WO2009139710A1 - Dérivés de quinuclidine et leur utilisation comme antagonistes des récepteurs muscariniques - Google Patents

Dérivés de quinuclidine et leur utilisation comme antagonistes des récepteurs muscariniques Download PDF

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Publication number
WO2009139710A1
WO2009139710A1 PCT/SE2009/050527 SE2009050527W WO2009139710A1 WO 2009139710 A1 WO2009139710 A1 WO 2009139710A1 SE 2009050527 W SE2009050527 W SE 2009050527W WO 2009139710 A1 WO2009139710 A1 WO 2009139710A1
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alkyl
formula
compound
group
phenyl
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PCT/SE2009/050527
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English (en)
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Rhonan Ford
Antonio Mete
Ian Millichip
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Astrazeneca Ab
Argenta Discovery Ltd.
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Publication of WO2009139710A1 publication Critical patent/WO2009139710A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • 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

Definitions

  • the present invention relates to substituted alkyl esters of polycyclic amino alcohols, a process for their preparation, pharmaceutical compositions containing them, a process for preparing pharmaceutical compositions, their use in therapy and intermediates of use in their preparation.
  • Muscarinic receptors are a G-protein coupled receptor (GPCR) family having five family members M 1 , M 2 , M 3 , M 4 and M5. Of the five muscarinic subtypes, three (M 1 , M 2 and M 3 ) are known to exert physiological effects on human lung tissue.
  • GPCR G-protein coupled receptor
  • Parasympathetic nerves are the main pathway for reflex bronchoconstriction in human airways and mediate airway tone by releasing acetylcholine onto muscarinic receptors.
  • Airway tone is increased in patients with respiratory disorders such as asthma and chronic obstructive pulmonary disease (COPD), and for this reason muscarinic receptor antagonists have been developed for use in treating airway diseases.
  • Muscarinic receptor antagonists often called anticholinergics in clinical practice, have gained widespread acceptance as a first-line therapy for individuals with COPD, and their use has been extensivley reviewed in the literature (e.g. Lee et al, Current Opinion in Pharmacology 2001,1, 223-229).
  • muscarinic receptor antagonists When used to treat respiratory disorders, muscarinic receptor antagonists are typically administered by inhalation. However, when administered by inhalation a significant proportion of the muscarinic receptor antagonist is often absorbed into the systemic circulation resulting in reported side effects such as dry mouth. Additionally, the majority of muscarinic antagonists have a relatively short duration of action requiring that they be administered several times a day. Such a multiple-daily dosing regime is not only inconvenient to the patient but also creates a significant risk of inadequate treatment due to patient non-compliance associated with the frequent repeat dosing schedule.
  • R 1 is selected from one of the groups of formula (a), (b), (c) or (d)
  • R 4 is Ci-C ⁇ -alkyl or a hydrogen atom
  • R 5a and R 5b are, independently, a Ci-C ⁇ -alkyl group or halogen; m and p are, independently, 0, 1, 2 or 3;
  • R 6a , R 6b , R 6e and R 6f are independently selected from the group consisting of aryl, aryl- fused-heterocycloalkyl, heteroaryl, Ci-C 6 -alkyl and C 3 -C 7 -cycloalkyl;
  • R 6c , R 6d and R 6g are, independently, -OH, Ci-C 6 -alkyl, hydroxy-Ci-C 6 -alkyl, nitrile, a group CONR 7 2 or a hydrogen atom;
  • R 7 is Ci-C ⁇ -alkyl or a hydrogen atom
  • Ar 1 is aryl, heteroaryl or C 3 -C 7 -cycloalkyl
  • Ar 2 and Ar 3 are, independently, aryl, heteroaryl or C 3 -C 7 -cycloalkyl
  • Q is an oxygen atom, -CH 2 -, -CH 2 CH 2 - or a bond; and wherein aryl is an aromatic carbocyclic ring; heteroaryl is an aromatic ring systems comprising at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulphur; and heterocycloalkyl is a 4-8 membered non-aromatic monocyclic or bicyclic ring comprising at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulphur;
  • Y is -CH 2 - or, -CH 2 CH 2 - or -CH 2 CH 2 CH 2 -,
  • n 1, 2, 3 or 4, and within each grouping CR 2 R 3 , R 2 and R 3 each independently represent hydrogen or a Ci -4 alkyl group;
  • Het 1 represents a 5-membered heteroaryl ring containing 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulphur, said 5-membered heteroaryl ring is substituted by a phenyl group wherein said phenyl group may be optionally substituted by one or more substituents independently selected from cyano, nitro, halogen, hydroxyl, Ci -6 alkoxy, NH 2 , NH(Ci -6 alkyl), N(Ci -6 alkyl) 2 , S(Ci -6 alkyl) and Q -6 alkyl, wherein said Ci -6 alkyl may be optionally substituted by one or more substituents independently selected from halogen and hydroxyl; or alternatively Het 1 represents a 5,6-fused bicyclic heteroaryl ring containing 2, 3 or 4 heteroatoms independently selected from nitrogen oxygen and sulphur, said 5,6-fused bicyclic heteroaryl ring may be optionally substituted by one or more substituents independently selected
  • X represents a pharmaceutically acceptable anion of a mono or polyvalent acid.
  • the compounds of formula (I) comprise an anion X associated with the positive charge on the quaternary nitrogen atom.
  • the anion X may be any pharmaceutically acceptable anion of a mono or polyvalent (e.g. bivalent) acid.
  • X may be an anion of a mineral acid, for example chloride, bromide, iodide, sulfate, nitrate or phosphate; or an anion of a suitable organic acid, for example acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, methanesulphonate, p-toluenesulphonate, benzenesulphonate, napadisylate (naphthalene-l,5-disulphonate) (e.g. a heminapadisylate), l-hydroxy-2-naphthoate or l-hydroxynaphthalene-2-sulphonate.
  • a mineral acid for example chloride,
  • Heteroaryl denotes aromatic ring systems comprising at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, and includes monocyclic and bicyclic heteroaromatic rings.
  • 5 to 6 membered heteroaryl rings according to the present invention include thienyl, furanyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, oxazolyl, oxadiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl and triazolyl.
  • bicyclic heteroaromatic rings include fused bicyclic ring systems wherein both rings are aromtaic or, alternatively, one ring is aromatic and the other ring is non-aromatic.
  • heteroaryl groups may be linked through carbon or nitrogen.
  • Examples of 5 to 6 membered heteroaryl rings according to the present invention include thienyl, furanyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, oxazolyl, oxadiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl and triazolyl.
  • Examples of bicyclic heteroaromatic rings include indolyl, indazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl.
