WO2012025474A1 - Composés indazole - Google Patents

Composés indazole Download PDF

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Publication number
WO2012025474A1
WO2012025474A1 PCT/EP2011/064348 EP2011064348W WO2012025474A1 WO 2012025474 A1 WO2012025474 A1 WO 2012025474A1 EP 2011064348 W EP2011064348 W EP 2011064348W WO 2012025474 A1 WO2012025474 A1 WO 2012025474A1
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WIPO (PCT)
Prior art keywords
compound
formula
pharmaceutically acceptable
salt
compounds
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PCT/EP2011/064348
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English (en)
Inventor
Simon Teanby Hodgson
Panayiotis Alexandrou Procopiou
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Glaxo Group Limited
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Publication of WO2012025474A1 publication Critical patent/WO2012025474A1/fr

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system

Definitions

  • the present invention relates to indazole compounds, pharmaceutical compositions containing such compounds and to their use in therapy.
  • CCR4 CC-chemokine receptor 4
  • PCT patent application PCT/EP2010/052307 discloses a series of indazole derivatives as CCR4 anatgonists.
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof for use in therapy, in particular in the treatment of a disease or condition for which a CCR4 receptor antagonist is indicated.
  • a method of treating a disease or condition for which a CCR4 receptor antagonist is indicated in a subject in need thereof which comprises administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a disease or condition for which a CCR4 receptor antagonist is indicated.
  • the present invention relates to a compound of formula (I) or a salt thereof, particularly a pharmaceutically acceptable salt thereof
  • R is d. 18 alkyl
  • X is (i) (CH 2 )m in which m is 2, 3 or 4;
  • R is Ci_i 8 alkyl
  • X is a cyclohexyl group.
  • R is d. 18 alkyl.
  • a compound of formula (I), (IA) or (IB) in which R is C h alky! such as ethyl, propyl, isopropyl, n-butyl, n-pentyl and n-hexyl.
  • R is methyl.
  • Specific compounds according to the invention include Examples 1 - 13 as described herein or a salt thereof.
  • d. ⁇ alkyl is used to describe a group comprising a linear or branched alkyl group containing from 1 to 18, 1 to 12 or 2 to 6 carbon atoms repsectively. Suitable examples of such groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t- butyl, pentyl, hexyl, heptyl and octyl.
  • the present invention covers compounds of formula (I) as the free base and as salts thereof, for example as a pharmaceutically acceptable salt thereof.
  • the invention relates to compounds of formula (I) or a pharmaceutically acceptable salt thereof.
  • salts of the compounds of formula (I) are desirably pharmaceutically acceptable.
  • suitable pharmaceutically acceptable salts can include acid or base addition salts.
  • a pharmaceutically acceptable salt may be readily prepared by using a desired acid or base as appropriate. The resultant salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
  • a pharmaceutically acceptable base addition salt can be formed by reaction of a compound of formula (I) with a suitable inorganic or organic base, (e.g. triethylamine, ethanolamine, triethanolamine, choline, arginine, lysine or histidine), optionally in a suitable solvent, to give the base addition salt which is usually isolated, for example, by crystallisation and filtration.
  • a suitable inorganic or organic base e.g. triethylamine, ethanolamine, triethanolamine, choline, arginine, lysine or histidine
  • Pharmaceutically acceptable base salts include ammonium salts, alkali metal salts such as those of sodium and potassium, alkaline earth metal salts such as those of calcium and magnesium and salts with organic bases, including salts of primary, secondary and tertiary amines, such as isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexyl amine and N-methyl-D-glucamine.
  • Other non-pharmaceutically acceptable salts e.g. formates, oxalates or trifluoroacetates, may be used, for example in the isolation of the compounds of formula (I), and are included within the scope of this invention.
  • the invention includes within its scope all possible stoichiometric and non-stoichiometric forms of the salts of the compounds of formula (I).
  • the invention includes within its scope all possible stoichiometric and non-stoichiometric forms of the solvates of the compounds of formula (I).
  • the invention encompasses all prodrugs, of compounds of formula (I) and pharmaceutically acceptable salts thereof, which upon administration to the recipient are capable of providing (directly or indirectly) a compound of formula (I) or a pharmaceutically acceptable salt thereof, or an active metabolite or residue thereof.
  • Such derivatives are recognizable to those skilled in the art, without undue experimentation. Nevertheless, reference is made to the teaching of Burger's Medicinal Chemistry and Drug Discovery, 5 th Edition, Vol 1 : Principles and Practice, which is incorporated herein by reference to the extent of teaching such derivatives.
