WO2008084236A1 - Composés chimiques 635: pyridopyrimidinediones en tant qu'inhibiteurs pde4 - Google Patents

Composés chimiques 635: pyridopyrimidinediones en tant qu'inhibiteurs pde4 Download PDF

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WO2008084236A1
WO2008084236A1 PCT/GB2008/000081 GB2008000081W WO2008084236A1 WO 2008084236 A1 WO2008084236 A1 WO 2008084236A1 GB 2008000081 W GB2008000081 W GB 2008000081W WO 2008084236 A1 WO2008084236 A1 WO 2008084236A1
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alkyl
compound
optionally substituted
alkoxy
heteroaryl
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PCT/GB2008/000081
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English (en)
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Roger Victor Bonnert
Theresa Humphries
Simon Fraser Hunt
Hitesh Jayantilal Sanganee
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Astrazeneca Ab
Astrazeneca Uk Limited
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Publication of WO2008084236A1 publication Critical patent/WO2008084236A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • 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
    • A61P11/06—Antiasthmatics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention concerns pyridopyrimidine derivatives having pharmaceutical activity, to processes for preparing such derivatives, to pharmaceutical compositions comprising such derivatives and to the use of such derivatives as active therapeutic agents.
  • Phosphodiesterases work by converting cAMP or cGMP to AMP and GMP, or the inactive nucleotide forms incapable of activating downstream signalling pathways.
  • the inhibition of PDEs leads to the accumulation of cAMP or cGMP, and subsequent activation of downstream pathways.
  • PDEs comprise a large family of second messengers with 11 families and over 50 isoforms. In addition splice variants have been described for each isoform.
  • the PDEs can be cAMP-specific (PDE4, 7, 8, 10), cGMP specific (PDE5, 6, 9) or have dual specificity (PDEl, 2, 3, 11).
  • cAMP is generated from ATP at the inner leaflet of the plasma membrane through the action of GPCR-regulated adenylate cyclase. Once cAMP is generated, the only way to terminate the signal is through phosphodiesterase action, degrading cAMP into 5'-AMP. Increased concentrations of cAMP are translated into cellular responses mainly by activation of cAMP-dependent protein kinase (PKA).
  • PKA cAMP-dependent protein kinase
  • the specific activity of PKA is in part regulated by the sub-cellular localization of PKA, which limits the phosphorylation of PKA to substrates in its near vicinity.
  • the downstream events caused by activation of PKA appear poorly elucidated and involve many components in the initiation of signalling cascades.
  • PDE4s have been shown to have abundant roles in regulating cell desensitisation, adaptation, signal cross-talk, cAMP compartmentalization and feedback loops, and are major regulators of cAMP homeostasis.
  • the physiological role implicated for elevated cAMP levels include: 1) broad suppression the activity of many imunocompetent cells; 2) induction of airway smooth muscle relaxation; 3) suppression of smooth muscle mitogenesis; and, 4) has beneficial modulatory effects on the activity of pulmonary nerves.
  • PDE4 has been found to be the predominant cAMP metabolising isozyme family in immune and inflammatory cells and, along with the PDE3 family, a major contributor to cAMP metabolism in airway smooth muscle.
  • PDE4 selective inhibitors for the treatment of inflammatory and immune disorders including asthma, rhinitis, bronchitis, COPD, arthritis and psoriasis.
  • a number of compounds for example rolipram, tibenelast and denbufylline
  • PDE4 inhibitors for example cilomilast, roflumilast and AWD 12- 281
  • cilomilast for example cilomilast, roflumilast and AWD 12- 281
  • AWD 12- 281 has been described having significantly reduced risk of emetic side effects in animal models of emesis, thus providing the potential for an increased therapeutic ratio.
  • the present invention discloses novel pyridopyrimidine derivatives that are inhibitors of human PDE4 and are thereby useful in therapy.
