The present invention relates to novel anti-inflammatory and anti-allergic compounds of the androstane series and to processes for their preparation. The present invention also relates to pharmaceutical formulations containing the compounds and to therapeutic uses thereof, particularly for the treatment of inflammatory and allergic conditions.

Glucocorticosteroids which have anti-inflammatory properties are known and are widely used for the treatment of inflammatory disorders or diseases such as asthma and rhinitis. For example, US Patent 4335121 discloses 6a, 9a-Difluoro- 17a- (I-oxopropoxy)-l I P-hydroxy-16a-methyl-3-oxo-androsta-1, 4-diene-17p- carbothioic acid S-fluoromethyl ester (known by the generic name of fluticasone propionate) and derivatives thereof. The use of glucocorticoids generally, and especially in children, has been limited in some quarters by concerns over potential side effects. The side effects that are feared with glucocorticoids include suppression of the Hypothalamic-Pituitary-Adrenal (HPA) axis, effects on bone growth in children and on bone density in the elderly, ocular complications (cataract formation and glaucoma) and skin atrophy. Certain glucocorticoid compounds also have complex paths of metabolism wherein the production of active metabolites may make the pharmacodynamics and pharmacokinetics of such compounds difficult to understand. Whilst the modern steroids are very much safer than those originally introduced it remains an object of research to produce new molecules which have excellent anti-inflammatory properties, with predictable pharmacokinetic and pharmacodynamic properties, with an attractive side effect profile, and with a convenient treatment regime.

Certain novel androstane derivatives are disclosed in W002/12265, W002/12266 (Glaxo Group) and W002/00679 (Novartis), these three documents being published after the earliest priority date of this patent application.

We have identified a novel series of glucocorticoids, which substantially meets these objectives.

Thus, according to one aspect of the invention, there is provided a compound of formula (I)

wherein R, represents C1 6 alkyl or C, 6 haloalkyl ; R2 represents a 4-7 membered non-aromatic ring containing 1-3 heteroatoms selected from O, N and S optionally substituted with one or more methyl, ethyl or halogen groups; R3 represents hydrogen, methyl (which may be in either the a or 3 configuration) or methylene ; R4 and R5 are the same or different and each represents hydrogen or halogen ; and represents a single or a double bond; and salts and solvates thereof.

Examples of salts of compounds of formula (1) include physiologically acceptable salts which may be formed with basic compounds (such as when R2 contains a secondary nitrogen atom) eg. acetate, benzoate, citrate, succinate, lactate, tartrate, fumarate and maleat.

Examples of solvates include hydrates.

References hereinafter to a compound according to the invention includes both compounds of formula (I) and salts and solvates thereof, particularly pharmaceutical acceptable salts and solvates.

It will be appreciated that the invention includes within its scope all stereoisomers of the compounds of formula (i) and mixtures thereof.

Preferably, the absolute stereochemistry will be as shown in the representation of compounds of formula (I). We prefer to employ the compound of formula (I) in the form of a single diastereoisomer.

Examples of C, 6 haloalkyl that Ri may represent include C1 6 alkyl substituted by 1-3 halogen atoms, preferably 1 halogen atom. Preferred halogen atoms are selected from bromine, chlorine and fluorine.

We prefer R, to represent fluoromethyl, chloromethyl, bromomethyl or 2'- fluoroethyl, especially fluoromethyl.

Non-aromatic rings for R2 include rings that are saturated or partially unsaturated (eg. containing one double bond). Preferably, R2 will be a saturated ring.

We prefer that R2 contains 1 or 2 heteroatoms, especially 1 heteroatom. We prefer that the heteroatom (s) are selected from O and S. We prefer R2 to be a 4-6 membered ring, especially a 4 or 5 membered ring, particularly a 5-membered ring.

Example R2 groups include tetrahydrofuranyl (eg tetrahydrofuran-2-yl and tetrahydrofuran-3yl), tetrahydrothiophenyl (eg tetrahydrothiophen-2-yl), thietanyl (eg thietan-3-yl), 1,3-dithiolanyl (eg 1, 3-dithiothan-2-yl), 1,3-dioxolanyl (eg 1,3-dioxolan- 2-yl) and pyrrolidinyl, and substituted derivatives thereof eg 2-methyl- tetrahydrofuran-2-yl, 3-methyl-tetrahydrofuran-2-yl and N-methyl-2-pyrrolidinyl. Other examples of substituted derivatives include 2-methyl-1-3,-dioxolan-2-yl, 2-methyl-1- 3,-dithiolan-2-yl, 2-methyl-tetrahydrothiophen-2-yl, 3-methyl-tetrahydrofuran-3-yl. A further example of group R2 is 2-ethyl-tetrahydrofuran-2-yl. Examples of 6 membered groups include 1,3-dithian-2-yl and tetrahydro-4H-pyran-4-yl.

We prefer that R2 represents a 4-7 membered non-aromatic ring containing 1-3 heteroatoms selected from O, N and S optionally substituted with one or more methyl, ethyl or halogen groups. Generally we prefer that R2 is not substituted or is substituted by 1 methyl group, and especially is not substituted. However one class of compounds of particular interest is that in which R2 is substituted by methyl at the point of attachment to the carbonyl moiety (as exemplified, for example, by 2-methyl- 1,3-dioxolan-2-yl, 2-methyl-tetrahydrofuran-2-yl, 2-methyl-tetrahydrothiophen-2-yl, 3- methyl-tetrahydrofuran-3-yl, 3-methyl-tetrahydrothiophen-3-yl). Preferably a heteroatom is present in the 2-position.

We prefer R3 to represent methyl, especially methyl in the a configuration.

Compounds of formula (I) in which R4 and R5, which can be the same or different, each represents hydrogen, fluorine or chlorine, particularly hydrogen or fluorine, are preferred. Especially preferred are compounds in which both R4 and R5 are fluorine.

Preferably, represents a double bond.

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

Preferred compounds of formula (I) include : 6a, 9a-Difluoro-11 [3-hydroxy-16a-methyl-3-oxo-17a- (tetrahydrofuran-2S- ylcarbonyl) oxy-androsta-1,4-diene-17p-carbothioic acid S-fluoromethyl ester; 6a, 9a-Difluoro-11 ß-hydroxy-1 6a-methyl-3-oxo-1 7a-(tetrahydrofuran-2R- ylcarbonyl) oxy-androsta-1,4-diene-17p-carbothioic acid S-fluoromethyl ester;

6a, 9a-Dif ! uoro-11 p-hydroxy-16a-methyi-3-oxo-17a- (tetrahydrofuran-3- ylcarbonyl) oxy-androsta-1,4-diene-17p-carbothioic acid S-fluoromethyl ester; 6a, 9α-Difluoro-17α-(1,3-dithiolan-2-ylcarbonyl)oxy-11ß-hydro xy-16α-methyl-3-oxo- androsta-1, 4-diene-17p-carbothioic acid S-fluoromethyl ester ; 6a, 9α-Difluoro-11ß-hydroxy-16α-methyl-17α-(1-methyl-L-proly l) oxy-3-oxo-androsta- 1, 4-diene-17ß-carbothioic acid S-fluoromethyl ester; 6a, 9a-Difluoro-11 i-hydroxy-16a-methyl-3-oxo-17a- (thietan-3-ylcarbonyl) oxy- androsta-1,4-diene-17p-carbothioic acid S-fluoromethyl ester; 6a, 9α-Difluoro-11ß-hydroxy-16α-methyl-3-oxo-17α-(tetrahydro thiophen-2- ylcarbonyl) oxy-androsta-1,4-diene-17p-carbothioic acid S-fluoromethyl ester; 6a, 9α-Difluroo-11ß-hydroxy-16α-methyl-3-oxo-17α-(2-methyl-t etrahydrofuran-2R- ylcarbonyl) oxy-androsta-1,4-diene-1 7ß-carbothioic acid S-fluoromethyl ester; <BR> <BR> <BR> <BR> 6a, 9a-Difluoro-11 i-hydroxy-16a-methyl-3-oxo-17a- (2-methyl-tetrahydrofuran-2S- ylcarbonyl) oxy-androsta-1,4-diene-1 7ß-carbothioic acid S-fluoromethyl ester; <BR> <BR> <BR> <BR> 6α,9α-Difluroo-17α-(1,3-dioxolan-2-ylcarbonyl)oxy-11ß-hy droxy-16α-methyl-3-oxo- androsta-1,4-diene-17p-carbothioic acid S-fluoromethyl ester; 6a, 9a-Difluoro-1 1 i-hydroxy-16a-methyl-3-oxo-17a- [ (2R, 3S)-3-methyl- tetrahydrofuran-2-ylcarbonyl] oxy-androsta-1,4-diene-17p-carbothioic acid S- fluoromethyl ester; 6a, 9α-Difluoro-11ß-hydroxy-16α-methyl-3-oxo-17α-[(2R,3R)-3- methyl- tetrahydrofuran-2-ylcarbonyl] oxy-androsta-1,4-diene-1 7ß-carbothioic acid S- fluoromethyl ester; 6a, 9a-Difluoro-111 i-hydroxy-16a-methyl-17a- (2-methyl-1, 3-dioxolan-2- ylcarbonyl) oxy-3-oxo-androsta-1,4-diene-17p-carbothioic acid S-fluoromethyl ester; 6a, 9α-Difluoro-11ß-hydroxy-16α-methyl-17α-(2-methyl-1,3-dit hiolan-2- ylcarbonyl) oxy-3-oxo-androsta-1,4-diene-17p-carbothioic acid S-fluoromethyl ester; <BR> <BR> <BR> <BR> 6a, 9a-Difluoro-11 ß-hydroxy-1 6a-methyl-3-oxo-1 7a-(2-methyl-tetrahydrothiophen-2R- ylcarbonyl) oxy-androsta-1,4-diene-17p-carbothioic acid S-fluoromethyl ester; 6a, 9a-Difluoro-11 i-hydroxy-16a-methyl-3-oxo-17a- (2-methyl-tetrahydrothiophen-2S- ylcarbonyl) oxy-androsta-1,4-diene-17p-carbothioic acid S-fluoromethyl ester; 6a, 9a-Difluoro-1 1 3-hydroxy-16a-methyl-3-oxo-17a- (3-methyltetrahydrofuran-3R- ylcarbonyl) oxy-androsta-1,4-diene-17p-carbothioic acid S-fluoromethyl ester; 6a, 9a-Difluoro-11 i-hydroxy-16a-methyl-3-oxo-17a- (3-methyltetrahydrofuran-3S- ylcarbonyl) oxy-androsta-1, 4-diene-17ß-carbothioic acid S-fluoromethyl ester;

