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WO2006000401A1 - Oxazines substituees utilisees comme modulateurs du recepteur glucocorticoide - Google Patents

Oxazines substituees utilisees comme modulateurs du recepteur glucocorticoide Download PDF

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Publication number
WO2006000401A1
WO2006000401A1 PCT/EP2005/006762 EP2005006762W WO2006000401A1 WO 2006000401 A1 WO2006000401 A1 WO 2006000401A1 EP 2005006762 W EP2005006762 W EP 2005006762W WO 2006000401 A1 WO2006000401 A1 WO 2006000401A1
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WIPO (PCT)
Prior art keywords
compound
formula
methyl
compounds
cycloalkyl group
Prior art date
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Ceased
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PCT/EP2005/006762
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English (en)
Inventor
David House
Graham George Adam Inglis
Michael John Johnston
Haydn Terence Jones
Simon John Fawcett Macdonald
Philip Alan Skone
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Glaxo Group Ltd
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Glaxo Group Ltd
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Publication date
Priority claimed from GB0414427A external-priority patent/GB0414427D0/en
Priority claimed from GB0418031A external-priority patent/GB0418031D0/en
Application filed by Glaxo Group Ltd filed Critical Glaxo Group Ltd
Publication of WO2006000401A1 publication Critical patent/WO2006000401A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/40—Radicals substituted by oxygen atoms
    • C07D307/46—Doubly bound oxygen atoms, or two oxygen atoms singly bound to the same carbon atom

Definitions

  • the present invention relates to compounds which are non-steroidal glucocorticoid receptor modulators, pharmaceutical compositions comprising the compounds, the use of the compounds for the manufacture of medicaments particularly for the treatment of inflammatory and/or allergic conditions, processes for the preparation of the compounds, and chemical intermediates in the processes for the manufacture of the compounds.
  • Nuclear receptors are a class of structurally related proteins involved in the regulation of gene expression.
  • the steroid hormone receptors are a subset of this family whose natural ligands typically comprise endogenous steroids such as estradiol (estrogen receptor), progesterone (progesterone receptor) and Cortisol (glucocorticoid receptor).
  • estradiol estradiol
  • progesterone progesterone receptor
  • Cortisol glucocorticoid receptor
  • Glucocorticoids exert their actions at the glucocorticoid receptor (GR) through at least two intracellular mechanisms, transactivation and transrepression (see: Schacke, H, Docke, W-D. & Asadullah, K (2002) Pharmacol and Therapeutics 96: 23-43; Ray, A., Siegel, M.D., Prefontaine, K.E. & Ray, P. (1995) Chest 107: 139S; and Konig, H., Ponta, H., Rahmsdorf, HJ. & Herrlich, P. (1992) EMBO J 11: 2241-2246).
  • GR glucocorticoid receptor
  • Transactivation involves direct binding of the glucocorticoid receptor to distinct deoxyribonucleic acid (DNA) response elements (GREs) within gene promoters, usually but not always increasing the transcription of the downstream gene product.
  • GREs deoxyribonucleic acid
  • the GR can also regulate gene expression through an additional pathway (transrepression) in which the GR does not bind directly to DNA.
  • This mechanism involves interaction of the GR with other transcription factors, in particular NFkB and AP1 , leading to inhibition of their pro-transcriptional activity (Schacke, H, Docke, W-D. & Asadullah, K (2002) Pharmacol and Therapeutics 96: 23-43; Ray, A., Siegel, M.D., Prefontaine, K.E.
  • glucocorticoids that selectively modulate the transrepression pathway compared with the transactivation pathway may therefore have a superior anti-inflammatory to side-effect therapeutic index, allowing more effective and safer treatment of the patient.
  • This new class of glucocorticoids could be used to treat more effectively and more safely the whole spectrum of disease currently treated by current glucocorticoids.
  • glucocorticoids have proved useful in the treatment of inflammation, tissue rejection, auto-immunity, various malignancies, such as leukemias and lymphomas, Cushing's syndrome, rheumatic fever, polyarteritis nodosa, granulomatous polyarteritis, inhibition of myeloid cell lines, immune proliferation/apoptosis, HPA axis suppression and regulation, hypercortisolemia, modulation of the Th1/Th2 cytokine balance, chronic kidney disease, stroke and spinal cord injury, hypercalcemia, hypergylcemia, acute adrenal insufficiency, chronic primary adrenal insufficiency, secondary adrenal insufficiency, congenital adrenal hyperplasia, cerebral edema, thrombocytopenia and Little's syndrome.
  • malignancies such as leukemias and lymphomas, Cushing's syndrome, rheumatic fever, polyarteritis nodosa, granulomatous polyarteritis, inhibition of myeloid cell lines
  • Glucocorticoids are especially useful in disease states involving systemic inflammation such as inflammatory bowel disease, systemic lupus erythematosus, polyarteritis nodosa, Wegener's granulomatosis, giant cell arteritis, rheumatoid arthritis, osteoarthritis, seasonal rhinitis, allergic rhinitis, urticaria, angioneurotic edema, chronic obstructive pulmonary disease, asthma, tendonitis, bursitis, Crohn's disease, ulcerative colitis, autoimmune chronic active hepatitis, organ transplantation, hepatitis and cirrhosis.
  • Glucocorticoids have also been used as immunostimulants and repressors and as wound healing and tissue repair agents.
  • Glucocorticoids have also found use in the treatment of diseases such as inflammatory scalp alopecia, panniculitis, psoriasis, discoid lupus erythemnatosus, inflamed cysts, atopic dermatitis, pyoderma gangrenosum, pemphigus vulgaris, bullous pemphigoid, systemic lupus erythematosus, dermatomyositis, herpes gestationis, eosinophilic fasciitis, relapsing polychondritis, inflammatory vasculitis, sarcoidosis, Sweet's disease, type 1 reactive leprosy, capillary hemangiomas, contact dermatitis, atopic dermatitis, lichen planus, exfoliative dermatitus, erythema nodosum, acne, hirsutism, toxic epidermal necrolysis, erythema multiform, cutaneous
  • WO00/32584, WO02/10143, WO03/082827, WO/03082280 and DE10261874 disclose certain non-steroidal glucocorticoid receptor modulators.
  • the present invention provides compounds of formula (I):
  • R 1 represents a C 3 - 6 cycloalkyl group
  • C 3-6 cycloalkyl is meant a cycloalkyl group having 3 to 6 carbon atoms.
  • Examples of C 3-6 cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • R 1 represents a cyclopropyl group.
  • R 1 represents a cyclobutyl group.
  • R 1 represents a cyclopentyl group.
  • R 1 represents a cyclohexyl group.
  • the compounds of formula (I) each contain two chiral centres and there are four possible stereoisomers of each compound of formula (I). Further, at least one of the possible stereoisomers of each compound of formula (I) modulates the gluocorticoid receptor.
  • D1 and D2 are used herein to refer to the diastereomers of a compound of formula (I), based on the order of their elution using the chromatography methodology described herein (LCMS System A).
  • D1 refers to the first diastereomer to elute
  • D2 refers to the second diastereomer to elute.
  • D1 E1 , D1E2, D2E1 and D2E2 are used herein to refer to the isomers of a compound of formula (I), D1 E1 refers to the first enantiomer to elute, and D1 E2 refers to the second enantiomer to elute, during chiral separation of diastereomer D1 according to the methodology described herein.
  • D2E1 refers to the first enantiomer to elute
  • D2E2 refers to the second enantiomer to elute, during chiral separation of diastereomer D2 according to the methodology described herein.
  • a mixture of isomers such as a racemic mixture, may be preferred, for example, a mixture of all four isomers, or a racemic mixture of two isomers may be preferred, for example diastereomer D2.
  • the diastereomer D2 is preferred.
  • the isomer D2E2 is preferred.
  • the group R 1 represents cyclopentyl, preferably the compound is isomer D2E2.
