WO2009074590A1 - N- (2 { [1-phenyl-1h-indaz0l-4-yl] amino} propyl) -sulfonamide derivatives as non-steroidal glucocorticoid receptor ligands for the treatment of inflammations - Google Patents

N- (2 { [1-phenyl-1h-indaz0l-4-yl] amino} propyl) -sulfonamide derivatives as non-steroidal glucocorticoid receptor ligands for the treatment of inflammations Download PDF

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Publication number
WO2009074590A1
WO2009074590A1 PCT/EP2008/067160 EP2008067160W WO2009074590A1 WO 2009074590 A1 WO2009074590 A1 WO 2009074590A1 EP 2008067160 W EP2008067160 W EP 2008067160W WO 2009074590 A1 WO2009074590 A1 WO 2009074590A1
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methyl
amino
compound
indazol
formula
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PCT/EP2008/067160
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French (fr)
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Keith Biggadike
Hawa Diallo
David House
Simon John Fawcett Macdonald
Iain Mcfarlane Mclay
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Glaxo Group Limited
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Publication of WO2009074590A1 publication Critical patent/WO2009074590A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to non-steroidal glucocorticoid receptor binding compounds and a process for their preparation, to pharmaceutical compositions comprising the compounds and the preparation of said compositions, to intermediates, and to use of the compounds for the manufacture of a medicament for therapeutic treatment, particularly for the treatment of inflammation, allergy and/or auto-immune 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. et al. (2000) Lancet 355:1399-1403), slowing of growth (Allen, D. B. (2000) Allergy 55: suppl 62, 15-18), skin bruising (Pauwels, R.A., Lofdahl, CG. , Latinen, L.A. et al.
  • glucocorticoids that selectively modulate the transrepression pathway compared with the transactivation pathway may therefore have a superior anti-inflammatory to side- effect therapeutic index, allowing more effective and safer treatment of the patient.
  • This new class of glucocorticoids could be used to treat more effectively and more safely the whole spectrum of disease currently treated by current glucocorticoids.
  • glucocorticoids have proved useful in the treatment of inflammation, tissue rejection, auto-immunity, various malignancies, such as leukemias and lymphomas, Cushing's syndrome, rheumatic fever, polyarteritis nodosa, granulomatous polyarteritis, inhibition of myeloid cell lines, immune proliferation/apoptosis, HPA axis suppression and regulation, hypercortisolemia, modulation of the Th1/Th2 cytokine balance, chronic kidney disease, 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 gangrenos
  • Glucocorticoids are especially useful in disease states involving systemic inflammation such as inflammatory bowel disease, 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.
  • the present invention provides compounds of formula (I):
  • A is selected from the following groups:
  • X is selected from NH, CH 2 , S, S(O), S(O) 2 and O;
  • R 1 is selected from -C(O)N(R 2 )C(R 3 )(R 4 )C(O)NH 2 , -C(O)NHCH 2 CH(OH)CH 3 , -
  • R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are each independently selected from hydrogen and methyl; and salts thereof (hereinafter “compounds of the invention").
  • the present invention provides compounds of formula (Ib):
  • A is selected from the following groups:
  • X is selected from NH, CH 2 , S, S(O), S(O) 2 and O;
  • R 1 is selected from -C(O)N(R 2 )C(R 3 )(R 4 )C(O)NH 2 , -C(O)NHCH 2 CH(OH)CH 3 , -
  • R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are each independently selected from hydrogen and methyl; and salts thereof.
  • A is group (i):
  • X is NH
  • R 1 is selected from -C(O)N(R 2 )C(R 3 )(R 4 )C(O)NH 2 , -C(O)NHCH 2 CH(OH)CH 3 , - C(O)NHC 3-6 cycloalkyl, -C(O)NHheterocyclyl and -C(O)NR 8 R 9 wherein R 8 and R 9 together with the nitrogen atom to which they are attached are linked to form a heterocyclyl and wherein each heterocyclyl is optionally substituted by 1 or 2 groups independently selected from oxo, -C(O)NH 2 and -CH 2 OH;
  • R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are each independently selected from hydrogen and methyl; and salts thereof.
  • A is group (i):
  • X is NH
  • R 1 is -C(O)N(R 2 )C(R 3 )(R 4 )C(O)NH 2 .
  • R 1 is -C(O)NHCH 2 CH(OH)CH 3 .
  • R 1 is -C(O)NHC 3 - 6 cycloalkyl.
  • R 1 is -C(O)NHheterocyclyl.
  • R 1 is - C(O)NR 8 R 9 wherein R 8 and R 9 together with the nitrogen atom to which they are attached are linked to form a heterocyclyl.
  • R 1 is -C(O)N(R 2 )C(R 3 )(R 4 )C(O)NH 2 wherein R 2 and R 3 are each hydrogen and R 4 is methyl.
  • R 1 is -C(O)NHC 3 _ 6 cycloalkyl wherein the Cs- ⁇ cycloalkyl group is cyclopropyl.
  • R 1 is -C(O)NHheterocyclyl wherein the heterocyclyl contains 1 heteroatom.
  • R 1 is -C(O)NHheterocyclyl wherein the heteroatom is selected from sulfur and nitrogen.
  • R 1 is - C(O)NHheterocyclyl wherein the heterocyclyl is selected from tetrahydrothienyl and pyrrolidinyl.
  • R 1 is -C(O)NHheterocyclyl wherein the heterocyclyl is substituted by 1 or 2 oxo groups.
  • R 1 is -C(O)NR 8 R 9 wherein R 8 and R 9 together with the nitrogen atom to which they are attached are linked to form a heterocyclyl, wherein the heterocyclyl is selected from pyrrolidinyl and piperidinyl.
  • R 1 is -C(O)NR 8 R 9 wherein R 8 and R 9 together with the nitrogen atom to which they are attached are linked to form a heterocyclyl, wherein the heterocyclyl is substituted by one group selected from -CH 2 OH and -C(O)NH 2 .
  • R 1 is - C(O)NR 8 R 9 wherein R 8 and R 9 together with the nitrogen atom to which they are attached are linked to form a heterocyclyl, wherein the heterocyclyl is substituted by one -CH 2 OH group.
  • R 1 is in the meta position on the phenyl ring. In another embodiment R 1 is in the para position on the phenyl ring.
  • R 5 is hydrogen and R 6 is methyl. In another embodiment R 5 is methyl and R 6 is hydrogen.
  • R 7 is methyl
  • the compound of formula (I) is:
  • the compound of formula (I) is:
  • the compound of formula (I) is:
  • heterocyclyl' refers to a saturated 4-7 membered monocyclic ring containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen and sulphur.
  • monocyclic rings include pyrrolidinyl, azetidinyl, pyrazolidinyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, hydantoinyl, valerolactamyl, oxetanyl, dioxolanyl, dioxanyl, oxathiolanyl, oxathianyl, dithianyl, dihydrofuranyl, tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothien
  • the heterocyclyl is tetrahydrothienyl, pyrrolidinyl or piperidinyl.
  • the heterocyclyl is optionally substituted it may be substituted anywhere on the ring including on the nitrogen and/or sulphur atom/atoms.
  • the compounds of formula (I) may contain one or more chiral centres so there may be a number of possible stereoisomers, e.g. enantiomers or diastereomers, of each compound of formula (I).
  • Enantiomer 1 and Enantiomer 2 are used herein to refer to the enantiomers of a compound of formula (I), based on the order of their elution using the chiral chromatography methodology described herein.
  • Enantiomer 1 refers to the first enantiomer to elute and Enantiomer 2 refers to the second enantiomer to elute.
  • Diastereomer 1 and Diastereomer 2 are used herein to refer to the diastereomers of a compound of formula (I) based on their order of elution using the chiral chromatographic methodology described herein.
  • Diastereomer 1 refers to the first diastereomer to elute
  • Diastereomer 2 refers to the second diastereomer to elute.
  • regioisomer is used herein to refer to the regioisomers or structural isomers of a compound of formula (I), i.e. those compounds which have the same molecular formula but where the atoms are bonded together in different orders.
  • At least one stereoisomer e.g. one enantiomer of the racemate
  • the other stereoisomers may have similar activity, less activity, no activity or may have some antagonist activity in a functional assay.
  • the compounds of formula (I) may be formed as a single enantiomer or diastereomer, or mixture of isomers (e.g. racemic mixture).
  • the compound of formula (I) is Enantiomer 1.
  • the compound of formula (I) is Enantiomer 2.
  • the compound of formula (I) is Diastereomer 1.
  • the compound of formula (I) is Diastereomer 2.
  • the compounds of formula (I) may be formed as a mixture of enantiomers, such as a racemic mixture.
  • the compound of formula (I) is the racemic mixture (the racemate).
  • isomer and “stereoisomer” as used herein encompass enantiomer, diastereomer and/or regioisomer.
  • the compounds of the invention are glucocorticoid receptor binders. Accordingly, it has been found that at least one of the possible stereoisomers of each of the compounds of formula (I) binds to the glucocorticoid receptor.
  • At least one of the possible stereoisomers of each of the compounds of formula (I) has glucocorticoid receptor activity. Accordingly, at least one of the possible stereoisomers of each compound of formula (I) modulates the glucocorticoid receptor.
  • modulator refers to a compound which binds to the glucocorticoid receptor and acts as either an agonist, a partial agonist or an antagonist of the glucocorticoid receptor.
  • the compounds of the invention may provide agonism of the glucocorticoid receptor. Additionally, it appears that one or more of the possible stereoisomers of some of the compounds of formula (I) may possess advantageous selectivity in respect of maintaining transrepression activity whilst reducing the transactivation activity. These observations are believed to be indicative that the compounds of the invention provide anti-inflammatory properties with fewer or less severe related side effects.
  • 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.
  • polymorphs may exhibit polymorphism (i.e. the capacity to occur in different crystalline structures). These different crystalline forms are typically known as "polymorphs.”
  • the invention includes all such polymorphs. Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification.
  • polymorphs may be produced, for example, by changing or adjusting the reaction conditions or reagents, used in making the compound. For example, changes in temperature, pressure, or solvent may result in polymorphs. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions.
  • One embodiment of the invention provides a compound of formula (I) or a salt or solvate thereof. Another embodiment of the invention provides a compound of formula (I) or a salt thereof. Another embodiment of the invention provides a compound of formula (I) or a solvate thereof. Another embodiment of the invention provides a compound of formula (I) as the free base. A further embodiment of the invention provides a salt of a compound of formula (I) or a solvate thereof.
  • Salts and solvates of the compounds of formula (I) which are suitable for use in medicine are those wherein the counter-ion or associated solvent is pharmaceutically acceptable.
  • salts and solvates having non-pharmaceutically acceptable counter-ions or associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of formula (I) and their pharmaceutically acceptable salts and solvates.
  • 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 hydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic, sulphamic, sulphanilic, methanesulphonic, ethanesulphonic, formic and arylsulphonic (for example p-toluenesulphonic, benzenesulphonic, naphthalenesulphonic or naphthalenedisulphonic) acids.
  • Pharmaceutically acceptable base salts may include alkali metal salts such as those of sodium and potassium and alkaline earth metal salts such as those of calcium.
  • the compounds of formula (I) and pharmaceutically acceptable salts thereof may have beneficial anti-inflammatory and/or anti-allergic and/or auto-immune effects, particularly upon oral administration, demonstrated by, for example, their ability to bind to the glucocorticoid receptor and to elicit a response via that receptor.
  • the compounds of formula (I) and pharmaceutically acceptable salts thereof may be of use in the treatment of an inflammatory and/or allergic disorder and/or autoimmune condition.
  • Examples of disease states associated with glucocorticoid receptor activity include skin diseases such as eczema, psoriasis, allergic dermatitis, neurodermatitis, pruritis, exfoliative dermatitis, pemphigus and hypersensitivity reactions; inflammatory conditions of the nose, throat or lungs such as asthma (including allergen-induced asthmatic reactions), rhinitis (including seasonal (hayfever), allergic and vasomotor), nasal polyps, chronic obstructive pulmonary disease (COPD), interstitial lung disease, and fibrosis; inflammatory bowel conditions such as ulcerative colitis and Crohn's disease; auto-immune diseases such as rheumatoid arthritis, termporal arteritis, polyarteritis nodosa, polymyositis, ankylosing spondylitis, sarcoidosis, autoimmune hepatitis; cancers such as acute and lymphatic leukaemia, myeloma, lymphom
  • amphetamine or amphetamine-related drugs e.g. dextroamphetamine, methylamphetamine
  • Compounds having glucocorticoid receptor activity may also have utility in inducing suppression of the immune system during organ transplantation, in acute transplant reject, angioedema of the upper respiratory tract and anaphylactic shock.
  • Examples of disease states in which the compounds of formula (I) and pharmaceutically acceptable salts thereof may have utility include rheumatoid arthritis, asthma, COPD, allergy and rhinitis.
  • compounds of formula (I) and pharmaceutically acceptable salts thereof are expected to be of use in human or veterinary medicine, in particular as anti-inflammatory and/or anti-allergic agents.
  • Compounds of formula (I) and pharmaceutically acceptable salts thereof are also expected to be of use in the treatment of patients with an inflammatory and/or auto-immune condition.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of patients with an inflammatory and/or allergic condition.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of patients with rheumatoid arthritis, asthma, COPD, allergy and/or rhinitis.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of patients with skin disease.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of patients with eczema, psoriasis, allergic dermatitis, neurodermatitis, pruritis and/or hypersensitivity reactions for use in the treatment of patients with eczema, psoriasis, allergic dermatitis, neurodermatitis, pruritis and/or hypersensitivity reactions.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of patients with an inflammatory and/or auto-immune condition.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of patients with an inflammatory and/or allergic condition.
  • a compound of formula (I) 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.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of patients with rheumatoid arthritis.
  • a compound of formula (I) 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.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of patients with an inflammatory and/or auto-immune condition.
  • 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 of formula (I) or a pharmaceutically acceptable salt thereof.
  • a method for the treatment of a human or animal subject with rheumatoid arthritis, asthma, COPD, allergy and/or rhinitis comprises administering to said human or animal subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • a method for the treatment of a human or animal subject with rheumatoid arthritis 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 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 eczema, psoriasis, allergic dermatitis, neurodermatitis, pruritis and/or hypersensitivity reactions 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 an inflammatory and/or auto-immune condition 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) or a pharmaceutically acceptable salt or solvate 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 pharmaceutically acceptable diluents or carriers.
  • pharmaceutically acceptable diluents or carriers include, but are not limited to, aqueous or non-aqueous vehicles, thickening agents, isotonicity adjusting agents, antioxidants and/or preservatives.
  • 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.
  • the compounds of formula (I) or a pharmaceutically acceptable salt thereof may, for example, be formulated for oral, nasal, inhaled, buccal, sublingual, parenteral, topical rectal administration or other topical administration.
  • compositions for oral administration include solutions, syrups, elixirs, powders, granules, tablets and capsules which typically contain conventional excipients such as binding agents, fillers, lubricants, disintegrants, wetting agents, suspending agents, emulsifying agents, preservatives, buffer salts, flavouring, colouring and/or sweetening agents as appropriate. Dosage unit forms may be preferred as described below.
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • the tablets may also contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycollate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included.
  • Solid compositions of a similar type may also be employed as fillers in gelatin capsules.
  • excipients in this regard include lactose, starch, a cellulose, milk sugar or high molecular weight polyethylene glycols.
  • the agent may be combined with various sweetening or flavouring agents, colouring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.
  • Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol.
  • a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol.
  • Flavouring, preservative, dispersing and colouring agent can also be present.
  • Capsules can be made by preparing a powder mixture as described above, and filling formed gelatin sheaths.
  • Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture before the filling operation.
  • a disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.
  • suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
  • Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant and pressing into tablets.
  • a powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, an aliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or an absorption agent such as bentonite, kaolin or dicalcium phosphate.
  • a binder such as carboxymethylcellulose, an aliginate, gelatin, or polyvinyl pyrrolidone
  • a solution retardant such as paraffin
  • a resorption accelerator such as a quaternary salt
  • an absorption agent such as bentonite, kaolin or dicalcium phosphate.
  • the powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen.
  • a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen.
  • the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules.
  • the granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil. The lubricated mixture is then compressed into tablets.
  • the compounds of formula (I) and pharmaceutically acceptable salts thereof can also be combined with free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps.
  • a clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different unit dosages.
  • Oral fluids such as solutions, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound.
  • Syrups can be prepared by dissolving the compound in a suitably flavoured aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle.
  • Suspensions can be formulated by dispersing the compound in a non-toxic vehicle.
  • Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives, flavour additives such as peppermint oil or saccharin, and the like can also be added.
  • dosage unit compositions for oral administration can be microencapsulated. The composition can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax or the like.
  • the compounds of formula (I) or a pharmaceutically acceptable salt thereof can also be administered in the form of liposome emulsion delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is in the form of a tablet or capsule for oral administration.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is in the form of a solution, syrup or elixir for oral administration.
  • Topical administration includes administration by insufflation and inhalation.
  • preparation for topical 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.
  • 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.
  • Compositions which are non- pressurised and adapted to be administered topically to the nasal cavity are of particular interest. Suitable compositions contain water as the diluent or carrier for this purpose.
  • the compounds of formula (I) and/or pharmaceutically acceptable salts thereof may be formulated for intransal delivery.
  • a pharmaceutical composition comprising an aqueous suspension/solution of a compound of formula (I) and/or a pharmaceutically acceptable salt thereof and optionally one or more of each of the following; a suspending agent; a preservative; a wetting agent; a buffer; an isotonicity adjusting agent; and a taste-masking agent.
  • Compositions suitable for intranasal administration may optionally further contain other excipients, such as antioxidants (for example metabisulphite).
  • Aqueous compositions may be administered to the nose by nebulisation.
  • suspending agents examples include cellulose, carboxymethylcellulose, veegum, tragacanth, bentonite, methylcellulose and polyethylene glycols.
  • the suspending agent will be microcrystalline cellulose and carboxy methylcellulose sodium, for example used as the branded product Avicel RC591 (which typically contains 87-91% microcrystalline cellulose and 9 -13% carboxy methylcellulose sodium) or Avicel CL61 1.
  • compositions of the present invention may be protected from microbial contamination and growth by inclusion of a preservative.
  • pharmaceutically acceptable anti-microbial agents or preservatives that can be used in the composition include quaternary ammonium compounds (for example benzalkonium chloride, benzethonium chloride, cetrimide, cetylpyridinium chloride and myristyl picolinium chloride), alcoholic agents (for example chlorobutanol, phenylethyl alcohol and benzyl alcohol), antibacterial esters (for example esters of para-hydroxybenzoic acid), chelating agents such as disodium edetate (EDTA), and other anti-microbial agents such as chlorhexidine (for example in the form of the acetate or gluconate), potassium sorbate, chlorocresol, sorbic acid and its salts, polymyxin, methylparaben and propylparaben.
  • quaternary ammonium compounds for example benzalkonium chloride, benze
  • wetting agents any agent which is effective in wetting the particles and which is pharmaceutically acceptable can be used.
  • wetting agents that can be used are fatty alcohols, esters and ethers.
  • the wetting agent is a hydrophilic, non-ionic surfactant, for example polyoxyethylene (20) sorbitan monooleate (supplied as the branded product Polysorbate 80).
  • buffer substances include citric acid/sodium hydrogensulphate borate buffers, citric acid/citrate buffers, phosphates (sodium hydrogenorthophosphate, disodium hydrogenphosphate), trometamol or equivalent conventional buffers in order to adjust the pH value of the composition.
  • an isotonicity adjusting agent is to achieve isotonicity with body fluids, for example fluids of the nasal cavity, resulting in reduced levels of irritancy associated with many nasal compositions.
  • suitable isotonicity adjusting agents are glucose, glycerine, sorbitol, sodium chloride, dextrose and calcium chloride.
  • the isotonicity adjusting agent may be dextrose, for example, anhydrous dextrose.
  • taste-masking agents include sucralose, sucrose, saccharin or a salt thereof, fructose, dextrose, corn syrup, aspartame, acesulfame-K, xylitol, sorbitol, erythritol, ammonium glycyrrhizinate, thaumatin, neotame, mannitol, menthol, eucalyptus oil, camphor, a natural flavouring agent, an artificial flavouring agent, and combinations thereof.
  • the taste-masking agent is sucralose and/or menthol.
  • the compounds of formula (I) or a pharmaceutically acceptable salt thereof may be formulated for administration topically to the nose 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 composition.
  • 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.
  • Ointments, creams and gels may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agent and/or solvents.
  • bases may thus, for example, include water and/or an oil such as liquid paraffin or a vegetable oil such as arachis oil or castor oil, or a solvent such as polyethylene glycol.
  • Thickening agents and gelling agents which may be used according to the nature of the base include soft paraffin, aluminium stearate, cetostearyl alcohol, polyethylene glycols, woolfat, beeswax, carboxypolymethylene and cellulose derivatives, and/or glyceryl monostearate and/or non-ionic emulsifying agents.
  • Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents or thickening agents.
  • Powders for external application may be formed with the aid of any suitable powder base, for example, talc, lactose or starch.
  • Drops may be formulated with an aqueous or non-aqueous base also comprising one or more dispersing agents, solubilising agents, suspending agents or preservatives.
  • the compounds of formula (I) or a pharmaceutically acceptable salt thereof may be formulated as a dry powder for administration by inhalation.
  • 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.
  • Spray compositions for inhalation 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 or solvate 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 composition excipients well known in the art such as surfactants e.g. oleic acid, lecithin or an oligolactic acid derivative e.g. as described in WO94/21229 and WO98/34596 and cosolvents e.g. ethanol.
  • surfactants e.g. oleic acid, lecithin or an oligolactic acid derivative e.g. as described in WO94/21229 and WO98/34596
  • 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.
  • compositions of the invention 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 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 about 20 ⁇ g to 500 ⁇ g of a compound of formula (I).
  • Administration may be once daily or several times daily, for example 2, 3, 4 or 8 times, giving for example 1 , 2 or 3 doses each time.
  • the overall daily dose with an aerosol will be within the range from 100 ⁇ g to 10mg, preferably from 200 ⁇ g to 2000 ⁇ g.
  • the overall daily dose and the metered dose delivered by capsules and cartridges in an inhaler or insufflator will generally be double that delivered with aerosol 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 the invention in the selected propellant in an appropriate container, for example, with the aid of sonication or a high-shear mixer.
  • the process is desirably carried out under controlled humidity conditions.
  • the chemical and physical stability and the pharmaceutical acceptability of the aerosol 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 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.
  • 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.
  • 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.
  • Capsules and cartridges for use in an inhaler or insufflator may be formulated containing a powder mix for inhalation of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a suitable powder base such as lactose or starch.
  • a powder mix for inhalation of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a suitable powder base such as lactose or starch.
  • Each capsule or cartridge may generally contain from 20 ⁇ g to 10mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof may be presented without excipients such as lactose.
  • 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 but will generally be within the range of from 0.001 to 10% by weight. Generally, for most types of preparations, the proportion used will be within the range of from 0.005 to 1%, for example from 0.01 to 0.5%. However, in powders for inhalation or insufflation the proportion used will normally be within the range of from 0.1 to 5%.
  • 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.