6a,9a-Difluoro-11 3-hydroxy-16a-methyl-3-oxo-17a- (2-ethyl-tetrahydrofuran-2R- ylcarbonyl) oxy-androsta-1,4-diene-1 7ß-carbothioic acid S-fluoromethyl ester; 6a, 9a-Difluoro-11 ß-hydroxy-1 6a-methyl-3-oxo-1 7a-(2-ethyl-tetrahydrofuran-2S- ylcarbonyl) oxy-androsta-1,4-diene-17p-carbothioic acid S-fluoromethyl ester; 6a, 9a-Difluoro-1 7a-(1, 3-dithian-2-ylcarbonyl) oxy-1 1 ß-hydroxy-1 6a-methyl-3-oxo- androsta-1,4-diene-17p-carbothioic acid S-fluoromethyl ester; 6a, 9a-Difluoro-11 ß-hydroxy-1 6a-methyl-3-oxo-1 7a-(tetrahydro-4H-pyran-4- ylcarbonyl) oxy-androsta-1, 4-diene-1 (3-carbothioic acid S-fluoromethyl ester ; and salts and solvate theref.

The compounds of formula (I) have potentially beneficial anti-inflammatory or anti-allergic effects, particularly upon topical administration, demonstrated by, for example, their ability to bind to the glucocorticoid receptor and to illicit a response via that receptor with long lasting effect. Hence, the compounds of formula (I) are useful in the treatment of inflammatory and/or allergic disorders, especially in once- per-day therapy.

Examples of disease states in which the compounds of the invention have utility include skin diseases such as eczema, psoriasis, allergic dermatitis neurodermatitis, pruritis and hypersensitivity reactions; inflammatory conditions of the nose, throat or lungs such as asthma (including allergen-induced asthmatic reactions), rhinitis (including hayfever), nasal polyps, chronic obstructive pulmonary disease, interstitial lung disease, and fibrosis; inflammatory bowel conditions such as ulcerative colitis and Crohn's disease; and auto-immune diseases such as rheumatoid arthritis.

Compounds of the invention may also have use in the treatment of conjunctiva and conjunctivitis.

It will be appreciated by those skilled in the art that reference herein to treatment extends to prophylaxis as well as the treatment of established conditions.

As mentioned above, compounds of formula (I) are useful in human or veterinary medicine, in particular as anti-inflammatory and anti-allergic agents, especially in once-per-day therapy.

There is thus provided as a further aspect of the invention a compound of formula (I) or a physiologically acceptable salt or solvate thereof for use in human or veterinary medicine, particularly in the treatment of patients with inflammatory and/or allergic conditions, especially for treatment once-per-day.

According to another aspect of the invention, there is provided the use of a compound of formula (I) or physiologically acceptable salt or solvate thereof for the

manufacture of a medicament for the treatment of patients with inflammatory and/or allergic conditions, especially for treatment once-per-day.

In a further or alternative aspect, there is provided a method for the treatment of a human or animal subject with an inflammatory and/or allergic condition, which method comprises administering to said human or animal subject an effective amount of a compound of formula (I) or physiologically acceptable salt or solvate thereof, especially for administration once-per-day.

The compounds according to the invention may be formulated for administration in any convenient way, and the invention therefore also includes within its scope pharmaceutical compositions comprising a compound of formula (I) or physiologically acceptable salt or solvate thereof together, if desirable, in admixture with one or more physiologically acceptable diluents or carriers. Pharmaceutical compositions for once-per-day administration are of particular interest.

Further, there is provided a process for the preparation of such pharmaceutical compositions which comprises mixing the ingredients.

The compounds according to the invention may, for example, be formulated for oral, buccal, sublingual, parenteral, local or rectal administration, especially local administration.

Local administration as used herein, includes administration by insufflation and inhalation. Examples of various types of preparation for local administration include ointments, lotions, creams, gels, foams, preparations for delivery by transdermal patches, powders, sprays, aerosols, capsules or cartridges for use in an inhaler or insufflator or drops (e. g. eye or nose drops), solutions/suspensions for nebulisation, suppositories, pessaries, retention enemas and chewable or suckable tablets or pellets (e. g. for the treatment of aphthous ulcers) or liposome or microencapsulation preparations.

Advantageously compositions for topical administration to the lung include dry powder compositions and spray compositions.

Dry powder compositions for topical delivery to the lung may, for example, be presented in capsules and cartridges for use in an inhaler or insufflator of, for example, gelatine. Formulations generally contain a powder mix for inhalation of the compound of the invention and a suitable powder base such as lactose or starch.

Use of lactose is preferred. Each capsule or cartridge may generally contain between 20jng-10mg of the compound of formula (I) optionally in combination with another 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 or Diskhaler, see GB 2178965, 2129691 and 2169265) or metered in use (eg as in Turbuhaler, see EP 69715). An example of a unit-dose device is Rotahaler (see GB 2064336). The Diskus inhalation device comprises an elongate strip formed from a base sheet having a plurality of recesses spaced along its length and a lid sheet hermetically but peelably sealed thereto to define a plurality of containers, each container having therein an inhalable formulation containing a compound of formula (I) preferably combined with lactose. Preferably, the strip is sufficiently flexible to be wound into a roll. The lid sheet and base sheet will preferably have leading end portions which are not sealed to one another and at least one of the said leading end portions is constructed to be attached to a winding means. Also, preferably the hermetic seal between the base and lid sheets extends over their whole width. The lid sheet may preferably be peeled from the base sheet in a longitudinal direction from a first end of the said base sheet.

Pharmaceutical formulations which are non-pressurised and adapted to be administered as a dry powder topically to the lung via the buccal cavity (especially those which are free of excipient or are formulated with a diluent or carrier such as lactose or starch, most especially lactose) are of particular interest.

Spray compositions may for example be formulated as aqueous solutions or suspensions or as aerosols delivered from pressurised packs, such as a metered dose inhaler, with the use of a suitable liquefied propellant. Aerosol compositions suitable for inhalation can be either a suspension or a solution and generally contain the compound of formula (I) and a suitable propellant such as a fluorocarbon or hydrogen-containing chlorofluorocarbon or mixtures thereof, particularly hydrofluoroalkanes, especially 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n- propane or a mixture thereof. The aerosol composition may optionally contain additional formulation excipients well known in the art such as surfactants eg oleic acid or lecithin and cosolvens eg ethanol. One example formulation is excipient free and consists essentially of (eg consists of) compound of formula (I) (preferably in unsolvated form) (optionally in combination with another therapeutically active ingredient) and a propellant selected from 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3- heptafluoro-n-propane and mixture thereof. Another example formulation comprises particulate compound of formula (I), a propellant selected from 1,1,1,2- tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane and mixture thereof and a suspending agent which is soluble in the propellant eg an oligolactic acid or

derivative thereof as described in W094/21229. The preferred propellant is 1,1,1,2- tetrafluoroethane. Pressurised formulations will generally be retained in a canister (eg an aluminium canister) closed with a valve (eg a metering valve) and fitted into an actuator provided with a mouthpiece.