  • isomer D2E2 of the compound of formula (I) wherein the group R 1 represents cyclopentyl is characterised by having a retention time of about 18.3 min when eluted on an analytical chiral HPLC on a 25 x 0.46 cm Chiralpak AD column using a mobile phase of 5% ethanol in heptane at 1 mL/min.
  • Isomer D2E2 is the later running enantiomer of the racemic mixture of isomers D2E1 and D2E2.
  • Compounds of the invention which are of particular interest include: 2-[(1-cyclopentyl-1,2,3,4-tetrahydro-1-naphthalenyl)methyl]-3,3,3-trifluoro-2-hydroxy-/V-(4- methyl-1 -oxo-1 /-/-2,3-benzoxazin-6-yl)propanamide isomer D2E2; 2-[(1 -cyclopropyl-1 ,2,3,4-tetrahydro-1 -naphthalenyl)methyl]-3,3,3-trifluoro-2 ⁇ hydroxy- ⁇ /-(4- methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide isomer D2E2; 2-[(1-cyclobutyl-1 ,2,3,4-tetrahydro-1-naphthalenyl)methyl]-3,3,3-trifluoro-2-hydroxy- ⁇ /-(4- methyl-1 -oxo-1 /
  • the compounds of the invention may provide agonism of the glucocorticoid receptor.
  • At least one of the possible stereoisomers of each of the compounds of formula (I) binds to the glucocorticoid receptor. Further, it appears that at least one of the possible stereoisomers of each of the compounds of formula (I) has glucocorticoid receptor agonist activity. Additionally, it appears that at least one of the possible stereoisomers of each of the compounds of formula (I) possesses advantageous selectivity in respect of maintaining transrepression activity whilst reducing the transactivation activity.
  • At least one isomer e.g. an enantiomer in a diastereomer
  • the other isomers may have similar activity, less activity, no activity or may have some antagonist activity in a functional assay.
  • the group R 1 represents cyclopentyl
  • both the racemic mixture of isomers D2E1 and D2E2 ie. the diastereomer D2
  • the single isomer D2E2 alone have been shown to demonstrate glucocorticoid receptor agonist activity.
  • the invention includes physiologically functional derivatives of the compounds of formula (I).
  • physiologically functional derivative is meant a chemical derivative of a compound of formula (I) having the same physiological function as the free compound of formula (I) 1 for example, by being convertible in the body thereto and includes any pharmaceutically acceptable esters, carbonates and carbamates, solvates of compounds of formula (I) and solvates of any pharmaceutically acceptable esters, carbonates and carbamates or salts of compounds of formula (I), which, upon administration to the recipient, are capable of providing (directly or indirectly) compounds of formula (I) or active metabolite or residue thereof.
  • one embodiment of the invention embraces compounds of formula (I) and salts and solvates thereof.
  • Another embodiment of the invention embraces compounds of formula (I) and salts thereof.
  • a further embodiment of the invention embraces compounds of formula (I).
  • Solvates of the compounds of formula (I) and physiologically functional derivatives thereof which are suitable for use in medicine are those wherein the associated solvent is pharmaceutically acceptable.
  • solvates having non-pharmaceutically acceptable counter-ions or associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of formula (I) and their pharmaceutically acceptable salts, solvates, and physiologically functional derivatives.
  • solvates include hydrates.
  • the compounds of the invention are expected to have potentially beneficial anti ⁇ inflammatory or anti-allergic effects, particularly upon topical administration, demonstrated by, for example, their ability to bind to the glucocorticoid receptor and to illicit a response via that receptor. Hence, the compounds of the invention may be useful in the treatment of inflammatory and/or allergic disorders.
  • Examples of disease states in which the compounds of the invention are expected to have utility include skin diseases such as eczema, psoriasis, allergic dermatitis, neurodermatitis, pruritis and hypersensitivity reactions; inflammatory conditions of the nose, throat or lungs such as asthma (including allergen-induced asthmatic reactions), rhinitis (including hayfever), nasal polyps, chronic obstructive pulmonary disease (COPD), interstitial lung disease, and fibrosis; inflammatory bowel conditions such as ulcerative colitis and Crohn's disease; and auto-immune diseases such as rheumatoid arthritis.
  • skin diseases such as eczema, psoriasis, allergic dermatitis, neurodermatitis, pruritis and hypersensitivity reactions
  • inflammatory conditions of the nose, throat or lungs such as asthma (including allergen-induced asthmatic reactions), rhinitis (including hayfever), nasal polyps, chronic obstructive pulmonary disease (COPD
  • compounds of the invention are expected to be of use in human or veterinary medicine, in particular as anti-inflammatory and anti-allergic agents.
  • a compound of the invention for use in human or veterinary medicine, particularly in the treatment of patients with inflammatory and/or allergic conditions, such as rheumatoid arthritis, asthma, COPD, allergy or rhinitis.
  • a compound of the invention for use in for use in the treatment of patients with skin disease such as eczema, psoriasis, allergic dermatitis, neurodermatitis, pruritis and hypersensitivity reactions.
  • a compound of the invention for the manufacture of a medicament for the treatment of patients with inflammatory and/or allergic conditions, such as rheumatoid arthritis, asthma, COPD, allergy or rhinitis.
  • a compound of the invention for the manufacture of a medicament for the treatment of patients with skin disease such as eczema, psoriasis, allergic dermatitis, neurodermatitis, pruritis and hypersensitivity reactions.
  • a method for the treatment of a human or animal subject with an inflammatory and/or allergic condition comprises administering to said human or animal subject an effective amount of a compound of the invention.
  • a method for the treatment of a human or animal subject with for skin disease such as eczema, psoriasis, allergic dermatitis, neurodermatitis, pruritis and hypersensitivity reactions, which method comprises administering to said human or animal subject an effective amount of a compound of the invention.
  • the compounds according to the invention may be formulated for administration in any convenient way, and the invention therefore also includes within its scope pharmaceutical compositions comprising a compound of the invention together, if desirable, in admixture with one or more physiologically acceptable diluents or carriers.
  • the compounds of the invention may, for example, be formulated for oral, buccal, sublingual, parenteral, local rectal administration or other local administration.
  • Local administration includes administration by insufflation and inhalation.
  • preparation for local administration include ointments, lotions, creams, gels, foams, preparations for delivery by transdermal patches, powders, sprays, aerosols, capsules or cartridges for use in an inhaler or insufflator or drops (e.g. eye or nose drops), solutions/suspensions for nebulisation, suppositories, pessaries, retention enemas and chewable or suckable tablets or pellets (e.g. for the treatment of aphthous ulcers) or liposome or microencapsulation preparations.
  • Ointments, creams and gels may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agent and/or solvents.
  • bases may thus, for example, include water and/or an oil such as liquid paraffin or a vegetable oil such as arachis oil or castor oil, or a solvent such as polyethylene glycol.
  • Thickening agents and gelling agents which may be used according to the nature of the base include soft paraffin, aluminium stearate, cetostearyl alcohol, polyethylene glycols, woolfat, beeswax, carboxypolymethylene and cellulose derivatives, and/or glyceryl monostearate and/or non-ionic emulsifying agents.
  • Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents or thickening agents.
  • Powders for external application may be formed with the aid of any suitable powder base, for example, talc, lactose or starch.
  • Drops may be formulated with an aqueous or non ⁇ aqueous base also comprising one or more dispersing agents, solubilising agents, suspending agents or preservatives.
  • Spray compositions may for example be formulated as aqueous solutions or suspensions or as aerosols delivered from pressurised packs, such as a metered dose inhaler, with the use of a suitable liquefied propellant.
  • Aerosol compositions suitable for inhalation can be either a suspension or a solution and generally contain a compound of formula (I) and a suitable propellant such as a fluorocarbon or hydrogen-containing chlorofluorocarbon or mixtures thereof, particularly hydrofluoroalkanes, especially 1 ,1 ,1 ,2-tetrafluoroethane, 1 ,1,1,2,3,3,3-heptafluoro-n-propane or a mixture thereof.