  • a physician will determine the actual dosage which will be most suitable for an individual subject.
  • the specific dose level and frequency of dosage for any particular individual may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual undergoing therapy.
  • the daily dosage level of the agent may be in single or divided doses.
  • the daily dose as employed for adult human treatment may range from 0.5-100mg/kg body weight, for example from 0.5-60mg/kg body weight, which may be administered in 1 to 4 daily doses, for example, depending on the route of administration and the condition of the patient.
  • each unit will contain, for example 5mg to 1g of active ingredient.
  • the duration of treatment will be dictated by the rate of response rather than by arbitrary numbers of days.
  • the compounds of formula (I) or a pharmaceutically acceptable salt 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.
  • a compound of formula (I) or a pharmaceutically functional salt thereof formulated for oral administration In another embodiment there is provided a compound of formula (I) or a pharmaceutically functional salt thereof formulated for inhaled administration. In a further embodiment there is provided a compound of formula (I) or a pharmaceutically functional salt thereof 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
  • the other therapeutic ingredient(s) may be used in the form of salts, for example as alkali metal or amine salts or as acid addition salts, or prodrugs, or as esters, for example lower alkyl esters, or as solvates, for example hydrates to optimise the activity and/or stability and/or physical characteristics, such as solubility, of the therapeutic ingredient. It will be clear also that, where appropriate, the therapeutic ingredients may be used in optically pure form.
  • ⁇ 2 -adrenoreceptor agonists examples include salmeterol (which may be a racemate or a single enantiomer such as the R-enantiomer), salbutamol (which may be a racemate or a single enantiomer such as the /?-enantiomer), formoterol (which may be a racemate or a single diastereomer such as the /?,/?-diastereomer), salmefamol, fenoterol, carmoterol, etanterol, naminterol, clenbuterol, pirbuterol, flerbuterol, reproterol, bambuterol, indacaterol, terbutaline and salts thereof, for example the xinafoate (1-hydroxy-2-naphthalenecarboxylate) salt of salmeterol, the sulphate salt or free base of salbutamol or the fumarate salt of formoterol.
  • ⁇ 2 -adrenoreceptor agonists include those described in WO02/066422,
  • WO02/070490 WO02/076933, WO03/024439, WO03/072539, WO03/091204, WO04/016578, WO04/022547, WO04/037807, WO04/037773, WO04/037768, WO04/039762, WO04/039766, WO01/42193 and WO03/042160.
  • ⁇ 2 -adrenoreceptor agonists include: 3-(4- ⁇ [6-( ⁇ (2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl ⁇ amino) hexyl] oxy ⁇ butyl) benzenesulfonamide;
  • the ⁇ 2 -adrenoreceptor agonist may be in the form of a salt formed with a pharmaceutically acceptable acid selected from sulphuric, hydrochloric, fumaric, hydroxynaphthoic (for example 1- or 3-hydroxy-2-naphthoic), cinnamic, substituted cinnamic, triphenylacetic, sulphamic, sulphanilic, naphthaleneacrylic, benzoic, 4-methoxybenzoic, 2- or 4-hydroxybenzoic, 4-chlorobenzoic and 4-phenylbenzoic acid.
  • a pharmaceutically acceptable acid selected from sulphuric, hydrochloric, fumaric, hydroxynaphthoic (for example 1- or 3-hydroxy-2-naphthoic), cinnamic, substituted cinnamic, triphenylacetic, sulphamic, sulphanilic, naphthaleneacrylic, benzoic, 4-
  • Suitable anti-inflammatory agents include corticosteroids.
  • corticosteroids which may be used in combination with a compound of formula (I) or a pharmaceutically acceptable salt 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-
  • corticosteroids include fluticasone propionate, 6 ⁇ ,9 ⁇ -difluoro-11 ⁇ -hydroxy-16 ⁇ - methyl-17 ⁇ -[(4-methyl-1 ,3-thiazole-5-carbonyl)oxy]-3-oxo-androsta-1 ,4-diene-17 ⁇ - carbothioic acid S-fluoromethyl ester, 6 ⁇ ,9 ⁇ -difluoro-17 ⁇ -[(2-furanylcarbonyl)oxy]- 11 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-androsta-1 ,4-diene-17 ⁇ -carbothioic acid S- fluoromethyl ester, 6 ⁇ ,9 ⁇ -difluoro-11 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-17 ⁇ -(2, 2,3,3- tetramethycyclopropylcarbonyl)oxy-androsta-1 ,4-diene-17 ⁇ -carbothioic acid S- cyanomethyl ester and 6 ⁇ ,9 ⁇ -difluoro
  • the corticosteroid is 6 ⁇ ,9 ⁇ -difluoro-17 ⁇ -[(2- furanylcarbonyl)oxy]-1 1 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-androsta-1 ,4-diene-17 ⁇ - carbothioic acid S-fluoromethyl ester.
  • corticosteroids may include those described in WO02/088167, WO02/100879, WO02/12265, WO02/12266, WO05/005451 , WO05/005452, WO06/072599 and WO06/072600.
  • Non-steroidal compounds having glucocorticoid agonism that may possess selectivity for transrepression over transactivation and that may be useful in combination therapy include those covered in the following published patent applications and patents: WO03/082827, WO98/54159, WO04/005229, WO04/009017, WO04/018429, WO03/104195, WO03/082787, WO03/082280, WO03/059899, WO03/101932, WO02/02565, WO01/16128, WO00/66590, WO03/086294, WO04/026248, WO03/061651 , WO03/08277, WO06/000401 , WO06/000398, WO06/015870, WO06/108699, WO07/000334 and WO07/054294.
  • anti-inflammatory agents include non-steroidal anti-inflammatory drugs (NSAID's).
  • NSAID's non-steroidal anti-inflammatory drugs
  • NSAID's examples include sodium cromoglycate, nedocromil sodium, phosphodiesterase (PDE) inhibitors (for example, theophylline, PDE4 inhibitors or mixed PDE3/PDE4 inhibitors), leukotriene antagonists, inhibitors of leukotriene synthesis (for example montelukast), iNOS inhibitors, tryptase and elastase inhibitors, beta-2 integrin antagonists and adenosine receptor agonists or antagonists (e.g.
  • adenosine 2a agonists adenosine 2a agonists
  • cytokine antagonists for example chemokine antagonists, such as a CCR3 antagonist
  • inhibitors of cytokine synthesis or 5- lipoxygenase inhibitors.
  • An iNOS (inducible nitric oxide synthase inhibitor) is preferably for oral administration.
  • iNOS inhibitors include those disclosed in WO93/13055, WO98/30537, WO02/50021 , WO95/34534 and WO99/62875.
  • CCR3 inhibitors include those disclosed in WO02/26722.
  • the invention provides the use of the compounds of formula (I) or a pharmaceutically acceptable salt thereof in combination with a phosphodiesterase 4 (PDE4) inhibitor, especially in the case of a composition adapted for inhalation.
  • PDE4-specific inhibitor useful in this aspect of the invention may be any compound that is known to inhibit the PDE4 enzyme or which is discovered to act as a PDE4 inhibitor, and which are only PDE4 inhibitors, not compounds which inhibit other members of the PDE family, such as PDE3 and PDE5, as well as PDE4.
  • Compounds include c/s-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1- carboxylic acid, 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4- difluoromethoxyphenyl)cyclohexan-1 -one and c/s-[4-cyano-4-(3-cyclopropylmethoxy- 4-difluoromethoxyphenyl)cyclohexan-1-ol].
  • c/s-4-cyano-4-[3-(cyclopentyloxy)-4- methoxyphenyl]cyclohexane-1-carboxylic acid also known as cilomilast
  • salts, esters, pro-drugs or physical forms which is described in U.S. patent 5,552,438 issued 03 September, 1996; this patent and the compounds it discloses are incorporated herein in full by reference.
  • 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- ⁇ /M 2 /M 3 receptors.
  • exemplary compounds for administration via inhalation include ipratropium (for example, as the bromide, CAS 22254-24-6, sold under the name Atrovent), oxitropium (for example, as the bromide, CAS 30286-75- 0) and tiotropium (for example, as the bromide, CAS 136310-93-5, sold under the name Spiriva).
  • revatropate for example, as the hydrobromide, CAS 262586-79-8) and LAS-34273 which is disclosed in WO01/041 18.
  • Exemplary compounds for oral administration include pirenzepine (CAS 28797-61-7), darifenacin (CAS 133099-04-4, or CAS 133099-07-7 for the hydrobromide sold under the name Enablex), oxybutynin (CAS 5633-20-5, sold under the name Ditropan), terodiline (CAS 15793-40-5), tolterodine (CAS 124937-51-5, or CAS 124937-52-6 for the tartrate, sold under the name Detrol), otilonium (for example, as the bromide, CAS 26095-59-0, sold under the name Spasmomen), trospium chloride (CAS 10405- 02-4) and solifenacin (CAS 242478-37-1 , or CAS 242478-38-2 for the succinate also known as
  • anticholinergic agents include compounds which are disclosed in US patent application 60/487981 including, for example:
  • anticholinergic agents include compounds which are disclosed in US patent application 60/51 1009 including, for example: (enc/o)-3-(2-methoxy-2,2-di-thiophen-2-yl-ethyl)-8,8-dimethyl-8-azonia- bicyclo[3.2.1]octane iodide;
  • the invention provides a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, together with an H1 antagonist.
  • H1 antagonists include, without limitation, amelexanox, astemizole, azatadine, azelastine, acrivastine, brompheniramine, cetirizine, levocetirizine, efletirizine, chlorpheniramine, clemastine, cyclizine, carebastine, cyproheptadine, carbinoxamine, descarboethoxyloratadine, doxylamine, dimethindene, ebastine, epinastine, efletirizine, fexofenadine, hydroxyzine, ketotifen, loratadine, levocabastine, mizolastine, mequitazine, mianserin, noberastine, meclizine, norastemizole, olopata
  • the invention provides a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, together with an H3 antagonist (and/or inverse agonist).
  • H3 antagonists include, for example, those compounds disclosed in WO2004/035556 and in WO2006/045416.
  • Other histamine receptor antagonists which may be used in combination with a compound of formula (I) or a pharmaceutically acceptable salt thereof, include antagonists (and/or inverse agonists) of the H4 receptor, for example, the compounds disclosed in Jablonowski et al., J. Med. Chem. 46:3957-3960 (2003).
  • the invention thus provides, in another aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a PDE4 inhibitor.
  • the invention thus provides, in another aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a ⁇ 2 -adrenoreceptor agonist.
  • the invention thus provides, in another aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a corticosteroid.
  • the invention thus provides, in another aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with another non-steroidal GR agonist.
  • the invention thus provides, in another aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with an anticholinergic.
  • the invention thus provides, in another aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with an antihistamine.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a PDE4 inhibitor and a ⁇ 2 -adrenoreceptor agonist.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with an anticholinergic and a PDE-4 inhibitor.
  • the individual compounds of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical 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 together with another non-steroidal GR agonist.
  • the invention thus provides, in a further aspect, a pharmaceutical composition
  • a pharmaceutical composition comprising a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof together with an anticholinergic.
  • the invention thus provides, in a further aspect, a pharmaceutical composition
  • a pharmaceutical composition comprising a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof together with an antihistamine.
  • the invention thus provides, in a further aspect, a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a PDE4 inhibitor and a ⁇ 2 -adrenoreceptor agonist.
  • the invention thus provides, in a further aspect, a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with an anticholinergic and a PDE4 inhibitor.
  • the compounds of the invention may be prepared by the processes described below.
  • a process according to the invention for the preparation of compounds of formula (I) comprising coupling of a carboxylic acid of formula (II):
  • This coupling may be conducted, for example, using HATU (O-(7-azabenzotriazol-1- yl)- ⁇ /, ⁇ /, ⁇ /', ⁇ /-tetramethyluronium hexafluorophosphate) in the presence of a suitable base such as ⁇ /, ⁇ /-diisopropylethylamine in a suitable solvent such as DMF.
  • HATU O-(7-azabenzotriazol-1- yl)- ⁇ /, ⁇ /, ⁇ /', ⁇ /-tetramethyluronium hexafluorophosphate
  • a suitable base such as ⁇ /, ⁇ /-diisopropylethylamine
  • DMF suitable solvent
  • the coupling may also be conducted using alternative conditions for amide bond formation known in the art.
  • the compound of formula (II) may be obtained by deprotection of a suitable protected derivative, for example a compound of formula (III)
  • Deprotection may be conveniently conducted by hydrogenolysis over palladium on carbon in ethanol.
  • R 7 is as described above for compounds of formula (I).
  • the aziridine opening reaction may be performed, for example, by heating the aziridine (IV) and aminoindazole (V) in ⁇ /-methyl pyrrolidinone solution at 15O 0 C in a microwave.
  • the compound of formula (IV) may be obtained by the intramolecular cyclisation of a sulphonamide of formula (Vl):
  • Compounds of formula (Vl) may be prepared by reaction of mesitylenesulphonyl chloride with (2S)-2-amino-1-propanol in pyridine.
  • the reaction of (VII) with (VIII) may be performed in the presence of a copper (I) catalyst, such as copper (I) iodide and a weak base such as potassium carbonate or potassium phosphate and an amine ligand such as L-proline, cyclohexanediamine, ⁇ /, ⁇ /'-dimethylcyclohexanediamine or ⁇ /, ⁇ /'-dimethylethylenediamine in a variety of solvents including toluene, dioxane, ⁇ /, ⁇ /-dimethylformamide, ⁇ /, ⁇ /-dimethylacetamide and dimethylsulfoxide at a temperature in the range 60-160 0 C, most typically 11 O 0 C.
  • Representative procedures are reported in the literature: Synthesis 2005, 3, 496-499, J. Org. Chem., 2004, 69, 5578-5587 and J. Am. Chem. Soc, 2001 , 123, 7727-7729.
  • the intermediate of formula (Vl) may be prepared by coupling (S)-(+)-alaninol with mesityl chloride in pyridine.
  • An alternative process according to the invention for the preparation of compounds of formula (I) comprises coupling of an amine of formula (IX):
  • R 1 and R 7 are as defined above for compounds of formula (I), with ammonium formate and palladium on carbon in ethanol.
  • R 7 is as defined above for compounds of formula (I), with an amine of formula NH(R 2 )C(R 3 )(R 4 )C(O)NH 2 , NH 2 CH 2 C(OH)CH 3 , NH 2 -(C 3- 6 cycloalkyl), NH 2 -heterocyclyl or NHR 8 R 9 wherein R 2 , R 3 , R 4 , R 8 and R 9 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 conditions for amide bond formation known in the art.
  • the carboxylic acid (Xl) may be obtained by hydrolysis of the corresponding ester (XII): wherein R 7 is as defined above for compounds of formula (I).
  • R 7 is as defined above for compounds of formula (I), with an aldehyde of formula (XIV):
  • the aldehyde of formula (XIV) may be prepared from the ester of formula (XV):
  • ester of formula (XV) by reduction with diisobutylaluminium hydride in dichloromethane or as described in Tetrahedron Asymmetry 2006, 17, 1074.
  • the ester of formula (XV) may be prepared by suitable protection of alanine methyl ester.
  • the 4-amino-1-arylindazole of formula (XIII) may be prepared by reaction of an acid of formula (XVI):
  • R 7 is as defined above for compounds of formula (I), with concentrated H 2 SO 4 in methanol.
  • the 4-amino-1-arylindazole of formula (XVI) may be prepared from a 4-bromo-1- arylindazole of formula (XVII):
  • R 7 is as defined above for compounds of formula (I), by treatment with aqueous ammonia under pressure in the presence of copper (I) iodide catalyst.
  • Cyclisation may be conducted using lithium bis(trimethylsilyl)amide in DMF.
  • Hydrazones of formula (XVIII) may be prepared by reaction of an aldehyde of formula (XIX)
  • R 7 is as defined above for compounds of formula (I), with an aryl hydrazine of formula (XX)
  • the aldehyde of formula (XIX) may be reacted with the unprotected carboxylic acid of formula (XX), to give the hydrazone acid of formula (XVIII) which may be cyclised to give an indazole of formula (XVII).
  • aldehyde of formula (XIX) is known and may be prepared as described by Lulinski and Serwatowski in J. Org. Chem., 2003, 68, 5384-5387.
  • Aryl hydrazines of formula (XX) are either commercially available or may be prepared from the corresponding aniline by treatment with nitrous acid generated in situ from sodium nitrite followed by subsequent reduction of the resulting aryldiazonium ions with tin (II) chloride according to standard literature procedures (see, for example, J Med Chem 1991 , 34, 2895; J Med Chem 2000, 43, 4707, J Med Chem 2003, 46, 2012).
  • compositions including one or more compounds of formula (I) form an aspect of this invention.
  • compositions comprising a compound of the invention also constitute an aspect of the invention.
  • Solvates of compounds of formula (I) or salts thereof, which are not pharmaceutically acceptable, may be useful as intermediates in the preparation of other compounds of the invention.
  • 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.
  • the column was a 100mm x 20mm Supelco LCABZ++ with stationary phase particle size of 5 ⁇ m.
  • Solvents A: water + 0.1% formic acid
  • Solvents A: 0.1% Formic Acid + IOmMolar Ammonium Acetate. B: 95% Acetonitrile + 0.05% Formic Acid
  • UPLC/MS instrumentation consists of the following:
  • Aqueous solvent Water 0.1% Formic Acid + 1OmM Ammonium Acetate
  • UV sampling rate 40 points per second
  • MS scanning rate 0.2 second scan with a 0.1 second inter scan delay
  • Cycle time 2 minutes and 30 seconds
  • Circular dichroism was carried out on an Applied Photophysics Chirascan spectrophotometer at room temperature, using acetonitrile as solvent, over the range 200-350nm.
  • the Flashmaster2 is an automated multi user flash chromatography system which utilises disposable SPE cartridges (2g to 100g). 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 flow rates, gradient profile and collection conditions.
  • the system is equipped with a Knauer variable wavelength uv detector and 2 Gilson FC204 fraction collectors enabling automated peak cutting, collection and tracking.
  • the Flashmaster SOLO is an automated single user flash chromatography system which utilises disposable SPE cartridges (2g to 100g). It provides quaternary on-line solvent mixing to enable gradient methods to be run. Samples are logged in using the multi functional open access software which manages flow rates, gradient profile and collection conditions.
  • the system is equipped with a Knauer variable wavelength uv detector and a Gilson FC204 fraction collector enabling automated peak cutting, collection and tracking.
  • the Companion XL is an automated single user flash chromatography system which utilises disposable cartridges (12Og to 150Og). It provides binary on-line solvent mixing to enable gradient methods to be run. Samples are logged in using the multi functional open access software which manages flow rates, gradient profile and collection conditions.
  • the system is equipped with a variable wavelength uv detector and two Foxy 200 fraction collectors enabling automated peak cutting, collection and tracking.
  • the Companion is an automated single user flash chromatography system which utilises disposable cartridges (4g to 33Og). It provides binary on-line solvent mixing to enable gradient methods to be run. Samples are logged in using the multi functional open access software which manages flow rates, gradient profile and collection conditions. The system is equipped with a variable wavelength uv detector and two Foxy fraction collectors enabling automated peak cutting, collection and tracking. Solvents: Individual choice
  • Microwave chemistry was typically performed in sealed vessels, irradiating with a suitable microwave reactor system, such as a Biotage InitiatorTM Microwave Synthesiser.
  • An H-cubeTM is a continuous-flow reactor employing a mixed hydrogen-liquid flow stream with a 10% Pd/C cartridge. The sample was washed through the cartridge with ethanol (5-1OmI) and the combined solutions reduced to dryness under a stream of nitrogen to give the title compound as a yellow oil.
  • 3-lodobenzoic acid (12.4g) was dissolved in DMF (10OmL) and potassium carbonate (7.6g) was added. Benzyl bromide (6.5mL) was then added dropwise over approximately IOmins causing a slight exotherm to 24°C. The suspension was stirred at room temperature for 1.5hrs. 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).
  • 6-Methyl-1 H-indazol-4-amine hydrochloride 0.5g, 2.7mmol
  • phenylmethyl 3- iodobenzoate 0.9g, 2.6mmol
  • copper (I) iodide 14mg, 0.07mmol
  • potassium carbonate 1.2g, 8.68mmol
  • frans-/V,/V-dimethyl-1 ,2-cyclohexanediamine 20mg, 0.14mmol
  • Solvents A: 0.1% Trifluoroacetic Acid in Water.
  • the major isomer was isolated as a white solid, 461 mg.
  • the minor isomer was isolated as a green solid, 177mg.
  • Potassium carbonate (8.15g, 59mmol) was added followed by copper (I) iodide (0.284g, 1.5mmol) and 1 /?,2/?- ⁇ /, ⁇ /'-dimethyl-1 ,2-cyclohexanediamine (0.425g, 3.0mmol) and the mixture was heated to 1 1O 0 C for 5hr when LCMS showed absence of starting materials. The majority or the solvent was removed in vacuo and the residue was partitioned between ethyl acetate (500ml) and water (500ml). The emulsion which ensued was filtered through celite and separated.
  • the filtrate was evaporated (0.96g) and added to a mixed fraction (yellow solid, 6.81 g).
  • the purification procedure was repeated with this combined material; dissolved in ethyl acetate (ca. 55ml), then cyclohexane was added (100ml) to give a pale yellow solid; 5.49g.
  • This material still contained impurity and so it was combined with the concentrated filtrate (1.88g).
  • the purification procedure was repeated once more with ethyl acetate (70ml) and less cyclohexane (60ml) to give the title compound as a pale cream solid, (2.84g, 21 %).
  • UV Detection Range 215 to 330nm
  • Solvents A: 0.1% Trifluoroacetic Acid in Water.
  • Examples 1-11 were prepared according to the following procedure: The amines shown in the table below (O.O ⁇ mmol) were pre-weighed into Micronics tubes. Each acid or pair of acids, as shown in the table below, (30mg, O.O ⁇ mmol) in DMF (250 ⁇ l) were added to HATU (23mg, O.O ⁇ mmol) and DIPEA (30 ⁇ l, 0.18mmol). The solutions were left for 5min and then added to the tubes containing each amine. DMF was removed in a Genevac. The dried compounds were dissolved in chloroform (500 ⁇ l) and loaded onto a pre-washed 500mg aminopropyl cartridge (MeOH, 2ml, chloroform, 2ml). The compounds were recombined and purified on MDAP Atlantis column with formic acid modifier (acetonitrile/water solvents) used.
  • formic acid modifier acetonitrile/water solvents
  • Example 1 (minor regioisomer): N-((2/?)-2- ⁇ [1-(4- ⁇ [4-(Hydroxymethyl)-1- piperidinyllcarbonyl)phenyl)-6-methyl-1 H-indazol-4-yllamino)propyl)-2,4,6- trimethylbenzenesulfonamide
  • Solvents A: 0.1% Trifluoroacetic Acid in Water.
  • Example 2 ⁇ /-((1 SV2-fri-(3-fr2-(Hvdroxymethvn-1-DiDeridinyllcarbonyl>Dhenvn-6- methyl-1 H-indazol-4-yllamino)-1-methylethyl)-2,4,6-trimethylbenzenesulfonamide
  • Solvents A: 0.1% Trifluoroacetic Acid in Water.