Medicaments for administration by inhalation desirably have a controlled particle size. The optimum particle size for inhalation into the bronchial system is usually 1-10, um, preferably 2-5, um. Particles having a size above 201lm are generally too large when inhaled to reach the small airways. To achieve these particle sizes the particles of compound of formula (I) 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, prepared for example by a process which comprises mixing in a continuous flow cell in the presence of ultrasonic radiation a flowing solution of compound of formula (I) as medicament in a liquid solvent with a flowing liquid antisolvent for said medicament (eg as described in International Patent Application PCT/GB99/04368) or else by a process which comprises admitting a stream of solution of the substance in a liquid solvent and a stream of liquid antisolvent for said substance tangentially into a cylindrical mixing chamber having an axial outlet port such that said streams are thereby intimately mixed through formation of a vortex and precipitation of crystalline particles of the substance is thereby caused (eg as described in International Patent Application PCT/GB00/04327). 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 60-9011m and not less than 15% will have a MMD of less than 15jim.

Formulations for administration topically to the nose (eg for the treatment of rhinitis) include pressurised aerosol formulations and aqueous formulations administered to the nose by pressurised pump. Formulations which are non- pressurised and adapted to be administered topically to the nasal cavity are of particular interest. The formulation preferably contains water as the diluent or carrier for this purpose. Aqueous formulations for administration to the lung or nose may be provided with conventional excipients such as buffering agents, tonicity modifying agents and the like. Aqueous formulations may also be administered to the nose by nebulisation.

Other possible presentations include the following :

Ointments, creams and gels, may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agent and/or solvents. Such bases may thus, for example, include water and/or an oil such as liquid paraffin or a vegetable oil such as arachis oil or castor oil, or a solvent such as polyethylene glycol. Thickening agents and gelling agents which may be used according to the nature of the base include soft paraffin, aluminium stearate, cetostearyl alcohol, polyethylene glycols, woolfat, beeswax, carboxypolymethylene and cellulose derivatives, and/or glyceryl monostearate and/or non-ionic emulsifying agents.

Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents or thickening agents.

Powders for external application may be formed with the aid of any suitable powder base, for example, talc, lactose or starch. Drops may be formulated with an aqueous or non-aqueous base also comprising one or more dispersing agents, solubilising agents, suspending agents or preservatives.

Advantageously, the formulations of the invention may be buffered by the addition of suitable buffering agents.

The proportion of the active compound of formula (I) in the local compositions according to the invention depends on the precise type of formulation to be prepared but will generally be within the range of from 0.001 to 10% by weight. Generally, however for most types of preparations advantageously the proportion used will be within the range of from 0.005 to 1% and preferably 0.01 to 0.5%. However, in powders for inhalation or insufflation the proportion used will usually be within the range of from 0.1 to 5%.

Aerosol formulations are preferably arranged so that each metered dose or "puff"of aerosol contains 20, ug-2000, ug, preferably about 20gg-500gg of a compound of formula (I) optionally in combination with another therapeutically active ingredient.

Administration may be once daily or several times daily, for example 2,3,4 or 8 times, giving for example 1,2 or 3 doses each time. The overall daily dose with an aerosol will be within the range 100, ug-10mg preferably, 200pg-2000, ug. The overall daily dose and the metered dose delivered by capsules and cartridges in an inhaler or insufflator will generally be double those with aerosol formulations.

Since the compounds of formula (I) are long-acting, preferably the compound will be delivered once-per-day and the dose will be selected so that the compound

has a therapeutic effect in the treatment of respiratory disorders (eg asthma or COPD, particularly asthma) over 24 hours or more.

Topical preparations may be administered by one or more applications per day to the affected area; over skin areas occlusive dressings may advantageously be used. Continuous or prolonged delivery may be achieved by an adhesive reservoir system.

For internal administration the compounds according to the invention may, for example, be formulated in conventional manner for oral, parenteral or rectal administration. Formulations for oral administration include syrups, elixirs, powders, granules, tablets and capsules which typically contain conventional excipients such as binding agents, fillers, lubricants, disintegrants, wetting agents, suspending agents, emulsifying agents, preservatives, buffer salts, flavouring, colouring and/or sweetening agents as appropriate. Dosage unit forms are, however, preferred as described below.

Preferred forms of preparation for internal administration are dosage unit forms i. e. tablets and capsules. Such dosage unit forms contain from 0. 1 mg to 20mg preferably from 2.5 to 10mg of the compounds of the invention.

The compounds according to the invention may in general may be given by internal administration in cases where systemic adreno-cortical therapy is indicated.

In general terms preparations, for internal administration may contain from 0.05 to 10% of the active ingredient dependent upon the type of preparation involved. The daily dose may vary from 0.1 mg to 60mg, e. g. 5-30mg, dependent on the condition being treated, and the duration of treatment desired.

Slow release or enteric coated formulations may be advantageous, particularly for the treatment of inflammatory bowel disorders.

The pharmaceutical compositions according to the invention may also be used in combination with another therapeutically active agent, for example, a ß2 adrenoreceptor agonist, an anti-histamine or an anti-allergic. The invention thus provides, in a further aspect, a combination comprising the compound of formula (I) or a physiologically acceptable salt or solvate thereof together with another therapeutically active agent, for example, a ß2-adrenoreceptor agonist, an anti- histamine or an anti-allergic.

Examples of ii-adrenoreceptor agonists include salmeterol (eg as racemate or single enantiomer such as the s-enantiomer), salbutamol, formoterol, fenoterol or terbutaline and salts thereof, for example the xinafoate salt of salmeterol, the sulphate salt or free base of salbutamol or the fumarate salt of formoterol. Long-

acting ß2-adrenoreceptor agonists are preferred, especially those having a therapeutic effect over a 24 hour period.

Especially preferred long-acting p-adrenoreceptor agonists are compounds of formula (X) or a salt or solvate thereof, wherein: m is an integer of from 2 to 8; n is an integer of from 3 to 11, preferably from 3 to 7; with the proviso that m + n is 5 to 19, preferably 5 to 12; R"is-XSO, NR"R 17 wherein X is- (CH2) p- or C2-6 alkenylene ; R16 and R17 are independently selected from hydrogen, C1-6alkyl, C3-7cycloalkyl, C (O) NR18R19, phenyl, and phenyl (C1-4alkyl)-, or R16 and R'7, together with the nitrogen to which they are bonded, form a 5-, 6-, or 7-membered nitrogen containing ring, and R16 and R17 are each optionally substituted by one or two groups selected from halo, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, hydroxy-substituted C1-6alkoxy, -CO2R18, -SO2NR18R19, -CONR18r19, - NR18C(O)R19, or a 5-, 6-or 7-membered heterocylic ring; R18 and R19 are independently selected from hydrogen, C1-6alkyl, C3-6cycloalkyl, phenyl, and phenyl (C1 alkyl)-; and p is an integer of from 0 to 6, preferably from 0 to 4; R12 and R'3 are independently selected from hydrogen, C1-6alkyl, C1-6alkoxy, halo, phenyl, and C, 6haloalkyl ; and R14 and R'5 are independently selected from hydrogen and C1-4alkyl with the proviso that the total number of carbon atoms in R14 and R'5 is not more than 4.

In the compounds of formula (I) the group R"is preferably attached to the meta-position relative to the -O- (CH2) n- link.

R"preferably represents-SO2NR'6R'7wherein R16 and R17 are independently selected from hydrogen and C1-6alkyl, more preferably R"is-S02NH2.

R'4 and R'5 are preferably independently selected from hydrogen and methyl, more preferably R'4 and R'5 are both hydrogen.

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

More especially preferred compounds of formula (X) are compounds of formula (Xa) or a salt or solvate thereof, wherein R"is as defined above for formula (X).

Further more especially preferred compounds of formula (X) are compounds of formula (Xb): or a salt or solvate thereof, wherein R"is as defined above for formula (X).

In the compounds of formulae (Xa) and (Xb), the group R"is preferably attached to the meta-position relative to the-O-(CH2) 4-or-O-(CH2) 3-link respectively.

In the compounds of formulae (Xa) and (Xb), R"is preferably-SO2NR'6R17 wherein R16 and R'7 are independently selected from hydrogen and C, 6alkyl, more preferably R"is-S02NH2.

In the definition of R11 where'R16 and R'7 together with the nitrogen atom to which they are bonded, form a 5-, 6-, or 7-membered nitrogen containing ring', the term"5-, 6-, or 7-membered nitrogen containing ring"means a 5-, 6-, or 7- membered saturated or unsaturated ring which includes the sulfonamide nitrogen atom and optionally 1 or 2 other heteroatoms independently selected from nitrogen, sulphur, and oxygen. Suitable examples of such a ring include piperidinyl, morpholinyl, and piperazinyl.

In the definition of R", specifically the optional substituents on R and R the term"5-, 6-, or 7-membered heterocyclic ring"means a 5-, 6-, or 7-membered fully or partially saturated or unsaturated ring which includes 1,2,3 or 4 heteroatoms

independently selected from nitrogen, sulphur, and oxygen. Suitable examples of such a ring include pyrrolyl, furyl, thienyl, pyridinyl, pyrazinyl, pyridazinyl, imidazolyl, tetrazolyl, tetrahydrofuranyl, oxazolyl, thiazolyl, thiadiazolyl, piperidinyl, morpholinyl, and piperazinyl.

