ZA200503333B - Phenethanolamine derivative for the treatment of respiratory diseases - Google Patents

Description

PHENETHANOLAMINE DERIVATIVES FOR THE TREATMENT OF RESPIRATORY DISEASES

The present invention is concerned with phenethanolamine derivatives, processes for their preparation, compositions containing them and their use in medicine, particularly in the prophylaxis and treatment of respiratory diseases.

Certain phenethanolamine compounds are known in the art as having selective stimulant action at Bradrenoreceptors 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-phenylbutoxy)hexyllamino}methyi}-1,3- benzenedimethano! 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 3;-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 8,adrenoreceptors and having an advantageous profile of action.

According to the present invention, there is provided a compound of formula ({)]

R? i»

A qonANeRE —(CH,);

H

Rr’ 0) or a salt, solvate, or physiologically functionai derivative thereof, wherein: : m is an integer of from 2 to 8; : n is an integer of from 3 to 11, preferably from 3 t0 7; with the proviso that m + nis 5 to 19, preferably 5 to 12;

R'is SR®, SOR®, or SOR’, wherein R® is a Ca ;cycloalkyl or C3 ycycloalkenyl! group; :

R? and R® are independently selected from hydrogen, Csalkyl, C,salkoxy, halo, phenyl, and C, haloalkyl;

R'and R® are independently selected from hydrogen and C,_alkyl with the proviso that the total number of carbon atoms in R* and R® is not more than 4;

Ar is a group selected from

R’

R® rR’

N

7 ng © 4 \ J

R® 9°

R Br rR" R" (a) (b) (c) and 0} pes 0} . (d) wherein R® represents hydrogen, halogen, -(CH.),OR", -NR"'C(O)R"2, -NR''SO,R"2, -SO,NR'"'R'?, -NR"'R", -OC(O)R" or OC(O)NR"'R2, and R’ represents hydrogen, halogen, or Cy alkyl; or R® represents —NHR' and R’ and —-NHR" together form a 5 or 6- membered heterocyclic ring;

R® represents hydrogen, halogen, -OR'' or -NR''R'2

R'" represents hydrogen, halogen, haloC,4 alkyl, -OR', -NR". R®, -OC(O)R"™ or

OC(O)NR'R'%

R' and R" each independently represents hydrogen or C_, alkyl, or in the groups -NR''R™, -SO,NR''R' and -OC(O)NR'R', R"' and R™ independently represent hydrogen or C, alkyl or together with the nitrogen atom to which they are attached form a 5-, 6- or 7- membered nitrogen-containing ring,

RP" represents an aryl (eg phenyl or naphthyl) group which may be unsubstituted or substituted by one or more substituents selected from halogen, C4 alkyl, hydroxy, C,.4 alkoxy or halo C, alkyl; and q is zero or an integer from 1 to 4.

In a particular embodiment, the present invention provides compounds of formula (1) and salts, solvates and physiologically functional derivatives thereof, wherein formula (I) is as defined hereinabove, except that R® does not represent hydrogen. in the compounds of formuia (I) the group R' is preferably attached to the meta-position relative to the -O-(CH,),- link.

R' preferably represents SOR® or SO, R®, most preferably SO,R®.

R® preferably represents C, cycloalkyl, most preferably cyclopentyl.

R* and R® are preferably independently selected from hydrogen and methyl, more preferably R* and R® are both hydrogen. mis suitably 4, 5, or 6, and n is suitably 3, 4, 5 or 6. Preferably mis 5 or 6 and nis 3 or 4, such thatm + nis 8, 9 or 10, preferably 9. :

In the compounds of formula (I) the group Ar is preferably selected from groups (a) and (b) above. In said groups (a) and (b), when R® represents halogen this is preferably chlorine or fluorine. R' and R' preferably each independently represent hydrogen or methyl. R" preferably represents substituted phenyl. The integer q preferably represents zero or 1." Thus for example —(CH_.),OR"! preferably represents OH or -CH,OH:

NR''C(O)R" preferably represents —NHC(O)H: -ST NR" “R" preferabiy represents -SO,NH, or SO,NHCH;;

NR'R' preferably represents ~NH,; -OC(O)R™ preferably represents substituted benzoyloxy eg. OC(0)-CeH4-(;-CH,); and ~OC(O)N R"" R' preferably represents OC(O)N(CHy),.

When R® represents NHR™ and together with R” forms a 5- or 6- membered heterocyclic ring -NHR"-R’- preferably represents a group: -NH-CO-R™- where R' is an alkyl, alkenyl or alkyloxy moiety; -NH-S0,R"- where R™ is an alkyloxy moiety: -NH-R""- where Ris an alkyl or alkenyl moiety optionally substituted by COOR'® where

Ris Cy alkyi; 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):

HO HO HO HO” NF 0) (il) (iif) (iv)

HN HO

EY H,NSO, NSO, pos

HO xr Xr

HO OH v) (vi) (vii) (viii)

. H,N Cl Cl wo CT Xr oy

HO . N

NH, HN HN i cl CF, (ix) (x) (xi) (xii) o 0

I 3 (PCRICHCON (CH,),;NCO >

P HN ; i ile HO o s) x) (xiv) (xv)

I

0 > 0. > NO 05>

HN HN HN

HO HO

(xvi) (xvii) (xviii)

Wan! oe

HO HO HO

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

Most preferably Ar represents a group (i).

In a particularly preferred embodiment the present invention provides a compound of formula (la)

HOCH, RR

R

To W— —o0 es) (ta)

OH rR? or a salt, solvate, or physiologically functional derivative thereof, wherein: mis an integer of from 2 to 8; nis an integer of from 3 to 11, preferably from 3 to 7: with the proviso that m + nis 5 to 19, preferably 5 to 12;

R'is SR? SOR®, or SO,R®, wherein R® is a Cyscycloalkyl or Cs cycloalkenyl group;

R? and R? are independently selected from hydrogen, Cisalkyl, C;salkoxy, halo, phenyl, and C,shaloalkyl; and

R* and R® are independently selected from hydrogen and C,_alkyl with the proviso that the total number of carbon atoms in R* and R® is not more than 4.

In the compounds of formula (la) the group R' is preferably attached tc the meta-position relative to the -O-(CH.).- link.

R’ preferably represents SOR® or SO,R®, most preferably SO,R®.

R® preferably represents C, ; cycloalkyl, most preferably cyclopentyl.

R* and R® are preferably independently selected from hydrogen and methyl, more preferably R* and R°® are both hydrogen. m is suitabiy 4, 5, or 6, and n is suitably 2, 3, 4, 5 or 6. Preferably mis 5or6 and nis 3 or 4, suchthatm + nis 8, 9 or 10, preferably 9.

Preferred compounds of formulae (1) and (la) include: 4-{(1R)-2-[(6-{4-[3-(Cyclopentylsulfinyl)phenyl]butoxy}hexyl)amino}- 1-hydroxyethyi}-2- (hydroxymethyl)phenof; 41 R)-2-{(6-{4{3-(Cyciopentyisuifinyi)ohenyilbutoxy}hexyl)amino}-1-hydroxyethy!}-2- (hydroxymethyl)phenol (Isomer 1); 4-{(1R)-2-[(6-{4-{3-(Cyclopentylsulfinyl)phenyl]butoxy}hexyl)amino]-1-hydroxyethyl}-2- (hydroxymethyl)phenol (isomer 2); 4-{(1R)-2-{(6-{4-{3-(Cyclopentylsuifonyt)phenyi]butoxy}hexyl)amino]-1-hydroxyethyi}-2- (hydroxymethyl)phenol; 4-{(1R)-2-[(6-{4-[4-(Cyclopentylsulfonyl)phenyi]butoxy}hexyl)amino]-1-hydroxyethyl}-2- (hydroxymethyi)phenol; 4-((1R)-2-{{6-({4-{3-(Cyclohexylsulfonyl)phenyl]butyl}oxy)hexylJamino}-1-hydroxyethyt)-2- (hydroxymethyl)phenol; 4-((1R)-2-{[6-({4-[3-(3-Cyclopenten-1-yisulfonyl)phenyl]butyl}oxy)hexyllamino}-1- : hydroxyethyl)-2-(hydroxymethyl)phenol; : 4-({1R)-2-{{6-({5-{3-(Cyciopentyisuifonyi)phenyijpentyi}oxy)hexyijaminc}-1-hydroxyethy!)- 2-(hydroxymethyl)phenct; 4-((1R)-2-{[7-({3-{3-(Cyciopentylsulfonyl)phenyllpropyl}oxy)heptyllamino}-1-hydroxyethyt)- 2-(hydroxymethyi)pheno!;

4-((1R)-2-{[6-({4-[3-(Cyclopentylsulfonyl)-5-methyiphenyilbutyl}oxy)hexyl]Jamino}-1- h hydroxyethyl)-2-(hydroxymethyi)phenoi;

N-[5-((1R)-2-{[6-({4-[3-(Cyclopentyisulfonyl)phenyl]butyl}oxy)hexyllamino}-1- nydroxyethyi-2-hydroxyphenyimethanesulfonamide; 5S 4-((1R)-2-{16-({4-[3-(Cyclopentyisuifonyl)phenyi]buty!}oxy}hexyllamino}-1-hydroxyethyl)-2- fluorophenol; 6-{2-[(6-{4-[3-(Cyclopentyisulfonyl)phenyllbutoxy}hexyl)amino)-1-hydroxyethyi}-2- (hydroxymethyl)pyridin-3-ol; 5<{(1R)-2-{(6{4-[3-(Cyclopentylisuifonyl)phenyl]butoxy}hexyl)amino}- 1-hydroxyethyil}-8- hydroxy-3,4-dihydroquinolin-2(1H)-one; 5-{(1R)-2-[(6-{4-[3-(Cyclopentyisulfonyl)phenyl]butoxy}hexyl)amino}- 1-hydroxyethyi}-2- hydroxyphenyiformamide; and salts, solvates, and physiologically functional derivatives thereof.

A particularly preferred compound of formula (1) is: 4-{(1R)-2-[(6-{4-[3-(Cyclopentylsuifonyl)phenyl]butoxy}thexyljamino}- 1-hydroxyethyl}-2- (hydroxymethyt)phenol; and salts, solvates, and physiologically functional derivatives thereof. - it will be appreciated that the compounds of formula (!) and {ia) include two asymmetric centres, namely the carbon atom of the

CH- on group and, when R' represents SOR’, at the sulphur atom of the sulphoxide group The compounds may therefore exist in four different isomeric forms. The present invention includes both (S) and (R) enantiomers at both chiral centres either in substantially pure form or admixed in any proportions.

Similarly, where R* and R® are different groups, the carbon atom to which they are attached is an asymmetric centre and the present invention includes both (S) and (R) © 30 enantiomers at this centre either in substantially pure form or admixed in any proportions.

Thus the compounds of formula (1) and (ia) include ail enantiomers and diastereoisomers as well as mixtures thereof in any proportions.

Salts and solvates of compounds of formula (I) and (la) 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, ‘or

S example, for use as intermediates in the preparation of other compounds of formula (1) and (la) and their pharmaceutically acceptable salts, solvates, and physiologically functional derivatives.

By the term “physiologically functional derivative” is meant a chemical derivative of a compound of formula (I) or (la) having the same physiological function as the parent compound of formula (I) or (la) 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. Pharmaceutically 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, methanesuiphaonic, ethanesuiphonic, aryisuiphonic (for example p-toluenesuiphonic, m-toluenesuiphonic, benzenesulphonic, 4-chlorobenzenesulphonic, 4-bromobenzenesulphonic, 4-phenylbenzenesulphonic, naphthalenesulphonic or naphthalenedisulphonic), salicylic, glutaric, gluconic, tricarballylic, cinnamic, substituted cinnamic (for example, phenyl, methyl, cynao, 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-benzenediacryfic) 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.

Advantageously, preferred compounds of the invention such as 4-{(1R)-2-{(6-{4-{3- (cyclopentylsulfonyl)phenyl]butoxy}hexyl)amino]-1-hydroxyethyl}-2- (hydroxymethyi)phenol, are provided in the form of a crystalline salt, for example selected from those exemplified in the experimental section below. Particularly preferred salts

S include benzenesulfonate derivatives such as the p-toluenesulfonate, m-toluenesulfonate, 4-chlorobenzenesuifonate, 4-bromobenzenesulfonate, 4-phenylbenzenesulfonate and naphthalene-2-sulfonate salts.

Pharmaceutically acceptable esters of the compounds of formula (I) and (la) may have a hydroxyt group converted to a C,.galkyl, aryl, aryl C,, alkyl, or amino acid ester.

As mentioned above, the compounds of formula (I) and (la) are selective [- adrenoreceptor agonists as demonstrated using functional or reporter gene readout from cell lines transfected with human beta-adrenoreceptors, or membranes derived from these cells, as described below. Compounds according to the present invention also have the potential to combine long duration of effect with rapid onset of action. Furthermore, certain compounds have shown an improved therapeutic index in animal models relative to existing long-acting p-agonist bronchodilators. As such, compounds of the invention may be suitable for once-daily administration. Preferred compounds of the invention also exhibit relatively low absorption in the rat following oral administration. Whilst the compounds of the invention are principally intended for administration by inhalation, a certain proportion of the dose, which can be as much as 80%, may be swallowed by the patient, with the potential for unwanted systemic effects. Low oral absorption is therefore a desirable property for compounds of the invention.

Compounds of formula (1) and (la) and their pharmaceutically acceptable salts, solvates, and physiologically functional derivatives have use in the prophylaxis and treatment of clinical conditions for which a selective Bradrenoreceptor 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 z-adrenoreceptor agonist is indicated, which comprises administration of a therapeutically effective amount of a compound of formula {!) or /1a} or 2 pharmaceutically acceptable sal, scivate, or

S 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 (Dor (la)ora pharmaceutically 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 B2-adrenocreceptor agonist is indicated. In particular, there is provided a compound of formula {yor (:a)ora pharmacettically acceptabie salt, scivate, 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) or a pharmaceutically 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 (la) 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 for which a selective Br-adrenorecepior 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 (la) 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 le.g. $5 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 (la) or a pharmaceutically 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. eg. 0.05mg to 0.5mg. The dose range for adult humans is generally from 0.0005mg to 10mg per day and preferably 0.01mg to 1mg per day, most preferrably 0.05mg to 0.5mg.

While it is possible for the compound of formula (I) or (la) or a pharmaceutically acceptable salt, solvate, or physiologicaily functicnal derivative thereof tc be administered alone, it is preferable ic present it as a pharmaceutical formuiation.

Accordingly, the present invention further provides a pharmaceutical formulation comprising a compound of formula (I) or (la) 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 (la) 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 aercssis, nebuiisers 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 i2 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, lubricating, 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 irert liguid diluent. The tablets may optionally be coated or scored and may be formuiated sc as to prcvide 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 insuffiator. Powder blend formulations generally contain a powder mix for inhalation of the compound of the invention and a suitable powder basé (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 generaily contain between 20ug-10mg of the compound of formula (1) or (1a) optionally in combination with another therapeutically 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) or (ia) preferably combined with factose.

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 aerosois 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) or (fa) optionally in combination with ancther therapeutically active ingredient and a suitable propellant such as a fluorccarbon or hydrogen-containing chioroflucrecarbon or mixtures thereof, particularly hydroflucroalkanes, e.g. dichlorodifiucromethane, trichlorofiucromethane, dichlorotetra-fluoroethane, especially 1,1,1,2-tetraflucreethane, 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 an? cosclvents eg ethanc!. Pressurised formulations will generally be retained ina 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 1-10um, preferably 2-5pm. Particles having a size above 20um 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 60-90um and not less than 15% will have a MMD of less than 15um. intranasal sprays may be formuiated 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.

