WO2004039827A2 - Glucocorticosteroids having a specific 17a-sidechain useful as antiinflammatory agents - Google Patents

Glucocorticosteroids having a specific 17a-sidechain useful as antiinflammatory agents Download PDF

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Publication number
WO2004039827A2
WO2004039827A2 PCT/EP2003/012028 EP0312028W WO2004039827A2 WO 2004039827 A2 WO2004039827 A2 WO 2004039827A2 EP 0312028 W EP0312028 W EP 0312028W WO 2004039827 A2 WO2004039827 A2 WO 2004039827A2
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Prior art keywords
methyl
oxo
androsta
diene
oxy
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PCT/EP2003/012028
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French (fr)
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WO2004039827A3 (en
Inventor
Gillian Elizabeth Morton
Deborah Needham
Jeremy John Payne
John Martin Pritchard
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Glaxo Group Limited
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Priority to AU2003293631A priority Critical patent/AU2003293631A1/en
Publication of WO2004039827A2 publication Critical patent/WO2004039827A2/en
Publication of WO2004039827A3 publication Critical patent/WO2004039827A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J3/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by one carbon atom
    • C07J3/005—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by one carbon atom the carbon atom being part of a carboxylic function

Definitions

  • 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, we have identified a novel series of glucocorticosteroids.
  • R-i represents C*,- 6 alkyl or C* ⁇ - 6 haloalkyl
  • X represents O or S
  • R 2 represents C 3 - 8 cycloalkyl which optionally may be substituted by one or more groups selected from C**- 6 alkyl, oxo, or halogen
  • n is an integer from 1-6.
  • R 3 represents methyl, which may be in either the ⁇ or ⁇ configuration, or methylene
  • R 4 and R 5 are the same or different and each represents hydrogen, halogen or a methyl group; and represents a single or a double bond; and solvates thereof.
  • solvates include hydrates.
  • References hereinafter to a compound according to the invention includes both compounds of formula (I) and solvates thereof.
  • the absolute stereochemistry will be as shown in the representation of compounds of formula (I).
  • C**- 6 haloalkyl examples include a C* ⁇ - 6 alkyl group substituted by 1-3 halogen atoms, preferably 1 halogen atom. Preferred halogen atoms are selected from bromine, chlorine and fluorine. Examples of C*,. 6 alkyl that R-i may represent include methyl. We prefer R 1 to represent fluoromethyl, chloromethyl, bromomethyl or 2'-fluoroethyl, especially fluoromethyl.
  • R 2 represents C 3 . 8 cycloalkyl optionally substituted by one or more C*,- 6 alkyl groups.
  • C 3 . 8 cycloalkyl groups that R 2 may represent include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl and substituted derivatives such as tetramethylcyclopropyl (eg 2,2,3,3- tetramethylcyclopropyl), 2,2-dichlorocyclopropyl, 2,2-dichloro-1-methylcyclopropyl, 4-te/ ⁇ f-butylcyclohexyl and 4-oxo-cyclohexyl.
  • tetramethylcyclopropyl eg 2,2,3,3- tetramethylcyclopropyl
  • 2,2-dichlorocyclopropyl 2,2-dichloro-1-methylcyclopropyl
  • 4-te/ ⁇ f-butylcyclohexyl 4-oxo-cyclohexyl.
  • R 2 to represent cyclohexyl, cyclopentyl or cis-4-tert- butylcyclohexyl.
  • n 1 or 2, preferably 1.
  • X to represent S.
  • X to represent O.
  • R 3 represents methyl, especially methyl in the ⁇ configuration.
  • R 4 and R 5 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 R 4 and R 5 are both fluorine.
  • Preferred compounds of formula (I) include:
  • 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.
  • 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.
  • 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 fibros
  • Compounds of the invention may also have use in the treatment of conjunctiva and conjunctivitis.
  • compounds of formula (I) are useful in human or veterinary medicine, in particular as anti-inflammatory and anti-allergic agents.
  • a method for the treatment of a human or animal subject with an inflammatory and/or allergic condition comprises administering to said human or animal subject an effective amount of a compound of formula (I) or physiologically acceptable 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 solvate thereof together, if desirable, in admixture with one or more physiologically acceptable diluents or carriers.
  • 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 includes administration by insufflation and inhalation.
  • 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.
  • 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.
  • 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.
  • 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 a 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.
  • formulations of the invention may be buffered by the addition of suitable buffering agents.
  • Capsules and cartridges for use in an inhaler or insufflator may be formulated containing a powder mix for inhalation of a compound of the invention and a suitable powder base such as lactose or starch.
  • a powder mix for inhalation of a compound of the invention and a suitable powder base such as lactose or starch.
  • Each capsule or cartridge may generally contain between 20 ⁇ g-10mg of the compound of formula (I).
  • the compound of the invention may be presented without excipients such as lactose.
  • 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 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 ⁇ g-2000 ⁇ g, preferably about 20 ⁇ g-500 ⁇ g 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.
  • the overall daily dose with an aerosol will be within the range 100 ⁇ g-10mg preferably, 200 ⁇ g-2000 ⁇ g.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 compounds and pharmaceutical formulations according to the invention may be used in combination with or include one or more other therapeutic agents, for example selected from anti-inflammatory agents, anticholinergic agents (particularly an Mi, M 2 , M 1 /M 2 or M 3 receptor antagonist), other ⁇ 2 -adrenoreceptor agonists, antiinfective agents (e.g. antibiotics, antivirals), or antihistamines.
  • anti-inflammatory agents for example selected from anti-inflammatory agents, anticholinergic agents (particularly an Mi, M 2 , M 1 /M 2 or M 3 receptor antagonist), other ⁇ 2 -adrenoreceptor agonists, antiinfective agents (e.g. antibiotics, antivirals), or antihistamines.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with one or more other therapeutically active agents, for example selected from an anti-inflammatory agent (for example another corticosteroid or an NSAID), an anticholinergic agent, another ⁇ 2 -adrenoreceptor agonist, an antiinfective agent (e.g. an antibiotic or an antiviral), or an antihistamine.
  • an anti-inflammatory agent for example another corticosteroid or an NSAID
  • an anticholinergic agent for example another corticosteroid or an NSAID
  • another ⁇ 2 -adrenoreceptor agonist for example an anticholinergic agent
  • an antiinfective agent e.g. an antibiotic or an antiviral
  • an antihistamine for example selected from an anti-inflammatory agent (for example another corticosteroid or an NSAID), an anticholinergic agent, another ⁇ 2
  • Preferred combinations are those comprising one or two other therapeutic agents.
  • the other therapeutic ingredient(s) may be used in the form of salts, (e.g. as alkali metal or amine salts or as acid addition salts), or prodrugs, or as esters (e.g. lower alkyl esters), or as solvates (e.g. hydrates) to optimise the activity and/or stability and/or physical characteristics (e.g. solubility) of the therapeutic ingredient.
  • the therapeutic ingredients may be used in optically pure form.
  • 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 ⁇ 2 -adrenoreceptor agonist, an anti-histamine or an anti-allergic.
  • a combination comprising of compound of formula (I) or a physiologically acceptable salt or solvate thereof together with a ⁇ 2 -adrenoreceptor agonist is particularly preferred.
  • ⁇ 2 -adrenoreceptor agonists examples 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, the sulphate salt or free base of salbutamol or the fumarate salt of formoterol.
  • Long-acting ⁇ 2 -adrenoreceptor agonists are preferred, especially those having a therapeutic effect over a 24 hour period such as salmeterol or formoterol.
  • Preferred long acting ⁇ -adrenoreceptor agonists include those described in WO 0266 422A, WO 0227 0490, WO 0207 6933 and WO 0302 4439.
  • Especially preferred long-acting ⁇ 2 ⁇ adrenoreceptor agonists include compounds of formula(X):
  • n is an integer of from 3 to 11 , with the proviso that m + n is 5 to 19,
  • R 11 is -XSO 2 NR 16 R 17 wherein X is -(CH 2 ) P - or C 2 - 6 alkenylene;
  • R 16 and R 17 are independently selected from hydrogen, C* ⁇ - 6 alkyl, C 3 - cycloalkyl, C(O)NR 18 R 19 , phenyl, and phenyl (C ⁇ alkyl)-, or R 16 and R 17 , together with the nitrogen to which they are bonded, form a 5-, 6-, or
  • R 16 and R 17 are each optionally substituted by one or two groups selected from halo, C*
  • R 18 and R 19 are independently selected from hydrogen, C 1 . e alkyl,
  • R 12 and R 13 are independently selected from hydrogen, C* ⁇ - 6 alkyl, C**- 6 alkoxy, halo, phenyl, and C* ⁇ - 6 haloalkyl;
  • R 14 and R 15 are independently selected from hydrogen and C h alky! with the proviso that the total number of carbon atoms in R 14 and R 15 is not more than 4.
  • Suitable anti-inflammatory agents include NSAIDs.
  • Suitable NSAIDs include sodium cromoglycate, nedocromil sodium, phosphodiesterase (PDE) inhibitors (e.g. theophylline, PDE4 inhibitors or mixed PDE3/PDE4 inhibitors), leukotriene antagonists, inhibitors of leukotriene synthesis, iNOS inhibitors, tryptase and elastase inhibitors, beta-2 integrin antagonists and adenosine receptor agonists or antagonists (e.g. adenosine 2a agonists), cytokine antagonists (e.g. chemokine antagonists) or inhibitors of cytokine synthesis.
  • PDE phosphodiesterase
  • Suitable other ⁇ 2 -adrenoreceptor agonists include salmeterol (e.g. as the xinafoate), salbutamol (e.g. as the sulphate or the free base), formoterol (e.g. as the fumarate), fenoterol or terbutaline and salts thereof.
  • 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.
  • a PDE4 inhibitor which has 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.
  • 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).
  • LPDE 4 low affinity binding site
  • HPDE 4 high affinity binding site
  • 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.
  • 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 1nM 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 ⁇ M[3H]-cAMP as the substrate.
  • 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.
  • AWD-12-281 from elbion (Hofgen, N. et al. 15th EFMC Int Symp Med Chem (Sept 6- 10, Edinburgh) 1998, Abst P.98; CAS reference No. 247584020-9); a 9- benzyladenine derivative nominated NCS-613 (INSERM); D-4418 from Chiroscience and Schering-Plough; a benzodiazepine PDE4 inhibitor identified as CI-1018 (PD- 168787) and attributed to Pfizer; a benzodioxole derivative disclosed by Kyowa Hakko in WO99/16766; K-34 from Kyowa Hakko; V-11294A from Napp (Landells, L.J.