  • heterocycloalkyl denotes non-aromatic monocyclic and bicyclic rings comprising at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur.
  • heterocycloalkyl rings examples include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, homopiperazinyl, homopiperidinyl and azetidinyl.
  • Aryl denotes aromatic carbocyclic rings, for example phenyl or naphthyl.
  • the term 'aliphatic carbocyclic ring' denotes non-aromatic carbocyclic rings, both monocyclic and bicyclic. Examples of 3 to 8 membered aliphatic carbocyclic rings are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • cycloalkyl denotes saturated monocyclic carbocyclic rings. Cycloalkyl groups are monocyclic, for example cyclopentyl or cyclohexyl. Halogen is for example, fluorine, chlorine or bromine.
  • alkyl groups and moieties may be straight or branched chain and include, for example, methyl, ethyl, n- propyl, iso-propyl or tert-butyl.
  • alkylene denotes bivalent alkyl groups , e.g. -CH 2 -, -CH2CH2-, and -CH(CH 3 )CH 2 -.
  • alkylene groups may incorporate cycloalkyl rings, e.g. an example of a C 4 alkylene is
  • a group may be optionally substitued with one or more substituents the group may be unsubstituted or substituted; when substituted the group will generally be substitued with one, two or three substituents.
  • a hydroxyl moiety will not be attached to a carbon atom which is adjacent to a nitrogen atom.
  • R 1 is selected from one of the groups of formula (b) or (C)
  • R 6a and R 6b are independently selected from the group consisting of aryl, heteroaryl and C 3 -C 7 -cycloalkyl;
  • R 6c and R 6d are, independently, -OH, Ci-C ⁇ -alkyl, or a hydrogen atom;
  • Ar 2 and Ar 3 are, independently, aryl or heteroaryl; and
  • Q is an oxygen atom, -CH 2 - or a bond.
  • R 1 is a group of formula (c), wherein Ar 2 and Ar 3 are, independently, phenyl; Q is an oxygen atom; and R 6d is a hydrogen atom.
  • R 1 is a group of formula (b)
  • R 6a and R 6b are independently selected from the group consisting of aryl, heteroaryl and C 3 -C 7 -cycloalkyl; and R 6c is -OH, Ci-C ⁇ -alkyl, or a hydrogen atom.
  • R 6a and R 6b are independently selected from the group consisting of aryl (typically, phenyl) and heteroaryl (typically, thienyl); and
  • R 6c is -OH or Ci-C 6 -alkyl.
  • R 6a and R 6b will either both be aryl (typically, phenyl) or they will both be heteroaryl (typically, thienyl).
  • R 6a , R 6b , R 6e and R 6f are independently selected from the group consisting of aryl, heteroaryl, Ci-C ⁇ -alkyl and C 3 -C 7 -cycloalkyl. In an embodiment of the invention, R 6a , R 6b , R 6e and R 6f are independently selected from the group consisting of aryl, heteroaryl and C 3 -Cy-cycloalkyl.
  • R 6a , R 6b , R 6e and R 6f are independently selected from the group consisting of aryl and heteroaryl.
  • aryl is phenyl and heteroaryl is thienyl.
  • R 6c , R 6d and R 6g are, independently, -OH, Ci-C 6 -alkyl, hydroxy-Ci-C ⁇ -alkyl or a hydrogen atom.
  • R 6c , R 6d and R 6g are, independently, -OH, Ci-C ⁇ -alkyl or a hydrogen atom. In an embodiment of the invention, R 6c , R 6d and R 6g are, independently, -OH or C 1 -C 6 - alkyl.
  • Ar 2 and Ar 3 are, independently, aryl or heteroaryl. In an embodiment of the invention, Ar 2 and Ar 3 are both aryl, typically phenyl.
  • Q is an oxygen atom, -CH 2 - or a bond. In an embodiment of the invention, Q is an oxygen atom or a bond.
  • Y is -CH 2 - or -CH 2 CH 2 -. In an embodiment of the invention, Y is -CH 2 CH 2 -.
  • the ring containing Y depicted as a group of formula (III) below, is attached to the remainder of formula (I) by substitution at the 3 or 4 position.
  • the 3 and 4 positions of group (III) are located at the positions depicted in the representation of (III) below; the location of positions 3 and 4 depicted below applies when Y is -CH 2 -, -CH 2 CH 2 - or -CH 2 CH 2 CH 2 -.
  • Y is -CH 2 - or -CH 2 CH 2 -, and the substitution on the ring containing Y is in the 3 position.
  • n is 1, 2 or 3. In an embodiment of the invention n is 1.
  • Het 1 represents a 5-membered heteroaryl ring containing 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulphur, said 5-membered heteroaryl ring is substituted by a phenyl group wherein said phenyl group may be optionally substituted by one or more substituents independently selected from cyano, nitro, halogen, hydroxyl, Ci -4 alkoxy, NH 2 , NH(Ci -4 alkyl), N(Ci -4 alky I) 2 , S(Ci -4 alkyl) and Ci -4 alkyl, wherein said Ci -4 alkyl may be optionally substituted by one or more substituents independently selected from halogen and hydroxyl; or alternatively Het 1 represents a 5,6-fused bicyclic heteroaryl ring containing 2 or 3 heteroatoms independently selected from nitrogen oxygen and sulphur, said 5,
  • Het 1 represents a 5-membered heteroaryl ring containing 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulphur, said 5-membered heteroaryl ring is substituted by a phenyl group wherein said phenyl group may be optionally substituted by one or more substituents independently selected from halogen, hydroxyl, Ci -4 alkoxy, NH 2 , NH(Ci -4 alkyl), N(Ci -4 alkyl) 2 and Ci -4 alkyl, wherein said Ci -4 alkyl may be optionally substituted by one or more substituents independently selected from halogen and hydroxyl; or alternatively Het 1 represents a 5,6-fused bicyclic heteroaryl ring containing 2 or 3 heteroatoms independently selected from nitrogen oxygen and sulphur, said 5,6-fused bicyclic heteroaryl ring may be optionally substituted by one or more substituents independently selected from halogen, hydroxyl, Ci -4 alkoxy,
  • Het 1 represents a 5-membered heteroaryl ring containing 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulphur, said 5-membered heteroaryl ring is substituted by a phenyl group wherein said phenyl group may be optionally substituted by one or more substituents independently selected from halogen, hydroxyl, OMe and Ci -4 alkyl, wherein said Ci -4 alkyl may be optionally substituted by one or more substituents independently selected from halogen and hydroxyl; or alternatively Het 1 represents a 5,6-fused bicyclic heteroaryl ring containing 2 or 3 heteroatoms independently selected from nitrogen oxygen and sulphur, said 5,6-fused bicyclic heteroaryl ring may be optionally substituted by one or more substituents independently selected from halogen, hydroxyl, OMe and Ci -4 alkyl, wherein said Ci -4 alkyl may be optionally substituted by one or more substituents independently selected from halogen, hydroxyl
  • Het 1 represents a 5-membered heteroaryl ring containing 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulphur, said 5-membered heteroaryl ring is substituted by a phenyl group wherein said phenyl group may be optionally substituted by one or more substituents independently selected from halogen, hydroxyl, OMe and Ci -4 alkyl, wherein said Ci -4 alkyl may be optionally substituted by one or more substituents independently selected from halogen and hydroxyl.
