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  • C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
  • C07C255/34—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring with cyano groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by unsaturated carbon chains
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  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C17/00—Preparation of halogenated hydrocarbons
  • C07C17/26—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton
  • C07C17/263—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by condensation reactions
  • C07C17/2635—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by condensation reactions involving a phosphorus compound, e.g. Wittig synthesis
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  • C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
  • C07C255/33—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring with cyano groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by saturated carbon chains
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  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
  • C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
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  • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
  • C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
  • C07C45/30—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation with halogen containing compounds, e.g. hypohalogenation
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  • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
  • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
  • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
  • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
  • C07C45/69—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by addition to carbon-to-carbon double or triple bonds
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  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C47/00—Compounds having —CHO groups
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  • C07C47/26—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms containing hydroxy groups
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  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
  • C07C49/20—Unsaturated compounds containing keto groups bound to acyclic carbon atoms
  • C07C49/227—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing halogen
  • C07C49/233—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing halogen containing six-membered aromatic rings
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  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
  • C07C49/20—Unsaturated compounds containing keto groups bound to acyclic carbon atoms
  • C07C49/227—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing halogen
  • C07C49/237—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing halogen containing six-membered aromatic rings and other rings
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  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
  • C07C57/46—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings and other rings, e.g. cyclohexylphenylacetic acid
  • C07C57/50—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings and other rings, e.g. cyclohexylphenylacetic acid containing condensed ring systems
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  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
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  • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
  • C07D303/02—Compounds containing oxirane rings
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  • C07C2602/00—Systems containing two condensed rings
  • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
  • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
  • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

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; and 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.
• Glucocorticoids are especially useful in disease states involving systemic inflammation such as inflammatory bowel disease, systemic lupus erythematosus, polyarteritis nodosa,
• 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 and cutaneous
• WO05/003098 and WO05/030213 disclose certain non-steroidal glucocorticoid receptor modulators.
• the present invention provides compounds of formula (I):
• R represents a methyl or an ethyl group
• X represents N, C-H or C-CH 3 when X represents C-H or C-CH 3
• Y represents N when X represents N
• Y represents C-H
• R represents methyl.
• R represents ethyl.
• X represents C-H and Y represents N. In a further embodiment of the invention X represents C-CH 3 and Y represents N.
• X represents N and Y represents C-H.
• 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 glucocorticoid 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).
• D1 refers to the first diastereomer to elute
• D2 refers to the second diastereomer to elute.
• D1 E1 , D1 E2, 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
• 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 D1.
• the compound of formula (I) is the diastereomer D1.
• a single isomer may be preferred, for example the isomer D1 E1 or the isomer D1 E2. Therefore, in one embodiment of the invention the compound of formula (I)
• (I) is the enantiomer D1 E1.
• the compound of formula (I) is the enantiomer D1 E2.
• Diastereomer D1 is characterised by having a retention time of about 3.07 min when eluted using the chromatography methodology described herein (LCMS).
• diastereomer D2 has a retention time of about 3.11 min under the same conditions.
• isomer D1 is characterised by having a retention time of about 3.07 min when eluted using the chromatography methodology described herein (LCMS).
• LCMS chromatography methodology described herein
• diastereomer D2 has a retention time of about 3.11 min under the same conditions.
• Compounds of the invention which are of more particular interest include: 1 ,1 ,1 -Trifluoro-3-(1 -methyl-1 ,2,3,4-tetrahydro-1 -naphthalenyl)-2-[(5-quinolinylamino) methyl]-2-propanol D1 E1 ; 1 ,1 ,1 -Trif luoro-3-[(2-methyl-5-quinolinyl)amino]-2-[(1 -methyl-1 ,2,3,4-tetrahydro-1 - naphtha ( enyl)methyl]-2-propanol D1 E1 ;
• 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 invention includes physiologically functional derivatives of the compounds of formula (I).
• physiologically functional derivative a chemical derivative of a compound of formula (I) having the same physiological function as the free compound of formula (I), 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.
• 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 human or veterinary medicine, particularly 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 diseases 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.
