WO2012025474A1 - Indazole compounds - Google Patents

Abstract

Indazole compounds, processes for their preparation, pharmaceutical compositions containing such compounds and their use in therapy.

Description

INDAZOLE COMPOUNDS

Field of the Invention

The present invention relates to indazole compounds, pharmaceutical compositions containing such compounds and to their use in therapy.

Background of the Invention

Chemokines are believed to play an important role in immune and inflammatory responses in a number of diseases or conditions The CC-chemokine receptor 4 (hereafter CCR4) was originally cloned from a basophilic cell line (Power et al, J. Biol. Chem.; 270: 19495: 1995). Small molecule CCR4 receptor antagonists are known in the art, with examples of such being described in Andrews et al (Mol. Pharmacol 73: 855, 2008). PCT patent application PCT/EP2010/052307 discloses a series of indazole derivatives as CCR4 anatgonists.

Summary of the Invention

In a first aspect of the present invention, there is provided a compound of formula (I) or a salt thereof, in particular a pharmaceutically acceptable salt thereof

(I)

In a second aspect of the present invention, there is provided 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. In a third aspect of the present invention, there is provided 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. In a fourth aspect of the present invention, there is provided 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. In a fifth aspect of the present invention, there is provided 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. Detailed Description of the Invention

The present invention relates to a compound of formula (I) or a salt thereof, particularly a pharmaceutically acceptable salt thereof

(I)

wherein

R is d. ₁₈alkyl;

X is (i) (CH₂)m in which m is 2, 3 or 4;

(ii) phenyl; or

(iii) C₃.₇cycloalkyl It will be appreciated that when X is phenyl the attached groups can be substituted at an ortha, meta or para position.

In one embodiment there is provided a compound of formula (I A) or a salt thereof

(IA)

in which R is Ci_i₈alkyl.

In one embodiment X is a cyclohexyl group.

In a further embodiment there is formula (IB) or a salt thereof

(IB)

in which R is d.₁₈alkyl.

In one embodiment there is provided a compound of formula (I), (IA) or (IB) in which R is C^^alkyl. In a further embodiment there is provided a compound of formula (I), (IA) or (IB) in which R is C_halky! such as ethyl, propyl, isopropyl, n-butyl, n-pentyl and n-hexyl. In a further embodiment there is provided a compound of formula (1A) or (1 B) in which R is methyl. Specific compounds according to the invention include Examples 1 - 13 as described herein or a salt thereof. Throughout the present specification, unless otherwise stated the term " d.^alkyl", " d_ ₁₈alkyl" or " C_halky!" 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.

It will be appreciated that the present invention covers compounds of formula (I) as the free base and as salts thereof, for example as a pharmaceutically acceptable salt thereof. In one embodiment the invention relates to compounds of formula (I) or a pharmaceutically acceptable salt thereof.

Because of their potential use in medicine, salts of the compounds of formula (I) are desirably pharmaceutically acceptable. Suitable pharmaceutically acceptable salts can include acid or base addition salts. For a review on suitable salts see Berge et al., J. Pharm. Sci., 66: 1-19, (1977). Typically, 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. 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).

It will be appreciated that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as "solvates". For example, a complex with water is known as a "hydrate". Solvents with high boiling points and/or capable of forming hydrogen bonds such as water, xylene, /V-methyl pyrrolidinone, methanol and ethanol may be used to form solvates. Methods for identification of solvates include, but are not limited to, NMR and microanalysis. Solvates of the compounds of formula (I) are within the scope of the invention.

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. Certain of the compounds described herein may contain one or more chiral atoms so that optical isomers, e.g. - enantiomers or diastereoisomers may be formed. Accordingly, 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.

It will be appreciated from the foregoing that included within the scope of the invention are solvates, isomers and polymorphic forms of the compounds of formula (I) and salts thereof. The compounds of the invention may be made by a variety of methods, including standard chemistry. Any previously defined variable will continue to have the previously defined meaning unless otherwise indicated. Illustrative general synthetic methods are set out below and then specific compounds of the invention are prepared in the working Examples.

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

(II)

with a compound of formula (III) or an activated derivative thereof

(ill)

in which X is (CH₂)_m in which m is 2, 3 or 4; and R is as defined in formula (I).

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).

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]- Λ/'-ethylcarbodiimide hydrochloride) with N-hydroxybenztriazole in a suitable organic solvent (such as THF or dichloromethane) with a suitable base (such as

methylmorpoline).