In the definition of X, the term"alkenylene"includes both cis and trans structures. Suitable examples of alkenylene groups include-CH=CH-.

The compounds of formulae (X), (Xa) and (Xb) include an asymmetric centre, namely the carbon atom of the - CH- OH group. The present invention includes both (S) and (R) enantiomers either in substantially pure form or admixed in any proportions.

Similarly, where R'4 and R'5 are different groups, the carbon atom to which they are attached is an asymmetric centre and the present invention includes both (S) and (R) enantiomers at this centre either in substantially pure form or admixed in any proportions.

Thus the compounds of formulae (X), (Xa) and (Xb) include all enantiomers and diastereoisomers as well as mixtures thereof in any proportions.

The most preferred compound of formula (X) is 3- (4- { [6- ( { (2R)-2-Hydroxy-2- [4-hydroxy-3-(hydroxymethyl) phenyl] ethyl} amino)- hexyl] oxy} butyl) benzenesulfonamide or a salt or solvate thereof.

Salts and solvates of compounds of formulae (X), (Xa) and (Xb) which are suitable for use in medicine are those wherein the counterion or associated solvent is pharmaceutically acceptable. However, salts and solvates having non- pharmaceutically acceptable counterions or associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of formulae (X), (Xa) and (Xb) and their pharmaceutically acceptable salts and solvates.

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, methanesulphonic, ethanesulphonic, arylsulphonic (for example p-toluenesulphonic, benzenesulphonic, naphthalenesulphonic or naphthalenedisulphonic), salicylic, glutaric, gluconic, tricarballylic, cinnamic, substituted cinnamic (for example, phenyl,

methyl, methoxy or halo substituted cinnamic, including 4-methyl and 4- methoxycinnamic acid), ascorbic, oleic, naphthoic, hydroxynaphthoic (for example 1- or 3-hydroxy-2-naphthoic), naphthaleneacrylic (for example naphthalene-2-acrylic), benzoic, 4-methoxybenzoic, 2-or 4-hydroxybenzoic, 4-chlorobenzoic, 4- phenylbenzoic, benzeneacrylic (for example 1,4-benzenediacrylic) and isethionic acids. Pharmaceutically acceptable base salts include ammonium salts, alkali metal salts such as those of sodium and potassium, alkaline earth metal salts such as those of calcium and magnesium and salts with organic bases such as dicyclohexyl amine and N-methyl-D-glucamine.

Compounds of formula (X), (Xa) and (Xb) may be prepared by reference to Example X recited below, by analogous processes, or by other conventional processes known per se.

Since the compounds of formula (I) are long-acting, preferably the composition comprising the compound of formula (I) and the long-acting ß2- adrenoreceptor agonists will be delivered once-per-day and the dose of each will be selected so that the composition has a therapeutic effect in the treatment of respiratory disorders effect (eg in the treatment of asthma or COPD, particularly asthma) over 24 hours or more.

Examples of anti-histamines include methapyrilene or loratadine. Examples of anti-allergics include cromoglycate (eg as sodium), ketotifen and nedocromil (as as sodium). Examples of anti-cholinergics include ipratropium (eg as bromide), tiotropium, atropine or oxitropium. Any of the aforementioned substances may be employed in the form of alternative salts or solvates thereof.

Other suitable combinations include, for example, other anti-inflammatory agents eg. NSAIDs (eg. sodium cromoglycate, nedocromil sodium, PDE4 inhibitors, leukotriene antagonists, iNOS inhibitors, tryptase and elastase inhibitors, beta-2 integrin antagonists and adenosine 2a agonists)) or antiinfective agents (eg. antibiotics, antivirals).

Of particular interest is use of the compound of formula (I) in combination with a phosphodiesterase 4 (PDE4) inhibitor. The PDE4-specific inhibitor useful in this aspect of the invention may be any compound that is known to inhibit the PDE4 enzyme or which is discovered to act as a PDE4 inhibitor, and which are only PDE4 inhibitors, not compounds which inhibit other members of the PDE family as well as PDE4. Generally it is preferred to use a PDE4 inhibitor which has an iCgn ratio of about 0.1 or greater as regards the iCgo for the PDE4 catalytic form which binds rolipram with a high affinity divided by the iCgo for the form which binds rolipram with

a low affinity. For the purposes of this disclosure, the cAMP catalytic site which binds R and S rolipram with a low affinity is denominated the"low affinity"binding site (LPDE 4) and the other form of this catalytic site which binds rolipram with a high affinity is denominated the"high affinity"binding site (HPDE 4). This term"HPDE4" should not be confused with the term"hPDE4"which is used to denote human PDE4.

Initial experiments were conducted to establish and validate a [3H]-rolipram binding assay. Details of this work are given in the Binding Assays described in detail below.

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 ! Cgo ratio of about 0.1 or greater as regards the iCgn for the PDE4 catalytic form which binds rolipram with a high affinity divided by the Cgn for the form which binds rolipram with a low affinity.

A further refinement of this standard is that of one wherein the PDE4 inhibitor has an IC50 ratio of about 0.1 or greater; said ratio is the ratio of the ICgp value for competing with the binding of 1nM of [3H] R-rolipram to a form of PDE4 which binds rolipram with a high affinity over the iCgn value for inhibiting the PDE4 catalytic activity of a form which binds rolipram with a low affinity using 1 pM [3H]-cAMP as the substrate.

Examples of useful PDE4 inhibitors are: (R)- (+)-1- (4-bromobenzyl)-4- [ (3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone ; (R)- (+)-1- (4-bromobenzyl)-4- [ (3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone ; 3- (cyclopentyloxy-4-methoxyphenyl)-1- (4-N'- [N2-cyano-S-methyl- isothioureido] benzyl)-2-pyrrolidone ; cis 4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexan-1-carboxylic acid]; cis- [4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexan-1-ol] ; (R)- (+)-ethyl [4- (3-cyclopentyloxy-4-methoxyphenyl) pyrrolidine-2-ylidene] acetate; and (S)- (-)-ethyl [4- (3-cyclopentyloxy-4-methoxyphenyl) pyrrolidine-2-ylidene] acetate.

Most preferred are those PDE4 inhibitors which have an iCgn ratio of greater than 0.5, and particularly those compounds having a ratio of greater than 1.0.

Preferred compounds are cis 4-cyano-4- (3-cyclopentyloxy-4- methoxyphenyl) cyclohexan-1-carboxylic acid, 2-carbomethoxy-4-cyano-4- (3- cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexan-1-one and cis- [4-cyano-4-

(3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexan-1-ol] ; these are examples of compounds which bind preferentially to the low affinity binding site and which have an iCgn ratio of 0.1 or greater.

Other compounds of interest include: Compounds set out in U. S. patent 5,552,438 issued 03 September, 1996; this patent and the compounds it discloses are incorporated herein in full by reference. The compound of particular interest, which is disclosed in U. S. patent 5,552,438, is cis-4- cyano-4- [3- (cyclopentyloxy)-4-methoxyphenyl] cyclohexane-1-carboxylic acid (also known as cilomalast) and its salts, esters, pro-drugs or physical forms; AWD-12-281 from Astra (Hofgen, N. et al. 15th EFMC Int Symp Med Chem (Sept 6- 10, Edinburgh) 1998, Abst P. 98); a 9-benzyladenine derivative nominated NCS-613 (INSERM) ; D-4418 from Chiroscience and Schering-Plough ; a benzodiazepine PDE4 inhibitor identified as CI-1018 (PD-168787 ; Parke-Davis/Warner-Lambert); a benzodioxole derivative Kyowa Hakko disclosed in WO 9916766; V-11294A from Napp (Landells, L. J. et al. Eur Resp J [Annu Cong Eur Resp Soc (Sept 19-23, Geneva) 1998J 1998,12 (Suppl. 28): Abst P2393); roflumilast (CAS reference No 162401-32-3) and a pthalazinone (WO 9947505) from Byk-Gulden ; or a compound identified as T-440 (Tanabe Seiyaku; Fuji, K. et al. J Pharmacol Exp Ther, 1998, 284 (1) : 162).

Phosphodiesterase and Rolipram Binding Assays Assay method 1A Isolated human monocyte PDE4 and hrPDE (human recombinant PDE4) was determined to exist primarily in the low affinity form. Hence, the activity of test compounds against the low affinity form of PDE4 can be assessed using standard assays for PDE4 catalytic activity employing 1 p1M [3H] cAMP as a substrate (Torphy et al., J. of Biol. Chem., Vol. 267, No. 3 pp1798-1804, 1992).

Rat brain high speed supernatants were used as a source of protein and both enantiomers of [3H]-rolipram were prepared to a specific activity of 25.6 Ci/mmol.

Standard assay conditions were modified from the published procedure to be identical to the PDE assay conditions, except for the last of the cAMP : 50mM Tris HCI (pH 7.5), 5 mM MgC12, 50, uM 5'-AMP and 1 nM of [3H]-rolipram (Torphy et al., J. of Biol. Chem., Vol. 267, No. 3 pp1798-1804, 1992). The assay was run for 1 hour at 30° C. The reaction was terminated and bound ligand was separated from free ligand using a Brandel cell harvester. Competition for the high affinity binding site was assessed under conditions that were identical to those used for measuring low affinity PDE activity, expect that [3H]-cAMP was not present.