  • the compounds of formula (I) may be in crystalline or amorphous form. Furthermore, some of the crystalline forms of the compounds of formula (I) may exist as polymorphs, which are included within the scope of the present invention. Polymorphic forms of compounds of formula (I) may be characterized and differentiated using a number of conventional analytical techniques, including, but not limited to, X-ray powder diffraction (XRPD) patterns, infrared (IR) spectra, Raman spectra, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and solid state nuclear magnetic resonance (SSNMR). It will be appreciated that when X is a group such as cyclohexyl both cis and trans isomers are within the scope of the invention.
  • XRPD X-ray powder diffraction
  • IR infrared
  • Raman spectra Raman spectra
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • SSNMR solid state nuclear magnetic resonance
  • the present invention encompasses isomers of the compounds of formula (I) whether as individual isomers isolated such as to be substantially free of the other isomer (i.e. pure) or as mixtures (i.e. racemates and racemic mixtures).
  • An individual isomer isolated such as to be substantially free of the other isomer (i.e. pure) may be isolated such that less than 10%, particularly less than about 1 %, for example less than about 0.1 % of the other isomer is present.
  • Separation of isomers may be achieved by conventional techniques known to those skilled in the art, e.g. by fractional crystallisation, chromatography or HPLC.
  • Certain compounds of formula (I) may exist in one of several tautomeric forms. It will be understood that the present invention encompasses all tautomers of the compounds of formula (I) whether as individual tautomers or as mixtures thereof.
  • the present invention further provides for a process for the preparation of a compound of formula (I) or a salt thereof which comprises reacting a compound of formula (II) or a salt thereof
  • the compound of formula (II) and the carboxylic acid of formula (III) are reacted under amide forming conditions that are familiar to those skilled in the art. Such reactions may be carried out in a suitable organic solvent (e.g. DMF or acetonitrile) with a base (e.g. DIPEA or triethylamine) in the presence of a suitable activating group (e.g. HATU or TBTU).
  • a suitable organic solvent e.g. DMF or acetonitrile
  • DIPEA e.g. DIPEA or triethylamine
  • a suitable activating group e.g. HATU or TBTU
  • the compounds of formula (II) and carboxylic acid of formula (III) may also be reacted in the presence of a carbodiimide activating reagent (such as A/-[3-(dimethylamino)propyl]- ⁇ /'-ethylcarbodiimide hydrochloride) with N-hydroxybenztriazole in a suitable organic solvent (such as THF or dichloromethane) with a suitable base (such as
  • the compounds of formula (II) and carboxylic acid of formula (III) may also be reacted in the presence of an activating reagent such as 1-chloro N,N,2-trimethyl-1-propen-1-amine in a suitable organic solvent (e.g. THF or dichloromethane) with a suitable base (e.g. DIPEA or triethylamine).
  • an activating reagent such as 1-chloro N,N,2-trimethyl-1-propen-1-amine in a suitable organic solvent (e.g. THF or dichloromethane) with a suitable base (e.g. DIPEA or triethylamine).
  • a suitable organic solvent e.g. THF or dichloromethane
  • DIPEA e.g. DIPEA or triethylamine
  • Examples of activated derivatives of the compounds of formula (III) can also be acid chlorides or acid anhydrides.
  • reaction between the compound of formula (II) and such compounds of formula (III) is typically carried out in an inert organic solvent (such as tetrahydrofuran, DMF, chloroform or dichloromethane) at ambient or lower temperature, optionally in the presence of a suitable base e.g. an organic base (such as triethylamine or diisopropylethylamine), an alkali metal carbonate (such as potassium carbonate) or an alkali metal hydrogen carbonate (such as sodium hydrogen carbonate).
  • an organic base such as triethylamine or diisopropylethylamine
  • an alkali metal carbonate such as potassium carbonate
  • an alkali metal hydrogen carbonate such as sodium hydrogen carbonate
  • the compound of formula (II) may be prepared by the method described in Scheme 1.
  • Reagents and conditions a) NH 2 NH 2 .H 2 0, 1-butanol, reflux, 92%; b) KOH, DMSO, 3-cyanobenzyl chloride, 60%; c) 5-chloro-2-thiophenesulfonyl chloride, pyridine, 85%; d) 1 M LiAIH 4 solution in ether, THF, 2M HCI, MeOH, 77%
  • the compounds of formula (III) can be obtained from commercial sources or by methods described herein.