  • PDE-4 and mixed PDE3/PDE4 inhibitors include those listed in WO01/13953, the disclosure of which is hereby incorporated by reference.
  • Suitable anticholinergic agents are those compounds that act as antagonists at the muscarinic receptor, in particular those compounds which are antagonists of the M** and M 2 receptors.
  • exemplary compounds include the alkaloids of the belladonna plants as illustrated by the likes of atropine, scopolamine, homatropine, hyoscyamine; these compounds are normally administered as a salt, being tertiary amines.
  • drugs are readily available from a number of commercial sources or can be made or prepared from literature data via, to wit: Atropine - CAS-51-55-8 or CAS-51-48-1 (anhydrous form), atropine sulfate - CAS- 5908-99-6; atropine oxide - CAS-4438-22-6 or its HCI salt - CAS-4574-60-1 and methylatropine nitrate - CAS-52-88-0.
  • Preferred anticholinergics include ipratropium (e.g. as the bromide), sold under the name Atrovent, oxitropium (e.g. as the bromide) and tiotropium (e.g. as the bromide) (CAS-139404-48-1 ).
  • methantheline CAS-53-46-3
  • propantheline bromide CAS- 50-34-9
  • anisotropine methyl bromide or Valpin 50 CAS- 80-50-2
  • clidinium bromide Quarzan, CAS-3485-62-9
  • copyrrolate Robotul
  • isopropamide iodide CAS-71-81-8
  • mepenzolate bromide U.S.
  • Suitable antihistamines include any one or more of the numerous antagonists known which inhibit H* ⁇ -receptors, and are safe for human use. All are reversible, competitive inhibitors of the interaction of histamine with H**-receptors. The majority of these inhibitors, mostly first generation antagonists, have a core structure, which can be represented by the following formula:
  • This generalized structure represents three types of antihistamines generally available: ethanolamines, ethylenediamines, and alkylamines.
  • first generation antihistamines include those which can be characterized as based on piperizine and phenothiazines.
  • Second generation antagonists which are non- sedating, have a similar structure-activity relationship in that they retain the core ethylene group (the alkylamines) or mimic the tertiary amine group with piperizine or piperidine.
  • Exemplary antagonists are as follows:
  • Ethanolamines carbinoxamine maleate, clemastine fumarate, diphenylhydramine hydrochloride, and dimenhydrinate.
  • Ethylenediamines pyrilamine amleate, tripelennamine HCI, and tripelennamine citrate.
  • Alkylamines chlropheniramine and its salts such as the maleate salt, and acrivastine.
  • Piperazines hydroxyzine HCI, hydroxyzine pamoate, cyclizine HCI, cyclizine lactate, meclizine HCI, and cetirizine HCI.
  • Piperidines Astemizole, levocabastine HCI, loratadine or its descarboethoxy analogue, and terfenadine and fexofenadine hydrochloride or another pharmaceutically acceptable salt.
  • Azelastine hydrochloride is yet another H-* receptor antagonist which may be used in combination with a PDE4 inhibitor.
  • Examples of preferred anti-histamines include methapyrilene and loratadine.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with a PDE4 inhibitor.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with a ⁇ 2 -adrenorecptor agonist.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with an anticholinergic.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with an antihistamine.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with a PDE4 inhibitor and a ⁇ 2 - adrenoreceptor agonist.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with an anticholinergic and a PDE-4 inhibitor.
  • compositions comprising a combination as defined above together with a pharmaceutically acceptable diluent or carrier represent a further aspect of the invention.
  • the individual compounds of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations. Appropriate doses of known therapeutic agents will be readily appreciated by those skilled in the art.
  • the compound of formula (II) may be reacted with a compound of formula R L wherein L represents a leaving group such as halogen atom or a tosyl or mesyl group or the like, for example, an appropriate alkyl or haloalkyl halide under standard conditions.
  • L represents a leaving group such as halogen atom or a tosyl or mesyl group or the like, for example, an appropriate alkyl or haloalkyl halide under standard conditions.
  • the reaction may be performed in an inert polar organic solvent e.g. N,N-dimethylformamide in the presence of a base e.g. potassium carbonate, sodium carbonate, sodium bicarbonate.
  • R-i represents fluoromethyl
  • the preferred haloalkyl halide reagent is bromofluoromethane.
  • the step typically comprises the addition of a reagent suitable for performing the esterification to the ester such as a compound of formula R 2 (CH 2 ) n COOH or an activated derivative thereof eg an activated ester, anhydride or halide thereof especially an acid halide eg the acid chloride in the presence of a mild base e.g. triethylamine.
  • a reagent suitable for performing the esterification to the ester such as a compound of formula R 2 (CH 2 ) n COOH or an activated derivative thereof eg an activated ester, anhydride or halide thereof especially an acid halide eg the acid chloride in the presence of a mild base e.g. triethylamine.
  • a mild base e.g. triethylamine.
  • the acid chloride would be employed in at least 2 times molar quantity relative to the compound of formula (III).
  • the second mole of acid chloride tends to react with the carboxylic acid moiety in the compound of formula (III) and would need to be removed by reaction with an amine such as diethylamine or 1-methylpiperazine.
  • an amine such as diethylamine or 1-methylpiperazine.
  • Compounds of formula (III) are either known or may be prepared in accordance with procedures described by G. H. Phillipps et al., (1994) Journal of Medicinal Chemistry, 37, 3717-3729.
  • step (a) will be performed in the presence of a solvent comprising methanol, water, tetrahydrofuran, dioxan or diethylene glygol dimethylether.
  • a solvent comprising methanol, water, tetrahydrofuran, dioxan or diethylene glygol dimethylether.
  • 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.
  • 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.
  • the oxidising agent is present in an amount of 1-9 molar equivalents relative to the amount of the starting material.
  • 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.
  • 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.
  • the oxidation step may comprise any suitable oxidation reaction, eg. one which utilises air and/or oxygen.
  • the solvent used in said reaction will preferably be methanol.
  • 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.
  • a suitable coupling agent eg. carbonyldiimidazole (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.
  • LCMS was conducted on a Supelcosil LCABZ+PLUS column (3.3 cm x 4.6 mm ID) eluting with 0.1% HCO 2 H and 0.01 M ammonium acetate in water (solvent A), and 0.05% HCO 2 H 5% water in acetonitrile (solvent B), using the following elution gradient 0-0.7 min 0%B, 0.7-4.2 min 100%B, 4.2-5.3 min 0%B, 5.3-5.5 min 0%B at a flow rate of 3 ml/min.
  • the mass spectra were recorded on a Fisons VG Platform spectrometer using electrospray positive and negative mode (ES+ve and ES-ve).
  • Example 1 17 ⁇ -(Cvclohexylmethylcarbonyl)oxy-6 ,9 -difluoro-11 ⁇ -hydroxy-16 ⁇ - methyl-3-oxo-androsta-1 ,4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester
  • Sodium bicarbonate (82mg, 0.98mmol) was added to a stirred solution of Intermediate 1 (475mg, 0.89mmol) in anhydrous DMF (5ml) and the mixture cooled to -20 °C.
  • Bromofluoromethane (272mg, 2.4mmol) was then added and the mixture stirred at -20 °C for 2h.
  • Example 2 was prepared from Intermediate 2 using a method similar to that described for Example 1. LCMS retention time 3.97 min, MH + 551.
  • Example 3 was prepared from Intermediate 3 using a method similar to that described for Example 1. LCMS retention time 4.02 min, MH + 583.
  • Example 4 was iolated as a minor product in the preparation of Example 3.
  • LCMS retention time 4.10 min, MH + 599, 601.
  • Example 5 was prepared from Intermediate 4 using a method similar to that described for Example 1. LCMS retention time 4.13 min, MH + 597.
  • Example 6 17o.-(4-Cvclohexylbutylcarbonyl)o ⁇ y-6 ⁇ ,9 ⁇ -difluoro-11 ⁇ -hydroxy-16 ⁇ - methyl-3-oxo-androsta-1 ,4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester
  • Example 6 was prepared from Intermediate 5 using a method similar to that described for Example 1. LCMS retention time 4.24 min, MH + 611.
  • Example 7 17 ⁇ -(Cvclopentylmethylcarbonv ⁇ oxy-6 ⁇ ,9 ⁇ -difluoro-11 ⁇ -hvdroxy-16 ⁇ - methyl-3-oxo-androsta-1 ,4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester
  • Example 7 was prepared from Intermediate 6 using a method similar to that described for Example 1. LCMS retention time 3.95 min, MH + 555.
  • Example 8 17 ⁇ -(2-Cvclopentylethylcarbonyl,oxy-6 ⁇ ,9 ⁇ -difluoro-11 ⁇ -hvdroxy-16 ⁇ - methyl-3-oxo-androsta-1 ,4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester
  • Example 8 was prepared from Intermediate 7 using a method similar to that described for Example 1. LCMS retention time 3.97 min, MH + 569.
  • Example 9 was prepared from Intermediate 8 using a method similar to that described for Example 1. LCMS retention time 3.72 min, MH + 541.
  • Example 10 was iolated as a minor product in the preparation of Example 9. LCMS retention time 3.80 min, MH + 557, 559.
  • Example 11 6 ,9 ⁇ -Difluoro-11 ⁇ -hvdroxy-16 ⁇ -methyl-3-oxo-17 ⁇ -r(2,2,3,3- tetramethylcvclopropyl)methylcarbonylloxy-androsta-1 ,4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester
  • Example 11 was prepared from Intermediate 9 using a method similar to that described for Example 1. LCMS retention time 3.96 min, MH + 583.
  • Example 12 17 ⁇ -r(2.2-Dichlorocvclopropyl .methylcarbonylloxy-ea.ga-difluoro-l 1 ⁇ - hvdroxy-16a-methyl-3-oxo-androsta-1 ,4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester
  • Example 12 was prepared from Intermediate 10 using a method similar to that described for Example 1.
  • the resulting diasteroisomers were separated by preparative HPLC on a Chiralcel ODH column (25cm x 1 inch) eluting with 15% ethanol in heptane (15ml/min flow rate) to give isomer A showing retention time 11.25 min and isomer B showing retention time 13.75 min. Both isomers showed MH + 595, 597, 599 in the mass spectrum.