  • the aerosol composition may optionally contain additional formulation excipients well known in the art such as surfactants e.g. oleic acid or lecithin and cosolvents e.g. ethanol.
  • formulations of the invention may be buffered by the addition of suitable buffering agents.
  • Capsules and cartridges for use in an inhaler or insufflator may be formulated containing a powder mix for inhalation of a compound of the invention and a suitable powder base such as lactose or starch.
  • a powder mix for inhalation of a compound of the invention and a suitable powder base such as lactose or starch.
  • Each capsule or cartridge may generally contain between from 20 ⁇ g to 10mg of the compound of formula (I).
  • the compound of the invention may be presented without excipients such as lactose.
  • the proportion of the active compound of formula (I) in the local compositions according to the invention depends on the precise type of formulation to be prepared but will generally be within the range of from 0.001 to 10% by weight. Generally, however for most types of preparations advantageously the proportion used will be within the range of from 0.005 to 1% and preferably from 0.01 to 0.5%. However, in powders for inhalation or insufflation the proportion used will be within the range of from 0.1 to 5%.
  • Aerosol formulations are preferably arranged so that each metered dose or "puff' of aerosol contains from 20 ⁇ g to 10mg preferably from 20 ⁇ g to 2000 ⁇ g, more preferably about 20 ⁇ g-500 ⁇ g of a compound of formula (I). Administration may be once daily or several times daily, for example 2, 3, 4 or 8 times, giving for example 1 , 2 or 3 doses each time.
  • the overall daily dose with an aerosol will be within the range from 100 ⁇ g to 10mg preferably, from 200 ⁇ g to 2000 ⁇ g.
  • the overall daily dose and the metered dose delivered by capsules and cartridges in an inhaler or insufflator will generally be double that delivered with aerosol formulations.
  • the particle size of the particular (e.g., micronised) drug should be such as to permit inhalation of substantially all the drug into the lungs upon administration of the aerosol formulation and will thus be less than 100 microns, desirably less than 20 microns, and, in particular, in the range of from 1 to 10 microns, such as from 1 to 5 microns, more preferably from 2 to 3 microns.
  • the formulations of the invention may be prepared by dispersal or dissolution of the medicament and a compound of the invention in the selected propellant in an appropriate container, for example, with the aid of sonication or a high-shear mixer.
  • the process is desirably carried out under controlled humidity conditions.
  • the chemical and physical stability and the pharmaceutical acceptability of the aerosol formulations according to the invention may be determined by techniques well known to those skilled in the art.
  • the chemical stability of the components may be determined by HPLC assay, for example, after prolonged storage of the product.
  • Physical stability data may be gained from other conventional analytical techniques such as, for example, by leak testing, by valve delivery assay (average shot weights per actuation), by dose reproducibility assay (active ingredient per actuation) and spray distribution analysis.
  • the stability of the suspension aerosol formulations according to the invention may be measured by conventional techniques, for example, by measuring flocculation size distribution using a back light scattering instrument or by measuring particle size distribution by cascade impaction or by the "twin impinger” analytical process.
  • twin impinger assay means "Determination of the deposition of the emitted dose in pressurised inhalations using apparatus A” as defined in British Pharmacopaeia 1988, pages A204-207, Appendix XVII C.
  • Such techniques enable the "respirable fraction" of the aerosol formulations to be calculated.
  • MDI canisters generally comprise a container capable of withstanding the vapour pressure of the propellant used such as a plastic or plastic-coated glass bottle or preferably a metal can, for example, aluminium or an alloy thereof which may optionally be anodised, lacquer-coated and/or plastic-coated (for example incorporated herein by reference WO96/32099 wherein part or all of the internal surfaces are coated with one or more fluorocarbon polymers optionally in combination with one or more non-fluorocarbon polymers), which container is closed with a metering valve.
  • the cap may be secured onto the can via ultrasonic welding, screw fitting or crimping.
  • MDIs taught herein may be prepared by methods of the art (e.g., see Byron, above and WO/96/32099).
  • the canister is fitted with a cap assembly, wherein a drug-metering valve is situated in the cap, and said cap is crimped in place.
  • the metering valves are designed to deliver a metered amount of the formulation per actuation and incorporate a gasket to prevent leakage of propellant through the valve.
  • the gasket may comprise any suitable elastomeric material such as, for example, low density polyethylene, chlorobutyl, black and white butadiene-acrylonitrile rubbers, butyl rubber and neoprene.
  • Suitable valves are commercially available from manufacturers well known in the aerosol industry, for example, from Valois, France (e.g. DF10, DF30, DF60), Bespak pic, UK (e.g. BK300, BK357) and 3M-Neotechnic Ltd, UK (e.g. SpraymiserTM).
  • a metering valve is crimped onto an aluminium can to form an empty canister.
  • the particulate medicament is added to a charge vessel and liquefied propellant is pressure filled through the charge vessel into a manufacturing vessel, together with liquefied propellant containing the surfactant.
  • the drug suspension is mixed before recirculation to a filling machine and an aliquot of the drug suspension is then filled through the metering valve into the canister.
  • an aliquot of the liquefied formulation is added to an open canister under conditions which are sufficiently cold to ensure formulation does not vaporise, and then a metering valve crimped onto the canister.
  • each filled canister is check- weighed, coded with a batch number and packed into a tray for storage before release testing.
  • the present invention provides a pharmaceutical aerosol formulation comprising a compound of formula (I) or a physiologically functional derivative thereof, and a fluorocarbon or hydrogen containing chlorofluorocarbon as propellant, optionally in combination with a surfactant and/or cosolvent.
  • Topical preparations may be administered by one or more applications per day to the affected area; over skin areas occlusive dressings may advantageously be used. Continuous or prolonged delivery may be achieved by an adhesive reservoir system.
  • the compounds according to the invention may, for example, be formulated in conventional manner for oral, parenteral or rectal administration.
  • Formulations for oral administration include syrups, elixirs, powders, granules, tablets and capsules which typically contain conventional excipients such as binding agents, fillers, lubricants, disintegrants, wetting agents, suspending agents, emulsifying agents, preservatives, buffer salts, flavouring, colouring and/or sweetening agents as appropriate.
  • Dosage unit forms are, however, preferred as described below.
  • the compounds according to the invention may in general be given by internal administration in cases where systemic adreno-cortical therapy is indicated.
  • Slow release or enteric coated formulations may be advantageous, particularly for the treatment of inflammatory bowel disorders.
  • the compound of formula (I) will be formulated for oral administration. In other embodiments the compounds of formula (I) will be formulated for inhaled administration.
  • the compound and pharmaceutical formulations according to the invention may be used in combination with or include one or more other therapeutic agents, for example selected from anti-inflammatory agents, anticholinergic agents (particularly an Mi/M 2 /M 3 receptor antagonist), ⁇ 2 -adrenoreceptor agonists, antiinfective agents (e.g. antibiotics, antivirals), or antihistamines.
  • anti-inflammatory agents particularly an Mi/M 2 /M 3 receptor antagonist
  • antiinfective agents e.g. antibiotics, antivirals
  • antihistamines e.g. antibiotics, antivirals
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with one or more other therapeutically active agents, for example selected from an anti-inflammatory agent (for example another corticosteroid or an NSAID), an anticholinergic agent, a ⁇ 2 - adrenoreceptbr agonist, an antiinfective agent (e.g. an antibiotic or an antiviral), or an antihistamine.
  • an anti-inflammatory agent for example another corticosteroid or an NSAID
  • an anticholinergic agent for example another corticosteroid or an NSAID
  • an anticholinergic agent for example another corticosteroid or an NSAID
  • an anticholinergic agent for example another corticosteroid or an NSAID
  • an anticholinergic agent for example another corticosteroid or an NSAID
  • an anticholinergic agent for example another corticosteroid or an NSAID
  • One embodiment of the invention encompasses combinations comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with a ⁇ 2 -adrenoreceptor agonist, and/or an anticholinergic, and/or a PDE-4 inhibitor.
