WO2010018132A1 - Composés - Google Patents

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Publication number
WO2010018132A1
WO2010018132A1 PCT/EP2009/060264 EP2009060264W WO2010018132A1 WO 2010018132 A1 WO2010018132 A1 WO 2010018132A1 EP 2009060264 W EP2009060264 W EP 2009060264W WO 2010018132 A1 WO2010018132 A1 WO 2010018132A1
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WO
WIPO (PCT)
Prior art keywords
compound
formula
pharmaceutically acceptable
purin
pyran
Prior art date
Application number
PCT/EP2009/060264
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English (en)
Inventor
Sebastien Andre Campos
Diane Mary Coe
Stephen Allan Smith
Naimisha Trivedi
Original Assignee
Smithkline Beecham Corporation
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Publication date
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Publication of WO2010018132A1 publication Critical patent/WO2010018132A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/16—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two nitrogen atoms

Definitions

  • the present invention relates to compounds, processes for their preparation, compositions containing them, to their use in the treatment of various disorders in particular allergic diseases and other inflammatory conditions for example allergic rhinitis and asthma, infectious diseases, cancer, and as vaccine adjuvants.
  • allergic diseases and other inflammatory conditions for example allergic rhinitis and asthma, infectious diseases, cancer, and as vaccine adjuvants.
  • Allergic diseases are associated with a Th2-biased immune-response to allergens.
  • Th2 responses are associated with raised levels of IgE, which, via its effects on mast cells, promotes a hypersensitivity to allergens, resulting in the symptoms seen, for example, in allergic rhinitis.
  • IgE immune-response to allergens
  • Th2/Th1 regulatory T cell response.
  • TLR7 ligands have been shown to reduce Th2 cytokine and enhance Th1 cytokine release in vitro and to ameliorate Th2-type inflammatory responses in allergic lung models in vivo (FiIi L. et al, J. All. Clin. Immunol., 2006: 118, 511-517; Moisan J.
  • interferon combinations can be highly effective at reducing viral load and in some subjects in eliminating viral replication.
  • many patients fail to show a sustained viral response and in these patients viral load is not controlled.
  • therapy with injected interferon may be associated with a number of unwanted adverse effects which are shown to affect compliance (Dudley T, et al, Gut, 2006: 55(9), 1362-3).
  • pDCs plasmacytoid dendritic cells
  • TLR7 and TLR9 plasmacytoid dendritic cells
  • stimulation of these receptors with viral RNA or DNA respectively can induce expression of interferon alpha.
  • R 1 is C 1-6 alkylamino, or C 1-6 alkoxy; m is an integer having a value of 2 or 3; n is an integer having a value of 0 to 3; p is an integer having a value of 1 or 2; and salts thereof.
  • n is 2.
  • n 1
  • a method of treatment of allergic diseases and other inflammatory conditions, infectious diseases, and cancer comprises administering to a human subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • a method of treatment of allergic rhinitis comprises administering to a human subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • a method of treatment of asthma comprises administering to a human subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable diluents or carriers.
  • a process for preparing a pharmaceutical composition which comprises admixing a compound of formula (I), or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable diluents or carriers.
  • R 1 , m, n, and p are as hereinbefore defined for a compound of formula (I) and R 2 is C 1-6 alkyl, and thereafter, if required, carrying out one or more of the following optional steps:
  • Salts may be formed using techniques well-known in the art, for example by precipitation from solution followed by filtration, or by evaporation of the solvent.
  • a pharmaceutically acceptable acid addition salt can be formed by reaction of a compound of formula (I) with a suitable strong acid (such as hydrobromic, hydrochloric, sulphuric, p-toluenesulphonic, methanesulphonic or naphthalenesulphonic acids), optionally in a suitable solvent such as an organic solvent, to give the salt which is usually isolated for example by crystallisation and filtration.
  • a suitable strong acid such as hydrobromic, hydrochloric, sulphuric, p-toluenesulphonic, methanesulphonic or naphthalenesulphonic acids
  • solvates complexes with solvents in which they are reacted or from which they are precipitated or crystallised. These complexes are known as "solvates".
  • a complex with water is known as a "hydrate”.
  • Solvents with high boiling points and/or solvents with a high propensity to form hydrogen bonds such as water, ethanol, /so-propyl alcohol, and N- methyl pyrrolidinone may be used to form solvates.
  • Methods for the identification of solvated include, but are not limited to, NMR and microanalysis.
  • Solvates of the compounds of formula (I) are within the scope of the invention.
  • the term solvate encompasses solvates of both a free base compound as well as any salt thereof.
