WO2008096127A2 - Bicyclo[2.2.1]hept-7-ylamine derivatives and their use as m3 muscarinic receptor modulators - Google Patents

Bicyclo[2.2.1]hept-7-ylamine derivatives and their use as m3 muscarinic receptor modulators Download PDF

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WO2008096127A2
WO2008096127A2 PCT/GB2008/000405 GB2008000405W WO2008096127A2 WO 2008096127 A2 WO2008096127 A2 WO 2008096127A2 GB 2008000405 W GB2008000405 W GB 2008000405W WO 2008096127 A2 WO2008096127 A2 WO 2008096127A2
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formula
hydroxy
alkyl
group
compound
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WO2008096127A3 (en
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Lilian Alcaraz
Nicholas Kindon
Jonathan Mark Sutton
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Argenta Discovery Ltd
Astrazeneca Ab
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/24—Oxygen atoms attached in position 8
    • C07D215/26—Alcohols; Ethers thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • 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 bicyclo[2.2.1]hept-7-ylamine derivatives, pharmaceutical compositions, methods for their preparation and use in the treatment of M3 muscarinic receptor mediated diseases, for example respiratory diseases.
  • 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 at. 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 etal. 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.
  • Tiotropium is a muscarinic antagonist marketed for the treatment of COPD.
  • muscarinic receptor modulators have been referred to.
  • US4353922 describes muscarinic modulators based upon a [2.2.1]azabicycloheptane ring system.
  • EP418716 and US005610163 describe various [3.2.1]azabicyclooctane ring systems.
  • WO06/017768 describes [3.3.1]azabicyclononane ring systems.
  • ⁇ 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, WO05/1 11004, WO06/023457 and WO06/023460, all of which use different linker radicals for covalently linking the M3 antagonist to the ⁇ 2-agonist.
  • A is an oxygen atom or group -N(R 12 )-;
  • R 1 is C r C 6 -alkyl or hydrogen; and R 2 is a group-Z-NR 9 R 10 ; and R 3 is a lone pair, or Ci-C 6 -alkyl; or
  • R 1 and R 3 together with the nitrogen to which they are attached form a heterocycloalkyl ring, and R 2 is a group -Z-NR 9 R 10 , or
  • R 1 and R 2 together with the nitrogen to which they are attached form a heterocycloalkyl ring, said ring being substituted by a group , -Z-NR 9 R 10 ; and R 3 is a lone pair, or CrC 6 -alkyl;
  • R 4 is selected from one of the groups of formula (a), (b), (c) or (d);
  • R 6 is C r C 6 -alkyl or a hydrogen atom
  • R 7a and R 7b are a C r C 6 -alkyl group or halogen
  • n and m are independently 0, 1 , 2 or 3;
  • R 8a and R 8b are independently selected from the group consisting of aryl, aryl-fused- heterocycloaikyl, heteroaryl, Ci-C 6 -alkyl, cycloalkyl;
  • R 8c is -OH, Ci-Ce-alkyl, hydroxy-CrCe-alkyl, nitrile, a group CONR 8d 2 or a hydrogen atom;
  • R 8d is C r C 6 -alkyl or a hydrogen atom
  • R 9 is a hydrogen atom or C r C 6 -alkyl
  • R 10 is an aryl(C r C 6 -alkyI)-, or heteroaryl(CrC 6 -alkyl) group, in which the C,-C 6 -alkyl group is optionally substituted by hydroxy;
  • R 12 is CrC 6 -alkyl or a hydrogen atom
  • Ar 1 is aryl, heteroaryl or cycloalkyl
  • Ar 2 are independently aryl, heteroaryl or cycloalkyl
  • Q is an oxygen atom, -CH 2 -, -CH 2 CH 2 - or a bond
  • Z is a linker
  • the compounds of formula (I) may be represented by formula (Ia) wherein R 1 , R 3 , R 4 , and A are as defined for formula (I), and L is a hydrocarbyl chain of up to 14 carbon atoms wherein one, two or three carbon atoms of the chain are replaced by groups independently selected from O 1 NR 45 , S, S(O), S(O) 2 , C(O)O, OC(O), NR 46 C(O), C(O)NR 47 , NR 48 S(O) 2 , S(O) 2 NR 49 , NR 50 C(O)NR 51 , NR 52 S(O) 2 NR 53 , OC(O)NR 54 , NR 55 C(O)O, provided that any heteroatoms in the chain are separated by at least 2 carbon atoms; and/or wherein up to four carbon atoms of the chain form part
  • Ci -6 alkyl and C 3-6 cycloalkyl may be optionally substituted by up to three substituents independently selected from halogen, hydroxyl and C 1-6 alkoxy; and the chain may comprise up to three of such rings each selected independently; wherein R 56 , R 65 and R 69 each independently represent Ci. 6 alkyl or C 3-6 cycloalkyl, wherein C 1 ⁇ alkyl and C 3-6 cycloalkyl may be optionally substituted by up to three substituents independently selected from halogen, hydroxyl, C 1-6 alkoxy; and
  • R 66 , R 67 , R 68 , R 70 , R 71 , R 72 and R 73 each independently represent hydrogen, or C 1-6 alkyl or C 3-6 cycloalkyl, wherein C 1-6 alkyl and C 3-6 cycloalkyl may be optionally substituted by up to three substituents independently selected from halogen, hydroxyl, C 1-6 alkoxy; or any of R 57 and R 58 , R 59 and R 60 , R 61 and R 62 or R 71 and R 72 , together with the nitrogen atom to which they are both attached, may form a 4 to 8 membered aliphatic heterocyclic ring, wherein the aliphatic heterocyclic ring may comprise up to three heteroatoms independently selected from N, O and S, wherein the ring may be optionally substituted by up to three substituents independently selected from halogen, hydroxyl and C 1-6 alkyl or C 3-6 cycloalkyl, wherein C 1-6 alkyl
  • 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 1-6 alkyl or C 3-6 cycloalkyl, wherein C 1 . 6 alkyl and C 3-6 cycloalkyl may be optionally substituted by one or more substituents independently selected from halogen and hydroxyl;
  • L 1 and/or L 3 may be linked to carbon atoms of the hydrocarbyl chain in linker L to form aliphatic rings of up to 6 ring atoms, wherein each ring may comprise up to three heteroatoms independently selected from N, O and S; and wherein, unless otherwise specified, each occurrence of alkyl, heterocycloalkyl, aryl, aryl-fused-heterocycloalkyl, heteroaryl, cycloalkyl, alkoxy, alkylene, alkenylene, alkynylene or aryl-fused-cycloalkyl may
  • the present invention provides a prodrug of a compound of formula (I) as herein defined, or a pharmaceutically acceptable salt thereof.
  • the present invention provides an N-oxide of a compound of formula (I) as herein defined, or a prodrug or pharmaceutically acceptable salt thereof.
  • the present invention provides a solvate (such as a hydrate) of a compound of formula (I) as herein defined, or an N-oxide, prodrug or pharmaceutically acceptable salt thereof.
  • the present invention provides compounds of formula (I), as defined above, wherein, unless otherwise specified, each occurrence of alkyl may be optionally substituted with one or more substituent groups chosen from C 1 -C 6 - haloalkyl, CrC 6 -alkoxy, CrC 6 -haloalkoxy, CN and halo; and each occurrence of heterocycloalkyl, aryl, aryl-fused-heterocycloalkyl, heteroaryl, cycloalkyl, alkoxy or aryl-fused-cycloalkyl may be optionally substituted with one or more substituent groups chosen from CrC 6 -alkyl, C r C 6 -haloalkyl, Ci-C 6 -haloalkoxy, C r C 6 -alkoxy, CN and halo.
  • the present invention provides compounds of formula (I), as defined above, wherein, unless otherwise specified, each occurrence of alkyl, heterocycloalkyl, aryl, aryl-fused-heterocycloalkyl, heteroaryl, cycloalkyl, alkoxy or aryl-fused-cycloalkyl is not substituted.
  • A is an oxygen atom
  • R 1 is C r C 6 -alkyl
  • R 2 is a group -Z-NR 9 R 10 and R 3 is a lone pair or C r C 6 -alkyl, 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 CrCeralkyl; 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 ;
  • R 4 is selected from one of the groups of formula (a), (b) or (c):
  • R 6 is a hydrogen atom
  • R and R are independently a C r C 6 -alkyl group or halogen
  • n and m are independently 0, 1, 2 or 3;
  • R 8a and R 8b are independently selected from the group consisting of aryl, heteroaryl, C r C 6 -alkyl, cycloalkyl; R is -OH, C r C 6 -alkyl, hydroxy-C r C 6 -alkyl, or a hydrogen atom;
  • R 9 is a hydrogen atom or C r C 6 -alkyl
  • R >1 ⁇ 0 u is a group ArCH(OH)CH 2 - or a group ArCH 2 CH 2 - wherein Ar is a group
  • a 1 , A 2 , A 3 and A 4 are, independently, hydrogen, halogen, trifluoromethyl, cyano, carboxy, hydroxy, nitro, S(O) 2 A 8 , NA 9 S(O) 2 A 10 , C(O)NA 11 A 12 , NA 13 C(O)A 14 , C 1-6 alky], C 1-6 alkoxy, C(O)(C 1-6 alkyl) or C(O)OC 1 - S alkyl; and A 3 can also be CH 2 OH, NHCHO, NHS(O) 2 NA 15 A 16 or NHSO 2 A 17 ;
  • a 5 , A 6 , A 7 , A 9 , A 11 , A 12 , A 13 , A 14 , A 15 or A 16 are, independently, hydrogen or C 1-6 alkyl;
  • a 8 , A 10 and A 17 are, independently, C 1-6 alkyl.
  • Ar is selected from wherein
  • a 1 , A 2 , and A 4 are, independently, hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy; and A 3 can also be CH 2 OH, NHCHO 1 NHS(O) 2 NA 15 A lb or NHSO 2 A 117.
  • a or A are independently selected from hydrogen or C 1-6 alkyl
  • C 1-6 alkyl examples include C 1-4 alkyl and C 1 ⁇ alkyl.
  • Ci -6 alkoxy examples include C 1-4 alkoxy and C 1-2 alkoxy.
  • Ar is selected from:
  • A is an oxygen atom
  • R 1 is C r C 6 -alkyl
  • R 2 is a group -Z-NR 9 R 10 and R 3 is a lone pair or C r C 6 -alkyl, 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 C r C 6 -alkyl; 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 ;
  • R 4 is selected from one of the groups of formula (a), (b) or (c):
  • Ar 1 is a phenyl group
  • R 6 is a hydrogen atom
  • n and m are 0;
  • R and R >8b are both a phenyl group; or, R and R are both a thienyl group, or R 38a is a phenyl group and R b is a cycloalkyl group, such as cyclopentyl or cyclohexyl;
  • R is -OH or C r C 6 -alkyl (especially methyl or ethyl); In a further embodiment, R is -OH;
  • Ar 2 is a phenyl ring
  • Q is an oxygen atom or alternatively a direct bond
  • R 80 is hydrogen, C 1-6 alkyl
  • R 9 is a hydrogen atom or Ci-C 6 -alkyl
  • R 10 is an ary ⁇ CrCe-alkyl)-, or heteroaryl(C r C 6 -alkyl) group, selected from the group
  • the radical -C(L 1 )(L 2 )-L-C(L 3 )(L 4 )- is
  • R 47 is conveniently hydrogen, but may also be d- 6 alkyl such as methyl or ethyl, or C 3-6 cycloalkyl such as cyclopropyl, B is a phenylene radical, and u is 1 or 2; or
  • Compounds of the invention are ⁇ 2-adrenergic binding compounds. Such compounds may be antagonists, partial agonists or full agonists. Compounds that are antagonists are useful tools, for example, for the generation of structure-activity relationships and as radioligands. Compounds that are partial or full agonists may be useful as pharmacological compounds for the treatment of the diseases described above. Compounds that are antagonists are conveniently those wherein Z 1 is a group of formula (Ic), whilst those that are partial or full agonists are conveniently those wherein Z 1 is a group of formula (Ib). Compounds of the invention exist in either the syn- or anti- forms;
  • the compounds of the invention are predominantly in the anti-endo configuration.
  • anti-, endo- Compounds of the invention can also exist as optical isomers since substituted bicyclic ring systems can lack a plane of symmetry.
  • the absolute configuration of the molecule can be defined using Cahn-lngold-Prelog rules to assign the R or S designation to each position. To avoid confusion the ring numbering used below is employed.
  • compounds of the invention include racemates, single enantiomers and mixtures of the enantiomers in any ratio, since all such forms have muscarinic M3 receptor modulating activity to varying extents.
  • a convenient class of compounds of the invention consists of compounds of formula (I) wherein the nitrogen attached to R 1 and R 3 is a tertiary nitrogen.
  • Another convenient class of compounds of the invention consists of compounds of formula (I) wherein the nitrogen attached to R 1 and R 3 is a quaternary nitrogen and carries a positive charge.
  • 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, anthracos
  • quaternary ammonium salts of the invention administered by inhalation is may be more than 12, or more than 24 hours for a typical dose.
  • administration by the parenteral route usually the oral route, may be convenient.
  • Another aspect of the invention is a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier or excipient.
  • Another aspect of the invention is the use of a compound of the invention for the manufacture of a medicament for the treatment or prevention of a disease or condition in which muscarinic M3 receptor activity and ⁇ 2-adrenergic activity are implicated.
  • Diseases or conditions in which muscarinic M3 receptor activity and ⁇ 2- adrenergic activity are implicated include respiratory-tract disorders, gastrointestinal- tract disorders and cardiovascular disorders. Specific examples of such diseases and conditions include those listed above.
  • Another aspect of the invention provides a compound of the invention for the treatment or prevention of a disease or condition in which muscarinic M3 receptor activity and ⁇ 2-adrenergic activity are implicated.
  • Diseases or conditions in which muscarinic M3 receptor activity and ⁇ 2-adrenergic activity are implicated include respiratory-tract disorders, gastrointestinal-tract disorders and cardiovascular disorders. Specific examples of such diseases and conditions include those listed above.
  • Another aspect of the invention provides a method of treatment of a disease or condition in which M3 muscarinic receptor activity and ⁇ 2-adrenergic activity are implicated comprising administration to a subject in need thereof a therapeutically effective amount of a compound of the invention.
  • Diseases or conditions in which muscarinic M3 receptor activity and ⁇ 2-adrenergic activity are implicated include respiratory-tract disorders, gastrointestinal-tract disorders and cardiovascular disorders. Specific examples of such diseases and conditions include those listed above.
  • Another aspect of the invention provides a compound of the invention for use in therapy.
  • 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 methoxycarbonyi and ethoxycarbonyl.
  • Alkyl as a group or part of a group refers to a straight or branched chain saturated hydrocarbon group having from 1 to 12, conveniently 1 to 6, carbon atoms, in the chain.
  • exemplary alkyl groups include methyl, ethyl, 1 -propyl and 2-propyl..
  • alkenyl as a group or part of a group refers to a straight or branched chain hydrocarbon group having from 2 to 12, conveniently 2 to 6, carbon atoms and one . carbon-carbon double bond in the chain.
  • alkenyl groups include ethenyl, 1-propenyl, and 2-propenyl.
  • Alkynyl as a group or part of a group refers to a straight or branched chain hydrocarbon group having from 2 to 12, conveniently 2 to 6, carbon atoms and one carbon-carbon triple bond in the chain.
  • exemplary alkenyl groups include ethynyl, 1- propynyl, and 2-propynyl.
  • Alkylamino means a -NH-alkyl group in which alkyl is as defined above.
  • exemplary alkylamino groups include methylamino and ethylamino.
  • Alkylene means an -alkyl- group in which alkyl is as defined previously.
  • exemplary alkylene groups include -CH 2 -, -(CH 2 ) 2 - and -C(CH 3 )HCH 2 -.
  • alkenylene means an -alkenyl- group in which alkenyl is as defined previously.
  • Alkynylene means an -alkynyl- group in which alkynyl is as defined previously.
  • exemplary alkenylene groups include -CC-, -CCCH 2 -, and -CH 2 CC-.
  • Alkylsulfinyl means a -SO-alkyl group in which alkyl is as defined above.
  • alkylsulfinyl groups include methylsulfinyl and ethylsulfinyl.
  • Alkylsulfonyl means a -SO 2 -alkyl group in which alkyl is as defined above.
  • exemplary alkylsulfonyl groups include methylsulfonyl and ethylsulfonyl.
  • Alkylthio means a -S-alkyl group in which alkyl is as defined above.
  • exemplary alkylthio groups include methylthio and ethylthio.
  • Aminoacyl means a -CO-NRR group in which R is as herein described.
  • Exemplary aminoacyl groups include -CONH 2 and -CONHCH 3 .
  • Aminoalkyl means an alkyl-NH 2 group-in which alkyl is as previously described. Exemplary aminoalkyl groups include -CH 2 NH 2 . “Aminosulfonyl” means a -SO 2 -NRR group in which R is as herein described.
  • Exemplary aminosulfonyl groups include -SO 2 NH 2 and -SO 2 NHCH 3 .
  • Aryl as a group or part of a group denotes an optionally substituted monocyclic or multicyclic aromatic carbocyclic moiety of from 6 to 14 carbon atoms, conveniently 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. Convenient arylalkyl groups contain a C 1 4 alkyl moiety.
  • Exemplary arylalkyl groups include benzyl, phenethyl and naphthlenemethyl. The aryl part thereof may be substituted by one or more substituent groups.
  • “Arylalkyloxy” means an aryl-alkyloxy- group in which the aryl and alkyloxy moieties are as previously described. Convenient arylalkyloxy groups contain a C 1 4 alkyl moiety.
  • Exemplary arylalkyl groups include benzyloxy. The aryl part thereof may be substituted by one or more substituent groups.
  • Aryl-fused-heterocycloalkyl means a monocyclic aryl ring, such as phenyl, fused to a heterocycloalkyl group, in which the aryl and heterocycloalkyl are as described herein.
  • Exemplary aryl-fused-heterocycloalkyl groups include tetrahydroquinolinyl, indolinyl, benzodioxinyl, benzodioxolyl, dihydrobenzofuranyl and isoindolonyl.
  • the aryl and heterocycloalkyl rings may each be substituted by one or more substituent groups.
  • the aryl-fused-heterocycloalkyl group may be attached to the remainder of the compound by any available carbon or nitrogen atom.
  • Aryloxy means an -O-aryl group in which aryl is described above.
  • Exemplary aryloxy groups include phenoxy. The aryl part thereof may be substituted by one or more substituent groups.
  • Cyclic amine is a special case of "Heterocycloalkyl” or “heterocyclic” and means an optionally substituted 3 to 8 membered monocyclic cycloalkyl ring system where one of the ring carbon atoms is replaced by nitrogen, and which may optionally contain an additional heteroatom selected from O, S or NR (where R is as described herein).
  • Exemplary cyclic amines include pyrrolidine, piperidine, morpholine, piperazine and ⁇ /-methylpiperazine.
  • the cyclic amine group may be substituted by one or more substituent groups.
  • Cycloalkyl means an optionally substituted saturated monocyclic or bicyclic ring system of from 3 to 12 carbon atoms, conveniently from 3 to 8 carbon atoms, and more conveniently from 3 to 6 carbon atoms.
  • Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • the cycloalkyl group may be substituted by one or more substituent groups.
  • 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. Convenient are fluoro or chloro.
  • Haloalkoxy means an -O-alkyl group in which the alkyl is substituted by one or more halogen atoms. Exemplary haloalkyl groups include trifluoromethoxy and difluoromethoxy.
  • Haloalkyl means an alkyl group which is substituted by one or more halo atoms. Exemplary haloalkyl groups include trifluoromethyl.
  • Heteroaryl as a group or part of a group denotes an optionally substituted aromatic monocyclic or multicyclic organic moiety of from 5 to 14 ring atoms, conveniently from 5 to 10 ring atoms, in which one or more of the ring atoms is/are element(s) other than carbon, for example nitrogen, oxygen or sulfur.
  • Examples of such groups include benzimidazolyl, benzoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, furyl, imidazolyl, ⁇ ndolyl, indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl, oxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, tetrazolyl, 1 ,3,4-thiadiazolyl, thiazolyl, thienyl and triazolyl groups.
  • the heteroaryl group may be may be substituted by one or more substituent groups.
  • the heteroaryl group may be attached to the remainder of the compound of the invention by any available carbon or nitrogen atom.
  • Heteroarylalkyl means a heteroaryl-alkyl- group in which the heteroaryl and alkyl moieties are as previously described. Convenient heteroarylalkyl groups contain a lower alkyl moiety. Exemplary heteroarylalkyl groups include pyridylmethyl. The heteroaryl part thereof may be substituted by one or more substituent groups. "Heteroarylalkyloxy” means a heteroaryl-alkyloxy- gro ⁇ p in which the heteroaryl and alkyloxy moieties are as previously described. Convenient 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.
  • the heteroaryl part thereof may be substituted by one or more substituent groups.
  • Heterocycloalkyl or “heterocyclic” means: (i) an optionally substituted cycloalkyl group of from 4 to 8 ring members which contains one or more heteroatoms selected from O, S or NR; (ii) a cycloalkyl group of from 4 to 8 ring members which contains CONR and CONRCO (examples of such groups include succinimidyl and 2-oxopyrrolidinyl).
  • the heterocycloalkyl group may be be substituted by one or more substituents groups.
  • the heterocycloalkyl group may be attached to the remainder of the compound by any available carbon or nitrogen atom.
  • “Lower alkyl” as a group means unless otherwise specified, an aliphatic hydrocarbon group which may be straight or branched having 1 to 4 carbon atoms in the chain, i.e. methyl, ethyl, propyl (propyl or /so-propyl) or butyl (butyl, /sobutyl or tert- butyl).
  • "Phenylene” means a -phenyl- group. Exemplary groups are 1,3-phenylene and 1 ,4-phenylene.
  • 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, xinafoates, succinates and the like; (iii) when R 3 is not a lone pair the compound of formula (I) has a quaternary ammonium group for which the counter-ion may be, for example, chloride, bro
  • Prodrug refers to a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis, reduction or oxidation) to a compound of the invention.
  • metabolic means e.g. by hydrolysis, reduction or oxidation
  • an ester prodrug of a compound of the invention containing a hydroxy group may be convertible by hydrolysis in vivo to the parent molecule.
  • Suitable esters of compounds of the invention containing a hydroxy group are for example acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis- ⁇ -hydroxynaphthoates, gentisates, isothionates, di-p-toluoyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates and quinates.
  • ester prodrug of a compound of the invention containing a carboxy group may be convertible by hydrolysis in vivo to the parent molecule.
  • ester prodrugs are those described by F. J. Leinweber, Drug Metab. Res., 1987, 18, 379.
  • Optionally substituted means optionally substituted with up to four susbtituents.
  • Optional substituent groups include acyl (e.g. -COCH 3 ), alkoxy (e.g., -
  • alkoxycarbonyl e.g. -COOCH 3
  • alkylamino e.g. -NHCH 3
  • alkylsulfinyl e.g. -SOCH 3
  • alkylsulfonyl e.g. -SO 2 CH 3
  • alkylthio e.g. -SCH 3
  • -NH 2 aminoacyl (e.g. - CON(CH 3 ) 2 ), aminoalkyl (e.g. -CH 2 NH 2 ), arylalkyl (e.g. -CH 2 Ph or -CH 2 -CH 2 -Ph), cyano, dialkylamino (e.g.
  • haloalkyl e.g. -CFJ, alkyl (e.g. -CH or -CH CHJ, -OH, -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. -SO 2 NH 2 , -SO 2 NHCH 3 ), 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.
  • Alkylene, alkenylene or alkynylene radicals may be optionally substituted.
  • Optional substituent groups in the foregoing radicals include alkoxy (e.g., -OCH 3 ), alkylamino (e.g. -NHCH 3 ), alkylsulfinyl (e.g. -SOCH 3 ), alkylsulfonyl (e.g. -SO 2 CH 3 ), alkylthio (e.g. -SCHJ, -NH 2 , aminoalkyl (e.g. -CH 0 NH 0 ), arylalkyl (e.g. -CH Ph or -CH -CH -Ph), cyano, dialkylamino (e.g.
  • -N(CHJJ, halo, haloalkoxy e.g. -OCF, or -OCHF 2
  • haloalkyl e.g. -CF 3
  • alkyl e.g. -CH 3 or -CH 2 CH 3
  • -OH e.g. -NO 2
  • haloalkyl e.g. -CF 3
  • alkyl e.g. -CH 3 or -CH 2 CH 3
  • -OH e.g. -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, E- and Z-forms, R-, S- and meso-forms, keto-, and enol-forms.
  • 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).
  • the present invention is also concerned with pharmaceutical formulations comprising, as an active ingredient, a compound of the invention.
  • Other compounds may be combined with compounds of this invention for the prevention and treatment of inflammatory diseases of the lung.
  • the present invention is also concerned with pharmaceutical compositions for preventing and treating respiratory-tract disorders such as chronic obstructive lung disease, chronic bronchitis, asthma, chronic respiratory obstruction, pulmonary fibrosis, pulmonary emphysema, and allergic rhinitis comprising a therapeutically effective amount of a compound of the invention and one or more other therapeutic agents.
  • Other compounds may be combined with compounds of this invention for the prevention and treatment of inflammatory diseases of the lung.
  • the invention includes a combination of an agent of the invention as hereinbefore described with one or more antiinflammatory, 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.
  • Convenient combinations would have two or three different pharmaceutical compositions.
  • Suitable therapeutic agents for a combination therapy with compounds of the invention include: One or more other bronchodilators such as PDE3 inhibitors;
  • Methyl xanthines such as theophylline
  • a corticosteroid for example fluticasone propionate, ciclesonide, mometasone furoate or budesonide, or steroids described in WO02/88167, WO02/12266,
  • a non-steroidal glucocorticoid receptor agonist A non-steroidal glucocorticoid receptor agonist
  • a leukotriene modulator for example montelukast, zafirlukast or pranlukast
  • protease inhibitors such as inhibitors of matrix metalloprotease for example MMP 12 and TACE inhibitors such as marimastat, DPC-333, GW-3333
  • Human neutrophil elastase inhibitors such as sivelestat and those described in
  • Phosphodiesterase-4 (PDE4) inhibitors for example roflumilast, arofylline, cilomilast, ONO-6126 or lC-485;
  • An antitussive agent such as codeine or dextramorphan
  • P2X7 anatgonists P2X7 anatgonists; iNOS inhibitors;
  • NSAID non-steroidal anti-inflammatory agent
  • ibuprofen or ketoprofen for example ibuprofen or ketoprofen
  • 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,
  • 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 for example rosuvastatin, mevastatin, lovastatin, simvastatin, pravastatin and fluvastatin;
  • Mucus regulators such as INS-37217, diquafosol, sibenadet, CS-003, talnetant, DNK- 333, MSI-1956, gefitinib; Antiinfective agents (antibiotic or antiviral), and antiallergic drugs including, but not limited to, antihistamines.
  • the weight ratio of the first and second active ingredients may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used.
  • any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dosage of a compound of the present invention.
  • the active compound may be administered by any convenient, suitable or effective route.
  • Suitable routes of administration are known to those skilled in the art, and include oral, intravenous, rectal, parenteral, topical, ocular, nasal, buccal and pulmonary.
  • prophylactic or therapeutic dose of a compound of the invention will, of course, vary depending upon a range of factors, including the activity of the specific compound that is used, the age, body weight, diet, general health and sex of the patient, time of administration, the route of administration, the rate of excretion, the use of any other drugs, and the severity of the disease undergoing treatment.
  • the daily dose range for inhalation will lie within the range of from about 0.1 ⁇ g to about 10 mg per kg body weight of a human, conveniently 0.1 ⁇ g to about 0.5 mg per kg, and more conveniently 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 " lO ⁇ g per kg to 100mg per kg, conveniently 40 ⁇ g per kg to 4 mg per kg.
  • compositions which comprise a compound of the invention and a pharmaceutically acceptable carrier.
  • composition is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) (pharmaceutically acceptable excipients) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
  • the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the invention, additional active ingredient(s), and pharmaceutically acceptable excipients.
  • compositions of the present invention comprise a compound of the invention as an active ingredient or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable rion-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 conveniently 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). Many types of DPI are known.
  • Microparticles for delivery by administration may be formulated with excipients that aid delivery and release.
  • microparticles may be formulated with large carrier particles that aid flow from the DPI into the lung.
  • Suitable carrier particles are known, and include lactose particles; they may have a mass median aerodynamic diameter of greater than 90 ⁇ m.
  • an example is: Compound of the invention 24 mg / canister Lecithin, NF Liq. Cone. 1.2 mg / canister
  • the active compounds may be dosed as described depending on the inhaler system used.
  • the administration forms may additionally contain excipients, such as, for example, propellants (e.g. Frigen in the case of metered aerosols), surface-active substances, emulsifiers, stabilizers, preservatives, flavorings, fillers (e.g. lactose in the case of powder inhalers) or, if appropriate, further active compounds.
  • the invention further provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above which comprises:
  • LG 1 represents a leaving group such as chloride, bromide, iodide, methanesulfonate or para-toluenesulfonate
  • L, L 2 , L 3 , L 4 , R 1 , R 4 , and A are as defined in formula (I), with a compound of formula (III), or a suitable salt thereof such as a hydrobromide, acetate or hydrochloride salt
  • Ar is as defined in formula (I) and P 1 is hydrogen or a protective group such as terf-butyldimethyl silyl in the presence of a base such as potassium carbonate, triethylamine or diisopropylethylamine, followed by removal of the protective group (e.g. using a hydrofluoric acid-pyridine complex); or
  • L, L 2 , L 3 , L 4 , A, R 1 and R 4 are as defined in formula (I), 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 pa/a-toluenesulfonate
  • P 2 represents a protective group (e.g. t ⁇ rt-butylcarbonyf)
  • L, L 2 , L 3 , L 4 , A and R 4 are as defined in formula (I), 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.
  • a protective group e.g. tert-butylcarbonyl
  • a suitable salt thereof e.g. hydrobromide, hydrochloride salt or acetate
  • a suitable reducing agent e.g. sodium cyanoborohydride, sodium triacetoxyborohydride, or hydrogen in the presence of a suitable palladium on carbon or platinum oxide catalyst
  • R 1 does not represent hydrogen, reacting a compound of formula (VII), or a suitable salt thereof wherein L, L 1 , L 2 , L 3 , L 4 , A, R 1 and R 4 are as defined in formula (I), 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-/s
  • Ar is as defined in formula (I) in the presence of a base (e.g. when P 3 is hydrogen, potassium carbonate, triethyiamine, diisopropylethylamine and, when P 3 is 3-nitrophenylsulfonyl, sodium hydride or lithium di-/so-propylamide), followed by removal of the protective groups (e.g. trifluoroacetic acid, thiophenol, thioacetic acid); or with a compound of formula (X), or a suitable salt thereof,
  • a base e.g. when P 3 is hydrogen, potassium carbonate, triethyiamine, 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
  • 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-propy!amide), followed by reduction of the ketone (e.g. using sodium borohydride or a borane/chiral catalyst complex), followed by removal of the protective groups (e.g. trifluoroacetic acid, thiophenol, thioacetic acid); or (f) When R 1 represents hydrogen, reacting a compound of formula (Xl)
  • a base e.g. when P 3 is hydrogen, potassium carbonate, triethylamine, diisopropylethylamine and, when P 3 is 3-nitrophenyls
  • L, L 1 , L 2 , L 3 , L 4 , A and R 4 are as defined in formula (I),
  • P 2 represents a protective group (e.g. terf-butylcarbonyl)
  • P 3 represents hydrogen or an activating group (e.g. 3-nitrophenylsulfonyl), with a compound of formula (VIII), (IX) or (X), or a suitable salt thereof, in the presence of a base (e.g. when P 3 is hydrogen, potassium carbonate, triethylamine, diisopropylethylamine and when P 3 is 3-nitrophenylsulfonyl, sodium hydride or lithium di-/so-propylamide), followed by removal of the protective groups (e.g. using trifluoroacetic acid, thiophenol, thioacetic acid); or (g) when L 3 and L 4 each represents hydrogen, reacting a compound of formula (XII)
  • Ar, L 1 L 1 , and L 2 are as defined in formula (I), P 1 is as defined in compound of formula (III), P 3 represents a protective group (e.g. 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
  • a base e.g. potassium carbonate, triethylamine, diisopropylethylamine
  • Ar, L, L 3 , L 4 , A, R 1 and R 4 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
  • Ar, L, L 3 , L 4 , A and R 4 are as defined in formula (I) and P 2 is as defined in compound of formula (Xl) with a suitable reducing agent (e.g. borane tetrahydrofuran complex), followed by removal of the protective group (e.g. using hydrofluoric acid- pyridine complex); and optionally after (a), (b), (c), (d), (e), (f), (g), (h), (i) or (j) carrying out one or more of the following:
  • a suitable reducing agent e.g. borane tetrahydrofuran complex
  • removal of the protective group e.g. using hydrofluoric acid- pyridine complex
  • the reaction may conveniently be carried out in an organic solvent such as ⁇ /, ⁇ /-dimethylformamide, ethanol, ⁇ -butanol or dimethyl sulfoxide, at a temperature, for example, in the range from 50 to 14O 0 C.
  • the reaction may conveniently be carried out in an organic solvent such as methanol, ethanol, dichloromethane, acetic acid N- methylpyrolidinone, or /V,/V-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, wherein L, L 3 , L 4 , R 1 ,, R 4 and A are as defined in formula (II), with a compound of formula (XVIII)
  • 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 60 0 C, followed by conversion of the resulting hydroxy! 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 , A and R 4 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 60 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 60 0 C.
  • benzylamine of-methyl benzylamine, 4-methoxybenzylamine or 2,4-methoxybenzylamine
  • a suitable reducing agent e.g. sodium cyanoborohydride or sodium triacetoxyborohydride
  • 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 , A, R 4 and R 1 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, te/t-butanol, tetrahydrofuran, dichloromethane, water, or a mixture thereof, at a temperature ranging from 25 to 100 0 C, or when LG 4 is chloride, sodium azide, in an organic solvent, for example, ether, tert-butanol, tetrahydrofuran, water, or a mixture thereof, at a temperature ranging from 25 to 100 0 C (Angewandte Chemie, 2005, 54, 5188), eventually followed by protection of the resulting amine (e.g. treatment with 3-nitrophenylsulfonyl chloride in the presence of a base such as pyridine).
  • a base such as pyridine
  • Compounds of formula (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°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).
  • Compounds of formula (Xl) may be prepared by reacting a compound of formula (XXI) wherein L 4 is a leaving group (e.g. hydroxyl or chloride), L, L 1 , L 2 , L 3 , L 4 , A, R 4 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
  • an organic solvent such as /V,/V-dimethylformamide, ⁇ /-methylpyrolidinone, tetrahydrofuran, ethanol, n-butanol or dimethyl sulfoxide
  • 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 (111), or a suitable salt thereof, in the presence of a suitable reducing agent (e.g.
  • an organic solvent such as methanol, ethanol, dichloromethane, acetic acid, ⁇ /-methypyrolidinone or ⁇ /, ⁇ /-dimethylformamide containing up to 10%w of water and acetic acid, followed by removal of the protective group (e.g. diluted hydrochloric acid or amberlyst-15 resin in methanol).