• Formulations for administration topically to the nose for example, for the treatment of rhinitis include pressurised aerosol formulations and aqueous formulations administered to the nose by pressurised pump. Formulations which are non-pressurised and adapted to be administered topically to the nasal cavity are of particular interest. Suitable formulations contain water as the diluent or carrier for this purpose. Aqueous formulations for administration to the lung or nose may be provided with conventional excipients such as buffering agents, tonicity modifying agents and the like. Aqueous formulations may also be administered to the nose by nebulisation.
• the compounds of the invention may be formulated as a fluid formulation for delivery from a fluid dispenser, for example a fluid dispenser having a dispensing nozzle or dispensing orifice through which a metered dose of the fluid formulation is dispensed upon the application of a user-applied force to a pump mechanism of the fluid dispenser.
• a fluid dispenser for example a fluid dispenser having a dispensing nozzle or dispensing orifice through which a metered dose of the fluid formulation is dispensed upon the application of a user-applied force to a pump mechanism of the fluid dispenser.
• Such fluid dispensers are generally provided with a reservoir of multiple metered doses of the fluid formulation, the doses being dispensable upon sequential pump actuations.
• the dispensing nozzle or orifice may be configured for insertion into the nostrils of the user for spray dispensing of the fluid formulation into the nasal cavity.
• a fluid dispenser of the aforementioned type is described and illustrated in WO05/044354, the entire content of which is hereby
• the dispenser has a housing which houses a fluid discharge device having a compression pump mounted on a container for containing a fluid formulation.
• the housing has at least one finger-operable side lever which is movable inwardly with respect to the housing to cam the container upwardly in the housing to cause the pump to compress and pump a metered dose of the formulation out of a pump stem through a nasal nozzle of the housing.
• the fluid dispenser is of the general type illustrated in Figures 30-40 of WO05/044354.
• 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.
• a pharmaceutical aerosol formulation comprising a compound of formula (I) and a fluorocarbon or hydrogen-containing chlorofluorocarbon as propellant, optionally in combination with a surfactant and/or cosolvent.
• a pharmaceutical formulation wherein the propellant is selected from 1 ,1 ,1 ,2-tetrafluoroethane, 1 ,1 ,1 ,2,3,3,3-heptafluoro-n-propane and mixtures thereof.
• 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 20 ⁇ g-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, m ore p referably about 20 ⁇ g to 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.
• 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 - adrenoreceptor 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 combinations comprising 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 f?-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.
• salmeterol e.g. as racemate or a single enantiomer such as the f?-enantiomer
• salbutamol formoterol
• salmefamol salmefamol
• fenoterol terbutaline
• 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.
• Examples of long acting ⁇ 2 -adrenoreceptor agonists 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.
• Suitable long-acting ⁇ 2 -adrenoreceptor agonists include compounds of formula (XX): or a salt or solvate thereof, wherein: 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, Ci -6 alkyl, C 3-7 cycloalkyl,
• R 26 and R 27 are each optionally substituted by one or two groups selected from halo, C-
• R 28 and R 29 are independently selected from hydrogen, C 1-6 alkyl,
• R 22 and R 23 are independently selected from hydrogen, Ci. 6 alkyl, C 1-6 alkoxy, halo, phenyl, and C 1-6 haloalkyl;
• R 24 and R 25 are independently selected from hydrogen and C 1-4 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:
• Suitable anti-inflammatory agents include non-steroidal anti-inflammatory drugs (NSAID'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) or inhibitors of cytokine synthesis, or 5-lipoxygenase inhibitors.
• PDE phosphodiesterase
• leukotriene antagonists inhibitors of leukotriene synthesis (e.g. montelukast), iNOS inhibitors, tryptase
• iNOS inducible nitric oxide synthase inhibitor
• 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-dif luoromethoxyphenyl)cyclohexan-1 -one and c/s-[4-cyano-4-(3- cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol].