  • Certain of the compounds of the invention may exist in tautomeric forms. It will be understood that the present invention encompasses all of the tautomers of the compounds of the invention whether as individual tautomers or as mixtures thereof.
  • the compounds of the invention may be in crystalline or amorphous form. Furthermore, some of the crystalline forms of the compounds of the invention may exist as polymorphs, all of which are included within the scope of the present invention. The most thermodynamically stable polymorphic form or forms of the compounds of the invention are of particular interest.
  • the compounds of formula (I) and pharmaceutically acceptable salts thereof may also be useful, as stand-alone or in combination as an adjuvant, in the treatment and/or prevention of immune-mediated disorders, including but not limited to inflammatory or allergic diseases such as asthma, allergic rhinitis and rhinoconjuctivitis, food allergy, hypersensitivity lung diseases, eosinophilic pneumonitis, delayed-type hypersensitivity disorders, atherosclerosis, pancreatitis, gastritis, colitis, osteoarthritis, psoriasis, sarcoidosis, pulmonary fibrosis, respiratory distress syndrome, bronchiolitis, chronic obstructive pulmonary disease, sinusitis, cystic fibrosis, actinic keratosis, skin dysplasia, chronic urticaria, eczema and all types of dermatitis.
  • inflammatory or allergic diseases such as asthma, allergic rhinitis and rhinoconjuctivitis, food allergy, hypersensitivity lung diseases, eos
  • the compounds of formula (I) and pharmaceutically acceptable salts thereof may also be useful in the treatment of infectious diseases including, but not limited to, those caused by hepatitis viruses (e.g. hepatitis B virus, hepatitis C virus), human immunodeficiency virus, papillomaviruses, herpesviruses, respiratory viruses (e.g. influenza viruses, respiratory syncytial virus, rhinovirus, metapneumovirus, parainfluenzavirus, SARS), and West Nile virus.
  • hepatitis viruses e.g. hepatitis B virus, hepatitis C virus
  • human immunodeficiency virus papillomaviruses
  • herpesviruses papillomaviruses
  • respiratory viruses e.g. influenza viruses, respiratory syncytial virus, rhinovirus, metapneumovirus, parainfluenzavirus, SARS
  • West Nile virus e.g. influenza viruses, respiratory syncytial virus,
  • the compounds of formula (I) and pharmaceutically acceptable salts thereof may also be useful in the treatment of various cancers, in particular the treatment of cancers that are known to be responsive to immunotherapy and including, but not limited to, renal cell carcinoma, lung cancer, breast cancer, colorectal cancer, bladder cancer, melanoma, leukaemia, lymphomas and ovarian cancer.
  • compounds of formula (I) and pharmaceutically acceptable salts thereof may be useful as therapeutic agents.
  • the compounds of formula (I) and pharmaceutically acceptable salts thereof may be formulated for administration in any convenient way.
  • the compounds of formula (I) and pharmaceutically acceptable salts thereof may, for example, be formulated for oral, topical, inhaled, intranasal, buccal, parenteral (for example intravenous, subcutaneous, intradermal, or intramuscular) or rectal administration.
  • the compounds of formula (I) and pharmaceutically acceptable salts thereof are formulated for oral administration.
  • the compounds of formula (I) and pharmaceutically acceptable salts thereof are formulated for topical administration, for example intranasal or inhaled administration.
  • Tablets and capsules for oral administration may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch, cellulose or polyvinyl pyrrolidone; fillers, for example, lactose, microcrystalline cellulose, sugar, maize starch, calcium phosphate or sorbitol; lubricants, for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica; disintegrants, for example, potato starch, croscarmellose sodium or sodium starch glycollate; or wetting agents such as sodium lauryl sulphate.
  • the tablets may be coated according to methods well known in the art.
  • compositions for intranasal administration include aqueous compositions administered to the nose by drops or by pressurised pump. Suitable compositions contain water as the diluent or carrier for this purpose.
  • Compositions for administration to the lung or nose may contain one or more excipients, for example one or more suspending agents, one or more preservatives, one or more surfactants, one or more tonicity adjusting agents, one or more co-solvents, and may include components to control the pH of the composition, for example a buffer system. Further, the compositions may contain other excipients such as antioxidants, for example sodium metabisulphite, and taste-masking agents. Compositions may also be administered to the nose or other regions of the respiratory tract by nebulisation.
  • Intranasal compositions may permit the compound(s) of formula (I) or (a) pharmaceutically acceptable salt(s) thereof to be delivered to all areas of the nasal cavities (the target tissue) and further, may permit the compound(s) of formula (I) or (a) pharmaceutically acceptable salt(s) thereof to remain in contact with the target tissue for longer periods of time.
