WO2003042230A1

WO2003042230A1 - Non-aromatic heterocyclic esters of furan-2-one-esters of 17. beta.-carboxyl or 17 . beta. -carbothio glucocorticoids

Info

Publication number: WO2003042230A1
Application number: PCT/EP2002/012656
Authority: WO
Inventors: Keith Biggadike; Paul Jones
Original assignee: Glaxo Group Limited
Priority date: 2001-11-12
Filing date: 2002-11-12
Publication date: 2003-05-22
Also published as: GB0127160D0

Abstract

A compound of formula (I), wherein R1 represents O, S or NH; 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 groups and/or halogen atoms; R3 represents hydrogen, methyl (which may be in either the α or β 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.

Description

NON-AROMATIC HETEROCYCLIC ESTERS OF FURAN-2-ONE-ESTERS OF 17. BETA.-CARBOXYL OR 17 . BETA. -CARBOTHIO GLUCOCORTICOIDS

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. However, glucocorticosteroids in general may suffer from the disadvantage of causing unwanted systemic effects following administration. WO94/13690, WO94/14834, WO92/13873, WO92/13872, WO 97/24365, WO 97/24367 and WO 97/24368 all disclose glucocorticosteroids which are alleged to possess anti-inflammatory activity coupled with reduced systemic potency.

The present invention provides a novel group of compounds which possess useful anti-inflammatory activity whilst having little or no systemic activity. Thus, the compounds of the present invention represent a safer alternative to those known glucocorticoids which have poor side-effect profiles.

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

wherein

Ri represents O, S or NH; 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 (eg 1 or 2) methyl groups and/or halogen atoms;

R₃ represents hydrogen, methyl (which may be in either the α or β 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 (I) 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 maleate.

Examples of solvates include hydrates.

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 R₂ to be a 4-6 membered ring, especially a 4 or 5 membered ring.

Example R₂ groups include tetrahydrofuranyl (eg tetrahydrofuran-2-yl and tetrahydrofuran-3-yl), thietanyl (eg thietan-3-yl), 1 ,3-dithiolanyl (eg 1 ,3-dithiothan-2- yl), pyranyl (eg pyran-4-yl) and pyrrolidinyl, and substituted derivatives eg methyl substituted derivatives such as N-methyl-2-pyrrolidinyl.

References hereinafter to a compound according to the invention includes both compounds of formula (I) and salts and solvates thereof, particularly pharmaceutically 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). In particular the compounds of formula (I) contain an asymmetric centre at the point of attachment of the lactone moiety. Thus, the invention includes within its scope both diastereoisomers at this asymmetric centre and mixtures thereof.

We prefer R^ to represent O or S, especially S.

R_T can be bonded to the alpha, beta or gamma carbon atoms of the lactone group,

We prefer that R_T is bonded to the alpha atom of the lactone group.

We prefer R₃ to represent methyl, especially methyl in the α configuration. Compounds in which R₃ represents methyl in the β configuration are also of particular interest.

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. Compounds in which represents a single bond are also of particular interest.

A particularly preferred group of compounds of the present invention are compounds of formula (I) in which Ri is S; R₂ is -C(=O)thietan-3yl, R₃ is methyl; R and R₅, which can be the same or different, each represents hydrogen or fluorine, especially fluorine, and represents a single or 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:

6α,9α-difluoro-11 β-hydroxy-16α-methyl-3-oxo-17α-(pyran-4-ylcarbonyl)oxy-androsta-

1 ,4-diene- 17β-carbothioic acid S-(2-oxo-tetrahydro-furan-3S-yl) ester. 6α,9α-Difluoro-11 β-hydroxy-16α-methyl-3-oxo-17α-(tetrahydrofuran-2S- ylcarbonyl)oxy-androsta-1 ,4-diene-17β-carbothioic acid S-(2-oxo-tetrahydro-furan- 3S-yl) ester.

6α,9α-Difluoro-11 β-hydroxy-16α-methyl-3-oxo-17α-(tetrahydrofuran-2R- ylcarbonyl)oxy-androsta-1 ,4-diene-17β-carbothioic acid S-(2-oxo-tetrahydro-furan- 3S-yl) ester.