Assay method 1 B Measurement of Phosphodiesterase Activity PDE activity was assayed using a [3H] cAMP SPA or [3H] cGMP SPA enzyme assay as described by the supplier (Amersham Life Sciences). The reactions were conducted in 96-well plates at room temperature, in 0.1 ml of reaction buffer containing (final concentrations): 50 mM Tris-HCI, pH 7.5,8.3 mM MgCI2, 1.7 mM EGTA, [3H] cAMP or [3H] cGMP (approximately 2000 dpm/pmol), enzyme and various concentrations of the inhibitors. The assay was allowed to proceed for 1 hr and was terminated by adding 50 ; ni of SPA yttrium silicate beads in the presence of zinc sulfate. The plates were shaken and allowed to stand at room temperature for 20 min. Radiolabeled product formation was assessed by scintillation spectrometry. f3H1R-rolipram binding assay The [3H] R-rolipram binding assay was performed by modification of the method of Schneider and co-workers, see Nicholson, et al., Trends Pharmacol. Sci., Vol. 12, pp. 19-27 (1991) and McHale et al., Mol. Pharmacol., Vol. 39,109-113 (1991). R- Rolipram binds to the catalytic site of PDE4 see Torphy et al., Mol. Pharmacol., Vol.

39, pp. 376-384 (1991). Consequently, competition for [3H] R-rolipram binding provides an independent confirmation of the PDE4 inhibitor potencies of unlabeled competitors. The assay was performed at 30°C for 1 hr in 0.5 pI buffer containing (final concentrations): 50 mM Tris-HCI, pH 7.5,5 mM MgClz, 0.05% bovine serum albumin, 2 nM [3H] R-rolipram (5.7 x 104 dpm/pmol) and various concentrations of non-radiolabeled inhibitors. The reaction was stopped by the addition of 2.5 mi of ice-cold reaction buffer (without [3H]-R-rolipram) and rapid vacuum filtration (Brandel Cell Harvester) through Whatman GF/B filters that had been soaked in 0.3% polyethylenimine. The filters were washed with an additional 7.5 mi of cold buffer, dried, and counted via liquid scintillation spectrometry.

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

The combination 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 pharmaceutically acceptable diluent or carrier represent a further aspect of the invention.

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

Appropriate doses of known therapeutic agents will be readily appreciated by those skilled in the art.

The compounds of formula (I) and salts and solvates thereof may be prepared by the methodology described hereinafter, constituting a further aspect of this invention.

A process according to the invention for preparing a compound of formula (I) comprises alkylation of a thioacid of formula (II)

wherein R2, R3, R4, R5 and"^-are as defined above.

In this process the compound of formula (II) may be reacted with, for example, an appropriate alkyl or haloalkyl halide under standard conditions.

When Ri represents fluoromethyl, the preferred haloalkyl halide reagent is bromofluoromethane.

Compounds of formula (II) may be prepared from the corresponding 17a- hydroxyl derivative of formula (ici) :

wherein R2, R3, R4, R5 and"---are as defined above, using for example, the methodology described by G. H. Phillipps et al., (1994) Journal of Medicinal Chemistry, 37,3717-3729. For example the compound of formula (III) may be reacted with a compound of formula R2COOH or an activated derivative thereof eg an activated ester, anhydride or halide (eg the acid chloride). The reaction may be

performed in the presence of an organic solvent eg triethylamine, usually together with dimethylaminopyridine (DMAP).

Compounds of formula (III) may be prepared in accordance with procedures described in GB 2088877B. Compounds of formula (III) may also be prepared by a process comprising the following steps: su 0 0 OH V SH HO CH3 H Ho CHa HO 3 w pH ' OH OH CH, :"'CH, Step (a) < sl CH3 Step (b) _/"CH3 F F F /V/O/_ (III) _ V F F F

Step (a) comprises oxidation of a solution containing the compound of formula (IV). Preferably, step (a) will be performed in the presence of a solvent comprising methanol, water, tetrahydrofuran, dioxan or diethylene glygol dimethylether. For example, so as to enhance yield and throughput, preferred solvents are methanol, water or tetrahydrofuran, and more preferably are water or tetrahydrofuran, especially water and tetrahydrofuran as solvent. Dioxan and diethylene glygol dimethylether are also preferred solvents which may optionally (and preferably) be employed together with water. Preferably, the solvent will be present in an amount of between 3 and 10vol relative to the amount of the starting material (1wt.), more preferably between 4 and 6 vol., especially 5 vol. Preferably the oxidising agent is present in an amount of 1-9 molar equivalents relative to the amount of the starting material. For example, when a 50% w/w aqueous solution of periodic acid is employed, the oxidising agent may be present in an amount of between 1.1 and 10wt. relative to the amount of the starting material (1wt.), more preferably between 1.1 and 3wt., especially 1.3wt. Preferably, the oxidation step will comprise the use of a chemical oxidising agent. More preferably, the oxidising agent will be periodic acid or iodic acid or a salt thereof. Most preferably, the oxidising agent will be periodic acid or sodium periodate, especially periodic acid. Alternatively (or in addition), it will also be appreciated that the oxidation step may comprise any suitable oxidation reaction, eg. one which utilises air and/or oxygen. When the oxidation reaction utilises air and/or oxygen, the solvent used in said reaction will preferably be methanol. Preferably, step (a) will involve incubating the reagents at room temperature or a little warmer, say around 25 °C eg for 2 hours. The compound of formula (V) may be isolated by recrystallisation from the reaction mixture by addition of an anti-solvent. A suitable anti-solvent for compound of formula (V) is water. Surprisingly we have discovered that it is highly desirable to control the conditions under which the compound of formula (V) is precipitated by addition of anti-solvent eg water. When the recrystallisation is performed using chilled water (eg water/ice mixture at a temperature of 0-5 °C) although better anti- solvent properties may be expected we have found that the crystalline product

produced is very voluminous, resembles a soft gel and is very difficult to filter.

Without being limited by theory we believe that this low density product contains a large amount of solvate solvent within the crystal lattice By contrast when conditions of around 10 °C or higher are used (eg around ambient temperature) a granular product of a sand like consistency which is very easily filtered is produced.

Under these conditions, crystallisation typically commences after around 1 hour and is typically completed within a few hours (eg 2 hours). Without being limited by theory we believe that this granular product contains little or no of solvate solvent within the crystal lattice.

Step (b) will typically comprise the addition of a reagent suitable for converting a carboxylic acid to a carbothioic acid eg. using hydrogen sulphide gas together with a suitable coupling agent eg. carbonyidiimidazole (CDI) in the presence of a suitable solvent eg. dimethylformamide.

Solvates of compounds of formula (I) which are not physiologically acceptable may be useful as intermediates in the preparation of compounds of formula (I) or physiologically acceptable solvates thereof.

The advantages of compounds of formula (I) and/or salts and solvates thereof may include the fact that the substances appear to demonstrate excellent anti-inflammatory properties, with predictable pharmacokinetic and pharmacodynamic behaviour, with an attractive side-effect profile (demonstrated, for example, by good selectivity for the glucocorticoid receptor over the progesterone receptor and/or increased selectivity for glucocorticoid receptor mediated transrepression over transactivation) and are compatible with a convenient regime of treatment in human patients, especially for once-per-day administration. Further advantages may include the fact that the substances have desirable physical and chemical properties which allow for ready manufacture and storage.

The following non-limiting Examples illustrate the invention: EXAMPLES General LCMS was conducted on a Supelcosil LCABZ+PLUS column (3.3 cm x 4.6 mm ID) eluting with 0.1% HCOsH and 0.01 M ammonium acetate in water (solvent A), and 0.05% HC02H 5% water in acetonitrile (solvent B), using the following elution gradient 0-0.7 min 0% B, 0.7-4.2 min 100% B, 4.2-5.3 min 0% B, 5.3-5.5 min 0% B at a flow rate of 3 ml/min. The mass spectra were recorded on a Fisons VG Platform spectrometer using electrospray positive and negative mode (ES+ve and ES-ve).