• 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
• 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). Also of interest are revatropate (e.g. as the hydrobromide, CAS 262586-79-8) and 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 60/487981 :
• 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:
• anticholinergic agents include compounds of formula (XXH) 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 sleeted from the group consisting of (Ci-C 6 )alkyl, (C 3 -Ci 2 )cycloalkyl, (C 3 - C 7 )heterocycloalkyl, (C 1 -C 6 )alkyl(C 3 -C 12 )cycloalkyl, (Ci-C
• R 45 is selected from the group consisting of (CrC 6 )alkyl, (C r C 6 )alkyl(C 3 -Ci 2 )cycloalkyl, (CrC 6 )alkyl(C 3 -C 7 )heterocycloalkyl, (C r C 6 )alkyl-aryl, (C r C 6 )alkyl-heteroaryl;
• R 46 is selected from the group consisting of (CrC6)alkyl, (C 3 -Ci 2 )cycloalkyl, (C 3 -
• R 47 and R 48 are, independently, selected from the group consisting of H, (CrC 6 )alkyl, (C 3 - C 12 )cycloalkyl, (C 3 -C 7 )heterocycloalkyl, (C r C 6 )alkyl(C 3 -C 12 )cycloalkyl, (C r C 6 )alkyl(C 3 - C 7 )heterocycloalkyl, (CrC 6 )alkyl-aryl, and (C r C 6 )alkyl-heteroaryl, including, for example: (Endo)-3-(2-methoxy-2,2-di-thiophen-2-yl-ethyl)-8,8-dimethyl-8-azonia- bicyclo[3.2.1]octane iodide;
• Suitable antihistamines include any one or more of the numerous antagonists known which inhibit H1 -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.
• anti-histamines examples include loratidine, desloratidine, fexofenadine and cetirizine.
• 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.
• 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 D1 E1 of the compound of formula (I) wherein the group R represents ethyl, X represents C-CH 3 and Y represents N is characterised in having a retention time in analytical chiral HPLC on a 25 x 0.46 cm Chiralcel OJ column using a mobile phase of
• Isomer D1 E2 of the compound of formula (I) wherein the group R represents ethyl, X represents C-CH 3 and Y represents N has a retention time of about 7.83 min under the same conditions.
• Preferred isomers of the compound 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 D1 ).
• a mixture of enantiomeric isomers e.g. a racemic mixture, such as a diastereomer D1
• D1 E1 of a compound of formula (I) e.g. a racemic mixture, such as diastereomer D1
• a mixture (e.g. racemic mixture) of enantiomeric isomers D1 E1 and D1 E2 may be prepared by chromatographic separation from a mixture of isomers D1 E1 , D1 E2, D2E1 and D2E2.
• 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 first process (A) according to the invention for the preparation of compounds of formula (I) comprises reaction of an epoxide of formula (II):
• R represents a methyl or an ethyl group.
• reaction will generally be performed in the presence of an inert solvent, such as N, N- dimethylformamide (DMF) and a base, such as potassium-f-butoxide, at a non-extreme temperature, for example, 0-120 0 C, and more suitably at room temperature.
• an inert solvent such as N, N- dimethylformamide (DMF)
• a base such as potassium-f-butoxide
• R represents a methyl or ethyl group
• sulphur ylides such as dimethylsulphonium methylide or more preferably dimethyloxosulphonium methylide.
• the latter is conveniently generated in situ from trimethyisulphoxonium iodide and sodium hydride in DMSO.
• R represents a methyl or ethyl group
• Oxidation of compounds of formula (V) to the ketones of formula (IV) may be performed by methods detailed in Oxidations in Organic Chemistry" M. Hudlicky, ACS, 1990 pp77- 84.
• ozonolysis is performed in an alcoholic solvent at a non-extreme temperature of -78 to 25 0 C and worked up with a reducing agent.
• the ozonolysis is carried out in methanol at -78 0 C and worked up with dimethyl sulphide.
• Compounds of formula (V) may be prepared by coupling a compound of formula (Vl):
• R represents a methyl or ethyl group
• Conversion of a compound of formula (Vl) into a compound of formula (V) may be performed using a palladium derivative as catalyst, a phosphine derivative as a ligand and a trialkyl[1-trifluomethyl)ethenyl]stannane in the presence of a copper(l) salt in an inert solvent at a non-extreme temperature of 25 - 150 0 C.
