Certain phenethanolamine compounds are known in the art as having selective stimulant action at ß2-adrenoreceptors and therefore having utility in the treatment of bronchial asthma and related disorders. Thus GB 2 140 800 describes phenethanolamine compounds including 4-hydroxy-a'- [ [ [6- {4-phenyibuoxy) hexyl] amino] methyl]-1, 3- benzenedimethanol 1-hydroxy-2-naphthalenecarboxylate (salmeterol xinafoate) which is now used clinically in the treatment of such medical conditions.

Although salmeterol and the other commercially available ß2-adrenoreceptor agonists are effective bronchodilators, the duration of action is approximately 12 hours, hence twice daily dosing is often required. There is therefore a clinical need for compounds having potent and selective stimulant action at pz-adrenoreceptors and having an advantageous profile of action.

According to the present invention, there is provided a compound of formula (I) or a salt, solvate, or physiologically functional derivative thereof, wherein: m is an integer of from 2 to 8; n is an integer of from 3 to 11, preferably from 3 to 7, with the proviso that the sum of m + n is from 5 to 19, preferably 5 to 12; R1 is-XSO2NR6R7 ; wherein X is- (CH2) p-or C2-6 alkenylene ;

p is an integer from 0 to 6, preferably 0 to 4; R6 and R7 are independently selected from hydrogen, C1-6alkyl, C3-7cycloalkyl, -CONR8R9, phenyl and phenyl (C14alkyl)-, or R6 and R7, together with the nitrogen atom to which they are bonded, form a 5-, 6-or 7- membered nitrogen-containing ring; and R6 and R7 are each independently optionally substituted by 1 or 2 groups independently selected from halo, C1-6alkyl, C1-6alkoxy, hydroxy-substituted C1-6alkoxy, C1-6haloalkyl, -CO2R8, -SO2R8R9, -CONR8R9, -NR8C(O)R9 or a 5-, 6-or 7-membered heterocyclic ring; R8 and R9 are independently selected from hydrogen, C1-6alkyl, C3-7cycloalkyl, phenyl and phenyl (C1-6alkyl)-; R2 and R3 are independently selected from hydrogen, C1-6alkyl, C1-6alkoxy, halo, phenyl and C1 6haloalkyl ; R4 and R5 are independently selected from hydrogen and C14 alkyl with the proviso that the total number of carbon atoms in R4 and R5 is not more than 4; Ar'is a group selected from

wherein R"represents hydrogen, ahlogen, -(CH2)qOR14, -NR14C(O)R15, -NR14SO2R15, - SO2NR14R15, -NR14R15, -OC(O)R16 or -OC(O)NR14R15, and Rlo represents hydrogen, halogen or C1-4alkyl ; or R11 reprsents -NHR17 and R10 and -NHR17 together form a 5-or 6-membered heterocyclic ring; R12 represents hydrogen, halogen, -OR14 or -NR14R15; R13 represents hydrogen, halogen, haloC1-4alkyl, -OR14, -NR14R15 -OC(O)R16 or - OC NR14R15 ; R14 and R15 each independently represents hydrogen or Cl-4 alkyl, or in the groups -NR14R15, -SO2NR14R15 and -OC(O)NR14R15, R14 and R"5 independently represent hydrogen or C1-4 alkyl or together with the nitrogen atom to which they are attached form a 5-, 6-or 7-membered nitrogen-containing ring,

R16 represents an aryl (eg phenyl or naphthyl) group which may be unsubstituted or substituted by one or more substituents selected from halogen, C14 alkyl, hydroxy, C1-4 alkoxy or halo C14 alkyl ; and q is zero or an integer from 1 to 4. and Ar2 is a mono-or bicyclic heteroaryl or a bicyclic aryl group.

In the definition of R1 where'R6 and R7 together with the nitrogen atom to which they are bonded, form a 5-, 6-, or 7-membered nitrogen containing ring', the term"5-, 6-, or 7- membered nitrogen containing ring"means a 5-, 6-, or 7-membered saturated or unsaturated ring which includes the sulfonamide nitrogen atom and optionally 1 or 2 other heteroatoms independently selected from nitrogen, sulphur, and oxygen. Suitable examples of such a ring include piperidinyl, morpholinyl, and piperazinyl.

In the definition of R', specifically the optional substituents on R5 and R7, the term"5-, 6-, or 7-membered heterocyclic ring"means a 5-, 6-, or 7-membered fully or partially saturated or unsaturated ring which includes 1,2, 3 or 4 heteroatoms independently selected from nitrogen, sulphur, and oxygen. Suitable examples of such a ring include pyrrolyl, furyl, thienyl, pyridinyl, pyrazinyl, pyridazinyl, imidazolyl, tetrazolyl, tetrahydrofuranyl, oxazolyl, thiazolyl, thiadiazolyl, piperidinyl, morpholinyl, and piperazinyl.

In the definition of X, the term alkenylene includes both cis and trans structures. Examples of suitable alkenylene groups include-CH=CH-. X preferably represents (CH2) p wherein p is 0,1 or 2, or C2-alkenylene.

R1 preferably represents-So2NR6R7 wherein R5 and R7 are independently selected from hydrogen and C1 6alkyl. More preferably R'is-S02NH2.

R4 and R5 are preferably independently selected from hydrogen and methyl, more preferably R4 and R5 are both hydrogen.

In the compounds of formula (1) R2 and R3 preferably each represent hydrogen.

The integer n is suitably 4,5 or 6 and m is suitably 3,4, 5 or 6. Preferably n is 5 or 6 and m is 3 or 4 such that m + n is 8,9 or 10, preferably 9.

In the compounds of formula (I) the group Ar1 is preferably selected from groups (a) and (b) above.

In said groups (a) and (b), when R11 represents halogen this. is preferably chlorine or fluorine, especially fluorine.

R14 and R15 preferably each independently represent hydrogen or methyl.

R'6 preferably represents substituted phenyl.

The integer q preferably represents zero or 1.

Thus for example-(CH2) qoR14 preferably represents OH or-CH20H ; -NR14C(O)R15 preferably represents-NHC (O) H; -SO2NR14R15 preferably represents-SO2NH2 or-SO2NHCH3 ; -NR14R15 preferably represents-NH2 ; -OC(O)R16 preferably represents substituted benzoyloxy eg. -OC (O)-C6H4- (p-CH3) ; and -OC(O) N R14R15 preferably represents-OC (O) N (CH3) 2.

When R11 represents NHR17 and together with Rlo forms a 5-or 6-membered heterocyclic ring -NHR17-R10-preferably represents a group: -NH-CO-R18 whiere R18 is an alkyl, and alkenyl or alkyloxy group; -NH-SO2R19 where R'9 is an alkyloxy group; -NH-R20 where R19 is an alkyl or alkenyl group optionally substituted by -COOR21 and R21 is C14 alkyl ; or - NH-CO-S, wherein said alkyl, and alkenyl groups and moieties contain 1 or 2 carbon atoms.

Particularly preferred groups (a) and (b) may be selected from the following groups (i) to (xxi):

wherein the dotted line in (xvi) and (xix) denotes an optional double bond.

Most preferably Ar'represents a group (i).

When used herein, the term"bicyclic aryl"refers to, unless otherwise defined, a bicyclic carbocyclic aromatic ring system containing up to 10 carbon atoms in the ring system, for instance naphthyl.

As used herein, the terms"heteroaryl ring"and"heteroaryl"refer to, unless otherwise defined, a monocyclic five-to seven-membered heterocyclic aromatic ring containing one or more heteroatoms selected from oxygen, nitrogen and sulfur or a fused bicyclic heterocyclic aromatic ring system containing at least one heteroatom selected from oxygen, nitrogen and sulfur. In a particular aspect a monocyclic heteroaryl ring contains 1-3 heteroatoms. Preferably, the heteroaryl ring has five or six ring atoms. Examples of monocyclic heteroaryl rings include, but are not limited to, furyl, thienyl (thiophenyl), pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl,

triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl.

Preferably, in a fused bicyclic heteroaryl ring system each ring has five or six ring atoms.