  • Suitable combinations are those comprising one or two other therapeutic agents.
  • the other therapeutic ingredient(s) may be used in the form of salts, (e.g. as alkali metal or amine salts or as acid addition salts), or prodrugs, or as esters (e.g. lower alkyl esters), or as solvates (e.g. hydrates) to optimise the activity and/or stability and/or physical characteristics (e.g. solubility) of the therapeutic ingredient.
  • the therapeutic ingredients may be used in optically pure form. Suitable combinations include a combination comprising of a compound of the invention together with a ⁇ 2 -adrenoreceptor agonist.
  • ⁇ 2 -adrenoreceptor agonists examples include salmeterol (e.g. as racemate or a single enantiomer such as the R-enantiomer), salbutamol, formoterol, salmefamol, fenoterol or terbutaline and salts thereof, for example the xinafoate salt of salmeterol, the sulphate salt or free base of salbutamol or the fumarate salt of formoterol.
  • the ⁇ 2 -adrenoreceptor agonists are long-acting ⁇ 2 -adrenoreceptor agonists for example;, those having a therapeutic effect over a 24 hour period such as salmeterol or formoterol.
  • Suitable long acting ⁇ 2 -adrenoreceptor agonists may include those described in WO 02/066422, WO 02/070490, WO 02/076933, WO 03/024439, WO 03/072539, WO 03/091204, WO 04/016578, WO 2004/022547, WO 2004/037807, WO 2004/037773, WO 2004/037768, WO 2004/039762, WO 2004/039766, WO01/42193 and WO03/042160.
  • Examples of long-acting ⁇ 2 -adrenoreceptor agonists may include compounds of formula
  • m is an integer of from 2 to 8; n is an integer of from 3 to 11 , with the proviso that m + n is 5 to 19,
  • R 21 is -XSO 2 NR 26 R 27 wherein X is -(CH 2 ) P - or C 2-6 alkenylene; R 26 and R 27 are independently selected from hydrogen, C 1-6 alkyl, C 3 .
  • R 26 and R 27 are each optionally substituted by one or two groups selected from halo, d -6 alkyl, Ci -6 haloalkyl, Ci -6 alkoxy, hydroxy- substituted C 1-6 alkoxy, -CO 2 R 28 , -SO 2 NR 28 R 29 , -CONR 28 R 29 , -NR 28 C(O)R 29 , or a 5-, 6- or 7-membered heterocylic ring; R 28 and R 29 are independently selected from hydrogen, Ci -6 alkyl, C 3 .
  • R 22 and R 23 are independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halo, phenyl, and C 1-6 haloalkyl; and R 24 and R 25 are independently selected from hydrogen and C ⁇ alkyl with the proviso that the total number of carbon atoms in R 24 and R 25 is not more than 4.
  • long-acting ⁇ 2 -adrenoreceptor agonists include: 3-(4- ⁇ [6-( ⁇ (2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl ⁇ amino) hexyl]oxy ⁇ butyl)benzenesulfonamide; 3-(3- ⁇ [7-( ⁇ (2R)-2-hydroxy-2-[4-hydroxy-3-hydroxymethyl)phenyl]ethyl ⁇ - amino)heptyl]oxy ⁇ propyl)benzenesulfonamide; 4- ⁇ (1 R)-2-[(6- ⁇ 2-[(2,6-dichlorobenzyl)oxy]ethoxy ⁇ hexyl)amino]-1 -hydroxyethyl ⁇ -2- (hydroxymethyl)phenol; 4- ⁇ (1 R)-2-[(6- ⁇ 4-[3-(cyclopentylsulfonyl)phenyl]butoxy ⁇ hexyl)amino]-1-
  • Suitable anti-inflammatory agents include corticosteroids.
  • Suitable corticosteroids which may be used in combination with the compounds of the invention are those oral and inhaled corticosteroids and their pro-drugs which have anti-inflammatory activity. Examples include methyl prednisolone, prednisolone, dexamethasone, fluticasone propionate, 6 ⁇ ,9 ⁇ -difluoro-11 ⁇ -hydroxy-16 ⁇ -methyl-17 ⁇ -[(4-methyl-1 ,3-thiazole-5- carbonyl)oxy]-3-oxo-androsta-1 ,4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester, 6 ⁇ ,9 ⁇ - difluoro-17 ⁇ -[(2-furanylcarbonyl)oxy]-11 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-androsta-1 ,4-diene- 17 ⁇ -carbothioic acid S-fluoromethyl ester, 6 ⁇ ,9 ⁇ -difluoro-11 ⁇ -hydroxy
  • the 17-propionate ester or the 17,21-dipropionate ester the 17-propionate ester or the 17,21-dipropionate ester
  • budesonide flunisolide
  • mometasone esters e.g. the furoate ester
  • triamcinolone acetonide e.g. the furoate ester
  • rofleponide triamcinolone acetonide
  • ciclesonide (16 ⁇ ,17-[[(R)-cyclohexylmethylene]bis(oxy)]-11 ⁇ ,21- dihydroxy-pregna-1,4-diene-3,20-dione
  • butixocort propionate RPFM 06541 , and ST- 126.
  • Preferred corticosteroids include fluticasone propionate, 6 ⁇ ,9 ⁇ -difluoro-11 ⁇ -hydroxy- 16 ⁇ -methyl-17 ⁇ -[(4-methyl-1 ,3-thiazole-5-carbonyl)oxy]-3-oxo-androsta-1 ,4-diene-17 ⁇ - carbothioic acid S-fluoromethyl ester and 6 ⁇ ,9 ⁇ -difluoro-17 ⁇ -[(2-furanylcarbonyl)oxy]-11 ⁇ - hydroxy-16 ⁇ -methyl-3-oxo-androsta-1,4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester, more preferably 6 ⁇ ,9 ⁇ -difluoro-17 ⁇ -[(2-furanylcarbonyl)oxy]-11 ⁇ -hydroxy-16 ⁇ -methyl-3- oxo-androsta-1,4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester.
  • Non-steroidal compounds having glucocorticoid agonism that may possess selectivity for transrepression over transactivation and that may be useful in combination therapy include those covered in the following patents: WO03/082827, WO01/10143, WO98/54159, WO04/005229, WO04/009016, WO04/009017, WO04/018429, WO03/104195, WO03/082787, WO03/082280, WO03/059899, WO03/101932, WO02/02565, WO01/16128, WO00/66590, WO03/086294, WO04/026248, WO03/061651 , WO03/08277.
  • Suitable anti-inflammatory agents include non-steroidal anti-inflammatory drugs (NSAID 1 S).
  • Suitable NSAID's include sodium cromoglycate, nedocromil sodium, phosphodiesterase (PDE) inhibitors (e.g. theophylline, PDE4 inhibitors or mixed PDE3/PDE4 inhibitors), leukotriene antagonists, inhibitors of leukotriene synthesis (e.g. montelukast), iNOS inhibitors, tryptase and elastase inhibitors, beta-2 integrin antagonists and adenosine receptor agonists or antagonists (e.g. adenosine 2a agonists), cytokine antagonists (e.g.
  • chemokine antagonists such as a CCR3 antagonist
  • Suitable other ⁇ 2 -adrenoreceptor agonists include salmeterol (e.g. as the xinafoate), salbutamol (e.g. as the sulphate or the free base), formoterol (e.g. as the fumarate), fenoterol or terbutaline and salts thereof.
  • An iNOS (inducible nitric oxide synthase inhibitor) is preferably for oral administration.
  • Suitable iNOS inhibitors include those disclosed in WO93/13055, WO98/30537, WO02/50021, WO95/34534 and WO99/62875.