  • Compounds of formula (XIV) 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,
  • an alcohol e.g. sodium borohydride
  • the protective group e.g. hydrofluoric acid-pyridine complex, tetrabutylamonium fluoride, diluted hydrochloric acid or amberlyst-15 resin in methanol
  • conversion of an alcohol into a suitable leaving group e.g. halogen, me
  • L, L 3 , L 4 , A and R 4 are as defined in formula (XV)
  • P 8 represents either R 4 as defined in compound of formula (XV) or P 2 as defined in compound of formula (XVI) and LG 6 represent hydroxyl or a leaving group (e.g. chloride) with a compound of formula (III), or a suitable salt thereof.
  • the reaction is conveniently carried out in the presence of an activating reagent, for example, carbonyldiimidazole or O-(7- azabenzotriazol-1 -yl)- ⁇ /, ⁇ /, ⁇ /', ⁇ /-tetramethyluroniumhexaf luorophosphate (HATU), in an organic solvent, for example, ⁇ /, ⁇ /-dimethylformamicle or dichloromethane, at a temperature, for example in the range from 0 to 60 0 C,
  • an activating reagent for example, carbonyldiimidazole or O-(7- azabenzotriazol-1 -yl)- ⁇ /, ⁇ /, ⁇ /', ⁇ /-tetramethyluroniumhexaf luorophosphate (HATU)
  • an organic solvent for example, ⁇ /, ⁇ /-dimethylformamicle or dichloromethane
  • the reaction is conveniently carried out in the presence of a base, for example, triethylamine or diisopropylethylamine in an organic solvent, for example, dichloromethane or tetrahydrofuran at a temperature, for example, in the range from 0 to 25 0 C.
  • a base for example, triethylamine or diisopropylethylamine
  • an organic solvent for example, dichloromethane or tetrahydrofuran
  • 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
  • L 1 L 1 , L 2 , L 3 , L 4 , P 2 and P 3 are as defined in compound of formula (Xl);
  • P 9 and P 10 represents an appropriate nitrogen protecting group, such as terf-butoxycarbonyl, followed by suitable deprotection (e.g. trifluoroacetic acid acid);
  • L, L 3 , and L 4 are as defined in compound of formula (XVlI), 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); - for compound of formula (XIX), P 9 represents P 2 , P 10 represents wherein L, L 3 , and L 4 are as defined in compound of formula (XIX), wherein P 11 and P 12 represent an acyclic or cyclic carbonyl protective group (e.g.
  • 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
  • R 1 , R 2 , and R 3 are as defined for formula (I) and LG 7 is a leaving group, for example, an O-alkyl, halogen or 1-imidazolyl group.
  • the reaction is conducted in the presence of a strong base such as NaH in a solvent such as toluene, THF or dichloromethane at a range of temperatures, convenientlybetween 0 0 C and the reflux temperature of the solvent.
  • Ar 2 and R 3 are as defined for formula (I) and LG 8 is a leaving group, for example, an O-alkyl, halogen or 1-imidazolyl group.
  • the reaction is conducted in the presence of a strong base such as NaH in a solvent such as toluene, THF ordichloromethane at a range of temperatures, conveniently between 0 0 C and the reflux temperature of the solvent.
  • reaction is conducted in the presence of a strong base such as NaH in a solvent such as toluene, THF, conveniently DMSO at a range of temperatures, conveniently between 0 °C and the reflux temperature of the solvent.
  • a strong base such as NaH
  • a solvent such as toluene, THF, conveniently DMSO at a range of temperatures, conveniently between 0 °C and the reflux temperature of the solvent.
  • Compounds of formula (XXVII) can be prepared from compounds of formula (XXXIV- a) by reaction with a suitable reducing agent, conveniently a bulky reducing agent such as LiAIH(O 1 Bu) 3 .
  • a suitable reducing agent conveniently a bulky reducing agent such as LiAIH(O 1 Bu) 3 .
  • the reaction is carried out in a polar organic solvent conveniently THF at a range of temperatures, conveniently from -78 °C up to the reflux temperature of the solvent.
  • Compounds of formula (XXXIV-a) can be prepared from compounds of formula (XXXV-a) by reaction with a tin reagent, conveniently Bu 3 SnH and a radical initiator, conveniently AIBN.
  • the reaction can be performed in a range of solvents, conveniently toluene, at a range of temperatures, conveniently between ambient temperature and the reflux temperature of the solvent.
  • the reaction is performed in a range of solvents, conveniently THF/DCM at a range of temperatures, conveniently between 0 and 100 0 C.
  • reaction by reaction with a tin reagent, conveniently Bu 3 SnH and a radical initiator, conveniently AIBN.
  • a tin reagent conveniently Bu 3 SnH and a radical initiator, conveniently AIBN.
  • the reaction can be performed in a range of solvents, conveniently toluenes at a range of temperatures, conveniently between ambient temperature and the reflux temperature of the solvent.
  • Compounds of formula (XXXVIII) may be prepared from compounds of formula (XXXIX) by reaction with a brominating agent, conveniently triphenylphosphine in carbon tetrabromide as solvent.
  • a brominating agent conveniently triphenylphosphine in carbon tetrabromide as solvent.
  • Compounds of formula (XXXIX) can be prepared from compounds of formula (XL) by reaction with a suitable reducing agent, conveniently sodium borohydride.
  • a suitable reducing agent conveniently sodium borohydride.
  • the reaction is carried out in a polar organic solvent conveniently THF at a range of temperatures, conveniently from -78 °C up to the reflux temperature of the solvent.
  • Compounds of formula (XL) can be prepared from compounds of formula (XLI) by analogous methods to those used to prepare compounds of formula (Xlll-a) from compounds of formula (XXVII).
  • reaction by reaction with an amine of formula (XXXVII).
  • the reaction is performed in a range of solvents, conveniently THF/DCM at a range of temperatures, conveniently between 0 and 100 0 C.
  • Compounds of Formula (XLIII) may be prepared from compounds of Formula (XLIV) by treatment with an organometallic reagent of Formula (XLV);
  • Mt is a metal species such as lithium or Mg-halide, especially a Grignard reagent in a suitable inert solvent such as THF or diethyl ether at a temperature between -78° and the reflux temperature of the solvent, convenientlyconveniently between 0° and ambient temperature.
  • a suitable inert solvent such as THF or diethyl ether
  • Compounds of Formula (XLIV) may be prepared from compounds of Formula (XLVI) by treatment with a compound of formula (XLVII);
  • R 1 is as described in formula (I) and LG 9 is a leaving group, especially a halogen group, optionally in the presence of a suitable solvent such as dichloromethane, in the absence or presence of a base such as diisopropylethylamine.
  • a suitable solvent such as dichloromethane
  • a base such as diisopropylethylamine
  • Compounds of Formula (XLVI) may be prepared from compounds of Formula (XLVIII) by reduction of the oxime with a suitable reducing agent, such as a borohydride reagent, specifically NaBH 4 ZNiCIa in a suitable solvent such as methanol at a suitable temperature, such as 20° C.
  • a suitable reducing agent such as a borohydride reagent, specifically NaBH 4 ZNiCIa in a suitable solvent such as methanol at a suitable temperature, such as 20° C.
  • Compounds of Formula (XLVIII) may be prepared from compounds of Formula (XXXIV-a) by treatment with hydroxylamine or a salt thereof in the presence of a suitable solvent such as methanol, optionally in the presence of a base such as sodium acetate, at a temperature between 0° C and the reflux temperature of the solvent, conveniently at ambient temperature.
  • a suitable solvent such as methanol
  • a base such as sodium acetate
  • the compounds of formula I have activity as pharmaceuticals, in particular as dual adrenergic ⁇ 2 receptor agonists and anticholinergic agents including muscarinic receptor (M1 , M2, and M3) antagonists, in particular M3 antagonists.
  • Diseases and conditions which may be treated with the compounds of formula (I) and their pharmaceutically acceptable salts include:
  • respiratory tract obstructive diseases of the airways including: asthma, including bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including aspirin and NSAID-induced) and dust-induced asthma, both intermittent and persistent and of all severities, and other causes of airway hyper-responsiveness; chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; farmer's lung and related diseases; hypersensitivity pneumonitis; lung fibrosis, including cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonias, fibrosis complicating anti-neoplastic therapy and chronic infection, including tuberculosis and aspergillosis and other fungal infections; complications of lung transplantation; vasculitic and thrombotic disorders of the lung vasculature
  • osteoarthritides associated with or including osteoarthritis/osteoarthrosis both primary and secondary to, for example, congenital hip dysplasia; cervical and lumbar spondylitis, and low back and neck pain; osteoporosis; rheumatoid arthritis and Still's disease; seronegative spondyloarthropathies including ankylosing spondylitis, psoriatic arthritis, reactive arthritis and undifferentiated spondarthropathy; septic arthritis and other infection- related arthopathies and bone disorders such as tuberculosis, including Potts' disease and Poncet's syndrome; acute and chronic crystal-induced synovitis including urate gout, calcium pyrophosphate deposition disease, and calcium apatite related tendon, bursal and synovial inflammation; Behcet's disease; primary and secondary Sjogren's syndrome; systemic sclerosis and limited scleroderma; systemic lupus erythemato
  • arthitides for example rheumatoid arthritis, osteoarthritis, gout or crystal arthropathy
  • other joint disease such as intervertebral disc degeneration or temporomandibular joint degeneration
  • bone remodelling disease such as osteoporosis, Paget's disease or osteonecrosis
  • polychondritits such as osteoporosis, Paget'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; panniculitisjcutaneous 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); vasGulitides; disorders of the proximal and peripheral veins including phlebitis and thrombosis, including deep vein thrombosis and complications of varicose veins;
  • oncology treatment of common cancers including prostate, breast, lung, ovarian, pancreatic, bowel and colon, stomach, skin and brain tumors and malignancies affecting the bone marrow (including the leukaemias) and lymphoproliferative systems, such as Hodgkin's and non-Hodgkin's lymphoma; including the prevention and treatment of metastatic disease and tumour recurrences, and paraneoplastic syndromes; and,
  • gastrointestinal tract Coeliac disease, proctitis, eosinopilic gastro-enteritis, mastocytosis, Crohn's disease, ulcerative colitis, microscopic colitis, indeterminant colitis, irritable bowel disorder, irritable bowel syndrome, non-inflammatory diarrhea, food-related allergies which have effects remote from the gut, e.g., migraine,, rhinitis and eczema.
  • the present invention provides a compound of formula (I) or a pharmaceutically-acceptable salt thereof as hereinbefore defined for use in therapy.
  • the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined in the manufacture of a medicament for use in therapy.
  • the term “therapy” also includes “prophylaxis” unless there are specific indications to the contrary.
  • the terms “therapeutic” and “therapeutically” should be construed accordingly.
  • Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the disease or condition in question.
  • Persons at risk of developing a particular disease or condition generally include those having a family history of the disease or condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the disease or condition.
  • the invention still further provides a method of treating, or reducing the risk of, an inflammatory disease or condition (including a reversible obstructive airways disease or condition) which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined.
  • the compounds of this invention may be used in the treatment of adult respiratory distress syndrome (ARDS), pulmonary emphysema, bronchitis, bronchiectasis, chronic obstructive pulmonary disease (COPD), asthma and rhinitis.
  • ARDS adult respiratory distress syndrome
  • COPD chronic obstructive pulmonary disease
  • the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated.
  • the daily dosage of the compound of the invention, if inhaled may be in the range from 0.05 micrograms per kilogram body weight ( ⁇ g/kg) to 100 micrograms per kilogram body weight ( ⁇ g/kg).
  • the daily dosage of the compound of the invention may be in the range from 0.01 micrograms per kilogram body weight ( ⁇ g/kg) to 100 milligrams per kilogram body weight (mg/kg).
  • the compounds of formula (I) and pharmaceutically acceptable salts thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (I) compound/salt (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • a pharmaceutically acceptable adjuvant diluent or carrier.
  • Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, "Pharmaceuticals - The Science of Dosage Form Designs", M. E. Aulton, Churchill Livingstone, 1988.
  • the pharmaceutical composition will convenientlycomprise from 0.05 to 99 %w (per cent by weight), more conveniently from 0.05 to 80 %w, still more conveniently from 0.10 to 70 %w, and even more conveniently from 0.10 to 50 %w, of active ingredient, all percentages by weight being based on total composition.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • compositions may be administered topically (e.g. to the skin or to the lung and/or airways) in the form, e.g., of creams, solutions, suspensions, heptafluoroalkane (HFA) aerosols and dry powder formulations, for example, formulations in the inhaler device known as the Turbuhaler ® ; or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules; or by parenteral administration in the form of solutions or suspensions; or by subcutaneous administration; or by rectal administration in the form of suppositories; or transdermally.
  • HFA heptafluoroalkane
  • Dry powder formulations and pressurized HFA aerosols of the compounds of the invention may be administered by oral or nasal inhalation.
  • the compound is desirably finely divided.
  • the finely divided compound conveniently has a mass median diameter of less than 10 ⁇ m, and may be suspended in a propellant 5.
  • a dispersant such as a C 8 -C 2 O fatty acid or salt thereof, (for example, oleic acid), a bile salt, a phospholipid, an alkyl saccharide, a perfluorinated or polyethoxylated surfactant, or other pharmaceutically acceptable dispersant.
  • the compounds of the invention may also be administered by means of a0 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,5 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.
  • the tablet may be coated with a suitable polymer dissolved in a readily volatile organic solvent.
  • the compound of the invention may be admixed with, for example, a vegetable oil or polyethylene glycol.
  • Hard gelatine capsules may contain granules of the compound using either the above- mentioned excipients for tablets.
  • liquid or semisolid formulations of the compound of the invention may be filled into hard gelatine capsules.
  • Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing the compound of the invention, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol.
  • Such liquid preparations may contain colouring agents, flavouring agents, saccharine and/or carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art.
  • the compounds of the invention may also be administered in conjunction with other compounds used for the treatment of the above conditions.
  • the invention therefore further relates to combination therapies wherein a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or formulation comprising a compound of the invention, is administered concurrently or sequentially or as a combined preparation with another therapeutic agent or agents, for the treatment of one or more of the conditions listed.
  • NSAIDs nonsteroidal anti-inflammatory agents
  • COX-1 / COX-2 inhibitors whether applied topically or systemically
  • piroxicam diclofenac
  • propionic acids such as naproxen, flurbiprofen, fenoprofen, ketoprofen and ibuprofen
  • fenamates such as mefenamic acid, indomethacin, sulindac, azapropazone, pyrazolones such as phenylbutazone, salicylates such as aspirin
  • selective COX-2 inhibitors such as meloxicam
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with a cytokine or agonist or antagonist of cytokine function, (including agents which act on cytokine signalling pathways such as modulators of the SOCS system) including alpha-, beta-, and gamma-interferons; insulin-like growth factor type I (IGF-1); interleukins (IL) including IL1 to 17, and interleukin antagonists or inhibitors such as anakinra; tumour necrosis factor alpha (TNF- ⁇ ) inhibitors such as anti-TNF monoclonal antibodies (for example infliximab; adalimumab, and CDP-870) and TNF receptor antagonists including immunoglobulin molecules (such as etanercept) and low-molecular-weight agents such as pentoxyfylline.
  • a cytokine or agonist or antagonist of cytokine function including agents which act on cytokine signalling
  • the invention relates. to a combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with a monoclonal antibody targeting B-Lymphocytes (such as CD20 (rituximab), MRA-alLI6R) or T-Lymphocytes (CTLA4-lg, HuMax 11-15).
  • B-Lymphocytes such as CD20 (rituximab), MRA-alLI6R) or T-Lymphocytes (CTLA4-lg, HuMax 11-15).
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with a modulator of chemokine receptor function such as an antagonist of CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for the C-C family); CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-C family) and CX 3 CRI for the C-X 3 -C family.
  • a modulator of chemokine receptor function such as an antagonist of CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for the C-C family); CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-C family) and CX 3 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-1 1) and MMP-9 and MMP-12, including agents such as doxycycline.
  • MMPs matrix metalloprotease
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a leukotriene biosynthesis inhibitor, 5-lipoxygenase (5-LO) inhibitor or 5-lipoxygenase activating protein (FLAP) antagonist such as; zileuton; ABT-761 ; fenleuton; tepoxalin; Abbott- 79175; Abbott-85761 ; a N-(5-substituted)-thiophene-2-alkylsulfonamide; 2,6-di-tert- butylphenolhydrazones; a methoxytetrahydropyrans such as Zeneca ZD-2138; the compound SB-210661 ; a pyridinyl-substituted 2-cyanonaphthalene compound such as L-739,010; a 2-cyanoquinoline compound such as L-746,530; or an indole or quinoline compound such as MK-591, MK
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a receptor antagonist for leukotrienes (LT) B4, LTC4, LTD4, and LTE4.
  • a receptor antagonist for leukotrienes (LT) B4, LTC4, LTD4, and LTE4 selected from the group consisting of the phenothiazin-3-1s such as L-651 ,392; amidino compounds such as CGS-25019c; benzoxalamines such as ontazolast; benzenecarboximidamides such as BIIL 284/260; and compounds such as zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP 45715A), and BAY x 7195.
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a phosphodiesterase (PDE) inhibitor such as a methylxanthanine including theophylline and aminophylline; a selective PDE isoenzyme inhibitor including a PDE4 inhibitor an inhibitor of the isoform PDE4D, or an inhibitor of PDE5.
  • PDE phosphodiesterase
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a histamine type 1 receptor antagonist such as cetirizine, loratadine, desloratadine, fexofenadine, acrivastine, terfenadine, astemizole, azelastine, levocabastine, chlorpheniramine, promethazine, cyclizine, or mizolastine; applied orally, topically or parenterally.
  • a histamine type 1 receptor antagonist such as cetirizine, loratadine, desloratadine, fexofenadine, acrivastine, terfenadine, astemizole, azelastine, levocabastine, chlorpheniramine, promethazine, cyclizine, or mizolastine
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a proton pump inhibitor (such as omeprazole) or a gastroprotective histamine type 2 receptor antagonist.
  • a proton pump inhibitor such as omeprazole
  • a gastroprotective histamine type 2 receptor antagonist such as a gastroprotective histamine type 2 receptor antagonist.
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an antagonist of the histamine type 4 receptor.
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an alpha-1/alpha-2 adrenoceptor agonist vasoconstrictor sympathomimetic agent, such as propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, tramazoline hydrochloride or ethylnorepinephrine hydrochloride.
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a chromone, such as sodium cromoglycate 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.
  • a compound of the invention or a pharmaceutically acceptable salt thereof, with an agent that modulates a nuclear hormone receptor such as PPARs.
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with an immunoglobulin (Ig) or Ig preparation or an antagonist or antibody modulating Ig function such as anti-lgE (for example omalizumab).
  • Ig immunoglobulin
  • Ig preparation or an antagonist or antibody modulating Ig function
  • anti-lgE for example omalizumab
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and another systemic or topically-applied anti-inflammatory agent, such as thalidomide or a derivative thereof, a retinoid, dithranol or calcipotriol.
  • 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, valaciciovir, 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-ad renoceptor 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-ad renoceptor blocker, an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin-2 receptor antagonist
  • ACE angiotensin-converting enzyme
  • angiotensin-2 receptor antagonist angiotensin-2 receptor antagonist
  • a lipid lowering agent such as a statin or a fibrate
  • a modulator of blood cell morphology
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a CNS agent such as an antidepressant (such as sertraline), an anti-Parkinsonian drug (such as deprenyl, L- dopa, ropinirole, pramipexole, a MAOB inhibitor such as selegine and rasagiline, a comP inhibitor such as tasmar, an A-2 inhibitor, a dopamine reuptake inhibitor, an 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 antidepressant (such as sertraline), an anti-Parkinsonian drug (such as deprenyl, L
  • NMDA antagonist a nicotine agonist, a dopamine agonist or an inhibitor of neuronal nitric oxide synthase), or an anti-Alzheimer's drug such as donepez ⁇ , rivastigmine, tacrine, a COX-2 inhibitor, propentofylline or metrifonate.
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an agent for the treatment of acute or chronic pain, such as a centrally or peripherally-acting analgesic (for example an opioid or derivative thereof), carbamazepine, phenytoin, sodium valproate, amitryptiline or other anti-depressant agent-s, paracetamol, or a non- steroidal anti-inflammatory agent.
  • 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
  • non- steroidal anti-inflammatory agent for example an opioid or derivative thereof
  • the present invention further relates to the combination of a compound of the invention, 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, or a pharmaceutically acceptable salt thereof can also be used in combination with an anti-osteoporosis agent including a hormonal agent such as raloxifene, or a biphosphonate such as alendronate.
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with a: (i) tryptase inhibitor; (ii) platelet activating factor (PAF) antagonist; (iii) interleukin converting enzyme (ICE) inhibitor; (iv) IMPDH inhibitor; (v) adhesion molecule inhibitors including VLA-4 antagonist; (vi) cathepsin; (vii) kinase inhibitor such as an inhibitor of tyrosine kinase (such as Btk, Itk, Jak3 or MAP, for example Gefitinib or lmatinib mesylate), a serine / threonine kinase (such as an inhibitor of a MAP kinase such as p38, JNK, protein kinase A, B or C, or IKK), or a kinase involved in cell cycle regulation (such as a cylin dependent 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 NKP-608C
  • SB-233412 talnetant
  • D-4418 elastase inhibitor
  • 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 CRTH2 antagonist
  • inhibitor of P38 agent modulating the function of Toll-like receptors (TLR),
  • agent modulating the activity of purinergic receptors such as P2X7
  • agent modulating the activity of purinergic receptors such as P2X7
  • inhibitor of transcription factor activation such as NFkB, API or STATS
  • GR-receptor a glucocorticoid receptor
  • the present invention provides a combination (for example for the treatment of COPD, asthma or allergic rhinitis) of a compound of formula (I) and one or more agents selected from the list comprising: o a non-steroidal glucocorticoid receptor (GR-receptor) agonist; o a PDE4 inhibitor including an inhibitor of the 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.
  • a compound of the invention, or a pharmaceutically acceptable salt thereof can also be used in combination with an existing therapeutic agent for the treatment of cancer, for example suitable agents include:
  • an antiproliferative/antineoplastic drug or a combination thereof, as used in medical oncology such as an alkylating agent (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan or a nitrosourea); an antimetabolite (for example an antifolate such as a fluoropyrimidine like 5-fluorouracil or tegaf ur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea, gemcitabine or paclitaxel); an antitumour antibiotic (for example an anthracycline such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin or mithramycin); an antimitotic agent (for example a vinca alkaloid such as
  • an inhibitor of growth factor function for example: a growth factor antibody (for example the anti-erbb2 antibody trastuzumab, or the anti-erbb1 antibody cetuximab [C225]), a farnesyl transferase inhibitor, a tyrosine kinase inhibitor or a serine/threonine kinase inhibitor, an inhibitor of the epidermal growth factor family (for example an EGFR family tyrosine kinase inhibitor such as N-(3-chloro-4- fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, AZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) or 6-acrylamido-N-(3-chloro-4-fluorophenyl
  • an agent used in antisense therapy for example one directed to one of the targets listed above, such as ISIS 2503, an anti-ras antisense;
  • an agent used in a gene therapy approach for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT
  • (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; or (ix) an agent used in an immunotherapeutic approach, for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies.
  • cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor
  • approaches to decrease T-cell anergy approaches using transfected immune
  • 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
  • HPLC system 3
  • Micromass Platform LCT with a C 18-re verse-phase column (100 x 3.0 mm i.d.
  • MS ionisation method Electrospray (positive ion).
  • MS ionisation method Electrospray (positive and negative ion).
  • MS ionisation method Electrospray (positive and negative ion).
  • MS ionisation method Electrospray (positive ion).
  • MS ionisation method - APCI positive ion and negative ions
  • MS ionisation method - APCI positive ion and negative ions
  • AIBN (2,2'-azobis(2-methylproprionitrile)
  • BOC-anhydride Di-fe/t-butyl dicarbonate
  • DCE 1 ,2-dichloroethane
  • DCM dichloromethane
  • DIPEA diisopropylethylamine
  • DMF /V,/V-dimethyl formamide
  • DMSO dimethylsulfoxide
  • EtOAc ethyl acetate
  • EtOH ethanol
  • HATL 0-(7-azabenzotria2ol-1-yl)- ⁇ /, ⁇ /, ⁇ / ⁇ /-tetramethyluroniumhexafluoro- phosphate
  • NaHCO 3 sodium hydrogen carbonate
  • NMP N-methyl pyrrolidone
  • TBDMS tert-butyldimethyl silyl
  • TEMPO 2,2,6,6-tetramethyl-1 -piperidinyloxy free radical
  • TFA trif luoroacetic acid
  • the reaction mixture was allowed to stir to RT overnight and was then partitioned between water and EtOAc and the combined organic extracts were concentrated in vacuo.
  • the crude product was triturated with saturated aqueous NaHCO 3 with the aid of prolonged sonication and then collected by filtration.
  • the solid residue was further purified by Companion automated chromatograpghy system, loading in EtOAc/MeOH and eluting from DCM to 5% MeOH/DCM to afford the title product.
  • Dess-Martin periodinane (1.22 g, 2.88 mmol) was added to ⁇ /-(2,2-dimethoxy- ethyl)-4-(2-hydroxy-ethyl)-benzamide (0.55 g, 2.17 mmol) in DCM (15 ml_. After 1hour, saturated aqueous NaHCO 3 (25 mL), sodium thiosulphate (25 mL) and EtOAc (80 mL) were added and the mixture shaken vigorously for 1 minute then separated.
  • HATU (8.30 g, 21.83 mmol) was added portion-wise over 10 minutes to a cooled 0 0 C stirred solution of 4-(hydroxymethyl)benzoic acid (2.60 g, 17.09 mmol), 2,2-dimethoxyethanamine (3.00 g, 28.53 mmol) and triethylamine (8.00 g, 79.06 mmol) in DMF (40 mL). After 1 hour the reaction mixture was quenched with water (200 mL) and extracted with EtOAc (6 x 350 mL). The organic extracts were combined, dried (MgSO 4 ), filtered and evaporated in vacuo.
  • Manganese(IV) oxide (3.38 ml_, 195.54 mmol) was added to stirred solution of /V-(2,2-dimethoxy-ethyl)-4-hydroxymethyl-benzamide (4.0O g, 16.72 mmol) in DCM (200 ml_) at room temperature. After 2 hours the mixture was filtered through a pad of Celite eluting with DCM and the solution evaporated in vacuo to give the crude aldehyde, which was used directly without characterisation.
  • the title compound was prepared from /V-(2,2-dimethoxy-ethyl)-4-formyl- benzamide and 7-(2-amino-ethyl)-4-hydroxy-3H-benzothiazol-2-one hydro chloride by similar methods to those employed in intermediates 7 and 13, and which was used directly without characterisation.
  • reaction mixture was diluted with EtOAc, washed with water and the organics were dried (Na 2 SO 4 ), filtered and solvent removed in vacuo.
  • the organics were then taken up in EtOAc (100 ml_) and washed a further 3 times with water, prior to being drying (MgSO 4 ), filtering and concentration in vacuo to give title compound as an orange gum.
  • the title compound was prepared from carbonic acid 7-(2- ⁇ tert- butoxycarbonyl-[2-(3-hydroxymethyl-phenyl)-ethyl]-amino ⁇ -ethyl)-2-oxo-2,3-dihydro- benzothiazol-4-yl ester tert-butyl ester by a similar method to that employed in intermediate 15.
  • the title compound was prepared from ⁇ 4-[2-(tert-butyl-dimethyi-silanyloxy)- ethyl]-phenyl ⁇ -acetaldehyde and 7-(2-amino-ethyl)-4-hydroxy-3H-benzothiazol -2-one hydrochloride by similar methods to the reductive amination and Boc-protection steps in intermediate 12.
  • a solution of the intermediate amino TBDMS ether in MeOH (20 mL) was converted to the amino alcohol by addition of concentrated aqueous HCI (2 mL). After 20 minutes, the mixture was concentrated in vacuo to give the crude de-silylated intermediate which was taken on to the BoC 2 O reaction to give the title compound.
  • the title compound was prepared from [3-(3-bromo-propoxy)-phenyl]- acetaldehyde and 7-(2-amino-ethyl)-4-hydroxy-3H-benzothiazol-2-one hydro chloride by similar methods to those used in intermediate 7.
  • the crude product was purified by HPLC (HPLC system 3) to give the desired product as a white solid.
  • the title compound was prepared from [4-(3-bromo-propoxy)-phenyl]- acetaldehyde and 7-(2-amino-ethyl)-4-hydroxy-3H-benzothiazol-2-one hydro chloride by similar methods to those used in intermediate 7.
  • the crude product was purified by HPLC (HPLC system 3) to give the desired product as a white solid.
  • the title compound was prepared from methanesulfonic acid 3-(3-formyl- phenoxy)-propyl ester and 7-(2-amino-ethyl)-4-hydroxy-3H-benzothiazol-2-one hydrochloride by similar methods to those used in intermediate 7.
  • the crude product was purified by HPLC (HPLC system 3) to give the desired product as a white solid.
  • the title compound was prepared from 3-(2,2-diethoxy-ethoxy)-N-methyl-N- (2-oxo-ethyl)-propionamide and 7-(2-aminoethyl)-4-hydroxybenzo[d]thiazol-2(3H)-one hydrochloride by similar methods to those employed in intermediates 7 and 13, respectively.
  • the title compound was prepared from ⁇ 5-[2-(tert-butyl-dimethyl-silanyloxy)- ethyl]-furan-2-yl ⁇ -acetic acid and 7-(2-aminoethyl)-4-hydroxybenzo[d]thiazol-2(3H)- one hydrobromide by similar methods to those employed in intermediates 21 and 27, respectively.
  • Copper(ll) sulfate pentahydrate (0.16 g, 0.64 mmol) and (but-3-ynyloxy)(tert- butyl)dimethylsilane (1.15 g, 6.24 mmol) were charged to a flask.
  • Water (12 ml_) and 2-methyl propan-1-ol (12 ml_) were added followed by azido-acetic acid ethyl ester (34% solution in DCM) (1.86 ml_, 6.07 mmol).
  • the resulting suspension was stirred vigorously and sodium L-ascorbate in water (1 M) (0.6 mL, 0.60 mmol) was added.
  • the title compound was prepared from ⁇ 4-[2-(tert-butyl-dimethyl-silanyloxy)- ethyl]-[1 ,2,3]triazol-1 -yl ⁇ -acetic acid ethyl ester by a similar method to that employed in intermediate 18.
  • the title compound was prepared from (4-amino-phenyl)-methanol and acryloyl chloride by a similar a method to that employed in intermediate 12.
  • the title compound was prepared from hydroxy-di-thiophen-2-yi-acetic acid (1S,2R,4S,7S)-7- ⁇ [(4-formyl-phenylcarbamoyl)-methyl]-methyl-amino ⁇ - bicyclo[2.2.1]hept-2-yl ester (Intermediate 52) and 7-((R)-2-amino-1-hydroxy-ethyi)-4- hydroxy-3H-benzothiazol-2-one hydrochloride by a similar a method to that employed in intermediate 55.
  • the crude product was purified by silica-gel chromatography (Companion, 12 g), eluting from [88:12] DCM/(2 M NH 3 in MeOH) to give the desired product as an off-white solid.
  • the title compound was prepared from hydroxy-di-thiophen-2-yl-acetic acid (1 S,2R,4S,7S)-7- ⁇ [2-(4-formyl-benzoyl amino)-ethyl]-methyl-amino ⁇ -bicyclo[2.2.1] hept-2-yl ester (Intermediate 52) and 5-[(R)-2-amino-1-(tert-butyl-dimethyl-silanyloxy)- ethyi]-8-hydroxy-1H-quinolin-2-one by similar methods to those employed in intermediates 55 and example 3, respectively.
  • the crude product was purified by HPLC (system 3), eluting from 5-50% MeCN/water (0.1% formic acid) and gave, after freeze drying, the desired product as white solid.
  • the title compound was prepared from hydroxy-di-thiophen-2-yl-acetic acid (1S,2R ! 4S,7S)-7- ⁇ [2-(4-formyl-phenylcarbamoyl)-ethyl]-methyl-amino ⁇ - bicyclo[2.2.1]hept-2-yl ester (Intermediate 61) and 5-[(R)-2-amino-1-(tert-butyl- dimethyl-silanyloxy)-ethyl]-8-hydroxy-1H-quinolin-2-one by similar methods to those employed in intermediates 55 and example 3, respectively.
  • the crude product was purified by HPLC (system 3), eluting from 5-50% MeCN/water (0.1% formic acid) and gave, after freeze drying, the desired product as white solid.
  • the title compound was prepared from 9-hydroxy-9H-xanthene-9-carboxylic acid (1 R,2S,3S)-2-ethyl-3- ⁇ [3-(4-formyl-phenoxy)-propyl]-methyl-amino ⁇ -cyclopentyl ester (Intermediate 63) and 7-((R)-2-amino-1-hydroxy-ethyl)-4-hydroxy-3H- benzothiazol-2-one hydrochloride by a similar method to that employed in intermediate 55.
  • the crude product was purified by HPLC (system 3), eluting from 10-25% MeCN/water (0.1% formic acid) and gave, after freeze drying, the desired product as white solid.
  • the title compound was prepared from hydroxy-di-thiophen-2-yl-acetic acid (1 S,2R,4S,7S)-7- ⁇ [2-(4-formyl-phenylcarbamoyl)-ethyl]-methyl-amino ⁇ - bicyclo[2.2.1]hept-2-yl ester (Intermediate 63) and 5-[(R) ⁇ 2-amino-1-(tert-butyl- dimethyl-silanyloxy)-ethyl]-8-hydroxy-1H-quinolin-2-one by similar methods to those employed in intermediates 55 and example 3, respectively.
  • the crude product was purified by HPLC (system 3), eluting from 10-25% MeCN/water (0.1% formic acid) and gave, after freeze drying, the desired product as white solid.
  • the title compound was prepared from (R)-cyclohexyl-hydroxy-phenyl-acetic acid (IS ⁇ R ⁇ S.ZSJ-y-fCS ⁇ formyl-phenoxyj-propyO-methyl-aminoJ-bicycIo [2.2.1]hept-2-yl ester (Intermediate 65) and 7-((R)-2-amino-1-hydroxy-ethyl)-4- hydroxy-3H-benzothiazol-2-one hydrochloride by a similar method to that employed in intermediate 55.
  • the crude product was purified by HPLC (system 3), eluting from 10-25% MeCN/water (0.1% formic acid) and gave, after freeze drying, the desired product as white solid.
  • the inhibitory effects of compounds of the present invention at the M3 muscarinic receptor and the ⁇ 2 adrenergic receptor may be determined by the following binding assays:
  • the affinity (plC 50 ) of compounds to the M 3 receptor is determined by competition binding of [ 3 H]N-methyl scopolamine (NMS) to CHO-K1 (Chinese Hamster Ovary) cell membranes expressing the human muscarinic acetylcholine M 3 receptor (M 3 -ACh) in a scintillation proximity assay (SPA) format.
  • SPA beads are precoated with membranes and then incubated at 2mg of beads per well with serial dilutions of compounds of the invention, [ 3 H]NMS at 0.2nM, half Kd (experimentally determined dissociation constant) and assay buffer (20 mM HEPES pH 7.4 containing 5 mM MgCI 2 ).
  • the assay is conducted in a final volume of 200 ⁇ L, in the presence of 1% (v/v) dimethyl sulphoxide (DMSO).