Examples of fused heterocyclic aromatic rings include, but are not limited to, quinolinyl, <BR> <BR> <BR> isoquinolinyl, quinazolinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, indolyl, indazolyl, pyrrolopyridinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl and benzothiadiazolyl.

The heteroaryl ring may attach to the rest of the molecule through any atom with a free valence.

In the compounds of formula (I) Ar2 preferably represents a monocyclic heteroaryl eg pyridyl, 2-thiophenyl, 3-thiophenyl or a bicyclic aryl group eg naphthyl.

It is to be understood that the present invention covers all combinations of particular and preferred groups described hereinabove.

The compounds of formula (I), include an asymmetric centre, namely the carbon atom of the group. The present invention includes both (S) and (R) enantiomers either in substantially pure form or admixed in any proportions.

Similarly, where R4 and R5 are different groups, the carbon atom to which they are attached is an asymmetric centre and the present invention includes both (S) and (R) enantiomers at this centre either in substantially pure form or admixed in any proportions.

Thus the compounds of formula (I), include all enantiomers and diastereoisomers as well as mixtures thereof in any proportions.

Salts and solvates of compounds of formula (I) which are suitable for use in medicine are those wherein the counterion or associated solvent is pharmaceutically acceptable. However, salts and solvates having non-pharmaceutically acceptable counterions or associated solvents are within the scope of the present invention, for example, for use as

intermediates in the preparation of other compounds of formula (I) and their pharmaceutical acceptable salts, solvates, and physiologically functional derivatives.

By the term"physiologically functional derivative"is meant a chemical derivative of a compound of formula (I) having the same physiological function as the free compound of formula (I) for example, by being convertible in the body thereto. According to the present invention, examples of physiologically functional derivatives include esters.

Suitable salts according to the invention include those formed with both organic and inorganic acids or bases. Pharmaceutical acceptable acid addition salts include those formed from hydrochloric, hydrobromic, sulphuric, citric, tartaric, phosphoric, lactic, pyruvic, acetic, trifluoroacetic, triphenylacetic, sulphamic, sulphanilic, succinic, oxalic, fumaric, maleic, malic, glutamic, aspartic, oxaloacetic, methanesulphonic, ethanesulphonic, arylsulponic (for example p-toluenesulphonic, benzenesulphonic, naphthalenesulphonic or naphthalenedisulphonic), salicylic, glutaric, gluconic, tricarballylic, cinnamic, substituted cinnamic (for example, methyl, methoxy or halo substituted cinnamic, including 4-methyl and 4-methoxycinnamic acid), ascorbic, oleic, naphthoic, hydroxynaphthoic (for example 1-or 3-hydroxy-2-naphthoic), naphthaleneacrylic (for example naphthalene-2-acrylic), benzoic, 4-methoxybenzoic, 2-or 4-hydroxybenzoic, 4-chlorobenzoic, 4-phenylbenzoic, benzeneacrylic (for example 1,4- benzenediacrylic) and isethionic acids. Pharmaceutically acceptable base salts include 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 such as dicyclohexyl amine and N-methyl-D-glucamine.

Pharmaceutically acceptable esters of the compounds of formula (I) may have a hydroxyl group converted to a C1 6alkyl, aryl, aryl C1 6 alkyl, or amino acid ester.

As mentioned above, the compounds of formula (I) are selective ps-adrenoreceptor agonists as demonstrated using functional or reporter gene readout from cell lines transfected with human beta-adrenoreceptors as described below. Compounds according to the present invention also have the potential to combine long duration of effect with rapid onset of action.

Therefore, compounds of formula (I) and their pharmaceutically acceptable salts, solvates, and physiologically functional derivatives have use in the prophylaxis and

treatment of clinical conditions for which a selective (32-adrenoreceptor agonist is indicated. Such conditions include diseases associated with reversible airways obstruction such as asthma, chronic obstructive pulmonary diseases (COPD) (e. g. chronic and wheezy bronchitis, emphysema), respiratory tract infection and upper respiratory tract disease (e. g. rhinitis, including seasonal and allergic rhinitis).

Other conditions which may be treated include premature labour, depression, congestive heart failure, skin diseases (e. g. inflammatory, allergic, psoriatic, and proliferative skin diseases), conditions where lowering peptic acidity is desirable (e. g. peptic and gastric ulceration) and muscle wasting disease.

Accordingly, the present invention provides a method for the prophylaxis or treatment of a clinical condition in a mammal, such as a human, for which a selective pz-adrenoreceptor agonist is indicated, which comprises administration of a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof. In particular, the present invention provides such a method for the prophylaxis or treatment of a disease associated with reversible airways obstruction such as asthma, chronic obstructive pulmonary disease (COPD), respiratory tract infection or upper respiratory tract disease. In a further aspect the present invention provides such a method for the prophylaxis or treatment of a clinical condition selected from premature labour, depression, congestive heart failure, skin diseases (e. g. inflammatory, allergic, psoriatic, and proliferative skin diseases), conditions where lowering peptic acidity is desirable (e. g. peptic and gastric ulceration) or muscle wasting disease.

In the alternative, there is also provided a compound of formula (I), or a pharmaceutical acceptable salt, solvate, or physiologically functional derivative thereof for use in medical therapy, particularly, for use in the prophylaxis or treatment of a clinical condition in a mammal, such as a human, for which a selective p2-adrenorecePtor agonist is indicated.

In particular, there is provided a compound of formula (I), or a pharmaceutical acceptable salt, solvate, or physiologically functional derivative thereof for the prophylaxis or treatment of a disease associated with reversible airways obstruction such as asthma, chronic obstructive pulmonary disease (COPD), respiratory tract infection or upper respiratory tract disease. In a further aspect, there is provided a compound of formula (I), or a pharmaceutical acceptable salt, solvate, or physiologically functional derivative thereof for the prophylaxis or treatment of a clinical condition selected from premature

labour, depression, congestive heart failure, skin diseases (e. g. inflammatory, allergic, psoriatic, and proliferative skin diseases), conditions where lowering peptic acidity is desirable (e. g. peptic and gastric ulceration) or muscle wasting disease.

The present invention also provides the use of a compound of formula (I), or a pharmaceutical acceptable salt, solvate, or physiologically functional derivative thereof in the manufacture of a medicament for the prophylaxis or treatment of a clinical condition for which a selective pz-adrenoreceptor agonist is indicated, for example a disease associated with reversible airways obstruction such as asthma, chronic obstructive pulmonary disease (COPD), respiratory tract infection or upper respiratory tract disease.

In a further aspect, there is provided a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof in the manufacture of a medicament for the prophylaxis or treatment of a clinical condition selected from premature labour, depression, congestive heart failure, skin diseases (e. g. inflammatory, allergic, psoriatic, and proliferative skin diseases), conditions where lowering peptic acidity is desirable (e. g. peptic and gastric ulceration) and muscle wasting disease.

The amount of a compound of formula (I), or a pharmaceutical acceptable salt, solvate or physiologically functional derivative thereof which is required to achieve a therapeutic effect will, of course, vary with the particular compound, the route of administration, the subject under treatment, and the particular disorder or disease being treated. The compounds of the invention may be administered by inhalation at a dose of from 0.0005mg to 10mg, preferably 0.005mg to 0.5mg for example 0.05mg to 0.5mg. The dose range for adult humans is generally from 0.0005mg to 10mg per day and preferably 0.01 mg to 1 mg per day, most preferably 0.05 to 0.5mg per day.

While it is possible for the compound of formula (1), or a pharmaceutical acceptable salt, solvate, or physiologically functional derivative thereof to be administered alone, it is preferable to present it as a pharmaceutical formulation.

Accordingly, the present invention further provides a pharmaceutical formulation comprising a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, and a pharmaceutically acceptable carrier or excipient, and optionally one or more other therapeutic ingredients.

Hereinafter, the term"active ingredient"means a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.

The formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), inhalation (including fine particle dusts or mists which may be generated by means of various types of metered dose pressurised aerosols, nebulisers or insufflators), rectal and topical (including dermal, buccal, sublingual and intraocular) administration although the most suitable route may depend upon for example the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.

Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules ; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water- in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.

A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.

Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and

thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example saline or water-for-injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

Dry powder compositions for topical delivery to the lung by inhalation may, for example, be presented in capsules and cartridges of for example gelatine, or blisters of for example laminated aluminium foil, for use in an inhaler or insufflator. Powder blend formulations generally contain a powder mix for inhalation of the compound of the invention and a suitable powder base (carrier/diluent/excipient substance) such as mono-, di or poly- saccharides (eg. lactose or starch). Use of lactose is preferred.

Each capsule or cartridge may generally contain between 201lg-10mg of the compound of formula (I) optionally in combination with another therapeutical active ingredient.

Alternatively, the compound of the invention may be presented without excipients.

Packaging of the formulation may be suitable for unit dose or multi-dose delivery. In the case of multi-dose delivery, the formulation can be pre-metered (eg as in Diskus, see GB 2242134, US Patent Nos. 6,632, 666,5, 860,419, 5,873, 360 and 5,590, 645 or Diskhaler, see GB 2178965,2129691 and 2169265, US Patent No. s 4,778, 054, 4,811, 731,5, 035,237, the disclosures of which are hereby incorporated by reference) or metered in use (eg as in Turbuhaler, see EP 69715 or in the devices described in US Patents No. 6,321, 747 the disclosures of which are hereby incorporated by reference).

An example of a unit-dose device is Rotahaler (see GB 2064336 and US Patent No.

4,353, 656, the disclosures of which are hereby incorporated by reference). The Diskus inhalation device comprises an elongate strip formed from a base sheet having a plurality of recesses spaced along its length and a lid sheet hermetically but peelably sealed thereto to define a plurality of containers, each container having therein an inhalable formulation containing a compound of formula (I) preferably combined with lactose.

Preferably, the strip is sufficiently flexible to be wound into a roll. The lid sheet and base sheet will preferably have leading end portions which are not sealed to one another and at least one of the said leading end portions is constructed to be attached to a winding means. Also, preferably the hermetic seal between the base and lid sheets extends over their whole width. The lid sheet may preferably be peeled from the base sheet in a longitudinal direction from a first end of the said base sheet.

Spray compositions for topical delivery to the lung by inhalation may for example be formulated as aqueous solutions or suspensions or as aerosols delivered from pressurised packs, such as a metered dose inhaler, with the use of a suitable liquefied propellant. Aerosol compositions suitable for inhalation can be either a suspension or a solution and generally contain the compound of formula (I) optionally in combination with another therapeutically active ingredient and a suitable propellant such as a fluorocarbon or hydrogen-containing chlorofluorocarbon or mixtures thereof, particularly hydrofluoroalkanes, e. g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetra- fluoroethane, especially 1,1, 1, 2-tetrafluoroethane, 1,1, 1,2, 3,3, 3-heptafluoro-n-propane or a mixture thereof. Carbon dioxide or other suitable gas may also be used as propellant.

The aerosol composition may be excipient free or may optionally contain additional formulation excipients well known in the art such as surfactants eg oleic acid or lecithin and cosolvens eg ethanol. Pressurised formulations will generally be retained in a canister (eg an aluminium canister) closed with a valve (eg a metering valve) and fitted into an actuator provided with a mouthpiece.

Medicaments for administration by inhalation desirably have a controlled particle size. The optimum particle size for inhalation into the bronchial system is usually 1-101lm, preferably 2-5, um. Particles having a size above 20, um are generally too large when inhaled to reach the small airways. To achieve these particle sizes the particles of the active ingredient as produced may be size reduced by conventional means eg by micronisation. The desired fraction may be separated out by air classification or sieving. Preferably, the particles will be crystalline. When an excipient such as lactose is employed, generally, the particle size of the excipient will be much greater than the inhaled medicament within the present invention. When the excipient is lactose it will typically be present as milled lactose, wherein not more than 85% of lactose particles will have a MMD of 60-90, um and not less than 15% will have a MMD of less than 15p. m.

Intranasal sprays may be formulated with aqueous or non-aqueous vehicles with the addition of agents such as thickening agents, buffer salts or acid or alkali to adjust the pH, isotonicity adjusting agents or anti-oxidants.

Capsules and cartridges or for example gelatin, or blisters of for example laminated aluminium foil, for use in an inhaler or insulator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.

Solutions for inhalation by nebulation may be formulated with an aqueous vehicle with the addition of agents such as acid or alkali, buffer salts, isotonicity adjusting agents or antimicrobials. They may be sterilised by filtration or heating in an autoclave, or presented as a non-sterile product.

Formulations for rectal administration may be presented as a suppository with the usual carriers such as cocoa butter or polyethylene glycol.

Formulations for topical administration in the mouth, for example buccally or sublingually, include lozenges comprising the active ingredient in a flavoured basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerin or sucrose an acacia.

Preferred unit dosage formulations are those containing an effective dose, as hereinbefore recited, or an appropriate fraction thereof, of the active ingredient.

It should be understood that in addition to the ingredients particularly mentioned above, the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.

The compounds and pharmaceutical formulations according to the invention may be used in combination with or include one or more other therapeutic agents, for example anti- inflammatory agents, anticholinergic agents (particularly an Mi, M2, Mi/M2 or M3 receptor antagonist), other p2-adrenoreceptor agonists, antiinfective agents (e. g. antibiotics, antivirals), or antihistamines. The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutical acceptable salt, solvate or physiologically functional derivative thereof together with one or more other therapeutically active agents, for example, an anti-inflammatory agent (for example a corticosteroid or an NSAID), an anticholinergic agent, another ps-adrenoreceptor agonist, an antiinfective agent (e. g. an antibiotic or an antiviral), or an antihistamine. Preferred are combinations comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with a corticosteroid,

and/or an anticholinergic, and/or a PDE-4 inhibitor. Preferred combinations are those comprising one or two other therapeutic agents.

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

Suitable anti-inflammatory agents include corticosteroids and NSAIDs. Suitable corticosteroids which may be used in combination with the compounds of the invention are those oral and inhaled corticosteroids and their pro-drugs which have anti- inflammatory activity. Examples include methyl prednisolone, prednisolone, dexamethasone, fluticasone propionate, 6a, 9a-difluoro-17a- [ (2-furanylcarbonyl) oxy]-11- hydroxy-16a-methyl-3-oxo-androsta-1, 4-diene-17p-carbothioic acid S-fluoromethyl ester, <BR> <BR> <BR> <BR> 6a, 9c-difluoro-11 ß-hydroxy-16cc-methyl-3-oxo-17a-propionyloxy-androsta-1, 4-diene-17ß- carbothioic acid S- (2-oxo-tetrahydro-furan-3S-yl) ester, beclomethasone esters (e. g. the 17-propionate ester or the 17,21-dipropionate ester), budesonide, flunisolide, mometasone esters (e. g. the furoate ester), triamcinolone acetonide, rofleponide, ciclesonide, butixocort propionate, RPR-106541, and ST-126. Preferred corticosteroids include fluticasone propionate, 6α,9α-difluoro-11ß-hydroxy-16α-methyl-17α-[(4-methyl- 1, 3-thiazole-5-carbonyl) oxy] -3-oxo-androsta-1, 4-diene-17p-carbothioic acid S- fluoromethyl ester and 6a, 9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11ß-hydroxy-16α - methyl-3-oxo-androsta-1, 4-diene-17p-carbothioic acid S-fluoromethyl ester, more <BR> <BR> <BR> <BR> preferably 6a, 9a-difluoro-17a- [ (2-furanylcarbonyl) oxy]-11 i-hydroxy-16a-methyl-3-oxo- androsta-1, 4-diene-17p-carbothioic acid S-fluoromethyl ester.