  • Example 4 (minor regioisomer): ⁇ /-[(1 S)-2-Amino-1-methyl-2-oxoethyll-4-(6- methyl-4- ⁇ r(1 /?)-1-methyl-2- ⁇ r(2,4,6-trimethylphenyl)sulfonyllamino)ethyllamino)-1 H- indazol-1 -vDbenzamide
  • Solvents A: 0.1% Trifluoroacetic Acid in Water.
  • Example 5 ⁇ /-(1 ,1-Dioxidotetrahvdro-3-thienyl)-4-(6-methyl-4- ⁇ r(2S)-2- ⁇ r(2,4,6- trimethylphenyl)sulfonyl1amino)propyl1amino)-1 H-indazol-1-yl)benzamide
  • Example 6 4-(6-Methyl-4-f[(2SV2-fr(2.4.6- trimethylphenyl)sulfonyllamino)propyllamino)-1 H-indazol-1-yl)-N-r(3S)-2-oxo-3- pyrrolidinyllbenzamide
  • Example 7 ⁇ /-K1 S)-2-Amino-1-methyl-2-oxoethyll-4-(6-methyl-4- ⁇ r(2S)-2- ⁇ r(2 ,4,6- trimethylphenyl)sulfonyl1amino)propyl1amino)-1 H-indazol-1-yl)benzamide
  • Example 8 /V-KI S)-2- ⁇ ri-(3- ⁇ r4-(hvdroxymethyl)-1-piperidinyllcarbonyl)phenyl)-6- methyl-1 H-indazol-4-yllamino)-1-methylethyll-2,4,6-trimethylbenzenesulfonamide
  • Example 10 (Diasteriomer 1):N-r(1SV2-fri-(3-fr3-(Hvdroxymethvn-1- piperidinyllcarbonyl)phenyl)-6-methyl-1H-indazol-4-yllamino)-1-methylethyll-2,4,6- trimethylbenzenesulfonamide
  • Example 11 (Diasteriomer 2): /V-r(1S)-2- ⁇ [1 -(3- ⁇ r3-(Hydroxymethyl)-1 - piperidinyl1carbonyl)phenyl)-6-methyl-1H-indazol-4-yl1amino)-1-methylethyl1-2,4,6- trimethylbenzenesulfonamide
  • the ability of compounds to bind to the glucocorticoid receptor was determined by assessing their ability to compete with an Alexa 555 fluorescently-labelled dexamethasone derivative. Compounds were solvated and diluted in DMSO, and transferred directly into assay plates. Fluorescent dexamethasone and a partially purified full length glucocorticoid receptor were added to the plates, together with buffer components to stabilise the GR protein and incubated at room temperature for 2hr 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. Dose response curves were constructed from which plC 50 values were estimated.
  • Examples 1 , 2, 4-18 and 20-37 have shown glucocorticoid binding with a plC 50 > 6.5 at least once in this assay.
  • Human Caucasian lung carcinoma A549 cell line (ECACC No. 86012804) has been stably transfected in house with a plasmid containing an ELAM promoter sequence that has a NFKB response element within it. Stimulation of the cell line with TNF ⁇ results in intracellular signal transduction and ultimately translocation of NFKB into the nucleus. This activates the inserted DNA sequence resulting in transcription of the integrated SPAP gene, which is quantified using a colorimetric assay. In this assay, GR agonist compounds inhibit NFKB driven transcription resulting in a decrease in signal.
  • the stably transfected cell line was grown as a monolayer in DMEM supplemented with FCS-HI (10%), Non-essential amino acids (1 %), L- Glutamine (2mM), Pen/Strep (1%) and Geneticin (50mg/ml).
  • NFKB agonist assay A 70% confluent T225 flask of A549 SPAP cells was harvested by centrifugation for 5min at 20Og, resuspended in assay buffer (DMEM supplemented with 10% FCS 2xHI, 2mM L-Glutamine,1 % Pen/Strep and Non essential amino acids) and diluted to 0.16 x 10 6 VmI. 60 ⁇ l of cell solution was dispensed to each well of clear Nunc 384-well plates, containing compound at the required concentration. Plates were incubated for 1 h at 37 0 C, 95% humidity, 5% CO 2 before 10 ⁇ l of TNF ⁇ was added at final concentration of 3.2ng/ml and then returned to the cell incubator for 15hr.
  • assay buffer DMEM supplemented with 10% FCS 2xHI, 2mM L-Glutamine,1 % Pen/Strep and Non essential amino acids
  • Plates were equilibrated to room temperature for 1 h prior to the addition of 25 ⁇ l of pNPP buffer (1 M Diethanolamine pH 9.8, 0.5mM MgCI 2 , 0.28M NaCI, 2mg/ml pNPP) to each well of assay plates.
  • the plates were covered to protect the reagents from light, and then incubated at room temperature for approximately 1 hr before reading them on an Ascent using a 405nm single filter. Dose response curves were constructed from which plC 50 values were estimated.
  • Examples 1-18 and 20-37 have shown plC 50 values of >6 at least once in the NFkB assay.
  • Human Caucasian lung carcinoma A549 cell line (ECACC No. 86012804) has been stably transfected in house with a plasmid containing a renilla luciferase reporter with an MMTV promoter. Stimulation of the cell line with GR agonists results in intracellular signal transduction and ultimately translocation of GR into the nucleus. This activates the inserted DNA sequence resulting in transcription of the integrated luciferase gene, which is quantified using a light emission.
  • the stably transfected cell line was grown as a monolayer in DMEM supplemented with FCS-HI (10%), Nonessential amino acids (1%), L-Glutamine (2mM), Pen/Strep (1 %) and Geneticin (50mg/ml).
  • a 90% confluent T175 flask of A549 MMTV cells was harvested by centrifugation for 5min at 20Og, resuspended in assay buffer (DMEM supplemented with 10% FCS 2xHI, 2mM Glutamax, Non essential amino acids and 25mM HEPES) and diluted to 0.1 x 10 6 /ml. 70 ⁇ l of cell solution was dispensed to each well of white Nunc 384-well plates, containing compound at the required concentration. Plates were incubated for 6hr at 37 C, 95% humidity, 5% CO 2 . Plates were equilibrated to room temperature for 1 hr prior to the addition of 10 ⁇ l of Renilla substrate to each well of assay plates. The plates were covered to protect the reagents from light, and then incubated at room temperature for approximately 15mins before reading them on a Viewlux. Dose response curves were constructed from which pEC 50 and maximum asymptote values were estimated.
  • a 90% confluent T175 flask of A549 MMTV cells was harvested by centrifugation for 5min at 20Og, resuspended in assay buffer (DMEM supplemented with 10% FCS 2xHI, 2mM Glutamax, Non essential amino acids and 25mM HEPES) and diluted to 0.1 x 10 6 /ml.
  • Dexamethasone was added to the cell solution to a concentration of 15nM. From a 75uM dexamethasone stock (DMSO solvent) 2OuI was added per 100ml of assay media and cells. 70 ⁇ l of cell solution was dispensed to each well of white Nunc 384-well plates, containing compound at the required concentration.
  • Plates were incubated for 24hr at 37 0 C, 95% humidity, 5% CO 2 . Plates were equilibrated to room temperature for 1 hr prior to the addition of 10 ⁇ l of Renilla substrate to each well of assay plates. The plates were covered to protect the reagents from light, and then incubated at room temperature for approximately 15mins before reading them on a Viewlux. Dose response curves were constructed from which plC 5 o values were estimated.
  • the following examples are partial or full agonists (i.e. have an average maximum asymptote of > 20%) in the NFkB assay and are partial or efficacy selective agonists
  • 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. 70ml of suspension cells were dispensed to each well of white Nunc 384- well plates, containing compounds at the required concentration. After 24hr 10 ⁇ l of Steadylite were added to each well of the plates. Plates were incubated in the dark for 10min before reading them on a Viewlux reader. Dose response curves were constructed from which pEC 50 values were estimated.
  • Examples 1-6, 8-13, 15, 16, 18, 19, 21 , 22, 25, 26, 29, 32, 33, 35 and 36 have shown an average pEC 50 ⁇ 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 enantiomer may have similar activity, less activity, no activity or may have some antagonist activity in the case of a functional assay.

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Abstract

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

Description

N- (2 { [1-PHENYL-1 H-INDAZ0L-4-YL] AMINO} PROPYL) -SULFONAMIDE
DERIVATIVES AS NON-STEROIDAL GLUCOCORTICOID RECEPTOR
LIGANDS FOR THE TREATMENT OF INFLAMMATIONS
The present invention relates to non-steroidal glucocorticoid receptor binding compounds and a process for their preparation, to pharmaceutical compositions comprising the compounds and the preparation of said compositions, to intermediates, and to use of the compounds for the manufacture of a medicament for therapeutic treatment, particularly for the treatment of inflammation, allergy and/or auto-immune 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. et al. (2000) Lancet 355:1399-1403), slowing of growth (Allen, D. B. (2000) Allergy 55: suppl 62, 15-18), skin bruising (Pauwels, R.A., Lofdahl, CG. , Latinen, L.A. et al. (1999) N Engl J Med 340:1948-1953), development of cataracts (Cumming, R.G., Mitchell, P. & Leeder, S. R. (1997) N Engl J Med 337:8- 14) and dysregulation of lipid and glucose metabolism (Faul, J. L., Tormey, W., Tormey, V. & Burke, C. (1998) BMJ 317:1491 ; and Andrews, R.C. & Walker, B.R. (1999) Clin Sci 96:513-523). The side-effects are serious enough often to limit the dose of glucocorticoid that can be used to treat the underlying pathology leading to reduced efficacy of treatment.
It has been suggested that excessive activation of the transactivation-GRE pathway may mediate some of these side-effects (see Schacke, H., Docke, W-D. & Asadullah, K. (2002) Pharmacol and Therapeutics 96:23-43). Development of glucocorticoids that selectively modulate the transrepression pathway compared with the transactivation pathway may therefore have a superior anti-inflammatory to side- effect therapeutic index, allowing more effective and safer treatment of the patient. This new class of glucocorticoids could be used to treat more effectively and more safely the whole spectrum of disease currently treated by current glucocorticoids.
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, 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, dermatomyositis, herpes gestationis, eosinophilic fasciitis, relapsing polychondritis, inflammatory vasculitis, sarcoidosis, Sweet's disease, type 1 reactive leprosy, capillary hemangiomas, contact dermatitis, atopic dermatitis, lichen planus, exfoliative dermatitis, erythema nodosum, acne, hirsutism, toxic epidermal necrolysis, erythema multiform and cutaneous T-cell lymphoma.
Glucocorticoids are especially useful in disease states involving systemic inflammation such as inflammatory bowel disease, 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.
There remains a need to find further compounds which bind to the glucocorticoid receptor.
In one embodiment, the present invention provides compounds of formula (I):
Figure imgf000004_0001
wherein
A is selected from the following groups:
Figure imgf000004_0002
(iv)
(ii)
Figure imgf000005_0001
(V) (vi)
X is selected from NH, CH2, S, S(O), S(O)2 and O;
R1 is selected from -C(O)N(R2)C(R3)(R4)C(O)NH2, -C(O)NHCH2CH(OH)CH3, -
C(O)NHC3-6cycloalkyl, -C(O)NHheterocyclyl and -C(O)NR8R9 wherein R8 and R9 together with the nitrogen atom to which they are attached are linked to form a heterocyclyl and wherein each heterocyclyl is optionally substituted by 1 or 2 groups independently selected from oxo, -C(O)NH2 and -CH2OH;
R2, R3, R4, R5, R6 and R7 are each independently selected from hydrogen and methyl; and salts thereof (hereinafter "compounds of the invention").
In another embodiment, the present invention provides compounds of formula (Ib):
Figure imgf000005_0002
wherein
A is selected from the following groups:
Figure imgf000005_0003
(iv)
(ii)
Figure imgf000006_0001
(V) (vi)
X is selected from NH, CH2, S, S(O), S(O)2 and O;
R1 is selected from -C(O)N(R2)C(R3)(R4)C(O)NH2, -C(O)NHCH2CH(OH)CH3, -
C(O)NHC3-6cycloalkyl, -C(O)NHheterocyclyl and -C(O)NR8R9 wherein R8 and R9 together with the nitrogen atom to which they are attached are linked to form a heterocyclyl and wherein each heterocyclyl is optionally substituted by 1 or 2 groups independently selected from oxo, -C(O)NH2 and -CH2OH;
R2, R3, R4, R5, R6 and R7 are each independently selected from hydrogen and methyl; and salts thereof.
In a further embodiment, the present invention provides compounds of formula (Ia):
Figure imgf000006_0002
wherein
A is group (i):
Figure imgf000006_0003
X is NH;
R1 is selected from -C(O)N(R2)C(R3)(R4)C(O)NH2, -C(O)NHCH2CH(OH)CH3, - C(O)NHC3-6cycloalkyl, -C(O)NHheterocyclyl and -C(O)NR8R9 wherein R8 and R9 together with the nitrogen atom to which they are attached are linked to form a heterocyclyl and wherein each heterocyclyl is optionally substituted by 1 or 2 groups independently selected from oxo, -C(O)NH2 and -CH2OH;
R2, R3, R4, R5, R6 and R7 are each independently selected from hydrogen and methyl; and salts thereof.
In one embodiment A is group (i):
Figure imgf000007_0001
In one embodiment X is NH.
In one embodiment R1 is -C(O)N(R2)C(R3)(R4)C(O)NH2. In another embodiment R1 is -C(O)NHCH2CH(OH)CH3. In another embodiment R1 is -C(O)NHC3-6cycloalkyl. In another embodiment R1 is -C(O)NHheterocyclyl. In a further embodiment R1 is - C(O)NR8R9 wherein R8 and R9 together with the nitrogen atom to which they are attached are linked to form a heterocyclyl.
In one embodiment R1 is -C(O)N(R2)C(R3)(R4)C(O)NH2 wherein R2 and R3 are each hydrogen and R4 is methyl.
In one embodiment R1 is -C(O)NHC3_6cycloalkyl wherein the Cs-βcycloalkyl group is cyclopropyl.
In one embodiment R1 is -C(O)NHheterocyclyl wherein the heterocyclyl contains 1 heteroatom. In another embodiment R1 is -C(O)NHheterocyclyl wherein the heteroatom is selected from sulfur and nitrogen. In another embodiment R1 is - C(O)NHheterocyclyl wherein the heterocyclyl is selected from tetrahydrothienyl and pyrrolidinyl. In a further embodiment R1 is -C(O)NHheterocyclyl wherein the heterocyclyl is substituted by 1 or 2 oxo groups.
In one embodiment R1 is -C(O)NR8R9 wherein R8 and R9 together with the nitrogen atom to which they are attached are linked to form a heterocyclyl, wherein the heterocyclyl is selected from pyrrolidinyl and piperidinyl. In another embodiment R1 is -C(O)NR8R9 wherein R8 and R9 together with the nitrogen atom to which they are attached are linked to form a heterocyclyl, wherein the heterocyclyl is substituted by one group selected from -CH2OH and -C(O)NH2. In a further embodiment R1 is - C(O)NR8R9 wherein R8 and R9 together with the nitrogen atom to which they are attached are linked to form a heterocyclyl, wherein the heterocyclyl is substituted by one -CH2OH group.
In one embodiment R1 is in the meta position on the phenyl ring. In another embodiment R1 is in the para position on the phenyl ring.
In one embodiment R5 is hydrogen and R6 is methyl. In another embodiment R5 is methyl and R6 is hydrogen.
In one embodiment R7 is methyl.
It is to be understood that the present invention covers all combinations of substituent groups described hereinabove.
In one embodiment, the compound of formula (I) is:
Λ/-((2R)-2-{[1-(4-{[4-(hydroxymethyl)-1-piperidinyl]carbonyl}phenyl)-6-methyl-1 H- indazol-4-yl]amino}propyl)-2,4,6-trimethylbenzenesulfonamide;
Λ/-((1 S)-2-{[1-(3-{[2-(hydroxymethyl)-1-piperidinyl]carbonyl}phenyl)-6-methyl-1 H- indazol-4-yl]amino}-1-methylethyl)-2,4,6-trimethylbenzenesulfonamide;
4-(6-methyl-4-{[(1 R)-1-methyl-2-{[(2,4,6-trimethylphenyl)sulfonyl]amino}ethyl]amino}-
1 H-indazol-1-yl)-N-[(3S)-2-oxo-3-pyrrolidinyl]benzamide;
Λ/-[(1 S)-2-amino-1-methyl-2-oxoethyl]-4-(6-methyl-4-{[(1 R)-1-methyl-2-{[(2,4,6- trimethylphenyl)sulfonyl]amino}ethyl]amino}-1 H-indazol-1-yl)benzamide;
Λ/-(1 ,1-dioxidotetrahydro-3-thienyl)-4-(6-methyl-4-{[(2S)-2-{[(2,4,6- trimethylphenyl)sulfonyl]amino}propyl]amino}-1H-indazol-1-yl)benzamide;
4-(6-methyl-4-{[(2S)-2-{[(2,4,6-trimethylphenyl)sulfonyl]amino}propyl]amino}-1 H- indazol-1-yl)-Λ/-[(3S)-2-oxo-3-pyrrolidinyl]benzamide;
Λ/-[(1 S)-2-amino-1-methyl-2-oxoethyl]-4-(6-methyl-4-{[(2S)-2-{[(2,4,6- trimethylphenyl)sulfonyl]amino}propyl]amino}-1 H-indazol-1-yl)benzamide;
Λ/-[(1 S)-2-{[1-(3-{[4-(hydroxymethyl)-1-piperidinyl]carbonyl}phenyl)-6-methyl-1 H- indazol-4-yl]amino}-1-methylethyl]-2,4,6-trimethylbenzenesulfonamide;
3-(6-methyl-4-{[(2S)-2-{[(2,4,6-trimethylphenyl)sulfonyl]amino}propyl]amino}-1 H- indazol-1-yl)-N-[(3S)-2-oxo-3-pyrrolidinyl]benzamide; Λ/-[(1 S)-2-{[1-(3-{[3-(hydroxymethyl)-1-piperidinyl]carbonyl}phenyl)-6-methyl-1 H- indazol-4-yl]amino}-1-methylethyl]-2,4,6-trimethylbenzenesulfonamide;
Λ/-[(1 S)-2-{[1-(3-{[3-(hydroxymethyl)-1-piperidinyl]carbonyl}phenyl)-6-methyl-1 H- indazol-4-yl]amino}-1-methylethyl]-2,4,6-trimethylbenzenesulfonamide;
/V-(1 ,1-dioxidotetrahydro-3-thienyl)-4-{6-methyl-4-[((2S)-2-{[(2!4,6- trimethylphenyl)sulfonyl]amino}propyl)amino]-1 /-/-indazol-1-yl}benzamide;
/V-(1 ,1-dioxidotetrahydro-3-thienyl)-4-{6-methyl-4-[((1 R)-1-methyl-2-{[(2!4,6- trimethylphenyl)sulfonyl]amino}ethyl)amino]-1 /-/-indazol-1-yl}benzamide;
4-{6-methyl-4-[((2S)-2-{[(2!4!6-trimethylphenyl)sulfonyl]amino}propyl)amino]-1 H- indazol-1-yl}-Λ/-[(3S)-2-oxo-3-pyrrolidinyl]benzamide;
4-{6-methyl-4-[((1 R)-1-methyl-2-{[(2!4!6-trimethylphenyl)sulfonyl]amino}ethyl)amino]-
1 H-indazol-1-yl}-/V-[(3S)-2-oxo-3-pyrrolidinyl]benzamide;
/V-[(1 S)-2-amino-1-methyl-2-oxoethyl]-4-{6-methyl-4-[((2S)-2-{[(2!4,6- trimethylphenyl)sulfonyl]amino}propyl)amino]-1 /-/-indazol-1-yl}benzamide;
/V-[(1 S)-2-amino-1-methyl-2-oxoethyl]-4-{6-methyl-4-[((1 R)-1-methyl-2-{[(2!4,6- trimethylphenyl)sulfonyl]amino}ethyl)amino]-1 /-/-indazol-1-yl}benzamide;
1-[(4-{6-methyl-4-[((2S)-2-{[(2!4!6-trimethylphenyl)sulfonyl]amino}propyl)amino]-1 H- indazol-1-yl}phenyl)carbonyl]-L-prolinamide;
1-[(4-{6-methyl-4-[((1 R)-1-methyl-2-{[(2!4,6- trimethylphenyl)sulfonyl]amino}ethyl)amino]-1 /-/-indazol-1-yl}phenyl)carbonyl]-L- prolinamide;
Λ/-((1 S)-2-{[1-(4-{[4-(hydroxymethyl)-1-piperidinyl]carbonyl}phenyl)-6-methyl-1 /-/- indazol-4-yl]amino}-1-methylethyl)-2,4,6-trimethylbenzenesulfonamide;
Λ/-((2R)-2-{[1-(4-{[4-(hydroxymethyl)-1-piperidinyl]carbonyl}phenyl)-6-methyl-1 H- indazol-4-yl]amino}propyl)-2,4,6-trimethylbenzenesulfonamide;
Λ/-((1 S)-2-{[1-(4-{[4-(hydroxymethyl)-1-piperidinyl]carbonyl}phenyl)-6-methyl-1 H- indazol-4-yl]amino}-1-methylethyl)-2,4,6-trimethylbenzenesulfonamide;
1-[(4-{6-methyl-4-[((2S)-2-{[(2!4!6-trimethylphenyl)sulfonyl]amino}propyl)amino]-1 H- indazol-1-yl}phenyl)carbonyl]-L-prolinamide;
1-[(4-{6-methyl-4-[((1 R)-1-methyl-2-{[(2!4,6- trimethylphenyl)sulfonyl]amino}ethyl)amino]-1 /-/-indazol-1-yl}phenyl)carbonyl]-L- prolinamide;
Λ/-(2-amino-2-oxoethyl)-4-{6-methyl-4-[((2S)-2-{[(2!4,6- trimethylphenyl)sulfonyl]amino}propyl)amino]-1 /-/-indazol-1-yl}benzamide;
/V-[(1 R)-2-amino-1-methyl-2-oxoethyl]-4-{6-methyl-4-[((2S)-2-{[(2!4,6- trimethylphenyl)sulfonyl]amino}propyl)amino]-1 /-/-indazol-1-yl}benzamide; /V-(2-amino-2-oxoethyl)-/V-methyl-4-{6-methyl-4-[((2S)-2-{[(2!4,6- trimethylphenyl)sulfonyl]amino}propyl)amino]-1/-/-indazol-1-yl}benzamide;
/V-(2-hydroxypropyl)-4-{6-methyl-4-[((2S)-2-{[(2,4,6- trimethylphenyl)sulfonyl]amino}propyl)amino]-1/-/-indazol-1-yl}benzamide;
/V-cyclopropyl-4-{6-methyl-4-[((2S)-2-{[(2,4,6- trimethylphenyl)sulfonyl]amino}propyl)amino]-1/-/-indazol-1-yl}benzamide;
Λ/-((1 S)-2-{[1-(4-{[3-(hydroxymethyl)-1-piperidinyl]carbonyl}phenyl)-6-methyl-1 H- indazol-4-yl]amino}-1-methylethyl)-2,4,6-trimethylbenzenesulfonamide;
Λ/-((1 S)-2-{[1-(4-{[2-(hydroxymethyl)-1-piperidinyl]carbonyl}phenyl)-6-methyl-1 H- indazol-4-yl]amino}-1-methylethyl)-2,4,6-trimethylbenzenesulfonamide;
Λ/-(2-amino-2-oxoethyl)-3-{6-methyl-4-[((2S)-2-{[(2!4,6- trimethylphenyl)sulfonyl]amino}propyl)amino]-1 /-/-indazol-1-yl}benzamide;
/V-[(1 R)-2-amino-1-methyl-2-oxoethyl]-3-{6-methyl-4-[((2S)-2-{[(2!4,6- trimethylphenyl)sulfonyl]amino}propyl)amino]-1 /-/-indazol-1-yl}benzamide;
/V-(2-amino-2-oxoethyl)-/V-methyl-3-{6-methyl-4-[((2S)-2-{[(2!4,6- trimethylphenyl)sulfonyl]amino}propyl)amino]-1 /-/-indazol-1-yl}benzamide;
Λ/-(2-hydroxypropyl)-3-{6-methyl-4-[((2S)-2-{[(2!4,6- trimethylphenyl)sulfonyl]amino}propyl)amino]-1 /-/-indazol-1-yl}benzamide;
Λ/-cyclopropyl-3-{6-methyl-4-[((2S)-2-{[(2!4,6- trimethylphenyl)sulfonyl]amino}propyl)amino]-1 /-/-indazol-1-yl}benzamide;
Λ/-((1 S)-2-{[1-(3-{[3-(hydroxymethyl)-1-piperidinyl]carbonyl}phenyl)-6-methyl-1 H- indazol-4-yl]amino}-1-methylethyl)-2,4,6-trimethylbenzenesulfonamide;
/V-(1 ,1-dioxidotetrahydro-3-thienyl)-4-{6-methyl-4-[((1 R)-1-methyl-2-{[(2!4,6- trimethylphenyl)sulfonyl]amino}ethyl)amino]-1 /-/-indazol-1-yl}benzamide;
/V-[(1 S)-2-amino-1-methyl-2-oxoethyl]-4-{6-methyl-4-[((2S)-2-{[(2!4,6- trimethylphenyl)sulfonyl]amino}propyl)amino]-1 /-/-indazol-1-yl}benzamide;
1-[(3-{6-methyl-4-[((2S)-2-{[(2!4,6-trimethylphenyl)sulfonyl]amino}propyl)amino]-1 H- indazol-1-yl}phenyl)carbonyl]-L-prolinamide;
/V-(1 ,1-dioxidotetrahydro-3-thienyl)-3-{6-methyl-4-[((2S)-2-{[(2!4,6- trimethylphenyl)sulfonyl]amino}propyl)amino]-1 /-/-indazol-1-yl}benzamide;
/V-(2-amino-1 !1-dimethyl-2-oxoethyl)-3-{6-methyl-4-[((2S)-2-{[(2!4,6- trimethylphenyl)sulfonyl]amino}propyl)amino]-1 /-/-indazol-1-yl}benzamide; or a salt thereof.