6α,9α-Difluoro- 11 β-hydroxy-16α-methyl-3-oxo-17α-(tetrahydrofuran-3- ylcarbonyl)oxy-androsta-1 ,4-diene-17β-carbothioic acid S-(2-oxo-tetrahydro-furan- 3S-yl) ester. 6α,9α-Difluoro-11 β-hydroxy-16α-methyl-3-oxo-17α-(thietan-3-ylcarbonyl)oxy- androsta-1 ,4-diene-17β-carbothioic acid S-(2-oxo-tetrahydro-furan-3S-yl) ester 6α,9α-Difluoro-17α-(1 ,3-dithiolan-2-ylcarbonyl)oxy-11 β-hydroxy-16α-methyl-3-oxo- androsta-1 ,4-diene-17β-carbothioic acid S- 2-oxo-tetrahydro-furan-3S-yl) ester, or a salt or solvate of any one thereof.

It will be appreciated that each of the above compounds of formula (I) includes the individual R and S diastereoisomers at the asymmetric centre at the point of attachment of the lactone moiety as well as the mixtures thereof. Thus, the individual R and S diastereoisomers isolated such as to be substantially free of the other diastereoisomer i.e. pure and mixtures thereof are included within the scope of the present invention. An individual R or S diastereoisomer isolated such as to be substantially free of the other diastereoisomer i.e. pure will preferably be isolated such that less than 10% preferably less than 1% especially less than 0.1 % of the other diastereoisomer is present.

The compounds of formula (I) have potentially beneficial anti-inflammatory or antiallergic 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. Hence, the compounds of formula (I) are useful in the treatment of inflammatory and/or allergic disorders. Further, compounds of formula (I) possess the advantage of having little or no systemic activity. Therefore, the compounds of the invention may represent a safer alternative to those known anti-inflammatory glucocorticoids which have poor side effect profiles.

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.

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.

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.

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.

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. 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. Each capsule or cartridge may generally contain between 20μg-10mg of the compound of formula (I). 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.

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 e.g. oleic acid or lecithin and cosolvents e.g. ethanol. One example formulation is excipient free and consists essentially of (eg consists of) a compound of formula (I) (optionally together with another 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 WO94/21229. 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- 10μm, preferably 2-5μm. Particles having a size above 20μm 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 60-90μm and not less than 15% will have a MMD of less than 15μm.

Formulations for administration topically to the nose include pressurised aerosol formulations and aqueous formulations administered to the nose by pressurised pump.

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:

Formulations for administration by external application.

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.

If appropriate, 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 1μg-2000μg eg 20μg-2000μg, preferably about 20μg-500μg of a compound of formula (I). 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. Preferably the compound of formula (I) is delivered once or twice daily. The overall daily dose with an aerosol will typically be within the range 10μg-10mg eg 100μg-10mg preferably, 200μg-2000μg.

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 β₂ adrenoreceptor agonist, an anti-histamine or an anti-allergic. The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a physiologically acceptable salt or solvate thereof together with another therapeutically active agent, for example, a β₂-adrenoreceptor agonist, an anti- histamine or an anti-allergic.

Examples of β₂-adrenoreceptor agonists include salmeterol (eg as racemate or a single enantiomer such as the R-enantiomer), salbutamol, formoterol, salmefamol, fenoterol or terbutaline and salts thereof, for example the xinafoate salt of salmeterol,

Long acting β₂-adrenoreceptor agonists such as salmeterol or formoterol are preferred. Preferred long acting β₂-adrenoreceptor agonists include those described in WO 0266 422A. Especially preferred long-acting β₂-adrenoreceptor agonists include 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 1 1 , with the proviso that m + n is 5 to 19, R¹¹ is -XSO₂NR¹⁶R¹⁷ wherein X is -(CH₂)_P- or C₂.₆ alkenylene;

