formula (I) wherein: (i) R 1 is CrCe-alkyl; and R 3 is lone pair or C r C 6 -alkyl; or
  • X is an alkylene, alkenylene or alkynylene group.
  • R 1 is H or Ci-C 6 -alkyl; and R 3 is a lone pair;
  • R 4 and R 5 are independently selected from the group consisting of aryl, heteroaryl and cycloalkyl
  • R 6 is -OH, CrC 6 -alkoxy, hydroxy-C r C 6 -alkyl or a hydrogen atom; the 5-membered ring containing W, V and A is selected from:
  • bond marked * is attached to the group R 4 R 5 R 6 C-, and the bond marked * * is attached to the group -XNR 1 (L a -Z 1 )R 3 ; and R 11 is as herein defined;
  • X is a CrC 2 alkylene group;
  • R 8 , R 11 and R 12 are, independently, hydrogen atom or CrCeralkyl group;
  • L a is divalent linker radical of formula (Ia);
  • a 1 , A 2 , and A 4 are, independently, hydrogen, halogen, C 1-6 alkyl
  • a 3 is CH 2 OH, NHCHO, NHS(O) 2 NA 15 A 16 or NHSO 2 A 17 ;
  • a 15 or A 16 are independently selected from hydrogen or C 1-6 alkyl; and
  • a 17 is C 1-6 alkyl;
  • each occurrence of alkyl may be optionally substituted with one or more substituent groups chosen from d-Ce-haloalkyl, C 1 -C 6 - haloalkoxy, CN and halo; and each occurrence of heterocycloalkyl, aryl, aryl-fused- heterocycloalkyl, heteroaryl, cycloalkyl, alkoxy, alkylene, alkenylene, alkynylene or aryl- fused-cycloalkyl may be optionally substituted with one or more substituent groups chosen from C r C 6 -alkyl, CrC 6 -haloalkyl, CrC 6 -haloalkoxy, CN and ha
  • the present invention provides a compound of formula (I) wherein R 1 is C r C 6 -alkyl; and R 3 is a lone pair.
  • the present invention provides a compound of formula (I) wherein R 1 is CrC 6 -alkyl; and R 3 is CrCValkyl and the nitrogen to which they are attached is quaternary and carries a positive charge.
  • the present invention provides a compound of formula (I) wherein X is Ci-C 6 alkylene. In another aspect X is C 1 -C 2 alkylene. In yet another aspect X is methylene.
  • the present invention provides a compound of formula (I) wherein the 5-membered ring containing W, V and A is:
  • the present invention provides a compound of formula (I) wherein R 11 is hydrogen or C 1 -C 3 alkyl,
  • the present invention provides a compound of formula (I) wherein the 5-membered ring containing W, V and A is: wherein the bond marked * is attached to the group R 4 R 5 R 6 C-, and the bond marked ** is attached to the group -XNR 1 (L a -Z 1 )R 3 ; and R 11 is as defined herein.
  • the present invention provides a compound of formula (I) wherein the 5-membered ring containing W, V and A is:
  • the present invention provides a compound of formula (I) wherein the 5-membered ring containing W, V and A is: wherein the bond marked * is attached to the group R 4 R 5 R 6 C-, and the bond marked * * is attached to the group -XNR 1 (L a -Z 1 )R 3 .
  • R 6 is hydroxy, C 1 -C 4 alkyl (such as methyl), C 1 -C 4 alkoxy (such as methoxy) or nitrile. In a further aspect R 6 is hydroxy, C 1 -C 4 alkyl (such as methyl). In a still further aspect R 6 is hydroxy.
  • the present invention provides a.compound of formula (I) wherein R 4 and R 5 are, independently, aryl (such as phenyl), C 4 -C 8 cycloalkyl (such as cyclopentyl or cyclohexyl) or heteroaryl (such as thiophenyl).
  • the present invention provides a compound of formula (I) wherein R 4 is aryl (such as phenyl) or heteroaryl (such as thiophenyl).
  • the present invention provides a compound of formula (I) wherein R 5 is C 4 -C 8 cycloalkyl (such as cyclopentyl or cyclohexyl), aryl (such as phenyl) or heteroaryl (such as thiophenyl).
  • R 5 is C 4 -C 8 cycloalkyl (such as cyclopentyl or cyclohexyl), aryl (such as phenyl) or heteroaryl (such as thiophenyl).
  • the present invention provides a compound of formula (I) wherein R 4 is aryl (for example phenyl) and R 5 is C 4 -C 8 cycloalkyl (for example cyclopentyl or cyclohexyl).
  • Z 1 is a group of formula (lb):
  • Z 1 is a group of formula (Ic): wherein, in each of these aspects, Ar represents a group selected from the following; ⁇
  • 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)(C 1-6 alkyl) or C(O)OC 1-6 alkyl;
  • 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, C 1-6 alkyl, and;
  • Z 1 is a group selected from
  • Z 1 is a group selected from:
  • L represents a linker comprising a hydrocarbyl chain of up to 12 carbon atoms, more conveniently 6 to 12 carbon atoms; or of up to 10 carbon atoms or of up to 8 carbon atoms, wherein
  • up to two 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 ; or independently selected from O, S, S(O), S(O) 2 , NR 46 C(O), C(O)NR 47 ; provided that in each case any heteroatoms in the chain are separated by at least 2 carbon atoms; and/or
  • up to four carbon atoms of the chain may form part of a mono- or bicyclic aliphatic, heteroaliphatic, aromatic or heteroaromatic ring having up to four heteroatoms independently selected from N, O or S, said ring comprising up to 10 ring atoms, and wherein the ring is optionally substituted by one or more substituents independently selected from halogen, S(O) 0-2 R 56 , NR 57 R 58 , S(O) 2 NR 59 R 60 , C(O)NR 61 R 62 , C(O)OR 63 ,- NR 64 S(O) 2 R 65 , NR 66 C(O)R 67 , NR 68 C(O)OR 69 , NR 70 C(O)NR 71 R 72 , OR 73 , C 1-6 alkyl and C 3 . 6 cycloalkyl, and wherein C 1-6 alkyl and C 3-6 cycloalkyl may be optionally substituted by up to
  • the chain may comprise up to two, or one of such rings each selected independently;
  • R 56 , R 65 and R 69 each independently represent C 1-4 alkyl or C 3-6 cycloalkyl, wherein C 1-4 alkyl and C 3-6 cycloalkyl may be optionally substituted by one or more. substituents independently selected from halogen, hydroxyl, C 1-4 alkoxy; and
  • R 45 , R 46 , R 47 , R 48 , R 49 , R 50 , R 51 , R 52 , R 53 , R 54 , R 55 , R 57 , R 58 , R 59 , R 60 , R 61 , R 62 , R 63 , R 64 , R 66 , R 67 , R 68 , R 70 , R 71 , R 72 and R 73 each independently represent hydrogen, C 1-4 alkyl or C 3-6 cycloalkyl, wherein C 1-4 alkyl and C 3-6 cycloalkyl may be optionally substituted by one or more substituents independently selected from halogen, hydroxyl, C 1-4 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
  • Examples of convenient ring systems which may be present.as part of the hydrocarbyl linker include . wherein the heterocyclyl ring is unsubstituted or substituted by 1 or 2 substituents independently selected from, halogen, C 1 ⁇ alkyl (optionally substituted by OR 121 ,
  • R -,133 represents Ci -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, hydroxyl, C 1-6 alkoxy; and p121 p122 p.123 p124 p125 p126 p127 p128 p129 p130 p131 p132 p134 p135 ⁇ p136 each independently represent hydrogen, Ci -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, hydroxyl, C 1-6 alkoxy; or any of R 122 and R 123 J R 127 and R 128 , R 129 and R 130 or R 134 and R 135 , together with the nitrogen atom to which they are both attached, may form a 4 to 8
  • the chain may additionally comprise up to two carbon-carbon double bonds or a single carbon-carbon double bond.
  • the chain may additionally comprise up to two carbon-carbon triple bonds or a single carbon-carbofi triple bond. • ;
  • each of L 1 , L 2 , .L 3 and L 4 represent independently hydrogen or a C 1-4 alkyl group; in addition L 1 and/or L 3 may be linked to a carbon atom of the hydrocarbyl chain in linker L to form an aliphatic ring of up to 6 ring atoms, which ring may comprise up to two heteroatoms independently selected from N, O and S.
  • said ring may, if an aliphatic ring system comprises up to 10, 9, 8, 7, 6, 5, 4 or 3 ring atoms, if an aromatic ring system then 10, 9, 6 or 5 ring atoms; each selected independently.
  • L 1 and L 2 each independently represent hydrogen, Ci -4 alkyl or ,C 3-6 cycloalkyl. More conveniently L 1 and L 2 are each hydrogen.
  • L 3 and L 4 each independently represent hydrogen, C 1-4 alkyl or C 3-6 cycloalkyl, which C 1-4 alkyl and C 3-6 cycloalkyl may be optionally substituted by one or more substituents independently selected from halogen and hydroxyl. More conveniently L 3 and L 4 are both hydrogen.
  • the radical -C(L 1 )(L 2 )-L-C(L 3 )(L 4 )- is selected from:
  • t is .0, 1 or 2
  • u is 1 or 2;
  • Ar is selected from: wherein
  • a , A , and A are, independently, hydrogen, halogen, C 1-6 alkyl, Ci -6 alkoxy; and A d can also be CH 2 OH, NHCHO, NHS(O) 2 NA 14 VV" or NHSO 2 A V 1 T7l ..
  • a or A are independently selected from hydrogen or Ci -6 alkyl
  • Examples of C 1-6 alkyl include C 1-4 alkyl and C 1-2 alkyl.
  • Examples of C 1-6 alkoxy include C 1-4 alkoxy and C 1-2 alkoxy.