• the preferred conditions are palladium acetate, triphenyl phosphine, tri-n-butyl[1-trifluomethyl)ethenyl]stannane (VII), copper(l) iodide in N,N-dimethyl formamide at 110 0 C.
• Analogues of compounds of formula (Vl) may also be employed in which the iodine is replaced with another leaving group e.g. bromine or triflate.
• R represents a methyl or ethyl group.
• Suitable 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 1 (2002) 2763-2793 and Tetrahedron Left (1985) 26: 5579-5580.
• a Wittig reaction on compound (VIII) may be carried out in a polar solvent such as diethylether, tetrahydrofuran, ethylene glycol, dimethylether, diglyme or dioxane, in the presence of a strong base, for example ⁇ -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 strong base for example ⁇ -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 Wittig reaction is carried out using methyltriphenyphosphonium bromide in diethyl ether as the solvent with n-butyl lithium or potassium f-butoxide as the base at a temperature of 0 0 C warming to room temperature.
• X' is Br, I or OTf where OTf is trifluomethanesulphonate and M is MgQ or ZnQ, where Q is Cl, Br or I.
• R represents a methyl or ethyl group.
• the reaction is carried out in a polar solvent such as tetrahydrofuran and diethylether at a temperature in the range of -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 preferably carried out with a magnesium bromide reagent in diethylether at -78 0 C in the presence of a CuBr. Me 2 S complex.
• the reaction is particularly suitable for use with compounds of formula (IX) in which X' is bromine atom.
• the reaction is preferably carried out in the presence of a complex of LiCI and CuCN.
• the reaction is preferably carried out using a compound of formula (IX) in which M is ZnQ where Q represents Br in the presence of a 2:1 LiCI.OuCN 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 (IX) in which X' is a bromine or an iodine atom.
• X' is I and ZnQ is ZnBr.
• the trifluoromethyl ketone intermediate of formula (IV) may alternatively be prepared from a compound of formula (Xl):
• R represents a methyl or ethyl group.
• a compound of formula (Xl) may be converted to the corresponding acid chloride by treatment with oxalyl chloride or thionyl chloride in the presence of a catalytic amount of N,N-dimethyl formamide in an inert solvent such as toluene or dichloromethane at a non-extreme temperature between 0 to 11O 0 C.
• Oxalyl chloride in toluene with a catalytic amount of dimethyl formamide at room temperature is preferred.
• the crude acid chloride may then be treated with an organic base such as pyridine and a trifluoroacetylating reagent such as trifluoroacetic anhydride in an inert solvent such as dichloromethane at a non-extreme temerature of 0 to 4O 0 C to afford the compound of formula (IV).
• organic base such as pyridine
• a trifluoroacetylating reagent such as trifluoroacetic anhydride in an inert solvent such as dichloromethane at a non-extreme temerature of 0 to 4O 0 C to afford the compound of formula (IV).
• the preferable conditions are pyridine and trifluoroacetic anhydride in dichloromethane at room temperature.
• compounds of formula (IV) may be prepared in a two stage process by conversion of compounds of formula (Xl) into its corresponding ester followed by conversion of the ester into (IV).
• conversion of an acid into its ester including those described in "Comprehensive Organic Transformations" R. C. Larock, VCH, 1989, pp966 - 972.
• the methyl ester is used and is prepared by treatment of a compound of formula (Xl) with methyl iodide and anhydrous potassium carbonate in acetone at room temperature.
• the ester is converted into a compound of formula (IV) by treatment with a solution of trifluoromethane in the presence of strong base in dry dimethyl formamide at -30 to +10 0 C.
• the strong base is potassium bis(trimethylsilyl)amide and the temperature is -10 0 C.
• the second variant the two stage process for the preparation of a compound of formula (IV) from a compound of formula (Xl), is preferred.
• R represents a methyl or ethyl group.
• the hydrolysis may be carried out in the presence of an inorganic base in solvent(s) including alcohols and water at a non-extreme temperature from 50 to 200 0 C.
• solvent(s) including alcohols and water
• the hydrolysis is performed using potassium hydroxide as base in a water/ethylene glycol mixture at reflux.
