WO2008017827A2 - Composés chimiques - Google Patents

Composés chimiques Download PDF

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Publication number
WO2008017827A2
WO2008017827A2 PCT/GB2007/002992 GB2007002992W WO2008017827A2 WO 2008017827 A2 WO2008017827 A2 WO 2008017827A2 GB 2007002992 W GB2007002992 W GB 2007002992W WO 2008017827 A2 WO2008017827 A2 WO 2008017827A2
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WIPO (PCT)
Prior art keywords
hydroxy
alkyl
group
compound
methyl
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PCT/GB2007/002992
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English (en)
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WO2008017827A3 (fr
Inventor
Harry Finch
Richard James Bull
Jonathan Mark Sutton
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Argenta Discovery Limited
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Priority claimed from PCT/GB2006/002956 external-priority patent/WO2007017669A1/fr
Priority claimed from GB0702383A external-priority patent/GB0702383D0/en
Application filed by Argenta Discovery Limited filed Critical Argenta Discovery Limited
Publication of WO2008017827A2 publication Critical patent/WO2008017827A2/fr
Publication of WO2008017827A3 publication Critical patent/WO2008017827A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • 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
    • C07D417/02—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

Definitions

  • This invention relates to oxazole and thiazole derivatives, pharmaceutical compositions, methods for their preparation and use in the treatment of diseases where enhanced M3 receptor activation is implicated.
  • Anti-cholinergic agents prevent the passage of, or effects resulting from the passage of, impulses through the parasympathetic nerves. This is a consequence of the ability of such compounds to inhibit the action of acetylcholine (Ach) by blocking its binding to the muscarinic cholinergic receptors.
  • M1 -M5 muscarinic acetylcholine receptors
  • M1 -M5 muscarinic acetylcholine receptors
  • M3 mAChRs mediate contractile responses (reviewed by Caulfield, 1993, Pharmac. Ther., 58, 319 - 379).
  • muscarinic receptors M1 , M2 and M3 have been demonstrated to be important and are localized to the trachea, the bronchi, submucosal glands and parasympathetic ganglia (reviewed in Fryer and Jacoby, 1998, Am J Resp Crit Care Med., 158 (5 part 3) S 154 - 160).
  • M3 receptors on airway smooth muscle mediate contraction and therefore bronchoconstriction. Stimulation of M3 receptors localised to submucosal glands results in mucus secretion.
  • vagal tone may either be increased (Gross et al. 1989, Chest; 96:984-987) and/or may provoke a higher degree of obstruction for geometric reasons if applied on top of oedematous or mucus-laden airway walls (Gross et al. 1984, Am Rev Respir Dis; 129:856-870).
  • M3 mAChR antagonists may be useful as therapeutics in these mAChR-mediated diseases.
  • Tiotropium (Spiriva TM) is a long-acting muscarinic antagonist currently marketed for the treatment of chronic obstructive pulmonary disease, administered by the inhaled route.
  • ipratropium is a muscarinic antagonist marketed for the treatment of COPD.
  • 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 and other muscarinic antagonists;
  • WO02/060532 describes the combination of ipratropium with ⁇ 2-agonists and
  • WO02/060533 describes the combination of oxotropium with ⁇ 2-agonists.
  • Other M3 antagonist / ⁇ 2-agonist combinations are described in WO04/105759 and WO03/087097.
  • Such bifunctional molecules provide bronchodilation through two separate modes of action whilst possessing single molecule pharmacokinetics.
  • Such a molecule might be easier to formulate for therapeutic use as compared to two separate compounds and might be more easily co-formulated with a third active ingredient, for example a steroid.
  • Such molecules are described in for example, WO04/074246, WO04/089892, WO05/111004, WO06/023457 and WO06/023460, all of which use different linker radicals for covalently linking the M3 antagonist to the ⁇ 2-agonist.
  • R 1 is CrC 6 -alkyl or hydrogen; and R 2 is hydrogen or a group -R 7 , -Z-Y-R 7 , -Z-NR 9 R 10 ; -Z-CO-NR 9 R 10 , -Z-NR 9 -C(O)O-R 7 , or ; -Z-C(O)-R 7 ; and R 3 is a lone pair, or R 3 is C r C 6 -alkyl in which case the nitrogen atom to which it is attached is a quaternary nitrogen and carries a positive charge; or
  • R 1 and R 3 together with the nitrogen to which they are attached form a heterocycloalkyl ring
  • R 2 is a lone pair or R 2 a group -R 7 , -Z-Y-R 7 , -Z-NR 9 R 10 , -Z-CO-NR 9 R 10 , -Z-NR 9 -C(O)O-R 7 ; or -Z-C(O)-R 7 , in which case the nitrogen atom to which it is attached is a quaternary nitrogen and carries a positive charge; or
  • R 1 and R 2 together with the nitrogen to which they are attached form a heterocycloalkyl ring, said ring being substituted by a group -Y-R 7 , -Z-Y-R 7 , -Z- NR 9 R 10 ; -Z-CO-NR 9 R 10 ; -Z-NR 9 -C(O)O-R 7 ; or ; -Z-C(O)-R 7 ; and R 3 is a lone pair, or R 3 is Ci-C 6 -alkyl in which case the nitrogen atom to which it is attached is a quaternary nitrogen and carries a positive charge;
  • R 4 and R 5 are independently selected from the group consisting of aryi, aryl-fused- heterocycloalkyl, heteroaryl, C r C 6 -alkyl, cycloalkyl;
  • R 6 is -OH, C r C 6 -alkyl, C r C 6 -alkoxy hydroxy-C r C 6 -alkyl, nitrile, a group CONR 8 2 or a hydrogen atom;
  • A is an oxygen or a sulfur atom
  • X is a C r C 12 -alkylene, C 2 -C 12 -alkenylene or C 3 -C 12 -alkynylene group;
  • R 7 is an C r C 6 -alkyl, aryl, aryl-fused-cycloalkyl, aryl-fused-heterocycloalkyl, heteroaryl, aryl(CrC 8 -alkyl)-, heteroary ⁇ CrCs-alkyl)-, cycloalkyl or heterocycloalkyl group;
  • R 8 is C r C 6 -alkyl or a hydrogen atom
  • Z is a CrC ⁇ -aikylene, C 2 -C 16 -alkenylene or C 2 -Ci 6 -alkynylene group;
  • Y is a bond or oxygen atom
  • R 9 and R 10 are independently a hydrogen atom, C r C 6 -alkyl, aryl, aryl-fused- heterocycloalkyl, aryl-fused-cycloalkyl, heteroaryl, aryl(CrC 6 -alkyl)-, or heteroaryl(C r C 6 -alkyl)- group; or R 9 and R 10 together with the nitrogen atom to which they are attached form a heterocyclic ring of 4-8 atoms, optionally containing a further nitrogen or oxygen atom;
  • each occurrence of alkyl, heterocycloalkyl, aryl, aryl-fused-heterocycloalkyl, heteroaryl, cycloalkyl, alkoxy, alkylene, alkenylene, alkynylene or aryl-fused-cycloalkyl may be optionally substituted;
  • R 1 is C r C 6 -alkyI
  • R 2 is a group -Z-NR 9 R 10
  • R 3 is a lone pair or R 3 is C r C 6 -alkyl in which case the nitrogen atom to which it is attached is a quaternary nitrogen and carries a positive charge.
  • R groups of the present invention include:
  • R ,10 groups of the present invention include:
  • X is an optionally substituted C 1 -C 3 alkylene group. More conveniently, X is a C 1 -C 2 alkylene group. Most conveniently, X is methylene.
  • each alkyl, heterocycloalkyl, aryl, aryl- fused-heterocycloalkyl, heteroaryl, cycloalkyl, alkoxy, alkylene, alkenylene, alkynylene or aryl-fused-cycloalkyl group of the compounds of fomula (I) is unsubstituted.
  • each alkenylene chain may contain 1 , 2 or 3 carbon-carbon double bonds and each alkynylene chain may contain up to 1 , 2 or 3 carbon-carbon triple bonds.
  • R 1 is CrC 6 -alkyl or hydrogen; and R 2 is a group-Z-NR 9 R 10 ; and R 3 is a lone pair, or R 3 is CrC 6 -a!kyl in which case the nitrogen atom to which it is attached is a quaternary nitrogen and carries a positive charge; or
  • R 1 and R 3 together with the nitrogen to which they are attached form a heterocycloalkyl ring
  • R 2 is a group -Z-NR 9 R 10 , in which case the nitrogen atom to which it is attached is a quaternary nitrogen and carries a positive charge
  • R 1 and R 2 together with the nitrogen to which they are attached form a heterocycloalkyl ring, said ring being substituted by a group , -Z-NR 9 R 10
  • R 3 is a lone pair, or R 3 is C r C 6 -alkyl in which case the nitrogen atom to which it is attached is a quaternary nitrogen and carries a positive charge
  • R 4 and R 5 are independently selected from the group consisting of aryl, aryl-fused- heterocycloalkyl, heteroaryl, C r C 6 -alkyl, cycloalkyl;
  • R 6 is -OH, C r C 6 -alkyl, C r C 6 -alkoxy hydroxy-C r C 6 -alkyl, nitrite, a group CONR 8 2 or a hydrogen atom;
  • A is an oxygen or a sulfur atom
  • X is a C r Ci 2 -alkylene, C 2 -C 12 -alkenylene or C 3 ⁇ C 12 -alkynylene group;
  • R 8 is CrCg-alkyl or a hydrogen atom
  • Z is a C 7 -C 1 i-alkylene, C 7 -C 1 r alkenylene or C 7 -C 1 r alkynylene group;
  • L represents a linker comprising a hydrocarbyl chain of 7 to 11 carbon atoms, wherein the chain may additionally comprise up to three carbon-carbon double bonds, and, wherein the chain may additionally comprise up to three carbon-carbon triple bonds;
  • L 1 and L 2 each independently represent hydrogen, Ci -6 alkyl or C 3-6 cycloalkyl;
  • L 3 and L 4 each independently represent hydrogen, C 1 ⁇ alkyl or C 3 . 6 cycloalkyl, wherein C 1-6 alkyl and C 3-6 cycloalkyl may be optionally substituted by one or more substituents independently selected from halogen and hydroxyl; and * denotes the point of attachement of the group of formula (I) to the non- aromatic nitrogen bearing R 1 and R 3 , and * * denotes the point of attachment to the group NR 9 R 10 ;
  • R 9 is a hydrogen atom or CVC 6 -alkyl
  • R 10 is an aryl(C r C 6 -alkyl)-, or heteroaryl(C r C 6 -alkyl) group, in which the C r C 6 -a!kyl group is optionally substituted by hydroxy;
  • alkyl, heterocycloalkyl, aryl, aryl-fused-heterocycloalkyl, heteroaryl, cycloalkyl, alkoxy, alkylene, alkenylene and alkynylene may be optionally substituted;
  • the present invention provides a prodrug of a compound of formula (Ia) as herein defined, or a pharmaceutically acceptable salt thereof.
  • the present invention provides an N-oxide of a compound of formula (Ia) 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 (Ia) as herein defined, or an N-oxide, prodrug or pharmaceutically acceptable salt thereof.