In another embodiment, the compound of formula (I) is:
Λ/-((2R)-2-{[1-(4-{[4-(hydroxymethyl)-1-piperidinyl]carbonyl}phenyl)-6-methyl-1 H- indazol-4-yl]amino}propyl)-2,4,6-trimethylbenzenesulfonamide; Λ/-((1 S)-2-{[1-(3-{[2-(hydroxymethyl)-1-piperidinyl]carbonyl}phenyl)-6-methyl-1 H- indazol-4-yl]amino}-1-methylethyl)-2,4,6-trimethylbenzenesulfonamide;
4-(6-methyl-4-{[(1 /?)-1-methyl-2-{[(2,4,6-trimethylphenyl)sulfonyl]amino}ethyl]amino}-
1 H-indazol-1-yl)-N-[(3S)-2-oxo-3-pyrrolidinyl]benzamide;
/V-[(1 S)-2-amino-1-methyl-2-oxoethyl]-4-(6-methyl-4-{[(1 R)-1-methyl-2-{[(2!4,6- trimethylphenyl)sulfonyl]amino}ethyl]amino}-1 /-/-indazol-1-yl)benzamide;
/V-(1 ,1-dioxidotetrahydro-3-thienyl)-4-(6-methyl-4-{[(2S)-2-{[(2!4,6- trimethylphenyl)sulfonyl]amino}propyl]amino}-1/-/-indazol-1-yl)benzamide;
4-(6-methyl-4-{[(2S)-2-{[(2!4!6-trimethylphenyl)sulfonyl]amino}propyl]amino}-1 H- indazol-1-yl)-Λ/-[(3S)-2-oxo-3-pyrrolidinyl]benzamide;
/V-[(1 S)-2-amino-1-methyl-2-oxoethyl]-4-(6-methyl-4-{[(2S)-2-{[(2!4,6- trimethylphenyl)sulfonyl]amino}propyl]amino}-1 H-indazol-1-yl)benzamide;
Λ/-[(1 S)-2-{[1-(3-{[4-(hydroxymethyl)-1-piperidinyl]carbonyl}phenyl)-6-methyl-1 H- indazol-4-yl]amino}-1-methylethyl]-2,4,6-trimethylbenzenesulfonamide;
3-(6-methyl-4-{[(2S)-2-{[(2!4!6-trimethylphenyl)sulfonyl]amino}propyl]amino}-1 H- indazol-1-yl)-N-[(3S)-2-oxo-3-pyrrolidinyl]benzamide;
Λ/-[(1 S)-2-{[1-(3-{[3-(hydroxymethyl)-1-piperidinyl]carbonyl}phenyl)-6-methyl-1 H- indazol-4-yl]amino}-1-methylethyl]-2,4,6-trimethylbenzenesulfonamide;
Λ/-[(1 S)-2-{[1-(3-{[3-(hydroxymethyl)-1-piperidinyl]carbonyl}phenyl)-6-methyl-1 H- indazol-4-yl]amino}-1-methylethyl]-2,4,6-trimethylbenzenesulfonamide; or a salt thereof.
In a further embodiment, the compound of formula (I) is:
Λ/-[(1 S)-2-amino-1-methyl-2-oxoethyl]-4-(6-methyl-4-{[(1 R)-1-methyl-2-{[(2!4,6- trimethylphenyl)sulfonyl]amino}ethyl]amino}-1 H-indazol-1-yl)benzamide;
4-(6-methyl-4-{[(2S)-2-{[(2,4,6-trimethylphenyl)sulfonyl]amino}propyl]amino}-1 H- indazol-1-yl)-Λ/-[(3S)-2-oxo-3-pyrrolidinyl]benzamide;
Λ/-[(1 S)-2-amino-1-methyl-2-oxoethyl]-4-(6-methyl-4-{[(2S)-2-{[(2!4,6- trimethylphenyl)sulfonyl]amino}propyl]amino}-1 H-indazol-1-yl)benzamide;
Λ/-[(1 S)-2-{[1-(3-{[4-(hydroxymethyl)-1-piperidinyl]carbonyl}phenyl)-6-methyl-1 H- indazol-4-yl]amino}-1-methylethyl]-2,4,6-trimethylbenzenesulfonamide;
Λ/-[(1 S)-2-{[1-(3-{[3-(hydroxymethyl)-1-piperidinyl]carbonyl}phenyl)-6-methyl-1 H- indazol-4-yl]amino}-1-methylethyl]-2,4,6-trimethylbenzenesulfonamide;
Λ/-[(1 S)-2-{[1-(3-{[3-(hydroxymethyl)-1-piperidinyl]carbonyl}phenyl)-6-methyl-1 H- indazol-4-yl]amino}-1-methylethyl]-2,4,6-trimethylbenzenesulfonamide; or a salt thereof. The term 'C3-6CyClOaIkYr as used herein refers to a saturated monocyclic hydrocarbon ring containing 3 to 6 carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In one embodiment the C3- 6cycloalkyl group is cyclopropyl.
The term 'heterocyclyl' as used herein refers to a saturated 4-7 membered monocyclic ring containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen and sulphur. Examples of such monocyclic rings include pyrrolidinyl, azetidinyl, pyrazolidinyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, hydantoinyl, valerolactamyl, oxetanyl, dioxolanyl, dioxanyl, oxathiolanyl, oxathianyl, dithianyl, dihydrofuranyl, tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothienyl, tetrahydrothiopyranyl, diazepanyl and azepanyl. In one embodiment the heterocyclyl is tetrahydrothienyl, pyrrolidinyl or piperidinyl. When the heterocyclyl is optionally substituted it may be substituted anywhere on the ring including on the nitrogen and/or sulphur atom/atoms.
The compounds of formula (I) may contain one or more chiral centres so there may be a number of possible stereoisomers, e.g. enantiomers or diastereomers, of each compound of formula (I).
The terms Enantiomer 1 and Enantiomer 2 are used herein to refer to the enantiomers of a compound of formula (I), based on the order of their elution using the chiral chromatography methodology described herein. Enantiomer 1 refers to the first enantiomer to elute and Enantiomer 2 refers to the second enantiomer to elute.
Similarly, the terms Diastereomer 1 and Diastereomer 2 are used herein to refer to the diastereomers of a compound of formula (I) based on their order of elution using the chiral chromatographic methodology described herein. Diastereomer 1 refers to the first diastereomer to elute, and Diastereomer 2 refers to the second diastereomer to elute.
It will be appreciated by those skilled in the art that although the absolute retention time on chromatography can be variable, the order of elution remains the same when the same column and conditions are employed. However, the use of a different chromatography column and conditions may alter the order of elution. The term regioisomer is used herein to refer to the regioisomers or structural isomers of a compound of formula (I), i.e. those compounds which have the same molecular formula but where the atoms are bonded together in different orders.
It will be appreciated by those skilled in the art that at least one stereoisomer (e.g. one enantiomer of the racemate) has the described activity. The other stereoisomers may have similar activity, less activity, no activity or may have some antagonist activity in a functional assay.
The compounds of formula (I) may be formed as a single enantiomer or diastereomer, or mixture of isomers (e.g. racemic mixture). Thus in one embodiment of the invention the compound of formula (I) is Enantiomer 1. In another embodiment of the invention the compound of formula (I) is Enantiomer 2. In another embodiment of the invention the compound of formula (I) is Diastereomer 1. In a further embodiment of the invention the compound of formula (I) is Diastereomer 2.
The compounds of formula (I) may be formed as a mixture of enantiomers, such as a racemic mixture. Thus, in one embodiment of the invention the compound of formula (I) is the racemic mixture (the racemate).
The terms "isomer" and "stereoisomer" as used herein encompass enantiomer, diastereomer and/or regioisomer.
The compounds of the invention are glucocorticoid receptor binders. Accordingly, it has been found that at least one of the possible stereoisomers of each of the compounds of formula (I) binds to the glucocorticoid receptor.
Further, it appears that at least one of the possible stereoisomers of each of the compounds of formula (I) has glucocorticoid receptor activity. Accordingly, at least one of the possible stereoisomers of each compound of formula (I) modulates the glucocorticoid receptor. The term "modulator" as used herein refers to a compound which binds to the glucocorticoid receptor and acts as either an agonist, a partial agonist or an antagonist of the glucocorticoid receptor.
The compounds of the invention may provide agonism of the glucocorticoid receptor. Additionally, it appears that one or more of the possible stereoisomers of some of the compounds of formula (I) may possess advantageous selectivity in respect of maintaining transrepression activity whilst reducing the transactivation activity. These observations are believed to be indicative that the compounds of the invention provide anti-inflammatory properties with fewer or less severe related side effects.
Included within the scope of the "compounds of the invention" are all solvates, hydrates, complexes, polymorphs, prodrugs, radiolabeled derivatives, stereoisomers and optical isomers of the compounds of formula (I) and salts thereof.
The compounds of the invention may exist in solid or liquid form. In the solid state, the compounds of the invention may exist in crystalline or 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 skilled artisan will further appreciate that certain compounds of the invention that exist in crystalline form, including the various solvates thereof, may exhibit polymorphism (i.e. the capacity to occur in different crystalline structures). These different crystalline forms are typically known as "polymorphs." The invention includes all such polymorphs. Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification. The skilled artisan will appreciate that different polymorphs may be produced, for example, by changing or adjusting the reaction conditions or reagents, used in making the compound. For example, changes in temperature, pressure, or solvent may result in polymorphs. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions.
One embodiment of the invention provides a compound of formula (I) or a salt or solvate thereof. Another embodiment of the invention provides a compound of formula (I) or a salt thereof. Another embodiment of the invention provides a compound of formula (I) or a solvate thereof. Another embodiment of the invention provides a compound of formula (I) as the free base. A further embodiment of the invention provides a salt of a compound of formula (I) or a solvate thereof.
Salts and solvates of the compounds of formula (I) which are suitable for use in medicine are those wherein the counter-ion or associated solvent is pharmaceutically acceptable. However, salts and solvates having non-pharmaceutically acceptable counter-ions or associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of formula (I) and their pharmaceutically acceptable salts and solvates.
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 hydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic, sulphamic, sulphanilic, methanesulphonic, ethanesulphonic, formic and arylsulphonic (for example p-toluenesulphonic, benzenesulphonic, naphthalenesulphonic or naphthalenedisulphonic) acids. Pharmaceutically acceptable base salts may include alkali metal salts such as those of sodium and potassium and alkaline earth metal salts such as those of calcium. Thus, in one embodiment there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof.
The compounds of formula (I) and pharmaceutically acceptable salts thereof may have beneficial anti-inflammatory and/or anti-allergic and/or auto-immune effects, particularly upon oral administration, demonstrated by, for example, their ability to bind to the glucocorticoid receptor and to elicit a response via that receptor. Hence, the compounds of formula (I) and pharmaceutically acceptable salts thereof may be of use in the treatment of an inflammatory and/or allergic disorder and/or autoimmune condition. Examples of disease states associated with glucocorticoid receptor activity include skin diseases such as eczema, psoriasis, allergic dermatitis, neurodermatitis, pruritis, exfoliative dermatitis, pemphigus and hypersensitivity reactions; inflammatory conditions of the nose, throat or lungs such as asthma (including allergen-induced asthmatic reactions), rhinitis (including seasonal (hayfever), allergic and vasomotor), nasal polyps, chronic obstructive pulmonary disease (COPD), interstitial lung disease, and fibrosis; inflammatory bowel conditions such as ulcerative colitis and Crohn's disease; auto-immune diseases such as rheumatoid arthritis, termporal arteritis, polyarteritis nodosa, polymyositis, ankylosing spondylitis, sarcoidosis, autoimmune hepatitis; cancers such as acute and lymphatic leukaemia, myeloma, lymphoma; nephritic syndrome; septic shock; adrenal insufficiency; ophthalmic inflammation and allergic conjunctivitis; obesity; diabetes; chronic inflammatory pain including musculoskeletal pain; lower back and neck pain; sprains and strains; neuropathic pain; sympathetically maintained pain; myositis; pain associated with cancer and fibromyalgia; pain associated with migraine; pain associated with influenza or other viral infections, such as the common cold; rheumatic fever; pain associated with functional bowel disorders such as non-ulcer dyspepsia, non-cardiac chest pain and irritable bowel syndrome; pain associated with myocardial ischemia; post operative pain; headache; toothache; and dysmenorrhea; psychiatric disease for example schizophrenia, depression (which term is used herein to include bipolar depression, unipolar depression, single or recurrent major depressive episodes with or without psychotic features, catatonic features, melancholic features, atypical features or postpartum onset, seasonal affective disorder, dysthymic disorders with early or late onset and with or without atypical features, neurotic depression and social phobia, depression accompanying dementia for example of the Alzheimer's type, schizoaffective disorder or the depressed type, and depressive disorders resulting from general medical conditions including, but not limited to, myocardial infarction, diabetes, miscarriage or abortion, etc), anxiety disorders (including generalised anxiety disorder and social anxiety disorder), panic disorder, agoraphobia, social phobia, obsessive compulsive disorder and post-traumatic stress disorder, memory disorders, including dementia, amnesic disorders and age- associated memory impairment, disorders of eating behaviours, including anorexia nervosa and bulimia nervosa, sleep disorders (including disturbances of circadian rhythm, dyssomnia, insomnia, sleep apnea and narcolepsy), withdrawal from abuse of drugs such as of cocaine, ethanol, nicotine, benzodiazepines, alcohol, caffeine, phencyclidine (phencyclidine-like compounds), opiates (e.g. cannabis, heroin, morphine), amphetamine or amphetamine-related drugs (e.g. dextroamphetamine, methylamphetamine) or a combination thereof. Compounds having glucocorticoid receptor activity may also have utility in inducing suppression of the immune system during organ transplantation, in acute transplant reject, angioedema of the upper respiratory tract and anaphylactic shock.
Examples of disease states in which the compounds of formula (I) and pharmaceutically acceptable salts thereof may have utility include rheumatoid arthritis, asthma, COPD, allergy and 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. Compounds of formula (I) and pharmaceutically acceptable salts thereof are also expected to be of use in the treatment of patients with an inflammatory and/or auto-immune condition.
There is thus provided as one aspect of the invention a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in therapy.
In another aspect of the invention there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of patients with an inflammatory and/or allergic condition.
In another aspect of the invention there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of patients with rheumatoid arthritis, asthma, COPD, allergy and/or rhinitis.
In another aspect of the invention there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of patients with rheumatoid arthritis.
In another aspect of the invention there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of patients with skin disease. In another aspect of the invention there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of patients with eczema, psoriasis, allergic dermatitis, neurodermatitis, pruritis and/or hypersensitivity reactions.
In a further aspect of the invention there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of patients with an inflammatory and/or auto-immune condition.
According to another aspect of the invention, there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of patients with an inflammatory and/or allergic condition.
According to another aspect of the invention, there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of patients with rheumatoid arthritis, asthma, COPD, allergy and/or rhinitis.
According to another aspect of the invention, there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of patients with rheumatoid arthritis.
According to another aspect of the invention, there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of patients with skin disease.
According to another aspect of the invention, there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of patients with eczema, psoriasis, allergic dermatitis, neurodermatitis, pruritis and/or hypersensitivity reactions.
According to a further 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 an inflammatory and/or auto-immune condition. In another aspect of the present invention, there is provided 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 of formula (I) or a pharmaceutically acceptable salt thereof.
In a another aspect, there is provided 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 of formula (I) or a pharmaceutically acceptable salt thereof.
In another aspect, there is provided a method for the treatment of a human or animal subject with rheumatoid arthritis 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 another aspect, there is provided 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 of formula (I) or a pharmaceutically acceptable salt thereof.
In another aspect, there is provided 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 of formula (I) or a pharmaceutically acceptable salt thereof.
In a further aspect, there is provided a method for the treatment of a human or animal subject with an inflammatory and/or auto-immune condition 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) or a pharmaceutically acceptable salt or solvate 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 pharmaceutically acceptable diluents or carriers. Examples of pharmaceutically acceptable diluents or carriers include, but are not limited to, aqueous or non-aqueous vehicles, thickening agents, isotonicity adjusting agents, antioxidants and/or preservatives.
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.
The compounds of formula (I) or a pharmaceutically acceptable salt thereof may, for example, be formulated for oral, nasal, inhaled, buccal, sublingual, parenteral, topical rectal administration or other topical administration.
For systemic administration the compounds of formula (I) and pharmaceutically acceptable salts thereof may, for example, be formulated in a conventional manner for oral, parenteral or rectal administration. Compositions for oral administration include solutions, syrups, elixirs, powders, granules, tablets and capsules which typically contain conventional excipients such as binding agents, fillers, lubricants, disintegrants, wetting agents, suspending agents, emulsifying agents, preservatives, buffer salts, flavouring, colouring and/or sweetening agents as appropriate. Dosage unit forms may be preferred as described below.
For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. The tablets may also contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycollate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included.
Solid compositions of a similar type may also be employed as fillers in gelatin capsules. Examples of excipients in this regard include lactose, starch, a cellulose, milk sugar or high molecular weight polyethylene glycols. For aqueous suspensions and/or elixirs, the agent may be combined with various sweetening or flavouring agents, colouring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.
Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavouring, preservative, dispersing and colouring agent can also be present.
Capsules can be made by preparing a powder mixture as described above, and filling formed gelatin sheaths. Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture before the filling operation. A disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.
Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant and pressing into tablets. A powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, an aliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or an absorption agent such as bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen. As an alternative to granulating, the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules. The granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil. The lubricated mixture is then compressed into tablets. The compounds of formula (I) and pharmaceutically acceptable salts thereof can also be combined with free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps. A clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different unit dosages.
Oral fluids such as solutions, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in a suitably flavoured aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle. Suspensions can be formulated by dispersing the compound in a non-toxic vehicle. Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives, flavour additives such as peppermint oil or saccharin, and the like can also be added. Where appropriate, dosage unit compositions for oral administration can be microencapsulated. The composition can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax or the like.
The compounds of formula (I) or a pharmaceutically acceptable salt thereof can also be administered in the form of liposome emulsion delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
In one embodiment the compound of formula (I) or a pharmaceutically acceptable salt thereof is in the form of a tablet or capsule for oral administration. In another embodiment the compound of formula (I) or a pharmaceutically acceptable salt thereof is in the form of a solution, syrup or elixir for oral administration.
Topical administration as used herein, includes administration by insufflation and inhalation. Examples of various types of preparation for topical 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.
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. Compositions which are non- pressurised and adapted to be administered topically to the nasal cavity are of particular interest. Suitable compositions contain water as the diluent or carrier for this purpose. The compounds of formula (I) and/or pharmaceutically acceptable salts thereof may be formulated for intransal delivery. According to one aspect of the invention there is provided a pharmaceutical composition comprising an aqueous suspension/solution of a compound of formula (I) and/or a pharmaceutically acceptable salt thereof and optionally one or more of each of the following; a suspending agent; a preservative; a wetting agent; a buffer; an isotonicity adjusting agent; and a taste-masking agent. Compositions suitable for intranasal administration may optionally further contain other excipients, such as antioxidants (for example metabisulphite). Aqueous compositions may be administered to the nose by nebulisation.
Examples of suspending agents include cellulose, carboxymethylcellulose, veegum, tragacanth, bentonite, methylcellulose and polyethylene glycols. In one embodiment the suspending agent will be microcrystalline cellulose and carboxy methylcellulose sodium, for example used as the branded product Avicel RC591 (which typically contains 87-91% microcrystalline cellulose and 9 -13% carboxy methylcellulose sodium) or Avicel CL61 1.
For stability purposes, the compositions of the present invention may be protected from microbial contamination and growth by inclusion of a preservative. Examples of pharmaceutically acceptable anti-microbial agents or preservatives that can be used in the composition include quaternary ammonium compounds (for example benzalkonium chloride, benzethonium chloride, cetrimide, cetylpyridinium chloride and myristyl picolinium chloride), alcoholic agents (for example chlorobutanol, phenylethyl alcohol and benzyl alcohol), antibacterial esters (for example esters of para-hydroxybenzoic acid), chelating agents such as disodium edetate (EDTA), and other anti-microbial agents such as chlorhexidine (for example in the form of the acetate or gluconate), potassium sorbate, chlorocresol, sorbic acid and its salts, polymyxin, methylparaben and propylparaben.