  • Suitable CCR3 inhibitors include those disclosed in WO02/26722.
  • PDE4-specific inhibitor useful in this aspect of the invention may be any compound that is known to inhibit the PDE4 enzyme or which is discovered to act as a PDE4 inhibitor, and which are only PDE4 inhibitors, not compounds which inhibit other members of the PDE family, such as PDE3 and PDE5, as well as PDE4.
  • Compounds of interest include c/s-4-cyano-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexan-1-carboxylic acid, 2-carbomethoxy-4-cyano-4-(3- cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1 -one and c/s-[4-cyano-4-(3- cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1 -ol].
  • c/s-4-cyano-4-[3- (cyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxylic acid also known as cilomilast
  • salts, esters, pro-drugs or physical forms which is described in U.S. patent 5,552,438 issued 03 September, 1996; this patent and the compounds it discloses are incorporated herein in full by reference.
  • AWD-12-281 from Elbion (Hofgen, N. et al. 15th EFMC lnt Symp Med Chem (Sept 6-10, Edinburgh) 1998, Abst P.98; CAS reference No. 247584020-9); a 9-benzyladenine derivative nominated NCS-613 (INSERM); D-4418 from Chiroscience and Schering-Plough; a benzodiazepine PDE4 inhibitor identified as Cl- 1018 (PD-168787) and attributed to Pfizer; a benzodioxole derivative disclosed by Kyowa Hakko in WO99/16766; K-34 from Kyowa Hakko; V-11294A from Napp (Landells, L.J.
  • Suitable anticholinergic agents are those compounds that act as antagonists at the muscarinic receptors, in particular those compounds which are antagonists of the M 1 or M 3 receptors, dual antagonists of the M 1 ZM 3 or M 2 /M 3 , receptors or pan-antagonists of the M 1 ZM 2 ZM 3 receptors.
  • Exemplary compounds for administration via inhalation include ipratropium (e.g. as the bromide, CAS 22254-24-6, sold under the name Atrovent), oxitropium (e.g. as the bromide, CAS 30286-75-0) and tiotropium (e.g. as the bromide, CAS 136310-93-5, sold under the name Spiriva).
  • revatropate e.g. as the hydrobromide, CAS 262586-79-8
  • LAS-34273 which is disclosed in WO01Z04118.
  • Exemplary compounds for oral administration include pirenzepine (CAS 28797-61-7), darifenacin (CAS 133099-04-4, or CAS 133099-07-7 for the hydrobromide sold under the name Enablex), oxybutynin (CAS 5633-20-5, sold under the name Ditropan), terodiline (CAS 15793-40-5), tolterodine (CAS 124937-51-5, or CAS 124937-52-6 for the tartrate, sold under the name Detrol), otilonium (e.g.
  • Suitable anticholinergic agents include compounds of formula (XXI), which are disclosed in US patent application 60Z487981 :
  • R 31 and R 32 are, independently, selected from the group consisting of straight or branched chain lower alkyl groups having preferably from 1 to 6 carbon atoms, cycloalkyl groups having from 5 to 6 carbon atoms, cycloalkyl-alkyl having 6 to 10 carbon atoms, 2-thienyl, 2-pyridyl, phenyl, phenyl substituted with an alkyl group having not in excess of 4 carbon atoms and phenyl substituted with an alkoxy group having not in excess of 4 carbon atoms;
  • X " represents an anion associated with the positive charge of the N atom.
  • X " may be but is not limited to chloride, bromide, iodide, sulfate, benzene sulfonate, and toluene sulfonate, including, for example: (3-endo)-3-(2,2-di-2-thienylethenyl)-8,8-dimethyl-8-azoniabicyclo[3.2.1]octane bromide; (3-encfo)-3-(2,2-diphenylethenyl)-8,8-dimethyl-8-azoniabicyclo[3.2.1]octane bromide; (3-enoO)-3-(2,2-diphenylethenyl)-8,8-dimethyl-8-azoniabicyclo[3.2.1]octane A- methylbenzenesulfonate; (3-enc/o)-8,8-dimethyl-3-[2-phenyl-2-(2-thienyl)ethenyl]-8-azoniabi
  • anticholinergic agents include compounds of formula (XXII) or (XXIII), which are disclosed in US patent application 60/511009:
  • R 41 represents an anion associated with the positive charge of the N atom.
  • R 41 may be but is not limited to chloride, bromide, iodide, sulfate, benzene sulfonate and toluene sulfonate;
  • R 42 and R 43 are independently selected from the group consisting of straight or branched chain lower alkyl groups (having preferably from 1 to 6 carbon atoms), cycloalkyl groups (having from 5 to 6 carbon atoms), cycloalkyl-alkyl (having 6 to 10 carbon atoms), heterocycloalkyl (having 5 to 6 carbon atoms) and N or O as the heteroatom, heterocycloalkyl-alkyl (having 6 to10 carbon atoms) and N or O as the heteroatom, aryl, optionally substituted aryl, heteroaryl, and optionally substituted heteroaryl;
  • R 44 is selected from the group consisting of (C
  • compounds useful in the present invention include: (Endo)-3-(2-methoxy-2,2-di-thiophen-2-yl-ethyl)-8,8-dimethyl-8-azonia- bicyclo[3.2.1]octane iodide; (Endo)-3-(2-cyano-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane iodide; (Endo)-3-(2-cyano-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane bromide; (Endo)-3-(2-carbamoyl-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane iodide; (Endo)-3-(2-cyano-2,2-di-
  • Suitable antihistamines include any one or more of the numerous antagonists known which inhibit H 1 -receptors, and are safe for human use.
  • First generation antagonists include derivatives of ethanolamines, ethylenediamines, and alkylamines, e.g diphenylhydramine, pyrilamine, clemastine, chloropheniramine.
  • Second generation antagonists which are non-sedating, include loratidine, desloratidine, terfenadine, astemizole, acrivastine, azelastine, levocetirizine fexofenadine and cetirizine.
  • Suitable anti-histamines include loratidine, desloratidine, fexofenadine and cetirizine.
  • the invention provides in one aspect, a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a physiologically functional derivative thereof, in admixture with one or more physiologically acceptable diluents or carriers which further comprises another therapeutically active agent.
  • a further aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a physiologically functional derivative thereof, in admixture with one or more physiologically acceptable diluents or carriers which further comprises a ⁇ 2 -adrenoreceptor agonist.
  • a combination comprising a compound of formula (I), or a physiologically functional derivative thereof, together with a PDE4 inhibitor.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, together with a PDE4 inhibitor.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with a ⁇ 2 -adrenoreceptor agonist.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with an anticholinergic.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with an antihistamine.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with a PDE4 inhibitor and a ⁇ 2 -adrenoreceptor agonist.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with an anticholinergic and a PDE-4 inhibitor.
  • compositions comprising a combination as defined above together with a pharmaceutically acceptable diluent or carrier represent a further aspect of the invention.
  • the individual compounds of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations. In one embodiment the individual compounds will be administered simultaneously in a combined pharmaceutical formulation. Appropriate doses of known therapeutic agents will be readily appreciated by those skilled in the art.
  • Isomer D2E1 of the compound of formula (I) wherein R 1 represents cyclopentyl is characterised in having a retention time in analytical chiral HPLC on a 25 x 0.46 cm Chiralpak AD column using a mobile phase of 5% ethanol in heptane eluting at 1 mL/min of about 14.2min.
  • Isomer D2E2 of the compound of formula (I) wherein R 1 represents cyclopentyl has a retention time of about 18.3min under the same conditions, and under the same conditions, isomers D1 E1 and D1 E2 elute at about 11.9min and 14.9min respectively.
  • Preferred isomers of the compounds of formula (I) may be prepared by chromatographic separation of the isomer from a mixture of enantiomeric isomers (e.g. a racemic mixture, such as a diastereomer D2).