  • R 1 is Ci-C ⁇ -alkyl ;
  • R 2 is a group -Z-NR 9 R 10 and R 3 is a lone pair or
  • R 3 is C r C 6 -alkyl, in which case the nitrogen atom to which it is attached is a quaternary nitrogen and carries a positive charge, or
  • R 1 and R 2 together with the nitrogen to which they are attached represent a heterocycloalkyl ring, said ring being substituted by a group -Z-NR 9 R 10 and R 3 is a lone pair or R 3 is C r C 6 -alkyl in which case the nitrogen atom to which it is attached is a quaternary nitrogen and carries a positive charge; or R 1 and R 3 together with the nitrogen to which they are attached represent a heterocycloalkyl ring, and R 2 is a group -Z-NR 9 R 10 in which case the nitrogen atom to which it is attached is a quaternary nitrogen and carries a positive charge;
  • R 4 is phenyl and R 5 is selected from the group consisting of aryl, heteroaryl, C 1 -C 6 - alkyl, cycloalkyl; or R 4 and R 5 are both heteroaryl;
  • R 6 is -OH or, C r C 6 -alkyl
  • R 8 is a hydrogen atom
  • A is an oxygen or a sulfur atom
  • X is a C r C 2 -alkylene group
  • Z is a divalent linker radical of formula (A):
  • L represents a linker comprising a hydrocarbyl chain of 7 to 11 carbon atoms, wherein the chain may additionally comprise up to three carbon-carbon double bonds, and, wherein the chain may additionally comprise up to three carbon-carbon triple bonds;
  • L 1 and L 2 each independently represent hydrogen, C 1-6 alkyl or C 3 . 6 cycloalkyl
  • 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; and * denotes the point of attachement of the group of formula (I) to the non- aromatic nitrogen bearing R 1 and R 3 , and * * denotes the point of attachment to the group NR 9 R 10 ;
  • R 9 is a hydrogen atom; and R 10 is selected from the group
  • the present invention provides a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, wherein R 1 is Ci-C 6 -alkyl; R 2 is a group -Z- NR 9 R 10 ; and R 3 is a lone pair or R 3 is a C r C 6 -alkyl in which case the nitrogen atom to which it is attached is a quaternary nitrogen and carries a positive charge.
  • the present invention provides compounds of formula (Ia) wherein the carbon to which R 4 , R 5 and R 6 are attached has the (R)- absolute configuration.
  • the present invention provides compounds of formula (Ia) wherein the non-aromatic nitrogen shown in formula (Ia) is a tertiary nitrogen.
  • the present invention provides quaternary ammonium salts of formula (Ia) wherein the non-aromatic nitrogen shown in formula (Ia) is quaternary nitrogen, carrying a positive charge.
  • the present invention provides a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 are independently selected from methyl, ethyl, n- or isopropyl, n-, sec- and tertbutyl; phenyl, 3,4- methylenedioxyphenyl, 3,4-ethylenedioxyphenyl, dihydrobenzofuranyl, naphthyl; pyridyl, pyrrolyl, pyrimidinyl, oxazolyl, isoxazolyl, benzisoxazolyl, benzoxazolyl, thiazolyl, benzthiazolyl, quinolyl, thienyl, benzthienyl, furyl, benzfuryl, imidazolyl, benzimidazolyl, isothiazolyl, benzisothiazolyl, pyrazolyl, isothiazolyl, triazolyl, benztriazo
  • the present invention provides a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, wherein (i) each of R 4 and R 5 is thienyl; or (ii) each of R 4 and R 5 is phenyl; or (iii) one of R 4 and R 5 is phenyl and the other is cyclopentyl or cyclohexyl; or (iv) one of R 4 and R 5 is thienyl, and the other is cyclopentyl or cyclohexyl.
  • the present invention provides a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, wherein R 6 is -OH.
  • the present invention provides a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, wherein R 8 is hydrogen.
  • the present invention provides a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, wherein R 10 is selected from:
  • the present invention provides a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, wherein A is an oxygen atom.
  • the present invention provides a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, wherein X is -CH 2 - or -CH 2 CH 2 -.
  • Compounds of the invention may be useful in the treatment or prevention of diseases in which activation of muscarinic receptors are implicated, for example the present compounds are useful for treating a variety of indications, including but not limited to respiratory-tract disorders such as chronic obstructive lung disease, chronic bronchitis of all types (including dyspnoea associated therewith), asthma (allergic and non-allergic; 'whez-infant syndrome'), adult/acute respiratory distress syndrome (ARDS), chronic respiratory obstruction, bronchial hyperactivity, pulmonary fibrosis, pulmonary emphysema, and allergic rhinitis, exacerbation of airway hyperreactivity consequent to other drug therapy, particularly other inhaled drug therapy, pneumoconiosis (for example aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis); gastrointestinal-tract
  • quaternary ammonium salts of the invention administered by inhalation is may be more than 12, or more than 24 hours for a typical dose.
  • parenteral route usually the oral route, may be preferred.
  • Another aspect of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention as shown in formula (Ia) and a pharmaceutically acceptable carrier 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 is implicated.
  • Acyl means a -CO-alkyl group in which the alkyl group is as described herein.
  • exemplary acyl groups include -COCH 3 and -COCH(CH 3 ) 2 .
  • Acylamino means a -NR-acyl group in which R and acyl are as described herein.
  • Exemplary acylamino groups include -NHCOCH 3 and -N(CH 3 )COCH 3 .
  • Alkoxy and “alkyloxy” means an -O-alkyl group in which alkyl is as described below.
  • Exemplary alkoxy groups include methoxy (-OCH 3 ) and ethoxy (-OC 2 H 5 ).
  • Alkoxycarbonyl means a -COO-alkyl group in which alkyl is as defined below.
  • Exemplary alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl.
  • Alkyl as a group or part of a group refers to a straight or branched chain saturated hydrocarbon group having from 1 to 12, preferably 1 to 6, carbon atoms, in the chain.
  • exemplary alkyl groups include methyl, ethyl, 1 -propyl and 2-propyl.
  • Alkenyl as a group or part of a group refers to a straight or branched chain hydrocarbon group having from 2 to 12, preferably 2 to 6, carbon atoms and one carbon-carbon double bond in the chain.
  • Exemplary alkenyl groups include ethenyl, 1-propenyl, and 2-propenyl.
  • Alkylamino means a -NH-alkyl group in which alkyl is as defined above.
  • exemplary alkylamino groups include methylamino and ethylamino.
  • Alkylene means an -alkyl- group in which alkyl is as defined previously.
  • exemplary alkylene groups include -CH 2 -, -(CH 2 ) 2 - and -C(CH 3 )HCH 2 -.
  • Alkenylene means an -alkenyl- group in which alkenyl is as defined previously.
  • Alkynylene means an -alkynyl- group in which -alkynyl- refers to a straight or branched chain hydrocarbon group having from 2 to 12, preferably 2 to 6, carbon atoms and one carbon-carbon triple bond in the chain.
  • exemplary alkynylene groups include ethynyl and propargyl.
  • Alkylsulfinyl means a -SO-alkyl group in which alkyl is as defined above.
  • alkylsulfinyl groups include methylsulfinyl and ethylsulfinyl.
  • Alkylsulfonyl means a -SO 2 -alkyl group in which alkyl is as defined above.
  • Exemplary alkylsulfonyl groups include methylsulfonyl and ethylsulfonyl.
  • Alkylthio means a -S-alkyl group in which alkyl is as defined above.
  • exemplary alkylthio groups include methylthio and ethylthio.
  • Aminoacyl means a -CO-NRR group in which R is as herein described.
  • Exemplary aminoacyl groups include -CONH 2 and -CONHCH 3 .
  • Aminoalkyl means an alkyl-NH 2 group in which alkyl is as previously described.
  • exemplary aminoalkyl groups include -CH 2 NH 2 .
  • aminosulfonyl means a -SO 2 -NRR group in which R is as herein described.
  • exemplary aminosulfonyl groups include -SO 2 NH 2 and -SO 2 NHCH 3 .
  • Aryl as a group or part of a group denotes an optionally substituted monocyclic or multicyclic aromatic carbocyclic moiety of from 6 to 14 carbon atoms, preferably from 6 to 10 carbon atoms, such as phenyl or naphthyl.
  • the aryl group may be substituted by one or more substituent groups.
  • Arylalkyl means an aryl-alkyl- group in which the aryl and alkyl moieties are as previously described. Preferred arylalkyl groups contain a C 1 4 alkyl moiety.
  • arylalkyl groups include benzyl, phenethyl and naphthlenemethyl.
  • Arylalkyloxy means an aryl-alkyloxy- group in which the aryl and alkyloxy moieties are as previously described. Preferred arylalkyloxy groups contain a C 1 4 alkyl moiety. Exemplary arylalkyl groups include benzyloxy.
  • 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, preferably from 3 to 8 carbon atoms, and more preferably from 3 to 6 carbon atoms.
  • Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • the cycloalkyl group may be substituted by one or more substituent groups.
  • Dialkylamino means a -N(alkyl)2 group in which alkyl is as defined above.
  • dialkylamino groups include dimethylamino and diethylamino.
  • Halo or halogen means fluoro, chloro, bromo, or iodo. Preferred are fluoro or chloro.
  • Haloalkoxy means an -O-alkyl group in which the alkyl is substituted by one or more halogen atoms. Exemplary haloalkyl groups include trifluoromethoxy and difluoromethoxy.
  • Haloalkyl means an alkyl group which is substituted by one or more halo atoms. Exemplary haloalkyl groups include trifiuoromethyl.
  • Heteroaryl as a group or part of a group denotes an optionally substituted aromatic monocyclic or multicyclic organic moiety of from 5 to 14 ring atoms, preferably from 5 to 10 ring atoms, in which one or more of the ring atoms is/are element(s) other than carbon, for example nitrogen, oxygen or sulfur.
  • Examples of such groups include benzimidazolyl, benzoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, furyl, imidazolyl, indolyl, indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl, oxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyi, 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.
  • ⁇ eteroarylalkyl means a heteroaryl-alkyl- group in which the heteroaryl and alkyl moieties are as previously described.
  • Preferred heteroarylalkyl groups contain a lower alkyl moiety.
  • Exemplary heteroarylalkyl groups include pyridylmethyl.
  • Heteroarylalkyloxy means a heteroaryl-alkyloxy- group in which the heteroaryl and alkyloxy moieties are as previously described.
  • Preferred heteroarylalkyloxy groups contain a lower alkyl moiety.
  • Exemplary heteroarylalkyloxy groups include pyridylmethyloxy.
  • Heteroaryloxy means a heteroaryloxy- group in which the heteroaryl is as previously described.
  • Exemplary heteroaryloxy groups include pyridyloxy.
  • 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 and CONRCO (examples of such groups include succinimidyl and 2-oxopyrrolidinyl).
  • the 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.
  • “Lower alkyl” as a group means unless otherwise specified, an aliphatic hydrocarbon group which may be straight or branched having 1 to 4 carbon atoms in the chain, i.e. methyl, ethyl, propyl (propyl or /so-propyl) or butyl (butyl, /so-butyl or tert- butyl).
  • Sulfonyl means a -SO 2 -alkyl group in which alkyl is as described herein.
  • exemplary sulfonyl groups include methanesulfonyl.
  • “Sulfonylamino” means a -NR-sulfonyl group in which R and sulfonyl are as described herein.
  • Exemplary sulfonylamino groups include -NHSO 2 CH 3 .
  • R means alkyl, aryl, or heteroaryl as described herein.
  • “Pharmaceutically acceptable salt” means a physiologically or toxicologically tolerable salt and includes, when appropriate, pharmaceutically acceptable base addition salts, pharmaceutically acceptable acid addition salts, and pharmaceutically acceptable quaternary ammonium salts.
  • pharmaceutically acceptable base addition salts that may be formed include sodium, potassium, calcium, magnesium and ammonium salts, or salts with organic amines, such as, diethylamine, ⁇ /-methyl-glucamine, diethanolamine or amino acids (e.g.