It will be appreciated that any agent which is effective in wetting the particles and which is pharmaceutically acceptable can be used. Examples of wetting agents that can be used are fatty alcohols, esters and ethers. In one embodiment the wetting agent is a hydrophilic, non-ionic surfactant, for example polyoxyethylene (20) sorbitan monooleate (supplied as the branded product Polysorbate 80).
Examples of buffer substances include citric acid/sodium hydrogensulphate borate buffers, citric acid/citrate buffers, phosphates (sodium hydrogenorthophosphate, disodium hydrogenphosphate), trometamol or equivalent conventional buffers in order to adjust the pH value of the composition.
The presence of an isotonicity adjusting agent is to achieve isotonicity with body fluids, for example fluids of the nasal cavity, resulting in reduced levels of irritancy associated with many nasal compositions. Examples of suitable isotonicity adjusting agents are glucose, glycerine, sorbitol, sodium chloride, dextrose and calcium chloride. In one embodiment the isotonicity adjusting agent may be dextrose, for example, anhydrous dextrose.
Examples of taste-masking agents include sucralose, sucrose, saccharin or a salt thereof, fructose, dextrose, corn syrup, aspartame, acesulfame-K, xylitol, sorbitol, erythritol, ammonium glycyrrhizinate, thaumatin, neotame, mannitol, menthol, eucalyptus oil, camphor, a natural flavouring agent, an artificial flavouring agent, and combinations thereof. In one embodiment the taste-masking agent is sucralose and/or menthol.
In one embodiment the compounds of formula (I) or a pharmaceutically acceptable salt thereof may be formulated for administration topically to the nose 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 composition. 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.
Ointments, creams and gels, may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agent and/or solvents. 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.
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, for example to the skin, 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 the compounds of formula (I) or a pharmaceutically acceptable salt thereof may be formulated as a dry powder for administration by inhalation. 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.
Spray compositions for inhalation 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 or solvate 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 composition excipients well known in the art such as surfactants e.g. oleic acid, lecithin or an oligolactic acid 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 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 about 20μg to 500μg of a compound of formula (I). Administration may be once daily or several times daily, for example 2, 3, 4 or 8 times, giving for example 1 , 2 or 3 doses each time. The overall daily dose with an aerosol will be within the range from 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 the invention in the selected propellant in an appropriate container, for example, with the aid of sonication or a high-shear mixer. The process is desirably carried out under controlled humidity conditions.
The chemical and physical stability and the pharmaceutical acceptability of the aerosol 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.
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.
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.
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.
Capsules and cartridges for use in an inhaler or insufflator, of for example gelatine, may be formulated containing a powder mix for inhalation of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a suitable powder base such as lactose or starch. Each capsule or cartridge may generally contain from 20μg to 10mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof. Alternatively, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be presented without excipients such as lactose.
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 but will generally be within the range of from 0.001 to 10% by weight. Generally, for most types of preparations, the proportion used will be within the range of from 0.005 to 1%, for example from 0.01 to 0.5%. However, in powders for inhalation or insufflation the proportion used will normally be within the range of from 0.1 to 5%.
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.
Typically, a physician will determine the actual dosage which will be most suitable for an individual subject. The specific dose level and frequency of dosage for any particular individual may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual undergoing therapy.
For oral administration to humans, the daily dosage level of the agent may be in single or divided doses. For systemic administration the daily dose as employed for adult human treatment may range from 0.5-100mg/kg body weight, for example from 0.5-60mg/kg body weight, which may be administered in 1 to 4 daily doses, for example, depending on the route of administration and the condition of the patient. When the composition comprises dosage units, each unit will contain, for example 5mg to 1g of active ingredient. The duration of treatment will be dictated by the rate of response rather than by arbitrary numbers of days.
The compounds of formula (I) or a pharmaceutically acceptable salt 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.
In one embodiment there is provided a compound of formula (I) or a pharmaceutically functional salt thereof formulated for oral administration. In another embodiment there is provided a compound of formula (I) or a pharmaceutically functional salt thereof formulated for inhaled administration. In a further embodiment there is provided a compound of formula (I) or a pharmaceutically functional salt thereof 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 and/or stability and/or physical characteristics, such as solubility, of the therapeutic ingredient. It will be clear also that, where appropriate, the therapeutic ingredients may be used in optically pure form.
Examples of β2-adrenoreceptor agonists include salmeterol (which may be a racemate or a single enantiomer such as the R-enantiomer), salbutamol (which may be a racemate or a single enantiomer such as the /?-enantiomer), formoterol (which may be a racemate or a single diastereomer such as the /?,/?-diastereomer), salmefamol, fenoterol, carmoterol, etanterol, naminterol, clenbuterol, pirbuterol, flerbuterol, reproterol, bambuterol, indacaterol, terbutaline and salts thereof, for example the xinafoate (1-hydroxy-2-naphthalenecarboxylate) salt of salmeterol, the sulphate salt or free base of salbutamol or the fumarate salt of formoterol. In one embodiment the β2-adrenoreceptor agonists are long-acting β2-adrenoreceptor agonists, for example, compounds which provide effective bronchodilation for about 12 hours or longer.
Other β2-adrenoreceptor agonists include those described in WO02/066422,
WO02/070490, WO02/076933, WO03/024439, WO03/072539, WO03/091204, WO04/016578, WO04/022547, WO04/037807, WO04/037773, WO04/037768, WO04/039762, WO04/039766, WO01/42193 and WO03/042160.
Examples of β2-adrenoreceptor agonists include: 3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino) hexyl] oxy} butyl) benzenesulfonamide;
3-(3-{[7-({(2R)-2-hydroxy-2-[4-hydroxy-3-hydroxymethyl) phenyl] ethyl}-amino) heptyl] oxy} propyl) benzenesulfonamide;
4-{(1 R)-2-[(6-{2-[(2, 6-dichlorobenzyl) oxy] ethoxy} hexyl) amino]-1-hydroxyethyl}-2- (hydroxymethyl) phenol; 4-{(1 /?)-2-[(6-{4-[3-(cyclopentylsulfonyl)phenyl]butoxy}hexyl)amino]-1-hydroxyethyl}-
2-(hydroxymethyl)phenol;
N-[2-hydroxyl-5-[(1 R)-1-hydroxy-2-[[2-4-[[(2R)-2-hydroxy-2- phenylethyl]amino]phenyl]ethyl]amino]ethyl]phenyl]formamide;
N-2{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-2-hydroxy-2-(8-hydroxy-
2(1 H)-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.
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 a compound of formula (I) or a pharmaceutically acceptable salt 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-OXO-17α-(2,2,3,3- tetramethycyclopropylcarbonyl)oxy-androsta-1 ,4-diene-17β- carbothioic acid S-cyanomethyl ester and 6α,9α-difluoro-11 β-hydroxy-16α-methyl- 17α-(1-methycyclopropylcarbonyl)oxy-3-oxo-androsta-1 ,4-diene-17β-carbothioic acid S-fluoromethyl ester, beclomethasone esters (for example the 17-propionate ester or the 17,21-dipropionate ester), budesonide, flunisolide, mometasone esters (for example mometasone furoate), triamcinolone acetonide, rofleponide, ciclesonide (16α,17-[[(/?)-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-carbothioic acid S- cyanomethyl ester and 6α,9α-difluoro-11 β-hydroxy-16α-methyl-17α-(1- methycyclopropylcarbonyl)oxy-3-oxo-androsta-1 ,4-diene-17β-carbothioic acid S- fluoromethyl ester. 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 and WO07/054294.
Examples of anti-inflammatory agents include non-steroidal anti-inflammatory drugs (NSAID's).
Examples of NSAID's include sodium cromoglycate, nedocromil sodium, phosphodiesterase (PDE) inhibitors (for example, theophylline, PDE4 inhibitors or mixed PDE3/PDE4 inhibitors), leukotriene antagonists, inhibitors of leukotriene synthesis (for example montelukast), iNOS inhibitors, tryptase and elastase inhibitors, beta-2 integrin antagonists and adenosine receptor agonists or antagonists (e.g. adenosine 2a agonists), cytokine antagonists (for example chemokine antagonists, such as a CCR3 antagonist) or inhibitors of cytokine synthesis, or 5- lipoxygenase inhibitors. An iNOS (inducible nitric oxide synthase inhibitor) is preferably for oral administration. Examples of iNOS inhibitors include those disclosed in WO93/13055, WO98/30537, WO02/50021 , WO95/34534 and WO99/62875. Examples of CCR3 inhibitors include those disclosed in WO02/26722.
In one embodiment the invention provides the use of the compounds of formula (I) or a pharmaceutically acceptable salt thereof in combination with a phosphodiesterase 4 (PDE4) inhibitor, especially in the case of a composition adapted for inhalation. The PDE4-specific inhibitor useful in this aspect of the invention may be any compound that is known to inhibit the PDE4 enzyme or which is discovered to act as a PDE4 inhibitor, and which are only PDE4 inhibitors, not compounds which inhibit other members of the PDE family, such as PDE3 and PDE5, as well as PDE4.
Compounds include c/s-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1- carboxylic acid, 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4- difluoromethoxyphenyl)cyclohexan-1 -one and c/s-[4-cyano-4-(3-cyclopropylmethoxy- 4-difluoromethoxyphenyl)cyclohexan-1-ol]. Also, c/s-4-cyano-4-[3-(cyclopentyloxy)-4- methoxyphenyl]cyclohexane-1-carboxylic acid (also known as cilomilast) and its salts, esters, pro-drugs or physical forms, which is described in U.S. patent 5,552,438 issued 03 September, 1996; this patent and the compounds it discloses are incorporated herein in full by reference.
Other compounds include AWD-12-281 from Elbion (Hofgen, N. et al. 15th EFMC lnt Symp Med Chem (Sept 6-10, Edinburgh) 1998, Abst P.98; CAS reference No. 247584020-9); a 9-benzyladenine derivative nominated NCS-613 (INSERM); D-4418 from Chiroscience and Schering-Plough; a benzodiazepine PDE4 inhibitor identified as CI-1018 (PD-168787) and attributed to Pfizer; a benzodioxole derivative disclosed by Kyowa Hakko in WO99/16766; K-34 from Kyowa Hakko; V-11294A from Napp (Landells, 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 (Glaxo Group Ltd), WO04/056823 (Glaxo Group Ltd) and WO04/103998 (Glaxo Group Ltd).
Examples of anticholinergic agents are those compounds that act as antagonists at the muscarinic receptors, in particular those compounds which are antagonists of the M1 or M3 receptors, dual antagonists of the M1ZM3 or M2/M3, receptors or pan- antagonists of the M-ι/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 (CAS 28797-61-7), darifenacin (CAS 133099-04-4, or CAS 133099-07-7 for the hydrobromide sold under the name Enablex), oxybutynin (CAS 5633-20-5, sold under the name Ditropan), terodiline (CAS 15793-40-5), tolterodine (CAS 124937-51-5, or CAS 124937-52-6 for the tartrate, sold under the name Detrol), otilonium (for example, as the bromide, CAS 26095-59-0, sold under the name Spasmomen), trospium chloride (CAS 10405- 02-4) and solifenacin (CAS 242478-37-1 , or CAS 242478-38-2 for the succinate also known as YM-905 and sold under the name Vesicare).
Other anticholinergic agents include compounds which are disclosed in US patent application 60/487981 including, for example:
(3-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 which are disclosed in US patent application 60/51 1009 including, for example: (enc/o)-3-(2-methoxy-2,2-di-thiophen-2-yl-ethyl)-8,8-dimethyl-8-azonia- bicyclo[3.2.1]octane iodide;
3-((enc/o)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propionitrile;
(enc/o)-8-methyl-3-(2!2,2-triphenyl-ethyl)-8-aza-bicyclo[3.2.1]octane;
3-((enc/o)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propionamide;
3-((enc/o)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propionic acid;
(enc/o)-3-(2-cyano-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane iodide;
(enc/o)-3-(2-cyano-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane bromide;
3-((enofo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propan-1-ol;
Λ/-benzyl-3-((enc/o)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propionamide;
(enc/o)-3-(2-carbamoyl-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane iodide;
1-benzyl-3-[3-((enc/o)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propyl]- urea;
1-ethyl-3-[3-((enc/o)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propyl]-urea;
Λ/-[3-((enc/o)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propyl]-acetamide;
Λ/-[3-((enc/o)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propyl]-benzamide;
3-((enc/o)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-di-thiophen-2-yl-propionitrile;
(enc/o)-3-(2-cyano-2!2-di-thiophen-2-yl-ethyl)-8,8-dimethyl-8-azonia- bicyclo[3.2.1]octane iodide;
Λ/-[3-((enc/o)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propyl]- benzenesulfonamide;
[3-((enc/o)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propyl]-urea;
Λ/-[3-((enc/o)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propyl]- methanesulfonamide; and/or
(enc/o)-3-{2,2-diphenyl-3-[(1-phenyl-methanoyl)-amino]-propyl}-8,8-dimethyl-8- azonia-bicyclo[3.2.1]octane bromide.
Further compounds include:
(enc/o)-3-(2-methoxy-2,2-di-thiophen-2-yl-ethyl)-8,8-dimethyl-8-azonia- bicyclo[3.2.1]octane iodide;
(enc/o)-3-(2-cyano-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane iodide;
(enc/o)-3-(2-cyano-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane bromide; (enc/o)-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)-8,8-dimethyl-8-azonia- bicyclo[3.2.1]octane iodide; and/or
(enc/o)-3-{2,2-diphenyl-3-[(1-phenyl-methanoyl)-amino]-propyl}-8,8-dimethyl-8- azonia-bicyclo[3.2.1]octane bromide.
In one embodiment the invention provides a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, together with an H1 antagonist. Examples of H1 antagonists include, without limitation, amelexanox, astemizole, azatadine, azelastine, acrivastine, brompheniramine, cetirizine, levocetirizine, efletirizine, chlorpheniramine, clemastine, cyclizine, carebastine, cyproheptadine, carbinoxamine, descarboethoxyloratadine, doxylamine, dimethindene, ebastine, epinastine, efletirizine, fexofenadine, hydroxyzine, ketotifen, loratadine, levocabastine, mizolastine, mequitazine, mianserin, noberastine, meclizine, norastemizole, olopatadine, picumast, pyrilamine, promethazine, terfenadine, tripelennamine, temelastine, trimeprazine and triprolidine, particularly cetirizine, levocetirizine, efletirizine and fexofenadine. In a further embodiment the invention provides a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, together with an H3 antagonist (and/or inverse agonist). Examples of H3 antagonists include, for example, those compounds disclosed in WO2004/035556 and in WO2006/045416. Other histamine receptor antagonists which may be used in combination with a compound of formula (I) or a pharmaceutically acceptable salt thereof, include antagonists (and/or inverse agonists) of the H4 receptor, for example, the compounds disclosed in Jablonowski et al., J. Med. Chem. 46:3957-3960 (2003).
The invention thus provides, in another aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a PDE4 inhibitor.
The invention thus provides, in another aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a β2-adrenoreceptor agonist. The invention thus provides, in another aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a corticosteroid.
The invention thus provides, in another aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with another non-steroidal GR agonist.
The invention thus provides, in another aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with an anticholinergic.
The invention thus provides, in another aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with an antihistamine.
The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a PDE4 inhibitor and a β2-adrenoreceptor agonist.
The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with an anticholinergic and a PDE-4 inhibitor.
The individual compounds of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical 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 together with another non-steroidal GR agonist.
The invention thus provides, in a further aspect, a pharmaceutical composition comprising a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof together with an anticholinergic.
The invention thus provides, in a further aspect, a pharmaceutical composition comprising a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof together with an antihistamine.
The invention thus provides, in a further aspect, a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a PDE4 inhibitor and a β2-adrenoreceptor agonist.
The invention thus provides, in a further aspect, a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with an anticholinergic and a PDE4 inhibitor.
The compounds of the invention may be prepared by the processes described below. A process according to the invention for the preparation of compounds of formula (I) comprising coupling of a carboxylic acid of formula (II):
Figure imgf000041_0001
with an amine of formula NH(R2)C(R3)(R4)C(O)NH2, NH2CH2CH(OH)CH3, NH2C3- ecycloalkyl, NH2heterocyclyl or NHR8R9 wherein A, R2, R3, R4, R5, R6, R7, R8, R9 and X 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 conditions for amide bond formation known in the art.
The compound of formula (II) may be obtained by deprotection of a suitable protected derivative, for example a compound of formula (III)
Figure imgf000041_0002
wherein A, R5, R6, R7 and X are as defined above for compounds of formula (I).
Deprotection may be conveniently conducted by hydrogenolysis over palladium on carbon in ethanol.
Compounds of formula (III) may be obtained by reaction of an aziridine of formula (IV):
Figure imgf000042_0001
(IV)
with a 4-amino-1-arylindazole of formula (V):
Figure imgf000042_0002
wherein R7 is as described above for compounds of formula (I).
The aziridine opening reaction may be performed, for example, by heating the aziridine (IV) and aminoindazole (V) in Λ/-methyl pyrrolidinone solution at 15O0C in a microwave.
The compound of formula (IV) may be obtained by the intramolecular cyclisation of a sulphonamide of formula (Vl):
Figure imgf000042_0003
(Vl) wherein A is as defined above for compounds of formula (I), stirred in dimethylformamide in the presence of potassium carbonate.
Compounds of formula (Vl) may be prepared by reaction of mesitylenesulphonyl chloride with (2S)-2-amino-1-propanol in pyridine.
Compounds of formula (V) may be prepared by reaction of the 1 H-indazol-4-amine of formula (VII):
Figure imgf000043_0001
wherein R7 is as defined above for compounds of formula (I), with an aryl iodide of formula (VIII)
Figure imgf000043_0002
(VI I I)
The reaction of (VII) with (VIII) may be performed in the presence of a copper (I) catalyst, such as copper (I) 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 Λ/,Λ/'-dimethylethylenediamine in a variety of solvents including toluene, dioxane, Λ/,Λ/-dimethylformamide, Λ/,Λ/-dimethylacetamide and dimethylsulfoxide at a temperature in the range 60-1600C, most typically 11 O0C. 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.
The intermediate of formula (Vl) may be prepared by coupling (S)-(+)-alaninol with mesityl chloride in pyridine.
An alternative process according to the invention for the preparation of compounds of formula (I) comprises coupling of an amine of formula (IX):
Figure imgf000043_0003
(IX) wherein R1 and R7 are as defined above for compounds of formula (I), with A-SO2-CI wherein A is as defined above for compounds of formula (I).
Compounds of formula (IX) may be obtained by the deprotection of compounds of formula (X):
Figure imgf000044_0001
wherein R1 and R7 are as defined above for compounds of formula (I), with ammonium formate and palladium on carbon in ethanol.
Compounds of formula (X) may be obtained by coupling a carboxylic acid of formula (Xl):
Figure imgf000044_0002
wherein R7 is as defined above for compounds of formula (I), with an amine of formula NH(R2)C(R3)(R4)C(O)NH2, NH2CH2C(OH)CH3, NH2-(C3- 6cycloalkyl), NH2-heterocyclyl or NHR8R9 wherein R2, R3, R4, R8 and R9 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 conditions for amide bond formation known in the art.
The carboxylic acid (Xl) may be obtained by hydrolysis of the corresponding ester (XII):
Figure imgf000045_0001
wherein R7 is as defined above for compounds of formula (I).
Compounds of formula (XII) may be obtained by reductive amination of a 4-amino-1- arylindazole of formula (XIII):
Figure imgf000045_0002
wherein R7 is as defined above for compounds of formula (I), with an aldehyde of formula (XIV):
Figure imgf000045_0003
(XIV) in the presence of sodium triacetoxyborohydride in dichloromethane and acetic acid.
The aldehyde of formula (XIV) may be prepared from the ester of formula (XV):
Figure imgf000045_0004
(XV) by reduction with diisobutylaluminium hydride in dichloromethane or as described in Tetrahedron Asymmetry 2006, 17, 1074. The ester of formula (XV) may be prepared by suitable protection of alanine methyl ester.
The 4-amino-1-arylindazole of formula (XIII) may be prepared by reaction of an acid of formula (XVI):
Figure imgf000046_0001
wherein R7 is as defined above for compounds of formula (I), with concentrated H2SO4 in methanol.
The 4-amino-1-arylindazole of formula (XVI) may be prepared from a 4-bromo-1- arylindazole of formula (XVII):
Figure imgf000046_0002
wherein R7 is as defined above for compounds of formula (I), by treatment with aqueous ammonia under pressure in the presence of copper (I) iodide catalyst.
Compounds of formula (XVII) may be prepared by cyclisation of a hydrazone of formula (XVIII)
Figure imgf000047_0001
wherein R7 is as defined above for compounds of formula (I).
Cyclisation may be conducted using lithium bis(trimethylsilyl)amide in DMF.
Hydrazones of formula (XVIII) may be prepared by reaction of an aldehyde of formula (XIX)
Figure imgf000047_0002
wherein R7 is as defined above for compounds of formula (I), with an aryl hydrazine of formula (XX)
Figure imgf000047_0003
(XX)
The aldehyde of formula (XIX) may be reacted with the unprotected carboxylic acid of formula (XX), to give the hydrazone acid of formula (XVIII) which may be cyclised to give an indazole of formula (XVII).
The aldehyde of formula (XIX) is known and may be prepared as described by Lulinski and Serwatowski in J. Org. Chem., 2003, 68, 5384-5387.
Aryl hydrazines of formula (XX) are either commercially available or may be prepared from the corresponding aniline by treatment with nitrous acid generated in situ from sodium nitrite followed by subsequent reduction of the resulting aryldiazonium ions with tin (II) chloride according to standard literature procedures (see, for example, J Med Chem 1991 , 34, 2895; J Med Chem 2000, 43, 4707, J Med Chem 2003, 46, 2012).
In addition, processes for preparing compositions including one or more compounds of formula (I) form an aspect of this invention.
Compositions comprising a compound of the invention also constitute an aspect of the invention.
Solvates of compounds of formula (I) or salts thereof, which are not pharmaceutically acceptable, may be useful as intermediates in the preparation of other compounds of the invention.
The following abbreviations are used throughout the specification:
BINAP (2,2'-Bis(diphenylphosphino)-1 ,1 '-binaphthyl)
Bn Benzyl
Cbz Benzyloxycarbonyl
CDCI3 Deuterochloroform
CO2 Carbon dioxide
DCM Dichloromethane
DIBAL-H Diisobutylaluminium hydride
DIPEA N,N-Diisoproylethlamine
DMF Λ/,Λ/-Dimethylformamide
DMSO Dimethylsulphoxide
EtOAc Ethyl acetate
EtOH Ethanol
HATU O-(7-Azabenzotriazol-1-yl)-Λ/,Λ/,Λ/',Λ/-tetrame hexafluorophosphate
HCI Hydrochloric acid
HPLC High pressure liquid chromatography hr Hours IMS Industrial methylated spirit
LCMS Liquid chromatography mass spectrometry
MDAP Mass directed auto purification
Me Methyl
MeCN Acetonitrile
MeOH Methanol min Minutes
NaHCO3 Sodium hydrogen carbonate
Na2SO4 Sodium sulphate
NMP N-methyl-2-pyrrolidinone
NMR Nuclear magnetic resonance
RT Room temperature
SPE Solid phase extraction
TBME f-Butyl methyl ether (1 ,1 -dimethylethyl methyl ether)
TFA Trifluoroacetic acid
THF Tetrahydrofuran tic Thin layer liquid chromatography tRET Retention time
The invention will now be illustrated by way of the following non-limiting examples.