  • Ar is selected from:
  • W is a group CR 8 , V is an oxygen atom and A is a nitrogen atom;
  • W is a group CR 8 , V is a sulfur atom and A is a nitrogen atom;
  • W is a group CR 8 , V is a nitrogen atom and A is an oxygen atom;
  • W is a group CR 8 , V is a nitrogen atom and A is a sulfur atom;
  • W is NR 11 , V is a nitrogen atom and A is an oxygen atom;
  • W is a nitrogen atom, V is NR 11 , and A is an oxygen atom;
  • W is a nitrogen atom, V is an oxygen atom and A is a nitrogen atom;
  • W is an oxygen atom, V is a nitrogen atom and A is a nitrogen atom.
  • R 8 may be hydrogen. . •
  • R 4 and R 5 may both be both phenyl and R 6 may be -OH.
  • a particular class of compounds of the invention consists of compounds of formula (I) wherein the non-aromatic nitrogen shown in formula (I) is a tertiary nitrogen.
  • Another particular class of compounds of the invention consists of quaternary ammonium salts of formula (I) wherein the non-aromatic nitrogen shown in formula (I) is quaternary nitrogen, carrying a positive charge.
  • a particular compound of the invention is:
  • R 4 , R 5 and R 6 can also give rise to enantiomers.
  • both enantiomers of the invention generally exhibit affinity at the M 3 receptor, although one enantiomer is generally favoured on criteria of potency at the M 3 receptor and/or selectivity against the M 2 receptor.
  • the absolute stereochemistry of the favoured enantiomer is known.
  • R 4 is a phenyl group
  • R 5 is a cyclohexyl or cyclopentyl group
  • R 6 is a hydroxyl group
  • the carbon atom to which they are attached has the R- absolute configuration as dictated by Cahn-lngold-Preiog rules.
  • Compounds of the invention may be useful in the treatment or prevention of diseases in which activation of muscarinic receptors are implicated, for example the present compounds are useful for treating a variety of indications, including but not limited to respiratory-tract disorders such as chronic obstructive lung disease (also known as chronic obstructive pulmonary disease or COPD), chronic bronchitis of all types (including dyspnoea associated therewith), asthma (allergic and non-allergic; 'whez- infant syndrome'), adult/acute respiratory distress syndrome (ARDS), chronic respiratory obstruction, bronchial hyperactivity, pulmonary fibrosis, pulmonary emphysema, and allergic rhinitis, exacerbation of airway hyperreactivity consequent to other drug therapy, particularly other inhaled drug therapy, pneumoconiosis (for example, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabaco
  • a compound of present invention is useful in the treatment or prevention of respiratory-tract disorders such as chronic obstructive lung disease (also known as chronic obstructive pulmonary disease, COPD), chronic bronchitis of all types (including dyspnoea associated therewith), asthma (allergic and non-allergic; 'whez- infant syndrome'), adult/acute respiratory distress syndrome (ARDS), chronic respiratory obstruction, bronchial hyperactivity, pulmonary fibrosis, pulmonary emphysema, and allergic rhinitis, exacerbation of airway hyperreactivity consequent to other drug therapy, particularly, other .
  • chronic obstructive lung disease also known as chronic obstructive pulmonary disease, COPD
  • chronic bronchitis of all types including dyspnoea associated therewith
  • asthma allergic and non-allergic; 'whez- infant syndrome'
  • adult/acute respiratory distress syndrome ARDS
  • chronic respiratory obstruction bronchial hyperactivity, pulmonary fibrosis,
  • pneumoconiosis for example aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis.
  • quaternary ammonium salts of the invention administered by inhalation is may be more than 12, or more than 24 hours for a typical dose.
  • administration by the parenteral route usually the oral route may be preferred.
  • Another. aspect of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a . compound of the invention and a pharmaceutically acceptable carrier, diluent or excipient.
  • Another aspect of the invention is the use of a compound of the invention for the manufacture of a medicament for the treatment or prevention of a disease or condition in which muscarinic M3 receptor activity and (32-adrenergic activity are implicated.
  • Diseases or conditions in which muscarinic M3 receptor activity and ⁇ 2- adrenergic activity are implicated include respiratory-tract disorders, gastrointestinal- tract disorders and cardiovascular disorders. Specific examples of such diseases and conditions include those listed above. :
  • Another aspect of the invention provides a compound of the .invention for the treatment or prevention of a disease or condition in which muscarinic M3 receptor activity and ⁇ 2-adrenergic activity are implicated.
  • Diseases or conditions in which muscarinic M3 receptor activity and ⁇ 2-adrenergic activity are implicated include respiratory-tract disorders, gastrointestinal-tract disorders and cardiovascular disorders. Specific examples of such diseases and conditions include those listed above. .
  • Another aspect of the invention provides a method of treatment of a disease or condition in which M3 muscarinic receptor activity and ⁇ 2-adrenergic activity are implicated comprising administration to a subject in need thereof a therapeutically effective amount of a compound of the invention.
  • Diseases or conditions in which muscarinic M3 receptor activity and ⁇ 2-adrenergic activity are implicated include respiratory-tract disorders, gastrointestinal-tract disorders and cardiovascular disorders. Specific examples of such diseases and conditions include those listed above.
  • Another aspect of the invention provides a compound of the invention for use in therapy.
  • 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, jn 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-a ' lkyl 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, conveniently 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, conveniently 2 to 6, carbon atoms and one or more carbon-carbon double bonds in the chain.
  • exemplary alkenyl groups include ethenyl, 1 -propenyl, and 2-propenyl.
  • Alkylamino means a -NH-alkyl group in which aikyl 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- refers to a straight or branched chain hydrocarbon group having from 2 to 12, conveniently 2 to 6, carbon atoms and one carbon-carbon triple bond in the chain.
  • exemplary alkynylene groups include ethynyl and propargyl.
  • Alkylsulfinyl means a -SO-alkyl group in which alkyl is as defined above.
  • exemplary alkylsulfinyl groups include methylsulfinyl and ethylsulfinyl.
  • Alkylsulfonyl or “sulfonyl” each means a -SO 2 -alkyl group in which alkyl is as defined above.
  • exemplary alkylsulfonyl groups include m ethyls u If onyl 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, conveniently from 6 to 10 carbon atoms, such as phenyl or naphthyl. Phenyl is an example of a convenient aryl group. The aryl group, specifically a. phenyl 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. Convenient arylalkyl groups contain a C 1 4 alkyl moiety.
  • arylalkyl groups include benzyl, phenethyl and naphthlenemethyl.
  • Arylalkyloxy means an aryl-alkyloxy- group in which the aryl and alkyloxy moieties are as previously described. Convenient arylalkyloxy groups contain a C 1 4 alkyl moiety. Exemplary arylalkyl groups include benzyloxy.
  • Aryl-fused-cycloalkyl means a monocyclic aryl ring, such as phenyl, fused to a cycloalkyl group, in which the aryl and cycloalkyl are as described herein.
  • Exemplary aryl-fused-cycloalkyl groups include tetrahydronaphthyl and indanyl.
  • the aryl and cycloalkyl rings may each be substituted by one or more substituent groups.
  • the aryl- fused-cycloalkyl group may be attached to the remainder of the compound by any available carbon atom.
  • 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, benxodioxolyl, 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.
  • Cyclic amine 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, conveniently from 3 to 8 carbon atoms* and more conveniently 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.
  • Cycloalkylalkyl means a cycloalkyl-alkyl- group in which the cycloalkyl and alkyl moieties are as previously described.
  • Exemplary monocyclic cycloalkylalkyl groups include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl.
  • Dendrimer means a multifunctional core group with a branching group attached to each functional site. Each branching site can be attached to another branching molecule and this process may be repeated multiple times.
  • 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 iod ⁇ . Most convenient 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, conveniently 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, benzothiazolyi, benzof ⁇ ranyl, 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 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. Convenient heteroarylalkyl groups contain a lower alkyl moiety. Exemplary heteroarylalkyl groups include pyridylmethyl. . "Heteroarylalkyloxy” means a heteroaryl-alkyloxy- group in which the heteroaryl and alkyloxy moieties are as previously described. Convenient heteroarylalkyloxy groups contain a lower alkyl moiety. Exemplary heteroarylalkyloxy groups include pyridylmethyloxy.
  • Heteroarylene means a -heteroaryl- group where heteroaryl is as described in "Heteroaryl” above which is linked to. two or more other groups.
  • exemplary groups include 2,5-furyl, 2,5-thienyl, 2,4-thiazolyl, 2,5-thiazolyl and 2,6-pyridyl.
  • Heteroaryloxy means a heteroaryloxy- group in which the heteroaryl is as previously described.
  • exemplary heteroaryloxy groups include pyridyloxy.
  • Heteroaryl-fused-cycloalkyl means a monocyclic heteroaryl group; such as pyridyl or furanyl, fused to a cycloalkyl group, in which heteroaryl and cycloalkyl are as previously described.
  • Exemplary heteroaryl-fused-cycloalkyl groups include tetrahydroquinolinyl and tetrahydrobenzofuranyl.
  • the heteroaryl and cycloalkyl rings may each be substituted by one or more substituent groups.
  • the heteroaryl-fused- cycloalkyl group may be attached to the remainder of the compound by any available carbon or nitrogen atom.
  • Heteroaryl-fused-heterocycloalkyl means a monocyclic heteroaryl group, such as pyridyl or furanyl, fused to a heterocycloalkyl group, in which heteroaryl and heterocycloalkyl are as previously described.
  • Exemplary heteroaryl-fused- heterocycloalkyl groups include dihydrodioxinopyridinyl, dihydropyrrolopyridinyl, dihydrofuranopyridinyl and dioxolopyridinyl.
  • the heteroaryl and heterocycloalkyl rings may each be substituted by one or more substituents groups.
  • the heteroaryl-fused- heterocycloalkyl group may be attached to the remainder of the compound by any available carbon or nitrogen atom. . . " •
  • Heterocycloalkyl 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 or
  • heterocycloalkyl group may be substituted by one or more substituent groups.
  • the heterocycloalkyl group may be attached to the remainder of the compound by any available carbon or nitrogen atom.
  • Heterocycloalkylalkyl means a heterocycloalkyl-alkyl- group in which the heterocycloalkyl and alkyl moieties are as previously described.
