WO2008135578A1 - Pyrazolo [3, 4-d] pyrimidine derivatives for the treatment of inflammation and/or allergic conditions - Google Patents

Pyrazolo [3, 4-d] pyrimidine derivatives for the treatment of inflammation and/or allergic conditions Download PDF

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Publication number
WO2008135578A1
WO2008135578A1 PCT/EP2008/055571 EP2008055571W WO2008135578A1 WO 2008135578 A1 WO2008135578 A1 WO 2008135578A1 EP 2008055571 W EP2008055571 W EP 2008055571W WO 2008135578 A1 WO2008135578 A1 WO 2008135578A1
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Prior art keywords
compound
pharmaceutically acceptable
methyl
acceptable salt
formula
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PCT/EP2008/055571
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French (fr)
Inventor
Keith Biggadike
Anthony William James Cooper
David House
Iain Mcfarlane Mclay
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Glaxo Group Limited
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Publication of WO2008135578A1 publication Critical patent/WO2008135578A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to non-steroidal compounds, a process for their preparation, pharmaceutical compositions comprising the compounds and the use of the compounds for the manufacture of a medicament, 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, HJ. & Herrlich, P. (1992) EMBO J 11 :2241-2246).
  • GR glucocorticoid receptor
  • Transactivation involves direct binding of the glucocorticoid receptor to distinct deoxyribonucleic acid (DNA) glucocorticoid 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.
  • glucocorticoids 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, LJ. , Smith, CJ. P. 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, C-G., Latinen, L.A. et al.
  • 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 dermatitus, erythema nodosum, acne, hirsutism, toxic epidermal necrolysis, erythema multiform and cutaneous
  • the present invention provides compounds of formula (I):
  • A is 2,3-dihydro-1-benzofuran-7-yl, 5-fluoro-2-methoxy-phenyl or 5-fluoro-2-hydroxy- phenyl;
  • R 1 is methyl or ethyl
  • R 2 is -N(R 3 )C(R 4 )(R 5 )CONHR 6 or
  • R 3 is hydrogen or methyl
  • R 4 is hydrogen and R 5 is hydrogen, methyl or hydroxymethyl, or R 4 and R 5 are each methyl;
  • R 6 is hydrogen or methyl; and salts thereof (hereinafter “compounds of the invention”).
  • Compounds of formula (I) contain one or two chiral centres. Thus 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.
  • Compounds of the invention may provide agonism of the glucocorticoid receptor. It will 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.
  • 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.
  • a single enantiomer or diastereomer or mixture of isomers may be preferred.
  • the invention provides compounds of formula (I) wherein A is 5- fluoro-2-methoxy-phenyl. In a further embodiment, the invention provides compounds of formula (I) wherein A is 2,3-dihydro-1-benzofuran-7-yl.
  • R 1 is methyl
  • R 2 is -N(R 3 )C(R 4 )(R 5 )CONHR 6 .
  • R 2 is
  • R 3 is hydrogen
  • R 4 and R 5 are each hydrogen. In a further embodiment, R 4 is hydrogen and R 5 is methyl.
  • R 6 is hydrogen
  • the compound of formula (I) is:
  • references herein to compounds of formula (I) and salts thereof covers the compounds of formula (I) as the free base or as salts thereof, for example as a pharmaceutically acceptable salt thereof.
  • One embodiment of the invention embraces compounds of formula (I) and salts and solvates thereof. Another embodiment of the invention embraces compounds of formula (I) and solvates thereof. A further embodiment of the invention embraces compounds of formula (I) as the free base.
  • compounds of formula (I) may be in the form of and/or may be administered as a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salts of the compounds according to formula (I) may be preferred over the respective free base or free acid because, for example, such salts impart greater stability or solubility to the molecule thereby facilitating formulation into a dosage form.
  • one embodiment of the invention encompasses compounds of formula (I) and pharmaceutically acceptable salts thereof.
  • salts refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. These pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively. Salts 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. Thus one embodiment of the invention embraces compounds of formula (I) and salts thereof.
  • Suitable salts according to the invention include those formed with both organic and inorganic acids or bases.
  • Pharmaceutically acceptable acid addition salts may include those formed from strong acids, for example hydrochloric, hydrobromic and sulphuric acids, and strong sulphonic acids such as tosic, camphorsulphonic and methanesulphonic acids.
  • Further pharmaceutically acceptable acid addition salts may include those formed from 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, hydroxy
  • Pharmaceutically acceptable base salts include alkali metal salts such as those of sodium and potassium. Further 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, 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
  • 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 noncrystalline 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.
  • the compounds of the invention may have the ability to crystallise in more than one form. This is a characteristic known as polymorphism, and it is understood that such polymorphic forms (“polymorphs”) are within the scope of the present invention. Polymorphism generally can occur as a response to changes in temperature or pressure or both and can also result from variations in the crystallisation process. Polymorphs can be distinguished by various physical characteristics known in the art such as x-ray diffraction patterns, solubility, and melting point.
  • the compounds of formula (I) and pharmaceutically acceptable salts thereof are modulators of the glucocorticoid receptor and may be useful in the treatment of diseases associated with glucocorticoid receptor activity.
  • diseases associated with glucocorticoid receptor activity include 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, Little's syndrome, inflammatory scalp a
  • Glucocorticoid receptor modulators may also be used as immunostimulants and repressors and as wound healing and tissue repair agents.
  • the compounds of formula (I) and pharmaceutically acceptable salts thereof are expected to have potentially beneficial anti-inflammatory and/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 formula (I) and pharmaceutically acceptable salts thereof may be of use in the treatment of inflammatory and/or allergic disorders.
  • inflammatory and/or allergic disease states in which the compounds of formula (I) and pharmaceutically acceptable salts thereof are expected to have utility include skin diseases such as eczema, psoriasis, allergic dermatitis, neurodermatitis, pruritis and hypersensitivity reactions; inflammatory conditions of the nose, throat or lungs such as asthma (including allergen-induced asthmatic reactions), rhinitis (including hayfever), nasal polyps, chronic obstructive pulmonary disease (COPD), interstitial lung disease, and fibrosis; inflammatory bowel conditions such as ulcerative colitis and Crohn's disease; and auto-immune diseases such as rheumatoid arthritis.
  • skin diseases such as eczema, psoriasis, allergic dermatitis, neurodermatitis, pruritis and hypersensitivity reactions
  • inflammatory conditions of the nose, throat or lungs such as asthma (including allergen-induced asthmatic reactions), rhinitis (including hayfever), nasal polyps
  • 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 patients with inflammatory and/or allergic conditions, such as rheumatoid arthritis, asthma, COPD, allergy and/or rhinitis.
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of rhinitis, for example allergic rhinitis.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of patients with skin disease such as eczema, psoriasis, allergic dermatitis, neurodermatitis, pruritis and/or hypersensitivity reactions.
  • a compound formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of patients with inflammatory and/or allergic conditions, such as rheumatoid arthritis, asthma, COPD, allergy and/or rhinitis.
  • the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of patients with rhinitis, for example allergic rhinitis.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of patients with 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 for example allergic 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 and/or carriers.
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof may be prepared by, for example, admixture at ambient temperature and atmospheric pressure.
  • compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof may be suitable for topical administration (which includes epicutaneous, inhaled, intranasal or ocular administration), enteral administration (which includes oral or rectal administration) or parenteral administration (such as by injection or infusion).
  • topical administration which includes epicutaneous, inhaled, intranasal or ocular administration
  • enteral administration which includes oral or rectal administration
  • parenteral administration such as by injection or infusion
  • the compounds of formula (I) and pharmaceutically acceptable salts thereof may, for example, be formulated for oral, buccal, sublingual, parenteral, local rectal administration or other local administration.
  • compositions may be in the form of, for example, solutions or suspensions (aqueous or non-aqueous), tablet, capsules, oral liquid preparations, powders, granules, lozenges, lotions, creams, ointments, gels, foams, reconstitutable powders or suppositories as required by the route of administration.
  • compositions containing a compound of formula (I) or a pharmaceutically acceptable salt thereof may contain from about 0.1 to about 99%, such as from about 10 to about 60%, by weight based on the total weight of the composition, of the compound of formula (I) or a pharmaceutically acceptable salt thereof, depending on the route of administration.
  • the dose of the compound used in the treatment of the abovementioned disorders will vary in the usual way with the seriousness of the disorders, the weight of the sufferer and other similar factors.
  • suitable unit does may be about 0.001 to about 100mg, for example about 0.001 to about 1 mg, and such unit doses may be administered more than once a day, for example two or three times a day. Such therapy may extend for a number of weeks or months.
  • Local administration includes administration by insufflation and inhalation.
  • preparation for local administration include ointments, lotions, creams, gels, foams, preparations for delivery by transdermal patches, powders, sprays, aerosols, capsules or cartridges for use in an inhaler or insufflator or drops (e.g. eye or nose drops), solutions/suspensions for nebulisation, suppositories, pessaries, retention enemas and chewable or suckable tablets or pellets (e.g. for the treatment of aphthous ulcers) or liposome or microencapsulation preparations.
  • the proportion of the active compound of formula (I) or a pharmaceutically acceptable salt thereof in the local compositions according to the invention depends on the precise type of composition to be prepared, and the route of administration, but will generally be within the range of from 0.001 to 10% by weight based on the total weight of the composition. Generally, for most types of preparations, the proportion used will be within the range of from 0.005 to 1%, for example from 0.01 to 1%, such as 0.01 to 0.5% by weight based on the total weight of the composition. However, in powders for inhalation or insufflation the proportion used will normally be within the range of from 0.1 to 5% by weight based on the total weight of the composition.
  • compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof may be suitable for topical administration, for example for intranasal or inhaled administration.
  • Inhaled administration involves topical administration to the lung, such as by aerosol or dry powder composition.
  • compositions suitable for intranasal or inhaled administration may conveniently be formulated as aerosols, solutions, suspensions, drops, gels or dry powders, optionally with one or more physiologically acceptable diluents and/or carriers such as aqueous or non-aqueous vehicles, thickening agents, isotonicity adjusting agents, antioxidants and/or preservatives.
  • the compound of formula (I) or pharmaceutically acceptable salt thereof may be in a particle-size- reduced form prepared by, for example, micronisation and milling.
  • the size-reduced (eg micronised) compound can be defined by a D 50 value of about 0.5 to about 10 microns (for example as measured using laser diffraction).
  • compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof are suitable for intranasal administration.
  • the compounds of formula (I) and pharmaceutically acceptable salts thereof may be formulated for intranasal use in man either as a solution composition or a suspension composition, for example as a solution composition such as an aqueous solution composition.