  • a suitable dosing regime for intranasal compositions would be for the patient to inhale slowly through the nose subsequent to the nasal cavity being cleared. During inhalation the composition would be administered to one nostril while the other is manually compressed. This procedure would then be repeated for the other nostril. Typically, one or two sprays per nostril would be administered by the above procedure one, two, or three times each day, ideally once daily.
  • intranasal compositions suitable for once-daily administration are particularly useful for once-daily administration.
  • Examples of pharmaceutically acceptable anti-microbial agents or preservatives include, but are not limited to, quaternary ammonium compounds (for example benzalkonium chloride, benzethonium chloride, cetrimide, cetylpyridinium chloride, lauralkonium chloride and myristyl picolinium chloride), mercurial agents (for example phenylmercuric nitrate, phenylmercuric acetate and thimerosal), 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, chlorocresol, sorbic acid and its salts (such as potassium sorbate) and polymyxin.
  • quaternary ammonium compounds for example benzalkonium chloride, benzethonium chloride,
  • Examples of pharmaceutically acceptable anti-fungal agents or preservatives include, but are not limited to, sodium benzoate, sorbic acid, sodium propionate, methylparaben, ethylparaben, propylparaben and butylparaben.
  • the preservative(s), if included, may be present in an amount of from 0.001 to 1% (w/w), such as from 0.015% to 0.5% (w/w) based on the total weight of the composition.
  • compositions may include one or more surfactants which functions to facilitate dissolution of the medicament particles in the aqueous phase of the composition.
  • the amount of surfactant used is an amount which will not cause foaming during mixing.
  • pharmaceutically acceptable surfactants include fatty alcohols, esters and ethers, such as polyoxyethylene (20) sorbitan monooleate (Polysorbate 80), macrogol ethers, and poloxamers.
  • the surfactant may be present in an amount of between about 0.01 to 10% (w/w), such as from 0.01 to 0.75% (w/w), for example about 0.5% (w/w), based on the total weight of the composition.
  • One or more tonicity adjusting agent(s) may be included to achieve tonicity with body fluids e.g. fluids of the nasal cavity, resulting in reduced levels of irritancy.
  • pharmaceutically acceptable tonicity adjusting agents include, but are not limited to, sodium chloride, dextrose, xylitol, calcium chloride, glucose, glycerine and sorbitol.
  • a tonicity-adjusting agent, if present, may be included in an amount of from 0.1 to 10% (w/w), such as from 4.5 to 5.5% (w/w), for example about 5.0% (w/w), based on the total weight of the composition.
  • compositions of the invention may be buffered by the addition of suitable buffering agents such as sodium citrate, citric acid, trometamol, phosphates such as disodium phosphate (for example the dodecahydrate, heptahydrate, dihydrate and anhydrous forms), or sodium phosphate and mixtures thereof.
  • suitable buffering agents such as sodium citrate, citric acid, trometamol, phosphates such as disodium phosphate (for example the dodecahydrate, heptahydrate, dihydrate and anhydrous forms), or sodium phosphate and mixtures thereof.
  • a buffering agent if present, may be included in an amount of from 0.1 to 5% (w/w), for example 1 to 3% (w/w) based on the total weight of the composition.
  • taste-masking agents include sucralose, sucrose, saccharin or a salt thereof, fructose, dextrose, glycerol, 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.
  • co-solvent(s) may be included to aid solubility of the medicament compound(s) and/or other excipients.
  • pharmaceutically acceptable co- solvents include, but are not limited to, propylene glycol, dipropylene glycol, ethylene glycol, glycerol, ethanol, polyethylene glycols (for example PEG300 or PEG400), and methanol.
  • the co-solvent is propylene glycol.
  • Co-solvent(s), if present, may be included in an amount of from 0.05 to 30% (w/w), such as from 1 to 25% (w/w), for example from 1 to 10% (w/w) based on the total weight of the composition.
  • a fluid dispenser may typically be used to deliver a fluid composition to the nasal cavities.
  • the fluid composition may be aqueous or non-aqueous, but typically aqueous.
  • Such a fluid dispenser may have 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.
  • Aqueous compositions containing a compound of formula (I) or a pharmaceutically acceptable salt thereof may also be delivered by a pump as disclosed in International Patent Application publication number WO2007/138084 (Glaxo Group Limited), for example as disclosed with reference to Figures 22-46 thereof, or as disclosed in United Kingdom patent application number GB0723418.0 (Glaxo Group Limited), for example as disclosed with reference to Figures 7-32 thereof.
  • the pump may be actuated by an actuator as disclosed in Figures 1-6 of GB0723418.0.