• Decarboxylation of the resultant product can be achieved thermally by heating in the presence or absence of a high boiling solvent at a non-extreme temperature of 100 to 200 0 C. Heating in diethyl glycol at 130 0 C is preferred.
• Conjugate addition of nucleophiles to the compound of formula (XIII) may be achieved by many methods including those detailed in "Organometallics in Synthesis” M. Schlosser (editor), Wiley 1994 pp283-376.
• the Grignard reagent is added to copper(l) fodide in an inert solvent such as diethyl ether or tetrahydrofuran and then compound (VIII) added at a non extreme temperature of -20 to 65 0 C.
• tetrahydrofuran is the solvent and the reaction is performed at O 0 C until all the reagents are combined and then at reflux.
• the compound of formula (XIII), 3,4-dihydro-1 (2H)-naphthalenylidenepropanedinitrile may be prepared from commercially available ⁇ -tetralone as described in the literature (see, for example, Russian Chemical Bulletin (Translation of Izvestiya Akademii Nauk, Seriya Khimicheskaya) 2003 52(10): 2235-2240).
• a second process (B) according to the invention for the preparation of compounds of formula (I) comprises reduction of a Schiff's base of formula (XIV):
• Reduction may be achieved by treatment with a variety of reducing agents such as sodium cyanoborohydride or sodium triacetoxyborohydride in a suitable solvent, for example, acetic acid.
• reducing agents such as sodium cyanoborohydride or sodium triacetoxyborohydride in a suitable solvent, for example, acetic acid.
• R represents a methyl or ethyl group with a quinolinamine or isoquinolinamine of formula (III).
• This reaction may be effected in a suitable solvent, such as acetic acid and may be facilitated by conducting the reaction in a microwave reactor.
• a suitable solvent such as acetic acid
• the Schiff's base (XIV) may be isolated from this reaction but may also be reduced in situ to give compound of formula (I) directly.
• R represents a methyl or ethyl group.
• Oxidation may be achieved using, for example, pyridine sulphur trioxide complex in DMSO in the presence of triethylamine.
• Compounds of .formula (XVI) may be prepared by dihydroxylation of compounds of formula (V) for example using potassium permanganate, osmium tetroxide or asymmetric dihydroxylation reagents such as AD-mix ⁇ and ⁇ as described by Sharpless in J Org Chem, 1992, 2768-2771.
• compositions comprising a compound of the invention also constitute an aspect of the invention.
• 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.
• LCMS spectra were recorded on an Hewlett-Packard 1050 or 1100 LC system and a Waters ZQ mass spectrometer with ES + and ES " ionisation, a 3 ⁇ m ABZ+PLUS 3.3cm x 4.6mm ID column was used at a flow rate of 3ml/min and injection volume of 5//I with the following gradient.
• Solvent A 0.1% Formic Acid + IOmMolar Ammonium Acetate: Solvent B: 95% Acetonitrile + 0.05% Formic Acid Gradient: Time A% B%
• Detection by UV was in the range 215 to 330nm using Sedere Sedex 55 at 40 0 C and a nitrogen gas flow at 2.2bar.
• LCUV analysis was performed using an Hewlett-Packard 1050 with a 30min gradient, a 3 ⁇ m ABZ+PLUS column with dimensions 3.3cm x 4.6mm ID was used with a 1 ml/min flow rate and injection volume of 5//I,with the following gradient:
• Solvent A 0.1% Formic Acid + IOmMolar Ammonium Acetate: Solvent B: 95% Acetonitrile + 0.05% Formic Acid
• Autop reparative HPLC was carried out using a Waters 600 gradient pump, Waters 2767 inject/collector, Waters Reagent Manager, Micromass ZMD mass spectrometer, Gilson Aspec waste collector and Gilson 115 post-fraction UV detector.
• the column used was typically a Supelco LCABZ++ column with dimension of 20mm internal diameter by 100mm in length.
• the stationary phase particle size is 5 ⁇ m.
• the flow rate was 20ml/min and the runtime was 15 minutes, which comprises a 10-minute gradient followed by a 5 minute column flush and re-equilibration step.
