WO2009050221A1 - Indazoles en tant que ligands de récepteurs glucocorticoïdes - Google Patents

Indazoles en tant que ligands de récepteurs glucocorticoïdes Download PDF

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Publication number
WO2009050221A1
WO2009050221A1 PCT/EP2008/063926 EP2008063926W WO2009050221A1 WO 2009050221 A1 WO2009050221 A1 WO 2009050221A1 EP 2008063926 W EP2008063926 W EP 2008063926W WO 2009050221 A1 WO2009050221 A1 WO 2009050221A1
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WIPO (PCT)
Prior art keywords
compound
methyl
amino
pharmaceutically acceptable
acceptable salt
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PCT/EP2008/063926
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English (en)
Inventor
Keith Biggadike
Anthony William James Cooper
David House
Iain Mcfarlane Mclay
Simon John Fawcett Macdonald
Philip Alan Skone
Gordon Gad Weingarten
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Glaxo Group Limited
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Publication of WO2009050221A1 publication Critical patent/WO2009050221A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics

Definitions

  • the present invention relates to non-steroidal compounds and a process for their preparation, to pharmaceutical compositions comprising the compounds and the preparation of said compositions, to intermediates, and to use of the compounds for the manufacture of a medicament for therapeutic treatment, particularly for the treatment of inflammation and/or allergic conditions.
  • 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, H.J. & 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 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, vasomotor 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 dermatitis, erythema nodosum, acne, hirsutism, toxic epidermal necrolysis, erythema multiform and cutaneous
  • the present invention provides compounds of formula (I):
  • R 1 and R 2 are each independently hydrogen or methyl; and salts thereof (hereinafter “compounds of the invention”).
  • R 1 and R 2 are both hydrogen. In another embodiment R 1 and R z are both methyl. In a further embodiment R 1 is hydrogen and R 2 is methyl.
  • the compound of formula (I) is: N-(2-amino-2-oxoethyl)-3- ⁇ 6-methyl-4-[(3,3,3-trifluoro-2-hydroxy-2- ⁇ [(1- methylethyl)(2-methylpropanoyl)amino]methyl ⁇ propyl)amino]-1 H-indazol-1- yl ⁇ benzamide;
  • the compounds of the invention may provide agonism of the glucocorticoid receptor.
  • the compounds of formula (I) each contain one or two chiral centre and there are up to 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.
  • modulator is used herein to refer to a compound which may, for example, be an agonist, a partial agonist or antagonist of the glucocorticoid receptor.
  • a modulator of the glucocorticoid receptor may be an agonist of the glucocorticoid receptor.
  • At least one isomer e.g. one enantiomer of the racemate
  • the other isomers may have similar activity, less activity, no activity or may have some antagonist activity in a functional assay.
  • enantiomer A and enantiomer B are used herein to refer to the enantiomers of a compound of formula (I), based on the order of their elution using the chiral chromatography methodology described herein.
  • Enantiomer A refers to the first enantiomer to elute
  • enantiomer B refers to the second enantiomer to elute.
  • diastereomer A and diastereomer B are used herein to refer to the diastereomers of a compound of formula (I) based on their order of elution using the chiral chromatographic methodology described herein.
  • Diastereomer A refers to the first diastereomer to elute
  • diastereomer B refers to the second diastereomer to elute.
  • One embodiment of the invention encompasses a compound of the invention in the form of a single enantiomer or diastereomer or mixture of isomers (e.g. racemic mixture).
  • the compound of the invention is in the form of a diastereomer or a mixture of diastereomers.
  • the compound of the invention is in the form of an enantiomer or a mixture of enantiomers (e.g. racemic mixture).
  • the compound of the invention is diastereomer A.
  • the compound of the invention is diastereomer B.
  • the compound of the invention is enantiomer A.
  • the compound of the invention is enantiomer B.
  • the compounds of the invention may exist in solid or liquid form. In the solid state, the compounds of the invention may exist in crystalline or non crystalline form, or as a mixture thereof.
  • pharmaceutically-acceptable solvates may be formed wherein solvent molecules are incorporated into the crystalline lattice during crystallization. Solvates may involve nonaqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine and ethyl acetate, or they may involve water as the solvent that is incorporated into the crystalline lattice.
  • Hydrates wherein water is the solvent that is incorporated into the crystalline lattice are typically referred to as "hydrates.” Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water. The invention includes all such solvates.
  • polymorphs may exhibit polymorphism (i.e. the capacity to occur in different crystalline structures). These different crystalline forms are typically known as "polymorphs".
  • the invention includes all such polymorphs. Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification.
  • polymorphs may be produced, for example, by changing or adjusting the reaction conditions or reagents, used in making the compound. For example, changes in temperature, pressure, or solvent may result in polymorphs. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions.
  • 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. Another embodiment of the invention embraces compounds of formula (I) and solvates thereof. A further embodiment of the invention embraces compounds of formula (I) as the free base.
  • Salts and solvates of the compounds of formula (I) which are suitable for use in medicine are those wherein the counter-ion or associated solvent is pharmaceutically acceptable.
  • salts and 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 thereof.
  • One embodiment of the invention embraces compounds of formula (I) and pharmaceutically acceptable salts thereof.
  • Suitable salts according to the invention include those formed with both organic and inorganic acids or bases.
  • suitable salts according to the invention are those formed with bases.
  • Pharmaceutically acceptable acid addition salts may include those formed from strong acids, for example hydrochloric, hydrobromic and sulphuric acids, and strong sulphonic acids such as tosic, camphorsulphonic and methanesulphonic acids.
  • Pharmaceutically acceptable base salts include alkali metal salts such as those of sodium and potassium.
  • the compounds of formula (I) and pharmaceutically acceptable salts thereof 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.
  • the compounds of formula (1) and pharmaceutically acceptable salts thereof may be of use in the treatment of inflammatory and/or allergic disorders.
  • inflammatory and/or allergic conditions 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), interstitial lung disease, and
  • rhinitis is used herein to refer to all types of rhinitis including allergic rhinitis such as seasonal rhinitis (for example hayfever) or perennial rhinitis, and non- allergic rhinitis or vasomotor rhinitis.
  • compounds of formula (I) and pharmaceutically acceptable salts thereof are expected to be of use in human or veterinary medicine, in particular as anti-inflammatory and/or anti-allergic agents.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in human or veterinary medicine, particularly in the treatment of inflammatory and/or allergic conditions, such as rheumatoid arthritis, asthma, COPD, allergy and/or rhinitis.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of skin disease such as eczema, psoriasis, allergic dermatitis, neurodermatitis, pruritis and/or hypersensitivity reactions
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of inflammatory and/or allergic conditions, such as rheumatoid arthritis, asthma, COPD, allergy and/or rhinitis
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of skin disease such as eczema, psoriasis, allergic dermatitis, neurodermatitis, pruritis and/or hypersensitivity reactions
  • a method for the treatment of a human or animal subject with an inflammatory and/or allergic condition such as rheumatoid arthritis, asthma, COPD, allergy and/or rhinitis, which method comprises administering to said human or animal subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof
  • a method for the treatment of a human or animal subject with rhinitis comprises administering to said human or animal subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof
  • a method for the treatment of a human or animal subject with skin disease such as eczema, psoriasis, allergic dermatitis, neurodermatitis, pruritis and/or hypersensitivity reactions, which method comprises administering to said human or animal subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the compounds of formula (I) and pharmaceutically acceptable salts thereof may be formulated for administration in any convenient way, and the invention therefore also includes within its scope pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together, if desirable, in admixture with one or more physiologically acceptable diluents or carriers.