  • a suitable dosing regime for an intranasal composition may be for the patient to inhale slowly through the nose subsequent to the nasal cavity being cleared. During inhalation, the composition may be administered to one nostril while the other is manually compressed. This procedure may then be repeated for the other nostril. Generally, one or two sprays per nostril may be administered by the above procedure up to two or three times each day.
  • the intranasal compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof are suitable for once daily administration.
  • each spray to the nostril may deliver from about 25 to about 100 ⁇ l_ of intranasal composition.
  • each spray to the nostril may deliver from about 1 to about 100 ⁇ g, for example about 1 to about 50 ⁇ g, of the compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof may permit the compound to be delivered to all areas of the nasal cavities (the target tissue) and further, may permit the compound to remain in contact with the target tissue for longer periods of time.
  • Compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, suitable for intranasal administration may optionally contain one or more suspending agents, one or more preservatives, one or more wetting agents and/or one or more isotonicity adjusting agents as desired.
  • compositions suitable for intranasal administration may optionally further contain other excipients such as antioxidants (for example sodium metabisulphite), taste-masking agents (for example menthol) and sweetening agents (for example dextrose, glycerol, saccharin and/or sorbitol).
  • excipients that may be employed in intranasal compositions include, for example, xylitol, potassium sorbate, EDTA, sodium citrate, citric acid, polysorbate 80 and Avicel CL61 1.
  • the suspending agent if included, will typically be present in the intranasal composition in an amount of between about 0.1 and 5%, such as between about 1.5 and 2.4%, by weight based on the total weight of the composition.
  • suspending agents include Avicel, carboxymethylcellulose, veegum, tragacanth, bentonite, methylcellulose and polyethylene glycols, e.g. microcrystalline cellulose or carboxy methylcellulose sodium.
  • Suspending agents may also be included in, for example, compositions suitable for inhaled, ocular and oral administration, as appropriate.
  • intranasal compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof may be protected from microbial or fungal contamination and growth by inclusion of a preservative.
  • pharmaceutically acceptable anti-microbial agents or preservatives may include quaternary ammonium compounds (e.g. benzalkonium chloride, benzethonium chloride, cetrimide and cetylpyridinium chloride), mercurial agents (e.g. phenylmercuric nitrate, phenylmercuric acetate and thimerosal), alcoholic agents (e.g. chlorobutanol, phenylethyl alcohol and benzyl alcohol), antibacterial esters (e.g.
  • esters of para-hydroxybenzoic acid include chelating agents such as disodium edetate (EDTA) and other anti-microbial agents such as chlorhexidine, chlorocresol, sorbic acid and its salts (such as potassium sorbate) and polymyxin.
  • chelating agents such as disodium edetate (EDTA)
  • other anti-microbial agents such as chlorhexidine, chlorocresol, sorbic acid and its salts (such as potassium sorbate) and polymyxin.
  • pharmaceutically acceptable anti-fungal agents or preservatives may include sodium benzoate.
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof which is benzalkonium chloride-free.
  • the preservative if included, may be present in an amount of between about 0.001 and about 1%, such as about 0.015%, by weight based on the total weight of the composition.
  • compositions which contain a suspended medicament may include a pharmaceutically acceptable wetting agent which functions to wet the particles of the medicament to facilitate dispersion thereof in the aqueous phase of the composition.
  • 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 e.g. oleic acid, lecithin or an oligolactic acid or derivative e.g. as described in WO94/21229 and WO98/34596 and cosolvents e.g. ethanol.
  • additional formulation excipients well known in the art such as surfactants e.g. oleic acid, lecithin or an oligolactic acid or derivative e.g. as described in WO94/21229 and WO98/34596 and cosolvents e.g. ethanol.
  • a pharmaceutical aerosol composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a fluorocarbon or hydrogen-containing chlorofluorocarbon as propellant, optionally in combination with a surfactant and/or a cosolvent.
  • the propellant is selected from 1 ,1 ,1 ,2- tetrafluoroethane, 1 ,1 ,1 ,2,3,3,3-heptafluoro-n-propane and mixtures thereof.
  • compositions of the invention may be buffered by the addition of suitable buffering agents.
  • Aerosol compositions may be presented in single or multidose quantities in sterile form in a sealed container, which may take the form of a cartridge or refill for use with an atomising device or inhaler.
  • the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve (metered dose inhaler), which is intended for disposal once the contents of the container have been exhausted.
  • Capsules and cartridges for use in an inhaler or insufflator may be formulated containing a powder mix for inhalation of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a suitable powder base such as lactose or starch.
  • a powder mix for inhalation of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a suitable powder base such as lactose or starch.
  • Each capsule or cartridge may generally contain from 20 ⁇ g to 10mg of the compound of formula (I).
  • 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.
  • Aerosol compositions 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 compositions.
  • the particle size of the particulate (e.g., micronised) drug should be such as to permit inhalation of substantially all the drug into the lungs upon administration of the aerosol composition 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.
  • compositions of the invention may be prepared by dispersal or dissolution of the medicament and a 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 compositions 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 compositions according to the invention may be measured by conventional techniques, for example, by measuring flocculation size distribution using a back light scattering instrument or by measuring particle size distribution by cascade impaction or by the "twin impinger” analytical process.
  • twin impinger assay means "Determination of the deposition of the emitted dose in pressurised inhalations using apparatus A” as defined in British Pharmacopaeia 1988, pages A204-207, Appendix XVII C.
  • Such techniques enable the "respirable fraction" of the aerosol compositions to be calculated.
  • MDI means a unit comprising a can, a secured cap covering the can and a composition 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 (e.g., 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 composition 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. 6,1 19,853; 6,179,1 18; 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. 6,1 19,853; 6,179,1 18; 6,315,112; 6,352,152; 6,390,291 ; and 6,679,374, as well as dose counter units such as, but not limited to, those described in U.S. Patent Nos. 6,360,739 and 6,431 ,168.
  • a metering valve is crimped onto an aluminium can to form an empty canister.
  • the particulate medicament is added to a charge vessel and liquefied propellant together with the optional excipients is pressure filled through the charge vessel into a manufacturing vessel.
  • the drug suspension is mixed before recirculation to a filling machine and an aliquot of the drug suspension is then filled through the metering valve into the canister.
  • a metering valve is crimped onto an aluminium can to form an empty canister.
  • the liquefied propellant together with the optional excipients and the dissolved medicament is pressure filled through the charge vessel into a manufacturing vessel.
  • an aliquot of the liquefied composition is added to an open canister under conditions which are sufficiently cold to ensure the composition 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.
  • compositions 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.
  • 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 compositions 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 depending on the vehicle and concentration used, may be either suspended or dissolved in the vehicle.
  • the compound of formula (I) or 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.
  • the compounds of formula (I) and pharmaceutically acceptable salts thereof may be formulated for inhaled administration.
  • the compounds of formula (I) and pharmaceutically acceptable salts thereof may be formulated for intranasal administration.
  • the compounds and pharmaceutical compositions according to the invention may be used in combination with or include one or more other therapeutic agents, for example selected from anti-inflammatory agents, anticholinergic agents (particularly an M 1 ZM 2 ZM 3 receptor antagonist), ⁇ 2 -adrenoreceptor agonists, antiinfective agents such as antibiotics or antivirals, or antihistamines.
  • other therapeutic agents for example selected from anti-inflammatory agents, anticholinergic agents (particularly an M 1 ZM 2 ZM 3 receptor antagonist), ⁇ 2 -adrenoreceptor agonists, antiinfective agents such as antibiotics or antivirals, or antihistamines.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with one or more other therapeutically active agents, for example selected from an anti-inflammatory agent such as a corticosteroid or an NSAID, an anticholinergic agent, a ⁇ 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
  • One embodiment of the invention encompasses combinations comprising one or two other therapeutic agents.
  • the other therapeutic ingredient(s) may be used in the form of salts, for example as alkali metal or amine salts or as acid addition salts, or prodrugs, or as esters, for example lower alkyl esters, or as solvates, for example hydrates, to optimise the activity andZor stability andZor 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.
  • the invention encompasses a combination comprising of a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a ⁇ 2 -adrenoreceptor agonist.
  • ⁇ 2 -adrenoreceptor agonists include salmeterol (e.g. as the racemate or a single enantiomer, such as the /?-enantiomer), salbutamol (e.g. as the racemate or a single enantiomer such as the R-enantiomer), formoterol (e.g.
  • the ⁇ 2 - adrenoreceptor agonists are long-acting ⁇ 2 -adrenoreceptor agonists, for example compounds which provide effective bronchodilation for about 12 hours or longer.
  • ⁇ 2 -adrenoreceptor agonists may include those described in
  • WO02/066422A WO02/070490, WO02/076933, WO03/024439, WO03/072539, WO 03/091204, WO04/016578, WO04/022547, WO04/037807, WO04/037773, WO04/037768, WO04/039762, WO04/039766, WO01/42193 and WO03/042160.
  • ⁇ 2 -adrenoreceptor agonists examples include:
  • 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 formula (I) and pharmaceutically acceptable salts thereof 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]-1 1 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-androsta-1 ,4-diene-17 ⁇ - carbothioic acid S-fluoromethyl ester (fluticasone furoate), 6 ⁇ ,9 ⁇ -difluoro-11 ⁇ - hydroxy-16 ⁇ -methyl-3-oxo-17 ⁇ -propionyloxy- androsta-1 ,4-diene-17 ⁇ -carbothioic acid S-(2-oxo-t
  • 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 ⁇ -carboxylic acid cyanomethyl ester and 6 ⁇ ,9 ⁇ -difluoro-11 ⁇
  • the corticosteroid is 6 ⁇ ,9 ⁇ -difluoro-17 ⁇ -[(2- furanylcarbonyl)oxy]-1 1 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-androsta-1 ,4-diene-17 ⁇ - 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, WO07/054294, WO07/122165, WO07/144327 and WO08/000777.
  • 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 (for example, adenosine 2a agonists), cytokine antagonists (for example, chemokine antagonists, such as a CCR3 antagonist) or inhibitors of cytokine synthesis, or 5- lipoxygenase inhibitors.
  • PDE phosphodiesterase
  • leukotriene antagonists inhibitors of leukotriene synthesis (for example, montelukast), iNOS inhibitors, tryptase and elastas
  • An iNOS inducible nitric oxide synthase inhibitor
  • Suitable iNOS inhibitors include those disclosed in WO93/13055, WO98/30537, WO02/50021 , WO95/34534 and WO99/62875.
  • Suitable CCR3 inhibitors include those disclosed in WO02/26722.
  • the invention provides the use of compounds of formula (I) and pharmaceutically acceptable salts thereof in combination with a phosphodiesterase 4 (PDE4) inhibitor, for example in the case of a composition adapted for inhalation.