  • a compound of the invention contains a basic group, such as an amino group
  • pharmaceutically acceptable acid addition salts that may be formed include hydrochlorides, hydrobromides, sulfates, phosphates, acetates, citrates, lactates, tartrates, mesylates, napadisylates (naphthalene- 1 ,5-disulfonates or naphthalene-1 -(sulfonic acid)-5-sulfonates), edisylates (ethane-1 ,2-disulfonates or ethane-1 -(sulfonic acid)-2-sulfonates), maleates, fumarates, succinates and the like; (iii) where a compound contains a quaternary ammonium group acceptable counter- ions may be, for example, chlorides, bromides, sulfates, methanesulfonates, benzenes
  • 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)
  • cyclic groups referred to above namely, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aryl-fused-heterocycloalkyl and cyclic amine may be substituted by one or more substituent groups.
  • Suitable optional substituent groups include acyl (e.g. -COCHJ, alkoxy (e.g., -OCHJ, alkoxycarbonyl (e.g. -COOCHJ, alkylamino (e.g.
  • alkylsulfinyl e.g. -SOCH 3
  • alkylsulfonyl e.g. -SO 2 CH 3
  • alkylthio e.g. - SCH 3
  • -NH 2 aminoacyl (e.g. -CON(CHs) 2 ), aminoalkyl (e.g. -CH 2 NH 2 ), arylalkyl (e.g. -CH Ph or -CH -CH -Ph), cyano, dialkylamino (e.g. -N(CHJJ, halo, haloalkoxy (e.g.
  • haloalkyl e.g. -CF 3
  • alkyl e.g. -CH 3 Or -CH 2 CH 3
  • -OH, -CHO, - NO 2 aryl (optionally substituted with alkoxy, haloalkoxy, halogen, alkyl or haloalkyl), heteroaryl (optionally substituted with alkoxy, haloalkoxy, halogen, alkyl or haloalkyl), heterocycloalkyl, aminoacyl (e.g. -CONH 2 , -CONHCH 3 ), aminosulfonyl (e.g.
  • acylamino e.g. -NHCOCH 3
  • sulfonylamino e.g. -NHSO 2 CH 3
  • heteroarylalkyl cyclic amine (e.g. morpholine), aryloxy, heteroaryloxy, arylalkyloxy (e.g. benzyloxy) and heteroarylalkyloxy.
  • Alkyl, alkoxy, alkylene or alkenylene groups may be optionally substituted. Suitable optional substituent groups include alkoxy (e.g., -OCH 3 ), alkylamino (e.g. -NHCH 3 ), alkylsulfinyl (e.g. -SOCHJ, alkylsulfonyl (e.g. -SO 0 CHJ, alkylthio (e.g. -SCHJ, -NH 2 , aminoalkyl (e.g. -CH 2 NH 2 ), arylalkyl (e.g. -CH 2 Ph or -CH 2 -CH 3 -Ph), cyano, dialkylamino (e.g.
  • halo haloalkoxy (e.g. -OCF 3 or -OCHF 2 ), haloalkyl (e.g. -CFJ, alkyl (e.g. -CH or -CH 0 CH ), -OH, -CHO, and -NO 2 .
  • Compounds of the invention may exist in one or more geometrical, optical, enantiomeric, diastereomeric and tautomeric forms, including but not limited to cis- and frans-forms, £- 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).
  • Convenient compounds of the invention include:
  • the present invention is also concerned with pharmaceutical formulations comprising, as an active ingredient, a compound of the invention.
  • Other compounds may be combined with compounds of this invention for the prevention and treatment of inflammatory diseases of the lung.
  • the present invention is also concerned with pharmaceutical compositions for preventing and treating respiratory-tract disorders such as chronic obstructive lung disease, chronic bronchitis, asthma, chronic respiratory obstruction, pulmonary fibrosis, pulmonary emphysema, and allergic rhinitis comprising a therapeutically effective amount of a compound of the invention and one or more other therapeutic agents.
  • the invention includes a combination of an agent of the invention as hereinbefore described with one or more anti-inflammatory, bronchodilator, antihistamine, decongestant or anti-tussive agents, said agents of the invention hereinbefore described and said combination agents existing in the same or different pharmaceutical compositions, administered separately or simultaneously.
  • Preferred combinations would have two or three different pharmaceutical compositions.
  • Suitable therapeutic agents for a combination therapy with compounds of the invention include: One or more other bronchodilators such as PDE3 inhibitors; Methyl xanthines such as theophylline;
  • a corticosteroid for example fluticasone propionate, ciclesonide, mometasone furoate or budesonide, or steroids described in WO02/88167, WO02/12266, WO02/100879, WO02/00679, WO03/35668, WO03/48181 , WO03/62259, WO03/64445, WO03/72592, WO04/39827 and WO04/66920;
  • a non-steroidal glucocorticoid receptor agonist for example fluticasone propionate, ciclesonide, mometasone furoate or budesonide, or steroids described in WO02/88167, WO02/12266, WO02/100879, WO02/00679, WO03/35668, WO03/48181 , WO03/62259, WO03/64445, WO03/72592, WO04/39827 and WO04/66920;
  • a leukotriene modulator for example montelukast, zafirlukast or pranlukast; protease inhibitors, such as inhibitors of matrix metalloprotease for example MMP12 and TACE inhibitors such as marimastat, DPC-333, GW-3333; Human neutrophil elastase inhibitors, such as sivelestat and those described in WO04/043942, WO05/021509, WO05/021512, WO05/026123, WO05/026124, WO04/024700, WO04/024701 , WO04/020410, WO04/020412, WO05/080372,
  • Phosphodiesterase-4 (PDE4) inhibitors for example roflumilast, arofylline, cilomilast,
  • An antitussive agent such as codeine or dextramorphan
  • P2X7 anatgonists P2X7 anatgonists; iNOS inhibitors; A non-steroidal anti-inflammatory agent (NSAID), for example ibuprofen or ketoprofen;
  • NSAID non-steroidal anti-inflammatory agent
  • a dopamine receptor antagonist A dopamine receptor antagonist
  • TNF- ⁇ inhibitors for example anti-TNF monoclonal antibodies, such as Remicade and CDP-870 and TNF receptor immunoglobulin molecules, such as Enbrel; A2a agonists such as those described in EP1052264 and EP1241176;
  • A2b antagonists such as those described in WO2002/42298;
  • Modulators of chemokine receptor function for example antagonists of CCR1 , CCR2,
  • DP1 or CRTH2 a thromboxane A 2 antagonist eg ramatrobant
  • Th1 or Th2 function Compounds which modulate Th1 or Th2 function, for example, PPAR agonists; lnterleukin 1 receptor antagonists, such as Kineret; lnterleukin 10 agonists, such as llodecakin; HMG-CoA reductase inhibitors (statins); for example rosuvastatin, mevastatin, lovastatin, simvastatin, pravastatin and fluvastatin;
  • Mucus regulators such as INS-37217, diquafosol, sibenadet, CS-003, talnetant, DNK-
  • Antiinfective agents antibiotic or antiviral
  • antiallergic drugs including, but not limited to, anti-histamines.
  • the weight ratio of the first and second active ingredients may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dosage of a compound of the present invention. In therapeutic use, the active compound may be administered by any convenient, suitable or effective route. Suitable routes of administration are known to those skilled in the art, and include oral, intravenous, rectal, parenteral, topical, ocular, nasal, buccal and pulmonary.
  • prophylactic or therapeutic dose of a compound of the invention will, of course, vary depending upon a range of factors, including the activity of the specific compound that is used, the age, body weight, diet, general health and sex of the patient, time of administration, the route of administration, the rate of excretion, the use of any other drugs, and the severity of the disease undergoing treatment.
  • the daily dose range for inhalation will lie within the range of from about 0.1 ⁇ g to about 10 mg per kg body weight of a human, preferably 0.1 ⁇ g to about 0.5 mg per kg, and more preferably 0.1 ⁇ g to 50 ⁇ g per kg, in single or divided doses. On the other hand, it may be necessary to use dosages outside these limits in some cases.
  • compositions suitable for administration by inhalation are known, and may include carriers and/or diluents that are known for use in such compositions.
  • the composition may contain 0.01-99% by weight of active compound.
  • a unit dose comprises the active compound in an amount of 1 ⁇ g to 10 mg.
  • suitable doses are 10 ⁇ g per kg to 100mg per kg, preferably 40 ⁇ g per kg to 4 mg per kg.
  • compositions which comprise a compound of the invention and a pharmaceutically acceptable carrier.
  • composition as in pharmaceutical 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.
  • 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.
  • a large number of systems are available with which aerosols of optimum particle size can be generated and administered, using an inhalation technique which is appropriate for the patient.
  • adaptors spacers, expanders
  • pear-shaped containers e.g. Nebulator®, Volumatic®
  • automatic devices emitting a puffer spray Autohaler®
  • metered aerosols in particular in the case of powder inhalers
  • 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 (Ia) 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 4 , R 5 , R 6 , 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
  • compounds of formula (III) represent compounds HNR 9 R 10 wherein R 9 and R 10 are as described above for compounds of formula (I) or (Ia), and P 1 is hydrogen or a protective group such as te/t-butyldimethyl silyl in the presence of a base such as potassium carbonate, triethyiamine or diisopropylethylamine, followed by removal of the protective group (e.g. using a hydrofluoric acid-pyridine complex); or (b) when L 1 represents hydrogen and R 1 does not represent hydrogen, reacting a compound of formula (IV), or a suitable salt thereof
  • L, L 2 , L 3 , L 4 , R 4 , R 5 , R 6 R 8 and X are as defined in formula (Ia), with a compound of formula (III) or a suitable salt thereof in the presence of a suitable reducing agent such as sodium cyanoborohydride, sodium triacetoxyborohydride, or hydrogen in the presence of a suitable palladium on carbon or platinum oxide catalyst; or
  • LG 1 represents a leaving group such as chloride, bromide, iodide, methanesulfonate or para-toluenesulfonate
  • P 2 represents a protective group (e.g. tert-butylcarbonyl)
  • L, L 2 , L 3 , L 4 , R 4 , R 5 , R 6 , R 8 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
  • R 4 when R 4 does not represent hydrogen, reacting a compound of formula (VII), or a suitable salt thereof wherein L 1 L 1 , L 2 , L 3 , L 4 , R 4 , R 5 , R 6 , R 8 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,
  • an activating group e.g. 3-nitrophenylsulfonyl
  • LG 2 represents a leaving group (e.g. chloride, bromide, iodide, methanesulfonate or para-toluenesulfonate) and P 1 is as defined in compound of formula (III) in the presence of a base (e.g. when P 3 is hydrogen, potassium carbonate, triethylamine, diisopropylethylamine and, when P 3 is 3-nitrophenylsulfonyl, sodium hydride or lithium di-/so-propylamide), followed by removal of the protective groups (e.g. using hydrofluoric acid-pyridine complex, thiophenol, thioacetic acid); or with a compound of formula (IX), or a suitable salt thereof,
  • a base e.g. when P 3 is hydrogen, potassium carbonate, triethylamine, diisopropylethylamine and, when P 3 is 3-nitrophenylsulfonyl, sodium hydride or lithium di-/so-
  • 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- nitropheny
  • L, L 1 , L 2 , L 3 , L 4 , R 4 , R 5 , R 6 , R 8 and X are as defined in formula (Ia),
  • P 2 represents a protective group (e.g. tert-butylcarbonyl)
  • P 3 represents hydrogen or an activating group (e.g. 3-nitrophenylsulfonyl)
  • ith a compound of formula (VIII), (IX) or (X), or a suitable salt thereof, in the presence of a base (e.g.