EXAMPLES
Synthetic Experimental 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 either CDCI3 or DMSO-c/6 on either a Bruker DPX 400 or Bruker Avance DRX or Varian Unity 400 spectrometer all working at 400 MHz. The internal standard used was either tetramethylsilane or the residual protonated solvent at 7.25ppm for CDCI3 or 2.50ppm for DMSO-c/6.
Mass Directed Autopreparative HPLC
System A:
Agilent 1100 series LC/MSD hardware, using electrospray positive mode (ES +ve) running chemstation 32 purification software.
Column: Zorbax Eclipse XDB-C18 prep HT (dimensions 212 x 100mm, 5μm packing), 20ml/min solvent speed.
Aqueous solvent = Water + 0.1% TFA Organic solvent = MeCN + 0.1% TFA
Specific gradients used:
Gradient 1 (collects on UV / mass ion trigger)
1 min 70% Water (0.1% TFA) : 30% MeCN (0.1%TFA) increasing over 9mins to 5% Water (0.1%TFA) : 95% MeCN (0.1 %TFA) to elute compounds. Gradient 2 (collects on UV only)
1 min 70% Water (0.1% TFA) : 30% MeCN (0.1%TFA) increasing over 9mins to 5% Water (0.1%TFA) : 95% MeCN (0.1 %TFA) to elute compounds.
Alternative System B (used where stated):
Carried out using a Micromass ZQ platform. The column was a 100mm x 20mm Supelco LCABZ++ with stationary phase particle size of 5μm.
Solvents: A: water + 0.1% formic acid
B: MeCN:water 95:5 + 0.05% formic acid Gradient 50-90% B over 10 minutes Flow rate 20ml_/min
LCMS System
The LCMS system used was as follows (unless otherwise stated) :
• 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 Hardware
UPLC/MS instrumentation consists of the following:
• 1 Waters Acquity Binary solvent Manager
• 1 Waters Acquity Sample Manager
• 1 Waters Acquity Column Oven
• 1 Waters Acquity Photo Diode Array
• 1 Waters ZQ Mass Spectrometer . 1 Polymer Labs ELSD PL1000
• 1 Computer System. XP SP2
Software
Waters MassLynx v4.1
Column
Acquity UPLC BEH C18 1.7μm 2.1 mm x 50mm
Column oven set to 40 degrees centigrade
Solvents
A:. Aqueous solvent = Water 0.1% Formic Acid + 1OmM Ammonium Acetate
B:. Organic solvent = MeCN: Water 95:5 +0.05% Formic Acid
Weak wash Solvent = MeOH: Water 50:50
Strong Wash Solvent = MeOH
Instrument settings
Injection volume: 0.5μl
Injection technique: Partial loop overfill
Weak Wash : 500μl
Strong Wash : 500μl UV detection: 220 to 330nm
UV sampling rate: 40 points per second
MS scan range: 100 to I OOOamu
MS scanning rate: 0.2 second scan with a 0.1 second inter scan delay
MS scan function: Electrospray with pos neg switching
Cycle time: 2 minutes and 30 seconds
Gradient
Figure imgf000053_0001
Circular Dichroism
Circular dichroism was carried out on an Applied Photophysics Chirascan spectrophotometer at room temperature, using acetonitrile as solvent, over the range 200-350nm.
Argonaut Flashmaster 2
The Flashmaster2 is an automated multi user flash chromatography system which utilises disposable SPE cartridges (2g to 100g). 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 flow rates, gradient profile and collection conditions. The system is equipped with a Knauer variable wavelength uv detector and 2 Gilson FC204 fraction collectors enabling automated peak cutting, collection and tracking.
Solvents:
[A] Cyclohexane • [B] Ethyl acetate
• [C] Dichloromethane
• [D] 50% Methanol/ DCM or 30% Methanol/ DCM +1 %triethylamine
Argonaut Flashmaster SOLO
The Flashmaster SOLO is an automated single user flash chromatography system which utilises disposable SPE cartridges (2g to 100g). It provides quaternary on-line solvent mixing to enable gradient methods to be run. Samples are logged in using the multi functional open access software which manages flow rates, gradient profile and collection conditions. The system is equipped with a Knauer variable wavelength uv detector and a Gilson FC204 fraction collector enabling automated peak cutting, collection and tracking.
Solvents: Individual choice ELSD Polymer labs ELS1000
ISCO Companion XL
The Companion XL is an automated single user flash chromatography system which utilises disposable cartridges (12Og to 150Og). It provides binary on-line solvent mixing to enable gradient methods to be run. Samples are logged in using the multi functional open access software which manages flow rates, gradient profile and collection conditions. The system is equipped with a variable wavelength uv detector and two Foxy 200 fraction collectors enabling automated peak cutting, collection and tracking.
Solvents: Individual choice
ISCO Companion
The Companion is an automated single user flash chromatography system which utilises disposable cartridges (4g to 33Og). It provides binary on-line solvent mixing to enable gradient methods to be run. Samples are logged in using the multi functional open access software which manages flow rates, gradient profile and collection conditions. The system is equipped with a variable wavelength uv detector and two Foxy fraction collectors enabling automated peak cutting, collection and tracking. Solvents: Individual choice
Biotaqe Initiator (Microwave Reactions)
Microwave chemistry was typically performed in sealed vessels, irradiating with a suitable microwave reactor system, such as a Biotage Initiator™ Microwave Synthesiser.
H-Cube Hvdrogenations
An H-cube™ is a continuous-flow reactor employing a mixed hydrogen-liquid flow stream with a 10% Pd/C cartridge. The sample was washed through the cartridge with ethanol (5-1OmI) and the combined solutions reduced to dryness under a stream of nitrogen to give the title compound as a yellow oil.
Intermediate 1 : (2S)-2-[(Mesitylsulfonyl)amino1propyl 2,4,6-trimethylbenzenesulfonate
Figure imgf000055_0001
To (S)(+) Alaninol (Oxford Asymmetry, 4.08g, 54.4mmol, 1 eq) in pyridine (170ml) was added mesityl chloride (2-mesitylenesulfonyl chloride) in one aliquot (25g, 114mmol). The colourless solution became orange-red and was stirred at room temperature under nitrogen for 27hr. Most of the pyridine was evaporated off and the residue was partitioned between ethyl acetate (250ml) and water (250ml). The layers were separated and the aqueous phase was extracted with more ethyl acetate (250ml). The combined organics were washed with 1 M HCI (2x100ml), water, saturated aqueous sodium bicarbonate (x2), brine, dried and evaporated to give an orange oil (19.65g, 82%). The oil was columned on 7734 silica (ca. 400ml) eluting with 4:1 cyclohexane/ethyl acetate to give the title compound as a clear oil that began to crystallise after two weeks (13.35g, 56%).
LCMS: tRET = 3.71 min, 87% ES +ve 457, 440; tRET = 1.45 min, 10.3% artefact. 400, 457. 1H NMR (400 MHz, CHLOROFORM-d) δppm 6.98 (s, 2H) 6.93 (s, 2H) 4.72 (d, 1 H) 3.84 (dd, 1 H) 3.77 (dd, 1 H) 3.46 - 3.56 (m, 1 H) 2.58 (s, 6H) 2.58 (s, 6H) 2.33 (s, 3H) 2.31 (S, 3H) 1.15 (d, 3H).
Intermediate 2: (2S)-2-Methyl-1-[(2,4,6-trimethylphenyl)sulfonyl1aziridine
Figure imgf000056_0001
Solid potassium carbonate (4.72g, 34.2mmol, 1.5eq) was added to (2S)-2- [(mesitylsulfonyl)amino]propyl 2,4,6-trimethylbenzenesulfonate (10.02g, 22.8mmol, 1eq) in dry DMF (100ml) and the mixture was stirred at room temperature for 1 hr. The mixture was filtered and the filtrate was evaporated off under high vacuum. The resulting white solid was partitioned between water and ethyl acetate. The aqueous phase was extracted with more ethyl acetate. The combined organics were washed with water, aqueous lithium chloride, brine, dried and evaporated. This gave the title compound as an oil that crystallised as a slightly pinky solid (5.05g, 93%). LCMS: tRET = 3.26min. 50% ES +ve 240; artefacts 21%; + poor integration of baseline at 4.6 and 4.7min.
1H NMR (400 MHz, CHLOROFORM-d) δppm 6.97 (s, 2H) 2.80 - 2.87 (m, 1 H) 2.70 (s, 6H) 2.63 - 2.68 (m, 1 H) 2.31 (s, 3H) 1.96 - 2.01 (m, 1 H) 1.26 (d, 3H).
Intermediate 3: Phenylmethyl 3-iodobenzoate
Figure imgf000056_0002
3-lodobenzoic acid (12.4g) was dissolved in DMF (10OmL) and potassium carbonate (7.6g) was added. Benzyl bromide (6.5mL) was then added dropwise over approximately IOmins causing a slight exotherm to 24°C. The suspension was stirred at room temperature for 1.5hrs. 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 (t, 1 H), 8.05 (dt, 1 H), 7.90 (dt, 1 H), 7.48-7.34 (m, 5H), 7.19 (t, 1 H) and 5.37 (s, 2H).
Intermediate 4: Phenylmethyl 3-(4-amino-6-methyl-1 /-/-indazol-1-yl)benzoate
Figure imgf000057_0001
6-Methyl-1 H-indazol-4-amine hydrochloride (0.5g, 2.7mmol), phenylmethyl 3- iodobenzoate (0.9g, 2.6mmol), copper (I) iodide (14mg, 0.07mmol), potassium carbonate (1.2g, 8.68mmol) and frans-/V,/V-dimethyl-1 ,2-cyclohexanediamine (20mg, 0.14mmol) were heated together in DMF (5ml_) at reflux overnight. The mixture was poured into water (15ml_) and ethyl acetate was added to dissolve the resulting oil. The suspension was then filtered through celite. The organic phase was separated, combined with a second ethyl acetate extract, washed successively with water and brine and then dried over anhydrous sodium sulphate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (75g) eluting with 1 to 5% gradient of ethyl acetate in dichloromethane to give the title compound as a light brown oil (0.3g).
1H-NMR: (CDCI3, 400 MHz) δ 8.46 (t, 1 H), 8.10 (s, 1 H), 8.06 (m, 1 H), 7.96 (m, 1 H), 7.61 (t, 1 H), 7.49 (m, 2H), 7.42 (m, 2H), 7.38 (m, 1 H), 6.96 (s, 1 H), 6.31 (s, 1 H), 5.44 (s, 2H), 4.15 (m, 2H), 2.42 (s, 3H).
Intermediate 5: Phenylmethyl 3-f6-methyl-4-r((2S)-2-fr(2.4.6- trimethylphenyl)sulfonyllamino)propyl)aminol-1H-indazol-1-yl)benzoate and phenylmethyl 3-f6-methyl-4-[((1 /?V1 -methyl-2-fr(2.4.6- trimethylphenyl)sulfonyllamino)ethyl)aminol-1H-indazol-1-yl)benzoate as a minor component
Figure imgf000058_0001
Regioisomer
Figure imgf000058_0002
(Minor component)
Three identical reactions were carried out as follows: (2S)-2-methyl-1 -[(2,4,6- trimethylphenyl)sulfonyl]aziridine (0.77g, 3.2mmol, 1.2 eq) and phenylmethyl 3-(4- amino-6-methyl-1 H-indazol-1-yl)benzoate (0.96g, 2.68mmol, 1.0 eq) in NMP (18ml) were heated in a Biotage Initiator microwave at 15O0C for a total of 10hr. The reactions were combined and partitioned between ethyl acetate and water. The aqueous was extracted with more ethyl acetate. Then the combined organics were washed with brine, dried and evaporated to give a brown oil, 21.4g (assumed to contain much NMP). The oil was columned on a C-18 reverse phase 33Og cartridge on the Companion System, eluting with 40 - 95% acetonitrile in water and 0.1% TFA. The acetonitrile was evaporated and the residue was partitioned between sodium bicarbonate and ethyl acetate. The combined organics were washed with brine, dried and evaporated to give a mixture of the title compounds as a brown foam (1.66g, 35%).
LCMS: (system B) tRET = 1.57min, 99%. 1H NMR (400 MHz, CHLOROFORM-d) δppm 8.44 (s, 1 H) 8.00 - 8.07 (m, 1 H) 7.92 -
7.98 (m, 2H) 7.60 (t, 1 H) 7.46 - 7.50 (m, 2H) 7.34 - 7.43 (m, 3H) 6.85 - 6.93 (m, 3H)
5.99 (s, 1 H) 5.41 (s, 2H) 3.53 - 3.63 (m, 1 H) 3.25 - 3.33 (m, 1 H) 3.15 - 3.24 (m, 1 H) 2.64 (s, 6H) 2.38 (s, 3H) 2.27 (s, 3H) 1.24 (d, 3H).
Intermediate 6: 3-{6-Methyl-4-[((2S)-2-{[(2A6- trimethylphenyl)sulfonyl1amino)propyl)amino1-1H-indazol-1-yl)benzoic acid and 3-{6- methyl-4-r((1 /?)-1-methyl-2-{r(2,4,6-trimethylphenyl)sulfonyl1amino)ethyl)amino1-1 H- indazol-1-yl)benzoic acid as a minor component
Figure imgf000059_0001
Phenylmethyl 3-{6-methyl-4-[((2S)-2-{[(2,4,6- trimethylphenyl)sulfonyl]amino}propyl)amino]-1 H-indazol-1-yl}benzoate (1g,
1.68mmol) was dissolved in 1 :1 ethyl acetate/ethanol (33.6ml) and hydrogenated over 10% palladium on charcoal at 5O0C in an H cube (flow rate 1 ml/min.) to give an orange solution. The solution was concentrated to give a brown oil and dried under vacuum to give a mixture of the title compounds as a pale yellow solid (790mg, 92.9%).
LCMS tRET = 3.74min. major product, 3.79min was minor product MH+ 507 MH" 505. 1H NMR (400 MHz, CHLOROFORM-d) δppm 8.46 (s, 1 H) 8.04 - 8.08 (m, 1 H) 8.01 (s, 1 H) 7.95 - 7.99 (m, 1 H) 7.62 (t, 1 H) 6.85 - 6.93 (m, 3H) 5.97 (s, 1 H) 3.69 - 3.77 (m, 1 H) 3.51 - 3.63 (m, 1 H) 3.25 - 3.34 (m, 1 H) 3.15 - 3.24 (m, 1 H) 2.64 (s, 6H) 2.38 (s, 3H) 2.26 (s, 3H) 1.23 (d, 3H).
Separation
The product was purified on a Waters Micromass Preparative LCMS system as follows:
• Column: 100 x 21.2mm ID, 5μm Luna Phenyl Hexyl
• Flow Rate: 20ml/min
• Injection Volume: 205μl
• Temp: RT
• UV Detection Range: 215 to 330nm
Solvents: A: 0.1% Trifluoroacetic Acid in Water.
B: 0.05% v/v Trifuoroacetic Acid in Acetonitrile Gradient: Time A% B%
0 60 40
1 60 40
25 40 60
25.2 1 99
28.2 1 99
28.5 60 40
30 60 40
The major isomer was isolated as a white solid, 461 mg.
LCMS; tRET = 3.7min, MH+ 507.2.
1H NMR (400 MHz, DMSOd6) δppm 13.27 (s, 1 H) 8.21 - 8.29 (m, 2H) 7.98 (dd, 1 H)
7.87 - 7.93 (m, 1 H) 7.69 (t, 1 H) 7.61 (d, 1 H) 6.90 (s, 2H) 6.75 (s, 1 H) 6.46 (t, 1 H) 5.84
(s, 1 H) 3.29 - 3.42 (m, 1 H) 3.13 - 3.23 (m, 1 H) 3.00 - 3.11 (m, 1 H) 2.55 (s, 6H) 2.30
(s, 3H) 2.14 (s, 3H) 1.02 (d, 3H).
The minor isomer was isolated as a green solid, 177mg.
LCMS; tRET = 3.75min, MH+ 507.2.
Intermediate 7: Phenylmethyl 4-iodobenzoate
Figure imgf000060_0001
To 4-iodobenzoic acid (15.62g, 63mmol, 1.05eq) in dry DMF (6vol, 90ml) was added potassium carbonate (8.7g, 63mmol, 1.05eq) and the suspension was stirred for 10min. Benzyl bromide (10.25g, 7.13ml, 60mmol, 1 eq) was then added over ca. 1 min. and the resulting suspension was stirred at room temperature under nitrogen for 6.25hr. The mixture was partitioned between ether (200ml) and water (200ml). The aqueous phase was extracted with more ether, then the combined organics were washed with water, aqueous lithium chloride, brine, dried and then evaporated to give the title compound as a white crystalline solid after leaving under vacuum (18.38g, 86%). LCMS; tRET = 3.81 min, 70% ES +ve 376, 356 (+ artefact 1.48min. 28%). 1H NMR (400 MHz, DMSOd6) δppm 7.92 (d, 2H) 7.74 (d, 2H) 7.46 (d, 2H) 7.35 - 7.42 (m, 3H) 5.34 (s, 2H).
Intermediate 8: Phenylmethyl 4-(4-amino-6-methyl-1 H-indazol-1-yl)benzoate
Figure imgf000061_0001
To a solution of the 6-methyl-1 H-indazol-4-amine (8.26g, 54.2mmol) in dry DMF (100ml) was added iodobenzoic acid benzyl ester (19g, 56.2mmol) followed by potassium carbonate (8.15g, 59mmol), 1 /?,2/?-Λ/,Λ/'-dimethyl-1 ,2-cyclohexanediamine (0.425g, 3.0mmol) and copper (I) iodide (0.284g, 1.5mmol). The mixture was heated to 11 O0C for 5hr when LCMS showed ca. 50% conversion. Potassium carbonate (8.15g, 59mmol) was added followed by copper (I) iodide (0.284g, 1.5mmol) and 1 /?,2/?-Λ/,Λ/'-dimethyl-1 ,2-cyclohexanediamine (0.425g, 3.0mmol) and the mixture was heated to 1 1O0C for 5hr when LCMS showed absence of starting materials. The majority or the solvent was removed in vacuo and the residue was partitioned between ethyl acetate (500ml) and water (500ml). The emulsion which ensued was filtered through celite and separated. The organics were washed with saturated sodium thiosulphate solution (250ml) then brine (250ml) and dried (sodium sulphate). The mixture was filtered and concentrated in vacuo. The residue (ca. 22g) was dissolved in DCM (100ml), placed on a silica (50Og) column, pre-eluted with cyclohexane and eluted with DCM (500ml), 2% ethyl acetate/DCM (1000ml), 3% ethyl acetate/DCM (2000ml), 4% ethyl acetate/DCM (1000ml), 5% ethyl acetate/DCM (2000ml) then 10% ethyl acetate/DCM (1000ml) to give the title compound as a pale yellow solid (5.6g, 27.9%). LCMS: tRET = 3.72min, MH+ 358.
1H NMR (400 MHz, CHLOROFORM-d) δppm 8.24 (d, 2H) 8.1 1 (s, 1 H) 7.85 (d, 2H) 7.49 (d, 2H) 7.35 - 7.45 (m, 3H) 7.00 (s, 1 H) 6.32 (s, 1 H) 5.41 (s, 2H) 2.40 (s, 3H).
The impure fractions (10g) were purified by CombiFlash Companion XL using a RediSep cartridge (75Og silica) eluting with a gradient of DCM/20% ethyl acetate/DCM over eight column volumes. This gave additional product (1.5g, 7.47%). 1H NMR (400 MHz, CHLOROFORM-d) δppm 8.37 (s, 1 H) 8.22 (d, 2H) 7.99 (d, 2H)
7.48 (d, 2H) 7.35 - 7.45 (m, 3H) 6.99 (s, 1 H) 6.15 (s, 1 H) 5.40 (s, 2H) 2.37 (s, 3H).
Alternative Preparation of Intermediate 8: Phenylmethyl 4-(4-amino-6-methyl-1 H- indazol-1 -vDbenzoate
To 4-iodobenzoic acid benzyl ester (12.61 g, 37.3mmol) in dry dioxane (20ml) was added 6-methyl-1 H-indazol-4-amine (5.48g, 37.3mmol), copper (I) iodide (71 mg, 0.37mmol), diaminocyclohexane (0.42g, 3.73mmol) and potassium phosphate (16.6g, 78.3mmol) washed in by more dry dioxane (30ml). The mixture was heated under reflux for 3.25hr. The mixture was allowed to cool gradually to RT. The mixture was partitioned between water and ethyl acetate and the aqueous phase was extracted with more ethyl acetate. The combined organics were washed with brine, dried and evaporated. This gave a brown solid, 13.58g. This was combined with 0.66g of crude material from a previous batch. The combined material was columned on 7734 silica (500ml) eluting with 10% ethyl acetate in DCM, then 20% ethyl acetate to give a brown/yellow solid, 5.12g. The material was dissolved in the minimum quantity of ethyl acetate at 6O0C (40ml). Then warm cyclohexane (70ml) was added and this gradually gave a precipitate which was then cooled in an ice bath and the solid was collected by vacuum filtration and washed with cyclohexane/ethyl acetate (4:1 , 40ml) to give the title compound as a beige solid (4.29g, 32%). LCMS; tRET = 3.77min, 98% ES +ve 358. 1H NMR (400 MHz, CHLOROFORM-d) δppm 8.25 (d, 2H) 8.1 1 (s, 1 H) 7.85 (d, 2H)
7.49 (d, 2H) 7.35 - 7.45 (m, 3H) 7.01 (s, 1 H) 6.32 (s, 1 H) 5.42 (s, 2H) 4.15 (s, 2H) 2.42 (s, 3H).
The filtrate was evaporated (0.96g) and added to a mixed fraction (yellow solid, 6.81 g). The purification procedure was repeated with this combined material; dissolved in ethyl acetate (ca. 55ml), then cyclohexane was added (100ml) to give a pale yellow solid; 5.49g. This material still contained impurity and so it was combined with the concentrated filtrate (1.88g). The purification procedure was repeated once more with ethyl acetate (70ml) and less cyclohexane (60ml) to give the title compound as a pale cream solid, (2.84g, 21 %).