  • PDE4-specific inhibitor 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].
  • Another compound is 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.
  • anticholinergic agents are those compounds that act as antagonists at the muscarinic receptors, in particular those compounds which are antagonists of the M 1 or M 3 receptors, dual antagonists of the M 1 ZM 3 or M 2 /M 3 , receptors or pan- antagonists of the M-
  • 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 WO01/041 18.
  • Exemplary compounds for oral administration include pirenzepine (for example, CAS 28797-61- 7), darifenacin (for example, CAS 133099-04-4, or CAS 133099-07-7 for the hydrobromide sold under the name Enablex), oxybutynin (for example, CAS 5633- 20-5, sold under the name Ditropan), terodiline (for example, CAS 15793-40-5), tolterodine (for example, 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 (for example, CAS 10405-02-4) and solifenacin (for
  • anticholinergic agents include compounds of formula (XXI), which are disclosed in US patent application 60/487981 :
  • R 31 and R 32 are, independently, selected from the group consisting of straight or branched chain lower alkyl groups having preferably from 1 to 6 carbon atoms, cycloalkyl groups having from 5 to 6 carbon atoms, cycloalkyl-alkyl having 6 to 10 carbon atoms, 2-thienyl, 2-pyridyl, phenyl, phenyl substituted with an alkyl group having not in excess of 4 carbon atoms and phenyl substituted with an alkoxy group having not in excess of 4 carbon atoms;
  • X " represents an anion associated with the positive charge of the N atom.
  • X " may be but is not limited to chloride, bromide, iodide, sulfate, benzene sulfonate, and toluene sulfonate, including, for example:
  • anticholinergic agents include compounds of formula (XXII) or (XXIII), which are disclosed in US patent application 60/51 1009:
  • R 41" represents an anion associated with the positive charge of the N atom;
  • R 41" may be but is not limited to chloride, bromide, iodide, sulfate, benzene sulfonate and toluene sulfonate;
  • R 42 and R 43 are independently selected from the group consisting of straight or branched chain lower alkyl groups (having preferably from 1 to 6 carbon atoms), cycloalkyl groups (having from 5 to 6 carbon atoms), cycloalkyl-alkyl (having from 6 to 10 carbon atoms), heterocycloalkyl (having from 5 to 6 carbon atoms) and N or O as the heteroatom, heterocycloalkyl-alkyl (having from 6 to 10 carbon atoms) and N or O as the heteroatom, aryl, optionally substituted aryl, heteroaryl, and optionally substituted heteroaryl;
  • R 44 is selected from the group consisting of (C 1 -C 6 )alkyl, (C 3 -C 12 )cycloalkyl, (C 3 -
  • R 45 is selected from the group consisting of (Ci-C 6 )alkyl, (d-C 6 )alkyl(C 3 -
  • Ci 2 cycloalkyl, (Ci-C 6 )alkyl(C 3 -C 7 )heterocycloalkyl, (C r C 6 )alkyl-aryl, (C r C 6 )alkyl- heteroaryl;
  • R 46 is selected from the group consisting of (Ci-C 6 )alkyl, (C 3 -Ci 2 )cycloalkyl, (C 3 -
  • R 47 and R 48 are, independently, selected from the group consisting of H, (C 1 -C 6 )alkyl,
  • C 6 )alkyl(C 3 -C 7 )heterocycloalkyl, (C 1 -C 6 )alkyl-aryl, and (C 1 -C 6 )alkyl-heteroaryl including, for example:
  • antihistamines include any one or more of the numerous antagonists known which inhibit H1-receptors, and are safe for human use.
  • First generation antagonists include derivatives of ethanolamines, ethylenediamines, and alkylamines, such as diphenylhydramine, pyrilamine, clemastine, chlorpheniramine.
  • Second generation antagonists which are non-sedating, include loratidine, desloratidine, terfenadine, astemizole, acrivastine, azelastine, levocetirizine fexofenadine and cetirizine.
  • anti-histamines examples include loratidine, desloratidine, fexofenadine, cetirizine, levocabastine, olopatadine, amlexanox and epinastine.
  • the invention provides a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with an H1 antagonist.
  • H1 antagonists include, without limitation, amelexanox, astemizole, azatadine, azelastine, acrivastine, brompheniramine, cetirizine, levocetirizine, efletirizine, chlorpheniramine, clemastine, cyclizine, carebastine, cyproheptadine, carbinoxamine, descarboethoxyloratadine, doxylamine, dimethindene, ebastine, epinastine, efletirizine, fexofenadine, hydroxyzine, ketotifen, loratadine, levocabastine, mizolastine, mequitazine, mianserin, noberastine, meclizine, norastemizole, olopatadine, picumast, pyrilamine, promethazine, terfenadine, tripelennamine, warmth and
  • the invention provides a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with an H3 antagonist (and/or inverse agonist).
  • H3 antagonists include, for example, those compounds disclosed in WO2004/035556 and in WO2006/045416.
  • Other histamine receptor antagonists which may be used in combination with the compounds of the present invention 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 provides a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a dual H1/H3 antagonist.
  • dual H1/H3 antagonists include 4-[(4-chlorophenyl)methyl]-2-( ⁇ (2R)-1-[4-(4- ⁇ [3-(hexahydro-1 H-azepin-1- yl)propyl]oxy ⁇ phenyl)butyl]-2-pyrrolidinyl ⁇ methyl)-1 (2/-/)-phthalazinone or a pharmaceutically acceptable salt thereof as described in priority application GB0607839.8.
  • 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.
  • 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 ⁇ 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 a corticosteroid.
  • the invention thus provides, in a further 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 a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with an anticholinergic.
  • 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 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 compositions.
  • the individual compounds will be administered simultaneously in a combined pharmaceutical composition.
  • 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 ogether 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 combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a PDE4 inhibitor and a ⁇ 2 -adrenoreceptor agonist.
  • the invention thus provides, in a further aspect, a pharmaceutical composition
  • a pharmaceutical composition comprising a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof together with an anticholinergic and a PDE-4 inhibitor.
  • a process (Method A) according to the invention for the preparation of compounds of formula (I), and salts thereof, comprises coupling of a carboxylic acid of formula (II):
  • R 3 , R 4 , R 5 and R 6 are as defined above for compounds of formula (I).
  • This coupling may be conducted, for example, using HATU (O-(7-azabenzotriazol-1- yl)- ⁇ /, ⁇ /, ⁇ /', ⁇ /-tetramethyluronium hexafluorophosphate) in the presence of a suitable base such as ⁇ /, ⁇ /-diisopropylethylamine in a suitable solvent such as DMF.
  • HATU O-(7-azabenzotriazol-1- yl)- ⁇ /, ⁇ /, ⁇ /', ⁇ /-tetramethyluronium hexafluorophosphate
  • a suitable base such as ⁇ /, ⁇ /-diisopropylethylamine
  • DMF suitable solvent
  • the coupling may also be conducted using alternative, conventional conditions for amide bond formation known in the art.
  • compounds of formula (I) may be prepared from the carboxylic acid (II) by two sequential amide couplings firstly with the amino acid HN(R 3 )C(R 4 )(R 5 )CO 2 H or D- proline followed by a second coupling with R 6 -NH 2 or ammonia, for example ammonia, wherein R 3 , R 4 , R 5 and R 6 are as defined above for compounds of formula
  • R 1 is as defined above for compounds of formula (I) and P is hydrogen or a suitable protecting group, for example a benzyl protecting group.
  • the epoxide opening reaction may be performed in a dipolar aprotic solvent such as ⁇ /, ⁇ /-dimethylformamide at a non-extreme temperature in the range 0-100 0 C, most commonly 2O 0 C (or room temperature) in the presence of a strong base such as potassium terf-butoxide.
  • a dipolar aprotic solvent such as ⁇ /, ⁇ /-dimethylformamide
  • a non-extreme temperature in the range 0-100 0 C, most commonly 2O 0 C (or room temperature)
  • a strong base such as potassium terf-butoxide.
  • P is a protecting group this group may be hydrolysed under these reaction conditions to give the carboxylic acid (II) directly or alternatively a separate deprotection stage may be required to afford (II).
  • Method B for preparing compounds of formula (I) comprises reaction of an epoxide of formula (III) directly with a 4-amino-1-arylpyrazolopyrimidine of formula (V)
  • R 1 is as defined above for compounds of formula (I), with an aryl iodide of formula (VII) or (VIII)
  • P is hydrogen or a suitable protecting group, for example a benzyl group, and R 2 is as defined above for compounds of formula (I).
  • the reaction of (Vl) with (VII) or (VIII) 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, ⁇ /, ⁇ /'-dimethylcyclohexanediamine or N, N'- dimethylethylenediamine in a variety of solvents including toluene, dioxane, N, N- dimethylformamide, ⁇ /, ⁇ /-dimethylacetamide and dimethylsulfoxide at a temperature in the range 60-160 0 C, most typically 1 1O 0 C.
  • 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, ⁇ /, ⁇ /'-dimethylcyclo
  • the aminopyrazole (IX) is commercially available.
  • Compounds of formula (I) in which A represents 5-fluoro-2-hydroxy-phenyl may be prepared by reaction of the compounds of formula (I) in which A represents 5-fluoro- 2-methoxy-phenyl with, for example, boron tribromide in dichloromethane solution.
  • Compounds of formula (I) may be prepared in the form of mixtures of enantiomers when mixtures of isomers are used as intermediates in the synthesis.
  • a compound of formula (III) as a racemic mixture of enantiomers will lead to a mixture of enantiomers in the final product.
  • These isomers may, if desired, be separated by conventional methods (eg. HPLC on a chiral column).
  • separation of isomers may be performed earlier in the synthesis, for example individual isomers of compounds of formula (III) 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.
  • Compounds of formula (I) and pharmaceutically acceptable salts thereof may be expected to demonstrate good anti-inflammatory and/or anti-allergic properties. They also may be expected to have an attractive side-effect profile, demonstrated, for example, by increased selectivity for the glucocorticoid receptor over the progesterone receptor and are expected to be compatible with a convenient regime of treatment in human patients.
  • Flashmaster Il is an automated multi-user flash chromatography system, available from Argonaut Technologies Ltd, which utilises disposable, normal phase, SPE cartridges (2g to 10Og). 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.
  • Autopreparative HPLC was carried out using a Waters 600 gradient pump, Waters 2767 inject/collector, Waters Reagent Manager, Micromass ZMD mass spectrometer, Gilson Aspec waste collector and Gilson 115 post-fraction UV detector.
  • the column used was typically a Supelco LCABZ++ column with dimension of 20mm internal diameter by 100mm in length.
  • the stationary phase particle size is 5 ⁇ m.