  • the present invention provides a compound of formula (I): wherein: E is N or CE 1 ; W is (CH 2 ) n ; Y is (CH 2 ) p ; n and p are, independently 0 or 1;
  • R 24 is tetrahydrothiopyran-4-yl, tetrahydrothiopyran-4-yl S-oxide or tetrahydrothiopyran-4- yl S-dioxide; or aryl or heteroaryl, each of which is optionally substituted by halogen, cyano, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, CF 3 , OCF 3 , Ci -4 alkylthio, S(O)(Ci -4 alkyl), S(O) 2 (Ci -4 alkyl) or C(O) 2 (Ci -4 alkyl);
  • R 2 is hydrogen, Ci -6 alkyl (optionally substituted by heteroaryl), optionally substituted aryl or optionally substituted heteroaryl;
  • R 1 is C 1-6 alkyl (optionally substituted by hydroxyl, Ci -6 alkoxy, aryl, aryloxy, phenyl(Ci- 6 alkoxy), heteroaryl, C 3-I0 cycloalkyl, CO 2 H, CO 2 (Ci -6 alkyl), NHC(O)O(Ci -6 alkyl) or NHC(O)R 3 ), C 3-6 cycloalkyl (optionally substituted by hydroxy, Ci -6 alkyl, phenyl, phenyl(Ci -6 alkyl), heteroaryl or heteroaryl(Ci -6 alkyl)), heterocyclyl (optionally substituted by Ci -6 alkyl, C(O)NH 2 or phenyl(Ci -6 alkyl)), aryl or heteroaryl; R 3 is Ci -6 alkyl or phenyl; the foregoing phenyl, aryl and heteroaryl moieties of R 1 , R 2 and R 3 are
  • R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 and R 23 are, independently, Ci -6 alkyl ⁇ optionally substituted by halogen, hydroxy, Ci -6 alkoxy, NH 2 , NH(Cj -6 alkyl), N(Ci -6 alkyl) 2 or heterocyclyl ⁇ , CH 2 (C 2-6 alkenyl), phenyl ⁇ itself optionally substituted by halogen, hydroxy, nitro, NH 2 , NH(Ci -4 alkyl), N(Ci -4 alkyl) 2 , S(O) 2 (Ci -4 alkyl), S(O) 2 NH 2 , S(O) 2 NH(Ci -4 alkyl), S(O) 2 N(C
  • Certain compounds of the present invention can exist in different isomeric forms (such as enantiomers, diastereomers, geometric isomers or tautomers).
  • the present invention covers all such isomers and mixtures thereof in all proportions. Enantiomerically pure forms are particularly desired.
  • a compound of formula (I) can be in the form of a co-crystal with another chemical entity and the invention encompasses all such co-crystals.
  • a pharmaceutically acceptable salt of a compound of formula (I) includes a salt prepared from a pharmaceutically acceptable non-toxic base, such as an inorganic or organic base.
  • a salt derived from an inorganic base is, for example, an aluminium, calcium, potassium, magnesium, sodium or zinc salt.
  • a salt derived from an organic base is, for example, a salt of a primary, secondary or tertiary amine, such as arginine, betaine, benzathine, caffeine, choline, chloroprocaine, cycloprocaine, N',N'- dibenzylethylenediamine, diethanolamine, diethylamine, 2-diethyl-aminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylendiamine, N-ethyl-morpholine, N-ethyl piperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, meglumine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, tertiary butylamine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine or thanolamine.
  • a pharmaceutically acceptable salt of a compound of formula (I) also includes a quaternary ammonium salt, for example where an amine group in a compound of formula (I) reacts with a C 1-1 O alkyl halide (for example a chloride, bromide or iodide) to form a quaternary ammonium salt.
  • a C 1-1 O alkyl halide for example a chloride, bromide or iodide
  • a pharmaceutically acceptable salt also includes a salt of pharmaceutically acceptable organic acid, such as a carboxylic or sulphonic acid, for example: an acetate, adipate, alginate, ascorbate, aspartate, benzenesulphonate (besylate), benzoate, butyrate, camphorate, camphorsulphonate (such as [(lS,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept- l-yl]methanesulfonic acid salt), camsylate, citrate, p-chlorobenzenesulphonate, cyclopentate, 2,5-dichlorobesyalte, digluconate, edisylate (ethane- 1,2-disulfonate or ethane- 1 -(sulfonic acid)-2-sulfonate), esylate, ethanesulphonate, fumarate, formate, 2- furoate, 3-fur
  • the stoichiometry of the salt is, for example, a hemi- salt, or a mono- or di-salt or tri-salt.
  • a pharmaceutically acceptable salt of a compound of formula (I) can be prepared in situ during the final isolation and purification of a compound, or by separately reacting the compound or N-oxide with a suitable organic or inorganic acid and isolating the salt thus formed.
  • a suitable salt can be a quaternary ammonium salt formed by the reaction of a primary, secondary or tertiary amine group in a compound of formula (I) with, for example, a C 1-6 alkyl halide (such as methyl iodide or methyl bromide).
  • a C 1-6 alkyl halide such as methyl iodide or methyl bromide
  • the compounds of the invention may exist as solvates (such as hydrates) and the present invention covers all such solvates.
  • an acid addition salt is a hydrochloride, dihydrochloride, hydrobromide, phosphate, sulfate, acetate, diacetate, fumarate, maleate, malonate, succinate, tartrate, citrate, oxalate, methanesulfonate or/7-toluenesulfonate.
  • Halogen includes fluorine, chlorine, bromine and iodine.
  • Halogen is, for example, fluorine or chlorine.
  • Alkyl moieties are straight or branched chain and are, for example, methyl, ethyl, n-propyl, iso-propyl or tert-butyl.
  • Haloalkyl is, for example C 2 Fs, CF 3 or CHF 2 .
  • Alkoxy is, for example, methoxy or ethoxy; and haloalkoxy is, for example OCF 3 or OCHF 2 .
  • Alkenyl is, for example, vinyl or prop-2-enyl.
  • Alkynyl is, for example, propargyl.
  • Cycloalkyl is a mono- or bi-cyclic ring systemwhich is saturated or unsaturated but not aromatic. It is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or bicyclo[3.1.1]heptenyl.