Suitable NSAIDs include sodium cromoglycate, nedocromil sodium, phosphodiesterase (PDE) inhibitors (e. g. theophylline, PDE4 inhibitors or mixed PDE3/PDE4 inhibitors), leukotriene antagonists, inhibitors of leukotriene synthesis, iNOS inhibitors, tryptase and elastase inhibitors, beta-2 integrin antagonists and adenosine receptor agonists or antagonists (e. g. adenosine 2a agonists), cytokine antagonists (e. g. chemokine antagonists) or inhibitors of cytokine synthesis. Suitable other ß2-adrenoreceptor agonists

include salmeterol (e. g. as the xinafoate), salbutamol (e. g. as the sulphate or the free base), formoterol (e. g. as the fumarate), fenoterol or terbutaline and salts thereof.

Of particular interest is use of the compound of formula (I) in combination with a phosphodiesterase 4 (PDE4) inhibitor or a mixed PDE3/PDE4 inhibitor. The PDE4- specific inhibitor useful in this aspect of the invention may be any compound that is known to inhibit the PDE4 enzyme or which is discovered to act as a PDE4 inhibitor, and which are only PDE4 inhibitors, not compounds which inhibit other members of the PDE family as well as PDE4. Generally it is preferred to use a PDE4 inhibitor which has an iCgn ratio of about 0.1 or greater as regards the iCgo for the PDE4 catalytic form which binds rolipram with a high affinity divided by the IC50 for the form which binds rolipram with a low affinity. For the purposes of this disclosure, the cAMP catalytic site which binds R and S rolipram with a low affinity is denominated the"low affinity"binding site (LPDE 4) and the other form of this catalytic site which binds rolipram with a high affinity is denominated the"high affinity"binding site (HPDE 4). This term"HPDE4"should not be confused with the term"hPDE4"which is used to denote human PDE4.

A method for determining IC50s ratios is set out in US patent 5,998, 428 which is incorporated herein in full by reference as though set out herein. See also PCT application WO 00/51599 for an another description of said assay.

The preferred PDE4 inhibitors of use in this invention will be those compounds which have a salutary therapeutic ratio, i. e. , compounds which preferentially inhibit cAMP catalytic activity where the enzyme is in the form that binds rolipram with a low affinity, thereby reducing the side effects which apparently are linked to inhibiting the form which binds rolipram with a high affinity. Another way to state this is that the preferred compounds will have an IC50 ratio of about 0.1 or greater as regards the Cgo for the PDE4 catalytic form which binds rolipram with a high affinity divided by the iCgn for the form which binds rolipram with a low affinity.

A further refinement of this standard is that of one wherein the PDE4 inhibitor has an IC50 ratio of about 0.1 or greater; said ratio is the ratio of the iCgn value for competing with the binding of 1nM of [3H] R-rolipram to a form of PDE4 which binds rolipram with a high

affinity over the tCgo value for inhibiting the PDE4 catalytic activity of a form which binds rolipram with a low affinity using 1 ptM [3H]-cAMP as the substrate.

Most preferred are those PDE4 inhibitors which have an Cgo ratio of greater than 0.5, and particularly those compounds having a ratio of greater than 1.0. Preferred compounds are cis 4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexan-1- carboxylic acid, 2-carbomethoxy-4-cyano-4- (3-cyclopropylmethoxy-4- difluoromethoxyphenyl) cyclohexan-1-one and cis- [4-cyano-4- (3-cyclopropylmethoxy-4- difluoromethoxyphenyl) cyclohexan-1-ol] ; these are examples of compounds which bind preferentially to the low affinity binding site and which have an tCgo ratio of 0.1 or greater.

Other compounds of interest include : Compounds set out in U. S. patent 5,552, 438 issued 03 September, 1996; this patent and the compounds it discloses are incorporated herein in full by reference. The compound of particular interest, which is disclosed in U. S. patent 5,552, 438, is cis-4-cyano-4- [3- (cyclopentyloxy)-4-methoxyphenyl] cyclohexane-1-carboxylic acid (also known as cilomalast) and its salts, esters, pro-drugs or physical forms; AWD-12-281 from Asta Medica (Hofgen, N. et al. 15th EFMC Int Symp Med Chem (Sept 6-10, Edinburgh) 1998, Abst P. 98; CAS reference No. 247584020-9); a 9-benzyladenine derivative nominated NCS-613 (INSERM) ; D-4418 from Chiroscience and Schering- Plough ; a benzodiazepine PDE4 inhibitor identified as CI-1018 (PD-168787) and attributed to Pfizer; a benzodioxole derivative disclosed by Kyowa Hakko in W099/16766 ; K-34 from Kyowa Hakko; V-11294A from Napp (Landells, L. J. et al. Eur Resp J [Annu Cong Eur Resp Soc (Sept 19-23, Geneva) 1998] 1998,12 (Suppl. 28): Abst P2393); roflumilast (CAS reference No 162401-32-3) and a pthalazinone (W099/47505, the disclosure of which is hereby incorporated by reference) from Byk-Gulden ; Pumafentrine, (-)-p- [ (4aR*, 1 ObS*) -9-ethoxy-1,2, 3,4, 4a, 1 Ob-hexahydro-8-methoxy-2- methylbenzo [c] [1,6] naphthyridin-6-yl]-N, N-diisopropylbenzamide which is a mixed PDE3/PDE4 inhibitor which has been prepared and published on by Byk-Gulden, now Altana ; arofylline under development by Almirall-Prodesfarma ; VM554/UM565 from Vemalis ; or T-440 (Tanabe Seiyaku; Fuji, K. et al. J Pharmacol Exp Ther, 1998,284 (1) : 162), and T2585.

Other possible PDE-4 and mixed PDE3/PDE4 inhibitors include those listed in WO01/13953, the disclosure of which is hereby incorporated by reference.

Suitable anticholinergic agents are those compounds that act as antagonists at the muscarinic receptor, in particular those compounds which are antagonists of the Mi and M2 receptors. Exemplary compounds include the alkaloid of the belladonna plants as illustrated by the likes of atropine, scopolamine, homatropine, hyoscyamine; these compounds are normally administered as a salt, being tertiary amines. These drugs, particularly the salt forms, are readily available from a number of commercial sources or can be made or prepared from literature data via, to wit: Atropine-CAS-51-55-8 or CAS-51-48-1 (anhydrous form), atropine sulfate-CAS-5908- 99-6; atropine oxide-CAS-4438-22-6 or its HCI salt-CAS-4574-60-1 and methylatropine nitrate-CAS-52-88-0.

Homatropine-CAS-87-00-3, hydrobromide salt-CAS-51-56-9, methylbromide salt- CAS-80-49-9.

Hyoscyamine (d, CAS-101-31-5, hydrobromide salt-CAS-306-03-6 and sulfate salt- CAS-6835-16-1.

Scopolamine-CAS-51-34-3, hydrobromide salt-CAS-6533-68-2, methylbromide salt- CAS-155-41-9.

Preferred anticholinergics include ipratropium (e. g. as the bromide), sold under the name Atrovent, oxitropium (e. g. as the bromide) and tiotropium (e. g. as the bromide) (CAS- 139404-48-1). Also of interest are: methantheline (CAS-53-46-3), propantheline bromide (CAS-50-34-9), anisotropine methyl bromide or Valpin 50 (CAS-80-50-2), clidinium bromide (Quarzan, CAS-3485-62-9), copyrrolate (Robinul), isopropamide iodide (CAS-71- 81-8), mepenzolate bromide (U. S. patent 2,918, 408), tridihexethyl chloride (Pathilone, CAS-4310-35-4), and hexocyclium methylsulfate (Tral, CAS-115-63-9). See also cyclopentolate hydrochloride (CAS-5870-29-1), tropicamide (CAS-1508-75-4), trihexyphenidyl hydrochloride (CAS-144-11-6), pirenzepine (CAS-29868-97-1), telenzepine (CAS-80880-90-9), AF-DX 116, or methoctramine, and the compounds disclosed in W001/04118, the disclosure of which is hereby incorporated by reference.