  • the flow rate was 20ml/min and the runtime was 15 minutes, which comprises a 10-minute gradient followed by a 5 minute column flush and re-equilibration step.
  • the LCMS system used was as follows:
  • Solvents A: 0.1% Formic Acid + IOmMolar Ammonium Acetate. B: 95% Acetonitrile + 0.05% Formic Acid
  • ⁇ /, ⁇ /-Diisopropylethylamine (15.23mL, 87.4mmol) and HATU (6.99g, 18.38mmol) were added sequentially to a stirred solution of 3-iodobenzoic acid (4.34g, 17.5mmol) in anhydrous DMF (10OmL) and the mixture was stirred under nitrogen for 10 min.
  • D- prolinamide (5g, 43.8mmol) was then added and the mixture stirred at room temperature for 3 hours and then allowed to stand for 5 days and was then partitioned between water (60OmL) and ethyl acetate (60OmL).
  • Example 4 ⁇ /-(2-Amino-2-oxoethyl)-3-(4- ⁇ r4-r5-fluoro-2-(methyloxy)phenyll-2- hvdroxy-4-methyl-2-(trifluoromethyl)pentyllamino)-6-methyl-1 H-pyrazolor3,4- c/1pyrimidin-1-yl)benzamide
  • the ability of compounds to bind to the glucocorticoid receptor was determined by assessing their ability to compete with an Alexa 555 fluorescently-labelled dexamethasone derivative. Compounds were solvated and diluted in DMSO, and transferred directly into assay plates. Fluorescent dexamethasone and a partially purified full length glucocorticoid receptor were added to the plates, together with buffer components to stabilise the GR protein (including stabilisation peptide (Panvera catalogue number P2815)) and incubated at room temperature for 2hrs in the dark. Binding of each compound was assessed by analysing the displacement of fluorescent ligand by measuring the decrease in fluorescence polarisation signal from the mixture.
  • Examples 1 to 4 have glucocorticoid binding with a plC 5 o >7.5 in this assay.
  • Human A549 lung epithelial cells were engineered to contain a secreted placental alkaline phosphatase gene under the control of the distal region of the NFkB dependent ELAM promoter as previously described in Ray, K.P., Farrow, S., Daly, M., Talabot, F. and Searle, N. "Induction of the E-selectin promoter by interleukin 1 and tumour necrosis factor alpha, and inhibition by glucocorticoids" Biochemical Journal (1997) 328: 707-15.
  • a T225 flask of CV-1 cells at a density of 80% confluency was washed with PBS, detached from the flask using 0.25% trypsin and counted using a Sysmex KX-21 N.
  • Cells were diluted in DMEM containing 10% Hyclone, 2mM L-Glutamate and 1 % Pen/Strep at 140 cells/ ⁇ l and transduced with 10% PRb-BacMam and 10% MMTV- BacMam.
  • 70 ml of suspension cells were dispensed to each well of white Nunc 384- well plates, containing compounds at the required concentration. After 24h 10 ⁇ l of Steady GIo were added to each well of the plates. Plates were incubated in the dark for 10 min before reading them on a Viewlux reader. Dose response curves were constructed from which pEC 5 o values were estimated.
  • Examples 1 to 4 show pEC 5 o ⁇ 6.5 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 isomer may have similar activity, less activity, no activity or may have some antagonist activity in the case of a functional assay.

Abstract

The present invention provides compounds of formula (I): a process for their preparation, pharmaceutical compositions comprising the compounds and the use of the compounds for the manufacture of a medicament for therapeutic treatment, particularly for the treatment of inflammation and/or allergic conditions.

Description

NOVEL COMPOUNDS
The present invention relates to non-steroidal compounds, a process for their preparation, pharmaceutical compositions comprising the compounds and the use of the compounds for the manufacture of a medicament, 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, HJ. & Herrlich, P. (1992) EMBO J 11 :2241-2246). Transactivation involves direct binding of the glucocorticoid receptor to distinct deoxyribonucleic acid (DNA) glucocorticoid 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, PJ. & Adcock, I. (1993) Trend Pharmacol Sci 14:436-441 ; and 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, LJ. , Smith, CJ. P. 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, C-G., 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 dermatitus, erythema nodosum, acne, hirsutism, toxic epidermal necrolysis, erythema multiform and cutaneous T-cell lymphoma.
In one embodiment, the present invention provides compounds of formula (I):
Figure imgf000004_0001
= chiral centre
(I) wherein
A is 2,3-dihydro-1-benzofuran-7-yl, 5-fluoro-2-methoxy-phenyl or 5-fluoro-2-hydroxy- phenyl;
R1 is methyl or ethyl;
R2 is -N(R3)C(R4)(R5)CONHR6 or
Figure imgf000004_0002
R3 is hydrogen or methyl;
R4 is hydrogen and R5 is hydrogen, methyl or hydroxymethyl, or R4 and R5 are each methyl; and
R6 is hydrogen or methyl; and salts thereof (hereinafter "compounds of the invention").
Compounds of formula (I) contain one or two chiral centres. Thus 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.
Compounds of the invention may provide agonism of the glucocorticoid receptor. It will 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.
A single enantiomer or diastereomer or mixture of isomers (e.g. racemic mixture) may be preferred.
In one embodiment, the invention provides compounds of formula (I) wherein A is 5- fluoro-2-methoxy-phenyl. In a further embodiment, the invention provides compounds of formula (I) wherein A is 2,3-dihydro-1-benzofuran-7-yl.
In one embodiment, R1 is methyl.
In one embodiment, R2 is -N(R3)C(R4)(R5)CONHR6.
In a further embodiment, R2 is
In one embodiment, R3 is hydrogen.
In one embodiment, R4 and R5 are each hydrogen. In a further embodiment, R4 is hydrogen and R5 is methyl.
In one embodiment, R6 is hydrogen.
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:
1-{[3-(4-{[4-(2,3-dihydro-1-benzofuran-7-yl)-2-hydroxy-4-methyl-2-
(trifluoromethyl)pentyl]amino}-6-methyl-1 H-pyrazolo[3,4-c/]pyrimidin-1- yl)phenyl]carbonyl}-D-prolinamide;
1-{[3-(4-{[4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2-
(trifluoromethyl)pentyl]amino}-6-methyl-1 H-pyrazolo[3,4-d]pyrimidin-1- yl)phenyl]carbonyl}-D-prolinamide; Λ/-[(1 R)-2-amino-1-methyl-2-oxoethyl]-3-(4-{[4-[5-fluoro-2-(methyloxy)phenyl]-2- hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1 /-/-pyrazolo[3,4- c/]pyrimidin-1-yl)benzamide;
Λ/-(2-amino-2-oxoethyl)-3-(4-{[4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2-
(trifluoromethyl)pentyl]amino}-6-methyl-1 /-/-pyrazolo[3,4-c/]pyrimidin-1-yl)benzamide; or a salt thereof.
Also included within the scope of the "compounds of the invention" are all solvates (including hydrates), complexes, polymorphic forms, prodrugs, radiolabeled derivatives, stereoisomers and optical isomers of the compounds of formula (I) and salts thereof.
It is to be understood that the references herein to compounds of formula (I) and salts thereof covers the compounds of formula (I) as the free base or as salts thereof, for example as a pharmaceutically acceptable salt thereof.
One embodiment of the invention embraces compounds of formula (I) and salts and solvates thereof. Another embodiment of the invention embraces compounds of formula (I) and solvates thereof. A further embodiment of the invention embraces compounds of formula (I) as the free base.
The skilled person will appreciate that compounds of formula (I) may be in the form of and/or may be administered as a pharmaceutically acceptable salt. Indeed, in certain embodiments of the invention, pharmaceutically acceptable salts of the compounds according to formula (I) may be preferred over the respective free base or free acid because, for example, such salts impart greater stability or solubility to the molecule thereby facilitating formulation into a dosage form. Thus one embodiment of the invention encompasses compounds of formula (I) and pharmaceutically acceptable salts thereof.
As used herein, the term "pharmaceutically acceptable salts" refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. These pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively. Salts 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. Thus one embodiment of the invention embraces compounds of formula (I) and salts thereof.
Suitable salts according to the invention include those formed with both organic and inorganic acids or bases. Pharmaceutically acceptable acid addition salts may include those formed from strong acids, for example hydrochloric, hydrobromic and sulphuric acids, and strong sulphonic acids such as tosic, camphorsulphonic and methanesulphonic acids. Further pharmaceutically acceptable acid addition salts may include those formed from 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-benzenediacrylic) and isethionic acids. Pharmaceutically acceptable base salts include alkali metal salts such as those of sodium and potassium. Further 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, 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 the invention may exist in solid or liquid form. In the solid state, the compounds of the invention may exist in crystalline or noncrystalline 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 compounds of the invention may have the ability to crystallise in more than one form. This is a characteristic known as polymorphism, and it is understood that such polymorphic forms ("polymorphs") are within the scope of the present invention. Polymorphism generally can occur as a response to changes in temperature or pressure or both and can also result from variations in the crystallisation process. Polymorphs can be distinguished by various physical characteristics known in the art such as x-ray diffraction patterns, solubility, and melting point.
The compounds of formula (I) and pharmaceutically acceptable salts thereof are modulators of the glucocorticoid receptor and may be useful in the treatment of diseases associated with glucocorticoid receptor activity. Examples of diseases associated with glucocorticoid receptor activity include 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, Little's syndrome, inflammatory scalp alopecia, panniculitis, psoriasis, discoid lupus erythemnatosus, inflamed cysts, atopic dermatitis, pyoderma gangrenosum, pemphigus vulgaris, bullous pemphigoid, systemic lupus erythematosus, dermatomyositis, herpes gestationis, eosinophilic fasciitis, relapsing polychondritis, inflammatory vasculitis, sarcoidosis, Sweet's disease, type 1 reactive leprosy, capillary hemangiomas, contact dermatitis, atopic dermatitis, lichen planus, exfoliative dermatitus, erythema nodosum, acne, hirsutism, toxic epidermal necrolysis, erythema multiform and cutaneous T-cell lymphoma. Disease states involving systemic inflammation include 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. Glucocorticoid receptor modulators may also be used as immunostimulants and repressors and as wound healing and tissue repair agents.
The compounds of formula (I) and pharmaceutically acceptable salts thereof are expected to have potentially beneficial anti-inflammatory and/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 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 disease states in which the compounds of formula (I) and pharmaceutically acceptable salts thereof are expected to have utility include skin diseases such as eczema, psoriasis, allergic dermatitis, neurodermatitis, pruritis and hypersensitivity reactions; inflammatory conditions of the nose, throat or lungs such as asthma (including allergen-induced asthmatic reactions), rhinitis (including hayfever), nasal polyps, chronic obstructive pulmonary disease (COPD), interstitial lung disease, and fibrosis; inflammatory bowel conditions such as ulcerative colitis and Crohn's disease; and auto-immune diseases such as rheumatoid arthritis.