  • DMSO dimethyl sulphoxide
  • [ 3 H]NMS is determined in the presence of 1 ⁇ M atropine. The plates are incubated for 16 hours at room temperature and then read on Wallac Microbeta TM using a normalised 3 H protocol. The plC 50 , defined as the negative logarithm of the concentration of compound required for 50% reduction in specific [ 3 H]-NMS binding, is determined.
  • the activity of compounds at the M 3 receptor is determined by competition binding of [ 3 H]N-methyl scopolamine (NMS) to CHO-K1 (Chinese Hamster Ovary) cell membranes expressing the human muscarinic acetylcholine M 3 receptor (M 3 -ACh) in a scintillation proximity assay (SPA) format.
  • NMS [ 3 H]N-methyl scopolamine
  • CHO-K1 Choinese Hamster Ovary cell membranes expressing the human muscarinic acetylcholine M 3 receptor (M 3 -ACh) in a scintillation proximity assay (SPA) format.
  • SPA scintillation proximity assay
  • SPA beads are precoated with membranes and then incubated at 2mg of beads per well with compounds of the invention, [ 3 H]NMS at 0.2nM, half Kd (experimentally determined dissociation constant) and assay buffer (20 mM HEPES pH 7.4 containing 5 mM MgCI 2 ).
  • the assay is conducted in a final volume of 200 ⁇ L, in the presence of 1% (v/v) dimethyl sulphoxide (DMSO).
  • Total binding of [ 3 H]NMS is determined in the absence of competing compound and non-specific binding of [ 3 H]NMS is determined in the presence of 1 ⁇ M atropine.
  • the plates are incubated for 16 hours at room temperature and then read on Wallac MicrobetaTM using a normalised 3 H protocol.
  • plC 50 determinations the assay is conducted using serial dilutions of compounds of the invention.
  • the plC 50 is defined as the negative logarithm of the concentration of compound required for 50% reduction in specific [ 3 H]-NIvIS binding.
  • spot test activity determinations compounds of the invention are incubated at a single 10 nM concentration using the protocol described above. The percentage inhibition of specific [ 3 H]NMS binding is reported.
  • Radioligand binding studies utilising [125l]-lodocyanopindolol and commercially available cell membranes expressing the human ⁇ 2 adrenergic receptor are used to assess the affinity of antagonists for ⁇ 2-adrenergic receptor.
  • Membranes and SPA-beads are incubated with [125l]-lodocyanopindolol and ⁇ 2 antagonist at various concentrations for 3 hours at ambient temperature in TRIS buffer.
  • the assay is performed in 96-well plates which are read using the Wallac Microbeta counter.
  • Cell preparation H292 cells are grown in 225cm2 flasks incubator at 37 0 C, 5% CO 2 in RPMI medium containing10% (v/v) FBS (foetal bovine serum) and 2 mM L-glutamine.
  • Adherent H292 cells re removed from tissue culture flasks by treatment with AccutaseTM cell detachment solution for 15 minutes. Flasks are incubated for 15 minutes in a humidified incubator at 37°C, 5% CO 2 . Detached cells are re- suspended in RPMI media (containing 10% (v/v) FBS and 2 mM L-glutamine) at 0.05 x 10 6 cells per mL 5000 ceils in 100 ⁇ l_ are added to each well of a tissue-culture- treated 96-well plate and the cells incubated overnight in a humidified incubator at 37°C, 5% CO 2 .
  • RPMI media containing 10% (v/v) FBS and 2 mM L-glutamine
  • the culture media is removed and cells are washed twice with 100 ⁇ L assay buffer and replaced with 50 ⁇ L assay buffer (HBSS solution containing 1 OmM HEPES pH7.4 and 5 mM glucose). Cells are rested at room temperature for 20 minutes after which time 25 ⁇ L of rolipram (1.2 mM made up in assay buffer containing 2.4% (v/v) dimethylsulphoxide) is added. Cells are incubated with rolipram for 10 minutes after which time test compounds are added and the cells are incubated for 60 minutes at room temperature. The final rolipram concentration in the assay is 300 ⁇ M and final vehicle concentration is 1.6% (v/v) dimethylsulphoxide. The reaction is stopped by removing supernatants, washing once with 100 ⁇ L assay buffer and replacing with 50 ⁇ L lysis buffer. The cell monolayer is frozen at -80 0 C for 30 minutes (or overnight).
  • HBSS solution containing 1 OmM HEPES pH7.4 and 5 m
  • the concentration of cAMP (cyclic adenosine monophosphate) in the cell lysate is determined using AlphaScreenTM methodology.
  • the frozen cell plate is thawed for 20 minutes on a plate shaker then 10 ⁇ L of the cell lysate is transferred to a 96-well white plate.
  • the AlphaScreenTM signal is measured using an En Vision spectrophotometer (Perkin-Elmer Inc.) with the recommended manufacturer's settings.
  • cAMP concentrations are determined by reference to a calibration curve determined in the same experiment using standard cAMP concentrations. Concentration response curves for agonists are constructed and data is fitted to a four parameter logistic equation to determine both the pEC 50 and Intrinsic Activity. Intrinsic Activity is expressed as a fraction relative to the maximum activity determined for for

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Abstract

The present invention provides compounds of formula (I) having muscarinic M3 receptor and β-adrenergic receptor modulating activity; processes for their preparation and their use in therapy; wherein A, R1, R2, R3 and R4 are defined herein.

Description

New Chemical Compounds
Field of the Invention This invention relates to bicyclo[2.2.1]hept-7-ylamine derivatives, pharmaceutical compositions, methods for their preparation and use in the treatment of M3 muscarinic receptor mediated diseases, for example respiratory diseases.
Background to the invention 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.
There are five subtypes of muscarinic acetylcholine receptors (mAChRs), termed M1-M5, and each is the product of a distinct gene and each displays unique pharmacological properties. mAChRs are widely distributed in vertebrate organs, and these receptors can mediate both inhibitory and excitatory actions. For example, in smooth muscle found in the airways, bladder and gastrointestinal tract, M3 mAChRs mediate contractile responses (reviewed by Caulfield, 1993, Pharmac. Ther., 58, 319 - 379).
In the lungs, 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.
Increased signalling through muscarinic acetylcholine receptors has been noted in a variety of different pathophysiological states including asthma and COPD. In COPD, vagal tone may either be increased (Gross et at. 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 etal. 1984, Am Rev Respir Dis; 129:856-870). In addition, inflammatory conditions can lead to a loss of inhibitory M2 receptor activity which results in increased levels of acetylcholine release following vagal nerve stimulation (Fryer et al, 1999, Life ScL, 64, (6-7) 449-455). The resultant increased activation of M3 receptors leads to enhanced airway obstruction. Thus the identification of potent muscarinic receptor antagonists would be useful for the therapeutic treatment of those disease states where enhanced M3 receptor activity is implicated. Indeed, contemporary treatment strategies currently support regular use of M3 antagonist bronchodilators as first-line therapy for COPD patients (Pauwels et al. 2001 , Am Rev Respir Crit Care Med; 163:1256-1276)
Incontinence due to bladder hypercontractility has also been demonstrated to be mediated through increased stimulation of M3 mAChRs. Thus M3 mAChR antagonists may be useful as therapeutics in these mAChR-mediated diseases.
Despite the large body of evidence supporting the use of anti-muscarinic receptor therapy for treatment of airway disease states, relatively few anti-muscarinic compounds are in use in the clinic for pulmonary indications. Thus, there remains a need for novel compounds that are capable of causing blockade at M3 muscarinic receptors, especially those compounds with a long duration of action, enabling a once-daily dosing regimen. Since muscarinic receptors are widely distributed throughout the body, the ability to deliver anticholinergic drugs directly to the respiratory tract is advantageous as it allows lower doses of the drug to be administered. The design and use of topically active drugs with a long duration of action and that are retained on the receptor or in the lung would allow reduction of unwanted side effects that could be seen with systemic administration of the same drugs.
Tiotropium (Spiriva ™) is a long-acting muscarinic antagonist currently marketed for the treatment of chronic obstructive pulmonary disease, administered by the inhaled route.
Figure imgf000003_0001
Tiotropium Additionally ipratropium is a muscarinic antagonist marketed for the treatment of COPD.
Figure imgf000004_0001
Ipratropium
Other muscarinic receptor modulators have been referred to. For example: US4353922 describes muscarinic modulators based upon a [2.2.1]azabicycloheptane ring system. EP418716 and US005610163 describe various [3.2.1]azabicyclooctane ring systems. WO06/017768 describes [3.3.1]azabicyclononane ring systems. [2.2.2]azabicyclooctane systems
(quinuclidines) have been previously described, for example in US2005/0209272 and WO06/048225. [3.1.0]azabicyclohexane systems have been described in, for example in WO06/035282. [3.2.1 ]azabicyclooctane systems have been described in for example WO06/035303.
The class of β2 adrenergic receptor agonists is well known. Many known β2-agonists, in particular, long-acting β2-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 β2 agonists are described in Expert Opin. Investig. Drugs 14 (7), 775-783 (2005). A well known β2-agonist pharmacophore is the moiety:
Figure imgf000004_0002
Also known in the art are pharmaceutical compositions that contain both a muscarinic antagonist and a β2-agonist for use in the treatment of respiratory disorders. For example, US2005/0025718 describes a β2-agonist in combination with tiotropium, oxotropium, ipratropium and other muscarinic antagonists; WO02/060532 describes the combination of ipratropium with β2-agonists and WO02/060533 describes the combination of oxotropium with β2-agonists. Other M3 antagonist / β2-agonist combinations are described in WO04/105759 and WO03/087097.
Also known in the art are compounds possessing both muscarinic receptor antagonist and β2-agonist activity present in the same molecule. 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, WO05/1 11004, WO06/023457 and WO06/023460, all of which use different linker radicals for covalently linking the M3 antagonist to the β2-agonist.
Summary of the Invention
According to the invention, there is provided a compound of formula (I):
Figure imgf000005_0001
wherein A is an oxygen atom or group -N(R12)-;
(i) R1 is CrC6-alkyl or hydrogen; and R2 is a group-Z-NR9R10; and R3 is a lone pair, or Ci-C6-alkyl; or
(ii) R1 and R3 together with the nitrogen to which they are attached form a heterocycloalkyl ring, and R2 is a group -Z-NR9R10, or
(iii) R1 and R2 together with the nitrogen to which they are attached form a heterocycloalkyl ring, said ring being substituted by a group , -Z-NR9R10; and R3 is a lone pair, or CrC6-alkyl;
R4 is selected from one of the groups of formula (a), (b), (c) or (d);
Figure imgf000006_0001
(a) (b) (C) (d)
R6 is CrC6-alkyl or a hydrogen atom;
R7a and R7b are a CrC6-alkyl group or halogen;
n and m are independently 0, 1 , 2 or 3;
R8a and R8b are independently selected from the group consisting of aryl, aryl-fused- heterocycloaikyl, heteroaryl, Ci-C6-alkyl, cycloalkyl;
R8c is -OH, Ci-Ce-alkyl, hydroxy-CrCe-alkyl, nitrile, a group CONR8d 2 or a hydrogen atom;
R8d is CrC6-alkyl or a hydrogen atom;
R9 is a hydrogen atom or CrC6-alkyl;
R10 is an aryl(CrC6-alkyI)-, or heteroaryl(CrC6-alkyl) group, in which the C,-C6-alkyl group is optionally substituted by hydroxy;
R12 is CrC6-alkyl or a hydrogen atom;
Ar1 is aryl, heteroaryl or cycloalkyl;
Ar2 are independently aryl, heteroaryl or cycloalkyl; and
Q is an oxygen atom, -CH2-, -CH2CH2- or a bond;
Z is a linker
-C(L3)(L4)-L-C(L1)(L2)-, wherein the compounds of formula (I) may be represented by formula (Ia)
Figure imgf000007_0001
wherein R1, R3, R4, and A are as defined for formula (I), and L is a hydrocarbyl chain of up to 14 carbon atoms wherein one, two or three carbon atoms of the chain are replaced by groups independently selected from O1 NR45, S, S(O), S(O)2, C(O)O, OC(O), NR46C(O), C(O)NR47, NR48S(O)2, S(O)2NR49, NR50C(O)NR51, NR52S(O)2NR53, OC(O)NR54, NR55C(O)O, provided that any heteroatoms in the chain are separated by at least 2 carbon atoms; and/or wherein up to four carbon atoms of the chain form part of a mono- or bicyclic aliphatic, heteroaliphatic, aromatic or heteroaromatic ring having up to three heteroatoms independently selected from N, O or S, said ring comprising up to 10 ring atoms, and wherein the ring is optionally substituted by up to three substituents independently selected from halogen, S(O)0-2R56, NR57R58, S(O)2NR59R60, C(O)NR61R62, C(O)OR63, NR64S(O)2R65, NR66C(O)R67, NR68C(O)OR69,
NR70C(O)NR71R72, OR73, C1-6 alkyl and C3.6cycloalkyl, and wherein Ci-6 alkyl and C3-6 cycloalkyl may be optionally substituted by up to three substituents independently selected from halogen, hydroxyl and C1-6 alkoxy; and the chain may comprise up to three of such rings each selected independently; wherein R56, R65 and R69 each independently represent Ci.6 alkyl or C3-6 cycloalkyl, wherein C1^ alkyl and C3-6 cycloalkyl may be optionally substituted by up to three substituents independently selected from halogen, hydroxyl, C1-6 alkoxy; and
R 45 rj46 ΓJ47 Q48 D49 Q50 rj51 Q52 D53 Q54 r)55 pS7 rj58 Q59 1360 o61 Q62 D63 Γ-I64 , n , ri , rι , π , n , ri , rι , ri , π , ri , ri , r"i , π , ri , π , π , π , ri ,
R66, R67, R68 , R70, R71, R72 and R73 each independently represent hydrogen, or C1-6 alkyl or C3-6 cycloalkyl, wherein C1-6 alkyl and C3-6 cycloalkyl may be optionally substituted by up to three substituents independently selected from halogen, hydroxyl, C1-6 alkoxy; or any of R57 and R58, R59 and R60, R61 and R62 or R71 and R72, together with the nitrogen atom to which they are both attached, may form a 4 to 8 membered aliphatic heterocyclic ring, wherein the aliphatic heterocyclic ring may comprise up to three heteroatoms independently selected from N, O and S, wherein the ring may be optionally substituted by up to three substituents independently selected from halogen, hydroxyl and C1-6 alkyl or C3-6 cycloalkyl, wherein C1-6 alkyl and C3-6 cycloalkyl may be optionally substituted by one or more substituents independently selected from halogen and hydroxyl; and wherein the chain may additionally comprise up to three carbon-carbon double bonds; wherein the chain may additionally comprise up to three carbon-carbon triple bonds;
L1 and L2 each independently represent hydrogen, Ci-6 alkyl or C3-6 cycloalkyl; L3 and L4 each independently represent hydrogen, C1-6 alkyl or C3-6 cycloalkyl, wherein C1.6 alkyl and C3-6 cycloalkyl may be optionally substituted by one or more substituents independently selected from halogen and hydroxyl; in addition L1 and/or L3 may be linked to carbon atoms of the hydrocarbyl chain in linker L to form aliphatic rings of up to 6 ring atoms, wherein each ring may comprise up to three heteroatoms independently selected from N, O and S; and wherein, unless otherwise specified, each occurrence of alkyl, heterocycloalkyl, aryl, aryl-fused-heterocycloalkyl, heteroaryl, cycloalkyl, alkoxy, alkylene, alkenylene, alkynylene or aryl-fused-cycloalkyl may be optionally substituted; or a pharmaceutically acceptable salt thereof.
In another aspect the present invention provides a prodrug of a compound of formula (I) as herein defined, or a pharmaceutically acceptable salt thereof.
In yet another aspect the present invention provides an N-oxide of a compound of formula (I) as herein defined, or a prodrug or pharmaceutically acceptable salt thereof.
In a further aspect the present invention provides a solvate (such as a hydrate) of a compound of formula (I) as herein defined, or an N-oxide, prodrug or pharmaceutically acceptable salt thereof.
In an additional aspect, the present invention provides compounds of formula (I), as defined above, wherein, unless otherwise specified, each occurrence of alkyl may be optionally substituted with one or more substituent groups chosen from C1-C6- haloalkyl, CrC6-alkoxy, CrC6-haloalkoxy, CN and halo; and each occurrence of heterocycloalkyl, aryl, aryl-fused-heterocycloalkyl, heteroaryl, cycloalkyl, alkoxy or aryl-fused-cycloalkyl may be optionally substituted with one or more substituent groups chosen from CrC6-alkyl, CrC6-haloalkyl, Ci-C6-haloalkoxy, CrC6-alkoxy, CN and halo.
In an alternative aspect, the present invention provides compounds of formula (I), as defined above, wherein, unless otherwise specified, each occurrence of alkyl, heterocycloalkyl, aryl, aryl-fused-heterocycloalkyl, heteroaryl, cycloalkyl, alkoxy or aryl-fused-cycloalkyl is not substituted.
In one subset of the compounds of the invention:
A is an oxygen atom;
R1 is CrC6-alkyl ; R2 is a group -Z-NR9R10 and R3 is a lone pair or CrC6-alkyl, or: R1 and R2 together with the nitrogen to which they are attached represent .a heterocycloalkyl ring, said ring being substituted by a group -Z-NR9R10 and R3 is a lone pair or CrCeralkyl; or:
R1 and R3 together with the nitrogen to which they are attached represent a heterocycloalkyl ring, and R2 is a group -Z-NR9R10;
R4 is selected from one of the groups of formula (a), (b) or (c):
Figure imgf000009_0001
(a) (b) (C)
R6 is a hydrogen atom;
R and R are independently a CrC6-alkyl group or halogen;
n and m are independently 0, 1, 2 or 3;
R8a and R8b are independently selected from the group consisting of aryl, heteroaryl, CrC6-alkyl, cycloalkyl; R is -OH, CrC6-alkyl, hydroxy-CrC6-alkyl, or a hydrogen atom;
R9 is a hydrogen atom or CrC6-alkyl;
R >1η0u is a group ArCH(OH)CH2- or a group ArCH2CH2- wherein Ar is a group
Figure imgf000010_0001
wherein
M1 is S, C(O), NA5, CA6A7, CH2CH2, CH=CH, CH2O or OCH2;
M2 is S, C(O), NA5, CA6A7, CH2CH2, CH=CH, CH2O or OCH2;
A1, A2, A3 and A4 are, independently, hydrogen, halogen, trifluoromethyl, cyano, carboxy, hydroxy, nitro, S(O)2A8, NA9S(O)2A10, C(O)NA11A12, NA13C(O)A14, C1-6 alky], C1-6 alkoxy, C(O)(C1-6 alkyl) or C(O)OC1-S alkyl; and A3 can also be CH2OH, NHCHO, NHS(O)2NA15A16 or NHSO2A17;
A5, A6, A7, A9, A11, A12, A13, A14, A15 or A16 are, independently, hydrogen or C1-6 alkyl; A8, A10 and A17 are, independently, C1-6 alkyl.
More conveniently Ar is selected from
Figure imgf000011_0001
wherein
M1 is S, CH=CH1 CH2O or OCH2;
M2 is S, CH=CH, CH2O or OCH2;
A1, A2, and A4 are, independently, hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy; and A3 can also be CH2OH, NHCHO1 NHS(O)2NA15Alb or NHSO2A 117.
A or A are independently selected from hydrogen or C1-6 alkyl;
A v 117Ms C1-S alkyl;
Examples of C1-6 alkyl include C1-4 alkyl and C1^ alkyl.
Examples of Ci-6 alkoxy include C1-4 alkoxy and C1-2 alkoxy.
More conveniently Ar is selected from:
Figure imgf000011_0002
wherein A1 , A2 and A4 are all hydrogen, A3 is CH2OH, NHCHO and M1 is CH=CH or S.
In a further subset of compounds of the invention:
A is an oxygen atom;
R1 is CrC6-alkyl ; R2 is a group -Z-NR9R10 and R3 is a lone pair or CrC6-alkyl, or: R1 and R2 together with the nitrogen to which they are attached represent a heterocycloalkyl ring, said ring being substituted by a group -Z-NR9R10 and R3 is a lone pair or CrC6-alkyl; or:
R1 and R3 together with the nitrogen to which they are attached represent a heterocycloalkyl ring, and R2 is a group -Z-NR9R10;
R4 is selected from one of the groups of formula (a), (b) or (c):
Figure imgf000012_0001
(a) (b) (C)
In the group (a):
Ar1 is a phenyl group; R6 is a hydrogen atom; n and m are 0;
In the group (b):
R and R >8b are both a phenyl group; or, R and R are both a thienyl group, or R 38a is a phenyl group and R b is a cycloalkyl group, such as cyclopentyl or cyclohexyl;
R is -OH or CrC6-alkyl (especially methyl or ethyl); In a further embodiment, R is -OH;
In the group (c):
Ar2 is a phenyl ring
Q is an oxygen atom or alternatively a direct bond R80 is hydrogen, C1-6 alkyl
(especially methyl) or -OH
R9 is a hydrogen atom or Ci-C6-alkyl;
R10 is an ary^CrCe-alkyl)-, or heteroaryl(CrC6-alkyl) group, selected from the group
Figure imgf000013_0001
Figure imgf000013_0002
In some compounds of the invention, the radical -C(L1)(L2)-L-C(L3)(L4)- is
(i) -(CH2)s-O-(CH2)t-B-(CH2)u-, wherein B is a phenylene radical and s is 2 or 3, t is O,
1 or 2, and u is 1 or 2; or
(ii) -(CH2)v-C(O)NR47-B-(CH2)u-, wherein v is 1 or 2 and R47, B is a phenylene radical, and u is 1 or 2; or
(iii) -(CH2)V-NR47C(O)-B-(CH2)U-, wherein v is 1 or 2, R47 is conveniently hydrogen, but may also be d-6 alkyl such as methyl or ethyl, or C3-6 cycloalkyl such as cyclopropyl, B is a phenylene radical, and u is 1 or 2; or
(iv) -(CH2)v-C(O)NR47-(CH2)w-; wherein w is 3-8 and v and R47 are as defined in case
(iii); or
(v) -(CH2)S-B-(CH2)U-, wherein B is a phenylene radical and s is 1 ,2 or 3 and u is 1 ,2 or 3
Compounds of the invention are β2-adrenergic binding compounds. Such compounds may be antagonists, partial agonists or full agonists. Compounds that are antagonists are useful tools, for example, for the generation of structure-activity relationships and as radioligands. Compounds that are partial or full agonists may be useful as pharmacological compounds for the treatment of the diseases described above. Compounds that are antagonists are conveniently those wherein Z1 is a group of formula (Ic), whilst those that are partial or full agonists are conveniently those wherein Z1 is a group of formula (Ib). Compounds of the invention exist in either the syn- or anti- forms;
Figure imgf000014_0001
syn- anti-
Compounds of the invention also exist with the group -AR4 in either the exo or endo orientation;
Figure imgf000014_0002
endo- exo-
Conveniently the compounds of the invention are predominantly in the anti-endo configuration.
Figure imgf000014_0003
anti-, endo- Compounds of the invention can also exist as optical isomers since substituted bicyclic ring systems can lack a plane of symmetry. The absolute configuration of the molecule can be defined using Cahn-lngold-Prelog rules to assign the R or S designation to each position. To avoid confusion the ring numbering used below is employed.
Figure imgf000014_0004
However, compounds of the invention include racemates, single enantiomers and mixtures of the enantiomers in any ratio, since all such forms have muscarinic M3 receptor modulating activity to varying extents.
A convenient class of compounds of the invention consists of compounds of formula (I) wherein the nitrogen attached to R1 and R3 is a tertiary nitrogen.
Another convenient class of compounds of the invention consists of compounds of formula (I) wherein the nitrogen attached to R1 and R3 is a quaternary nitrogen and carries a positive charge. 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; 'wheezy-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 disorders such as irritable bowel syndrome, spasmodic colitis, gastroduodenal ulcers, gastrointestinal convulsions or hyperanakinesia, diverticulitis, pain accompanying spasms of gastrointestinal smooth musculature; urinary-tract disorders accompanying micturition disorders including neurogenic pollakisuria, neurogenic bladder, nocturnal enuresis, psychosomatic bladder, incontinence associated with bladder spasms or chronic cystitis, urinary urgency or pollakiuria; motion sickness; and cardiovascular disorders such as vagally induced sinus bradycardia.
For treatment of respiratory conditions, administration by inhalation will often be convenient, and in such cases administration of compounds (!) which are quaternary ammonium salts will often be convenient. In many cases, the duration of action of quaternary ammonium salts of the invention administered by inhalation is may be more than 12, or more than 24 hours for a typical dose. For treatment of gastrointestinal-tract disorders and cardiovascular disorders, administration by the parenteral route, usually the oral route, may be convenient. Another aspect of the invention is a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier or excipient.
Another aspect of the invention is the use of a compound of the invention for the manufacture of a medicament for the treatment or prevention of a disease or condition in which muscarinic M3 receptor activity and β2-adrenergic activity are implicated. Diseases or conditions in which muscarinic M3 receptor activity and β2- adrenergic activity are implicated include respiratory-tract disorders, gastrointestinal- tract disorders and cardiovascular disorders. Specific examples of such diseases and conditions include those listed above.
Another aspect of the invention provides a compound of the invention for the treatment or prevention of a disease or condition in which muscarinic M3 receptor activity and β2-adrenergic activity are implicated. Diseases or conditions in which muscarinic M3 receptor activity and β2-adrenergic activity are implicated include respiratory-tract disorders, gastrointestinal-tract disorders and cardiovascular disorders. Specific examples of such diseases and conditions include those listed above.
Another aspect of the invention provides a method of treatment of a disease or condition in which M3 muscarinic receptor activity and β2-adrenergic activity are implicated comprising administration to a subject in need thereof a therapeutically effective amount of a compound of the invention. Diseases or conditions in which muscarinic M3 receptor activity and β2-adrenergic activity are implicated include respiratory-tract disorders, gastrointestinal-tract disorders and cardiovascular disorders. Specific examples of such diseases and conditions include those listed above.
Another aspect of the invention provides a compound of the invention for use in therapy.
Terminology
Unless otherwise qualified in the context in which they are used herein, the following terms have the following meanings: . "Acyl" means a -CO-alkyl group in which the alkyl group is as described herein. Exemplary acyl groups include -COCH3 and -COCH(CH3)2.
"Acylamino" means a -NR-acyl group in which R and acyl are as described herein. Exemplary acylamino groups include -NHCOCH3 and -N(CH3)COCH3. "Alkoxy" and "alkyloxy" means an -O-alkyl group in which alkyl is as described below. Exemplary alkoxy groups include methoxy (-OCH3) and ethoxy (-OC2H5). "Alkoxycarbonyl" means a -COO-alkyl group in which alkyl is as defined below. Exemplary alkoxycarbonyl groups include methoxycarbonyi and ethoxycarbonyl. "Alkyl" as a group or part of a group refers to a straight or branched chain saturated hydrocarbon group having from 1 to 12, conveniently 1 to 6, carbon atoms, in the chain. Exemplary alkyl groups include methyl, ethyl, 1 -propyl and 2-propyl..
"Alkenyl" as a group or part of a group refers to a straight or branched chain hydrocarbon group having from 2 to 12, conveniently 2 to 6, carbon atoms and one . carbon-carbon double bond in the chain. Exemplary alkenyl groups include ethenyl, 1-propenyl, and 2-propenyl.
"Alkynyl" as a group or part of a group refers to a straight or branched chain hydrocarbon group having from 2 to 12, conveniently 2 to 6, carbon atoms and one carbon-carbon triple bond in the chain. Exemplary alkenyl groups include ethynyl, 1- propynyl, and 2-propynyl.
"Alkylamino" means a -NH-alkyl group in which alkyl is as defined above. Exemplary alkylamino groups include methylamino and ethylamino.
"Alkylene means an -alkyl- group in which alkyl is as defined previously. Exemplary alkylene groups include -CH2-, -(CH2)2- and -C(CH3)HCH2-. "Alkenylene" means an -alkenyl- group in which alkenyl is as defined previously. Exemplary alkenylene groups include -CH=CH-, -CH=CHCH2-, and - CH2CH=CH-.
"Alkynylene" means an -alkynyl- group in which alkynyl is as defined previously. Exemplary alkenylene groups include -CC-, -CCCH2-, and -CH2CC-. "Alkylsulfinyl" means a -SO-alkyl group in which alkyl is as defined above.
Exemplary alkylsulfinyl groups include methylsulfinyl and ethylsulfinyl.
"Alkylsulfonyl" means a -SO2-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 -CONH2 and -CONHCH3.
"Aminoalkyl" means an alkyl-NH2 group-in which alkyl is as previously described. Exemplary aminoalkyl groups include -CH2NH2. "Aminosulfonyl" means a -SO2-NRR group in which R is as herein described.
Exemplary aminosulfonyl groups include -SO2NH2 and -SO2NHCH3.
"Aryl" as a group or part of a group denotes an optionally substituted monocyclic or multicyclic aromatic carbocyclic moiety of from 6 to 14 carbon atoms, conveniently from 6 to 10 carbon atoms, such as phenyl or naphthyl. 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. Convenient arylalkyl groups contain a C1 4 alkyl moiety.
Exemplary arylalkyl groups include benzyl, phenethyl and naphthlenemethyl. The aryl part thereof may be substituted by one or more substituent groups. "Arylalkyloxy" means an aryl-alkyloxy- group in which the aryl and alkyloxy moieties are as previously described. Convenient arylalkyloxy groups contain a C1 4 alkyl moiety. Exemplary arylalkyl groups include benzyloxy. The aryl part thereof may be substituted by one or more substituent groups.
"Aryl-fused-heterocycloalkyl" means a monocyclic aryl ring, such as phenyl, fused to a heterocycloalkyl group, in which the aryl and heterocycloalkyl are as described herein. Exemplary aryl-fused-heterocycloalkyl groups include tetrahydroquinolinyl, indolinyl, benzodioxinyl, benzodioxolyl, dihydrobenzofuranyl and isoindolonyl. The aryl and heterocycloalkyl rings may each be substituted by one or more substituent groups. The aryl-fused-heterocycloalkyl group may be attached to the remainder of the compound by any available carbon or nitrogen atom.
"Aryloxy" means an -O-aryl group in which aryl is described above. Exemplary aryloxy groups include phenoxy. The aryl part thereof may be substituted by one or more substituent groups.
"Cyclic amine" is a special case of "Heterocycloalkyl" or "heterocyclic" and means an optionally substituted 3 to 8 membered monocyclic cycloalkyl ring system where one of the ring carbon atoms is replaced by nitrogen, and which may optionally contain an additional heteroatom selected from O, S or NR (where R is as described herein). Exemplary cyclic amines include pyrrolidine, piperidine, morpholine, piperazine and Λ/-methylpiperazine. The cyclic amine group may be substituted by one or more substituent groups. "Cycloalkyl" means an optionally substituted saturated monocyclic or bicyclic ring system of from 3 to 12 carbon atoms, conveniently from 3 to 8 carbon atoms, and more conveniently from 3 to 6 carbon atoms. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl. The cycloalkyl group may be substituted by one or more substituent groups.
"Dialkylamino" means a -N(alkyl)2 group in which alkyl is as defined above.
Exemplary dialkylamino groups include dimethylamino and diethylamino.
"Halo" or "halogen" means fluoro, chloro, bromo, or iodo. Convenient are fluoro or chloro. "Haloalkoxy" means an -O-alkyl group in which the alkyl is substituted by one or more halogen atoms. Exemplary haloalkyl groups include trifluoromethoxy and difluoromethoxy.
"Haloalkyl" means an alkyl group which is substituted by one or more halo atoms. Exemplary haloalkyl groups include trifluoromethyl. "Heteroaryl" as a group or part of a group denotes an optionally substituted aromatic monocyclic or multicyclic organic moiety of from 5 to 14 ring atoms, conveniently from 5 to 10 ring atoms, in which one or more of the ring atoms is/are element(s) other than carbon, for example nitrogen, oxygen or sulfur. Examples of such groups include benzimidazolyl, benzoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, furyl, imidazolyl, ϊndolyl, indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl, oxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, tetrazolyl, 1 ,3,4-thiadiazolyl, thiazolyl, thienyl and triazolyl groups. The heteroaryl group may be may be substituted by one or more substituent groups. The heteroaryl group may be attached to the remainder of the compound of the invention by any available carbon or nitrogen atom.
"Heteroarylalkyl" means a heteroaryl-alkyl- group in which the heteroaryl and alkyl moieties are as previously described. Convenient heteroarylalkyl groups contain a lower alkyl moiety. Exemplary heteroarylalkyl groups include pyridylmethyl. The heteroaryl part thereof may be substituted by one or more substituent groups. "Heteroarylalkyloxy" means a heteroaryl-alkyloxy- groαp in which the heteroaryl and alkyloxy moieties are as previously described. Convenient heteroarylalkyloxy groups contain a lower alkyl moiety. Exemplary heteroarylalkyloxy groups include pyridylmethyloxy. The hetroaryl part thereof may be substituted by one or more substituent groups. "Heteroaryloxy" means a heteroaryloxy- group in which the heteroaryl is as previously described. Exemplary heteroaryloxy groups include pyridyloxy. The heteroaryl part thereof may be substituted by one or more substituent groups.
"Heterocycloalkyl" or "heterocyclic" means: (i) an optionally substituted cycloalkyl group of from 4 to 8 ring members which contains one or more heteroatoms selected from O, S or NR; (ii) a cycloalkyl group of from 4 to 8 ring members which contains CONR and CONRCO (examples of such groups include succinimidyl and 2-oxopyrrolidinyl). The heterocycloalkyl group may be be substituted by one or more substituents groups. The heterocycloalkyl group may be attached to the remainder of the compound by any available carbon or nitrogen atom.
"Lower alkyl" as a group means unless otherwise specified, an aliphatic hydrocarbon group which may be straight or branched having 1 to 4 carbon atoms in the chain, i.e. methyl, ethyl, propyl (propyl or /so-propyl) or butyl (butyl, /sobutyl or tert- butyl). "Phenylene" means a -phenyl- group. Exemplary groups are 1,3-phenylene and 1 ,4-phenylene.
"Sulfonyl" means a -SO2-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 -NHSO2CH3. 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. For example (i) where a compound of the invention contains one or more acidic groups, for example carboxy groups, pharmaceutically acceptable base addition salts that may be formed include sodium, potassium, calcium, magnesium and ammonium salts, or salts with organic amines, such as, diethylamine, Λ/-methyl-glucamine, diethanolamine or amino acids (e.g. lysine) and the like; (ii) where 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, xinafoates, succinates and the like; (iii) when R3 is not a lone pair the compound of formula (I) has a quaternary ammonium group for which the counter-ion may be, for example, chloride, bromide, sulfate, methanesulfonate, benzenesulfonate, toluenesulfonate (tosylate), napadisylate (naphthalene-1 ,5-disulfonate or naphthalene-1 -(sulfonic acid)-5-sulfonate), edisylate (ethane- 1 ,2-disulfonate or ethane-1 -(sulfonic acid)-2- sulfonate), isethionate (2-hydroxyethylsulfonate), phosphate, acetate, citrate, lactate, tartrate, mesylate, maleate, malate, fumarate, xinafoate, p-acetamidobenzoate and succinate; wherein the number of quaternary ammonium species balances the counter-ion such that compound of formula (I) has no net charge.
It will be understood that, as used herein, references to the compounds of the invention are meant to also include the pharmaceutically acceptable salts.