  • C 3-7 Cycloalkyl(Ci -4 alkyl) is, for example, cyclopentylCH 2 .
  • Cycloalkyloxy is, for example, cyclopropyloxy, cyclopentyloxy or cyclohexyloxy.
  • Cycloalkylalkoxy is, for example, (cyclopropyl)methoxy or 2-(cyclo ⁇ ropyl)ethoxy.
  • Heterocyclyl is a non-aromatic 5- or 6-membered ring optionally fused to one or more other non-aromatic rings and optionally fused to a benzene ring, comprising at least one heteroatom selected from the group comprising nitrogen, oxygen and sulphur.
  • Heterocyclyl is, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, isoindolyl, morpholinyl, 3,8-diazabicyclo[3.2.1]octyl, 8-azabicyclo[2.2.2]octyl, 2-oxa-6- azabicyclo[5.4.0]undeca-7,9,l 1-trienyl, 7-oxa-10-azabicyclo[4.4.0]deca-l,3,5-trienyL 6- thia-l,4-diazabicyclo[3.3.0]octa-4,7-dienyl, tetrahydropyranyl, azabicyclo[3.2.1]octyl, 1,2,3,4-tetrahydroquinolinyl, 1 ,4-diazepinyl, quinuclidinyl, 9-oxa-2,8-diazaspir
  • Ci-6 alkoxy(C] -6 )alkoxy is, for example, CH 3 OCH 2 O.
  • Dialkylaminoalkyl is, for example (CH 3 ) 2 NCH 2 or (CH 3 )(CH 3 CH 2 )NCH 2 .
  • Aryl is, for example, phenyl, naphthyl, indanyl or a tetralin (for example 1,2,3,4- tetrahydronaphthyl).
  • aryl is phenyl.
  • Heteroaryl is, for example, an aromatic 5- or 6-membered ring, optionally fused to one or more other rings, comprising at least one heteroatom selected from the group comprising nitrogen, oxygen and sulphur; or an N-oxide thereof, or an S-oxide or S- dioxide thereof.
  • Heteroaryl is, for example, furyl, thienyl (also known as thiophenyl), pyrrolyl, thiazolyl, isothiazolyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, [1,2,3]- thiadiazolyl, [l,2,4]-triazolyl, [l,2,3]-triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, benzo[b]furyl (also known as benzfuryl), benz[b]thienyl (also known as benzthienyl or benzthiophenyl), indazolyl, benzimidazolyl, 1,2,3-benztriazolyl, benzoxazolyl, 1,3-benzthiazolyl, 1,2,3-benzothiadiazolyl, an imidazopyridinyl
  • the present invention provides a compound of formula (I) wherein the phenyl, aryl and heteroaryl moieties of R 1 , R 2 and R 3 are, independently, optionally substituted by: halogen, oxo, cyano, nitro, hydroxy, S(O) q R 4 , OC(O)NR 5 R 6 , NR 7 R 8 , NR 9 C(O)R 10 , NR 11 C(O)NR 12 R 13 , S(O) 2 NR 14 R 15 , NR 16 S(O) 2 R 17 , C(O)NR 18 R 19 , C(O)R 20 , CO 2 R 21 , NR 22 CO 2 R 23 , Ci -6 alkyl, Ci -6 hydroxyalkyl, C -6 haloalkyl, Ci.
  • the present invention provides a compound of formula (I) wherein R 2 is hydrogen, Ci -6 alkyl, optionally substituted aryl or optionally substituted heteroaryl.
  • R 2 is hydrogen, Ci -6 alkyl, optionally substituted aryl or optionally substituted heteroaryl.
  • the present invention provides a compound of formula (I) wherein
  • E is CE 1 .
  • E is, for example, CH or CF.
  • the present invention provides a compound of formula (I) wherein Y and W are both CH 2 .
  • the present invention provides a compound of formula (I) wherein E 1 and G 1 are, independently, hydrogen or halogen (for example fluoro).
  • E 1 and G 1 are, independently, hydrogen or halogen (for example fluoro).
  • G 1 is hydrogen.
  • E 1 is fluoro.
  • the present invention provides a compound of formula (I) wherein R 24 is tetrahydrothiopyran-4-yl.
  • the present invention provides a compound of formula (I) wherein R 1 is Ci -6 alkyl mono-substituted by phenyl, naphthyl, phenoxy or heteroaryl; the phenyl, naphthyl and heteroaryl moieties being optionally substituted by halogen (such as fluoro or chloro), cyano, hydroxyl (when hydroxyl is on a heteroaryl ring the whole system may tautomerise such that the hydroxyl appears as an oxo group), Cj -4 alkyl (such as methyl), Ci -4 alkoxy (such as methoxy), CF 3 , phenyl, phenylthio, heteroaryl, phenyl(Ci -2 alkyl), C3-6 cycloalkyl, C 3-6 cycloalkyloxy, methylenedioxy, difluoromethylenedioxy, 1,2- ethylenedioxy, ethyleneoxy or NHR*; R* is Ci -6 alkyl mono-
  • the present invention provides a compound of formula (I) wherein heteroaryl is thiazolyl, pyrazolyl, imidazolyl, pyridinyl, benzo[b]furyl (also known as benzfuryl), benzimidazolyl, 1,3-benzthiazolyl, imidazo[l,2a]pyridinyl) or quinolinyl.