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 patients with inflammatory and/or allergic conditions, such as rheumatoid arthritis, asthma, COPD, allergy and/or rhinitis. In one embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of rhinitis, for example allergic rhinitis.
Further provided is a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of patients with 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 formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of patients with inflammatory and/or allergic conditions, such as rheumatoid arthritis, asthma, COPD, allergy and/or rhinitis. In one embodiment, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of patients with rhinitis, for example allergic 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 patients with 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 one embodiment, there is provided a method for the treatment of a human or animal subject with rhinitis, for example allergic 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 and/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 1 mg, and such unit doses may be administered more than once a day, for example two or three times a day. Such therapy may extend for a number of weeks or months.
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 (e.g. eye or nose drops), solutions/suspensions for nebulisation, suppositories, pessaries, retention enemas and chewable or suckable tablets or pellets (e.g. for the treatment of aphthous ulcers) or liposome or microencapsulation preparations.
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 pharmaceutically acceptable salt thereof may be in a particle-size- reduced form prepared by, for example, micronisation and milling. Generally, the size-reduced (eg 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 100 μl_ of intranasal composition. Further, generally, each spray to the nostril may deliver from about 1 to about 100 μg, for example about 1 to about 50 μg, 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 CL61 1.
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 e.g. oleic acid, lecithin or an oligolactic acid or derivative e.g. as described in WO94/21229 and WO98/34596 and cosolvents e.g. ethanol.
There is thus provided as a further aspect of the invention a pharmaceutical aerosol composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a fluorocarbon or hydrogen-containing chlorofluorocarbon 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 composition 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 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. 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). 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. Aerosol compositions 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 compositions.
In the case of suspension aerosol compositions, the particle size of the particulate (e.g., micronised) drug should be such as to permit inhalation of substantially all the drug into the lungs upon administration of the aerosol composition 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 compositions of the invention may be prepared by dispersal or dissolution of the medicament and a 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 compositions 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 compositions 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 Pharmacopaeia 1988, pages A204-207, Appendix XVII C. Such techniques enable the "respirable fraction" of the aerosol compositions 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 composition 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 (e.g., 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 composition 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,
TM
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. 6,1 19,853; 6,179,1 18; 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 compositions a metering valve is crimped onto an aluminium can to form an empty canister. The particulate medicament is added to a charge vessel and liquefied propellant together with the optional excipients is pressure filled through the charge vessel into a manufacturing vessel. The drug suspension is mixed before recirculation to a filling machine and an aliquot of the drug suspension is then filled through the metering valve into the canister. In one example bulk manufacturing method for preparing solution aerosol compositions, 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 composition is added to an open canister under conditions which are sufficiently cold to ensure the composition 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 according to the invention may, for example, be formulated in conventional manner for oral, nasal, parenteral or rectal administration. Compositions 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.
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 compositions 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, 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 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 compositions 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), β2-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, andZor 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 andZor stability andZor 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.
In one embodiment, the invention encompasses a combination comprising of a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a β2-adrenoreceptor agonist. Examples of β2-adrenoreceptor agonists include salmeterol (e.g. as the racemate or a single enantiomer, such as the /?-enantiomer), salbutamol (e.g. as the racemate or a single enantiomer such as the R-enantiomer), formoterol (e.g. as the racemate or a single diastereomer such as the /?,/?-diastereomer), salmefamol, fenoterol, carmoterol, etanterol, naminterol, clenbuterol, pirbuterol, flerobuterol, reproterol, bambuterol, indacaterol or 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.
Examples of β2-adrenoreceptor agonists may include those described in
WO02/066422A, WO02/070490, WO02/076933, WO03/024439, WO03/072539, WO 03/091204, 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 /?)-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]foramide,
N-2{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-2-hydroxy-2-(8-hydroxy-
2(1 /-/)-quinolinon-5-yl)ethylamine, and
5-[(/?)-2-(2-{4-[4-(2-amino-2-methyl-propoxy)-phenylamino]-phenyl}-ethylamino)-1- hydroxy-ethyl]-8-hydroxy-1 H-quinolin-2-one, and salts thereof.
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 formula (I) and pharmaceutically acceptable salts thereof 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]-1 1 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-11 β-hydroxy-16α-methyl- 3-0X0-17α-(2,2,3,3- tetramethycyclopropylcarbonyl)oxy-androsta-1 ,4-diene-17β- carboxylic acid cyanomethyl ester and 6α,9α-difluoro-1 1 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-[[(/?)-cyclohexylmethylene]bis(oxy)]-1 1 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-carboxylic acid 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. In one embodiment the corticosteroid is 6α,9α-difluoro-17α-[(2- furanylcarbonyl)oxy]-1 1 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, WO07/054294, WO07/122165, WO07/144327 and WO08/000777.
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 (for example, 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. Suitable iNOS inhibitors include those disclosed in WO93/13055, WO98/30537, WO02/50021 , WO95/34534 and WO99/62875. Suitable CCR3 inhibitors include those disclosed in WO02/26722.
In one embodiment, the invention provides the use of compounds of formula (I) and pharmaceutically acceptable salts thereof in combination with a phosphodiesterase 4 (PDE4) inhibitor, for example in the case of a composition adapted for inhalation. The PDE4-specific inhibitor 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]. Another compound is 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, LJ. 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*,106S*)-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_al. J Pharmacol Exp Ther,1998, 284(1 ): 162), and T2585.
Further compounds are disclosed in the published international patent application WO04/024728, PCT/EP2003/014867 (WO2004/056823) and PCT/EP2004/005494 (WO2004/103998 e.g. Example 399 or 544 disclosed therein), WO2005/058892, WO2005/090348, WO2005/090353, and WO2005/090354, all in the name of Glaxo Group Limited.
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 M-|/M2/M3 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 WO01/041 18. Exemplary compounds for oral administration include pirenzepine (for example, CAS 28797-61- 7), darifenacin (for example, CAS 133099-04-4, or CAS 133099-07-7 for the hydrobromide sold under the name Enablex), oxybutynin (for example, CAS 5633- 20-5, sold under the name Ditropan), terodiline (for example, CAS 15793-40-5), tolterodine (for example, 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 (for example, CAS 10405-02-4) and solifenacin (for example, CAS 242478-37-1 , or CAS 242478-38-2, or the succinate also known as YM-905 and sold under the name Vesicare).
Additional compounds are disclosed in WO 2005/037280, WO 2005/046586 and WO 2005/104745, incorporated herein by reference. The present combinations include, but are not limited to:
(3-enc/o)-3-(2,2-di-2-thienylethenyl)-8,8-dimethyl-8-azoniabicyclo[3.2.1]octane iodide;
(3-enc/o)-3-(2-cyano-2,2-diphenylethyl)-8,8-dimethyl-8-azoniabicyclo[3.2.1]octane bromide;
4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1- azoniabicyclo[2.2.2]octane bromide; and
(1 R,5S)-3-(2-cyano-2,2-diphenylethyl)-8-methyl-8-{2-[(phenylmethyl)oxy]ethyl}-8- azoniabicyclo[3.2.1]octane bromide.
Other anticholinergic agents include compounds of formula (XXI), which are disclosed in US patent application 60/487981 :
Figure imgf000028_0001
in which the preferred orientation of the alkyl chain attached to the tropane ring is endo; R31 and R32 are, independently, selected from the group consisting of straight or branched chain lower alkyl groups having preferably from 1 to 6 carbon atoms, cycloalkyl groups having from 5 to 6 carbon atoms, cycloalkyl-alkyl having 6 to 10 carbon atoms, 2-thienyl, 2-pyridyl, phenyl, phenyl substituted with an alkyl group having not in excess of 4 carbon atoms and phenyl substituted with an alkoxy group having not in excess of 4 carbon atoms;
X" represents an anion associated with the positive charge of the N atom. X" may be but is not limited to chloride, bromide, iodide, sulfate, benzene sulfonate, and toluene sulfonate, including, for example:
(3-enc/o)-3-(2,2-di-2-thienylethenyl)-8,8-dimethyl-8-azoniabicyclo[3.2.1]octane bromide;
(3-enc/o)-3-(2,2-diphenylethenyl)-8,8-dimethyl-8-azoniabicyclo[3.2.1]octane bromide; (3-enc/o)-3-(2,2-diphenylethenyl)-8,8-dimethyl-8-azoniabicyclo[3.2.1]octane 4- methylbenzenesulfonate;
(3-enc/o)-8,8-dimethyl-3-[2-phenyl-2-(2-thienyl)ethenyl]-8-azoniabicyclo[3.2.1]octane bromide; and/or
(3-enc/o)-8,8-dimethyl-3-[2-phenyl-2-(2-pyridinyl)ethenyl]-8- azoniabicyclo[3.2.1]octane bromide.