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, may be prepared by, for example, admixture at ambient temperature and atmospheric pressure.
  • compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof may be suitable for topical administration (which includes epicutaneous, inhaled, intranasal or ocular administration), enteral administration (which includes oral or rectal administration) or parenteral administration (such as by injection or infusion).
  • topical administration which includes epicutaneous, inhaled, intranasal or ocular administration
  • enteral administration which includes oral or rectal administration
  • parenteral administration such as by injection or infusion
  • the compounds of formula (I) and pharmaceutically acceptable salts thereof may, for example, be formulated for oral, buccal, sublingual, parenteral, local rectal administration or other local administration.
  • compositions may be in the form of, for example, solutions or suspensions (aqueous or non-aqueous), tablet, capsules, oral liquid preparations, powders, granules, lozenges, lotions, creams, ointments, gels, foams, reconstitutable powders or suppositories as required by the route of administration.
  • compositions containing a compound of formula (I) or a pharmaceutically acceptable salt thereof may contain from about 0.1 to about 99%, such as from about 10 to about 60%, by weight based on the total weight of the composition, of the compound of formula (I) or a pharmaceutically acceptable salt thereof, depending on the route of administration.
  • the dose of the compound used in the treatment of the abovementioned disorders will vary in the usual way with the seriousness of the disorders, the weight of the sufferer and other similar factors.
  • suitable unit does may be about 0.001 to about 100mg, for example about 0.001 to about 1 mg, and such unit doses may be administered more than once a day, for example two or three times a day. Such therapy may extend for a number of weeks or month.
  • the compounds of formula (I) and pharmaceutically acceptable salts thereof 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 (for example eye or nose drops), solutions/suspensions for nebulisation, suppositories, pessaries, retention enemas and chewable or suckable tablets or pellets (for example for the treatment of aphthous ulcers) or liposome or microencapsulation preparations.
  • the proportion of the active compound of formula (I) or a pharmaceutically acceptable salt thereof in the local compositions according to the invention depends on the precise type of composition to be prepared, and the route of administration, but will generally be within the range of from 0.001 to 10% by weight based on the total weight of the composition. Generally, for most types of preparations, the proportion used will be within the range of from 0.005 to 1 %, for example from 0.01 to 1%, such as 0.01 to 0.5% by weight based on the total weight of the composition. However, in powders for inhalation or insufflation the proportion used will normally be within the range of from 0.1 to 5% by weight based on the total weight of the composition.
  • compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof may be suitable for topical administration, for example for intranasal or inhaled administration.
  • Inhaled administration involves topical administration to the lung, such as by aerosol or dry powder composition.
  • compositions suitable for intranasal or inhaled administration may conveniently be formulated as aerosols, solutions, suspensions, drops, gels or dry powders, optionally with one or more physiologically acceptable diluents and/or carriers such as aqueous or non-aqueous vehicles, thickening agents, isotonicity adjusting agents, antioxidants and/or preservatives.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof may be in a particle-size- reduced form prepared by, for example, rnicronisation and milling.
  • the size-reduced (e.g. micronised) compound can be defined by a D 50 value of about 0.5 to about 10 microns (for example as measured using laser diffraction).
  • compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof are suitable for intranasal administration.
  • the compounds of formula (I) and pharmaceutically acceptable salts thereof may be formulated for intranasal use in man either as a solution composition or a suspension composition, for example as a solution composition such as an aqueous solution composition.
  • a suitable dosing regime for an intranasal composition may be for the patient to inhale slowly through the nose subsequent to the nasal cavity being cleared. During inhalation, the composition may be administered to one nostril while the other is manually compressed. This procedure may then be repeated for the other nostril. Generally, one or two sprays per nostril may be administered by the above procedure up to two or three times each day.
  • the intranasal compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof are suitable for once daily administration.
  • each spray to the nostril may deliver from about 25 to about 100 ⁇ l_ of intranasal composition.
  • each spray to the nostril may deliver from about 1 to about 100 ⁇ g, for example about 1 to about 50 ⁇ g, of the compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof may permit the compound to be delivered to all areas of the nasal cavities (the target tissue) and further, may permit the compound to remain in contact with the target tissue for longer periods of time.
  • Compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, suitable for intranasal administration may optionally contain one or more suspending agents, one or more preservatives, one or more wetting agents and/or one or more isotonicity adjusting agents as desired.
  • compositions suitable for intranasal administration may optionally further contain other excipients such as antioxidants (for example sodium metabisulphite), taste-masking agents (for example menthol) and sweetening agents (for example dextrose, glycerol, saccharin and/or sorbitol).
  • excipients that may be employed in intranasal compositions include, for example, xylitol, potassium sorbate, EDTA, sodium citrate, citric acid, polysorbate 80 and Avicel CL611.
  • the suspending agent if included, will typically be present in the intranasal composition in an amount of between about 0.1 and 5%, such as between about 1.5 and 2.4%, by weight based on the total weight of the composition.
  • suspending agents include Avicel, carboxymethylcellulose, veegum, tragacanth, bentonite, methylcellulose and polyethylene glycols, e.g. microcrystalline cellulose or carboxy methylcellulose sodium.
  • Suspending agents may also be included in, for example, compositions suitable for inhaled, ocular and oral administration, as appropriate.
  • intranasal compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof may be protected from microbial or fungal contamination and growth by inclusion of a preservative.
  • pharmaceutically acceptable anti-microbial agents or preservatives may include quaternary ammonium compounds (e.g. benzalkonium chloride, benzethonium chloride, cetrimide and cetylpyridinium chloride), mercurial agents (e.g. phenylmercuric nitrate, phenylmercuric acetate and thimerosal), alcoholic agents (e.g. chlorobutanol, phenylethyl alcohol and benzyl alcohol), antibacterial esters (e.g.
  • esters of para-hydroxybenzoic acid include chelating agents such as disodium edetate (EDTA) and other anti-microbial agents such as chlorhexidine, chlorocresol, sorbic acid and its salts (such as potassium sorbate) and polymyxin.
  • chelating agents such as disodium edetate (EDTA)
  • other anti-microbial agents such as chlorhexidine, chlorocresol, sorbic acid and its salts (such as potassium sorbate) and polymyxin.
  • pharmaceutically acceptable anti-fungal agents or preservatives may include sodium benzoate.
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof which is benzalkonium chloride-free.
  • the preservative if included, may be present in an amount of between about 0.001 and about 1 %, such as about 0.015%, by weight based on the total weight of the composition.