  • the present invention provides a compound of formula (I) wherein R 1 is benzyl or (CH 2 )heteroaryl; the phenyl and heteroaryl moieties being optionally substituted by halogen (such as fluoro or chloro), cyano, hydroxyl, CM alkyl (such as methyl), C M alkoxy (such as methoxy), phenyl or phenyl(CH 2 ); wherein the immediately foregoing phenyl moieties are optionally substituted by halogen (such as fluoro or chloro) or cyano.
  • halogen such as fluoro or chloro
  • the present invention provides a compound of formula (I) wherein heteroaryl is imidazolyl, pyridinyl, imidazo[l,2a]pyridinyl) or quinolinyl.
  • the present invention provides a compound of formula (I) wherein R 1 is Ci -6 alkyl (optionally substituted by hydroxy, aryl, C 3-7 cycloalkyl, CO 2 (C] -6 alkyl) or NHC(O)R 3 ), aryl or heteroaryl (for example pyridyl, benzimidazolyl, furyl or 1,4- dihydropyrido[2,3-d]pyrimidinyl); and R 3 is phenyl.
  • Aryl is, for example, phenyl.
  • the present invention provides a compound of formula (I) wherein the foregoing phenyl, aryl and heteroaryl moieties of R 1 and R 3 are, independently, optionally substituted by: halogen, hydroxy, CO 2 (Ci-O alkyl), Ci -6 alkyl, C] -6 hydroxyalkyl or C i-6 alkoxy.
  • the present invention provides a compound of formula (I) wherein R 1 is heterocyclyl (optionally substituted by Ci -6 alkyl), for example R 1 is pyrrolyl, piperidinyl or morpholinyl, each optionally substituted by Ci -6 alkyl (such as methyl or ethyl).
  • R 1 is heterocyclyl (optionally substituted by Ci -6 alkyl)
  • R 1 is pyrrolyl, piperidinyl or morpholinyl, each optionally substituted by Ci -6 alkyl (such as methyl or ethyl).
  • the present invention provides a compound of formula (I) wheein
  • R 2 is hydrogen or CH 2 (heteroaryl); the heteroaryl being optionally substituted by halogen, hydroxy, CO 2 (Ci -6 alkyl), Ci -6 alkyl, Ci -6 hydroxyalkyl or Ci -6 alkoxy (for example the heteroaryl is optionally substituted by halo, such as fluoro).
  • R 2 is hydrogen.
  • the heteroaryl of R 2 is, for example, imidazo[l,2-a]pyridinyl.
  • the compounds of the present invention can be prepared as described below, by using or adapting the methods described in the Examples, or by using or adapting methods known in the art. Intermediates are either know in the art or can be prepared by using or adapting methods described in the art.
  • the invention provides a process for the preparation of a compound of formula (I) wherein R 2 is hydrogen and R 1 is CH 2 -R", where R" is the remainder of the R 1 group, which comprises removing the Boc protecting group from a compound of formula (II)
  • G 1 , E, Y, W and R 24 are as defined in formula (I), (for example with an acid such as trifluoroacetic acid or hydrochloric acid) and reacting the product so formed with a suitable carbaldehyde R"CH(O) wherein R" is as defined above, in a suitable solvent (such as methanol or N-methyl-pyrrolidinone), in the presence of an acid catalyst (such as acetic acid), optionally in the presence of trimethyl orthoformate, and then adding a suitable reducing agent (such as a borohydride, for example sodium cyanoborohydride or sodium triacetoxyborohydride); the process being conducted at room temperature (such as from 0- 3O 0 C).
  • a suitable solvent such as methanol or N-methyl-pyrrolidinone
  • an acid catalyst such as acetic acid
  • trimethyl orthoformate trimethyl orthoformate
  • a suitable reducing agent such as a borohydride, for example sodium cyanoborohydride or sodium tri
  • a compound of formula (II) wherein G 1 , E, Y, W and R 24 are as defined in formula (I), can be prepared by condensing a compound of formula (IV): wherein G 1 , E, Y, W and R 24 are as defined in formula (I), with a suitable carbonylating agent such as carbonyl diimidazole or ethyl chlorformate in the presence of a suitable base such as sodium hydride. The process is carried out at a suitable temperature, generally between 0 0 C and the boiling point of the solvent, in a suitable solvent such as tetrahydrofuran.
  • a suitable carbonylating agent such as carbonyl diimidazole or ethyl chlorformate
  • a compound of formula (IV) wherein G 1 , E, Y, W and R 24 are as defined in formula (I), can be prepared by reacting a compound of formula (V):
  • Y and W are as defined in formula (I).
  • the process is carried out at a suitable temperature, generally between 0 0 C and the boiling point of the solvent, in a suitable solvent such as dichloromethane.
  • the process is optionally carried out in the presence of a base and a coupling reagent such as HATU, HOAT, HOBT or DIEA.