  • Het 1 represents a 5-membered heteroaryl ring containing 2 or 3 heteroatoms independently selected from nitrogen and oxygen, said 5-membered heteroaryl ring is substituted by a phenyl group wherein said phenyl group may be optionally substituted by one or more substituents independently selected from halogen, hydroxyl, OMe and Ci -4 alkyl.
  • 5-membered heteroaryl rings examples include thiazole, [l,2,4]oxadiazole, [l,3,4]oxadiazole, isoxazole, [l,2,3]triazole, pyrazole and oxazole.
  • a more specific example of a 5-membered heteroaryl ring according to the embodiments described herein is isoxazole.
  • Examples of 5,6-fused bicyclic heteroaryl rings according to the embodiments described herein include benzoxazole and oxazolo[4,5- ⁇ ]pyridine.
  • a further aspect of the present invention provides a compound of formula (IA)
  • R 1 is a group of formula (b)
  • R 6a and R 6b are independently selected from the group consisting of aryl, heteroaryl and C 3 -C 7 -cycloalkyl;
  • R 6c is -OH, Ci-C ⁇ -alkyl, or a hydrogen atom; aryl is an aromatic carbocyclic ring; and heteroaryl is an aromatic ring systems comprising at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulphur; r is 0, 1 or 2; each occurrence of R 7 independently represents halogen, hydroxyl, Ci -4 alkyl, OMe, CF 3 , CN or OCF 3 ; J represents N or C; one of D, E and G represents N; another of D, E and G represents N or CH; and the last of D, E and G represents N, CH, O or S; provided that at least two of J, D, E and G independently represent N, O or S; and X represents a pharmaceutically acceptable anion of a mono or polyvalent acid.
  • a further aspect of the present invention provides a compound of formula (IB)
  • R 1 is a group of formula (b)
  • R >6a a and i ⁇ R>6b are independently selected from the group consisting of aryl, heteroaryl and C 3 -C 7 -cycloalkyl;
  • R 6c is -OH, Ci-C ⁇ -alkyl, or a hydrogen atom; aryl is an aromatic carbocyclic ring; and heteroaryl is an aromatic ring systems comprising at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulphur; s is 0, 1 or 2; each R 8 independently represents halogen, hydroxyl, Ci -4 alkyl, OMe, CF 3 or OCF 3 ;
  • Z represents CH or N
  • Y represents S, O or NR 10 wherein R 10 represents H or Ci -4 alkyl; R 2 , R 3 and n are as defined in formula (I); and X represents a pharmaceutically acceptable anion of a mono or polyvalent acid.
  • a further aspect of the present invention provides a compound of formula (IC)
  • R 1 is a group of formula (c)
  • Ar 2 and Ar 3 are, independently, an aromatic carbocyclic ring
  • Q is an oxygen atom or -CH 2 -;
  • R 6d is H; r is 0, 1 or 2; each occurrence of R 7 independently represents halogen, hydroxyl,
  • J represents N or C; one of D, E and G represents N; another of D, E and G represents N or CH; and the last of D, E and G represents N, CH, O or S; provided that at least two of J, D, E and G independently represent N, O or S; and X represents a pharmaceutically acceptable anion of a mono or polyvalent acid.
  • the stereochemical configuration at the 3- position of the ring containing Y is (R), as designated by the Cahn-Ingold-Prelog system.
  • the (R) stereoisomer of this embodiment may be present as a mixture with the (S) stereoisomer.
  • the (R) stereoisomer may be present in a racemic (1:1) mixture with the (S) stereoisomer.
  • a further aspect of this embodiment provides an optically pure compound of formula (I) wherein the stereochemical configuration at the 3- position of the ring containing Y is (R).
  • optically pure is defined in terms of enantiomeric excess (e.e.), which is calculated from the ratio of the difference between the amounts of the respective enantiomers present and the sum of these amounts, expressed as a percentage.
  • enantiomeric excess e.e.
  • An optically pure compound according to the present invention has an e.e. of at least 90%.
  • an optically pure compound has an e.e. of at least 95%.
  • an optically pure compound has an e.e. of at least 98%.
  • the compound of formula (I) is selected from:
  • the present invention provides a process for the preparation of compounds of formula (I) wherein R 1 is a group of formula (b) or (c), which comprises reacting a compound of formula (X) wherein R 6a , R 6b , R 6c , R 6d , Ar 2 , Ar 3 , and Q are as defined in formula (I), or a ester, acid anhydride or acid halide thereof,
  • R 6a , R 6b , R 6c , R 6d , Ar 2 , Ar 3 , and Q are as defined in formula (I) and subsequently reacting (XII) with a compound HeI 1 R 2 R 3 -LG, wherein LG is a leaving group (e.g. halogen) and Het 1 , R 2 and R 3 are as defined in formula (I): and optionally
  • reaction of compound (X) may be conveniently conducted in the presence of a suitable solvent such as heptane, tetrahydrofuran, toluene or dichloromethane at a temperature in the range of 0 to 100 0 C.
  • compound (X) may conveniently react via an acid halide (e.g. chloride) as may be prepared by reacting the acid with a suitable reagent (e.g. thionyl chloride or oxalyl chloride) in a suitable solvent such as dichloromethane or toluene, at a temperature in the range of 0 to 100 0 C.
  • a suitable solvent e.g. chloride
  • reaction of compounds (XII) and Het 1 R 2 R 3 -LG may be conveniently conducted in the presence of a suitable solvent such as chloroform, dichloromethane or acetonitrile at a temperature in the range of 0 to 100 0 C.