"Prodrug" refers to a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis, reduction or oxidation) to a compound of the invention. For example an ester prodrug of a compound of the invention containing a hydroxy group may be convertible by hydrolysis in vivo to the parent molecule. Suitable esters of compounds of the invention containing a hydroxy group, are for example acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-β-hydroxynaphthoates, gentisates, isothionates, di-p-toluoyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates and quinates. As another example an ester prodrug of a compound of the invention containing a carboxy group may be convertible by hydrolysis in vivo to the parent molecule. Examples of ester prodrugs are those described by F. J. Leinweber, Drug Metab. Res., 1987, 18, 379.
It will be understood that, as used in herein, references to the compounds of the invention are meant to also include the prodrug forms. "Saturated" pertains to compounds and/or groups which do not have any carbon-carbon double bonds or carbon-carbon triple bonds.
Optionally substituted" means optionally substituted with up to four susbtituents. Optional substituent groups include acyl (e.g. -COCH3), alkoxy (e.g., -
OCH3), alkoxycarbonyl (e.g. -COOCH3), alkylamino (e.g. -NHCH3), alkylsulfinyl (e.g. -SOCH3), alkylsulfonyl (e.g. -SO2CH3), alkylthio (e.g. -SCH3), -NH2, aminoacyl (e.g. - CON(CH3)2), aminoalkyl (e.g. -CH2NH2), arylalkyl (e.g. -CH2Ph or -CH2-CH2-Ph), cyano, dialkylamino (e.g. -N(CHJJ, halo, haloalkoxy (e.g. -OCF, or -OCHF0), haloalkyl (e.g. -CFJ, alkyl (e.g. -CH or -CH CHJ, -OH, -NO2, aryl (optionally substituted with alkoxy, haloalkoxy, halogen, alkyl or haloalkyl), heteroaryl (optionally substituted with alkoxy, haloalkoxy, halogen, alkyl or haloalkyl), heterocycloalkyl, aminoacyl (e.g. -CONH2, -CONHCH3), aminosulfonyl (e.g. -SO2NH2, -SO2NHCH3), acylamino (e.g. -NHCOCH3), sulfonylamino (e.g. -NHSO2CH3), heteroarylalkyl, cyclic amine (e.g. morpholine), aryloxy, heteroaryloxy, arylalkyloxy (e.g. benzyloxy) and heteroarylalkyloxy. Alkylene, alkenylene or alkynylene radicals may be optionally substituted.
Optional substituent groups in the foregoing radicals include alkoxy (e.g., -OCH3), alkylamino (e.g. -NHCH3), alkylsulfinyl (e.g. -SOCH3), alkylsulfonyl (e.g. -SO2CH3), alkylthio (e.g. -SCHJ, -NH2, aminoalkyl (e.g. -CH0NH0), arylalkyl (e.g. -CH Ph or -CH -CH -Ph), cyano, dialkylamino (e.g. -N(CHJJ, halo, haloalkoxy (e.g. -OCF, or -OCHF2), haloalkyl (e.g. -CF3), alkyl (e.g. -CH3 or -CH2CH3), -OH, and -NO2.
Compounds of the invention may exist in one or more geometrical, optical, enantiomeric, diastereomeric and tautomeric forms, including but not limited to cis- and frans-forms, E- and Z-forms, R-, S- and meso-forms, keto-, and enol-forms.
Unless otherwise stated a reference to a particular compound includes all such isomeric forms, including racemic and other mixtures thereof. Where appropriate such isomers can be separated from their mixtures by the application or adaptation of known methods (e.g. chromatographic techniques and recrystallisation techniques).
Where appropriate such isomers may be prepared by the application of adaptation of known methods (e.g. asymmetric synthesis). In one embodiment, the present invention provides a compound of formula (I) selected from:
Hydroxy-di-thiophen-2-yl-acetic acid (1 S,2R,4S,7S)-7-{[2-(4-{[(R)-2-hydroxy-2-
(4-hydroxy-2-oxo-2,3-dihydro-benzothiazol-7-yl)-ethylamino]-methyl}-benzoylamino)- ethyl]-methyl-amino}-bicyclo[2.2.1 ]hept-2-yl ester; Hydroxy-di-thiophen-2-yl-acetic acid (1S,2R,4S,7S)-7-{[3-(4-{[(R)-2-hydroxy-2-
(4-hydroxy-2-oxo-2,3-dihydro-benzothiazol-7-yl)-ethylamino]-methyl}-phenoxy)- propyl]-methyl-amino}-bicyclo[2.2.1 ]hept-2-yl ester;
Hydroxy-di-thiophen-2-yl-acetic acid (1 S,2R,4S,7S)-7-{[2-(4-{[(R)-2-hydroxy-2-
(8-hydroxy-2-oxo-1 ,2-dihydro-quinolin-5-yl)-ethylamino]-methyl}-benzoylamino)- ethyl]-methyl-amino}-bicyclo[2.2.1]hept-2-yl ester;
Hydroxy-di-thiophen-2-yl-acetic acid 7-{[3-(2-hydroxy-ethyl)-benzyl]-methyl- amino}-bicyclo[2.2.1]hept-2-yl acetate;
Hydroxy-di-thiophen-2-yl-acetic acid (1 S,2R,4S,7S)-7-{[(4-{[(R)-2-hydroxy-2-
(4-hydroxy-2-oxo-2,3-dihydro-benzothiazol-7-yl)-ethylamino]-methyl}- phenylcarbamoyO-methylj-methyl-aminoJ-bicyclop^.ilhept^-yl ester; Hydroxy-di-thiophen-2-yl-acetic acid (1 S,2R,4S,7S)-7-{[(4-{[(R)-2-hydroxy-2-
(8-hydroxy-2-oxo-1 ,2-dihydro-quinolin-5-yl)-ethylamino]-methyl}-phenylcarbamoyl)- methyl]-methyl-amino}-bicyclo[2.2.1]hept-2-yl ester;
Hydroxy-di-thiophen-2-yl-acetic acid (1 S,2R,4S,7S)-7-{[2-(4-{[(R)-2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydro-quinolin-5-yl)-ethylamino]-methyl}-benzoylamino)- ethyl]-methyl-amino}-bicyclo[2.2.1]hept-2-yl ester;
Hydroxy-di-thiophen-2-yl-acetic acid (1 S,2R,4S,7S)-7-{[2-(4-{[(R)-2-hydroxy-2- (4-hydroxy-2-oxo-2,3-dihydro-benzothiazol-7-yl)-ethylamino]-methyl}-phenyl- carbamoyl)-ethyl]-methyl-amino}-bicyclo[2.2.1]hept-2-yl ester Hydroxy-di-thiophen-2-yl-acetic acid (1S,2R,4S,7S)-7-{[(4-{[(R)-2-hydroxy-2-
(8-hydroxy-2-oxo-1 ,2-dihydro-quinolin-5-yl)-ethylamino]-methyl}-phenylcarbamoyl)- methyl]-methyl-amino}-bicyclo[2.2.1 ]hept-2-ylester g-Hydroxy-ΘH-xanthene-g-carboxylic acid (1 S,2R,4S,7S)-7-{[3-(4-{[(R)-2- hydroxy-2-(4-hydroxy-2-oxo-2,3-dihydro-benzothiazol-7-yl)-ethylamino]-methyl}- phenoxy)-propyl]-methyl-amino}-bicyclo[2.2.1]hept-2-yl ester
; θ-Hydroxy-ΘH-xanthene-θ-carboxylic acid (1S,2R,4S,7S)-7-{[3-(4-{[(R)-2- hydroxy-2-(8-hydroxy-2-oxo-1 ,2-dihydro-quinolin-5-yl)-ethylamino]-methyl}-phenoxy)- propyl]-methyl-amino}-bicyclo[2.2.1]hept-2-yl ester;
(R)-Cyclohexyl-hydroxy-phenyl-acetic acid (1 S,2R,4S,7S)-7-{[3-(4-{[(R)-2- hydroxy-2-(4-hydroxy-2-oxo-2,3-dihydro-benzothiazol-7-yl)-ethylamino]-methyl}- phenoxy)-propyl]-methyl-amino}-bicyclo[2.2.1 ]hept-2-yl ester;
(R)-Cyclohexyl-hydroxy-phenyl-acetic acid (1 S,2R,4S,7S)-7-{[3-(4-{[(R)-2- hydroxy-2-(8-hydroxy-2-oxo-1 ,2-dihydro-quinolin-5-yl)-ethylamino]-methyl}-phenoxy)- propyl]-methyi-amino}-bicyclo[2.2.1 ]hept-2-yl ester; and pharmaceutically acceptable salts thereof.
Other convenient compounds of the invention include:
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Each of the compounds identified above, taken alone or with any combination of the other compounds identified herein represents an independent aspect of the invention.
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. Thus the present invention is also concerned with pharmaceutical compositions for preventing and treating respiratory-tract disorders such as chronic obstructive lung disease, chronic bronchitis, asthma, chronic respiratory obstruction, pulmonary fibrosis, pulmonary emphysema, and allergic rhinitis comprising a therapeutically effective amount of a compound of the invention and one or more other therapeutic agents. Other compounds may be combined with compounds of this invention for the prevention and treatment of inflammatory diseases of the lung. Accordingly the invention includes a combination of an agent of the invention as hereinbefore described with one or more antiinflammatory, 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. Convenient 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;
A leukotriene modulator, for example montelukast, zafirlukast or pranlukast; protease inhibitors, such as inhibitors of matrix metalloprotease for example MMP 12 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,
WO05/082863, WO05/082864, WO03/053930;
Phosphodiesterase-4 (PDE4) inhibitors, for example roflumilast, arofylline, cilomilast, ONO-6126 or lC-485;
Phosphodiesterase-7 inhibitors;
An antitussive agent, such as codeine or dextramorphan;
Kinase inhibitors, particularly P38 MAPKinase inhibitors;
P2X7 anatgonists; iNOS inhibitors;
A non-steroidal anti-inflammatory agent (NSAID), for example ibuprofen or ketoprofen;
A dopamine receptor antagonist;
TNF-α 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,
CCR3, CXCR2, CXCR3, CX3CR1 and CCR8, such as SB-332235, SB-656933, SB- 265610, SB-225002, MCP-1(9-76), RS-504393, MLN-1202, INCB-3284; Compounds which modulate the action of prostanoid receptors, for example a PGD2
(DP1 or CRTH2), or a thromboxane A2 antagonist eg ramatroban; Compounds which modulate Th1 or Th2 function, for example, PPAR agonists; lnterleukin 1 receptor antagonists, such as Kineret; lnterleukin 10 agonists, such as llodecakin;
HMG-CoA reductase inhibitors (statins); for example rosuvastatin, mevastatin, lovastatin, simvastatin, pravastatin and fluvastatin;
Mucus regulators such as INS-37217, diquafosol, sibenadet, CS-003, talnetant, DNK- 333, MSI-1956, gefitinib; Antiinfective agents (antibiotic or antiviral), and antiallergic drugs including, but not limited to, antihistamines.
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.
The magnitude of 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. In general, the daily dose range for inhalation will lie within the range of from about 0.1 μg to about 10 mg per kg body weight of a human, conveniently 0.1 μg to about 0.5 mg per kg, and more conveniently 0.1 μg to 50μg 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. Conveniently, a unit dose comprises the active compound in an amount of 1 μg to 10 mg. For oral administration suitable doses are "lOμg per kg to 100mg per kg, conveniently 40μg per kg to 4 mg per kg.
Another aspect of the present invention provides pharmaceutical compositions which comprise a compound of the invention and a pharmaceutically acceptable carrier. The term "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. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the invention, additional active ingredient(s), and pharmaceutically acceptable excipients.
The pharmaceutical 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. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable rion-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.
For delivery by inhalation, the active compound is conveniently in the form of microparticles. They may be prepared by a variety of techniques, including spray- drying, freeze-drying and micronisation.
By way of example, 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). Propellants suitable for use in a PMDI are known to the skilled person, and include CFC-12, HFA-134a, HFA-227, HCFC-22 (CCI2F2) and HFA-152 (C2H4F2) and isobutane. In a convenient embodiment of the invention, a composition of the invention is in dry powder form, for delivery using a dry powder inhaler (DPI). Many types of DPI are known.
Microparticles for delivery by administration may be formulated with excipients that aid delivery and release. For example, in a dry powder formulation, 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 μm.
In the case of an aerosol-based formulation, an example is: Compound of the invention 24 mg / canister Lecithin, NF Liq. Cone. 1.2 mg / canister
Trichlorofluoromethane, NF 4.025 g / canister Dichlorodifluorometriane, NF 12.15 g / canister.
The active compounds may be dosed as described depending on the inhaler system used. In addition to the active compounds, 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.
For the purposes of inhalation, 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. In addition to the use of adaptors (spacers, expanders) and pear-shaped containers (e.g. Nebulator®, Volumatic®), and automatic devices emitting a puffer spray (Autohaler®), for 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). Additionally, compounds of the invention may be delivered in multi-chamber devices thus allowing for delivery of combination agents.
Methods of Synthesis The invention further provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above which comprises:
(a) when L1 represents hydrogen and R1 does not represent hydrogen, reacting a compound of formula (I!)
Figure imgf000030_0001
wherein LG1 represents a leaving group such as chloride, bromide, iodide, methanesulfonate or para-toluenesulfonate, and L, L2, L3, L4, R1, R4, and A are as defined in formula (I), with a compound of formula (III), or a suitable salt thereof such as a hydrobromide, acetate or hydrochloride salt
Figure imgf000030_0002
wherein Ar is as defined in formula (I) and P1 is hydrogen or a protective group such as terf-butyldimethyl silyl in the presence of a base such as potassium carbonate, triethylamine or diisopropylethylamine, followed by removal of the protective group (e.g. using a hydrofluoric acid-pyridine complex); or
(b)when L1 represents hydrogen and R1 does not represent hydrogen, reacting a compound of formula (IV), or a suitable salt thereof
Figure imgf000030_0003
wherein L, L2, L3, L4, A, R1 and R4 are as defined in formula (I), 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
(c) when L1 represents hydrogen and R1 represents hydrogen, reacting a compound of formula (V)
Figure imgf000031_0001
wherein LG1 represents a leaving group such as chloride, bromide, iodide, methanesulfonate or pa/a-toluenesulfonate, P2 represents a protective group (e.g. tθrt-butylcarbonyf) and L, L2, L3, L4, A and R4 are as defined in formula (I), 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
(d) when L1 represents hydrogen and R1 represents hydrogen, reacting a compound of formula (Vl)
Figure imgf000031_0002
wherein L, L2, L3, L4, A and R4 are as defined in formula (I), P2 represents a protective group (e.g. tert-butylcarbonyl) with a compound of formula (III), or a suitable salt thereof (e.g. hydrobromide, hydrochloride salt or acetate), in the presence of a suitable reducing agent (e.g. sodium cyanoborohydride, sodium triacetoxyborohydride, or hydrogen in the presence of a suitable palladium on carbon or platinum oxide catalyst), followed by removal of the protective group (e.g. treatment with hydrochloric or trifluoroacetic acid); or (e) when R1 does not represent hydrogen, reacting a compound of formula (VII), or a suitable salt thereof
Figure imgf000032_0001
wherein L, L1, L2, L3, L4, A, R1 and R4 are as defined in formula (I), P3 represents hydrogen or an activating group (e.g. 3-nitrophenylsulfonyl) with a compound of formula (VIII), or a suitable salt thereof,
Figure imgf000032_0002
wherein Ar is as defined in formula (I), LG2 represents a leaving group (e.g. chloride, bromide, iodide, methanesulfonate or para-toluenesulfonate) and P1 is as defined in compound of formula (III) in the presence of a base (e.g. when P3 is hydrogen, potassium carbonate, triethylamine, diisopropylethylamine and, when P3 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,
Figure imgf000032_0003
wherein Ar is as defined in formula (I) in the presence of a base (e.g. when P3 is hydrogen, potassium carbonate, triethyiamine, diisopropylethylamine and, when P3 is 3-nitrophenylsulfonyl, sodium hydride or lithium di-/so-propylamide), followed by removal of the protective groups (e.g. trifluoroacetic acid, thiophenol, thioacetic acid); or with a compound of formula (X), or a suitable salt thereof,
Figure imgf000032_0004
wherein Ar is as defined in formula (I), LG2 represents a leaving group (e.g. chloride, bromide, iodide, methanesulfonate or para-toluenesulfonate) in the presence of a base (e.g. when P3 is hydrogen, potassium carbonate, triethylamine, diisopropylethylamine and, when P3 is 3-nitrophenylsulfonyl, sodium hydride or lithium di-/so-propy!amide), 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 R1 represents hydrogen, reacting a compound of formula (Xl)
Figure imgf000033_0001
wherein L, L1, L2, L3, L4, A and R4 are as defined in formula (I), P2 represents a protective group (e.g. terf-butylcarbonyl), P3 represents hydrogen or an activating group (e.g. 3-nitrophenylsulfonyl), with a compound of formula (VIII), (IX) or (X), or a suitable salt thereof, in the presence of a base (e.g. when P3 is hydrogen, potassium carbonate, triethylamine, diisopropylethylamine and when P3 is 3-nitrophenylsulfonyl, sodium hydride or lithium di-/so-propylamide), followed by removal of the protective groups (e.g. using trifluoroacetic acid, thiophenol, thioacetic acid); or (g) when L3 and L4 each represents hydrogen, reacting a compound of formula (XII)
Figure imgf000033_0002
wherein Ar, L, L1, and L2 are as defined in formula (I), P1 is as defined in compound of formula (III), P3 represents a protective group (e.g. tert-butylcarbonyl or 3- nitrophenylsulfonyl) with a compound of formula (XIII), or a suitable salt thereof,
Figure imgf000034_0001
wherein A, R4 and R1 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 L3 and L4 represents hydrogen, reacting a compound of formula (XIV)
Figure imgf000034_0002
wherein Ar, L1 L1, and L2 are as defined in formula (I), P1 is as defined in compound of formula (III), P3 represents a protective group (e.g. terf-butylcarbonyl or 3- nitrophenylsulfonoyl), LG3 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 L1 and L2 each represents hydrogen and R1 do not represent hydrogen, reacting a compound of formula (XV), or a suitable salt thereof,
Figure imgf000034_0003
wherein Ar, L, L3, L4, A, R1 and R4 are as defined in formula (I) and P1 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,
(j) when L1 and L2 each represents hydrogen and R1 represents hydrogen, reacting a compound of formula (XVI)
Figure imgf000035_0001
wherein Ar, L, L3, L4, A and R4 are as defined in formula (I) and P2 is as defined in compound of formula (Xl) with a suitable reducing agent (e.g. borane tetrahydrofuran complex), followed by removal of the protective group (e.g. using hydrofluoric acid- pyridine complex); and optionally after (a), (b), (c), (d), (e), (f), (g), (h), (i) or (j) carrying out one or more of the following:
• converting the compound obtained to a further compound of the invention
• forming a pharmaceutically acceptable salt of the compound.
In process variants (a), (c), (e), (f) and (h), the reaction may conveniently be carried out in an organic solvent such as Λ/,Λ/-dimethylformamide, ethanol, π-butanol or dimethyl sulfoxide, at a temperature, for example, in the range from 50 to 14O0C. In process variants (b), (d) and (g), the reaction may conveniently be carried out in an organic solvent such as methanol, ethanol, dichloromethane, acetic acid N- methylpyrolidinone, or /V,/V-dimethylformamide containing up to 10%w of water and acetic acid.
In process variants (i) and (j), the reaction may conveniently be carried out in an organic solvent such as tetrahydrofuran, at a temperature, for example, in the range from 0 to 800C.
Compounds of formula (II) may be prepared by reacting a compound of formula (XVII), or a suitable salt thereof,
Figure imgf000036_0001
wherein L, L3, L4, R1,, R4 and A are as defined in formula (II), with a compound of formula (XVIII)
L Mt (XVIII)
wherein L2 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 600C, followed by conversion of the resulting hydroxy! group into 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 6O0C, 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, Λ/,Λ/-dimethylformamide or dimethylsulfoxide at a temperature, for example in the range from -78 to 6O0C. Compounds of formula (V) may be prepared by reacting a compound of formula (XIX)
Figure imgf000036_0002
wherein P2, L, L3, L4, A and R4are 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 600C, followed by conversion of the resulting hydroxyl group into a suitable leaving group (e.g. chloride, bromide, iodide, methanesulfonate or para-toluenesulfonate).
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, Λ/,Λ/-dimethylformamide or dimethylsulfoxide at a temperature, for example in the range from -78 to 600C.
Compounds of formula (VII) in which L1 represents hydrogen and L, L2, L3, L4, A and R4 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, Λ/,Λ/-dimethylformamide or dimethylsulfoxide at a temperature, for example in the range from 25 to 850C, 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, of-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, Λ/-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. hydrogen and a suitable catalyst (Palladium on carbon or palladium hydroxide), 2,3- dichloro-5,6-dicyanobenzoquinone (DDQ), or ammonium cerium nitrate (CAN)) in an organic solvent, for example, ethanol, methanol, tetrahydrofuran, dichloromethane, acetonitrile, water, or a mixture thereof, at a temperature ranging from 25 to 800C, 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);
Compounds of formula (VII) may be prepared by reacting a compound of formula (XX)
Figure imgf000037_0001
wherein. LG4 is a leaving group (e.g. hydroxyl or chloride), L, L1, L2, L3, L4, A, R4 and R1 are as defined in formula (VII), with reagents such as, when LG4 is hydroxyl, diphenylphosphonic azide, in a presence of an amine (e.g. triethylamine), in an organic, solvent, for example, te/t-butanol, tetrahydrofuran, dichloromethane, water, or a mixture thereof, at a temperature ranging from 25 to 1000C, or when LG4 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 1000C (Angewandte Chemie, 2005, 54, 5188), eventually followed by protection of the resulting amine (e.g. treatment with 3-nitrophenylsulfonyl chloride in the presence of a base such as pyridine). Compounds of formula (III), (VIII), (IX) and (X) are known in the literature or may be prepared using known techniques.
Compounds of formula (Xl) in which L1 represents hydrogen may be prepared by (a) reacting a compound of formula (V) with sodium azide in an organic solvent, for example, tetrahydrofuran, Λ/,Λ/-dimethylformamide or dimethylsulfoxide at a temperature, for example in the range from 25 to 85°C, followed by reduction of the resulting azido compound using a suitable reducing agent (e.g. triphenylphosphine or hydrogen) in an organic solvent for example, tetrahydrofuran and water, eventually followed by protection of the resulting amine (e.g. treatment with 3-nitrophenylsulfonyl chloride in the presence of a base such as pyridine); or (b) reacting a compound of formula (Vl) with an amine (e.g. benzylamine, a-methyl benzylamine, 4-methoxybenzyl amine or 2,4-methoxybenzyl amine), followed by reduction of the resulting imine using a suitable reducing agent (e.g. sodium cyanoborohydride, sodium triacetoxyborohydride) in an organic solvent such as methanol, ethanol, dichloromethane, acetic acid /V-methylpyrolidinone, or N,N- dimethylformamide containing up to 10%w of water and acetic acid, followed by removal of the resulting benzyl protective group using the appropriate reagent (e.g. hydrogen and a suitable catalyst (Palladium on carbon or palladium hydroxide), 2,3- dichloro-5,6-dicyanobenzoquinone (DDQ), or ammonium cerium nitrate (CAN)) in an organic solvent, for example, ethanol, methanol, tetrahydrofuran, dichloromethane, acetonitrile, water, or a mixture thereof, at a temperature ranging from 25 to 800C, eventually followed by protection of the resulting amine (e.g. treatment with 3- nitrophenylsulfonyl chloride in the presence of a base such as pyridine).
Compounds of formula (Xl) may be prepared by reacting a compound of formula (XXI)
Figure imgf000039_0001
wherein L4 is a leaving group (e.g. hydroxyl or chloride), L, L1, L2, L3, L4, A, R4 and P2 are as defined in formula (Xl), with reagents such as, when LG4 is hydroxyl, diphenylphosphonic azide, in a presence of an amine (e.g. triethylamine), in an organic solvent, for example, te/f-butanol, tetrahydrofuran, dichloromethane, water, or a mixture thereof, at a temperature ranging from 25 to 1000C, or when LG4 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 1000C (Angewandte Chemie, 2005, 54, 5188), eventually followed by protection of the resulting amine (e.g. treatment with 3-nitrophenylsulfonyl chloride in the presence of a base such as pyridine). Compounds of formula (XII) can be prepared by (a) reacting a compound of formula (XXII)
Figure imgf000039_0002
wherein P5 is hydrogen or a protective group (e.g. tert-butyldimethylsilyl, tetrahydropyran) and L, L1 and L2 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 P3 is hydrogen and sodium hydride or lithium di-/so-propylamide when P3 is 3-nitrophenylsulfonyl) in an organic solvent such as /V,/V-dimethylformamide, Λ/-methylpyrolidinone, tetrahydrofuran, ethanol, n-butanol or dimethyl sulfoxide, at a temperature, for example, in the range from 50 to 1400C. When reacting with compound of formula (X), this is followed by reduction of the ketone (e.g. using sodium borohydride or a borane/chiral catalyst complex). Appropriate selective removal of the protective group (e.g. hydrofluoric acid-pyridine complex, tetrabutylamonium fluoride, diluted hydrochloric acid or amberlyst-15 resin in methanol) and oxidation of the resulting alcohol into the corresponding aldehyde with a suitable oxidating agent (pyridinium chlorochromate, Dess-martin reagent or Swem reagent) lead to compound of formula
(XII); or
(b) reacting a compound of formula (XXIlI)
Figure imgf000040_0001
(XXIII) wherein P6 and P7 represent an acyclic or cyclic carbonyl protective group (e.g. dimetoxy or diethoxy acetal, 1 ,3-dioxolane or 1 ,3-dioxane) and L, L1, L2, and P3 are as defined in formula (XII), with a compound of formula (VlII), (IX) or (X), or a suitable salt thereof, in the presence of a base (e.g. potassium carbonate, triethylamine or diisopropylethylamine when P3 is hydrogen and sodium hydride or lithium di-/so- propylamide when P3 is 3-nitrophenylsulfonyl) in an organic solvent such as N, N- dimethylformamide, Λ/-methylpyrolidinone, tetrahydrofuran, ethanol, n-butanol or dimethyl sulfoxide, at a temperature, for example, in the range from 50 to 140°C. When reacting with compound of formula (X), this is followed by reduction of the ketone (e.g. using sodium borohydride or a borane/chiral catalyst complex). Removal of the protective group (e.g. diluted hydrochloric acid or amberlyst-15 resin in methanol) lead to compound of formula (XlI); or
(c) when L1 represents hydrogen, reacting a compound of formula (XXIV)
Figure imgf000040_0002
wherein P5 is hydrogen or a protective group (e.g. tert-butyldimethylsilyl, tetrahydropyran) and, L and L2 are as defined in formula (XII), with a compound of formula (III), or a suitable salt thereof, in the presence of a suitable reducing agent (e.g. sodium cyanoborohydride, sodium triacetoxyborohydride, or hydrogen in the presence of a suitable palladium on carbon or platinum oxide catalyst) in an organic solvent such as methanol, ethanol, dichloromethane, acetic acid, N- methypyrolidinone or /V,Λ/-dimethylformamide containing up to 10%w of water and acetic acid, followed by appropriate selective removal of the protective group (e.g. hydrofluoric acid-pyridine complex, tetrabutylamonium fluoride, diluted hydrochloric acid or amberlyst-15 resin in methanol) and oxidation of the resulting alcohol into the corresponding aldehyde with a suitable oxidating agent (pyridinium chlorochromate, Dess-Martin reagent or Swern reagent); or (d) when R1 represents hydrogen, reacting a compound of formula (XXV)
Figure imgf000041_0001
wherein P6 and P7 represent an acyclic or cyclic carbonyl protective group (e.g. dimethoxy or diethoxy acetal, 1 ,3-dioxolane or 1 ,3-dioxane) and, L and L2 are as defined in formula (XII), with a compound of formula (111), or a suitable salt thereof, in the presence of a suitable reducing agent (e.g. sodium cyanoborohydride, sodium triacetoxyborohydride, or hydrogen in the presence of a suitable palladium on carbon or platinum oxide catalyst) in an organic solvent such as methanol, ethanol, dichloromethane, acetic acid, Λ/-methypyrolidinone or Λ/,Λ/-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)
Figure imgf000041_0002
wherein L, L3, L4, A and R4 are as defined in formula (XV), P8 represents either R4 as defined in compound of formula (XV) or P2 as defined in compound of formula (XVI) and LG6 represent hydroxyl or a leaving group (e.g. chloride) with a compound of formula (III), or a suitable salt thereof.
When LG6 represents hydroxyl, the reaction is conveniently carried out in the presence of an activating reagent, for example, carbonyldiimidazole or O-(7- azabenzotriazol-1 -yl)-Λ/,Λ/,Λ/',Λ/-tetramethyluroniumhexaf luorophosphate (HATU), in an organic solvent, for example, Λ/,Λ/-dimethylformamicle or dichloromethane, at a temperature, for example in the range from 0 to 600C,
When LG6 represents chloride, the reaction is conveniently carried out in the presence of a base, for example, triethylamine or diisopropylethylamine in an organic solvent, for example, dichloromethane or tetrahydrofuran at a temperature, for example, in the range from 0 to 250C.
- for compound of formula (VII), P represents R , P represents
Figure imgf000042_0001
wherein L, L1, L2, L3, L4 and P3 are as defined in compound of formula (VII); - for compound of formula (Xl), P9 represents P2, P10 represents
Figure imgf000042_0002
wherein L1 L1, L2, L3, L4, P2 and P3 are as defined in compound of formula (Xl);
- for compound of formula (XIII), P9 and P10 represents represents an appropriate nitrogen protecting group, such as terf-butoxycarbonyl, followed by suitable deprotection (e.g. trifluoroacetic acid acid);
- for compound of formula (XVII), P9 represents R4, P10 represents
Figure imgf000042_0003
wherein L, L3, and L4 are as defined in compound of formula (XVlI), wherein
P11 and P12 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); - for compound of formula (XIX), P9 represents P2, P10 represents
Figure imgf000043_0001
wherein L, L3, and L4 are as defined in compound of formula (XIX), wherein P11 and P12 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);
- for compound of formula (XX), P9 represents R4, P10 represents
Figure imgf000043_0002
wherein L, L1, L2, L3, and L4 are as defined in compound of formula (XX), wherein P14 represent an acid protective group (e.g. methyl, ethyl or tert-butyl), followed by suitable deprotection (e.g. lithium hydroxide or sodium hydroxide, trifluoroacetic acid, hydrochloric acid);
- for compound of formula (XXI), P9 represents P2, P10 represents
Figure imgf000043_0003
wherein L, L1, L2, L3, and L4 are as defined in compound of formula (XXI), wherein P14 represent an acid protective group (e.g. methyl, ethyl or tert-butyl), followed by suitable deprotection (e.g. lithium hydroxide or sodium hydroxide, trifluoroacetic acid, hydrochloric acid);
- for compound of formula (XXVI), P9 represents P8, P10 represents
Figure imgf000043_0004
Compounds of formula (XIII) in which A is an oxygen atom may be prepared according to the route outlined in Scheme 1 ;
Figure imgf000044_0001
(XXXVl) (XXXV-a) (XXXIV-a)
Figure imgf000044_0003
(Xlll-b) (XXXVIII)
Scheme 1 wherein W is as defined in compound of formula (I), when R1 do not represent hydrogen, P9 represents R1; when R1 represents hydrogen then P9 represents an appropriate nitrogen protecting group, such as terf-butoxycarbonyl.
Compounds of formula (Xlll-a) wherein R4is the group of formula (a), and R38, Ar1 and R80 are as defined above for formula (I) may be prepared from compounds of formula (XXVII) wherein R9 and R10 are as defined above, by reaction with a compound of formula (XXVIII):
Figure imgf000045_0001
(XXVIII)
wherein Ar1, R80 and n are as defined for formula (I). The reaction may take place in a range of non-nucleophilic organic solvents such as DMF or toluene at a range of temperatures, conveniently between 00C and the reflux temperature of the solvent.
Compounds of formula (XXVII) may be prepared using methods described in WO07/017670.
Compounds of formula (Xlll-a) in which W is the group of formula (b) as defined above, may be prepared from compounds of formula (XXVII) by reaction with a compound of formula (XXIX):
Figure imgf000045_0002
wherein R1, R2, and R3 are as defined for formula (I) and LG7 is a leaving group, for example, an O-alkyl, halogen or 1-imidazolyl group. The reaction is conducted in the presence of a strong base such as NaH in a solvent such as toluene, THF or dichloromethane at a range of temperatures, convenientlybetween 0 0C and the reflux temperature of the solvent.
Compounds of formula (XXIX) wherein R1, R2, and R3 are as defined for formula (I) and LG7 is an O-alkyl, halogen or 1-imidazolyl group can be prepared from compounds of formula (XXX) by known methods.
Figure imgf000045_0003
(XXX) Compounds of formula (XXX) are well known in the art and are readily available or can be prepared by known methods such as those described in WO01/041 18
Compounds of formula (Xlll-a) in which W is the group of formula (c) as defined above,. may be prepared from compounds of formula (XXVII) by reaction with a compound of formula (XXXI):
Figure imgf000046_0001
wherein Ar2 and R3 are as defined for formula (I) and LG8 is a leaving group, for example, an O-alkyl, halogen or 1-imidazolyl group. The reaction is conducted in the presence of a strong base such as NaH in a solvent such as toluene, THF ordichloromethane at a range of temperatures, conveniently between 0 0C and the reflux temperature of the solvent.
Figure imgf000046_0002
(XXXII)
Compounds of formula (XXXI)) can be prepared from compounds of formula (XXXII) by known methods.
Compounds of formula (XXXII) are well known in the art and are readily available or can be prepared by known methods.
Compounds of formula (Xlll-a) in which W is the group of formula (d) as defined above and R3 is -OH, may be prepared from compounds of formula (XXVII) by reaction with a compound of formula (XXXIII):
Figure imgf000046_0003
(XXXlIl) The reaction is conducted in the presence of a strong base such as NaH in a solvent such as toluene, THF, conveniently DMSO at a range of temperatures, conveniently between 0 °C and the reflux temperature of the solvent.
Compounds of formula (XXXIII) are well known in the art and are readily available or can be prepared by known methods.
Compounds of formula (XXVII) can be prepared from compounds of formula (XXXIV- a) by reaction with a suitable reducing agent, conveniently a bulky reducing agent such as LiAIH(O1Bu)3. The reaction is carried out in a polar organic solvent conveniently THF at a range of temperatures, conveniently from -78 °C up to the reflux temperature of the solvent.
Compounds of formula (XXXIV-a) can be prepared from compounds of formula (XXXV-a) by reaction with a tin reagent, conveniently Bu3SnH and a radical initiator, conveniently AIBN. The reaction can be performed in a range of solvents, conveniently toluene, at a range of temperatures, conveniently between ambient temperature and the reflux temperature of the solvent.
Compounds of formula (XXXV-a) can be prepared from compounds of formula (XXXVI) by reaction with an amine formula (XXXVII)):
R9R10NH (XXXVII)
The reaction is performed in a range of solvents, conveniently THF/DCM at a range of temperatures, conveniently between 0 and 100 0C.
Compounds of formula (XXXVI) are known in the art: J. Chem. Soc. Perkin Trans I (1975) 1767-1773; Synthesis (1997), 155-166.