  • a compound of formula (V) wherein m, G 1 and E are as defined in formula (I), can be prepared by reacting a compound of formula (VII):
  • the present invention provides processes for the preparation of compounds of formula (I).
  • the compounds of formula (I) have activity as pharmaceuticals, in particular as modulators of PDE 4 receptor activity, and may be used in the treatment of inflammatory diseases, asthma or COPD.
  • 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
  • arthritides 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
  • polychondritis such as 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; panniculitis;cutaneous lymphomas, non-melanoma skin
  • eyes blepharitis; conjunctivitis, including perennial and vernal allergic conjunctivitis; ulceris; anterior and posterior uveitis; choroiditis; autoimmune; degenerative or inflammatory disorders affecting the retina; ophthalmitis including sympathetic ophthalmitis; sarcoidosis; infections including viral , fungal, and bacterial; 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;
  • 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; vulvo- vaginitis; Peyronie's disease; erectile dysfunction (both male and female);
  • allograft rejection acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea or following blood transfusion; or chronic graft versus host disease;
  • CNS Alzheimer's disease and other dementing disorders including CJD and nvCJD; amyloidosis; multiple sclerosis and other demyelinating syndromes; cerebral atherosclerosis and vasculitis; temporal arteritis; myasthenia gravis; acute and chronic pain (acute, intermittent or persistent, whether of central or peripheral origin) including visceral pain, headache, migraine, trigeminal neuralgia, atypical facial pain, joint and bone pain, pain arising from cancer and tumor invasion, neuropathic pain syndromes including diabetic, post-herpetic, and HIV-associated neuropathies; neurosarcoidosis; central and peripheral nervous system complications of malignant, infectious or autoimmune processes; 11.
  • cardiovascular atherosclerosis, affecting the coronary and peripheral circulation; pericarditis; myocarditis , inflammatory and auto-immune cardiomyopathies including myocardial sarcoid; ischaemic reperfusion injuries; endocarditis, valvulitis, and aortitis including infective (for example syphilitic); vasculitides; disorders of the proximal and peripheral veins including phlebitis and thrombosis, including deep vein thrombosis and complications of varicose veins;
  • 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; or,
  • 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.
  • a method for treating a PDE 4 mediated disease state in a mammal which comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof.
  • the invention also provides a compound of the formula (I), or a pharmaceutically acceptable salt thereof, for use in therapy.
  • the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in therapy (for example modulating PDE 4 enzymatic activity).
  • the invention further provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of:
  • 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 vascula
  • 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
  • arthritides 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; panniculitis;cutaneous lymphomas, non-melanoma skin
  • eyes blepharitis; conjunctivitis, including perennial and vernal allergic conjunctivitis; ulceris; anterior and posterior uveitis; choroiditis; autoimmune; degenerative or inflammatory- disorders affecting the retina; ophthalmitis including sympathetic ophthalmitis; sarcoidosis; infections including viral , fungal, and bacterial;
  • gastrointestinal tract glossitis, gingivitis, periodontitis; oesophagitis, including reflux; eosinophilic gastro-enteritis, mastocytosis, Crohn's disease, colitis including ulcerative colitis, proctitis, pruritis ani; coeliac disease, irritable bowel syndrome, and food-related allergies which may have effects remote from the gut (for example migraine, rhinitis or eczema); 7. abdominal: hepatitis, including autoimmune, alcoholic and viral; fibrosis and cirrhosis of the liver; cholecystitis; pancreatitis, both acute and chronic;
  • nephritis including interstitial and glomerulonephritis; nephrotic syndrome; cystitis including acute and chronic (interstitial) cystitis and thinner'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; 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;
  • cardiovascular atherosclerosis, affecting the coronary and peripheral circulation; pericarditis; myocarditis , inflammatory and auto-immune cardiomyopathies including myocardial sarcoid; ischaemic reperfusion injuries; endocarditis, valvulitis, and aortitis including infective (for example syphilitic); vasculitides; disorders of the proximal and peripheral veins including phlebitis and thrombosis, including deep vein thrombosis and complications of varicose veins;
  • oncology treatment of common cancers including prostate, breast, lung, ovarian, pancreatic, bowel and colon, stomach, skin and brain tumors and malignancies affecting the bone marrow (including the leukaemias) and lymphoproliferative systems, such as Hodgkin's and non-Hodgkin's lymphoma; including the prevention and treatment of metastatic disease and tumour recurrences, and paraneoplastic syndromes; or, 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; in a mammal (for example man).
  • the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of asthma ⁇ such as bronchial, allergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthma (for example late asthma or airways hyper-responsiveness) ⁇ ; or COPD.
  • asthma such as bronchial, allergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthma (for example late asthma or airways hyper-responsiveness) ⁇ ; or COPD.
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof is useful in the treatment of COPD.
  • the present invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of asthma ⁇ such as bronchial, allergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthma (for example late asthma or airways hyper- responsiveness) ⁇ ; or COPD.