  • Example 13 17 -f(2,2-Dichloro-1 -methylcvclopropyl)methylcarbonylloxy-6 ⁇ ,9 ⁇ - difluoro-11 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-androsta-1 ,4-diene-17 ⁇ -carbothioic acid S- fluoromethyl ester
  • Example 13 was prepared from Intermediate 11 using a method similar to that described for Example 1.
  • the resulting diasteroisomers were separated by preparative HPLC on a Chiralcel ODH column (20cm x 2inch) eluting with 20% ethanol in heptane (50ml/min flow rate) to give isomer A showing retention time 7.5 min and isomer B showing retention time 9 min. Both isomers showed MH + 609, 611 , 613 in the mass spectrum.
  • Example 14 17 ⁇ -(Cvclopentylmethylcarbonyl)oxy-6 ⁇ ,9 ⁇ -difluoro-11 ⁇ -hydroxy-16 ⁇ - methyl-3-oxo-androsta-1.4-diene-17 ⁇ -carboxylic acid fluoromethyl ester
  • Example 14 was prepared from Intermediate 12 using a method similar to that described for Example 1. LCMS retention time 3.80 min, MH + 539.
  • Example 15 17 ⁇ -(Cvclohexylmethylcarbonyl)oxy-6 ⁇ ,9 -difluoro-11 ⁇ -hydroxy-16 ⁇ - methyl-3-oxo-androsta-1 ,4-diene-17 ⁇ -carboxylic acid fluoromethyl ester
  • Example 15 was prepared from Intermediate 13 using a method similar to that described for Example 1. LCMS retention time 3.90 min, MH + 553.
  • Example 16 9 ⁇ -Chloro-17 ⁇ -(cvclohexylmethylcarbonyl)oxy-6 ⁇ -fluoro-11 ⁇ -hvdroxy- 16 ⁇ -methyl-3-oxo-androsta-1 ,4-diene-17 ⁇ -carboxylic acid methyl ester
  • Example 17 9 ⁇ -Chloro-17 ⁇ -(cvclohexylmethylcarbonyl)o ⁇ y-6 ⁇ -fluoro-11 ⁇ -hydro ⁇ y- 16 ⁇ -methyl-3-oxo-androsta-1 ,4-diene-17 ⁇ -carboxylic acid fluoromethyl ester
  • Example 17 was prepared from Intermediate 14 using a method similar to that described for Example 1. LCMS retention time 3.95 min, MH ⁇ 569,571.
  • Example 18 17 ⁇ -(Cvclopentylmethylcarbonv0oxy-6 ⁇ ,9 ⁇ -difluoro-11 ⁇ -hydroxy-16 ⁇ - methyl-3-oxo-androsta-1 ,4-diene-17 ⁇ -carboxylic acid chloromethyl ester
  • Example 19 17 ⁇ -(Cvclopentylmethylcarbonyl)o ⁇ y-6 ⁇ ,9 ⁇ -difluoro-11 ⁇ -hydroxy-16 ⁇ - methyl-3-oxo-androsta-1 ,4-diene-17 ⁇ -carbothioic acid S-chloromethyl ester
  • Example 19 was prepared from Intermediate 6 using a method similar to that described for Example 18: LCMS retention time 3.87 min, MH + 571 ,573.
  • Example 20 9 -Chloro-17 ⁇ -(cvclohexylmethylcarbonyl)oxy-6 ⁇ -fluoro-11 ⁇ -hydroxy- 16 ⁇ -methyl-3-oxo-androsta-1 ,4-diene-17 ⁇ -carboxylic acid chloromethyl ester
  • Example 20 was prepared from Intermediate 14 using a method similar to that described for Example 18: LCMS retention time 3.99 min, MH + 585,587.
  • Example 21 6 ⁇ ,9 ⁇ -Difluoro-11 ⁇ -hvdroxy-16 ⁇ -methyl-3-oxo-17 ⁇ -(4-oxo- cyclohexylmethylcarbonyl.oxy-androsta-1 ,4-diene-17 ⁇ -carboxylic acid methyl ester
  • Example 21 was prepared from Intermediate 15 using a method similar to that described for Example 16: LCMS retention time 3.33 min, MH + 549.
  • Example 22 6 ⁇ ,9 ⁇ -Difluoro-11 ⁇ -hvdroxy-16 ⁇ -methyl-3-oxo-17 ⁇ -(c/s-4-fe/f-butyl- cyclohe ⁇ ylmethylcarbonyl)oxy-androsta-1 ,4-diene-17 ⁇ -carbothioic acid S- fluoromethyl ester
  • Example 22 was prepared from Intermediate 16 using a method similar to that described for Example 1 : LCMS retention time 4.21 min, MH + 625.
  • a mixture of polystyrene-carbodiimide (Argonaut, 2g) was heated in a microwave at 135 °C for 60min at 150 watts and then cooled.
  • An aliquot (0.4g) of the resin was transferred to a glass vial and treated with a solution of Intermediate 17 (0.126mmol) in tetrahydrofuran (2ml) and the mixture heated in a microwave to 135 °C for 15min at 150 watts.
  • Example 24 was prepared from Intermediate 18 using a method similar to that described for Example 23: LCMS retention time 4.20 min, MH + 591.
  • Pharmacological activity may be assessed in functional in vitro assays of glucocorticoid agonist activity.
  • the functional assay based on that described by K. P. Ray et aL, Biochem J. (1997), 328, 707-715 provides a measure of transrepressive activity of a glucocorticoid agonist.
  • A549 cells stably transfected with a reporter gene containing the NF- ⁇ B responsive elements from the ELAM gene promoter coupled to sPAP (secreted alkaline phosphatase) are treated with test compounds at appropriate doses for 1 hour at 37°C.
  • the cells are 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.
  • TNF tumour necrosis factor
  • Dose response curves are constructed from which EC 5 o values may be estimated.
  • the EC 50 values for compounds of Examples 1 to 24 were ⁇ 10nM.
  • the functional assay based on that described by R.J.H. Austin et aL, Eur Resp J. (2002) 20,1386-1392 measures the ability of compounds to directly transactivate gene expression.
  • A549 cells stably transfected with a reporter gene containing the glucocorticoid responsive region of the mouse mammary tumour virus long terminal repeat (MMTV-LTR) coupled to renilla luciferase were treated with test compounds at appropriate doses for 6 hour at 37°C.
  • the amount of luciferase activity present within the cells is then determined by measuring the light emitted following incubation with a suitable substrate. Dose response curves were constructed from which EC 50 values were estimated and from which maximal responses are calculated relative to Dexamethasone (100%).

Abstract

A compound of formula (I): whereinR1 represents C1-6 alkyl or C1-6 haloalkyl;X represents O or S;R2 represents C3-8 cycloalkyl which optionally may be substituted by one or more groups selected from C1-6 alkyl, oxo, or halogen n is an integer from 1-6.R3 represents methyl, which may be in either the ( or ( configuration, or methylene;R4 and R5 are the same or different and each represents hydrogen, halogen or a methyl group;and represents a single or a double bond;and solvates thereof.

Description

Novel Compounds
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, we have identified a novel series of glucocorticosteroids.
Thus, according to one aspect of the invention, there is provided a compound of formula (I)
Figure imgf000002_0001
wherein
R-i represents C*,-6 alkyl or C*ι-6 haloalkyl;
X represents O or S; R2 represents C3-8 cycloalkyl which optionally may be substituted by one or more groups selected from C**-6 alkyl, oxo, or halogen n is an integer from 1-6.
R3 represents 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, halogen or a methyl group; and represents a single or a double bond; and solvates thereof.
Examples of solvates include hydrates. References hereinafter to a compound according to the invention includes both compounds of formula (I) and solvates thereof.
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).
Examples of C**-6 haloalkyl that R** may represent include a C*ι-6 alkyl group substituted by 1-3 halogen atoms, preferably 1 halogen atom. Preferred halogen atoms are selected from bromine, chlorine and fluorine. Examples of C*,.6 alkyl that R-i may represent include methyl. We prefer R1 to represent fluoromethyl, chloromethyl, bromomethyl or 2'-fluoroethyl, especially fluoromethyl.
We prefer R2 to represent C3.8 cycloalkyl optionally substituted by one or more C*,-6 alkyl groups.
Examples of C3.8 cycloalkyl groups that R2 may represent include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl and substituted derivatives such as tetramethylcyclopropyl (eg 2,2,3,3- tetramethylcyclopropyl), 2,2-dichlorocyclopropyl, 2,2-dichloro-1-methylcyclopropyl, 4-te/ιf-butylcyclohexyl and 4-oxo-cyclohexyl.
We particularly prefer R2 to represent cyclohexyl, cyclopentyl or cis-4-tert- butylcyclohexyl.
We prefer n to represent 1 or 2, preferably 1. In some embodiments we prefer X to represent S. In other embodiments we prefer X to represent O.