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). Such methodology is described in Schmidt et al (Synthesis, 1988, 475). Examples of activated derivatives of the compounds of formula (III) can also be acid chlorides or acid anhydrides. The 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).

The compound of formula (II) may be prepared by the method described in Scheme 1.

Scheme 1

Reagents and conditions: a) NH₂NH₂.H₂0, 1-butanol, reflux, 92%; b) KOH, DMSO, 3-cyanobenzyl chloride, 60%; c) 5-chloro-2-thiophenesulfonyl chloride, pyridine, 85%; d) 1 M LiAIH₄ 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. hydrogenolysis of a benzyl or benzyloxycarbonyl group or reductive removal of a 2',2',2'-trichloroethoxycarbonyl group using zinc in acetic acid) as appropriate. Other suitable amine protecting groups include trifluoroacetyl (- COCF₃) which may be removed by base catalysed hydrolysis.

It will be appreciated that in any of the routes described above, the precise order of the synthetic steps by which the various groups and moieties are introduced into the molecule may be varied. It will be within the skill of the practitioner in the art to ensure that groups or moieties introduced at one stage of the process will not be affected by subsequent transformations and reactions, and to select the order of synthetic steps accordingly.

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.

As used herein, 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. Furthermore, the term "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. 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, chronic glomerulonephritis, sepsis, adult respiratory distress syndrome, multiple sclerosis, memory impairment (including Alzheimer's disease), pain and cancer.

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)

The term "disease or condition for which a CCR4 inhibitor is indicated", is intended to include any or all of the above disease states.

In one embodiment the disease or condition for which a CCR4 inhibitor is indicated is selected from asthma, COPD, rhinitis, idiopathic pulmonary fibrosis, psoriasis and contact dermatitis. In a particular emdodiment the disease or condition for which a CCR4 inhibitor is indicated is asthma.

While it is possible that for use in therapy, 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. In accordance with another aspect of the invention there is also provided 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.

Further provided is a pharmaceutical composition 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. Further provided is 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.

Since 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).

Pharmaceutical 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.

Pharmaceutical 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).

In one embodiment the pharmaceutical composition is adapted for oral administration.

Pharmaceutical 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.

For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. 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. Moreover, when desired or necessary, 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. As an alternative to granulating, the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules. The granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil. The lubricated mixture is then compressed into tablets. The compounds of 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. Where appropriate, 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.

Pharmaceutical compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.

For treatments of the eye or other external tissues, for example mouth and skin, the compositions are preferably applied as a topical ointment or cream. When formulated in an ointment, the active ingredient may be employed with either a paraffinic or a water- miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an oil-in-water cream base or a water-in-oil base.

Pharmaceutical 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.

Pharmaceutical 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.

For compositions suitable and/or adapted for inhaled administration, it is preferred that 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, e.g. for inhaled administration, 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.

Where 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

1 , 1 , 1 ,2,3,3,3-heptafluoropropane and 1 , 1 , 1 ,2-tetrafluoroethane. 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.

For pharmaceutical compositions suitable and/or adapted for inhaled administration, the pharmaceutical composition may be a dry powder inhalable composition. Such a 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. Preferably, 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. lactose monohydrate and/or is preferably inhalation-grade and/or fine-grade lactose. Preferably, 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. 50-300 microns) in diameter, and/or 50% or more of the lactose particles being less than 100 microns in diameter. Optionally, 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. Most importantly, it is preferable that about 3 to about 30% (e.g. about 10%) (by weight or by volume) of the particles are less than 50 microns or less than 20 microns in diameter. For example, without limitation, a suitable inhalation-grade lactose is E9334 lactose (10% fines) (Borculo Domo Ingredients, Hanzeplein 25, 8017 JD Zwolle, Netherlands).

Optionally, in particular for dry powder inhalable compositions, 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. 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.

Pharmaceutical compositions adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.

Pharmaceutical 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. A therapeutically effective amount of a compound of the present invention will depend upon a number of factors including, for example, the age and weight of the subject, the precise condition requiring treatment and its severity, the nature of the formulation, and the route of administration, and will ultimately be at the discretion of the attendant physician or veterinarian. In the pharmaceutical composition, 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. The compounds of the invention and may be employed alone or in combination with other therapeutic agents. 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. Preferably, 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. Thus in a further aspect, there is provided a combination comprising a compound of the invention and at least one other pharmaceutically active agent. Thus in one aspect, 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/M₂/M₃ receptor antagonist), p₂-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 p₂-adrenoreceptor agonist, an anti-allergy agent, an antiinfective agent (such as an antibiotic or an antiviral), or an antihistamine.