R ⁶ and R¹⁷ are independently selected from hydrogen, C^alkyl, C₃.₇cycloalkyl,

C(O)NR¹⁸R¹⁹, phenyl, and phenyl (C_1-4alkyl)-, 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, C_halky!, C^haloalkyl,

C^alkoxy, hydroxy-substituted C^alkoxy, -CO₂R¹⁸, -SO₂NR¹⁸R¹⁹, -CONR¹⁸R¹⁹, -

NR¹⁸C(O)R¹⁹, or a 5-, 6- or 7-membered heterocylic ring;

R¹⁸and R¹⁹are independently selected from hydrogen, C_halky!,

C₃.₆cycloalkyl, phenyl, and phenyl (C_1-4alkyl)-; and p is an integer of from 0 to 6, preferably from 0 to 4;

R¹² and R¹³ are independently selected from hydrogen, C_halky!, C^alkoxy, halo, phenyl, and d.₆haloalkyl; and

R¹⁴ and R¹⁵ are independently selected from hydrogen and C_1-4alkyl with the proviso that the total number of carbon atoms in R¹⁴ and R¹⁵ is not more than 4.

Examples of anti-histamines include methapyrilene or loratadine.

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 compounds 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 IC5Q ratio of about 0.1 or greater as regards the IC50 for the PDE4 catalytic form which binds rolipram with a high affinity divided by the IC50 for the form which binds rolipram with a low affinity. For the purposes of this disclosure, the cAMP catalytic site which binds R and S rolipram with a low affinity is denominated the "low affinity" binding site (LPDE 4) and the other form of this catalytic site which binds rolipram with a high affinity is denominated the "high affinity" binding site (HPDE 4). This term "HPDE4" should not be confused with the term "hPDE4" which is used to denote human PDE4.

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 IC50 ratio of about 0.1 or greater as regards the IC50 for the PDE4 catalytic form which binds rolipram with a high affinity divided by the IC50 for the form which binds rolipram with a low affinity.

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 IC50 value for competing with the binding of 1 nM of [^HJR-rolipram to a form of PDE4 which binds rolipram with a high affinity over the IC50 value for inhibiting the PDE4 catalytic activity of a form which binds rolipram with a low affinity using 1 μM[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 IC50 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 c/s-[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 IC50 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 c/s-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_aj. 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) 1998] 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 μM [³H]cAMP as a substrate (Torphy et al.. J. of Biol. Chem., Vol. 267, No. 3 pp1798-1804, 1992).

Rat brain high speed supematants 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 MgCI₂, 50 μM 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 [ H]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 μl 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.

r³H1R-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 μl buffer containing (final concentrations): 50 mM Tris-HCI, pH 7.5, 5 mM MgCI₂, 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 ml 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 ml of cold buffer, dried, and counted via liquid scintillation spectrometry.

The invention thus provides, in a further aspect, a combination comprising a 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.

Thus, according to a first process (A), a compound of formula (I) may be prepared by treating a compound of formula (II)

in which R₂, R₃, R₄, R₅ and are as defined hereinbefore for compounds of formula (I) and X represents OH, SH or an activated derivative thereof such as a triazole or a mixed anhydride, with a compound of formula (III)

and salts thereof, in which Z represents OH, NH₂ or SH.

Compounds of formula (I) wherein Ri represents O or S may also be prepared according to a second process (B) in which a compound of formula (II) in which R₂,

R₃, R , R₅ and are as defined hereinbefore and X represents OH or SH or their corresponding salts, is treated with a compound of formula (IV) or formula (V)

in which Q represents a suitable leaving group (such as CI, Br, OSO₂A wherein A is, for example CH₃, CF₃, p-CH₃C₆H₄), under standard methods.

The above general process (B) employing compounds of formula (IV) can be used to prepare compounds of formula (I) in which R^ is linked to the alpha, beta, or gamma carbon atoms of the lactone group. Compounds of formula (I) wherein Ri represents O or S may be prepared according to the above process (B) by alkylation of a compound of formula (II) wherein X represents OH or SH respectively, with a compound of formula (IV) wherein Q represents a suitable leaving group using methods known in the art, or an adaptation of those methods.