  • a compound of the invention, or a pharmaceutically acceptable salt thereof for the therapeutic treatment of a mammal, such as man, said ingredient is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition. Therefore in another aspect the present invention provides a pharmaceutical composition which comprises a compound of the formula (I), or a pharmaceutically acceptable salt thereof (active ingredient), and a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the present invention provides 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.
  • the pharmaceutical 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), inhalation, oral, rectal or parenteral administration.
  • the compounds of this invention may be formulated by means known in the art.
  • 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 1 g of active ingredient.
  • Each patient may receive, for example, a dose of 0.001 mgkg "1 to 100 mgkg "1 , for example in the range of 0.1 mgkg '1 to 20 mgkg '1 , of the active ingredient administered, for example, 1 to 4 times per day.
  • the invention further relates to a combination therapy 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.
  • the compounds of the invention may be combined with agents listed below.
  • Non-steroidal anti-inflammatory agents including nonselective cyclo-oxygenase COX-I / 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, intramus
  • 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-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 signal
  • the invention relates to a combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with a monoclonal antibody targeting B- Lymphocytes (such as CD20 (rituximab), MRA-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, or a pharmaceutically acceptable salt thereof, 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 ,
  • 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; for example collagenase-1 (MMP-I), 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, or a pharmaceutically acceptable salt thereof, and a leukotriene biosynthesis inhibitor, 5 -lipoxygenase (5-LO) inhibitor or 5 -lipoxygenase activating protein (FLAP) antagonist such as; zileuton; ABT-761; fenleuton; tepoxalin; Abbott-79175; Abbott-85761; a N-(5-substituted)-thiophene-2-alkylsulfonamide; 2,6-di-tert-butylphenolhydrazones; a methoxytetrahydropyrans such as Zeneca ZD-2138; the compound SB-210661; a pyridinyl-substituted 2-cyanonaphthalene compound such as L-739,010; a 2- cyanoquinoline compound such as L-746,530; or an indole or quinoline compound such as MK-591, M
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a receptor antagonist for leukotrienes (LT) B4, LTC4, LTD4, and LTE4.
  • a receptor antagonist for leukotrienes (LT) B4, LTC4, LTD4, and LTE4 selected from the group consisting of the phenothiazin-3-yls 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- 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 hydrochlor
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an anticholinergic agent including muscarinic receptor (Ml, M2, and M3) antagonist such as atropine, hyoscine, glycopyrrrolate, ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine.
  • Ml, M2, and M3 antagonist such as atropine, hyoscine, glycopyrrrolate, ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine.
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a beta-adrenoceptor agonist (including beta receptor subtypes 1-4) such as isoprenaline, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, or pirbuterol, 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, or a pharmaceutically acceptable salt thereof, and a chromone, such as sodium cromoglycate or nedocromil sodium.
  • a chromone such as sodium cromoglycate or nedocromil sodium.
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with a glucocorticoid, such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide or mometasone furoate.
  • a glucocorticoid such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide or mometasone furoate.
  • 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-IgE (for example omalizumab).
  • an immunoglobulin (Ig) or Ig preparation or an antagonist or antibody modulating Ig function such as anti-IgE (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.
  • another systemic or topically- applied anti-inflammatory agent such as thalidomide or a derivative thereof, a retinoid, dithranol or calcipotriol.
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and combinations of aminosalicylates and sulfapyridine such as sulfasalazine, mesalazine, balsalazide, and olsalazine; and immunomodulatory agents such as the thiopurines, and corticosteroids such as budesonide.
  • aminosalicylates and sulfapyridine such as sulfasalazine, mesalazine, balsalazide, and olsalazine
  • immunomodulatory agents such as the thiopurines, and corticosteroids such as budesonide.
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with an antibacterial agent such as a penicillin derivative, a tetracycline, a macrolide, a beta-lactam, a fluoroquinolone, metronidazole, an inhaled aminoglycoside; an antiviral agent including acyclovir, famciclovir, valaciclovir, ganciclovir, cidofovir, amantadine, rimantadine, ribavirin, zanamavir and oseltamavir; a protease inhibitor such as indinavir, nelfinavir, ritonavir, and saquinavir; a nucleoside reverse transcriptase inhibitor such as didanosine, lamivudine, stavudine, zalcitabine or zidovudine; or a non-nucleoside reverse transcripta
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a cardiovascular agent such as a calcium channel blocker, a beta-adrenoceptor blocker, an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin-2 receptor antagonist; a lipid lowering agent such as a statin or a fibrate; a modulator of blood cell morphology such as pentoxyfylline; thrombolytic, or an anticoagulant such as a platelet aggregation inhibitor.
