WO2009050244A1 - Indazoles as glucocorticoid receptor ligands - Google Patents

Indazoles as glucocorticoid receptor ligands Download PDF

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Publication number
WO2009050244A1
WO2009050244A1 PCT/EP2008/063986 EP2008063986W WO2009050244A1 WO 2009050244 A1 WO2009050244 A1 WO 2009050244A1 EP 2008063986 W EP2008063986 W EP 2008063986W WO 2009050244 A1 WO2009050244 A1 WO 2009050244A1
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WIPO (PCT)
Prior art keywords
methyl
compound
amino
pharmaceutically acceptable
acceptable salt
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PCT/EP2008/063986
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French (fr)
Inventor
Keith Biggadike
Anthony William James Cooper
David House
Iain Mcfarlane Mclay
John Edward Robinson
Gordon Gad Weingarten
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Glaxo Group Limited
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Publication of WO2009050244A1 publication Critical patent/WO2009050244A1/en

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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

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 C 1-3 alkyl or -(CH 2 ) n -phenyl, or
  • R 1 and R 2 together with the nitrogen atom to which they are attached, are linked to form
  • R 3 is -CH 2 CONH 2 or -CH(CH 3 )CONH 2 and n is O or 1 ; and salts thereof (hereinafter “compounds of the invention”).
  • R 1 and R 2 are each independently ethyl or isopropyl. In another embodiment R 1 is -(CH 2 ) n -phenyl and R 2 is isopropyl. In another embodiment R 1 and R 2 , together with the nitrogen atom to which they are attached, are linked to form
  • R 3 is -CH 2 CONH 2 . In another embodiment R 3 is - CH(CH 3 )CONH 2 .
  • R 3 is -CH(CH 3 )CONH 2 in the (S) configuration. In another embodiment R 3 is -CH(CH 3 )CONH 2 Jn the (R) configuration.
  • n is O. In another embodiment n is 1.
  • the compound of formula (I) is:
  • the compound of formula (I) is:
  • the compound of formula (I) is:
  • alkyl as used herein as a group or a part of a group refers to a straight or branched hydrocarbon chain containing the specified number of carbon atoms.
  • C ⁇ Csalkyl means a straight or branched alkyl containing at least 1 and at most 3 carbon atoms.
  • alkyl as used herein include, but are not limited to, methyl, ethyl, n-propyl and isopropyl.
  • 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 a 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 and 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 acids and bases.
  • Pharmaceutically acceptable acid addition salts include those formed from hydrochloric, hydrobromic, sulphuric, citric, tartaric, phosphoric, lactic, pyruvic, acetic, trifluoroacetic, triphenylacetic, sulphamic, sulphanilic, succinic, oxalic, fumaric, maleic, malic, glutamic, aspartic, oxaloacetic, methanesulphonic, ethanesulphonic, arylsulphonic (for example p-toluenesulphonic, benzenesulphonic, naphthalenesulphonic or naphthalenedisulphonic), salicylic, glutaric, gluconic, tricarballylic, cinnamic, substituted cinnamic (for example, phenyl, methyl, methoxy or halo substituted cinnamic,
  • Pharmaceutically acceptable base salts include ammonium salts, for example those formed with pharmaceutically acceptable organic primary, secondary, and tertiary amines including aliphatic amines, aromatic amines, aliphatic diamines, and hydroxy alkylamines such as methylamine, ethylamine, 2-hydroxyethylamine, diethylamine, TEA, ethylenediamine, ethanolamine, diethanolamine, and cyclohexylamine; alkali metal salts such as those of lithium, sodium and potassium, alkaline earth metal salts such as those of calcium and magnesium, aluminum, and zinc salts; carbonates and bicarbonates of a pharmaceutically acceptable metal cation such as sodium, potassium, lithium, calcium, magnesium, aluminum, and zinc; and salts with organic bases such as dicyclohexylamine and ⁇ /-methyl-D-glucamine.
  • organic bases such as dicyclohexylamine and ⁇ /-methyl-D-glucamine.
  • 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 (I) 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.
  • 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 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 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.
  • suitable unit does may be about 0.001 to about 100mg, for example about 0.001 to about 1mg, 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.
  • 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, micronisation 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. Typically, 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.
  • Intranasal 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.
  • examples of 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. Preservatives may be included in composition suitable for other routes of administration as appropriate.
  • 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.
  • 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 excipients 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.
  • a pharmaceutical aerosol 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.
  • 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 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 Pharmacopoeia 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,
  • 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 propella ⁇ t 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), p 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), p 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 ⁇ 2 -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
  • a ⁇ 2 -adrenoreceptor agonist 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
  • 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.
  • ⁇ 2 -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 R-enantiomer), formoterol (which may be a racemate or a single diastereomer such as the R,R-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 ⁇ 2 -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, 4-
  • 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 MtIM 2 IM 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 60/487981 including, for example:
  • anticholinergic agents include compounds which are disclosed in US patent application 60/511009 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;
  • 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, olopata
  • 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 et al., 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 ⁇ ⁇ -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 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
  • 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
  • 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 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)
  • R 1 and R 2 are as defined above for compounds of formula (I) with an amine R 3 NH 2 wherein R 3 is as defined above for compounds of formula (I).
  • This coupling may be conducted, for example, using HATU (O-(7-azabenzot ⁇ azoM- yl)- ⁇ /, ⁇ /, ⁇ /', ⁇ /-tetramethyluron ⁇ um hexafluorophosphate) in the presence of a suitable base such as ⁇ /, ⁇ /-d ⁇ sopropylethylam ⁇ ne in a suitable solvent such as DMF
  • HATU O-(7-azabenzot ⁇ azoM- yl)- ⁇ /, ⁇ /, ⁇ /', ⁇ /-tetramethyluron ⁇ um hexafluorophosphate
  • a suitable base such as ⁇ /, ⁇ /-d ⁇ sopropylethylam ⁇ ne
  • DMF suitable solvent
  • 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 3 represents -CH 2 CONH 2
  • the carboxylic acid (II) may be obtained by deprotection of a suitable protected derivative (III)
  • R 1 and R 2 are as defined above for compounds of formula (I) and P 1 represents a suitable ester protecting group, for example a benzyl or tert-butyl ester
  • P 1 represents a suitable ester protecting group
  • 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 P.J. Kocienski (Georg Thieme Verlag 1994).
  • P 1 represents a suitable ester protecting group as defined above for compound (III) with an amine of formula R 1 R 2 NH 2 wherein R 1 and R 2 are as defined above for compounds of formula (I).
  • the reaction may be carried out in a conventional organic solvent, for example dichloromethane, THF, DMF or acetonitrile at a temperature from -10 0 C to 100 0 C, for example at room temperature.
  • the reaction may be conducted in a microwave reactor at for example 100°C to 130 0 C in for example DMF or alternatively in the absence of solvent.
  • P 1 is an ester protecting group as defined above for compounds of formula (III) with an 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 tosylate (IV) may react further under these reactions conditions to give an epoxide (V).
  • the epoxide (V) may be deliberately prepared by cyclisation of the tosylate (IV) using, for example, polymer supported carbonate resin in a suitable solvent such as tetrahydrofuran.
  • aminoindazole of formula (Vl) may be prepared by reaction of 6-methyl-1 H- indazol-4-amine (VIII):
  • 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 ligand such as L-proline, cyclohexanediamine, ⁇ /./V-dimethylcyclohexanediamine or ⁇ /./V-dimethylethylenediamine in a variety of solvents including toluene, dioxane, ⁇ /, ⁇ /-dimethylformamide, ⁇ /, ⁇ /-dimethylacetamide and dimethylsulfoxide at a temperature in the range 60-160 0 C, most typically 110 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 (XII)
  • aminoindazoles of formula (Vl) may be prepared from the corresponding bromoindazoles of formula (XIV)
  • 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 tris(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 (XV) may be prepared by reaction of 4-methyl-2,6- dinitrobenzaldehyde (XII) with a hydrazine of formula (XIII).
  • Aryl hydrazines (XIII) 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 (XVI)
  • 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 (XVI) may be prepared by treating the triol (XVII)
  • the compound of formula (XVII) may be prepared by treating a compound of formula (XVIII)
  • 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 (XVIII) may be prepared by treating a compound of formula (XIX)
  • 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°C, for example at 0 0 C rising to room temperature.
  • a compound of formula (XIX) 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 0 0 C 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°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 0 C 1 for example at room temperature.
  • This oxidation may be conducted using either batch or flow processes.
  • 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
  • Solvents A: 0.1% Formic Acid + 1OmM 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 N-ox ⁇ e (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 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°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 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 (1 M in THF, 265mL, 132.5mmol).
  • the title compound was prepared via a 'flow' process using a CPC Cytos Lab System Two solutions were prepared Solution A, 2-(t ⁇ fluoromethyl)-1 ,2,3- propanetriol (4 5g, 27 ⁇ mmol), ⁇ /, ⁇ /, ⁇ /', ⁇ /-tetramethyl-1 ,6-hexaned ⁇ am ⁇ ne (3OmL, 139mmol) in dichloromethane (55OmL) Solution B, p-toluenesulphonyl chloride (21 4g 111mmol) 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
  • 6-Methyl-1 /-/-indazol-4-amine (5.48g, 37.3mmol), copper (I) iodide (71 mg, 0.37mmol), frans-1 ,2-cyclohexanediamine (420mg, 0.37mmol) and tripotassium phosphate (16.6g, 78.3mmol) were added to a solution of phenylmethyl 4-iodobenzoate (12.61g, 37.3mmol) in 1 ,4-dioxane (2OmL). More 1 ,4-dioxane (3OmL) was added and the mixture heated under reflux for 3 hours 15 min and then allowed to gradually cool to room temperature and partitioned between water and ethyl acetate.
  • Bis(1-methylethyl)amine (0.048mL, 0.345mmol) was added to a solution of phenylmethyl 3-[6-methyl-4-( ⁇ [2-(trifluoromethyl)-2-oxiranyl]methyl ⁇ amino)-1 /-/- indazol-1-yl]benzoate (0.11g, 0.229mmol) in dry acetonitrile (2mL) and the mixture left at room temperature for 18 hours. More bis(1-methylethyl)amine (0.1mL) was then added and the mixture allowed to stand at room temperature for a further 72 hours.
  • Example 1 ⁇ /-(2-Amino-2-oxoethyl)-3-f4-r(2- ⁇ rethyl(1-methylethyl)amino1methyl>- 3,3,3-trifluoro-2-hvdroxypropyl)amino1-6-methvH H-indazol-1-yl>benzamide
  • HATU (13.5mg, 0.0356mmol) was added to a solution of 3- ⁇ 4-[(2- ⁇ [ethyl(1- methylethyl)amino]methyl ⁇ -3,3,3-trifluorc-2-hydroxypropyl)amino]-6-methyl-1/-/- indazol-1-yl ⁇ benzoic acid (17mg, 0.0356mmol) in DMF (0.5ml_) and the mixture stirred at room temperature for 10 min. Glycinamide hydrochloride (4mg, 0.0356mmol) and ⁇ /, ⁇ /-diisopropylethylamine (0.0185mL, 0.107mmol) were then added and the mixture stirred at 2O 0 C for 18 hours. The solvent was removed under a stream of nitrogen and the residue purified by mass directed autopreparation to give the title compound.
  • Example 2 ⁇ /-(2-Amino-2-oxoethyl)-3- ⁇ 4-r(2-frbis(1 -methylethyl)amino1methyl ⁇ -3.3.3- trifluoro-2-hvdroxypropyl)aminol-6-methyl-1 /-/-i ⁇ dazol-1-yl)benzamide
  • Example 4 ⁇ /-(2-Amino-2-oxoethyl)-3-(6-methyl-4-f(3,3.3-trifluoro-2-hvdroxy-2-f[(1- methylethyl)(phenylmethyl)aminolmethyl)propyl)amino1-1 H-indazol-1-yl)benzamide
  • Example 4-A enantiomer A, 3mg
  • Example 4-B enantiomer B, 3mg
  • Example 6 ⁇ /-f ⁇ ffl-2-Amino-1-methyl-2-oxoethyll-3-(4-ff2-(3.4-dihvdro-1 (2H)- quinolinylmethyl)-3,3.3-trifluoro-2-hvdroxypropynamino ' y-6-methyl-1/-/-indazol-1- vDbenzamide
  • ⁇ /, ⁇ /-D ⁇ sopropylethylamine (0.079mL, 0.451 mmol) and HATU (36mg, 0.095mmol) were added to a solution of 3-(4- ⁇ [2-(3,4-dihydro-1 (2H)-quinolinylmethyl)-3,3,3- trifluoro-2-hydroxypropyl]amino ⁇ -6-methyl-1 /-/-indazol-1-yl)benzoic acid (47.3mg, 0.09mmol) in anhydrous DMF (1.7mL) and the mixture stirred at room temperature under nitrogen for 10 min.
  • D-Alaninamide hydrochloride (28.1 mg, 0.225mmol) was then added and stirring continued at room temperature for 7 hours when the mixture was partitioned between water and ethyl acetate.
  • the organic phase was separated, combined with a second ethyl acetate extract, washed successively with aqueous sodium bicarbonate and water, dried through a hydrophobic frit and evaporated.
  • the residue was dissolved in a mixture of DMSO and methanol and purified by mass directed autopreparation. Product containing fractions were combined and partitioned between dichloromethane and saturated aqueous sodium bicarbonate.