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 exampie buccally or sublinguaily, 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 selected from anti-inflammatory agents, anticholinergic agents (particularly an M,, Mz, My/M, or M; receptor antagonist), other Bradrenoreceptor 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 pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with one or more other therapeutically active agents, for example selected from an anti-inflammatory agent (for example a corticosteroid or an NSA!D), an anticholinergic agent, another f.- adrenoreceptor agonist, an antiinfective agent (e.g. an antbiotic or an antiviral), or an antihistamine. Preferred are combinations comprising a compound of formuia (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 aiso 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 ceimbination with the compounds of the invention are those oral and inhaled corticosteroids and their prodrugs which have anti- inflammatory activity. Examples include methyl prednisolone, predniscione, dexamethasone, fluticasone propionate, 6a,9a-diflucro-17a-{(2-furanylcarbony!)oxy}-11p-

hydroxy-16a-methyi-3-oxo-androsta-1,4-diene-17B-carbothioic acid S-fluoromethyl ester, 6a,9a-difluoro-11p-hydroxy-16a-methyl-3-oxo-17a-propionyloxy- androsta-1,4-diene-178- carbothioic acid S-(2-oxo-tetrahydro-furan-3S-yi) ester, beclomethasone esters (e.g. the 17-propionate ester or the 17,2'-dipropicnhals ester, tudesonide, flunisclide, mometasone esters (e.g. the furoate ester), triamcinolone acetonide, rofleponide, ciclesonide, butixocort propionate, RPR-106541, and ST-126. Preferred corticosteroids include fluticasone propionate, 6a,9a-difluoro-11p-hydroxy-16a-methyl-17a-[(4-methyl- 1,3-thiazole-5-carbonyl)oxy}-3-oxo-androsta-1,4-diene-173-carbothioic acid S- fluoromethyl ester and 6a,9a-diflucro-17a-[(2-furanylcarbonyl)oxy]-11p-hydroxy-16a- methyl-3-oxo-androsta-1,4-diene-17B-carbothicic acid S-fluoromethyl ester, more preferably 6a,Sa-difluoro-17a-[(2-furanylcarbonyl)oxy]-118-hydroxy-16a-methyl-3-oxo- androsta-1,4-diene-17p-carbothioic acid S-fluoromethyl ester.

Suitabie 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), cylckine antagonists (e.g. chemokine antagonists) or inhibitors cf cytokine synthesis. Suitabie cther 3-adrencreceptor 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) or (la) 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 IC5q ratio of about 0.1 or greater as regards the ICsq for the PDE4 catalytic form which binds rolipram with a high affinity divided by the ICs for the form which binds rolipram with a : low affinity. For the purposes of this disclosure, the cAMP cataiytic 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 tern "hPDE4" which is used to denote human PDE4. :

A method for determining ICsgs 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 WC D0/E4EQQ for an ansther 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 ICs, ratio of about 0.1 or greater as regards the ICsq for the

PDE4 catalytic form which binds rolipram with a high affinity divided by the IC5q 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 ICs ratio of about 0.1 or greater; said ratio is the ratio of the ICgq value for competing with the binding of nM of {3H]R-rolipram to a foom of PDE4 which binds rolipram with a high affinity over the ICsq value for inhibiting the PDE4 catalytic activity of a form which binds rolipram with a low affinity using 1 pMISHI-cAMP as the substrate.

Most preferred are those PDE4 inhibitors which have an ICgq 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-cyano4-(3-cyclopropyimethoxy-4- difluoromethoxyphenyl)cyciochexan-1-ol); these are examples of compounds which bind preferentially to the low affinity binding site and which have an ICs 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-methoxyphenyijcyclohexane-i-carboxylic acid (aise known as cilomalast) and its salts, esters, pro-drugs or physical forms;

AWD-12-281 from elbion (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-

Dlough; 2 benzodiazepine PDE4 inhibitor identified as CIi-1018 (PD-168787) and attributed to Pfizer; a benzodioxole derivative disclosed by Kyowa Hakko in WO99/16766;

K-34 from Kyowa Hakko; V-11294A from Napp (Landells, 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*,10bS*)-9-ethoxy-1,2,3,4,4a,10b-hexahydro-8-methoxy-2- methylbenzo[c][1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamide which is a mixed

PDE3/PDE4 inhibitor which has been prepared and published on by Byk-Gulden, now

Altana; arofylline under development by Almirall-Prodesfarma; VM554/UM565 from

Vernalis; or T-440 (Tanabe Seiyaku; Fuji, K. et al. J Pharmacol Exp Ther, 1998, 284(1): 16 162), and T2585.

Other possible PDE4 and mixed PDE3/PDE4 inhibitors include those listed in

WO001/13953, 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 M, and

M: receptors. Exemplary compounds include the alkaloids 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 - CAS4438-22-6 or its HCI salt - CAS4574-60-1 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, f) - CAS-101-31-5, hydrobromide salt - CAS-306-03-6 and suifate sait -

CAS-6835-16-1.

Scopolamine - CAS-51-34-3, hydrobromide salt - CAS-6533-68-2, methylbromide salt-

CAS-15541-9.

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- 50-34-90), arisotropine methy! bromide or Valpin 80 /CAS- 80-50-2), clidinium bromide (Quarzan, CAS-3485-62-9), copyrrofate (Robinu!), isopropamide iodide (CAS-71- 81-8), mepenzolate bromide (U.S. patent 2,918,408), tridihexethyl chloride (Pathilone,

CAS-4310-354), and hexocyclium methylsulfate (Tral, CAS-115-63-9). See also cyclopentolate hydrochloride (CAS-5870-29-1), tropicamide (CAS-1508-754), 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 Hi-receptor antagonists) include any one or more of the numerous antagonists known which inhibit Hy-receptors, and are safe for human use. All are reversible, competitive inhibitors of the interaction of histamine with

Hi-receptors. The majority of these inhibitors, mostly first generation antagonists, have a core structure, which can be represented by the following formula:

Ar

Nudboi a TT ON

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 piperizine or piperidine. Exemplary antagonists are as follows:

Ethanolamines: carbinoxamine maleate, clemastine fumarate, diphenylhydramine hydrochloride, and dimenhydrinate.

Ethyienediamines: pyrilamine amleate, tripeiennamine HCI, and tripelennamine citrate.

Alkyiamines: chlorcpheniramine and its salts such as the maieate salt, and acrivastine.

Piperazines: hydroxyzine HC!, 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 pharmaceutically acceptable salt.

Azelastine hvdrochloride is vet another H. receptor antagonist which mav 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) or (la) or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with a PDE4 inhibitor. Preferably, the invention provides a combination comprising a compound of formula (la) or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with a preferred PDE4 inhibitor as described hereinabove, e.g. cis-4-cyano-4-[3- (cyclopentyioxy)-4-methoxyphenyi]cyciohexane-1-carboxyiic acid.

The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or (la) or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with a corticosteroid. Preferably, the invention provides a combination comprising a compound of formula (fa) or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with a preferred corticosteroid as described hereinabove, e.g. fluticasone propionate, 6a,9a- difluoro-11p-hydroxy-16a-methyl-17 a-[(4-methyl-1,3-thiazole-5-carbonyl)oxy]-3-oxo- androsta-1,4-diene-17p-carbothioic acid S-fluoromethy! ester and 6a,9a-difluoro-17a-[(2- furanylcarbonyl)oxy]-11p-hydroxy-16a-methyl-3-oxo-androsta-1,4-diene-17p-carbothioic acid S-fluoromethyl ester.

The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or (la) or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with an anticholinergic. Preferably, the invention provides a combination comprising a compound of formula (la) or a pharmaceutically © acceptable salt, solvate or physiologically functional derivative thereof together with a preferred anticholinergic as described hereinabove, e.g. ipratropium, oxitropium or tiotropium

The invention thus provides, in a further aspect, a combination comprising a compound of formula (1) or (la) or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with an antihistamine. Preferably, the invention provides a combination comprising a compound of formula fla) or a pharmaceutically 5S acceptable salt, solvate or physiologically functional derivative thereof together with a preferred antihistamine as described hereinabove.

The invention thus provides, in a further aspect, a combination comprising a compound of formula (1) or (la) or a phammaceutically acceptable salt, solvate or physiologically functional derivative thereof together with a PDE4 inhibitor and a corticosteroid.

Preferably, the invention provides a combination comprising a compound of formula (la) or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with a preferred antihistamine and a preferred corticosteroid as described hereinabove.

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

Preferably, the invention provides a combination comprising a compound of formula (la) or a pharmaceutically acceptabie salt, soivate or physiologically functional derivative thereof together with a preferred PDE4 inhibitor and a preferred anticholinergic as described hereinabove.

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 fermula (1) or (la) or a salt, solvate, or physiolegically functional derivative thereof which comprises a process as defined below foliowed by the following steps in any order: ’

(i) optional removal of any protecting groups; "7 (ii) optional separation of an enantiomer from a mixture of enantiomers; (iii) optional conversion of one compound of formula (I) to a different compound of formula 0 eg. sorversicn of a compound wherein R! is

SR® to a compound wherein R' is SOR® or SO,R®, or conversion of a compound wherein R' is SOR® to a compound wherein R' is SO,R%; (iv) optional conversion of a compound wherein R® represents cycloalkenyl to a compound wherein R® represents cycloalkyl, eg. by hydrogenation; (v) optional conversion of the product to a corresponding salt, solvate, or physiologically functional derivative thereof.

In one general process (a), a compound of formula (I) or (la), may be obtained by deprotection of a protected intermediate, for example of formula (li): 2

R rR!

R'&— oumesnconso-on—()

CR ta ey or a salt or solvate thereof, wherein R', R2, R% R%, R%, m, and n are as defined for the compound of formula (1) or (1a), R" represents an optionally protected form of Ar; and R%® and R? are each independently either hydrogen or a protecting group, provided that the compound of formula (lI) contains at least one protecting group.

Optionally protected forms of the preferred groups Ar may be selected from: & N

R20 R70 HCONH RZ0 ES 0 RZ0 R20 R®0 (ia) (iia) (iia) (iva)

“Y OY OT “LY 2 2 2 Z

RPO R?0 R%Z0 R*¥0 (ia) (iia) (iia) vay rRZ0

H,CSO,NH H,NSO, HNSO, = or 9 Tr Bp C (va) (via) (viia) (viiia)

HN lo] cl ~ t

NH, RZ0 H, H,N ) cl CF, (ixa) (xa) (xia) (xiia) i I porn (CH),NCO\ Nes > HN , } Offeror offer RZ0’ fo} fo) {xiiia) (xiva) (xva)

o

Ox Oxo - |.

J } a v= v

Des OY RZN

RZ0 RZ0 : g (xvia) (xviia) (xviiia)

OOCH,

HN

AN NN :

RZ0 Ro R20 (xixa) (xxa) (xxia) wherein R* and R® are each independently either hydrogen or a protecting group provided that at least one of RZ? and RZ is a protecting group,and the dotted line in (xvia) and (xixa) denotes an optional double bond. it will be appreciated that to obtain a compound of formula (1a) in this and the other processes described herein, R" represents the structure (ia) above.

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 16 protecting groups represented by RZ and R® are esters such as acetate ester, aralkyl groups such as benzyl, diphenylmethyl, or triphenylmethyl, and tetrahydropyranyi.

Examples of suitable amino protecting groups represented by R?® include benzyl, a- methylbenzyl, diphenyimethyi, triphenyimethyl, benzyloxycarbony!, tert-butoxycarbonyl, and acy! 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 (il) to facilitate the selective removal of one group in the presence of another, thus enabling selective functicnalisation of a single amine or hydroxy! function. For example, the =CHCH) group may be orthogonally protected as -CHOR?' 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 (see above).

The deprotection to yield a compound of formula (I) or (la) may be effected using conventional techniques. Thus, for example, when R%, R®, and/or R® is an aralkyl group, this may be cleaved by hydrogenolysis in the presence of a metal catalyst (e.g. palladium on charcoal).

When R® and/or R* is tetrahydropyranyl this may be cleaved by hydrolysis under acidic conditions. Acyl! groups represented by R® may be removed by hydrolysis, for example with a base such as sodium hydroxide, or a group such as trichloroethoxycarbonyt may be removed by reduction with, for example, zinc and acetic acid. Other deprotection methods may be {curd in Thecdora W Greene (see above).

In a particular embodiment of process (a), when Ar represents a group of structure (i), eg. as in formula (la), RZ and R® may together represent a protecting group as in the compound of formula (111).

Nah . EE - ot

R* RO

OR? 05 rR? {my or a salt or solvate thereof, wherein R', R?, R3, R%, R%, R®, R?', m, and n are as defined for the compound of formuia (}) R* and R? are independently selected from hydrogen,

Cisalkyi, or aryl or R* and R® together form a Cs; alkyl group. In a preferred aspect, both R* and R® are methyl.

A compound of formula (lll) may be converted to a compound of formula (1) 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 2s an acid ‘for example, ‘cluenesu'zhenic acid) or a salt (such as pyridinium tosylate) at normal or elevated temperature. it will be appreciated that the protecting groups R%?, R%, R® and R? (including the cyclised protecting group formed by R¥? and R® as depicted in formula (lll) 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 R¥ and R* together form a protecting group as in formula (lll) this protecting group is removed together with any protecting group on the

CH(OH) moiety, followed by removal of R%.

Compounds of formulae (ll) and (I!) wherein R® and R*' represent hydrogen may be prepared from the corresponding compound of formula (IV): 0] —f R? =

TL 45 \ 3

R'® CR*R*— (CH,},—0—(CH,); rR’ (Iv) or a salt or solvate thereof, wherein R', R?, R?, R*, R®, R'®, m, and n are as defined for the compound of formula (Il) or (li1).

The conversion of a compound of formula (IV) to a compound of formula (11) or (lll) may be effected by treatment with a base, for example a non-aqueous base, such as potassium trimethyisilanolate, or an aqueous base such as aqueous sodium hydroxide, in a suitable solvent such as tetrahydrofuran.

Compounds of formuta (iV) wherein R' represents a group SR® may be prepared from the corresponding compound of formula (V): :

Oo

I o—1 R? iW orton rand TX

R 2% LH rR Vv wherein R%, R? R% R% R'™, m, and n are as defined for formula (Il) and L is a leaving group, for example a halo group, (preferably iodo); by reaction with a compound R®SH in the presence of 1,1 bis-(diphenyl phosphine) ferrocene, tris(dibenzylidene acetone) di-palladium, N-methylpyrrolidinone and an organic base such as triethylamine. The sulfide product initially obtained from this reaction may if desired be oxidised to give the corresponding compound of formula (IV) wherein R' represents a group SOR®. Oxidation may be carried out using conventional oxidising agents, for example sodium periodate, in a suitable solvent, for example an alcohol such as ethanol, or a peracid, for example, metachloroperbenzoic acid in a suitable solvent such as dichloromethane, or hydrogen peroxide in a suitable solvent such as acetic acid.

When R' represents SOR® the product may initially be cbiained as a mixture of diastereoisomers. These may be separated by conventionai methods, for example using chiral chromatography, such as chiral HPLC. Altematively the sulphoxides can be prepared selectively in one of the diastereomeric forms by the use of a chiral oxidising agent. --- A compound of formula (IV) wherein R' represents SO,R® may be prepared by oxidation of a corresponding compound of formula (IV) wherein R' represents SOR® or SR® by reaction with a peracid, for example metachloroperbenzoic acid. When a sulfide (ie R' represents SR®) is employed as the starting material, the peracid should be used in excess, to ensure complete oxidation. A sulphoxide starting material may conveniently be employed as a mixture of diastereoisomers. it will be appreciated by those skilled in the art that whilst it is possible to react a compound of formula (V) with a compound R°®SH wherein R® represents either a cycloalkyl or cycloalkenyl group, any subsequent oxidation step effected on a compound (Iv) wherein R® represents a cycloaikeny! group, will aiso result in oxidation of said cycloalkenyl group. However, compounds (IV) wherein R' represents SOR® or SO,R® wherein R® is a cycloalkenyl group may be prepared by the methodology described in process (b) hereinbelow.

Compounds of formula (IV) may also be prepared by methods analogous to processes (c) and (d) below, for example by reacting a compound of formula (VI) with a compound of formula (XVII) as defined hereinbelow.

A compound of formula (V) may be prepared by coupling a compound of formula (VI): 0 0}

Rr" NH or a salt or solvate thereof, wherein R" is as defined for the compound of formula (V) with a compound of formula (VII):

R?

L

L'CR'R(CH,),—O —(CH,), (vii) rR? wherein R*, R%, L, m and n are as defined for the compound of formula (V) and L' is a leaving group, for example a halo group (typically bromo or iodo) or a sulfonate such as an alkyl sulfonate (typically, methanesulfonate), an arylsulfonate (typically, toluenesulfonate), or a haloalkyl sulfonate (typically, trifluoromethanesulfonate).

The coupling of a compound of formula (VI) with a compound of formula (VII) 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 exampie N,N- dimethylformamide or tetrahydrofuran.

Compounds of formuia (VI) may be prepared for example as described in WO 02/066422.