It will be appreciated that when the compound of the present invention is 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.

One embodiment of the invention encompasses combinations comprising one or two other therapeutic agents. 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. Further examples of 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.

Examples of p₂-adrenoreceptor agonists 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. In one embodiment, the β ₂- adrenoreceptor agonists are long-acting β 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).

Examples of 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. For example, anticholinergic agents include muscarinic receptor antagonists, in particular, compounds which are antagonists of the or M₃ receptors, dual antagonists of Mi/M₃ or M₂/M₃ receptors or pan antagonists of Mi/M₂/M₃ 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. Examples of H1 antagonists include, without limitation, amelexanox, astemizole, azatadine, azelastine, acrivastine, brompheniramine, cetirizine, levocetirizine, efletirizine, chlorpheniramine, clemastine, cyclizine, carebastine, cyproheptadine, carbinoxamine, descarboethoxyloratadine, doxylamine, dimethindene, ebastine, epinastine, efletirizine, fexofenadine, hydroxyzine, ketotifen, loratadine, levocabastine, mizolastine, mequitazine, mianserin, noberastine, meclizine, norastemizole, olopatadine, picumast, pyrilamine, promethazine, terfenadine, tripelennamine, temelastine, trimeprazine and triprolidine, particularly cetirizine, levocetirizine, efletirizine and fexofenadine. In a further embodiment the invention provides a combination comprising a compound of the invention together with an H3 antagonist (and/or inverse agonist). Examples of H3 antagonists include, for example, those compounds disclosed in WO2004/035556 and in WO2006/045416. Other 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. montelukast), an 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.

Other 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.

The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical composition and thus pharmaceutical compositions comprising a combination as defined above together with a pharmaceutically acceptable diluent or carrier represent a further aspect of the invention.

In one aspect, 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. Preferably 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 (RA) is a further inflammatory disease where combination therapy may be contemplated. Thus in a further aspect, 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. Other 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 ibrufen).

It will be clear to a person skilled in the art that, where appropriate, the other therapeutic ingredient(s) may be used in the form of salts, for example as alkali metal or amine salts or as acid addition salts, or prodrugs, or as esters, for example lower alkyl esters, or as solvates, for example hydrates, to optimise the activity and/or stability and/or physical characteristics, such as solubility, of the therapeutic ingredient. It will be clear also that, where appropriate, the therapeutic ingredients may be used in optically pure form.

The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical composition and thus pharmaceutical compositions comprising a combination as defined above together with a pharmaceutically acceptable diluent or carrier represent a further aspect of the invention.

The individual compounds of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical compositions. Preferably, 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.

General Experimental Details

Analytical LCMS Analytical LCMS was conducted on one of the following systems A to E.

The 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.

Experimental details of LCMS systems A-E as referred to herein are as follows:

System A

Column: 50 mm x 2.1 mm ID, 1.7 μηι Acquity ultra performance liquid chromatography

Flow Rate: 1 mL/min.

Temp.: 40°C

Solvents: A: 0.1 % v/v formic acid in water

B: 0.1 % v/v formic acid in acetonitrile

Gradient: Time (min) A% B%

0 97 3

1.5 0 100

1.9 0 100

2.0 97 3

System B

Column: 30 mm x 4.6 mm ID, 3.5 μηι Sunfire C₁₈ column

Flow Rate: 3 mL/min.

Temp.: 30°C

Solvents: A: 0.1 % v/v solution of formic acid in water

B: 0.1 % v/v solution of formic acid in acetonitrile Gradient: Time (min) A% B%

0 97 3

0.1 97 3

4.2 0 100

4.8 0 100

4.9 97 3 5.0 97

System C

Column: 50 mm x 4.6 mm ID, 3.5 μηη XBridge Ci₈ column

Flow Rate: 3 mL/min.

Temp.: 30°C

Solvents: A: 10 mM ammonium bicarbonate in water adjusted to pH10 with ammonia solution

B: Acetonitrile

Gradient: Time (min) A%

0 99

0.1 99

4.0 3

5.0 3

System D

Column: 50 mm x 2.1 mm ID, 1.7 μηη Acquity UPLC BEH C₁₈

Flow Rate: 1 mL/min.