  • Dry powder compositions for topical delivery to the lung by inhalation may, for example, be presented in capsules and cartridges of for example gelatine, or blisters of for example laminated aluminium foil, for use in an inhaler or insufflator.
  • Powder blend compositions generally contain a powder mix for inhalation of the compound of formula (I) or a pharmaceutically acceptable salt thereof and a suitable powder base (carrier/diluent/excipient substance) such as mono-, di-, or polysaccharides (for example lactose or starch).
  • a composition suitable for inhaled administration may be incorporated into a plurality of sealed dose containers provided on medicament pack(s) mounted inside a suitable inhalation device.
  • the containers may be rupturable, peelable, or otherwise openable one-at-a-time and the doses of the dry powder composition administered by inhalation on a mouthpiece of the inhalation device, as known in the art.
  • the medicament pack may take a number of different forms, for instance a disk-shape or an elongate strip.
  • Representative inhalation devices are the DISKHALERTM and DISKUSTM devices, marketed by GlaxoSmithKline.
  • a dry powder inhalable composition may also be provided as a bulk reservoir in an inhalation device, the device then being provided with a metering mechanism for metering a dose of the composition from the reservoir to an inhalation channel where the metered dose is able to be inhaled by a patient inhaling at a mouthpiece of the device.
  • exemplary marketed devices of this type are TURBUHALERTM (AstraZeneca), TWISTHALERTM (Schering) and CLICKHALERTM (Innovata.)
  • a further delivery method for a dry powder inhalable composition is for metered doses of the composition to be provided in capsules (one dose per capsule) which are then loaded into an inhalation device, typically by the patient on demand.
  • the device has means to rupture, pierce or otherwise open the capsule so that the dose is able to be entrained into the patient's lung when they inhale at the device mouthpiece.
  • ROTAHALERTM GaxoSmithKline
  • HANDIHALERTM Boehringer Ingelheim.
  • Pressurised aerosol compositions suitable for inhalation can be either a suspension or a solution and may contain a compound of formula (I) or a pharmaceutically acceptable salt thereof and a suitable propellant such as a fluorocarbon or hydrogen- containing chlorofluorocarbon or mixtures thereof, particularly hydrofluoroalkanes, especially 1 ,1 ,1 ,2-tetrafluoroethane, 1 ,1 ,1 ,2,3,3,3-heptafluoro-n-propane or a mixture thereof.
  • the aerosol composition may optionally contain additional composition excipients well known in the art such as surfactants e.g. oleic acid, lecithin or an oligolactic acid or derivative thereof e.g.
  • 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, wool-fat, beeswax, carboxypolymethylene and cellulose derivatives, and/or glyceryl monostearate and/or non-ionic emulsifying 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) and pharmaceutically acceptable salts thereof may, for example, be formulated for transdermal delivery by composition into patches or other devices (e.g. pressurised gas devices) which deliver the active component into the skin.
  • the compounds of formula (I) and pharmaceutically acceptable salts thereof may also be formulated as suppositories, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
  • compositions may contain antibody(ies) or antibody fragment(s) or an antigenic component including but not limited to protein, DNA, live or dead bacteria and/or viruses or virus-like particles, together with one or more components with adjuvant activity including but not limited to aluminium salts, oil and water emulsions, heat shock proteins, lipid A preparations and derivatives, glycolipids, other TLR agonists such as CpG DNA or similar agents, cytokines such as GM-CSF or IL-12 or similar agents.
  • antibody(ies) or antibody fragment(s) or an antigenic component including but not limited to protein, DNA, live or dead bacteria and/or viruses or virus-like particles, together with one or more components with adjuvant activity including but not limited to aluminium salts, oil and water emulsions, heat shock proteins, lipid A preparations and derivatives, glycolipids, other TLR agonists such as CpG DNA or similar agents, cytokines such as GM-CSF or IL-12 or similar agents.
  • the compounds of formula (I) and pharmaceutically acceptable salts thereof may also be used in combination with one or more other agents which may be useful in the prevention or treatment of viral infections for example immune therapies (e.g. interferon or other cytokines/chemokines, cytokine/chemokine receptor modulators, cytokine agonists or antagonists and similar agents); and therapeutic vaccines, antifibrotic agents, anti-inflammatory agents such as corticosteroids or non-steroidal anti-inflammatory agents (NSAIDs) and similar agents.