  • Example 6-A diastereomer A, 4.14mg
  • Example 6-B diastereomer B, 5.64mg
  • Example 7 ⁇ /-(2-Amino-2-oxoethyl)-3-r6-methyl-4- ⁇ 3.3.3-trifluoro-2-hvdroxy-2-r(2- methyl-3,4-dihvdro-1 (2/-/)-quinolinyl)methvnpropyl)amino)-1/-/-indazol-1-vnbenzamide
  • Example 8 /V-(2-amino-2-oxoethyl)-3-[4-( ⁇ 2-r(dimethylamino)methyll-3.3.3-trifluoro-2- hvdroxypropyl>amino)-6-methyl-1 /-/-indazol-1-yllbenzamide
  • 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 to 9 show pEC 50 > 7.5 in this assay.
  • Examples 1 to 9 show pEC 50 ⁇ 8.5 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

The present invention provides compounds of formula (I), 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.

Description

INDAZOLES AS GLUCOCORTICOID RECEPTOR LIGANDS
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). Man-made ligands to these receptors play an important role in human health, in particular the use of glucocorticoid agonists to treat a wide range of inflammatory conditions.
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). 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. Recently, it has been shown that 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. & Ray, P. (1995) Chest 107:139S). Many of the genes involved in the inflammatory response are transcriptionally activated through the NFkB and AP1 pathways and therefore inhibition of this pathway by glucocorticoids may explain their anti-inflammatory effect (see: Barnes, P.J. & Adcock, I. (1993) Trend Pharmacol Sci 14: 436-441 ; Cato, A.C. & Wade, E. (1996) Bioessays 18: 371-378). Despite the effectiveness of glucocorticoids in treating a wide range of conditions, a number of side-effects are associated with pathological increases in endogenous Cortisol or the use of exogenous, and particularly systemically administered, glucocorticoids. These include reduction in bone mineral density (Wong, C.A., Walsh, L.J., Smith, CJ. et al. (2000) Lancet 355:1399-1403), slowing of growth (Allen, D.B. (2000) Allergy 55: suppl 62, 15-18), skin bruising (Pauwels, R.A., Lofdahl, CG. , Latinen, L.A. et al. (1999) N Engl J Med 340:1948-1953), development of cataracts (Cumming, R.G., Mitchell, P. & Leeder, S. R. (1997) N Engl J Med 337:8- 14) and dysregulation of lipid and glucose metabolism (Faul, J. L, Tormey, W., Tormey, V. & Burke, C. (1998) BMJ 317:1491 ; and Andrews, R.C. & Walker, B.R. (1999) Clin Sci 96:513-523). The side-effects are serious enough often to limit the dose of glucocorticoid that can be used to treat the underlying pathology leading to reduced efficacy of treatment.
Current known 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, 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 T-cell lymphoma.
The present invention provides compounds of formula (I):
Figure imgf000004_0001
wherein
R1 and R2 are each independently C1-3alkyl or -(CH2)n-phenyl, or
R1 and R2, together with the nitrogen atom to which they are attached, are linked to form
Figure imgf000004_0002
R3 is -CH2CONH2 or -CH(CH3)CONH2 and n is O or 1 ; and salts thereof (hereinafter "compounds of the invention").
In one embodiment R1 and R2 are each independently ethyl or isopropyl. In another embodiment R1 is -(CH2)n-phenyl and R2 is isopropyl. In another embodiment R1 and R2, together with the nitrogen atom to which they are attached, are linked to form
Figure imgf000004_0003
In one embodiment R3 is -CH2CONH2. In another embodiment R3 is - CH(CH3)CONH2.
In one embodiment R3 is -CH(CH3)CONH2 in the (S) configuration. In another embodiment R3 is -CH(CH3)CONH2Jn the (R) configuration.
In one embodiment n is O. In another embodiment n is 1.
It is to be understood that the present invention encompasses all combinations of the substituent groups described above.
In one embodiment, the compound of formula (I) is:
N-(2-amino-2-oxoethyl)-3-{4-[(2-{[ethyl(1-methylethyl)amino]methyl}-3,3,3-trifluoro-2- hydroxypropyl)amino]-6-methyl-1 H-indazol-1-yl}benzamide;
N-(2-amino-2-oxoethyl)-3-{4-[(2-{[bis(1-methylethyl)amino]methyl}-3,3,3-trifluoro-2- hydroxypropyl)amino]-6-methyl-1 H-indazol-1-yl}benzamide;
N-(2-amino-2-oxoethyl)-3-{6-methyl-4-[(3,3,3-trifluoro-2-hydroxy-2-{[(1- methylethyl)(phenyl)amino]methyl}propyl)amino]-1 H-indazol-1-yl}benzamide;
N-(2-amino-2-oxoethyl)-3-{6-methyl-4-[(3,3,3-trifluoro-2-hydroxy-2-{[(1- methylethyl)(phenylmethyl)amino]methyl}propyl)amino]-1 H-indazol-1-yl}benzamide;
N-(2-amino-2-oxoethyl)-3-{6-methyl-4-[(3,3,3-trifluoro-2-hydroxy-2-{[(1- methylethyl)(phenylmethyl)amino]methyl}propyl)amino]-1 H-indazol-1-yl}benzamide enantiomer A;
N-(2-amino-2-oxoethyl)-3-{6-methyl-4-[(3,3,3-trifluoro-2-hydroxy-2-{[(1- methylethyl)(phenylmethyl)amino]methyl}propyl)amino]-1 H-indazol-1-yl}benzamide enantiomer B;
N-(2-amino-2-oxoethyl)-3-(4-{[2-(3,4-dihydro-1 (2H)-quinolinylmethyl)-3,3,3-trifluoro-2- hydroxypropyl]amino}-6-methyl-1 H-indazol-1 -yl)benzamide;
N-(2-amino-2-oxoethyl)-3-(4-{[2-(3,4-dihydro-1(2H)-quinolinylmethyl)-3,3,3-trifluoro-2- hydroxypropyl]amino}-6-methyl-1 H-indazol-1 -yl)benzamide enantiomer A;
N-(2-amino-2-oxoethyl)-3-(4-{[2-(3,4-dihydro-1(2H)-quinolinylmethyl)-3,3,3-trifluoro-2- hydroxypropyl]amino}-6-methyl-1 H-indazol-1 -yl)benzamide enantiomer B;
N-[(1 S)-2-amino-1-methyl-2-oxoethyl]-3"(4-{[2-(3,4-dihydro-1 (2H)-quinolinylmethyl)-
3,3,3-trifluoro-2-hydroxypropyl]amino}-6-methyl-1 H-indazol-1-yl)benzamide; N-[(1 S)-2-amino-1-methyl-2-oxoethyl]-3-(4-{[2-(3,4-dihydro-1 (2H)-quinolinylmethyl)- 3,3,3-trifluoro-2-hydroxypropyl]amino}-6-methyl-1 H-indazol-1-yl)benzamide diastereomer A;
N-[(1 S)-2-amino-1-methyl-2-oxoethyl]-3-(4-{[2-(3,4-dihydro-1 (2H)-quinolinylmethyl)- 3,3,3-trifluoro-2-hydroxypropyl]amino}-6-methyl-1 H-indazol-1-yl)benzamide diastereomer B;
N-(2-amino-2-oxoethyl)-3-[6-methyl-4-({3,3,3-trifluoro-2-hydroxy-2-[(2-methyl-3,4- dihydro-1 (2H)-quinolinyl)methyl]propyl}amino)-1 H-indazol-1 -yljbenzamide; Λ/-(2-amino-2-oxoethyl)-3-[4-({2-[(dimethylamino)methyl]-3,3,3~trifluoro-2- hydroxypropyl}amino)-6-methyl-1 H-indazol-1 -yl]benzamide;
^-[(i ^^-amino-i-metriyl^-oxoethyll-S-^-^-tCdimethylarninoJrnethylJ-S.S.S-trifluoro- 2-hydroxypropyl}amino)-6-methyl-1 H-indazol-1 -yl]benzamide; or a salt thereof.
In another embodiment, the compound of formula (I) is:
N-(2-amino-2-oxoethyl)-3-{4-[(2-{[ethyl(1-methylethyl)amino]methyl}-3,3,3-trifluoro-2- hydroxypropyl)amino]-6-methyl-1 H-indazol-1 -yljbenzamide;
N-(2-amino-2-oxoethyl)-3-{4-[(2-{[bis(1-methylethyl)amino]methyl}-3,3,3-trifluoro-2- hydroxypropyl)amino]-6-methyl-1 H-indazol-1-yl}benzamide;
N-(2-amino-2-oxoethyl)-3-{6-methyl-4-[(3,3,3-trifluoro-2-hydroxy-2-{[(1- methylethyl)(phenyl)amino]methyl}propyl)amino]-1 H-indazol-1-yl}benzamide;
N-(2-amino-2-oxoethyl)-3-{6-methyl-4-[(3,3,3-trifluoro-2-hydroxy-2-{[(1- methylethyl)(phenylmethyl)amino]methyl}propyl)amino]-1 H-indazol-1-yl}benzamide;
N-(2-amino-2-oxoethyl)-3-{6-methyl-4-[(3,3,3-trifluoro-2-hydroxy-2-{[(1- methylethyl)(phenylmethyl)amino]methyl}propyl)amino]-1 H-indazol-1-yl}benzamide enantiomer A;
N-(2-amino-2-oxoethyl)-3-{6-methyl-4-[(3,3>3-trifluoro-2-hydroxy-2-{[(1- methylethyl)(phenylmethyl)amino]methyl}propyl)amino]-1 H-indazol-1 -yl}benzamide enantiomer B;
N-(2-amino-2-oxoethyl)-3-(4-{[2-(3,4-dihydro-1 (2H)-quinolinylmethyl)-3,3,3-trifluoro-2- hydroxypropyl]amino}-6-methyl-1 H-indazol-1 -yl)benzamide;
N-(2-amino-2-oxoethyl)-3-(4-{[2-(3,4-dihydro-1 (2H)-quinolinylmethyl)-3,3,3-trifluoro-2- hydroxypropyl]amino}-6-methyl-1 H-indazol-1 -yl)benzamide enantiomer A;
N-(2-amino-2-oxoethyl)-3-(4-{[2-(3,4-dihydro-1 (2H)-quinolinylmethyl)-3,3,3-trifluoro-2- hydroxypropyl]amino}-6-methyl-1 H-indazol-1 -yl)benzamide enantiomer B;
N-[(1 S)-2-amino-1-methyl-2-oxoethyl]-3-(4-{[2-(3,4-dihydro-1 (2H)-quinolinylmethyl)-
3,3,3-trifluoro-2-hydroxypropyl]amino}-6-methyl-1 H-indazol-1-yl)benzamide; N-[(1 S)-2-amino-1-methyl-2-oxoethyl]-3-(4-{[2-(3,4-dihydro-1 (2H)-quinolinylmethyl)- 3,3,3-trifluoro-2-hydroxypropyl]amino}-6-methyl-1 H-indazol-1-yl)benzamide diastereomer A;
N-[(1 S)-2-amino-1-methyl-2-oxoethyl]-3-(4-{[2-(3,4-dihydro-1 (2H)-quinolinylmethyl)- 3,3,3-trifIuoro-2-hydroxypropyl]amino}-6-methyl-1 H-indazol-1-yl)benzamide diastereomer B;
N-(2-amino-2-oxoethyl)-3-[6-methyl-4-({3,3,3-trifluoro-2-hydroxy-2-[(2-methyl-3,4- dihydro-1 (2H)-quinolinyl)methyl]propyl}amino)-1 H-indazol-1-yl]benzamide; or a salt thereof.
In a further embodiment, the compound of formula (I) is:
N-(2-amino-2-oxoethyl)-3-{6-methyl-4-[(3,3,3-trifluoro-2-hydroxy-2-{[(1- methylethyl)(phenylmethyl)amino]methyl}propyl)amino]-1 H-indazol-1-yl}benzamide;
N-(2-amino-2-oxoethyl)-3-{6-methyl-4-[(3,3,3-trifluoro-2-hydroxy-2-{[(1- methylethyl)(phenylmethyl)amino]methyl}propyl)amino]-1 H-indazol-1-yl}benzamide enantiomer B;
N-(2-amino-2-oxoethyl)-3-(4-{[2-(3,4-dihydro-1 (2H)-quinolinylmethyl)-3,3,3-trifluoro-2- hydroxypropyl]amino}-6-rnethyl-1 H-indazol-1-yl)benzamide;
N-(2-amino-2-oxoethyl)-3-(4-{[2-(3,4-dihydro-1(2H)-quinolinylmethyl)-3,3,3-trifluoro-2- hydroxypropyl]amino}-6-methyl-1 H-indazol-1-yl)benzamide enantiomer A;
N-[(1 S)-2-amino-1-methyl-2-oxoethyl]-3-(4-{[2-(3,4-dihydro-1 (2H)-quinolinylmethyl)-
3,3,3-tπfluoro-2-hydroxypropyl]amino}-6-methyM H-indazol-1-yl)benzamide;
N-[(1 S)-2-amino-1-methyl-2-oxoethyl]-3-(4-{[2-(314-dihydro-1 (2H)-quinolinylmethyl)-
3,3,3-trifluoro-2-hydroxypropyl]amino}-6-methyl-1 H-indazol-1-yl)benzamide diastereomer A;
N-(2-amino-2-oxoethyl)-3-[6-methyl-4-({3,3,3-trifluoro-2-hydroxy-2-[(2-methyl-3,4- dihydro-1 (2H)-quinolinyl)methyl]propyl}amino)-1 H-indazol-1-yl]benzamide; or a salt thereof.