Compounds of formula (VII) may be prepared from a comesponding dihaloalkane of formula (Vill):

LCR RY(CH,),L” (vin) wherein R?, R® and m are as defined for compounds of formula (I) and each L' represents a halo, typically bromo; by reaction with an alcohol of formula (1X): rR?

L

HO(CH,); {iX)

Rr? wherein R?, R?, L and n are as defined for compounds of formula (VII). it will be appreciated that wher the group L In compounds cf formula (Vil) represents bromo, this may, if desired, be exchanged for an iodo substituent by reaction with iodine in the presence of an alkyl lithium, such as n-butyl lithium, in a solvent such as tetrahydrofuran.

The coupling of compounds (VIII) and (IX) may be effected in the presence of an -—-inorganic base, such as aqueous sodium hydroxide, under phase transfer conditions in the presence of an ammonium salt such as tetraalkylammonium bromide.

Compounds of formula (VIII) and (IX) are known or may be prepared by standard methods. © 25 Compounds of formuia (1), (i) or (iil) may aiso be prepared as described in processes {b)- {e) below.

Thus in a further process (b) a compound of formula (I), (Il) or (lll) wherein R' represents a group SO,R® and R® represents a cycloalkenyl group may be prepared from a compound of formuta (X): / (CH,), CH==CHR®

R? CH rd so, \

R'® — CHCH,NRP®CR'R® — (CH,);——0——(CH,), (CH,),CH==CHR™ : OR? Rr? x) wherein R?, R®, R* R% m and n are as defined for formula (I), R" is an optionally protected form of Ar, R® and R* each independently represent hydrogen or a protecting group, each R?* independently represents hydrogen or C,salkyi, and x and y each represent 0, 1 or 2; by effecting ring closure to form a cycloalkenyl group.

Ring closure may be effected by olefin metathesis chemistry. in this method a compound of formula (X) is reacted with a ruthenium catalyst (Grubbs catalyst) such as benzylidene- bis(tricyclohexylphosphine)-dichlororuthenium, or a molybdenum (Schrock) catalyst, to effect formation of the desired cycloalkene moiety, with concomitant generation of ethylene or a substituted ethylene, preferably as a gas. R? is preferably a small moiety, eg. hydrogen or methyl, most preferably hydrogen. Preferably a ruthenium catalyst is employed. The catalyst may if desired be polymer-supported. A review of metathesis chemistry and catalysts is given by

S J Connon and S Blechert, Angew. Chem. Int. Ed. 2003, 42, 1900.

A compound of formula (X) may be prepared by reacting a compound of formula (XI):

R'*CHCH,NR®CR'R*(CH,),O(CH,), ,CH——CH,

wherein R%, R®, R", R®, R?', m and n are as hereinbefore defined for compounds of formula (X), with a compound of formula (Xii): . : —_— 28 rR / (CH,),CH=—=CHR

SO,CH 2

Cr oH CHR

Rr? (XIN) wherein R?, R®, R%, x and y are as defined for formula (X) and L? is halo eg. bromo.

In this method, a compound of formula (XI) is initially reacted with a sterically hindered borane compound eg. a cyclic borane derivative such as 8-borabicyclo[3.3.1]nonane, thexylborane, catecholborane or disiamylborane, and followed by coupling with the compound (Xi!) in the presence of a catalyst such as palladium acetate, PdCl,, Pd(PPhs),, or Pdydba); and a phosphine such as (triphenylphosphine, (di-tert- butylphosphino)biphenyl, tricyclohexylphosphine, ~ triisopropylphosphine, tricyclopentylphosphine, or tri-tert-butylphosphine; and a base such as aqueous potassium or sodium phosphate, potassium or sodium carbonate, or sodium acetate.

A compound of formula (XI) may be prepared for example by reacting a compound of formula (XI):

R'*—CHCH,NR™H (xii)

La wherein R', R® and R?' are as hereinbefore defined; ’ with a compound of formula (XiV): 1 4-3 =

L'CR'R(CH,),,-0-(CH,), ,CH=CH, ov)

wherein L', R*, R®, m and n are as defined for formula (Vil).

Compounds of formula (XIil) are known in the art (for example EP-A 0947438 or WO 02/070430) or may be readilv prepared bv a person skilled in the ant.

Further details concerning preparation of compounds (Xlil) wherein R* is a group (v) can be found in DE3524990; conceming the preparation of compounds (XIII) wherein R" is a group (ii), (viii), and (xvi) in EP-A-162576; concerning the preparation of compounds (XIII) wherein R'is a group (iv) in EP-A-220054; concerning the preparation of compounds (XH) wherein R" is a group (xi) in GB2165542 and conceming the preparation of compounds (XIII) wherein R* is a group (c) in GB2230523.

A compound of formula (XIV) may be prepared by standard methods, e.g.from the corresponding dihaloalkane and hydroxyalkene by conventional chemistry, typically in the presence of an inorganic base, such as aqueous sodium hydroxide, under phase transfer conditions in the presence of an ammonium salt such as tetraalkylammonium bromide.

A compound of formula (XII) may be prepared by reacting a compound of formula (XV): rR? . ~ 12

Xv)

R® with a base, such a lithium bis(trimethylsilyl)amide in a solvent such as tetrahydrofuran, followed by reaction with an alkenyl halide of formula:

L%CH,),CH==CHR® . or, where x and y in formula (XI) each have different values by stepwise reaction with each of L3(CH,),CH=CHR? and L}(CH,),CH=CHR?.

Alternatively, where x and/or y represent zero, the moiety ~SC,CH(CH=CHR®), or

—SO,CH,CH=CHR* may be coupled directly with the aromatic ring by conventional methods.

Compounds of formiua (Xv) may 0€ prepared oy siandarc methods eg. as described In

Tet. Letts. 1994, 35, 9063.

It will be appreciated that a compound of formula (IV) wherein R' represents ~SO,R® and

R® represents cycloalkenyl may also be prepared by the method of process (b), using a compound of formula (XVI): 0)

R"~ y ono oo CH, (Xvi) wherein R*, R%, R', m and n are as defined for compounds of formula (iI), which in tum may be prepared by reacting a compound of formula (VI) with a compound of formula (XIV) in an analogous manner to the reaction cf a compound (XI) with a compound (XIV).

It will further be appreciated that the step of forming the cycloalkenyl group R®, may be carried out at any convenient stage of the reaction. However, in order to retain the cycloalkenyl moiety, this step should be camied out after any stages involving hydrogenation, hydroboration or oxidation reactions. in a further process (c), a compound of formula (1), (il) or (Ill) may be obtained by alkylation of an amine of formula (Xi):

R'S—CHCH,NR™H ) Loa xm) wherein R'®, represents an optionally protected form of Ar and R® and R*' are each independently either hydrogen or a protecting group, eg. as defined hereinabove for formula (il); }

with a compound of formula (XVI): ~ :

R'

I~ dns —_———

L'CR*R¥(CH,), —O J XVI

Rr? wherein R!, R?, R®, R*, R®, m, and n are as defined for the compound of formula (I) and L' is a leaving group such as halo (typically bromo) or a sulfonate eg a haloalkyl sulfonate (typically trifluoromethane sulfonate), followed by removal of any protecting groups present by conventional methods as described above for the deprotection of compounds of formula (11).

The reaction of a compound of formula (XIII) with a compound of formula (XVII) is optionally effected in the presence of an organic base such as a trialkylamine, for example, diisopropylethylamine, and in a suitable solvent for example dimethyl formamide.

A compound of formula (XVII) may be prepared by reacting an olefin of formula (XIV): 1 45 =

L'CR'R®(CH,),-O-(CH,), ,CH=CH, XV) wherein L', R% R® m and n are as defined for formula (XI), with a compound of formula (XVII).

R?

R!

L2 ’ R]® ov wherein R', R? and R? are as defined hereinabove for formula (}) and L? is a halo, eg. bromo;

in an analogous manner to the reaction of a compound (XI) with a compound (XII) as described hereinabove in process (b); or by reacting a compound (Xiv}; with a compound of formuia (Xii; foliowed py a metathesis reaction as described in process (b) hereinabove.

Compounds of formula (XVIII) wherein R' is SR®, SOR®, or SO,R® and R® represents a cycloalkyl group are commercially available or may be prepared by methods well known to the person skilled in the art.

A compound of formula (XVII) may also be prepared by reduction of a compound of formula (XX) as defined hereinafter.

In a yet further process (d) a compound of formula (1), (Il) or (lil) may be obtained by reduction of a compound of formula (XIX): 2

R R'

ROCHCHNRCR'R (CH), —O —(CH,),, — oR?

RS

(XIX) wherein R', R?, R?, R*, R®, m and n are as defined for formula (I), R' represents an optionally protected form of Ar and R® and R? are each independently hydrogen or a protecting group as defined above.

The reduction may be effected by any suitable method such as hydrogenation in the presence of a catalyst, for example, palladium/charcoal or platinum oxide.

It will be understood by those skilled in the art that if R' contains a cycloalkenyl moiety this will also be hydrogenated to the corresponding cycloalkyl moeity. Hence this method is ] not appropriate when it is desired to obtained a product wherein R' contains a cycloalkenyl group.

It will be appreciated that where R' represents Ar and R® and R?' each represent hydregen, the reduction will yield a compound of formula (f), but where one or more of

R', R® and R? contains or represents a protecting group then reduction will yield a compound of formula (ll) or (lll), which may then be deprotected to give a compound of formula (I).

A compound of formula (XIX) may be prepared by reacting a compound of formula (Xi):

RE

OR?* (Xt) as hereinbefore defined with a compound of formula (XX): . R?

R!

L'CR'R}(CH,)—O0—— w= (XX) rR? wherein R', R?, R®, R* R® m, and n are as defined for the compound of formula (I) and L' is as defined for the compound of formula (VI) hereinabove.

The reaction of a compound of formuia (XIll) with a compound of formula (XX) is optionally effected in the presence of an organic base such as a trialkylamine, for example, diisopropylethylamine, and in a suitable solvent for example

N,N-dimethylformamide.

A compound of formula (XX) may be prepared by coupling a compound of formula (XVIil):

R?

RY

L2 ’ Pa cv) as hereinbefore defined, with a compound of formula (XX!):

L'CR'R®(CH,) O(CH,),, == (XX1) wherein 1! R% RS m and n are as defined ahove ‘or scmoounds of formula XV

Alternatively, a compound of formula (XIX) may be prepared by reacting a compound of formula (XVIII) as hereinbefore defined with a compound of formula (XXI1): 0 o—r

PR dryS —_—

R CR'R*— (CHy)y—— 0—— (CH,),;,—— C==CH (XX) or a sait or soivate thereof, wherein R*, R°, m, n and R™ are as defined for the compound of formula (XIX), followed by opening of the oxazolidinone ring as described in process (a).

The coupling of a compound of formula (XVIil) with a compound of formuia (XX!) or (XXi) is conveniently effected in the presence of a catalyst system such as bis (triphenylphosphine) palladium dichicride and in the presence of a copper cataiyst eg. cuprous iodide, with an organic base such as a trialkylamine, for example, triethylamine, in a suitable solvent, for example acetonitrile or dimethylformamide.

A compound of formula (XXII) may be prepared by coupling a compound of formula (V1) as hereinbefore defined with a compound of formula (XXI) as hereinbefore defined.

The coupling of a compound of formula (VI) with a compound of formula (XX!) may be effected in the presence of a base, such as a metal hydride, for example sodium hydride, or an inorganic base such as caesium carbonate, in an aprotic solvent, for example dimethylformamide. ’ Compounds of formula (XC(I) may be prepared from the corresponding dihaloalkane and hydroxyalkyne by conventional chemistry, typically in the presence cf an inorganic base, such as aqueous sodium hydroxide, under phase transfer conditions in the presence of an ammonium salt such as tetraalkylammonium bromide.

In a further process (e) a compound of formula (1), (Il) or (Il) may be prepared by reacting a compound of formula (XXIII): :

RH.

OR” Co (XX) wherein R'is as hereinbefore defined and L2 is a leaving group as defined above for

L'orl% or a compound of formula (XXIV):

R'* 0] (XXIV) wherein R" is as hereinbefore defined with an amine of formula (XXV): 2

R ]! erro. oe (XXV)

Rr? followed by removal of any protecting groups present by conventional methods as described above for the deprotection of compounds of formula (il).

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

Compounds of formula (3CXii) and (XXIV) may be prepared by methods known in the art.

A compound of formula (XXV) may be prepared by reacting a compound of formula (XVII) with an amine R®NH,.

In a further process {i} a COMPOUNG Gi {OIG (yy wip SF wii, hay oe prepared by remoyz! of a chiral auxiliary from a compound of formula (la):

Rr? rR!

I PHOHARTORCHD —0—(CH,),

OR? rR (1a) wherein R' = R®, m and n are as defined for formula (!}, R" represents an cptionally protected form of Ar, R* represent hydrogen or a protecting group and RZ represents a chiral auxiliary.

A “chiral auxiliary” is a moiety that is introduced into a molecule to influence the sterecchemistry of the preduct formed, and is removed in whole or part at a later time. A chiral auxiliary may simuitanecusiy function as a protecting group.

Many chiral auxiliaries are commercially available, and persons skilled in the art would choose one based on the properties desired i.e. the absolute stereochemistry desired and compatibility with the processes being used. Chiral auxiliaries suitable for use in this process include but are not limited to the S-isomer and/or the R-isomer of phenyl glycinol and substituted derivatives thereof.

The chiral auxiliary is preferably a moiety of the formula: = ad or a single enantiomer thereof, wherein R? represents C, alkyl or optionally substituted phenyl or benzy! wherein the optional substitution is one or more independently selected from C,ealkyl, halogen, hydroxy, Csealkoxy or nitro e.g. para-hydroxyphenyl.

More preferably the chiral auxiliary is a moiety:

R% hd OH wherein R? is as defined above. Alternatively it may be a moiety of formula:

RY, por wherein R? is as defined above.

Preferably R® represents pheny: optionally substituted as described above. Most preferably R? represents unsubstituted phenyl.

The chiral auxiliary in this process may typically be removed by hydrogenolysis using for example a palladium on carbon catalyst or preferably using palladium hydroxide (Pearlman's catalyst). Advantageously when Peariman’s catalyst is used the removal of the chiral auxiliary is most efficient. This method of removal is especially suitable where

R'" is phenyl or a substituted phenyl. Alternatively the nitrogen, to which the auxiliary is attached, may be derivatised under oxidising conditions to form the N-oxide before elimination by heating to give a secondary amine. : A compound of formula (lla) may be prepared by methods analogous to those described above, for example process (C).

A detailed description of a proces analogous to Route (e) may be found in published

International Application Number WQO/0186278.

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 Se vanes. will De within the skit! of the practitioner in the art to ensure that groups or moieties introduced at one stage of the process wil! not be affected by subsequent transformations and reactions, and to select the order of synthetic steps accordingly.

Thus for example, as previously indicated, where it is desired that R® in the final product represents a cycloalkenyl moiety, this should be introduced after any hydrogenation, hydroboration or oxidation reactions.

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

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

In a preferred embodiment, in any of the processes described above, R" represents a group (ia):

R®0 (ia) such that the final product is a compound cf formula (la).

According to a further aspect, the present invention provides a novel intermediate for the preparation of compounds of formula {I) and/or (ia) for example:

a compound of formula (II) (I) (IV) (X) or (XIX) as defined above, or as named in the specific examples hereinbelow, or an optical isomer, a salt, or a protected derivative thereof.

Brief description of the drawings:

Figure 1 shows an X-ray powder diffraction pattern of 4-{(1R)-2-[(6-{4-[3- (cyclopentylsulfonyl)phenyi]butoxy}hexyl)amino}-1-hydroxyethyl}-2-(hydroxymethyl)phenol 4-chlorobenzene sulfonate.

Figure 2 shows an X-ray powder diffraction pattem of 4-{(1R)-2-[(6{4-[3- (cyclopentyisulfonyl)phenyl]butoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyt)phenol 4-biphenyl sulfonate.

Figure 3 shows an X-ray powder diffraction pattem of the naphthalene-2-suifonate salt of 4-{(1R)-2-[(6-{4-[3-(cyclopentyisulfonyl)phenyli]butoxy}hexyl)amino]-1-hydroxyethyi}-2- (hydroxymethyl)phenol.