• Organic solvent MeCN: water 95:5 +0.05% formic acid
• Microwave reactions were conducted using a Smith Creator 300 watt monomode microwave reactor.
• the flask was cooled to -1O 0 C and the lithium tri-n-butylstannane solution was then transferred dropwise via a syringe to the copper(l)iodide suspension.
• the mixture was stirred at -10 0 C for 0.5h, cooled to -78 0 C then treated dropwise with 2-bromotrifluoropropene (1.32g, 7.5 mmole). Stirring was continued for a further 0.5h followed by 1 h at room temperature. Volatiles were removed in vacuo and the residue was dissolved in ether (100ml), filtered and the solvent was removed to give an oil. Purification was by distillation.
• AD-mix ⁇ (1 Og), AD-mix ⁇ (1 Og), f-butanol (20ml) and water (20ml) were added and stirring continued for 22h.
• the solid was filtered off and washed with ether (3x50ml), more ether (200ml) was added to the filtrate, which was then carefully added to aqueous sodium metabisulphite solution (300ml) and stirred for 10min, when effervescence had ceased.
• the layers were separated and the aqueous layer was re-extracted with ether (200ml).
• the crude product was purified on a 5g silica Bond Elut cartridge eluting with 1 :1 cyclohexane:dichloromethane followed by a 10:1 to 3:1 gradient of cyclohexane:ethyl acetate to give the title compound (177mg, 60%).
• the solution was degassed by evacuating and filling the flask with nitrogen four times.
• the solution was then immediately immersed in a 11O 0 C oil bath, left to react for 3.5 h, cooled to room temperature then partitioned between water (100ml) and cyclohexane (100ml). The layers were separated and the aqueous layer was extracted with further cyclohexane (100ml).
• the combined extracts were dried over anhydrous sodium sulphate and evaporated and the residue was applied to a silica Solid Phase Extraction (SPE) cartridge. Elution with cyclohexane gave the title compound (1.36g) containing some residual impurities. This was used without additional purification.
• SPE Solid Phase Extraction
• the crude product was purified on a 5Og silica cartridge using a Flashmaster 2 system with a 0-100% gradient of ethyl acetate in cyclohexane over 40min to give the title compound (74.3mg, 43%) as a mixture of diastereomers.
• Example 1-D1 (racemic diastereomer 1) (10mg) and Example 1-D2 (racemic diastereomer 2) (8.9mg).
• Example 1-D1 (racemic diastereomer 1) was separated into its enantiomers using a 2 x 25 cm Chiralpak AD column eluting with 60% ethanol in heptane with a flow rate of 15 ml/min to yield Example 1 -D1 E1 (enantiomer 1 of diastereomer 1 ) eluting around 3.8 min and Example 1-D1 E2 (enantiomer 2 of diastereomer 1) around 6.8 min.
• Example 1-D1 E1 (enantiomer 1 of diastereomer 1) Analytical chiral HPLC (25 x 0.46 cm Chiralpak AD column, 60% ethanol in heptane eluting at 1 ml/min): retention time 3.14 min. LCMS: MH + 415 19 F-NMR: (CDCI 3 ) -80.31
• the crude product was purified on a 5Og silica cartridge using a Flashmaster 2 system with a 0-100% gradient of ethyl acetate in cyclohexane over 80 min to give the title compound (91.6 mg, 71 %) as a mixture of diastereomers.
• Example 2-D1 (racemic diastereomer 1) (7.1 mg) and Example 2-D2 (racemic diastereomer 2) (5.5mg).
• Example 2-D1 (racemic diastereomer 1) was separated into its enantiomers using a 2 x 25 cm Chiralpak AD column eluting with 40% ethanol in heptane with a flow rate of 15 ml/min to yield Example 2-D1 E1 (enantiomer 1 of diastereomer 1 ) eluting around 3.9 min and Example 2-D1 E2 (enantiomer 2 of diastereomer 1) around 7.5 min.