Further anticholinergic agents include compounds of formula (XXII) or (XXIII), which are disclosed in US patent application 60/51 1009:
(XXII) (XXIII)
Figure imgf000029_0001
wherein: the H atom indicated is in the exo position;
R41" represents an anion associated with the positive charge of the N atom; R41" may be but is not limited to chloride, bromide, iodide, sulfate, benzene sulfonate and toluene sulfonate;
R42 and R43 are independently selected from the group consisting of straight or branched chain lower alkyl groups (having preferably from 1 to 6 carbon atoms), cycloalkyl groups (having from 5 to 6 carbon atoms), cycloalkyl-alkyl (having from 6 to 10 carbon atoms), heterocycloalkyl (having from 5 to 6 carbon atoms) and N or O as the heteroatom, heterocycloalkyl-alkyl (having from 6 to 10 carbon atoms) and N or O as the heteroatom, aryl, optionally substituted aryl, heteroaryl, and optionally substituted heteroaryl;
R44 is selected from the group consisting of (C1-C6)alkyl, (C3-C12)cycloalkyl, (C3-
C7)heterocycloalkyl, (Ci-C6)alkyl(C3-Ci2)cycloalkyl, (CrC6)alkyl(C3-
C7)heterocycloalkyl, aryl, heteroaryl, (Ci-C6)alkyl-aryl, (CrC6)alkyl-heteroaryl, -OR45,
-CH2OR45, -CH2OH, -CN, -CF3, -CH2O(CO)R46, -CO2R47, -CH2NH2, -
CH2N(R47)SO2R45, -SO2N(R47XR48), -CON(R47)(R48), -CH2N(R48)CO(R46), -
CH2N(R48)SO2(R46), -CH2N(R48)CO2(R45), -CH2N(R48)CONH(R47);
R45 is selected from the group consisting of (Ci-C6)alkyl, (d-C6)alkyl(C3-
Ci2)cycloalkyl, (Ci-C6)alkyl(C3-C7)heterocycloalkyl, (CrC6)alkyl-aryl, (CrC6)alkyl- heteroaryl;
R46 is selected from the group consisting of (Ci-C6)alkyl, (C3-Ci2)cycloalkyl, (C3-
C7)heterocycloalkyl, (C1-C6)alkyl(C3-C12)cycloalkyl, (CrC6)alkyl(C3-
C7)heterocycloalkyl, aryl, heteroaryl, (C1-C6)alkyl-aryl, (C1-C6)alkyl-heteroaryl;
R47 and R48 are, independently, selected from the group consisting of H, (C1-C6)alkyl,
(C3-C12)cycloalkyl, (C3-C7)heterocycloalkyl, (C1-C6)alkyl(C3-C12)cycloalkyl, (C1-
C6)alkyl(C3-C7)heterocycloalkyl, (C1-C6)alkyl-aryl, and (C1-C6)alkyl-heteroaryl, including, for example:
(endo)-3-(2-methoxy-2,2-di-thiophen-2-yl-ethyl)-8,8-dimethyl-8-azonia- bicyclo[3.2.1]octane iodide;
3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propionitrile;
(endo)-8-methyl-3-(2,2,2-triphenyl-ethyl)-8-aza-bicyclo[3.2.1]octane;
3-((endo)-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-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propan-1-ol;
Λ/-benzyl-3-((endo)-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-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propyl]-acetamide;
/V-β-^endo^δ-methyl-δ-aza-bicycloβ^.iloct-S-yl^^-diphenyl-propyO-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,δ-dimethyl-δ-azonia- bicyclo[3.2.1]octane iodide;
Λ/-[3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propyl]- benzenesulfonamide;
^-((endo^δ-methyl-δ-aza-bicycloβ^.iloct-S-yl^^-diphenyl-propyO-urea;
Λ/-[3-((endo)-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)-δ,δ-dimethyl-δ-azonia- bicyclo[3.2.1]octane iodide;
(endo)-3-(2-cyano-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane iodide;
(endo)-3-(2-cyano-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane bromide;
(endo)-3-(2-carbamoyl-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane iodide;
(endo)-3-(2-cyano-2,2-di-thiophen-2-yl-ethyl)-δ,δ-dimethyl-δ-azonia- bicyclo[3.2.1]octane iodide; and/or
(endo)-3-{2,2-diphenyl-3-[(1-phenyl-methanoyl)-amino]-propyl}-8,8-dimethyl-8- azonia-bicyclo[3.2.1]octane bromide.
Examples of antihistamines (also referred to as H 1 -receptor antagonists) include any one or more of the numerous antagonists known which inhibit H1-receptors, and are safe for human use. First generation antagonists, include derivatives of ethanolamines, ethylenediamines, and alkylamines, such as diphenylhydramine, pyrilamine, clemastine, chlorpheniramine. Second generation antagonists, which are non-sedating, include loratidine, desloratidine, terfenadine, astemizole, acrivastine, azelastine, levocetirizine fexofenadine and cetirizine.
Examples of anti-histamines include loratidine, desloratidine, fexofenadine, cetirizine, levocabastine, olopatadine, amlexanox and epinastine. 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 another 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 the present invention 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). In a further embodiment, the invention provides a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a dual H1/H3 antagonist. Examples of dual H1/H3 antagonists include 4-[(4-chlorophenyl)methyl]-2-({(2R)-1-[4-(4-{[3-(hexahydro-1 H-azepin-1- yl)propyl]oxy}phenyl)butyl]-2-pyrrolidinyl}methyl)-1 (2/-/)-phthalazinone or a pharmaceutically acceptable salt thereof as described in priority application GB0607839.8.
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.
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 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 a corticosteroid.
The invention thus provides, in a further 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 a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with an anticholinergic.
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 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 compositions. In one embodiment, the individual compounds will be administered simultaneously in a combined pharmaceutical composition. 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 ogether 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 combination of 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 combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof together with an anticholinergic and a PDE-4 inhibitor. A process (Method A) according to the invention for the preparation of compounds of formula (I), and salts thereof, comprises coupling of a carboxylic acid of formula (II):
Figure imgf000035_0001
(H)
wherein A and R1 are as defined above for compounds of formula (I) with an amine
HN(R3)C(R4)(R5)CONHR6 or
Figure imgf000035_0002
wherein R3, R4, R5 and R6 are as defined above for compounds of formula (I).
This coupling may be conducted, for example, using HATU (O-(7-azabenzotriazol-1- yl)-Λ/,Λ/,Λ/',Λ/-tetramethyluronium hexafluorophosphate) in the presence of a suitable base such as Λ/,Λ/-diisopropylethylamine 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 compounds of formula (I) may be prepared from the carboxylic acid (II) by two sequential amide couplings firstly with the amino acid HN(R3)C(R4)(R5)CO2H or D- proline followed by a second coupling with R6-NH2 or ammonia, for example ammonia, wherein R3, R4, R5 and R6 are as defined above for compounds of formula
(I)-
Compounds of formula (II) may be prepared by reaction of an epoxide of formula
Figure imgf000035_0003
wherein A is as defined above for compounds of formula (I), with a 4-amino-1-arylpyrazolopyrimidine of formula (IV)
Figure imgf000036_0001
(IV)
wherein R1 is as defined above for compounds of formula (I) and P is hydrogen or a suitable protecting group, for example a benzyl protecting group.
The epoxide opening reaction may be performed in a dipolar aprotic solvent such as Λ/,Λ/-dimethylformamide at a non-extreme temperature in the range 0-1000C, most commonly 2O0C (or room temperature) in the presence of a strong base such as potassium terf-butoxide. When P is a protecting group this group may be hydrolysed under these reaction conditions to give the carboxylic acid (II) directly or alternatively a separate deprotection stage may be required to afford (II).
Compounds of formula (III) have been described in racemic form in WO04/063163. The compound of formula (III) wherein A represents 5-fluoro-2-methoxy-phenyl has also been described as separate enantiomers in US2005/234250, WO05/040145, Bioorg. Med. Chem. Letters. 2006, 16, 654-657 and in J Org Chem. 2007, 72, 292- 294.
An alternative process (Method B) for preparing compounds of formula (I) comprises reaction of an epoxide of formula (III) directly with a 4-amino-1-arylpyrazolopyrimidine of formula (V)
Figure imgf000036_0002
(V) wherein R1 and R2 are as defined above for compounds of formula (I), under similar conditions to those described for the preparation of compounds of formula (II).
Compounds of formula (IV) and (V) are novel and form another aspect of the invention, and may be prepared by reaction of a 1H-pyrazolopyrimidine-4-amine of formula (Vl):
Figure imgf000037_0001
wherein R1 is as defined above for compounds of formula (I), with an aryl iodide of formula (VII) or (VIII)
Figure imgf000037_0002
wherein P is hydrogen or a suitable protecting group, for example a benzyl group, and R2 is as defined above for compounds of formula (I).
The reaction of (Vl) with (VII) or (VIII) 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/,Λ/'-dimethylcyclohexanediamine or N, N'- dimethylethylenediamine in a variety of solvents including toluene, dioxane, N, N- dimethylformamide, Λ/,Λ/-dimethylacetamide and dimethylsulfoxide at a temperature in the range 60-1600C, most typically 1 1O0C. 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. Compounds of formula (Vl) may be prepared by reaction of 4-cyano-5-aminopyrazole (IX):
Figure imgf000038_0001
with either acetonitrile or propionitrile in the presence of methanolic ammonia under pressure at high temperature (2000C). Representative procedures are described in J. Org. Chem., 1961 , 26, 4967-4974 (acetonitrile) and Tetrahedron, 1968, 24, 5861- 5870 (propionitrile).
The aminopyrazole (IX) is commercially available.
Compounds of formula (VII), wherein P is a protecting group, and compounds of formula (VIII) may be prepared from commercially available 3-iodobenzoic acid by appropriate protection or reaction with amines HR2 under standard conditions.
Compounds of formula (I) in which A represents 5-fluoro-2-hydroxy-phenyl may be prepared by reaction of the compounds of formula (I) in which A represents 5-fluoro- 2-methoxy-phenyl with, for example, boron tribromide in dichloromethane solution.
Compounds of formula (I) may be prepared in the form of mixtures of enantiomers when mixtures of isomers are used as intermediates in the synthesis. For example, the use of a compound of formula (III) as a racemic mixture of enantiomers will lead to a mixture of enantiomers in the final product. These isomers may, if desired, be separated by conventional methods (eg. HPLC on a chiral column).
Alternatively, separation of isomers may be performed earlier in the synthesis, for example individual isomers of compounds of formula (III) 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.
Compounds of formula (I) and pharmaceutically acceptable salts thereof may be expected to demonstrate good anti-inflammatory and/or anti-allergic properties. They also may be expected to have an attractive side-effect profile, demonstrated, for example, by increased selectivity for the glucocorticoid receptor over the progesterone receptor and are expected to be compatible with a convenient regime of treatment in human patients.
The invention will now be illustrated by way of the following non-limiting examples.
EXAMPLES
SYNTHETIC EXPERIMENTAL
Abbreviations
Figure imgf000040_0001
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 (2g to 10Og). 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.
NMR
1H NMR spectra were recorded in DMSO-c/6 or CDCI3 on a Bruker DPX 400 working at 400 MHz. The internal standard used was either tetramethylsilane or the residual protonated solvent at 2.50 ppm for DMSO-c/6. Mass Directed Autopreparative HPLC
Autopreparative HPLC was carried out using a Waters 600 gradient pump, Waters 2767 inject/collector, Waters Reagent Manager, Micromass ZMD mass spectrometer, Gilson Aspec waste collector and Gilson 115 post-fraction UV detector. The column used was typically a Supelco LCABZ++ column with dimension of 20mm internal diameter by 100mm in length. The stationary phase particle size is 5μm. The flow rate was 20ml/min and the runtime was 15 minutes, which comprises a 10-minute gradient followed by a 5 minute column flush and re-equilibration step.
Solvent A: Aqueous solvent = water + 0.1% formic acid.
Solvent B: Organic solvent = MeCN: water 95:5 +0.05% formic acid
Specific gradients used were dependent upon the retention time in the analytical system. For 1.5-2.2 min, 0-30% B, 2.0-2.8 min, 5-30% B, 2.5-3.0 min, 15-55% B, 2.8- 4.0 min, 30-80% B and 3.8-5.5 min, 50-90% B.