  • “Hydrocarbyl” means a straight or branched chain saturated or unsaturated hydrocarbon group having from 1 to 14, or conveniently 1 to 12, or more conveniently 1 -8, or more conveniently still 1 -4, carbon atoms in the chain. Where possible, the chain may comprise up to three carbon-carbon double bonds or up to three carbon- carbon triple bonds. . . • ' "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, /sobutyl or tert- butyl).
  • Phenylene means -a -phenyl- group. Exemplary groups are 1 ,3-phenylene and 1 ,4-phenylene.
  • “Sulfonylamino” means a -NR-sulfonyl group in which R and sulfonyl are as described herein.
  • Exemplary sulfonylamino groups include -NHSO 2 CH 3 .
  • a substituent designatation R in any of the above definitions means hydrogen, alkyl, aryl, or heteroaryl as described herein, and when two R groups are present on a group (for example on -SO 2- NRR) then the R groups can be the same or different.
  • “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. lysine) and the like;
  • organic amines such as, diethylamine, ⁇ /-methyl- glucamine, diethanolamine or amino acids (e.g. lysine) and the like
  • amino acids e.g. lysine
  • salts that may be formed include hydrochlorides, hydrobromides, sulfates, phosphates, acetates, citrates, lactates; tartrates, mesylates, napadisylate (naphthalene-1 ,5-disulfonate or naphthalene-1 - (sulfonic acid)-5-sulfonate), edisylate (ethane-1 ,2-disulfonate or ethane-1 -(sulfonic acid)- 2 ⁇ sulfonate), maleates, fumarates, succinates 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, methanesulfonate, benzenesulf
  • the present invention covers all permissible ratios of cationic ammonium species to counter-ion, for example hemi-napadisylate and napadisylate.
  • references to the compounds of the invention are meant to also include the pharmaceutically acceptable salts.
  • “Prodrug” refers to a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis, reduction or oxidation) to a compound of the invention. Suitable groups for forming pro-drugs are described in 'The Practice of Medicinal Chemistry, 2 nd Ed. pp561 -585 (2003) and in F. J. Leinweber, Drug Metab. Res., , 18, 379. (1987) 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.
  • cyclic groups referred to above namely, aryl, heteroaryl, cycloalkyl,. aryl- fused-cycloalkyl, heteroaryl-fused-cycloalkyl, heterocycloalkyl, aryl-fused- heterocycloalkyl, heteroaryl-fused-heterocycloalkyl and cyclic amine are unsubstituted or substituted by one or more of the same or different substituent groups.
  • substituents include -Cl, -F, -CH 3 , -OCH 3 , -OH, -CN, -COOCH 3 , -CONH 2 ,
  • a first class of substituent includes acyl (e.g. -COCHJ, alkoxy (e.g., -OCHJ, alkoxycarbonyl (e.g. -COOCH 3 ), alkylamino (e.g. -NHCH 3 ), alkylsulfinyl (e.g. -SOCH 3 ), alkylsulfonyl (e.g. -SO 0 CHJ, alkylthio (e.g. -SCHJ, -NH 2 , aminoacyl (e.g. -CON(CH 3 ) 2 ), aminoalkyl (e.g. -CH 0 NHJ, cyano, dialkylamino (e.g.
  • haloalkoxy e.g. -OCF, or -OCHFJ
  • haloalkyl e.g. -CFJ, alkyl (e.g. -CH, or -CH CHJ, -OH, -CHO
  • -COOH e.g. -COOH, -NO 2 , aminoacyl (e.g. -CONH 2 , -CONHCH 3 ), aminosulfonyl (e.g. -SO 2 NH 2 , - SO 2 NHCH 3 ), acylamino (e.g. -NHCOCH 3 ) and sulfonylamino (e.g. -NHSO 2 CH 3 ); and (b)a second class of substituent includes arylalkyl (e.g. -CH 2 Ph or
  • aryl e.g. morpholine
  • aryloxy, heteroaryloxy, arylalkyloxy e.g. benzyloxy
  • heteroarylalkyloxy the cyclic part of any of which being optionally substituted by any of the first class of substituent referred to above (for example alkoxy, haloalkoxy, halogen, alkyl and haloalkyl).
  • Alkylene or alkenylene groups may be optionally substituted. Suitable optional substituent groups include alkoxy (e.g., -OCH 3 ), alkylamino (e.g. -NHCH 3 ), alkylsulfinyl
  • alkylsulfonyl e.g. -SO 2 CH 3
  • alkylthio e.g. -SCH 3
  • -NH 2 aminoalkyl (e.g. -CH 2 NH 2 ), arylalkyl (e.g. -CH 2 Ph or -CH 2 -CH 2 -Ph), cyano, dialkylamino (e.g. -N(CHJJ, halo, haloalkoxy (e.g. -OCF, or -OCHFJ, haloalkyl (e.g. -CFJ, alkyl (e.g. - CH, or -CH CH J, -OH, -CHO, and -NO 2 .
  • haloalkyl e.g. -CFJ
  • Compounds of the invention may exist in one or more geometrical, optical, enantiomeric, diastereomeric and tautomeric forms, including but not limited to cis- and /rans-forms, E- and Z-forms, R-, S- and meso-forms, keto-, and enol-forms. Unless otherwise stated a reference to a particular compound includes all such isomeric forms, including racemic and other mixtures thereof. Where appropriate such isomers can be separated from their mixtures by the application or adaptation of known methods (e.g. chromatographic techniques and recrystallisation techniques). Where appropriate such isomers may be prepared by the application of adaptation of known methods (e.g. asymmetric synthesis).
  • R 1 is H or Ci-C 6 -alkyl, such as methyl or ethyl; and R 3 is a lone pair or CrC 6 -alkyl, such as methyl or ethyl.
  • R 1 and R 3 together with the nitrogen to which' they are attached form a heterocycloalkyl ring.
  • R 1 and R 3 together with the nitrogen to which they are attached may form a monocyclic ring of from 3 to 7 ring atoms, in which the hetero-atoms are nitrogen.
  • examples of such rings include azetidinyl, piperidinyl, piperazinyl, N-substituted piperazinyl such as methylpiperazinyl, and pyrrolidinyl rings.
  • R 1 is methyl or ethyl
  • R 3 is a lone pair, methyl or ethyl
  • L a and Z 1 are as defined above.
  • R 1 is hydrogen, methyl or ethyl
  • R 3 is a lone pair, methyl or ethyl
  • L a and Z 1 are as defined above.
  • R 4 and R 5 may be independently selected from any of those aryl, aryl-fused- heterocycloalkyl, heteroaryl, CVCe-alkyl, or cycloalkyl groups specifically mentioned in the discussion of R 5 above.
  • R 6 may be -OH, a hydrogen atom, CrC 6 -alkyl such as methyl or ethyl, C r C 6 -alkoxy such as methoxy or ethoxy, hydroxy-C r C 6 -alkyl such as hydroxymethyl, nitrile, or a group CONR 8 2 wherein each R 8 is independently C 1 -C 6 - alkyl such as methyl or ethyl, or a hydrogen atom.
  • R 6 is -OH.
  • Convenient combinations of R 4 and R 5 , especially when R 6 is -OH include those wherein (i) each of R 4 and R 5 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) each of R 4 and R 5 is optionally substituted phenyl; (iii) one of R 4 and R 5 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 4 and R 5 is optionally substituted monocyclic heteroaryl of 5 or 6 ring atoms such as pyridyl, thien
  • R 4 and R 5 are phenyl and the other is cycloalkyl, especially cyclohexyl, or (ii) when both R 4 and R 5 are phenyl.
  • the carbon atom to which R 4 , R 5 and R 6 are attached can be an asymmetric centre so compounds of the invention may be in the form of single enantiomers or mixtures of enantiomers. Examples of configurations of this carbon atom include:
  • the divalent heterocyclic radical B has been defined as a 5-membered heterocyclic ring selected from the group;
  • the group R 11 may be selected from a hydrogen atom or a C 1 -C 3 -BIkVl, especially a methyl group.
  • X may be an alkylene, alkenylene or alkynylene radical, it is convenient that it be alkylene, for example ethylene or methylene. • ' .
  • L 1 , L 2 , L 3 and L 4 are defined above.
  • L 1 , L 2 , L 3 and L 4 are hydrogen or C 1-3 alkyl.
  • Up to three of the carbon atoms of the hydrocarbyl group L may be substituted with groups as defined above.
  • the group L is an alkylene chain, moreconveniently C 5 -C 7 -alkylene, or one of the carbon atoms is replaced by a. group selected from O, NR 46 C(O) or C(O)NR 47 .
  • Up to four carbon atoms of the chain may form part of a mono- or bicyclic aliphatic, heteroaliphatic, aromatic or heteroaromatic ring as described in the definition of L above.
  • One convenient combination is for four of the carbon atoms to be incorporated into a phenyl ring to give a 1 ,4-phenylene, or a 1 ,3-phenyIene group.
  • the radical Z 1 is a moiety having ⁇ 2-adrenoreceptor binding activity, such as a ⁇ 2 agonist group as defined above. • .
  • Compounds of the invention are ⁇ 2-adrenergic binding compounds. Such compounds may be antagonists, partial agonists or full agonists. Compounds that are antagonists are useful tools, for example, for the generation of structure-activity relationships and as radioligands. Compounds that are partial or full agonists may be useful as pharmacological compounds for the treatment of the diseases described above. Compounds that are antagonists are conveniently those wherein Z 1 is a group of formula (Ic), whilst those that are partial or full agonists are conveniently those wherein Z 1 is a group of formula (Ib).
  • the group Ar is (i) a 4-hydroxy-3- hydroxymethyl-phenyl group, (ii) a 3-formylamino-4-hydroxy-phenyl group, or especially, (iii) an 8-hydroxy-2-oxo-1 ,2-dihydroquinolinyl group or (iv) a 4-hydroxy-2- oxo-2,3-dihydro-benzothiazolyl group.
  • groups of formula (Ic) it is convenient that the group Ar is a 4-hydroxy-2-oxo-2,3-dihydro-benzothiazolyl group.