Suitable antihistamines (also referred to as H1-receptor antagonists) include any one or more of the numerous antagonists known which inhibit Hi-receptors, and are safe for human use. All are reversible, competitive inhibitors of the interaction of histamine with H1-receptors. The majority of these inhibitors, mostly first generation antagonists, have a core structure, which can be represented by the following formula:

This generalized structure represents three types of antihistamines generally available : ethanolamines, ethylenediamines, and alkylamines. In addition, other first generation antihistamines include those which can be characterized as based on piperizine and phenothiazines. Second generation antagonists, which are non-sedating, have a similar structure-activity relationship in that they retain the core ethylene group (the alkylamines) or mimic the tertiary amine group with piperazine or piperidine. Exemplary antagonists are as follows : Ethanolamines : carbinoxamine maleat, clemastine fumarate, diphenylhydramine hydrochloride, and dimenhydrinate.

Ethylenediamines : pyrilamine amleate, tripelennamine HCI, and tripelennamine citrate.

Alkylamines : chloropheniramine and its salts such as the maleate salt, and acrivastine.

Piperazines: hydroxyzine HCI, hydroxyzine pamoate, cyclizine HCI, cyclizine lactate, meclizine HCI, and cetirizine HCI.

Piperidines: Astemizole, levocabastine HCI, loratadine or its descarboethoxy analogue, and terfenadine and fexofenadine hydrochloride or another pharmaceutical acceptable salt.

Azelastine hydrochloride is yet another H1 receptor antagonist which may be used in combination with a PDE4 inhibitor.

Examples of preferred anti-histamines include methapyrilene and loratadine.

The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutical acceptable salt, solvate or physiologically functional derivative thereof together with a PDE4 inhibitor.

The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with a corticosteroid.

The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with an anticholinergic.

The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with an antihistamine.

The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutical acceptable salt, solvate or physiologically functional derivative thereof together with a PDE4 inhibitor and a corticosteroid.

The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutical acceptable salt, solvate or physiologically functional derivative thereof together with an anticholinergic and a PDE-4 inhibitor.

The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a physiologically 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 formulations. Appropriate doses of known therapeutic agents will be readily appreciated by those skilled in the art.

According to a further aspect of the invention, there is provided a process for preparing a compound of formula (I), or a salt, solvate, or physiologically functional derivative thereof which comprises a process (a), (b), (c) or (d) as defined below followed by the following steps in any order: (i) optional removal of any protecting groups; (ii) optional separation of an enantiomer from a mixture of enantiomers; (iii) optional conversion of the product to a corresponding salt, solvate, (iv) optional conversion of a group R', R2 and/or R3 to another group R', R2 and/or R3.

In the following description of synthetic routes, R', R2, R3, R4, R5, m and n are as defined for formula (I) and Ar'a, P'and P2 are as defined for formula (II) below unless indicated otherwise. In one general process (a), a compound of formula (1), may be obtained by deprotection of a protected intermediate, for example of formula (tt) :

or a salt or solvate thereof, wherein R', R2, R3, R4, R5, m and n are as defined for the compounds of formula (I), Ar'a represents an optionally protected form of Ar1 and P1 and p2 each independently represents either hydrogen or a protecting group, provided that the compound of formula (II) contains at least one protecting group.

Preferred groups Ar1a may be selected from:

wherein P3 and P4 are each independently either hydrogen or a protecting group provided that at least one of P3 and P4 is a protecting group, and the dotted line in (xvia) and (xixa) denotes an optional double bond. It will be appreciated from the foregoing structures that where Ar1 is a group (vii), (xi), (xii), (xiii) or (xiv) protection is not required.

Suitable protecting groups may be any conventional protecting group such as those described in"Protective Groups in Organic Synthesis"by Theodora W Greene and Peter G M Wuts, 3rd edition (John Wiley & Sons, 1999). Examples of suitable hydroxyl protecting groups represented by P3 and P4 are esters such as acetate ester, aralkyl groups such as benzyl, diphenylmethyl, or triphenylmethyl, and tetrahydropyranyl.

Examples of suitable amino protecting groups represented by p2 include benzyl, a- methylbenzyl, diphenylmethyl, triphenylmethyl, benzyloxycarbonyl, tert-butoxycarbonyl, and acyl groups such as trichloroacetyl or trifluoroacetyl.

As will be appreciated by the person skilled in the art, use of such protecting groups may include orthogonal protection of groups in the compounds of formula (II) to facilitate the selective removal of one group in the presence of another, thus enabling selective functionalisation of a single amino or hydroxyl function. For example, the-CH (OH) group may be orthogonally protected as-CH (OP') using, for example, a trialkylsilyl group such as triethylsilyl. A person skilled in the art will also appreciate other orthogonal protection strategies, available by conventional means as described in Theodora W Greene and Peter G M Wuts (see above).

The deprotection to yield a compound of formula (I), may be effected using conventional techniques. Thus, for example, when P P3, and/or P4 is an aralkyl group, this may be

cleaved by hydrogenolysis in the presence of a metal catalyst (e. g. palladium on charcoal).

When P3 and/or P4 is tetrahydropyranyl this may be cleaved by hydrolysis under acidic conditions. Acyl groups represented by P2 may be removed by hydrolysis, for example with a base such as sodium hydroxide, or a group such as trichloroethoxycarbonyl may be removed by reduction with, for example, zinc and acetic acid. Other deprotection methods may be found in Theodora W Greene and Peter G M Wuts (see above). In a particular embodiment of process (a), P3 and P4 may together represent a protecting group as in the compound of formula (III) : or a salt or solvate thereof, wherein R, R2 R3 R4 R5 R5 R7 p1 p2 m and n are as defined for the compound of formula (I), R22 and R23 are independently selected from hydrogen, Chalky), or aryl or R22 and R22 together form a C37cycloalkyl ring. In a preferred aspect, both R22 and R23 are methyl.

The compound of formula (III) may be converted to a compound of formula (I), by hydrolysis with dilute aqueous acid, for example acetic acid or hydrochloric acid in a suitable solvent or by transketalisation in an alcohol, for example ethanol, in the presence of a catalyst such as an acid (for example, toluenesulphonic acid) or a salt (such as pyridinium tosylat) at normal or elevated temperature.

It will be appreciated that the protecting groups P', p2, p3 and P4 (including the cyclise protecting group formed by P3 and P4 as depicted in formula (III) may be removed in a single step or sequentially. The precise order in which protecting groups are removed will in part depend upon the nature of said groups and will be readily apparent to the skilled worker. Preferably, when P3 and P4 together form a protecting group as in formula (III) this protecting group is removed together with any protecting group on the CH (OH) moiety, followed by removal of p2. Compounds of formulae (II) and (III) wherein P1 and P2 are hydrogen may be prepared from the corresponding compound of formula (IV).

or a salt or solvate thereof, wherein R1, R2, R3, R4, R5, Ar1a, m and n are as defined for the compound of formula (II) or (III).

The conversion of a compound of formula (IV) to a compound of formula (II) or (vil) may be effected by treatment with a base, for example a non-aqueous base, such as potassium trimethylsilanolate, or an aqueous base such as aqueous sodium hydroxide, in a suitable solvent such as tetrahydrofuran.

Compounds of formula (IV) may be prepared by reacting a compound of formula (V): wherein Ar'a is as defined for formula (II) ; with a compound of formula (Vl) :

wherein L is a leaving group such as halo (typically chloro, bromo or iodo) or a sulphonate (typically methanesulphonate) and R', R2, R3, R4, R5, n and m are as defined for compounds of formula (I).

The coupling of a compound of formula (V) with a compound of formula (VI) may be effected in the presence of a base, such as a metal hydride, for example sodium hydride, or an inorganic base such as cesium carbonate, in an aprotic solvent, for example N, N- dimethylformamide.

Compounds of formula (V) may be prepared by ring closure of a compound of formula (Vil) : wherein Ar'a is as hereinbefore defined and R24 is C16alkyl, for example tert-butyl, or aryl, for example phenyl. The ring closure may be effected by treatment with a base, such as a metal hydride, for example sodium hydride, in the presence of an aprotic solvent, for example, N, N-dimethylformamide.

The compound of formula (VII) may be prepared from the corresponding halide of formula (VIII) : wherein Ar'a and Y are as hereinbefore defined, by reaction with a protected amine HN (COOR24) 2, wherein R24 is as defined for the compound of formula (VII), in the presence of an inorganic base such as cesium carbonate, followed by selective removal of one of the COOR24 groups, for example by treatment with an acid such as trifluoroacetic acid, and subsequent reduction of the keto function by any suitable method,

for example by treatment with borane, in the presence of a chiral catalyst, such as CBS- oxazaborolidine, in a suitable solvent such as tetrahydrofuran.