  • 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-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 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-butylcarbonyl or 3- nitrophenylsulfonoyl), LG 3 represents a leaving group (e.g. chloride, bromide, iodide, methanesulfonate or para-toluenesulfonate), with a compound of formula (XIII) or a suitable salt thereof, in the presence of a base (e.g. potassium carbonate, triethylamine, diisopropylethylamine), followed by removal of the protective groups (e.g. trifluoroacetic acid, thiophenol, thioacetic acid); or (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, triethy
  • L, L 3 , L 4 , R 1 , R 4 , R 5 R 6 , R 8 , A, 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
  • the reaction may conveniently be carried out in an organic solvent such as ⁇ /, ⁇ /-dimethylformamide, ethanol, n-butanol or dimethyl sulfoxide, at a temperature, for example, in the range from 50 to 140 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
  • Compounds of formula (II) may be prepared by reacting a compound of formula (XVII), or a suitable salt thereof,
  • L Mt (XVlK) wherein L 2 is as defined in formula (II) and Mt represents a metal such as lithium or magnesium, or aluminium or boron (e.g. methyllithium, methylmagnesium bromide, lithium aluminium hydride, sodium borohydride) in an organic solvent, for example, tetrahydrofuran or ether, at a temperature, for example in the range from 0 to 6O 0 C, followed by conversion of the resulting hydroxyl group into a suitable leaving group (e.g. chloride, bromide, iodide, methanesulfonate or para-toluenesulfonate).
  • a suitable leaving group e.g. chloride, bromide, iodide, methanesulfonate or para-toluenesulfonate.
  • Compounds of formula (IV) may be prepared by reacting a compound of formula (XVII) with a compound of formula (XVIII) in an organic solvent, for example, tetrahydrofuran or ether, at a temperature, for example in the range from 0 to 6O 0 C, followed by oxidation of the resulting hydroxyl group with a suitable 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
  • P 2 , L, L 3 , L 4 , R 4 , R 5 , R 6 , R 8 , A, 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 60 0 C, followed by conversion of the resulting hydroxyl group into a suitable leaving group (e.g. chloride, bromide, iodide, methanesulfonate or para-toluenesulfonate).
  • an organic solvent for example, tetrahydrofuran or ether
  • Compounds of formula (Vl) may be prepared by reacting a compound of formula (XVIII) with a compound of formula (XIX), followed by oxidation of the resulting hydroxyl group with a suitable oxidating agent (e.g. Swern reagent, Dess-Martin reagent or pyridiniumchlorochromate) in an organic solvent such as dichloromethane, ⁇ /, ⁇ /-dimethylformamide or dimethylsulfoxide at a temperature, for example in the range from -78 to 6O 0 C.
  • a suitable oxidating agent e.g. Swern reagent, Dess-Martin reagent or pyridiniumchlorochromate
  • an organic solvent such as dichloromethane, ⁇ /, ⁇ /-dimethylformamide or dimethylsulfoxide at a temperature, for example in the range from -78 to 6O 0 C.
  • Compounds of formula (VII) in which L 1 represents hydrogen and L, L 2 , L 3 , L 4 , R 1 , R 4 , R 5 , R 6 , R 8 , A, and X are as defined in formula (VII) may be prepared by (a) reacting a compound of formula (II) with sodium azide, in an organic solvent for example, tetrahydrofuran, ⁇ /, ⁇ /-dimethylformamide or dimethylsulfoxide at a temperature, for example in the range from 25 to 85 0 C, followed by reduction of the resulting azido compound using a suitable reducing agent (e.g.
  • triphenylphosphine in an organic solvent for example, tetrahydrofuran and water, and eventually followed by protection of the resulting amine (e.g. treatment with 3-nitrophenylsulfonyl chloride in the presence of a base such as pyridine); or, (b) reacting a compound of formula (IV) with an amine (e.g. benzylamine, ⁇ -methyl benzylamine, 4-methoxybenzylamine or 2,4-methoxybenzylamine) followed by reduction of the resulting imine using a suitable reducing agent (e.g.
  • sodium cyanoborohydride or sodium triacetoxyborohydride in an organic solvent such as methanol, ethanol, dichloromethane, acetic acid, ⁇ /-methylpyrolidinone or N, N- dimethylformamide containing up to 10%w of water and acetic acid, followed by removal of the resulting benzyl protective group using the appropriate reagent (e.g.
  • a suitable catalyst Palladium on carbon or palladium hydroxide
  • DDQ 2,3- dichloro-5,6-dicyanobenzoquinone
  • CAN ammonium cerium nitrate
  • an organic solvent for example, ethanol, methanol, tetrahydrofuran, dichloromethane, acetonitrile, water, or a mixture thereof, at a temperature ranging from 25 to 80 0 C, and eventually followed by protection of the resulting amine (e.g. treatment with 3- nitrophenylsulfonyl chloride in the presence of a base such as pyridine);
  • LG 4 is a leaving group (e.g. hydroxyl or chloride), L, L 1 , L 2 , L 3 , L 4 , R 1 , R 4 , R 5 , R 6 , R 8 , A, 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, fert-butanol, tetrahydrofuran, dichloromethane, water, or a mixture thereof, at a temperature ranging from 25 to 100°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 0 C (Angewandte Chemie, 2005, 54, 5188), eventually followed by protection of the resulting amine (e.g. treatment with 3-nitrophenylsuifonyl chloride in the presence of a base such as pyridine).
  • a base such as pyridine
  • Compounds of formula (Xl) in which L 1 represents hydrogen may be prepared by (a) reacting a compound of formula (V) with sodium azide in an organic solvent, for example, tetrahydrofuran, ⁇ /, ⁇ /-dimethylformamide or dimethylsulfoxide at a temperature, for example in the range from 25 to 85 0 C, followed by reduction of the resulting azido compound using a suitable reducing agent (e.g. triphenylphosphine or hydrogen) in an organic solvent for example, tetrahydrofuran and water, eventually followed by protection of the resulting amine (e.g.
  • a suitable reducing agent e.g. triphenylphosphine or hydrogen
  • a compound of formula (Vl) with an amine (e.g. benzylamine, a- methyl benzylamine, 4-methoxybenzyl amine or 2,4-methoxybenzyl amine), followed by reduction of the resulting imine using a suitable reducing agent (e.g.
  • a suitable catalyst Palladium on carbon or palladium hydroxide
  • 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, 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.
  • 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) in 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 0 C.
  • 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 0 C.
  • 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.
  • 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, ⁇ /-methypyrolidinone or /V, ⁇ /-dimethylformamide containing up to 10%w of water and acetic acid, followed by removal of the protective group (e.g. diluted hydrochloric acid or amberlyst-15 resin in methanol).
  • Compounds of formula (XIV) 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, 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 (111), or a suitable salt thereof.
  • the reaction is conveniently carried out in the presence of an activating reagent, for example, carbonyldiimidazole or O-(7- azabenzotriazol-1 -yl)- ⁇ /, ⁇ /, ⁇ /', ⁇ /-tetramethyluroniumhexafluorophosphate (HATU), in an organic solvent, for example, ⁇ /, ⁇ /-dimethylformamide or dichloromethane, at a temperature, for example in the range from 0 to 6O 0 C
  • an activating reagent for example, carbonyldiimidazole or O-(7- azabenzotriazol-1 -yl)- ⁇ /, ⁇ /, ⁇ /', ⁇ /-tetramethyluroniumhexafluorophosphate (HATU)
  • an organic solvent for example, ⁇ /, ⁇ /-dimethylformamide or dichloromethane
  • LG 6 represents chloride
  • the reaction is conveniently carried out in the presence of a base, for example, trieth
  • LG 7 represent a hydroxyl, an esther (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 te/f-butoxycarbonyl, followed by suitable deprotection (e.g. trifluoroacetic acid acid);
  • P 9 represents R 4
  • P 10 represents
  • L, L 3 , and L 4 are as defined in compound of formula (XVII), wherein P 11 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 11 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 9 represents P 2
  • P 10 represents wherein L, L 3 , and L 4 are as defined in compound of formula (XIX) 1 wherein P 11 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);
  • 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 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);
  • 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 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
  • R in compounds of formula (I) or (Ia) is a group of formula it will be recognised by those skilled in the art that a similar set of reactions as described above may be used, employing a compound of formula (Ilia) in place of a compound of formula (III), optionally suitably protected, or a suitable salt thereof such as a hydrobromide, hydrochloride or acetate salt
  • R 5 M (XLVI) wherein R 4 and R 5 are as defined in general formula (I) and 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, preferably between -78 0 C and the reflux temperature of the solvent.
  • R 1 is as defined in general formula (I).
  • the reaction is performed in a range of solvents, preferably THF/DCM at a range of temperatures, preferably between 0 and 100 0 C.
  • reaction by reaction with a brominating agent such as N-bromosuccinimide in the presence of a radical initiator such as AIBN or benzoyl peroxide.
  • a brominating agent such as N-bromosuccinimide
  • a radical initiator such as AIBN or benzoyl peroxide.
  • the reaction can be carried out in suitable solvents, such as CCI 4 , or chlorobenzene at a range of temperatures, preferably between ambient temperature and the reflux temperature of the solvent.
  • compounds of formula (XXXI) can be prepared from compounds of general formula (XXX) 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.
  • Compounds of general formula (XLV) can be prepared from compounds of formula (XLIII) using methods described above for the preparation of compounds of formula (XXX) from compounds of formula (XXIX).
  • Compounds of formula (Xll-a) wherein -NR 1 R 3 is a secondary amine may be prepared from compounds of formula (Xll-a) wherein -NR 1 R 3 is a -NH 2 group by reductive alkylation with a suitably substituted aldehyde.
  • the reaction is carried out in the presence of a reducing agent such as sodium cyanoborohydride or sodium borohydride, preferably sodium triacetoxyborohydride in a range of organic solvents, preferably dichloroethane.
  • Compounds of formula (Xll-e) may be prepared from compounds of formula (Xll-d) by alkylation or reductive alkylation methods as described above and according to standard methods well-known to those skilled in the art.
  • Compounds of formula (Xll-d) can be prepared from compounds of general formula (XXXV):
  • a reducing agent such as lithium aluminium hydride, diisobutyl aluminium hydride, or borane in a range of aprotic solvents such as diethyl ether, or THF or preferably by hydrogenation in the presence of a catalyst such as Raney Nickel in a suitable solvent such as EtOAc or EtOH at a range of temperatures from room temperature to the reflux temperature of the solvent.
  • Compounds of general formula (XXXV) can be prepared from compounds of general formula (XXVI l-a) by reaction with a source of cyanide ion such as acetone cyanohydrin or an inorganic cyanide, preferably sodium cyanide, in the presence of a non-nucleophilic base such as tetramethyl guanidine, in a range of solvents, preferably ethanol, at a range of temperatures, preferably between ambient temperature and the reflux temperature of the solvent.
  • a source of cyanide ion such as acetone cyanohydrin or an inorganic cyanide, preferably sodium cyanide
  • a non-nucleophilic base such as tetramethyl guanidine
  • Compounds of formula (Xlll-c) can be prepared from compounds of formula (Xlll-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 (Xlll-b) can be prepared from compounds of formula (Xlll-a) by reaction with an alkylating agent of formula (XLVIII):
  • R f is a C 1-6 alkyl group and Y 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.
  • a base such as sodium hydride
  • a solvent such as THF from O 0 C to the reflux temperature of the solvent.
  • Compounds of general formula (Xlll-h) can be prepared from compounds of formula (Xlll-g) using methods described above for the preparation of compounds of formula (Xlll-e) from compounds of formula (Xlll-d).
  • Compounds of general formula (Xlll-g) can be prepared from compounds of formula (XXXIX) using methods described above for the preparation of compounds of formula (Xlll-d) from compounds of formula (XXXV).
  • Compounds of general formula (Xlll-f) can be prepared from compounds of formula (XXVII-b) using methods described above for the preparation of compounds of formula (Xlll-a) from compounds of formula (XXVII-a).