  • Compounds of formula (III) may also be obtained by reaction of an appropriate dicarboxylic acid and an appropriate alcohol in the presence of acid and then isolating the monoester by chromatography or distillation.
  • Compounds of formula (I) can be converted to a further compound of formula (I) by transterification using an appropriate alcohol, optionally in the presence of an acid or base catalyst. It will be appreciated that in any of the routes described above it may be advantageous to protect one or more functional groups. Examples of protecting groups and the means for their removal can be found in T. W. Greene 'Protective Groups in Organic Synthesis' (3 rd edition, J. Wiley and Sons, 1999).
  • Suitable amine protecting groups include acyl (e.g. acetyl, carbamate (e.g. 2',2',2'-trichloroethoxycarbonyl, benzyloxycarbonyl or t- butoxycarbonyl) and arylalkyl (e.g. benzyl), which may be removed by hydrolysis (e.g. using an acid such as hydrochloric acid in dioxane or trifluoroacetic acid in dichloromethane) or reductively (e.g.
  • Suitable amine protecting groups include trifluoroacetyl (- COCF 3 ) which may be removed by base catalysed hydrolysis.
  • the compounds of formula (I) and salts thereof are believed to be inhibitors of CC chemokine receptor activity, particularly CCR4 receptor activity, and thus have potential utility in the treatment of diseases or conditions for which a CCR4 compound is indicated.
  • the present invention thus provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in therapy.
  • the compound of formula (I) or pharmaceutically acceptable salt thereof can be for use in the treatment of a disease or condition for which a CCR4 receptor antagonist is indicated.
  • the present invention thus provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of a disease or condition for which a CCR4 receptor antagonist is indicated. Also provided is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a disease or condition for which a CCR4 receptor antagonist is indicated. Also provided is a method of treating a disease or conditions for which a CCR4 receptor antagonist is indicated in a subject in need thereof which comprises administering a therapeutically effective amount of compound of formula (I) or a pharmaceutically acceptable salt thereof. Suitably the subject in need thereof is a mammal, particularly a human.
  • the term "effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician.
  • therapeutically effective amount means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder.
  • the term also includes within its scope amounts effective to enhance normal physiological function.
  • CCR4 antagonists are believed to be useful in the treatment of a variety of diseases or conditions such as immunoregulatory, inflammatory and/or allergic diseases.
  • diseases or conditions such as immunoregulatory, inflammatory and/or allergic diseases.
  • Examples include: asthma, chronic obstructive pulmonary disease (COPD) including chronic bronchitis and emphysema, idiopathic pulmonary fibrosis, atopic or contact dermatitis, urticaria, allergic rhinitis (seasonal or perennial), vasomotor rhinitis, nasal polyps, allergic conjunctivitis, vernal conjunctivitis, occupational conjunctivitis, infective conjunctivitis, eosinophilic syndromes, eosinophilic granuloma, psoriasis, rheumatoid arthritis, ulcerative colitis, Crohn's disease, thrombosis, reperfusion injury of the myocardium and brain
  • CCR4 antagonists are also believed to be useful in the treatment of diseases or conditions such as allergic bronchopulmonary aspergillosis, allergic fungal sinusitis, severe asthma with fungal sensitization and diseases involving a pathogenic role for fungi including invasion or colonisation (such as invasive aspergillosis, aspergilloma or candidiasis)
  • disease or condition for which a CCR4 inhibitor is indicated is intended to include any or all of the above disease states.
  • the disease or condition for which a CCR4 inhibitor is indicated is selected from asthma, COPD, rhinitis, idiopathic pulmonary fibrosis, psoriasis and contact dermatitis.
  • the disease or condition for which a CCR4 inhibitor is indicated is asthma.
  • a compound of formula (I) as well as pharmaceutically acceptable salts thereof may be administered as the raw chemical, it is common to present the active ingredient as a pharmaceutical composition.
  • the present invention therefore provides in a further aspect a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt and one or more or pharmaceutically acceptable carriers, diluents and/or excipients.
  • the compounds of the formula (I) and pharmaceutically acceptable salts are as described above.
  • the carrier(s), diluent(s) or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.
  • a process for the preparation of a pharmaceutical composition including admixing a compound of the formula (I), or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the pharmaceutical composition can be for use in the treatment of any of the conditions described herein.