Compounds of formula (XXXVII) are well known in the art and can be prepared by known methods, or are commercially available, or may be prepared by methods described above.
Compounds of formula (Xlll-b) may be prepared from compounds of formula
(XXXVIII) by reaction with a tin reagent, conveniently Bu3SnH and a radical initiator, conveniently AIBN. The reaction can be performed in a range of solvents, conveniently toluenes at a range of temperatures, conveniently between ambient temperature and the reflux temperature of the solvent.
Compounds of formula (XXXVIII) may be prepared from compounds of formula (XXXIX) by reaction with a brominating agent, conveniently triphenylphosphine in carbon tetrabromide as solvent.
Compounds of formula (XXXIX) can be prepared from compounds of formula (XL) by reaction with a suitable reducing agent, conveniently sodium borohydride. The reaction is carried out in a polar organic solvent conveniently THF at a range of temperatures, conveniently from -78 °C up to the reflux temperature of the solvent.
Compounds of formula (XL) can be prepared from compounds of formula (XLI) by analogous methods to those used to prepare compounds of formula (Xlll-a) from compounds of formula (XXVII).
Compounds of formula (XLI) can be prepared from compounds of formula (XLII):
Figure imgf000048_0001
by reaction with an amine of formula (XXXVII). The reaction is performed in a range of solvents, conveniently THF/DCM at a range of temperatures, conveniently between 0 and 1000C.
Compounds of formula (XLII) are described in GB2075503.
Figure imgf000049_0001
(XXXIV-a)
Figure imgf000049_0002
(XLIlI) (XLIV)
Scheme 2
The preparation of compounds of formula (XLIII) wherein A is a group NR37, W is a group (b) and R1 and R2 are all as described in formula (i) above, and and R3 is OH, is outlined in Scheme 2.
Compounds of Formula (XLIII) may be prepared from compounds of Formula (XLIV) by treatment with an organometallic reagent of Formula (XLV);
R2 - Mt (XLV)
Where Mt is a metal species such as lithium or Mg-halide, especially a Grignard reagent in a suitable inert solvent such as THF or diethyl ether at a temperature between -78° and the reflux temperature of the solvent, convenientlyconveniently between 0° and ambient temperature. Compounds of Formula (XLV) are known in the art or may be prepared according to known methods.
Compounds of Formula (XLIV) may be prepared from compounds of Formula (XLVI) by treatment with a compound of formula (XLVII);
Figure imgf000049_0003
(XLVII) Wherein R1 is as described in formula (I) and LG9 is a leaving group, especially a halogen group, optionally in the presence of a suitable solvent such as dichloromethane, in the absence or presence of a base such as diisopropylethylamine. Compounds of formula (XLVII) are commercially available or readily prepared according to the literature.
Compounds of Formula (XLVI) may be prepared from compounds of Formula (XLVIII) by reduction of the oxime with a suitable reducing agent, such as a borohydride reagent, specifically NaBH4ZNiCIa in a suitable solvent such as methanol at a suitable temperature, such as 20° C.
Compounds of Formula (XLVIII) may be prepared from compounds of Formula (XXXIV-a) by treatment with hydroxylamine or a salt thereof in the presence of a suitable solvent such as methanol, optionally in the presence of a base such as sodium acetate, at a temperature between 0° C and the reflux temperature of the solvent, conveniently at ambient temperature.
Compounds of formula (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXIV), (XXV) and (XXVIII), (XXIX), (XXX) and (XXXI) are either commercially available, known in the literature, or can be readily prepare by those skilled in the art using one of the process described above or using known techniques.
Compounds of formula (Xlll-a) and (Xlll-b) exist in two enantiomeric forms which can be separated by chiral preparative HPLC using conditions know to those skilled in the art and exemplified below. Alternatively, as the absolute configuration of compounds (Xlll-a) and (Xlll-b) are dictated by the absolute configuration of compounds (XXXVI) and (XLII) respectively, and compounds (XXXVI) and (XLII) are known in the literature (see EP0074856A2) one skilled in the art will recognise that use of homochiral starting material will deliver homochiral product of defined stereochemistry.
It will be appreciated by those skilled in the art that in the processes of the present invention certain functional groups such as hydroxyl or amino groups in the reagents may need to be protected by protecting groups. Thus, the preparation of the compounds of formula (I) may involve, at an appropriate stage, the removal of one or more protecting groups. The protection and deprotection of functional groups is described in 'Protective
Groups in Organic Chemistry', edited by J.W.F. McOmie, Plenum Press (1973) and 'Protective Groups in Organic Synthesis', 3rd edition, T.W. Greene and P.G.M. Wuts, Wiley-lnterscience (1999).
Compounds of formula (I) can be converted into further compounds of formula (I) using standard procedures.
The compounds of formula I have activity as pharmaceuticals, in particular as dual adrenergic β2 receptor agonists and anticholinergic agents including muscarinic receptor (M1 , M2, and M3) antagonists, in particular M3 antagonists. Diseases and conditions which may be treated with the compounds of formula (I) and their pharmaceutically acceptable salts include:
1. 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, and pulmonary hypertension; antitussive activity including treatment of chronic cough associated with inflammatory and secretory conditions of the airways, and iatrogenic cough; acute and chronic rhinitis including rhinitis medicamentosa, and vasomotor rhinitis; perennial and seasonal allergic rhinitis including rhinitis nervosa (hay fever); nasal polyposis; acute viral infection including the common cold, and infection due to respiratory syncytial virus, influenza, coronavirus (including SARS) or adenovirus; or eosinophilic esophagitis;
2. bone and joints: arthritides 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 erythematosus, mixed connective tissue disease, and undifferentiated connective tissue disease; inflammatory myopathies including dermatomyositits and polymyositis; polymalgia rheumatica; juvenile arthritis including idiopathic inflammatory arthritides of whatever joint distribution and associated syndromes, and rheumatic fever and its systemic complications; vasculitides including giant cell arteritis, Takayasu's arteritis, Churg-Strauss syndrome, polyarteritis nodosa, microscopic polyarteritis, and vasculitides associated with viral infection, hypersensitivity reactions, cryoglobulins, and paraproteins; low back pain; Familial Mediterranean fever, Muckle-Wells syndrome, and Familial Hibernian Fever, Kikuchi disease; drug-induced arthalgias, tendonititides, and myopathies;
3. pain and connective tissue remodelling of musculoskeletal disorders due to injury [for example sports injury] or disease: 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, scleroderma, mixed connective tissue disorder, spondyloarthropathies or periodontal disease (such as periodontitis);
4. 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; panniculitisjcutaneous lymphomas, non-melanoma skin cancer and other dysplastic lesions; drug-induced disorders including fixed drug eruptions;
5. eyes: blepharitis; conjunctivitis, including perennial and vernal allergic conjunctivitis; iritis; anterior and posterior uveitis; choroiditis; autoimmune; degenerative or inflammatory disorders affecting the retina; ophthalmitis including sympathetic ophthalmitis; sarcoidosis; infections including viral , fungal, and bacterial;
6. 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);
7. 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);
9. 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;
10. CNS: Alzheimer's disease and other dementing disorders including CJD and nvCJD; amyloidosis; multiple sclerosis and other demyelinating syndromes; cerebral atherosclerosis and vasculitis; temporal arteritis; myasthenia gravis; acute and chronic pain (acute, intermittent or persistent, whether of central or peripheral origin) including visceral pain, headache, migraine, trigeminal neuralgia, atypical facial pain, joint and bone pain, pain arising from cancer and tumor invasion, neuropathic pain syndromes including diabetic, post-herpetic, and HIV-associated neuropathies; neurosarcoidosis; central and peripheral nervous system complications of malignant, infectious or autoimmune processes;
11. other auto-immune and allergic disorders including Hashimoto's thyroiditis, Graves' disease, Addison's disease, diabetes mellitus, idiopathic thrombocytopaenic purpura, eosinophilic fasciitis, hyper-lgE syndrome, antiphospholipid syndrome;
12. other disorders with an inflammatory or immunological component; including acquired immune deficiency syndrome (AIDS), leprosy, Sezary syndrome, and paraneoplastic syndromes;
13. 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); vasGulitides; disorders of the proximal and peripheral veins including phlebitis and thrombosis, including deep vein thrombosis and complications of varicose veins;
14. oncology: treatment of common cancers including prostate, breast, lung, ovarian, pancreatic, bowel and colon, stomach, skin and brain tumors and malignancies affecting the bone marrow (including the leukaemias) and lymphoproliferative systems, such as Hodgkin's and non-Hodgkin's lymphoma; including the prevention and treatment of metastatic disease and tumour recurrences, and paraneoplastic syndromes; and,
15. gastrointestinal tract: Coeliac disease, proctitis, eosinopilic gastro-enteritis, mastocytosis, Crohn's disease, ulcerative colitis, microscopic colitis, indeterminant colitis, irritable bowel disorder, irritable bowel syndrome, non-inflammatory diarrhea, food-related allergies which have effects remote from the gut, e.g., migraine,, rhinitis and eczema.
Thus, the present invention provides a compound of formula (I) or a pharmaceutically-acceptable salt thereof as hereinbefore defined for use in therapy. In a further aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined in the manufacture of a medicament for use in therapy.
In the context of the present specification, the term "therapy" also includes "prophylaxis" unless there are specific indications to the contrary. The terms "therapeutic" and "therapeutically" should be construed accordingly.
Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the disease or condition in question. Persons at risk of developing a particular disease or condition generally include those having a family history of the disease or condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the disease or condition.
The invention still further provides a method of treating, or reducing the risk of, an inflammatory disease or condition (including a reversible obstructive airways disease or condition) which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined.
In particular, 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. For the above-mentioned therapeutic uses the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated. For example, the daily dosage of the compound of the invention, if inhaled, may be in the range from 0.05 micrograms per kilogram body weight (μg/kg) to 100 micrograms per kilogram body weight (μg/kg).
Alternatively, if the compound is administered orally, then the daily dosage of the compound of the invention may be in the range from 0.01 micrograms per kilogram body weight (μg/kg) to 100 milligrams per kilogram body weight (mg/kg).
The compounds of formula (I) and pharmaceutically acceptable salts thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (I) compound/salt (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier. 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.
Depending on the mode of administration, the pharmaceutical composition will convenientlycomprise from 0.05 to 99 %w (per cent by weight), more conveniently from 0.05 to 80 %w, still more conveniently from 0.10 to 70 %w, and even more conveniently 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 (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined, in association with a pharmaceutically acceptable adjuvant, diluent or carrier. The invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined with a pharmaceutically acceptable adjuvant, diluent or carrier.
The pharmaceutical compositions may be administered topically (e.g. to the skin or to the lung and/or airways) in the form, e.g., of creams, solutions, suspensions, heptafluoroalkane (HFA) aerosols and dry powder formulations, for example, formulations in the inhaler device known as the Turbuhaler®; or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules; or by parenteral administration in the form of solutions or suspensions; or by subcutaneous administration; or by rectal administration in the form of suppositories; or transdermally. Dry powder formulations and pressurized HFA aerosols of the compounds of the invention may be administered by oral or nasal inhalation. For inhalation, the compound is desirably finely divided. The finely divided compound conveniently has a mass median diameter of less than 10 μm, and may be suspended in a propellant 5. mixture with the assistance of a dispersant, such as a C8-C2O 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 a0 dry powder inhaler. The inhaler may be a single or a multi dose inhaler, and may be a breath actuated dry powder inhaler.
One possibility is to mix the finely divided compound of the invention with 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,5 melezitose, lactitol, maltitol, trehalose, sucrose, mannitol; and starch. Alternatively the finely divided compound may be coated by another substance. The powder mixture may also be dispensed into hard gelatine capsules, each containing the desired dose of the active compound.
Another possibility is to process the finely divided powder into spheres which break up during the inhalation procedure. This spheronized powder may be filled into the drug reservoir of a multidose inhaler, for example, that known as the Turbuhaler® in which a dosing unit meters the desired dose which is then inhaled by the patient. With this system the active ingredient, with or without a carrier substance, is delivered to the patient. For oral administration 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. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide. Alternatively, the tablet may be coated with a suitable polymer dissolved in a readily volatile organic solvent. For the preparation of soft gelatine capsules, 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. Optionally 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.
In particular, for the treatment of the inflammatory diseases such as (but not restricted to) rheumatoid arthritis, osteoarthritis, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), psoriasis, and inflammatory bowel disease, the compounds of the invention may be combined with the following agents: nonsteroidal anti-inflammatory agents (hereinafter NSAIDs) including non-selective cyclo- oxygenase COX-1 / COX-2 inhibitors whether applied topically or systemically (such as piroxicam, diclofenac, propionic acids such as naproxen, flurbiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac, azapropazone, pyrazolones such as phenylbutazone, salicylates such as aspirin); selective COX-2 inhibitors (such as meloxicam, celecoxib, rofecoxib, valdecoxib, lumarocoxib, parecoxib and etoricoxib); cyclo-oxygenase inhibiting nitric oxide donors (CINODs); glucocorticosteroids (whether administered by topical, oral, intramuscular, intravenous, or intra-articular routes); methotrexate; leflunomide; hydroxychloroquine; d-penicillamine; auranofin or other parenteral or oral gold preparations; analgesics; diacerein; intra-articular therapies such as hyaluronic acid derivatives; and nutritional supplements such as glucosamine.
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-α) inhibitors such as anti-TNF monoclonal antibodies (for example infliximab; adalimumab, and CDP-870) and TNF receptor antagonists including immunoglobulin molecules (such as etanercept) and low-molecular-weight agents such as pentoxyfylline.
In addition 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).
The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with a modulator of chemokine receptor function such as an antagonist of CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for the C-C family); CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-C family) and CX3CRI for the C-X3-C family.
The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with an inhibitor of matrix metalloprotease (MMPs), i.e., the stromelysins, the collagenases, and the gelatinases, as well as aggrecanase; especially collagenase-1 (MMP-1), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-10), and stromelysin-3 (MMP-1 1) and MMP-9 and MMP-12, including agents such as doxycycline. The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a leukotriene biosynthesis inhibitor, 5-lipoxygenase (5-LO) inhibitor or 5-lipoxygenase activating protein (FLAP) antagonist such as; zileuton; ABT-761 ; fenleuton; tepoxalin; Abbott- 79175; Abbott-85761 ; a N-(5-substituted)-thiophene-2-alkylsulfonamide; 2,6-di-tert- butylphenolhydrazones; a methoxytetrahydropyrans such as Zeneca ZD-2138; the compound SB-210661 ; a pyridinyl-substituted 2-cyanonaphthalene compound such as L-739,010; a 2-cyanoquinoline compound such as L-746,530; or an indole or quinoline compound such as MK-591, MK-886, and BAY x 1005.
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. selected from the group consisting of the phenothiazin-3-1s such as L-651 ,392; amidino compounds such as CGS-25019c; benzoxalamines such as ontazolast; benzenecarboximidamides such as BIIL 284/260; and compounds such as zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP 45715A), and BAY x 7195.
The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a phosphodiesterase (PDE) inhibitor such as a methylxanthanine including theophylline and aminophylline; a selective PDE isoenzyme inhibitor including a PDE4 inhibitor an inhibitor of the isoform PDE4D, or an inhibitor of PDE5.
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.
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. 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. The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with an agent that modulates a nuclear hormone receptor such as PPARs.
The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with an immunoglobulin (Ig) or Ig preparation or an antagonist or antibody modulating Ig function such as anti-lgE (for example omalizumab).
The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and another systemic or topically-applied anti-inflammatory agent, such as thalidomide or a derivative thereof, a retinoid, dithranol or calcipotriol.
The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and combinations of aminosalicylates and sulfapyridine such as sulfasalazine, mesalazine, balsalazide, and olsalazine; and immunomodulatory agents such as the thiopurines, and corticosteroids such as budesonide.
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, valaciciovir, ganciclovir, cidofovir, amantadine, rimantadine, ribavirin, zanamavir and oseltamavir; a protease inhibitor such as indinavir, nelfinavir, ritonavir, and saquinavir; a nucleoside reverse transcriptase inhibitor such as didanosine, lamivudine, stavudine, zalcitabine or zidovudine; or a non-nucleoside reverse transcriptase inhibitor such as nevirapine or efavirenz.
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-ad renoceptor 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.
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 donepezϋ, rivastigmine, tacrine, a COX-2 inhibitor, propentofylline or metrifonate. The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an agent for the treatment of acute or chronic pain, such as a centrally or peripherally-acting analgesic (for example an opioid or derivative thereof), carbamazepine, phenytoin, sodium valproate, amitryptiline or other anti-depressant agent-s, paracetamol, or a non- steroidal anti-inflammatory agent.
The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with a parenterally or topically-applied (including inhaled) local anaesthetic agent such as lignocaine or a derivative thereof. A compound of the present invention, or a pharmaceutically acceptable salt thereof, can also be used in combination with an anti-osteoporosis agent including a hormonal agent such as raloxifene, or a biphosphonate such as alendronate.
The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with a: (i) tryptase inhibitor; (ii) platelet activating factor (PAF) antagonist; (iii) interleukin converting enzyme (ICE) inhibitor; (iv) IMPDH inhibitor; (v) adhesion molecule inhibitors including VLA-4 antagonist; (vi) cathepsin; (vii) kinase inhibitor such as an inhibitor of tyrosine kinase (such as Btk, Itk, Jak3 or MAP, for example Gefitinib or lmatinib mesylate), a serine / threonine kinase (such as an inhibitor of a MAP kinase such as p38, JNK, protein kinase A, B or C, or IKK), or a kinase involved in cell cycle regulation (such as a cylin dependent kinase); (viii) glucose-6 phosphate dehydrogenase inhibitor; (ix) kinin-B.subi . - or B.sub2. -receptor antagonist; (x) anti- gout agent, for example colchicine; (xi) xanthine oxidase inhibitor, for example allopurinol; (xii) uricosuric agent, for example probenecid, sulfinpyrazone or benzbromarone; (xiii) growth hormone secretagogue; (xiv) transforming growth factor (TGFβ); (xv) platelet-derived growth factor (PDGF); (xvi) fibroblast growth factor for example basic fibroblast growth factor (bFGF); (xvii) granulocyte macrophage colony stimulating factor (GM-CSF); (xviii) capsaicin cream; (xix) tachykinin NK.subi. or NK.sub3. receptor antagonist such as NKP-608C, SB-233412 (talnetant) or D-4418; (xx) elastase inhibitor such as UT-77 or ZD-0892; (xxi) TNF-alpha converting enzyme inhibitor (TACE); (xxii) induced nitric oxide synthase (iNOS) inhibitor; (xxiii) chemoattractant receptor-homologous molecule expressed on TH2 cells, (such as a
CRTH2 antagonist); (xxiv) inhibitor of P38; (xxv) agent modulating the function of Toll-like receptors (TLR), (xxvi) agent modulating the activity of purinergic receptors such as P2X7; (xxvii) inhibitor of transcription factor activation such as NFkB, API or STATS; or (xxviii) a glucocorticoid receptor (GR-receptor) agonist.
In a further aspect 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. A compound of the invention, or a pharmaceutically acceptable salt thereof, can also be used in combination with an existing therapeutic agent for the treatment of cancer, for example suitable agents include:
(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 tegaf ur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea, gemcitabine or paclitaxel); an antitumour antibiotic (for example an anthracycline such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin or mithramycin); an antimitotic agent (for example a vinca alkaloid such as vincristine, vinblastine, vindesine or vinorelbine, or a taxoid such as taxol or taxotere); or a topoisomerase inhibitor (for example an epipodophyllotoxin such as etoposide, teniposide, amsacrine, topotecan or a camptothecin); (ii) 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 5α-reductase such as finasteride; (iii) an agent which inhibits cancer cell invasion (for example a metalloproteinase inhibitor like marimastat or an inhibitor of urokinase plasminogen activator receptor function);
(iv) an inhibitor of growth factor function, for example: a growth factor antibody (for example the anti-erbb2 antibody trastuzumab, or the anti-erbb1 antibody cetuximab [C225]), a farnesyl transferase inhibitor, a tyrosine kinase inhibitor or a serine/threonine kinase inhibitor, an inhibitor of the epidermal growth factor family (for example an EGFR family tyrosine kinase inhibitor such as N-(3-chloro-4- fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, AZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) or 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3- morpholinopropoxy)quinazolin-4-amine (Cl 1033)), an inhibitor of the platelet-derived growth factor family, or an inhibitor of the hepatocyte growth factor family; (v) an antiangiogenic agent such as one which inhibits the effects of vascular endothelial growth factor (for example the anti-vascular endothelial cell growth factor antibody bevacizumab, a compound disclosed in WO 97/22596, WO 97/30035, WO 97/32856 or WO 98/13354), or a compound that works by another mechanism (for example linomide, an inhibitor of integrin αvβ3 function or an angiostatin); (vi) a vascular damaging agent such as combretastatin A4, or a compound disclosed in WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 or WO 02/08213;
(vii) 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; (viii) an agent used in a gene therapy approach, for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT
(gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; or (ix) an agent used in an immunotherapeutic approach, for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies. The following non-limiting Examples illustrate the invention.
General Experimental Details: 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. Where thin layer chromatography (TLC) has been used, 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 NH2-silica gel refers to Isolute® flash NH2 prepacked cartridges (Argonaut/IST).
All compounds containing a basic centre(s) and purified by reversed-phase HPLC were obtained as the TFA salt, unless stated otherwise.
Preparative HPLC conditions: HPLC system 1
C18-reverse-phase column (100 x 22.5 mm i.d. Genesis column with 7 μm particle size), eluting using linear gradients of mixtures of solvent A (water with 0.1 % TFA) and solvent B (acetonitrile with 0.1% TFA) at a flow rate of 5 mL/min with UV detection set at 230 nm. HPLC system 2
Phenyl hexyl column (250 x 21.20 mm i.d. Luna column with 5 μm particle size), eluting using linear gradients of mixtures of solvent A (water with 0.1% TFA) and solvent B (acetonitrile with 0.1% TFA) at a flow rate of 18 mL/min with UV detection set at 254 nm. HPLC system 3
C18-reverse-phase column (250 x 21.20 mm Phenomenex Gemini column with 5 μm particle size), eluting using linear gradients of mixtures of solvent A (water with 0.1% formic acid) and solvent B (acetonitrile with 0.1% formic acid) at a flow rate of 5-10 mL/min with UV detection set at 230 nm. HPLC system 4
C8-reverse-phase column (50 x 19 mm i.d. Symmetry column with 5.0 μm particle size), eluting using linear gradients of mixtures of solvent A (water with 0.1% TFA) and solvent B (acetonitrile with 0.1% TFA) at a flow rate of 18.5 mL/min with UV detection set at 220 nm. HPLC system 5
Purification was by reversed phase preparative HPLC using a SunFire™ Prep C18 OBD™ 5 micron 19 x 50 mm column (Waters Corporation) eiuting using linear gradients of mixtures of solvent A (water with 0.1% TFA) and solvent B (acetonitrile with 0.1% TFA) over 11 minutes at a flow rate of 20 mL/min with UV detection set at
220 nm.
The Liquid Chromatography Mass Spectroscopy (LC-MS) systems used:
LC-MS method 1
Micromass Platform LCT with a C 18-re verse-phase column (100 x 3.0 mm i.d.
Higgins Clipeus with 5 μm particle size), elution with solvent A (water with 0.1% formic acid) and solvent B (acetonitrile with 0.1% formic acid). Gradient:
Gradient - Timeflow mL/min %A %B
0.00 1.0 95 5
1.00 1.0 95 5
15.00 1.0 5 95
20.00 1.0 5 95
22.00 1.0 95 5
25.00 1.0 95 5
Detection - MS, ELS, UV (100 μL split to MS with in-line UV detector). MS ionisation method - Electrospray (positive ion).
LC-MS method 2
Micromass Platform LCT with a C18-reverse-phase column (30 x 4.6 mm i.d. Phenomenex Luna 3 μm particle size), elution with solvent A (water with 0.1 % formic acid) and solvent B (acetonitrile with 0.1% formic acid). Gradient:
Gradient - - Timeflow mL/min %A %B
0.00 2.0 95 5
0.50 2.0 95 5
4.50 2.0 5 95
5.50 2.0 5 95 6.00 2.0 95 5
Detection - MS, ELS, UV (100 μl_ split to MS with in-line UV detector). MS ionisation method - Electrospray (positive and negative ion).
LC-MS method 3
Waters Micromass ZQ with a C18-reverse-phase column (30 x 4.6 mm i.d. Phenomenex Luna 3 μm particle size), elution with solvent A (water with 0.1% formic acid) and solvent B (acetonitrile with 0.1 % formic acid). Gradient:
Gradient - Timeflow mL/min %A %B
0.00 2.0 95 5
0.50 2.0 95 5
4.50 2.0 5 95
5.50 2.0 5 95
6.00 2.0 95 5
Detection - MS, ELS, UV (100 μL split to MS with in-line UV detector).
MS ionisation method - Electrospray (positive and negative ion).
LC-MS method 4
Waters ZMD with a C18-reverse-phase column (30 x 4.6 mm i.d. Phenomenex Luna with 3 μm particle size), elution with solvent A (water with 0.1% formic acid) and solvent B (acetonitrile with 0.1% formic acid). Gradient:
Gradient - - Timeflow ml_/mιn %A %B
0.00 2.0 95 5
0.50 2.0 95 5
4.50 2.0 5 95
5.50 2.0 5 95
6.00 2.0 95 5
Detection - MS, ELS, UV (200μL/min split to MS with in-line Waters 996 DAD detection). MS ionisation method - Electrospray (positive and negative ion). LC-MS method 5
Waters Micromass ZQ with a C18-reverse-phase column (100 x 3.0 mm Higgins Clipeus with 5 μm particle size), elution with A: water + 0.1% formic acid; B: acetonitrile + 0.1 % formic acid. Gradient:
Gradient - Time flow ml/min %A %B
0.00 1.0 95 5
1.00 1.0 95 5
15.00 1.0 5 95
20.00 1.0 5 95
22.00 1.0 95 5
25.00 1.0 95 5
Detection - MS, ELS, UV (100 μl split to MS with in-line UV detector at 254nm) MS ionisation method - Electrospray (positive ion).
LC-MS method 6 (intermediates)
Hewlett Packard 1100 MSD using C8-reverse-phase column (50 x 2.1 mm i.d. XBridge with 3.5 μm particle size), elution with solvent A (water with 5% methanol and 0.1% ammonium acetate) and solvent B (acetonitrile). Gradient:
Gradient - Time flow mL/min %A %B 0.00 1.0 95 5
2.50 1.0 5 95 3.00 1.0 5 95
3.10 1.0 95 5
3.50 1.0 95 5
Detection - MS, UV (in-line UV detector). MS ionisation method - APCI (positive ion and negative ions).
LCMS 7/7' (final compounds)
Agilent 1100 series LC/MSD with C18-reverse-phase column (50 x 2.1 mm i.d. Waters Symmetry column with 3.5 μm particle size), eluting using linear gradients of mixtures of solvent A (water with 0.1% TFA) and solvent B (acetonitrile with 0.1% TFA) at a flow rate of 1 mL/min. System 7 System T
Gradient - Time flow mL/min %A %B %A %B 0.00 1.0 95 5 5 95
1.00 1.0 95 5 5 95
9.00 1.0 5 95 50 50
10.00 1.0 5 95 50 50
Detection - Mass APCI or multimode (APCI + ESI) with UV detection set at 220 nm.
LCMS 8 (Compounds)
Agilent 1100 series using a Waters Sunfire C18 reverse-phase column (30 x 4.6 mm, 2.5 μm particle size), eluting using linear gradients of mixtures of solvent A (water with 0.1 % TFA) and solvent B (acetonitrile with 0.1% TFA) at a flow rate of 2.5 mL/min.
Gradient - Time flow mL/min %A %B
0.00 2.5 95 5
0.30 2.5 95 5
2.70 2.5 5 95 2.80 2.5 5 95
2.90 2.5 95 5
Detection - MS, UV (in-line UV detector). MS ionisation method - APCI (positive ion and negative ions).
Abbreviations used in the experimental section: AIBN = (2,2'-azobis(2-methylproprionitrile) BOC-anhydride = Di-fe/t-butyl dicarbonate DCE = 1 ,2-dichloroethane DCM = dichloromethane
DIPEA = diisopropylethylamine DMF = /V,/V-dimethyl formamide DMSO = dimethylsulfoxide EtOAc = ethyl acetate EtOH = ethanol
HCI = hydrochloric acid IMS = industrially methylated spirit
. HATL) = 0-(7-azabenzotria2ol-1-yl)-Λ/,Λ/,Λ/^Λ/-tetramethyluroniumhexafluoro- phosphate
HPLC = high performance liquid chromatography MeOH = methanol
Min = minutes
NaHCO3 = sodium hydrogen carbonate
NaOH = Sodium hydroxide
Na2SO4 = Sodium sulphate NH4CI = Ammonium chloride
NMP = N-methyl pyrrolidone
PMB = para-methoxybenzyl pTSA = para-toluenesulphonic acid
RT = room temperature Rf = retention factor (TLC)
Rt = retention time (LCMS or HPLC)
SCX-2 = strong cation exchange resin
TBDMS = tert-butyldimethyl silyl
TEMPO = 2,2,6,6-tetramethyl-1 -piperidinyloxy free radical TFA = trif luoroacetic acid
THF = tetrahydrofuran
TLC = thin layer chromatography
Intermediates: Intermediate 1
(1S,4S,5R,7R)-7-(Benzyl-methyl-amino)-5-bromo-bicyclo[2.2.1]heptan-2-one
Figure imgf000069_0001
A solution of (1 S,2R,3R,5S)-2,3-dibromo-bicyclo[3.2.0]heptan-6-one (7.1 g, 26.5 mmol) in 150 mL DCM was stirred under a N2 atmosphere and N-benzylmethylamine (7.06 g, 7.52 mmol) was added drop-wise. The reaction was stirred at ambient temperature for 33 hours before being washed with water, brine, dried (MgSO4) and concentrated in vacuo. Purification by chromatography on an ISCO companion column of silica ge) eluting with 0-15% Et2O-cyclohexanes gave of the title product as a yellow solid. 1H NMR (CDCI3, 400 MHz): δ 1.77-1.80 (1H, m), 2.10 (3H1 s), 2.20- 2.30 (1 H, m), 2.65-2.73 (1 H, m), 2.80-3.00 (4H, m), 3.40-3.60 (2H, m), 4.75-4.85 (1 H, m), 7.20-7.40 (5H, m).
Yield: 6.39 g, 78%.
Intermediate 2 (1S,4S,7S)-7-(Benzyl-methyl-amino)-bicyclo[2.2.1]heptan-2-one
Figure imgf000070_0001
A solution of (1 S,4S,5R,7R)-7-(benzyl-methyl-amino)-5-bromo- bicyclo[2.2.1]heptan-2-one (5 g, 16.2 mmol) in 80 mL toluene was degassed prior to addition of 2,2'-azobis (2-methoxyproprionitrile) (266 mg, 1.6 mmol). The reaction was heated to 80 0C for 1.5 hours and allowed to cool to ambient temperature. The reaction was extracted into 1 M HCI (150 mL), washed with Et2O then cooled in an ice bath and neutralised with Na2CO3 (solid). Following addition of NaOH (1 M solution) to give a pH -10, the reaction was extracted with ethyl acetate, the combined organics dried (Na2SO4), filtered and concentrated in vacuo to an orange oil which solidified on standing. 1H NMR (CDCI3, 400 MHz): δ 1.37-1.52 (2 H, m), 2.00-2.29 (7 H, m), 2.60-2.71 (3 H, m), 3.49 (2 H, dd, J = 13, 42 Hz), 7.21-7.34 (5 H, m).
Yield: 3.50 g, 94%.
Intermediate 3 (1S,2R,4S,7S)-7-(Benzyl-methyl-amino)-bicyclo[2.2.1]heptan-2-ol
Figure imgf000070_0002
A solution of (1 S,4S,7S)-7-(benzyl-methyl-amino)-bicyclo[2.2.1]heptan-2-one (3.5 g, 15.28 mmol) in THF (80 ml_) was cooled in an ice bath. Lithium tri(t- butoxy)aluminium hydride (5.8 g, 22.9 mmol) was added in portions over 15 min. The reaction was stirred at 00C for 1.5 hours then quenched with NH4CI (10 ml_) and the solid removed by filtration. The solid was washed with EtOAc and the filtrate was washed with water, dried (Na2SO4), filtered and evaporated. Purification by chromatography using 30-70% EtOAc-cyclohexane as eluent gave the title compound as a pale oil. Yield: 3.0 g, 85%.
LC-MS (Method 2): Rt 0.76 min, m/z 232 [MH]+.
Intermediate 4
((1 S,2R,4S,7S)-2-Hydroxy-bicyclo[2.2.1]hept-7-yl)-methyl-carbamic acid tert- butyl ester
Figure imgf000071_0001
A solution of (1S,2R,4S,7S)-7-(benzyl-methyl-amino)-bicyclo[2.2.1]heptan-2-ol (1.63 g, 7.05 mmol) and di-tert butyldicarbonate (1.69 g, 7.75 mmol) in dry EtOH (40 mL) was degassed using Argon and 20 wt% palladium hydroxide on carbon (230 mg) added. The reaction was stirred under an atmosphere of hydrogen (hydrogen balloon) for 18 hours. The reaction was purged with nitrogen and then filtered through Celite and the filtrate concentrated in vacuo to give the title compound which was used without further purification Yield: 1.70 g, Quant.. LC-MS (Method 2): Rt 2.89 min, m/z 242 [MH]+.
Intermediate 5 Hydroxy-di-thiophen-2-yl-acetic acid (1S,2R,4S,7S)-7-(tert-butoxycarbonyl- methyl-amino)-bicyclo[2.2.1 ]hept-2-yl ester
Figure imgf000072_0001
A stirred solution of ((1 S,2R,4S,7S)-2-hydroxy-bicyclo[2.2.1]hept-7-yl)-methyl- carbamic acid tert-butyl ester (1.70 g, 7.05 mmol) and hydroxy-di-thiophen-2-yl-acetic acid ethyl ester (1.98 g, 7.40 mmol) in toluene (125 mL) in an round-bottomed flask fitted with a short-path distillation head. Sodium methoxide (400 mg, 7.40 mmol) was added portion-wise and then the reaction mixture was gradually heated in an aluminium block. At -130 ° (block temp, only) MeOH /EtOH started to distil off. Heating was continued to -140 0C whereupon toluene started to distil over. After - 50 mL of toluene was collected. A further 50 mL toluene was collected and the reaction cooled. The mixture was partitioned between saturated aqueous NH4CI and EtOAc.The organics were dried (Na2SO4), filtered and concentrated in vacuo to give the crude product. The pure product was obtained after purification on an lsolute silica-gel cartridge, loading in DCM and eluting with 5-10% EtO Ac/petrol (40-60 0C) to give the desired product as clear oil that solidified on standing.
Yield: 2.28 g, 70%.
LC-MS (Method 2): Rt 4.28 min, m/z 464 [MH]+.