  • 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:
  • bronchodilators such as PDE3 inhibitors; Methyl xanthines such as theophylline; A corticosteroid, for example fluticasone propionate, ciclesonide, morhetasone furoate or budesonide, or steroids described in WO02/88167, WO02/12266, WO02/100879, WO02/00679, WO03/35668, WO03/48181 , WO03/62259, WO03/64445,
  • a non-steroidal glucocorticoid receptor agonist A non-steroidal glucocorticoid receptor agonist
  • 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
  • WO04/024700 WO04/024701 , WO04/020410, WO04/020412, WO05/080372, WO05/082863, WO05/082864, WO03/053930;
  • Phosphodiesterase-4 (PDE4) inhibitors for example roflumilast, arofylline, c ⁇ omilast,
  • An antitussive agent such as codeine or dextramorphan
  • Kinase inhibitors particularly P38 MAPKinase inhibitors
  • P2X7 anatgonists P2X7 anatgonists; iNOS inhibitors;
  • NSAID non-steroidal anti-inflammatory agent
  • ibuprofen or ketoprofen for example ibuprofen or ketoprofen
  • dopamine receptor antagonist for example ibuprofen or ketoprofen
  • 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,
  • Th1 or Th2 Compounds which modulate Th1 or Th2 function, for example, PPAR agonists; lnterleukin 1 receptor antagonists, such as Kineret; interleukin 10 agonists, such as llodecakin;
  • HMG-CoA reductase inhibitors for example rosuvastatin, mevastatin, lovastatin, simvastatin, pravastatin and fluvastatin; Mucus regulators such as INS-37217, diquafosol, sibenadet, CS-003, talnetant, DNK-
  • Antiinfective agents antibiotic or antiviral
  • antiallergic drugs including, but not limited to, anti-histamines.
  • the present invention privides a combination comprising a compound of formula (I) and an inhaled corticosteroid (for example fluticasone propionate, ciclesonide, mometasone furoate or budespnide), or an inhaled PDE 4 inhibitor (for example roflumilast, cilomilast, Tofimilast).
  • an inhaled corticosteroid for example fluticasone propionate, ciclesonide, mometasone furoate or budespnide
  • an inhaled PDE 4 inhibitor for example roflumilast, cilomilast, Tofimilast
  • 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 10Omg per kg, preferably 40 ⁇ g per kg to 4 mg per kg. .
  • compositions which comprise a compound of the invention and a pharmaceutically acceptable carrier.
  • composition is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) (pharmaceutically acceptable excipients) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
  • the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the invention, additional active ingredient(s), and pharmaceutically acceptable excipients. .
  • compositions of the present invention comprise a compound of the invention as an active ingredient or a pharmaceutically acceptable salt thereof, . and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic bases or acids and organic bases or acids, and salts of quaternary ammonium compounds with pharmaceutically acceptable counter-ions.
  • the active compound is preferably in the form of microparticles. They may be prepared by a variety of techniques, including spray- drying, freeze-drying and micronisation.
  • a composition of the invention may be prepared as a suspension for delivery from a nebuliser or as an aerosol in a liquid propellant, for example for use in a pressurised metered dose inhaler (PMDI).
  • PMDI pressurised metered dose inhaler
  • Propellants suitable for use in a PMDI are known to the skilled person, and include CFC-12, HFA-134a, HFA-227, HCFC-22 ' (CCI 2 F 2 ) and HFA-152 (C 2 H 4 F 2 ) and isobutane.
  • a composition of the invention is in dry powder form, for delivery using a dry powder inhaler (DPI).
  • DPI dry powder inhaler
  • Microparticles for delivery by administration may be formulated with excipients that aid delivery and release.
  • microparticles may be formulated with large carrier particles that aid flow from the DPI into the lung.
  • Suitable carrier particles are known, and include lactose particles; they may have a mass median aerodynamic diameter of greater than 90 ⁇ m.
  • the active compounds may be dosed as described depending on the inhaler system used.
  • the administration forms may additionally contain excipients, such as, for example, propellants ⁇ e.g. Frigen in the case of metered aerosols), surface-active substances, emulsifiers, stabilizers, preservatives, flavorings, fillers (e.g. lactose in the case of powder inhalers) or, if appropriate, further active compounds.
  • 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 compounds of the invention of the present invention can be prepared according to the procedures of the following schemes and examples, using appropriate materials, and are further exemplified by the following specific examples. Moreover, by utilising the procedures described with the disclosure contained herein, one of ordinary skill in the art can readily prepare additional compounds of the present invention claimed herein. The compounds illustrated in the examples are not, however, to be construed as forming the only genus that is considered as the invention. The examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.
  • the compounds of the invention may be isolated in the form of their pharmaceutically acceptable salts, such as those described previously herein above. It may be necessary to protect reactive functional groups (e.g. hydroxy, amino, thio or carboxy) in intermediates used in the preparation of compounds of the invention to avoid their unwanted participation in a reaction leading to the formation of the compounds.
  • reactive functional groups e.g. hydroxy, amino, thio or carboxy
  • Conventional protecting groups for example those described by T. W. Greene and P. G. M. Wuts in "Protective groups in organic chemistry” John Wiley and Sons, 1999, may be used.
  • the invention further provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above which comprises:
  • LG 1 represents a leaving group such as chloride, bromide, iodide, methanesulfonate or para-toluenesulfonate
  • L, L 2 , L 3 , L 4 , R 1 , R 4 , R 5 , R 6 , A, W, V and X and R 8 are as defined in formula (Ia), with a compound of formula (III), or a suitable salt thereof such as a hydrobromide, acetate or hydrochloride salt
  • P 1 is hydrogen or a protective group such as ferf-butyldimethyl silyl in the presence of a base such as potassium carbonate, triethylamine or diisopropylethylamine, followed by removal of the protective group (e.g.
  • 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) and L, L 2 , L 3 , L 4 , R 4 , R 5 , R 6 , R 8 A, W, V and X are as defined in formula (Ia), with a compound of formula (III), or a suitable salt thereof (e.g. hydrobromide, hydrochloride salt or acetate), in the presence of a base (e.g. potassium carbonate, triethylamine or diisopropylethylamine) followed by removal of the protective group (e.g. treatment with hydrochloric or trifluoroacetic acid); or
  • a base e.g. potassium carbonate, triethylamine or diisopropylethylamine
  • P 2 represents a protective group (e.g. tert-butylcarbonyl) with-a compound of formula (III), or a suitable salt thereof (e.g. hydrobromide, hydrochloride salt or acetate), in the presence of a suitable reducing agent (e.g. sodium cyanoborohydride, sodium triacetoxyborohydride, or hydrogen in the presence of a suitable palladium on carbon or platinum oxide catalyst), followed by removal of the protective group (e.g. treatment with hydrochloric or trifluoroacetic acid); or (e)when R 4 does not represent hydrogen, reacting a compound of formula (VII), or a suitable salt thereof
  • a protective group e.g. tert-butylcarbonyl
  • a suitable salt thereof e.g. hydrobromide, hydrochloride salt or acetate
  • a suitable reducing agent e.g. sodium cyanoborohydride, sodium triacetoxyborohydride, or hydrogen in the presence of a suitable palladium
  • L, L 1 , L 2 , L 3 , L 4 , R 1 , R 4 , R 5 , R 6 , R 8 A, W, V and X are as defined in formula (Ia)
  • P 3 represents hydrogen or an activating group (e.g. 3-nitrophenylsulfonyl) with a compound of formula (VIII), 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-
  • 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
  • the protective groups e.g. trifluoroacetic acid, thiophenol, thioacetic acid
  • a compound of formula (X) or a suitable salt thereof
  • 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 4 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
  • L, L 1 , L 2 , L 3 , L 4 , R 4 , R 5 , R 6 , R 8 A, W, V and X are as defined in formula (Ia),
  • P 2 represents a protective group (e.g. terf-butylcarbonyl)
  • P 3 represents hydrogen or an activating group (e.g. 3-n ⁇ trophenylsulfonyl)
  • ith a compound of formula (VIII), (IX) or (X), or a suitable salt thereof, in the presence of a base (e.g.
  • P 3 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
  • L, L 1 , and L 2 are as defined in formula (Ia)
  • P 1 is as defined in compound of formula (III)
  • P 3 represents a protective group (e.g. tert-butylcarbonyl or 3- nitrophenylsulfonyl) with a compound of formula (XIII), or a suitable salt thereof,
  • R 4 , R 5 , R 6 , R 1 , R 8 , A 1 W, V and X are as defined in formula (I), in the presence of a suitable reducing agent (e.g. sodium cyanoborohydride, sodium triacetoxyborohydride, or hydrogen in the presence of a suitable palladium on carbon or platinum oxide catalyst), followed by removal of the protective groups (e.g. treatment with hydrochloric or trifluoroacetic acid thiophenol, thioacetic acid); or (h) when one or both of L 3 and L 4 . represents hydrogen, reacting a compound of formula (XIV)
  • a suitable reducing agent e.g. sodium cyanoborohydride, sodium triacetoxyborohydride, or hydrogen in the presence of a suitable palladium on carbon or platinum oxide catalyst
  • the protective groups e.g. treatment with hydrochloric or trifluoroacetic acid thiophenol, thioacetic acid
  • L, L 1 , and L 2 are as defined in formula (Ia), P 1 is as defined in compound of formula (III), P 3 represents a protective group (e.g. terf-butylcarbohyl 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 (i) when L 1 and L 2 each represents hydrogen and R 4 do not represent hydrogen, reacting a compound of formula (XV), or a suitable salt thereof,
  • a base e.g. potassium carbonate, tri
  • L, L 3 , L 4 , R 1 , R 4 , R 5 R 6 , R 8 , A, W, V and X are as defined in formula (I) and 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
  • L 1 L 3 , L 4 , R 4 , R 5 , R 6 , A, W, V and X are as defined in formula (I) and 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 reaction may conveniently be carried out in an organic solvent such as ⁇ /, ⁇ /-dimethylformamide, ethanol, />butanol or dimethyl sulfoxide, at a temperature, for example, in the range from 50 to 14O 0 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
  • 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 oxidating agent (e.g. Swem reagent, Dess-Martin reagent or pyridiniumchlorochromate) in an organic solvent such as dichloromethane, /V, ⁇ /-dimethylformamide or dimethylsulfoxide at a temperature, for example in the range from -78 to 60°C.