A compound of formula (VI) may be prepared by coupling a compound of formula (IX) : <BR> <BR> <BR> <BR> <BR> LCR4R5 (CHa) O (CH2) m-2C CH<BR> <BR> <BR> <BR> (IX) wherein L is a leaving group as defined for formula (VI) ; with a compound of formula (X): Wherein L'is a leaving group as hereinbefore defined for L and R', R2, R3, are as hereinbefore defined, followed by reduction.

The coupling of a compound of formula (IX) with a compound of formula (X) is conveniently effected in the presence of a catalyst system such as bis (triphenyphosphine) palladium dichloride with an organic base such as a trialkylamine, for example diisopropylethylamine, in a suitable solvent for example acetonitrile or dimethylformamide or using the base as solvent. The resulting alkyne may then be reduced, either with or without being isolated to form the desired saturated alcohol. The reduction may be effected by any suitable method such a hydrogenation in the presence of a catalyst, for example palladium/charcoal or platinum oxide.

Compounds of formula (X) are commercially available or may be prepared by methods well known to the person skilled in the art.

A compound of formula (IX) may be prepared by reacting a compound of formula (XI) : HO (CH2) C=CH

Wherein m is as defined for formula (I) with a dihaloalkane of formula (XI 1) : Y1CR4R5(CH2)nY2 (XII) wherein R4, R5 and n are as hereinbefore defined and Y'and y2 each represent halo.

The reaction of compounds (XI) and (XII) is typically effected in the presence of an inorganic base, such as sodium hydroxide under phase transfer conditions in the presence of a tetra-alkylammonium salt, eg. tetrabutylammonium bromide.

Compounds of formulae (XI) and (XII) are available commercially or can be prepared by standard methods.

A compound of formula (IV) may also be prepared by reacting a compound of formula (V) with a compound of formula (IX), to form a compound of formula (XIII), followed by reaction with a compound of formula (X):

(IV) Alternatively, compounds of formula (II) and (III) wherein P2 is either hydrogen or a protecting group may be prepared by any of the processes described hereinafter.

In a further process (b) a compound of formula (I) may be obtained by reacting a compound of formula (XIV) : Wherein Ar is as defined above, with a compound of formula (Vl) :

Wherein L is a leaving group such as halo (typically chloro, bromo or iodo) or a sulphonate (typically methanesulphonate) and R', R2, R3, R4, R5, n and m are as defined for compounds of formula (I).

The reaction of compounds of formula (XIV) and (VI) is optionally effected in the presence of an organic base, such as a trialkylamine, for example triethylamine, and in a suitable solvent, for example an amide such as DMF.

Compounds of formula (XIV) may be prepared by methods well known in the art. Thus for example they may be readily prepared by a person skilled in the art, from the corresponding halide of formula (XV): wherein Ar'a is as hereinbefore defined and Y is halo eg. bromo.

The conversion of a compound of formula (XV) to a compound of formula (XIV) may be effected by reaction with sodium azide in a suitable solvent, for example N, N- dimethylformamide, to give the corresponding compound wherein Y denotes N3. The carbonyl group may then be reduced to the corresponding alcohol by any suitable method, for example by treatment with borane, in the presence of a chiral catalyst, such as (R)-tetrahydro-1-methyl-3, 3-diphenyl-1H, 3H-pyrrolo [1,2-c] [1,3, 2] oxazaborole, in a suitable solvent such as tetrahydrofuran. The azide group may be reduced to the

corresponding amine group by any suitable method, for example by catalytic hydrogenation in the presence of a catalyst such as palladium/charcoal or platinum oxide.

Further details concerning preparation of compounds (XIV) wherein Ar1 is a group (v) in DE3524990; concerning the preparation of compounds (XIV) wherein Ar is a group (ii), (viii), and (xvi) in EP-A-162576; concerning the preparation of compounds (XIV) wherein Ar is a group (iv) in EP-A-220054; concerning the preparation of compounds (XIV) wherein Ar is a group (xi) in GB2165542 and concerning the preparation of compounds (XIV) wherein Ar is a group (c) in GB2230523.

Compounds of formula (XV) are known compounds or may readily be prepared by those skilled in the art using known methods.

In a further process (c) a compound of formula (I), may be prepared by reacting a compound of formula (XVI) : wherein Ar la is as defined for formula (II) and L is a leaving group as hereinbefore defined, with an amine of formula (XVII) : wherein R', R2, R3, R4, R5, n and m are as defined for formula (II).

The reaction may be effected using conventional conditions for such displacement reactions.

Compounds of formula (XVI) may be prepared by methods known in the art. Thus for example, compounds (XVI) wherein Ar is a group (xvi) may be prepared as described in EP-A-147719.

Compounds of formula (XVII) may be prepared by reacting a compound of formula (VI) with an amine P2NH2, followed by removal of the protecting group P2.

According to a further process (d) compounds of formula (I) wherein one of R4 and R5 represents hydrogen may be prepared by; (i) reacting a compound of formula (XIV) : Wherein Ar1a is as hereinbefore defined and R25 represents hydrogen or a chiral auxiliary, with a compound of formula (XVIII) : wherein R', R2, R3, R4, n and m are as hereinbefore defined; followed where necessary by removal of the chiral auxiliary R25 ; or (ii) reacting a compound of formula (XIX) : wherein Ar'a is as hereinbefore defined; with an amine of formula (XVII) :

as hereinbefore defined, under conditions suitable to effect reductive amination, for example in the presence of a reducing agent such as a borohydride, typically tetramethylammonium (triacetoxy) borohydride.

When process (di) involves use of a chiral auxiliary this is preferably the S-isomer and/or the R-isomer of phenyl glycinol. The reaction may be effected as described in International Application Number WO/0196278.

A compound of formula (XVIII) may be prepared by methods known in the art, for example via a compound of formula (VI) as hereinbefore defined.

A compound of formula (XIX) may also be prepared from a corresponding alcohol, which may itself be obtained from a compound of formula (XVI) as hereinbefore defined, using standard methods well known to those skilled in the art.

It will be appreciated that in any of the routes (a) to (d) 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. It will also be appreciated that in the processes (b), (c) and (d) appropriate protecting groups may be employed if necessary and/or desired and removed at any suitable stage of the synthesis, eg. in the last stage, as described in process (a).

The enantiomeric compounds of the invention may be obtained (i) by separation of the components of the corresponding racemic mixture, for example, by means of a chiral chromatography column, enzymic resolution methods, or preparing and separating suitable diastereoisomers, or (ii) by direct synthesis from the appropriate chiral intermediates by the methods described above.

Optional conversions of a compound of formula (I), to a corresponding salt may conveniently be effected by reaction with the appropriate acid or base. Optional conversion of a compound of formula (I), to a corresponding solvate or physiologically functional derivative may be effected by methods known to those skilled in the art.

According to a further aspect, the present invention provides novel intermediates for the preparation of compounds of formula (I), for example : compounds of formula For a better understanding of the invention, the following Examples are given by way of illustration.

SYNTHETIC EXAMPLES Throughout the examples, the following abbreviations are used: LCMS: Liquid Chromatography Mass Spectrometry MS mass spectrum RT: retention time THF: tetrahydofuran DMF: N, N-dimethylformamide EtOAc: ethyl acetate EtOH : ethanol MeOH : methanol bp : boiling point ca : circa h: hour (s) min: minute (s) All temperatures are given in degrees centigrade.

Silica gel refers to Merck silica gel 60 Art number 7734.

Flash silica gel refers to Merck silica gel 60 Art number 9385.

Biotage refers to prepacked silica gel cartridges containing KP-Sil run on flash 12i chromatography module.

SPE Bond Elut are prepacked cartridges used in parallel purifications, normally under vacuum. These are commercially available from Varian.