  • compositions which contain a suspended medicament may include a pharmaceutically acceptable wetting agent which functions to wet the particles of the medicament to facilitate dispersion thereof in the aqueous phase of the composition.
  • wetting agents include fatty alcohols, esters and ethers, such as polyoxyethylene (20) sorbitan monooleate (polysorbate 80).
  • the wetting agent may be present in the composition in an amount of between about 0.001 and about 1 %, for example between about 0.005% and about 1 %, by weight based on the total weight of the composition.
  • Wetting agents may be included in compositions suitable for other routes of administration, e.g. for inhaled or ocular administration, as appropriate.
  • An isotonicity adjusting agent may be included to achieve isotonicity with body fluids e.g. fluids of the nasal cavity, resulting in reduced levels of irritancy.
  • body fluids e.g. fluids of the nasal cavity
  • isotonicity adjusting agents include sodium chloride, dextrose, xylitol and calcium chloride.
  • An isotonicity agent may be included in the composition in an amount of between about 0.1 and 10%, such as about 4.5% by weight based on the total weight of the composition.
  • Isotonicity adjusting agents may also be included in, for example, compositions suitable for inhaled, ocular, oral and parenteral forms of administration, as appropriate.
  • intranasal compositions may be buffered by the addition of suitable buffering agents such as sodium citrate, citric acid, phosphates such as disodium phosphate (for example dodecahydrate, heptahydrate, dihydrate and anhydrous forms) or sodium phosphate and mixtures thereof. Buffering agents may also be included in compositions suitable for other routes of administration, as appropriate.
  • suitable buffering agents such as sodium citrate, citric acid, phosphates such as disodium phosphate (for example dodecahydrate, heptahydrate, dihydrate and anhydrous forms) or sodium phosphate and mixtures thereof.
  • Buffering agents may also be included in compositions suitable for other routes of administration, as appropriate.
  • compositions for administration topically to the nose for example, for the treatment of rhinitis include pressurised aerosol compositions and aqueous compositions administered to the nose by pressurised pump.
  • the present invention encompasses compositions which are non-pressurised and adapted to be administered topically to the nasal cavity. Suitable compositions contain water as the diluent or carrier for this purpose.
  • Aqueous compositions for administration to the lung or nose may be provided with conventional excipie ⁇ ts such as buffering agents, tonicity modifying agents and the like. Aqueous compositions may also be administered to the nose by nebulisation.
  • the compounds of formula (I) and pharmaceutically acceptable salts thereof may be formulated as a fluid composition 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 composition 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 composition 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 composition, 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 composition 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 incorporated herein by reference.
  • the dispenser has a housing which houses a fluid discharge device having a compression pump mounted on a container for containing a fluid compositions.
  • 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 composition 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.
  • 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) or a pharmaceutically acceptable salt thereof 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.
  • a suitable propellant such as a fluorocarbon or hydrogen-containing chlorofluorocarbon or mixtures thereof, particularly hydrofluoroalkanes, especially 1 ,1 ,1 ,2- tetrafluoroethane, 1 ,1 ,
  • the aerosol composition may optionally contain additional formulation excipients well known in the art such as surfactants for example, oleic acid, lecithin or an oligolactic acid or derivative such as those described in WO94/21229 and WO98/34596 and cosolvents, for example ethanol.
  • additional formulation excipients well known in the art such as surfactants for example, oleic acid, lecithin or an oligolactic acid or derivative such as those described in WO94/21229 and WO98/34596 and cosolvents, for example ethanol.
  • a pharmaceutical aerosol formulation comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a fluorocarbon or hydrogen-containing chlorofluorocarbon or mixtures thereof as propellant, optionally in combination with a surfactant and/or a cosolvent.
  • the propellant is selected from 1 ,1 ,1 ,2-tetrafluoroethane, 1 ,1 ,1 ,2,3,3,3-heptafluoro-n-propane and mixtures thereof.
  • compositions of the invention may be buffered by the addition of suitable buffering agents.
  • Aerosol compositions may be presented in single or multidose quantities in sterile form in a sealed container, which may take the form of a cartridge or refill for use with an atomising device or inhaler.
  • the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve (metered dose inhaler), which is intended for disposal once the contents of the container have been exhausted.
  • Capsules and cartridges for use in an inhaler or insufflator may be formulated containing a powder mix for inhalation of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a suitable powder base such as lactose or starch.
  • a powder mix for inhalation of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a suitable powder base such as lactose or starch.
  • Each capsule or cartridge may generally contain from 20 ⁇ g to 10mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof may be presented without excipients such as lactose.
  • a composition suitable for inhaled administration may be incorporated into a plurality of sealed dose containers (e.g. containing the dry powder composition) mounted longitudinally in a strip or ribbon inside a suitable inhalation device.
  • the container is rupturable or peel- openable on demand and the dose of e.g. the dry powder composition may be administered by inhalation via a device such as the DISKUSTM device, marketed by GlaxoSmithKline.
  • the DISKUSTM inhalation device is, for example, described in GB2242134A, and in such a device, at least one container for the composition in powder form (the container or containers preferably being a plurality of sealed dose containers mounted longitudinally in a strip or ribbon) is defined between two members peelably secured to one another; the device comprises: a means of defining an opening station for the said container or containers; a means for peeling the members apart at the opening station to open the container; and an outlet, communicating with the opened container, through which a user can inhale the composition in powder form from the opened container.
  • the proportion of the active compound of formula (I) or pharmaceutically acceptable salt thereof 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, for most types of preparations, the proportion used will be within the range of from 0.005 to 1 %, for example from 0.01 to 0.5%. However, in powders for inhalation or insufflation the proportion used will normally 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 from 20 ⁇ g to 500 ⁇ g of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • 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 particulate (for example, 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 a compound of formula (I) or a pharmaceutically acceptable salt thereof may be prepared by dispersal or dissolution of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the selected propellant in an appropriate container, for example, with the aid of sonicatio ⁇ 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 means a unit comprising a can, a secured cap covering the can and a formulation metering valve situated in the cap.
  • MDI system includes a suitable channelling device. Suitable channelling devices comprise for example, a valve actuator and a cylindrical or cone-like passage through which medicament may be delivered from the filled canister via the metering valve to the nose or mouth of a patient such as a mouthpiece actuator.
  • 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 (for example, see Byron, above and WO96/32099).
  • 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 metallic internal surface of the can is coated with a fluoropolymer, most preferably blended with a non-fluoropolymer.
  • the metallic internal surface of the can is coated with a polymer blend of polytetrafluoroethylene (PTFE) and polyethersulfone (PES).
  • the whole of the metallic internal surface of the can is coated with a polymer blend of polytetrafluoroethylene (PTFE) and polyethersulfone (PES).
  • 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, bromobutyl, EPDM, 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).
  • the MDIs may also be used in conjunction with other structures such as, without limitation, overwrap packages for storing and containing the MDIs, including those described in U.S. Patent Nos. 6,119,853; 6,179,118; 6,315,112; 6,352,152; 6,390,291 ; and 6,679,374, as well as dose counter units such as, but not limited to, those described in U.S. Patent Nos. 6,360,739 and 6,431 ,168.