  • a mixture (e.g. racemic mixture) of enantiomeric isomers D2E1 and D2E2 may be prepared by chromatographic separation from a mixture of isomers D1E1 , D1 E2, D2E1 and D2E2.
  • racemic mixture of isomers D2E1 and D2E2 of the compound of formula (I) wherein R 1 represents cyclopentyl (diastereomer D2) has an LCMS: t ret of about 4.02min
  • racemic mixture of isomers D1 E1 and D1E2 of the compound of formula (I) wherein R 1 represents cyclopentyl (diastereomer D1) has an LCMS: t ret of about 3.87min under the conditions described for LCMS System A.
  • the invention also provides a mixture (e.g. a racemic mixture) of isomers D1 E1 , D1 E2, D2E1 and D2E2.
  • a mixture e.g. a racemic mixture
  • a process according to the invention for the preparation of compounds of formula (I) comprises treatment of a compound of formula (II):
  • R 1 represents a C 3-6 cycloalkyl group
  • R 10 represents an activating group, for example, trimethylsilyl (TMS).
  • TMS trimethylsilyl
  • the reaction will generally be performed in the presence of an inert solvent, such as dimethylformamide (DMF) and a base, such as caesium fluoride (CsF) at a non- extreme temperature, for example, 0-120 0 C, and more suitably at room temperature.
  • an inert solvent such as dimethylformamide (DMF)
  • a base such as caesium fluoride (CsF)
  • reaction of compound of formula (II) and a compound of formula (III) wherein R 10 represents TMS may be effected in a solvent such as DMF in the presence of excess (5 equivalents) lithium fluoride (LiF) or caesium carbonate (Cs 2 CO 3 ) at a non- extreme temperature, for example, between room temperature and 100 0 C, preferably at room temperature, wherein the compound of formula (III) is present in a large excess (10 equivalents).
  • a solvent such as DMF
  • excess lithium fluoride
  • Cs 2 CO 3 caesium carbonate
  • R 10 represents a trialkylsilyl group
  • the final step may include deprotection using a suitable reagent, for example, when R 10 is TMS it may be removed by treatment with TBAF (tetrabutylammonium fluoride) in tetrahydrofuran.
  • TBAF tetrabutylammonium fluoride
  • R 1 represents a C 3-6 cycloalkyl group, by treatment with an activating agent and 6-amino-4-methyl-1H-2,3-benzoxazin-1-one.
  • an activating agent is thionyl chloride.
  • the reaction is generally effected in the presence of a suitable solvent, for example, dimethylacetamide or dimethylformamide. in the presence of thionyl chloride at a non- extreme temperature.
  • a suitable solvent for example, dimethylacetamide or dimethylformamide.
  • thionyl chloride at a non- extreme temperature.
  • the reaction may be carried out in dimethylacetamide in the presence of thionyl chloride at a temperature of -15 to 25 0 C, such as -5 0 C
  • compounds of formula (IV) may be prepared by reaction of compounds of formula (V):
  • suitable oxidising agents include ozone, potassium permanganate or sodium periodate with a catalytic ruthenium salt.
  • suitable oxidising conditions include bromination followed by treatment with permanganate (see Y.-L.Wu et a/., Tetrahedron Lett., 2002, 43, 2427-2430).
  • Suitable oxidising conditions include osmium tetroxide/terf-butylhydroperoxide, osmium tetroxide/sodium periodate and MoOPH (oxodiperoxymolybdenum-pyridine-hexamethylphosphoric triamide) (as set out in, for example in Oxidations in Organic Chemistry, ACS Monograph 186, M. Hudlicky, 1990).
  • Ozonolysis may be carried out in any suitable solvent, for example methanol or dichloromethane or mixtures of those solvents in a ratio between 100:0 and 0:100. The ozonolysis may take place over a temperature range -78 0 C to 0 0 C.
  • A is -CO-2- furanyl
  • the ozonolysis is optimally carried out in methanol at -78 0 C.
  • a variety of work-up conditions may be used to decompose ozonide intermediates; those work-up conditions include treatment with Me 2 S, Ph 3 P or H 2 O 2 . In this case, dimethylsulphide is preferred.
  • R 1 represents a C 3-6 cycloalkyl group and X' is selected from Br 1 1 and OTf
  • the source of Pd(O) may for example be Pd(OAc) 2 , PdCI 2 (MeCN) 2 , Pd(PPh 3 ) or Pd 2 (dba) 3 .
  • the reaction is carried out in the presence of a phosphine ligand, for example Ph 3 P, (2-furyl) 3 P or (o-tolyl) 3 P.
  • a phosphine ligand for example Ph 3 P, (2-furyl) 3 P or (o-tolyl) 3 P.
  • the reaction is carried out at a temperature in the range of 25 0 C to 140 0 C.
  • the reaction solvent is preferably an aprotic solvent and it may, for example, be selected from toluene, xylene, benzene or DMF.
  • 2-furyl tributylstannane and carbon monoxide
  • palladium acetate palladium acetate
  • triphenylphosphine in toluene at 110 0 C.
  • General conditions for reactions of this type are described in further detail in: J. K. Stille et al., J. Org. Chem., 1990, 55, 3114-3118 and R. Grigg et al., Tetrahedron, 2001, 57, 1347-1359.
  • OTf represents OSO 2 CF 3 , known as triflate.
  • olefinating reagents include Wittig reagents, for example methyltriphenylphosphonium salts. Peterson, Tebbe, Petasis and Lombardo reagents are also suitable. Reactions of this type are described in further detail in: R. C. Hartley et al., J. Chem. Soc, Perkin Trans.
  • a Wittig reaction on compound (VII) may suitably be carried out in a polar solvent, for example a solvent selected from diethylether, tetrahydrofuran, ethylene glycol, dimethylether, diglyme or dioxane, in the presence of a strong base, for example n-BuLi, sec-BuLi, f-BuLi, LDA, LiHMDS, NaHMDS, KHMDS, NaH or KO 1 Bu, at a temperature in the range of -78 0 C to +70 0 C.
  • a polar solvent for example a solvent selected from diethylether, tetrahydrofuran, ethylene glycol, dimethylether, diglyme or dioxane
  • a strong base for example n-BuLi, sec-BuLi, f-BuLi, LDA, LiHMDS, NaHMDS, KHMDS, NaH or KO 1 Bu, at a temperature in the range of -78 0 C to +
  • a Wittig reaction is carried out using methyltriphenyphosphonium bromide in Et 2 O as the solvent with n-BuLi or KO f Bu as the base at a temperature of 0 0 C warming to room temperature.
  • X' is as defined above for compounds of formula (Vl) and M' is MgQ or ZnQ, where Q is Cl, Br or I
  • R 1 represents a C 3-6 cycloalkyl group
  • the compound of formula (IX) can be prepared in situ by reaction of R 1 zinc halide with acryloyl chloride in the presence of a palladium(O) source and can then be further reacted with compounds of formula (VIII) as defined above to afford compound of formula (VII).
  • the reaction is carried out in a polar solvent, for example a solvent selected from tetrahydrofuran and diethylether at a temperature in the range of from -78 0 C to +25 0 C.
  • M' is a magnesium halide
  • the reaction is preferably carried out in the presence of a copper(l) salt.
  • the reaction is carried out with a magnesium bromide reagent in diethylether at -78 0 C in the presence of a CuBrMe 2 S complex.
  • the reaction is particularly suitable for use with compounds of formula (VIII) in which X' is bromine atom.
  • M 1 is a zinc halide
  • the reaction is carried out in the presence of a complex of LiCI and CuCN.
  • the reaction is carried out using a compound of formula (VIII) in which M 1 is ZnQ where Q represents Br in the presence of a 2:1 LiChCuCN complex as well as one equivalent of TMSCI in THF at -78 0 C.
  • the reaction is particularly suitable for use with compounds of formula (VIII) in which X' is a bromine or an iodine atom.