Intermediates

Intermediate 1: 6a, 9a-Difluoro-11 ß-hvdroxv-16a-methvl-3-oxo-17a-(tetrahvdrofuran- 2S-vicarbonvl) oxv-androsta-1. 4-diene-17ß-carbothioic acid A solution of 6α,9α-difluoro-11ß,17α-dihydroxy-16α-methyl-3-oxo-andro sta-1, 4- diene-17ß-carbothioic acid (prepared in accordance with the procedure described in GB 2088877B) (1g, 2.42mmol) in anhydrous dichloromethane (20ml) and triethylamine (0.88ml, 6.32mmol) was treated at <5 °C under nitrogen with a solution of S-tetrahydro-2-furoyl chloride (6.32mmol) in anhydrous dichloromethane (5ml) over approximately 2min. The solution was stirred at <5 °C for 1 h and then diluted with dichloromethane (20ml) and washed successively with 5% sodium hydrogen carbonate solution (20ml), 1M hydrochloric acid (20ml) and water (20ml). The organic solution was dried (Na2SO4) and evaporated to give an cream foam (1.58g) which was dissolved in acetone (30ml) and treated with 1-methylpiperazine (1ml, 9mmol). After 2.5h the solution was slowly added to a stirred mixture of 2M hydrochloric acid (55ml) and ice (55ml) and the precipitate was collected and dried in vacuo to give the title compound as a white solid (1.08g, 87.4%): LCMS retention time 3.46min, m/z 511 MH+ Intermediate 2: 6a. 9a-Difluoro-11 ß-hydroxy-16a-methyl-3-oxo-17a-(tetrahydrofuran- 2R-vlcarbonvl) oxv-androsta-1. 4-diene-17ß-carbothioic acid Prepared using methods similar to that described for Intermediate 1.

LCMS retention time 3.45min, m/z 511 MH+ Intermediate 3 : 6α, 9α-Difluoro-11ß-hydroxy-16α-metyyl-3-oxo-17α-(tetrahydro furan- 3-ylcarbonyl) oxv-androsta-1. 4-diene-17ß-carbothioic acid Prepared using methods similar to that described for Intermediate 1.

LCMS retention time 3.39min, m/z 511 MH+ Intermediate 4: 6a, 9α-Difluoro-17α-(1,3-dithiolan-2-ylcvarbonyl)oxo-11ß-hydr oxy-16α- methyl-3-oxo-androsta-1,4-dienen-17ß-carbothioic acid Prepared using methods similar to that described for Intermediate 1.

LCMS retention time 3.75min, m/z 545 MH+ Intermediate 5: 6a, 9a-Difluoro-11 3-hydroxv-16a-methyl-17a- (1-methyl-L-prolyl) oxv- 3-oxo-androsta-1, 4-diene-17ß-carbothioic acid Prepared using methods similar to that described for Intermediate 1.

LCMS retention time 2.56min, m/z 524 MH+ Intermediate 6: 6a, 9a-Difluoro-1113-hvdroxv-16a-methvl-3-oxo-17a- (thietan-3- ylcarbonyl)oxy-androsta-1,4-diene-17ß-carbothioic acid Prepared using methods similar to that described for Intermediate 1.

LCMS retention time 3.73min, m/z 513 MH+

Intermediate 7: 6a, 9a-Difluoro-11 ß-hydroxy-16a-methvl-3-oxo-17a- (tetrahydrothiophen-2-ylcarbonyl)oxy-androsta-1,4-dienen-17à Ÿ-carbothioicacid Prepared using methods similar to that described for Intermediate 1.

LCMS retention time 3. 93min, m/z 527 MH+ Intermediate 8: 6a, 9α-Difluoro-11ß-hydroxy-16α-methyl-3-oxo-17α-(2-methyl- tetrahydrofuran-2-ylcarbonyl)oxy-androsta-1, 4-diene-17ß-carbothioic acid Prepared using methods similar to that described for Intermediate 1.

LCMS retention time 3.97min, m/z 525 MH+ Intermediate 9: 6a, 9a-Difluoro-17a- (1, 3-dioxolan-2-vlcarbonyl) oxv-11 a-hydrox-y-16a- methyl-3-oxo-androsta-1, 4-diene-17ß-carbothioic acid Prepared using methods similar to that described for Intermediate 1.

LCMS retention time 3.27min, m/z 513 MH+ Intermediate 10: 6α, 9a-Difluoro-11 ß-hvdroxv-16a-methvl-3-oxo-17a-r (2RS, 3SR)-3- methvl-tetrahvdrofuran-2-vlcarbonviloxv-androsta-1. 4-diene-17Q-carbothioic acid Prepared using (2RS, 3SR)-3-methyl-2-tetrahydrofuroic acid (prepared according to the method of WO 92/01696) and using a method similar to that described for Intermediate 1 LCMS retention time 3.77,3.87min, m/z 525 MH+ Intermediate 11: 6a, 9a-Difluoro-11 3-hvdroxv-16a-methvl-17a- (2-methvl-1, 3- idoxolan-2-ylcarbonyl)oxy-3-oxo-androsta-1,4-diene-17ß-carb othioicacid Prepared using methods similar to that described for Intermediate 1.

LCMS retention time 3.43min, m/z 527 MH+ Intermediate 12: 6a, 9α-Difluoro-11ß-hydroxy-16α-methyl-17α-(2-methyl-1, 3- dithiolan-2-ylcarbonyl)oxy-3-oxo-androsta-1,4-diene-17ß-car bothioicacid Prepared using methods similar to that described for Intermediate 1.

LCMS retention time 3.81 min, m/z 559 MH+ Intermediate 13: 6a, 9a-Difluoro-11 a-hvdroxy-16a-methyl-3-oxo-17a- (2-methvl- tetrahvdrothiophen-2-vicarbonvl) oxy-androsta-1. 4-diene-17a-carbothioic acid Prepared using methods similar to that described for Intermediate 1.

LCMS retention time 3.79min, m/z 541 MH+ Intermediate 14: 6a, 9α-Difluoro-11ß-hydroxy-16α-methyl-3-oxo-17α-(3- methvltetrahvdrofuran-3-ylcarbonvl) oxv-androsta-1, 4-diene-17ß-carbothioic acid Prepared using methods similar to that described for Intermediate 1.

LCMS retention time 3.59min, m/z 525 MH+ Intermediate 15: 6a, 9a-Difluoro-11 ß-hvdroxy-16a-methvl-3-oxo-17a-(2-ethvl- tetrahvdrofuran-2-vicarbonvl) oxy-androsta-1, 4-diene-17f3-carbothioic acid

Prepared using methods similar to that described for Intermediate 1.

LCMS retention time 3.92min, m/z 539 MH+ Intermediate 16: 6a, 9a-Difluoro-17a- (1, 3-dithian-2-ylcarbonvl) oxv-11(3-hvdroxv-16a- methyl-3-oxo-androsta-1, 4-diene-17ß-carbothioic acid Prepared using methods similar to that described for Intermediate 1.

LCMS retention time 4.29min, m/z 559 MH+ Intermediate 17: 6a, 9α-Difluoro-11ß-hydroxy-16α-methyl-3-oxo-17α-(tetrahydro -4H- pyran-4-ylcarbonyl)oxy-androsta-1,4-diene-17ß-carbothioic acid Prepared using methods similar to that described for Intermediate 1.

LCMS retention time 3.53min, m/z 525 MH+ Examples Example 1: 6a, 9a-Difluoro-11 ß-hvdroxv-16a-methvl-3-oxo-17a-(tetrahvdrofuran-2S- vlcarbonyl) oxv-androsta-1. 4-diene-17a-carbothioic acid S-fluoromethyl ester Sodium hydrogen carbonate (109mg, 1.3mmol) was added to a solution of Intermediate 1 (600mg, 1.18mmol) in anhydrous N, N-dimethylformamide (6ml) and the mixture cooled to-20 °C under nitrogen. Bromofluoromethane (0.15ml, 2.7mmol) was added and the mixture was stirred at-20 °C for 2h. Diethylamine (0. 6ml, 5.8mmol) was added and the mixture stirred at-20 °C for 15min and then added to vigorously stirred 2M hydrochloric acid (25ml). Water (75ml) was added and after stirring for a further 30min the white precipitate was collected and dried in vacuo (591 mg). This material was purified was column chromatography on silica gel to give the title compound as a white solid (307mg, 48%): LCMS retention time 3.41 min, m/z 543 MH+.

Example 2: 6a. 9α-Difloro-11ß-hydroxy-16α-methyl-3-oxo-17α-(tetrahydrof uran-2R- vlcarbonvl) oxv-androsta-1. 4-diene-17a-carbothioic acid S-fluoromethvl ester Prepared from Intermediate 2 using methods similar to that described for Example 1.

LCMS retention time 3.38min, m/z 543 MH+ Example 3: 6a. 9a-Difluoro-11 a-hydroxv-16a-methvl-3-oxo-17a- (tetrahvdrofuran-3- ylcarbonyl)oxy-androsta-1,4-diene-17ß-carbothioic acid S-fluoromethyl ester Prepared from Intermediate 3 using methods similar to that described for Example 1.

LCMS retention time 3.38min, m/z 543 MH+ Example 4: 6a, 9α-Difluoro-17α-(1,3-dithiolan-2-ylcarbonyl)oxy-11ß-hydro xy-16α- methvl-3-oxo-androsta-1, 4-diene-1773-carbothioic acid S-fluoromethvl ester Prepared from Intermediate 4 using methods similar to that described for Example 1.

LCMS retention time 3.60min, m/z 577 MH+

Example 5: 6a, 9α-Difluoro-11ß-hydroxy-16α-methyl-17α-(1-methyl-L-propy l)oxy-3- oxo-androsta-1, 4-diene-17ß-carbothioic acid S-fluoromethyl ester Prepared from Intermediate 5 using methods similar to that described for Example 1.