  • immune therapies e.g. interferon or other cytokines/chemokines, cytokine/chemokine receptor modulators, cytokine agonists or antagonists and similar agents
  • therapeutic vaccines e.g. interferon or other cytokines/chemokines, cytokine/chemokine receptor modulators, cytokine agonists or antagonists and similar agents
  • antifibrotic agents e.g. interferon or other cytokines/chemokines, cytokine/chem
  • the compounds of formula (I) and pharmaceutically acceptable salts thereof may be used in combination with one or more other agents which may be useful in the prevention or treatment of cancer, for example chemotherapeutics such as alkylating agents, topoisomerase inhibitors, antimetabolites, antimitotic agents, kinase inhibitors and similar agents; monoclonal antibody therapy such as trastuzumab, gemtuzumab and other similar agents; and hormone therapy such as tamoxifen, goserelin and similar agents.
  • chemotherapeutics such as alkylating agents, topoisomerase inhibitors, antimetabolites, antimitotic agents, kinase inhibitors and similar agents
  • monoclonal antibody therapy such as trastuzumab, gemtuzumab and other similar agents
  • hormone therapy such as tamoxifen, goserelin and similar agents.
  • compositions according to the invention may also be used alone or in combination with at least one other therapeutic agent in other therapeutic areas, for example gastrointestinal disease.
  • compositions according to the invention may also be used in combination with gene replacement therapy.
  • the invention includes in a further aspect a combination comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, together with at least one other therapeutically active agent.
  • compositions may be presented in unit-dose forms containing a predetermined amount of active ingredient per unit dose.
  • a unit may contain, as a non-limiting example, 0.5 mg to 1 g of a compound of formula (I) or a pharmaceutically acceptable salt thereof, depending on the condition being treated, the route of administration, and the age, weight, and condition of the patient.
  • Preferred unit-dosage compositions are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.
  • Such pharmaceutical compositions may be prepared by any of the methods well- known in the pharmacy art.
  • R 1 , m, n, and p are as hereinbefore defined for a compound of formula (I) and R 2 is C 1-6 alkyl, and thereafter, if required, carrying out one or more of the following optional steps:
  • a compound of formula (II) is dissolved in a suitable solvent in the presence of a solution of a suitable acid, for example a solution of hydrogen chloride in 1 ,4-dioxane and stirred at a suitable temperature, for example ambient temperature for a suitable period of time, for example 12-24 hours.
  • a suitable acid for example a solution of hydrogen chloride in 1 ,4-dioxane
  • the solvent is removed under reduced pressure and the residue dissolved in a suitable solvent, for example methanol, and loaded onto an ion-exchange cartridge, for example an aminopropyl SPE cartridge.
  • the cartridge is eluted with a suitable solvent, for example methanol and the solvent removed to give a compound of formula (I).
  • a compound of formula (II) may be prepared by reaction of a compound of formula ), for example a salt of a compound of formula (III) such as the trifluoroacetate salt:
  • R 1 is as hereinbefore defined for a compound of formula (I) and R 2 is as hereinbefore defined for a compound of formula (II), with a compound of formula (XV):
  • X is a halo group, for example a bromo group
  • m, n, and p are as hereinbefore defined for a compound of formula (I).
  • the trifluoroacetate salt of a compound of formula (III) and a suitable base are suspended in a suitable solvent, for example DMF, and heated to a suitable temperature, for example 50-60 0 C, under a suitable atmosphere, for example an atmosphere of nitrogen, for a suitable period of time, for example 45-60 minutes.
  • a suitable temperature for example 50-60 0 C
  • a suitable atmosphere for example an atmosphere of nitrogen
  • the mixture is cooled to a suitable temperature, for example ambient temperature
  • a compound of formula (XV) added and stirring continued at ambient temperature for a suitable period of time, for example 18-24 hours.
  • the solvent is evaporated under reduced pressure and the residue partitioned between a suitable solvent, for example DCM, and water.
  • the crude product is then isolated from the organic phase and purified by conventional techniques such as column chromatography.
  • a compound of formula (II) wherein m is 2 may be prepared by reaction of a compound of formula (IV):
  • R 1 is as hereinbefore defined for a compound of formula (I) and R 2 is as hereinbefore defined for a compound of formula (II), with a compound of formula (XXII):
  • n and p are as hereinbefore defined for a compound of formula (I) and X is a leaving group, for example a halo group such as a bromo group.
  • Additional compound of formula (XXII) and the solution of a suitable base, for example potassium f-butoxide, in a suitable solvent, for example THF, may be added and the mixture heated at a suitable temperature, for example 65-75 0 C for a further suitable period of time, for example 70-75 hours.
  • a suitable temperature for example 65-75 0 C for a further suitable period of time, for example 70-75 hours.
  • the mixture is then cooled, and quenched with water, extracted with a suitable organic solvent, for example DCM, the organic phase is isolated and evaporated.
  • the crude product is then purified by, for example, chromatography.