  • overwrap packages for storing and containing the MDIs, including those described in U.S. Patent Nos. 6,119,853; 6,179,118; 6,315,112; 6,352,152; 6,390,291 ; and 6,679,374, as well as dose counter units such as, but not limited to, those described in U.S. Patent Nos. 6,360,739 and 6,431 ,168.
  • 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 together with the optional excipients is pressure filled through the charge vessel into a manufacturing vessel.
  • 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.
  • a metering valve is crimped onto an aluminium can to form an empty canister.
  • the liquefied propellant together with the optional excipients and the dissolved medicament is pressure filled through the charge vessel into a manufacturing vessel.
  • an aliquot of the liquefied formulation is added to an open canister under conditions which are sufficiently cold to ensure the 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.
  • Ointments, creams (for example an oil-in-water or water-in-oil composition such as an emulsion) 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.
  • Topical preparations may also optionally contain one or more solubilising agents and/or skin penetration-enhancing agents and/or surfactants and/or fragrances and/or preservatives and/or 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.
  • compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof which is suitable for ocular administration.
  • Such compositions may optionally contain one or more suspending agents, one or more preservatives, one or more wetting/lubricating agents and/or one or more isotonicity adjusting agents.
  • ophthalmic wetting/lubricating agents may include cellulose derivatives, dextran 70, gelatine, liquid polyols, polyvinyl alcohol and povidone such as cellulose derivatives and polyols.
  • the compounds of formula (I) and pharmaceutically acceptable salts thereof may, for example, be formulated in conventional manner for oral, nasal, 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 may be preferred as described below.
  • the compounds of formula (I) and pharmaceutically acceptable salts thereof may in general be given by internal administration in cases wherein systemic glucocorticoid receptor agonist therapy is indicated.
  • Slow release or enteric coated formulations may be advantageous, particularly for the treatment of inflammatory bowel disorders.
  • Fluid unit dosage forms for parenteral administration may be prepared using a compound of formula (I) or a pharmaceutically acceptable salt thereof and a sterile vehicle which may be aqueous or oil based.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof depending on the vehicle and concentration used, may be either suspended or dissolved in the vehicle.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof may be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, preservatives and buffering agents may be dissolved in the vehicle.
  • the composition may be frozen after filling into the vial and the water removed under vacuum.
  • the lyophilised parenteral composition may be reconstituted with a suitable solvent just prior to administration.
  • Parenteral suspensions may be prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilisation cannot be accomplished by filtration.
  • the compound may be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle.
  • a surfactant or wetting agent may be included in the composition to facilitate uniform distribution of the compound.
  • the compounds of formula (I) and pharmaceutically acceptable salts thereof may be formulated for oral administration. In other embodiments, the compounds of formula (I) and pharmaceutically acceptable salts thereof may be formulated for inhaled administration. In further embodiments, the compounds of formula (I) and pharmaceutically acceptable salts thereof may be formulated for intranasal administration.
  • the compounds 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 M 1 ZM 2 ZM 3 receptor antagonist), ⁇ 2 -adrenoreceptor agonists, antiinfective agents such as antibiotics or antivirals, or antihistamines.
  • other therapeutic agents for example selected from anti-inflammatory agents, anticholinergic agents (particularly an M 1 ZM 2 ZM 3 receptor antagonist), ⁇ 2 -adrenoreceptor agonists, antiinfective agents such as antibiotics or antivirals, or antihistamines.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with one or more other therapeutically active agents, for example selected from an anti-inflammatory agent such as a corticosteroid or an NSAID, an anticholinergic agent, a ⁇ r adrenoreceptor agonist, an antiinfective agent such as an antibiotic or an antiviral, or an antihistamine.
  • an anti-inflammatory agent such as a corticosteroid or an NSAID
  • an anticholinergic agent such as a corticosteroid or an NSAID
  • an anticholinergic agent such as a corticosteroid or an NSAID
  • an anticholinergic agent such as an antibiotic or an antiviral
  • an antihistamine such as an antibiotic or an antiviral
  • One embodiment of the invention encompasses combinations comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a ⁇ 2 -adrenor
  • One embodiment of the invention encompasses combinations comprising one or two other therapeutic agents.
  • the other therapeutic ingredient(s) may be used in the form of salts, for example as alkali metal or amine salts or as acid addition salts, or prodrugs, or as esters, for example lower alkyl esters, or as solvates, for example hydrates to optimise the activity and/or stability and/or physical characteristics, such as solubility, of the therapeutic ingredient. It will be clear also that, where appropriate, the therapeutic ingredients may be used in optically pure form.
  • ⁇ .-adrenoreceptor agonists include salmeterol (which may be a racemate or a single enantiomer such as the R-enantiomer), salbutamol (which may be a racemate or a single enantiomer such as the f?-enantiomer), formoterol (which may be a racemate or a single diastereomer such as the f?,f?-diastereomer), salmefamol, fenoterol, carmoterol, etanterol, naminterol, clenbuterol, pirbuterol, flerbuterol, reproterol, bambuterol, indacaterol, terbutaline and salts thereof, for example the xinafoate (1-hydroxy-2-naphthalenecarboxylate) salt of salmeterol, the sulphate salt or free base of salbutamol or the fumarate salt of formoterol.
  • ⁇ 2 -adrenoreceptor agonists include those described in WO02/066422,
  • WO02/070490 WO02/076933, WO03/024439, WO03/072539, WO03/091204, WO04/016578, WO04/022547, WO04/037807, WO04/037773, WO04/037768, WO04/039762, WO04/039766, WO01/42193 and WO03/042160.
  • ⁇ 2 -adrenoreceptor agonists include: 3-(4- ⁇ [6-( ⁇ (2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl ⁇ amino) hexyl] oxy ⁇ butyl) benzenesulfonamide;
  • the ⁇ z -adrenoreceptor agonist may be in the form of a salt formed with a pharmaceutically acceptable acid selected from sulphuric, hydrochloric, fumaric, hydroxynaphthoic (for example 1- or 3-hydroxy-2-naphthoic), cinnamic, substituted cinnamic, triphenylacetic, sulphamic, sulphanilic, naphthaleneacrylic, benzoic, 4-methoxybenzoic, 2- or 4-hydroxybenzoic, 4-chlorobenzoic and 4-phenylbenzoic acid.
  • a pharmaceutically acceptable acid selected from sulphuric, hydrochloric, fumaric, hydroxynaphthoic (for example 1- or 3-hydroxy-2-naphthoic), cinnamic, substituted cinnamic, triphenylacetic, sulphamic, sulphanilic, naphthaleneacrylic, benzoic,
  • Suitable anti-inflammatory agents include corticosteroids.