  • the zinc reagent R 1 ZnQ is coupled with acryloyl chloride in the presence of a palladium(O) source such as Pd(OAc) 2 , PdCI 2 (MeCN) 2 , Pd(PPh 3 ) 4 or Pd 2 (dba) 3 with a phosphine ligand such as Ph 3 P, (2-furyl) 3 P or (o-tolyl) 3 P over a temperature range of from -25 0 C to +75 0 C in an ether solvent such as THF, dioxane or ether.
  • a phosphine ligand such as Ph 3 P, (2-furyl) 3 P or (o-tolyl) 3 P
  • Optimal conditions are in THF at 0 0 C.
  • the vinyl ketone (IX) may be isolated or used in situ as described above.
  • R 1 represents a C 3-6 cycloalkyl group using a formaldehyde source such as trioxymethylene, paraformaldehyde or formaldehyde itself along with a secondary amine salt such as dimethylamine hydrochloride or methylanilinium trifluoroacetate.
  • Suitable solvents include THF and dioxane with temperatures in the range O 0 C to 100 0 C.
  • Optimally methylanilinium trifluoroacetate and paraformaldehyde are used in THF with a temperature range 25 0 C to 7O 0 C.
  • the vinyl ketone (IX) generated by this method is isolated before reaction with (VIII) as outlined above.
  • compositions comprising a compound of the invention also constitute an aspect of the invention.
  • Solvates of compounds of formula (I), or physiologically functional derivatives thereof or salts thereof, which are not physiologically acceptable may be useful intermediates in the preparation of other compounds of formula (I) or physiologically functional derivatives or salts thereof.
  • Compounds of the invention may be expected to demonstrate good anti-inflammatory properties. They also may be expected to have an attractive side-effect profile, demonstrated, for example, by increased selectivity for glucocorticoid receptor mediated transrepression over transactivation and are expected to be compatible with a convenient regime of treatment in human patients.
  • Solvents A: 0.1% Formic Acid + IOmMolar Ammonium Acetate. B: 95% Acetonitrile + 0.05% Formic Acid
  • Mass Spectra The mass spectra were recorded on Waters Micromass ZQ spectrometer using electrospray positive and negative ionisation modes (ES+ve and ES-ve).
  • Circular Dichroism Circular dichroism was carried out on a Jasco Spectrophotometer Model J-720 at room temperature in MeCN as a solvent in the range 350 - 200 nm
  • NMR 1 H NMR spectra were obtained in CDCI 3 on a Bruker DPX 400 spectrometer working at 400.13 MHz and 9.4 Tesla using as internal standard the signal from the residual protonated solvent at 7.25 ppm.
  • Mass Directed Autoprep Purification was carried out using a Waters Micromass ZQ platform (ES + and ES " ionisation) and a Supelcosil ABZ+plus column of internal diameter 10 cm x 21.2 mm with particle size 5 ⁇ m.
  • Solvents A Water + 0.1 % formic acid
  • B MeCN:water 95:5 + 0.05% formic acid
  • Method A is the process for the conversion of 2-iodophenylalkyl ketone such as Intermediate 1 into a keto-amide such as Intermediate 5 via a four stage process.
  • the four stages are firstly a methylenation, then a "one pot" palladium based cyclisation, carbonylation and furylation, followed by ozonolysis with a basic work-up and finally amide formation.
  • cyclopentylzinc bromide 25 mL, 0.5 M in THF, 12.5 mmoles
  • tetrakis(triphenylphosphine) palladium(O) 145 mg, 0.125 mmoles, 1 mol%)
  • acryloyl chloride 1.1 mL, 13.5 mmoles
  • 6-amino-4-methyl- 1H-2,3-benzoxazin-1-one (127 mg, 0.72 mmole) was added in dimethylacetamide (3 mL) and the solution became dark brown. The ice-methanol bath was removed and stirring was continued for 4 hours. The reaction was then partitioned between 2 M HCI (60 mL) and DCM (60 mL). The aqueous layer was then extracted with a further portion of DCM (30 mL). The combined organic extracts were dried over magnesium sulfate and the solvent removed under vacuum to give a crude product.
  • CF 3 SiMe 3 (55 ⁇ l_, 0.372 mmol) was then added. After approximately 16 hours stirring at 25 0 C under nitrogen, the reaction mixture was partitioned between 1 M HCI (50 mL) and DCM (30 mL). The aqueous layer was extracted with a further portion of DCM (30 mL). The DCM extracts were dried on sodium sulfate and the solvent was removed to give a crude product.
  • Example 1 The reaction product Example 1 was purified by chromatography on silica, eluting with (1) cyclohexane-ethyl acetate 15% and then (2) cyclohexane-ethyl acetate 20% to give recovered starting material, diastereomer D2 (Example 1a) and diastereomer D1 (in order of elution).
  • Diastereomer D2 and diastereomer D1 i.e. isomers D2E1/D2E2 and D1 E1/D1E2 respectively
  • diastereomer D2 was contaminated with starting material that necessitated repeated purification.
  • the final distribution of products was: starting material (3 mg, 9%); diastereomer D1 , (4.7 mg, 13%) and diastereomer D2 (Example 1a) (6.2 mg, 17%).
  • Example 1a was further preparatively separated into its enantiomers (isomers D2E1 and D2E2) using a 2 x 25cm Chiralpak AD column eluting with 5% EtOH in heptane with a flow rate of 15 mL/min.
  • Enantiomer 1 i.e. isomer D2E1
  • Example 1b Enantiomer D2E2
  • Racemic diastereomer D1 i.e. Racemic mixture of isomers D1E1 and D1E2 of 2-K1 -cvclopentyl-1.2.3.4-tetrahvdro-1 -naphthalenyl)methyl1-3,3,3-trifluoro-2-hvdroxy-N-(4- methyl-1 -oxo-1 H-2,3-benzoxazin-6-vPpropanamide
  • LCMS t ret 3.87 min; 515 (MH) + ; 532 (MNH 4 ) + ; 513 (MH)
  • 1 H-NMR ⁇ H (CDCI 3 , 400 MHz) 8.27 (d, 1 H), 8.13 (br.
  • 1 H-NMR ⁇ 5 H (CDCI 3 , 400 MHz) 8.98 (br.
  • Diastereomer 2 enantiomer 1 i.e. Isomer D2E1 of 2-r(1-cvclopentyl-1,2,3,4-tetrahvdro-1-naphthalenyl)metrivn-3,3,3- trifluoro-2-hydroxy-N-(4-methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide
  • Analytical chiral HPLC 25 x 0.46 cm Chiralpak AD column, 5% EtOH in heptane eluting at 1 mL/min) retention time 14.2 min.
  • Example 1b (Diastereomer 2 enantiomer 2) i.e. Isomer D2E2 of 2-f(1 -cyclopentyl-1 ,2,3,4-tetrahydro-1 -naphthalenyl)methvn-3,3,3-trifluoro-2-hvdroxy-N-(4- methyl-1 -oxo-1 H-2,3-benzoxazin-6-yl)propanamide Analytical chiral HPLC (25 x 0.46 cm Chiralpak AD column, 5% EtOH in heptane eluting at 1 mL/min) retention time 18.3 min.
  • the compounds of Examples 1a and 1b are binders and agonists of the glucocorticoid receptor.
  • Example 2-D1 was separated into its enantiomers using a 2 x 25 cm Chiralpak AD column eluting with 5% EtOH in heptane with a flow rate of 15 mL/min.
  • Example 2-D1E1 (enantiomer 1 of diastereomer 1) Analytical chiral HPLC (25 x 0.46 cm Chiralpak AD column, 5% EtOH in heptane eluting at 1 ml_/min) retention time 11.9 min.
  • Example 2-D1E2 (enantiomer 2 of diastereomer 1) Analytical chiral HPLC (25 x 0.46 cm Chiralpak AD column, 5% EtOH in heptane eluting at 1 mL/min) retention time 14.9 min.