Temp.: 40°C

Solvents: A: 0.1% v/v solution of trifluoroacetic acid in water

B: 0.1 % v/v solution of trifluoroacetic acid in acetonitrile

Gradient: Time (min) A% B%

0 97 3

1.5 0 100

1.9 0 100

2.0 97 3

System E

Column: 30 mm x 4.6 mm ID, 3.5 μηη Sunfire C₁₈ column

Flow Rate: 3 mL/min. Temp.: 30°C

Solvents: A: 0.1 % v/v solution of trifluoroacetic acid in water

B: 0.1 % v/v solution of trifluoroacetic acid in acetonitrile

Gradient: Time (min) A% B%

0 97 3

0.1 97 3

4.2 0 100

4.8 0 100

4.9 97 3

5.0 97 3

System F

Column: 50 mm x 2.1 mm ID, 1.7 μηι Acquity UPLC BEH Ci₈ column

Flow Rate: 1 mL/min.

Temp.: 40°C

Solvents: A: 10 mM ammonium bicarbonate in water adjusted to pH10 with ammonia solution

B: Acetonitrile

Gradient: Time (min) A% B%

0 99 1

1.5 3 97

1.9 3 97

2.0 0 100

Mass directed auto-preparative HPLC

Crude products were purified by MDAP HPLC by one of the following methods A-C. The run time was 15 min unless otherwise stated. The UV detection for all methods 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. Method A:

Method A was conducted on a Sunfire Ci₈ column (typically 150 mm x 30 mm i packing diameter) at ambient temperature. The solvents employed were:

A = 0.1 % v/v solution of Formic acid in water

B = 0.1 % v/v solution of Formic acid in acetonitrile.

The gradient employed was:

Method B:

Method B was conducted on a Sunfire C₁₈ column (typically 150 mm x 30 mm i.d. 5 μηι packing diameter) at ambient temperature. The solvents employed were:

A = 0.1 % v/v solution of trifluoroacetic acid in water

B = 0.1 % v/v solution of trifluoroacetic acid in acetonitrile.

The gradient employed was:

Method C:

Method C was conducted on an XBridge Ci₈ 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.

B = acetonitrile.

The gradient employed was: Time (min) Flow Rate (mL/min) % A % B

0 40 99 1

1 40 99 1

10 40 70 30

11 40 1 99

15 40 1 99

Method D:

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:

A = 0.1 % v/v solution of Formic Acid in Water.

B= 0.05% v/v solution of Formic Acid in 95% Acetonitrile plus 5% Water.

The gradient employed was:

Abbreviations:

The following list provides definitions of certain abbreviations as used herein. It will be appreciated that the list is not exhaustive, but the meaning of those abbreviations not herein below defined will be readily apparent to those skilled in the art. Ac (acetyl)

Bu (butyl)

DCM (dichloromethane)

DEAD (diethyl azodicarboxylate)

DIAD (diisopropyl azodicarboxylate)

DMF (A/,A/-dimethylformamide) DMSO (dimethylsulfoxide)

Et (ethyl)

EtOAc (ethyl acetate)

h (hour/hours)

HATU [0-(7-Azabenzotriazol-1-yl)-N, N, NT, N'-tetramethyluronium

hexafluorophosphate

HCI (Hydrochloric acid)

L (liters)

M (molar)

MDAP (mass directed auto-preparative HPLC)

Me (methyl)

MeOH (methanol)

Ph (phenyl)

'Pr (isopropyl)

Si (Silica)

SPE (solid phase extraction)

TBAD (te/f-butyl azodicarboxylate)

TBD (1 , 3,4,6,7, 8-hexahydro-2/-/-pyrimido[1 ,2-a]pyrimidine)

TBTU [0-(benzothazol-1-yl)-/V,/\/,/\/',/\/'-tetramethyluronium tetrafluoroborate]

TEA (triethylamine)

TFA (trifluoroacetic acid)

THF (tetrahydrofuran)

TLC (thin layer chromatography)

TMS (trimethylsilyl)

All references to ether are to diethyl ether and brine refers to a saturated aqueous solution of NaCI.