  • a suitable oxidating agent e.g. Swem reagent, Dess-Martin reagent or pyridiniumchlorochromate
  • an organic solvent such as dichloromethane, /V, ⁇ /-dimethylformamide or dimethylsulfoxide at a temperature, for
  • P 2 , L, L 3 , L 4 , R 4 , R 5 , R 6 , R 8 , A, W, V 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.
  • a compound of formula (IV) reacting a compound of formula (IV) with an amine (e.g. benzylamine, D-methyl benzylamine, 4-methoxybenzyla.mine 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, /V-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, D-methyl benzylamine, 4-methoxybenzyla.mine or 2,4-methoxybenzylamine
  • a suitable reducing agent e.g. sodium cyanoborohydride or sodium triacetoxyborohydr
  • 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 8O 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), L, L 1 , L 2 , L 3 , L 4 ,.
  • R 1 , R 4 , R 5 , R 6 , R 8 , A, W, V and X are as defined in formula (VII), 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, tert-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, /V, ⁇ /-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. treatment with 3-nitrophenylsulfonyi chloride in the presence of a base such as pyridine); or
  • a suitable reducing agent e.g. triphenylphosphine or hydrogen
  • a compound of formula (Vl) reacting 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. sodium cyanoborohydride, sodium triacetoxyborohydride) in an organic solvent such as methanol, ethanol, dichloromethane, acetic acid ⁇ /-methylpyrolidinone, or N 1 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, a- methyl benzylamine, 4-methoxybenzyl amine or 2,4-methoxybenzyl amine
  • a suitable reducing agent e.g. sodium cyanoborohydride
  • a suitable catalyst Palladium on carbon or palladium hydroxide
  • 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, eventually followed by protection of the resulting amine (e.g. treatment with 3- nitrophenylsulfonyl chloride in the presence of a base such as pyridine).
  • L 4 is a leaving group (e.g. hydroxyl or chloride)
  • L, L 1 , L 2 , L 3 , L 4 , R 4 , R 5 , R 6 , R 8 , A, W, V 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),.
  • an amine e.g. triethylamine
  • 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, ferf-butanol, tetrahydrofuran, water, or a mixture thereof, at a temperature ranging from 25 to
  • Compounds of formula (XII) can be prepared by (a) reacting a compound of formula (XXil) 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), (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
  • an organic solvent such as ⁇ /, ⁇ /-dimethylformamide, ⁇ /-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 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 a suitable salt thereof, in the presence of a suitable reducing agent (e.g. sodium cyanoborohydride, sodium triacetoxyborohydride, or hydrogen in the presence of a suitable palladium on carbon or platinum oxide catalyst) in an organic .
  • a suitable reducing agent e.g. sodium cyanoborohydride, sodium triacetoxyborohydride, or hydrogen in the presence of a suitable palladium on carbon or platinum oxide catalyst
  • solvent such as methanol, ethanol, dichloromethane, acetic acid, ⁇ /-methypyrolidinone or ⁇ /, ⁇ /-dimethylformamide containing up to 10%w of water and acetic acid, followed by 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 oxidation of the resulting alcohol into the corresponding aldehyde with a suitable oxidating agent (pyridinium chlorochromate, Dess-Martin reagent or. Swern reagent); or
  • 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 a suitable salt thereof, in the presence of a suitable reducing agent (e.g.
  • an organic solvent such as methanol, ethanol, dichloromethane, acetic acid, /V-methypyr ⁇ lidinone or ⁇ /, ⁇ /-dimethylforrnamide 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) can be prepared by converting compound of formula (XII), or a precursor to compound of formula (XII) 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, Compounds of formula (XV) and (XVI) can be prepared by similar methods by reacting a compound of formula (XXVI)
  • L, L 3 , L 4 , R 4 , R 5 , R 6 , R 8 , A, W, V and X are as defined in formula (XV)
  • P 8 represents either R 3 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 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)- ⁇ /, ⁇ /,/V', ⁇ /-tetramethyluroniumhexafluorophosphate (HATU), in an organic solvent, for example, ⁇ /, ⁇ /-dimethylformamide or dichloromethane, at a temperature, for example in the range from 0 to 6O 0 C,
  • an activating reagent for example, carbonyldiimidazole or O-(7- azabenzotriazol-1 -yl)- ⁇ /, ⁇ /,/V', ⁇ /-tetramethyluroniumhexafluorophosphate (HATU)
  • an organic solvent for example, ⁇ /, ⁇ /-dimethylformamide or dichloromethane
  • LG 7 represent a hydroxyl, an ether (e.g. methoxy, ethoxy), a leaving group (e.g.
  • L, L 1 , L 2 , L 3 , L 4 and P 3 are as defined in compound of formula (VII); - for compound of formula (Xl), P 9 represents P 2 , P 10 represents
  • P 9 and P 10 represents an appropriate nitrogen protecting group, such as terf-butoxycarbonyl, followed by suitable deprotection (e.g. trifluoroacetic acid acid);
  • L, L 3 , and L 4 are as defined in compound of formula (XVII), wherein
  • P and P represent an acyclic or cyclic carbonyl protective group (e.g. dimethoxy or diethoxy acetal, 1 ,3-dioxolane or 1 ,3-dioxane), followed by suitable deprotection (e.g. diluted hydrochloric acid or amberlyst-15 resin in methanol);
  • acyclic or cyclic carbonyl protective group e.g. dimethoxy or diethoxy acetal, 1 ,3-dioxolane or 1 ,3-dioxane
  • suitable deprotection e.g. diluted hydrochloric acid or amberlyst-15 resin in methanol
  • L, L , and L are as defined in compound of formula (XIX), wherein P and P 12 represent an acyclic or cyclic carbonyl protective group (e.g. dimethoxy or diethoxy acetal, 1 ,3-dioxolane or 1 ,3-dioxane), followed by suitable deprotection (e.g. diluted hydrochloric acid or amberlyst-15 resin in methanol);
  • P and P 12 represent an acyclic or cyclic carbonyl protective group (e.g. dimethoxy or diethoxy acetal, 1 ,3-dioxolane or 1 ,3-dioxane), followed by suitable deprotection (e.g. diluted hydrochloric acid or amberlyst-15 resin in methanol);
  • L, L 1 , L 2 , L 3 , and L 4 are as defined in compound of formula (XX), wherein P 14 represent an acid protective group (e.g. methyl, ethyl or tert-butyl), followed by suitable deprotection (e.g. lithium hydroxide or sodium hydroxide, trifluoroacetic acid, hydrochloric acid); - for compound of formula (XXI), P 9 represents P 2 , P 10 represents
  • L, L 1 , L 2 , L 3 , and L 4 are as defined in compound of formula (XXI), wherein P 14 represent an acid protective group (e.g. methyl, ethyl or tert-butyl), followed by suitable deprotection (e.g. lithium hydroxide or sodium hydroxide, trifluoroacetic acid, hydrochloric acid);
  • P 14 represent an acid protective group (e.g. methyl, ethyl or tert-butyl)
  • suitable deprotection e.g. lithium hydroxide or sodium hydroxide, trifluoroacetic acid, hydrochloric acid
  • L, L 3 , and L 4 are as defined in compound of formula (XXVI), wherein P 14 represent an acid protective group (e.g. methyl, ethyl or tert-butyl), followed by suitable deprotection (e.g. lithium hydroxide or sodium hydroxide, trifluoroacetic acid, hydrochloric acid);
  • P 14 represent an acid protective group (e.g. methyl, ethyl or tert-butyl)
  • suitable deprotection e.g. lithium hydroxide or sodium hydroxide, trifluoroacetic acid, hydrochloric acid
  • Compounds of general formula (LX-a) may be prepared from compounds of general formula (LXI) using methods described below for the preparation of compounds of formula (LXII) from compounds of formula (LXIII).
  • compounds of formula (LX-a) are prepared from compounds of formula (LXIV) as described below.
  • LG represents a leaving group such as bromide, chloride, iodide, by reaction with an amine of formula (LXVl):
  • R c R d R e N represents appropriately substituted amine.
  • the reaction is performed in a range of solvents, typically a mixture of THF/DCM or acetonitrile/chloroform at a range of temperatures, typically between 0 and the reflux temperature, or more typically, ' in acetonitrile at a temperature between 0 and 50° C, most typically at 50°C.
  • reaction by reaction with a brominating agent such as N-bromosuccinimide in the presence of a radical initiator such as AlBN or benzoyl peroxide.
  • a brominating agent such as N-bromosuccinimide
  • a radical initiator such as AlBN or benzoyl peroxide.
  • The. reaction can be carried out in. suitable solvents, such as CCI 4 , at a range of temperatures, typically between ambient temperature and the reflux temperature of the solvent.
  • compounds of formula (LXIII) can be prepared from compounds of general formula (LXVII) by palladium-catalysed cyclisation using a palladium catalyst such as bis(dibenzylideneacetone)palladium in the presence of a ligand such as triphenylphosphine and a base such as sodium tert-butoxide in a solvent such as THF from room temperature to the reflux temperature of the solvent.
  • a palladium catalyst such as bis(dibenzylideneacetone)palladium in the presence of a ligand such as triphenylphosphine and a base such as sodium tert-butoxide in a solvent such as THF from room temperature to the reflux temperature of the solvent.
  • M represents a metallic counterion such as Li or MgBr.
  • the reaction may take place in an aprotic organic solvent such as THF or diethyl ether at a range of temperatures, typically between -78 0 C and the reflux temperature of the solvent.
  • Compounds of general formula (LXXV) can be prepared from compounds of formula (LXXlV) using methods described above for the preparation of compounds of formula (LXVII) from compounds of formula (LXXI).
  • Compounds of formula (LX-f) can be prepared from compounds of formula (LX-a) by reaction with a reducing agent such as triethylsilane in the presence of an acid such as trifluoroacetic acid in a solvent such as DCM from room temperature to the reflux temperature of the solvent.
