WO2003072592A1 - 17.alpha-cycloalkyl/cycloylkenyl esters of alkyl-or haloalkyl-androst-4-en-3-on-11.beta.,17.alpha.-diol 17.beta.-carboxylates as anti-inflammatory agents - Google Patents

17.alpha-cycloalkyl/cycloylkenyl esters of alkyl-or haloalkyl-androst-4-en-3-on-11.beta.,17.alpha.-diol 17.beta.-carboxylates as anti-inflammatory agents Download PDF

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Publication number
WO2003072592A1
WO2003072592A1 PCT/GB2003/000183 GB0300183W WO03072592A1 WO 2003072592 A1 WO2003072592 A1 WO 2003072592A1 GB 0300183 W GB0300183 W GB 0300183W WO 03072592 A1 WO03072592 A1 WO 03072592A1
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Prior art keywords
methyl
oxo
androsta
diene
carboxylic acid
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PCT/GB2003/000183
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French (fr)
Inventor
Keith Biggadike
Gillian Elizabeth Morton
Deborah Needham
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Glaxo Group Limited
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Priority claimed from GB0200787A external-priority patent/GB0200787D0/en
Priority claimed from GB0224828A external-priority patent/GB0224828D0/en
Priority claimed from GB0225285A external-priority patent/GB0225285D0/en
Application filed by Glaxo Group Limited filed Critical Glaxo Group Limited
Priority to AU2003202044A priority Critical patent/AU2003202044A1/en
Publication of WO2003072592A1 publication Critical patent/WO2003072592A1/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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
    • A61P5/44—Glucocorticosteroids; Drugs increasing or potentiating the activity of glucocorticosteroids