SCX-2 is a solid phase extraction column pre-packed with benzene sulfonic acid resin available from International Sorbent Technology.

LCMS was conducted on a Supelcosil LCABZ+PLUS column (3.3 cm x 4.6 mm ID) eluting with 0. 1 % HCO2H and 0.01 M ammonium acetate in water (solvent A), and 0.05% HCO2H 5% water in acetonitrile (solvent B), using the following elution gradient 0-0.7 min 0% B, 0.7-4. 2 min 100% B, 4.2-5. 3 min 0% B, 5.3-5. 5 min 0% B at a flow rate of 3 ml/min. The mass spectra were recorded on a Fisons VG Platform spectrometer using electrospray positive and negative mode (ES+ve and ES-ve).

Example 1 8-(4-ff6-(f (2R)-2-Hydroxy-2-r4-hydroxy-3- (hvdroxvmethvl) phenvllethvlamino) hex iloxvbutl) naphthalene-2-suifonamide acetate i) 8-lodonaphthalene-2-sulfonic acid 8-Aminonaphthalene-2-sulfonic acid (2.23g) was dissolved in water (16mi) containing potassium hydroxide (0.556g) with warming and potassium nitrite (0.85g) was added.

This solution was cooled to 21° (a little precipitation occurred) and was added dropwise over 35 min to 1 M sulfuric acid (14ml) with stirring, keeping the internal temperature at-2° to 0°. After stirring for a further 10min, a solution of potassium iodide (2g) in water (1 Oml) was added dropwise over 5min. The mixture was stirred at 21° for 2h and then on a steam bath for 1h. The cooled solution was concentrated to 10ml and ethanol added till no further precipitation occurred. The solid was removed by filtration and leached with ethanol. The filtrate was concentrated to 30ml and the precipitate was collected by filtration, washed with ethanol and dried to give the title compound (0.256g) LCMS RT=3.87min. The filtrate was evaporated to dryness and the residue was triturated with ethanol to give further title compound (0.396g), similar to the first crop above. ii) 8-lodonaphthalene-2-sulfonamide 8-lodonaphthalene-2-sulfonic acid (0.652g) was refluxed with phosphorus oxychloride (5ml) for 2h. The solution was evaporated to dryness and the residue was mixed cautiously with 0.880 aqueous ammonia solution (5ml). The mixture was again refluxed for 2h and allowed to cool. The precipitate was collected by filtration, washed with water and dried to give the crude product. This was dissolved in 10% methanol in ethyl acetate and loaded onto a 10g Bond Elut cartridge that had been conditioned with dichloromethane. Elution with ethyl acetate gave the title compound (0.266g) LCMS RT=3.25 min. iii) 8-r4-(f6-f (5R)-5-(2, 2-dimethVI-4H-1. 3-benzodioxin-6-vl)-2-oXo-1, 3-oxazolidin-3- yllhexvloxv) but-1-vnvllnaphthalene-2-sulfonamide<BR> (5R)-3- [6- (But-3-ynyloxy) hexyl]-5- (2, 2-dimethyl-4H-1, 3-benzodioxin-6-yl)-1, 3-oxazolidin-2- one (0.18g) was stirred with 8-iodonaphthalene-2-sulfonamide (0.167g) in acetonitrile : triethylamine (1: 1, 4ml) under nitrogen for 5min. Cuprous iodide (0. 01g) and dichlorobis (triphenylphosphine) palladium (0.02g) were added and the mixture was stirred for 1.5h under nitrogen at 21°. The mixture was evaporated to dryness and the residue was loaded onto a 10 g Bond Elut cartridge in dichloromethane. The cartridge was eluted

successively with dichloromethane, diethyl ether and ethyl acetate to give the title compound (0. 128g), LCMS RT=3.68min. iv) 8-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-ox o-1,3-oxazolidin-3- <BR> <BR> <BR> vllhexyloxv) buyllnaphthalene-2-sulfonamide<BR> <BR> <BR> <BR> <BR> 8- [4- ( {6- [ (5R)-5- (2, 2-Dimethyl-4H-1, 3-benzodioxin-6-yl)-2-oxo-1, 3-oxazolidin-3- yl] hexyl} oxy) but-1-ynyl] naphthalene-2-sulfonamide (0.128g) was stirred with platinum oxide (0.022g) in ethyl acetate (3ml) under hydrogen for 3h. The catalyst was removed by filtration and the filter cake was leached with ethyl acetate. The combined filtrates were evaporated to give the title compound (0. 12g), LCMS RT=3.74min. v) 8-f4-j (6-fr (2R)-2- (2, 2-Dimethvl-4H-1, 3-benzodioxin-6-yl)-2- <BR> <BR> <BR> hvdroxvethv) oxylbutylnaphthalene-2-sulfonamide<BR> <BR> <BR> <BR> <BR> 8- [4- ( {6- [ (5R)-5- (2, 2-Dimethyl-4H-1, 3-benzodioxin-6-yl)-2-oxo-1, 3-oxazolidin-3- yl] hexyl} oxy) butyl] naphthalene-2-sulfonamide (0.12g) was stirred in THF (3ml) while purging with a vigorous stream of nitrogen for 5min. Potassium trimethylsilanolate (0. 12g) was added and the mixture was stirred at reflux under nitrogen for 1h. The mixture was partitioned between dichloromethane and pH 6.4 phosphate buffer and the aqueous layer was extracted with more dichloromethane. The combined organic layers were washed with water, dried (MgS04) and concentrated. The residue was purified on silica gel (50g), eluting successively with ethyl acetate, 10% then 25% methanol in ethyl acetate to give the title compound (0.071 g), LCMS RT=3.06min. vi) 8-(4-ff6-(f (2R)-2-Hvdroxy-2-f4-hvdroxv-3- (hydroxvmethvl) phenyl]ethyl}amino)hexyl]oxy}butyl)naphthalene-2-sulfonamide acetate 8-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2- hydroxyethyl] amino} hexyl) oxy] butyl} naphthalene-2-sulfonamide (0.70g) was stirred with acetic acid (2ml) and water (1ml) at 70° for 35min before evaporating to dryness. The residue was re-evaporated with acetic acid to give the title compound (0.085g) LCMS RT=2.72min, ES+ve 545 (MH) +.

Example 2 4- (4- {r6- ( { (2R)-2-Hvdroxv-2-r4-hvdroxv-3- (hvdroxvmethvl) phenvllethvlamino) hexylloxv) butl)-2-thiophenesulfonamide acetate

i) 4 j(6-f (5R)-5- (2, 2-Dimethvl-4H-1, 3-benzodioxin-6-vl)-2-oxo-1, 3-oxazolidin-3- yl]hexyl}oxy)-1-butyn-1-yl]-2-thiophenesulfonamide 4-Bromo-2-thiophenesulfonamide (150mg) (W09843971 A1) was dissolved in diethylamine (8ml). Copper (I) iodide (6mg) and dichlorobis (triphenylphosphine) palladium (II) (11mg) were added and the mixture heated at 70°C, under nitrogen. A solution of <BR> <BR> <BR> <BR> (5R)-3- [6- (3-butyn-1-yloxy) hexyl]-5- (2, 2-dimethyl-4H-1, 3-benzodioxin-6-yl)-1, 3-oxazolidin- 2-one (W002066422 A1) (250mg) in diethylamine (2ml) was added dropwise and the reaction heated for 6h. The reaction was cooled to room temperature and treated with water. The mixture was extracted with ethyl acetate. The organic phases were combined, dried (MgS04) and evaporated in vacuo. The residue was purified by chromatography, on a 40g silica biotage cartridge, eluting with ethyl acetate-cyclohexane (50: 50) to give the title compound, (1 50mg). LCMS RT = 3.45 min ii) 4-[4-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1, 3-oxazolidin-3- yllhexvlToxv) butyll-2-thiophenesulfonamide Platinum (IV) oxide (50mg) was flushed with nitrogen and treated with a solution of 4- [4- <BR> <BR> <BR> <BR> ( {6- [ (5R)-5- (2, 2-dimethyl-4H-1, 3-benzodioxin-6-yf)-2-oxo-1, 3-oxazolidin-3-yl] hexyl} oxy)-1- butyn-1-yl]-2-thiophenesulfonamide (150mg) in ethyl acetate (3ml) and ethanol (3ml). The reaction mixture was stirred under hydrogen for 6 h, adding fresh catalyst (40mg) after 2h and 4h. The reaction mixture was flushed with nitrogen and filtered to remove the catalyst and evaporated in vacuo. The residue was purified by chromatography on a silica SPE cartridge, eluting with a stepped gradient of ethyl acetate-cyclohexane mixtures to give the title compound (102mg). LCMS RT = 3.48 min iii) 4-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2- hydroxyethvllaminohexyl) oxvlbutyl-2-thiophenesulfonamide Potassium trimethylsilanolate (92mg) was added to a solution of 4- [4- ( {6- [ (5R)-5- (2, 2- dimethyl-4H-1, 3-benzodioxin-6-yl)-2-oxo-1, 3-oxazolidin-3-yl] hexyl} oxy) butyl]-2- thiophenesulfonamide (102mg) in dry tetrahydrofuran (10ml). The mixture was heated at 80°C under nitrogen for 45min. Water was added and the mixture extracted with ethyl acetate. The combined extracts were dried (MgS04) and evaporated in vacuo. The residue was purified by chromatography on a silica SPE cartridge, eluting with DCM- MeOH-NH3 (aq) (100: 10: 1) to give the title compound (76mg).