We prefer R3 to represent methyl, especially methyl in the α 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 R4and R5 are both 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:
17α-(Cyclohexylmethylcarbonyl)oxy-6α,9α-difluoro-11 β-hydroxy-16α-methyl-3-oxo- androsta-1 ,4-diene-17β-carbothioic acid S-fluoromethyl ester 17α-(Cyclohexylmethylcarbonyl)oxy-9α-fluoro-11 β-hydroxy-16β-methyl-3-oxo- androsta-1 ,4-diene-17β-carbothioic acid S-fluoromethyl ester 17α-(2-Cyclohexylethylcarbonyl)oxy-6α,9α-difluoro-11 β-hydroxy-16α-methyl-3-oxo- androsta-1 ,4-diene-17β-carbothioic acid S-fluoromethyl ester 17α-(2-Cyclohexylethylcarbonyl)oxy-6α,9α-difluoro-11 β-hydroxy-16α-methyl-3-oxo- androsta-1 ,4-diene-17β-carbothioic acid S-chloromethyl ester 17α-(3-Cyclohexylpropylcarbonyl)oxy-6α,9α-difluoro-11 β-hydroxy-16α-methyl-3-oxo- androsta-1 ,4-diene-17β-carbothioic acid S-fluoromethyl ester
17α-(4-Cyclohexylbutylcarbonyl)oxy-6α,9α-difluoro-11 β-hydroxy-16α-methyl-3-oxo- androsta-1 ,4-diene-17β-carbothioic acid S-fluoromethyl ester 17α-(Cyclopentylmethylcarbonyl)oxy-6α,9α-difluoro-11 β-hydroxy-16α-methyl-3-oxo- androsta-1 ,4-diene-17β-carbothioic acid S-fluoromethyl ester 17α-(2-Cyclopentylethylcarbonyl)oxy-6α,9α-difluoro-11 β-hydroxy-16α-methyl-3-oxo- androsta-1 ,4-diene-17β-carbothioic acid S-fluoromethyl ester 17α-(Cyclobutylmethylcarbonyl)oxy-6α,9α-difluoro-11 β-hydroxy-16α-methyl-3-oxo- androsta-1 ,4-diene-17β-carbothioic acid S-fluoromethyl ester 17α-(Cyclobutylmethylcarbonyl)oxy-6 ,9α-difluoro-11 β-hydroxy-16 -methyl-3-oxo- androsta-1 ,4-diene-17β-carbothioic acid S-chloromethyl ester
17α-[(2,2,3,3-Tetramethylcyclopropyl)methylcarbonyl]oxy-6α,9α-difluoro-11 β- hydroxy-16α-methyl-3-oxo-androsta-1 ,4-diene-17β-carbothioic acid S-fluoromethyl ester
17α-[(2,2-Dichlorocyclopropyl)methylcarbonyl]oxy-6α,9α-difluoro-11 β-hydroxy-16α- methyl-3-oxo-androsta-1 ,4-diene-17β-carbothioic acid S-fluoromethyl ester
17α-[(2,2-Dichloro-1 -methylcyclopropyl)methylcarbonyl]oxy-6α,9α-difluoro-11 β- hydroxy-16α-methyl-3-oxo-androsta-1 ,4-diene-17β-carbothioic acid S-fluoromethyl ester
17α-(Cyclopentylmethylcarbonyl)oxy-6α,9α-difluoro-11 β-hydroxy-16α-methyl-3-oxo- androsta-1 ,4-diene-17β-carboxylic acid fluoromethyl ester 17α-(Cyclohexylmethylcarbonyl)oxy-6α,9α-difluoro-11 β-hydroxy-16α-methyl-3-oxo- androsta-1 ,4-diene-17β-carboxylic acid fluoromethyl ester
9α-Chloro-17α-(cyclohexylmethylcarbonyl)oxy-6 -fluoro-11 β-hydroxy-16α-methyl-3- oxo-androsta-1,4-diene-17β-carboxylic acid methyl ester 9α-Chloro-17α-(cyclohexylmethylcarbonyl)oxy-6α-fluoro-11 β-hydroxy-16α-methyl-3- oxo-androsta-1,4-diene-17β-carboxylic acid fluoromethyl ester
17α-(Cyclopentylmethylcarbonyl)oxy-6α,9α-difluoro-11 β-hydroxy-16α-methyl-3-oxo- androsta-1,4-diene-17β-carboxylic acid chloromethyl ester
17α-(Cyclopentylmethylcarbonyl)oxy-6α,9α-difluoro-11 β-hydroxy-16α-methyl-3-oxo- androsta-1 ,4-diene-17β-carbothioic acid S-chloromethyl ester
9α-Chloro-17α-(cyclohexylmethylcarbonyl)oxy-6α-fluoro-11 β-hydroxy-16α-methyl-3- oxo-androsta-1 ,4-diene-17β-carboxylic acid chloromethyl ester
6α,9α-Difluoro-11 β-hydroxy-16α-methyl-3-oxo-17α-(4-oxo- cyclohexylmethylcarbonyl)oxy-androsta-1 ,4-diene-17β-carboxylic acid methyl ester 6α,9α-Difluoro-11 β-hydroxy-16α-methyl-3-oxo-17α-(c/s-4-terf-butyl- cyclohexylmethylcarbonyl)oxy-androsta-1 ,4-diene-17β-carbothioic acid S- fluoromethyl ester
6α,9α-Difluoro-11 β-hydroxy-16α-methyl-3-oxo-17α-(c/s-4-terf-butyl- cyclohexylmethylcarbonyl)oxy-androsta-1 ,4-diene-17β-carboxylic acid methyl ester 6α,9α-Difluoro-11 β-hydroxy-16α-methyl-3-oxo-17α-(^rans-4-te -butyl- cyclohexylmethylcarbonyl)oxy-androsta-1 ,4-diene-17β-carboxylic acid methyl ester
Particularly preferred examples are
17α-(Cyclohexylmethylcarbonyl)oxy-6α,9α-difluoro-11 β-hydroxy-16α-methyl-3-oxo- androsta-1 ,4-diene-17β-carbothioic acid S-fluoromethyl ester
17α-(Cyclopentylmethylcarbonyl)oxy-6α,9α-difluoro-11 β-hydroxy-16 -methyl-3-oxo- androsta-1,4-diene-17β-carboxylic acid fluoromethyl ester
17 -(Cyclohexylmethylcarbonyl)oxy-6α,9α-difluoro-11 β-hydroxy-16α-methyl-3-oxo- androsta-1 ,4-diene-17β-carboxylic acid fluoromethyl ester 9α-Chloro-17α-(cyclohexylmethylcarbonyl)oxy-6α-fluoro-11 β-hydroxy-16α-methyl-3- oxo-androsta-1 ,4-diene-17β-carboxylic acid methyl ester
9α-Chloro-17α-(cyclohexylmethylcarbonyl)oxy-6α-fluoro-11 β-hydroχy-16α-methyl-3- oxo-androsta-1 ,4-diene-17β-carboxylic acid fluoromethyl ester 17α-(Cyclopentylmethylcarbonyl)oxy-6 ,9α-difluoro-11 β-hydroxy-16α-methyl-3-oxo- androsta-1,4-diene-17β-carboxylic acid chloromethyl ester 6α,9α-Difluoro-11 β-hydroxy-16α-methyl-3-oxo-17α-(c/s-4-fe/Y-butyl- cyclohexylmethylcarbonyl)oxy-androsta-1 ,4-diene-17β-carboxylic acid methyl ester
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.
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 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 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 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 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.
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.
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 a 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.
Advantageously, the formulations of the invention may be buffered by the addition of suitable buffering agents.
Capsules and cartridges for use in an inhaler or insufflator, of for example gelatine, may be formulated containing a powder mix for inhalation of a 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 such as lactose.
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 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 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. The overall daily dose with an aerosol will be within the range 100μg-10mg preferably, 200μg-2000μg. 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.
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 compounds and pharmaceutical formulations according to the invention may be used in combination with or include one or more other therapeutic agents, for example selected from anti-inflammatory agents, anticholinergic agents (particularly an Mi, M2, M1/M2 or M3 receptor antagonist), other β2-adrenoreceptor agonists, antiinfective agents (e.g. antibiotics, antivirals), or antihistamines. The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with one or more other therapeutically active agents, for example selected from an anti-inflammatory agent (for example another corticosteroid or an NSAID), an anticholinergic agent, another β2-adrenoreceptor agonist, an antiinfective agent (e.g. an antibiotic or an antiviral), or an antihistamine. Preferred are combinations comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with a β2-adrenoreceptor agonist, and/or an anticholinergic, and/or a PDE-4 inhibitor. Preferred combinations are those comprising one or two other therapeutic agents.
It will be clear to a person skilled in the art that, where appropriate, the other therapeutic ingredient(s) may be used in the form of salts, (e.g. as alkali metal or amine salts or as acid addition salts), or prodrugs, or as esters (e.g. lower alkyl esters), or as solvates (e.g. hydrates) to optimise the activity and/or stability and/or physical characteristics (e.g. solubility) of the therapeutic ingredient. It will be clear also that where appropriate, the therapeutic ingredients may be used in optically pure form.
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. A combination comprising of compound of formula (I) or a physiologically acceptable salt or solvate thereof together with a β2-adrenoreceptor agonist is particularly preferred.
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, the sulphate salt or free base of salbutamol or the fumarate salt of formoterol. Long-acting β2-adrenoreceptor agonists are preferred, especially those having a therapeutic effect over a 24 hour period such as salmeterol or formoterol.
Preferred long acting β -adrenoreceptor agonists include those described in WO 0266 422A, WO 0227 0490, WO 0207 6933 and WO 0302 4439.
Especially preferred long-acting β2~adrenoreceptor agonists include compounds of formula(X):
Figure imgf000011_0001
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,
R11 is -XSO2NR16R17 wherein X is -(CH2)P- or C2-6 alkenylene;
R16 and R17 are independently selected from hydrogen, C*ι-6alkyl, C3- cycloalkyl, 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 R16 and R17are each optionally substituted by one or two groups selected from halo, C*|.6alkyl, C*ι-6haloalkyl,
C,-6alkoxy, hydroxy-substituted C^alkoxy, -CO2R18, -SO2NR18R19, -CONR 8R19, - NR18C(O)R19, or a 5-, 6- or 7-membered heterocylic ring;
R18and R19are independently selected from hydrogen, C1.ealkyl,
C3.6cycloalkyl, phenyl, and phenyl (Chalky!)-; and p is an integer of from 0 to 6, preferably from 0 to 4; R12 and R13 are independently selected from hydrogen, C*ι-6alkyl, C**-6alkoxy, halo, phenyl, and C*ι-6haloalkyl; and
R14 and R15 are independently selected from hydrogen and Chalky! with the proviso that the total number of carbon atoms in R14 and R15 is not more than 4.
Suitable anti-inflammatory agents include NSAIDs.
Suitable NSAIDs include sodium cromoglycate, nedocromil sodium, phosphodiesterase (PDE) inhibitors (e.g. theophylline, PDE4 inhibitors or mixed PDE3/PDE4 inhibitors), leukotriene antagonists, inhibitors of leukotriene synthesis, iNOS inhibitors, tryptase and elastase inhibitors, beta-2 integrin antagonists and adenosine receptor agonists or antagonists (e.g. adenosine 2a agonists), cytokine antagonists (e.g. chemokine antagonists) or inhibitors of cytokine synthesis. Suitable other β2-adrenoreceptor agonists include salmeterol (e.g. as the xinafoate), salbutamol (e.g. as the sulphate or the free base), formoterol (e.g. as the fumarate), fenoterol or terbutaline and salts thereof.