  • a suitable solvent such as chloroform, dichloromethane or acetonitrile
  • respiratory tract obstructive diseases of the airways including: asthma, including bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including aspirin and NS AID-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 vascul
  • 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; 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
  • 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);
  • 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 spondylo
  • skin psoriasis, atopic dermatitis, contact dermatitis or other eczematous dermatoses, and delayed-type hypersensitivity reactions; phyto- and photodermatitis; seborrhoeic dermatitis, dermatitis herpetiformis, lichen planus, lichen sclerosus et atrophica, pyoderma gangrenosum, skin sarcoid, discoid lupus erythematosus, pemphigus, pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitides, toxic erythemas, cutaneous eosinophilias, alopecia areata, male-pattern baldness, Sweet's syndrome, Weber-Christian syndrome, erythema multiforme; cellulitis, both infective and non-infective; panniculitis;cutaneous lymphomas, non-melanoma
  • eyes blepharitis; conjunctivitis, including perennial and vernal allergic conjunctivitis; ulceris; anterior and posterior uveitis; choroiditis; autoimmune; degenerative or inflammatory disorders affecting the retina; ophthalmitis including sympathetic ophthalmitis; sarcoidosis; infections including viral , fungal, and bacterial; 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);
  • abdominal hepatitis, including autoimmune, alcoholic and viral; fibrosis and cirrhosis of the liver; cholecystitis; pancreatitis, both acute and chronic; 8. genitourinary: nephritis including interstitial and glomerulonephritis; nephrotic syndrome; cystitis including acute and chronic (interstitial) cystitis and Hunner's ulcer; acute and chronic urethritis, prostatitis, epididymitis, oophoritis and salpingitis; vulvovaginitis; Peyronie's disease; erectile dysfunction (both male and female);
  • allograft rejection acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea or following blood transfusion; or chronic graft versus host disease;
  • CNS Alzheimer's disease and other dementing disorders including CJD and nvCJD; amyloidosis; multiple sclerosis and other demyelinating syndromes; cerebral atherosclerosis and vasculitis; temporal arteritis; myasthenia gravis; acute and chronic pain (acute, intermittent or persistent, whether of central or peripheral origin) including visceral pain, headache, migraine, trigeminal neuralgia, atypical facial pain, joint and bone pain, pain arising from cancer and tumor invasion, neuropathic pain syndromes including diabetic, post-herpetic, and HIV-associated neuropathies; neurosarcoidosis; central and peripheral nervous system complications of malignant, infectious or autoimmune processes;
  • cardiovascular atherosclerosis, affecting the coronary and peripheral circulation; pericarditis; myocarditis , inflammatory and auto-immune cardiomyopathies including myocardial sarcoid; ischaemic reperfusion injuries; endocarditis, valvulitis, and aortitis including infective (for example syphilitic); vasculitides; disorders of the proximal and peripheral veins including phlebitis and thrombosis, including deep vein thrombosis and complications of varicose veins; 14.
  • oncology treatment of common cancers including prostate, breast, lung, ovarian, pancreatic, bowel and colon, stomach, skin and brain tumors and malignancies affecting the bone marrow (including the leukaemias) and lymphoproliferative systems, such as Hodgkin's and non-Hodgkin's lymphoma; including the prevention and treatment of metastatic disease and tumour recurrences, and paraneoplastic syndromes; and,
  • gastrointestinal tract Coeliac disease, proctitis, eosinopilic gastro-enteritis, mastocytosis, Crohn's disease, ulcerative colitis, microscopic colitis, indeterminant colitis, irritable bowel disorder, irritable bowel syndrome, non-inflammatory diarrhea, food- related allergies which have effects remote from the gut, e.g., migraine, rhinitis and eczema.
  • the present invention further provides a compound of formula (I), as hereinbefore defined for use in therapy.
  • the invention provides the use of a compound of formula (I), 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.
  • a further aspect of the invention provides a method of treating a disease state in a mammal suffering from, or at risk of, said disease, which comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula (I) as hereinbefore defined.
  • the present invention also provides a compound of formula (I) as hereinbefore defined, for treating chronic obstructive pulmonary disease (COPD) (such as irreversible COPD).
  • COPD chronic obstructive pulmonary disease
  • the present invention also provides a compound of formula (I) as hereinbefore defined, for treating asthma.
  • the present invention also provides the use of a compound of formula (I) as hereinbefore defined, in the treatment of chronic obstructive pulmonary disease (COPD) (such as irreversible COPD).
  • COPD chronic obstructive pulmonary disease
  • the present invention also provides the use of a compound of formula (I) as hereinbefore defined, in the treatment of asthma.
  • the present invention also provides the use of a compound of formula (I) as hereinbefore defined, in the manufacture of a medicament for use in the treatment of chronic obstructive pulmonary disease (COPD) (such as irreversible COPD).
  • COPD chronic obstructive pulmonary disease
  • the present invention also provides the use of a compound of formula (I) as hereinbefore defined, in the manufacture of a medicament for use in the treatment of asthma.
  • the present invention further provides a method of treating chronic obstructive pulmonary disease (COPD) (such as irreversible COPD), in a warm-blooded animal, such as man, which comprises administering to a mammal in need of such treatment an effective amount of a compound of formula (I) as hereinbefore defined.
  • COPD chronic obstructive pulmonary disease
  • the present invention further provides a method of treating asthma in a warm-blooded animal, such as man, which comprises administering to a mammal in need of such treatment an effective amount of a compound of formula (I) as hereinbefore defined.
  • a compound of the invention for the therapeutic treatment of a warm- blooded animal, such as man, said ingredient is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
  • the present invention provides a pharmaceutical composition that comprises a compound of the invention as hereinbefore defined and a pharmaceutically acceptable adjuvant, diluent or carrier.
  • a process for the preparation of said composition which comprises mixing active ingredient with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the pharmaceutical composition will, for example, comprise from 0.05 to 99%w (per cent by weight), such as from 0.05 to 80%w, for example from 0.10 to 70%w, such as from 0.10 to 50%w, of active ingredient, all percentages by weight being based on total composition.
  • compositions of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by topical (such as to the lung and/or airways or to the skin), oral, rectal or parenteral administration.
  • topical such as to the lung and/or airways or to the skin
  • the compounds of this invention may be formulated by means known in the art into the form of, for example, aerosols, dry powder formulations, tablets, capsules, syrups, powders, granules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible powders, suppositories, ointments, creams, drops and sterile injectable aqueous or oily solutions or suspensions.
  • a suitable pharmaceutical composition of this invention is one suitable for oral administration in unit dosage form, for example a tablet or capsule, which contains between 0.1 mg and Ig of active ingredient.
  • a pharmaceutical composition of the invention is one suitable for intravenous, subcutaneous or intramuscular injection.
  • Each patient may receive, for example, an intravenous, subcutaneous or intramuscular dose of O.Olmgkg "1 to lOOmgkg "1 of the compound, for example in the range of O.lmgkg "1 to 20mgkg “1 of this invention, the composition being administered 1 to 4 times per day.