  • compositions for the treatment of diseases or conditions for which a CCR4 inhibitor is indicated comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising 0.05 to 1000mg of a compound of formula (I) or a pharmaceutical salt thereof and 0.1 to 2g of one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the compounds of formula (I) are intended for use in pharmaceutical compositions it will be readily understood that they are each preferably provided in substantially pure form, for example, at least 60% pure, more suitably at least 75% pure and preferably at least 85% pure, especially at least 98% pure (% in a weight for weight basis).
  • compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose.
  • Preferred unit dosage compositions are those containing a daily dose or sub-dose, or an appropriate fraction thereof, of an active ingredient. Such unit doses may therefore be administered more than once a day.
  • Preferred unit dosage compositions are those containing a daily dose or sub-dose (for administration more than once a day), as herein above recited, or an appropriate fraction thereof, of an active ingredient.
  • compositions may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, inhaled, intranasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route.
  • Such compositions may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) or excipient(s).
  • the pharmaceutical composition is adapted for oral administration.
  • compositions adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • Powders suitable for incorporating into tablets or capsules may be prepared by reducing the compound to a suitable fine size (e.g. by micronisation) and mixing with a similarly prepared pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing and coloring agent can also be present.
  • Capsules may 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, glidants, lubricants, sweetening agents, flavours, 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.
  • 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 the present invention can also be combined with a 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 solution, 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 flavored 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, flavor additive such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, and the like can also be added.
  • dosage unit compositions for oral administration can be microencapsulated.
  • the formulation 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 the invention can also be administered in the form of liposome 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.
  • Pharmaceutical compositions adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time.
  • compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
  • compositions are preferably applied as a topical ointment or cream.
  • the active ingredient may be employed with either a paraffinic or a water- miscible ointment base.
  • the active ingredient may be formulated in a cream with an oil-in-water cream base or a water-in-oil base.
  • compositions adapted for topical administrations to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.
  • compositions adapted for topical administration in the mouth include lozenges, pastilles and mouth washes.
  • Pharmaceutical compositions adapted for rectal administration may be presented as suppositories or as enemas.
  • Dosage forms for nasal or inhaled administration may conveniently be formulated as aerosols, solutions, suspensions, gels or dry powders.
  • the compound of the invention is in a particle-size-reduced form, and more preferably the size-reduced form is obtained or obtainable by micronisation.
  • the preferable particle size of the size-reduced (e.g. micronised) compound or salt is defined by a D50 value of about 0.5 to about 10 microns (for example as measured using laser diffraction).
  • Aerosol formulations can comprise a solution or fine suspension of the active substance in a pharmaceutically acceptable aqueous or non- aqueous solvent. Aerosol formulations can be presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomising device or inhaler. Alternatively the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve (metered dose inhaler) which is intended for disposal once the contents of the container have been exhausted.
  • a metering valve metered dose inhaler
  • the dosage form comprises an aerosol dispenser
  • it preferably contains a suitable propellant under pressure such as compressed air, carbon dioxide or an organic propellant such as a hydrofluorocarbon (HFC).
  • suitable HFC propellants include
  • the aerosol dosage forms can also take the form of a pump-atomiser.
  • the pressurised aerosol may contain a solution or a suspension of the active compound. This may require the incorporation of additional excipients e.g. co-solvents and/or surfactants to improve the dispersion characteristics and homogeneity of suspension formulations. Solution formulations may also require the addition of co-solvents such as ethanol. Other excipient modifiers may also be incorporated to improve, for example, the stability and/or taste and/or fine particle mass characteristics (amount and/or profile) of the formulation.
  • the pharmaceutical composition may be a dry powder inhalable composition.
  • a dry powder inhalable composition can comprise a powder base such as lactose, glucose, trehalose, mannitol or starch, the compound of formula (I) or salt thereof (preferably in particle-size-reduced form, e.g. in micronised form), and optionally a performance modifier such as L-leucine or another amino acid and/or metals salts of stearic acid such as magnesium or calcium stearate.
  • the dry powder inhalable composition comprises a dry powder blend of lactose and the compound of formula (I) or salt thereof.
  • the lactose is preferably lactose hydrate e.g.
  • the particle size of the lactose is defined by 90% or more (by weight or by volume) of the lactose particles being less than 1000 microns (micrometres) (e.g. 10-1000 microns e.g. 30-1000 microns) in diameter, and/or 50% or more of the lactose particles being less than 500 microns (e.g. 10-500 microns) in diameter. More preferably, the particle size of the lactose is defined by 90% or more of the lactose particles being less than 300 microns (e.g. 10-300 microns e.g.