Of particular interest is use of the 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 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. For the purposes of this disclosure, the cAMP catalytic site which binds R and S rolipram with a low affinity is denominated the "low affinity" binding site (LPDE 4) and the other form of this catalytic site which binds rolipram with a high affinity is denominated the "high affinity" binding site (HPDE 4). This term "HPDE4" should not be confused with the term "hPDE4" which is used to denote human PDE4.
A method for determining IC50 ratios is set out in US Patent 5,998,428, which is incorporated herein in full by reference as though set out herein. See also PCT application WO 00/57599 for another description of said assay. The preferred PDE4 inhibitors of use in this invention will be those compounds which have a salutary therapeutic ratio, i.e., compounds which preferentially inhibit cAMP catalytic activity where the enzyme is in the form that binds rolipram with a low affinity, thereby reducing the side effects which apparently are linked to inhibiting the form which binds rolipram with a high affinity. Another way to state this is that the preferred compounds will have an IC50 ratio of about 0.1 or greater as regards the 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 1nM 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.
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 elbion (Hofgen, N. et al. 15th EFMC Int Symp Med Chem (Sept 6- 10, Edinburgh) 1998, Abst P.98; CAS reference No. 247584020-9); a 9- benzyladenine derivative nominated NCS-613 (INSERM); D-4418 from Chiroscience and Schering-Plough; a benzodiazepine PDE4 inhibitor identified as CI-1018 (PD- 168787) and attributed to Pfizer; a benzodioxole derivative disclosed by Kyowa Hakko in WO99/16766; K-34 from Kyowa Hakko; V-11294A from Napp (Landells, L.J. et aL Eur Resp J [Annu Cong Eur Resp Soc (Sept 19-23, Geneva) 1998] 1998, 12 (Suppl. 28): Abst P2393); roflumilast (CAS reference No 162401-32-3) and a pthalazinone (WO99/47505, the disclosure of which is hereby incorporated by reference) from Byk-Gulden; Pumafentrine, (-)-p-[(4aR*,10jbS*)-9-ethoxy- 1 ,2,3,4,4a,10b-hexahydro-8-methoxy-2-methylbenzo[c][1 ,6]naphthyridin-6-yl]-N,N- diisopropylbenzamide which is a mixed PDE3/PDE4 inhibitor which has been prepared and published on by Byk-Gulden, now Altana; arofylline under development by Almirall-Prodesfarma; VM554/UM565 from Vernalis; or T-440 (Tanabe Seiyaku; Fuji, K. et aL J Pharmacol Exp Ther,1998, 284(1): 162), and T2585.
Other possible PDE-4 and mixed PDE3/PDE4 inhibitors include those listed in WO01/13953, the disclosure of which is hereby incorporated by reference.
Suitable anticholinergic agents are those compounds that act as antagonists at the muscarinic receptor, in particular those compounds which are antagonists of the M** and M2 receptors. Exemplary compounds include the alkaloids of the belladonna plants as illustrated by the likes of atropine, scopolamine, homatropine, hyoscyamine; these compounds are normally administered as a salt, being tertiary amines. These drugs, particularly the salt forms, are readily available from a number of commercial sources or can be made or prepared from literature data via, to wit: Atropine - CAS-51-55-8 or CAS-51-48-1 (anhydrous form), atropine sulfate - CAS- 5908-99-6; atropine oxide - CAS-4438-22-6 or its HCI salt - CAS-4574-60-1 and methylatropine nitrate - CAS-52-88-0.
Homatropine - CAS-87-00-3, hydrobromide salt - CAS-51-56-9, methylbromide salt -
CAS-80-49-9.
Hyoscyamine (d, I) - CAS-101-31-5, hydrobromide salt - CAS-306-03-6 and sulfate salt - CAS-6835-16-1. Scopolamine - CAS-51-34-3, hydrobromide salt - CAS-6533-68-2, methylbromide salt- CAS-155-41 -9.
Preferred anticholinergics include ipratropium (e.g. as the bromide), sold under the name Atrovent, oxitropium (e.g. as the bromide) and tiotropium (e.g. as the bromide) (CAS-139404-48-1 ). Also of interest are: methantheline (CAS-53-46-3), propantheline bromide (CAS- 50-34-9), anisotropine methyl bromide or Valpin 50 (CAS- 80-50-2), clidinium bromide (Quarzan, CAS-3485-62-9), copyrrolate (Robinul), isopropamide iodide (CAS-71-81-8), mepenzolate bromide (U.S. patent 2,918,408), tridihexethyl chloride (Pathilone, CAS-4310-35-4), and hexocyclium methylsulfate (Tral, CAS-115-63-9). See also cyclopentolate hydrochloride (CAS-5870-29-1 ), tropicamide (CAS-1508-75-4), trihexyphenidyl hydrochloride (CAS-144-11-6), pirenzepine (CAS-29868-97-1 ), telenzepine (CAS-80880-90-9), AF-DX 116, or methoctramine, and the compounds disclosed in WO01/04118, the disclosure of which is hereby incorporated by reference.
Suitable antihistamines (also referred to as H**-receptor antagonists) include any one or more of the numerous antagonists known which inhibit H*ι -receptors, and are safe for human use. All are reversible, competitive inhibitors of the interaction of histamine with H**-receptors. The majority of these inhibitors, mostly first generation antagonists, have a core structure, which can be represented by the following formula:
Figure imgf000015_0001
This generalized structure represents three types of antihistamines generally available: ethanolamines, ethylenediamines, and alkylamines. In addition, other first generation antihistamines include those which can be characterized as based on piperizine and phenothiazines. Second generation antagonists, which are non- sedating, have a similar structure-activity relationship in that they retain the core ethylene group (the alkylamines) or mimic the tertiary amine group with piperizine or piperidine. Exemplary antagonists are as follows:
Ethanolamines: carbinoxamine maleate, clemastine fumarate, diphenylhydramine hydrochloride, and dimenhydrinate.
Ethylenediamines: pyrilamine amleate, tripelennamine HCI, and tripelennamine citrate. Alkylamines: chlropheniramine and its salts such as the maleate salt, and acrivastine.
Piperazines: hydroxyzine HCI, hydroxyzine pamoate, cyclizine HCI, cyclizine lactate, meclizine HCI, and cetirizine HCI. Piperidines: Astemizole, levocabastine HCI, loratadine or its descarboethoxy analogue, and terfenadine and fexofenadine hydrochloride or another pharmaceutically acceptable salt.
Azelastine hydrochloride is yet another H-* receptor antagonist which may be used in combination with a PDE4 inhibitor.
Examples of preferred anti-histamines include methapyrilene and loratadine.
The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with a PDE4 inhibitor.
The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with a β2-adrenorecptor agonist.
The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with an anticholinergic.
The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with an antihistamine.
The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with a PDE4 inhibitor and a β2- adrenoreceptor agonist.
The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with an anticholinergic and a PDE-4 inhibitor.
The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a 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 solvates thereof may be prepared by the methodology described hereinafter, constituting a further aspect of this invention.
The compounds of formula (I) 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 reaction of a carboxylic acid (X=O) or carbothioicacid (X=S) of formula (II)
Figure imgf000017_0001
wherein R2, R3, R , R5, X, n and are as defined above.
In this process the compound of formula (II) may be reacted with a compound of formula R L wherein L represents a leaving group such as halogen atom or a tosyl or mesyl group or the like, for example, an appropriate alkyl or haloalkyl halide under standard conditions. For example the reaction may be performed in an inert polar organic solvent e.g. N,N-dimethylformamide in the presence of a base e.g. potassium carbonate, sodium carbonate, sodium bicarbonate.
Alternatively, compounds of formula (I) may be prepared by reaction of a carboxylic acid (X=O) or carbothioicacid (X=S) of formula (II) with an appropriate polymer supported O-alkylisourea under microwave conditions as described by S. Crosignani et a , Organic Letters, (2003), 5, 853-856.
Compounds of formula (II) may conveniently be employed as salts when such salts may be prepared in crystalline form.
When R-i represents fluoromethyl, the preferred haloalkyl halide reagent is bromofluoromethane.
Compounds of formula R---L are either known or may be prepared by known methods.
Compounds of formula (II) may be prepared from the corresponding 17α-hydroxyl derivative of formula (III):
Figure imgf000018_0001
wherein X, 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. The step typically comprises the addition of a reagent suitable for performing the esterification to the ester such as a compound of formula R2(CH2)nCOOH or an activated derivative thereof eg an activated ester, anhydride or halide thereof especially an acid halide eg the acid chloride in the presence of a mild base e.g. triethylamine. Generally the acid chloride would be employed in at least 2 times molar quantity relative to the compound of formula (III). The second mole of acid chloride tends to react with the carboxylic acid moiety in the compound of formula (III) and would need to be removed by reaction with an amine such as diethylamine or 1-methylpiperazine. Compounds of formula (III) are either known or may be prepared in accordance with procedures described by G. H. Phillipps et al., (1994) Journal of Medicinal Chemistry, 37, 3717-3729.
Compounds of formula (II) are new and form an aspect of the invention.
Compounds of formula (III) may also be prepared by a process comprising the following steps:
Figure imgf000019_0001
Step (a) comprises oxidation of a solution containing the compound of formula (IV) to give the carboxylic acid (III, X = O);
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 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 the carboxylic acid (III, X = O) into the carbothioic acid (III, X = S) eg. using hydrogen sulphide gas together with a suitable coupling agent eg. carbonyldiimidazole (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.
Compounds of formula (I) and/or solvates thereof demonstrate good anti- inflammatory properties, with predictable pharmacokinetic and pharmacodynamic behaviour. They also have an attractive side-effect profile, demonstrated, for example, by increased 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. The following non-limiting Examples illustrate the invention:
EXAMPLES General Chromatographic purification was performed using pre-packed Bond Elut silica gel cartridges available commercially from Varian or by flash chromatography on prepacked Biotage silica columns. These cartridges were pre-conditioned with dichloromethane prior to use. 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 : 17α-(Cvclohexylmethylcarbonyl)oxy-6α,9α-difluoro-11 β-hydroxy-16α- methyl-3-oxo-androsta-1 ,4-diene-17β-carbothioic acid To a stirred and cooled (ice) solution of 6 ,9α-difluoro-11 β,17α-dihydroxy-16α- methyl-3-oxo-androsta-1 ,4-diene-17β-carbothioic acid (G. H. Phillipps et al., (1994) Journal of Medicinal Chemistry, 37, 3717-3729) (500mg, 1.21mmol) and triethylamine (245mg, 2.42mmol) in anhydrous dichloromethane (20ml) was added a solution of cyclohexymethylcarbonyl chloride (2.91 mmol) in anhydrous dichloromethane (5ml). The mixture was stirred under nitrogen for 2h and then washed successively with aqueous sodium bicarbonate (75ml), 1M hydrochloric acid (75ml), water (75ml) and dried through a hydrophobic frit and evaporated. The residual solid was dissolved in dioxane (25ml), 1-methylpiperazine (485mg, 4.84mmol) was added and the mixture stirred at room temperature for 2h. The mixture was then added slowly to a vigorously stirred solution of 2M hydrochloric acid (50ml) and ice (50ml). The resulting precipitate was filtered off and dried to yield the title compound as a white solid (475mg): LCMS retention time 4.41 min.