• Example 2-D1 E1 (enantiomer 1 of diastereomer 1) Analytical chiral HPLC (25 x 0.46 cm Chiralpak AD column, 40% ethanol in heptane eluting at 1 ml/min): retention time 3.22 min. LCMS: MH + 429 19 F-NMR: (CDCI 3 ) -80.37
• Example 2-D2 (racemic diastereomer 2) was separated into its enantiomers using a 2 x 25 cm Chiralpak AD column eluting with 3% ethanol in heptane with a flow rate of 15 ml/min to yield Example 2-D2E1 (enantiomer 1 of diastereomer 2) eluting around 13.3 min and Example 2-D2E2 (enantiomer 2 of diastereomer 2) around 16.7 min.
• Example 3-D2 racemic diastereomer 2
• Example 3-D1 racemic diastereomer 1
• Example 3-D1 (racemic diastereomer 1) was separated into its enantiomers using a 2 x 25 cm Chiralcel OD column eluting with 10% ethanol in heptane with a flow rate of 15 ml/min to yield Example 3-D1 E1 (enantiomer 1 of diastereomer 1 ) eluting around 6.9 min and Example 3-D1 E2 (enantiomer 2 of diastereomer 1 ) around 9.4 min.
• Example 3-D2 (racemic diastereomer 2) was separated into its enantiomers using a 2 x 25 cm Chiralcel OD column eluting with 10% ethanol in heptane With a flow rate of 15 ml/min to yield Example 3-D2E1 (enantiomer 1 of diastereomer 2) eluting around 9.0 min and Example 3-D2E2 (enantiomer 2 of diastereomer 2) around 12.4 min.
• Example 4-D2 (racemic diastereomer 2) (45mg) and Example 4-D1 (racemic diastereomer 1 ) (35mg).
• Example 4-D1 (racemic diastereomer 1)
• Example 4-D1 (racemic diastereomer 1) was separated into its enantiomers using a 2 x
• Example 4-D1 E1 enantiomer 1 of diastereomer 1
• Example 4-D1 E2 enantiomer 2 of diastereomer 1 around 8.1 min.
• Example 5-D1 (racemic diastereomer 1) (8mg).
• Example 5-D1 (racemic diastereomer 1) was separated into its enantiomers using a 2 x 25 cm Chiralcel OJ column eluting with 15% ethanol in heptane with a flow rate of 15 ml/min to yield Example 5-D1 E1 (enantiomer 1 of diastereomer 1 ) eluting around 6 min and Example 5-D1E2 (enantiomer 2 of diastereomer 1) around 9 min.
• This enantiomer was further purified by application to a 2g silica SPE cartridge eluting with heptane followed by 0 to 25% diethylether in cyclohexane gradient.
• Example 5-D2 (racemic diastereomer 2) was separated into its enantiomers using a 2 x 25 cm Chiralpak AD column eluting with 5% ethanol in heptane with a flow rate of 15 ml/min.
• Example 5-D2E1 (enantiomer 1 of diastereomer 2) eluting around 8.5 min and Example 5-D2E2 (enantiomer 2 of diastereomer 2) around 10.5 min.
• 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) or using in house reagents. Compounds were solvated and diluted in DMSO, and transferred directly into assay plates. Fluorescent glucocorticoid and partially purified glucocorticoid receptor with a stabilisation peptide were added to the plates and incubated at 22°C for 2 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 , 1-D1 E1 , 1-D2, 2-D1 , 2D1-E1 , 2-D2, 2-D2E1 , 3-D1 , 3-D1 E2, 3-D2, 3-D2E1 , 3-D2E2, 4-D1 , 4-D1 E2, 4-D2, 5-D1 , 5-D1 E1 , 5-D2, 5-D2E1 , 6-D1 and 6-D2 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, K.P., 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. 1997328 707-15.
• the plCso values for Examples 1-D1, 1-D1 E1 , 2-D1 , 2-D1 E1, 2-D2E1 , 3-D1 , 3-D1 E2, 3- D2E1 , 4-D1 , 4-D1 E2, 5-D1 , 5-D1 E1 and 6-D1 are > 7.5 for the NFkB assay.
• Human A549 lung epithelial cells or human MG63 osteosarcoma were engineered to contain a renialla 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, IJ. Mometasone furoate is a less specific glucocorticoid than fluticasone propionate. European Respiratory Journal 2002 20 1386-1392).

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