  • 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 (fluticasone furoate), 6 ⁇ ,9 ⁇ -d
  • 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, 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-16 ⁇ -methyl-3-oxo-17 ⁇ -(2, 2,3,3- tetramethycyclopropylcarbonyl)oxy-androsta-1 ,4-diene-17 ⁇ -carbothioic acid S- cyanomethyl ester and 6 ⁇ ,9 ⁇ -difluoro
  • the corticosteroid is 6 ⁇ ,9 ⁇ -difluoro-17 ⁇ -[(2- furanylcarbonyl)oxy]-11 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-androsta-1 ,4-diene-17 ⁇ - carbothioic acid S-fluoromethyl ester.
  • corticosteroids may include those described in WO02/088167, WO02/100879, WO02/12265, WO02/12266, WO05/005451 , WO05/005452, WO06/072599 and WO06/072600.
  • 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 published patent applications and patents: WO03/082827, WO98/54159, WO04/005229, 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, WO06/000401 , WO06/000398, WO06/015870, WO06/108699, WO07/000334 and WO07/054294.
  • anti-inflammatory agents include non-steroidal anti-inflammatory drugs (NSAID's).
  • NSAID's non-steroidal anti-inflammatory drugs
  • NSAID's examples include sodium cromoglycate, nedocromil sodium, phosphodiesterase (PDE) inhibitors (for example, theophylline, PDE4 inhibitors or mixed PDE3/PDE4 inhibitors), leukotriene antagonists, inhibitors of leukotriene synthesis (for example montelukast), iNOS inhibitors, tryptase and elastase inhibitors, beta-2 integrin antagonists and adenosine receptor agonists or antagonists (e.g.
  • adenosine 2a agonists adenosine 2a agonists
  • cytokine antagonists for example chemokine antagonists, such as a CCR3 antagonist
  • inhibitors of cytokine synthesis or 5- lipoxygenase inhibitors.
  • An iNOS (inducible nitric oxide synthase inhibitor) is preferably for oral administration.
  • iNOS inhibitors include those disclosed in WO93/13055, WO98/30537, WO02/50021 , WO95/34534 and WO99/62875.
  • CCR3 inhibitors include those disclosed in WO02/26722.
  • the invention provides the use of the compounds of formula (I) or a pharmaceutically acceptable salt thereof in combination with a phosphodiesterase 4 (PDE4) inhibitor, especially in the case of a formulation adapted for inhalation.
  • 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 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].
  • 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 (for example, as the bromide, CAS 22254-24-6, sold under the name Atrovent), oxitropium (for example, as the bromide, CAS 30286-75- 0) and tiotropium (for example, as the bromide, CAS 136310-93-5, sold under the name Spiriva).
  • revatropate for example, as the hydrobromide, CAS 262586-79-8) and LAS-34273 which is disclosed in WO01/04118.
  • 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 (for example, as the bromide, CAS 26095-59-0, sold under the name Spasmomen), trospium chloride (CAS 10405- 02-4) and solifenacin (CAS 242478-37-1 , or CAS 242478-38-2 for the succinate also known as
  • anticholinergic agents include compounds which are disclosed in US patent application 60Z487981 including, for example:
  • anticholinergic agents include compounds which are disclosed in US patent application 60/511009 including, for example:
  • the invention provides a combination comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, together with an H1 antagonist.
  • H1 antagonists include, without limitation, amelexanox, astemizole, azatadine, azelastine, acrivastine, brompheniramine, cetirizine, levocetirizine, efletirizine, chlorpheniramine, clemastine, cyclizine, carebastine, cyproheptadine, carbinoxamine, descarboethoxyloratadine, doxylamine, dimethindene, ebastine, epinastine, efletirizine, fexofenadine, hydroxyzine, ketotifen, loratadine, levocabastine, mizolastine, mequitazine, mianserin, noberastine, meclizine, norastemizole, olopatadine, picumast, pyrilamine, promethazine, terfenadine, tripelennamine, warmth and
  • the invention provides a combination comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, together with an H3 antagonist (and/or inverse agonist).
  • H3 antagonists include, for example, those compounds disclosed in WO2004/035556 and in WO2006/045416.
  • Other histamine receptor antagonists which may be used in combination with the compounds of formula (I), or a pharmaceutically acceptable salt thereof, include antagonists (and/or inverse agonists) of the H4 receptor, for example, the compounds disclosed in Jablonowski ef a/., J. Med. Chem. 46:3957-3960 (2003).
  • the invention thus provides, in another aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a PDE4 inhibitor.
  • the invention thus provides, in another aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a ⁇ 2 -adrenoreceptor agonist.
  • the invention thus provides, in another aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a corticosteroid.
  • the invention thus provides, in another aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with another non-steroidal GR agonist.
  • the invention thus provides, in another aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with an anticholinergic.
  • the invention thus provides, in another aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with an antihistamine.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt 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) or a pharmaceutically acceptable salt thereof together with an anticholinergic and a PDE-4 inhibitor.
  • 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 readily be appreciated by those skilled in the art.
  • compositions comprising a combination as defined above together with a pharmaceutically acceptable diluent or carrier represent a further aspect of the invention.
  • the invention thus provides, in a further aspect, a pharmaceutical composition
  • a pharmaceutical composition comprising a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof together with another therapeutically active agent.
  • the invention thus provides, in a further aspect, a pharmaceutical composition comprising a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a PDE4 inhibitor.
  • the invention thus provides, in a further aspect, a pharmaceutical composition comprising a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a ⁇ 2 -adrenoreceptor agonist.
  • the invention thus provides, in a further aspect, a pharmaceutical composition
  • a pharmaceutical composition comprising a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a corticosteroid.
  • the invention thus provides, in a further aspect, a pharmaceutical composition
  • a pharmaceutical composition comprising a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof together with another non-steroidal GR agonist.
  • the invention thus provides, in a further aspect, a pharmaceutical composition
  • a pharmaceutical composition comprising a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof together with an anticholinergic.
  • the invention thus provides, in a further aspect, a pharmaceutical composition
  • a pharmaceutical composition comprising a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof together with an antihistamine.
  • the invention thus provides, in a further aspect, a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a PDE4 inhibitor and a ⁇ 2 -adrenoreceptor agonist.
  • the invention thus provides, in a further aspect, a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with an anticholinergic and a PDE4 inhibitor.
  • the present invention also provides a process for the preparation of compounds of formula (I) comprising reaction of a carboxylic acid of formula (II)
  • This coupling may be conducted, for example, using HATU (O-(7-azabenzotriazol-1- yl)- ⁇ /, ⁇ /, ⁇ /', ⁇ /-tetramethyluronium hexafluorophosphate) in the presence of a suitable base such as ⁇ /, ⁇ /-diisopropylethylamine in a suitable solvent such as DMF.
  • HATU O-(7-azabenzotriazol-1- yl)- ⁇ /, ⁇ /, ⁇ /', ⁇ /-tetramethyluronium hexafluorophosphate
  • a suitable base such as ⁇ /, ⁇ /-diisopropylethylamine
  • DMF suitable solvent
  • the coupling may also be conducted using alternative, conventional conditions for amide bond formation known in the art.