Intermediate 1 Monomethyl glutarate

Glutaric anhydride (500 mg, 4.38 mmol) in methanol (5 mL) was treated with triethylamine (1.22 mL, 8.76 mmol) and the homogeneous mixture was stood at room temperature O/N and then evaporated under reduced pressure. The residue was dissolved in ethyl acetate, washed with 2M HCI, brine, dried (MgS0₄), and evaporated under reduced pressure to give the title compound as a colourless oil. NMR δ (DMSO-cfe) 12.0 (1 H, br s), 3.58 (3H, s), 2.33 (2H, t, J 7 Hz), 2.25 (2H, t, J 7 Hz), 1.77-1.67 (2H, m). Similarly were prepared Intermediates 2 - 8

Intermediate 2

Monoethyl glutarate ^cr ^ ^ "OH

NMR δ (DMSO-cfe) 12.0 (1 H, br s), 4.05 (2H, q, J 7 Hz), 2.31 (2H, t, J 7 Hz), 2.24 (2H, t, J 7 Hz), 1.77-1.68 (2H, m), 1.17 (3H, t, J 7 Hz).

Intermediate 3

Mono n-propyl glutarate

o o

\/ ^,O^/''\/\/'' ^,OH

NMR δ (DMSO-cfe) 12.1 (1 H, br s), 3.96 (2H, t, J 7 Hz), 2.32 (2H, t, J 7 Hz), 2.24 (2H, t, J 7 Hz), 1.78-1.69 (2H, m), 1.62-1.52 (2H, m).

Intermediate 4

Mono isopropyl glutarate

NMR δ (DMSO-cfe) 12.0 (1 H, br s), 4.82 (1 H, m), 2.27 (2H, t, J 7 Hz), 2.24 (2H, t, J 7 Hz), 1.76-1.67 (2H, m), 1.17 (6H, d, J 7 Hz). Intermediate 5

Mono-n-butyl glutarate

NMR δ (DMSO-de) 12.0 (1 H, br s), 4.01 (2H, t, J 7 Hz), 2.32 (2H, t, J 7 Hz), 2.24 (2H, t, J 7 Hz), 1.77-1.68 (2H, m), 1.58-1.50 (2H, m), 1.37-1.27 (2H, m), 0.88 (3H, t, J 7 Hz).

Intermediate 6

Mono n-propyl succinate

NMR δ (CDCI₃) 11.2 (1 H, br s), 3.92 (2H, t, J 7 Hz), 2.56-2.46 (4H, m), 1.56-1.46 (2H, m), 0.79 (3H, t, J 7 Hz).

Intermediate 7

Mono n-pentyl succinate

NMR δ (CDCIa) 11.0 (1 H, br s), 4.01 (2H, t, J 7 Hz), 2.62-2.50 (4H, m), 1.59-1.50 (2H, m), 1.30-1.20 (4H, m), 0.81 (3H, t, J 7 Hz).

Intermediate 8

Mono n-hexyl succinate

NMR δ (CDCIa) 11.0-8.8 (1 H, br), 4.10 (2H, t, J 7 Hz), 2.72-2.61 (4H, m), 1.67-1.54 (2H, m), 1.41-1.25 (6H, m), 0.90 (3H, t, J 7 Hz).

Intermediate 9

4-(Methyloxy)-1 H-indazol-3-amine

A mixture of 2-fluoro-6-(methyloxy)benzonitrile (available from Apollo) (10 g, 66 mmol) and hydrazine hydrate (9.63 mL, 198 mmol) in n-butanol (100 mL) was heated at reflux under nitrogen for 18 hours. The reaction mixture was allowed to cool, water (300 mL) was added, and the organic phase was removed. The solid in the aqueous phase was collected by filtration and dried in vacuo at 40°C to give a white solid (0.6g). The butanol phase was evaporated in vacuo, and the residue and the aqueous mother liquors were combined and extracted using ethyl acetate (2 x 200 mL). The combined ethyl acetate extractions were dried over magnesium sulphate and evaporated in vacuo. The residue was dissolved in DCM and applied to a 100g silica cartridge. This was eluted with cyclohexane (500 ml), cyclohexane-ethyl acetate (1 : 1v/v, 500 mL) and ethyl acetate (500 mL). The required fractions were combined and evaporated in vacuo to give the title compound (9.92 g, 92%) as an off-white solid. LCMS (System A) RT = 0.5 min, ES+ve m/z 164 (M+H)⁺.