Thus, for example, a compound of formula (I) wherein R^ represents O may be prepared by alkylation of a compound of formula (II) wherein X represents OH conveniently in the form of an appropriate salt (such as alkali metal e.g. sodium or quarternaryammonium salt) with a compound of formula (IV) wherein Q represents a suitable leaving group, preferably chlorine, bromine or mesylate. The alkylation reaction is preferably carried out in the presence of a solvent, suitably a polar solvent, under inert conditions, for example, nitrogen or the like, conveniently at a temperature of between about 0°C to 100°C. Suitable polar solvents may include acetone, dimethylformamide, dimethyl acetamide, dimethylsulphoxide, dichloromethane or chloroform.

Similarly, compounds of formula (I) wherein R^ represents S can be prepared according to the above process (B) by alkylation of a compound of formula (II) wherein X represents SH with a compound of formula (IV) wherein Q represents a suitable leaving group by adaptation of the methods described by Phillipps et al, Journal of Medicinal Chemistry, 1994, 37, 3717-3729. Thus, a compound of formula

(I) wherein R^ represents S may be prepared by alkylation of the corresponding compound of formula (II) wherein X represents SH conveniently in the form of an appropriate salt (such as alkali metal e.g. sodium or quarternaryammonium salt) with a compound of formula (IV) wherein Z represents a suitable leaving group as described hereinabove for similar alkylation reactions.

Alternatively, compounds of formula (I) wherein R-| represents O or S may be prepared according to the above process (B) by alkylation of a compound of formula

(II) wherein X represents OH or SH with a compound of formula (IV) wherein Q represents OH under Mitsunobu conditions using triphenylphosphine and a dialkyl azodicarboxylate, or by using Vilsmeier methodology as described by Barrett and Procopiou in the Journal of the Chemical Society, Chemical Communications, 1995, 1403-1404. A compound of formula (I) wherein Ri represents S and is bonded to the beta carbon atom of the lactone group may also be prepared by reacting the corresponding compound of formula (II) wherein X represents SH with a compound of formula (V). For example, by Michael addition of the compound of formula (II) with the compound of formula (V) in the presence of a base such as potassium carbonate and in a suitable solvent such as dimethylformamide.

Compounds of formula (I) may also be prepared from other compounds of formula (I) thereof using conventional interconversion procedures such as epimerisation or esterification. Thus, a process for preparing a compound of formula (I) by interconversion of another compound of formula (I) (process C) constitutes a further aspect of the present invention.

Compounds of formula (I) having a 1 ,2 single bond may be prepared by partial reduction of the corresponding 1 ,2 double bond compound by conventional methods. Thus, for example, by hydrogenation of the corresponding compound of formula (I) or of an intermediate used for the preparation of a compound of formula (I) using a palladium catalyst, conveniently in a suitable solvent e.g. ethyl acetate or preferably by using tris(triphenylphosphine) rhodium (I) chloride (known as Wilkinson's catalyst), conveniently in a suitable solvent such as toluene, ethyl acetate or ethanol.

It will be appreciated by those skilled in the art that it may be desirable to use protected derivatives of intermediates used in the preparation of compounds of formula (I). Thus, the above processes may require deprotection as an intermediate or final step to yield the desired compound. Thus, according to another process (D), a compound of formula (I) may be prepared by subjecting a protected derivative of a compound of formula (I) to reaction to remove the protecting group or groups present, constituting a further aspect of the present invention.

Protection and deprotection of functional groups may be effected using conventional means. Thus, hydroxyl groups may be protected using any conventional hydroxyl protecting group, for example, as described in Protective Groups in Organic Chemistry, Ed. J.F.W. McOmie (Plenum Press, 1973) or Protective Groups in Organic Synthesis by Theodora W. Green (John Wiley and Sons, 1991 ). Examples of suitable hydroxyl protecting groups includes groups selected from alkyl (e.g. t-butyl or methoxymethyl), aralkyl (e.g. benzyl, diphenylmethyl or triphenylmethyl), heterocyclic groups such as tetrahydropyranyl, acyl (e.g. acetyl or benzoyl) and silyl groups such as trialkylsilyl (e.g. t-butyldimethylsilyl). The hydroxyl protecting groups may be removed by conventional techniques. Thus, for example alkyl, silyl, acyl and heterocyclic groups may be removed by solvolysis, e.g. by hydrolysis under-acidic or basic conditions. Aralkyl groups such as triphenylmethyl may be similarly be removed by solvolysis, e.g. by hydrolysis under acidic conditions. Aralkyl groups such as benzyl may be cleaved by hydrogenolysis in the presence of a Noble metal catalyst such as palladium-on-charcoal.