The term "alkyl" as used herein as a group or a part of a group refers to a straight or branched hydrocarbon chain containing the specified number of carbon atoms. For example, C^Csalkyl means a straight or branched alkyl containing at least 1 and at most 3 carbon atoms. Examples of "alkyl" as used herein include, but are not limited to, methyl, ethyl, n-propyl and isopropyl.
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.
The term "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. In one embodiment, a modulator of the glucocorticoid receptor may be an agonist of the glucocorticoid receptor.
It will further be appreciated by those skilled in the art that at least one isomer (e.g. one enantiomer of a racemate) has the described activity. The other isomers may have similar activity, less activity, no activity or may have some antagonist activity in a functional assay.
The terms 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 and enantiomer B refers to the second enantiomer to elute.
Similarly, the terms 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, and diastereomer B refers to the second diastereomer to elute.
It will be appreciated by those skilled in the art that although the absolute retention time on chromatography can be variable, the order of elution remains the same when the same column and conditions are employed. However, the use of a different chromatography column and conditions may alter the order of elution.
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). Thus in one embodiment the compound of the invention is in the form of a diastereomer or a mixture of diastereomers. In another embodiment the compound of the invention is in the form of an enantiomer or a mixture of enantiomers (e.g. racemic mixture). In another embodiment of the invention, the compound of the invention is diastereomer A. In another embodiment of the invention, the compound of the invention is diastereomer B. In another embodiment of the invention, the compound of the invention is enantiomer A. In a further embodiment of the invention, the compound of the invention is enantiomer B.
It will be appreciated by those skilled in the art that as rotation of the aryl-carbonyl bond becomes less facile due to ortho substitution on the aromatic ring, atropisomerism may be observed thus creating the possibility of four isomers enantiomer A, atropisomer A; enantiomer A, atropisomer B; enantiomer B, atropisomer A; and enantiomer B, atropisomer B. Where the atropisomers are separated without separation of the enantiomers at the fixed chiral centre these are referred to as racemic atropisomers A and B. Any comment relating to the biological activity of an isomer or stereoisomer should be taken to include these atropisomers. It will be appreciated by those skilled in the art that where there is a non equilibrium ratio of atropisomers, this ratio may move towards the equilibrium ratio.
Included within the scope of the "compounds of the invention" are all solvates (including hydrates), complexes, polymorphs, prodrugs, radiolabeled derivatives, stereoisomers and optical isomers of the compounds of formula (I) and salts thereof.
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. For compounds of the invention that are in crystalline form, the skilled artisan will appreciate that 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. Solvates 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.
The skilled artisan will further appreciate that certain compounds of the invention that exist in crystalline form, including the various solvates thereof, 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. The skilled artisan will appreciate that different 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. However, 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 acids and bases. Pharmaceutically acceptable acid addition salts include those formed from hydrochloric, hydrobromic, sulphuric, citric, tartaric, phosphoric, lactic, pyruvic, acetic, trifluoroacetic, triphenylacetic, sulphamic, sulphanilic, succinic, oxalic, fumaric, maleic, malic, glutamic, aspartic, oxaloacetic, methanesulphonic, ethanesulphonic, arylsulphonic (for example p-toluenesulphonic, benzenesulphonic, naphthalenesulphonic or naphthalenedisulphonic), salicylic, glutaric, gluconic, tricarballylic, cinnamic, substituted cinnamic (for example, phenyl, methyl, methoxy or halo substituted cinnamic, including 4-methyl and 4-methoxycinnamic acid), ascorbic, oleic, naphthoic, hydroxynaphthoic (for example 1- or 3-hydroxy-2-naphthoic), naphthaleneacrylic (for example naphthalene-2-acrylic), benzoic, 4-methoxybenzoic, 2- or 4-hydroxybenzoic, 4-chlorobenzoic, 4-phenylbenzoic, benzeneacrylic (for example 1 ,4-benzeπediacrylic) and isethionic acids. Pharmaceutically acceptable base salts include ammonium salts, for example those formed with pharmaceutically acceptable organic primary, secondary, and tertiary amines including aliphatic amines, aromatic amines, aliphatic diamines, and hydroxy alkylamines such as methylamine, ethylamine, 2-hydroxyethylamine, diethylamine, TEA, ethylenediamine, ethanolamine, diethanolamine, and cyclohexylamine; alkali metal salts such as those of lithium, sodium and potassium, alkaline earth metal salts such as those of calcium and magnesium, aluminum, and zinc salts; carbonates and bicarbonates of a pharmaceutically acceptable metal cation such as sodium, potassium, lithium, calcium, magnesium, aluminum, and zinc; and salts with organic bases such as dicyclohexylamine and Λ/-methyl-D-glucamine.
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. Hence, the compounds of formula (I) and pharmaceutically acceptable salts thereof may be of use in the treatment of inflammatory and/or allergic disorders.
Examples of 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.
The term "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.
It will be appreciated by those skilled in the art that reference herein to treatment extends to prophylaxis as well as the treatment of established conditions. As mentioned above, 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.
There is thus provided as a further aspect of the invention 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.
There is thus provided as a further aspect of the invention a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of rhinitis.
Further provided is 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.
According to another aspect of the invention, there is provided the use of 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.
According to another aspect of the invention, there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of rhinitis.
According to yet to another aspect of the invention, there is provided the use of 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.
In a further or alternative aspect, there is provided 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. In a further or alternative aspect, there is provided a method for the treatment of a human or animal subject with 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.
In yet a further or alternative aspect, there is provided 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.
Further, there is provided a process for the preparation of such pharmaceutical compositions which comprises mixing the ingredients. 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.
Pharmaceutical 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). 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.
Pharmaceutical 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. Generally, 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. However, as a general guide, suitable unit does may be about 0.001 to about 100mg, for example about 0.001 to about 1mg, 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 as used herein includes administration by insufflation and inhalation. Examples of various types of 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. In one embodiment, pharmaceutical 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.
Generally, 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.
For compositions suitable for intranasal or inhaled administration, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be in a particle-size- reduced form prepared by, for example, micronisation and milling. Generally, the size-reduced (e.g. micronised) compound can be defined by a D50 value of about 0.5 to about 10 microns (for example as measured using laser diffraction).
In one embodiment, pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof are suitable for intranasal administration. For example, 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. In one embodiment, the intranasal compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof are suitable for once daily administration. Typically, each spray to the nostril may deliver from about 25 to about 100μL of intranasal composition. Further, generally, each spray to the nostril may deliver from about 1 to about 100μg, for example about 1 to about 50μg, of the compound of formula (I) or a pharmaceutically acceptable salt thereof. Intranasal 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. Examples of 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.
For stability purposes, 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. Examples of 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), 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. Examples of pharmaceutically acceptable anti-fungal agents or preservatives may include sodium benzoate. In one embodiment, there is provided 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. Preservatives may be included in composition suitable for other routes of administration as appropriate.
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. Typically, the amount of wetting agent used will not cause foaming of the dispersion during mixing. Examples of 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. Examples of 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.
Further, 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.
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. In one embodiment, 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 excipients 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. 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. In one embodiment, 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. 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. There is thus provided as a further aspect of the invention 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.
According to another aspect of the invention, there is provided a pharmaceutical aerosol 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.
The formulations 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. Alternatively, 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, of for example gelatine, 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. Each capsule or cartridge may generally contain from 20μg to 10mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof. Alternatively, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be presented without excipients such as lactose.
Optionally, in particular for dry powder inhalable compositions, 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 DISKUS™ device, marketed by GlaxoSmithKline. The DISKUS™ 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 20μg to 10mg, preferably from 20μg to 2000μg, more preferably from 20μg to 500μg 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 100μg to 10mg, preferably from 200μg to 2000μg. 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.
In the case of suspension 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 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. Thus, for example, 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. As used herein reference to the "twin impinger" assay means "Determination of the deposition of the emitted dose in pressurised inhalations using apparatus A" as defined in British Pharmacopoeia 1988, pages A204-207, Appendix XVII C. Such techniques enable the "respirable fraction" of the aerosol formulations to be calculated. One method used to calculate the "respirable fraction" is by reference to "fine particle fraction" which is the amount of active ingredient collected in the lower impingement chamber per actuation expressed as a percentage of the total amount of active ingredient delivered per actuation using the twin impinger method described above.
The term "metered dose inhaler" or 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). Preferably 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.
In one embodiment of the invention the metallic internal surface of the can is coated with a fluoropolymer, most preferably blended with a non-fluoropolymer. In another embodiment of the invention the metallic internal surface of the can is coated with a polymer blend of polytetrafluoroethylene (PTFE) and polyethersulfone (PES). In a further embodiment of the invention 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. Spraymiser™).
In various embodiments, 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.
Conventional bulk manufacturing methods and machinery well known to those skilled in the art of pharmaceutical aerosol manufacture may be employed for the preparation of large-scale batches for the commercial production of filled canisters. Thus, for example, in one bulk manufacturing method for preparing suspension aerosol formulations 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 propellaπt 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. In one example bulk manufacturing method for preparing solution aerosol formulations, 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.
In an alternative process, 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.
Typically, in batches prepared for pharmaceutical use, 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. Such 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.
In one embodiment, there is provided a pharmaceutical composition 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. Examples of ophthalmic wetting/lubricating agents may include cellulose derivatives, dextran 70, gelatine, liquid polyols, polyvinyl alcohol and povidone such as cellulose derivatives and polyols.
For internal administration 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. In preparing solutions, 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. Optionally, adjuvants such as a local anaesthetic, preservatives and buffering agents may be dissolved in the vehicle. To enhance the stability, 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.
In some embodiments, 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 M1ZM2ZM3 receptor antagonist), p2-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 β2-adrenoreceptor agonist, an antiinfective agent such as an antibiotic or an antiviral, or an antihistamine. One embodiment of the invention encompasses combinations comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a β2-adrenoreceptor agonist, andZor an anticholinergic, and/or a PDE-4 inhibitor, andZor an antihistamine. One embodiment of the invention encompasses combinations comprising one or two other therapeutic agents.
It will be clear to a person skilled in the art that, where appropriate, 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.
Examples of β2-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 R-enantiomer), formoterol (which may be a racemate or a single diastereomer such as the R,R-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. In one embodiment the β2-adrenoreceptor agonists are long-acting β2-adrenoreceptor agonists, for example, compounds which provide effective bronchodilation for about 12 hours or longer.
Other β2-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.
Examples of β2-adrenoreceptor agonists include: 3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino) hexyl] oxy} butyl) benzenesulfonamide;
3-(3-{[7-({(2R)-2-hydroxy-2-[4-hydroxy-3-hydroxymethyl) phenyl] ethyl}-amino) heptyl] oxy} propyl) benzenesulfonamide;
4-{(1 R)-2-[(6-{2-[(2, 6-dichlorobenzyl) oxy] ethoxy} hexyl) amino]-1-hydroxyethyl}-2- (hydroxymethyl) phenol; 4-{(1 R)-2-[(6-{4-[3-(cyclopentylsulfonyl)phenyl]butoxy}hexyl)amino]-1-hydroxyethyl}-
2-(hydroxymethyl)phenol;
N-[2-hydroxyl-5-[(1 R)- 1 -hydroxy-2-[[2-4-[[(2R)-2-hydroxy-2- phenylethyl]amino]phenyl]ethyl]amino]ethyl]phenyl]formamide;
N-2{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-2-hydroxy-2-(8-hydroxy-
2(1 AV)-puinolinon-5-yl)ethylamine; and
5-[(f?)-2-(2-{4-[4-(2-amino-2-methyl-propoxy)-phenylamino]-phenyl}-ethylamino)-1- hydroxy-ethyl]-8-hydroxy-1 H-quinolin-2-one.
The β2-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.
Suitable anti-inflammatory agents include corticosteroids. Examples of 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, 6α,9α-difluoro-11 β-hydroxy-16α-methyl- 17α-[(4-methyl-1 ,3-thiazole-5-carbonyl)oxy]-3-oxo-androsta-1 ,4-diene-17β- carbothioic acid S-fluoromethyl ester, 6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]- 11 β-hydroxy-16α-methyl-3-oxo-androsta-1 ,4-diene-17β-carbothioic acid S- fluoromethyl ester (fluticasone furoate), 6α,9α-difluoro-11 β-hydroxy-16α-methyl-3- oxo-17α-propionyloxy- androsta-1 ,4-diene-17β-carbothioic acid S-(2-oxo-tetrahydro- furan-3S-yl) ester, 6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-(2,2,3,3- tetramethycyclopropylcarbonyl)oxy-androsta-1 ,4-diene-17β-carbothioic acid S- cyanomethyl ester and 6α,9α-difluoro-11 β-hydroxy-16α-methyl-17α-(1- methycyclopropylcarbonyl)oxy-3-oxo-androsta-1 ,4-diene-17β-carbothioic acid S- fluoromethyl ester, beclomethasone esters (for example the 17-propionate ester or the 17,21-dipropionate ester), budesonide, flunisolide, mometasone esters (for example mometasone furoate), triamcinolone acetonide, rofleponide, ciclesonide (16α,17-[[(R)-cyclohexylmethylene]bis(oxy)]-11 β,21-dihydroxy-pregna-1 ,4-diene- 3,20-dione), butixocort propionate, RPR-106541 , and ST-126. In one embodiment corticosteroids include fluticasone propionate, 6α,9α-difluoro-11 β-hydroxy-16α- methyl-17α-[(4-methyl-1 ,3-thiazole-5-carbonyl)oxy]-3-oxo-androsta-1 ,4-diene-17β- carbothioic acid S-fluoromethyl ester, 6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]- 11 β-hydroxy-16α-methyl-3-oxo-androsta-1 ,4-diene-17β-carbothioic acid S- fluoromethyl ester, 6α,9α-difluoro-11 β-hydroxy-16α-methyl-3-oxo-17α-(2,2,3,3- tetramethycyclopropylcarbonyl)oxy-androsta-1 ,4-diene-17β-carbothioic acid S- cyanomethyl ester and 6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-(1- methycyclopropylcarbonyl)oxy-3-oxo-androsta-1 ,4-diene-17β-carbothioic acid S- fluoromethyl ester. In one embodiment the corticosteroid is 6α,9α-difluoro-17α-[(2- furanylcarbonyl)oxy]-11 β-hydroxy-16α-methyl-3~oxo-androsta-1 ,4-diene-17β- carbothioic acid S-fluoromethyl ester.