Intermediate 6 Hydroxy-di-thiophen-2-yl-acetic acid (1S,2R,4S,7S)-7-methylamino- bicyclo[2.2.1]hept-2-yl ester
Figure imgf000072_0002
A rapidly stirred solution of hydroxy-di-thiophen-2-yl-acetic acid (1 S^R^SJSJ-y-^ert-butoxycarbonyl-methyl-aminoJ-bicyclop^.1 ]hept-2-yl ester (3.28 g, 7.08 mmol) in [1 :1] THF/dioxane (40 mL) at RT was treated drop-wise with 2M aqueous HCI (40 mL). The reaction mixture was warmed to 55 0C for 2 hours and the reaction mixture was cooled to RT and then neutralised with saturated aqueous
NaHCO3. The reaction mixture was extracted with EtOAc and the combined organic extracts washed with brine (150 ml_) prior to drying (MgSO4), filtering and concentrating in vacuo to afford the title product. The product was used without further purification.
Yield: 2.38 g, 93%.
LC-MS (Method 2): Rt 2.26 min, m/z 364 [MH]+.
Intermediate 7 [2-(4-Hydroxy-2-oxo-2,3-dihydro-benzothiazol-7-yl)-ethyl]-(4-nitro-benzyl)- carbamic acid tert-butyl ester
Figure imgf000073_0001
7-((R)-2-amino-1-hydroxy-ethyl)-4-hydroxy-3H-benzothiazol-2-one hydrochloride (5 g, 20.33 mmol) (prepared according to WO2007/027133), 4- nitrobenzaldehyde (3.06 g, 20.33 mmol) and acetic acid (1.20 mL) were stirred in a mixture of NMP (40 mL) and MeOH (10 mL) for 1 hour. The mixture was cooled in an ice-bath and sodium triacetoxyborohydride (6.44 g, 30.52 mmol) was added portion- wise over 10 minutes. The resulting mixture was then stirred at 0 0C for 30 minutes then allowed to warm to RT and stirred overnight. The reaction was poured into water (400 mL) and extracted with EtOAc (3 x 100 mL). The combined organic solutions was washed with water, brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude material was re-dissolved in a mixture of DCM (100 mL) and DMF (20 mL) and di-tert-butyl dicarbonate (4.87 g, 22.33 mmol) was added. The resulting mixture was stirred overnight. Further di-tert-butyl dicarbonate (2 g) was added and the mixture stirred overnight. The reaction was then concentrated and poured into a mixture of water (200 mL) and EtOAc (3 x2 00 mL). The combined organic extratcs were washed with 880 ammonia solution (100 mL), water, brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with i-hexane to 1:1 ethyl acetate to give the compound as a yellow foam
Yield: 5.4 g (82%).
1H NMR (400 MHz, Cf6-DMSO, 90 0C) δ 8.16 - 8.11 (m, 2H), 7.44 (d, J = 9.0
Hz, 2H), 6.75 (d, J = 8.5 Hz, 1H)1 6.67 (d, J = 8.2 Hz, 1H), 4.45 (s, 2H), 3.41 (t, J = 6.9 Hz, 2H), 2.68 (t, J = 7.2 Hz, 2H), 1.36 (s, 9H) + 2 exchangeable H's not observed.
LC-MS (Method 3): Rt 3.55 min, m/z 444 [M-H].
Intermediate 8
(4-Amino-benzyl)-[2-(4-hydroxy-2-oxo-2,3-dihydro-ben2othiazol-7-yl)-ethyl]- carbamic acid tert-butyl ester
Figure imgf000074_0001
[2-(4-Hydroxy-2-oxo-2,3-dihydro-benzothiazol-7-yl)-ethyl]-(4-nitro-benzyl)- carbamic acid tert-butyl ester (2.2 g, 4.94 mmol) and 10% palladium on carbon (0.526 g) in THF (100 mL) at 20 °C, were hydrogenated under 4 bar at 20 0C for 18 hours. The reaction mixture was filtered through Celite and the filter pad washed with THF (2 x 100 mL). The combined filtrate and washings were evaporated. The residue was re-dissolved in THF (100 mL) and further 10% palladium on carbon (0.526 g) was added and the resulting mixture hydrogenated under 4 bar at 20 0C for 18 hours. The reaction mixture was filtered through Celite and the filter pad was washed with THF (2 x 100 mL). The combined filtrate and washings were concentrated in vacuo and azeotroped with toluene (100 mL) to give the compound as a yellow solid.
Yield: 2.0 g (97%).
1H NMR (400 MHz, d6-DMSO) δ 6.89 (d, J = 8.5 Hz, 2H), 6.72 - 6.65 (m, 2H),
6.56 - 6.51 (m, 2H), 4.70 (s, 2H), 4.14 (s, 2H), 3.25 (t, J = 7.3 Hz, 2H), 2.59 (t, J = 7.4 Hz, 2H), 1.38 (s, 9H) + 2 exchangeable H's not observed.
LC-MS (Method 3): Rt 2.72 min, m/z 414 [M-H]. Intermediate 9
[4-(2-Bromo-acetylamino)-benzyl]-[2-(4-hydroxy-2-oxo-2,3-dihydro- benzothiazol-7-yl)-ethyl]-carbamic acid tert-butyl ester
Figure imgf000075_0001
A cooled 0 0C solution of (4-amino-benzyl)-[2-(4-hydroxy-2-oxo-2,3-dihydro- benzothiazol-7-yl)-ethyl]-carbamic acid tert-butyl ester (0.61 g, 1.47 mmol) in DMF (20 ml_) was treated with solid NaHCO3 (140 mg, 1.61 mmol) and allowed to stir for 15 minutes prior to drop-wise addition of bromo-acetyl bromide (0.26 ml_, 2.94 mmol) over 10 minutes at 0 0C. The reaction mixture was allowed to stir to RT overnight and was then partitioned between water and EtOAc and the combined organic extracts were concentrated in vacuo. The crude product was triturated with saturated aqueous NaHCO3 with the aid of prolonged sonication and then collected by filtration. The solid residue was further purified by Companion automated chromatograpghy system, loading in EtOAc/MeOH and eluting from DCM to 5% MeOH/DCM to afford the title product.
LC-MS (method 2): Rt 3.45 min, m/z 536, 538 [MH]+.
Intermediate 10 4-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-N-(2,2-dimethoxy-ethyl)-benzamide
Figure imgf000075_0002
To a stirred solution of 4-(2-(tert-butyldimethylsilyloxy)ethyl)benzoic acid (0.70 g, 2.50 mmol), (Nucleic Acids Research 1997, 25(12), 2352-2358) in dry DMF (10 mL) was added di(1 H-imidazol-1-yl)methanone (0.52 g, 3.21 mmol). After 1 hour 2,2- dimethoxyethanamine (0.69 g, 6.56 mmol) was added and the solution allowed to stir at RT for a further 30 minutes. The solution was diluted with ethyl acetate, washed with water (x3) and brine then evaporated in vacuo. Purification was undertaken by silica gel chromatography, eluting with ethyl acetate: iso-hexanes, [1 :2] to afford the title compound.
Yield: 0.85 g (93%).
1H NMR (400 MHz1 CDCL3) δ 7.72 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 8.2 Hz, 2H), 6.35 - 6.27 (m, 1 H), 4.52 (t, J = 5.3 Hz, 1 H), 3.84 (t, J = 6.8 Hz, 2H), 3.63 (t, J = 5.6 Hz, 2H), 3.47 (s, 6H), 2.88 (t, J = 6.8 Hz, 2H), 0.89 (s, 9H), 0.00 (s, 6H).
Intermediate 11 N-(2,2-Dirnethoxy-ethyl)-4-(2-hydroxy-ethyl)-benzamide
Figure imgf000076_0001
4-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-N-(2,2-dimethoxy-ethyl)-benzamide (0.83 g, 2.26 mmol) was dissolved in tetrabutylammonium fluoride (10 ml of a 1 M solution in THF). After 0.5 h, the solution was diluted with ethyl acetate and washed with a little water and brine. The aqueous washings were combined, extracted with ethyl acetate and the combined ethyl acetate solution was evaporated in vacuo. Purification was by silica gel chromatography eluting with dichloromethane:methanol, 10:1.
Yield 0.55 g (96%) 1H NMR (400 MHz, CDCI3) δ 7.72 (d, J = 38.1 Hz, 2H), 7.32 (d, J = 38.1 Hz,
2H), 6.34 - 6.25 (m, 1 H), 4.49 <t, J = 19.9 Hz1 1 H), 3.94 - 3.84 (m, 2H), 3.60
(t, J = 19.9 Hz1 2H), 3.44 (s, 6H)1 2.92 (t, J = 17.4 Hz1 4H.
Intermediate 12 ΛK2,2-Dimethoxy-ethyl)-4-(2-oxo-ethyI)-benzamide
Figure imgf000077_0001
Dess-Martin periodinane (1.22 g, 2.88 mmol) was added to Λ/-(2,2-dimethoxy- ethyl)-4-(2-hydroxy-ethyl)-benzamide (0.55 g, 2.17 mmol) in DCM (15 ml_. After 1hour, saturated aqueous NaHCO3 (25 mL), sodium thiosulphate (25 mL) and EtOAc (80 mL) were added and the mixture shaken vigorously for 1 minute then separated. The EtOAc solution was washed with saturated aqueous NaHCO3 (25 ml) and brine, dried (Na2SO4), filtered and evaporated in vacuo (bath temperature <300C) to give the crude intermediate aldehyde 0.48g (88%). A solution of 7-(2-aminoethyl)-4- hydroxybenzo[d]thiazol-2(3H)-one hydrochloride (0.54 g, 2.19 mmol) and acetic acid (0.12 mL) in NMP (15 mL) and water (5 mL) was added to the crude Λ/-(2,2- dimethoxyethyl)-4-(2-oxoethyl)benzamide (0.48 g, 1.91 mmol). Sodium triacetoxyborohydride (0.70 g) was then added and the mixture stirred at room temperature for 30 minutes. The reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO3 (50 mL). The aqueous layer was further extracted with EtOAc (x4) and the combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to give the crude amine intermediate compound in NMP (~5 mL). Boc2O (0.57 ml, 2.5 mmol) was added to the crude /V- (2,2-dimethoxyethyl)-4-(2-(2-(4-hydroxy-2-oxo-2,3-dihydrobenzo[d]thiazoI-7- yl)ethylamino)ethyl)benzamide in NMP (~5 mL) and DCM (10 mL). After 1 hour, the reaction mixture was diluted with EtOAc and washed with water and dried (Na2SO4), filtered and concentrated in vacuo. Purification was by silica gel chromatography eluting with EtOAc/iso-hexanes, [2:1] afforded the title product.
Yield 0.38 g (32%, 3 steps). 1H NMR (400 MHz, de-DMSO, 90 0C) δ 8.01 - 8.11 (m, 1 H), 7.75 (d, J = 8.2
Hz, 2H), 7.22 (d, J = 8.2 Hz, 2H), 6.76 (d, J = 8.4 Hz, 1H), 6.68 (d, J = 8.4 Hz, 1 H), 4.51 (t, J = 5.5 Hz, 1 H), 3.36 (t, J = 5.6 Hz, 2H), 3.27 - 3.33 (m, 4H), 3.30 (s, 6H), 2.77 (t, J = 7.6 Hz, 2H), 2.64 (t, J = 7.3 Hz, 2H), 1.34 (s, 9H)
Intermediate 13 [2-(4-Hydroxy-2-oxo-2,3-dihydro-benzothiazol-7-yl)-ethyl]-{2-[4-(2-oxo- ethylcarbamoyl)-phenyl]-ethyl}-carbamic acid tert-butyl ester
Figure imgf000078_0001
{2-[4-(2,2-dimethoxy-ethylcarbamoyl)-phenyl]-ethyl}-[2-(4-hyclroxy-2-oxo-2,3- dihydro-benzothiazol-7-yl)-ethyl]-carbamic acid tert-butyl ester (2.1 g, 3.8 mmol) in acetic acid (20 ml_) and water (20 mL) was heated at 50 0C for 6 hours. After cooling, the reaction mixture was diluted with ethyl acetate (300 mL), washed with water (4 x 10OmL), dried (Na2SO4), filtered and concentrated in vacuo to give the title compound which was used directly without characterisation.
Intermediate 14 /V-(2,2-Dimethoxy-ethyl)-4-hydroxymethyl-benzamJde
Figure imgf000078_0002
HATU (8.30 g, 21.83 mmol) was added portion-wise over 10 minutes to a cooled 0 0C stirred solution of 4-(hydroxymethyl)benzoic acid (2.60 g, 17.09 mmol), 2,2-dimethoxyethanamine (3.00 g, 28.53 mmol) and triethylamine (8.00 g, 79.06 mmol) in DMF (40 mL). After 1 hour the reaction mixture was quenched with water (200 mL) and extracted with EtOAc (6 x 350 mL). The organic extracts were combined, dried (MgSO4), filtered and evaporated in vacuo. The crude product was purified by flash silica chromatography, eluting with EtOAc/iso-hexanes [3:1] to afford the title compound. LC-MS (method 2): Rt 2.19 min, m/z 240 [MH]+.
1H NMR (300 MHz, CDCI3) δ 7.77 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H),
6.40 - 6.27 (m, 1 H), 4.76 (s, 2H), 4.50 (t, J = 5.4 Hz, 1 H), 3.61 (t, J = 5.4 Hz,
2H), 3.44 (s, 6H) Intermediate 15
/V-(2,2-Dimethoxy-ethyl)-4-formyl-benzamide
Figure imgf000079_0001
Manganese(IV) oxide (3.38 ml_, 195.54 mmol) was added to stirred solution of /V-(2,2-dimethoxy-ethyl)-4-hydroxymethyl-benzamide (4.0O g, 16.72 mmol) in DCM (200 ml_) at room temperature. After 2 hours the mixture was filtered through a pad of Celite eluting with DCM and the solution evaporated in vacuo to give the crude aldehyde, which was used directly without characterisation.
Yield: 3.9 g (98%).
Intermediate 16 [2-(4-Hydroxy-2-oxo-2,3-dihydro-benzothiazol-7-yl)-ethyl]-[4-(2-oxo-et hylcarbamoyl)-benzyl]-carbamic acid tert-butyl ester
Figure imgf000079_0002
The title compound was prepared from /V-(2,2-dimethoxy-ethyl)-4-formyl- benzamide and 7-(2-amino-ethyl)-4-hydroxy-3H-benzothiazol-2-one hydro chloride by similar methods to those employed in intermediates 7 and 13, and which was used directly without characterisation.
Intermediate 17 (3-Acetoxymethyl-phenyl)-acetic acid methyl ester
Figure imgf000080_0001
A solution of methyl 2-(3-(bromomethyl)phenyl)acetate (1 g, 4.11 mmol) and sodium acetate (0.337 g, 4.11 mmol) in DMA (15 ml_) were heated under microwave at irradiation at 120 0C (powermax) for 40 minutes. The procedure was repeated a further 5 times (6 g in total 2-(3-(bromomethyl)phenyl)acetate reacted). The combined reaction mixtures were diluted with EtOAc (70 ml_) and washed with water (3x70ml) and the organics were dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as a gum.
Yield: 4.77g (93%)
1H NMR (400 MHz, d6- DMSO) δ 7.35 - 7.29 (m, 1H), 7.28 - 7.21 (m, 3H),
5.05 (s, 2H), 3.69 (s, 2H), 3.61 (s, 3H), 2.08 - 2.04 (m, 3H).
Intermediate 18
(3-Hydroxymethyl-phenyl)-acetic acid
Figure imgf000080_0002
Lithium hydroxide monohydrate (2.66 mL, 95.62 mmol) was added to (3- acetoxymethy!-phenyl)-acetic acid methyl ester (4.25 g, 19.12 mmol) in THF (40 mL) and water (40 mL) at 25 CC under nitrogen. The resulting suspension was stirred at 25 0C for 2 hours. The reaction mixture was cooled on ice and 2.5 M HCI (50 mL) was added and the THF removed in vacuo, the remaining aqueous layer was extracted with ethyl acetate and the combined organics, were dried (MgSO4), filtered and solvent removed in vacuo to give title compound as a coloured gum. Yield: 3.30 g (quant.)
1H NMR (400 MHz, d6-DMSO) δ 7.26 (t, J = 7.6 Hz, 1H), 7.22 - 7.16 (m, 2H), 7.11 (d, J = 7.2 Hz, 1 H), 4.47 (s, 2H), 3.54 (s, 2H).
Intermediate 19 ^-(tert-Butyl-dimethyl-silanyloxymethyO-phenyll-acetic acid
Figure imgf000081_0001
Imidazole (3.26 g, 47.84 mmol) and TBDMS-CI (3.46 g, 22.96 mmol) were added to a solution in DMF (32 ml_) of (3-hydroxymethyl-phenyl)-acetic acid (3.18 g, 19.14 mmol) at 25 0C. The resulting mixture was stirred at 50 0C for 2 hours. The reaction mixture was cooled to RT and left to stir overnight then heated to 50 0C for 8 hours. A further quantity of TBDMS-CI (0.12 equiv.) and imidazole (0.25 equiv.) were added and warming was continued overnight.. The reaction mixture was diluted with EtOAc, washed with water and the organics were dried (Na2SO4), filtered and solvent removed in vacuo. The organics were then taken up in EtOAc (100 ml_) and washed a further 3 times with water, prior to being drying (MgSO4), filtering and concentration in vacuo to give title compound as an orange gum.
Yield: 4g (75%) 1H NMR (400 MHz, d6-DMSO) δ 7.34 - 7.28 (m, 1 H), 7.26 - 7.20 (m, 2H), 7.19
- 7.14 (m, 1 H), 4.75 - 4.70 (m, 2H), 3.60 - 3.54 (m, 2H), 0.97 - 0.91 (m, 9H), 0.13 - 0.08 (m, 6H).
Intermediate 20 2-[3-(tert-Butyl-dimethyl-siIanyloxymethyl)-phenyl]-/V-[2-(4-hydroxy-2-oxo-2,3- dihydro-benzothiazol-7-yl)-ethyl]-acetamide
Figure imgf000081_0002
The title compound was prepared from [3-(tert-butyl-dimethyl- silanyloxymethyl)-phenyl]-acetic acid and 7-(2-amino-ethyl)-4-hydroxy-3H- benzothiazol-2-one hydrobromide by a similar method to that employed in intermediate 14.
Yield: 5.9 g (90%). 1H NMR (400 MHz, d6-DMSO) δ 8.14 (t, J = 5.5 Hz, 1H), 7.28 (t, J = 7.6 Hz,
1 H), 7.23 - 7.17 (m, 2H), 7.13 (d, J = 7.4 Hz, 1 H), 6.79 (d, J = 8.2 Hz, 1H), 6.71 (d, J = 8.2 Hz, 1 H), 4.72 (s, 2H), 3.40 (s, 2H), 2.73 (s, 2H), 2.63 (t, J = 7.3 Hz, 2H), 0.96 - 0.87 (m, 9H), 0.13 - 0.04 (m, 6H).
Intermediate 21
Carbonic acid 7-(2-{tert-butoxycarbonyl-[2-(3-hydroxymethyl-phenyl)-ethyl]- amino}-ethyl)-2-oxo-2,3-dihydro-benzothiazol-4-yl ester tert-butyl ester
Figure imgf000082_0001
Borane tetrahydrofuran complex (1 M in THF; 49.1 mL, 49.08 mmol) was added drop-wise over a period of 15 minutes to a stirred suspension in THF (60 mL) of 2-[3-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-N-[2-(4-hydroxy-2-oxo-2,3- dihydro-benzothiazol-7-yl)-ethyl]-acetamide (5.8 g, 12.27 mmol) at 50 °C. The resulting solution was then refluxed for 75 minutes, cooled to RT and MeOH added cautiously until effervescence ceased (-60 mL). The solvents were removed in vacuo and the residue was taken up in MeOH and 3 mL of concentrated aqueous HCI were added and the reaction mixture was refluxed for 1 hour. The solvents were removed in vacuo to give title intermediate amino alcohol as a yellow foam (4.93 g, quant.). The residue was taken up in MeOH (50 mL) and triethylamine (6.35 ml, 45.52 mmol) and BoC2O (7.27 mL, 31.30 mmol) were added. The resulting solution was stirred at room temperature for 30 minutes then the MeOH was removed in vacuo and the residue was partitioned between EtOAc and water. The organics were washed with water, brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by silica-gel chromatography, eluting with [2:1] hexane/EtOAc to give title compound as a white foam. Yield: 3.18 g (41%).
1H NMR (400 MHz, d6-DMSO) δ 7.26 - 7.20 (m, 1 H), 7.18 - 7.11 (m, 2H), 7.10 - 7.04 (m, 1H), 7.04 - 6.93 (m, 2H), 5.16 - 5.09 (m, 1 H), 4.51 - 4.44 (m, 2H), 3.38 - 3.33 (m, 2H), 3.31 - 3.23 (m, 2H), 2.77 - 2.65 (m, 4H), 1.52 - 1.46 (m, 9H), 1.37 - 1.24 (m, 9H). Intermediate 22
Carbonic acid 7-[2-(tert-butoxycarbonyl-{2-[4-(2-hydroxy-ethyl)-phenyl]-ethyl}- amino)-ethyl]-2-oxo-2,3-dihydro-benzothiazol-4-yl ester tert-butyl ester
Figure imgf000083_0001
The title compound was prepared from carbonic acid 7-(2-{tert- butoxycarbonyl-[2-(3-hydroxymethyl-phenyl)-ethyl]-amino}-ethyl)-2-oxo-2,3-dihydro- benzothiazol-4-yl ester tert-butyl ester by a similar method to that employed in intermediate 15.
Yield: 1.3g (42%) LC-MS (Method 6): Rt 2.35 min, m/z 541 [M-H].
Intermediate 23 {4-[2-(tert-ButyI-dimethyl-silanyloxy)-ethyl]-phenyl}-acetaldehyde
Figure imgf000083_0002
The title compound was synthesised from 2-{4-[2-(tert-butyl-dimethyl- silanyloxy)ethyl]-phenyl}-ethanol (prepared according to WO9843956) by a similar Dess-Martin oxidation method used in the synthesis of intermediate 12, which was used directly without characterisation.
Intermediate 24
Carbonic acid 7-[2-(tert-butoxycarbonyl-{2-[4-(2-hydroxy-ethyl)-phenyl]-ethyl}- amino)-ethylJ-2-oxo-2,3-dihydrσ-benzothiazol-4-yl ester tert-butyl ester
Figure imgf000084_0001
The title compound was prepared from {4-[2-(tert-butyl-dimethyi-silanyloxy)- ethyl]-phenyl}-acetaldehyde and 7-(2-amino-ethyl)-4-hydroxy-3H-benzothiazol -2-one hydrochloride by similar methods to the reductive amination and Boc-protection steps in intermediate 12. Prior to bis-Boc protection to give the title compound, a solution of the intermediate amino TBDMS ether in MeOH (20 mL) was converted to the amino alcohol by addition of concentrated aqueous HCI (2 mL). After 20 minutes, the mixture was concentrated in vacuo to give the crude de-silylated intermediate which was taken on to the BoC2O reaction to give the title compound.
1H NMR (400 MHz, d6-DMSO, 90 0C) δ 12.02 - 11 .94 (m, 1 H), 7.16 - 6.90 (m, 6H), 4.28 - 4.18 (m, 1H), 3.64 - 3.54 (m, 2H), 3.36 (t, J = 7.0 Hz, 2H), 3.29 (t, J = 7.3 Hz, 2H), 2.76 - 2.64 (m, 6H), 1.49 (s, 9H), 1.33 (s, 9H).
Intermediate 25
Carbonic acid 7-[2-(tert-butoxycarbonyl-{2-[4-(2-oxo-ethyl)-phenyl]-ethyl}- amino)-ethyl]-2-oxo-2,3-dihydro-benzothiazol-4-yl ester tert-butyl ester
Figure imgf000084_0002
The title compound was prepared from carbonic acid 7-[2-(tert- butoxycarbonyl-{2-[4-(2-hydroxy-ethyl)-phenyl]-ethyl}-amino)-ethyl]-2-oxo-2,3- dihydro-benzothiazol-4-yl ester tert-butyl ester by a similar Dess-Martin oxidation method used in the synthesis of intermediate 12, which was used directly without characterisation. Intermediate 26
2-[3-(3-Bromo-propoxy)-phenyl]-ethanol
Figure imgf000085_0001
A solution of 3-(2-hydroxy-ethyl)-phenol (10 g, 72.46 mmol), 1 ,3- dibromopropane (22 mL, 0.218 mol) and K2CO3 (16 g, 0.115 mol) in acetone (80 mL) was warmed to 60 0C overnight. The reaction mixture was cooled, filtered then concentrated in vacuo. The residue was purified by silica-gel chromatography, eluting from 25-50% EtOAc/pentane to give the title compound as a colourless oil. Yield: 16.69 g (89%).
TLC Rf (25% EtOAc/pentane) = 0.33.
1H NMR (400 MHz, CDCI3) 57.21 (m, 1 H), 6.84-6.73 (m, 3H), 4.08 (t, J = 6 Hz, 2H), 3.81 (m, 2H), 3.58 (t, J = 6.5 Hz, 2H), 2.81 (t, J = 6.5 Hz, 2H), 2.29 (m, 2H), 1.81 (br s, 1H).
Intermediate 27 [3-(3-Bromo-propoxy)-phenyl]-acetaldehyde
Figure imgf000085_0002
Dess-Martin periodinane (25 g, 58.90 mmol) was added to 2-[3-(3-bromo- propoxy)-phenyl]-ethanol (13.8 g, 53.20 mmol) in DCM (300 mL). After 1 hour, saturated aqueous NaHCO3 (25 mL) and sodium thiosulphate (25 mL) were added and the mixture stirred vigorously for 30 minutes then separated. The DCM extract dried (Na2SO4), filtered and evaporated in vacuo to give the crude aldehyde as a white solid. This material was purified by chromatography, gradient eluting from 2.5- 10% EtOAc/pentane to afford the title compound as a yellow oil. Yield: 8.5 g (90%)
TLC Rf (10% EtOAc/pentane) = 0.46.
1H NMR (400 MHz, CDCI3) $9.71 (t, J = 2.4 Hz, 1 H), 7.25 (m, 1H), 6.86-6.70 (m, 3H), 4.08 (t, J = 6 Hz, 2H), 3.62 (d, J = 2.4 Hz, 2H), 3.58 (t, J = 6 Hz, 2H), 2.29 (m, 2H).
Intermediate 28 {2-[3-(3-Bromo-propoxy)-phenyl]-ethyl}-[2-(4-hydroxy-2-oxo-2,3-dihydro- benzothiazol-7-yl)-ethyl]-carbamicacid tert-butyl ester
Figure imgf000086_0001
The title compound was prepared from [3-(3-bromo-propoxy)-phenyl]- acetaldehyde and 7-(2-amino-ethyl)-4-hydroxy-3H-benzothiazol-2-one hydro chloride by similar methods to those used in intermediate 7. The crude product was purified by HPLC (HPLC system 3) to give the desired product as a white solid.
LC-MS (method 5): Rt 12.36 min, m/z 551 , 553 [MH]+.
Intermediate 29 2-[4-(3-Bromo-propoxy)-phenyl]-ethanol
Figure imgf000086_0002
The title compound was prepared from 4-(2-hydroxy-ethyl)-phenol by a similar method to that employed in intermediate 26.
Yield: 9.0 g (97%).
TLC Rf (10% EtOAc/pentane) = 0.16.
1H NMR (400 MHz, CDCI3) 57.12 (m, 2H), 6.84 (m, 2H), 4.07 (t, J = 5.8 Hz, 2H), 3.78 (t, J = 6.4 Hz, 2H), 3.59 (t, J = 6.4 Hz, 2H), 2.79 (t, J = 6.4 Hz, 2H),
2.29 (m, 2H), 1.71 (br s, 1 H).
Intermediate 30 [4-(3-Bromo-propoxy)-phenyl]-acetaldehyde
Figure imgf000086_0003
The title compound was prepared from 2-[4-(3-bromo-propoxy)-phenyl]- ethanol by a similar method to that employed in intermediate 27. TLC Rf (10% EtOAc/pentane) = 0.58.
1H NMR (400 MHz, CDCI3) £9.71 (t, J = 2.4 Hz, 1 H), 7.12 (m, 2H), 6.90 (m, 2H), 4.09 (t, J = 5.8 Hz, 2H), 3.62 (d, J = 2.4 Hz, 2H), 3.61 (t, J = 6.4 Hz, 2H), 2.31 (m, 2H).
Intermediate 31
{2-[4-(3-Bromo-propoxy)-phenyl]-ethyl}-[2-(4-hydroxy-2-oxo-2,3-dihydro- benzothiazol-7-yl)-ethyl]-carbamic acid tert-butyl ester
Figure imgf000087_0001
The title compound was prepared from [4-(3-bromo-propoxy)-phenyl]- acetaldehyde and 7-(2-amino-ethyl)-4-hydroxy-3H-benzothiazol-2-one hydro chloride by similar methods to those used in intermediate 7. The crude product was purified by HPLC (HPLC system 3) to give the desired product as a white solid.
LC-MS (method 5): Rt 12.30 min, m/z 551 , 553 [MH]+.
Intermediate 32
Methanesulfonic acid 3-(3-formyl-phenoxy)-propyl ester
Figure imgf000087_0002
3-Bromo-1-propanol (3.94 mL, 45.04 mmol) and K2CO3 (6.22 g, 45.04 mmol) were added to 3-hydroxybenzaldehyde (5 g, 40.94 mmol) in acetonitrile (100 mL). The resulting mixture was stirred at reflux for 5 hours under nitrogen. The reaction mixture was cooled to room temperature and partitioned between EtOAc and ice- cold, dilute aqueous sodium hydroxide, the organic layer was washed with aqueous brine, dried (Na2SO4), filtered and the solvent removed in vacuo. The residue was dissolved in DCM (30 mL) and treated with triethylamine (5.71 mL, 40.94 mmol). The solution was cooled to 0 °C and treated drop-wise with methanesulphonyl chloride (3.19 mL, 40.94 mmol). The reaction mixture was stirred at 0 0C for 10 minutes and then at room temperature for 1 hour. The mixture was washed twice with aqueous brine, dried, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography, eluting with 33% EtOAc in isohexane to afford the title compound as a colorless oil.
Yield: 5.20 g, (49.%). 1H NMR (400 MHz, CDCI3) δ 9.98 (s, 1H), 7.50 - 7.43 (m, 2H), 7.40 - 7.39 (m,
1H), 7.20 - 7.16 (m, 1 H)1 4.46 (t, J = 6.2 Hz, 2H), 4.17 (t, J = 5.9 Hz, 2H), 3.01
(s, 3H), 2.30 - 2.23 (m, 2H).
Intermediate 33 Methanesulfonic acid 3-[3-({tert-butoxycarbonyl-[2-(4-hydroxy-2-oxo-2, 3-dihydro-benzothiazol-7-yl)-ethyl]-amino}-methyl)-phenoxy]-propyl ester
Figure imgf000088_0001
The title compound was prepared from methanesulfonic acid 3-(3-formyl- phenoxy)-propyl ester and 7-(2-amino-ethyl)-4-hydroxy-3H-benzothiazol-2-one hydrochloride by similar methods to those used in intermediate 7. The crude product was purified by HPLC (HPLC system 3) to give the desired product as a white solid. LC-MS (method 6): Rt 2.01 min, m/z 551 [M-H].
Intermediate 34 (1-AcryIoyl-piperidin-3-ylrηethyl)-[2-(4-hydroxy-2-oxo-2,3-dihydro-ben2 othiazol-7-yl)-ethyl]-carbamIc acid tert-butyl ester
Figure imgf000088_0002
A solution of acryloyl chloride of (3.53 mL, 43.45 mmol) in dry THF (15 mL) was added drop-wise to a solution of piperidin-3-ylmethanol (5 g, 43.45 mmol) and pyridine (3.86 mL) in dry THF (200 mL) at -200C. The resulting mixture was stirred O Q QO for 30 minutes then allowed to warm to RT. Aqueous 2 M HCI solution (50 mL) was then added and the layers separated. The aqueous was extracted with EtOAc (2 x 200 mL) and the combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (50 g Varian cartridge), eluting with 50-100% EtOAc/hexane to give the intermediate acrylamide alcohol (2.17 g) as an unstable clear oil which was used immediately. A solution of pyridine sulphur trioxide (2.82 g) in DMSO (20 mL) was added to a solution of intermediate 1-(3-hydroxymethyl-piperidin-1-yl)-propenone (1 g, 5.92 mmol) and triethylamine (2.47 mL, 18.59 mmol) in DCM (20 mL) at -10 °C. The resulting mixture was stirred at this temperature for 15 minutes and the reaction mixture was poured into brine (60 mL) and then extracted with EtOAc (3 x 150 mL). The combined organic solutions were washed with brine, dried (Na2SO4), filtered and evaporated to give the intermediate aldehyde (0.80 g) as an unstable gum which was used without further purification. The title compound was prepared from this material and 7-(2-amino-ethyl)-4-hydroxy-3H-benzothiazol-2-one hydrochloride by similar methods to those employed for intermediate 7.
1H NMR (400 MHz, d6-DMSO) δ 6.77 (d, J = 8.2 Hz, 1 H), 6.71 - 6.58 (m, 2H), 5.99 (dd, J = 16.8, 2.4 Hz, 1 H), 5.58 (dd, J = 10.5, 2.3 Hz, 1 H), 4.03 - 3.88 (m, 2H), 3.39 - 3.31 (m, 2H), 3.04 - 2.95 (m, 5H), 2.73 - 2.64 (m, 2H), 1.76 - 1.62 (m, 2H), 1.39 - 1.29 (m, 1 1 H).
Intermediate 35
(4-formylthiazol-2-yl) carbamic acid tert-butyl ester
Figure imgf000089_0001
The title compound was prepared from (4-formylthiazol-2-yl) carbamic acid tert-butyl ester and 7-(2-aminoethyl)-4-hydroxybenzo[d]thiazol-2(3H)-one hydrochloride by a similar method to that employed in intermediate 7. LC-MS (method 2): Rt 2.21 min, m/z 421 [M-H].
Intermediate 36
(4-formylthiazol-2-yl) carbamic acid tert-butyl ester
Figure imgf000090_0001
A solution of (4-formylthiazol-2-yl) carbamic acid tert-butyl ester 4.67 g, 11.5 mmol) in DCM (13 mL) was treated drop-wise with TFA. After stirring at RT for 2 hours the reaction mixture was concentrated in vacuo and the crude residue was passed down a MeOH-equilibrated SCX-2 cartridge, eluting with DCIWMeOH [1 :1], then 2 M NH3 in MeOH) to elute the desired product which was used without further purification.
Yield: 3.58 g (quantitative).
LC-MS (method 3): Rt 0.38 & 1.54 min, m/z 323 [MH]+.
Intermediate 37
(2-Amino-thiazol-4-ylmethyl)-[2-(4-hydroxy-2-oxo-2,3-dihydro-benzothia zol-7-yl)-ethyl]-carbamic acid tert-butyl ester
Figure imgf000090_0002
The title compound was prepared from (4-formylthiazol-2-yl) carbamic acid tert-butyl ester by a similar BoC2O protection step employed in intermediate 7. LC-MS (method 3): Rt 2.29 min, m/z 423 [M-H].
Intermediate 38 [2-(2-Bromo-acetylamino)-thiazol-4-ylmethyl]-[2-(4-hydroxy-2-oxo-2,3-d ihydro-benzothiazol-7-yl)-ethyl]-carbamic acid tert-butyl ester
Figure imgf000090_0003
The title compound was prepared from (2-amino-thiazol-4-ylmethyl)-[2-(4- hydroxy-2-oxo-2,3-dihydro-benzothiazol-7-yl)-ethyl]-carbamic acid tert -butyl ester by a similar method to that employed in intermediate 9. LC-MS (method 5): Rt 9.17 min, m/z 543, 545 [M-H].