  • certain compounds of formula (I) may be prepared from the carboxylic acid (II) by two sequential amide couplings firstly with an amino acid followed by a second coupling with ammonia, for example sequential couplings of the carboxylic acid (II) with glycine and then ammonia would provide a compound of formula (I) in which R 1 and R 2 are both hydrogen.
  • the carboxylic acid (II) may be obtained by deprotection of a suitable protected derivative (III)
  • P 1 represents a suitable ester protecting group, for example a benzyl or tert- butyl ester.
  • a suitable ester protecting group for example a benzyl or tert- butyl ester.
  • deprotection may be conveniently conducted by hydrogenolysis over palladium on carbon in ethanol.
  • tert-butyl ester protection deprotection can be conducted by hydrolysis under acidic conditions.
  • Alternative protecting groups suitable for use according to the present invention are well known to those skilled in the art and may be used in a conventional manner. See, for example, "Protective groups in organic synthesis" by T. W. Greene and P.G.M. Wuts (John Wiley & sons 1999) or "Protecting Groups" by PJ. Kocienski (Georg Thieme Verlag 1994).
  • Intermediates of formula (III) may be obtained by reaction of an amine of formula (IV) with 2-methylpropanoic acid or an activated derivative thereof.
  • P 1 represents a suitable ester protecting group as defined above for compound (III).
  • Acylations of an amine (IV) with 2-methylpropanoic acid may be carried out in a conventional organic solvent, for example ⁇ /, ⁇ /-dimethy
  • the reaction may be carried out at a temperature from -10°C to 100 0 C, for example at room temperature.
  • 2-methylpropanoic acid may, for example, be activated as it's acid chloride which may then be reacted with an amine (IV) in a conventional organic solvent, for example dichloromethane, in the presence of a base, for example N 1 N- diisopropylethylamine.
  • a conventional organic solvent for example dichloromethane
  • a base for example N 1 N- diisopropylethylamine.
  • the reaction may be carried out at a temperature from -10 0 C to 100°C, for example at room temperature.
  • P 1 is an ester protecting group as defined above for compounds of formula (III) with iso-propylamine.
  • the reaction may be carried out in a conventional organic solvent, for example dichloromethane, THF or acetonitrile at a temperature from 10 0 C to 100 0 C, for example at room temperature.
  • P 1 is an ester protecting group as defined above for compounds of formula (III) with the epoxy tosylate of formula (VII)
  • reaction of (Vl) with (VII) may be conducted for example in the presence of ytterbium triflate or bismuth chloride in a suitable organic solvent for example dichloromethane or acetonitrile.
  • a suitable organic solvent for example dichloromethane or acetonitrile.
  • the tosylates (V) may react further under these reactions conditions to give the epoxide (VIII)
  • P 1 is an ester protecting group as defined above for compounds of formula (III).
  • addition of tetrahydrofuran and polymer supported carbonate resin results in cyclisation of the tosylate (V) to give the epoxide (VIII).
  • the epoxides (VIII) can also be converted to intermediate (IV) by reaction with iso- propylamine.
  • aminoindazoles of formula (Vl) may be prepared by reaction of 6-methyl-1 H- indazol-4-amine (IX)-
  • P 1 is an ester protecting group as defined above for compounds of formula (III).
  • This N-arylation reaction may be performed in the presence of a copper(l) catalyst, such as copper(l) iodide and a weak base such as potassium carbonate or potassium phosphate and an amine hgand such as L-proline, cyclohexanediamine, ⁇ /. ⁇ /'-dimethylcyclohexanediamine or ⁇ /./V-dimethylethylenediamine in a variety of solvents including toluene, dioxane, ⁇ /, ⁇ /-dimethylformamide, ⁇ /, ⁇ /-dimethylacetam ⁇ de and dimethylsulfoxide at a temperature in the range 60-160 0 C, most typically 11O 0 C.
  • Representative procedures are reported in the literature Synthesis 2005, 3, 496-499, J. Org. Chem., 2004, 69, 5578-5587 and J. Am. Chem. Soc, 2001 , 123, 7727-7729.
  • P 1 is an ester protecting group as defined above for compounds of formula (III), may be prepared by reaction of 4-methyl-2,6-dinitrobenzaldehyde (XIII)
  • aminoindazoles of formula (Vl) may be prepared from the corresponding bromoindazoles of formula (XV)
  • P 1 is an ester protecting group as defined above for compounds of formula (III), by palladium catalysed amination with benzophenone imine followed by acid hydrolysis of the intermediate imines using methodology described by Wolfe in Tetrahedron Letters, 38, 6367-6370.
  • P 1 is an ester protecting group as defined above for compounds of formula (III).
  • This intramolecular N-arylation may be conducted using palladium catalysis of the type described by Buchwald in Topics in Current Chemistry, 2002, 219, 131-209.
  • the cyclisation may be effected using t ⁇ ' s(dibenzylideneacetone)dipalladium(0), racemic-BINAP (2,2'- bis(diphenylphosphino)-1 ,1 '-binaphthyl) and tripotassium phosphate in toluene or 1 ,4-dioxane at reflux temperature.
  • Hydrazones of formula (XVI) may be prepared by reaction of 4-methyl-2,6- dinitrobenzaldehyde (XIII) with a hydrazine of formula (XIV).
  • Aryl hydrazines (XIV) are either commercially available or may be prepared from the corresponding aniline by treatment with nitrous acid generated in situ from sodium nitrite followed by subsequent reduction of the resulting aryldiazonium ions with tin(ll) chloride according to standard literature procedures (see, for example, J Med Chem 1991 , 34, 2895; J Med Chem 2000 43: 4707, J Med Chem 2003 46: 2012).
  • the intermediate epoxy tosylate (VII) may be prepared by treating a compound of formula (XVII)
  • the reaction may be carried out in a conventional organic solvent, for example dichloromethane and may be conducted using either a batch or a flow process.
  • the reaction may be carried out at a temperature from -10 0 C to 100 0 C, for example at room temperature for a batch process or at about 50 0 C for a flow process.
  • Compound (XVII) may be prepared by treating the triol (XVIII)
  • the compound of formula (XVIII) may be treated with 4-methylsulphonyl chloride in the presence of an organic base, for example /V,/ ⁇ /,W,/ ⁇ /-tetramethyl-1 ,6- hexanediamine, in dichloromethane at room temperature.
  • a compound of formula (XVIII) may be prepared by treating a compound of formula (XIX)
  • reaction may be carried out in a conventional organic solvent, for example ethanol and may be conducted using either a batch or a flow process.
  • the reaction may be carried out at a temperature from -10 0 C to 100 0 C, for example at room temperature for a batch process or at about 80 0 C for a flow process.
  • a compound of formula (XIX) may be prepared by treating a compound of formula (XX)
  • the reaction may be carried out in a conventional organic solvent, for example tetrahydrofuran or dichloromethane and may be conducted using either a batch or a flow process.
  • the reaction may be carried out at a temperature from -10 0 C to 100 0 C, for example at 0 0 C rising to room temperature
  • a compound of formula (XX) may be prepared by oxidation of 1 ,3-dibenzylglycerol.