Compounds of formulae (III), (IV) and (V) are either generally known compounds or may be prepared by methods analogous to those described in the art for preparing the known compounds of formula (III), (IV) and (V) or may be prepared by the methods described herein.

Compounds of formula (II) wherein X represents SH may be prepared from the corresponding 17α-hydroxyl derivative of formula (VI):

_2 r-,₃ r-, r_5 wherein R , R , R , R 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 step typically comprises the addition of a reagent suitable for performing the esterification to the ester such as an optionally substituted hetero cycloalkylcarbonyl halide in the presence of a mild base eg. triethylamine. Generally the carbonyl halide would be employed in at least 2 times molar quantity relative to the compound of formula (VI). The second mole of carbonyl halide tends to react with the thioacid moiety in the compound of formula (VI) and would need to be removed by reaction with an amine such as diethylamine. Compounds of formula (VI) may be prepared in accordance with procedures described in GB 2088877B.

Compounds of formula (VI) may also be prepared by a process comprising the following steps:

Step (a) comprises oxidation of a solution containing the compound of formula (VII). 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 (VIII) may be isolated by recrystallisation from the reaction mixture by addition of an anti-solvent. A suitable anti-solvent for compound of formula (VIII) is water. Surprisingly we have discovered that it is highly desirable to control the conditions under which the compound of formula (VIII) 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 solvated 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 solvated 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. carbonyldiimidazole (CDI) in the presence of a suitable solvent eg. dimethylformamide.

The following non-limiting Examples illustrate the invention:

EXAMPLES

General

Biotage refers to prepacked silica gel cartridges containing KP-Sil run on flash 12i chromatography module. LCMS was conducted on a Supelcosil LCABZ+PLUS column (3.3 cm x 4.6 mm ID) eluting with 0.1% HCO₂H and 0.01 M ammonium acetate in water (solvent A), and 0.05% HCO₂H 5% water in acetonitrile (solvent B), using the following elution gradient 0-0.7 min 0%B, 0.7-4.2 min 100%B, 4.2-5.3 min 0%B, 5.3-5.5 min 0%B at a flow rate of 3 ml/min. The mass spectra were recorded on a Fisons VG Platform spectrometer using electrospray positive and negative mode (ES+ve and ES-ve). Intermediates

Intermediate 1 : 6α,9α-difluoro-11 β-hvdroxy-16α-methyl-3-oxo-17α-(pyran-4- ylcarbonyl)oxy-androsta-1 ,4-diene-17β-carbothioic acid

A solution of 6 , 9α-difluoro-11 β, 17α-dihydroxy-16α-methyl-3-oxo-androsta-1 ,4- diene-17β-carbothioic acid (prepared in accordance with the procedure described in GB 2088877B) (1g, 2.42mmol) in anhydrous dichloromethane (30ml) and triethylamine (0.88ml, 6.32mmol) was treated at <5 °C with a solution of pyran-4- carbonyl chloride (939mg, 6.32mmol) in anhydrous dichloromethane (5ml) under an atmosphere of nitrogen. The solution was stirred at <5 °C for 45min and then diluted with dichloromethane (60ml) and washed successively with 5% aqueous sodium hydrogen carbonate solution (30ml), 1 M hydrochloric acid (30ml) and water (30ml) and dried (anhydrous magnesium sulphate) and evaporated to leave a solid residue. This material was dissolved in acetone (30ml) and 1-methylpiperazine (1 ml, 9mmol) added. After 3 h at room temperature the solution was added portionwise to a vigorously stirred mixture of 2M hydrochloric acid (55ml) and ice (55ml). The resulting precipitate was collected, washed with water and dried in vacuo to give the title compound as a cream coloured solid (1.2g, 94%) LCMS retention time 3.53min, m/z 525 MH⁺.