Figure 4 shows an X-ray powder diffraction pattern of 4-{(1R)-2-{(6-{4-[3- (cyclopentyisuifonyiipheryfbutoxyihexyljarminc]-1-hydroxyethyl-2-(hydroxymethyl)phercl 4-bromobenzene sulfonate. :

Figure 5 shows an X-ray powder diffraction pattern of 4-{(1R)-2-{(6-{4-[3- (cyclopentylsulfonyl)phenyi]butoxy}hexyl)amino]-1-hydroxyethyi}-2-(hydroxymethyl)phenol 3-toluene sulfonate.

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: oo LC: Liquid Chromatography

LCMS: Liquid Chromatography Mass Spectrometry.

RT : retention time

THF : tetrahydofuran

DMF : N,N-dimethyiformamide

MeCN : acetonitrile ’ PPh; : triphenylphosphine

AcOH : glacial acetic acid

E'QAz : eth! acglate

PE: petroleum ether

EtOH : ethanol 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-Sii 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.

NMR experiments at 400MHz (unless specified otherwise).

LCMS was conducted on a Supelcosil LCABZ+PLUS column (3.3 cm x 4.6 mm ID) eluting with 0.1% HCO,H and 0.01 M ammonium acetate in water (solvent A), and 0.05% HCO. H 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 100%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).

The XRPD analysis shown in the Figures were performed on a Phillips X'pert Pro powder diffractometer, Model PW3040/60, serial number DY 1379 using an X'Celerator detector.

The method runs from 2 to 40 degrees 2Theta with 0.0167 degree 2Theta step size and a 31.75 seconds collection time at each step.

Example 1 4-{(1R)-2-[(6-{4-[3-(Cyciopentylsuffinvi}phenyijbutoxylhexyilaming]- 1-hvdroxyethyi}-2- (hydroxymethyl)phenoi acetate

Co i) 6-Bromohexyi 4-(3-bromophenyl)butyi ether

A stired mixture of 4—-{3-bromophenyl) butan-1-ol (18 g) ( EP 0 895 752A1), 1,6 dibromchexane 48 ml, fstebublammenium bromide (1E 3) and 809% aguzcus sodium hydroxide solution (500 mi) was stirred for 2 days at ambient temperature. The mixture was poured into water (1000 ml) and extracted into ethyl acetate. The combined extracts were washed with water, dried (Na,SQ,) and evaporated. The residual oil was purified on the biotage eluting with light petroleum (40-60 °C), and then light petroleum (40-60 °C) - ether (9:1). The appropriate fractions were evaporated to give the title compound (18 g)

LCMS RT=4.34 min. ii) 6-Bromohexyl 4-(3-iodophenyi)butyl ether

A solution of n-butyl lithium in hexane (1.6 M; 50 ml ) was added to a stirred solution of 6- bromophenyl 4-(3-bromophenyl)butyl ether (21 g) in dry THF (150 ml) at —85 °C under 16 nitrogen. After 15 min a solution of iodine (19.8 g) in THF (100 ml) was added dropwise over 20 min. The solution was then allowed to warm up to 0 °C and aqueous sodium bisulphite was added. The mixture was poured into water and extracted into ether. The combined extracts were dried (Na,SO,) and evaporated. The residue was purified by flash silica ge! cciumn chromatography (1 kg} eluting with cyclohexane — ether (3:1). The appropriate fractions were evaporated to give the title compound (17 g). LCMS RT=4.41 min. ii) Di(tert-butvl) 2-(2,2-dimethyl-4H-1.3-benzodioxin-6-yl)-2-oxoethylimidodicarbonate

Cesium carbonate (70.49) was added to a stirred suspension of 2-bromo-1-(2,2-dimethyi- 4H-1,3-benzodioxin-6-yl)ethanone, (Glaxo, DE 3513885, 1985) (61.8g) and di-t-butyl iminodicarboxylate (47.15g) in acetonitrile (600ml) under nitrogen. After vigorous stirring at 21° for 24 h the mixture was diluted with water (ca800ml) and the product was extracted with diethyl ether (1litre, then 200ml). The combined organic layers were washed with brine, dried (MgSO) and concentrated to ca400ml. The white crystals were collected by filtration, washed with diethyl ether and dried to give the title compound oo (24.4g) 5 (CDCl3) 7.78(1H, dd, J 8, 2Hz), 7.65 (1H, brs), 6.87(1H, d, J 8Hz), 4.97(2H, s), 4.88(2H, s), 1.56(6H, s) and 1.48 (18H, s) . Further concentration of the mother liquors gave additional product (13.8g). A third crop (7.1g) was obtained by chromatographing the mother figuors on silica gel, evaporating the appropriate eluate and triturating with diethyl ether.

iv) tert-Buty 1 2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxoethylcarbamate

Trifluoroacetic acid (92ml) was added to a stirred solution of di(tert-butyl) 2-(2,2-dimethyl- &H-7.3-benzodicxin-6-vi)-Z-oxoetnyiimidodicarbonaie, ‘352.85¢" ir dichicromethane

S (3.6litres) at 21° and the reaction was stirred for 1.5 h. Aqueous NaOH solution (1.75litres) was added and after 10 min the phases were separated. The organic layer was washed with water, dried (MgSO,) and evaporated to an oil. This was stored under high vacuum overnight and then triturated with hexane:ether (3:1) to give the crude product (226.61g). This was purified by recrystaliisation from diethyl ether to give the title compound (122.78g). Further product (61.59) was obtained from the mother liquors by evaporation and chromatography on a Biotage using 15% ethyl acetate in hexane. LCMS

RT = 3.37min.

Vv} tert-Butyi (2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yi }-2-hydroxyethyicarbamate

A 2M solution of borane - dimethyl sulphide in THF {28ml) was added slowly to a 1M solution of (R)-tetrahydro-1-methyl-3,3-diphenyl-1 H,3H-pyrrolo[1,2-c]{1,3,2]oxazaborole in toluene (56ml) at 0° under nitrogen. A solution of tert-butyl 2-(2,2-dimethyl-4H-1,3- benzodioxin-6-yl)-2-oxocethylcarbamate, (108.2g) in THF (1.3litres) was added slowly keeping the temperature below 5° followed by 2M soiution of borane - dimethy! sulphide in

THF (252mi) over 50 min. After 1 h, 2M HCI {(170mi) was added with cooling and the mixture was partitioned between ethyl acetate and water. The organic fayer was washed with saturated NaHCO; solution and brine and dried (MgSO,). The solution was concentrated and the product purified by chromatography on flash silica gel (800g), eluting successively with hexane:ethyl acetate (4:1 then 3:1) to give the title compound (93.3g), LCMS RT = 3.31min. Ce vi) (SR}-5-(2.2-Dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one tert-Butyl (2R)-2-(2,2-dimethyl-4H-1 .3-benzodioxin-6-yl)-2-hydroxyethylcarbamate, (86.379) in DMF (600ml) was added dropwise to a stirred suspension of sodium hydride (60% oil dispersion, 11.9g) in DMF (160ml) with cooling such that the internal temperature : remained at 0° under nitrogen. The mixture was stirred at 21° for 2 h. The mixture was recooled to 0° and 2M HC! (134ml) was added. The mixture was diluted with water and the product was extracted with ethyl acetate twice. The solution was washed with brine twice, dried (MgSO) and evaporated to give the title compound (63.55g) LCMS RT = 2.65min.

vii) (5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-y1)-3-{6-[4-(3-iodophenyi}butoxylhexyl}- 1,3-oxazolidin-2-one

Sodium hydride (60% dispersion in oil 1.26 g) was added to a stirred, cooled (ice-bath) sciuticn of (ER)-2-12,2-Cimeihy 45-1, 2-cenncdicxin-8-y ,-E-cxazciidincne E47 5, mn Cy

DMF (50 ml) under nitrogen and the mixture was stirred for 15 min at § °C. A solution of 6-bromohexyl 4-(3-iodophenyl)butyl ether (10.7 g) in DMF (30 ml) was then added dropwise over 10 min. The mixture was stirred for 2 h at ambient temperature, then poured into aqueous solution of ammonium chloride and extracted into ethyl acetate. The combined extracts were washed with water, dried (Na,SO,) and evaporated. The residue was purified on biotage (90 g cartridge ) eluting with ether - hexane (3:2) to give the title compound (9.8 g). LCMS RT= 4.20 min. viii) (5R)-3-(6-{4-[3-(Cyclopentylthio)phenyllbutoxythexyl}-5-(2,2-dimethyl-4H-1.3- benzodioxin-6-yi}-1,3-oxazolidin-2-one

A stirred solution of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-y1)-3-{6-{4-(3- iodophenyl)butoxy]hexyl}-1,3-oxazolidin-2-one (1.8g), 1,1 bis(diphenyiphosphino) ferrocene (86 mg) and tris( dibenzylideneacetone) di palladium (180mg) was stirred at room temperature in 1-methyl-2-pyrrolidinone (10mi) and triethylamine (2m!) for 10 min under nitrogen. Cyciopenty! mercaptan (0.63mi) was added and the mixture was heated at 60°C for 1 h. The mixture was cooled, poured into water and extracted into dichloromethane. The extracts were dried (Na_;SQO,) and evaporated. The residual oil was purified on a biotage cartridge (90g) using ether-hexane (3:2) as eluent changing to ether. The appropriate fractions were evaporated to give the title compound (1.07g).

LCMS RT = 4.31 min. : ix) (5R)-3-(6-{4-[3-(Cyclopentylisulfinyl)phenyilbutoxylhexyl)-5-(2,2-dimethyl-4H-1,3- benzodioxin-6-yl)-1,3-oxazolidin-2-one

Sodium periodate (1.59) was added to a stimed solution of (SR)-3-(6{4-[3- (cyclopentylthio)phenyl]butoxy}hexyl)-5-(2,2-dimethyl-4 H-1,3-benzodioxin-6-yi)-1,3- oxazolidin-2-one (1.0g) in ethano! (20ml) and water (10ml) at room temperature. After 2 h . the solution was concentrated jn-vacuo (ca 50% vol), diluted with water and extracted into dichloromethane. The extracts were dried {(Na,SO;) ard evaporated to dryness. The residual oil was purified on a biotage cartridge (40g) using ethyl acetate as the eluent.

The appropriate fractions were evaporated to give the title compound ( 0.68g). LCMS RT =3.66min x} (1R)-2-[(6-{4-[3-(Cyclopentyisulfinyl}phenyllbutoxy}thexyl)amino]-1-(2,2-dimethyl-4 H- 1.3-benzodioxin-6-vilethanol

A stimed mixture of (5R)-3-(6-{4-{3-(cyciopentyisuifinyi)phenyijbutoxyjhexyi)}-5-(2,2- dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-0xazolidin-2-one (0.14g) and potassium trimethyl silanolate (0.45g) in tetrahydrofuran (10ml) was heated to reflux for 2 h. The mixture was poured into phoshate buffer solution (pH 5, 50mi) and extracted into ethyl acetate. The extracts were washed with water, dried (Na,SO,) and evaporated. The residual oil was purified on a biotage cartridge (8g) using dichloromethane-ethanol-0.88 ammonia (100:8:1) as eluent. The appropriate fractions were evaporated to give the title compound (0.11g) LCMS RT = 2.89 min. xi) 44{1R)-2-[{6-{4-13-(Cyciopentyisulfinyl}phenyilbutoxythexyi)aminej-1-rydroxyethyi}-2- ’ (hydroxymethyl)phenol acetate

A stimed solution of (1R)-2-[(6-{4-{3-(cyclopentyisulfinyl}phenyl]butoxy}hexyl)amino]-1- (2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol (0.1g) in glacial acetic acid (5ml) and water (0.2m) was heated at 82 °C for 40 min. The solution was evaporated to dryness to give the title compound as a clear cil { 0.0753). LCMS = 2.61 min, ES+ve 532 (MH").

Example 2 4-{(1R)-2-[(6-{4-[3-(Cyclopentylsulfinyl)phenyllbutoxy}hexyl)aminol]-1-hydroxyethyi}-2- (hydroxymethyl)phenol acetate (isomer 1) i) (5R)-3-(6-{4-[3-(Cyclopentylsulfinyl\phenyllbutoxythexyt)-5-(2,2-dimethyl-4H-1.3- benzodioxin-6-yl)-1,3-oxazolidin-2-one (isomer 1)

Prepared using methods similar to those described in Example 1 ix)

Separation of diastereoisomers was achieved using a chiracel OD column (5 cm x 20 cm) using heptane-ethanol (4:1) as eluent. The title compound was obtained as a clear oil (0.198g). LCMS RT = 3.69 min. © ii) (1R)-2-[(6-{4-]3-(Cyciopentyisuifinyi)phenyilbutoxythexyl)aminol-1-(2,2-dimethyl-4H-1,3- benzodioxin-6-yl)ethanc! (isomer 1)

Prepared using methods similar to those described in Example 1 x)

LCMS RT = 2.80 min.

ii) 4-{(1R)-2-[(6-{4-[3-(Cyclopentyisulfinyl)phenyl]butoxythexyl)amino]-1-hydroxyethy(}-2- (hydroxymethyi)phenol acetate (Isomer 1) }

Prepared using methods similar to those described in Example 1 xi)

CMS RT =232 min, E8xve S32 (ME.

Example 3 : 4-{(1R)-2-[(6-{4-[3-{Cyclopentyisulfinyl)phenyllbutoxy}hexyl)aminol]-1-hydroxyethyi}-2- (hydroxymethyl)phenol acetate (isomer 2) i) (SR)-3-(6-{4-[3-(Cyclopentylsulfinyliphenyilbutoxythexyl}-5-(2.2-dimethyl-4H-1,3- benzodioxin-6-yl)-1,3-oxazolidin-2-one (Isomer 2)

Prepared using methods to those described in Example 1 ix)

LCMS RT = 2.68 min. ii) (1R)-2-](6-{4-[3-(Cyclopentyisulfinyl)phenyilbutoxy}hexyl)amino}-1-(2 2-dimethyl-4H- 1,3-benzodioxin-6-yl)ethanol (Isomer 2)

Prepared using methods similar to those described in Example 1 x)

LCMS RT = 2.89 min. iii} 4A{(1R)-2-[(6{4-[3-(Cyclopentylsulfinyi)phenyllbutoxy}thexyl)amino]-1-hydroxyethyi}-2- (hydroxymethyl)phenol acetate (isomer 2)

Prepared using methods similar to those described in Example 1 xi)

LCMS RT = 2.60 min, ES+ve 532 (MH").