  • a compound of formula (IV) may be prepared by reaction of a compound of formula (III), for example a salt of a compound of formula (III) such as the trifluoroacetate salt, with a compound of formula (V): wherein X is a leaving group, for example a halo group such as a bromo group.
  • a mixture of the trifluoroacetate salt of a compound of formula (III), a suitable base, for example potassium carbonate, and a compound of formula (V) in a suitable solvent, for example N,N-dimethylformamide is heated at a suitable temperature, for example 55-65°C for a suitable period of time, for example 18-24 hours.
  • the reaction mixture is then cooled to a suitable temperature, for example ambient temperature, diluted with a suitable organic solvent, for example DCM, and washed with water.
  • the aqueous phase is extracted with further organic solvent, for example DCM, the combined organic phases dried, and evaporated to dryness.
  • the crude product is then purified by conventional means, such as chromatography.
  • a compound of formula (III), for example a salt of a compound of formula (III) such as the trifluoroacetate salt may be prepared by deprotection of a compound of formula (Vl): wherein R 1 is as hereinbefore defined for a compound of formula (I), R 2 is as hereinbefore defined for a compound of formula (II), and P is a protecting group, for example a tetrahydro-2H-pyran-2-yl group, in the presence of a suitable acid, for example trifluoroacetic acid.
  • a solution of a compound of formula (VII) in a suitable solvent for example methanol
  • a suitable solvent for example methanol
  • a suitable alkoxide for example sodium methoxide
  • a suitable solvent for example methanol
  • the reaction mixture is concentrated under reduced pressure and partitioned between a suitable organic solvent, for example ethyl acetate, and a suitable aqueous medium, for example saturated aqueous ammonium chloride solution.
  • the organic phase is separated, washed, for example with brine, and dried by, for example passing through a hydrophobic frit.
  • the solvent is then removed under reduced pressure.
  • a compound of formula (VII) may be prepared by reaction of a compound of formula (VIII):
  • a compound of formula (VIII) is dissolved in a suitable solvent, for example chloroform, and cooled to a suitable temperature, for example 0-0.5 0 C.
  • a suitable halogenating agent such as N-bromosuccinimide
  • the solution is stirred at a suitable temperature, for example 2-3°C for a suitable period of time, for example 30- 45 minutes then allowed to warm to a suitable temperature, for example ambient temperature, and stirred for a suitable period of time, for example 5-7 hours.
  • the reaction mixture is then washed with water and the organic phase dried and separated from the aqueous phase using, for example, a hydrophobic frit.
  • the organic solvent is then removed and the crude product purified by, for example, chromatography.
  • a compound of formula (VIII) wherein R 1 is C 1-6 alkoxy may be prepared by reaction of a compound of formula (IX):
  • T is a suitable leaving group, for example a halogen atom, for example a fluorine atom or a chlorine atom, with a solution of a compound of formula (X):
  • R 1 group in the compound of formula (X) is the same as the R 1 group in the solvent of formula (XS).
  • a compound of formula (X) such as sodium f-butoxide
  • a solvent of formula (XS) is added to a solvent of formula (XS).
  • the mixture is stirred until homogeneous, then a compound of formula (IX) is added.
  • the reaction mixture is heated to a suitable temperature, for example 100 0 C, for a suitable period of time, for example 12-18 hours.
  • the solvent is substantially removed under reduced pressure and partitioned between a suitable solvent, for example diethyl ether, and water.
  • the organic phase is separated and the aqueous phase re-extracted with further solvent.
  • the organic layers are then isolated, combined, dried using a suitable drying agent, for example anhydrous magnesium sulphate.
  • the drying agent is removed by filtration and the solvent removed from the product under reduced pressure.
  • the crude product may be purified by conventional means, such as chromatography.
  • R 1 is d- ⁇ alkylamino
  • a compound of formula (Xl) is added to a solution of a compound of formula (IX) in a suitable dry solvent, for example dry ethylene glycol, at a suitable temperature, for example ambient temperature, under a suitable inert atmosphere, for example an atmosphere of nitrogen.
  • a suitable temperature for example 1 10-13O C
  • the reaction is then cooled to a suitable temperature, for example ambient temperature, diluted with a suitable solvent, for example ethyl acetate, and washed with water.
  • the organic layer is dried with a suitable drying agent, for example anhydrous magnesium sulphate, filtered and concentrated under reduced pressure to yield a compound of formula (VIII) wherein R 1 is Ci -6 alkylamino.