The following intermediates were prepared by an analogous method to Intermediate 1 :

Intermediate 2: 6α,9α-Difluoro-11 β-hvdroxy-16 -methyl-3-oxo-17α-(tetrahydrofuran- 2S-ylcarbonyl,oxy-androsta-1 ,4-diene-17β-carbothioic acid LCMS retention time 3.46min, m/z 511 MH⁺

Intermediate 3: 6α.9α-Difluoro-11 β-hvdroxy-16α-methyl-3-oxo-17α-(tetrahydrofuran- 2R-ylcarbonyl)oxy-androsta-1 ,4-diene-17β-carbothioic acid LCMS retention time 3.45min, m/z 511 MH⁺

Intermediate 4: 6α.9α-Difluoro-11 β-hvdroxy-16 -methyl-3-oxo-17α-(tetrahvdrofuran- 3-ylcarbonyl)oxy-androsta-1 ,4-diene-17β-carbothioic acid LCMS retention time 3.39min, m/z 511 MH⁺

Intermediate 5: 6α.9α-Difluoro-11 β-hvdroxy-16 -methyl-3-oxo-17α-(thietan-3- ylcarbonyl,oxy-androsta-1 ,4-diene-17β-carbothioic acid LCMS retention time 3.73min, m/z 513 MH⁺

Intermediate 6: 6α,9α-Difluoro-17α-, 1 ,3-dithiolan-2- ylcarbonyl,oxy-11 β-hvdroxy- 16α-methyl-3-oxo-androsta-1 ,4-diene-17β-carbothioic acid LCMS retention time 3.75min, m/z 545 MH⁺

Examples

Example 1 : 6α.9α-difluoro-11 β-hvdroxy-16α-methyl-3-oxo-17α-(pyran-4- ylcarbonyl)oxy-androsta-1 ,4-diene-17β-carbothioic acid S-(2-oxo-tetrahvdro-furan- 3S-yl) ester

A solution of Intermediate 1 (259mg, 0.494mmol) and methanesulfonic acid 2-oxo- tetrahydro-furan-3R-yl ester (180mg, 1mmol) in anhydrous N,N-dimethylformamide (2.5ml) was treated with anhydrous pyridine (0.081 ml, 1 mmol). The solution was stirred for 24h and was then treated with 2M hydrochloric acid (0.35ml), heated to 60°C and treated with a further quantity of 2M hydrochloric acid (1.2ml). The mixture was stirred at 60°C for 5 min and water (6ml) was then added dropwise. The resulting suspension was allowed to cool to room temperature and the product was collected by filtration, washed with water and dried in vacuo. Purification by Biotage silica gel column chromatography using chloroform/ethyl acetate (20:1 to 2:1 ) as eluant afforded the title compound (152mg, 51%) as a white solid, LCMS retention time 3.30min, m/z 609 MH⁺

Example 2: 6α,9α-Difluoro-11 β-hvdroxy-16α-methyl-3-oxo-17α-(tetrahvdrofuran-2S- ylcarbonyl)oxy-androsta-1 ,4-diene-17β-carbothioic acid S-(2-oxo-tetrahydro-furan- 3S-yl) ester

Example 2 was prepared from Intermediate 2 using a method analogous to that described for Example 1. LCMS retention time 3.26min, m/z 595 MH⁺

Example 3: 6α,9α-Difluoro-11 β-hvdroxy-16α-methyl-3-oxo-17α-(tetrahydrofuran-2R- ylcarbonvDoχy-androsta-1 ,4-diene-17β-carbothioic acid S-.2-oxo-tetrahydro-furan- 3S-yl) ester

Example 3 was prepared from Intermediate 3 using a method analogous to that described for Example 1. LCMS retention time 3.28min, m/z 595 MH⁺