  • the intravenous, subcutaneous and intramuscular dose may be given by means of a bolus injection.
  • the intravenous dose may be given by continuous infusion over a period of time.
  • each patient will receive a daily oral dose, which is approximately equivalent to the daily parenteral dose, the composition being administered 1 to 4 times per day
  • Another suitable pharmaceutical composition of this invention is one suitable for inhaled administration, inhalation being a particularly useful method for administering the compounds of the invention when treating respiratory diseases such as chronic obstructive pulmonary disease (COPD) or asthma.
  • COPD chronic obstructive pulmonary disease
  • the compounds of formula (I) may be used effectively at doses in the ⁇ g range, for example 0.1 to 500 ⁇ g, 0.1 to 50 ⁇ g, 0.1 to 40 ⁇ g, 0.1 to 30 ⁇ g, 0.1 to 20 ⁇ g, 0.1 to 10 ⁇ g, 5 to 10 ⁇ g, 5 to 50 ⁇ g, 5 to 40 ⁇ g, 5 to 30 ⁇ g, 5 to 20 ⁇ g, 5 to 10 ⁇ g, 10 to 50 ⁇ g, 10 to 40 ⁇ g 10 to 30 ⁇ g, or 10 to 20 ⁇ g of active ingredient.
  • a pharmaceutical composition comprising a compound of the invention as hereinbefore defined, in association with a pharmaceutically acceptable adjuvant, diluent or carrier, which is formulated for inhaled administration.
  • metered dose inhaler devices When administered by inhalation, metered dose inhaler devices may be used to administer the active ingredient, dispersed in a suitable propellant and with or without additional excipients such as ethanol, surfactants, lubricants or stabilising agents.
  • Suitable propellants include hydrocarbon, chlorofiuorocarbon and hydrofiuoroalkane (e.g. heptafluoroalkane) propellants, or mixtures of any such propellants.
  • Preferred propellants are P 134a and P227, each of which may be used alone or in combination with other propellants and/or surfactant and/or other excipients.
  • Nebulised aqueous suspensions or, preferably, solutions may also be employed, with or without a suitable pH and/or tonicity adjustment, either as a unit-dose or multi-dose formulations.
  • Dry powder inhalers may be used to administer the active ingredient, alone or in combination with a pharmaceutically acceptable carrier, in the later case either as a finely divided powder or as an ordered mixture.
  • the dry powder inhaler may be single dose or multi-dose and may utilise a dry powder or a powder-containing capsule.
  • Metered dose inhaler, nebuliser and dry powder inhaler devices are well known and a variety of such devices are available.
  • the invention further relates to combination therapies wherein a compound of the invention 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.
  • the compounds of the invention may be combined with agents listed below.
  • Non-steroidal anti-inflammatory agents including non-selective cyclo-oxygenase COX-I / COX-2 inhibitors whether applied topically or systemically
  • piroxicam 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
  • the present invention still further relates to the combination of a compound of the invention 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-I); interleukins (IL) including ILl 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 pathways such as modulators of the SOCS
  • the invention relates to a combination of a compound of the invention with a monoclonal antibody targeting B-Lymphocytes (such as CD20 (rituximab), MRA-aIL16R and T-Lymphocytes, CTLA4-Ig, HuMax 11-15).
  • B-Lymphocytes such as CD20 (rituximab), MRA-aIL16R and T-Lymphocytes, CTLA4-Ig, HuMax 11-15.
  • the present invention still further relates to the combination of a compound of the invention with a modulator of chemokine receptor function such as an antagonist of CCRl, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCRlO and CCRl 1 (for the C-C family); CXCRl, CXCR2, CXCR3, CXCR4 and CXCR5
  • a modulator of chemokine receptor function such as an antagonist of CCRl, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCRlO and CCRl 1 (for the C-C family); CXCRl, CXCR2, CXCR3, CXCR4 and CXCR5
  • the present invention further relates to the combination of a compound of the invention 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-IO), and stromelysin-3 (MMP-11) and MMP-9 and MMP-12, including agents such as doxycycline.
  • MMPs matrix metalloprotease
  • the present invention still further relates to the combination of a compound of the invention 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 and a receptor antagonist for leukotrienes (LT) B4, LTC4, LTD4, and LTE4 selected from the group consisting of the phenothiazin-3-ls 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.
  • LT leukotrienes
  • the present invention still further relates to the combination of a compound of the invention 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 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 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 and an antagonist of the histamine type 4 receptor.
  • the present invention still further relates to the combination of a compound of the invention and an alpha- l/alpha-2 adrenoceptor agonist vasoconstrictor sympathomimetic agent, such as propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, tramazoline hydrochloride or ethylnorepinephrine hydrochloride.
  • an alpha- l/alpha-2 adrenoceptor agonist vasoconstrictor sympathomimetic agent such as propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochlor
  • the present invention still further relates to the combination of a compound of the invention and a beta-adrenoceptor agonist (including beta receptor subtypes 1-4) such as isoprenaline, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, pirbuterol, or indacaterol or a chiral enantiomer thereof.
  • a beta-adrenoceptor agonist including beta receptor subtypes 1-4
  • the present invention further relates to the combination of a compound of the invention 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 with a glucocorticoid, such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide or mometasone furoate.
  • a glucocorticoid such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide or mometasone furoate.
  • the present invention further relates to the combination of a compound of the invention 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 together with an immunoglobulin (Ig) or Ig preparation or an antagonist or antibody modulating Ig function such as anti-IgE (for example omalizumab).
  • Ig immunoglobulin
  • Ig preparation or an antagonist or antibody modulating Ig function such as anti-IgE (for example omalizumab).
  • anti-IgE for example omalizumab
  • the present invention further relates to the combination of a compound of the invention 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 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 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 together with an antibacterial agent such as a penicillin derivative, a tetracycline, a macrolide, a beta-lactam, a fluoroquinolone, metronidazole, an inhaled aminoglycoside; an antiviral agent including acyclovir, famciclovir, valaciclovir, ganciclovir, cidofovir, amantadine, rimantadine, ribavirin, zanamavir and oseltamavir; a protease inhibitor such as indinavir, nelfinavir, ritonavir, and saquinavir; a nucleoside reverse transcriptase inhibitor such as didanosine, lamivudine, stavudine, zalcitabine or zidovudine; or a non-nucleoside reverse transcriptase inhibitor such as nevirapine
  • the present invention still further relates to the combination of a compound of the invention and a cardiovascular agent such as a calcium channel blocker, a beta- adrenoceptor blocker, an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin-2 receptor antagonist; a lipid lowering agent such as a statin or a fibrate; a modulator of blood cell morphology such as pentoxyfylline; thrombolytic, or an anticoagulant such as a platelet aggregation inhibitor.