Intermediate 2: 17α-(Cvclohexylmethylcarbonyl)oxy-9 -fluoro-11 β-hydroxy-16β- methyl-3-oxo-androsta-1 ,4-diene-17β-carbothioic acid Prepared from 11 β,17α-dihydroxy-9α-fluoro-16β-methyl-3-oxo-androsta-1,4-diene- 17β-carbothioic acid (G. H. Phillipps et aL, (1994) Journal of Medicinal Chemistry, 37, 3717-3729) using methods similar to that described for Intermediate 1. LCMS retention time 4.21 min.
Intermediate 3: 17α-(2-Cvclohexylethylcarbonyl)oxy-6α,9α-difluoro-11 β-hydroxy-16α- methyl-3-oxo-androsta-1 ,4-diene-17β-carbothioic acid
Prepared from using methods similar to that described for Intermediate 1. LCMS retention time 4.47 min.
Intermediate 4: 17α-(3-Cvclohexylpropylcarbonyl)oxy-6α,9α-difluoro-11 β-hydroxy- 16 -methyl-3-oxo-androsta-1 ,4-diene-17β-carbothioic acid Prepared using methods similar to that described for Intermediate 1. LCMS retention time 4.77 min.
Intermediate 5: 17α-(4-Cvclohexylbutylcarbonyl)oxy-6o.,9α-difluoro-11 β-hydroxy-16α- methyl-3-oxo-androsta-1 ,4-diene-17β-carbothioic acid Prepared using methods similar to that described for Intermediate 1. LCMS retention time 4.92 min.
Intermediate 6: 17α-(Cvclopentylmethylcarbonyl)oxy-6α,9α-difluoro-11 β-hvdroxy- 16α-methyl-3-oxo-androsta-1 ,4-diene-17β-carbothioic acid Prepared using methods similar to that described for Intermediate 1. LCMS retention time 4.16 min.
Intermediate 7: 17α-(2-Cvclopentylethylcarbonyl)oxy-6 ,9α-difluoro-11 β-hvdroxy- 16α-methyl-3-oxo-androsta-1.4-diene-17β-carbothioic acid Prepared using methods similar to that described for Intermediate 1. LCMS retention time 4.34 min.
Intermediate 8: 17α-(Cvclobutylmethylcarbonyl)oxy-6α,9α-difluoro-11 β-hydroxy-16α- methyl-3-oxo-androsta-1 ,4-diene-17β-carbothioic acid Prepared using methods similar to that described for Intermediate 1. LCMS retention time 4.09 min. Intermediate 9: 6α,9α-Difluoro-11 β-hvdroxy-16α-methyl-3-oxo-17α-r(2.2.3,3- tetramethylcvclopropyl)methylcarbonvHoxy-androsta-1 ,4-diene-17β-carbothioic acid Prepared using methods similar to that described for Intermediate 1. LCMS retention time 4.31 min.
Intermediate 10: 17α-r(2.2,-Dichlorocvclopropyl)methylcarbonvnoxy-6α,9α-difluoro- 11 β-hvdroxy-16α-methyl-3-oxo-androsta-1 ,4-diene-17β-carbothioic acid Prepared using methods similar to that described for Intermediate 1. LCMS retention time 4.06 min.
Intermediate 11 : 17α-r(2,2,-Dichloro-1-methylcvclopropyl)methylcarbonyl1oxy-6α,9α- difluoro-11 β-hydroxy-16α-methyl-3-oxo-androsta-1 ,4-diene-17β-carbothioic acid Prepared using methods similar to that described for Intermediate 1. LCMS retention time 4.18 min.
Intermediate 12: 17α-(Cvclopentylmethylcarbonyl)oxy-6α,9α-difluoro-11 β-hydroxy- 16α-methyl-3-oxo-androsta-1 ,4-diene-17β-carboxylic acid Prepared using methods similar to that described for Intermediate 1. LCMS retention time 3.59 min.
Intermediate 13: 17 -(Cvclohexylmethylcarbonyl)oxy-6α.9α-difluoro-11 β-hvdroxy- 16α-methyl-3-oxo-androsta-1 ,4-diene-17β-carboxylic acid Prepared using methods similar to that described for Intermediate 1. LCMS retention time 3.73 min.
Intermediate 14: 9 -Chloro-l7α-(cyclohexylmethylcarbonyl.oxy-6α-fluoro-11 β- hvdroχy-16α-methyl-3-oxo-androsta-1 ,4-diene-17β-carboxylic acid Prepared using methods similar to that described for Intermediate 1. LCMS retention time 3.06 min.
Intermediate 15: 6 ,9α-Difluoro-11 β-hvdroxy-16α-methyl-3-oxo-17α-(4-oxo- cvclohexylmethylcarbonvOoχy-androsta-1 ,4-diene-17β-carboxylic acid
Prepared using methods similar to that described for Intermediate 1. LCMS retention time 3.20 min. Intermediate 16: 6α,9 -Difluoro-11β-hvdroxy-16α-methyl-3-oxo-17α-(c/s-4-fe/t-butyl- cyclohexylmethylcarbonyl)oxy-androsta-1 ,4-diene-17β-carbothioic acid
Prepared using methods similar to that described for Intermediate 1. LCMS retention time 4.73 min.
Intermediate 17: 6α,9 -Difluoro-11 β-hvdroxy-16α-methyl-3-oxo-17α-(c/s-4-ferf-butyl- cyclohexylmethylcarbonyl)oxy-androsta-1 ,4-diene-17β-carboxylic acid
Prepared using methods similar to that described for Intermediate 1. LCMS retention time 4.19 min.
Intermediate 18: 6α,9 -Difluoro-11 β-hydroxy-16α-methyl-3-oxo-17a-(trans-4-tert- butyl-cycloheχylmethylcarbonyl)oxy-androsta-1 ,4-diene-17β-carboxylic acid
Prepared using methods similar to that described for Intermediate 1. LCMS retention time 4.26 min.
Examples
Example 1 : 17α-(Cvclohexylmethylcarbonyl)oxy-6 ,9 -difluoro-11 β-hydroxy-16α- methyl-3-oxo-androsta-1 ,4-diene-17β-carbothioic acid S-fluoromethyl ester Sodium bicarbonate (82mg, 0.98mmol) was added to a stirred solution of Intermediate 1 (475mg, 0.89mmol) in anhydrous DMF (5ml) and the mixture cooled to -20 °C. Bromofluoromethane (272mg, 2.4mmol) was then added and the mixture stirred at -20 °C for 2h. Diethylamine (83mg, 1.14mmol) was added and the mixture stirred at -20 °C for 15min. The mixture was added to 2M hydrochloric acid (17ml), diluted with water and the resulting precipitate was filtered off and purified on a Bond Elut cartridge eluting firstly with dichloromethane and then 30% ethyl acetate in cyclohexane to give the title compound as an off white solid (264mg): LCMS retention time 3.91 min, MH+ 569. Example 2: 17α-(Cvclohexylmethylcarbonyl)oxy-9α-fluoro-1 1 β-hvdroχy-16β-methyl- 3-oxo-androsta-1 ,4-diene-17β-carbothioic acid S-fluoromethyl ester
Example 2 was prepared from Intermediate 2 using a method similar to that described for Example 1. LCMS retention time 3.97 min, MH+ 551.
Example 3: 17α-(2-Cvclohexylethylcarbonyl)oxy-6α,9α-difluoro-11 β-hydroxy-16α- methyl-3-oxo-androsta-1 ,4-diene-17β-carbothioic acid S-fluoromethyl ester
Example 3 was prepared from Intermediate 3 using a method similar to that described for Example 1. LCMS retention time 4.02 min, MH+583.
Example 4: 17α-(2-Cvclohexylethylcarbonyl)oxy-6α,9α-difluoro-11 -hydroxy-16α- methyl-3-oxo-androsta-1 ,4-diene-17β-carbothioic acid S-chloromethyl ester
Example 4 was iolated as a minor product in the preparation of Example 3. LCMS retention time 4.10 min, MH+ 599, 601.
Example 5: 17α-(3-Cvclohexylpropylcarbonyl)oxy-6α,9α-difluoro-11 β-hvdroxy-16α- methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid S-fluoromethyl ester
Example 5 was prepared from Intermediate 4 using a method similar to that described for Example 1. LCMS retention time 4.13 min, MH+597.
Example 6: 17o.-(4-Cvclohexylbutylcarbonyl)oχy-6α,9α-difluoro-11 β-hydroxy-16α- methyl-3-oxo-androsta-1 ,4-diene-17β-carbothioic acid S-fluoromethyl ester
Example 6 was prepared from Intermediate 5 using a method similar to that described for Example 1. LCMS retention time 4.24 min, MH+ 611.
Example 7: 17α-(Cvclopentylmethylcarbonvπoxy-6α,9α-difluoro-11 β-hvdroxy-16α- methyl-3-oxo-androsta-1 ,4-diene-17β-carbothioic acid S-fluoromethyl ester
Example 7 was prepared from Intermediate 6 using a method similar to that described for Example 1. LCMS retention time 3.95 min, MH+ 555. Example 8: 17α-(2-Cvclopentylethylcarbonyl,oxy-6α,9α-difluoro-11 β-hvdroxy-16α- methyl-3-oxo-androsta-1 ,4-diene-17β-carbothioic acid S-fluoromethyl ester
Example 8 was prepared from Intermediate 7 using a method similar to that described for Example 1. LCMS retention time 3.97 min, MH+ 569.