  • the oxidation may be carried out using 3A molecular sieves, N- methylmorpholine ⁇ /-oxide and tetrapropylammonium perruthenate in dichloromethane at OX to reflux, for example at room temperature.
  • the oxidation may be carried out using aqueous sodium hypochlorite, saturated sodium bicarbonate solution and 2,2,6,6-tetramethyl-1-piperidinyloxy free radical in toluene at 0 0 C to 50 0 C, for example at room temperature.
  • the oxidation may be carried out using sulphur trioxide-pyridine complex in the presence of base such as triethylamine in dimethylsulphoxide at 10 0 C to 50°C, for example at room temperature.
  • This oxidation may be conducted using either batch or flow processes.
  • Certain compounds of formulae (II), (III), (IV), (V), (Vl) 1 (VII), (VIII), (X), (XII), (XIV), (XV), (XVI), (XVII) and (XIX) may be new and form an aspect of the present invention.
  • Compounds of formula (I) may be prepared in the form of mixtures of enantiomers or diastereomers when mixtures of isomers are used as intermediates in the synthesis. These isomers may, if desired, be separated by conventional methods (For example by HPLC on a chiral column).
  • separation of isomers may be performed earlier in the synthesis, for example individual isomers of compounds of formula (II), (III), (IV), (V), (VII) and (VIII) may be employed which may obviate the need to perform a separation of isomers as a final stage in the synthesis.
  • the later process is, in theory, more efficient and is therefore preferred.
  • the Flashmaster Il is an automated multi-user flash chromatography system, available from Argonaut Technologies Ltd, which utilises disposable, normal phase, SPE cartridges (2 g to 100 g). It provides quaternary on-line solvent mixing to enable gradient methods to be run. Samples are queued using the multi-functional open access software, which manages solvents, flow-rates, gradient profile and collection conditions.
  • the system is equipped with a Knauer variable wavelength UV-detector and two Gilson FC204 fraction-collectors enabling automated peak cutting, collection and tracking.
  • the column was a 100mm x 20mm Supelco LCABZ++ with stationary phase particle size of 5 ⁇ m.
  • Solvents A: water + 0.1 % formic acid
  • Solvents A: 0.1 % Formic Acid + IOmMolar Ammonium Acetate. B: 95% Acetonitrile + 0.05% Formic Acid
  • Powdered 3A Molecular sieve (5Og) was dried at 100 0 C in a vacuum oven.
  • the sieves and ⁇ /-methylmorpholine ⁇ /-oxide (35.1 g, 300mmol) were suspended in dry dichloromethane (70OmL) before 1 ,3-dibenzyloxy-2-propanol (41 ml_, 165mmol) in dichloromethane (10OmL) was added to the stirred suspension.
  • the mixture was stirred under an atmosphere of nitrogen for 90 minutes before tetrapropylammonium perruthenate (3g, 8.53mmol) was added. (The reaction was sufficiently exothermic to cause the dichloromethane to boil and therefore a reflux condenser was fitted).
  • the reaction mixture was diluted with ethyl acetate (15mL) and water (15mL), stirred and the organic extract was separated and washed with 5%w/v sodium chloride (2 x 1 OmL) and water (1 OmL). The separated organic extract was concentrated in vacuo to give the title compound as an oil which solidified (0.75g).
  • the 1 H-NMR spectrum of the product was concordant with a reference sample.
  • the title compound was prepared via a 'flow' process using a CPC Cytos Lab System made up of a 47mL reactor block with two Jasco PU - 2080Plus HPLC pumps. Reactor temperature was maintained at 60 0 C via a Huber Unistat 360 unit.
  • Solution A 1 ,3-dibenzyloxy-2-propanol 120g, 440mmol) in acetonitrile (489mL).
  • Solution B - tetrapropylammonium perruthenate (7.72g, 22mmol, 5mol%) and ⁇ /-methylmorpholine ⁇ /-oxide (87.5g, 748mmol) in acetonitrile (611mL).
  • Solutions A and B were pumped through the Cytos Lab system in the ratio of solution A to solution B of 1 : 1.25 with a total flow rate of 7.8mL/min and residence time of 6 min. This gave a total reaction time of 2 hours 21 minutes.
  • the reaction mixture was washed sequentially with 1M HCI (5OmL), 1% aqueous sodium chloride solution (2 x 25mL) and a mixture of 1% sodium chloride (25mL) and saturated sodium bicarbonate (5mL) solution.
  • the separated organic extract was concentrated in vacuo to give the title compound (6.41 g) as a dark brown oil.
  • the 1 H-NMR spectrum was concordant with a reference sample and showed the presence of residual toluene (8.8%) and starting material (ca 3%).
  • the title compound was prepared via a 'flow' process using a CPC Cytos Lab System made up of a 32mL reactor block with two Jasco PU - 2080Plus HPLC pumps. Reactor temperature was maintained at 22°C via a Huber Unistat 360 unit. The reactor outlet was fitted with a I OOpsi backflow regulator.
  • Solution A 1 ,3-bis[(phenylmethyl)oxy]-2-propanone (71.64g, 265mmol) and trimethyl(trifluoromethyl)silane (86.67g, 96mL, 609.5mmol) in tetrahydrofuran (99mL).
  • Solution B - tetrabutylammonium fluoride (1M in THF, 265mL, 132.5mmol).
  • the separated aqueous phase was further extracted with ethyl acetate (25OmL) and the combined organic extracts were washed with 2M HCI (20OmL), water (20OmL) 1 saturated sodium bicarbonate (20OmL), water (20OmL) and saturated brine (20OmL) before being dried over anhydrous sodium sulphate and concentrated under reduced pressure to give an oil (72.8g).
  • This oil was purified on a Flash silica column (80Og) with cyclohexane:ethyi acetate (5:1) to give the title compound (49g) as an oil which crystallised on standing.
  • the title compound was prepared via a 'flow' process using a CPC Cytos Lab System. Two solutions were prepared.
  • Solution A 2-(trifluoromethyl)-1 ,2 l 3- propanetriol (4.5g, 27.8mmol), ⁇ /./y ⁇ /'. ⁇ /'-tetramethyl-i .e-hexanediamine (3OmL, 139mmol) in dichloromethane (55OmL).
  • Solution B p-toluenesulphonyl chloride (21.4g, 111 mmol) in dichloromethane (55OmL).
  • 6-Methyl-1 H-indazol-4-amine hydrochloride 0.5g, 2.7mmol
  • phenylmethyl 3- iodobenzoate 0.9g, 2.6mmol
  • copper (I) iodide 14mg, 0.07mmol
  • potassium carbonate 1.2g, 8.68mmol
  • frans- ⁇ /,/V-dimethyl-1 ,2-cyclohexanediamine 20mg, 0.14mmol
  • iso-Propylamine (4.95mL, 58.19mmol) was added to a solution of phenylmethyl 3-(6- methyl-4- ⁇ [3,3,3-trifluoro-2-hydroxy-2-( ⁇ [(4- methylphenyl)sulfonyl]oxy ⁇ methyl)propyl]amino ⁇ -1H-indazol-1-yl)benzoate (7.6g, 11.64mmol) in dry THF (5OmL) and the mixture stirred at 2O 0 C for 18 hours. The mixture was concentrated and the residue partitioned between dichloromethane (25OmL) and water (10OmL). The organic phase was separated, dried over anhydrous sodium sulphate and concentrated to ca.