Example 4 4-{(1R)-2-[(6{4-[3-(Cyclonentyisulfonyl)phenyllbutoxy}thexyl)aminol]-1-hydroxyethyi}-2- {hydroxymethyl)phenol acetate i) (5R)-3-(6-{4-{3-(Cyclopentylsulfonyl)phenvilbutoxythexyl}-5-(2,2-dimethyl-4H-1,3- benzodioxin-6-yl)-1,3-oxazolidin-2-one 3—Chloroperoxybenzoic acid {0.088g) was added to a stirred, cooled {ice-bath) solution of (5R)-3-(6-{4-[3-(cyciopentyisulfinyi)phenyilbutoxy}hexyi)-5-(2,2-dimethyi-4H-1,3- benzodioxin-6-yl)-1,3-oxazolidin-2-one (0.097g) in DCM (10mi). The solution was stirred for 0.5 h at room temperature. The sclution was diluted with DCM and washed with 2N

NaOH solution, water, dried (Na,SO.) and evaporated to give the title compound (0.085g)

LCMS RT = 3.78 min. ii) (1R}-Z-[(6-{4-13-(Cyciopentyisuifony: jpNeNyiDUOKy Ee Xy BITC] 1-1 2, E-GuTiEssy =i 1,3-benzodioxin-6-yl)ethanol

A stimed mixture of (5R)-3-(6-{4-{3-(Cyclopentyisulfonyl)phenyi]butoxy}hexyl)-5-(2,2- dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one and potassium trimethyl! silanolate (240mg) in THF (6ml) was heated to reflux for 1.5 h. The mixture was poured into phoshate buffer solution (pH 5) and extracted into DCM. The extracts were washed with water, dried (Na,SO.) and evaporated to give the title compound (120mg). LCMS RT = 2.93 min. iii} 4-{(1R)-2-[(6-{4-[3-(Cvclopentyisulfonyl)phenyllbutoxylhexyllaminol-1-hydroxyethyi}-2- (hydroxymethyl)phenol acetate

A stired solution of (1R)-2-{(6-{4-[3-(Cyciopentyisulfonyl)phenyl]butoxy}hexyl)amino]-1- (2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol (110mg) in glacial AcOH (5m!) and water (0.3ml) was heated at 85 °C for 40 min. The solution was evaporated to dryness and the residue was purified by Biotage™ column chromatography on silica using DCM-EtOH- ammcnia (50:8:1) as eluent. The residue was dissolved in MeOH, treated with giacial

AcOH and the soivent was removed to give the fitle compound {76mg}. LCMS RT=2.6min

ES+ve 548

Example 5 4-{(1R)-2-[(6-{4-[4-(Cyclopentyisulfonyl)phenyl]butoxylhexyl)amino]-1-hydroxyethyl}-2- (hydroxymethyl)phenol acetate i) 1-{4-[(6-Bromohexylloxylbut-1-ynyl}-4-(cyclopentyisulfonyl)benzene

A stirred solution of 4-bromophenyl! cyclopentyl sulfone (EP683172 A1) (0.5 g) and N,N- diisopropylethylamine (3.33ml) in DMF (15ml) was treated with dichlorobis(triphenylphosphine) palladium (1) (60mg) and copper iodide (13.68 mg). The . solution was heated tc 70° under nitrogen and a solution of 4-[(6-bromohexyl)oxylbut-1- yne (DE 3513885 A1) and N,N-diisopropyiethylamine (1.66mi) in DMF (5mi) was added dropwise. The mixture was stirred at 70° for 19 h. The reaction mixture was cooled to room {emperature, poured onto water and extracted 3 times with EtOAc. The extracts were dried {MgSQ,) and evaporated in vacuo. The residual ofl was purified on a silica

SPE bond elut cartridge (100g), using a gradient of 0% to 30% diethyl ether in cyclohexane (Gradmaster™). The appropriate fractions were evaporated to give the title compound (280mg). LCMS RT =3.93 min ii) (1R)-2-{[6-({4-{4-(Cyclopentylsulfonyl)phenyilbut-3-ynylloxylhexyllamino}-1-(2,2- dimethyi-4H-1,3-benzodioxin-6-yl)ethano!

To a stirred solution of 1-{4-[(6-bromohexyl}oxy]but-1-ynyi}-4-(cyclopentylsulfonyl) benzene (280mg) in DMF (10ml) were added (1R)-2-amino-1-(2,2-dimethyl-4H-1,3- benzodioxin-6-yl)ethanol (WO 0266422 A1) (170mg) and diisopropylethylamine (165).

The mixture was heated at 50° for 22 h before being allowed to cool to room temperature.

The mixture was dissolved in EtOAC, washed with brine, dried (MgSO) and evaporated to dryness. The residual oil was purified on a silica bond elut SPE cartridge (10g), gradient 0% to 30% [MeOH — aqueous ammonia (10:1)] in DCM (Gradmaster™). The appropriate fractions were evaporated to give the title compound (127mg) LCMS RT =2.87 min ii) (1R)-2-[(6-{4-[4-(Cyclopentylsulfonyl)phenyl]butoxy}hexyi)aminol-1-(2,2-dimethyl-4H- 1,3-benzodioxin-6-yl}ethano!

A solution of (1R)-2-{6-({4-[4-(cycicpentyisuifonyl)phenylibut-3-ynyi}oxylhexyllamino}-1- (2.2-dimethyi-4H-1,3-benzodioxin-6-yi)ethanoi (127mg) in EtOAc (10mi} was hydrogenated over a palladium on carbon catalyst (50% water by weight, 6.35mg) for 19 h. The catalyst was removed by filtration and the filtrate was evaporated to dryness. The residual oil was purified on a silica bond elut SPE cartridge (5g), gradient 0% to 20 % [MeOH - aqueous ammonia(10:1)] in DCM (Gradmaster™). The appropriate fractions were evaporated to give the title compound (65mg) LCMS RT= 2.85 min iv) 4-{(1R)-2-[(6-{4-[4-(Cyclopentylsulfonyl)phenyllbutoxylhexyl)amino]-1-hydroxyethyl}-2- : (hydroxymethyliphenol acetate

Prepared using the method described in Example 1xi)

LCMS RT =2.60 min, ES+ve 548 (MH)"

Example 6 © 4<((1R)-2[6-{{4-3-{Cyclohexyisuifonvilphenyilbutylloxy)hexyllamino}-1-hydroxyethyl)-2- {hydroxymethvi)phenol acetate i) 3-Bromophenyi cycishesyl sulfide

To a stimed solution of 3-bromobenzenethiol (5.00g) in DMF (100ml) was added cyclohexyl bromide (4.31g) and potassium carbonate (7.31g). The mixture was stirred at room temperature under nitrogen for 18 h. The reaction mixture was partitioned between

ZN 53 and SICAC. The organic phase wss aashed ath tring and dried MoT.

S Filtration and removai of the soivent under reduced pressure gave the title compound (3.89g). Tic (silica) (4:1 cyclohexane - diethyl ether) Rf=0.90. ii} 3-Bromophenyl cyclohexyl sulfone

A stirred solution of 3-bromophenyl cyclohexyl sulfide (3.89g) in DCM (200ml) under nitrogen was treated with meta-chloroperbenzoic acid (57% pure, 8.69g), and stirred at room temperature for 1.5 h. The reaction mixture was poured into water and washed with aqueous sodium sulphite until no peracid remained. The organic phase was washed with brine and dried (MgSO,). Filtration and removal of the solvent under reduced pressure gave the title compound (3.63g). LCMS RT = 3.33 min. iii) 1-{4-[(6-Bromohexyi)oxyl-1-butyn-1-yi}-3-(cyclohexylsulfonyl)benzene

Prepared using method described in Example 5 i)

LCMS RT =3.98 min. iv) (1R}-2-4]6-({4-[3-(Cycichexyisuifonyiiphenyii-3-butyn-1-yloxylhexylamino}-1-(2,2- dimethyl-4H-1,3-benzodioxin-6-yi)ethanol

Prepared using method described in example 5 ii)

LCMS RT =2.92 min. v) (1R)-2-{[6-({4-{3-{Cyciohexylsulfonyllphenyilbutylloxylhexyllamino}-1-(2.2-dimethyl-4H- 1,3-benzodioxin-6-yl)ethanol

Prepared using method described in example 5 iii)

LCMS RT =2.94 min. vi) 4-((1R)-2-{[6-({4-[3-(Cyclohexylsuifonyl)phenyllbutyiloxy)hexyllamino}-1-hydroxyethyl)- : 2-(hydroxymethyl)phenol acetate

Prepared using the method described in Example 1xi)

LCMS RT =2.62 min, ES+ve 561 (MH) "*

Exampie?

4-((1R)-2-{I6-({4-[3-(3-Cyclopenten-1-yisuifonyl)phenyllbutyl}oxy)hexyflamino}-1- hydroxyethyl}-2-(hydroxymethyi)phenoi acetate : 1D) A-{(i-AllYiDUi-3-enyiSuniony-3- Ciscoe ncenie

To a stirred solution of 3-bromophenyl methyi sulfone (Tet. Lett. 1884, 35, 8063; 4.749) in

THF (200ml) at -78° under nitrogen was added a solution of lithium bis(trimethylsilyl)amide (19ml, 1.06M in THF) dropwise. The mixture was stirred for 25 min before a solution of allyl bromide (2.44g) in THF (10ml) was added. The mixture was allowed to stir at -78° for 1.5 h then quenched with an aqueous solution of ammonium chloride. The product was extracted with EtOAc, and the organic phase washed with brine, dried (MgSOQ,) and evaporated to dryness. The residual oil was purified on a silica

SPE bond elut cartridge (100g) using a gradient of 5% - 40% diethyl ether in cyclohexane (Gradmaster™). The appropriate fractions were evaporated to give the title compound (1.66g) LCMS RT = 3.40 min. ii) 4-[(6-Bromohexyl)oxy]-1-butene

A mixture of 1,6-dibromohexane (18.30g), 3-butene-1-ol (2.15mi), and tetrabutylammenium bromide (0.81g) were stirred vigorously with 10N NaOH (25m) at room temperature under nitrogen for 18h. The reaction mixture was partitioned between water and EtOAc. The organic phase was washed with brine, dried {MgSO,), and evaporated to dryness. The residual oil was purified on a silica SPE bond elut cartridge (100g). The excess 1,6-dibromohexane was eluted with cyclohexane. Elution with 5% diethyl ether in cyclohexane and removal of the solvent under reduced pressure gave the title compound (4.529). Tic - silica (5% diethyl ether in cyclohexane) Rf=0.44. ee = iii) (5R)-3-[6-(3-Buten-1-yloxy)hexyll-6-(2,2-dimethyi-4H-1,3-benzodioxin-6-y1)-1,3- oxazolidin-2-one

To a solution of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (WO 0266422) (2.00g) in DMF (25ml) under nitrogen was added sodium hydride (60% dispersion in mineral oil, 0.38g) and the mixture was stirred at room temperature for 15 min. A solution of 4-[(6-bromohexyl)oxy}-1-butene (2.07g) in DMF (565ml) was added dropwise and the mixture stimed for 3h. The reaction was quenched with water and partitioned between water and EtOAc. The organic phase was washed with brine, dried (MgSO), and evaporated to dryness. The residual oil was purified on a silica SPE bond elut cartridge (50g) using a gradient of 10% - 30% EtOAc in cyclohexane (Gradmaster™).

The appropriate fractions were evaporated to give the title compound (2.66g) LCMS RT = 3.47 min.

MOEESE I 0-Dimethy LH Sohenradiogin Ao 2 8 TART LD near 4 Sh da 1-yilsulfonyi}phenylbutylloxythexyl)-1,3-oxazolidin-2-one

To a solution of (5R)-3-[6-(3-buten-1-yloxy)hexyl]-5-(2,2-dimethyl-4H-1,3-benzodioxin-6- yl)-1,3-oxazolidin-2-one (1.00g) in THF (2ml) was added a 0.5M solution of 9- borabicyclo[3.3.1]Jnonane (9-BBN) in THF (6ml). The solution was stirred at room temperature under nitrogen for 2 h. Tripotassium phosphate (1.05g) in water (1.5ml) was added followed by 1-[(1-allyibut-3-enyl)sulfonyl]-3-bromobenzene (0.78g), palladium acetate (6mg), and PPh; (13mg). The mixture was heated at 60° with vigorous stirring for 22 h. The mixture was allowed to return to room temperature then partitioned between water and EtOAc. The organic phase was washed with brine, dried (MgSO,), and evaporated to dryness. The residual oil was purified on silica SPE bond elut cartridge (50g) using a gradient of 30% - 50% EtOAc in cyclohexane (Gradmaster™). The appropriate fractions were evaporated to give the title compound (1.20g) LCMS RT = 3.91 min.

Vv) (SR)-3-[6-{{4-[3-(3-Cyciopenten-1-visulfony!)phenyilbutylioxy}hexyil-5-(2 2-dimethyl- 4H-1,3-benzodioxin-6-yi}-*,3-cxazoiidin-2-one

A solution of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yt)-3-(6-{[4-(3-{[1-(2-propen-1-yl)- 3-buten-1-yl]sulfonyl}phenyl)butyfloxy}hexyl)-1,3-oxazolidin-2-one (0.5g) in DCM (25m) was deoxygenated for 5 min. Benzylidene-bis(tricyclohexylphosphine)-dichiororuthenium (32mg) was added and the mixture heated at reflux under nitrogen for 55 min. The reaction was allowed to cool and the residue was applied to a silica SPE bond elut cartridge (10g). Elution using EtOAc-cyclohexane (2:3) gave the title compound (0.38g).

LCMS RT = 3.70 min. vi) (1R)-2-{[6-({4-[3-(3-Cyclopenten-1-visulfonyi)phenyllbutylloxy)hexyllamino}-1-{2 2- dimethyl-4H-1,3-benzodioxin-6-vi)ethanol

Co To a stirred solution of (5R)-3-[6-({4-[3-(3-cyclopenten-1-yisulfonyl)phenyl]butyl}oxy) hexyl}-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yi)-1,3-oxazolidin-2-one (360mg) in THF (12mi) was added potassium trimethylsilanolate (0.11g) and the mixture heated at 70° for 2 h. Further potassium trimethylsilanolate was added (0.05g), and again after 4 h. After 6h the mixture was allowed to cool and partitioned between EtOAc and water. The organic phase was washed with brine, dried (MgSQ,), and evaporated to dryness. The residual oil was purified on silica SPE bond elut cartridge (10g) using a gradient of MeOH in DCM (0-7%) (Gradmaster™). The appropriate fractions were evaporated to give the title compound (120mg) LCMS RT = 2.79 min. vii) 4{(1R)-2-{[6-({4{3-(3-Cyclopenten-1-yisulfonyl)phenyllbutylloxy)hexyllamino}-1- hydroxyethyl)-2-(hydroxymethyi)phenol acetate

Prepared using the method described in Example 1xi) (PG 49791) LCMS RT =2.53 min,

ES+ve 545 (MH) "*

Example 8 4-((1R)-2-{[6-({5-[3-(Cyclopentyisulfonyl)phenyflpentyl}oxy)hexyllamino}-1-hydroxyethyl}- 2-(hydroxymethyi)phenol acetate i) 1-Bromo-3-{cyciopentylthiolbenzene lodocyciopentane (3.93mi) was added to a mixture of 3-bromobenzenethioi and potassium carbonate (5.4g) in acetone (50ml) and the reaction was stirred under nitrogen for 1.5h. A further portion of iodocyclopentane (2m!) was added and the mixture was stirred for 1h. The solvent was evaporated and the residue was partitioned between water and EtOAc. he combined organic extracts were washed with NaCH (2N), brine and dried (Na,SO,4). The resuiting oii was purified using bictage™ chromatography on silica using cyclohexane as eluant to give the title compound (3.6g). LCMS RT=4.1min ii) 1-{Cyclopentyithio)-3-iodobenzene

To a solution of 1-(cyclopentylthio)-3-bromobenzene (3.6g) in dry THF (40ml) at -60° under nitrogen was added n-butyl! lithium (10ml, 1.6M in hexanes). After stirring for 15min a solution of iodine (4.3g) in dry THF (30ml) was added dropwise and the solution was allowed to warm to 0°. Wet THF was added to the brown solution, followed by aqueous sodium sulphite. The resulting colourless solution was extracted with diethyl ether and the combined organic extracts were washed with water, brine and dried (Na,;SOQ4). The solvent was evaporated and the residue was purified by column chromatography on silica using cyclohexane as eluant. This gave the title compound (1.8g). LCMS RT=4.1min ii} i-(Cyciopentyisulforyl}-3-icdobenzene

To a solution of the 1-{cyclopentyithic)-3-icdobenzene (1.8g) in DCM (40m) at 0° was added m-chioroperbenzoic acid (4.3g) porficnwise. The mixture was stirred for 2h at RT and the solution was washed with aqueous sodium suiphite solution. The organic phase was applied to a pad of alumina and was eluted using cyclohexane - EtOAc (1:1). This gave the title compound as a pale yellow foam (1.7g). LCMS RT=3.3min iv) /1SR\V-E-12 2-Dimethvi-dH-1._3-benzodioxin-6-vI}-3-I6-/4-pentvn-1-vioxvihexvil-1.3-

S$ oxazolidin-2-one

A soiution of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (Example 1vi) (500mg) in DMF (15ml) under nitrogen at 0° was treated with sodium hydride (60% dispersion in mineral oil, 86mg) and the mixture stirred at 20° for 10 min. A solution of 6-bromohexyl 4-pentyn-1-yl ether (WO 02/066422) (545mg) in DMF (1ml) was added and the mixture stirred at 20° for 18 h. Phosphate buffer solution (pH 6.5) and water were added and the mixture was extracted with EtOAc. The extract was washed with water and dried (Na,SO,). Solvent evaporation in vacuo gave a residue, which was purified by flash chromatography on silica gel. Elution with EIOAc-PE (2:3) gave the title compound {730mg}. LCMS RT = 3.48mir. v) (5R)-3-16-({5]3-(Cyclopentyisulfonyl)phenyl]-4-pentyn-1-yiloxylhexyl]-5-(2,2-dimethy!- 4H-1,3-benzodioxin-6-yl}-1,3-oxazolidin-2-one

A solution of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl}-3-[6-(4-pentyn-1-yloxy)hexyi]- 1,3-oxazoelidin-2-cne (207mg) and 1-{cycicpentyisulfony!)-3-icdcbenzene (Example 8iii.) (202mg) in MeCN (8mi) and triethylamine (4m) was deoxygenated by tubtling a nitrogen stream through for 10 min. Copper (I) iodide (i0mg) and dichlorobis(triphenylphosphine)palladium (il) (18mg) were added and the mixture stirred at 20° for 4 h. The solvent was evaporated in vacuo and the residues purified by using a

SPE silica bond elut cartridge (10g, silica). Elution with DCM (1vol), EtOAc-cyclohexane (1:4) (3vols), (1:3) (1vol) then (1:1) (3vols) gave the title compound (243mg). LCMS RT = 3.79min. vi) (5R)}-3-[6{5{3-(Cyclopentyisulfonyl}phenylipentylloxy)hexyi]-5-(2,2-dimethyl-4H-1,3- benzodioxin-6-yl)-1,3-oxazolidin-2-one

A solution of (5R)-3-[6-({5-[3-(cyclopentylsuifonyl)phenyi]-4-pentyn-1-yljoxy)hexyl]-5-(2,2- "_ dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (215mg) in EtOAc (10mi) and

EtOH (10m) was hydrogenated over platinum oxide (30mg). When hydrogen uptake had ceased the mixture was filtered through celite and the solvent was evaporated in vacuo to give the title compound (200mg). LCMS RT = 3.83min.

vii) (1R)-2-{[6-({5{3-(Cyclopentyisulfonyl)phenyllpentyl}oxy)hexyllamino}-1-(2.2-dimethyl- 4H-1,3-benzodioxin-6-yllethanol :

Prepared using methods similar to those described in Example 1x.