  • a cardiovascular agent such as a calcium channel blocker, a beta-adrenoceptor blocker, an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin-2 receptor antagonist
  • ACE angiotensin-converting enzyme
  • angiotensin-2 receptor antagonist angiotensin-2 receptor antagonist
  • a lipid lowering agent such as a statin or a fibrate
  • a modulator of blood cell morphology such as
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a CNS agent such as an antidepressant (such as sertraline), an anti-Parkinsonian drug (such as deprenyl, L-dopa, ropinirole, pramipexole, a MAOB inhibitor such as selegine and rasagiline, a comP inhibitor such as tasmar, an A-2 inhibitor, a dopamine reuptake inhibitor, an NMDA antagonist, a nicotine agonist, a dopamine agonist or an inhibitor of neuronal nitric oxide synthase), or an anti-Alzheimer's drug such as donepezil, rivastigmine, tacrine, a COX-2 inhibitor, propentofylline or metrifonate.
  • a CNS agent such as an antidepressant (such as sertraline), an anti-Parkinsonian drug (such as deprenyl, L
  • the present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an agent for the treatment of acute or chronic pain, such as a centrally or peripherally-acting analgesic (for example an opioid or derivative thereof), carbamazepine, phenytoin, sodium valproate, amitryptiline or other anti-depressant agents, 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 Imatinib mesylate), a serine / threonine kinase (such as an inhibitor of
  • -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
  • xi ⁇ growth hormone secretagogue
  • transforming growth factor (TGF ⁇ ) 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 NK.subl.
  • NKP-608C SB-233412 (talnetant) or D-4418
  • elastase inhibitor such as UT-77 or ZD-0892
  • TACE TNF-alpha converting enzyme inhibitor
  • iNOS induced nitric oxide synthase
  • chemoattractant receptor-homologous molecule expressed on TH2 cells such as a CRTH2 antagonist
  • inhibitor of p38 agent modulating the function of Toll-like receptors (TLR),
  • agent modulating the activity of purinergic receptors such as P2X7
  • inhibitor of transcription factor activation such as NFkB, API, or STATS
  • a glucocorticoid receptor GR-receptor
  • the present invention provides a pharmaceutical product comprising, in combination, a first active ingredient which is a compound of formula (I), or a pharmaceutically acceptable salt thereof, 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 ⁇ 2 -adrenoceptor agonist that may be used in the pharmaceutical product according to this embodiment 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.
  • the ⁇ 2 -adrenoceptor agonist of this embodiment may be a long-acting ⁇ 2 -agonists, for example salmeterol (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.
  • Examples of a protease inhibitor that may be used in the pharmaceutical product according to this embodiment include an inhibitor of neutrophil elastase or an inhibitor of MMP12.
  • 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.
  • triamcinolone e.g. as acetonide
  • flunisolide e.g. as acetonide
  • flumoxonide e.g. as flumoxonide
  • rofleponide e.g. as propionate ester
  • butixocort e.g. as propionate ester
  • prednisolone prednisone
  • tipredane steroid esters e.g.
  • a muscarinic receptor antagonist for example a Ml, M2 or M3 antagonist, such as a M3 antagonist
  • ipratropium e.g. as bromide
  • tiotropium e.g. as bromide
  • oxitropium e.g. as bro
  • a quinuclidine derivative such as 3(R)-(2-hydroxy-2,2- dithien-2-ylacetoxy)- 1 -(3 -phenoxypropy I)- 1 -azonia-bicyclo [2.2.2] octane bromide as disclosed in US 2003/0055080, quinuclidine derivatives as disclosed in WO 2003/087096 and WO 2005/115467 and DE 10050995; or GSK 656398 or GSK 961081.
  • 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.
  • a compound of the invention, or a pharmaceutically acceptable salt thereof, can also be used in combination with an existing therapeutic agent for the treatment of cancer, for example suitable agents include:
  • an antiproliferative/antineoplastic drug or a combination thereof, as used in medical oncology such as an alkylating agent (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan or a nitrosourea); an antimetabolite (for example an antifolate such as a fluoropyrimidine like 5-fluorouracil or tegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea, gemcitabine or paclitaxel); an antitumour antibiotic (for example an anthracycline such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin or mithramycin); an antimitotic agent (for example a vinca alkaloid such as vincri
  • an agent which inhibits cancer cell invasion for example a metalloproteinase inhibitor like marimastat or an inhibitor of urokinase plasminogen activator receptor function
  • an inhibitor of growth factor function for example: a growth factor antibody (for example the anti-erb b2 antibody trastuzumab, or the anti-erb bl 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-fluorophenyi)-7-methoxy-6-(3- morpholinopropoxy)quinazolin-4-amine (gefitinib, AZD1839), N-(3-ethynylphenyl)-6,7
  • a growth factor antibody for example
  • 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); (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 aber
  • ionisation was effected by electrospray ionisation (ES), or atmospheric pressure chemical ionisation (APCI), or multimode ionisation, a combination of ES ionisation and APCI.
  • ES electrospray ionisation
  • APCI atmospheric pressure chemical ionisation
  • multimode ionisation a combination of ES ionisation and APCI.
  • values for m/z are given, generally only ions which indicate the parent mass are reported, and the mass ions quoted are the positive or negative mass ions: [M] + , [M+H] + or [M-H] ' ;
  • the title and sub-title compounds of the examples and methods were named using the index name program from Advanced Chemistry Development Inc, version 8.00 or were named using the index name program from Ogham and stereochemical descriptors added by hand.