  • ⁇ /, ⁇ f-diisopropylethylamine (0.1 ml_) and HATU (46mg) were added to a solution of 3- ⁇ 6-methyl-4-[(3,3,3-trifluoro-2-hydroxy-2- ⁇ [(1-methylethyl)(2- methylpropanoyl)amino]methyl ⁇ propyl)amino]-1 H-indazol-1-yl ⁇ benzoic acid (60mg, 0.115mmol) in DMF (1.5mL) and the mixture stirred at 2O 0 C under nitrogen for 10 min. Glycinamide hydrochloride (32mg) was then added and stirring continued at room temperature overnight.
  • Example 1-A enantiomer A, 14.0mg
  • Example 1-B enantiomer B, 14.2mg
  • Example 2 ⁇ /-K1 RV2-Amino-1-methyl-2-oxoethvn-3- ⁇ 6-methyl-4-f(3.3,3-trifluoro-2- hvdroxy-2-(f(1-methylethyl)(2-methylpropanoyl)aminolmethyl)propyl)aminol-1 H- indazol-1 -yl>benzamide
  • Example 2-A diastereomer A, 21.1 mg
  • Example 2-B diastereomer B, 19.3mg
  • Example 3 A/-(2-Amino-1 ,1-dimethyl-2-oxoethylV3-(6-methyl-4-r(3.3.3-trifluoro-2- hydroxy-2-([(1-methylethyl)(2-methylpropanoyl)aminolmethyl>propyl)aminol-1 H- indazol-1 -vDbenzamide
  • the ability of compounds to bind to the glucocorticoid receptor was determined by assessing their ability to compete with an Alexa 555 fluorescently-labelled dexamethasone derivative. Compounds were solvated and diluted in DMSO, and transferred directly into assay plates. Fluorescent dexamethasone and a partially purified full length glucocorticoid receptor were added to the plates, together with buffer components to stabilise the GR protein and incubated at room temperature for 2hrs in the dark. Binding of each compound was assessed by analysing the displacement of fluorescent ligand by measuring the decrease in fluorescence polarisation signal from the mixture.
  • Examples 1 to 3 show plC 50 > 7.0 in this 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 (1997) 328: 707-15.
  • Examples 1 , 1-A, 2, 2-A, 2-B and 3 show pEC 5 o ⁇ 9.0 in this assay.
  • a T225 flask of CV-1 cells at a density of 80% confluency was washed with PBS, detached from the flask using 0.25% trypsin and counted using a Sysmex KX-21 N.
  • Cells were diluted in DMEM containing 10% Hyclone, 2mM L-Glutamate and 1 % Pen/Strep at 140 cells/ ⁇ l and transduced with 10% PRb-BacMam and 10% MMTV- BacMam.
  • 70 ml of suspension cells were dispensed to each well of white Nunc 384- well plates, containing compounds at the required concentration. After 24h 10 ⁇ l of Steadylite were added to each well of the plates. Plates were incubated in the dark for 10 min before reading them on a Viewlux reader. Dose response curves were constructed from which pEC 5 o values were estimated.
  • Examples 1 to 3 show pEC 50 ⁇ 8 in this assay.
  • At least one isomer for example, an enantiomer in a mixture of isomers (such as a racemate) has the described activity.
  • the other enantiomer may have similar activity, less activity, no activity or may have some antagonist activity in the case of a functional assay.

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Abstract

La présente invention concerne des composés représentés par la formule (I): des compositions pharmaceutiques renfermant ces composés ainsi que la préparation de ces compositions, des intermédiaires et l'utilisation desdits composés pour la fabrication d'un médicament à action thérapeutique, en particulier pour le traitement des manifestations inflammatoires et/ou allergiques.
PCT/EP2008/063926 2007-10-19 2008-10-16 Indazoles en tant que ligands de récepteurs glucocorticoïdes WO2009050221A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7728030B2 (en) 2006-12-21 2010-06-01 Astrazeneca Ab Chemical compounds 572
US8030340B2 (en) 2006-11-23 2011-10-04 Astrazeneca Ab Indazolyl sulphonamide derivatives useful as glucocorticoid modulators
US8211930B2 (en) 2008-05-20 2012-07-03 Astrazeneca Ab Phenyl and benzodioxinyl substituted indazoles derivatives

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005003098A1 (fr) * 2003-07-01 2005-01-13 Schering Aktiengesellschaft Derives de pentanol substitues par un heterocycle, procede de production de ces composes et leur utilisation comme agents anti-inflammatoires
WO2007046747A1 (fr) * 2005-10-20 2007-04-26 Astrazeneca Ab Sulfonamides bicycliques innovants utilisables en tant que modulateurs du recepteur des glucocorticoides dans le traitement des maladies inflammatoires
WO2007122165A1 (fr) * 2006-04-20 2007-11-01 Glaxo Group Limited Nouveaux composés
WO2008043789A1 (fr) * 2006-10-13 2008-04-17 Glaxo Group Limited Nouveaux composés

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005003098A1 (fr) * 2003-07-01 2005-01-13 Schering Aktiengesellschaft Derives de pentanol substitues par un heterocycle, procede de production de ces composes et leur utilisation comme agents anti-inflammatoires
WO2007046747A1 (fr) * 2005-10-20 2007-04-26 Astrazeneca Ab Sulfonamides bicycliques innovants utilisables en tant que modulateurs du recepteur des glucocorticoides dans le traitement des maladies inflammatoires
WO2007122165A1 (fr) * 2006-04-20 2007-11-01 Glaxo Group Limited Nouveaux composés
WO2008043789A1 (fr) * 2006-10-13 2008-04-17 Glaxo Group Limited Nouveaux composés

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8030340B2 (en) 2006-11-23 2011-10-04 Astrazeneca Ab Indazolyl sulphonamide derivatives useful as glucocorticoid modulators
US7728030B2 (en) 2006-12-21 2010-06-01 Astrazeneca Ab Chemical compounds 572
US8143290B2 (en) 2006-12-21 2012-03-27 Astrazeneca Ab Chemical compounds 572
US8211930B2 (en) 2008-05-20 2012-07-03 Astrazeneca Ab Phenyl and benzodioxinyl substituted indazoles derivatives
US8916600B2 (en) 2008-05-20 2014-12-23 Astrazeneca Ab Phenyl and benzodioxinyl substituted indazoles derivatives
US9512110B2 (en) 2008-05-20 2016-12-06 Astrazeneca Ab Phenyl and benzodioxinyl substituted indazoles derivatives
US9738632B2 (en) 2008-05-20 2017-08-22 Astrazeneca Ab Phenyl and benzodioxinyl substituted indazoles derivatives

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