Example 4: 6α.9α-Difluoro-11 β-hydroxy-16 -methyl-3-oxo-17α-(tetrahydrofuran-3- ylcarbonyl)oxy-androsta-1.4-diene-17β-carbothioic acid S-(2-oxo-tetrahvdro-furan- 3S-yl) ester

Example 4 was prepared from Intermediate 4 using a method analogous to that described for Example 1. LCMS retention time 3.26min, m/z 595 MH⁺

Example 5: 6α.9α-Difluoro-11 β-hvdroxy-16α-methyl-3-oxo-17α-,thietan-3- ylcarbonyl)oxy-androsta-1 ,4-diene-17β-carbothioic acid S-(2-oxo-tetrahvdro-furan- 3S-yl) ester

Example 5 was prepared from Intermediate 5 using a method analogous to that described for Example 1. LCMS retention time 3.48min, m/z 597 MH⁺

Example 6: 6α.9α-Difluoro-17α-(1.3-dithiolan-2- ylcarbonyl,oxy-11 β-hvdroxy-16α- methyl-3-oxo-androsta-1.4-diene-17β-carbothioic acid S- 2-oxo-tetrahydro-furan-3S- yl) ester

Example 6 was prepared from Intermediate 6 using a method analogous to that described for Example 1. LCMS retention time 3.46min, m/z 629 MH⁺

Pharmacological Activity In Vitro 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-κB 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 1-6 showed an EC₅₀ values of <20nM.

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 application of which this description and claims forms part may be used as a basis for priority in respect of any subsequent application. The claims of such subsequent application may be directed to any feature or combination of features described herein. They may take the form of product, composition, process, or use claims and may include, by way of example and without limitation, the following claims.

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

Claims

1. A compound of formula (I)

wherein

R_T represents O, S or NH; 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 groups and/or halogen atoms;

R₃ represents hydrogen, methyl (which may be in either the α or β configuration) or methylene; R₄ and R₅ are the same or different and each represents hydrogen or halogen; and ^rrrr: represents a single or a double bond; and salts and solvates thereof.

2. A compound as claimed in claim 1 in which R^ is O or S.

3. A compound as claimed in claim 1 or claim 2 in which R^ is bonded to the alpha atom of the lactone group.

4. A compound as claimed in any of the proceeding claims in which R₃ represents methyl.

5. A compound as claimed in claim 4 in which R₃ is methyl in the α configuration.

6. A compound as claimed in claim 4 in which R₃ is in the β configuration.

7. A compound as claimed in any one of the preceding claims in which Ri is S; R₂ is -C(=O)thietan-3yl, R₃ is methyl; R₄ and R₅, which can be the same or different, each represents hydrogen or fluorine, especially fluorine, and represents a single or a double bond.

8. A compound as claimed in claim 1 which is:

6α,9α-difluoro-11 β-hydroxy-16α-methyl-3-oxo-17α-(pyran-4-ylcarbonyl)oxy- androsta-1 ,4-diene-17β-carbothioic acid S-(2-oxo-tetrahydro-furan-3S-yl) ester. 6α,9α-Difluoro-11 β-hydroxy-16α-methyl-3-oxo-17α-(tetrahydrofuran-2S- ylcarbonyl)oxy-androsta-1 ,4-diene-17β-carbothioic acid S-(2-oxo-tetrahydro- furan-3S-yl) ester.

6α,9α-Difluoro-11 β-hydroxy-16α-methyl-3-oxo-17α-(tetrahydrofuran-2R- ylcarbonyl)oxy-androsta-1 ,4-diene-17β-carbothioic acid S-(2-oxo-tetrahydro- furan-3S-yl) ester.

6α,9α-Difluoro-11 β-hydroxy-16α-methyl-3-oxo-17α-(tetrahydrofuran-3- ylcarbonyl)oxy-androsta-1 ,4-diene-17β-carbothioic acid S-(2-oxo-tetrahydro- furan-3S-yl) ester.