  • Compounds of general formula (XXVII-b) can be prepared from compounds of formula (XXXVIII) using methods described above for the preparation of compounds of formula (XXXIl) from compounds of formula (XXXI).
  • Compounds of Formula (LII) may be prepared from compounds of Formula (L) by employing a similar sequence of reactions as used to prepare compounds of Formula (Xlll-a) from compounds of Formula (XXXIV) in Scheme 1 above.
  • Compounds of formula (L) wherein R 4 and R 5 are the same may be prepared from compounds of Formula (XLIX) 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 (L) wherein R 4 and R 5 are dissimilar may be prepared from compounds of Formula (XLIX) by converting to an intermediate amide, preferably 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) or (Ia).
  • such intermediate compounds are selected from the group including 5-[(R)-1-(tert-butyl ⁇ dimethyl-silanyloxy)-2-(9- ⁇ [2-(cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]- methyl-amino ⁇ -nonylamino)-ethyl]-8-hydroxy-1 H-quinolin-2-one; 5-[(R)-1-(tert-butyl- dimethyl-silanyloxy)-2-(9- ⁇ [2-(hydroxy-diphenyl-methyl)-oxazol-5-ylmethyl]-methyl- amino ⁇ -nonylamino)-ethyl]-8-(4-methoxy-benzyloxy)-1 /-/-quinolin-2-one; 5-[(R)-1 - hydroxy-2-(9- ⁇ [2-(hydroxy-)-(
  • such intermediate compounds are selected from the group including 5-[(f?)-1 -(tert-butyl-dimethyl-silanyloxy)-2-(9- ⁇ [2-(hydroxy-diphenyl- methyl)-oxazol-5-ylmethyl]-methyl-amino ⁇ -nonylamino)-ethyl]-8-(4-methoxy- benzyloxy)-1 H-quinolin-2-one; 5-[(R)-1 -hydroxy-2-(9- ⁇ [2-(hydroxy-diphenyl-methyl)- oxazol-5-ylmethyl]-methyl-amino ⁇ -nonylamino)-ethyl]-8-(4-methoxy-benzyloxy)-1 H- quinolin-2-one; and [2-(hydroxy-diphenyl-methyl)-oxazol-5-ylmethyl]-dimethyl-(9-oxo- nonyl)-ammonium bromide.
  • the compounds of formula (I) and (Ia) 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) or (Ia) and their pharmaceutically acceptable salts include:
  • respiratory tract obstructive diseases of the airways including: asthma, including bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including aspirin and NSAID-induced) and dust-induced asthma, both intermittent and persistent and of all severities, and other causes of airway hyper-responsiveness; chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; farmer's lung and related diseases; hypersensitivity pneumonitis; lung fibrosis, including cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonias, fibrosis complicating anti-neoplastic therapy and chronic infection, including tuberculosis and aspergillosis and other fungal infections; complications of lung transplantation; vasculitic and thrombotic disorders of the lung vasculature
  • osteoarthritides associated with or including osteoarthritis/osteoarthrosis both primary and secondary to, for example, congenital hip dysplasia; cervical and lumbar spondylitis, and low back and neck pain; osteoporosis; rheumatoid arthritis and Still's disease; seronegative spondyloarthropathies including ankylosing spondylitis, psoriatic arthritis, reactive arthritis and undifferentiated spondarthropathy; septic arthritis and other infection- related arthopathies and bone disorders such as tuberculosis, including Potts' disease and Poncet's syndrome; acute and chronic crystal-induced synovitis including urate gout, calcium pyrophosphate deposition disease, and calcium apatite related tendon, bursal and synovial inflammation; Behcet's disease; primary and secondary Sjogren's syndrome; systemic sclerosis and limited scleroderma; systemic lupus erythemato
  • arthitides for example rheumatoid arthritis, osteoarthritis, gout or crystal arthropathy
  • other joint disease such as intervertebral disc degeneration or temporomandibular joint degeneration
  • bone remodelling disease such as osteoporosis, Paget's disease or osteonecrosis
  • polychondritits such as osteoporosis, Paget's
  • skin psoriasis, atopic dermatitis, contact dermatitis or other eczematous dermatoses, and delayed-type hypersensitivity reactions; phyto- and photodermatitis; seborrhoeic dermatitis, dermatitis herpetiformis, lichen planus, lichen sclerosus et atrophica, pyoderma gangrenosum, skin sarcoid, discoid lupus erythematosus, pemphigus, pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitides, toxic erythemas, cutaneous eosinophilias, alopecia areata, male-pattern baldness, Sweet's syndrome, Weber-Christian syndrome, erythema multiforme; cellulitis, both infective and non-infective; panniculitis;cutaneous lymphomas, non-melanoma
  • eyes blepharitis; conjunctivitis, including perennial and vernal allergic conjunctivitis; ulceris; anterior and posterior uveitis; choroiditis; autoimmune; degenerative or inflammatory disorders affecting the retina; ophthalmitis including sympathetic ophthalmitis; sarcoidosis; infections including viral , fungal, and bacterial;
  • gastrointestinal tract glossitis, gingivitis, periodontitis; oesophagitis, including reflux; eosinophilic gastro-enteritis, mastocytosis, Crohn's disease, colitis including ulcerative colitis, proctitis, pruritis ani; coeliac disease, irritable bowel syndrome, and food-related allergies which may have effects remote from the gut (for example migraine, rhinitis or eczema);
  • abdominal hepatitis, including autoimmune, alcoholic and viral; fibrosis and cirrhosis of the liver; cholecystitis; pancreatitis, both acute and chronic; 8. genitourinary: nephritis including interstitial and glomerulonephritis; nephrotic syndrome; cystitis including acute and chronic (interstitial) cystitis and Hunner's ulcer; acute and chronic urethritis, prostatitis, epididymitis, oophoritis and salpingitis; 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;
  • cardiovascular atherosclerosis, affecting the coronary and peripheral circulation; pericarditis; myocarditis , inflammatory and auto-immune cardiomyopathies including myocardial sarcoid; ischaemic reperfusion injuries; endocarditis, valvulitis, and aortitis including infective (for example syphilitic); vasculitides; disorders of the proximal and peripheral veins including phlebitis and thrombosis, including deep vein thrombosis and complications of varicose veins;
  • oncology treatment of common cancers including prostate, breast, lung, ovarian, pancreatic, bowel and colon, stomach, skin and brain tumors and malignancies affecting the bone marrow (including the leukaemias) and lymphoproliferative systems, such as Hodgkin's and non-Hodgkin's lymphoma; including the prevention and treatment of metastatic disease and tumour recurrences, and paraneoplastic syndromes; and,
  • 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 (Ia) or a pharmaceutically-acceptable salt thereof as hereinbefore defined for use in therapy.
  • the present invention provides the use of a compound of formula (Ia) or a pharmaceutically acceptable salt thereof as hereinbefore defined in the manufacture of a medicament for use in therapy.
  • the term “therapy” also includes “prophylaxis” unless there are specific indications to the contrary.
  • the terms “therapeutic” and “therapeutically” should be construed accordingly.
  • Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the disease or condition in question.
  • Persons at risk of developing a particular disease or condition generally include those having a family history of the disease or condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the disease or condition.
  • the invention still further provides a method of treating, or reducing the risk of, an inflammatory disease or condition (including a reversible obstructive airways disease or condition) which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (Ia) 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 may be in the range from 0.01 micrograms per kilogram body weight ( ⁇ g/kg) to 100 milligrams per kilogram body weight (mg/kg).
  • the compounds of formula (Ia) 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 (Ia) compound/salt (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • a pharmaceutically acceptable adjuvant diluent or carrier.
  • Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, "Pharmaceuticals - The Science of Dosage Form Designs", M. E. Aulton, Churchill Livingstone, 1988.
  • the pharmaceutical composition will preferably comprise from 0.05 to 99 %w (per cent by weight), more preferably from 0.05 to 80 %w, still more preferably from 0.10 to 70 %w, and even more preferably from 0.10 to 50 %w, of active ingredient, all percentages by weight being based on total composition.
  • the present invention also provides a pharmaceutical composition comprising a compound of formula (Ia) 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 (Ia) or a pharmaceutically acceptable salt thereof as hereinbefore defined with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • compositions may be administered topically (e.g. to the skin or to the lung and/or airways) in the form, e.g., of creams, solutions, suspensions, heptafluoroalkane (HFA) aerosols and dry powder formulations, for example, formulations in the inhaler device known as the Turbuhaler ® ; or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules; or by parenteral administration in the form of solutions or suspensions; or by subcutaneous administration; or by rectal administration in the form of suppositories; or transdermally.
  • HFA heptafluoroalkane
  • Dry powder formulations and pressurized HFA aerosols of the compounds of the invention may be administered by oral or nasal inhalation.
  • the compound is desirably finely divided.
  • the finely divided compound preferably has a mass median diameter of less than 10 ⁇ m, and may be suspended in a propellant mixture with the assistance of a dispersant, such as a C 8 -C 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. Also liquid or semisolid formulations of the compound of the invention may be filled into hard gelatine capsules.
  • Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing the compound of the invention, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol.
  • Such liquid preparations may contain colouring agents, flavouring agents, saccharine and/or carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art.
  • the compounds of the invention may also be administered in conjunction with other compounds used for the treatment of the above conditions.
  • the invention therefore further relates to combination therapies wherein a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or formulation comprising a compound of the invention, is administered concurrently or sequentially or as a combined preparation with another therapeutic agent or agents, for the treatment of one or more of the conditions listed.
  • NSAIDs nonsteroidal anti-inflammatory agents
  • COX-1 / COX-2 inhibitors whether applied topically or systemically
  • piroxicam diclofenac
  • propionic acids such as naproxen, flurbiprofen, fenoprofen, ketoprofen and ibuprofen
  • fenamates such as mefenamic acid, indomethacin, sulindac, azapropazone, pyrazolones such as phenylbutazone, salicylates such as aspirin
  • selective COX-2 inhibitors such as meloxicam
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with a cytokine or agonist or antagonist of cytokine function, (including agents which act on cytokine signalling pathways such as modulators of the SOCS system) including alpha-, beta-, and gamma-interferons; insulin-like growth factor type I (IGF-1); interleukins (IL) including IL1 to 17, and interleukin antagonists or inhibitors such as anakinra; tumour necrosis factor alpha (TNF- ⁇ ) inhibitors such as anti-TNF monoclonal antibodies (for example infliximab; adalimumab, and CDP-870) and TNF receptor antagonists including immunoglobulin molecules (such as etanercept) and low-molecular-weight agents such as pentoxyfyliine.
  • a cytokine or agonist or antagonist of cytokine function including agents which act on cytokine signal
  • the invention relates to a combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with a monoclonal antibody targeting B-Lymphocytes (such as CD20 (rituximab), MRA-alLI6R) or T-Lymphocytes (CTLA4-lg, HuMax 11-15).
  • B-Lymphocytes such as CD20 (rituximab), MRA-alLI6R
  • T-Lymphocytes CLA4-lg, HuMax 11-15.
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with a modulator of chemokine receptor function such as an antagonist of CCR1 , CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR1 1 (for the C-C family); CXCR1 , CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-C family) and CX 3 CRI for the C-X 3 -C family.
  • a modulator of chemokine receptor function such as an antagonist of CCR1 , CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR1 1 (for the C-C family); CXCR1 , CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with an inhibitor of matrix metalloprotease (MMPs), i.e., the stromelysins, the collagenases, and the gelatinases, as well as aggrecanase; especially collagenase-1 (MMP-1), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-10), and stromelysin-3 (MMP-11) and MMP-9 and MMP-12, including agents such as doxycycline.