  • a reducing agent such as triethylsilane
  • an acid such as trifluoroacetic acid
  • Compounds of formula (LX-h) can be prepared from compounds of formula (LX-a) by reaction with an alkylating agent of formula (LXXVI):
  • R f is C r C 6 -alkyl and LG is a leaving group such as halogen, tosylate, mesylate.
  • the reaction is performed in the presence of a base such as sodium hydride in a solvent such as THF from O 0 C to the reflux temperature of the solvent.
  • Compounds of general formula (LXXVII) can be prepared from compounds of formula (LXXVIII) using methods described above for the preparation of compounds of formula (LXV) from compounds of formula (LXIII).
  • compounds of formula (LXIV) may be prepared from compounds of formula (LXXIV) as illustrated in Scheme 12 below;
  • Compounds of formula (LXXXIII) may be prepared from compounds of formula (LXXIV) using methods analogous to those used in the preparation of compounds of formula (V) from compounds of formula (Vl) as described above.
  • Compounds of Formula (LX-b) may be prepared from compounds of Formula (LXXXIV) by employing a similar sequence of reactions as used to prepare compounds of Formula (LX-a) from compounds of Formula (LXII) in Scheme 1 above.
  • Compounds of formula (LXXXIV) wherein R 4 and R 5 are the same maybe prepared from compounds of Formula (LXXV) where R is a suitable alkyl group (such as ethyl or methyl) by treatment with an appropriate organometallic reagent such as a Grignard reagent, in a suitable solvent such as THF or diethyl ether.
  • Compounds of Formula (LXXXIV) wherein R 4 and R 5 are dissimilar may be prepared from compounds of Formula (LXXV) by converting to an intermediate amide, typically a Weinreb amide, and performing the introduction of R 4 and R 5 through their respective organometallic reagents in a stepwise manner.
  • the present invention also comprises intermediate compounds having utility in the synthesis of the compounds of formula (I).
  • such intermediate compounds are selected from the group including cyclohexyl-(5-methyl-oxazol-2-yl)- phenyl-methanol; (5-bromomethyl-oxazol-2-yl)-cyclohexyl-phenyl-methanol; (5- bromomethyl-oxazol-2-yl)-cyclopentyI-phenyl-methanoI; (5-bromomethyl-oxazol-2-yl)- diphenyl-methanol; (5-dimethylaminomethyl-oxazol-2-yl)-diphenyl-methanol; (5- methylaminomethyl-oxazol ⁇ -yO-diphenyl-methanoli cyclopentyl-C ⁇ -methylaminomethyl- oxazol-2-yl)-phenyl-methanoI; [5-( ⁇ [3-(4
  • such intermediate compounds are selected from the group including cyclopentyl-(5-methylaminomethyl-oxazol-2-yl)-phenyl-methanol; [5-( ⁇ [3-(4- [1 ,3]dioxolan-2-yl-phenoxy)-propyl]-methyl-amino ⁇ -methyl)-oxazol-2-yl]-diphenyl- methanol; 4-(3- ⁇ [2-(Hydroxy-diphenyl-methyl)-oxazol-5-ylmethyl]-methyl-amino ⁇ -propoxy)- benzaldehyde; and 5- ⁇ (R)-1 -(tert-Butyl-dimethyl-silanyloxy)-2-[4-(3- ⁇ [2-(hydroxy-diphenyl- - methyl)-oxazol-5-ylmethyl]-methyl-arhino ⁇ -propoxy)-benzylamino]-ethyl ⁇ -8-(4-(4-
  • 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 arid 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;
  • COPD chronic obstructive pulmonary disease
  • bronchitis including infectious and
  • 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
  • juvenile arthritis including idiopathic inflammatory arthritides of whatever joint distribution and associated syndromes, and rheumatic fever and its systemic complications; vasculitides including gjant cell arteritis, Takayasu's arteritis, Churg-Strauss syndrome, polyarteritis nodosa, microscopic polyarteritis, and vasculitides associated with viral infection, hypersensitivity reactions, cryoglobulins, and paraproteins; low back pain; Familial Mediterranean fever, Muckle-Wells syndrome, and Familial Hibernian Fever, Kikuchi disease; drug-induced arthalgias, tendonititides, and myopathies; .
  • vasculitides including gjant cell arteritis, Takayasu's arteritis, Churg-Strauss syndrome, polyarteritis nodosa, microscopic polyarteritis, and vasculitides associated with viral infection, hypersensitivity reactions, cryoglobulin
  • 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 reperfusio ⁇ injuries; endocarditis, valvulitis, and aortitis including infective (for example syphilitic); vasculitides; disorders of the proximal and peripheral veins including phlebitis and thrombosis, including deep vein thrombosis and complications of varicose veins;
  • oncology treatment of common cancers including prostate, breast, lung, ovarian, pancreatic, bowel and colon, stomach, skin and brain tumors and malignancies affecting the bone marrow (including the leukaemias) and lymphoproliferative systems, such as .
  • Hodgkin's and non-Hodgkin's lymphoma including the prevention and treatment of metastatic disease and tumour recurrences, and paraneoplastic syndromes; and,
  • 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 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 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 maybe 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 e.g., a pharmaceutically . acceptable 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.
  • the pharmaceutical 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 20 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 20 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 dioxide.
  • a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide.
  • the tablet may be coated with a suitable polymer dissolved in a readily volatile organic solvent.
  • the compound of the invention may be admixed with, for example, a vegetable oil or polyethylene glycol.
  • Hard gelatine capsules may contain granules of the compound using either the above-mentioned excipients for tablets.
  • liquid or semisolid formulations of the compound of the invention may be filled into hard gelatine capsules.
  • Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing the compound of the invention, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol.
  • Such liquid preparations may contain colouring agents, flavouring agents, saccharine and/or carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art.
  • the compounds of the invention may also be administered in conjunction with other compounds used for the treatment of the above conditions.
  • the invention therefore further relates to combination therapies wherein a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or formulation comprising a compound of the invention, is administered concurrently or sequentially or as a combined preparation with another therapeutic agent or agents, for the treatment of one or more of the conditions listed.
  • NSAIDs non-steroidal anti-inflammatory agents
  • COX-1 / COX-2 inhibitors whether applied topically or systemically (such as piroxicam, diclofenac, propionic acids such as naproxen, flurbiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac, azapropazone, pyrazolones such as phenylbutazone, salicylates such as aspirin); selective COX-2 inhibitors (such as mel
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with a cytokine or agonist or antagonist of cytokine function, (including agents which act on cytokine signalling pathways such as modulators of the SOCS system) including alpha-, beta-, and gamma-interferons; insulin-like growth factor type I (IGF-1); interleukins (IL) including IL1 to 17, and interleukin antagonists or inhibitors such as anakinra; tumour necrosis factor alpha (TNF- ⁇ ) inhibitors such as anti-TNF monoclonal antibodies (for example infliximab; adalimumab, and CDP-870) and TNF receptor antagonists including immunoglobulin molecules (such as etanercept) and low-molecular-weight agents such as pentoxyfylline.
  • a cytokine or agonist or antagonist of cytokine function including agents which act on cytokine signalling
  • the invention relates to a combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with a monoclonal antibody targeting B- Lymphocytes (such as CD20 (rituximab), MRA-alLI6R) . or T-Lymphocytes (CTLA4-lg,
  • 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);
  • 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);
  • 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-1 1 ) 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-cyanpnaphthalene compound such as L-739,010; a .2- cyanoquinoline compound such as L-746,530; or an ⁇ ndole or quinoline compound such as MK-591
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a receptor antagonist for leukotrienes (LT) B4, LTC4,. LTD4, and LTE4.
  • a receptor antagonist for leukotrienes (LT) B4, LTC4,. LTD4, and LTE4 selected from the group consisting of the phenothiazin-3-1 s 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-
  • 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.
  • 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, oxymetazoline hydrochloride,
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a chromone, such as sodium cromoglycate 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.
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with an agent that modulates a nuclear hormone receptor such as PPARs.
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with an immunoglobulin (Ig) or Ig preparation or an antagonist or antibody modulating Ig function such as anti-lgE (for example omalizumab).
  • Ig immunoglobulin
  • Ig preparation or an antagonist or antibody modulating Ig function
  • anti-lgE for example omalizumab
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and another systemic or topically-applied antiinflammatory agent, such as thalidomide or a derivative thereof, a retinoid, dithranol or calcipotriol.
  • another systemic or topically-applied antiinflammatory 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 transcript
  • 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, ropiiiirole, 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 (
  • 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 non-steroidal anti-inflammatory agent.
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with a parenterally or topically-applied (including inhaled) local anaesthetic agent such as lignocaine or a derivative thereof.
  • a compound of the present invention, or a pharmaceutically acceptable salt thereof can also be used in combination with an anti-osteoporosis agent including a hormonal agent such as raloxifene, or a biphosphonate such as alendronate.
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with a: (i) tryptase inhibitor; (ii) platelet activating factor (PAF) antagonist; (iii) interleukin converting enzyme (ICE) inhibitor; (iv) IMPDH inhibitor; (v) adhesion molecule inhibitors including VLA-4 antagonist; (vi) cathepsin; (vii) kinase inhibitor such as an inhibitor of tyrosine kinase (such as Btk, Itk, Jak3 or MAP, for example Gefitinib or lmatinib mesylate), a serine / threonine kinase, (such as an inhibitor of 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 kinas
  • - or B.sub2. -receptor antagonist for example colchicine
  • anti-gout agent for example colchicine
  • xanthine oxidase inhibitor for example allopurinol
  • uricosuric agent for example probenecid, sulfinpyrazone or benzbromarone
  • growth hormone secretagogue for example probenecid, sulfinpyrazone or benzbromarone
  • transforming for example colchicine
  • anti-gout agent for example colchicine
  • uricosuric agent for example probenecid, sulfinpyrazone or benzbromarone
  • growth hormone secretagogue for example probenecid, sulfinpyrazone or benzbromarone
  • TGF ⁇ platelet-derived growth factor
  • PDGF platelet-derived growth factor
  • bFGF fibroblast growth factor for example basic fibroblast growth factor
  • GM-CSF granulocyte macrophage colony stimulating factor
  • capsaicin cream tachykinin NK.subi . or NK.sub3.