Examples of 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.
Examples of anti-inflammatory agents include non-steroidal anti-inflammatory drugs (NSAID's).
Examples of NSAID's 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), cytokine antagonists (for example chemokine antagonists, such as a CCR3 antagonist) or inhibitors of cytokine synthesis, or 5- lipoxygenase inhibitors. An iNOS (inducible nitric oxide synthase inhibitor) is preferably for oral administration. Examples of iNOS inhibitors include those disclosed in WO93/13055, WO98/30537, WO02/50021 , WO95/34534 and WO99/62875. Examples of CCR3 inhibitors include those disclosed in WO02/26722.
In one embodiment 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. The 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]. Also, c/s-4-cyano-4-[3-(cyclopentyloxy)-4- methoxyphenyl]cyclohexane-1 -carboxylic acid (also known as cilomilast) and its salts, esters, pro-drugs or physical forms, which is described in U.S. patent 5,552,438 issued 03 September, 1996; this patent and the compounds it discloses are incorporated herein in full by reference.
Other compounds include 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 CI-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. et al. Eur Resp J [Annu Cong Eur Resp Soc (Sept 19-23, Geneva) 1998] 1998, 12 (Suppl. 28): Abst P2393); roflumilast (CAS reference No 162401-32- 3) and a pthalazinone (WO99/47505, the disclosure of which is hereby incorporated by reference) from Byk-Gulden; Pumafentrine, (-)-p-[(4aR*,10ftS*)-9-ethoxy- 1 ,2,3,4,4a,10b-hexahydro-8-methoxy-2-methylbenzo[c][1 ,6]naphthyridin-6-yl]-N,N- diisopropylbenzamide which is a mixed PDE3/PDE4 inhibitor which has been prepared and published on by Byk-Gulden, now Altana; arofylline under development by Almirall-Prodesfarma; VM554/UM565 from Vernalis; or T-440 (Tanabe Seiyaku; Fuji, K. et_aj. J Pharmacol Exp Ther,1998, 284(1): 162), and T2585. Further compounds are disclosed in the published international patent application WO04/024728 (Glaxo Group Ltd), WO04/056823 (Glaxo Group Ltd) and WO04/103998 (Glaxo Group Ltd).
Examples of anticholinergic agents are those compounds that act as antagonists at the muscarinic receptors, in particular those compounds which are antagonists of the M1 or M3 receptors, dual antagonists of the M1ZM3 or M2/M3, receptors or pan- antagonists of the MtIM2IM3 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). Also of interest are 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 YM-905 and sold under the name Vesicare).
Other anticholinergic agents include compounds which are disclosed in US patent application 60/487981 including, for example:
(3-endo)-3-(2,2-di-2-thienylethenyl)-8,8-dimethyl-8-azoniabicyclo[3.2.1]octane bromide;
(3-endo)-3-(2,2-diphenylethenyl)-8,8-dimethyl-8-azoniabicyclo[3.2.1]octane bromide;
(3-encto)-3-(2,2-diphenylethenyl)-8,8-dimethyl-8-azoniabicyclo[3.2.1]octane 4- methylbenzenesulfonate;
(3-encfo)-8,8-dimethyl-3-[2-phenyl-2-(2-thienyl)ethenyl]-8-azoniabicyclo[3.2.1]octane bromide; and/or
(3-eπdo)-8,8-dimethyl-3-[2-phenyl-2-(2-pyridinyl)ethenyl]-8- azoniabicyclo[3.2.1]octane bromide.
Further anticholinergic agents include compounds which are disclosed in US patent application 60/511009 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;
3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propionitrile;
(encfo)-8-methyl-3-(2,2,2-triphenyl-ethyl)-8-aza-bicyclo[3.2.1]octane;
3-((encfo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propionamide;
3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propionic acid;
(endo)-3-(2-cyano-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane iodide;
(endo)-3-(2-cyano-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane bromide;
3-((e/?do)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propan-1-ol;
Λ/-benzyl-3-((enc/o)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propionamide;
(endo)-3-(2-carbamoyl-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane iodide;
1-benzyl-3-[3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propyl]- urea;
1-ethyl-3-[3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propyl]-urea;
Λ/-[3-((eπdo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propyl]-acetamide;
Λ/-[3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propyl]-benzamide;
3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-di-thiophen-2-yl-propionitrile;
(endo)-3-(2-cyano-2,2-di-thiophen-2-yl-ethyl)-8,8-dimethyl-8-azonia- bicyc!o[3.2.1]octane iodide;
Λ/-[3-((e/7do)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propyl]- benzenesulfonamide;
[3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propyl]-urea;
Λ/-[3-((e/7do)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propyl]- methanesulfonamide; and/or
(endo)-3-{2,2-diphenyl-3-[(1-phenyl-methanoyl)-amino]-propyl}-8,8-dimethyl-8- azonia-bicyclo[3.2.1]octane bromide.
Further compounds include:
(endo)-3-(2-methoxy-2,2-di-thiophen-2-yl-ethyl)-8,8-dimethyl-8-azonia- bicyclo[3.2.1]octane iodide;
(eπc/o)-3-(2-cyano-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane iodide;
(eno/o)-3-(2-cyano-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane bromide; (endo)-3-(2-carbamoyl-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane iodide;
(e/7cfo)-3-(2-cyano-2,2-di-thiophen-2-yl-ethyl)-8,8-dimethyl-8-azonia- bicyclo[3.2.1]octane iodide; and/or
(eA7cyo)-3-{2,2-diphenyl-3-[(1-phenyl-methanoyl)-amino]-propyl}-8,8-dimethyl-8- azonia-bicyclo[3.2.1]octane bromide.
In one embodiment the invention provides a combination comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, together with an H1 antagonist. Examples of 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, temelastine, trimeprazine and triprolidine, particularly cetirizine, levocetirizine, efletirizine and fexofenadine. In a further embodiment 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). Examples of 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 et al., 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 βϊ-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 β2-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. In one embodiment, 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.
The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical composition and thus pharmaceutical 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 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 β2-adrenoreceptor agonist.
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 corticosteroid.
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 another non-steroidal GR agonist.
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 an anticholinergic.
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 an antihistamine.
The invention thus provides, in a further aspect, a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a PDE4 inhibitor and a β2-adrenoreceptor agonist.
The invention thus provides, in a further aspect, 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)
Figure imgf000035_0001
wherein R1 and R2 are as defined above for compounds of formula (I) with an amine R3NH2 wherein R3 is as defined above for compounds of formula (I).
This coupling may be conducted, for example, using HATU (O-(7-azabenzotπazoM- yl)-Λ/,Λ/,Λ/',Λ/-tetramethyluronιum hexafluorophosphate) in the presence of a suitable base such as Λ/,Λ/-dιιsopropylethylamιne in a suitable solvent such as DMF The coupling may also be conducted using alternative, conventional conditions for amide bond formation known in the art
Alternatively 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 R3 represents -CH2CONH2
The carboxylic acid (II) may be obtained by deprotection of a suitable protected derivative (III)
Figure imgf000035_0002
wherein R1 and R2 are as defined above for compounds of formula (I) and P1 represents a suitable ester protecting group, for example a benzyl or tert-butyl ester In the case of the benzyl protecting group, deprotection may be conveniently conducted by hydrogenolysis over palladium on carbon in ethanol In the case of 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 P.J. Kocienski (Georg Thieme Verlag 1994).
Intermediates of formula (III) may be obtained by reaction of a tosylate of formula (IV) or an epoxide of formula (V)
Figure imgf000036_0001
Figure imgf000036_0002
1 = chiral centre
wherein P1 represents a suitable ester protecting group as defined above for compound (III) with an amine of formula R1R2NH2 wherein R1 and R2 are as defined above for compounds of formula (I). The reaction may be carried out in a conventional organic solvent, for example dichloromethane, THF, DMF or acetonitrile at a temperature from -100C to 1000C, for example at room temperature. Alternatively the reaction may be conducted in a microwave reactor at for example 100°C to 1300C in for example DMF or alternatively in the absence of solvent.
Compounds of formula (IV) may be prepared by reaction of a 4-amino-1-arylindazole of formula (Vl)
Figure imgf000036_0003
wherein P1 is an ester protecting group as defined above for compounds of formula (III) with an epoxy tosylate of formula (VII)
Figure imgf000037_0001
" = chiral centre (VII)
The 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. The tosylate (IV) may react further under these reactions conditions to give an epoxide (V). Alternatively, the epoxide (V) may be deliberately prepared by cyclisation of the tosylate (IV) using, for example, polymer supported carbonate resin in a suitable solvent such as tetrahydrofuran.
The aminoindazole of formula (Vl) may be prepared by reaction of 6-methyl-1 H- indazol-4-amine (VIII):
Figure imgf000037_0002
with an iodobenzene of formula (IX)
Figure imgf000037_0003
(IX)
wherein P1 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 ligand such as L-proline, cyclohexanediamine, Λ/./V-dimethylcyclohexanediamine or Λ/./V-dimethylethylenediamine in a variety of solvents including toluene, dioxane, Λ/,Λ/-dimethylformamide, Λ/,Λ/-dimethylacetamide and dimethylsulfoxide at a temperature in the range 60-1600C, most typically 1100C. 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.
Alternatively compounds of formula (Vl) may be prepared by similar reaction of 6- methyl-4-nitro-1 H-indazole (X)
Figure imgf000038_0001
with an iodobenzene of formula (IX) followed by reduction of the nitro group by, for example, hydrogenation over palladium on carbon.
The amino and nitro indazoles of formulae (VIII) and (X) have been described in the literature: Journal of the Chemical Society, 1955, 2412-2423.
Alternatively the intermediate 4-nitro-1-arylindazoles of formula (Xl)
Figure imgf000038_0002
wherein P1 is an ester protecting group as defined above for compounds of formula (III), may be prepared by reaction of 4-methyl-2,6-dinitrobenzaldehyde (XII)
Figure imgf000038_0003
with a phenylhydrazine of formula (XIII)
Figure imgf000039_0001
(XIII) wherein P1 is an ester protecting group as defined above for compounds of formula (III), followed by base catalysed cyclisation of the intermediate phenylhydrazones using the methodology described in the literature: Berichte, 1925, 58B, 1369-1375.
Alternatively aminoindazoles of formula (Vl) may be prepared from the corresponding bromoindazoles of formula (XIV)
Figure imgf000039_0002
wherein P1 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.
Compounds of formula (XIV) may be prepared by cyclisation of hydrazones of formula (XV)
Figure imgf000039_0003
wherein P1 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. For example, the cyclisation may be effected using tris(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 (XV) may be prepared by reaction of 4-methyl-2,6- dinitrobenzaldehyde (XII) with a hydrazine of formula (XIII).
4-Methyl-2,6-dinitrobenzaldehyde (XII) is known and may be prepared as described by Lulinski and Serwatowski in J. Org. Chem., 2003, 68, 5384-5387.
Aryl hydrazines (XIII) 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 (XVI)
Figure imgf000040_0001
with a polymer supported carbonate resin. 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 -100C to 1000C, for example at room temperature for a batch process or at about 500C for a flow process.
Compound (XVI) may be prepared by treating the triol (XVII)
F3C OH HO^y^OH
(XVII) with 4-methylbenzenesulphonyl chloride in the presence of an organic base, for example pyridine. The reaction may be carried out at a temperature of from -100C to 1000C, for example at room temperature. Alternatively, when a flow process is used, the compound of formula (XVIII) may be treated with 4-methylsulphonyl chloride in the presence of an organic base, for example Λ/,Λ/,Λ/',Λ/'-tetramethyl-1 ,6- hexanediamine, in dichloromethane at room temperature.
The compound of formula (XVII) may be prepared by treating a compound of formula (XVIII)
Figure imgf000041_0001
(XVlII)
with a transition metal catalyst, for example 5% palladium on carbon, in the presence of a hydrogen atmosphere. The 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 -100C to 1000C, for example at room temperature for a batch process or at about 800C for a flow process.
A compound of formula (XVIII) may be prepared by treating a compound of formula (XIX)
Figure imgf000041_0002
(XlX)
with trimethyl(trifluoromethyl)silane and tetra-n-butylammonium fluoride. 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 -100C to 100°C, for example at 00C rising to room temperature.
A compound of formula (XIX) may be prepared by oxidation of 1 ,3-dibenzylglycerol. In one embodiment, the oxidation may be carried out using 3A molecular sieves, N- methylmorpholine Λ/-oxide and tetrapropylammonium perruthenate in dichloromethane at 00C to reflux, for example at room temperature. In another embodiment, 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 00C to 50°C, for example at room temperature. In a further embodiment, the oxidation may be carried out using sulphur trioxide-pyridine complex in the presence of base such as triethylamine in dimethylsulphoxide at 100C to 500C1 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), (VII), (IX), (Xl), (XIII), (XIV), (XV) and (XVI) 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).