LCMS retention time 2.45min, m/z 556 MH+ Example 6: 6a, 9α-Difluroo-11ß-hydroxy-16α-metyyl-3-oxo-17α-(thietan-3- ylcarbonyl)oxy-androsta-1,4-diene-17ß-carbothioic acid S-fluoromethvl ester Prepared from Intermediate 6 using methods similar to that described for Example 1.

LCMS retention time 3.59min, m/z 545 MH+ Example 7: 6a, 9a-Difluoro-11ß-hydroxv-16a-methvl-3-oxo-17a-(tetrahvdrothi ophen- 2-vlcarbonvl) oxy-androsta-1. 4-diene-17a-carbothioic acid S-fluoromethyl ester Prepared from Intermediate 7 using methods similar to that described for Example 1.

The resulting diasteroisomers were separated by preparative HPLC on a Chiralcel OD column eluting with 20% ethanol in heptane (50ml/min flow rate, room temperature) to give isomer A showing retention time 11.5 min and isomer B showing retention time 17min. Both isomers showed MH+ 559 in the mass spectrum.

Example 8: 6a, 9a-Difluoro-11 ß-hvdroxy-16a-methvl-3-oxo-17a-(2-methvl- tetrahvdrofuran-2-v) oxv-androsta-1, 4-diene-17ß-carbothioic acid S- fluoromethvl ester Prepared from Intermediate 8 using methods similar to that described for Example 1.

The resulting diasteroisomers were separated by preparative HPLC on a Chiralcel OD column eluting with 10% ethanol in heptane (50ml/min flow rate, room temperature) to give isomer A showing retention time 21 min and isomer B showing retention time 23.5min. Both isomers showed MH+ 557 in the mass spectrum.

Example 9: 6a. 9a-Difluoro-17a- (1. 3-dioxolan-2-ylcarbonvl) oxy3-hydroxv-16a- methvl-3-oxo-androsta-1, 4-diene-17ß-carbothioic acid S-fluoromethvl ester Prepared from Intermediate 9 using methods similar to that described for Example 1.

LCMS retention time 3.35min, m/z 545 MH+ Example 10: 6a, 9a-Difluoro-113-hvdroxv-16a-methvl-3-oxo-17a-r (2RS, 3SR)-3- methvl-tetrahvdrofuran-2-vlcarbonvlloxv-androsta-1. 4-diene-1 (3-carbothioic acid S- fluoromethvl ester Prepared from Intermediate 10 using methods similar to that described for Example 1. The resulting diasteroisomers were separated by preparative HPLC on a Chiralcel OD column eluting with 10% ethanol in heptane (50ml/min flow rate, room temperature) to give isomer A showing retention time 18 min and isomer B showing retention time 21.5min. Both isomers showed MH+ 557 in the mass spectrum.

Example 11: 6α, 9a-Difluoro-11 3-hvdroxv-16a-methvl-17a- (2-methvl-1. 3-dioxolan-2- vlcarbonvl) oxv-3-oxo-androsta-1, 4-diene-17ß-carbothioic acid S-fluoromethyl ester Prepared from Intermediate 11 using methods similar to that described for Example 1. LCMS retention time 3.35min, m/z 559 MH+ Example 12: 6a. 9a-Difluoro-11 ß-hvdroxy-16a-methvl-17a-(2-methvl-1, 3-dithiolan-2- vtcarbonvt) oxy-3-oxo-androsta-1, 4-diene-17ß-carbothioic acid S-fluoromethyl ester Prepared from Intermediate 12 using methods similar to that described for Example 1. LCMS retention time 3.55min, m/z 591 MH+ Example 13: 6a, 9α-Difluoro-11ß-hydroxy-16α-metyl-3-oxo-17α-(2-methyl- tetrahydrothiophen-2-ylcvarbonyl)oxy-androsta-1,4-diene-17ß -carbothioic acid S- fluoromethyl ester Prepared from Intermediate 13 using methods similar to that described for Example 1. The resulting diasteroisomers were separated by preparative HPLC on a Chiralcel OD column eluting with 10% ethanol in heptane (50ml/min flow rate, room temperature) to give isomer A showing retention time 15.5min and isomer B showing retention time 20.5. Both isomers showed MH+ 573 in the mass spectrum.

Example 14 : 6α, 9a-Difluoro-11 ß-hvdroxv-16a-methvl-3-oxo-17a-(3- methyltetrahvdrofuran-3-vlcarbonvl) oxy-androsta-1, 4-diene-17a-carbothioic acid S- fluoromethvl ester Prepared from Intermediate 14 using methods similar to that described for Example 1. The resulting diasteroisomers were separated by preparative HPLC on a Chiralpak ad column eluting with 15% IPA in heptane (20min flow rate, room temperature) to give isomer A showing retention time 14.5 min and isomer B showing retention time 18min. Both isomers showed MH+ 557 in the mass spectrum.

Example 15: 6a. 9α-Difluoro-11ß-hydroxy-16α-methyl-3-oxo-17α-(2-ethyl- tetrahydrofuran-2-vlcarbonvl) oxv-androsta-1, 4-diene-17p-carbothioic acid S- fluoromethyl ester Prepared from Intermediate 15 using methods similar to that described for Example 1. The resulting diasteroisomers were separated by preparative HPLC on a Chiralcel OD column eluting with 15% IPA in heptane (20min flow rate, room temperature) to give isomer A showing retention time 19.1 min and isomer B showing retention time 25.5min. Both isomers showed MH+ 571 in the mass spectrum.

Example 16: 6α, 9α-Difluoro-17α-(1,3-dithian-2-ylcarbonyl)oxy-11ß-hydroxy -16α- methyl-3-oxo-androsta-1, 4-diene-17ß-carbothioic acid S-fluoromethyl ester Prepared from Intermediate 16 using methods similar to that described for Example 1. LCMS retention time 3.64min, m/z 591 MH+

Example 17: 6α, 9a-Difluoro-11 3-hvdroxv-16a-methvl-3-oxo-17a- (tetrahvdro-4H- pvran-4-vlcarbonvl) oxv-androsta-1, 4-diene-17ß-carbothioic acid S-fluoromethvl ester Prepared from Intermediate 17 using methods similar to that described for Example 1. LCMS retention time 3.42min, mlz 557 MH+ Preparation of long actina Q-adrenoreceptor agonist Example X: 3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3- (hvdroxvmethvl) phenyl]ethyl}amino)-hexy]oxy}butyl)benzenesulfonamide acetate i) Di (tert-butyl) 2- (2, 2-dimethyl-4H-1, 3-benzodioxin-6-vl)-2-oxoethlimidodicarbonate Cesium carbonate (70.4g) was added to a stirred suspension of 2-bromo-1- (2, 2- dimethyl-4H-1, 3-benzodioxin-6-yl) ethanone, (Glaxo, DE 3513885,1985) (61.8g) and di-t-butyl iminodicarboxylate (47.15g) in acetonitrile (600mi) under nitrogen. After vigorous stirring at 21°C for 24 h the mixture was diluted with water (ca800ml) and the product was extracted with diethyl ether (1 litre, then 200ml). The combined organic layers were washed with brine, dried (MgS04) and concentrated to ca400ml.

The white crystals were collected by filtration, washed with diethyl ether and dried to give the title compound (24.4g) 8 (CDCl3) 7.78 (1 H, dd, J 8, 2Hz), 7.65 (1 H, 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 liquors on silica gel, evaporating the appropriate eluate and triturating with diethyl ether. ii) tert-Butvl 2- (2, 2-dimethvl-4H-1, 3-benzodioxin-6-vl)-2-oxoethvlcarbamate Trifluoroacetic acid (92mi) was added to a stirred solution of di (tert-butyl) 2- (2, 2- dimethyl-4H-1, 3-benzodioxin-6-yl)-2-oxoethylimidodicarbonate, (352.55g) in dichloromethane (3.61itres) at 21°C and the reaction was stirred for 1.5 h. Aqueous NaOH solution (1.751itres) was added and after 10 min the phases were separated.