Intermediate 39 3-(2,2-Diethoxy-ethoxy)-propionic acid benzyl ester
Figure imgf000091_0001
A mixture of benzyl acrylate (60.4 g, 372 mmol) and glycolaldehyde diethyl acetal (10.16 g, 74.5 mmol) in dry THF (70 mL) was stirred vigorously and Triton B (1.7 mL, 5 mol%) was added. The RM became dark brown gradually over about 0.5 minutes during which an exotherm was noted. The reaction mixture was concentrated in vacuo and purified directly over silica-gel (330 g, Companion) eluting from 0-100% EtOAc/cyclohexane to give the title compound as acolourless oil.
Yield 9.7 g (44%)
1H NMR (400 MHz, CDCI3) 57.34-7.29 (m, 5H), 5.13 (s, 2H), 4.58 (t, J = 5.2
Hz, 1H), 3.80, (t, J = 6.4 Hz, 2H), 3.67 (m, 2H), 3.54 (m, 2H), 3.46 (d, J = 5.2 Hz, 2H), 2.64 (t, J = 6.4 Hz, 2H), 1.20 (t, J = 7 Hz, 6H).
Intermediate 40 3-(2,2-Diethoxy-ethoxy)-propionic acid
Figure imgf000091_0002
10% Palladium on carbon (161 mg, 1 mol%) was added to a solution of 3- (2,2-diethoxy-ethoxy)-propionic acid benzyl ester (4.38 g, 14.8 mmol) in EtOAc (44 mL) and stirred vigorously under a hydrogen atmosphere at RT. After stirring under hydrogen atmosphere overnight the reaction mixture was filtered over Celite, washed with EtOAc, and concentrated in vacuo to afford a colourless liquid.
Yield: 3.05 g (Quantitative).
1H NMR (400 MHz, CDCI3) .54.62 (t, J = 5.3 Hz, 1 H), 3.77, (t, J = 6.1 Hz, 2H),
3.70 (m, 2H), 3.57 (m, 2H), 3.52 (d, J = 5.3 Hz, 2H), 2.64 (t, J = 6.1 Hz, 2H),
1.20 (t, J = 7 Hz, 6H).
Intermediate 41 3-(2,2-Diethoxy-ethoxy)-ΛA-(2-hydroxy-ethyl)-ΛA-methyl-propionamide
Figure imgf000092_0001
The title compound was prepared from (2-amino-thiazol-4-ylmethyl)-[2-(4- hydroxy-2-oxo-2,3-dihydro-benzothiazol-7-yl)-ethyl]-carbamic acid tert-butyl ester and 2-(methylamino)ethanol by a similar method to that employed in intermediate 10. 1H NMR (400 MHz, CDCI3) 54.61 (m, 1 H), 3.82, (m, 2H), 3.77 (m, 2H), 3.68 (m, 2H)1 3.56 (m, 2H), 3.51 (d, J = 5.2 Hz, 2H), 3.50 (m, 2H)1 3.09 (s, 3H), 2.98 (s, 1 H), 2.67 (m, 2H), 1.21 (m, 6H).
Intermediate 42
3-(2,2-Diethoxy-ethoxy)-Λ^methyl-Λ^(2-oxo-ethyl)-propionamide
Figure imgf000092_0002
The title compound was prepared from 3-(2,2-diethoxy-ethoxy)~N-(2-hydroxy- ethyl)-Λ/-methyl-propionamideby a similar method to that employed in intermediate 27.
LC-MS (method 3): Rt 2.02 min, m/z 284 [M+Na], 302 [M+MeCN].
Intermediate 43 [2-(4-Hydroxy-2-oxo-2,3-dlhydro-benzothiazol-7-yl)-ethyl]-(2-{methyl-[3-(2-oxo- ethoxy)-propionyl]-amino}-ethyl)-carbamic acid tert-butyl ester
Figure imgf000092_0003
The title compound was prepared from 3-(2,2-diethoxy-ethoxy)-N-methyl-N- (2-oxo-ethyl)-propionamide and 7-(2-aminoethyl)-4-hydroxybenzo[d]thiazol-2(3H)-one hydrochloride by similar methods to those employed in intermediates 7 and 13, respectively.
LC-MS (method 3): Rt 2.52 min, m/z 480 [M-H]. Intermediate 44
{5-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-furan-2-yI}-acetic acid methyl ester
Figure imgf000093_0001
The title compound was prepared from [5-(2-hydroxy-ethyl)-furan-2-yl]-acetic acid methyl ester by a similar method to that employed in intermediate 19. LC-MS (method 6): Rt 2.51 min, m/z 299 [MH]+.
1H NMR (400 MHz, CDCI3) δ 6.1 1 (d, J = 3.1 Hz, 1 H), 5.99 (d, J = 3.1 Hz, 1 H), 3.83 (t, J = 6.9 Hz, 2H), 3.72 (s, 3H), 3.64 (s, 2H), 2.81 (t, J = 6.9 Hz, 2H),
0.87 (s, 9H), 0.01 (s, 6H).
Intermediate 45 {S-^-^ert-Butyl-dimethyl-silanyloxyJ-ethylJ-furan^-y^-acetic acid
Figure imgf000093_0002
The title compound was prepared from [5{5-[2-(tert-Butyl-dimethyl-silanyloxy)- ethyl]-furan-2-yl}-acetic acid methyl ester by a similar method to that employed in intermediate 18. LC-MS (method 6): Rt 1.72 min, m/z 283 [M-H].
1H NMR (400 MHz, CDCI3) 5 6.14 (d, J = 2.8 Hz, 1 H), 6.00 (d, J = 3.1 Hz, 1 H),
3.83 (t, J = 6.8 Hz, 2H), 3.68 (s, 2H), 2.82 (t, J = 6.9 Hz, 2H), 0.87 (s, 9H),
0.01 (s, 6H).
Intermediate 46
Carbonic acid 7-[2-(tert-butoxycarbonyl-{2-[5-(2-oxo-ethyl)-furan-2-yl]-ethyl}- amino)-ethyl]-2-oxo-2,3-dihydro-benzothiazol-4-yl ester tert-butyl ester
Figure imgf000094_0001
The title compound was prepared from {5-[2-(tert-butyl-dimethyl-silanyloxy)- ethyl]-furan-2-yl}-acetic acid and 7-(2-aminoethyl)-4-hydroxybenzo[d]thiazol-2(3H)- one hydrobromide by similar methods to those employed in intermediates 21 and 27, respectively.
LC-MS (method 6): Rt 2.17 min, m/z 545 [M-H].
Intermediate 47
{4-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-[1 ,2,3]triazol-1-yl}-acetic acid ethyl ester
Figure imgf000094_0002
Copper(ll) sulfate pentahydrate (0.16 g, 0.64 mmol) and (but-3-ynyloxy)(tert- butyl)dimethylsilane (1.15 g, 6.24 mmol) were charged to a flask. Water (12 ml_) and 2-methyl propan-1-ol (12 ml_) were added followed by azido-acetic acid ethyl ester (34% solution in DCM) (1.86 ml_, 6.07 mmol). The resulting suspension was stirred vigorously and sodium L-ascorbate in water (1 M) (0.6 mL, 0.60 mmol) was added. The suspension was stirred for 68 hours, then the mixture was partially evaporated and diluted with water and extracted thrice with EtOAc. The organic phase was washed with brine, dried, filtered and concentrated in vacuo. The residue was ourified by silica-gel cartridge (Biotage 40S) ekuting with 1% triethylamine in [4:1] to [3:1] iso-hexane/EtOAc to give the title compound as a colourless oil.
LC-MS (method 6): Rt 2.19 min, m/z 314 [MH]+.
1H NMR (300 MHz, CDCL3) δ 7.50 (s, 1H), 5.12 (s, 2H), 4.26 (q, J = 7.1 Hz,
2H), 3.89 (t, J = 6.5 Hz, 2H), 2.97 (t, J = 6.1 Hz, 2H), 1.30 (t, J = 6.6 Hz, 3H),
0.88 (s, 9H), 0.02 (s, 6H).
Intermediate 48
{4-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-[1 ,2,3]triazoM -yl}-acetic acid
Figure imgf000095_0001
The title compound was prepared from {4-[2-(tert-butyl-dimethyl-silanyloxy)- ethyl]-[1 ,2,3]triazol-1 -yl}-acetic acid ethyl ester by a similar method to that employed in intermediate 18.
LC-MS (method 6): Rt 1.57 min, m/z 286 [MH]+.
1H NMR (400 MHz, d6-DMSO) δ 7.82 (s, 1 H), 5.21 (s, 2H)1 3.81 (t, J = 6.9 Hz,
2H), 2.82 (t, J = 6.8 Hz, 2H), 2.33 (t, J = 1.8 Hz, OH), 0.85 (s, 9H), 0.00 (s,
6H).
Intermediate 49
Carbonic acid 7-[2-(tert-butoxycarbonyl-{2-[4-(2-oxo-ethyl)-[1 ,2,3]triazol-1 -yl]- ethyl}-amino)-ethy!]-2-oxo-2,3-dihydro-benzothiazol-4-yl ester tert-butyl ester
Figure imgf000095_0002
The title compound was prepared from {4-[2-(tert-butyl-dimethyl-silanyloxy)- ethyl]-[1 ,2,3]triazol-1-yl}-acetic acidand 7-(2-aminoethyl)-4-hydroxybenzo[d] thiazol- 2(3H)-one hydrobromide by similar methods to those employed in intermediates 21 and 27, respectively. LC-MS (method 6): Rt 1.90 min, m/z 546 [M-H].
Intermediate 50 4-HydroxymethyI-/V-(2-oxo-ethyl)-benzarnide
Figure imgf000095_0003
The title compound was prepared from Λ/-(2,2-dimethoxy-ethyl)-4- hydroxymethyl-benzamide (Intermediate 14) by similar a method to that employed in intermediates 13.
LC-MS (method 2): Rt 1.80 min, m/z 194 [MH]+.
Intermediate 51
Hydroxy-di-thiophen-2-yl-acetic acid (1S,2R,4S,7S)-7-{[2-(4-hydroxy methyl- benzoylamino)-ethyl]-methyl-amino}-bicyclo[2.2.1]hept-2-yl ester
Figure imgf000096_0001
A mixture of hydroxy-di-thiophen-2-yl-acetic acid (1 S,2R,4S,7S)-7- methylamino-bicyclo[2.2.1]hept-2-yl ester (250 mg, 0.69 mmol), (Intermediate 6), 4- hydroxymethyl-Λ/-(2-oxo-ethyl)-benzamide (146 mg, 0.76 mmol) and sodium triacetoxy borohydride (160 mg, 0.76 mmol) in dry NMP (8.5 ml_) were stirred at RT for 18 hours. The reaction mixture was quenched via addition of saturated aqueous NaHCO3 prior to extracting with EtOAc. The phases were separated and the organic layer was washed successively with water and brine, dried (NaSO4), then concentrated in vacuo. The crude product was passed down a MeOH equilibrated SCX-2 cartridge, prior to elution with 2M NH3 (MeOH). Further purification by silica- gel chromatography, eluting from 0-10% MeOH/DCM gave the title compound as a white foam.
Yield: 171 mg (46%).
LC-MS (method 2): Rt 2.45 min, m/z 541 [MH]+.
Intermediate 52
Hydroxy-di-thiophen-2-yl-acetic acid (1 S,2R,4S,7S)-7-{[2-(4-f ormyl-benzoyl amino)-ethyl]-methyl-amino}-bicyclo[2.2.1]hept-2-yl ester
Figure imgf000097_0001
The title compound was prepared from hydroxy-di-thiophen-2-yl-acetic acid (1S,2R,4S,7S)-7-{[2-(4-hydroxymethyl-benzoylamino)-ethyl]-methyl-amino}- bicyclo[2.2.1]hept-2-yl ester and by a similar a method to that employed in intermediates 15.
LC-MS (method 3): Rt 2.46 & 2.51 min, m/z 539 [MH]+.
Intermediate 53 4-(3-Bromo-propoxy)-benzaldehyde
Figure imgf000097_0002
The title compound was prepared from 4-hydroxybenzaldehyde and 1 ,3- dibromopropane by a similar a method to that employed in intermediate 26. LC-MS (Method 2): Rt 3.47 min, m/z 243, 245 [MH]+
Intermediate 54
Hydroxy-di-thiophen-2-yl-acetic acid (1 S,2S,4R,7R)-2-{[3-(4-f ormyl-phenoxy)- propyl]-methyI-amino}-bicyclo[2.2.1Jhept-7-yl ester
Figure imgf000097_0003
A solution of hydroxy-di-thiophen-2-yl-acetic acid (1S,2R,4S,7S)-7- methylamino-bicyclo[2.2.1]hept-2-yl ester (Intermediate 6) (250 mg, 0.69 mmol), 4-(3- bromo-propoxy)-benzaldehyde (250 mg, 1.03 mmol) and diisopropylethylamine (360 μL, 2.06 mmol) in MeCN was warmed to 75 0C for 18 hours, then at 85 0C for a further 4 hours. The reaction mixture was concentrated in vacuo then purified by chromatography on a flash silica-gel lsolute cartridge (20 g, 70 mL), elυting from 0-
1 % MeOH/DCM to give the desired product as an beige oil. Yield: 300 mg (83%).
LC-MS (method 2): Rt 2.65 min, m/z 526 [MH]+.
Intermediate 55
Hydroxy-di-thiophen-2-yl-acetic acid (1 S,2R,4S,7S)-7-{[3-(4-{[(R)-2-(tert-butyl- dimethyl-silanyloxy)-2-(8-hydroxy-2-oxo-1,2-dihydro-quinolin -S-yO-ethylaminol-methyll-phenoxyJ-propyn-methyl-aminol-bicyclo^^. 1]hept- 2-yl ester
Figure imgf000098_0001
A solution of hydroxy-di-thiophen-2-yl-acetic acid (1 S,2R,4S,7S)-7-{[2-(4- formyl-ben2oylamino)-ethyl]-methyl-amino}-bicyclo[2.2.1]hept-2-yl ester (135 mg, 0.25 mmol) and 5-[(R)-2-amino-1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-8-hydroxy-1H- quinolin-2-one (276 mg, 0.825 mmol) (prepared according to WO2007/102771 ) was stirred in dry methanol (9 mL) in the presence of 3Λ molecular sieves at RT for 20 hours. Sodium triacetoxyborohydride (174 mg, 0.825 mmol) was added to the reaction mixture and stirred at RT for 30 minutes and was then quenched via addition of saturated aqueous NaHCO3 prior to extracting with EtOAc. The phases were separated and the organic layer was washed successively with water and brine, dried (NaSO4), then concentrated in vacuo. The crude product was purified by silica-gel chromatography (20 g lsolute cartridge), eluting from 0-5% MeOH/DCM to give the desired product as an off-white solid.
LC-MS (method 2): Rt 2.52 min, m/z 844 [MH]+.
Intermediate 56
Hydroxy-di-thiophen-2-yl-acetic acid (1 S,2R,4S,7S)-7-{[3-(2-hydroxy-ethyl)- benzyI]-methyl-amino}-bicyclo[2.2.1]hept-2-yl ester
Figure imgf000099_0001
The title compound was prepared from hydroxy-di-thiophen-2-yl-acetic acid (1S,2R,4S,7S)-7-methylamino-bicyclo[2.2.1]hept-2-yl ester (Intermediate 6) and 2-(3- bromomethyl-phenyl)-ethanol (prepared according to EP 472449) by a similar a method to that employed in intermediate 54.
LC-MS (method 6): Rt 2.27 min, m/z 498 [MH]+.
Intermediate 57 2-Bromo-/V-(4-hydroxymethyl-phenyl)-acetamide
Figure imgf000099_0002
The title compound was prepared from (4-amino-phenyl)-methanol and acryloyl chloride by a similar a method to that employed in intermediate 12.
LC-MS (method 3): Rt 2.27 min, m/z 244 & 246 [MH]+.
Intermediate 58
Hydroxy-di-thiophen-2-yl-acetic acid (1 S,2R,4S,7S)-7-{[(4-hydroxymethyl- phenylcarbamoyl)-methyl]-methyl-amino}-bicyclo[2.2.13hept-2-yl ester
Figure imgf000099_0003
The title compound was prepared from 2-bromo-Λ/-(4-hydroxymethyl-phenyl)- acetamide and hydroxy-di-thiophen-2-yl-acetic acid (1S,2R,4S,7S)-7-methylamino- bicyclo[2.2.1]hept-2-yl ester (Intermediate 6) by a similar a method to that employed in intermediate 54.
LC-MS (method 3): Rt 2.65 min, m/z 527 [MH]+. Intermediate 59
Hydroxy-di-thiophen-2-yl-acetic acid (1 S,2R,4S,7S)-7-{[(4-f ormyl- phenylcarbamoyl)-methyi]-methyl-amino}-bicyclo[2.2.1]hept-2-yl ester
Figure imgf000100_0001
The title compound was prepared from hydroxy-di-thiophen-2-yl-acetic acid (1Sl2R,4S,7S)-7-{[(4-hydroxymethyl-phenylcarbamoyl)-methyl]-methyl-amino}- bicyclo[2.2.1]hept-2-yl ester by a similar a method to that employed in intermediate 15. LC-MS (method 3): Rt 3.12 min, m/z 525 [MH]+.
Intermediates 60
3-{[(1S,2R,4S,7S)-2-(2-Hydroxy-2,2-di-thiophen-2-yI-acetoxy)-bicyclo[2.2.1]hept-
7-yl]-methyl-amino}-propionic acid
Figure imgf000100_0002
A solution of hydroxy-di-thiophen-2-yl-acetic acid (1 S,2R,4S,7S)-7- methylamino-bicyclo[2.2.1]hept-2-yl ester (200 mg, 0.551 mmol) (Intermediate 6) and acrylic acid (42 μl_, 0.606 mmol) in DCM (5 mL) in a sealed tube was warmed to 50 0C for 18 hours, then 75 °C for a further 1 hour. The reaction mixture was cooled and concentrated in vacuo then 'chased' with toluene to afford the title compound as a white solid.
LC-MS (method 3): Rt 2.43 min, m/z 436 [MH]+.
Intermediate 61
Hydroxy-di-thiophen-2-yl-acetic acid (1 S,2R,4S,7S)-7-{[2-(4-f ormyl- phenylcarbamoyl)-ethyl]-methyl-amino}-bicyclo[2.2.1]hept-2-yl ester
Figure imgf000101_0001
The title compound was prepared from hydroxy-di-thiophen-2-y)-acetic acid (1 S,2R,4S,7S)-7-methylamino-bicycJo[2.2.1]hept-2-yl ester (Intermediate 6) and (A- amino-phenyl)-methanol by a similar method to that employed in intermediate 14. LC-MS (method 2): Rt 2.59 min, m/z 539 [MH]+.
Intermediate 62 θ-Hydroxy-ΘH-xanthene-θ-carboxylic acid (1 S,2R,4S,7S)-7-methyIamino- bicyclo[2.2.1]hept-2-yl ester
Figure imgf000101_0002
The title compound was prepared from ((1S,2R,4S,7S)-2-hydroxy- bicyclo[2.2.1]hept-7-yl)-methyl-carbarnic acid tert-butyl ester (Intermediate 4) and 9- hydroxy-9H-xanthene-9-carboxylic acid methyl ester by similar methods to those employed in intermediates 5 and 6, respectively.
LC-MS (method 2): Rt 2.31 min, m/z 366 [MH]+.
Intermediate 63
9-Hydroxy-9H-xanthene-9-carboxylic acid (1 R,2S,3S)-2-ethyl-3-{[3-(4-formyl- phenoxy)-propyl]-methyl-amino}-cyclopentyl ester
Figure imgf000101_0003
The title compound was prepared from 9-hydroxy-9H-xanthene-9-carboxylic acid (1S,2R,4S,7S)-7-methylamino-bicyclo[2.2.1]hept-2-yl ester and 4-(3-bromo- propoxy)-benzaldehyde (Intermediate 53) by a similar method to that employed in intermediate 54.
LC-MS (method 3): Rt 2.52 min, m/z 528 [MH]+.
Intermediate 64
(R)-Cyclohexyl-hydroxy-phenyl-acetic acid (1S,2R,4S,7S)-7-methylamino- bicyclo[2.2.1]hept-2-yl ester
Figure imgf000102_0001
The title compound was prepared from ((1 S,2R,4S,7S)-2-hydroxy- bicyclo[2.2.1]hept-7-yl)-methyl-carbamic acid tert-butyl ester (Intermediate 4) and (R)-Cyclohexyl-hydroxy-phenyl-acetic acid methyl ester by similar methods to those employed in intermediates 5 and 6, respectively.
LC-MS (method 3): Rt 2.59 min, m/z 358 [MH]+.
Intermediate 65
(R)-Cyc!ohexyi-hydroxy-phenyl-acetic acid (1 S,2R,4S,7S)-7-{[3-(4-f ormyl- phenoxy)-propyI]-methyl-amino}-bicyclo[2.2.1]hept-2-yl ester
Figure imgf000102_0002
The title compound was prepared from (R)-cyclohexyl-hydroxy-phenyl-acetic acid (1 S,2R,4S,7S)-7-methylamino-bicyclo[2.2.1 ]hept-2-yl ester and 4-(3-bromo- propoxy)-benzaldehyde (Intermediate 53) by a similar method to that employed in intermediate 54.
LC-MS (method 3): Rt 2.82 min, m/z 520 [MH]+.
Compounds 1-13 were also prepared:
Compound 1 Hydroxy-di-thiophen-2-yl-acetic acid (1 S,2R,4S,7S)-7-{[2-(4-{2-[2-(4-hydroxy-2- oxo-2,3-dihydro-benzothiazol-7-yl)-ethylamino]-ethyl}-benzoylamino)-ethyl]- methyl-amino}-bicyclo[2.2.1]hept-2-yl ester trifluoroacetic acid
Figure imgf000103_0001
[2-(4-Hydroxy-2-oxo-2,3-dihydro-benzothiazol-7-yl)-ethyl]-{2-[4-(2-oxo- ethylcarbamoyl)-phenyl]-ethyl}-carbamic acid tert-butyl ester (3.8 mmol) (Intermediate 13) was dissolved in NMP (10 ml_) and acetic acid (0.23 ml) was added. An aliquot of this solution (0.29 mL) was added to the reaction vessel containing hydroxy-di- thiophen-2-yl-acetic acid (1S,2R,4S,7S)-7-methylamino-bicyclo[2.2.1]hept-2-yl ester (0.075 mmol) (Intermediate 6) in NMP (0.1 mL). The reaction was shaken for 5 minutes and then sodium triacetoxyborohydride (0.15 mL of a 1.14 molar solution in NMP, 0.17 mmol) was added and the reaction mixture shaken for 16 hours. MeOH (0.5 mL) was added and the solution applied to TsOH-65 resin (0.2 g) loading with MeOH, then eluting with 2 M ammonia in methanol to give the crude Boc- intermediate after concentration in vacuo. Formic acid (0.5 mL) was added was added to the crude reaction mixture and the solution was stirred at RT for 2 hours. The reaction was concentrated in vacuo, dissolved in DMSO (0.4 mL) then purified by HPLC (system 5)
LC-MS (method 8): Rt 1.46 min, m/z 748 [MH]+.
The following compounds shown in table were prepared using a similar method to that described for Compound 1 using the appropriate β2-substituted aldehyde intermediates and hydroxy-di-thiophen-2-yl-acetic acid (1 S,2R,4S,7S)-7- methylamino-bicyclo[2.2.1]hept-2-yl ester (Intermediate 6), to give the title compounds as TFA salts (analysis undertaken using LC-MS method 8 unless otherwise stated): beo tahizonzl7--
J
Figure imgf000104_0001
Figure imgf000105_0001
[* =
Compound 8
Hydroxy-di-thiophen-2-yI-acetic acid (1 S,2R,4S,7S)-7-{[3-(3-{[2-(4-hydroxy-2- oxo-2,3-dihydro-benzothiazol-7-yl)-ethylamino]-methyl}-piperidin-1-yl)-3-oxo- propyl]-methyl-amino}-bicyclo[2.2.1]hept-2-yl ester trifluoroacetic acid
Figure imgf000106_0001
(1-Acryloyl-piperidin-3-ylmethyl)-[2-(4-hydroxy-2-oxo-2,3-dihydro-ben2 othiazol-7-yl)-ethyf]-carbamic acid tert-butyl ester (3.8 mmol) (Intermediate 34) was dissolved in NMP (10 mL) and acetic acid (0.23 mL) added. An aliquot of this solution (0.29 mL) was added to the reaction vessel containing hydroxy-di-thiophen- 2-yl-acetic acid (1S,2R,4S,7S)-7-methylamino-bicyclo [2.2.1]hept-2-yl ester (0.075 mmol) (Intermediate 6) in NMP (0.1 mL). The reaction was shaken for for 5 days at 70 0C. MeOH (0.5 mL) was added and the solution applied to TsOH-65 resin (0.2 g) loading with MeOH, then eluting with 2 M ammonia in methanol to give the crude Boc-intermediate after concentration in vacuo. Formic acid (0.5 mL) was added was added to the crude reaction mixture and the solution was stirred at RT for 2 hours. The reaction was concentrated in vacuo, dissolved in DMSO (0.4 mL) then purified by HPLC (system 5)
LC-MS (method 8): Rt 1.52 min, m/z 726 [MH]+.
Compound 9
Hydroxy-di-thiophen-2-yl-acetic acid (1 S,2R,4S,7S)-7-{[(4-{[2-(4-hydroxy-2-oxo- 2,3-dihydro-benzothiazol-7-yI)-ethyIamino]-methyl}-phenyl carbamoyl)-methyl]- methyl-amino}-bicyclo[2.2.1]hept-2-yl ester trifluoacetate
Figure imgf000106_0002
[4-(2-Bromo-acetylamino)-benzyl]-[2-(4-hydroxy-2-oxo-2,3-dihydro-benzo thiazol-7-yl)-ethyl]-carbamic acid tert-buty! ester (1.2 mmol) (Intermediate 9) was dissolved in NMP (4 ml_) and an aliquot (100 uL) of this solution were added to the reaction vessel containing hydroxy-di-thiophen-2-yl-acetic acid (1 S,2R,4S,7S)-7- methylamino-bicyclo[2.2.1]hept-2-yl ester (0.075 mmol) (0.025 mmol) (Intermediate 6) and triethylamine (0.066 mmol) in NMP (200 uL). The reaction mixture was allowed to stand at 20 0C for 6 hours. MeOH (0.6 ml_) was added and the solution applied to TsO-H65 resin (0.2 g) eluting with methanol, then with 3.5 M ammonia in MeOH to elute the Boc-intermediate. Formic acid (0.5 ml_) was added was added to the crude reaction mixture and the solution was stirred at RT for 2 hours. The reaction was concentrated in vacuo, dissolved in DMSO (0.4 mL) then purified by HPLC (system 5)
LC-MS (method 8): Rt 1.40 min, m/z 719.9 [MH]+.
Compound 10 Hydroxy-di-thiophen-2-yl-acetic acid (1 S,2R,4S,7S)-7-{[(4-{[2-(4-hydroxy-2-oxo- 2,3-dihydro-benzothiazol-7-yl)-ethylamino]-methyl}-thiazol-2- ylcarbamoylj-methyπ-methyl-aminoj-bicyclo^^.i ]hept-2-yl ester trifluoroacetic acid
Figure imgf000107_0001
The title compound was prepared from [2-(2-bromo-acetylamino)-thiazol-4-ylmethyl]- [2-(4-hydroxy-2-oxo-2,3-dihydro-benzothiazol-7-yl)-ethyl]-carbamic acid tert-butyl ester (Intermediate 38) and hydroxy-di-thiophen-2-yl-acetic acid (1S,2R,4S,7S)-7- methylamino-bicyclo[2.2.1]hept-2-yl ester (Intermediate 6) by a similar method to that employed in Compound 9.
LC-MS (method 3): Rt 1.39 min, m/z 726.9 [MH]+.
Compound 11 Hydroxy-di-thiophen-2-yl-acetic acid (1 S,2R,4S,7S)-7-{[3-(3-{[2-(4-hydroxy-2- oxo-2,3-dihydro-benzothiazol-7-yl)-ethylamino]-methyl}-phenoxy)-propyl]- methyl-amino}-bicyclo[2.2.1]hept-2-yl ester trifluoroacetic acid
Figure imgf000108_0001
Methanesulfonic acid 3-[3-({tert-butoxycarbonyl-[2-(4-hydroxy-2-oxo-2, 3-dihydro-benzothiazol-7-yl)-ethyi]-amino}-methyl)-phenoxy]-propyl ester (1.076 g) (Intermediate 33) and triethylamine (0.404 g) were dissolved in sufficient NMP to give 2 mL of solution. An aliquot (50 μl_) of this solution was added to a reaction vessel containing hydroxy-di-thiophen-2-yl-acetic acid (1S,2R,4S,7S)-7-methylamino- bicyclo[2.2.1]hept-2-yl ester (Intermediate 6) in NMP (100 μl_). The reaction mixture was heated at 85 0C for 18 hours. MeOH (0.7 mL) was added and the solution was applied to TsOH-65 resin (0.2 g) eluting with methanol, then with 3.5 M ammonia in MeOH to elute the Boc-intermediate. The fractions containing the products were evaporated. Formic acid (0.5 mL) was added was added to the crude reaction mixture and the solution was stirred at RT for 2 hours. The reaction was concentrated in vacuo, dissolved in DMSO (0.4 mL) then purified by HPLC (system 5) LC-MS (method 8): Rt 1.49 min, m/z 720.9 [MH]+.
The following compounds shown in table were prepared using a similar method to that described for Compound 11 using the appropriate β2-substituted aldehyde intermediates and hydroxy-di-thiophen-2-yl-acetic acid (1S,2R,4S,7S)-7- methylamino-bicyclo[2.2.1]hept-2-yl ester (Intermediate 6), to give the title compounds as TFA salts (analysis undertaken using LC-MS method 8):
Figure imgf000109_0001
The invention will now be illustrated but not limited by the following Examples:
Example 1
Hydroxy-di-thiophen-2-yl-acetic acid (1 S,2R,4S,7S)-7-{[2-(4-{[(R)-2-hydroxy-2-(4- hydroxy-2-oxo-2,3-dihydro-benzothiazol-7-yl)-ethy1amino]-methyl}- benzoylamino)-ethyl]-methyl-amino}-bicyclo[2.2.1]hept-2-yl ester
Figure imgf000109_0002
The title compound was prepared from hydroxy-di-thiophen-2-yi-acetic acid (1S,2R,4S,7S)-7-{[(4-formyl-phenylcarbamoyl)-methyl]-methyl-amino}- bicyclo[2.2.1]hept-2-yl ester (Intermediate 52) and 7-((R)-2-amino-1-hydroxy-ethyi)-4- hydroxy-3H-benzothiazol-2-one hydrochloride by a similar a method to that employed in intermediate 55. The crude product was purified by silica-gel chromatography (Companion, 12 g), eluting from [88:12] DCM/(2 M NH3 in MeOH) to give the desired product as an off-white solid.
Yield: 104 mg (55%).
LC-MS (method 5): Rt 5.55 min, m/z 749 [MH]+.
Example 2
Hydroxy-di-thiophen-2-yl-acetic acid (1 S,2R,4S,7S)-7-{[3-(4-{[(R)-2-hydroxy-2-(4- hydroxy-2-oxo-2,3-dihydro-ben2othiazol-7-yl)-ethylamino3-methyl}-phenoxy)- propyl]-methyl-amino}-bicyclo[2.2.1]hept-2-yl ester formic acid
Figure imgf000110_0001
The title compound was prepared from hydroxy-di-thiophen-2-yl-acetic acid (1 S,2S,4R,7R)-2-{[3-(4-formyl-phenoxy)-propyl]-methyl-amino}-bicyclo[2.2.1 ] hept-7- yl ester (Intermediate 54) and 7-((R)-2-amino-1 -hydroxy-ethyl)-4-hydroxy-3H- benzothiazol-2-one hydrochloride by a similar method to that employed in intermediate 55. The crude product was purified by HPLC (system 3) eluting from 10- 25% MeCN/water (+0.1% HCO2H) over 20 min. Freeze-drying afforded the title compound as a white fluffy solid. LC-MS (method 5): Rt 5.50 min, m/z 736 [MH]+.
Example 3
Hydroxy-di-th iophen-2-yl-acetic acid (1 S,2R,4S,7S)-7-{[2-(4-{[(R)-2-hydroxy-2-(8- hydroxy-2-oxo-1,2-dihydro-quinolin-5-yl)-ethylamino]-methyl}-benzoyJamino)- ethyl]-methyl-amino}-bicyclo[2.2.1Jhept-2-yI ester formic acid
Figure imgf000111_0001
A solution of anti hydroxy-di-thiophen-2-yl-acetic acid (1S,2R,4S,7S)-7-{[2-(4- {[(R)-2-(tert-butyl-dimethyl-silanyloxy)-2-(8-hydroxy-2-oxo-1 ,2-dihydro-quinolin-5-yl) ethyi amino]-methyl}-benzoylamino)-ethyl]-methyl-amino}-bicyclo[2.2.1]hept-2-yl ester (175 mg, 0.21 mmol) (Intermediate 55) in THF (8 mL) under nitrogen was treated with triethylamine trihydrofluoride (85 μl_, 0.52 mmol). After stirring at RT overnight, the reaction mixture was neutralised with saturated NaHCO3 (aq) and extracted with DCM. The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by HPLC (system 3), eluting from 10-25% MeCN/water (0.1% formic acid) over 15 minutes and gave, after freeze drying, the desired product as white solid.
Yield: 75 mg (47%).
LC-MS (method 5): Rt 5.32 min, m/z 730 [MH]+.
Example 4
Hydroxy-di-thiophen-2-yl-acetic acid 7-{[3-(2-hydroxy-ethyI)-benzyl]-m ethyl-amino}-bicyclo[2.2.1]hept-2-yl acetate trifluoroacetic acid
Figure imgf000111_0002
The title compound was prepared from (R)-cyclohexyl-hydroxy-phenyl-acetic acid (1S,2R,4S,7S)-7-{[3-(2-hydroxy-ethyl)-benzyl]-methyl-amino}-bicyclo [2.2.1 jhept- 2-yl (Intermediate 59) and 7~((R)-2-amino-1-hydroxy-ethyl)-4-hydroxy-3H- benzothiazol-2-one hydrochloride by similar methods to those employed in intermediates 27 and 51 , respectively.
LC-MS (method 7): Rt 2.97 min, m/z 706 [MH]+. Example 5
Hydroxy-di-thiophen-2-yl-acetic acid (1 S,2R,4S,7S)-7-{[(4-{[(R)-2-hydroxy-2-(4- hydroxy-2-oxo-2,3-dihydro-benzothiazol-7-yl)-ethylamino]-methyl}- phenylcarbamoyl)-methyl]-methyl-am)no}-bJcyclo[2.2.1]hept-2-yl ester
Figure imgf000112_0001
The title compound was prepared from hydroxy-di-thiophen-2-yl-acetic acid (1S,2R,4S,7S)-7-{[(4-formyl-phenylcarbamoyl)-methyl]-methyl-amino}- bicyclo[2.2.1]hept-2-yl ester (Intermediate 59) and 7-((R)-2-amino-1-hydroxy-ethyl)-4- hydroxy-3H-benzothiazol-2-one hydrochloride by a similar method to that employed in intermediate 55. Purification by silica-gel cartridge (Companion, 4g), eluting with DCM to DCM/2 M NH3 in MeOH [88:12], afforded the title compound. LC-MS (method 5): Rt 6.10 min, m/z 735 [MH]+.