LCMS
The LCMS system used was as follows:
• 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 A% B%
0.00 100 0
0.70 100 0
4.20 0 100
5.30 0 100
5.50 100 0
Intermediate 1 : 6-Methyl-1 /-/-pyrazolor3,4-c/lpyrimidin-4-amine
Figure imgf000042_0001
3-Amino-4-pyrazolecarbonitrile (5g, 46mmol) and anhydrous acetonitrile (36ml_, 0.69mol) in 2M ammonia / methanol (10OmL) were stirred and heated to 2000C (400 psi) in a steel pressure vessel for 48 hours. The reaction mixture was cooled and the precipitate was filtered, washed with methanol followed by ethyl acetate and finally ether and then dried in vacuo to yield the title compound (3.05g). LCMS: tRET = 0.62 min; MH+ = 150
Intermediate 2: 1-[(3-lodophenyl)carbonyl1-D-prolinamide
Figure imgf000042_0002
Λ/,Λ/-Diisopropylethylamine (15.23mL, 87.4mmol) and HATU (6.99g, 18.38mmol) were added sequentially to a stirred solution of 3-iodobenzoic acid (4.34g, 17.5mmol) in anhydrous DMF (10OmL) and the mixture was stirred under nitrogen for 10 min. D- prolinamide (5g, 43.8mmol) was then added and the mixture stirred at room temperature for 3 hours and then allowed to stand for 5 days and was then partitioned between water (60OmL) and ethyl acetate (60OmL). The organic phase was separated, washed successively with aqueous sodium bicarbonate, water, 2M hydrochloric acid and brine, passed through a hydrophobic frit and evaporated to give the title compound as an orange gum (2.221 g). LCMS: tRET = 2.34 min; MH+ = 345
Intermediate 3: 1-{r3-(4-Amino-6-methyl-1 H-pyrazolor3,4-c/lpyrimidin-1- yl)phenyllcarbonyl)-D-prolinamide
Figure imgf000042_0003
A mixture of 6-methyl-1 /-/-pyrazolo[3,4-c/]pyrimidin-4-amine (70mg, 0.47mmol), copper (I) iodide (18mg, 0.094mmol), potassium carbonate (130mg, 0.94mmol), (IR^R^Λ/'-dimethylcyclohexane-i ^-diamine (27mg, 0.19mmol) and 1-[(3- iodophenyl)carbonyl]-D-prolinamide (194mg, 0.563mmol) in anhydrous DMF (1.5mL) was heated overnight at 1 1O0C under nitrogen. The dark brown reaction solution was decanted from the insoluble material, filtered, washing with a minimum of DMF and the solution purified by mass directed autopreparation to give the title compound as a pale orange gum (75.8mg). LCMS: tRET = 2.03 min; MH+ = 366
Intermediate 4: Phenylmethyl 3-iodobenzoate
Figure imgf000043_0001
3-lodobenzoic acid (12.4g, 50mmol) was dissolved in DMF (10OmL) and potassium carbonate (7.6g, 55mmol) was added. Benzyl bromide (6.5mL, 55mmol) was then added dropwise over approximately 10 minutes causing a slight exotherm to 24°C. The suspension was stirred at room temperature for 1.5 hours. The suspension was then poured into water (approximately 30OmL) and was extracted with diethyl ether. The combined organic phase was back washed with water and brine and dried over sodium sulfate. The solvent was stripped to yield a crude product as a colourless oil (17.Og). The crude product was applied to a silica gel column and was eluted with cyclohexane-ethyl acetate (95:5) to give the title compound as a colourless oil (13.08g).
1H NMR (400MHz, CDCI3) 8.41 (1 H, t), 8.05 (1 H, dt), 7.90 (1 H, dt), 7.48-7.34 (5H, m), 7.19 (1 H, t) and 5.37 (2H, s)
Intermediate 5: Phenylmethyl 3-(4-amino-6-methyl-1 /-/-pyrazolor3,4-c/lpyrimidin-1- vDbenzoate
Figure imgf000043_0002
A mixture of 6-methyl-1 /-/-pyrazolo[3,4-c/]pyrimidin-4-amine (650mg, 4.36mmol), copper (I) iodide (166mg, 0.872mmol), potassium carbonate (1.2g, 8.68mmol), (1/?,2/?)-Λ/,Λ/-dimethylcyclohexane-1 ,2-diamine (248mg, 1.74mmol) and phenylmethyl 3-iodobenzoate (1.77g, 5.23mmol) in anhydrous DMF (14mL) was heated at 11 O0C under nitrogen for 17 hours. The dark brown reaction solution was decanted from the insoluble material, filtered, washing through with DMF and ethyl acetate. The filtrate was then partitioned between water and ethyl acetate. The aqueous phase was back-extracted with ethyl acetate and the combined organic extracts were washed sequentially with water (x3) and brine and dried by passage through a hydrophobic frit and evaporated to leave a beige coloured solid (1.677g). This crude product was purified by slica gel chromatography on a Flashmaster Il (2x50g cartridges) eluting firstly with 0-10% ethyl acetate in dichloromethane over 30min and then flushing sequentially with 20% ethyl acetate in dichloromethane (20OmL), 50% ethyl acetate in dichloromethane (10OmL), 100% ethyl acetate (20OmL) and 5% methanol in ethyl acetate (10OmL). The product was eluted in the 100% ethyl acetate and the product containing fractions were combined and evaporated to give the title compound as a white solid (605mg). LCMS: tRET = 3.24/3.29 min; MH+ = 360
Intermediate 6: 3-(4-{[4-[5-Fluoro-2-(methyloxy)phenyl1-2-hvdroxy-4-methyl-2- (trifluoromethyl)pentyl1amino)-6-methyl-1 H-pyrazolo[3,4-c/lpyrimidin-1-yl)benzoic acid
Figure imgf000044_0001
To a solution of phenylmethyl 3-(4-amino-6-methyl-1 H-pyrazolo[3,4-c/]pyrimidin-1- yl)benzoate (48.2mg, 0.134mmol) in Λ/,Λ/-dimethylformamide (1.1 mL) was added racemic 2-{2-[5-fluoro-2-(methyloxy)phenyl]-2-methylpropyl}-2-
(trifluoromethyl)oxirane (which may be prepared as described in WO 04/063163) (39.2mg, 0.134mmol) followed by potassium te/f-butoxide (17.36mg, 0.154mmol). The reaction was stirred at room temperature for 2.5 hours when LCMS indicated that the desired reaction was being accompanied by hydrolysis of the benzyl ester. After stirring overnight, more potassium terf-butoxide (30mg, 0.267mmol) and racemic 2-{2-[5-fluoro-2-(methyloxy)phenyl]-2-methylpropyl}-2-
(trifluoromethyl)oxirane (38mg, 0.13mmol) were added and the mixture stirred over the weekend. The mixture was the diluted with methanol and the solution purified by mass-directed autopreparation to give the title compound (51.6mg). LCMS: tRET = 4.01 min; MH+ = 562
Example 1 : 1-{r3-(4-{r4-(2,3-Dihydro-1-benzofuran-7-yl)-2-hvdroxy-4-methyl-2-
(trifluoromethyl)pentyllamino)-6-methyl-1 H-pyrazolor3,4-c/lpyrimidin-1- yl)phenyllcarbonyl)-D-prolinamide
Figure imgf000045_0001
A mixture of 1-{[3-(4-amino-6-methyl-1 H-pyrazolo[3,4-c/]pyrimidin-1- yl)phenyl]carbonyl}-D-prolinamide (37.5mg, 0.1026mmol), racemic 7-{1 ,1-dimethyl-2- [2-(trifluoromethyl)-2-oxiranyl]ethyl}-2,3-dihydro-1-benzofuran (which may be prepared as described in WO 04/063163) (29.4mg, 0.1026mmol) and potassium tert- butoxide (24.8mg, 0.22mmol) in anhydrous DMF (0.85ml_) was stirred at room temperature overnight. The mixture was the diluted with methanol and the solution purified by mass-directed autopreparation. Product containing fractions were combined and partitioned between dichloromethane and aqueous sodium bicarbonate. The organic phase was separated, washed with water and evaporated to give the title compound as a white solid (29.8mg). LCMS: tRET = 3.46 min; MH+ = 652
Example 2: 1 -fr3-(4-fr4-r5-Fluoro-2-(methyloxy)phenyll-2-hvdroxy-4-methyl-2-
(trifluoromethyl)pentyllamino)-6-methyl-1 H-pyrazolor3,4-dlpyrimidin-1- yl)phenyl1carbonyl)-D-prolinamide
Figure imgf000045_0002
Method A Λ/,Λ/-Diisopropylethylamine (0.039ml_, 0.226mmol) was added to a solution of 3-(4- {[4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2-
(trifluoromethyl)pentyl]amino}-6-methyl-1 /-/-pyrazolo[3,4-c/]pyrimidin-1-yl)benzoic acid (25.4mg, 0.0452mmol) in anhydrous DMF (0.5ml_) under nitrogen. HATU (18.1 mg, 0.0476mmol) was then added followed after 10min by D-prolinamide (12.9mg, 0.113mmol). The mixture stirred at room temperature overnight and then diluted with methanol and purified by mass directed autopreparation. Product containing fractions were combined and partitioned between dichloromethane and aqueous sodium bicarbonate. The aqueous phase was back-extracted with dichloromethane and the combined organic extracts were washed successively with water and brine, dried by passage through a hydrophobic frit and evaporated to give the title compound as a white gum (20.6mg). LCMS: tRET = 3.45 min; MH+ = 658
Method B
Prepared similarly to Example 1 from racemic 2-{2-[5-fluoro-2-(methyloxy)phenyl]-2- methylpropyl}-2-(trifluoromethyl)oxirane (which may be prepared as described in WO
04/063163) and 1-{[3-(4-amino-6-methyl-1 H-pyrazolo[3,4-c/]pyrimidin-1- yl)phenyl]carbonyl}- D-prolinamide.