LCMS RT = 2.53min. viii} 4-((1R)-2-{[6-({5-[3-(Cyclopentyisulfonyl)phenyllpentylloxylhexyllamino}-1- hydroxyethyl)-2-(hydroxymethyi)phenol acetate

Prepared using methods similar to those described in Example 1xi.

LCMS RT = 2.67 min ES +ve 562 (MH)".

Example 9 4-((1R)-2{[7-({3-[3-(Cyclopentylsulfonyl)phenyllpropyl}oxy)heptyllamino}-1-hydroxyethyi}- 2-{hydroxymethyl)phenot acetate i) (5R)-5-(2 2-Dimethyi-4H-1,3-benzodioxin-6-v1)-3-[7-(2-propyn-1-yioxy)heptyl]-1,3- oxazolidin-2-one

Prepared using methods similar to those described in Example 8iv.

LCMS RT = 3.44min. ii) (BR)-3-[7-{{3-{3-{Cyciopentyisuifcnyilphenvi]-2-propvn-1-yiloxyihepiyii-5-(2 2-dimethyi- 4H-1,3-benzodioxin-6-yi}-1,3-0xazolidin-2-one

Prepared using methods similar to those described in Example 8v.

LCMS RT = 3.75min. iii) (5R)-3-[7-({3-[3-(Cyclopentylsulfonyl)phenylilpropylloxy)heptyll-5-(2,2-dimethyl-4H-1,3- benzodioxin-6-yl)-1,3-oxazolidin-2-one ”

Prepared using methods similar to those described in Example 8vi.

LCMS RT = 3.76min. iv) (1R)}-2-{[7-({3-[3-(Cyclopentyisulfonvi)phenyllpropyl}oxy)heptyllamino}-1-(2,2-dimethyl- 4H-1,3-benzodioxin-6-yl)ethanol - Prepared using methods similar to those described in Example 1x.

LCMS RT = 2.86min. v) 4-((iR¥2-{[7-({3-3-{Cyciopenty'suionyiphenyiipropylloxyleptyliaminol-1- hydroxyethyl)-2-(hydroxymethyi)phenoi acetate

Prepared using methods similar to those described in Example 1xi.

LCMS RT = 2.59 min ES +ve 548 (MH)".

Exampie 10 4-((1R)-2-{]6-({4-[3-(Cyclopentyisuifonyi}-5-methyiphenyilbutylloxylhexyllamino}-1- hydroxyethyl)-2-(hydroxymethyi)phenol acetate i) 1-(Cyclopentyithio)-3-iodo-5-methylbenzene

A mixture of 1,3-diiodo-5-methylbenzene (2.00g), tris(dibenzylideneacetone)dipaliadium (0) (20mg), bis(diphenylphosphino)ferrocene (22mg), triethylamine (1.5m) and 1-methyl- 2-pyrrolidinone (3ml) were stirred at to 20° under nitrogen for 1 h. Cyclopentanethiol (0.15mi) was added and the mixture was heated to 60° for 18 h. The mixtue was cooled to 20° and was treated with phosphate buffer solution (pH 6.5) and water. The mixture was extracted with EtOAc and the extract dried (Na,SO,). Solvent evaporation in vacuo gave a residue which was purified by Flashmaster™ chromatography (silica, 70g). Elution with cyclohexane gave the title compound (444mg). LCMS RT = 4.21min. ii} 1-(Cyclopentylsulfonyl}-3-iodo-5-methylbenzene

A solution of 1-(cyciopentyithio)}-3-iodo-5-methylbenzene (440mg) in DCM (20m) at 20° under nitrogen was treatec with 3-chloroperoxybernzoic acid {1.046g, 57-86% pure) and the mixture stirred at 20° for 2 h. 0.5M Aqueous sodium metabisulphite solution was added and the mixture was vigorously stirred at 20° for 18 h. The layers were separated and the organic phase washed with 0.5M aqueous sodium metabisulphite solution. The organic phase was dried (Na,S0O,) and the solvent evaporated in vacuo. The residue was purified using a SPE bond elut cartridge (2 x 10g, silica). Elution with DCM (5 vols) gave the title compound (425mg). LCMS RT = 3.36min. ii) (5R)-3-[6-{{4-{3-(Cyclopentyisulfonyl)-5-methyiphenyi]-3-butyn-1-yiloxyihexyl}-5-(2,2- dimethyi-4H-1,3-benzodioxin-6-yi)-1,3-oxazolidin-2-one

Prepared using methods similar to those described in Example 8v using (5R)-3-[6-(but-3- ynyloxy)hexyl]-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one © (W00266422).

LCMS RT = 3.81min.

Iv) (5R)-3-6({4-[3-(Cyclopentyisuifonyi}-5-methylphenyilbutyi}oxy)hexyil-5-(2,2-dimethvi- 4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one

Prepared using methods similar to those described in Example 8vi.

LCMS RT = 3.86min. :

RL A Dasma Susy EEC REY Out OX SKY ATUNO = 1 £27 dimethyl-4H-1,3-benzadioxin-6-yl)ethanol

Prepared using methods similar to those described in Example 1x.

LCMS RT = 2.91min. vi) 4-((1R)-2-{[6-({4-{3-(Cyclopentyisulfonyl}-5-methylphenyllbutyl}oxy)hexyllamino}-1- hydroxyethyl)-2-(hydroxymethyl}phenol acetate (salt)

Prepared using methods similar to those described in Example 1x.

LCMS RT = 2.66 min ES +ve 562 (MH)".

Exampie 11 N-[5-((1R)-24{[6-({4-{3{Cyclopentyisulfonyl)phenyilbutylloxyihexyllamino}-1- hydroxyethyl)-2-hydroxyphenyllmethanesulfonamide i) 1-{4-[(6-Bromohexylloxy]-1-butyn-1-vi}-3-(cyclopentylsulfonyi)benzene

A solution of 4-{(6-tramchexyijoxy]-1-butyne (DE 3513885 A?) (288.9 mg) and 1- (cyclopentyisuifonyi}-3-iodokbenzene {5CC mg) in MeCN (2C mi) and triethyiamine (345 wi) was treated with copper iodide (11.78 mg) and dichlorobis(triphenylphosphine)palladium(il) (43.4 mg) and stirred at room temperature for 3h. The reaction mixture was partitioned between EtOAc and water, the organic phase was dried (MgSO,4) and concentrated in vacuo. The mixture was purified by column chromatography (SPE bond elut, gradient O to 40% diethyl! ether in cyclohexane) to afford - the title compound.

LCMS RT = 3.83 min 441(M+NH,)* ii) 1-{4-[(6-Bromohexyl)oxylbutyl}-3-(cyclopentyisulfonyl)benzene

To an evacuated flask, containing palladium on carbon [50% water by weight] (43 mg) was added a solution of 1-{4-[(6-bromohexyl)oxy}-1-butyn-1-yl}-3-(cyclopentylsulfonyl) benzene {304 mg) in EtOAc (10 mi). The mixture was hydrogenated for 18 h. The catalyst was filtered off and the filtrate was concentrated in vacuo to afford title compound. LCMS

RT = 3.92 min :

iii) N-{5-(Bromoacetyl}-2-[(phenylmethyi}oxylphenyi}-N- (phenylmethylYmethanesuifonamide

A solution of N-{5-acetyi-2-[(phenyimethyl)oxy]phenyl}-N-(phenyimethyl) ~etharssi¥onemits Mad Cherm 4377 20 387.02 1448 on THE BT mwas treated with phenyitrimethylammonium tribromide (1.08 g) at <10° and stirred for 6h. The reaction mixture was quenched with chilled water and then filtered. The filtrate was partitioned between diethyl ether and water, the organic phase was dried (MgSO,) and the solvent was removed in vacuo. The mixture was purified by column chromatography on silica (SPE bond elut, gradient 0 to 45% EtOAc-cyclohexane) to afford the title compound. LCMS RT = 3.48 min iv) N-{5-((1R)-1-Hydroxy-2-{[(1S)-2-hydroxy-1-phenylethyllamino}ethyl)-2- [(phenyimethyl)oxylphenyl}-N-(phenylmethylimethanesulfonamide

A solution of N-{5-(bromoacetyl)-2-[(phenylmethyt)oxy]phenyl}-N-(phenylmethyl) methanesulfonamide (570 mg) in THF (15 mi) was treated with N,N-diisopropylethylamine (0.41 ml) and (S)-(+)-2-phenyiglycinol (191.8 mg). The mixture was stired at room temperature for 5h. The solvent was removed in vacuo and the resulting solid was suspended in dry MeOH (15 mi). The resulting suspension was cooled to 0°, treated with calcium carbonate (353 mg) and stirred for 0.5h. The reaction mixture was treated with

NaBH, (88.8 mg), porticnwise at 3° and was then allowed tc warm {c room temperature and stirred for 64h. The mixture was concentrated in vacuo and the residue was partitioned between EtOAc and water. The organic phase was dried (MgSO,) and concentrated in vacuo. The mixture was purified by column chromatography (SPE, gradient 0 to 15% [MeOH-ammonia (10:1)] in DCM) to afford the title compound (360mg).

LCMSRT275min - - v) N-{5-[(1R)-2-Amino-1-hydroxvethyi]-2-hydroxyphenyl}methanesulfonamide

To an evacuated flask containing palladium hydroxide (70.8 mg) and palladium on carbon [50% water by weight] (70.8 mg) was added a solution of N-{5-((1R)-1-hydroxy-2-{[(1S)-2- hydroxy-1-phenylethyllamino}ethyl)-2-[(phenylmethyl)oxy]phenyl}-N- . (phenylmethyl)methanesulfonamide (354 mg) in EtOH (15 ml) and AcOH (3 mi). The mixture was hydrogenated for 19h. The catalysts were filtered off and the filtrate concentrated in vacuo. The mixture was purified by column chromatography (Oasis cartridge, 0 to 50% MeOH in water) to afford the title compound. LCMS RT = 0.35 min vi) N-[5-((1R)-2-{[6-({4-[3-(cyclopentyisulfonyl)phenyilbutylloxy)hexyllamino}-1- hydroxyethyl)-2-hydroxyphenyilmethanesulfonamide :

N-{5-{(1R)-2-Amino-1-hydroxyethyl]-2-hydroxyphenyi}methanesulfonamide (33.2 mg) was added fz 2 soivfion of TASB nromaorey ay Tn RTA sin ngntisi on Pherae (Example 1v.) (50 mg) in DMF (5 ml). The reaction mixture was treated with N,N- diisopropylethylamine (29.3 ul) and stirred at room temperature for 113h. The reaction mixture was partitioned between EtOAc and water and the organic extracts were washed with ammonium chloride, dried (MgSO,) and concentrated in vacuo. The residue was purified by column DCM) to afford the title compound. LCMS RT = 2.73 min 610(M+H)"

Example 12 4-((1R)-2-{[6-({4-[3-(Cyclopentylsulfonyl)phenyl]butyl}oxy)hexyllamino}-1-hydroxyethyl)-2- fluorophenol i) 2-Azido-1-[4-(benzyloxy)-3-flucrophenyilethanone

A solution of 2-bromo-1-{4-(benzyloxy)-3-fluorophenyllethanone (J. Med. Chem. 1980, 23, 738-744) (1g) in dry DMF (2.5mL) was cooled to 15° and treated portionwise with sodium azide (220mg). After complete addition the reaction mixture was stirred for a further 1h.

The reacticn mixture was partitioned between EtOAc and water. The organic phase was washed with water and ‘he combined aqueous phase back extracted with £t0OAc. The combined organic phases were washed with sat. NaHCO, three times and the combined washes back extracted with EtOAc. The combined organic phase was washed with brine, dried (MgSO,) and concentrated in vacuo. The residue was purified by column chromatography on silica, eluting with hexane-EtOAc (4:1 and 2:1) to give the title compound (810mg). LCMS RT= 3.61 min. ii) {(1R)-2-Azido-1-[4-(benzyloxy)-3-fluorophenyilethanol

Borane-dimethyisulphide solution in THF (2M, 0.03 mL) was added to a solution of (R)-2- methyl-CBS-oxazaborolidine in toluene (1M, 0.06mL) at 0° with stiming. The reaction mixture was stirred for 15 min prior to the dropwise addition of a solution of 2-azido-1-[4-

Co (benzyloxy)-3-flucrophenyllethanone (100mg) in THF. Further Borane-dimethylsulphide in THF (2M, 0.03mL) was added dropwise and the reaction mixture stirred at 0° for 2h. 2M HClq (2mL) was added dropwise and the reaction mixture stirred for 10 min prior to partitioning the reaction mixture between diethy! ether and water. The organic phase was washed twice with 2M HCl), three times with sat. NaHCOsq), water and brine. The organic phase was dried and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with DCM to give the title compound (470mg). LCMS

RT= 3.36 min.

S iii) (1R}-2-Amino-1-[4-(benzyloxy)-3-fluarophenyllethana!