The organic layer was washed with water, dried (MgS04) 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 recrystallisation from diethyl ether to give the title compound (122. 78g). Further product (61.5g) was obtained from the mother liquors by evaporation and chromatography on a Biotage using 15% ethyl acetate in hexane. LCMS RT = 3.37min. iii) tert-Butvl (2R)-2-(2, 2-dimethVl-4H-1, 3-benzodioxin-6-yl)-2-hvdroXvethv ! carbamate A 2M solution of borane-dimethyl sulphide in THF (28moi) was added slowly to a 1 M 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°C under nitrogen. A solution of tert-butyl 2- (2, 2-dimethyl-4H-1, 3-benzodioxin-6-yl)-2-oxoethylcarbamate, (108.2g) in THF

(1.31itres) was added slowly keeping the temperature below 5°C followed by 2M solution of borane-dimethyl sulphide in THF (252moi) over 50 min. After 1 h, 2M HCI (170mol) was added with cooling and the mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated NaHCO3 solution and brine and dried (MgSO4). 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 = 3.31 min. iv)(5R)-5-(2, 2-DimethYl-4H-1g3-benzodioxin-6-vl)-1w3-oxazolidin-2-one tert-Butyl (2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl carbamate, (86.37g) in DMF (600moi) 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°C under nitrogen. The mixture was stirred at 21 °C for 2 h. The mixture was recooled to 0°C and 2M HCI (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 (MgS04) and evaporated to give the title compound (63.55g) LCMS RT = 2.66min. v) 6-Bromohexyl but-3-vnvl ether 3-Butyn-1-ol (42.4moi) was stirred vigorously with 1,6-dibromohexane (260mi) and tetrabutylammonium bisulphate (2. 4g) in 50% aqueous sodium hydroxide solution (200mi) under nitrogen for 3 days. Water (ca 700ml) was added and the organic layer was separated. The aqueous layer was extracted twice with dichloromethane (2 x 100mi) and the combined organic layers were washed with water, dried (MgS04) and concentrated. The residue in petroleum ether (bp 40-60°) was loaded onto a column of silica gel (1.5kg) and the column was eluted with petroleum ether (bp 40- 60°C), then 10% diethyl ether in petroleum ether (bp 40-60°C) to give the title compound (103. 3g), 8 (CDCI3) 3.56 (2H, t, J 7Hz), 3.47 (2H, t, J 7Hz), 3.42 (2H, t, J 7Hz), 2.45 (2H, m), 1.99 (1 H, t, J 2Hz), 1.87 (2H, m), 1.60 (2H, m) and 1.50 to 1.33 (4H, m). vi) (5R)-3-r6- (But-3-vnvloxv) hexvll-5- (2. 2-dimethil-4H-1. 3-benzodioxin-6-vl)-1, 3- oxazolidin-2-one (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin -2-one (10g) in DMF (100ml) was added dropwise to a stirred suspension of sodium hydride (60% oil dispersion, 2.33g) in DMF (50mi) with stirring under nitrogen and maintaining the internal temperature at 0°C. Stirring was continued at 0-5°C for 1 h. The mixture was recooled to 0°C and a solution of 6-bromohexyl but-3-ynyl ether (14.7g) in DMF

(50ml) was added over 1 min. The mixture was then stirred at 20-30°C for 2 h. 2M HCI (9ml) was added and the mixture was partitioned between water and diethyl ether. The aqueous layer was extracted with more diethyl ether and the combined organic layers were washed twice with brine. After drying (MgS04) the solution was concentrated and loaded onto a column of silica gel (600g) set up in diethyl ether: petroleum ether (bp 40-60°C) (1: 2). The column was eluted successively with this mixture, then (1: 1) and then diethyl ether to give the title compound (13. 88g) LCMS RT = 3.45min. vii)3-r4- (6-r (5R)-5- (2s2-Dimethvl-4H-1. 3-benzodioxin-6-vl)-2-oxo-1, 3-oxazolidin-3- vllhexvloxv) but-1-vnvllbenzenesulfonamide (5R)-3- [6- (But-3-ynyloxy) hexyl]-5- (2, 2-dimethyl-4H-1, 3-benzodioxin-6-yl)-1, 3- oxazolidin-2-one (1.79g) was stirred with 3-iodobenzene sulphonamide (1.4g) in acetonitrile : triethylamine (1: 1, 42ml) under nitrogen for 10 min. Cuprous iodide (0.083g) and dichlorobis (triphenylphosphine) palladium (0.192g) were added and the mixture was stirred for 17 h under nitrogen at 21°C. The mixture was evaporated to dryness and the residue was chromatographed on silica gel (250g) in 30% ethyl acetate: petroleum ether (bp 40-60°), then 50%, then 75% and finally ethyl acetate to give the title compound (2.35g), LCMS RT = 3.44min. viii)3-f4- (6-J(5R)-5- (2, 2-Dimethvl-4H-1, 3-benzodioxin-6-l)-2-oxo-1, 3-oxazolidin-3- yl]hexyl}oxy)butyllbenzenesulfonamide 3- [4- ( {6- [ (5R)-5- (2, 2-Dimethyl-4H-1, 3-benzodioxin-6-yl)-2-oxo-1, 3-oxazolidin-3- yl] hexyl} oxy) but-1-ynyl] benzenesulfonamide (2.35g) was stirred with platinum oxide (0.3g) in THF (30ml) under hydrogen for 2 h. The catalyst was removed by filtration using a filter aid and the filter cake was leached with ethyl acetate. The combined filtrates were passed through silica gel (200g) in ethyl acetate and the eluate was evaporated to give the title compound (2. 32g), LCMS RT = 3.49min. ix)3-f4-r (6-ff (2R)-2- (2. 2-Dimethvl-4H-1, 3-benzodioxin-6-yl)-2- <BR> <BR> <BR> <BR> hydroxyethyllaminolhexyi) oxylbutyllbenzenesulfonamide<BR> <BR> <BR> <BR> <BR> 3- [4- ( {6- [ (5R)-5- (2, 2-Dimethyl-4H-1, 3-benzodioxin-6-yl)-2-oxo-1, 3-oxazolidin-3- yl] hexyl} oxy) butyl] benzenesulfonamide (0.43g) was stirred in THF (10ml) while purging with a vigorous stream of nitrogen for 5 min. Potassium trimethylsilanoate (0.43g) was added and the mixture was stirred at 70°C under nitrogen for 2.5 h. The mixture was partitioned between dichloromethane and pH 6.4 phosphate buffer and the aqueous layer was extracted with more dichloromethane. The combined organic layers were washed with water, dried (MgS04) and concentrated. The residue was purified on silica gel (60g), eluting successively with ethyl acetate: petroleum ether

(bp 40-60°C) (1: 1), ethyl acetate, 10% then 20% methanol in ethyl acetate to give the title compound (0.286g), LCMS RT = 2.56min. x) 3- (4-{[6-({(2R)-2-Hyroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl] ethyl}amino)- hexvlloxv} butvl) benzenesulfonamide acetate 3- {4- [ (6- { [ (2R)-2- (2, 2-dimethyl-4H-1, 3-benzodioxin-6-yi)-2- hydroxyethyl] amino} hexyl) oxy] butyl} benzenesulfonamide (0.283g) was stirred with acetic acid (8ml) and water (4ml) at 70° for 35 min before evaporating to dryness.

The residue was re-evaporated twice with toluene to give the title compound (0.318g) LCMS RT = 2.34min, ES +ve 495 (MH) +.

Pharmacological Activity Pharmacological activity was assessed in a functional in vitro assay of glucocorticoid agonist activity which is generally predictive of anti-inflammatory or anti-allergic activity in vivo.

The functional assay was based on that described by K. P. Ray et al., Biochem J.

(1997), 328,707-715. A549 cells stably transfected with a reporter gene containing the NF-xB responsive elements from the ELAM gene promoter coupled to sPAP (secreted alkaline phosphatase) were treated with test compounds at appropriate doses for 1 hour at 37°C. The cells were then stimulated with tumour necrosis factor (TNF, 10ng/ml) for 16 hours, at which time the amount of alkaline phosphatase produced is measured by a standard colourimetric assay. Dose response curves were constructed from which EC50 values were estimated.

In this test the compounds of Examples 1 to 17 showed an EC50 value of <1 nM.

Screen for progesterone receptor activity The human breast cancer cell line T47D has been reported to upregulate an endogenous alkaline phosphatase in response to progestins (Di Lorenzo et al., Cancer Research (1991) 51,4470-4475. T47D cells were seeded into 96 well plates at a density of 1x105 cells per well and grown overnight at 37°C. Steroids were dissolved in DMSO, added to the cells (final DMSO concentration 0.7%), and incubated for 24 hours at 37°C. The cells were then washed with PBS and lysed with RIPA buffer (1% IGEPAL, 0.5% Na deoxycholate, 0.1% SDS in phosphate buffered saline). Alkaline phosphatase activity was measured spectrophotometrically (405nm) using p-nitrophenylphosphate (1.5mg/ml) as a substrate dissolved in 1 M diethanolamine, 0.28M NaCI, 0.5mM Mec12. Dose response curves were constructed from which ECro values were estimated.

Compounds were tested for progesterone activity in accordance with the above screen and the selectivity was determined by dividing the ED50 at the progesterone receptor by the ED50 at the glucocorticoid receptor.

The selectivity of Example 2 was 246 and Example 4 was 209 (compare fluticasone propionate : selectivity = 18).

In further experiments the following additional data was obtained: Compound Selectivity Fluticasone propionate 82 Example 2 1099 Example 4 1192 Example 6 500 Example 8A 49425 8B 63855 Example 11 1620 Example 13A 2650 13B 1955

Throughout the specification and the claims which follow, unless the context requires otherwise, the word'comprise', and variations such as'comprises'and 'comprising', will be understood to imply the inclusion of a stated integer or step or group of integers but not to the exclusion of any other integer or step or group of integers or steps.

The patents and patent applications described in this application are herein incorporated by reference.