LCMS RT = 2.70 min

iv) 4-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3- (hydroxymethyl) phenyllethylamino) hexvlloxvlbutyl)-2-thiophenesulfonamide acetate A solution of 4-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-h ydroxyethyl] amino} hexyl) oxy] butyl}-2-thiophenesulfonamide (76mg) in glacial acetic acid (2ml) and water (1ml), was heated at 80°C for 30 min. The reaction mixture was evaporated in vacuo, to give the title compound (82mg).

LCMS RT = 2.55 min, ES+ve 501 (MH) +.

Example 3 5-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3- (hvdroxvmethvl) phenylethyl}amino)hexyl]oxy}butyl)-2-thiophenesulfonamide acetate i) 5-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-ox o-1,3-oxazolidin-3- Ilhexyloxv)-1-butyn-1-vll-2-thiophenesulfonamide Prepared using methods similar to those described in Example 2i.

LCMS RT = 3.65 min ii) 5-f4- (f6-r (5R)-5- (2, 2-Dimethvl-4H-1, 3-benzodioxin-6-vl)-2-oxo-1, 3-oxazolidin-3- vllhexyloxv) butvll-2-thiophenesulfonamide Prepared using methods similar to those described in Example 2 ii.

LCMS RT = 3.64 min iii) 5-{4-[ (6-{(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2- hydroxyethyl]amino}hexyl)oxy]butyl}-2-thiophenesulfonamide Prepared using methods similar to those described in Example 2 iii. LCMS RT = 2.70 min iv) 5- (4-fr6- ( (2R)-2-Hvdroxv-2-r4-hvdroxv-3- (hvdroxvmethvl) henyl]ethyl}amino)hexyl]oxy}butyl)-2-thiohenesulfonamide acetate Prepared using methods similar to those described in Example 2 iv.

LCMS RT = 2.41 min, ES+ve 501 (MH) +.

Example 4 6-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3- (hvdroxvmethvl) phenyl]ethyl}amino)hexyl]oxy}butyl)-2-pyridinesulfonamide

i) 6-Bromopyridine-2 (1H)-thione 2,6-Dibromopyridine (400 mg) was added to a mixture of sodium methoxide (227mg) and methyl 3-mercaptopropionate (0.437 ml) in dimethylformamide (10 mi) at 0°C. The mixture was then heated to 70 °C for 1.5h and then evaporated under reduced pressure.

The residue was dissolved in methanol (5 ml) and treated with sodium methoxide (227 mg) and the solution was heated to reflux for 1 h. The solvent was removed under reduced pressure and the residue was partitioned between water and diethyl ether. The aqueous phase was separated and acidified with acetic acid and the solid that formed was collected by filtration to give the title compound (114 mg) LCMS RT=3.79 min ii) 6-Bromopyridine-2-sulfonamide 6-Bromopyridine-2 (1H)-thione (114 mg) was added to a mixture of bromine (0.061 ml) in water (3.6 ml) and ice (1.8g) and the mixture was stirred at 0°C for 2 h. Aqueous ammonia (2 ml) was added and the mixture was stirred for 1 h at 20 °C and then heated to reflux. The reaction mixture was filtered while hot and then allowed to crystallise. The solid was collected by filtration and then purified by chromatography on a 10 g silica SPE cartridge eluting with ethyl acetate-cyclohexane (3: 2) to give the title comound (63mg) LCMS RT=1. 6 min iii) 6-r4- (f6- [ (5R)-5- (2, 2-Dimethvl-4H-1, 3-benzodioxin-6-vl)-2-oxo-1, 3-oxazolidin-3- yl]hexyl}oxy)-1-butyn-1-yl]-2-pyridinesulfonamide Prepared using methods similar to those described in Example 2 (i).

LCMS RT = 3.20 min iv) 6-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-ox o-1,3-oxazolidin-3- vi1hexvi} oxv) butvi1-2-pyridinesuifonamide Prepared using methods similar to those described in Example 2 (ii).

LCMS RT = 3.31 min v) 6-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2- hydroxvethyllaminolhexvl) oxylbutyll-2-pyridinesulfonamide Prepared using methods similar to those described in Example 2 (iii).

LCMS RT = 2.51

vi) 6- (4-6- ( { (2R)-2-Hvdroxv-2-r4-hvdroxv-3- (hydroxvmethvl) phenvllethvlamino) hexvlloxvbutvl)-2-pyridinesulfonamide formate Prepared using methods similar to those described in Exmaple 2 (iv).

LCMS RT = 2.12 min, ES+ve 496 (M+H) +.

BIOLOGICAL ACTIVITY In vitro measurements of compound potency and intrinsic activity at the human Beta 1, 2 and 3 receptor.

Method 1 The potencies of the compounds were determined using frog melanophores transfected with the human beta 2 adrenoreceptor. The cells were incubated with melatonin to induce pigment aggregation. Pigment dispersal was induced by compounds acting on the human beta 2 adrenoreceptor. The beta 2 agonist activity of Examples 1,2, 3 and 4 was assessed by their ability to induce a change in light transmittance across a melanophore monolayer (a consequence of pigment dispersal). In this assay the potency of compounds at the human beta-2 receptor is expressed as a pECeo value. Compounds of Examples 1- 4 had a pEC50 of >6.

Method 2 Potency of Example 1 at the human beta 1 and 3 receptors and potency of Examples 2,3 and 4 at the human beta 2,1 and 3 receptors was also determined using Chinese hamster ovary cells co-expressing the human receptor with a reporter gene. Studies were performed using either whole cells or membranes derived from those cells.

The three beta-receptors are coupled via the Gs G-protein to cause a stimulation of adenylate cyclase resulting in increased levels of cAMP in the cell. For direct cAMP measurements either membranes or frozen cells have been used with either the HitHunter enzyme fragment complementation kit (DiscoveRx) or the Fp2 fluorescence polarisation kit (Perkin Elmer) to quantify the levels of cAMP present. These assays provide a measure of agonist potency and intrinsic activity of the compounds at the various receptors.

The reporter gene in the cells has also been used to quantify potency at the beta 1 and 3 receptors. This is a reporter of cAMP levels using the cAMP response element upstream

of a firefly luciferase gene. After stimulation of the receptor with an agonist an increase in the level of luciferase is measured as a quantification of the level of cAMP in the cell.

In this assay the potency of compounds at the human beta-2 receptor is expressed as a pEC50 value. Compounds of Examples 2-4 had a pEC50 of >6.

The application of which this description and claims forms part may be used as a basis for priority in respect of any subsequent application. The claims of such subsequent application may be directed to any feature or combination of features described herein.

They may take the form of product, composition, process, or use claims and may include, by way of example and without limitation, the following claims.