Example 9: 17α-(Cvclobutylmethylcarbonyl)oxy-6α,9α-difluoro-11 β-hvdroxy-16α- methyl-3-oxo-androsta-1 ,4-diene-17β-carbothioic acid S-fluoromethyl ester
Example 9 was prepared from Intermediate 8 using a method similar to that described for Example 1. LCMS retention time 3.72 min, MH+ 541.
Example 10: 17α-(Cvclobutylmethylcarbonyl)oxy-6α,9 -difluoro-11 β-hydroxy-16α- methyl-3-oxo-androsta-1 ,4-diene-17β-carbothioic acid S-chloromethyl ester
Example 10 was iolated as a minor product in the preparation of Example 9. LCMS retention time 3.80 min, MH+ 557, 559.
Example 11 : 6 ,9α-Difluoro-11 β-hvdroxy-16α-methyl-3-oxo-17α-r(2,2,3,3- tetramethylcvclopropyl)methylcarbonylloxy-androsta-1 ,4-diene-17β-carbothioic acid S-fluoromethyl ester
Example 11 was prepared from Intermediate 9 using a method similar to that described for Example 1. LCMS retention time 3.96 min, MH+ 583.
Example 12: 17α-r(2.2-Dichlorocvclopropyl .methylcarbonylloxy-ea.ga-difluoro-l 1 β- hvdroxy-16a-methyl-3-oxo-androsta-1 ,4-diene-17β-carbothioic acid S-fluoromethyl ester
Example 12 was prepared from Intermediate 10 using a method similar to that described for Example 1. The resulting diasteroisomers were separated by preparative HPLC on a Chiralcel ODH column (25cm x 1 inch) eluting with 15% ethanol in heptane (15ml/min flow rate) to give isomer A showing retention time 11.25 min and isomer B showing retention time 13.75 min. Both isomers showed MH+ 595, 597, 599 in the mass spectrum. Example 13: 17 -f(2,2-Dichloro-1 -methylcvclopropyl)methylcarbonylloxy-6α,9α- difluoro-11 β-hydroxy-16α-methyl-3-oxo-androsta-1 ,4-diene-17β-carbothioic acid S- fluoromethyl ester
Example 13 was prepared from Intermediate 11 using a method similar to that described for Example 1. The resulting diasteroisomers were separated by preparative HPLC on a Chiralcel ODH column (20cm x 2inch) eluting with 20% ethanol in heptane (50ml/min flow rate) to give isomer A showing retention time 7.5 min and isomer B showing retention time 9 min. Both isomers showed MH+609, 611 , 613 in the mass spectrum.
Example 14: 17α-(Cvclopentylmethylcarbonyl)oxy-6α,9α-difluoro-11β-hydroxy-16α- methyl-3-oxo-androsta-1.4-diene-17β-carboxylic acid fluoromethyl ester
Example 14 was prepared from Intermediate 12 using a method similar to that described for Example 1. LCMS retention time 3.80 min, MH+ 539.
Example 15: 17α-(Cvclohexylmethylcarbonyl)oxy-6α,9 -difluoro-11 β-hydroxy-16α- methyl-3-oxo-androsta-1 ,4-diene-17β-carboxylic acid fluoromethyl ester
Example 15 was prepared from Intermediate 13 using a method similar to that described for Example 1. LCMS retention time 3.90 min, MH+ 553.
Example 16: 9α-Chloro-17α-(cvclohexylmethylcarbonyl)oxy-6α-fluoro-11 β-hvdroxy- 16α-methyl-3-oxo-androsta-1 ,4-diene-17β-carboxylic acid methyl ester
Sodium carbonate (118mg, 1.12mmol) and methyl iodide (185mg, 1.3mmol) were added to a solution of Intermediate 14 (200mg, 0.37mmol) in anhydrous DMF (3ml) and the mixture stirred under nitrogen for 3h. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed twice with water and evaporated. The residue was crystallised fro methanol to yield the title compound as a white solid (82mg): LCMS retention time 3.91 min, MH+ 551 ,553.
Example 17: 9α-Chloro-17α-(cvclohexylmethylcarbonyl)oχy-6α-fluoro-11 β-hydroχy- 16α-methyl-3-oxo-androsta-1 ,4-diene-17β-carboxylic acid fluoromethyl ester Example 17 was prepared from Intermediate 14 using a method similar to that described for Example 1. LCMS retention time 3.95 min, MH÷ 569,571.
Example 18: 17α-(Cvclopentylmethylcarbonv0oxy-6α,9α-difluoro-11β-hydroxy-16α- methyl-3-oxo-androsta-1 ,4-diene-17β-carboxylic acid chloromethyl ester
Sodium carbonate (314mg, 2.96mmol) was added to a stirred solution of Intermediate 12 (150mg, 0.296mmol) in anhydrous DMF (5ml) and the mixture stirred for 30min and then cooled in ice. Chloroiodomethane (0.058ml, O.δmmol) was then added and the mixture stirred at room temperature for 16h. More chloroiodomethane (0.02ml) was then added and stirring continued for a further 16h when diethylamine (0.039ml, 0.38mmol) was added. The mixture was added to 2M hydrochloric acid (10ml), diluted with water (10ml) and extracted with dichloromethane (10ml). The organic extract was washed successively with aqueous sodium bicarbonate and brine (10ml of each) and dried and evaporated. The residue was purified on a Bond Elut cartridge eluting firstly cyclohexane:ethyl acetate 9:1 and finally ethyl acetate:cyclohexane 9:1 as eluant to give the title compound (130mg): LCMS retention time 3.80 min, MH+ 555,557
Example 19: 17α-(Cvclopentylmethylcarbonyl)oχy-6α,9α-difluoro-11 β-hydroxy-16α- methyl-3-oxo-androsta-1 ,4-diene-17β-carbothioic acid S-chloromethyl ester
Example 19 was prepared from Intermediate 6 using a method similar to that described for Example 18: LCMS retention time 3.87 min, MH+ 571 ,573.
Example 20: 9 -Chloro-17α-(cvclohexylmethylcarbonyl)oxy-6α-fluoro-11 β-hydroxy- 16α-methyl-3-oxo-androsta-1 ,4-diene-17β-carboxylic acid chloromethyl ester
Example 20 was prepared from Intermediate 14 using a method similar to that described for Example 18: LCMS retention time 3.99 min, MH+ 585,587.
Example 21 : 6α,9α-Difluoro-11 β-hvdroxy-16α-methyl-3-oxo-17α-(4-oxo- cyclohexylmethylcarbonyl.oxy-androsta-1 ,4-diene-17β-carboxylic acid methyl ester Example 21 was prepared from Intermediate 15 using a method similar to that described for Example 16: LCMS retention time 3.33 min, MH+549.
Example 22: 6α,9α-Difluoro-11 β-hvdroxy-16α-methyl-3-oxo-17α-(c/s-4-fe/f-butyl- cycloheχylmethylcarbonyl)oxy-androsta-1 ,4-diene-17β-carbothioic acid S- fluoromethyl ester
Example 22 was prepared from Intermediate 16 using a method similar to that described for Example 1 : LCMS retention time 4.21 min, MH+625.
Example 23: 6α,9α-Difluoro-11 β-hvdroxy-16α-methyl-3-oxo-17α-(c/s-4-ferf-butyl- cvcloheχylmethylcarbonyl)oxy-androsta-1.4-diene-17β-carboxylic acid methyl ester
A mixture of polystyrene-carbodiimide (Argonaut, 2g) was heated in a microwave at 135 °C for 60min at 150 watts and then cooled. An aliquot (0.4g) of the resin was transferred to a glass vial and treated with a solution of Intermediate 17 (0.126mmol) in tetrahydrofuran (2ml) and the mixture heated in a microwave to 135 °C for 15min at 150 watts. The mixture was cooled, the resin was removed by filtration, the filtrate was evaporated and the residue purified by mass directed HPLC on a Supelco LCABZ++ column (10cm x 2cm) using a gradient of 0.1% aqueous formic acid (Solvent A) and 95:5:0.05 acetontrile:water:formic acid (Solvent B) to give the title compound (7.2mg) : LCMS retention time 4.16 min, MH+591.
Example 24: 6α.9α-Difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-(fra/7s-4-tetf-butyl- cvclohexylmethylcarbonvDoxy-androsta-1 ,4-diene-17β-carboxylic acid methyl ester
Example 24 was prepared from Intermediate 18 using a method similar to that described for Example 23: LCMS retention time 4.20 min, MH+ 591.
Pharmacological Activity
Pharmacological activity may be assessed in functional in vitro assays of glucocorticoid agonist activity.
The functional assay based on that described by K. P. Ray et aL, Biochem J. (1997), 328, 707-715 provides a measure of transrepressive activity of a glucocorticoid agonist. 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) are treated with test compounds at appropriate doses for 1 hour at 37°C. The cells are 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 are constructed from which EC5o values may be estimated.
The EC50 values for compounds of Examples 1 to 24 were <10nM.
The functional assay based on that described by R.J.H. Austin et aL, Eur Resp J. (2002) 20,1386-1392 measures the ability of compounds to directly transactivate gene expression. A549 cells stably transfected with a reporter gene containing the glucocorticoid responsive region of the mouse mammary tumour virus long terminal repeat (MMTV-LTR) coupled to renilla luciferase were treated with test compounds at appropriate doses for 6 hour at 37°C. The amount of luciferase activity present within the cells is then determined by measuring the light emitted following incubation with a suitable substrate. Dose response curves were constructed from which EC50 values were estimated and from which maximal responses are calculated relative to Dexamethasone (100%).
Compound of Examples 1 to 6, 8, 11 , 12A, 13B, 15 to 18, 20, 22 to 24 showed maximal responses of <20% in this assay.
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):
Figure imgf000032_0001
wherein
Ri represents C*-6 alkyl or C*,-6 haloalkyl;
X represents O or S;
R2 represents C3-8 cycloalkyl which optionally may be substituted by one or more groups selected from Chalky!, oxo, or halogen n is an integer from 1-6.
R3 represents 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, halogen or a methyl group; and represents a single or a double bond; and solvates thereof.