  • the particle size of the lactose is defined by 90% or more of the lactose particles being less than 100-200 microns in diameter, and/or 50% or more of the lactose particles being less than 40-70 microns in diameter.
  • a suitable inhalation-grade lactose is E9334 lactose (10% fines) (Borculo Domo Ingredients, Hanzeplein 25, 8017 JD Zwolle, Netherlands).
  • a pharmaceutical composition for inhaled administration can 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 can be administered by inhalation via the device such as the DISKUS TM device, marketed by GlaxoSmithKline.
  • the DISKUS T inhalation device is for example described in GB 2242134 A, and in such a device at least one container for the pharmaceutical 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 pharmaceutical composition in powder form from the opened container.
  • the compounds of the invention thereof may be formulated as a fluid formulation 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 formulation 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 formulation 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 formulation, 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 formulation into the nasal cavity.
  • a fluid dispenser of the aforementioned type is described and illustrated in WO-A-2005/044354, 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 formulation.
  • 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 formulation out of a pump stem through a nasal nozzle of the housing.
  • a particularly preferred fluid dispenser is of the general type illustrated in Figures 30-40 of WO-A-2005/044354.
  • compositions adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
  • compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the composition isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the compositions may be presented in unit- dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
  • each dosage unit for oral or parenteral administration preferably contains from 0.01 to 3000 mg, more preferably 0.5 to 1000 mg, of a compound of the invention calculated as the free base.
  • Each dosage unit for nasal or inhaled administration preferably contains from 0.001 to 50 mg, more preferably 0.01 to 5 mg, of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, calculated as the free base.
  • the pharmaceutically acceptable compounds the invention can be administered in a daily dose (for an adult patient) of, for example, an oral or parenteral dose of 0.01 mg to 3000 mg per day or 0.5 to 1000 mg per day, or a nasal or inhaled dose of 0.001 to 50 mg per day or 0.01 to 5 mg per day, of the compound of the formula (I) or a pharmaceutically acceptable salt thereof, calculated as the free base.
  • This amount may be given in a single dose per day or more usually in a number (such as two, three, four, five or six) of sub-doses per day such that the total daily dose is the same.
  • An effective amount of a salt thereof may be determined as a proportion of the effective amount of the compound of formula (I) per se.
  • Combination therapies according to the present invention thus comprise the administration of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof, and the use of at least one other pharmaceutically active agent.
  • combination therapies according to the present invention comprise the administration of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one other pharmaceutically active agent.
  • the compound(s) of the invention and the other pharmaceutically active agent(s) may be administered together in a single pharmaceutical composition or separately and, when administered separately this may occur simultaneously or sequentially in any order.
  • the amounts of the compound(s) of the invention and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • a combination comprising a compound of the invention and at least one other pharmaceutically active agent.
  • the compound 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 (including a steroid), anticholinergic agents (particularly an Mi/M 2 /M 3 receptor antagonist), p 2 -adrenoreceptor agonists, anti-allergy agents, antiinfective agents (such as antibiotics or antivirals), or antihistamines.
  • the invention thus provides, in a further aspect, a combination pharmaceutical product 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 p 2 -adrenoreceptor agonist, an anti-allergy agent, 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 p 2 -adrenoreceptor agonist
  • an anti-allergy agent such as an antibiotic or an antiviral
  • an antiinfective agent such as an antibiotic or an antiviral
  • an antihistamine such as an antibiotic or an antiviral
  • the compound of the present invention when administered in combination with other therapeutic agents normally administered by the inhaled, intravenous, oral or intranasal route, that the resultant pharmaceutical composition may be administered by the same routes. Alternatively the individual components of the composition may be administered by different routes.
  • Suitable anti-inflammatory agents include corticosteroids.
  • Anti-inflammatory corticosteroids are well known in the art. Representative examples include fluticasone propionate, beclomethasone 17-propionate ester, beclomethasone 17,21-dipropionate ester, dexamethasone or an ester thereof, mometasone or an ester thereof (e.g. mometasone furoate), ciclesonide, budesonide, flunisolide, methyl prednisolone, prednisolone, and dexamethasone.