  • a cardiovascular agent such as a calcium channel blocker, a beta- adrenoceptor blocker, an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin-2 receptor antagonist
  • ACE angiotensin-converting enzyme
  • angiotensin-2 receptor antagonist angiotensin-2 receptor antagonist
  • a lipid lowering agent such as a statin or a fibrate
  • a modulator of blood cell morphology such as pentoxyfylline
  • the present invention further relates to the combination of a compound of the invention and a CNS agent such as an antidepressant (such as sertraline), an anti-Parkinsonian drug (such as deprenyl, L-dopa, ropinirole, pramipexole, a MAOB inhibitor such as selegine and rasagiline, a comP inhibitor such as tasmar, an A-2 inhibitor, a dopamine reuptake inhibitor, an NMDA antagonist, a nicotine agonist, a dopamine agonist or an inhibitor of neuronal nitric oxide synthase), or an anti- Alzheimer's drug such as donepezil, rivastigmine, tacrine, a COX-2 inhibitor, propentofylline or metrifonate.
  • a CNS agent such as an antidepressant (such as sertraline), an anti-Parkinsonian drug (such as deprenyl, L-dopa, ropinirole, pr
  • the present invention still further relates to the combination of a compound of the invention 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 for example an opioid or derivative thereof
  • paracetamol for example an opioid or derivative thereof
  • 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 together with a parenterally or topically-applied (including inhaled) local anaesthetic agent such as lignocaine or a derivative thereof.
  • a parenterally or topically-applied (including inhaled) local anaesthetic agent such as lignocaine or a derivative thereof.
  • a compound of the present invention can also be used in combination with an anti- osteoporosis agent including a hormonal agent such as raloxifene, or a biphosphonate such as alendronate.
  • a hormonal agent such as raloxifene
  • a biphosphonate such as alendronate.
  • the present invention still further relates to the combination of a compound of the invention 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 Imatinib 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 de
  • -receptor antagonist for example colchicine
  • anti-gout agent for example colchicine
  • xanthine oxidase inhibitor for example allopurinol
  • uricosuric agent for example probenecid, sulfinpyrazone or benzbromarone
  • growth hormone secretagogue for example transforming growth factor (TGF ⁇ );
  • PDGF platelet-derived growth factor
  • fibroblast growth factor for example basic fibroblast growth factor (bFGF);
  • GM-CSF granulocyte macrophage colony stimulating factor
  • capsaicin cream for example tachykinin NKl or NK3 receptor antagonist such as NKP-608C, SB-233412 (talnetant) or D-4418;
  • elastase inhibitor such as UT-77 or ZD-0892
  • TNF-alpha-1 for example colchicine
  • xanthine oxidase inhibitor for example allopurinol
  • uricosuric agent for example
  • iNOS chemoattractant receptor-homologous molecule expressed on TH2 cells, (such as a CRTH2 antagonist);
  • inhibitor of P38 agent modulating the function of Toll-like receptors (TLR),
  • agent modulating the activity of purinergic receptors such as P2X7; or
  • inhibitor of transcription factor activation such as NFkB, API, or STATS.
  • a compound of the invention can also be used in combination with an existing therapeutic agent for the treatment of cancer, for example suitable agents include:
  • an antiproliferative/antineoplastic drug or a combination thereof, as used in medical oncology such as an alkylating agent (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan or a nitrosourea); an antimetabolite (for example an antifolate such as a fluoropyrimidine like 5-fluorouracil or tegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea, gemcitabine or paclitaxel); an antitumour antibiotic (for example an anthracycline such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin or mithramycin); an antimitotic agent (for example a vinca alkaloid such as vincri
  • a cytostatic agent such as an antioestrogen (for example tamoxifen, toremifene, raloxifene, droloxifene or iodoxyfene), an oestrogen receptor down regulator (for example fulvestrant), an antiandrogen (for example bicalutamide, flutamide, nilutamide or cyproterone acetate), a LHRH antagonist or LHRH agonist (for example goserelin, leuprorelin or buserelin), a progestogen (for example megestrol acetate), an aromatase inhibitor (for example as anastrozole, letrozole, vorazole or exemestane) or an inhibitor of 5 ⁇ -reductase such as finasteride; (iii) an agent which inhibits cancer cell invasion (for example a metalloproteinase inhibitor like marimastat or an inhibitor of urokinase plasm
  • an 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 ⁇ v ⁇ 3 function or an angiostatin);
  • 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
  • a compound that works by another mechanism for example linomide, an inhibitor of integrin ⁇ v ⁇ 3 function or an angiostatin
  • vascular damaging agent such as combretastatin A4, or a compound disclosed in WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 or WO 02/08213;
  • an agent used in antisense therapy for example one directed to one of the targets listed above, such as ISIS 2503, an anti-ras antisense;
  • an agent used in a gene therapy approach for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; or (ix) an agent used in an immunotherapeutic approach, for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies.
  • GDEPT gene-directed enzyme pro-drug therapy
  • the present invention provides a pharmaceutical product comprising, in combination, a first active ingredient which is a compound of formula (I) as hereinbefore described, and at least one further active ingredient selected from:-
  • the pharmaceutical product according to this embodiment may, for example, be a pharmaceutical composition comprising the first and further active ingredients in admixture.
  • the pharmaceutical product may, for example, comprise the first and further active ingredients in separate pharmaceutical preparations suitable for simultaneous, sequential or separate administration to a patient in need thereof.
  • the pharmaceutical product of this embodiment is of particular use in treating respiratory diseases such as asthma, COPD or rhinitis.
  • Examples of a phosphodiesterase inhibitor that may be used in the pharmaceutical product according to this embodiment include a PDE4 inhibitor such as an inhibitor of the isoform PDE4D, a PDE3 inhibitor and a PDE5 inhibitor.
  • PDE4 inhibitor such as an inhibitor of the isoform PDE4D
  • PDE3 inhibitor a PDE3 inhibitor
  • PDE5 inhibitor examples include the compounds (Z)-3-(3,5-dichloro-4-pyridyl)-2-[4-(2-indanyloxy-5-methoxy-2-pyridyl]propenenitrile,
  • ⁇ 2 -adrenoceptor agonist examples include metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol (e.g. as sulphate), formoterol (e.g. as fumarate), salmeterol (e.g. as xinafoate), terbutaline, orciprenaline, bitolterol (e.g. as mesylate), pirbuterol or indacaterol.