A solution of (1R)-2-azido-1-[4-(benzyloxy)-3-fluorophenyljethanol (410mg) in THF (8mL) and water (2mL) was treated with PPh, (410mg) and stirred for 1h prior to addition of a further portion of PPh; (220mg). After stirring for a further 4h the reaction mixture was concentrated in vacuo and the residue partitioned between EtOAc and water. The organic phase was washed three times with 5% NaHCOsqq , dried (MgSO,) and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with DCM, 1% MeOH in DCM, 2% MeOH in DCM, 5% MeOH containing 0.5% EtsN in

DCM, and finally 20% MeOH containing 1% Et;N in DCM ) to give the title compound (260mg). LCMS RT= 2.16 min. iv) (1R)-2-{[6-({4-[3-(Cyclopentyisulfonyl)phenyilbutylloxy)hexyllamino}-1 -{3-fluoro-4- [(phenyimethyi)oxylphenyilethanol

Prepared similarly to example 11(vi) from (1 R)-2-Amino-1-{4-(benzyloxy)-3- fluorophenyljethanol to give the title compound. LCMS RT = 3.15 min v) 4-((1R)-2-[6-({443-(Cyclopentyisulfonyl)phenyilbutyl}oxy)hexyllamino}-1- hydroxyethyl)-2-fluorophenol

To an evacuated flask containing palladium on carbon [50% water by weight] was added a solution of (1R)-2-{[6-({4-[3-(cyclopentylsulfonyt)phenyl]butyl}oxy)hexyllamino}-1 -{3- fluoro-4-[(phenylmethyl)oxylphenyl}ethanol (37 mg) in. EtOAc (8 ml) and AcOH (2 ml). The reaction mixture was hydrogenated for 4h. The catalyst was filtered off and the filtrate ~ concentrated in vacuo to give the title compound. LCMS RT = 2.60 min 535(M+H)*

Example 13 6-{2-[(6-{4-[3-(Cyclopentyisulfonyl)phenyllbutoxy}hexyl)aminol-1-hydroxyethyl}-2-

Co (hydroxymethyl)pyridin-3-ol acetate i) 2-[(6-{4-{3(Cyclopentyisuifonyliohenyllbutoxyihexyl)amino]-i-(2-phenyi-4H- [1,3]dioxino{5.4-blpyridin-6-vl)ethanol :

Prepared using methods similar to those described in example 11vi) using 2-amino-1-(2- phenyl-4H-[1,3]dioxino[5,4-b]pyridin-6-yl)ethanol (EP220054A2) to afford the title compound. LCMS RT = 2.95 min ii) 6-4{2-[(6-{4-[3-(Cyclopentyisulfonyl)phenvilbutoxythexyl)amino]-1-hydroxyethyi}-2- {hydroxymethyi)pyridin-3-ol :

A solution of 2-[(6-{4-[3-(cyclopentylsulfonyl)phenyl]butoxy}hexyl)amino}-1-(2-phenyl-4H- [1,3]dioxino[5,4-b}pyridin-6-yl)ethanol (61 mg) in water (5 ml) and glacial acetic acid (5 ml) was heated under reflux for 0.5h. The reaction mixture was concentrated in vacuo to afford the title compound. LCMS RT = 2.63 min 548(M+H)"

Example 14 5-{{1R)-2-{(6-{4-{3-(Cyclopentyisulfonyi)phenyiibutoxylhexyllamincl-1-hydroxvethylt-8- hydroxy-3,4-dihydroguinolin-2(1H)-one acetate i) 5-(1R)-2-(Benzylamino)-1-hydroxyethyil-8-(benzyloxy)quinolin-2(1H)-one 8-(Benzyloxy)-5-[(2R)-oxiran-2-ylJquinolin-2(1H}one (0.102g) (WO 9525104), was dissolved in benzylamine {0.5mi) and heated in a microwave oven for 15min at 150°.

Excess benzylamine was remcved by evapcration or a rotary evaporator and the residue was purified on a silica SPE bond eiut cartridge using MeOH/DCM-0.880 ammonia mixtures, to give the title compound (106mg). LCMS RT=2.30min i) 5-{(1R)-2-[6-({4-[3-(Cyclopentylsulfonyl)phenyllbutylloxy)hexyll(phenylimethyl)aminol- 1-hydroxyethyl}-8-[(phenylmethyl}oxyl-2(1H)-quinolinone 5(1R)-2-(Benzylamino)-1-hydroxyethyl]-8-(benzyloxy)quinolin-2(1H)-one (40mg) was dissolved in MeCN (2ml). N,N,-diisopropylethylamine (0.03ml) and 1-{4-[(6- bromohexyl)oxy]butyl}-3-(cyclopentyisulfonyl)benzene (Example 1v) (30mg) were added and the reaction mixture was heated at 80° under nitrogen for 48h. The mixture was then diluted with water and extracted with EtOAc. The organic phases were combined, dried (MgSO.), and evaporated in vacuo. The residue was purified on a silica SPE bond elut cartridge, eluting with EtOAc — cyclohexane mixtures, to give the title compound, (13mg) © LCMSRT=3.1 min ii) S5{(1R)-2-[(6-{4-i3-{Cvclopentyisuifonyi)phenylibutoxylhexylamino}-1-hydroxyethyi}-8- hydroxyquinolin-2{1#)-cne acetate

5-{(1R)-2-[[6~({4-[3-(Cyclopentylsulfonyl)phenyl]butyt}oxy)hexyl](phenyimethyl)amino]-1- hydroxyethy!}-8-[(phenyimethyl)oxy]-2(1H)-quinolinone (13mg) was -dissolved in EtOH (10ml) and glacial acetic acid (0.5ml) added. The solution was hydrogenated using 10%

CEuGSIUTY On Caroon (Suro Wael Oy Weigh, « img) aia <u pasadiim nyaroxide on carbon (4mg) for 20 h. The catalyst was removed by filtration and the filtrate was evaporated in vacuo. The residue was purified on an isolute aminopropyl cartridge (2g), eluting with MeOH-DCM mixtures. Evaporation of the appropriate fractions with AcOH gave a mixture of the title compound, (4mg). LCMS RT= 2.52min ES+ve 585 (MH)" and 5- {(1R)-2-{(6-{4-[3-(Cyclopentylisulfonyl)phenyi]butoxy}hexyl)amino}-1-hydroxyethyi}-8- hydroxy-3,4-dihydroquinolin-2(1H)-one acetate

LCMS RT= 2.52min, ES+ve 587 (MH)

Example 15 5-{(1R)-2-[(6-{4-[3-(Cyclopentylsuifonyl)phenyilbutoxylhexyl}amino}-1-hydroxyethyi}-2- hydroxyphenylformamide acetate i) N-Benzyl-6-{4-[3-(cyclopentyisulfonyl)phenyllbutoxythexan-1-amine 1-{4-[(6-Bromchexyl)oxy]buty!}-3-(cyclopentyisuifcnyl)benzene (Example 11ii) (50mg) was dissolved in benzylamine (0.5mi), and heated in a microwave oven at 150° for 10min.

Excess benzylamine was removed in vacuc and the residue purified on a siiica SPE bond elut cartridge, eiuting with EtOAc — cyclohexane mixtures, to give the title compound, (40mg) LCMS RT= 2.74min ii) 5-{(1R)-2-[Benzyl(6-{4-[3-(cyclopentyisulfonyl)phenyilbutoxy}thexyl)amino]-1- hydroxyethyl}-2-(benzyloxy)phenylformamide . e

N-Benzyl-6-{4-[3-(cyclopentylsuifonyl)phenyl]butoxy}hexan-1-amine (40mg) was dissolved in dry THF (0.25mi) and {5-{(2R)-2-oxiranyi]-2-[(phenylmethyl)oxy]phenyi}formamide (23mg) (Organic Process Research & Development 1998, 2, 96-99), added. The reaction mixture was heated in a microwave oven for 3h at 150°. The solvent was removed and the residue purified on a silica SPE bond elut cartridge, eluting with EtOAc — cyclohexane mixtures to give the title compound, (17mg) LCMS RT= 3.1 min iii) 5-{(1R)-2-{(6-{4-[3-{Cyciopentyisuifonyi}phenyilbutoxy}hexyilamino]-1i-hydroxyethyi}-2- hydroxyphenyiformamide acetate : 5-{(1R)-2-[Benzyi(6-{4-[3-(cyclopentylsuifonyi)phenyl]butoxy}thexyl)aminoj-1- hydroxyethyl}-2-(benzyloxy)phenylformamide (17mg) was dissolved in EtOH (10mi) and glacial acetic acid (1ml) added. The solution was hydrogenated using 10% palladium on carbon (50% water by weight, 7 mg) and 20% palladium hydroxide on carbon (7mg) for 20 h. The catalyst was removed by filtration and the filtrate was evaporated in vacuo. The residue was purified on an isoiute aminopropyi carnage (2g), eiuting witn MeOr-DCM mixtures. Evaporation of the appropriate fractions with AcOH gave the title compound, (5mg) LCMS RT= 2.53min, ES+ve 561 (MH)*

Example 16 i) 4-{(1R)-2-[(6-{4-{3-(Cyclopentylsulfonyl}phenyllbutoxylhexyilaminol-1-hydroxyethyi}-2- (hydroxymethyl)phenol 4-{(1R)-2-{(6-{4-{3-(Cyclopentyisulfonyl)phenyi]butoxy}hexyl)amino]-1-hydroxyethyl}-2- (hydroxymethyl)phenol acetate (3.19g) (Example 4iii.) was purified by chromatography on a biotage™ column of silica using DCM-MeOH-0.880 ammonia (100:8:1 followed by 90:10:1) to give the title compound (1.6g). LCMS RT = 2.6min

Example 17 .

The foliowing salts of the compound of Example 16 were prepared as described beiow:

L-Aspartate salt: A hot solution of L-aspartic acid (2.55g) in water (250ml) was added to a solution of the free base (10g) in ethanol (100ml). The resulting solution was evaporated to an oil which was re-evaporated twice with water to ensure removal of ethanol affording the title salt as a gum. 'H NMR (DMSO, 400 MHz) & ppm 1.27 (m, 4H), 1.42-1.66 (m, 12H), 1.71-1.88 (m, 4H), 2.29 (dd, J=6.7, 16.0 Hz, 1H), 2.55 (dd, J=7.5, 16.0 Hz, 1H), 2.76 (m, 6H), 3.31 (t, J=6.4

Hz, 2H), 3.34 (t, J=6.4 Hz, 2H), 3.50 (t, J=7.1 Hz, 1H), 3.75 (m, 1H), 4.46 (s, 2H), 4.68 (dd, J=3.4, 9.5 Hz, 1H), 6.73 (d, J=8.2 Hz, 1H), 7.01 (dd, J=2.0, 8.2 Hz, 1H), 7.29 (d,

J=2.0 Hz, 1H), 7.56 (m, 2H), 7.69 (m, 2H). © 30 Sulfamate salt: A solution of sulfamic acid (1.86g) in water (50ml) was added to a solution of the free base (10g) in ethanol (100ml). The resuiting solution was evaporated to an oil which was re-evapcrated twice with water to ensure removal of ethanol affording the title salt as a gum.. 'H NMR (DMSO, 400 MHz) © ppm 1.28 (m, 4H), 1.43-1.67 (m, 12H), 1.71-1.88 (m, 4H), 2.71 (t, J=7.3 Hz, 2H), 2.92 (m, 3H), 3.03 (dd, J=2.7, 12.5 Hz, 1H), 3.32 (t, J=6.4 Hz, 2H),

3.35 (t, J=6.4 Hz, 2H), 3.76 (m, 1H), 4.48 (d, J=4.8 Hz, 2H), 4.56 (s, br, 2H), 4.78 (d, br

J=10.1 Hz, 1H), 5.03 (t, J=5.3 Hz, 1H), 56.97 (s, br, 1H), 6.75 (d, J=8.2 Hz, 1H), 7.05 (dd,

J=2.1, 8.2 Hz, 1H), 7.33 (d, J=2.1 Hz, 1H), 7.66 (m, 2H), 7.69 (m, 2H), 8.44 (s, br, 2H), 3.45 (8, "ny.

Napthalene-2-sulfonate salt: A solution of the free base (55mg) in propan-2-ol (0.5m!) was added to napthalene-2-sulfonic acid hydrate (27mg) pre-weighed into a vial. The mixture was warmed to give a solution then cooled and left to stir at room temperature for 2 hours. The resulting solid was isolated by filtration, washed with a little propan-2-ol and dried at 50°C under vacuum, to give crystals of the title compound. 'H NMR (DMSO, 400 MHz) & ppm 1.27 (m, 4H), 1.43-1.66 (m, 12H), 1.71-1.89 (m, 4H), 2.71 (t, J=7.6 Hz, 2H), 2.91 (m, 3H), 3.03 (m, 1H), 3.31 (t, J=6.6 Hz, 2H), 3.35 (t, J=6.6

Hz, 2H), 3.76 (m, 1H). 4.48 (s. 2H), 4.76 (dd, J=2.5, 10.5 Hz, 1H), 5.98 (s, br, 1H), 6.75 (d,

J=8.2 Hz, 1H), 7.05 (dd, J=2.2, 8.2 Hz, 1H), 7.33 (d, J=2.2 Hz, 1H), 7.52 (m, 2H), 7.56 (m, 2H), 7.69 (m, 2H), 7.72 (d, J=1.8 Hz, 1H), 7.86 (d, J=8.7 Hz, 1H), 7.90 (m, 1H), 7.97 (m, 1H), 8.14 (s, 1H), 8.42 (s, br, 2H), 9.42 (s, 1H).

The XRPD pattem of this product is shown in Figure 3.

Example 18

The following saits of the compound of Example 16 were prepared as described below. i) 4{(1R)-2-[(6-{4-[3-(Cyclopentyisulfonyl)phenyllbutoxythexyllamino]-1-hydroxyethyl}-2- (hydroxymethyl)phenol 4-methylbenzenesulfonate

A solution of 4-{(1R)-2-[(6-{4-[3-(cyclopentyisulfonyl)phenyl]butoxy}hexyl)amino]-1- ~--25 hydroxyethyl}-2-(hydroxymethyl)phenol (25mg) in MeOH (0.45mi) was added to p- toluene sulphonic acid (3.5mg) and the resulting solvent was removed. EtOAc (0.45ml). was added and the resulting mixture was agitated in a mini-reactor shaker block while alternately heating and cooling over 4 days. The precipitate was collected to give crystals of the title compound & (CD,OD) 7.74-7.67 (4H, m), 7.58-7.50 (2H, m), 7.34 (1H, d), 7.22 (2H, 0.5AA'BB’), 7.15 (1H, dd), 6.78 (1H, d), 4.85 (1H, dd), 4.63 (2H, s), 3.66 (1H, m), . 3.47-3.37 (4H, 2xt), 3.14-2.97 (4H, 2xm), 2.75 (2H, t), 2.35 (3H, 5) 2.03-1.35 (20H, 5xm) (i) 4-{(1R}-2-{(6-{4-[3-(Cyclopentyisulfonyl)phenyllbutoxythexyl)aminol-1-hydroxyethyl}-2- (hydroxymethyl)ohenol 4-chicrobenzene sulfonate

4-Chlorobenzene sulfonic acid (19mg) was added to a solution of 4-{(1R)-2-[(6-{4{3- (cyclopentylsulfonyl)phenyllbutoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol (55mg) (dissolved by gentie warming) in propan-2-oi (0.5ml) at 21°. After a few minutes crysiais nao separates Out. THESE WEIS CONSTIEG, Gina nindEa Wiwy propan-e=t. iS Give crystals of the title compound, § (DMSO-dg) 9.40 (1H,s), 8.42 (2H, br s),7.72 - 7.67 (2H, m), 7.62 - 7.55 (4H, m), 7.38 (2H, m), 7.32 (1H, d, J 2Hz), 7.05 (1H, dd, J 2,8 Hz), 6.75 (1H, d, J 8Hz), 5.97 (1H, br s), 5.00 (1H, v br s), 4.76 (1H, br d, J 9 Hz), 4.49 (2H, s), 3.75 (1H m), 3.32 (4H, partially obscured t), 3.10 - 2.87 (4H, 2m), 2.71 (2H, t, J 7Hz), 1.90 - 1.25 (20H, m).

The XRPD patter of this product is shown in Figure 1. (ii) 4-{(1R)-2-[(6-{4-[3-(Cyclopentyisulfonyi)phenyilbutoxy}thexyl)amino]-1-hydroxyethyl}- 2-(hydroxymethyliphenol 4-bromobenzene sulfonate

This was prepared similarly to example 18 (ii) above, to give crystals of the title compound. & (DMSO-dg) 9.40 (1H, brs), 8.35 (2H, v brs), 7.72 - 7.68 (2H, m), 7.59 - 7.55 (2H, m), 7.52 (4H, m), 7.33 (1H, d, J 2Hz), 7.05 (1H, dd, J 2,8 Hz), 6.75 (1H, d, J 8Hz), 5.95 (1H, brs), 5.01 (1H, t, J SHz)), 4.75 (1H, br d, J 10 Hz), 4.48 (2H, d, J 5Hz), 3.75 (1H m), 3.38 - 3.28 (4H, partially obscured 2t), 3.05 - 2.87 (4H, 2m), 2.71 (2H, t, J 7Hz), 1.90 - 1.25 (20K, m).

The XRPD pattem of this product is given in Figure 4. (iv) 4{(1R)-2-[(6-{4-[3-(Cyclopentyisulfonyl)phenyilbutoxythexyl)aminol-1-hydroxyethyi}- 2-(hydroxymethyl)phenol 3-toluene sulfonate

This was prepared similarly to example 18 (ii) above to give crystals of the title compound. & (DMSO-dg) 9.40 (1H, br s), 8.35 (2H, v br s), 7.72 - 7.67 (2H, m), 7.58 - 7.55 (2H, m), 7.42 (1H, brs), 7.38 (1H, brd, J 7Hz), 7.33 (1H, d, J 2Hz), 7.18 (1H, t, JT Hz), 710 (1H, : br d, J 7 Hz), 7.04 (1H, dd, J 2,8 Hz), 6.75 (1H, d, J 8Hz), 5.95 (1H, br s), 5.02 (1H, t, J 5Hz)), 4.76 (1H, br d, J 10 Hz), 4.48 (2H, d, J 5Hz), 3.75 (1H, m), 3.38 - 3.28 (4H, partially obscured 2t), 3.06 - 2.88 (4H, 2m), 2.70 (2H, t, J 7Hz), 2.29 (3H. s) 1.90 - 1.27 (20H, m).