  • anti-inflammatory corticosteroids are described in WO 02/12266 A1 (Glaxo Group Ltd), in particular, the compounds of Example 1 ( 6a,9a-difluoro-17a-[(2-furanylcarbonyl)oxy]-1 i p-hydroxy-16a-methyl-3-oxo- androsta-1 ,4-diene-17p-carbothioic acid S-fluoromethyl ester) and Example 41 (6a, 9a- difluoro-1 i p-hydroxy-16a-methyl-17a-[(4-methyl-1 ,3-thiazole-5-carbonyl)oxy]-3-oxo- androsta-1 ,4-diene-17p-carbothioic acid S-fluoromethyl ester), or a pharmaceutically acceptable salt thereof.
  • p 2 -adrenoreceptor agonists examples include salmeterol (e.g. as racemate or a single enantiomer such as the R-enantiomer), salbutamol, formoterol, salmefamol, fenoterol or terbutaline and salts thereof, for example the xinafoate salt of salmeterol, the sulphate salt or free base of salbutamol or the fumatrate salt of formoterol.
  • the ⁇ 2 - adrenoreceptor agonists are long-acting ⁇ 2 -adrenoreceptor agonists, for example, those having a therapeutic effect over a 24 hour period, such as salmeterol or formoterol.
  • a further example of a agonist is the compound 4- ⁇ (1 R)-2-[(6- ⁇ 2-[(2,6- dichlorophenyl)methoxy]ethoxy ⁇ hexyl)amino]-1-hydroxyethyl ⁇ -2-(hydroxyethyl)phenol triphenylacetete (Vilanterol Trifenatate).
  • anticholinergic compounds which may be used in combination with a compound of formula (I) or a pharmaceutically acceptable salt thereof are described in WO 03/011274 A2 and WO 02/069945 A2 / US 2002/0193393 A1 and US 2002/052312 A1.
  • anticholinergic agents include muscarinic receptor antagonists, in particular, compounds which are antagonists of the or M 3 receptors, dual antagonists of Mi/M 3 or M 2 /M 3 receptors or pan antagonists of Mi/M 2 /M 3 receptors such as ipratropium bromide, oxitropium bromide or tiotropium bromide.
  • An anti-histamine usable in a combination of a compound of the invention can for example be methapyrilene or H1 antagonists.
  • 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, olopat
  • the invention provides a combination comprising a compound of the invention 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 suitable combinations include, for example combinations comprising a compound of the invention together with other anti-inflammatory agents such as an anti-flammatory corticosteroid; or a non-steroidal anti-inflammatory drug (NSAID) such as leukotriene antagonist (e.g.
  • NSAID non-steroidal anti-inflammatory drug
  • iNOS inhibitor a tryptase inhibitor, IKK2 inhibitors, a p38 inhibitor, Syk inhibitors, an elastase inhibitor, a beta-2 integrin antagonist, an adenosine a2a agonist, a chemokine antagonist such as a CCR3 antagonist, a mediator release inhibitor such as sodium chromoglycate, a 5-lipoxygenase inhibitor, a DP1 antagonist, a DP2 antagonist, a CTTh2 inhibitor, a pl3K delta inhibitor, an ITK inhibitor, a LP (lysophosphatidic) inhibitor and a FLAP (five lipoxygenase activating protein) inhibitor.
  • Suitable combinations include a compound of the invention together with an anti- nfective agent (e.g. an antibiotic or an antiviral), an anti-hypertensive agent, an antithrombotic agent, a statin or a cholinesterase inhibitor.
  • an anti- nfective agent e.g. an antibiotic or an antiviral
  • an anti-hypertensive agent e.g. an antibiotic or an antiviral
  • an antithrombotic agent e.g. an antithrombotic agent
  • statin e.g. an anti-hypertensive agent
  • a statin e.g. an anti-hypertensive agent
  • a statin e.g. an antithrombotic agent
  • compositions comprising a combination as defined above together with a pharmaceutically acceptable diluent or carrier represent a further aspect of the invention.
  • the present invention also provides for so-called "triple combination" therapy, comprising a compound of the invention together with 2 -adrenoreceptor agonist and an anti-inflammatory corticosteroid.
  • this combination is for treatment and/or prophylaxis of asthma, COPD or allergic rhinitis.
  • the 2 -adrenoreceptor agonist and/or the anti-inflammatory corticosteroid can be as described above and/or as described in WO 03/030939 A1.
  • a representative example of such a "triple” combination comprises a compound of the invention, salmeterol or a pharmaceutically acceptable salt (e.g. salmeterol xinafoate) and fluticasone propionate.