2. A compound as claimed in claim 1 wherein R-* represents a C**-6 alkyl group substituted by 1 , 2 or 3 halogen atoms.
3. A compound as claimed in claim 2 wherein the C*j-6 alkyl group is substituted by 1 halogen atom.
4. A compound as claimed in claim 3 wherein Ri represents fluoromethyl, chloromethyl, bromomethyl or 2'-fluoroethyl.
5. A compound as claimed in claim 4 wherein R-- represent fluoromethyl.
6. A compound as claimed in claim 1 wherein Ri represents methyl.
7. A compound as claimed in any one of claims 1 to 6 where R2 represents a C3.8 cycloalkyl group.
8. A compound as claimed in claim 7 wherein R2 represents cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl and substituted derivatives such as tetramethylcyclopropyl (eg 2,2,3,3- tetramethylcyclopropyl), 2,2-dichlorocyclopropyl, 2,2-dichloro-1-methylcyclopropyL 4-fetιf-butylcyclohexyl and 4-oxo-cyclohexyl.
9. A compound as claimed in claim 7 or claim 8 wherein R2 represents a cyclohexyl, cyclopentyl or a c/s-4-terf-butylcyclohexyl group.
10. A compound as claimed in any one of claims 1 to 9 wherein n represents 1
11. A compound as claimed in any one of claims 1 to 10 wherein R3 represents methyl.
12. A compound as claimed in claim 1 wherein R3 represents methyl in the α configuration.
13. A compound as claimed in any one of the preceding claims wherein R4 and R5 which can be the same or different each represents hydrogen, fluorine or chlorine.
14. A compound as claimed in claim 13 wherein R and R5 are both fluorine.
15. A compound as claimed in any one of the preceding claims wherein represents a double bond.
16. A compound as claimed in any one of the preceding claims wherein the compound is 17α-(Cyclohexylmethylcarbonyl)oxy-6 ,9α-difluoro-11 β-hydroxy-16α-methyl-3-oxo- androsta-1 ,4-diene-17β-carbothioic acid S-fluoromethyl ester 17 -(Cyclohexylmethylcarbonyl)oxy-9α-fluoro-11 β-hydroxy-16β-methyl-3-oxo- androsta-1,4-diene-17β-carbothioic acid S-fluoromethyl ester 17α-(2-Cyclohexylethylcarbonyl)oxy-6α,9α-difluoro-11 β-hydroxy-16α-methyl-3-oxo- androsta-1 ,4-diene-17β-carbothioic acid S-fluoromethyl ester 17α-(2-Cyclohexylethylcarbonyl)oxy-6α,9α-difluoro-11 β-hydroxy-16α-methyl-3-oxo- androsta-1 ,4-diene-17β-carbothioic acid S-chloromethyl ester
17α-(3-Cyclohexylpropylcarbonyl)oxy-6α,9α-difluoro-11 β-hydroxy-16α-methyl-3-oxo- androsta-1 ,4-diene-17β-carbothioic acid S-fluoromethyl ester 17α-(4-Cyclohexylbutylcarbonyl)oxy-6α,9α-difluoro-11 β-hydroxy-16α-methyl-3-oxo- androsta-1 ,4-diene-17β-carbothioic acid S-fluoromethyl ester
17α-(Cyclopentylmethylcarbonyl)oxy-6α,9α-difluoro-11 β-hydroxy-16 -methyl-3-oxo- androsta-1 ,4-diene-17β-carbothioic acid S-fluoromethyl ester
17α-(2-Cyclopentylethylcarbonyl)oxy-6α,9α-difluoro-11 β-hydroxy-16α-methyl-3-oxo- androsta-1 ,4-diene-17β-carbothioic acid S-fluoromethyl ester
17α-(Cyclobutylmethylcarbonyl)oxy-6α,9α-difluoro-11 β-hydroxy-16α-methyl-3-oxo- androsta-1 ,4-diene-17β-carbothioic acid S-fluoromethyl ester
17α-(Cyclobutylmethylcarbonyl)oxy-6α,9α-difluoro-11 β-hydroxy-16α-methyl-3-oxo- androsta-1 ,4-diene-17β-carbothioic acid S-chloromethyl ester 17α-[(2,2,3,3-Tetramethylcyclopropyl)methylcarbonyljoxy-6α,9α-difluoro-11 β- hydroxy-16 -methyl-3-oxo-androsta-1 ,4-diene-17β-carbothioic acid S-fluoromethyl ester
17α-[(2,2-Dichlorocyclopropyl)methylcarbonyl]oxy-6α,9α-difluoro-11 β-hydroxy-16α- methyl-3-oxo-androsta-1 ,4-diene-17β-carbothioic acid S-fluoromethyl ester 17α-[(2,2-Dichloro-1 -methylcyclopropyl)methylcarbonyl]oxy-6α,9α-difluoro-11 β- hydroxy-16α-methyl-3-oxo-androsta-1 ,4-diene-17β-carbothioic acid S-fluoromethyl ester
17α-(Cyclopentylmethylcarbonyl)oxy-6α,9α-difluoro-11 β-hydroxy-16α-methyl-3-oxo- androsta-1 ,4-diene-17β-carboxylic acid fluoromethyl ester 17α-(Cyclohexylmethylcarbonyl)oxy-6α,9α-difluoro-11 β-hydroxy-16α-methyl-3-oxo- androsta-1 ,4-diene-17β-carboxylic acid fluoromethyl ester
9α-Chloro-17α-(cyclohexylmethylcarbonyl)oxy-6α-fluoro-11 β-hydroxy-16α-methyl-3- oxo-androsta-1 ,4-diene-17β-carboxylic acid methyl ester
9α-Chloro-17α-(cyclohexylmethylcarbonyl)oxy-6α-fluoro-11 β-hydroxy-16α-methyl-3- oxo-androsta-1 ,4-diene-17β-carboxylic acid fluoromethyl ester
17α-(Cyclopentylmethylcarbonyl)oxy-6α,9α-difluoro-11 β-hydroxy-16α-methyl-3-oxo- androsta-1 ,4-diene-17β-carboxylic acid chloromethyl ester
17α-(Cyclopentylmethylcarbonyl)oxy-6α,9α-difluoro-11 β-hydroxy-16α-methyl-3-oxo- androsta-1 ,4-diene-17β-carbothioic acid S-chloromethyl ester 9α-Chloro-17α-(cyclohexylmethylcarbonyl)oxy-6α-fluoro-11 β-hydroxy-16α-methyl-3- oxo-androsta-1 ,4-diene-17β-carboxylic acid chloromethyl ester 6α,9α-Difluoro-11 β-hydroxy-16α-methyl-3-oxo-17α-(4-oxo- cyclohexylmethylcarbonyl)oxy-androsta-1 ,4-diene-17β-carboxylic acid methyl ester 6α,9α-Difluoro-11 β-hydroxy-16α-methyl-3-oxo-17α-(c/s-4-ferf-butyl- cyclohexylmethylcarbony[)oxy-androsta-1 ,4-diene-17β-carbothioic acid S- fluoromethyl ester
6α,9α-Difluoro-11 β-hydroxy-16α-methyl-3-oxo-17α-(c/s-4-ferf-butyl- cyclohexylmethylcarbonyl)oxy-androsta-1 ,4-diene-17β-carboxylic acid methyl ester, or
6α,9α-Difluoro-11 β-hydroxy-16α-methyl-3-oxo-17α-(/ra/.s-4-ferf-butyl- cyclohexylmethylcarbonyl)oxy-androsta-1 ,4-diene-17β-carboxylic acid methyl ester
17. A compound as claimed in claim 16 wherein the compound is 17α-(Cyclohexylmethylcarbonyl)oxy-6α,9α-difluoro-11 β-hydroxy-16α-methyl-3-oxo- androsta-1 ,4-diene-17β-carbothioic acid S-fluoromethyl ester
17α-(Cyclopentylmethylcarbonyl)oxy-6α,9 -difluoro-11 β-hydroxy-16 -methyl-3-oxo- androsta-1 ,4-diene-17β-carboxylic acid fluoromethyl ester
17α-(Cyclohexylmethylcarbonyl)oxy-6α,9α-difluoro-11 β-hydroxy-16α-methyl-3-oxo- androsta-1 ,4-diene-17β-carboxylic acid fluoromethyl ester
9α-Chloro-17α-(cyclohexylmethylcarbonyl)oxy-6α-fluoro-11 β-hydroxy-16α-methyl-3- oxo-androsta-1 ,4-diene-17β-carboxylic acid methyl ester
9α-Chloro-17α-(cyclohexylmethylcarbonyl)oxy-6α-fluoro-11 β-hydroxy-16α-methyl-3- oxo-androsta-1 ,4-diene-17β-carboxylic acid fluoromethyl ester 17α-(Cyclopentylmethylcarbonyl)oxy-6α,9α-difluoro-11 β-hydroxy-16α-methyl-3-oxo- androsta-1 ,4-diene-17β-carboxylic acid chloromethyl ester, or
6α,9α-Difluoro-11 β-hydroxy-16α-methyl-3-oxo-17α-(c/s-4-ferf-butyl- cyclohexylmethylcarbonyl)oxy-androsta-1 ,4-diene-17β-carboxylic acid methyl ester.
18. A compound of formula (I) as defined in any one of claims 1 to 17 or a physiologically acceptable solvate thereof for use in veterinary or human medicine.
19. Use of a compound of formula (I) as defined in any one of claims 1 to 17 or a physiologically acceptable solvate thereof for the manufacture of a medicament for the treatment of inflammatory and/or allergic conditions.
20. A pharmaceutical composition comprising a compound of formula (I) as defined in any one of claim 1 to 17 or a physiologically acceptable solvate thereof together, if desirable, in admixture with one or more physiologically acceptable diluents or carriers.
21. A pharmaceutical aerosol formulation comprising a compound of formula (I) as defined in any one of claims 1 to 17 or a physiologically acceptable solvate thereof, and a fluorocarbon or hydrogen-containing chlorofluoro carbon as propellant, optionally in combination with a surfactant and/or a cosolvent.
22. A pharmaceutical composition according to claim 20 or 21 which further comprises another therapeutically active agent.
23. A pharmaceutical composition according to claim 22 in which said another therapeutically active agent is a β2-adrenoreceptor agonist.
24. A method for the treatment of a human or animal subject with an anti- inflammatory and/or allergic condition, which method comprises administering to said human or animal subject an effective amount of a compound of formula (I) as defined in any one of claims 1 to 17 or a physiologically acceptable solvate thereof.
25. A compound of formula (II)
Figure imgf000036_0001
wherein R2, R3,R , R5, X, n and are as defined above.
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