The XRPD pattem of this product is given in Figure 5. (v) 4-{(1R)-2-{(6-{4-3-(Cyclopentylsuifonvi)phenyilbutoxyihexyilamino]-1-hydroxyethyi}-2- (hydroxymethyl)phenoi 4-biphenyl sulfonate

This was prepared similarly to example 18 (ii) above to give crystals of the title compound. &(DMSO-ds) 8.31 (1H, br s), 7.72 - 7.64 (6H, m), 7.61 (2H, m), 7.58 - 7.54 (2H, m), 7.46

(2H, br t, J 7Hz), 7.36 (1H, tt, J 1,7H2), 7.30 (1H, d, J 1 Hz), 7.03 (1H, dd, J 1,8 Hz), 6.73 (1H, d, J 8Hz), 5.70 (1H, br s), 4.97 (1H, t, J 5Hz)), 4.75 (1H, m), 4.48 (2H, d, J 5Hz), 3.78 (1H m), 3.40 - 3.20 (4H, partially obscured 2t), 2.98 - 2.80 (4H, 2m), 2.70 (2H, t, J 7Hz), 1.90 - V.ZE Zh, Ty.

The XRPD pattern of this product is shown in Figure 2.

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 of Examples * — 4 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 test compounds was assessed by their ability to induce a change in fight transmittance across a melanophore menciayer (a corseguence of pigment dispersal). Al the human beta 2 adrenoreceptor, compounds of said examples had ICs, values below 1 uM.

Method 2

Potency of compounds of the invention at the human beta 2, 1 and 3 receptors was also -25-- 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 FP? fluorescence polarisation kit (Perkin Eimer) 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 fireflv luciferase gene. After stimulation of the receptor with an agonist an increase in the ievel of iuciferase 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 pECs, value. Compounds of Examples 2-9 and 11-15 had a pECs 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 ‘cllowing claims.

Claims (1)

1. Acompound cfformula iv 2 R i» Ar—CHCHNHCRIR(CH,)—0 —(CH,); OH R® m or a salt, solvate, or physiologically functional derivative thereof, wherein: m is an integer of from 2 to 8; and nis an integer of from 3 to 11; with the proviso that m + nis 5to 19; R'is SR SOR®, or SOR’, } wherein R® is a Cs scycioalkyi or Cy cycloaikeny! group; R? and R® are independently selected from hydrogen, Cisalkyl, Ciealkoxy, halo, phenyl, and Cqshaloalkyi; R* and R® are independently selected from hydrogen and C,,alky! with the proviso that the total number of carbon atoms in R* and R® is not more than4; ~~ Ar is a group selected from )

R’ 8 o R R N o ~ 7s 1! \ J 0 NN R (] R Br RY RY (a) (b) (c) and C 0} (d) wherein R® represents hydrogen, halogen, -(CH,);OR"", -NR''C(O)R", -NR"'SO,R?, -SO,NR'R'? -NR'R'?, -OC(O)R" or OC(O)NR''R", and R represents hydrogen, halogen, or Cy alkyl; or R® represents -NHR'" and R’ and -NHR' together form a 5- or 6- membered heterocyclic ring;

10. SL R® represents hydrogen, halogen, -OR"' or -NR''R'%; R' represents hydrogen, halogen, haloC.. alkyl, -OR", -NR'" R'2, -OC(O)R™ or OC(O)NR'"R'%, R'' and R'? each independently represents hydrogen or C4 alkyl, or in the groups - NR'R', -SO,NR'R'™ and -OC(O)NR"R™, R" and R' independently represent hydrogen or Cq4 2iky! or together with the nitrogen alom lo which they are attached form a 5-, 6- or 7- membered nitrogen-containing ring, )

PCT/EP2003/012035 R" 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, C4 alkoxy or halo C44 alkyl; and OD gis zero or an integer from 1 10 4.

2. A compound of formula (1) or a salt, solvate of physiologically functional derivative thereof, wherein formula (1) is as defined in claim 1, except that R® does not represent hydrogen.

3. A compound according to claim 1 or claim 2 wherein R' represents ~SO;R®.

4. A compound according to any of claims 1 to 3 wherein R® represents a

Cs.7 cycloalkyl group.

5. A compound according to any of claims 1 to 4 wherein R? and R® each represent hydrogen.

6. A compound according to any of claims 1 to 5 wherein R* and R® are independently selected from hydrogen and methyl.

7. A compound according to any of claims 1 to 6 wherein Ar is selected from a group (a) or (b): rR’ 8 8 R R N LL ] NN R'° R'° (a) (b) 72 AMENDED SHEET

8. A compound of formula (la): HOCH, Rr? i ,— = al 45 — OO — Ho—()—gronanor R(CH,),, 0] SW (1a) OH Rr? or a salt, solvate, or physiologically functional derivative thereof, wherein: m is an integer of from 2 to 8; and nis an integer of from 3 to 11; with the proviso that m + nis 5 to 19; R'is SR®, SORE, or SOR, wherein R® is a Cascycloalkyl or Cs;cycloalkenyl group; R? and R® are independently selected from hydrogen, C,salkyl, Cialkoxy, halo, phenyl, i5 and Cishaloalkyl; and : R* and R® are independently selected from hydrogen and C,4alkyi with the proviso that the total number of carbon atoms in R* and R® is not more than 4.

9. A compound according to any of claims 1 to 8 wherein mis 5 or 6 and n is 3 or 4.

10. A compound of formula (1) or (Ia) selected from: ] i 4{(1R)-2-[(6-{4-[3-(Cyclopentyisulfinyl)phenyilbutoxy}hexyl)amino}- -hydroxyethyl}-2- ~~ - - (hydroxymethyl)phenol; 4-{(1R)-2-[(6-{4-{3-(Cyclopentyisuifinyl)phenyi]butoxy}hexyl)amino]-1-hydroxyethyl}-2- (hydroxymethyl)phenol (Isomer 1); 4-{(1R)-2-[(6-{4-13-(Cyclopentylsulfinyl)phenyl]butoxy}hexyl)amino]-1-hydroxyethyl}-2- ’ (hydroxymethyl)phenol! (Iscmer 2); 4-{(1R)-2-{(6-{4-{3-(Cyciopentyisulfonyl)phenyl] butoxy}hexyi)aminc}-1-hydroxyethyi}-2- (hydroxymethyl)phenol; 4-{(1 R)-2-[(6-{4-14-(Cyclopentyisulfonyi}pheny tutayihesgyliaming-t-hydrosyethyl}-2- (hydroxymethyi)phenol;

4-((1R)-2-{[6-({4-{3-(Cyciohexyisulfonyl)phenyi]butyl}oxy)hexyllamino}-1-hydroxyethyl)-2- (hydroxymethyi)phenol; : 4-((1R)-2-{[6-({4-[3-(3-Cyclopenten-1-yisulfonyl)phenyl]butyl}oxy)hexyflamino}-1- SYOTSKyey remy arTay net, enen 4-((1R)-2-{[6-({5-[3~(Cyclopentyisulfonyl)phenyl}pentyl}oxy}hexyllamino}-1-hydroxyethyl)- 2-(hydroxymethyt)phenol; : 4-((1R)-2-{[7-({3-[3-(Cyclopenty!sulfonyi)phenyl]propyl}oxy)heptyllamino}-1-hydroxyethyl)- 2-(hydroxymethyl)phenol; 4-((1R)-2-{[6-({4-[3(Cyclopentyisulfonyl)-5-methylphenyl]butyl}oxy)hexyljamino}-1- hydroxyethyi}-2-(hydroxymethyi)phenol; N-[5-((1R)-2-{[6-({4-[3-(Cyclopentyisulfonyl)phenyi]butyl}oxy)hexyllamino}-1- hydroxyethyl)-2-hydroxyphenyljmethanesulfonamide; 4-((1R)-2-{[6-({4-[3-(Cyclopentylisulfonyl)phenyi]butyl}oxy)hexyflamino}-1-hydroxyethyl)-2- fluorophenol; 6-{2-[(6-{4-[3-(Cyclopentylsulfonyl)phenyl]butoxy}hexy!)amino}- 1-hydroxyethy(}-2- {hydroxymethyl)pyridin-3-ol; 5-{(1R)-2-{(6{4-[3-(Cyclopentyisulfonyl)phenyl]butoxy}hexyl Jamino}-1-hydroxyethyl}-8- hydroxy-3,4-dihydroquinolin-2(1H)-one; 5-{(1 R)-2-[(6-{4-]3-(Cyciopentyisuifony!}phenyiibutoxy}hexyl)amino}-1 -hydroxyethyf}-2- hydroxypheryiformamide; and salts, solvates, and physiologically functional derivatives thereof.

11. A compound of formula (1) or (la) which is: 4-{(1R)-2-[(6-{4-{3-(Cyclopentyisulfonyl)phenyilbutoxy}hexyl)amino]- 1-hydroxyethyl}-2- (hydroxymethyl)phenol; : Co. i or a salt, solvate, or physiologically functional derivative thereof.

12. A compound according to any of claims 1 to 11 in the form of a salt formed with an arylsulphonic acid.

13. A compound according to any of claim 8, claim 9 or claim 12 which is selected from: 4{(1R)-2-{(6-{4-[3-(cyciopentyisulfonyi)phenyl]butoxy}hexyi)aminoc}- 1 -hydroxyethyi}-2- (hydroxymethy!) phenol 4-methyibenzenesulfonate; 4-{(1R)-2-{(6-{4-[3-(cyclopentylsulfonyl)phenyi]butoxy}hexyl)amino}-1-hydroxyethyl}-2- (hydroxymethyi)phenol 4-bromcbenzene sulfonate;

PCT/EP2003/012035 4-{(1R)-2-[(6-{4-[3-(cyclopentylsulfonyl)phenyilbutoxy}hexyl)amino]-1-hydroxyethyi}- 2-(hydroxymethyl)phenol 4-chlorobenzene sulfonate 4-{(1R)-2-[(6-{4-[3-(cyclopentylsulfonyl)phenyi]butoxy}hexyl)amino]j-1- hydroxyethyl}-2-(hydroxymethyl)pheno! 3-toluene sulfonate; 4{iR)-2-1B=413-(C, Ci CEaNt, Bushy EEN SUIT Ky NE Ry a TUNS Lm Ny SIS KY EY 2-(hydroxymethyl) phenol 4-biphenyl sulfonate; and 4-{(1R)-2-[(6-{4-[3-(cyclopentyisulfonyl)phenyl]butoxy} hexyl)amino}]-1-hydroxyethyl}-2-(hydroxymethyl)phenol, naphthalene-2-sulfonate.

14. A compound according to claim 13 wherein the salt is in crystalline form.

15. A compound of formula (I) or (la) according to any of claims 1 to 14 or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof for use in medical therapy. 16

16. A pharmaceutical formulation comprising a compound of formula (1) or (1a) according to any of claims 1 to 14 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.

17. A combination comprising a compound of formula (I) or (la) according to any of claims 1 to 14 or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, and one or more other therapeutic ingredients.

18. The use of a compound of formula (I) or (la) according to any of claims 1 to 14 or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative oo 3 thereof in the manufacture of a medicament for the prophylaxis or treatment of a clinical condition for which a selective [3,-adrenoreceptor agonist is indicated. 75 AMENDED SHEET

PCT/EP2003/012035

19. A process for the preparation of a compound of formula (I) or (la) according to any of claims 1 to 14 or a salt, solvate, or physiologically functional derivative thereof, which comprises: (a) cepioieciion of a proieciea inermeaiarte, for example of formuia (ii): 2 R rR! R'®— CHCHANRECR'R(CH,),— 0 —(CHy); OR? R® 10) or a salt or solvate thereof, wherein R’, R?, R®, R*, R®, m, and n are as defined for the compound of formula (1), R'® represents an optionally protected form of Ar; and R? and R?' are each independently either hydrogen or a protecting group, provided that the compound of formula (II) contains at least one protecting group; (b) reaction of a compound of formula (X): y (CH,),CH==CHR® R? CH Ng \ R'® — CHCH,NR*CR*R®— (CH,);——0——(CH,), (CH,),CH ==CHR -- Ce mm OR? r? —_—— oo. — (X) wherein R?, R®, R*, R®, R'®, R?, R?, m and n are as defined for formula (Il) each R* independently represents hydrogen or C,4alkyl, and x and y each represent 0, 1 or 2; to effect ring closure; (c) alkylation of an amine of formula (XI): 76 AVIENDED SHEET

R'$—CHCHNR®H (xm Loa wherein R%, R®, R® and R* are each independently either hydrogen or a protecting group with a compound of formula (XVIl): Rr? R! L'CR*R*(CH,);—0—(CH,); xvir) 3 wherein R', R?, R%, R*, R®, m, and n are as defined for the compound of formula (i) and L' is a leaving group; : (d) reduction of a compound of formula (XIX): Rr? ! R! RCHCH NR CRIRI(CH ly —O0 — (CH,),, —— OR

RS . (XIX) Wherein R', R%, R®, R*, R®, m and n are as defined for formula (I), R" represents an =~ ~~ =~ ~~~ optionally protected form of Ar and R® and R* are each independently hydrogen or a protecting group as defined above. (e) reacting a compound of formula (XXIII): Rigo oR" (OHI)

wherein R'%is as hereinbefore defined and L2 is a leaving group as defined above for L'ort% :

G7 @ COMpOuna Gi i0NMwa (AAV R"® } 0] (XXIV)

wherein R'® is as hereinbefore defined with an amine of formula (XXV): 2 ] R' RZHNCR'R®(CH,),—0 — (CH), ~ (XXv) Rr? wherein R', R%, R®, R*, R%, R®, m and n are as defined for formula (Il); or

{f) removal of a chirai auxiiiary from a compound of foirmuia {lia} R? R' RHC CRI Cr —O0—(CH,), OR* R® (lla) RE wherein R' — R®, m and n are as defined for formula (1), R" represents an optionally protected form of Ar, R?' represent hydrogen or a protecting group and R” represents a chiral auxiliary. followed by the following steps in any order: (i) opfiionai removal of any protecting groups; (ii) optional! separation of an enantiomer from a mixture of enantiomers;

PCT/EP2003/012035 (iil) optional conversion of one compound of formula (I) to a different compound of formula (1) eg. conversion of a compound wherein R! is SR® to a compound wherein R* is SOR® or SO,R®, or conversion of a compound wherein R' is SOR® to a compound wherein R’ is SCoR’, (iv) optional conversion of a compound wherein R® represents cycloalkenyl to a compound wherein R® represents cycloalkyl, eg. by hydrogenation; (v) optional conversion of the product to a corresponding salt, solvate, or physiologically functional derivative thereof.

20. An intermediate selected from a compound of formula (il) (II) (IV) (X) and (XIX) as hereinbefore defined.

21. A substance or composition for use in a method for the prophylaxis or treatment of a clinical condition for which a selective ,-adrenoreceptor agonist is indicated, said substance or composition comprising a compound of formula (1) or (la) according to any of claims 1 to 14 or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, and said method comprising administering said substance or composition.

22. A compound according to any one of claims 1, or 2, or 8, or 10, or 11, or 15, or 20, substantially as herein described with reference to and as illustrated in any of the examples and accompanying drawings. _ 23. __ A substance or composition for use in a method of treatment or prevention oo ] according to claim 15, or claim 21, substantially as herein described with reference to and as illustrated in any of the examples and accompanying drawings.

24. A formulation according to claim 16, substantially as herein described with reference to and as illustrated in any of the examples and accompanying drawings.

25. A combination according to claim 17, substantially as herein described with reference to and as illustrated in any of the examples and accompanying drawings. 79 AMENDED SHEET

PCT/EP2003/012035

26. Use according to claim 18, substantially as herein described with reference to and as illustrated in any of the examples and accompanying drawings.

27. A process according to claim 19, substantially as herein described with reference ic and 83 ..u3WEEl Nn aNy STINE SXETpPE3 and ECCI pan, ng STEVIE. 80 AMENDED SHEET