1H NMR (400 MHz, CHLOROFORM-d) δppm 8.24 (d, 2H) 8.09 (s, 1 ) 7.85 (d, 2H) 7.49 (d, 2H) 7.35 - 7.45 (m, 3H) 7.01 (s, 1 H) 6.32 (s, 1 H) 5.42 (s, 2H) 4.15 (s, 2H) 2.41 (s, 3H). Intermediate 9: Phenylmethyl 4-{6-methyl-4-r((2S)-2-{[(2,4,6- trimethylphenyl)sulfonyl1amino)propyl)amino1-1 H-indazol-1-yl)benzoate and phenylmethyl 4-{6-methyl-4-[((1 R)- 1 -methyl-2-{[(2,4,6- trimethylphenyl)sulfonyl1amino)ethyl)amino1-1H-indazol-1-yl)benzoate as a minor component
Figure imgf000063_0001
To (2S)-2-methyl-1-[(2,4,6-trimethylphenyl)sulfonyl]aziridine (0.6g, 2.5mmol, 1.1 eq) was added 6-methyl-1 H-indazol-4-amine (0.81g, 2.27mmol, 1eq) and dry NMP (15ml). The solution was heated in a Biotage Initiator microwave at 15O0C for 4hr and 40min. The dark brown solution was partitioned between water (150ml) and ethyl acetate (150ml). The aqueous phase was extracted with more ethyl acetate and the combined organics were washed with brine and evaporated to a brown oil, 4.55g. The oil was purified on a 2Og C-18 cartridge using the Tlashmaster Personal, eluting with 40% acetonitrile in water plus 0.1 % TFA initially, then gradually to 50% and 60%. The acetonitrile was evaporated off and the aqueous was made basic before extracting with ethyl acetate. The organics were washed with brine, dried and evaporated to give a brown oil (1.Og, 74%), after leaving under high vacuum. LCMS: tRET = 4.26min, 92% ES +ve 597, tRET = 4.40min, 3% 597, 836. The oil was dissolved in DCM and re-evaporated (including high vacuum) to give the title compound as a brown foam (0.93g, 69%).
1H NMR (400 MHz, CHLOROFORM-d) δppm 8.25 (d, 2H) 7.94 - 8.05 (m, 1 H) 7.84 (d, 2H) 7.47 - 7.51 (m, 2H) 7.35 - 7.45 (m, 3H) 6.91 - 7.00 (m, 3H) 6.03 (s, 1 H) 5.41 (s, 2H) 3.52 - 3.62 (m, 1 H) 3.26 - 3.37 (m, 1 H) 3.15 - 3.23 (m, 1 H) 2.62 (s, 6H) 2.39 (s, 3H) 2.28 (s, 3H) 1.23 (d, 3H).
Intermediate 10: 4-f6-Methyl-4-r((2SV2-f[(2.4.6- trimethylphenyl)sulfonyllamino)propyl)aminol-1H-indazol-1-yl)benzoic acid and 4-{6- methyl-4-r((1 /?)-1-methyl-2-{r(2,4,6-trimethylphenyl)sulfonyllamino)ethyl)aminol-1 H- indazol-1-vDbenzoic acid as a minor component.
Figure imgf000064_0001
Phenylmethyl 4-{6-methyl-4-[((2S)-2-{[(2,4,6- trimethylphenyl)sulfonyl]amino}propyl)amino]-1 H-indazol-1-yl}benzoate (1g,
1.68mmol) was dissolved in DCM (33.6ml) and hydrogenated over 10% Pd/C at 250C in an H-cube, 1 ml/min., to give a yellow solution. LCMS indicated about 45% hydrogenation. The solution was concentrated in vacuo to give a yellow oil. This was redissolved in 1 :1 ethyl acetate/ethanol and hydrogenated over 10% palladium on charcoal at 4O0C in an H-cube, 1 ml/min, to give a yellow solution. LCMS indicated complete hydrogenation. The solution was concentrated in vacuo to give a mixture of the title compounds as a yellow solid (770mg, 90.6%). LCMS (system B) tRET = 1.21 min MH+ 507 (4:1 with minor regioisomer). 1H NMR (400 MHz, CHLOROFORM-d) δppm 8.15 - 8.22 (m, 2 H) 8.05 (s, 1 H) 7.79 - 7.85 (m, 2 H) 6.90 - 6.95 (m, 3 H) 6.04 (s, 1 H) 3.71 - 3.77 (m, 1 H) 3.54 - 3.63 (m, 1 H) 3.30 - 3.38 (m, 1 H) 3.16 - 3.24 (m, 1 H) 2.66 (s, 6 H) 2.43 (s, 3 H) 2.27 (s, 3 H) 1.23 (d, 3 H).
Separation
The product was purified on a Waters Micromass Preparative LCMS system as follows:
• Column: 100 x 21.2mm ID, 5μm Luna Phenyl Hexyl
• Flow Rate: 20ml/min
• Injection Volume: 250μl
• Temp: RT
• UV Detection Range: 215 to 330nm Solvents: A: 0.1% Trifluoroacetic Acid in Water.
B: 0.05% v/v Trifuoroacetic Acid in Acetonitrile
Figure imgf000065_0002
The title compound was isolated as a green solid (384mg).
LCMS: tRET = 3.82min, MH+ 507.17.
1H NMR (400 MHz, DMSOd6) δppm 8.25 (s, 1 H) 8.08 (d, 2H) 7.85 (d, 2H) 7.58 (d,
1 H) 6.80 - 6.87 (m, 3H) 5.82 (s, 1 H) 3.30 - 3.41 (m, 1 H) 3.08 - 3.19 (m, 1 H) 2.97 -
3.07 (m, 1 H) 2.51 (s, 6H) 2.27 (s, 3H) 2.09 (s, H) 1.00 (d, 3H).
Intermediate 11 : Methyl /V-MphenylmethyDoxyicarbonvD-L-alaninate
Figure imgf000065_0001
To alanine methyl ester hydrochloride (9.73g, 69.71 mmol) in a stirred mixture of ethyl acetate (175ml) and saturated aqueous sodium bicarbonate (175ml), cooled to 0-50C (ice bath), was added benzyl chloroformate (10.9ml, 76.37mmol) dropwise over ca. 20min. Stirring was continued for 18hr as the temperature rose to 200C then the layers were separated. The aqueous phase was further extracted with ethyl acetate (100ml) then the combined extracts were washed with 1 M HCI (150ml), dried (sodium sulphate) and evaporated in vacuo. The residue was evaporated from DCM to obtain a colourless liquid (16.07g, 97.2%).
1H NMR (400 MHz, CHLOROFORM-d) δppm 7.31 - 7.41 (m, 5H) 5.32 (br. s., 1 H) 5.13 (s, 2H) 4.35 - 4.45 (m, 1 H) 3.74 (s, 3H) 1.42 (d, 3H).
Intermediate 12: Phenylmethyl [(1 S)-1-methyl-2-oxoethyl1carbamate
Figure imgf000066_0001
A stirred solution of methyl N-{[(phenylmethyl)oxy]carbonyl}-L-alaninate (6g, 25.3mmol) in DCM (200ml), under nitrogen, was cooled to -780C (acetone/CO2 bath) then treated with a 1 M DCM solution of DIBAL-H (50.6ml, 50.6mmol) dropwise over ca. 30mins. Stirring was continued at -780C for 3hr then the mixture was quenched by the addition of 1 M HCI (150ml). After warming to room temp the mixture was diluted with DCM (100ml) and water (100ml). The layers were separated and the aqueous phase was further extracted with DCM (100ml). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo. The residue was applied to a
100g silica SPE cartridge and eluted with a DCM/ethyl acetate gradient (0-25%
EtOAc over 40mins) to obtain the title compound as a pale straw-coloured oil
(3.486g, 66.5%).
Although the title compound appears pure by TLC, NMR showed it to contain some impurities.
1H NMR (400 MHz, CHLOROFORM-d) δppm 9.56 (s, 1 H) 7.30 - 7.40 (m, 6H) 5.41
(br. s., 1 H) 5.14 (s, 2H) 4.28 - 4.38 (m, 1 H) 1.33 - 1.43 (m, 3H).
Intermediate 13: 3-f2-r(2.6-Dibromo-4- methylphenvDmethylidenelhvdrazinolbenzoic acid
Figure imgf000066_0002
2,6-Dibromo-4-methylbenzaldehyde (150Og, 5.39mol) and 3-hydrazinobenzoic acid (820.2g, 5.39mol) were suspended in methanol (12.75L) under a nitrogen atmosphere and heated to 400C. After 2hr, heating was stopped and the reaction mixture was cooled to 00C and stirred for 30min. The precipitate was filtered and washed with chilled methanol (1.5L) and dried in vacuo at 55°C to afford the title compound (2121.8g). LCMS: tRET = 3.96min; MH+ = 411/413/415.
Intermediate 14: 3-(4-Bromo-6-methyl-1 H-indazol-1-yl)benzoic acid
Figure imgf000067_0001
A solution of 3-{2-[(2,6-dibromo-4-methylphenyl)methylidene]hydrazino}benzoic acid (105Og) in DMF (3.46L) was cooled to 100C under nitrogen. Lithium bis(trimethylsilyl)amide solution (1 M in THF, 6.34L) was then added while maintaining the temperature below 150C. The stirred solution was heated at 70 ± 3°C for 64hr and then the reaction mixture was cooled to 5°C and quenched sequentially with the slow addition of water (4.2L), 5M hydrochloric acid (2.62L) and water (3.68L). The resulting slurry was stirred at 5°C for 1 hr 34min, filtered and washed successively with purified water (1 L and then 2.1 L at 5 ± 5°C) and methanol (2 x 1 L at 5 ± 5°C). The solid was dried in vacuo at 500C to afford the title compound (742.9g). LCMS: tRET = 3.71 min; MH+ = 331 , 333.
Intermediate 15: 3-(4-Amino-6-methyl-1 H-indazol-1 -vDbenzoic acid
Figure imgf000067_0002
A suspension of 3-(4-bromo-6-methyl-1 H-indazol-1 -yl)benzoic acid (1450.5g, 4.38mol) and copper (I) iodide (42.47g, 0.22mol, 5mol%) in aqueous ammonia (0.88sg, 13.5L) was heated in a sealed pressure vessel until a pressure of 7 Bar ± 0.3 Bar was generated (contents temperature ~78°C). Stirring was continued for a period of ca. 2 days. The reaction mixture was cooled to 200C and then charged in to a Controlled Lab Reactor fitted with a 5M HCI scrubber. The solution was heated at reflux to remove excess ammonia by gradually raising the contents temperature to >90°C - end point pH 7.87. The reaction mixture was then cooled to 60 ± 3°C and acetic acid (725ml_, 12.7mol) was added slowly to form a precipitate - end point pH= 5.68. The batch was cooled to 5 ± 3°C and stirred for 825min. The slurry was filtered and washed with water (3 x 4.5L). The solid was dried in vacuo at 500C to afford the title compound (1 112.3g). LCMS: tRET = 2.93 min; MH+ = 268.
Intermediate 16: Methyl 3-(4-amino-6-methyl-1 H-indazol-1-yl)benzoate
Figure imgf000068_0001
A stirred suspension of 3-(4-amino-6-methyl-1 H-indazol-1-yl)benzoic acid (1Og, 37.4mmol) in methanol (150ml) was treated with cone, sulphuric acid (2.5ml, 46.9mmol) and heated at reflux for 18hr. LCMS showed >96% desired product. After cooling to RT the mixture was concentrated in vacuo. The residue was partitioned between saturated aqueous NaHCC>3 (300ml) and DCM (300ml). The layers were separated and the aqueous phase was further extracted with DCM (200ml). The combined organic extracts were washed with brine (200ml), dried (Na2SO4) and evaporated in vacuo. The residue was applied to a 100g silica SPE cartridge and eluted with a DCM/ethyl acetate gradient (0-25% EtOAc over 40mins) to obtain the title compound as a beige-coloured solid (7.77g, 73.8%).
LCMS: tRET = 3.24min, MH+ 282.
1H NMR (400 MHz, CHLOROFORM-d) δppm 8.41 (t, 1 H) 8.09 (d, 1 H) 8.01 (dt, 1 H)
7.93 (dd, 1 H) 7.60 (t, 1 H) 6.95 (s, 1 H) 6.30 (s, 1 H) 4.14 (br. s., 2H) 3.97 (s, 3H) 2.41
(s, 3H).
Intermediate 17: Methyl 3-(6-methyl-4-{[(2S)-2-
({[(phenylmethyl)oxy1carbonyl)amino)propyl1amino)-1H-indazol-1-yl)benzoate
Figure imgf000069_0001
A stirred solution of methyl 3-(4-amino-6-methyl-1 H-indazol-1-yl)benzoate (3.62g, 12.88mmol) and phenylmethyl [(1 S)-1-methyl-2-oxoethyl]carbamate (3.47g, 16.75mmol) in DCM (50ml), under nitrogen, was treated with acetic acid (0.737ml, 12.88mmol). After 15min sodium triacetoxyborohydride (5.46g, 25.8mmol) was added and stirring was continued for 18hr. LCMS showed ca. 5% remaining amino indazole. The reaction mixture was diluted with DCM (150ml) and washed with saturated aqueous NaHCOβ (200ml). The layers were separated and the aqueous phase was further extracted with DCM (100ml). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo. The residue was applied to a 10Og silica
SPE cartridge and eluted with a cyclohexane/ethyl acetate gradient (0-50% ethyl acetate over 60min) to obtain a beige-coloured foam (5.231 g, 86%).
LCMS showed the product to be 91 % pure, NMR showed the product contains minor impurities.
The product was repurified on a 100g silica SPE cartridge eluting with a cyclohexane/diethyl ether gradient (0-100% ether over 40min). Fractions were pooled in 2 batches (pure by tic and slightly impure by tic) and evaporated. The residue from each batch was triturated with ether to obtain:-
1 ) white solid, 3.29g., 54.1 %. LCMS: tRET = 3.75min, MH+ 473.
1H NMR (400 MHz, CHLOROFORM-d) δppm 8.40 (t, 1 H) 8.07 (s, 1 H) 8.01 (dt, 1 H) 7.93 (dd, 1 H) 7.59 (t, 1 H) 7.28 - 7.37 (m, 5H) 6.87 (s, 1 H) 6.11 (s, 1 H) 5.13 (s, 2H) 4.16 (s, 1 H) 3.96 (s, 3H) 3.35 - 3.45 (m, 1 H) 3.23 - 3.33 (m, 1 H) 2.41 (s, 3H) 1.32 (d, 3H).
2) cream-coloured solid, 0.493g. LCMS: tRET = 3.75min, MH+ 473. 1H NMR (400 MHz, CHLOROFORM-d) δppm 8.38 - 8.43 (m, 1 H) 8.07 (s, 1 H) 7.98 - 8.03 (m, 1 H) 7.90 - 7.95 (m, 1 H) 7.59 (t, 1 H) 7.29 - 7.37 (m, 5H) 6.86 (s, 1 H) 6.11 (s, 1 H) 5.13 (s, 2H) 4.11 - 4.22 (m, 1 H) 3.96 (s, 3H) 3.35 - 3.46 (m, 1 H) 3.23 - 3.33 (m, 1 H) 2.41 (s, 3H) 1.32 (d, 3H).
The ether triturates from the isolation of 1 ) and 2) above were combined and evaporated in vacuo to obtain a beige coloured foam (0.803g, 13.19%).
Intermediate 18: 3-(6-Methyl-4-f[(2SV2-
({r(phenylmethyl)oxylcarbonyl)amino)propyllamino)-1H-indazol-1-yl)benzoic acid
Figure imgf000070_0001
A stirred solution of methyl 3-(6-methyl-4-{[(2S)-2-
({[(phenylmethyl)oxy]carbonyl}amino)propyl]amino}-1 H-indazol-1-yl)benzoate (3.227g, 6.83mmol) in methanol (25ml) and THF (25ml) was treated with 2M sodium hydroxide (25ml, 50.0mmol). After stirring for 30min LCMS showed complete reaction. 2M HCI (25ml) was added making the pH of the reaction ca. pH4 (indicator paper). The mixture was extracted with ethyl acetate (x2) then the combined organic extracts were dried (IS^SC^) and evaporated in vacuo. The residue was evaporated from DCM to obtain the title compound as a pale beige-coloured foam (3.193g,
102%).
LCMS: tRET = 3.54 min, MH+ = 459.
1H NMR (400 MHz, DMSOd6) δppm 13.24 (br. s., 1 H) 8.40 (s, 1 H) 8.23 (t, 1 H) 7.98
(dd, 1 H) 7.90 (dt, 1 H) 7.69 (t, 1 H) 7.27 - 7.37 (m, 5H) 6.78 (s, 1 H) 6.51 (t, 1 H) 6.19
(s, 1 H) 5.03 (s, 2H) 3.83 - 3.93 (m, 1 H) 3.27 - 3.37 (m, 1 H) 3.07 - 3.16 (m, 1 H) 2.34
(s, 3H) 1.12 - 1.19 (m, 3H). (1H NMR consistent with structure containing a small amount of ethyl acetate and DCM).
Examples 1-11 were prepared according to the following procedure: The amines shown in the table below (O.OΘmmol) were pre-weighed into Micronics tubes. Each acid or pair of acids, as shown in the table below, (30mg, O.OΘmmol) in DMF (250μl) were added to HATU (23mg, O.OΘmmol) and DIPEA (30μl, 0.18mmol). The solutions were left for 5min and then added to the tubes containing each amine. DMF was removed in a Genevac. The dried compounds were dissolved in chloroform (500μl) and loaded onto a pre-washed 500mg aminopropyl cartridge (MeOH, 2ml, chloroform, 2ml). The compounds were recombined and purified on MDAP Atlantis column with formic acid modifier (acetonitrile/water solvents) used.
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Example 1 (minor regioisomer): N-((2/?)-2-{[1-(4-{[4-(Hydroxymethyl)-1- piperidinyllcarbonyl)phenyl)-6-methyl-1 H-indazol-4-yllamino)propyl)-2,4,6- trimethylbenzenesulfonamide
Figure imgf000073_0002
The product was purified on a Waters Micromass Preparative LCMS system as follows:
• Column: 100 x 21.2mm ID, 5μm Luna C18 (2)
• Flow Rate: 20ml/min
• Injection Volume: 250μl
• Temp: RT
• UV Detection Range: 215 to 330nm
Solvents: A: 0.1% Trifluoroacetic Acid in Water.
B: 0.05% v/v Trifuoroacetic Acid in Acetonitrile
Figure imgf000073_0003
Figure imgf000074_0002
Yield; 7.1 mg.
LCMS: tRET = 3.41 min, MH+ 604.
1H NMR (400 MHz, DMSOd6) δppm 8.31 (s, 1 H) 7.73 - 7.81 (m, 2H) 7.64 - 7.73 (m,
1 H) 7.53 - 7.59 (m, 2H) 7.10 (s, 1 H) 6.98 (s, 2H) 6.84 (s, 1 H) 5.96 (s, 1 H) 4.27 - 4.37
(m, 1 H) 3.91 - 4.00 (m, 1 H) 3.26 - 3.33 (m, 2H) 3.13 - 3.20 (m, 1 H) 2.94 - 3.06 (m,
2H) 2.65 - 2.76 (m, 2H) 2.55 (s, 6H) 2.30 (s, 3H) 2.21 (s, 3H) 1.65 - 1.77 (m, 3H) 1.17
(s, 3H).
Example 2: Λ/-((1 SV2-fri-(3-fr2-(Hvdroxymethvn-1-DiDeridinyllcarbonyl>Dhenvn-6- methyl-1 H-indazol-4-yllamino)-1-methylethyl)-2,4,6-trimethylbenzenesulfonamide
Figure imgf000074_0001
LCMS (system B): tRET = 1.13min, MH+ 604.
1H NMR (400 MHz, CHLOROFORM-d) δppm 8.31 (s, 3H) 8.03 (s, 1 H) 7.98 (d, 1 H) 7.84 (d, 1 H) 7.49 (t, 1 H) 6.86 (s, 2H) 6.75 (s, 1 H) 5.92 (s, 1 H) 5.68 (d, 1 H) 4.46 - 4.57 (m, 2H) 3.49 - 3.58 (m, 1 H) 3.38 - 3.49 (m, 2H) 3.16 - 3.27 (m, 2H) 2.81 - 2.92 (m, 1 H) 2.57 - 2.68 (m, 6H) 2.32 (s, 3H) 2.24 (s, 3H) 1.86 - 1.95 (m, 2H) 1.71 - 1.82 (m, 3H) 1.17 (d, 3H).
Example (minor reαioisomer): 4-(6-Methyl-4-fr(1 /?V1-methyl-2-fr(2.4.6- trimethylphenyl)sulfonyllamino)ethyllamino)-1 H-indazol-1-yl)-N-r(3S)-2-oxo-3- pyrrolidinyllbenzamide
Figure imgf000075_0001
The product was purified on a Waters Micromass Preparative LCMS system as follows:
• Column: 100 x 21.2mm ID, 5μm Luna C18 (2)
• Flow Rate: 20ml/min
• Injection Volume: 335μl
• Temp: RT
• UV Detection Range: 215 to 330nm
Solvents: A: 0.1% Trifluoroacetic Acid in Water.
B: 0.05% v/v Trifuoroacetic Acid in Acetonitrile
Figure imgf000075_0002
Yield; 3.5mg.
LCMS (system B): tRET = 1.1 min, MH+ 589.
1H NMR (400 MHz, DMSOd6) δppm 8.76 (d, 1 H) 8.34 (s, 1 H) 8.04 (d, 2H) 7.79 -
7.90 (m, 3H) 7.67 (t, 1 H) 6.92 - 6.98 (m, 2H) 6.83 - 6.88 (m, 1 H) 6.02 (d, 1 H) 4.72 -
4.84 (m, 1 H) 4.54 - 4.64 (m, 1 H) 3.53 - 3.63 (m, 1 H) 3.22 - 3.30 (m, 2H) 2.90 - 3.02
(m, 1 H) 2.64 - 2.76 (m, 2H) 2.56 (s, 6H) 2.30 - 2.39 (m, 4H) 2.22 (s, 3H) 1.18 (d, 3H). Example 4 (minor regioisomer): Λ/-[(1 S)-2-Amino-1-methyl-2-oxoethyll-4-(6- methyl-4-{r(1 /?)-1-methyl-2-{r(2,4,6-trimethylphenyl)sulfonyllamino)ethyllamino)-1 H- indazol-1 -vDbenzamide
Figure imgf000076_0001
The product was purified on a Waters Micromass Preparative LCMS system as follows:
• Column: 100 x 21.2mm ID, 5μm Luna C18 (2)
• Flow Rate: 20ml/min
• Injection Volume: 335μl
• Temp: RT
• UV Detection Range: 215 to 330nm
Solvents: A: 0.1% Trifluoroacetic Acid in Water.
B: 0.05% v/v Trifuoroacetic Acid in Acetonitrile
Figure imgf000076_0002
Yield; 2.5mg.
LCMS (system B): tRET 1.13 min, MH+ 577.
1H NMR (400 MHz, DMSOd6) δppm 8.49 (d, 1 H) 8.34 (s, 1 H) 8.07 (d, 2H) 7.81 (d,
2H) 7.60 - 7.71 (m, 1 H) 7.40 (s, 1 H) 6.96 (s, 2H) 6.85 (s, 1 H) 6.02 (d, 1 H) 4.40 - 4.48 (m, 1 H) 3.54 - 3.63 (m, 1 H) 2.90 - 3.01 (m, 1 H) 2.66 - 2.75 (m, 1 H) 2.56 (s, 3H) 2.32 (s, 3H) 2.22 (s, 3H) 1.35 (d, 3H) 1.17 (d, 3H).