  • a compound of formula (IX) may be prepared by reaction of a compound of formula (XII): wherein P is as hereinbefore defined for a compound of formula (Vl), T is as hereinbefore defined for a compound of formula (IX), and V is a suitable leaving group, for example a halogen atom, for example a chlorine atom, with an alcoholic solution of ammonia, for example a solution of ammonia in /so-propyl alcohol.
  • a compound of formula (XII) is heated with an alcoholic solution of ammonia, for example a 2M solution of ammonia in /so-propyl alcohol, at a suitable temperature, for example 50-60 0 C, for a suitable period of time, for example 5-6 hours.
  • the reaction mixture is then left to stand at a suitable temperature, for example ambient temperature, for a suitable period of time, for example 12-18 hours.
  • a further quantity of the alcoholic solution of ammonia for example a 2M solution of ammonia in /so-propyl alcohol, is added to break up the resultant cake and the reaction mixture heated for a further period of time, for example 8-10 hours, until the reaction is complete.
  • a compound of formula (IX) may also be prepared by reaction of a compound of formula (XIII):
  • T is as hereinbefore defined for a compound of formula (IX), and V is as hereinbefore defined for a compound of formula (Xl), with a compound of formula (XIV)
  • P u is a suitable precursor to the protecting group P, for example a 3,4- dihydro-2H-pyranyl group, followed by reaction with an alcoholic solution of ammonia, for example a solution of ammonia in /so-propyl alcohol.
  • a suspension of the resultant solid in an alcoholic solution of ammonia for example a 2M solution of ammonia in /so-propyl alcohol is heated under a suitable inert atmosphere, for example an atmosphere of nitrogen, at a suitable temperature, for example 60-70 ° C, for a suitable period of time, for example 4-5 hours with an attached condenser.
  • a suitable inert atmosphere for example an atmosphere of nitrogen
  • the reaction mixture is poured into water and allowed to cool for a suitable period of time, for example 12-18 hours.
  • the resultant precipitate is isolated by filtration and dried.
  • a compound of formula (IX) may also be prepared by reaction of a compound of formula (XIIIA)
  • T is fluorine
  • a suitable protecting agent for example a silylating agent such as N,O-bis(trimethylsilyl)acetamide
  • the reaction mixture is heated to a suitable temperature, for example 8-12 ° C and stirring maintained for a suitable period of time, for example 1-2 hours.
  • the mixture is then quenched by additon of 1 M sodium carbonate.
  • the organic layer is cooled to 0 ° C with stirring.
  • the precipitated solid is then collected by, for example, filtration and dried.
  • a compound of formula (XII) may be prepared by reaction of a compound of formula (XIII) with a compound of formula (XIV).
  • a suitable organic solvent for example ethyl acetate, followed by p-toluenesulfonic acid.
  • the mixture is heated to a suitable temperature, for example 50-60 0 C and then a compound of formula (XIV) added.
  • the reaction mixture is then heated at a suitable temperature, for example 50-60 0 C for a suitable period of time, for example 4-5 hours.
  • the solvent is then removed from the reaction mixture under reduced pressure to yield a compound of formula (XII).
  • a compound of formula (XV) wherein m is 2 may be prepared by reaction of a compound of formula (XVI):
  • a compound of formula (XVI) in a suitable solvent for example dry DCM is added a compound of formula (XVII) and the mixture stirred and cooled in an ice bath.
  • a solution of triphenylphosphine in a suitable solvent for example DCM, dropwise over a period of time, for example, 20 minutes.
  • the mixture is stirred in the cold bath and allowed to gradually warm to a suitable temperature, for example ambient temperature, gradually over a suitable period of time, for example 16-20 hours.
  • the precipitate is collected by filtration and washed with a little solvent, for example DCM, then the volume of the filtrate is reduced by evaporation.
  • the crude product sample is then purified by, for example, chromatography.
  • a compound of formula (XVI) may be prepared by reduction of a compound of formula (XVIII): P (XVIII)
  • a solution of a suitable reducing agent for example an ether solution of lithium aluminium hydride solution in a suitable solvent for example diethyl ether
  • a suitable atmosphere for example an atmosphere of nitrogen at a suitable temperature, for example 0-5 0 C.
  • a solution of a compound of formula (XVIII) in a suitable solvent for example diethyl ether
  • a suitable temperature for example 0-5 0 C
  • stirring is continued for a further period of time, for example 2-4 hours at a suitable temperature, for example 0-5 0 C, then allowed to warm to a suitable temperature, for example ambient temperature over a suitable period of time, for example 14-18 hours.
  • the mixture is cooled, for example in an ice bath, and treated with successive dropwise addition of water, an aqueous base, for example 15% aqueous NaOH solution, and water.
  • the mixture is stirred for a suitable period of time, for example 1-2 hours, then filtered, the residue washed with diethyl ether, and the filtrate evaporated under reduced pressure.