Intermediate 10

3-{[3-Amino-4-(methyloxy)-1 H-indazol hyl}benzonitrile

To a solution of ground potassium hydroxide (6.75 g, 120 mmol) in DMSO (300 mL) at room temperature under nitrogen was added 4-(methyloxy)-1 /-/-indazol-3-amine (for a preparation see Intermediate 9)(7.85 g, 48.1 mmol), and this gave a deep red solution. After 5 minutes 3-(chloromethyl)benzonitrile (8.84 g, 58.3 mmol) was added in one portion. The reaction mixture was stirred for 20 minutes and then poured into water (500 mL), forming an emulsion. This was extracted using chloroform (3x500mL). The combined organic solutions were washed with water (400 mL) and passed through a hydrophobic frit. The solvent was removed in vacuo, the residue was applied to a 340 g silica cartridge, and eluted with a gradient of 0-100% ethyl acetate in cyclohexane over 8CV. This gave an orange solid which was treated with ethyl acetate (10 mL) and cyclohexane (90 mL). The solid was collected by filtration and washed with cyclohexane (50 mL). The solid was dried in vacuo to give the title compound (7.89 g, 59%) as a pale orange solid. LCMS (System A) RT = 0.93 min, ES+ve m/z 279 (M+H)⁺. Intermediate 11 5-Chloro- V-[1-[(3-cyanophenyl)methyl]-4-(methyloxy)-1H-indazol-3-yl]-2- thiophenesulfonamide

To 3-{[3-amino-4-(methyloxy)-1 /-/-indazol-1-yl]methyl}benzonitrile (for a preparation see Intermediate 10)(7.89 g, 28.3 mmol) was added a solution of 5-chloro-2-thiophenesulfonyl chloride (Aldrich)(6.15 g, 28.3 mmol) in pyridine (9.17 mL, 1 13 mmol) under nitrogen at room temperature. Reaction was exothermic and went deep red. After 40 minutes the reaction mixture was separated between ethyl acetate (500 mL) and 2N hydrochloric acid (500 mL). The aqueous phase was washed with ethyl acetate (400 mL). The combined organic solutions were dried over magnesium sulphate and evaporated in vacuo. The deep red residue was dissolved in DCM and applied to a 340g silica cartridge. The cartridge was eluted with a gradient of 0-10% ethyl acetate in dichloromethane over 8CV. Evaporation of the appropriate fractions gave the title compound (1 1.1 g, 85%) as an off- white solid. LCMS (System A) RT=1.15 min, ES+ve m/z 459/461 (M+H)⁺.

Intermediate 10

W-[1-{[3-(Aminomethyl)phenyl]methyl}-4-(methyloxy)-1 H-indazol-3-yl]-5-chloro-2- thiophenesulfonamide hydrochloride

To a cooled, 0°C, solution of 5-chloro-/V-[1-[(3-cyanophenyl)methyl]-4-(methyloxy)-1 /-/- indazol-3-yl]-2-thiophenesulfonamide (for a preparation see Intermediate 1 1)(1 1.1 g, 24.2 mmol) in THF (150 mL) was added, dropwise maintaining temp below 10°C, 1.0M lithium aluminium hydride solution in ether (60.5 mL, 60.5 mmol), effervescence occurred, and the suspension was stirred at room temperature for one hour. The reaction was quenched by addition of water (7 mL), followed by a 2.0M solution of sodium hydroxide (42.5 mL). After stirring for 30 minutes the solid was removed by filtration and washed with THF. The combined filtrate and washings were treated with 140g SCX silica. This was filtered and washed with methanol (1 L), and then 10% 2N hydrochloric acid in methanol (2 L). The required fractions were combined and concentrated. The resultant solid was collected by filtration and washed with water. The solid was dried in vacuo to give the title compound (9.3 g, 77%) as a white solid. LCMS (System A) RT=0.85 min, ES+ve m/z 463/465 (M+H)⁺.