  • NKP-608C such as 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; (xxvii) inhibitor of transcription factor activation such as NFkB, API or STATS; or (xxviii) a glucocorticoid receptor (GR-receptor) agonist.
  • TLR Toll-like receptors
  • P2X7 agent modulating the activity of purinergic receptors
  • inhibitor of transcription factor activation such as NFkB, API or STATS
  • GR-receptor glucocorticoid 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 isof ⁇ rm PDE4D; o a modulator of chemokine receptor function (such as a CCR1 receptor antagonist); o a steroid (such as budesonide); and o an inhibitor of p38 kinase function.
  • GR-receptor non-steroidal glucocorticoid receptor
  • PDE4 inhibitor including an inhibitor of the isof ⁇ rm PDE4D
  • o a modulator of chemokine receptor function such as a CCR1 receptor antagonist
  • o a steroid such as budesonide
  • an inhibitor of p38 kinase function for example for the treatment of
  • 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 flu ⁇ ropyrimidine 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 ayinca alkaloid such
  • a cytostatic agent such as an antioestrogen (for example tamoxifen, toremifene, raloxifene, droloxifene or iodoxyfene), an oestrogen receptor down regulator (for example fulvestrant), an a ' ntiandrogen (for example bicalutamide, flutamide, nilutamide or cyproterone acetate), a LHRH antagonist or LHRH agonist (for example goserelin, leuprorelin or buserelin), a progestogen (for example megestrol acetate), an aromatase inhibitor (for example as anastrozole, letrozole, vorazole or exemestane) or an inhibitor of 5 ⁇ -reductase such as finasteride; (Hi) an agent which inhibits cancer cell invasion (for example a metalloproteinase inhibitor like marimastat or an inhibitor of urokina), an
  • an agent used in antisense therapy for example one. directed, to one of the targets listed above, such as ISIS 2503, an anti-ras antisense;
  • an agent used in' a gene therapy approach for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; or
  • an agent used in an immunotherapeutic approach for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies.
  • cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor
  • 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 prepacked SCX-2 cartridge refers to Isolute ® SCX-2, a strong cation exchange sorbent (Argonaut/IST).
  • Purification over NH 2 silica gel refers to Isolute ® flash NH 2 prepacked cartridges (Argonaut/IST).
  • Phenyl hexyl column 250 x 21.20 mm Ld. Luna column with 5 ⁇ m particle size), eluting using linear gradients of mixtures of solvent A (water with 0.1% TFA) and solvent B (acetonitrile with 0.1 % TFA) at a flow rate of 18 ml_/min with UV detection set at 254 nm.
  • HPLC system 4 C8-reverse-phase column (50 x 19 mm Ld. " Symmetry column with 5.0 ⁇ m particle size), eluting using linear gradients of mixtures of solvent A (water with 0.1 % TFA) and solvent B (acetonitrile with 0.1 % TFA) at a flow rate of 20 mL/min with UV detection set at 220 nm.
  • Micromass Platform LCT with a C18-reverse-phase column (100 x 3.0 mm i.d. Higgins Clipeus with 5 ⁇ m particle size), elution with solvent A (water with 0.1 % formic acid) and solvent B (acetonitrile with 0.1 % formic acid).
  • MS ionisation method Electrospray (positive ion).
  • MS ionisation method Electrospray (positive and negative ion).
  • MS ionisation method Electrospray (positive and negative ion).
  • MS ionisation method - APCI positive ion and negative ions
  • Agilent 1100 series LG/MSD with C18-reverse-phase column (50 x 2.1 mm i.d. Waters Symmetry column with 3.5 ⁇ m particle size), eluting using linear gradients of mixtures of solvent A (water with 0.1% TFA) and solvent B (acetonitrile with 0.1 % TFA) at a flow rate of 1 mL/min.
  • MS ionisation method - APCI positive ion and negative ions
  • AIBN (2,2'-azobis(2-methylproprionitrile)
  • BOC-anhydride Di-t ⁇ /t-butyl dicarbonate .
  • CDI 1 ,1 '-carbonyl diimidazole
  • DIPEA diisopropylethylamine
  • DMF /V, ⁇ /-di methyl formamide
  • HATU O-(7-azabenzotriazol-1 -yl)- ⁇ /, ⁇ /, ⁇ /' ⁇ /-tetramethyluroniumhexafluoro- phosphate
  • NaHCO 3 sodium hydrogen carbonate
  • NaOH Sodium hydroxide
  • TEMPO 2,2,6,6-tetramethyl-1 -piperidinyloxy free radical
  • the title compound was prepared from (5-methyl-oxazol-2-yl)-diphenyl-methanol by a similar method to. that disclosed in WO200.7/017669.
  • the title compound was prepared from [5-(2-benzylamino-ethyl)-oxazol-2-yl]-diphenyl- methanol using a similar procedure to that disclosed in WO2007/017669.
  • the title compound was prepared from 4-nitro-benzaldehyde and 7-(2-amino-ethyl)-4- hydroxy-3H-benzothiazol-2-one hydrochloride by similar methods to those employed in intermediates 19-21 , respectively.
  • Dess-Martin periodinane (1.22 g, 2.88 mmol) was added to /V-(2,2-dimethoxy-ethyl)-4- (2-hydroxy-ethyl)-benzamide (0.55 g, 2.17 mmol) in DCM (15 mL. After 1 hour, saturated aqueous NaHCO 3 (25 mL), sodium thiosulphate (25 mL) and EtOAc (80 mL) were added and the mixture shaken vigorously for 1 minute then separated.
  • tert-Butyldimethylchlorosilane (4.07 mL, 21 .89 mmo! was added to a stirred solution of methyl 3-(2-hydroxyethyl)benzoate (3.30 g, 18.31 mmol) a ⁇ d Imidazole (3.70 g, 54.35 mmol) in dry DMF (30 mL) cooled in an ice bath. After 45 minutes, the reaction mixture was diluted with ethyl acetate, washed with water (x 3) and evaporated in vacuo. The resulting gum was dissolved in iso-hexanes and passed through a pad of silica-g ⁇ l eluting with iso-hexanes followed by EtOAc/DCM [1 :10] to afford the title compound.
  • Lithium hydroxide (2.0 g, 83 mmol) as a suspension in water (20 ml_) was added to methyl 3-(2-(tert-butyldimethylsilyloxy)ethyl)benzoate (5.1 g, 20.04 mmol) in MeOH (60 mL). The resulting suspension was stirred at room temperature for 16 hours. The mixture was then partitioned between 10% aqueous acetic acid (200 mL) and EtOAc (300 mL). The EtOAc solution was washed with water (x 3), dried (Na 2 SO 4 ), filtered and concentrated in vacuo.
  • the title compound was prepared from 3-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]- benzoic acid and 7-(2-amino-ethyl)-4-hydroxy-3H-benzothiazol-2-one hydro chloride by similar methods to those employed in intermediates 23-25.
  • the title compound was prepared from ⁇ 2-[3-(2,2-dimethoxy-ethylcarbamoyl)-phenyl]- ethyl ⁇ -[2-(4-hydroxy-2-oxo-2,3-dihydro-benzothiazol-7-yl)-ethyl] carbamic acid tert- butyl ester hydro chloride by a similar method to. that used in intermediate 26.
  • HATU (8.30 g, 21.83 mmol) was added portion-wise over 10 minutes 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 hour the reaction mixture was quenched with water (200 mL) and extracted with EtOAc (6 x 350 mL). The organic extracts were combined, dried (MgSO 4 ), filtered and evaporated in vacuo. The crude product was purified by flash silica chromatography, eluting with EtOAc/iso-hexanes ⁇ 3:1] to afford the title compound.
  • the title compound was prepared from /V-(2,2-dimethoxy-ethyl)-4-formyl-benzamide and 7-(2-amino-ethyl)-4-hydroxy-3H-benzothiazol-2-one hydro chloride by similar methods to those employed in intermediates 25 and 26. . .
  • the title compound was prepared from (3-acetoxymethyl-phenyl)-acetic acid methyl ester by a similar method to that used in intermediate 30 to give the title compound, as a coloured gum.
  • the title compound was prepared from (3-hydroxymethyl-phenyl)-acetic acid by a similar method to that used in intermediate 29 to give the title compound as an orange gum.
  • the title compound was prepared from ⁇ 4-[2-(tert-butyl-dimethyl-siianyIoxy)-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 in intermediate 26.
  • 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 minutes, the mixture was concentrated in vacuo to give the crude de-silylated intermediate which was taken on to the BoC 2 O reaction to give the title compound.
  • the title compound was prepared from carbonic acid 7-[2-(tert-butoxycarbonyl- ⁇ 2-[4- (2-hydroxy-ethyl)-phenyl]-ethyl ⁇ -amino)-ethyl]-2-oxo-2,3-dihydro-benzothiazol-4-yI ester tert-butyl ester by a similar Dess-Martin oxidation method used in the synthesis . of intermediate 26.
  • the title compound was prepared from carbonic acid 7-[2-(tert-butoxycarbonyl- ⁇ 2-[3- (2-hydroxy-ethoxy)-phenyl]-ethyl ⁇ -amiho)-ethyl]-2-oxo-2,3-dihydro-benzothiazol-4-yl ester tert-butyl ester by a similar Dess-Martin oxidation method used in the synthesis of intermediate 26.
  • the title compound was prepared from [3-(3-bromo-propoxy)-phenyl]-acetal dehyde and 7-(2-amino-ethyl)-4-hydroxy-3H-benzothiazol-2-one hydro chloride by similar methods to those employed for intermediate 26.
  • the crude product was purified by HPLC (HPLC system 3) to give the desired product as a white solid.
  • the title compound was prepared from [4-(3-bromo-propoxy)-phenyl]-acetaldehyde and 7-(2-amino-ethyl)-4-hydroxy-3H-benzothiazol-2-one hydro chloride by similar methods to those employed for intermediate 26.