  • Example 2-D2 was separated into its enantiomers using a 2 x 25 cm Chiralpak AD column eluting with 5% EtOH in heptane with a flow rate of 15 mL/min.
  • Example 2-D2E1 enantiomer 1 eluted around 19.7 min (0.3 mg) and
  • Example 2-D2E2 enantiomer 2 eluted around 22.2 min (0.4 mg).
  • Example 2-D2E1 (enantiomer 1 of diastereomer 2) Analytical chiral HPLC (25 x 0.46 cm Chiralpak AD column, 5% EtOH in heptane eluting at 1 mL/min) retention time 14.2 min.
  • Example 2-D2E2 (enantiomer 2 of diastereomer 2) Analytical chiral HPLC (25 x 0.46 cm Chiralpak AD column, 5% EtOH in heptane eluting at 1 mL/min) retention time 18.3 min.
  • Example 3 2-f (1 -cvcloproDyl-1.2.3.4-tetrahvdro-1 -naphthale ⁇ v ⁇ methvn-S.S.S-trifluoro ⁇ -hvdroxy-A/- ⁇ - methyl-1 -oxo-1 H-2.3-benzoxazin-6-yl)propanamide
  • Cesium fluoride (36.5 mg, 2.4 mmoles) was dried at 12O 0 C for 1 hour then suspended in dry DMF (0.5 mL) and 3-(1-cyclopropyl-1 ,2,3,4-tetrahydro-1-naphthalenyl)-A/-(4-methyl-1- oxo-1 /-/-2,3-benzoxazin-6-yl)-2-oxopropanamide (Intermediate 8) (50 mg, 0.12 mmole) was added.
  • Example 3-D2 (racemic diastereomer 2) LCMS: t ret 3.67 min; 487 (MH) + ; 485 (MH) " 1 H-NMR: ⁇ H (CDCI 3 , 400 MHz) 8.98 (s, 1H), 8.35 (m, 2H), 7.69 (dd, 1H), 7.25 (m, 4H), 2.97-2.75 (m, 5H), 2.6 (s, 3H), 2.20 (m, 1H), 1.87 (m, 1H), 1.78 (m, 2H), 0.9 (m, 1H), 0.38 (m, 2H), 0.12 (m, 1H), -0.33 (m, 1 H)
  • Example 3-D2 was separated into its enantiomers using a 2 x 25 cm Chiralpak AD column eluting with 10% EtOH in heptane with a flow rate of 15 mL/min.
  • Example 2-D2E1 enantiomer 1
  • Example 3-D2E2 enantiomer 1 e
  • Example 4-D2 was separated into its enantiomers using a 2 x 25 cm Chiralpak AD column eluting with 5% EtOH in heptane with a flow rate of 15 mL/min.
  • Example 3-D2E1 enantiomer 1
  • Example 3-D2E2 enantiomer 2
  • Example 3-D2E2 was further purified by preparative TLC eluting with cyclohexane:EtOAc 3:1 to give a final yield of 1.3 mg.
  • Example 5 24(1 -cvclohexyl-1 ,2.3.4-tetrahvdro-1 -naDhthalenv ⁇ methyll-3,3,3-trifluoro-2-hvdroxy- ⁇ /-(4- methyl-1 -oxo-1 /-/-2,3-benzoxazin-6-yl)propanamide
  • Cesium fluoride (26.5 mg, 174 ⁇ moles) was dried in a round bottomed flask at 12O 0 C for 2 hours. The flask was filled with nitrogen and cooled to room temperature.
  • Example 5-D2 (racemic diastereomer 2) LCMS: t ret 4.10 min; 529 (MH) + ; 527 (MH) " 1 H-NMR: ⁇ H (CDCI 3 , 400 MHz) 8.97 (s, 1H), 8.32 (d, 1H), 8.27 (s, 1H), 7.68 (dd, 1H), 7.38 (d, 1H), 7.28 (m, 1H), 7.22 (m, 2H), 3.09 (d, 1 H), 2.85 (s, 1H), 2.72 (m, 2H), 2.61 (m, 4H), 2.01-1.42 (m, 5H, excess), 1.32-0.95 (m, 10H)
  • Example 5-D2 (10.5 mg) was separated into its enantiomers using a 2 x 25 cm Chiralpak AD column eluting with 10% EtOH in heptane with a flow rate of 15 mL/min.
  • Example 4- D2E1 (enantiomer 1) eluted around 8.4 min (
  • Glucocorticoid receptor binding assay The ability of compounds to bind to the glucocorticoid receptor was determined by assessing their ability to compete with fluorescent-labelled glucocortioid using a kit supplied by Pan Vera (Madison, Wl, USA). Compounds were solvated and diluted in DMSO, and transferred directly into assay plates. Fluorescent glucocortioid and partially purified glucocorticoid receptor were added to the plates and incubated at 4°C for 16 hours in the dark. Binding of the compound was assessed by analysing the displacement of fluorescent ligand by measuring the decrease in fluorescence polarisation signal from the mixture.
  • the plC 50 values for compounds of Examples 1-D1 , 1a-D2, 1b-D2E2, 2-D1 , 2-D2, 2- D1 E2, 2-D2E2, 3-D1, 3-D2, 3-D2E2, 4-D1, 4-D2, 4-D2E2, 5-D1 , 5-D2 and 5-D2E2 are > 7 for the glucocorticoid receptor binding assay.
  • Human A549 lung epithelial cells were engineered to contain a secreted placental alkaline phosphatase gene under the control of the distal region of the NFkB dependent ELAM promoter as previously described in Ray, KP. , Farrow, S., Daly, M., Talabot, F. and Searle, N. "Induction of the E-selectin promoter by interleukin 1 and tumour necrosis factor alpha, and inhibition by glucocorticoids" Biochemical Journal. 1997 328 707-15.
  • the plC 50 values for the diastereomers Examples 3-D2, 4-D2 and 5-D2 and for the single enantiomers Examples 3-D2E2, 4-D2E2 and 5-D2E2 are > 7.5 Examples 1a-D2 and 3-D2 and for the single enantiomer Examples 1b-D2E2, 2-D2E2 and 5-D2E2 are >8 for the NFkB assay.
  • Glucocorticoid mediated Transactivation of MMTV driven gene expression Human A549 lung epithelial cells or human MG63 osteosarcoma were engineered to contain a renilla luciferase gene under the control of the distal region of the LTR from the mouse mammary tumour virus as previously described (Austin, R.H., Maschera, B., Walker, A., Fairbairn, L., Meldrum, E., Farrow, S. and Uings, I.J. Mometasone furoate is a less specific glucocorticoid than fluticasone propionate. European Respiratory Journal 2002 20 1386-1392).
  • Diastereomer Examples 1a-D2 and 2-D2 and enantiomer Examples 1 b-D2E2 and 2-D2E2 have reduced efficacy in both A549 and MG63 cell lines.

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Abstract

L'invention concerne des composés représentés par la formule (I), dans laquelle R1 représente un groupe cycloalkyle C3-6 ou un dérivé physiologiquement fonctionnel de celui-ci. Par ailleurs, l'utilisation concerne des composés utilisés dans la fabrication de médicaments destinés particulièrement au traitement des états inflammatoires et/ou allergiques; des procédés de préparation de ces composés; ainsi que des intermédiaires chimiques utilisés dans les procédés de fabrication de ces composés.
PCT/EP2005/006762 2004-06-28 2005-06-22 Oxazines substituees utilisees comme modulateurs du recepteur glucocorticoide Ceased WO2006000401A1 (fr)

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WO2012123311A1 (fr) 2011-03-11 2012-09-20 Glaxo Group Limited Dérivés pyrdinyl- et pyrazinyl-méthyloxy-aryle utiles en tant qu'inhibiteurs de la tyrosine kinase de la rate (syk)
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