  • 6-Fluoro-imidazo[l,2-a]pyridine-2-carboxylic acid (900 mg, 5 mmol) was suspended in THF (10 ml) and IM borane/THF solution (25 ml, 25 mmol) added. The reaction was heated at reflux for 3h, cooled to room temperature. Methanol (20 ml) added and mixture heated at reflux for a further Ih. The solvent was removed by evaporation, and the residue dissolved in methanol (25ml). Concentrated hydrochloric acid (5 ml) was added and the mixture heated at reflux for Ih.
  • 6-fluoroimidazo[l,2-a]pyridin-2-yl)methanol was dissoved in DCM (20 ml) and manganese dioxide (5 g, 57 mmol) added and the reaction mixture heated at reflux for Ih. Mixture cooled to room temperature and filtered through celite, the filtrate evaporated and the residue purified by flash chromatography on silica using hexane:ethyl acetate (3:1) as eluent to afford the sub-title compound (170 mg, 20%).
  • Example 8 3 -(cis-4- ⁇ [(6-chloroimidazo[ 1 ,2-a]pyridin-2-yl)methyl]amino ⁇ cyclohexyl)-6-fluoro- 1 -
  • 6-Chloro-imidazo[l,2-a]pyridine-2-carboxylic acid (0.4 g, 2 mmol) was dissolved in dry THF (10 ml) and 1.0M borane/THF solution (5 ml, 5 mmol) was added, and the mixture heated at reflux for 2h. Mixture was quenched with methanol (2 ml), acidified with 3 drops of concentrated hydrochloric acid and heated at reflux for 15 min. The mixture was then adsorbed on to SCX resin, washed well with methanol and the crude alcohol intermediate eluted with 10% aqueous ammonia in methanol.
  • Step (b) 3-(cis-4- ⁇ [(6-chloroimidazo[ 1 ,2-a]pyridin-2-yl)methyl]amino ⁇ cyclohexyl)-6- fluoro-l-(tetrahydro-2H-thiopyran-4-yl)pyrido[2,3-d]pyrimidine-2,4(lH,3H)-dione 3-(cis-4-aminocyclohexyl)-6-fluoro-l-(tetrahydro-2H-thiopyran-4-yl)pyrido[2,3- d]pyrimidine-2,4(lH,3H)-dione (160 mg, 0.42 mmol), 6-chloro-imidazo[l,2-a]pyridine-2- carbaldehyde (76.5 mg, 0.425 mmol ) and acetic acid (28.58 mg, 27.25 ul) were dissolved in methanol (10 ml) and stirred at room
  • Example 3 The following examples were prepared in a similar manner to Example 3. ⁇ The compounds were named were named using the index name program from Ogham and stereochemical descriptors added by hand. (See www.cvesopen.com/products/applications/ogham.html)) R 1 in the structural fragment presented in the table below shows the point of attachment to the structure directly below.
  • the assay uses recombinant Human Phosphodiesterase B2 (PDE4B2) produced in house (PrAZLO 163), stored at -20 0 C. This assay is based on the observation that 5'AMP, the product of the reaction catalysed by PDE4, binds preferentially to yttrium silicate SPA beads (Amersham Biosciences, UK) compared to the substrate, cAMP.

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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
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Abstract

La présente invention concerne un composés de formule (I), dans laquelle les variables sont telles que définies présentement, un processus destiné à la préparation de ce composé, et l'utilisation de celui-ci dans le traitement d'un trouble à médiation PDE 4.
PCT/GB2008/000081 2007-01-11 2008-01-10 Composés chimiques 635: pyridopyrimidinediones en tant qu'inhibiteurs pde4 WO2008084236A1 (fr)

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CN106414443A (zh) * 2014-06-03 2017-02-15 诺华股份有限公司 吡啶并嘧啶二酮衍生物
CN106459041A (zh) * 2014-06-03 2017-02-22 诺华股份有限公司 嘧啶并[4,5‑b]喹啉‑4,5(3H,10H)‑二酮衍生物

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WO2007004958A1 (fr) * 2005-07-04 2007-01-11 Astrazeneca Ab Dérivés de pyridopyrimidine en tant qu'inhibiteurs de pde4 pour le traitement de maladies inflammatoires et immunes
WO2007108750A1 (fr) * 2006-03-22 2007-09-27 Astrazeneca Ab Dérivés de pyridopyrimidine et leur utilisation comme inhibiteurs de pde4

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106414443A (zh) * 2014-06-03 2017-02-15 诺华股份有限公司 吡啶并嘧啶二酮衍生物
CN106459041A (zh) * 2014-06-03 2017-02-22 诺华股份有限公司 嘧啶并[4,5‑b]喹啉‑4,5(3H,10H)‑二酮衍生物
CN106459041B (zh) * 2014-06-03 2018-10-16 诺华股份有限公司 嘧啶并[4,5-b]喹啉-4,5(3H,10H)-二酮衍生物
CN106414443B (zh) * 2014-06-03 2018-10-26 诺华股份有限公司 吡啶并嘧啶二酮衍生物

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