  • MMPs matrix metalloprotease
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a leukotriene biosynthesis inhibitor, 5-lipoxygenase (5-LO) inhibitor or 5-lipoxygenase activating protein (FLAP) antagonist such as; zileuton; ABT-761 ; fenleuton; tepoxalin; Abbott- 79175; Abbott-85761 ; a N-(5-substituted)-thiophene-2-alkylsulfonamide; 2,6-di-tert- butylphenolhydrazones; a methoxytetrahydropyrans such as Zeneca ZD-2138; the compound SB-210661 ; a pyridinyl-substituted 2-cyanonaphthalene compound such as L- 739,010; a 2-cyanoquino!ine compound such as L-746,530; or an indole or quinoline compound such as MK-591
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a receptor antagonist for leukotrienes (LT) B4, LTC4, LTD4, and LTE4.
  • a receptor antagonist for leukotrienes (LT) B4, LTC4, LTD4, and LTE4 selected from the group consisting of the phenothiazin-3-1s such as L-651 ,392; amidino compounds such as CGS-25019c; benzoxalamines such as ontazolast; benzenecarboximidamides such as BIIL 284/260; and compounds such as zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP 45715A), and BAY x 7195.
  • the present invention still further relates to the combination of a compound of the invention, or
  • PDE PDE inhibitor
  • 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.
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a histamine type 1 receptor antagonist such as cetirizine, loratadine, desloratadine, fexofenadine, acrivastine, terfenadine, astemizole, azelastine, levocabastine, chlorpheniramine, promethazine, cyclizine, or mizolastine; applied orally, topically or parenterally.
  • a histamine type 1 receptor antagonist such as cetirizine, loratadine, desloratadine, fexofenadine, acrivastine, terfenadine, astemizole, azelastine, levocabastine, chlorpheniramine, promethazine, cyclizine, or mizolastine
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a proton pump inhibitor (such as omeprazole) or a gastroprotective histamine type 2 receptor antagonist.
  • a proton pump inhibitor such as omeprazole
  • a gastroprotective histamine type 2 receptor antagonist such as a gastroprotective histamine type 2 receptor antagonist.
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an antagonist of the histamine type 4 receptor.
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an alpha-1/alpha-2 adrenoceptor agonist vasoconstrictor sympathomimetic agent, such as propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, tramazoline hydrochloride or ethylnorepinephrine hydrochloride.
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a chromone, such as sodium cromoglycate or nedocromil sodium.
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with a glucocorticoid, such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide or mometasone furoate.
  • a glucocorticoid such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide or mometasone furoate.
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with an agent that modulates a nuclear hormone receptor such as PPARs.
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with an immunoglobulin (Ig) or Ig preparation or an antagonist or antibody modulating Ig function such as anti-lgE (for example omalizumab).
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and another systemic or topically-applied anti-inflammatory agent, such as thalidomide or a derivative thereof, a retinoid, dithranol or calcipotriol.
  • a compound of the invention or a pharmaceutically acceptable salt thereof
  • another systemic or topically-applied anti-inflammatory agent such as thalidomide or a derivative thereof, a retinoid, dithranol or calcipotriol.
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and combinations of aminosalicylates and sulfapyridine such as sulfasalazine, mesalazine, balsalazide, and olsalazine; and immunomodulatory agents such as the thiopurines, and corticosteroids such as budesonide.
  • aminosalicylates and sulfapyridine such as sulfasalazine, mesalazine, balsalazide, and olsalazine
  • immunomodulatory agents such as the thiopurines, and corticosteroids such as budesonide.
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with an antibacterial agent such as a penicillin derivative, a tetracycline, a macrolide, a beta-lactam, a fluoroquinolone, metronidazole, an inhaled aminoglycoside; an antiviral agent including acyclovir, famciclovir, valaciclovir, ganciclovir, cidofovir, amantadine, rimantadine, ribavirin, zanamavir and oseltamavir; a protease inhibitor such as indinavir, nelfinavir, ritonavir, and saquinavir; a nucleoside reverse transcriptase inhibitor such as didanosine, lamivudine, stavudine, zalcitabine or zidovudine; or a non-nucleoside reverse transcripta
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a cardiovascular agent such as a calcium channel blocker, a beta-adrenoceptor blocker, an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin-2 receptor antagonist; a lipid lowering agent such as a statin or a fibrate; a modulator of blood cell morphology such as pentoxyfylline; thrombolytic, or an anticoagulant such as a platelet aggregation inhibitor.
  • a cardiovascular agent such as a calcium channel blocker, a beta-adrenoceptor blocker, an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin-2 receptor antagonist
  • ACE angiotensin-converting enzyme
  • angiotensin-2 receptor antagonist angiotensin-2 receptor antagonist
  • a lipid lowering agent such as a statin or a fibrate
  • a modulator of blood cell morphology such as
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a CNS agent such as an antidepressant (such as sertraline), an anti-Parkinsonian drug (such as deprenyl, L- dopa, ropinirole, pramipexole, a MAOB inhibitor such as selegine and rasagiline, a comP inhibitor such as tasmar, an A-2 inhibitor, a dopamine reuptake inhibitor, an NMDA antagonist, a nicotine agonist, a dopamine agonist or an inhibitor of neuronal nitric oxide synthase), or an anti-Alzheimer's drug such as donepezil, rivastigmine, tacrine, a COX-2 inhibitor, propentofylline or metrifonate.
  • a CNS agent such as an antidepressant (such as sertraline), an anti-Parkinsonian drug (such as deprenyl, L-
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an agent for the treatment of acute or chronic pain, such as a centrally or peripherally-acting analgesic (for example an opioid or derivative thereof), carbamazepine, phenytoin, sodium valproate, amitryptiline or other anti-depressant agent-s, paracetamol, or a nonsteroidal anti-inflammatory agent.
  • analgesic for example an opioid or derivative thereof
  • carbamazepine for example an opioid or derivative thereof
  • phenytoin for example an opioid or derivative thereof
  • sodium valproate for example an opioid or derivative thereof
  • amitryptiline or other anti-depressant agent-s sodium valproate
  • paracetamol paracetamol
  • nonsteroidal anti-inflammatory agent for example an opioid or derivative thereof
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with a parenterally or topically-applied (including inhaled) local anaesthetic agent such as lignocaine or a derivative thereof.
  • a parenterally or topically-applied (including inhaled) local anaesthetic agent such as lignocaine or a derivative thereof.
  • a compound of the present invention can also be used in combination with an anti-osteoporosis agent including a hormonal agent such as raloxifene, or a biphosphonate such as alendronate.
  • an anti-osteoporosis agent including a hormonal agent such as raloxifene, or a biphosphonate such as alendronate.
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with a: (i) tryptase inhibitor; (ii) platelet activating factor (PAF) antagonist; (iii) interleukin converting enzyme (ICE) inhibitor; (iv) IMPDH inhibitor; (v) adhesion molecule inhibitors including VLA-4 antagonist; (vi) cathepsin; (vii) kinase inhibitor such as an inhibitor of tyrosine kinase (such as Btk, Itk, Jak3 or MAP, for example Gefitinib or lmatinib mesylate), a serine / threonine kinase (such as an inhibitor of a MAP kinase such as p38, JNK, protein kinase A, B or C, or IKK), or a kinase involved in cell cycle regulation (such as a cylin dependent kinase
  • - or B.sub2. -receptor antagonist for example colchicine;
  • xi xanthine oxidase inhibitor, for example allopurinol;
  • uricosuric agent for example probenecid, sulfinpyrazone or benzbromarone;
  • xiii growth hormone secretagogue;
  • PDGF platelet-derived growth factor;
  • PDGF platelet-derived growth factor
  • fibroblast growth factor for example basic fibroblast growth factor (bFGF);
  • GM-CSF granulocyte macrophage colony stimulating factor (GM-CSF);
  • GM-CSF granulocyte macrophage colony stimulating factor
  • capsaicin cream for example tachykinin NK.subi .
  • NKP-608C SB-233412 (talnetant) or D-4418
  • elastase inhibitor such as UT-77 or ZD-0892
  • TACE TNF-alpha converting enzyme inhibitor
  • iNOS induced nitric oxide synthase
  • chemoattractant receptor-homologous molecule expressed on TH2 cells such as a CRTH2 antagonist
  • inhibitor of P38 agent modulating the function of Toll-like receptors (TLR),
  • agent modulating the activity of purinergic receptors such as P2X7
  • inhibitor of transcription factor activation such as NFkB, API or STATS
  • a glucocorticoid receptor GR-receptor
  • the present invention provides a combination (for example for the treatment of COPD, asthma or allergic rhinitis) of a compound of formula (I) and one or more agents selected from the list comprising: o a non-steroidal glucocorticoid receptor (GR-receptor) agonist; o a PDE4 inhibitor including an inhibitor of the isoform PDE4D; o a modulator of chemokine receptor function (such as a 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 isoform 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 COPD, asthma
  • a compound of the invention, or a pharmaceutically acceptable salt thereof, can also be used in combination with an existing therapeutic agent for the treatment of cancer
  • suitable agents include: (i) an antiproliferative/antineoplastic drug or a combination thereof, as used in medical oncology, such as an alkylating agent (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan or a nitrosourea); an antimetabolite (for example an antifolate such as a fluoropyrimidine like 5-fluorouracil or tegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea, gemcitabine or paclitaxel); an antitumour antibiotic (for example an anthracycline such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin,
  • a cytostatic agent such as an antioestrogen (for example tamoxifen, toremifene, raloxifene, droloxifene or iodoxyfene), an oestrogen receptor down regulator (for example fulvestrant), an antiandrogen (for example bicalutamide, flutamide, nilutamide or cyproterone acetate), a LHRH antagonist or LHRH agonist (for example goserelin, leuprorelin or buserelin), a progestogen (for example megestrol acetate), an aromatase inhibitor (for example as anastrozole, letrozole, vorazole or exemestane) or an inhibitor of 5 ⁇ -reductase such as finasteride; (iii) an agent which inhibits cancer cell invasion (for example a metalloproteinase inhibitor like marimastat or an inhibitor of urokinase plasm
  • an inhibitor of growth factor function for example: a growth factor antibody (for example the anti-erbb2 antibody trastuzumab, or the anti-erbb1 antibody cetuximab [C225]), a farnesyl transferase inhibitor, a tyrosine kinase inhibitor or a serine/threonine kinase inhibitor, an inhibitor of the epidermal growth factor family (for example an EGFR family tyrosine kinase inhibitor such as N.-(3-chloro-4- fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, AZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) or 6-acrylamido-N.-(3-chloro-4-fluorophen
  • an agent used in antisense therapy for example one directed to one of the targets listed above, such as ISIS 2503, an anti-ras antisense;
  • an agent used in a gene therapy approach for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT
  • Silica gel used for medium pressure column chromatography is 0.035 to 0.070 mm (220 to 440 mesh) (e.g. Fluka silica gel 60), and an applied pressure up to 10 psi accelerated column elution.
  • TLC thin layer chromatography
  • it refers to silica gel TLC using plates, typically 3 x 6 cm silica gel on aluminium foil plates with a fluorescent indicator (254 nm) (e.g. Fluka 60778). All solvents and commercial reagents were used as received.
  • Purification by 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 i.d. Luna column with 5 ⁇ m particle size
  • 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).
  • AIBN (2,2'-azobis(2-methylproprionitrile)
  • HATU 0-(7-azabenzotriazol-1 -y ⁇ )-N,N,N'N -tetramethyluroniumhexaf luoro- phosphate
  • NaHCO 3 sodium hydrogen carbonate
  • TFA trifluoroacetic acid
  • THF tetrahydrofuran
  • Example 1 5-F(/?)-2-(9-fr2-(Cvclohexyi-hvdroxy-phenyl-methyl)-oxazol-5-ylmethvil-methvl- aminol-nonylaminoV1-hvdroxy-ethyll-8-hydroxy-1 /y-quinolin-2-one naphthalene-1 ,5-disulfonate.