Alternatively, 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 invention will now be illustrated by way of the following non-limiting examples.
EXAMPLES
General
Abbreviations
BINAP (2,2'-bis(diphenylphosphino)-1 ,1'-binaphthyl)
CDCI3 Deuterochloroform
DCM Dichloromethane
DMF Λ/, Λ/-Dimethylformamide
DMSO Dimethylsulphoxide
Et Ethyl
EtOAc Ethyl acetate
EtOH Ethanol
HATU O-(7-Azabenzotriazol-1-yl)-Λ/,Λ/,Λ/',Λ/'-tetramethyluronium hexafluorophosphate
HCI Hydrochloric acid
HPLC High pressure chromatography
1Pr lsopropyl
KOH Potassium hydroxide
LCMS Liquid chromatography/mass spectrometry
Me Methyl
MeCN Acetonitrile
MeOH Methanol
MgSO4 Magnesium sulphate
NaCI Sodium chloride
NMR Nuclear magnetic resonance nPr N-propyl
RT Room temperature
SPE Solid phase extraction
TBAF Tetra-n-butyl ammonium fluoride
TFA Trifluoroacetic acid
THF Tetrahydrofuran
Chromatographic purification
Chromatographic purification was performed using pre-packed silica gel cartridges. 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.
Mass Directed Autopreparative HPLC
Purifications were carried out using a Micromass ZQ platform. The column was a 100mm x 20mm Supelco LCABZ++ with stationary phase particle size of 5μm.
Solvents: A: water + 0.1 % formic acid
B: MeCN:water 95:5 + 0.05% formic acid Gradient 50-90% B over 10 minutes Flow rate 20 mL/min
LCMS System
The LCMS systems used were as follows: System A:
• Column: 3.3cm x 4.6mm ID, 3μm ABZ+PLUS from Supelco
• Flow Rate: 3mL/min
• Injection Volume: 5μL
• Temp: RT
• UV Detection Range: 215 to 330nm
Solvents: A: 0.1 % Formic Acid + IOmMolar Ammonium Acetate. B: 95% Acetonitrile + 0.05% Formic Acid
Gradient: Time (min) A% B%
0 100 0
0.7 100 0
4.2 0 100
5.3 0 100
5.5 100 0 System B:
• Column: 50mm x 2.1 mm ID, 1.7μm Acquity UPLC BEH Ci8
• Flow Rate: 1 mL/min
• Injection Volume: 0.5μL
• Temp: 4O0C
• UV Detection Range: 220 to 330nm
Solvents: A: 0.1% Formic Acid + 1OmM Ammonium Acetate. B: 95% Acetonitrile + 0.05% Formic Acid
Gradient: Time (mm) A% B%
0 97 3
0.1 97 3
1.4 0 100
1.9 0 100
2 97 3
NMR
1H NMR spectra were recorded in either CDCI3 or DMSOd6 on either a Bruker DPX 400 or Bruker Avance DRX or Varian Unity 400 spectrometer all working at 400 MHz. The internal standard used was either tetramethylsilane or the residual protonated solvent at 7.25 ppm for CDCI3 Or 2.50 ppm for DMSOd6.
Intermediate 1 : 1.3-Bisf(phenylmethyl)oxy1-2-propanone
Figure imgf000045_0001
Method A
Powdered 3A Molecular sieve (5Og) was dried at 1000C in a vacuum oven. The sieves and Λ/-methylmorpholine N-ox\άe (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 was stirred at 210C for 23 hr before being filtered through Celite It was then washed with 2M HCI (40OmL) and saturated brine (50OmL) The combined aqueous washings were filtered through Celite and re-extracted with dichloromethane (50OmL) and then this was washed with saturated brine (20OmL) The organic extracts were combined, dried over anhydrous magnesium sulphate and concentrated under reduced pressure to give a dark oil (43.6g). Diethyl ether (ca 20OmL) was added and the resultant black solid was filtered off. The filtrate was concentrated under reduced pressure to give the title compound (42g) as a grey white solid
1H-NMR (CDCI3, 400 MHz) δ ppm 7.31 - 7.40 (m, 10 H) 4.59 (s, 4 H) 4.26 (s, 4 H) LCMS (System A) tRET = 3.27 mm, MH+ = 288
Method B
A mixture of sodium hypochlorite (10OmL, 13%w/v) and saturated sodium bicarbonate (25mL) was added in one portion to a stirred solution of 1 ,3-dιbenzyloxy- 2-propanol (10g), 2,2,6,6-tetramethyl-1-piperιdιnyloxy free radical, (TEMPO) (0 3g) in toluene (4OmL) The biphasic mixture was stirred at 20-250C for 15 minutes when HPLC analysis showed reaction to be complete. The reaction mixture was stirred for a total of 25 minutes at 23°C The reaction mixture was separated and the organic extract was washed with 5%w/v sodium thiosulphate solution (4OmL) and separated. The organic extract was washed with 1 %w/v sodium chloride solution (2 x 25mL) The organic extract was then concentrated in vacuo to give an oil which crystallised on standing to give the title compound (8.8g). The 1H-NMR spectrum of the product was concordant with a reference sample
Method C
A mixture of sulphur trioxide/pyridine complex (2.33g) and triethylamine (2.05mL) in DMSO (3mL) was stirred to give a pale yellow solution. To this was added a solution of 1 ,3-dιbenzyloxy-2-propanol (1g) in DMSO (1ml) over 2 minutes. (The reaction mixture was kept in a water bath). The temperature of the reaction mixture reached 300C. After 10 minutes the water bath was removed and the reaction mixture was stirred at room temperature (ca 20 - 25°C) for 3hr. 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 (1OmL) The separated organic extract was concentrated in vacuo to give the title compound as an oil which solidified (0.75g) The 1H-NMR spectrum of the product was concordant with a reference sample Method D
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°C via a Huber Unistat 360 unit.
Two solutions were prepared. Solution A - 1 ,3-dibenzyloxy-2-propanol 120g, 440mmol) in acetonitrile (489mL). Solution B - tetrapropylammonium perruthenate (7.72g, 22mmol, 5mol%) and Λ/-methylmorpholine Λ/-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 total reacted solution was split equally into 2 batches and each was concentrated in vacuo. Diethyl ether (25OmL) was added before being washed successively with sodium sulphite, brine, cupric sulphate then filtered through Celite, dried and evaporated. The batches were recombined to give upon evaporation in vacuo the title compound (71.64g). The 1H-NMR spectrum of the product was concordant with a reference sample.
Intermediate 2: 1.1 ,1-Trifluoro-3-r(phenylmethyl)oxy1-2-lf(phenylmethyhoxylmethyl>- 2-propanol
Figure imgf000047_0001
Method A
To a solution of 1 ,3-bis[(phenylmethyl)oxy]-2-propanone (42g, 155mmol) in anhydrous tetrahydrofuran (60OmL) was added trimethyl(trifluoromethyl)silane (35mL, 236mmol). The mixture was then cooled in an ice/ethanol bath to -30C before tetrabutylammonium fluoride (1 M in THF, 18OmL, 180mmol) was added dropwise (initial 1 OmL of addition resulted in a slight exotherm with the temperature rising to 9°C before being allowed to cool to 6°C and then the addition was resumed, the temperature dropping to the range of -1 °C to +3°C). The addition was completed after 30 minutes. The mixture was stirred for a further 4hr during which gas was evolved all the time and then 2M HCI (75OmL) was added with stirring. Diethyl ether (60OmL) was added and the separated aqueous phase was re-extracted with diethyl ether (1 x 60OmL, 1 x 30OmL) and the combined organic extracts were washed with saturated brine (30OmL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to give an oil (52.9g). This oil was purified via flash chromatography (Silica, 80Og) using cyclohexane:ethyl acetate (9:1) as eluent to give the title compound, as a yellow oil (39.5g).
1H-NMR: (CDCI3, 400 MHz) δ ppm 7.29 - 7.39 (m, 10 H) 4.60 (s, 4 H) 3.72 (s, 4 H)
3.38 (s, 1 H).
LCMS (System A): tREτ = 3.69 min; MH+ = 358
Method B
A mixture of 1 ,3-bis[(phenylmethyl)oxy]-2-propanone (2g),
(trifluoromethyl)trimethylsilane (2.56mL, 2.3 equivalents) in dichloromethane (2OmL) was stirred and cooled to 00C. A solution of 1 M tetrabutylammonium fluoride in THF (4mL) was added dropwise over 3minutes. Initial addition of a few drops gave an exotherm of 100C. Throughout the addition the batch temperature was maintained below 10°C. After completing the addition the dark brown mixture was stirred at +5°C for 5 minutes when HPLC analysis indicated the reaction to be complete. The reaction mixture was stirred for an additional 5 minutes and then washed with 1 M HCI (2 x 15mL), saturated sodium bicarbonate (15mL) and 1 %w/v aqueous sodium chloride solution (2 x 15mL). The organic extract was concentrated in vacuo to give the title compound (2.5g) as a dark oil. The 1H-NMR spectrum was concordant with a reference sample.
Method C
A solution of tetrabutylammonium fluoride trihydrate (2.9g) in THF (5mL) was added cautiously over 3 minutes to a stirred and cooled (+15°C) solution of 3- bis[(phenylmethyl)oxy]-2-propanone (5g) and (trifluoromethyl)trimethylsilane (7.5mL) in toluene. There was an exotherm and a lot of gas evolution on addition of the first 1 mL of TBAF solution and the temperature rose from 18 to 400C. The mixture was stirred at 15-300C for a further 2 minutes and then cooled to +100C while carrying out an HPLC analysis. The reaction mixture was washed sequentially with 1 M 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 1H-NMR spectrum was concordant with a reference sample and showed the presence of residual toluene (8.8%) and starting material (ca Method D
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.
Two solutions were prepared. 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 (1 M in THF, 265mL, 132.5mmol).
Solutions A and B were pumped through the Cytos Lab System with a flow rate of 6.4mL/min and a 5 minute residence time giving a total reaction time of 82 minutes. The reaction mixture was quenched with 2M HCI (3OmL) and then divided into 2 equal batches. Diethyl ether (10OmL) was added, extracted and then washed with brine (2 x 10OmL), dried (MgSO4) and evaporated to give a residue (82.99g). Part of the residue was taken up in dichloromethane and applied to SPE silica cartridges. Using 10% hexane in dichloromethane as eluant and concentration of the relevant 15mL fractions, the title compound was obtained. The bulk of the crude sample was purified on the Combiflash Companion XL, 8g of material was run on a 12Og column with a solvent gradient of 10%-70% dichloromethane in hexane as eluent. Any mixed fractions from each run were combined and re-purified in an identical manner. All pure fractions were combined and evaporated to give the title compound (68.68g). The 1H-NMR spectrum was concordant with a reference sample.
Intermediate 3: 2-(Trifluoromethyl)-1.2,3-propanetriol
F3C OH
Method A
A solution of 1 ,1 ,1-trifluoro-3-[(phenylmethyl)oxy]-2-{[(phenylmethyl)oxy]methyl}-2- propanol (98.9g, 290.9mmol) in ethanol (175OmL) was added to 5% palladium on carbon (9.73g, wet, Degussa, E101 HoIW) under nitrogen. The mixture was then stirred under an atmosphere of hydrogen using a Wright valve in a 5L hydrogenation vessel. After approximately 3hr most of the theoretical volume of hydrogen had been taken up (approximately a further 1 L of hydrogen had been taken up overnight). After stirring under hydrogen overnight, the catalyst was filtered off through a pad of Celite and the pad washed with ethanol. The filtrate and washings were then concentrated under reduced pressure and the residue azeotroped (x2) with dichloromethane whereupon the residue solidified. This material was left on the vacuum pump at 400C overnight to give the title compound as an off-white solid (48.56g).
1H-NMR: (CDCI3, 400 MHz) δ ppm 5.65 (s, 1 H) 4.89 (t, 2 H) 3.54 (d, J=5.8 Hz, 4 H).
LCMS (System A): tRET = 0.42 min; MH" = 159
Method B
Preparation employing the Thales H-Cube hydrogenator and milligat pump in full hydrogen mode. A solution of 1 ,1 ,1-trifluoro-3-[(phenylmethyl)oxy]-2- {[(phenylmethyl)oxy] methyl}-2-propanol (58g) in ethanol (58OmL) was prepared. The flow rate was 1.3mL/min, the temperature was set to 800C and the cartridge employed was a 10%Pd/C Cat Cart 70 which was replaced every 2 hr. Any fractions which still contained starting material and the mono benzyl intermediate were reprocessed. All pure fractions were combined and evaporated to give the title compound (26.48g). The 1H-NMR spectrum was concordant with a reference sample.
Intermediate 4j 3.3,3-Trifluoro-2-hydroxy-2-({f(4- methylphenyl)sulfonylloxy)methyl)propyl 4-methylbenzenesulfonate
Figure imgf000050_0001
Method A
To a stirred and cooled (ice) solution of 2-(trifluoromethyl)-1 ,2,3-propanetriol (18.9g, 118mmol) in pyridine (20OmL) was added p-toluenesulphonyl chloride (67g, 351 mmol) to give an orange solution. The ice bath was removed after 45 minutes and stirring was continued for 21 hr during which time a precipitate was formed. Most of the pyridine was removed under reduced pressure and the residue was partitioned between ethyl acetate (50OmL) and water (30OmL). The separated aqueous phase was further extracted with ethyl acetate (25OmL) and the combined organic extracts were washed with 2M HCI (20OmL), water (20OmL), 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 ethyl acetate (5 1) to give the title compound (49g) as an oil which crystallised on standing 1H-NMR (CDCI3, 400 MHz) δ ppm 7.78 (d, J=8 3 Hz, 4 H) 7 38 (d, J=8.3 Hz, 4 H) 4 18 (s, 4 H) 3.66 (s, 1 H) 2 48 (s, 6 H) LCMS (System A) tRET = 3 62 mm, MNH4 + 486.