Example 1

Methyl 5-{[(3-{[3-{[(5-chloro-2-thienyl)sulfonyl]amino}-4-(methyloxy)-1 H-indazol-1- yl]methyl}phenyl)methyl]amino

A solution of monomethyl ester of glutaric acid (32 mg, 0.22 mmol) in DMF (2 mL) was treated with A/-[3-(dimethylamino)propyl]-/\/'-ethylcarbodiimide hydrochloride (54 mg, 0.28 mmol) and /V-hydroxybenztriazole hydrate (43 mg, 0.28 mmol). The reaction mixture was stirred for 10 min. /V-methylmorpholine (0.1 mL, 0.9 mmol) was added, then Λ/-[1-{[3- (aminomethyl)phenyl]methyl}-4-(methyloxy)-1 /-/-indazol-3-yl]-5-chloro-2- thiophenesulfonamide (for a preparation see Intermediate 10)(100mg, 0.22 mmol). The reaction mixture was stirred at room temperature for 1 h, LCMS indicated complete reaction. The reaction mixture was then diluted with EtOAc (15 mL), and washed with water (2x10 mL), 2M HCI (2x10 mL), saturated sodium bicarbonate (1x10 mL), brine, dried (MgS0₄), filtered, and the solvent was removed in vacuo to give a white foam (129 mg). This was dissolved in MeOH-DMSO (1 : 1 , 2 mL) and purified by MDAP (Method A)using formic acid system collecting fraction with RT=8.63 min. The solvent was removed under reduced pressure to give the title compound (98 mg, 77%) as a white solid: LCMS (System A) RT=1.05 min, ES+ve m/z 591/593 (M+H)⁺.

Examples 2 - 12 were prepared in a similar way to Example 1. Example 2

Ethyl 5-{[(3-{[3-{[(5-chloro-2-thienyl)sulfonyl]amino}-4-(methyloxy)-1 H-indazol-1- yl]methyl}phenyl)methyl]amino

LCMS (System A) RT=1.10 min, ES+ve m/z 605/607 (M+H)⁺.

Example 3

Propyl 5-{[(3-{[3-{[(5-chloro-2-thienyl)sulfonyl]amino}-4-(methyloxy)-1 H-indazol-1- yl]methyl}phenyl)methyl]amino

LCMS (System A) RT=1.15 min, ES+ve m/z 619/621 (M+H)⁺.

Example 4

Butyl 5-{[(3-{[3-{[(5-chloro-2-thienyl)sulfonyl]amino}-4-(methyloxy)-1 H-indazol-1- yl]methyl}phenyl)methyl]amino}-5-oxopentanoate

LCMS (System A) RT=1.21 min, ES+ve m/z 633/635 (M+H)⁺.

Example 5

1-Methylethyl 5-{[(3-{[3-{[(5-chloro-2-thienyl)sulfonyl]amino}-4-(methyloxy)-1 H- indazol-1 -yl]methyl}phenyl)met anoate

LCMS (System A) RT=1.15 min, ES+ve m/z 619/621 (M+H)⁺. Example 6

Ethyl 4-{[(3-{[3-{[(5-chloro-2-thienyl)sulfonyl]amino}-4-(methyloxy)-1 H-indazol-1- yl]methyl}phenyl)methyl]amino}-4-oxobutanoate

LCMS (System A) RT=1.08 min, ES+ve m/z 591/593 (M+H)⁺.

Example 7

Butyl 4-{[(3-{[3-{[(5-chloro-2-thienyl)sulfonyl]amino}-4-(methyloxy)-1 H-indazol-1- yl]methyl}phenyl)methyl]amino}-4-oxobutanoate

LCMS (System A) RT=1.20 min, ES+ve m/z 619/621 (M+H)⁺.

Example 8

1-Methylethyl 4-{[(3-{[3-{[(5-chloro-2-thienyl)sulfonyl]amino}-4-(methyloxy)-1 H- indazol-1 -yl]methyl}phenyl)meth noate

LCMS (System A) RT=1.13 min, ES+ve m/z 605/607 (M+H)⁺. Example 9

Propyl 4-{[(3-{[3-{[(5-chloro-2-thienyl)sulfonyl]amino}-4-(methyloxy)-1 H-indazol-1- yl]methyl}phenyl)methyl]amino}-4-oxobutanoate

LCMS (System A) RT=1.14 min, ES+ve m/z 605/607 (M+H)⁺.

Example 10

Methyl 4-{[(3-{[3-{[(5-chloro-2-thienyl)sulfonyl]amino}-4-(methyloxy)-1 H-indazol-1- yl]methyl}phenyl)methyl]amino}-4-oxobutanoate

LCMS (System A) RT=1.04 min, ES+ve m/z 577/579 (M+H)⁺.

Example 11

Pentyl 4-{[(3-{[3-{[(5-chloro-2-thienyl)sulfonyl]amino}-4-(methyloxy)-1 H-indazol-1- yl]methyl}phenyl)methyl]amino}-4-oxobutanoate

LCMS (System A) RT=1.25 min, ES+ve m/z 633/635 (M+H)⁺.