  • metaproterenol isoproterenol
  • isoprenaline albuterol
  • albuterol e.g. as sulphate
  • formoterol e.g. as fumarate
  • salmeterol e.g. as xinafoate
  • terbutaline e.g. as xinafoate
  • bitolterol e.g. as mesylate
  • the ⁇ 2 -adrenoceptor agonist of this embodiment may be a long-acting ⁇ 2 -agonists, for example salmeterol (e.g. as xinafoate), formoterol (e.g. as fumarate), bambuterol (e.g. as hydrochloride), carmoterol (TA 2005, chemically identified as 2(1H)-Quinolone, 8- hydroxy-5-[l-hydroxy-2-[[2-(4-methoxy-phenyl)-l-methylethyl]-amino]ethyl]- monohydrochloride, [R-(R*, R*)] also identified by Chemical Abstract Service Registry Number 137888-11-0 and disclosed in U.S.
  • salmeterol e.g. as xinafoate
  • formoterol e.g. as fumarate
  • bambuterol e.g. as hydrochloride
  • carmoterol TA 2005, chemically identified
  • Patent No 4,579,854 indacaterol (CAS no 312753-06-3; QAB-149), formanilide derivatives e.g. 3-(4- ⁇ [6-( ⁇ (2R)-2-[3- (formylamino)-4-hydroxyphenyl]-2-hydroxyethyl ⁇ amino)hexyl]oxy ⁇ -butyl)- benzenesulfonamide as disclosed in WO 2002/76933, benzenesulfonamide derivatives e.g.
  • Examples of a modulator of chemokine receptor function that may be used in the pharmaceutical product according to this embodiment include a CCRl receptor antagonist.
  • Examples of an inhibitor of kinase function that may be used in the pharmaceutical product according to this embodiment include a p38 kinase inhibitor and an IKK inhibitor.
  • protease inhibitor examples include an inhibitor of neutrophil elastase or an inhibitor of MMP 12.
  • Examples of a steroidal glucocorticoid receptor agonist that may be used in the pharmaceutical product according to this embodiment include budesonide, fluticasone (e.g. as propionate ester), mometasone (e.g. as furoate ester), beclomethasone (e.g. as 17- propionate or 17,21-dipropionate esters), ciclesonide, loteprednol (as e.g. etabonate), etiprednol (as e.g. dicloacetate), triamcinolone (e.g.
  • Examples of a modulator of a non-steroidal glucocorticoid receptor agonist that may be used in the pharmaceutical product according to this embodiment include those described in WO2006/046916.
  • the NMR spectra were measured on a Varian Unity Inova spectrometer at a proton frequency of either 300 or 400 or 500 MHz, or on a Bruker DRX spectrometer at a proton frequency of 400 or 500 MHz, or on a Bruker Avance spectrometer with a proton frequency of 600 MHz or or on a Bruker Avance DPX 300 spectrometer with a proton frequency of 300 MHz.
  • the MS spectra were measured on either an Agilent 1100 MSD G1946D spectrometer or a Hewlett Packard HPl 100 MSD G1946A spectrometer. Names were generated using the Autonom 2000 (version 4.01.305) software supplied by MDL.
  • TLC Thin Layer Chromatography
  • THF tetrahydrofuran
  • Example 1 (R)-3-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-l-(5-phenyl-isoxazol-3- ylmethyl)-l-azonia-bicyclo[2.2.2]octane chloride a) Hydroxy-di-thiophen-2-yl-acetic acid ethyl ester
  • Example 3 (R)-3-(9-Hydroxy-9H-xanthene-9-carbonyloxy)-l-(5-phenyl-isoxazol-3- ylmethyl)-l-azonia-bicyclo[2.2.2]octane chloride a) 9- ⁇ ydroxy-9H-xanthene-9-carboxylic acid (i?)-(l-aza-bicyclo[2.2.2]oct-3-yl) ester
  • 9-Hydroxy-9H-xanthene-9-carboxylic acid methyl ester (prepared in accordance to the method of WO2001004118, Example I-lg) (500 mg) and (i?)-quinuclidin-3-ol (298 mg) were refluxed in toluene (25 mL) containing sodium hydride (23 mg) for 20 hours. The reaction was cooled, washed with water (50 mL), dried (MgSO 4 ) and evaporated.
  • the oil was purified on silica eluting with 10% methanol in dichloromethane containing 2% triethylamine and then ethyl acetate containing 2% triethylamine to afford the sub-titled compound as a white solid (290 mg).
  • the aqueous phase was washed with ethyl acetate (2 x 20 mL) and basif ⁇ ed to pH 9 with sodium hydroxide.
  • the aqueous was extracted with ethyl acetate (3 x 30 mL).
  • the combined organic extracts were washed with water (4 x 30 mL) and dried over magnesium sulfate to afford the titled compound as a colourless glass (1000 mg).
  • the affinity (pICso) of compounds to the M 3 receptor was determined by competition binding of [ 3 H]N-methyl scopolamine (NMS) to CHO-Kl (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 were precoated with membranes and then incubated at 2mg of beads per well with with serial dilutions of the 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 MgCl 2 ). The assay was conducted in a final volume of 200 ⁇ L, in the presence of 1% (v/v) dimethyl sulphoxide (DMSO). Total binding of [ 3 H]NMS was determined in the absence of competing compound and non-specific binding of [ 3 H]NMS was determined in the presence of 1 ⁇ M atropine.
  • DMSO dimethyl sulphoxide
  • the plates were incubated for 16 hours at room temperature and then read on Wallac Microbeta TM using a normalised 3 H protocol.
  • the pICso defined as the negative logarithm of the concentration of compound required for 50% reduction in specific [ 3 H]-NMS binding, was determined. Table 1 shows the pICso figures for some representative Examples.
  • the extent of plasma protein binding was determined via equilibrium dialysis of a compound between human plasma and aqueous buffer at 37°C and determination of the concentration of compound in the plasma and buffer by HPLC -MS/MS.
  • Dialysis cells (molecular weight cut-off 5000) were prepared by rinsing with water followed by soaking in the dialysis buffer for a minimum of 1 hour.
  • the dialysis buffer was isotonic buffered saline pH 7.4.
  • Stock solutions of compound in dimethylsulphoxide were prepared at a concentration of 0.5mM. Frozen pooled Human plasma was obtained from volunteers.
  • the stock DMSO solution of a compound was added to the plasma at a ratio of 10 ⁇ l of DMSO to each ml of plasma. This gave a 1% DMSO in plasma solution with each compound at a concentration of 5 ⁇ M.
  • Dialysis cells were then prepared and one half of the cell filled with 750 ⁇ l of dialysis buffer and the other half of the cell with 750 ⁇ l of plasma solution of compound. Once prepared the cells were sealed and placed in an incubator box at 37°C. These cells were then rotated for a minimum of 4 hours to equilibrate.