LCMS: tRET = 3.46 min; MH+ = 658
Example 3j Λ/-r(1f?)-2-Amino-1-methyl-2-oxoethyll-3-(4-{r4-r5-fluoro-2-
(methyloxy)phenyl1-2-hvdroxy-4-methyl-2-(trifluoromethyl)pentyl1amino)-6-methyl-1H- pyrazolor3,4-c/lpyrimidin-1-yl)benzamide
Figure imgf000046_0001
Λ/,Λ/-Diisopropylethylamine (0.0738mL, 0.425mmol) was added to a solution of 3-(4- {[4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2-
(trifluoromethyl)pentyl]amino}-6-methyl-1 H-pyrazolo[3,4-c/]pyrimidin-1-yl)benzoic acid (47.6mg, 0.085mmol) in anhydrous DMF (0.66mL) under nitrogen. HATU (33.8mg, 0.0889mmol) was then added followed after 10min by D-alaninamide hydrochloride (26.4mg, 0.212mmol). The mixture was stirred at room temperature for 5 hours and then allowed to stand at room temperature for 4 days. The resulting yellow solution was diluted with methanol and purified by mass directed autopreparation. Product containing fractions were combined and partitioned between dichloromethane and aqueous sodium bicarbonate. The aqueous phase was back-extracted with dichloromethane and the combined organic extracts were washed successively with water and brine, dried by passage through a hydrophobic frit and evaporated to give the title compound as an off-white gum (32.4mg). LCMS: tRET = 3.46 min; MH+ = 632
Example 4: Λ/-(2-Amino-2-oxoethyl)-3-(4-{r4-r5-fluoro-2-(methyloxy)phenyll-2- hvdroxy-4-methyl-2-(trifluoromethyl)pentyllamino)-6-methyl-1 H-pyrazolor3,4- c/1pyrimidin-1-yl)benzamide
Figure imgf000047_0001
Λ/,Λ/-Diisopropylethylamine (0.0695ml_, 0.399mmol) was added to a solution of 3-(4- {[4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2-
(trifluoromethyl)pentyl]amino}-6-methyl-1 H-pyrazolo[3,4-c/]pyrimidin-1-yl)benzoic acid (44.8mg, 0.0798mmol) in anhydrous DMF (0.6ml_) under nitrogen. HATU (31.8mg, 0.0836mmol) was then added followed after 10min by glycinamide hydrochloride (22mg, 0.199mmol). The mixture was stirred at room temperature for 5 days and then diluted with methanol and purified by mass directed autopreparation. Product containing fractions were combined and partitioned between dichloromethane and aqueous sodium bicarbonate. The aqueous phase was back-extracted with dichloromethane and the combined organic extracts were washed successively with water and brine, dried by passage through a hydrophobic frit and evaporated to give the title compound as an off-white solid (23.46mg). LCMS: tRET = 3.40 min; MH+ = 618
BIOLOGICAL EXPERIMENTAL
Glucocorticoid receptor binding assay
The ability of compounds to bind to the glucocorticoid receptor was determined by assessing their ability to compete with an Alexa 555 fluorescently-labelled dexamethasone derivative. Compounds were solvated and diluted in DMSO, and transferred directly into assay plates. Fluorescent dexamethasone and a partially purified full length glucocorticoid receptor were added to the plates, together with buffer components to stabilise the GR protein (including stabilisation peptide (Panvera catalogue number P2815)) and incubated at room temperature for 2hrs in the dark. Binding of each compound was assessed by analysing the displacement of fluorescent ligand by measuring the decrease in fluorescence polarisation signal from the mixture.
Examples 1 to 4 have glucocorticoid binding with a plC5o >7.5 in this assay.
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 MgC^). Dose response curves were constructed from which EC50 values were estimated.
Examples 1 to 4 show plC50 >8 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 Steady GIo 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 pEC5o values were estimated.
Examples 1 to 4 show pEC5o <6.5 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 isomer 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 imgf000050_0001
* = chiral centre
(I) wherein
A is 2,3-dihydro-1-benzofuran-7-yl, 5-fluoro-2-methoxy-phenyl or 5-fluoro-2-hydroxy- phenyl; R1 is methyl or ethyl;
R2 is -N(R3)C(R4)(R5)CONHR6 or
Figure imgf000050_0002
R3 is hydrogen or methyl;
R4 is hydrogen and R5 is hydrogen, methyl or hydroxymethyl, or R4 and R5 are each methyl; and
R6 is hydrogen or methyl; or a salt thereof.
2. A compound according to claim 1 wherein A is 5-fluoro-2-methoxy-phenyl.
3. A compound according to claim 1 or claim 2 wherein R1 is methyl.
4. A compound according to any one of the preceding claims wherein R2 is - N(R3)C(R4)(R5)CONHR6.
5. A compound according to claim 4 wherein R3 is hydrogen.
6. A compound according to claim 4 or claim 5 wherein R4 is hydrogen and R5 is methyl.
7. A compound according to any one of claims 4 to 6 wherein R6 is hydrogen.
8. A compound substantially as described in any one of Examples 1 to 4, or a salt thereof.
9. A compound which is:
1-{[3-(4-{[4-(2,3-dihydro-1-benzofuran-7-yl)-2-hydroxy-4-methyl-2- (trifluoromethyl)pentyl]amino}-6-methyl-1 H-pyrazolo[3,4-c/]pyrimidin-1- yl)phenyl]carbonyl}-D-prolinamide;
1-{[3-(4-{[4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2- (trifluoromethyl)pentyl]amino}-6-methyl-1 H-pyrazolo[3,4-d]pyrimidin-1- yl)phenyl]carbonyl}-D-prolinamide;
Λ/-[(1 R)-2-amino-1-methyl-2-oxoethyl]-3-(4-{[4-[5-fluoro-2-(methyloxy)phenyl]-2- hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1 H-pyrazolo[3,4- c/]pyrimidin-1-yl)benzamide;
Λ/-(2-amino-2-oxoethyl)-3-(4-{[4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2- (trifluoromethyl)pentyl]amino}-6-methyl-1 H-pyrazolo[3,4-c/]pyrimidin-1-yl)benzamide; or a salt thereof.
10. A compound as claimed in any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, for use in human or veterinary medicine.
11. A compound as claimed in any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, for use in the treatment of inflammatory and/or allergic conditions.
12. A compound as claimed in any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, for use in the treatment of rheumatoid arthritis, asthma, COPD, allergy and/or rhinitis.
13. A compound as claimed in any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, for use in the treatment of rhinitis.
14. A compound as claimed in any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, for use in the treatment of patients with skin disease.
15. A compound as claimed in any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, for use in the treatment of patients with eczema, psoriasis, allergic dermatitis, neurodermatitis, pruritis and/or hypersensitivity reactions.
16. Use of a compound as claimed in any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of patients with inflammatory and/or allergic conditions.
17. Use of a compound as claimed in any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of patients with rheumatoid arthritis, asthma, COPD, allergy and/or rhinitis.
18. Use of a compound as claimed in any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of patients with rhinitis.
19. Use of a compound as claimed in any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of patients with skin disease.
20. Use of a compound as claimed in any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of patients with 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 9, 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 9, or a pharmaceutically acceptable salt thereof.
23. 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 as claimed in any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof.
24. 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 9, or a pharmaceutically acceptable salt thereof.
25. 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 9, or a pharmaceutically acceptable salt thereof.
26. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, if desirable, in admixture with one or more physiologically acceptable diluents and/or carriers.
27. A pharmaceutical composition according to claim 26, wherein said composition is adapted for intranasal delivery.
28. A pharmaceutical composition according to claim 26 which further comprises another therapeutically active agent.
29. A combination comprising a compound as claimed in any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, together with one or more other therapeutically active agents.
30. A process for the preparation of a compound of formula (I), or a salt thereof, which comprises:
a) coupling of a carboxylic acid of formula (II):
Figure imgf000054_0001
wherein A and R1 are as defined in claim 1 with an amine HN(R3)C(R4)(R5)CONHR6 or
Figure imgf000054_0002
wherein R3, R4, R5 and R6 are as defined above for compounds of formula (I),
b) coupling of a carboxylic acid of formula (II)
Figure imgf000054_0003
wherein A is as defined in claim 1 with an amine HN(R3)C(R4)(R5)CO2H or D-proline, followed by a second coupling with R6-NH2 or ammonia, wherein R3, R4, R5 and R6 are as defined in claim 1 , or
c) reacting an epoxide of formula (III)
Figure imgf000054_0004
wherein A is as defined in claim 1 , with a 4-amino-1-arylpyrazolopyrimidine of formula (IV)
Figure imgf000055_0001
(IV) wherein R1 and R2 are as defined in claim 1.
PCT/EP2008/055571 2007-05-08 2008-05-06 Pyrazolo [3, 4-d] pyrimidine derivatives for the treatment of inflammation and/or allergic conditions WO2008135578A1 (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7728030B2 (en) 2006-12-21 2010-06-01 Astrazeneca Ab Chemical compounds 572
US8030340B2 (en) 2006-11-23 2011-10-04 Astrazeneca Ab Indazolyl sulphonamide derivatives useful as glucocorticoid modulators
US8211930B2 (en) 2008-05-20 2012-07-03 Astrazeneca Ab Phenyl and benzodioxinyl substituted indazoles derivatives
CN111574384A (en) * 2020-06-12 2020-08-25 上海馨远医药科技有限公司 Preparation method of chiral 1-amino-2-propanol

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006108699A1 (en) * 2005-04-14 2006-10-19 Glaxo Group Limited Indazoles as glucocorticoid receptor ligands
WO2007054294A1 (en) * 2005-11-09 2007-05-18 Glaxo Group Limited Pyrazolo-pyrimidine derivatives as anti-inflammatory agents
WO2007122165A1 (en) * 2006-04-20 2007-11-01 Glaxo Group Limited Novel compounds

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006108699A1 (en) * 2005-04-14 2006-10-19 Glaxo Group Limited Indazoles as glucocorticoid receptor ligands
WO2007054294A1 (en) * 2005-11-09 2007-05-18 Glaxo Group Limited Pyrazolo-pyrimidine derivatives as anti-inflammatory agents
WO2007122165A1 (en) * 2006-04-20 2007-11-01 Glaxo Group Limited Novel compounds

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8030340B2 (en) 2006-11-23 2011-10-04 Astrazeneca Ab Indazolyl sulphonamide derivatives useful as glucocorticoid modulators
US7728030B2 (en) 2006-12-21 2010-06-01 Astrazeneca Ab Chemical compounds 572
US8143290B2 (en) 2006-12-21 2012-03-27 Astrazeneca Ab Chemical compounds 572
US8211930B2 (en) 2008-05-20 2012-07-03 Astrazeneca Ab Phenyl and benzodioxinyl substituted indazoles derivatives
US8916600B2 (en) 2008-05-20 2014-12-23 Astrazeneca Ab Phenyl and benzodioxinyl substituted indazoles derivatives
US9512110B2 (en) 2008-05-20 2016-12-06 Astrazeneca Ab Phenyl and benzodioxinyl substituted indazoles derivatives
US9738632B2 (en) 2008-05-20 2017-08-22 Astrazeneca Ab Phenyl and benzodioxinyl substituted indazoles derivatives
CN111574384A (en) * 2020-06-12 2020-08-25 上海馨远医药科技有限公司 Preparation method of chiral 1-amino-2-propanol

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