Example 12

Hexyl 4-{[(3-{[3-{[(5-chloro-2-thienyl)sulfonyl]amino}-4-(methyloxy)-1 H-indazol-1- yl]methyl}phenyl)methyl]amino}-4-oxobutanoate

LCMS (System A) RT=1.31 min, ES+ve m/z 647/649 (M+H)⁺. Example 13

Methyl 4-((3-((3-(5-chlorothiophene-2-sulfonamido)-4-methoxy-1H-indazol-1- yl)methyl)benzyl)carbamoyl)benzoate

A solution of A/-(1-(3-(aminomethyl)benzyl)-4-methoxy-1 /-/-indazol-3-yl)-5- chlorothiophene-2-sulfonamide hydrochloride salt (for a preparation see Intermediate 10) (105.5 mg, 0.21 mmol) and methyl 4-chlorocarbonylbenzoate (50.3 mg, 0.25 mmol) in pyridine (1 ml_) was stirred at room temperature for 3 h. More acid chloride (5 mg) was added and the mixture was stirred at RT for another 2 h. LCMS indicated the presence of starting material and more acid chloride (5 mg) was added and the mixture stirred over the weekend. The mixture was concentrated in a blow-down unit under nitrogen and the residue was dissolved in DMSO-MeOH (1 : 1 ; 2 ml_) and purified by MDAP (Method A) collecting the fractions with RT=10.23 min. The solvent was removed in a blow-down unit under nitrogen to give the title compound (30 mg, 23%) as a white solid: LCMS (System A) RT=1.16 min, ES+ve m/z 62 ⁺.

Biological Test Methods

Compounds may be tested for CCR4 activity in the following assay. T35S1- GTPvS SPA Binding Assays for CCR4 Antagonist Activity

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 MgCI₂, 100mM NaCI, 0.05% BSA, 40ug/ml Saponin and pH adjusted to 7.4 using KOH 5M) to generate a 3μg/well final assay concentration (FAC) membrane and 250μg/well FAC bead, solution.

After 60 minutes pre-coupling on ice, GDP was added to give a 4.4uM FAC. [35S]-GTPyS made in assay buffer was then added to the bead/membrane solution to give a 0.33nM FAC. Human MDC was added to the bead/membrane/[35S]-GTPYS suspension to give an FAC that exhibits 80% of the maximal agonist response (EC80). The bead/membrane/[35S]-GTPYS/Agonist suspension was dispensed into white Greiner polypropylene 384-well plates (45μΙ/ννβΙΙ), containing 0.5μΙ of compound. The final assay solution (45.5μΙ) 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.

All tested compounds were found to have plC50≥ 6.5 and < 8.0. Examples 1 , 2, 3, 5, 6, and 8 - 10 were found to have a plC50≥ 7.0 and < 8.0.

All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.

Claims

1. Acompound of formula (I) or a salt thereof

(I)

wherein

R is d_₁₈alkyl;

X is (i) (CH₂)_m in which m is 2, 3 or 4;

(ii) phenyl; or

(iii) C₃-₇cycloalkyl.

2. A compound according to claim 1 which is a compound of formula (IA) or a salt thereof

(IA)

in which R is Ci.i₈alkyl.

3. A compound according to claim 1 which is a compound of formula (IB) or a salt thereof

(IB)

in which R is Ci_i₈alkyl.

4. A compound according to any one of claims 1 - 3 or a salt thereof in which R is C₂. ₆alkyl.

5. A compound according to claim 4 or a salt thereof in which R is ethyl, propyl, isopropyl, n-butyl, n -penyl and n-hexyl.

6. A compound which is any of one of Examples 1 - 13 or a salt thereof.

7. A pharmaceutical composition which comprises a compound as defined in any one of claims 1 - 6 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.

8. A combination pharmaceutical product comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 - 6 together with one or more other therapeutically active agents.

9. A compound as defined in any of claims 1 - 6 or a pharmaceutically acceptable salt thereof for use in therapy.

10. A compound as defined in any one of claims 1 - 6 or a pharmaceutically acceptable salt thereof for use in the treatment of a disease or condition for which a CCR4 receptor antagonist is indicated.

11. The use of a compound as defined in any of claims 1 - 6 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.

12. 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 compound as defined in any of claims 1 - 6 or a pharmaceutically acceptable salt thereof.