  • a further representative example of a "triple” combination comprises a compound of the invention, 4- ⁇ (1 R)-2-[(6- ⁇ 2-[(2,6- dichlorophenyl)methoxy]ethoxy ⁇ hexyl)amino]-1-hydroxyethyl ⁇ -2-(hydroxyethyl)phenol triphenylacetete (Vilanterol Trifenatate) and 6a,9a-difluoro-17a-[(2-furanylcarbonyl)oxy]- 1 ip-hydroxy-16a-methyl-3-oxo-androsta-1 ,4-diene-17p-carbothioic acid S-fluoromethyl ester (fluticasone furoate).
  • Rheumatoid arthritis is a further inflammatory disease where combination therapy may be contemplated.
  • the present invention provides a compound of the invention in combination with a further therapeutic agent useful in the treatment of rheumatoid arthritis, said combination being useful for the treatment of rheumatoid arthritis.
  • the compound 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 NSAIDS, corticosteroids, COX-2 inhibitors, cytokine inhibitors, anti-TNF agents, inhibitors of oncostatin M, anti-malarials, immunosuppressive and cytostatics.
  • Anti-TNF agents include infliximab (Remicade), etanercept (Enbrel) and adalimum (Humira).
  • Other "biological" treatments include anakinra (Kineret), Rituximab, Lymphostat-B, BAFF/APRIL inhibitors and CTLA-4-lg or mimetics thereof.
  • cytokine inhibitors include lefluonomide (Arava).
  • Further second line drugs include gold preparations (Auranofin (Ridaura tablets) or Aurothiomalate (Myocrisin injection)), medicines used for malaria: (Hydroxychloroquine (Plaquenil)), medicines that suppress the immune system (Azathioprine (Imuran, Thioprine), methotrexate (Methoblastin, Ledertrexate, Emethexate), cyclosporine (Sandimmun, Neoral)), Cyclophosphamide (Cycloblastin), Cytoxan, Endoxan), D-Penicillamine (D-Penamine), Sulphasalazine (Salazopyrin), nonsteroidal anti inflammatory drugs (including aspirin and ib dur).
  • 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.
  • compositions comprising a combination as defined above together with a pharmaceutically acceptable diluent or carrier represent a further aspect of the invention.
  • 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 be readily appreciated by those skilled in the art.
  • Analytical LCMS was conducted on one of the following systems A to E.
  • UV detection to all systems was an averaged signal from wavelength of 220 nm to 350 nm and mass spectra were recorded on a mass spectrometer using alternate-scan positive and negative mode electrospray ionization.
  • Solvents A: 0.1 % v/v formic acid in water
  • Solvents A: 0.1 % v/v solution of formic acid in water
  • Solvents A: 10 mM ammonium bicarbonate in water adjusted to pH10 with ammonia solution
  • Solvents A: 0.1% v/v solution of trifluoroacetic acid in water
  • Solvents A: 0.1 % v/v solution of trifluoroacetic acid in water
  • Solvents A: 10 mM ammonium bicarbonate in water adjusted to pH10 with ammonia solution
  • Method A was conducted on a Sunfire Ci 8 column (typically 150 mm x 30 mm i packing diameter) at ambient temperature.
  • the solvents employed were:
  • Method B was conducted on a Sunfire C 18 column (typically 150 mm x 30 mm i.d. 5 ⁇ packing diameter) at ambient temperature.
  • the solvents employed were:
  • Method C was conducted on an XBridge Ci 8 column (typically 150 mm x 19 mm i.d. 5 packing diameter) at ambient temperature.
  • the solvents employed were:
  • A 10 mM aqueous ammonium bicarbonate adjusted to pH 10 with ammonia solution.
  • the gradient employed was: Time (min) Flow Rate (mL/min) % A % B
  • Method D was conducted on an ATLANTIS dC18 column (typically 100 mm x 19 mm i.d. 5 m packing diameter).
  • the solvents employed were:
  • DIAD diisopropyl azodicarboxylate
  • Examples 2 - 12 were prepared in a similar way to Example 1.
  • Antagonist potency was determined by a radioligand [35S]-GTPyS competition assay. Briefly, CCR4 expressing CHO membranes were homogenised by passing through a 23G needle. These membranes were then adhered to WGA-coated Leadseeker SPA beads in assay buffer (20mM HEPES, 10mM MgCI 2 , 100mM NaCI, 0.05% BSA, 40ug/ml Saponin and pH adjusted to 7.4 using KOH 5M) to generate a 3 ⁇ g/well final assay concentration (FAC) membrane and 250 ⁇ g/well FAC bead, solution.