Method B
The title compound was prepared via a 'flow' process using a CPC Cytos Lab System Two solutions were prepared Solution A, 2-(tπfluoromethyl)-1 ,2,3- propanetriol (4 5g, 27 δmmol), Λ/,Λ/,Λ/',Λ/-tetramethyl-1 ,6-hexanedιamιne (3OmL, 139mmol) in dichloromethane (55OmL) Solution B, p-toluenesulphonyl chloride (21 4g 111mmol) in dichloromethane (55OmL)
Solutions A and B were pumped through a CPC Cytos reactor (reactor volume 47mL) at a flow rate each of 2 35mL/mιn It was noted that the pressure for the pump containing solution B was fluctuating After 110 minutes, the reaction was abandoned as it was evident that the pumps were not operating 1 1 The collected material was quenched into saturated aqueous ammonium chloride and the aqueous phase re- extracted with dichloromethane (x3). The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated to give a residue which was discarded The pump was replaced and the remainder of the reagents were reacted The collected material was quenched into saturated aqueous ammonium chloride and the aqueous phase re-extracted with dichloromethane (x3) The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated to give a residue which was adsorbed onto silica and eluted over a silica column (12g) with dichloromethane hexane (1 1) Four fractions were eluted and fraction 4 gave the title compound (2 31 g) The 1H-NMR spectrum was concordant with a reference sample
Intermediate 5 f2-(Trιfluoromethvl)-2-oxιranyllmethvl 4-methvlbenzenesulfonate
Figure imgf000051_0001
Method A A solution 3,3-trifluoro-2-hydroxy-2-({[(4-methylphenyl) sulfoπyl]oxy}methyl)propyl 4-methylbenzenesulfonate (186.5g, 398.5mmol) in dichloromethane (250OmL) was stirred under nitrogen whilst polymer supported carbonate resin (Fluka, ca. 3.5mmoles carbonate/g resin, 232g) was added. The mixture was stirred at room temperature overnight. The resin was filtered off and washed with dichloromethane. The combined filtrate and washings were concentrated under reduced pressure to give the title compound (116.2g) as a brown oil.
1H-NMR: (CDCI3, 400 MHz) δ ppm 7.80 (d, J=8.3 Hz, 2 H) 7.38 (d, J=8.0 Hz, 2 H) 4.41 (d, .M 1.9 Hz, 1 H) 4.29 (d, J=11.9 Hz, 1 H) 3.14 (d, J=4.8 Hz, 1 H) 3.01 (dd, J=4.5, 1.5 Hz, 1 H) 2.47 (s, 3 H). LCMS (System A): tRET = 3.2 min; MNH4 + = 314
Method B
3,3,3-Trifluoro-2-hydroxy-2-({[(4-methylphenyl) sulfonyl]oxy}methyl)propyl 4- methylbenzenesulfonate (14.29g, 29mmol) in dichloromethane (75mL) was pumped through a cartridge containing PS-carbonate resin (not pre-swelled) (3mmol/g, 25g, 75mmol) at 675 microlitres/min. The temperature was set to approx. 500C by wrapping a Whatman thin film heater around the cartridge. The pressure was regulated at 40psi. After all the reagent had been aspirated, the column was washed through with dichloromethane - at this point the column started to leak slightly and the back pressure regulator had to be removed to reduce the pressure. The collected solution was concentrated in vacuo to afford the title compound (7.24g). The 1H-NMR spectrum was concordant with a reference sample.
Intermediate 6: Phenvlmethyl 3-(4-amino-6-methyl-1 /-/-indazol-1-vhbenzoate
Figure imgf000052_0001
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) and frans-Λ/, /V-dimethyl-1 ,2-cyclohexanediamine (20mg, 0.14mmol) were heated together in DMF (5mL) at reflux overnight. The mixture was poured into water (15ml_) and ethyl acetate was added to dissolve the resulting oil. The suspension was then filtered through celite. The organic phase was separated, combined with a second ethyl acetate extract, washed successively with water and brine and then dried over anhydrous sodium sulphate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (75g) eluting with 1 to 5% gradient of ethyl acetate in dichloromethane to give the title compound as a light brown oil (0.3g).
1H-NMR: (CDCI3, 400 MHz) δ 8.46 (t, 1 H), 8.10 (s, 1 H), 8.06 (m, 1 H), 7.96 (m, 1 H), 7.61 (t, 1 H), 7.49 (m, 2H), 7.42 (m, 2H), 7.38 (m, 1 H), 6.96 (s, 1 H), 6.31 (s, 1 H), 5.44 (s, 2H), 4.15 (m, 2H), 2.42 (s, 3H)
Intermediate 7: 1.1-Dimethylethyl 3-(4-amino-6-methyl-1 /-V-indazol-1-yl)benzoate
Figure imgf000053_0001
1 ,1-Dimethylethyl 3-iodobenzoate (10.2g, 33.55mmol), copper (I) iodide (64mg, 0.335mmol), frans-1 ,2-cyclohexanediamine (380mg, 2.7mmol) and tripotassium phosphate (14.94g, 70.46mmol) were added to a solution of 6-methyl-1 H-indazol-4- amine (4.93g, 33.55mmol) in dry 1 ,4-dioxane (35mL) and the mixture heated to 11 O0C under nitrogen for 18 hours. The mixture was then cooled and poured into water (50OmL) and extracted with ethyl acetate (50OmL). The organic phase was separated, dried over anhydrous magnesium sulphate and evaporated under reduced pressure and the residue was purified by chromatography on a silica gel cartridge (33Og) using a Combiflash Companion XL system and a gradient of cyclohexane and ethyl acetate to give the title compound as a pale brown glassy solid (10g). LCMS (System A): tRET = 4.57 min; MH+ = 324
Intermediate 8: Phenylmethyl 4-(4-amJno-6-methyl-1 H-indazol-1-yl)benzoate
Figure imgf000054_0001
6-Methyl-1 /-/-indazol-4-amine (5.48g, 37.3mmol), copper (I) iodide (71 mg, 0.37mmol), frans-1 ,2-cyclohexanediamine (420mg, 0.37mmol) and tripotassium phosphate (16.6g, 78.3mmol) were added to a solution of phenylmethyl 4-iodobenzoate (12.61g, 37.3mmol) in 1 ,4-dioxane (2OmL). More 1 ,4-dioxane (3OmL) was added and the mixture heated under reflux for 3 hours 15 min and then allowed to gradually cool to room temperature and partitioned between water and ethyl acetate. The aqueous phase was extracted once more with ethyl acetate and the combined organic extracts were washed with brine and dried and evaporated to give a brown solid (13.58g). This crude product was combined with material (0.66g) from a similar reaction and purified by column chromatography on silica gel (Merck 7734, 50OmL) eluting initially with 10% and finally with 20% ethyl acetate in dichloromethane. Evaporation of product containing fractions gave a brown-yellow solid (5.12g) which was dissolved in ethyl acetate (4OmL) at 60° and warm cyclohexane (7OmL) was added. The mixture was then cooled in ice and the precipitate was collected by filtration, washed with cyclohexane:ethyl acetate (4:1 , 4OmL) and dried to give the title compound as a beige solid (4.29g). LCMS (System A): tRET = 3.77 min; MNH4 + = 358
Intermediate 9: Phenylmethyl 3-(6-methyl-4-ir3.3.3-trifluoro-2-hvdroxy-2-g[(4- methylphenyl)sulfonyl1oxy>methyl)propyπamino>-1 /-/-indazol-1-yl)benzoate
Figure imgf000054_0002
4A Molecular sieves (300mg), [2-(trifluoromethyl)-2-oxiranyl]methyl A- methylbenzenesulfonate (1.8g, 6.08mmol) and ytterbium (III) triflate (630mg, 1.014mmol) were added to a solution of phenylmethyl 3-(4-amino-6-methyl-1 H- indazol-1-yl)benzoate (1.81g, 5.07mmol) in dry acetontrile (5mL) and the mixture stirred under nitrogen at 20°C for 72 hours. The solvent was then evaporated, dichloromethane (2OmL) was added and the mixture filtered and the filtrate purified by silica gel chromatography using a Flashmaster Il (10Og cartridge) eluting with a gradient of cyclohexane and ethyl acetate to give the title compound as a brown glassy solid (2.3g). LCMS (System A): tRET = 4.08 min; MH+ = 654
Intermediate 10: Phenylmethyl 3-f6-methyl-4-ffl2-(trifluoromethvh-2- oxiranvπmethyl)amino)-1 /-/-indazol-1-yllbenzoate
Figure imgf000055_0001
Polymer supported carbonate resin (3mmol/g, 0.437g) and 4A molecular sieves (0.5g) were added to a solution of phenylmethyl 3-(6-methyl-4-{[3,3,3-trifluoro-2- hydroxy-2-({[(4-methylphenyl)sulfonyl]oxy}methyl)propyl]amino}-i H-indazol-1- yl)benzoate (1g, 1.53mmol) in dry THF (2OmL) and the mixture gently agitated for 18 hours. The mixture was then filtered, washing through with THF (2 x 1 OmL) and the filtrate evaporated to give the title compound as a brown gum (0.737g). LCMS (System B): tRET = 1.51 min; MH+ = 482
Intermediate 11 : 1 ,1-Dimethylethyl 3-(6-methyl-4-fr3.3.3-trifluoro-2-hvdroxy-2-(fl(4- methvlphenvl)sulfonvl1oxv>methvl)propvl1amino)-1 /-/-indazol-1-yl)benzoate
Figure imgf000055_0002
4A Molecular sieves (100mg), [2-(trifluoromethyl)-2-oxiranyl]methyl 4- methylbenzenesulfonate (352mg, 1.19mmol) and ytterbium (III) triflate (123mg, 0.199mmol) were added to a solution of 1 ,1-dimethylethyl 3-(4-amino-6-methyl-1 H- indazol-1-yl)benzoate (320mg, 0.99mmol) in dry acetontrile (1.5mL) and the mixture stirred at 2O0C for 6 hours when more ytterbium (III) triflate (123mg) was added and stirring continued for a further 18 hours. A further portion of ytterbium (III) triflate (123mg) was then added and the mixture stirred for a further 18 hours. The solvent was then evaporated, dichloromethane (1OmL) was added and the mixture filtered and the filtrate purified by silica gel chromatography using a Flashmaster Il (50g cartridge) eluting with a gradient of cyclohexane and ethyl acetate to give the title compound as a pale brown glassy solid (2.3g). LCMS (System A): tRET = 4.10 min; MH+ = 620
Intermediate 12: 1 , 1 -Dimethylethyl 3-r6-methyl-4-(ir2-(trif1uoromethyl)-2- oxiranyllmethyl>amino)-1 /-/-indazol-1 -ylibenzoate
Figure imgf000056_0001
Prepared similarly to Intermediate 10 from 1 ,1-dimethylethyl 3-(6-methyl-4-{[3,3,3- trif|uoro-2-hydroxy-2-({[(4-methylphenyl)sulfonyl]oxy}methyl)propyl]amino}-1 H- indazol-1-yl)benzoate.
LCMS: tRET = 3.93 min; MH+ = 448
Intermediate 13: Phenylmethyl 3-{4-r(2-{rethyl(1-methylethyl)amino1methyl>-3,3,3- trifluoro-2-hvdroxypropyl)amino1-6-methyl-1 /-/-indazol-1-yl)benzoate
Figure imgf000056_0002
Ethyl(1-methylethyl)amine (40mg, 0.459mmol) was added to a solution of phenylmethyl 3-[6-methyl-4-({[2-(trifluoromethyl)-2-oxiranyl]methyl}amino)-1 /-/- indazol-1-yl]benzoate (100mg, 0.153mmol) in dry dichloromethane (4mL) and the mixture left at 2O0C for 18 hours. Purification on a 10g silica gel SPE cartridge using a gradient of cyclohexane and ethyl acetate gave the title compound as a colourless gum (67mg). LCMS (System B): tRET = 1.44 min; MH+ = 569
Intermediate 14: 3-{4-f(2-{fEthyl(1-methylethyl)aminolmethylV3.3.3-trifluoro-2- hvdroxypropyl)amino1-6-methyl-1 /-/-indazol-1-yllbenzoic acid
Figure imgf000057_0001
A solution of phenylmethyl 3-{4-[(2-{[ethyl(1-methylethyl)amino]methyl}-3,3,3-trifluoro- 2-hydroxypropyl)amino]-6-methyl-1 /-/-indazol-1-yl}benzoate (67mg) in ethanol (2OmL) was hydrogenated at 2O0C over 10% Palladium on carbon using an H-cube apparatus operating at a pressure of 1 bar and a flow rate of 1mL/min. Removal of the solvent under a stream of nitrogen afforded the title compound. LCMS (System B): tRET = 0.99 min; MH+ = 479
Intermediate 15: Phenylmethyl 3-f4-r(2-ffbis(1-methylethyl)aminolmethyl}-3,3,3- trifluoro-2-hvdroxypropyl)aminol-6-methyl-1/-/-indazol-1-yl>benzoate
Figure imgf000057_0002
Bis(1-methylethyl)amine (0.048mL, 0.345mmol) was added to a solution of phenylmethyl 3-[6-methyl-4-({[2-(trifluoromethyl)-2-oxiranyl]methyl}amino)-1 /-/- indazol-1-yl]benzoate (0.11g, 0.229mmol) in dry acetonitrile (2mL) and the mixture left at room temperature for 18 hours. More bis(1-methylethyl)amine (0.1mL) was then added and the mixture allowed to stand at room temperature for a further 72 hours. The solvent was removed, more bis(1-methylethyl)amine (0.1 mL) was added and the mixture heated in a microwave reactor at 1000C for 10 min. The mixture was evaporated and the residue dissolved in dichloromethane (5ml) and purified on a 10g silica gel SPE cartridge using a gradient of cyclohexane and ethyl acetate to give the title compound as a colourless oil (40mg). LCMS (System A): tRET = 3.99 min; MH+ = 583
Intermediate 16: 3-(4-f(2-frBis(1-methylethyl)amino1methyl)-3,3,3-trifluoro-2- hvdroxypropyl)aminol-6-methyl-1 A7-indazol-1-yl)benzoic acid
Figure imgf000058_0001
Prepared similarly to Intermediate 14 by hydrogenolysis of phenylmethyl 3-{4-[(2-
{[bis(1-methylethyl)amino]methyl}-3,3,3-trifluoro-2-hydroxypropyl)amino]-6-methyl-
1 /-/-indazol-1 -yljbenzoate.