  • a suitable solvent for example DCM, is added to the residue and the solution dried by, for example, passing through a hydrophobic frit. The solvent is then evaporated under reduced pressure to give a compound of formula (XVI).
  • a compound of formula (XVIII) may be prepared by reaction of a compound of formula (XIX):
  • n and p are as hereinbefore defined for a compound of formula (I), with a compound of formula (XX):
  • R 3 is as hereinbefore defined for a compound of formula (XVIII).
  • a suitable solvent for example dry DCM
  • a suitable temperature for example 0-5 0 C
  • a suitable atmosphere for example an atmosphere of nitrogen
  • a solution of a compound off formula (XX) in a suitable solvent for example dry DCM is added dropwise over a suitable period of time, for example 30-50 minutes (rapid gas evolution may be observed).
  • the cooling bath is removed and the mixture allowed to warm to a suitable temperature, for example ambient temperature, over a suitable period of time, for example 12-18 hours.
  • the reaction mixture is then purified by, for example, column chromatography, the appropriate fractions combined and evaporated under reduced pressure to give a compound of formula (XVIII).
  • a compound of formula (XV) wherein m is 3 may be prepared by reaction of a compound of formula (XIX) with a compound of formula (XXI):
  • X is a halo group, for example a bromo group.
  • a mixture of a compound of formula (XIX), a compound of formula (XXI), tetrabutylammonium bisulphate, and a suitable base for example 50% aqueous sodium hydroxide solution
  • a suitable temperature for example ambient temperature
  • a suitable period of time for example 18-24 hours.
  • the mixture is diluted with water and extracted with a suitable solvent, for example Et 2 O, dried, for example, over Na 2 SO 4 , filtered and evaporated under reduced pressure.
  • the reaction mixture is then purified by, for example, column chromatography, the appropriate fractions combined and evaporated under reduced pressure to give a compound of formula (XV) wherein m is 3.
  • A1 Dihydropyran/paratoluene sulphonic acid e.g. 50 0 C for 1 hour
  • ammonia/iPrOH e.g. 60°C for 4 hours
  • 2,6-Dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (36.9 g) was heated with 2M ammonia in isopropanol (250 ml.) at 50°C for 5 hours. After standing at ambient temperature overnight, a further quantity of 2M ammonia in isopropanol (100 ml.) was added to break up the resultant cake and the reaction mixture was heated for a further 9 hours until the reaction was complete. To the reaction mixture was added water (70 ml.) and the yellow solid filtered off.
  • the sample was loaded onto a silica column (5Og) in dichloromethane and purified by chromatography on Flashmaster Il using a 0-25% ethyl acetate in cyclohexane gradient over 40 mins., (collecting all 45ml fractions).
  • the waste was evaporated and the residue purified by chromatrography on silica (5Og) on a Flashmaster Il using a gradient of 0-25% ethyl acetate in cyclohexane over 40 mins., (collecting all 45ml fractions).
  • the appropriate fractions were combined and evaporated in vacuo to give the title compound as a colourless liquid (0.42 g).
  • Blood samples of up to 200ml were obtained from healthy human donors. Whole blood in 25ml volumes was overlaid onto 15ml Ficoll gradients in Leucosep tubes, and centrifuged at 100Og for 20 min. Cells in the band at the plasma/histopaque interface were carefully removed and washed twice with PBS (centrifuged at 40Og for 5 min to harvest). The final pellet was resuspended in freezing medium (90% Heat- inactivated serum, 10% DMSO) to a cell concentration of 4x10 7 cells/ml. The resuspended cells were then cryopreserved (frozen) using a rate controlled freezer, and stored at -14O 0 C for up to 4 months.
  • freezing medium 90% Heat- inactivated serum, 10% DMSO

Abstract

L'invention porte sur des composés de la formule (I) : R1 représentant alkylamino en C1-6, ou alcoxy en C1-6; m étant un entier ayant une valeur de 2 ou 3; n étant un entier ayant une valeur de 0 à 3; p étant un entier ayant une valeur de 1 ou 2, et sur des sels de ceux-ci, qui sont des inducteurs d'interféron humain. Les composés qui induisent un interféron humain peuvent s’utiliser dans le traitement de divers troubles, par exemple le traitement de maladies allergiques ou autres états inflammatoires, par exemple la rhinite allergique et l'asthme, le traitement de maladies infectieuses et du cancer, et peuvent également s’utiliser en tant qu'adjuvants de vaccin.
PCT/EP2009/060264 2008-08-11 2009-08-07 Composés WO2010018132A1 (fr)

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