Example 5: Λ/-(1 ,1-Dioxidotetrahvdro-3-thienyl)-4-(6-methyl-4-{r(2S)-2-{r(2,4,6- trimethylphenyl)sulfonyl1amino)propyl1amino)-1 H-indazol-1-yl)benzamide
Figure imgf000077_0001
LCMS (system B): tRET = 1.17 min, MH+ 624.
1H NMR (600 MHz, DMSOd6) δppm 8.83 (d, 1 H) 8.27 (s, 1 H) 8.04 (d, 2H) 7.85 (d, 2H) 7.59 (d, 1 H) 6.86 (s, 2H) 6.83 (s, 1 H) 6.43 (t, 1 H) 5.85 (s, 1 H) 4.70 - 4.76 (m, 1 H) 3.48 - 3.56 (m, 2H) 3.16 - 3.23 (m, 4H) 3.05 - 3.13 (m, 2H) 2.55 (s, 6H) 2.29 (s, 3H) 2.13 (s, 3H) 1.04 (d, 3H).
Example 6: 4-(6-Methyl-4-f[(2SV2-fr(2.4.6- trimethylphenyl)sulfonyllamino)propyllamino)-1 H-indazol-1-yl)-N-r(3S)-2-oxo-3- pyrrolidinyllbenzamide
Figure imgf000077_0002
LCMS: tRET = 3.24 min, MH+ 589.
1H NMR (600 MHz, DMSOd6) δ ppm 8.76 (d, 1 H) 8.26 (s, 1 H) 8.05 (d, 2H) 7.81 - 7.88 (m, 3H) 7.59 (d, 1 H) 6.85 (s, 2H) 6.82 - 6.84 (m, 1 H) 6.43 (t, 1 H) 5.85 (s, 1 H) 4.59 (s, 1 H) 3.22 - 3.29 (m, 3H) 3.15 - 3.20 (m, 2H) 3.02 - 3.09 (m, 1 H) 2.55 (s, 6H) 2.30 (s, 3H) 2.13 (s, 3H) 2.01 - 2.09 (m, 1 H) 1.01 - 1.07 (m, 3H).
Example 7: Λ/-K1 S)-2-Amino-1-methyl-2-oxoethyll-4-(6-methyl-4-{r(2S)-2-{r(2 ,4,6- trimethylphenyl)sulfonyl1amino)propyl1amino)-1 H-indazol-1-yl)benzamide
Figure imgf000078_0001
LCMS: tRET = 3.25min, MH+ 577.
1H NMR (600 MHz, DMSOd6) δppm 8.52 (d, 1 H) 8.27 (s, 1 H) 8.08 (d, 2H) 7.82 (d, 2H) 7.61 (d, 1 H) 7.42 (s, 1 H) 6.85 (s, 2H) 6.82 (s, 1 H) 6.44 (t, 1 H) 4.41 - 4.48 (m, 1 H) 3.14 - 3.21 (m, 1 H) 3.02 - 3.10 (m, 1 H) 2.54 (s, 6H) 2.29 (s, 3H) 2.11 (s, 3H) 1.36 (d, 3H) 1.03 (d, 3H).
Example 8: /V-KI S)-2-{ri-(3-{r4-(hvdroxymethyl)-1-piperidinyllcarbonyl)phenyl)-6- methyl-1 H-indazol-4-yllamino)-1-methylethyll-2,4,6-trimethylbenzenesulfonamide
Figure imgf000078_0002
LCMS (system B): tRET = 1.17min, MH+ 507.
1H NMR (600 MHz, DMSOd6) δppm 8.23 (s, 1 H) 7.77 (d, 1 H) 7.57 - 7.64 (m, 3H) 7.32 (d, 1 H) 6.88 (s, 2H) 6.73 (s, 1 H) 5.84 (s, 1 H) 3.36 - 3.44 (m, 2H) 3.26 - 3.33 (m, 2H) 3.14 - 3.21 (m, 3H) 3.03 - 3.10 (m, 2H) 2.75 - 2.82 (m, 1 H) 2.55 (s, 6H) 2.29 (s, 3H) 2.14 (s, 3H) 1.59 - 1.82 (m, 3H) 1.03 (d, 3H).
Example 9: 3-(6-Methyl-4-{r(2S)-2-{[(2,4,6- trimethylphenyl)sulfonyl1amino)propyl1amino)-1 H-indazol-1-yl)-N-[(3S)-2-oxo-3- pyrrolidinylibenzamide
Figure imgf000078_0003
LCMS (system B): tRET = 1.12min, MH+ 507. 1H NMR (600 MHz, DMSOd6) δppm 8.83 - 8.90 (m, 1H) 8.26 (s, 1H) 8.19 (s, 1H)
7.83 - 7.89 (m, 3H) 7.62 - 7.68 (m, 1H) 7.55 - 7.61 (m, 1H) 6.88 (s, 2H) 6.75 (s, 1H)
5.84 (s, 1H) 4.56 - 4.62 (m, 1H) 3.35 - 3.42 (m, 2H) 3.21 - 3.28 (m, 2H) 3.14 - 3.21 (m, 2H) 3.02 - 3.09 (m, 1H) 2.52 - 2.58 (m, 6H) 2.33 - 2.40 (m, 1H) 2.29 (s, 3H) 2.15 (s, 3H) 2.02 - 2.08 (m, 1 H) 1.03 (s, 3H).
Example 10 (Diasteriomer 1):N-r(1SV2-fri-(3-fr3-(Hvdroxymethvn-1- piperidinyllcarbonyl)phenyl)-6-methyl-1H-indazol-4-yllamino)-1-methylethyll-2,4,6- trimethylbenzenesulfonamide
Figure imgf000079_0001
Example 10 was separated on chiral pak AD, mobile phase; 30% EtOH/heptane; tRET = 14.0min.
Yield 5.2mg.
LCMS: tRET = 3.4min, MH+ 604,.
1H NMR (250 MHz, DMSOd6) δppm 8.27 (s, 1H) 7.77 (d, 1H) 7.53 - 7.68 (m, 3H)
7.33 (d, 1H) 6.89 (s, 2H) 6.76 (s, 1H) 6.40 (t, 1H) 5.85 (s, 1H) 4.39 - 4.58 (m, 1H)
3.13 - 3.24 (m, 2H) 3.04 - 3.11 (m, 1H) 2.56 (s, 6H) 2.28 (s, 3H) 2.15 (s, 3H) 1.13 -
1.82 (m, 5H) 1.04 (d, 3H).
Example 11 (Diasteriomer 2): /V-r(1S)-2-{[1 -(3-{r3-(Hydroxymethyl)-1 - piperidinyl1carbonyl)phenyl)-6-methyl-1H-indazol-4-yl1amino)-1-methylethyl1-2,4,6- trimethylbenzenesulfonamide
Figure imgf000079_0002
Example 11 was separated on chiral pak AD, mobile phase; 30% EtOH/heptane; tRET = 18.0min. Yield 4.2mg.
LCMS: tRET = 3.4min, MH+ 604.
1H NMR (250 MHz, DMSOd6) δppm 8.23 (s, 1H) 7.77 (d, 1H) 7.53 - 7.68 (m, 3H)
7.33 (d, 1H) 6.88 (s, 2H) 6.76 (s, 1H) 6.40 (t, 1H) 5.84 (s, 1H) 4.39 - 4.58 (m, 1H)
3.49 - 3.68 (m, 1H) 3.03 - 3.22 (m, 3H) 2.58 (s, 6H) 2.27 (s, 3H) 2.15 (s, 3H) 1.11 -
1.82 (m, 6H) 1.04 (s, 3H).
The following Examples of mixtures of formula (Ic) and formula (1d) were similarly prepared:
Figure imgf000080_0001
Figure imgf000080_0002
Figure imgf000081_0001
Figure imgf000082_0001
The following Examples were similarly prepared:
Figure imgf000082_0002
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
BIOLOGICAL EXAMPLES
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 and incubated at room temperature for 2hr 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. Dose response curves were constructed from which plC50 values were estimated.
Examples 1 , 2, 4-18 and 20-37 have shown glucocorticoid binding with a plC50 > 6.5 at least once in this assay.
Compounds possessing agonism in the NFkB assay, possessing reduced efficacy in the MMTV agonist assay and reduced activity at the progesterone receptor are believed to have the desired profile for providing anti-inflammatory activity with reduced side effect liability.
NFKB assay
A549 SPAP cells
Human Caucasian lung carcinoma A549 cell line (ECACC No. 86012804) has been stably transfected in house with a plasmid containing an ELAM promoter sequence that has a NFKB response element within it. Stimulation of the cell line with TNFα results in intracellular signal transduction and ultimately translocation of NFKB into the nucleus. This activates the inserted DNA sequence resulting in transcription of the integrated SPAP gene, which is quantified using a colorimetric assay. In this assay, GR agonist compounds inhibit NFKB driven transcription resulting in a decrease in signal. The stably transfected cell line was grown as a monolayer in DMEM supplemented with FCS-HI (10%), Non-essential amino acids (1 %), L- Glutamine (2mM), Pen/Strep (1%) and Geneticin (50mg/ml).
NFKB agonist assay A 70% confluent T225 flask of A549 SPAP cells was harvested by centrifugation for 5min at 20Og, resuspended in assay buffer (DMEM supplemented with 10% FCS 2xHI, 2mM L-Glutamine,1 % Pen/Strep and Non essential amino acids) and diluted to 0.16 x 106VmI. 60μl of cell solution was dispensed to each well of clear Nunc 384-well plates, containing compound at the required concentration. Plates were incubated for 1 h at 370C, 95% humidity, 5% CO2 before 10μl of TNFα was added at final concentration of 3.2ng/ml and then returned to the cell incubator for 15hr. Plates were equilibrated to room temperature for 1 h prior to the addition of 25μl of pNPP buffer (1 M Diethanolamine pH 9.8, 0.5mM MgCI2, 0.28M NaCI, 2mg/ml pNPP) to each well of assay plates. The plates were covered to protect the reagents from light, and then incubated at room temperature for approximately 1 hr before reading them on an Ascent using a 405nm single filter. Dose response curves were constructed from which plC50 values were estimated.
Examples 1-18 and 20-37 have shown plC50 values of >6 at least once in the NFkB assay.
MMTV Assay
A549 MMTV cells
Human Caucasian lung carcinoma A549 cell line (ECACC No. 86012804) has been stably transfected in house with a plasmid containing a renilla luciferase reporter with an MMTV promoter. Stimulation of the cell line with GR agonists results in intracellular signal transduction and ultimately translocation of GR into the nucleus. This activates the inserted DNA sequence resulting in transcription of the integrated luciferase gene, which is quantified using a light emission. The stably transfected cell line was grown as a monolayer in DMEM supplemented with FCS-HI (10%), Nonessential amino acids (1%), L-Glutamine (2mM), Pen/Strep (1 %) and Geneticin (50mg/ml).
MMTV Agonist assay
A 90% confluent T175 flask of A549 MMTV cells was harvested by centrifugation for 5min at 20Og, resuspended in assay buffer (DMEM supplemented with 10% FCS 2xHI, 2mM Glutamax, Non essential amino acids and 25mM HEPES) and diluted to 0.1 x 106/ml. 70μl of cell solution was dispensed to each well of white Nunc 384-well plates, containing compound at the required concentration. Plates were incubated for 6hr at 37 C, 95% humidity, 5% CO2. Plates were equilibrated to room temperature for 1 hr prior to the addition of 10μl of Renilla substrate to each well of assay plates. The plates were covered to protect the reagents from light, and then incubated at room temperature for approximately 15mins before reading them on a Viewlux. Dose response curves were constructed from which pEC50 and maximum asymptote values were estimated.
MMTV Antagonist assay
A 90% confluent T175 flask of A549 MMTV cells was harvested by centrifugation for 5min at 20Og, resuspended in assay buffer (DMEM supplemented with 10% FCS 2xHI, 2mM Glutamax, Non essential amino acids and 25mM HEPES) and diluted to 0.1 x 106/ml. Dexamethasone was added to the cell solution to a concentration of 15nM. From a 75uM dexamethasone stock (DMSO solvent) 2OuI was added per 100ml of assay media and cells. 70μl of cell solution was dispensed to each well of white Nunc 384-well plates, containing compound at the required concentration. Plates were incubated for 24hr at 370C, 95% humidity, 5% CO2. Plates were equilibrated to room temperature for 1 hr prior to the addition of 10μl of Renilla substrate to each well of assay plates. The plates were covered to protect the reagents from light, and then incubated at room temperature for approximately 15mins before reading them on a Viewlux. Dose response curves were constructed from which plC5o values were estimated.
The following examples are partial or full agonists (i.e. have an average maximum asymptote of > 20%) in the NFkB assay and are partial or efficacy selective agonists
(i.e. have an average maximum asymptote of >20% and < 85%) in the MMTV agonist assay:
Examples 1-10, 12-14, 16, 24 and 32.
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. 70ml of suspension cells were dispensed to each well of white Nunc 384- well plates, containing compounds at the required concentration. After 24hr 10μl of Steadylite were added to each well of the plates. Plates were incubated in the dark for 10min before reading them on a Viewlux reader. Dose response curves were constructed from which pEC50 values were estimated.
Examples 1-6, 8-13, 15, 16, 18, 19, 21 , 22, 25, 26, 29, 32, 33, 35 and 36 have shown an average pEC50 ≤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 enantiomer may have similar activity, less activity, no activity or may have some antagonist activity in the case of a functional assay.
Throughout the specification and the claims which follow, unless the context requires otherwise, the word 'comprise', and variations such as 'comprises' and 'comprising', will be understood to imply the inclusion of a stated integer or step or group of integers but not to the exclusion of any other integer or step or group of integers or steps.
The application of which this description and claims forms part may be used as a basis for priority in respect of any subsequent application. The claims of such subsequent application may be directed to any feature or combination of features described herein. They may take the form of product, composition, process, or use claims and may include, by way of example and without limitation, the following claims.
The patents, patent applications and other references described in this application are herein incorporated by reference.

Claims

1. A compound of formula (I):
Figure imgf000092_0001
wherein
A is selected from the following groups:
Figure imgf000092_0002
(iv)
(ii)
Figure imgf000092_0003
(V) (vi)
X is selected from NH, CH2, S, S(O), S(O)2 and O;
R1 is selected from -C(O)N(R2)C(R3)(R4)C(O)NH2, -C(O)NHCH2CH(OH)CH3, - C(O)NHC3-6cycloalkyl, -C(O)NHheterocyclyl and -C(O)NR8R9 wherein R8 and R9 together with the nitrogen atom to which they are attached are linked to form a heterocyclyl and wherein each heterocyclyl is optionally substituted by 1 or 2 groups independently selected from oxo, -C(O)NH2 and -CH2OH;
R2, R3, R4, R5, R6 and R7 are each independently selected from hydrogen and methyl; or a salt thereof.
2. A compound according to claim 1 wherein A is group (i):
Figure imgf000093_0001
(i)
3. A compound according to claim 1 or claim 2 wherein X is NH.
4. A compound according to any one of claims 1 to 3 wherein R1 is -C(O)N(R2)C(R3)(R4)C(O)NH2.
5. A compound according to claim 4 wherein R2 and R3 are each hydrogen and R4 is methyl.
6. A compound according to any one of claims 1 to 3 wherein R1 is -C(O)NHC3- 6cycloalkyl.
7. A compound according to claim 6 wherein the C3-6cycloalkyl group is cyclopropyl.
8. A compound according to any one of claims 1 to 3 wherein R1 is - C(O)NHheterocyclyl.
9. A compound according to claim 8 wherein the heterocyclyl contains 1 heteroatom.
10. A compound according to claim 9 wherein the heteroatom is selected from sulphur and nitrogen.
11. A compound according to claim 9 or claim 10 wherein the heterocyclyl is selected from tetrahydrothienyl and pyrrolidinyl.
12. A compound according to any one of claims 8 to 11 wherein the heterocyclyl is substituted by 1 or 2 oxo groups.
13. A compound according to any one of claims 1 to 3 wherein R1 is -C(O)NR8R9 wherein R8 and R9 together with the nitrogen atom to which they are attached are linked to form a heterocyclyl wherein the heterocyclyl is selected from pyrrolidinyl and piperidinyl.
14. A compound according to claim 13 wherein the heterocyclyl is substituted by one -CH2OH group.
15. A compound according to any one of the preceding claims wherein R5 is hydrogen and R6 is methyl.
16. A compound according to any one of claims 1 to 14 wherein R5 is methyl and R6 is hydrogen.
17. A compound according to any one of the preceding claims wherein R7 is methyl.
18. A compound substantially as described in any one of Examples 1 to 37, or a salt thereof.
19. A compound which is:
Λ/-((2R)-2-{[1-(4-{[4-(hydroxymethyl)-1-piperidinyl]carbonyl}phenyl)-6-methyl-1 H- indazol-4-yl]amino}propyl)-2,4,6-trimethylbenzenesulfonamide; Λ/-((1 S)-2-{[1-(3-{[2-(hydroxymethyl)-1-piperidinyl]carbonyl}phenyl)-6-methyl-1 H- indazol-4-yl]amino}-1-methylethyl)-2,4,6-trimethylbenzenesulfonamide; 4-(6-methyl-4-{[(1 /?)-1-methyl-2-{[(2,4,6-trimethylphenyl)sulfonyl]amino}ethyl]amino}- 1 H-indazol-1-yl)-N-[(3S)-2-oxo-3-pyrrolidinyl]benzamide; Λ/-[(1 S)-2-amino-1-methyl-2-oxoethyl]-4-(6-methyl-4-{[(1 R)-1-methyl-2-{[(2!4,6- trimethylphenyl)sulfonyl]amino}ethyl]amino}-1H-indazol-1-yl)benzamide; /V-(1 ,1-dioxidotetrahydro-3-thienyl)-4-(6-methyl-4-{[(2S)-2-{[(2!4,6- trimethylphenyl)sulfonyl]amino}propyl]amino}-1H-indazol-1-yl)benzamide; 4-(6-methyl-4-{[(2S)-2-{[(2,4,6-trimethylphenyl)sulfonyl]amino}propyl]amino}-1 H- indazol-1-yl)-Λ/-[(3S)-2-oxo-3-pyrrolidinyl]benzamide; Λ/-[(1 S)-2-amino-1-methyl-2-oxoethyl]-4-(6-methyl-4-{[(2S)-2-{[(2!4,6- trimethylphenyl)sulfonyl]amino}propyl]amino}-1 H-indazol-1-yl)benzamide; Λ/-[(1 S)-2-{[1-(3-{[4-(hydroxymethyl)-1-piperidinyl]carbonyl}phenyl)-6-methyl-1 H- indazol-4-yl]amino}-1-methylethyl]-2,4,6-trimethylbenzenesulfonamide; 3-(6-methyl-4-{[(2S)-2-{[(2,4,6-trimethylphenyl)sulfonyl]amino}propyl]amino}-1 H- indazol-1-yl)-N-[(3S)-2-oxo-3-pyrrolidinyl]benzamide; Λ/-[(1 S)-2-{[1-(3-{[3-(hydroxymethyl)-1-piperidinyl]carbonyl}phenyl)-6-methyl-1 H- indazol-4-yl]amino}-1-methylethyl]-2,4,6-trimethylbenzenesulfonamide; Λ/-[(1 S)-2-{[1-(3-{[3-(hydroxymethyl)-1-piperidinyl]carbonyl}phenyl)-6-methyl-1 H- indazol-4-yl]amino}-1-methylethyl]-2,4,6-trimethylbenzenesulfonamide; or a salt thereof.
20. A compound according to claim 19 which is:
Λ/-[(1 S)-2-amino-1-methyl-2-oxoethyl]-4-(6-methyl-4-{[(1 R)-1-methyl-2-{[(2!4,6- trimethylphenyl)sulfonyl]amino}ethyl]amino}-1 H-indazol-1-yl)benzamide; 4-(6-methyl-4-{[(2S)-2-{[(2,4,6-trimethylphenyl)sulfonyl]amino}propyl]amino}-1 H- indazol-1-yl)-Λ/-[(3S)-2-oxo-3-pyrrolidinyl]benzamide; /V-[(1 S)-2-amino-1-methyl-2-oxoethyl]-4-(6-methyl-4-{[(2S)-2-{[(2,4,6- trimethylphenyl)sulfonyl]amino}propyl]amino}-1 H-indazol-1-yl)benzamide; Λ/-[(1 S)-2-{[1-(3-{[4-(hydroxymethyl)-1-piperidinyl]carbonyl}phenyl)-6-methyl-1 H- indazol-4-yl]amino}-1-methylethyl]-2,4,6-trimethylbenzenesulfonamide; Λ/-[(1 S)-2-{[1-(3-{[3-(hydroxymethyl)-1-piperidinyl]carbonyl}phenyl)-6-methyl-1 H- indazol-4-yl]amino}-1-methylethyl]-2,4,6-trimethylbenzenesulfonamide; Λ/-[(1 S)-2-{[1-(3-{[3-(hydroxymethyl)-1-piperidinyl]carbonyl}phenyl)-6-methyl-1 H- indazol-4-yl]amino}-1-methylethyl]-2,4,6-trimethylbenzenesulfonamide; or a salt thereof.
21. A compound as claimed in any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, for use in therapy.
22. A compound as claimed in any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, for use in the treatment of patients with an inflammatory and/or allergic condition.
23. A compound as claimed in any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, for use in the treatment of patients with rheumatoid arthritis, asthma, COPD, allergy and/or rhinitis.
24. A compound as claimed in any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, for use in the treatment of patients with skin disease.
25. A compound as claimed in any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, for use in the treatment of patients with eczema, psoriasis, allergic dermatitis, neurodermatitis, pruritis and/or hypersensitivity reactions.
26. Use of a compound as claimed in any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of patients with an inflammatory and/or allergic condition.
27. Use of a compound as claimed in any one of claims 1 to 20, 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.
28. Use of a compound as claimed in any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of patients with skin disease.
29. Use of a compound as claimed in any one of claims 1 to 20, 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.
30. 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 20 or a pharmaceutically acceptable salt thereof.
31. 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 20 or a pharmaceutically acceptable salt thereof.
32. 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 20 or a pharmaceutically acceptable salt thereof.
33. 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 20 or a pharmaceutically acceptable salt thereof.
34. A pharmaceutical composition comprising a compound of formula (I) as claimed in any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, in admixture with one or more pharmaceutically acceptable diluents or carriers.
35. A process for the preparation of a compound of formula (I) as claimed in any one of claims 1 to 20 comprising coupling of a carboxylic acid of formula (II):
Figure imgf000097_0001
(II)
with an amine of formula NH(R2)C(R3)(R4)C(O)NH2, NH2CH2CH(OH)CH3, NH2C3- βcycloalkyl, NH2heterocyclyl or NHR8R9 wherein A, R2, R3, R4, R5, R6, R7, R8, R9 and X are as defined in claim 1.
36. A compound of formula (II)
Figure imgf000097_0002
(N) wherein A, R , R , R and X are as defined in claim 1.
PCT/EP2008/067160 2007-12-12 2008-12-10 N- (2 { [1-phenyl-1h-indaz0l-4-yl] amino} propyl) -sulfonamide derivatives as non-steroidal glucocorticoid receptor ligands for the treatment of inflammations WO2009074590A1 (en)

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