  • the crude product was purified by HPLC (HPLC system 3) to give the desired product as a white solid.
  • the title compound was prepared from 4-(2-hydroxyethyl)phenol and 2-bromo-1 ,1- diethoxyethane by a similar method to that employed for intermediate 49.
  • the intermediate dimethylacetal of the title compound was prepared from [2-[4-(2,2- dimethoxy-ethoxy)-phenyl] ⁇ ethanol and 7-(2-amino-ethyl)-4-hydroxy-3H-benzothiazol- 2-one acetate by similar methods to those employed for intermediates 26 and 50, respectively..
  • the intermediate dimethylacetal of the title compound was prepared from [4-(2,2- dimethoxy-ethoxy)-phenyl]-methanol and 7-(2-amino-ethyl)-4-hydroxy-3H- benzothiazol-2-one hydrochloride by similar methods to those employed for intermediates 34, 19 and 20, respectively.
  • the dimethyl acetal was converted into the title aldehyde following hydrolysis as for intermediate 27, and was used directly.
  • the title compound was prepared from 2-(2-thienyl)ethanol by similar a method to that 5 employed in intermediate 29.
  • Triphenylphosphine (13.04 g, 49.71 mmol), followed by carbon tetrabromide (15.71 g, 47.38 mmol) were added in one portion to ⁇ 5-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]- thiophen-2-yl ⁇ -methanol (10.94 g, 40.15 mmol) in DCM (20 mL) at 0 0 C under nitrogen. The resulting solution was stirred at room temperature for 1 hour. The reaction mixture was cooled to 0 0 C and treated with tetraethylammonium cyanide (8.96 g, 57.34 mmol), added in one portion.
  • TBDMS-CI (10.35 g, 68.69 mmol) was added to a stirred solution of imidazole (4.68 g, 68.69 mmol), and 2-hydroxymethyl-1 H-benzoimidazoie-5-carboxylic acid (6.00 g, 31 .22 mmol) in DMF (50 ml_) at 20 0 C. The resulting solution was stirred at 20 0 C for 1 hour. To the mixture was then added THF (50 ml_) followed with ice-bath cooling by a solution.of K 2 CO 3 (6.04 g, 43.71. mmol) in Water (50 mL).
  • the mixture was stirred at 0 0 C for 20 minutes and then diluted with water (200 mL) and extracted with diethyl ether.
  • the aqueous layer was acidified by addition of acetic acid and then extracted with EtOAc, the organic layers were combined, washed twice with water before being ' dried (Na s O 4 ) and filtered.
  • the solvent was removed in vacuo until solid precipitated out; the solid was filtered off and washed with a little ether to yield 2.15 g of product.
  • the mother liquors were diluted with iso-hexane to precipitate a further 4.35 g of the desired product.
  • the title compound was prepared from 4-hydroxy-7- ⁇ 2-[(2-hydroxymethyl-1 H- benzoimidazol-5-ylmethyl)-amino]-ethyl ⁇ -3H-benzothiazol-2-one by a similar method to that employed in intermediate 20.

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Abstract

La présente invention porte sur un composé de formule (I) présentant une activité à la fois antagoniste du récepteur M3 et agoniste β2 ; sur une composition incluant un tel composé ; sur l'utilisation d'un tel composé en thérapie (telle que l'asthme ou le COPD) ; sur un procédé de traitement d'un patient par un tel composé, dans lequel R1, R3, R4, R5, R6, La, Z1, W, V, A et X sont tels que définis présentement.
PCT/GB2008/000407 2007-02-07 2008-02-06 Composés hétrocycliques contenant de l'azote utiles comme modulateurs bifonctionnels de récepteurs m3 et de récepteurs bétâ-2 WO2008096129A1 (fr)

Applications Claiming Priority (4)

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GB0702415.1 2007-02-07
GB0702415A GB0702415D0 (en) 2007-02-07 2007-02-07 New chemical compound
GB0702381A GB0702381D0 (en) 2007-02-07 2007-02-07 Compounds and their use
GB0702381.5 2007-02-07

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Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010123766A1 (fr) 2009-04-23 2010-10-28 Theravance, Inc. Composes diamides ayant un antagoniste du recepteur muscarinique et une activite agoniste des recepteurs adrenergiques beta2
WO2011012896A2 (fr) 2009-07-31 2011-02-03 Astrazeneca Ab Composés - 801
WO2011081937A1 (fr) 2009-12-15 2011-07-07 Gilead Sciences, Inc. Composés de type corticostéroïde-bêta-agoniste-antagoniste muscarinique pour applications thérapeutiques
US8148373B2 (en) 2008-02-06 2012-04-03 Astrazeneca Ab Compounds
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
JP2014519508A (ja) * 2011-06-10 2014-08-14 キエスィ ファルマチェウティチ エス．ピー．エー． ムスカリン受容体拮抗薬及びβ２アドレナリン受容体作動薬活性を有する化合物
US9233108B2 (en) 2011-11-11 2016-01-12 Almirall, S.A. Cyclohexylamine derivatives having β2 adrenergic agonist and M3 muscarinic antagonist activities
US9315463B2 (en) 2010-05-13 2016-04-19 Almirall, S.A. Cyclohexylamine derivatives having β2 adrenergic agonist and M3 muscarinic antagonist activities
US9518050B2 (en) 2012-12-18 2016-12-13 Almirall, S.A. Cyclohexyl and quinuclidinyl carbamate derivatives having β2 adrenergic agonist and M3 muscarinic antagonist activity
US9562039B2 (en) 2013-02-27 2017-02-07 Almirall, S.A. Salts of 2-amino-1-hydroxyethyl-8-hydroxyquinolin-2(1H)-one derivatives having both β2 adrenergic receptor agonist and M3 muscarinic receptor antagonist activities
US9579316B2 (en) 2013-07-25 2017-02-28 Almirall, S.A. Salts of 2-amino-1-hydroxyethyl-8-hydroxyquinolin-2(1H)-one derivatives having both muscarinic receptor antagonist and β2 adrenergic receptor agonist activities
US9643961B2 (en) 2010-05-13 2017-05-09 Almirall, S.A. Cyclohexylamine derivatives having β2 adrenergic antagonist and M3 muscarinic antagonist activities
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

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WO2004089892A2 (fr) * 2003-04-01 2004-10-21 Theravance, Inc. Diarylmethyle et composes apparentes
WO2006023460A2 (fr) * 2004-08-16 2006-03-02 Theravance, Inc. Composes a activite agoniste pour recepteur ?2 adrenergique et antagoniste pour recepteur muscarinique
WO2007017669A1 (fr) * 2005-08-08 2007-02-15 Argenta Discovery Ltd. Derives d'azole et de thiazole et utilisation de ceux-ci
WO2008017827A2 (fr) * 2006-08-08 2008-02-14 Argenta Discovery Limited Composés chimiques
WO2008023157A1 (fr) * 2006-08-21 2008-02-28 Argenta Discovery Limited Composés et leur utilisation

Patent Citations (5)

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Publication number Priority date Publication date Assignee Title
WO2004089892A2 (fr) * 2003-04-01 2004-10-21 Theravance, Inc. Diarylmethyle et composes apparentes
WO2006023460A2 (fr) * 2004-08-16 2006-03-02 Theravance, Inc. Composes a activite agoniste pour recepteur ?2 adrenergique et antagoniste pour recepteur muscarinique
WO2007017669A1 (fr) * 2005-08-08 2007-02-15 Argenta Discovery Ltd. Derives d'azole et de thiazole et utilisation de ceux-ci
WO2008017827A2 (fr) * 2006-08-08 2008-02-14 Argenta Discovery Limited Composés chimiques
WO2008023157A1 (fr) * 2006-08-21 2008-02-28 Argenta Discovery Limited Composés et leur utilisation

Cited By (22)

* 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
US8629271B2 (en) 2008-02-06 2014-01-14 Astrazeneca Ab Compounds
US8148373B2 (en) 2008-02-06 2012-04-03 Astrazeneca Ab Compounds
US8329729B2 (en) 2008-05-13 2012-12-11 Astrazeneca Ab Quinuclidine derivatives as muscarinic M3 receptor antagonists
EP3210981A1 (fr) 2009-04-23 2017-08-30 Theravance Respiratory Company, LLC Composés de diamide contenant une activité d'antagoniste du récepteur muscarinique et d'agoniste du récepteur adrénergique bêta 2
WO2010123766A1 (fr) 2009-04-23 2010-10-28 Theravance, Inc. Composes diamides ayant un antagoniste du recepteur muscarinique et une activite agoniste des recepteurs adrenergiques beta2
US8455483B2 (en) 2009-07-31 2013-06-04 Astrazeneca Ab Compounds—801
US8476265B2 (en) 2009-07-31 2013-07-02 Astrazeneca Ab Compounds-801
WO2011012896A2 (fr) 2009-07-31 2011-02-03 Astrazeneca Ab Composés - 801
WO2011081937A1 (fr) 2009-12-15 2011-07-07 Gilead Sciences, Inc. Composés de type corticostéroïde-bêta-agoniste-antagoniste muscarinique pour applications thérapeutiques
US9643961B2 (en) 2010-05-13 2017-05-09 Almirall, S.A. Cyclohexylamine derivatives having β2 adrenergic antagonist and M3 muscarinic antagonist activities
US9315463B2 (en) 2010-05-13 2016-04-19 Almirall, S.A. Cyclohexylamine derivatives having β2 adrenergic agonist and M3 muscarinic antagonist activities
JP2014519508A (ja) * 2011-06-10 2014-08-14 キエスィ ファルマチェウティチ エス．ピー．エー． ムスカリン受容体拮抗薬及びβ２アドレナリン受容体作動薬活性を有する化合物
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
US9757383B2 (en) 2011-11-11 2017-09-12 Almirall, S.A. Cyclohexylamine derivatives having β2 adrenergic agonist and M3 muscarinic antagonist activities
US10300072B2 (en) 2011-11-11 2019-05-28 Almirall, S.A. Cyclohexylamine derivatives having β2 adrenergic agonist and M3 muscarinic antagonist activities
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

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