6α,9α-Difluoro-11 β-hydroxy-16α-methyl-3-oxo-17α-(thietan-3-ylcarbonyl)oxy- androsta-1 ,4-diene-17β-carbothioic acid S-(2-oxo-tetrahydro-furan-3S-yl) ester or

6α,9α-Difluoro-17α-(1 ,3-dithiolan-2-ylcarbonyl)oxy-11 β-hydroxy-16α-methyl-

3-oxo-androsta-1 ,4-diene-17β-carbothioic acid S- 2-oxo-tetrahydro-furan-3S- yl) ester, or a salt or solvate of anyone thereof.

A compound of formula (I) as claimed in any one of claims 1 to 8 or a physiologically salt or solvent thereof for use in veterinary or human medicine, in particular as anti-inflammatory and anti-allergic agents.

10. Use of a compound of formula (I) as defined in any of claims 1 to 8 or a physiologically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of inflammatory and/or allergic conditions.

11. 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.

12. A pharmaceutical composition comprising a compound of formula (I) as defined in any of claims 1 to 9 or a physiologically acdeptable salt or solvate thereof together, if desirable, in admixture with one or more physiologically acceptable diluents or carriers.

13. A pharmaceutical composition as claimed in claimed 12 for administration by external application.

14. A pharmaceutical aerosol formulation comprising a compound of formula (I) as defined in any of claims 1 to 9 or a physiologically acceptable solvate thereof, and a fluorocarbon or hydrogen-containing chlorofluorocarbon as propellant, optionally in combination with a surfactant and or a cosolvent.

15. A pharmaceutical composition according to claim 12 which further comprises another therapeutically active agent.

16. A pharmaceuitcal composition according to claim 15 in which said another therapeutically active agent is a β₂-adrenoreceptor agonist.

17. A pharmaceutical composition according to claim 16 in which said β₂- adrenoreceptor agonist is a compound 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 , with the proviso that m + n is 5 to 19,

R ¹ is -XSO₂NR¹⁶R¹⁷ wherein X is -(CH₂)_P- or C₂.₆ alkenylene;

R¹⁶ and R¹⁷ are independently selected from hydrogen, C_halky!, C₃_

₇cycloalkyl, C(O)NR¹⁸R¹⁹, phenyl, and phenyl (C^alkyl)-, or R¹⁶ and R¹⁷, together with the nitrogen to which they are bonded, form a 5- , 6-, or 7- membered nitrogen containing ring, and R ⁶ and R¹⁷are each optionally substituted by one or two groups selected from halo, C_halky!,

C^haloalkyl, C ealkoxy, hydroxy-substituted C^alkoxy, -CO₂R¹⁸, -

SO₂NR¹⁸R¹⁹, -CONR¹⁸R¹⁹, -NR¹⁸C(O)R¹⁹, or a 5-, 6- or 7-membered heterocylic ring; R¹⁸and R¹⁹are independently selected from hydrogen, C_halky!,

C₃-₆cycloalkyl, phenyl, and phenyl (C^alkyl)-; and p is an integer of from 0 to 6, preferably from 0 to 4;

R¹² and R¹³ are independently selected from hydrogen, C_halky!, C^alkoxy, halo, phenyl, and C_Leihaloalkyl; and R¹⁴ and R¹⁵ are independently selected from hydrogen and C^alkyl with the proviso that the total number of carbon atoms in R¹⁴ and R¹⁵ is not more than

4.

18. A pharmaceutical composition according to claim 17 in which the 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.

19. A process for preparing a compound of formula (I) as defined in claim 1 which comprises treating a compound of formula (II):

and salts thereof, in which Z represents OH, NH₂ or SH.

20. A process for preparing a compound of formula (I) as defined in claim 2, in which a compound of formula (II) as defined in claim 19 in which R₂, R₃, R₄, R₅ and are as defined hereinbefore and X represents OH or SH or their corresponding salts, is treated with a compound of formula (IV) or formula (V)

21. A compound a formula (II):

in which R₂, R₃, R₄, R₅ and are as defined hereinbefore for compounds of formula (I) and X represents OH, SH or an activated derivative thereof such as a triazole or a mixed anhydride.