  • Dunkin-Hartley guinea-pigs 300 - 60Og were supplied by a designated breeding establishment. Animals were dosed with test compound or vehicle either by inhalation in conscious guinea-pigs or by intratracheal instillation (0.5ml/kg) under recoverable gaseous anaesthesia (5% halothane). Animals were allowed to recover from the anaesthesia prior to the measurement of bronchoconstriction. Up to 48 hours post-dosing guinea-pigs were terminally anaesthetized with sodium pentobarbitone (60 mg/kg), the trachea cannulated for artificial ventilation and the jugular vein was cannulated for intravenous administration of methacholine.
  • the guinea-pigs were ventilated using a constant volume respiratory pump (Harvard Rodent Ventilator model 683) at a rate of 60 breath/min and a tidal volume of 5 ml/kg during surgical preparation.
  • Lung function (lung resistance and compliance) was measured in anaesthetised and ventilated guinea-pigs using a pulmonary measurement Flexivent system (SCIREQ, Montreal, Canada) connected to the tracheal cannulae.
  • SCIREQ pulmonary measurement Flexivent system
  • the animals were ventilated (quasi-sinusoidal ventilation pattern) at 60 breaths/min at a tidal volume of 5 ml/kg.
  • a positive end expiratory pressure of 2-3 CmH 2 O was applied.
  • Respiratory resistance was measured using the Flexivent "snapshot" facility (1 second duration, 1 Hz frequency). Lung resistance and compliance was measured before and after intravenous administration of methacholine (3, 10 and 30 ug/kg). The peak increase in resistance following methacholine challenge was calculated and the effect of the test compound on methacholine-induced lung function changes was calculated.
  • Guinea pigs (450-55Og) supplied by Harlan UK or David Hall, Staffs UK and acclimatised to the in-house facilities for a minimum of three days before use. Guinea pigs were randomly assigned into treatment groups and weighed. Each animal was lightly anaesthetised (4% Halothane) and administered compound or vehicle intranasally
  • Saliva production was calculated by subtracting the pre-weighed weight of the pad from each 5 minute period post weighed pad and these numbers added together to produce an accumulation of saliva over 15 minutes. Each 5 minute period could be analysed in addition to the whole 15 minute recording period. Baseline production of saliva was assumed to be constant and multiplied by three to produce a reading for baseline saliva production over 15 minutes.
  • Inhibition of saliva produced by the compound could be calculated by using the following equation: (l-(Test-baseline)/(Veh-baseline))* 100.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur des composés représentés par la formule (I) dans laquelle R1, R2, R3, Het1, n, Y et X sont tels que définis dans la description, sur un procédé pour leur fabrication, sur des compositions pharmaceutiques les contenant, sur un procédé pour la fabrication des compositions pharmaceutiques, sur leur utilisation en thérapie et sur des intermédiaires utiles dans leur fabrication.
PCT/SE2009/050527 2008-05-13 2009-05-12 Dérivés de quinuclidine et leur utilisation comme antagonistes des récepteurs muscariniques WO2009139710A1 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8207193B2 (en) 2006-11-14 2012-06-26 Astrazeneca Ab Quiniclidine derivatives of (hetero) arylcycloheptanecarboxylic acid as muscarinic receptor antagonists
US8329729B2 (en) 2008-05-13 2012-12-11 Astrazeneca Ab Quinuclidine derivatives as muscarinic M3 receptor antagonists
CN103755698A (zh) * 2014-01-06 2014-04-30 万特制药(海南)有限公司 一锅法制备阿地溴铵的工艺
CN103755699A (zh) * 2014-01-06 2014-04-30 万特制药(海南)有限公司 一种2-羟基-2,2-二噻吩-2-基乙酸-1-氮杂二环[2,2,2]辛-3(r)-基酯制备方法
WO2015062560A1 (fr) 2013-10-29 2015-05-07 Zentiva, K.S. Procédé applicable dans l'industrie pour la préparation de bromure d'aclidinium de grande pureté

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001004118A2 (fr) * 1999-07-14 2001-01-18 Almirall Prodesfarma S.A. Nouveaux derives de quinuclidine et compositions medicales les contenant
WO2002053564A2 (fr) * 2000-12-28 2002-07-11 Almirall Prodesfarma Ag Nouveaux derives de quinuclidine et compositions medicinales contenant ces derniers
WO2006048225A1 (fr) * 2004-11-02 2006-05-11 Novartis Ag Derives de la quinuclidine et leur utilisation en tant qu'antagonistes du recepteur m3 muscarinique
WO2008075005A1 (fr) * 2006-12-19 2008-06-26 Astrazeneca Ab Dérivés quinuclidinol utilisés en tant qu'antagonistes du récepteur muscarinique

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001004118A2 (fr) * 1999-07-14 2001-01-18 Almirall Prodesfarma S.A. Nouveaux derives de quinuclidine et compositions medicales les contenant
WO2002053564A2 (fr) * 2000-12-28 2002-07-11 Almirall Prodesfarma Ag Nouveaux derives de quinuclidine et compositions medicinales contenant ces derniers
WO2006048225A1 (fr) * 2004-11-02 2006-05-11 Novartis Ag Derives de la quinuclidine et leur utilisation en tant qu'antagonistes du recepteur m3 muscarinique
WO2008075005A1 (fr) * 2006-12-19 2008-06-26 Astrazeneca Ab Dérivés quinuclidinol utilisés en tant qu'antagonistes du récepteur muscarinique

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8207193B2 (en) 2006-11-14 2012-06-26 Astrazeneca Ab Quiniclidine derivatives of (hetero) arylcycloheptanecarboxylic acid as muscarinic receptor antagonists
US8329729B2 (en) 2008-05-13 2012-12-11 Astrazeneca Ab Quinuclidine derivatives as muscarinic M3 receptor antagonists
WO2015062560A1 (fr) 2013-10-29 2015-05-07 Zentiva, K.S. Procédé applicable dans l'industrie pour la préparation de bromure d'aclidinium de grande pureté
CN105683186A (zh) * 2013-10-29 2016-06-15 赞蒂瓦有限合伙公司 工业上适用的用于制备高纯度阿地溴铵的方法
CN103755698A (zh) * 2014-01-06 2014-04-30 万特制药(海南)有限公司 一锅法制备阿地溴铵的工艺
CN103755699A (zh) * 2014-01-06 2014-04-30 万特制药(海南)有限公司 一种2-羟基-2,2-二噻吩-2-基乙酸-1-氮杂二环[2,2,2]辛-3(r)-基酯制备方法

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