LCMS (System A): tRET = 3.11 min; MH+ = 493
Intermediate 17: Phenylmethyl 3-f6-methyl-4-r(3.3.3-trifluoro-2-hvdroxy-2-W1- methylethyl)(phenyl)amino1methyl)propyl)amino1-1 H-indazol-1-yl)benzoate
Figure imgf000058_0002
A mixture of phenylmethyl 3-[6-methyl-4-({[2-(trifluoromethyl)-2- oxiranyl]methyl}amino)-1H-indazol-1-yl]benzoate (0.11g, 0.229mmol) and (1- methylethyl)phenylamine (0.5mL) was irradiated in a microwave reactor at 10O0C for two periods of 10 min followed by two periods of 20 min at which point LCMS indicated complete reaction. The mixture was poured directly onto a 2Og silica gel SPE cartridge and eluted with a gradient of cyclohexane and ethyl acetate to give the title compound as a colourless gum (60mg). LCMS (System A): tRET = 4.37 min; MH+ = 617
Intermediate 18: 3-f6-Methyl-4-r(3,3,3-trifluoro-2-hvdroxy-2-fr(1- methylethyl)(phenyl)aminolmethyl)propyl)amino1-1 /-/-indazol-1 -vDbenzoic acid
Figure imgf000059_0001
A solution of phenylmethyl 3-{6-methyl-4-[(3,3,3-trifIuoro-2-hydroxy-2-{[(1- methylethyl)(phenyl)amino]methyl}propyl)amino]-1H-indazol-1-yl}benzoate (60mg, 0.0974mmol) in ethanol (1 OmL) was hydrogenated at 250C over 10% Palladium on carbon using an H-cube apparatus operating at a pressure of 50 psi and a flow rate of 1mL/min. Removal of the solvent afforded the title compound (40mg). LCMS (System A): tREτ = 3.97 min; MH+ = 527
Intermediate 19: 1.1-Dimethylethyl 3-(6-methyl-4-r(3.3.3-trifluoro-2-hvdroxy-2-ff(1- methylethyl)(phenylmethyl)aminolmethyl>propyl)amino1-1 /-/-indazol-1-yl)benzoate
Figure imgf000059_0002
A mixture of 1 ,1-dimethylethyl 3-(6-methyl-4-{[3,3,3-trifluoro-2-hydroxy-2-({[(4- methylphenyl)sulfonyl]oxy}methyl)propyl]amino}-1/-/-indazol-1-yl)benzoate (0.146g) and (1-methylethyl)(phenylmethyl)amine (0.2mL) was irradiated in a microwave reactor at 1000C for 15 min. The mixture was cooled and dissolved in dichloromethane (1 mL) and purified on a 2Og silica gel SPE cartridge eluted with a gradient of cyclohexane and ethyl acetate to give the title compound as a colourless oil (86mg). LCMS (System A): tREτ = 4.44 min; MH+ = 597
Intermediate 20: 3-(6-Methyl-4-r(3.3.3-trifluoro-2-hvdroxy-2-fr(1- methylethyl)(phenylmethyl)aminolmethyl)propyl)aminol-1A7-indazol-1-yl)benzoic acid hydrochloride
Figure imgf000060_0001
1 ,1-Dimethylethyl 3-{6-methyl-4-[(3,3,3-trifluoro-2-hydroxy-2-{[(1- methylethyl)(pheπylmethyl)amino]methyl}propyl)amino]-1 /-/-indazol-1-yl}benzoate (85mg) was treated with hydrogen chloride in dioxan (4M, 4ml_) at 2O0C for 18 hours and then evaporated to give the title compound (82mg). LCMS (System B): tRET = 1.42 min; MH+ = 541
Intermediate 21 : Phenylmethyl 3-(4-(r2-(3.4-dihvdro-1(2H)-quinolinylmethyl)-3.3.3- trifluoro-2-hvdroxypropyllamino)-6-methyl-1 H-indazol-1-yl)benzoate
Figure imgf000060_0002
A mixture of phenylmethyl 3-[6-methyl-4-({[2-(trifluoromethyl)-2- oxiranyl]methyl}amino)-1 H-indazol-1-yl]benzoate (85mg. 0.177mmol) and 1 ,2,3,4- tetrahydroquinoline (47mg, 0.353mmol) in DMF (0.5mL) was irradiated in a microwave reactor at 13O0C for 30 min. The mixture was blown to dryness under a stream of nitrogen and the residue purified by mass directed autopreparation to give the title compound as a pale yellow glass (40mg). LCMS (System B): tRET = 1.67 min; MH+ = 629
Intermediate 22: 3-(4-fl2-(3,4-Dihvdro-1 (2H)-quinolinylmethyl)-3.3.3-trifluoro-2- hvdroxypropyllamino}-6-methyl-1 /-/-indazol-1-yl)benzoic acid
Figure imgf000061_0001
Prepared similarly to Intermediate 14 by hydrogenolysis of phenylmethyl 3-(4-{[2-
(3,4-dιhydro-1 (2H)-quιnolιnylmethyl)-3,3,3-trιfluoro-2-hydroxypropyl]amιno}-6-methyl-
1 H-ιndazol-1-yl)benzoate
LCMS (System B) tREτ = 1 39 mm, MH+ = 525
Intermediate 23 Phenylmethyl 3-f6-methyl-4-(|3,3,3-trιfluoro-2-hvdroxy-2-r(2-methyl- 3.4-dιhvdro-1 (2H)-αuιnolιnyl)methvnpropyl>amιno)-1 H-ιndazol-1 -yllbenzoate
Figure imgf000061_0002
A mixture of phenylmethyl 3-[6-methyl-4-({[2-(trιfluoromethyl)-2- oxιranyl]methyl}amιno)-1 /-/-ιndazol-1-yl]benzoate (85mg, O 177mmol) and 2-methyl- 1 ,2,3,4-tetrahydroquιnolιne (51 mg, O 353mmol) in DMF (O 5ml_) was irradiated in a microwave reactor at 1000C for 15 mm and then at 13O0C for 30 mm. The mixture was blown to dryness under a stream of nitrogen and the residue purified by mass directed autopreparation to give the title compound as a white solid (19mg). LCMS (System B) tREτ = 1 65 mm, MH+ = 615
Intermediate 24 3-f6-Methyl-4-((3.3.3-trιfluoro-2-hvdroxy-2-r(2-methyl-3.4-dιhvdro- 1 (2H)-quιnolιnyl)methyl1propyl>amιno)-1 /-/-ιndazol-1-yllbenzoιc acιd
Figure imgf000061_0003
A solution of phenylmethyl 3-[6-methyl-4-({3,3,3-trifluoro-2-hydroxy-2-[(2-methyl-3,4- dihydro-1 (2/-/)-quinolinyl)methyl]propyl}amino)-1 /-/-indazol-1-yl]benzoate (18mg) in ethanol (1 OmL) was hydrogenated at 250C over 10% Palladium on carbon using an H-cube apparatus operating at a pressure of 50 psi. The product was flushed from the cartridge with DMF (5mL) and methanol (1 OmL). Removal of the solvents in vacuo afforded the impure title compound (13.8mg) which was used without further purification. LCMS (System B): tRET = 1 -43 min; MH+ = 539
Intermediate 25: Phenylmethyl 3-r4-({2-f(dimethylamino)methyll-3.3.3-trifluoro-2- hvdroxypropyl>amino)-6-methyl-1/-/-indazol-1-yllbenzoate
Figure imgf000062_0001
Dimethylamine (21 mg, 0.459mmol) 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}-1 H-indazol-1-yl)benzoate (1 OOmg, 0.153mmol) in dry dichloromethane (4mL) and the mixture left at 2O0C for 18 hours. Purification on a 10g silica gel SPE cartridge using a gradient of cyclohexane and ethyl acetate gave the title compound as a colourless gum (80mg). LCMS (System B): tRET = 1 -28 min; MH+ = 527
Intermediate 26: 3-r4-({2-f(Dimethylamino)methyll-3.3,3-trifluoro-2- hvdroxypropyl)amino)-6-methyl-1 /-/-indazol-1-vflbenzoic acid
Figure imgf000062_0002
Prepared similarly to Intermediate 14 by hydrogenolysis of phenylmethyl 3-[4-({2-
[(dimethylamino)methyl]-3,3,3-trifluoro-2-hydroxypropyl}amino)-6-metriyl-1 /-/-indazol-
1-yl]benzoate.
LCMS (System B): tRET = 0.88 min; MH+ = 437
Example 1 : Λ/-(2-Amino-2-oxoethyl)-3-f4-r(2-{rethyl(1-methylethyl)amino1methyl>- 3,3,3-trifluoro-2-hvdroxypropyl)amino1-6-methvH H-indazol-1-yl>benzamide
Figure imgf000063_0001
HATU (13.5mg, 0.0356mmol) was added to a solution of 3-{4-[(2-{[ethyl(1- methylethyl)amino]methyl}-3,3,3-trifluorc-2-hydroxypropyl)amino]-6-methyl-1/-/- indazol-1-yl}benzoic acid (17mg, 0.0356mmol) in DMF (0.5ml_) and the mixture stirred at room temperature for 10 min. Glycinamide hydrochloride (4mg, 0.0356mmol) and Λ/,Λ/-diisopropylethylamine (0.0185mL, 0.107mmol) were then added and the mixture stirred at 2O0C for 18 hours. The solvent was removed under a stream of nitrogen and the residue purified by mass directed autopreparation to give the title compound. LCMS (System B)' tRET = 0.86 min; MH+ = 535
Example 2: Λ/-(2-Amino-2-oxoethyl)-3-{4-r(2-frbis(1 -methylethyl)amino1methyl}-3.3.3- trifluoro-2-hvdroxypropyl)aminol-6-methyl-1 /-/-iπdazol-1-yl)benzamide
Figure imgf000063_0002
Prepared similarly to Example 1 from 3-{4-[(2-{[bis(1-methylethyl)amino]methyl}- 3,3,3-trifluoro-2-hydroxypropyl)amino]-6-methyl-1 H-indazol-1-yl}benzoic acid and glycinamide hydrochloride. LCMS (System A): tRET = 2.69 min; MH+ = 549 Example 3: Λ/-(2-Amino-2-oxoethyl)-3-|6-methyl-4-f(313.3-trifluoro-2-hvdroxy-2-ff(1 ■ methylethyl)(phenyl)amino1methyl)propyl)arninol-1 /-/-indazol-1-yl)benzamide
Figure imgf000064_0001
Prepared similarly to Example 1 from 3-{6-methyl-4-[(3,3,3-trifluoro-2-hydroxy^2-{[(1- methylethyl)(phenyl)amino]methyl}propyl)amino]-1 /-/-indazol-1-yl}benzoic acid and glycinamide hydrochloride. LCMS (System A): tRET = 3.51 min; MH+ = 583
Example 4: Λ/-(2-Amino-2-oxoethyl)-3-(6-methyl-4-f(3,3.3-trifluoro-2-hvdroxy-2-f[(1- methylethyl)(phenylmethyl)aminolmethyl)propyl)amino1-1 H-indazol-1-yl)benzamide
Figure imgf000064_0002
Prepared similarly to Example 1 from 3-{6-methyl-4-[(3,3,3-trifluoro-2-hydroxy-2-{[(1- methylethyl)(phenylmethyl)amino]methyl}propyl)amino]-1 /-/-indazol-1-yl}benzoic acid hydrochloride and glycinamide hydrochloride. LCMS (System B): tRET = 1.27 min; MH+ = 597
12mg of this mixture of enantiomers was resolved by chiral HPLC on a 2 x 25cm Chiralcel OD column eluted with heptane : ethanol 4 : 1 with a flow rate of 15 mL/min to provide Example 4-A (enantiomer A, 3mg) and Example 4-B (enantiomer B, 3mg).