  • Oxaly) chloride (19 g, 0.15 mol) was added over 15 min to a solution of phenylglyoxylic acid (20 g, 0.13 mol) and 5 drops of DMF in dry DCM (100 m!_).
  • the reaction mixture was stirred at RT for 3 hours after which the solvent was removed in vacuo.
  • the residue was taken up in dry DCM (50 ml_) and the solution was added over 30 minutes to a mixture of propargyl amine (7.3 g, 0.13 mol) and triethylamine (13.5 g, 0.13 mol) in dry DCM (100 ml_) at 0 0 C.
  • the mixture was allowed to warm to RT overnight.
  • Trifluoromethane sulphonic acid (42.5 mL, 0.48 mol) was added dropwise to a solution of 2-oxo-2-phenyl- ⁇ /-prop-2-ynyl-acetamide (74.88 g, 0.40 mol) in 1 ,4- dioxane (600 mL). The resulting solution was heated at 90 0 C for 20 hours. The reaction mixture was cooled to RT and concentrated in vacuo. The residue was partitioned between DCM and concentrated aqueous ammonia and adjusted to pH 10 by addition of 1 M NaOH (aq). The aqueous phase was separated and then further extracted with DCM.
  • the aqueous phase was extracted with EtOAc and the combined organic layers were washed with 10% citric acid solution (aq), saturated NaHCO 3 (aq), brine, dried (Na 2 SO 4 ), and filtered.
  • the solvent was evaporated in vacuo to afford a white solid. This was triturated with diethyl ether and collected by filtration, washed with diethyl ether, and dried at 45 °C in vacuo to afford the title compound as a white solid.
  • the mother liquors were concentrated and the residue purified by column chromatography over silica gel using a gradient of 5-10% ETOAc/cyclohexane to afford a second batch of semi-pure product.
  • Example 1 step h, diastereomer 2).
  • Example 1 The title compound was prepared by methods analogous to those used in Example 1 step c and d, employing (5 ⁇ methyl-oxazol-2-yl)-phenyl ⁇ methanone (Example 1 , intermediate b) and cyclopentylmagnesium chloride.
  • the reaction mixture was partitioned between 10% lithium chloride (aq) and EtOAc and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried (Na 2 SO 4 ), filtered, and concentrated in vacuo.
  • the residual yellow oil was purified by column chromatography over silica gel using a gradient of 0-10% MeOH/DCM as eluent, then passed through a SCX-2cartridge, and liberated using a 2 M ammonia solution in MeOH. Evaporation of the solvent in vacuo afforded the title compound.
  • the title compound was prepared from 9- ⁇ [2-(cyclopentyl-hydroxy-phenyl-methyl)- oxazol-5-ylmethyl]-methyl-amino ⁇ -nonanal and 5-[(f?)-2-annino ⁇ 1 -(terf-butyl-dimethyl- silanyloxy)-ethyl]-8-hydroxy-1 W-quinolin-2-one (prepared according to
  • Example 1 The title compound was prepared by methods analogous to those used in Example 1 step c and d, employing (5-methyl-oxazol-2-yl)-phenyl-methanone (Example 1 , intermediate b) and phenylmagnesium bromide.
  • Example 3 The title compound was prepared from (5-bromomethyl-oxazol-2-yl)-diphenyl- methanol (Example 3, intermediate a) and 9-methylamino-nonan-1 -ol (prepared according to JP1992-31818) by a similar method to that employed in Example 1 , steps f.
  • the title compound was prepared from 5-[(F?)-1-(tert-butyl-dimethyl-silanyloxy)-2-(9- ⁇ [2-(hydroxy-diphenyl-methyl)-oxazol-5-ylmethyl]-methyl-amino ⁇ -nonylamino)-ethyl]-8- (4-methoxy-benzyloxy)-1 /-/-quinolin-2-one by a similar method to that employed in Example 1 , step i.
  • the crude product was purified by HPLC (HPLC system 3), eluting with water/MeCN (+0.1% diethylamine) instead of water/MeCN (+0.1 % formic acid).
  • LC-MS (method 2): Rt 2.21 min, m/z 759 [MH]+.
  • step b A mixture in DMF (2 ml_) of cyclopentyl-(5-methylaminomethyl-oxazol-2-yl)-phenyl- methanol (Example 2, step b: first eluting enantiomer) (0.25 g, 0.87 mmol), 8-bromo- 1 ,1 -dimethoxy-octane (J. Med. Chem. 1989, 32(6), 1319) (0.22 g, 0.88 mmol), caesium carbonate (0.58 g, 1.78 mmol) and water (50 ⁇ l_, 2.77 mmol) was stirred at RT for 48 hours. The resulting solution was concentrated in vacuo and the residue was partitioned between water (20 m!_) and DCM (20 ml_). The aqueous layer was further extracted with DCM (20 ml_) and the combined organic layer was dried
  • the title compound was prepared from cyclopentyl-(5-methylaminomethyl-oxazol-2- yl)-phenyl-methanol (Example 2, step b: first eluting enantiomer), 10-bromo-1 ,1- dimethoxy-decane and 5-[(fl)-2-amino-1 -(tert-butyl-dimethylsilanyloxy) ethyl]-8-(4- methoxybenzyloxy)-1 H-quinolin-2-one (Example 3, intermediate f) by similar methods to those employed in Example 4, steps a, b and Example 3, steps g, h and i.
  • the crude product was purified by HPLC (HPLC system 3) to give the desired product as a diformate salt,
  • Example 3 The title compound was prepared from (5-bromomethyl-oxazol-2-yl)-diphenyl- methanol (Example 3, intermediate a) and dimethylamine by a similar method to that employed in Example 2, step b.
  • the title compound was prepared from [2-(hydroxy-diphenyl-methyl)-oxazol-5- ylmethyl]-dimethyl-(9-oxo-nonyl)-ammonium bromide and 5-[(F?)-2-amino-1-(tert- butyl-dimethylsilanyloxy) ethyl]-8-(4-methoxybenzyloxy)-1 H-quinolin-2-one (Example 3, intermediate f) by similar methods to those employed in Example 3, steps g, h and i.
  • the crude product was purified by HPLC (HPLC system 3) to give the desired product as a diformate salt,
  • the title compound was prepared from (5-methylaminomethyl-oxazol-2-yl)-diphenyl ⁇ methanol (Example 7, intermediate a), 10-bromo-1 ,1 -dimethoxy-decane (Example 5, intermediate a) and 5-[(R)-2-a.m ⁇ uo- ⁇ -(tert-butyl-dimethyls ⁇ anyloxy) ethyl]-8-(4- methoxy benzyloxy)-1 /-/-quinolin-2-one (Example 3, intermediate f) by similar methods to those employed in Example 4, steps a, b and Example 3, steps g, h and i.
  • the crude product was purified by HPLC (HPLC system 3) to give the desired product as a formate salt.
  • Example 9 was prepared using similar methods to those used for the preparation of Example 6, employing (/ I ?)-cyclohexyl-(5-dimethyIaminomethyl-oxazol-2-yI)-phenyl- methanol in place of (5-dimethylaminomethyl-oxazol-2-yl)-diphenyl-methanol.
  • LC-MS (method 5): Rt 5.75 min, m/z 659 [M]+.
  • Example 10 was prepared using similar methods to those used for the preparation of Example 6, employing (fl)-cyclohexyl-(5-dimethylaminomethyl-oxazol-2-yl)-phenyl- methanol in place of (5-dimethylaminomethyl-oxazol-2-yl)-diphenyl-methanol and 7- ((F?)-2-amino-1 -hydroxy-ethyl)-4-hydroxy-3H-benzothiazol-2-one (prepared according to WO 2007027134) instead of 5-[(R)-2-Amino-1 -(tert-butyl-dimethylsilanyloxy)ethyl]- 8-(4-methoxybenzyloxy)-1 H-quinolin-2-one.
  • the compounds of the invention may be tested for pharmaceutical activity using assays know in the art, such as for example:
  • Radioligand binding studies utilising [ 3 H]-N-methyl scopolamine ([ 3 H]-NMS) and commercially available cell membranes expressing the human muscarinic receptors (M2 and M3) were used to assess the affinity of muscarinic antagonists for M2 and M3 receptors.
  • Membranes in TRIS buffer were incubated in 96-well plates with [ 3 H]- NMS and M3 antagonist at various concentrations for 3 hours. Membranes and bound radioligand were then harvested by filtration and allowed to dry overnight. Scintillation fluid was then added and the bound radioligand counted using a Canberra Packard Topcount scintillation counter
  • the half-life of antagonists at each muscarinic receptor was measured using the alternative radioligand [ 3 H]-QNB and an adaptation of the above affinity assay. Antagonists were incubated for 3 hours at a concentration 10-fold higher than their Ki, as determined with the [ 3 H]-QNB ligand, with membranes expressing the human muscarinic receptors. At the end of this time, [ 3 H]-QNB was added to a concentration 25-fold higher than its Kd for the receptor being studied and the incubation continued for various time periods from 15 minutes up to 180 minutes. Membranes and bound radioligand were then harvested by filtration and allowed to dry overnight. Scintillation fluid was then added and the bound radioligand counted using a Canberra Packard Topcount scintillation counter.
  • the rate at which [3H]-QNB is detected binding to the muscarinic receptors is related to the rate at which the antagonist dissociates from the receptor, ie. to the half life of the antagonists on the receptors.
  • Example 2 had a binding Ki of 0.85nM at the M3 receptor, whilst Example 7 had a binding Ki of 1.1nM.
  • Radioligand binding studies utilising [ 125 l]-lodocyanopindolol and commercially available cell membranes expressing the human ⁇ 2 adrenergic receptor were used to assess the affinity of antagonists for ⁇ 2 -adrenergic receptor.
  • Membranes and SPA- beads were incubated with [ 125 l]-lodocyanopindolol and ⁇ 2 antagonist at various concentrations for 3 hours at room temperature in TRIS buffer. The assay was performed in 96-well plates which were read using the Wallac Microbeta counter.
  • Example 5 exhibited a binding Ki of 43nM
  • Example 8 a binding Ki of 69nM
  • Example 2 had a binding Ki of 99nM.
  • CHO cells expressing the human M3 receptor were seeded and incubated overnight in 96 well collagen coated plates (black-wall, clear bottom) at a density of 50000 / 75 ⁇ l of medium in 3% serum.
  • a calcium-sensitive dye (Molecular Devices, Cat # R8041) was prepared in HBSS buffer with the addition of 5mM probenecid (pH 7.4).
  • An equal volume of the dye solution (75 ⁇ l) was added to the cells and incubated for 45 minutes followed by addition of 50 ⁇ l of muscarinic antagonists or vehicle. After a further 15 minutes the plate was read on a FLEXstationTM (excitation 488nm, emission 525nm) for 15 seconds to determine baseline fluorescence.
  • the muscarinic agonist Carbachol was then added at an EC 80 concentration and the fluorescence measured for a further 60 seconds.
  • the signal was calculated by subtracting the peak response from the mean of the baseline fluorescence in control wells in the absence of antagonist. The percentage of the maximum response in the presence of antagonist was then calculated in order to generate IC 50 curves.
  • Some compounds of the invention were tested in this assay and were found to have IC50 values of ⁇ 500nM.
  • Example 2 had an 1C50 value of of 209nM, whilst Example 7 had an IC50 value of 35nM.