  • assay buffer 20mM HEPES, 10mM MgCI 2 , 100mM NaCI, 0.05% BSA, 40ug/ml Saponin and pH adjusted to 7.4 using KOH 5M
  • the final assay solution (45.5 ⁇ ) was then sealed, spun using a centrifuge and then incubated at room temp for 3 - 6 hours. Plates were then read on a Viewlux instrument and luminescence was then plotted as a percentage of the maximum inhibitional response elicited by an IC100 of a standard antagonist. Examples 1 - 13 were tested in the above assay.

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Abstract

L'invention concerne des composés indazole, des procédés pour leur préparation, des compositions pharmaceutiques contenant de tels composés et leur utilisation en thérapie.
PCT/EP2011/064348 2010-08-24 2011-08-22 Composés indazole WO2012025474A1 (fr)

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WO2002012266A1 (fr) 2000-08-05 2002-02-14 Glaxo Group Limited Derives de 17-beta-carbothioate-17-alpha-arylcarbonyloxyloxy androstane utilises comme anti-inflammatoires
US20020052312A1 (en) 2000-05-30 2002-05-02 Reiss Theodore F. Combination therapy of chronic obstructive pulmonary disease using muscarinic receptor antagonists
WO2002069945A2 (fr) 2001-03-07 2002-09-12 Boehringer Ingelheim Pharma Gmbh & Co. Kg Nouvelles preparations de medicaments a base d'anticholinergiques et d'inhibiteurs pde-iv
US20020193393A1 (en) 2001-03-07 2002-12-19 Michel Pairet Pharmaceutical compositions based on anticholinergics and PDE-IV inhibitors
WO2003011274A2 (fr) 2001-07-27 2003-02-13 Glaxo Group Limited Methode therapeutique
WO2003030939A1 (fr) 2001-10-05 2003-04-17 Glaxo Group Limited Therapies pour le traitement de maladies respiratoires
WO2004035556A1 (fr) 2002-10-16 2004-04-29 Glaxo Group Limited Piperazines, (1,4) diazepines, et 2,5-diazabicyclo (2.2.1) heptanes substitues en tant qu'antagonistes de l'histamine h1 et/ou h3 ou antagonistes inverses de l'histamine h3
WO2004108717A1 (fr) * 2003-06-04 2004-12-16 Astrazeneca Ab Composes de sulphonamide qui modulent l'activite des recepteurs de chimiokine (ccr4)
WO2005044354A1 (fr) 2003-11-03 2005-05-19 Glaxo Group Limited Distributeur de fluides
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GB2242134A (en) 1990-03-02 1991-09-25 Glaxo Group Ltd Inhalation device
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WO2002012266A1 (fr) 2000-08-05 2002-02-14 Glaxo Group Limited Derives de 17-beta-carbothioate-17-alpha-arylcarbonyloxyloxy androstane utilises comme anti-inflammatoires
WO2002069945A2 (fr) 2001-03-07 2002-09-12 Boehringer Ingelheim Pharma Gmbh & Co. Kg Nouvelles preparations de medicaments a base d'anticholinergiques et d'inhibiteurs pde-iv
US20020193393A1 (en) 2001-03-07 2002-12-19 Michel Pairet Pharmaceutical compositions based on anticholinergics and PDE-IV inhibitors
WO2003011274A2 (fr) 2001-07-27 2003-02-13 Glaxo Group Limited Methode therapeutique
WO2003030939A1 (fr) 2001-10-05 2003-04-17 Glaxo Group Limited Therapies pour le traitement de maladies respiratoires
WO2004035556A1 (fr) 2002-10-16 2004-04-29 Glaxo Group Limited Piperazines, (1,4) diazepines, et 2,5-diazabicyclo (2.2.1) heptanes substitues en tant qu'antagonistes de l'histamine h1 et/ou h3 ou antagonistes inverses de l'histamine h3
WO2004108717A1 (fr) * 2003-06-04 2004-12-16 Astrazeneca Ab Composes de sulphonamide qui modulent l'activite des recepteurs de chimiokine (ccr4)
WO2005044354A1 (fr) 2003-11-03 2005-05-19 Glaxo Group Limited Distributeur de fluides
WO2006045416A1 (fr) 2004-10-19 2006-05-04 F. Hoffmann-La Roche Ag Derives de quinoline
WO2008089307A2 (fr) * 2007-01-18 2008-07-24 Lexicon Pharmaceuticals, Inc. Méthodes et compositions utilisés dans le traitement de la douleur, de l'inflammation et du cancer

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