Example 4-A (enantiomer A): Analytical chiral HPLC (25 x 0.46 cm Chiralcel OD column, heptane : ethanol 4 : 1 eluting at 1 mL/min): tRET = 18.1 min LCMS (System A): tREτ = 3.42 min; MH+ = 597 Example 4-B (enantiomer B): Analytical chiral HPLC (25 x 0.46 cm Chiralcel OD column, heptane : iso-ethanol 4 : 1 eluting at 1 mL/min): tRET = 22.7 min LCMS (System A): tRET = 3.42 min; MH+ = 597
Example 5: Λ/-(2-Amino-2-oxoethyl)-3-(4-ff2-(3.4-dihvdro-1 (2H)-quinolinylmethyl)- 3,3,3-trifluoro-2-hvdroxypropynamino)-6-methyl-1 H-indazol-1-yl)benzamide
Figure imgf000065_0001
Prepared similarly to Example 1 from 3-(4-{[2-(3,4-dihydro-1 (2H)-quinolinylmethyl)- 3,3!3-trifluoro-2-hydroxypropyl]amino}-6-methyl-1 /-/-indazol-1-yl)benzoic acid and glycinamide hydrochloride. LCMS (System B): tRET = 1 24 min; MH+ = 581
Ca. 32.8mg of this mixture of enantiomers was resolved by chiral HPLC on a 2 x 25cm Chiralpak 1A column eluted with heptane : ethanol 65 : 35 with a flow rate of 15 mL/min to provide Example 5-A (enantiomer A, 10.9mg) and Example 5-B (enantiomer B, 13.2mg).
Example 5-A (enantiomer A): Analytical chiral HPLC (25 x 0.46 cm Chiralpak 1A column, heptane : ethanol 65 : 35 eluting at 1 mL/min): tReτ = 23.6 min LCMS (System A): tRET = 3.47 min; MH+ = 581
Example 5-B (enantiomer B): Analytical chiral HPLC (25 x 0.46 cm Chiralpak 1A column, heptane : ethanol 65 : 35 eluting at 1 mL/min): tREτ = 29.4 min LCMS (System A): tRET = 3.47 min; MH+ = 581 Example 6: Λ/-fπffl-2-Amino-1-methyl-2-oxoethyll-3-(4-ff2-(3.4-dihvdro-1 (2H)- quinolinylmethyl)-3,3.3-trifluoro-2-hvdroxypropynamino'y-6-methyl-1/-/-indazol-1- vDbenzamide
Figure imgf000066_0001
Λ/,Λ/-Dϋsopropylethylamine (0.079mL, 0.451 mmol) and HATU (36mg, 0.095mmol) were added to a solution of 3-(4-{[2-(3,4-dihydro-1 (2H)-quinolinylmethyl)-3,3,3- trifluoro-2-hydroxypropyl]amino}-6-methyl-1 /-/-indazol-1-yl)benzoic acid (47.3mg, 0.09mmol) in anhydrous DMF (1.7mL) and the mixture stirred at room temperature under nitrogen for 10 min. D-Alaninamide hydrochloride (28.1 mg, 0.225mmol) was then added and stirring continued at room temperature for 7 hours when the mixture was partitioned between water and ethyl acetate. The organic phase was separated, combined with a second ethyl acetate extract, washed successively with aqueous sodium bicarbonate and water, dried through a hydrophobic frit and evaporated. The residue was dissolved in a mixture of DMSO and methanol and purified by mass directed autopreparation. Product containing fractions were combined and partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The aqueous phase was re-extracted with dichloromethane and the combined organic extracts were washed successively with water and brine, dried through a hydrophobic frit and evaporated to give the title compound (24.6mg). LCMS: tRET = 3.51 min; MH+ = 595
21 mg of this mixture of diastereomers was resolved by chiral HPLC on a 2 x 25cm Chiralpak 1A column eluted with heptane : EtOH 6 : 4 + 0.1 % TFA with a flow rate of 15 mL/min to provide Example 6-A (diastereomer A, 4.14mg) and Example 6-B (diastereomer B, 5.64mg).
Example 6-A (diastereomer A): Analytical chiral HPLC (25 x 0.46 cm Chiralpak 1A column, heptane : EtOH 6 : 4 + 0.1 % TFA eluting at 1 mL/min): tREτ = 11.4 min LCMS (System A): tRET = 3.52 min; MH+ = 595 Example 6-B (diastereomer B): Analytical chiral HPLC (25 x 0.46 cm Chiralpak 1A column, heptane : EtOH 6 : 4 + 0.1 % TFA eluting at 1 mL/min): tREτ = 16.4 min LCMS (System A): tRET = 3.51 min; MH+ = 595
Example 7; Λ/-(2-Amino-2-oxoethyl)-3-r6-methyl-4-α3.3.3-trifluoro-2-hvdroxy-2-r(2- methyl-3,4-dihvdro-1 (2/-/)-quinolinyl)methvnpropyl)amino)-1/-/-indazol-1-vnbenzamide
Figure imgf000067_0001
Prepared similarly to Example 1 from impure 3-[6-methyl-4-({3,3,3-trifluoro-2- hydroxy-2-[(2-methyl-3,4-dihydro-1 (2/-/)-quinolinyl)methyl]propyl}amino)-1/-/-indazol- 1-yl]benzoic acid and glycinamide hydrochloride. LCMS (System B): tRET = 1.30 min; MH+ = 595
Example 8: /V-(2-amino-2-oxoethyl)-3-[4-({2-r(dimethylamino)methyll-3.3.3-trifluoro-2- hvdroxypropyl>amino)-6-methyl-1 /-/-indazol-1-yllbenzamide
Figure imgf000067_0002
Prepared similarly to Example 1 from 3-[4-({2-[(dirnethylamino)methyl]-3,3,3-trifluoro-
2-hydroxypropyl}amino)-6-methyl-1 /-/-indazol-1-yl]benzoic acid and glycinamide hydrochloride.
LCMS (System B): tRET = 0.63 min; MH+ = 493
Example 9: N-U'l R)-2-amino-1 -methyl-2-oxoethyl1-3-r4-({2-f(dimethylamino)methyll- 3,3.3-trifluoro-2-hvdroxypropyl}amino)-6-methyl-1 /-/-indazol-1-vnbenzamide
Figure imgf000068_0001
Prepared similarly to Example 1 from 3-[4-({2-[(dimethylamino)methyl]-3,3,3-trifluoro-
2-hydroxypropyl}amino)-6-methyl-1H-indazol-1-yl]benzoic acid and D-alaninamide hydrochloride.
LCMS (System B): tRET = 0.66 min; MH+ = 507
BIOLOGICAL EXPERIMENTAL
Glucocorticoid mediated Transrepression of NFkB activity
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.
Compounds were solvated and diluted in DMSO, and transferred directly into assay plates such that the final concentration of DMSO was 0.7%. Following the addition of cells (4OK per well), plates were incubated for 1 hr prior to the addition of 3ng/ml human recombinant TNFα. Following continued incubation for 16hr, alkaline phosphatase activity was determined by measuring the change in optical density at 405nM with time following the addition of 0.7 volumes of assay buffer (1 mg/ml p- nitrophenylphosphate dissolved in 1 M diethanolamine, 0.28M NaCI, 0.5mM MgCI2). Dose response curves were constructed from which EC50 values were estimated.
Examples 1 to 9 show pEC50 > 7.5 in this assay.
Assay for Progesterone Receptor Activity 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/ μl 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 μl 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 pEC50 values were estimated.
Examples 1 to 9 show pEC50 <8.5 in this assay.
In describing examples according to their activity in the assays above, it will be appreciated that 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.
Throughout the specification and the claims which follow, unless the context requires otherwise, the word 'comprise', and variations such as 'comprises' and 'comprising', will be understood to imply the inclusion of a stated integer or step or group of integers but not to the exclusion of any other integer or step or group of integers or steps.
The application of which this description and claims forms part may be used as a basis for priority in respect of any subsequent application. The claims of such subsequent application may be directed to any feature or combination of features described herein. They may take the form of product, composition, process, or use claims and may include, by way of example and without limitation, the following claims.
The patents and patent applications described in this application are herein incorporated by reference.

Claims

1. A compound of formula (I):
Figure imgf000070_0001
wherein
R1 and R2 are each independently C1-3alkyl or -(CH2)n-phenyl, or
R1 and R2, together with the nitrogen atom to which they are attached, are linked to form
Figure imgf000070_0002
R3 is -CH2CONH2 or -CH(CH2)CONH2 and n is 0 or 1 ; or a salt thereof.
2. A compound according to claim 1 wherein R1 and R2 are each independently ethyl or isopropyl.
3. A compound according to claim 1 wherein R1 is -(CH2)n-phenyl and R2 is isopropyl.
4. A compound according to claim 1 wherein R1 and R2, together with the nitrogen atom to which they are attached, are linked to form
Figure imgf000071_0001
5. A compound according to any one of the preceding claims wherein R3 is CH2CONH2.
6. A compound according to any one of claims 1 to 4 wherein R3 is CH(CH3)CONH2.
7. A compound according to claim 6 wherein R3 is in the (S) configuration.
8. A compound according to any one of the preceding claims wherein n is 0.
9. A compound according to any one of claims 1 to 7 wherein n is 1.
10. A compound as described in any one of Examples 1 to 7 or a salt thereof.
11 A compound which is:
N-(2-amino-2-oxoethyl)-3-{6-methyl-4-[(3,3,3-trifluoro-2-hydroxy-2-{[(1- methylethyl)(phenylmethyl)amino]methyl}propyl)amino]-1H-iπdazol-1-yl}benzamide;
N-(2-amino-2-oxoethyl)-3-{6-methyl-4-[(3,3,3-trifluoro-2-hydroxy-2-{[(1- methylethy!)(phenylmethyl)amino]methyl}propyl)amino3-1 H-indazol-1-y]}benzamide
Enantiomer B;
N-(2-amino-2-oxoethyl)-3-(4-{[2-(3,4-dihydro-1(2H)-quinolinylmethyl)-3,3,3-trifluoro-2- hydroxypropyl]amino}-6-methy]-1 H-indazo[-1-yl)benzarnide;
N-(2-amino-2-oxoethyl)-3-(4-{[2-(3,4-dihydro-1<2H)-quinolinylmethyl)-3,3,3-trifluoro-2- hydroxypropyl]amino}-6-methyl-1H-indazol-1-yl)benzamide Enantiomer A;
N-[(1 S)-2-amino-1-methyl-2-oxoethyl]-3-(4-{[2-(3,4-dihydro-1 (2H)-quinolinylmethyl)-
3,3,3-trifluoro-2-hydroxypropyl]amino}-6-methyl-1 H-indazol-1-yl)benzamide;
N-[(1 S)-2-amino-1-methyl-2-oxoethyl]-3-(4-{[2-(3,4-dihydro-1(2H)-quinolinylmethyl)-
3,3,3-trifluoro-2-hydroxypropyl]amino}-6-methyl-1 H-indazol-1-yl)benzamide
Diastereomer A;
N-(2-amino-2-oxoethyl)-3-[6-methyl-4-({3,3,3-trifluoro-2-hydroxy~2-[(2-methyl-3,4- dihydro-1 (2H)-quinolinyl)methyl]propyl}amino)-1H-indazol-1-yl]benzamide; or a salt thereof.
12 A compound as claimed in any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, for use in human or veterinary medicine.
13 A compound as claimed in any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, for use in the treatment of inflammatory and/or allergic conditions.
14 A compound as claimed in any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, for use in the treatment of rheumatoid arthritis, asthma, COPD, allergy and/or rhinitis.
15 A compound as claimed in any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, for use in the treatment of skin disease.
16 A compound as claimed in any one of claims 1 to 11 , or a pharmaceutically acceptable salt thereof, for use in the treatment of eczema, psoriasis, allergic dermatitis, neurodermatitis, pruritis and/or hypersensitivity reactions.
17 Use of a compound as claimed in any one of claims 1 to 11 , or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of inflammatory and/or allergic conditions.
18 Use of a compound as claimed in any one of claims 1 to 11 , or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of rheumatoid arthritis, asthma, COPD, allergy and/or rhinitis.
19 Use of a compound as claimed in any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of skin disease.
20 Use of a compound as claimed in any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of eczema, psoriasis, allergic dermatitis, neurodermatitis, pruritis and/or hypersensitivity reactions.
21 A method for the treatment of a human or animal subject with an inflammatory and/or allergic condition, which method comprises administering to said human or animal subject an effective amount of a compound as claimed in any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof.
22. A method for the treatment of a human or animal subject with rheumatoid arthritis, asthma, COPD, allergy and/or rhinitis, which method comprises administering to said human or animal subject an effective amount of a compound as claimed in any one of claims 1 to 11 , or a pharmaceutically acceptable salt thereof.
23. A method for the treatment of a human or animal subject with skin disease, which method comprises administering to said human or animal subject an effective amount of a compound as claimed in any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof.
24. A method for the treatment of a human or animal subject with 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 as claimed in any one of claims 1 to 11 , or a pharmaceutically acceptable salt thereof.
25. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, if desirable, in admixture with one or more physiologically acceptable diluents or carriers.
26. A combination comprising a compound as claimed in any one of claims 1 to 11 , or a pharmaceutically acceptable salt thereof, together with one or more other therapeutically active agents.
27. A process for the preparation of a compound of formula (I) as claimed in any one of claims 1 to 11 , or a salt thereof, comprising reaction of a carboxylic acid of formula (II)
Figure imgf000074_0001
with an amine R3NH2 wherein R1, R2 and R3 are as defined in claim 1.
28. A compound of formula (II)
Figure imgf000074_0002
wherein R1 and R2 are as defined in claim 1.
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