  • Tracheae were removed from adult male Dunkin Hartley Guinea pigs and dissected free of adherent tissue before being cut open longitudinally in a line opposite the muscle. Individual strips of 2-3 cartilage rings in width were cut and suspended using cotton thread in 10ml water-jacketed organ baths and attached to a force transducer ensuring that the tissue is located between two platinum electrodes. Responses were recorded via a MPI OOW/Ackowledge data acquisition system connected to a PC. Tissues were equilibrated for one hour under a resting tone of 1g and were then subjected to electrical field stimulation at a frequency of 80Hz with a pulse width of 0.1 ms, a unipolar pulse, triggered every 2 minutes.
  • a "voltage-response" curve was generated for each tissue and a submaximal voltage then applied to every piece of tissue according to its own response to voltage. Tissues were washed with Krebs solution and allowed to stabilize under stimulation prior to addition of test compound. Concentration response curves were obtained by a cumulative addition of test compound in half-log increments. Once the response to each addition had reached a plateau the next addition was made. Percentage inhibition of EFS-stimulated contraction is calculated for each concentration of each compound added and dose response curves constructed using Graphpad Prism software and the EC 50 calculated for each compound. Onset time and duration of action studies were performed by adding the previously determined EC 50 concentration of compound to EFS contracted tissues and the response allowed to plateau.
  • Example 2 had an EC50 value of 153nM.
  • Control 9 ⁇ M Isoproterenol (max stimulation obtained, lowest counts) Blank: 0.1 nM Isoproterenol 1 % DMSO (no stimulation, highest counts)
  • Detection positive control 10 ⁇ M cAMP (1/200 dilution of 1OmM stock, then 1/5 in assay)
  • Detection negative control stimulation buffer Standard Isoproterenol and Formoterol (EC50 ⁇ 7nM, 0.05nM respectively)
  • Example 2 had an EC50 value of 37nM.
  • mice Male Guinea pigs (Dunkin Hartley), weighing 500-60Og housed in groups of 5 were individually identified. Animals were allowed to acclimatize to their local surroundings for at least 5 days. Throughout this time and study time animals were allowed access to water and food ad libitum.
  • Guinea pigs were anaesthetized with the inhaled anaesthetic Halothane (5%).
  • Test compound or vehicle (0.25 - 0.50 ml/kg) was administered intranasally. Animals were placed on a heated pad and allowed to recover before being returned to their home cages.
  • guinea pigs were terminally anaesthetized with Urethane (250 ⁇ g/ml, 2ml/kg).
  • Urethane 250 ⁇ g/ml, 2ml/kg.
  • the jugular vein was cannulated with a portex i.v. cannula filled with heparinised phosphate buffered saline (hPBS) (10U/ml) for i.v. administration of methacholine.
  • hPBS heparinised phosphate buffered saline
  • the trachea was exposed and cannulated with a rigid portex cannula and the oesophagus cannulated transorally with a flexible portex infant feeding tube.
  • the spontaneously breathing animal was then connected to a pulmonary measurement system (EMMS, Hants, UK) consisting of a flow pneumotach and a pressure transducer.
  • EMMS pulmonary measurement system
  • Hants UK
  • the tracheal cannula was attached to a pneumotach and the oesophageal cannula attached to a pressure transducer.
  • the oesophageal cannula was positioned to give a baseline resistance of between 0.1 and 0.2cmH20/ml/s.
  • a 2 minute baseline reading was recorded before i.v. administration of methacholine (up to 30 ⁇ g/kg, 0.5ml/kg).
  • a 2 minute recording of the induced constriction was taken from the point of i.v. administration.
  • the software calculated a peak resistance and a resistance area under the curve (AUC) during each 2 minute recording period which were used to analyse the bronchoprotective effects of test compounds
  • Guinea pigs (450-55Og) supplied by Harlan UK or David Hall, Staffs UK and acclimatised to the in-house facilities for a minimum of three days before use. Guinea pigs were randomly assigned into treatment groups and weighed. Each animal was lightly anaesthetised (4% Halothane) and administered compound or vehicle intranasally (0.5ml/kg) at up to 24 hours before challenge with pilocarpine. At the test time point, guinea pigs were terminally anaesthetised with urethane (25% solution in H20, 1.5g/kg).
  • Saliva production was calculated by subtracting the pre-weighed weight of the pad from each 5 minute period post weighed pad and these numbers added together to produce an accumulation of saliva over 15 minutes. Each 5 minute period could be analysed in addition to the whole 15 minute recording period. Baseline production of saliva was assumed to be constant and multiplied by three to produce a reading for baseline saliva production over 15 minutes.

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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
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Abstract

La présente invention a pour objet des composés de formule (Ia): où A, X et R1-R8 sont tels que définis dans la présente, lesdits composés étant utiles pour traiter des maladies dans lesquelles les récepteurs M3 et bêta2 sont impliqués, telles que des maladies des voies respiratoires; des compositions qui comprennent lesdits composés; des utilisations desdits composés dans une thérapie (telle que de l'asthme ou de la BPCO); et des méthodes pour traiter un patient avec de tels composés.
PCT/GB2007/002992 2006-08-08 2007-08-07 Composés chimiques WO2008017827A2 (fr)

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GBPCT/GB2006/002956 2006-08-08
PCT/GB2006/002956 WO2007017669A1 (fr) 2005-08-08 2006-08-08 Derives d'azole et de thiazole et utilisation de ceux-ci
GB0702383A GB0702383D0 (en) 2007-02-07 2007-02-07 Chemical compound
GB0702383.1 2007-02-07

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Cited By (21)

* Cited by examiner, † Cited by third party
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WO2008096129A1 (fr) * 2007-02-07 2008-08-14 Argenta Discovery Ltd Composés hétrocycliques contenant de l'azote utiles comme modulateurs bifonctionnels de récepteurs m3 et de récepteurs bétâ-2
WO2008096143A1 (fr) * 2007-02-07 2008-08-14 Argenta Discovery Ltd Nouveau sel
WO2008096136A1 (fr) * 2007-02-07 2008-08-14 Argenta Discovery Ltd Combinaison inédite
WO2008096126A1 (fr) * 2007-02-07 2008-08-14 Argenta Discovery Ltd COMBINAISON D'UN ANTAGONISTE DU RÉCEPTEUR MUSCARINIQUE ET D'UN AGONISTE DE L'ADRÉNORÉCEPTEUR β2
WO2008096149A2 (fr) * 2007-02-07 2008-08-14 Argenta Discovery Ltd Sel inédit
WO2008096128A1 (fr) * 2007-02-07 2008-08-14 Argenta Discovery Ltd Dérivés de l'oxazole et du thiazole et leurs utilisations
WO2010015792A1 (fr) * 2008-08-06 2010-02-11 Argenta Discovery Limited Composés hétérocycliques contenant de l'azote utiles comme modulateurs bifonctionnels des récepteurs m3 et des récepteurs bêta-2
WO2011081937A1 (fr) 2009-12-15 2011-07-07 Gilead Sciences, Inc. Composés de type corticostéroïde-bêta-agoniste-antagoniste muscarinique pour applications thérapeutiques
US8207193B2 (en) 2006-11-14 2012-06-26 Astrazeneca Ab Quiniclidine derivatives of (hetero) arylcycloheptanecarboxylic acid as muscarinic receptor antagonists
US8329729B2 (en) 2008-05-13 2012-12-11 Astrazeneca Ab Quinuclidine derivatives as muscarinic M3 receptor antagonists
US9233108B2 (en) 2011-11-11 2016-01-12 Almirall, S.A. Cyclohexylamine derivatives having β2 adrenergic agonist and M3 muscarinic antagonist activities
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
WO2018108089A1 (fr) 2016-12-14 2018-06-21 北京硕佰医药科技有限责任公司 Classe de composés bifonctionnels de structure de sel d'ammonium quaternaire
US10005771B2 (en) 2014-09-26 2018-06-26 Almirall, S.A. Bicyclic derivatives having β2 adrenergic agonist and M3 muscarinic antagonist activities
US10287282B2 (en) 2014-12-31 2019-05-14 Angion Biomedica Corp. Methods and agents for treating disease
US10456390B2 (en) 2013-07-25 2019-10-29 Almirall, S.A. Combinations comprising MABA compounds and corticosteroids
US11459319B2 (en) 2014-08-11 2022-10-04 Angion Biomedica Corp. Cytochrome P450 inhibitors and uses thereof

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EP0323864A2 (fr) * 1988-01-08 1989-07-12 Merck Sharp & Dohme Ltd. Oxadiazoles lipophiles
EP0462573A1 (fr) * 1990-06-18 1991-12-27 Mitsubishi Chemical Corporation Pyrazolcarboxamides et compositions insecticides, miticides et fongicides pour l'agriculture et l'horticulture
WO1997030994A1 (fr) * 1996-02-22 1997-08-28 Pfizer Research And Development Company, N.V./S.A. Oxa- et thia-diazoles utilises comme antagonistes des recepteurs muscariniques
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US6242448B1 (en) * 1998-12-17 2001-06-05 American Home Products Corporation Trisubstituted-oxazole derivatives as serotonin ligands

Cited By (28)

* 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
AU2008212649B2 (en) * 2007-02-07 2011-05-19 Astrazeneca Ab Combination of a muscarinic receptor antagonist and a beta-2-adrenoceptor agonist
WO2008096128A1 (fr) * 2007-02-07 2008-08-14 Argenta Discovery Ltd Dérivés de l'oxazole et du thiazole et leurs utilisations
WO2008096129A1 (fr) * 2007-02-07 2008-08-14 Argenta Discovery Ltd Composés hétrocycliques contenant de l'azote utiles comme modulateurs bifonctionnels de récepteurs m3 et de récepteurs bétâ-2
WO2008096149A2 (fr) * 2007-02-07 2008-08-14 Argenta Discovery Ltd Sel inédit
WO2008096143A1 (fr) * 2007-02-07 2008-08-14 Argenta Discovery Ltd Nouveau sel
WO2008096149A3 (fr) * 2007-02-07 2008-10-16 Argenta Discovery Ltd Sel inédit
WO2008096136A1 (fr) * 2007-02-07 2008-08-14 Argenta Discovery Ltd Combinaison inédite
WO2008096126A1 (fr) * 2007-02-07 2008-08-14 Argenta Discovery Ltd COMBINAISON D'UN ANTAGONISTE DU RÉCEPTEUR MUSCARINIQUE ET D'UN AGONISTE DE L'ADRÉNORÉCEPTEUR β2
US8329729B2 (en) 2008-05-13 2012-12-11 Astrazeneca Ab Quinuclidine derivatives as muscarinic M3 receptor antagonists
WO2010015792A1 (fr) * 2008-08-06 2010-02-11 Argenta Discovery Limited Composés hétérocycliques contenant de l'azote utiles comme modulateurs bifonctionnels des récepteurs m3 et des récepteurs bêta-2
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
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
US10300072B2 (en) 2011-11-11 2019-05-28 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
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
US11459319B2 (en) 2014-08-11 2022-10-04 Angion Biomedica Corp. Cytochrome P450 inhibitors and uses thereof
US10005771B2 (en) 2014-09-26 2018-06-26 Almirall, S.A. Bicyclic derivatives having β2 adrenergic agonist and M3 muscarinic antagonist activities
US10287282B2 (en) 2014-12-31 2019-05-14 Angion Biomedica Corp. Methods and agents for treating disease
US10851095B2 (en) 2014-12-31 2020-12-01 Angion Biomedica Corp. Methods and agents for treating disease
US11434234B2 (en) 2014-12-31 2022-09-06 Angion Biomedica Corp. Methods and agents for treating disease
WO2018108089A1 (fr) 2016-12-14 2018-06-21 北京硕佰医药科技有限责任公司 Classe de composés bifonctionnels de structure de sel d'ammonium quaternaire

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