Example 6
Hydroxy-di-thiophen-2-yl-acetic acid (1 S,2R,4S,7S)-7-{[(4-{[(R)-2-hydroxy-2-(8- hydroxy-2-oxo-1 ,2-dihydro-quinolin-5-yl)-ethylamino]-methyl}- phenylcarbamoyl)-methyl]-methyl-amino}-bicyclo[2.2.1]hept-2-yl ester
Figure imgf000112_0002
The title compound was prepared from hydroxy-di-thiophen-2-yl-acetic acid (1S,2R,4S,7S)-7-{[(4-formyl-phenylcarbamoyl)-methyl]-methyl-amino}- bicyclo[2.2.1]hept-2-yl ester (Intermediate 59) and 5-[(R)-2-amino-1-(tert-butyl- dimethyl-silanyloxy)-ethyl]-8-hydroxy-1 H-quinolin-2-one by similar methods to those employed in intermediates 55 and example 3, respectively. Purification by silica-gel cartridge (Companion, 4g), eluting with DCM to DCM/2 M NH3 in MeOH [88:12], afforded the title compound.
LC-MS (method 5): Rt 5.84 min, m/z 729 [MH]+.
Example 7
Hydroxy-di-thiophen-2-yl-acetic acid (1 S,2R,4S,7S)-7-{[2-(4-{[(R)-2-hydroxy-2-(8- hydroxy-2-oxo-1,2-dihydro-quinolin-5-yl)-ethylamino]-methyl}-benzoylamino)- ethyl]-methyl-amino}-bicyclo[2.2.1]hept-2-yl ester diformic acid
Figure imgf000113_0001
The title compound was prepared from hydroxy-di-thiophen-2-yl-acetic acid (1 S,2R,4S,7S)-7-{[2-(4-formyl-benzoyl amino)-ethyl]-methyl-amino}-bicyclo[2.2.1] hept-2-yl ester (Intermediate 52) and 5-[(R)-2-amino-1-(tert-butyl-dimethyl-silanyloxy)- ethyi]-8-hydroxy-1H-quinolin-2-one by similar methods to those employed in intermediates 55 and example 3, respectively. The crude product was purified by HPLC (system 3), eluting from 5-50% MeCN/water (0.1% formic acid) and gave, after freeze drying, the desired product as white solid.
LC-MS (method 5): Rt 5.32 min, m/z 743 [MH]+.
Example 8
Hydroxy-di-thiophen-2-yl-acetic acid (1 S,2R,4S,7S)-7-{[2-(4-{[(R)-2-hydroxy-2-(4- hydroxy-2-oxo-2,3-dihydro-benzothiazol-7-yl)-ethylamino]-methyl}- phenylcarbamoylj-ethylj-methyl-aminoj-bicyclo^^.ijhept^-yl ester diformic acid
Figure imgf000113_0002
The title compound was prepared from hydroxy-di-thiophen-2-yl-acetic acid
(1 S,2R,4S,7S)-7-{[2-(4-formyl-phenylcarbamoyl)-ethyl]-methyl-amino}- bicyclo[2.2.1]hept-2-yl ester (Intermediate 61) and 7-((R)-2-amino-1-hydroxy-ethyl)-4- hydroxy-3H-benzothiazol-2-one hydrochloride by a similar method to that employed in intermediate 55. The crude product was purified by HPLC (system 3), editing from 5-50% MeCN/water (0.1% formic acid) and gave, after freeze drying, the desired product as white solid.
LC-MS (method 5): Rt 5.73 min, m/z 749 [MH]+.
Example 9
Hydroxy-di-thiophen-2-yI-acetic acid (1 S,2R,4S,7S)-7-{[(4-{[(R)-2-hydroxy-2-(8- hydroxy-2-oxo-1,2-dihydro-quinoIin-5-yl)-ethylamino]-methyl}- phenylcarbamoyO-methyll-methyl-aminoj-bicycIo^^.ilhept^-ylester diformic acid
Figure imgf000114_0001
The title compound was prepared from hydroxy-di-thiophen-2-yl-acetic acid (1S,2R!4S,7S)-7-{[2-(4-formyl-phenylcarbamoyl)-ethyl]-methyl-amino}- bicyclo[2.2.1]hept-2-yl ester (Intermediate 61) and 5-[(R)-2-amino-1-(tert-butyl- dimethyl-silanyloxy)-ethyl]-8-hydroxy-1H-quinolin-2-one by similar methods to those employed in intermediates 55 and example 3, respectively. The crude product was purified by HPLC (system 3), eluting from 5-50% MeCN/water (0.1% formic acid) and gave, after freeze drying, the desired product as white solid.
LC-MS (method 5): Rt 5.56 min, m/z 743 [MH]+.
Example 10 θ-Hydroxy-SH-xanthene-θ-carboxylic acid (1 S,2R,4S,7S)-7-{[3-(4-{[(R)-2- hydroxy-2-(4-hydroxy-2-oxo-2,3-dihydro-benzothiazol-7-yl)-ethylamino]- methyl}-phenoxy)-propyl]-methyl-amino}-bicyclo[2.2.1]hept-2-yl ester
Figure imgf000115_0001
The title compound was prepared from 9-hydroxy-9H-xanthene-9-carboxylic acid (1 R,2S,3S)-2-ethyl-3-{[3-(4-formyl-phenoxy)-propyl]-methyl-amino}-cyclopentyl ester (Intermediate 63) and 7-((R)-2-amino-1-hydroxy-ethyl)-4-hydroxy-3H- benzothiazol-2-one hydrochloride by a similar method to that employed in intermediate 55. The crude product was purified by HPLC (system 3), eluting from 10-25% MeCN/water (0.1% formic acid) and gave, after freeze drying, the desired product as white solid.
LC-MS (method 5): Rt 5.82 min, m/z 738 [MH]+.
Example 11
9-Hydroxy-9H-xanthene-9-carboxyIic acid (1 S,2R,4S,7S)-7-{[3-(4-{[(R)-2- hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydro-quinolin-5-yl)-ethylamino]-methyl}- phenoxy)-propyl]-methyl-amino}-bicyclo[2.2.1Jhept-2-yl ester formic acid
Figure imgf000115_0002
The title compound was prepared from hydroxy-di-thiophen-2-yl-acetic acid (1 S,2R,4S,7S)-7-{[2-(4-formyl-phenylcarbamoyl)-ethyl]-methyl-amino}- bicyclo[2.2.1]hept-2-yl ester (Intermediate 63) and 5-[(R)~2-amino-1-(tert-butyl- dimethyl-silanyloxy)-ethyl]-8-hydroxy-1H-quinolin-2-one by similar methods to those employed in intermediates 55 and example 3, respectively. The crude product was purified by HPLC (system 3), eluting from 10-25% MeCN/water (0.1% formic acid) and gave, after freeze drying, the desired product as white solid.
LC-MS (ADD): Rt 5.65 min, m/z 732 [MH]+.
Example 12 (R)-Cyclohexyl-hydroxy-phenyl-acetic acid (1 S,2R,4S,7S)-7-{[3-(4-{[(R)-2- hydroxy-2-(4-hydroxy-2-oxo-2,3-dihydro-benzothiazol-7-yl)-ethylamino]- methyl}-phenoxy)-propyl]-methyl-amino}-bicyclo[2.2.1]hept-2-yl ester formic acid
Figure imgf000116_0001
The title compound was prepared from (R)-cyclohexyl-hydroxy-phenyl-acetic acid (IS^R^S.ZSJ-y-fCS^Φformyl-phenoxyj-propyO-methyl-aminoJ-bicycIo [2.2.1]hept-2-yl ester (Intermediate 65) and 7-((R)-2-amino-1-hydroxy-ethyl)-4- hydroxy-3H-benzothiazol-2-one hydrochloride by a similar method to that employed in intermediate 55. The crude product was purified by HPLC (system 3), eluting from 10-25% MeCN/water (0.1% formic acid) and gave, after freeze drying, the desired product as white solid.
LC-MS (ADD): Rt 6.72 min, m/z 730 [MH]+.
Example 13
(R)-Cyclohexyl-hydroxy-phenyl-acetic acid (1 S,2R,4S,7S)-7-{[3-(4-{[(R)-2- hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydro-quinolin-5-yl)-ethyIamino]-methyl}- phenoxy)-propyl]-methyl-amino}-bicyclo[2.2.1]hept-2-yl ester formic acid
Figure imgf000116_0002
The title compound was prepared from (R)-cyclohexyl-hydroxy-phenyl-acetic acid (1S,2R,4S,7S)-7-{[3-(4-formyl-phenoxy)-propyl]-methyl-amino}-bicyclo [2.2.1]hept-2-yl ester (Intermediate 65) and 5-[(R)-2-amino-1-(tert-butyl-dimethyl- silanyloxy)-ethyl]-8-hydroxy-1 H-quinolin-2-one by similar methods to those employed in intermediates 55 and example 3, respectively The crude product was purified by HPLC (system 3), eluting from 10-25% MeCN/water (0.1% formic acid) and gave, after freeze drying, the desired product as white solid. LC-MS (ADD): Rt 6.53 min, m/z 724 [MH]+.
BIOLOGICAL ASSAYS
The inhibitory effects of compounds of the present invention at the M3 muscarinic receptor and the β2 adrenergic receptor, may be determined by the following binding assays:
Muscarinic 3 receptor binding assay
The affinity (plC50) of compounds to the M3 receptor is determined by competition binding of [3H]N-methyl scopolamine (NMS) to CHO-K1 (Chinese Hamster Ovary) cell membranes expressing the human muscarinic acetylcholine M3 receptor (M3-ACh) in a scintillation proximity assay (SPA) format. SPA beads are precoated with membranes and then incubated at 2mg of beads per well with serial dilutions of compounds of the invention, [3H]NMS at 0.2nM, half Kd (experimentally determined dissociation constant) and assay buffer (20 mM HEPES pH 7.4 containing 5 mM MgCI2). The assay is conducted in a final volume of 200 μL, in the presence of 1% (v/v) dimethyl sulphoxide (DMSO). Total binding of [3H]NMS is determined in the absence of competing compound and non-specific binding of
[3H]NMS is determined in the presence of 1 μM atropine. The plates are incubated for 16 hours at room temperature and then read on Wallac Microbeta™ using a normalised 3H protocol. The plC50, defined as the negative logarithm of the concentration of compound required for 50% reduction in specific [3H]-NMS binding, is determined.
Muscarinic 3 receptor binding assays (plC50 and spot test activity determinations)
The activity of compounds at the M3 receptor is determined by competition binding of [3H]N-methyl scopolamine (NMS) to CHO-K1 (Chinese Hamster Ovary) cell membranes expressing the human muscarinic acetylcholine M3 receptor (M3-ACh) in a scintillation proximity assay (SPA) format.
SPA beads are precoated with membranes and then incubated at 2mg of beads per well with compounds of the invention, [3H]NMS at 0.2nM, half Kd (experimentally determined dissociation constant) and assay buffer (20 mM HEPES pH 7.4 containing 5 mM MgCI2). The assay is conducted in a final volume of 200 μL, in the presence of 1% (v/v) dimethyl sulphoxide (DMSO). Total binding of [3H]NMS is determined in the absence of competing compound and non-specific binding of [3H]NMS is determined in the presence of 1 μM atropine. The plates are incubated for 16 hours at room temperature and then read on Wallac Microbeta™ using a normalised 3H protocol.
For plC50 determinations the assay is conducted using serial dilutions of compounds of the invention. The plC50 is defined as the negative logarithm of the concentration of compound required for 50% reduction in specific [3H]-NIvIS binding. For spot test activity determinations compounds of the invention are incubated at a single 10 nM concentration using the protocol described above. The percentage inhibition of specific [3H]NMS binding is reported.
Compounds 1-13 were tested for binding to the M3 receptor and the following results obtained:
Figure imgf000118_0001
* = M3 binding plC50 (nM) reported
β- Adrenergic Receptor Radioligand Binding Assay
Radioligand binding studies utilising [125l]-lodocyanopindolol and commercially available cell membranes expressing the human β2 adrenergic receptor are used to assess the affinity of antagonists for β2-adrenergic receptor. Membranes and SPA-beads are incubated with [125l]-lodocyanopindolol and β2 antagonist at various concentrations for 3 hours at ambient temperature in TRIS buffer. The assay is performed in 96-well plates which are read using the Wallac Microbeta counter.
Where tested, Compounds 1 -13 were tested in the β2 binding assay and were found to have a β2 plC50 of >5. Assay for adrenergic β2 mediated cAMP production
Cell preparation H292 cells are grown in 225cm2 flasks incubator at 370C, 5% CO2 in RPMI medium containing10% (v/v) FBS (foetal bovine serum) and 2 mM L-glutamine. Experimental Method
Adherent H292 cells re removed from tissue culture flasks by treatment with Accutase™ cell detachment solution for 15 minutes. Flasks are incubated for 15 minutes in a humidified incubator at 37°C, 5% CO2. Detached cells are re- suspended in RPMI media (containing 10% (v/v) FBS and 2 mM L-glutamine) at 0.05 x 106 cells per mL 5000 ceils in 100 μl_ are added to each well of a tissue-culture- treated 96-well plate and the cells incubated overnight in a humidified incubator at 37°C, 5% CO2. The culture media is removed and cells are washed twice with 100 μL assay buffer and replaced with 50 μL assay buffer (HBSS solution containing 1 OmM HEPES pH7.4 and 5 mM glucose). Cells are rested at room temperature for 20 minutes after which time 25 μL of rolipram (1.2 mM made up in assay buffer containing 2.4% (v/v) dimethylsulphoxide) is added. Cells are incubated with rolipram for 10 minutes after which time test compounds are added and the cells are incubated for 60 minutes at room temperature. The final rolipram concentration in the assay is 300 μM and final vehicle concentration is 1.6% (v/v) dimethylsulphoxide. The reaction is stopped by removing supernatants, washing once with 100 μL assay buffer and replacing with 50 μL lysis buffer. The cell monolayer is frozen at -80 0C for 30 minutes (or overnight).
AlphaScreen™ cAMP detection
The concentration of cAMP (cyclic adenosine monophosphate) in the cell lysate is determined using AlphaScreen™ methodology. The frozen cell plate is thawed for 20 minutes on a plate shaker then 10 μL of the cell lysate is transferred to a 96-well white plate. 40 μL of mixed AlphaScreen™ detection beads pre-incubated with biotinylated cAMP, is added to each well and the plate incubated at room temperature for 10 hours in the dark. The AlphaScreen™ signal is measured using an En Vision spectrophotometer (Perkin-Elmer Inc.) with the recommended manufacturer's settings. cAMP concentrations are determined by reference to a calibration curve determined in the same experiment using standard cAMP concentrations. Concentration response curves for agonists are constructed and data is fitted to a four parameter logistic equation to determine both the pEC50 and Intrinsic Activity. Intrinsic Activity is expressed as a fraction relative to the maximum activity determined for formoterol in each experiment.
The compounds of Examples 1-13 were tested in the M3 receptor binding and β2 cAMP functional assays and the following results obtained:
Figure imgf000120_0001
Intrinsic activity relative to Formoterol is shown in parenthesis. NT = Not tested

Claims

CLAIMS:
1. A compound of formula (I);
Figure imgf000121_0001
wherein
A is an oxygen atom or group -N(R12)-;
(i) R1 is d-Ce-alkyl or hydrogen; and R2 is a group-Z-NR9R10;; and R3 is a lone pair, or Ci-C6-alkyl; or
(ii) R1 and R3 together with the nitrogen to which they are attached form a heterocycloalkyl ring, and R2 is a group -Z-NR9R10, or
(iii) R1 and R2 together with the nitrogen to which they are attached form a heterocycloalkyl ring, said ring being substituted by a group , -Z-NR9R10; and R3 is a lone pair, or d-Cβ-alkyl;
R4 is selected from one of the groups of formula (a), (b), (c) or (d);
Figure imgf000121_0002
R6 is CrC6-alkyl or a hydrogen atom;
R7a and R7b are a CrC6-alkyl group or halogen;
n and m are independently 0, 1 , 2 or 3; R8a and R8b are independently selected from the group consisting of aryl, aryl-fused- heterocycloalkyl, heteroaryl, d-Cβ-alkyl, cycloalkyl;
R8c is -OH, Ci-Cβ-alkyl, hydroxy-CrC6-alkyl, nitrile, a group CONR8d 2 or a hydrogen atom;
R8d is CrC6-alkyl or a hydrogen atom;
R9 is a hydrogen atom or CrC6-alkyl;
R10 is an aryl(Ci-C6-alkyl)-, or heteroaryl(CrC6-alkyl) group, in which the CrC6-alkyl group is optionally substituted byup to three groups independently chosen from C1- C6-haloalkyl, CrC6-alkoxy, CrC6-haloalkoxy, CN and halo; and the aryl or heteroaryl group may be optionally substituted with up to three substituent groups independently chosen from CrC6-alkyl, C^Ce-haloalkyl, Ci-C6-haloalkoxy, CrC6-alkoxy, CN and halo.
R12 is CrC6-alkyl or a hydrogen atom;
Ar1 is aryl, heteroaryl or cycloalkyl;
Ar2 are independently aryl, heteroaryl or cycloalkyl; and
Q is an oxygen atom, -CH2-, -CH2CH2- or a bond;
Z is a linker
-C(L3)(L4)-L-C(L1)(L2)-, wherein the compounds of formula (I) may be represented by formula (Ia)
Figure imgf000122_0001
wherein R1, R3, R4, and A are as defined for formula (I), and
L is a hydrocarbyl chain of up to 14 carbon atoms wherein one, two or three carbon atoms of the chain are replaced by groups independently selected from O, NR45, S, S(O), S(O)2, C(O)O, OC(O), NR46C(O), C(O)NR47, NR48S(O)2, S(O)2NR49, NR50C(O)NR51, NR52S(O)2NR53, OC(O)NR54, NR55C(O)O, provided that any heteroatoms in the chain are separated by at least 2 carbon atoms; and/or wherein up to four carbon atoms of the chain form part of a mono- or bicyclic aliphatic, heteroaliphatic, aromatic or heteroaromatic ring having up to four heteroatoms independently selected from N, O or S, said ring comprising up to 10 ring atoms, and wherein the ring is optionally substituted by up to three substituents independently selected from halogen, S(O)0-2R5e, NR57R58, S(O)2NR59R60, C(O)NR61R62, C(O)OR63, NR64S(O)2R65, NR66C(O)R67, NR68C(O)OR69, NR70C(O)NR71R72, OR73, C1* alkyl and C3* cycloalkyl, and wherein CL6 alkyl and C3-6 cycloalkyl may be optionally substituted by up to three substituents independently selected from halogen, hydroxyl and Ci-6alkoxy; and the chain may comprise up to three of such rings each selected independently; wherein R56, R65 and R69 each independently represent Ci-6 alkyl or C3-6 cycloalkyl, wherein C1-6 alkyl and C3.6 cycloalkyl may be optionally substituted by up to three substituents independently selected from halogen, hydroxyl, C1-6 alkoxy; and
R 45 Q46 r>47 D48 Q49 D50 Q51 Q52 rj54 D55 Q57 Q58 D59 Q60 r>62 , ι > , n , i t , π , rt , ri , n ,
Figure imgf000123_0002
π , ri , n , ri , π , n ,
Figure imgf000123_0001
, π ,
R63, R64, R66, R67, R68 , R70, R71, R72 and R73 each independently represent hydrogen, or C1-6 alkyl or C3.6 cycloalkyl, wherein C1* alkyl and C3.6 cycloalkyl may be optionally substituted by up to three substituents independently selected from halogen, hydroxyl, C1-6 alkoxy; or any of R57 and R58, R59 and R60, R61 and R62 or R71 and R72, together with the nitrogen atom to which they are both attached, may form a 4 to 8 membered aliphatic heterocyclic ring, wherein the aliphatic heterocyclic ring may comprise up to three heteroatoms independently selected from N, O and S, wherein the ring may be optionally substituted by up to three substituents independently selected from halogen, hydroxyl and C1-6 alkyl or C3-6 cycloalkyl, wherein C1-6 alkyl and C3.6 cycloalkyl may be optionally substituted by one or more substituents independently selected from halogen and hydroxyl; and wherein the chain may additionally comprise up to three carbon-carbon double bonds; wherein the chain may additionally comprise up to three carbon-carbon triple bonds; L1 and L2 each independently represent hydrogen, Ci-6 alkyl or C3.6 cycloalkyl;
L3 and L4 each independently represent hydrogen, C1-6 alkyl or C3-6 cycloalkyl, wherein Ci.6 alkyl and C3-6 cycloalkyl may be optionally substituted by one or more substituents independently selected from halogen and hydroxyl; in addition L1 and/or L3 may be linked to carbon atoms of the hydrocarbyl chain in linker L to form aliphatic rings of up to 6 ring atoms, wherein each ring may comprise up to three heteroatoms independently selected from N, O and S; and wherein, unless otherwise specified, each occurrence of alkyl, heterocycloalkyl, aryl, aryl-fused-heterocycloalkyl, heteroaryl, cycloalkyl, alkoxy, alkylene, alkenylene, alkynylene or aryl-fused-cycloalkyl may be optionally substituted; or a pharmaceutically acceptable salt thereof.
2. A compound of formula (I) as claimed in claim 1 , or a pharmaceutically acceptable salt thereof, wherein
A is an oxygen atom;
R1 is CrC6-alkyl ; R2 is a group -Z-NR9R10 and R3 is a lone pair or CrC6-alkyl, or:
R1 and R2 together with the nitrogen to which they are attached represent a heterocycloalkyl ring, said ring being substituted by a group -Z-NR9R10 and R3 is a lone pair or CrC6-alkyl; or:
R1 and R3 together with the nitrogen to which they are attached represent a heterocycloalkyl ring, and R2 is a group -Z-NR9R10;
R is selected from one of the groups of formula (a), (b) or (c):
Figure imgf000124_0001
(a) (b) (C)
R6 is a hydrogen atom;
R >7a a „n„d_! R o7b are independently a d-C6-alkyl group or halogen; n and m are independently 0, 1 , 2 or 3;
R8a and R8b are independently selected from the group consisting of aryl, heteroaryl, Ci-C6-alkyl, cycloalkyl;
R is -OH, CrC6-alkyl, hydroxy-Ci-C6-alkyl, or a hydrogen atom;
R9 is a hydrogen atom or CrC6-alkyl;
R10 is a group ArCH(OH)CH2- or a group ArCH2CH2- wherein Ar is a group selected from
Figure imgf000125_0001
and wherein
M1 is S, C(O), NA5, CA6A7, CH2CH2, CH=CH, CH2O or OCH2;
M2 is S, C(O), NA5, CAbA\ CH2CH2, CH=CH, CH2O or OCH2;
A1, A2, A3 and A4 are, independently, hydrogen, halogen, trifluoromethyl, cyano, carboxy, hydroxy, nitro, S(O)2A8, NA9S(O)2A10, C(O)NA11A12, NA13C(O)A14, C1-6 alkyl, C1-6 alkoxy, C(O)(C1-6 alkyl) or C(O)OC1-6 alkyl; and A3 can also be CH2OH, NHCHO, NHS(O)2NA15A16 or NHSO2A17;
A5, A6, A7, A9, A11, A12, A13, A14, A15 or A16 are, independently, hydrogen or C1-6 alkyl; A8, A10 and A17 are, independently, Ci-6 alkyl.
3. A compound of formula (I) as claimed in claim 2, or a pharmaceutically acceptable salt thereof, wherein Ar is selected from:
Figure imgf000126_0001
wherein
M1 is S, CH=CH1 CH2O or OCH2;
M2 is S, CH=CH1 CH2O or OCH2;
A1, A2, and A4 are, independently, hydrogen, halogen, C1-6 alkyl, Ci-6 alkoxy; and A3 can also be CH2OH, NHCHO, NHS(O)2NA15A16 or NHSO2A17;
A or A are independently selected from hydrogen or C1-6 alkyl;
A1' is C1-6 alkyl.
4. A compound of formula (I) as claimed in claim 3, or a pharmaceutically acceptable salt thereof, wherein Ar is selected from the group
Figure imgf000126_0002
wherein A1 , A2 and A4 are all hydrogen, A3 is CH2OH, NHCHO and M1 is CH=CH or S.
5. A compound of formula (I) as claimed in any preceding claim, or a pharmaceutically acceptable salt thereof, wherein
A is an oxygen atom;
R1 is CrC6-alkyl ; R2 is a group -Z-NR9R10 and R3 is a lone pair or CrC6-alkyl, or: R1 and R2 together with the nitrogen to which they are attached represent a heterocycloalkyl ring, said ring being substituted by a group -Z-NR9R10 and R3 is a lone pair or Ci-C6-alkyl; or:
R1 and R3 together with the nitrogen to which they are attached represent a heterocycloalkyl ring, and R2 is a group -Z-NR9R10;
R4 is selected from one of the groups of formula (a), (b) or (c):
Figure imgf000127_0001
(a) (b) (C)
in the group (a):
Ar1 is a phenyl group; R6 is a hydrogen atom; n and m are 0;
in the group (b):
R8a and Fr" are both a phenyl group; or, R and R ° are both a thienyl group, or R 3'8a is a phenyl group and R8b is a cycloalkyl group;
R80 is -OH or CrC6-alkyl
in the group (c):
Ar2 is a phenyl ring; Q is an oxygen atom;
R8c is hydrogen, C1-6 alkyl or OH;
R9 is a hydrogen atom or CrC6-alkyl;
R10 is an aryl(CrC6-alkyl)-, or heteroaryl^-Ce-alkyl) group, selected from the group
Figure imgf000128_0001
Figure imgf000128_0002
6. A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any preceding claim where the radical -C(L1)(L2)-L-C(L3)(L4)- is (i) -(CH2)s-O-(CH2)t-B-(CH2)u-, wherein B is a phenylene radical and s is 2 or 3, t is 0, 1 or 2, and u is 1 or 2; or
(ii) -(CH2)v-C(O)NR47-B-(CH2)u-, wherein v is 1 or 2 and R47, B is a phenylene radical, and u is 1 or 2; or
(iii) -(CH2)V-NR47C(O)-B-(CH2)U-, wherein v is 1 or 2, R47 is hydrogen OrC1-6 alkyl or C3-6 cycloalkyl, B is a phenylene radical, and u is 1 or 2; or
(iv) -(CH2)v-C(O)NR47-(CH2)w-; wherein w is 3-8 and v and R47 are as defined in(iii) above; or
(v) -(CH2)S-B-(CH2)U-, wherein B is a phenylene radical and s is 1 ,2 or 3 and u is 1 ,2 or 3.
7. A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-6 and in the anti-, endo- form
Figure imgf000128_0003
anti-, endo-
8. A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 and selected from the group consisting of:
Hydroxy-di-thiophen-2-yl-acetic acid (1 S,2R,4S,7S)-7-{[2-(4-{[(R)-2- hydroxy-2-(4-hydroxy-2-oxo-2,3-dihydro-benzothia2ol-7-yl)-ethylamino]-methyl}- benzoylamino)-ethyl]-methyl-amino}-bicyclo[2.2.1]hept-2-yl ester; Hydroxy-di-thiophen-2-yl-acetic acid (1S,2RJ4S,7S)-7-{[3-(4-{[(R)-2-hydroxy-2-
(4-hydroxy-2-oxo-2,3-dihydro-benzothiazol-7-yl)-ethylamino]-methyl}-phenoxy)- propyl]-methyl-amino}-bicyclo[2.2.1 ]hept-2-yl ester;
Hydroxy-di-thiophen-2-yl-acetic acid (1 S,2R,4S,7S)-7-{[2-(4-{[(R)-2-hydroxy-2- (8-hydroxy-2-oxo-1 ,2-dihydro-quinolin-5-yl)-ethylamino]-methyl}-benzoylamino)- ethyl]-methyl-amino}-bicyclo[2.2.1]hept-2-yl ester;
Hydroxy-di-thiophen-2-yl-acetic acid 7-{[3-(2-hydroxy-ethyl)-benzyl]-methyl- amino}-bicyclo[2.2.1 ]hept-2-yl acetate;
Hydroxy-di-thiophen-2-yl-acetic acid (1 S,2R,4S,7S)-7-{[(4-{[(R)-2-hydroxy-2- (4-hydroxy-2-oxo-2,3-dihydro-benzothiazol-7-yl)-ethylamino]-methyl}- phenylcarbamoyl)-methyl]-methyl-amino}-bicyclo[2.2.1]hept-2-yl ester;
Hydroxy-di-thiophen-2-yI-acetic acid (1 S,2R,4S,7S)-7-{[(4-{[(R)-2-hydroxy-2- (8-hydroxy-2-oxo-1 ,2-dihydro-quinolin-5-yl)-ethylamino]-methyl}-phenylcarbamoyl)- methyl]-methyl-amino}-bicyclo[2.2.1]hept-2-yl ester;
Hydroxy-di-thiophen-2-yl-acetic acid (1 S,2R,4S,7S)-7-{[2-(4-{[(R)-2-hydroxy-2- (8-hydroxy-2-oxo-1 ,2-dihydro-quinolin-5-yl)-ethylamino]-methyl}-benzoylamino)- ethyl]-methyl-amino}-bicyclo[2.2.1 ]hept-2-yl ester;
Hydroxy-di-thiophen-2-yl-acetic acid (1 S,2R,4S,7S)-7-{[2-(4-{[(R)-2-hydroxy-2- (4-hydroxy-2-oxo-2,3-dihydro-benzothiazol-7-yl)-ethylamino]-methyl}-phenyl- carbamoyl)-ethyl]-methyl-amino}-bicyclo[2.2.1 ]hept-2-yl ester Hydroxy-di-thiophen-2-yl-acetic acid (1 S,2R,4S,7S)-7-{[(4-{[(R)-2-hydroxy-2-
(8-hydroxy-2-oxo-1 ,2-dihydro-quinolin-5-yl)-ethylamino]-methyl}-phenylcarbamoyl)- methyl]-methyl-amino}-bicyclo[2.2.1]hept-2-ylester
9-Hydroxy-9H-xanthene-9-carboxylic acid (1 S,2R,4S,7S)-7-{[3-(4-{[(R)-2- hydroxy-2-(4-hydroxy-2-oxo-2,3-dihydro-benzothiazol-7-yl)-ethylamino]-methyl}- phenoxy)-propyl]-methyl-amino}-bicyclo[2.2.1]hept-2-yl ester
9-Hydroxy-9H-xanthene-9-carboxylic acid (1S,2R,4S,7S)-7-{[3-(4-{[(R)-2- hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydro-quinolin-5-yl)-ethylamino]-methyl}-phenoxy)- propyl]-methyl-amino}-bicyclo[2.2.1]hept-2-yl ester;
(R)-Cyclohexyl-hydroxy-phenyl-acetic acid (1 S,2R,4S,7S)-7-{[3-(4-{[(R)-2- hydroxy-2-(4-hydroxy-2-oxo-2,3-dihydro-benzothiazoI-7-yl)-ethylamino]-methyl}- phenoxy)-propyl]-methyl-amino}-bicyclo[2.2.1]hept-2-yl ester; and (R)-Cyclohexyl-hydroxy-phenyl-acetic acid (1 S,2R,4S,7S)-7-{[3-(4-{[(R)-2- hydroxy-2-(8-hydroxy-2-oxo-1 ,2-dihydro-quinolin-5-yl)-ethylamino]-methyl}-phenoxy)- propyl]-methyl-amino}-bicyclo[2.2.1]hept-2-yl ester.
9. A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-8 for use in therapy.
10. A pharmaceutical composition comprising a compound of formula (I) as claimed in any of claims 1 to 8, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
11. A pharmaceutical composition as claimed in claim 10 in a form suitable for inhalation.
12. Use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any of claims 1 to 8 for the manufacture of a medicament for use in the treatment of prevention of a disease or condition in which M3 muscarinic receptor activity and β-adrenergic receptor activity is implicated.
13. A method of treatment of a disease or condition in which M3 muscarinic receptor activity and β-adrenergic receptor activity is implicated comprising administration to a subject in need thereof of an effective amount of a compound of formula (I) as claimed in any of claims 1 to 8 or a pharmaceutically acceptable salt thereof.
14. Use as claimed in claim 12 or a method of treatment as claimed in claim 13, wherein the disease or condition is of the respiratory tract.
15. Use as claimed in claim 12 or a method of treatment as claimed in claim 13, wherein the disease or condition is chronic obstructive lung disease, chronic bronchitis, asthma, chronic respiratory obstruction, bronchial hyperactivity, pulmonary fibrosis, pulmonary emphysema, or allergic rhinitis.
16. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 8 in combination with (i) an inhaled corticosteroid such as fluticasone propionate, ciclesonide, mometasone furoate or budesonide and/or (ii) an inhaled PDE4 inhibitor, such as rofiumilast, cilomilast or tofimilast.
17. A process for the preparation of a compound of formula (I) as claimed in claim 1 , or a pharmaceutically acceptable salt thereof, which comprises; a) reacting a compound of formula (II)
Figure imgf000131_0001
wherein LG1 represents a leaving group such as chloride, bromide, iodide, methanesulfonate or para-toluenesulfonate, and L, L2, L3, L4, R4, and A are as defined in formula (I), and R1 is as defined in formula (I) or is a suitable protecting group, with a compound of formula (III), or a suitable salt thereof
Figure imgf000131_0002
wherein Ar is as defined in formula (I) and P1 is hydrogen or a protective group in the presence of a base, followed by removal of the protective; or
b) reacting a compound of formula (IV), or a suitable salt thereof
Figure imgf000131_0003
wherein L1 L2, L3, L4, A, and R4 are as defined in formula (I), and R1 is as defined in formula (I) or is a suitable protecting group, with a compound of formula (111) or a suitable salt thereof in the presence of a suitable reducing agent, followed by removal of any protecting groups; or
c) reacting a compound of formula (VII), or a suitable salt thereof
Figure imgf000132_0001
wherein L, L1, L2, L3, L4, A, and R4 are as defined in formula (I) and R1 is as defined in formula (I) or is a suitable protecting group, P3 represents hydrogen or an activating group with a compound of formula (VIII), or (IX) or a suitable salt thereof,
Figure imgf000132_0002
wherein Ar is as defined in formula (I), LG2 represents a leaving and P1 is as defined in compound of formula (III) in the presence of a base, followed by removal of any protective and activating groups; or
d) reacting a compound of formula (XII)
Figure imgf000132_0003
wherein Ar, L, L1, and L2 are as defined in formula (I), P1 is as defined in compound of formula (III), P3 represents a protective group, with a compound of formula (XIII), or a suitable salt thereof,
Figure imgf000132_0004
wherein A, R4 and R1 are as defined in formula (I), or R1 is a suitable protecting group, in the presence of a suitable reducing agent, followed by removal of the protective groups; or e). reacting a compound of formula (XIV)
Figure imgf000133_0001
wherein Ar, L, L1, and L2 are as defined in formula (I), P1 is as defined in compound of formula (III), P3 represents a protective group, LG3 represents a leaving group, with a compound of formula (XIII) or a suitable salt thereof, in the presence of a base, followed by removal of the protective groups.
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