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.
  • Ri represents represents C ⁇ . 6 alkyl or C ⁇ haloalkyl
  • R 2 represents C 3 - ⁇ cycloalkyl or C 3 . 8 cycloalkenyl either of which may be optionally substituted by one or more groups selected from Ci-e alkyl, oxo, methylene, halogen or phenyl, which phenyl substituent may be further substituted with one or more groups selected from C ⁇ alkyl, Ci-e alkoxy or halogen;
  • 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 represent hydrogen or halogen; 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 ⁇ e haloalkyl that R ⁇ may represent include C ⁇ - 6 alkyl substituted by 1-3 halogen atoms, preferably 1 halogen atom. Preferred halogen atoms are selected from bromine, chlorine and fluorine. Examples of d- ⁇ alkyl that R may represent include methyl.
  • Ri prefer Ri to represent fluoromethyl, chloromethyl, bromomethyl or 2'-fluoroethyl, especially fluoromethyl or chloromethyl.
  • C 3 . 8 cycloalkyl groups that R 2 may represent include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl and substituted derivatives such as methylcyclopropyl (eg 1-methylcyclopropyl), exomethylenecyclobutyl (eg 3- exomethylenecyclobutyl) and tetramethylcyclopropyl (eg 2,2,3,3- tetramethylcyclopropyl).
  • methylcyclopropyl eg 1-methylcyclopropyl
  • exomethylenecyclobutyl eg 3- exomethylenecyclobutyl
  • tetramethylcyclopropyl eg 2,2,3,3- tetramethylcyclopropyl
  • Examples of C 3 . 8 cycloalkenyl groups that R 2 may represent include alkenyl groups containing 1 or more double bonds (not being aromatic groups) such as cyclohexenyl (eg cyclohex-2,3-enyl).
  • R 2 to represent C 3 . 8 cycloalkyl optionally substituted by one or more methyl and/or halogen groups.
  • R 2 to represent C 3 . 6 cycloalkyl, more preferably C 3 .-, cycloalkyl, optionally substituted by one or more methyl or chlorine groups.
  • R 2 to represent 2,2,3,3- tetramethylcyclopropyl.
  • Another preference is for R 2 to represent 1- methylcyclopropyl, cyclopentyl and cyclohexyl.
  • R 2 we also prefer R 2 to represent C 3 - 6 cycloalkyl substituted by methylene.
  • R 3 to represent methyl. In some preferred embodiments methyl is in the ⁇ configuration. In other preferred embodiments, R 3 represents 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. Compounds where R 4 is chlorine and R 5 is fluorine, and where R 4 is fluorine and R 5 is hydrogen are also preferred. Preferably, represents a double bond.
  • 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.
  • 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.
  • 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 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.
  • compositions according to the invention may also be used in combination with another therapeutically active agent, for example, a ⁇ 2 adrenoreceptor agonist, an anti-histamine or an anti-allergic.
  • another therapeutically active agent for example, a ⁇ 2 adrenoreceptor agonist, an anti-histamine or an anti-allergic.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a physiologically acceptable salt or solvate thereof together with another therapeutically active agent, for example, a ⁇ 2 -adrenoreceptor agonist, an anti- histamine or an anti-allergic.
  • ⁇ 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 ⁇ 2 -adrenoreceptor agonists include those described in WO 02066422, WO02070490 and WO02076933.
  • Especially preferred long-acting ⁇ 2 -adrenoreceptor agonists include compounds of formula(X):
  • m is an integer of from 2 to 8; n is an integer of from 3 to 11 , with the proviso that m + n is 5 to 19, R 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, d-ealkyl, C 3 - 7 cycloalkyl,
  • R 16 and R 17 are each optionally substituted by one or two groups selected from halo, d-ealkyl, d-ehaloalkyl,
  • R 18 and R 19 are independently selected from hydrogen, C h alky!,
  • R 2 and R 13 are independently selected from hydrogen, C h alky!, d. 6 alkoxy, halo, phenyl, and C ⁇ - 6 haloalkyl;
  • anti-histamines examples include methapyrilene or loratadine.
  • suitable combinations include, for example, other anti-inflammatory agents eg. NSAIDs (eg. PDE4 inhibitors, leukotriene antagonists, iNOS inhibitors, tryptase and elastase inhibitors, beta-2 integrin antagonists and adenosine 2a agonists)) or antiinfective agents (eg. antibiotics, antivirals).
  • NSAIDs eg. PDE4 inhibitors, leukotriene antagonists, iNOS inhibitors, tryptase and elastase inhibitors, beta-2 integrin antagonists and adenosine 2a agonists
  • antiinfective agents eg. antibiotics, antivirals.
  • 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
  • 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.
  • 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.
  • IC50 ratio of about 0.1 or greater is the ratio of the IC50 value for competing with the binding of 1 nM of [ 3 H]R-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 examples include: (R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone; (R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone; 3-(cyclopentyloxy-4-methoxyphenyl)-1-(4-N'-[N2-cyano-S-methyl- isothioureido]benzyl)-2-pyrrolidone; cis 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylic acid]; cis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol];
  • 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 Astra Hofgen, N. et_ ⁇ 15th EFMC Int Symp Med Chem (Sept 6- 10, Edinburgh) 1998, Abst P.98
  • a 9-benzyladenine derivative nominated NCS-613 INERM
  • D-4418 from Chiroscience and Schering-Plough
  • a benzodiazepine PDE4 inhibitor identified as CI-1018 (PD-168787; Parke-Davis/Wamer-Lambert)
  • Isolated human monocyte PDE4 and hrPDE (human recombinant PDE4) was determined to exist primarily in the low affinity form.
  • the activity of test compounds against the low affinity form of PDE4 can be assessed using standard assays for PDE4 catalytic activity employing 1 ⁇ M [ H]cAMP as a substrate (Torphy et al.. J. of Biol. Chem., Vol. 267, No. 3 pp1798-1804, 1992).
  • Rat brain high speed supernatants were used as a source of protein and both enantiomers of [ 3 H]-rolipram were prepared to a specific activity of 25.6 Ci/mmol.
  • Standard assay conditions were modified from the published procedure to be identical to the PDE assay conditions, except for the last of the cAMP: 50mM Tris HCI (pH 7.5), 5 mM MgCI 2 , 50 ⁇ M 5'-AMP and 1 nM of [ 3 H]-rolipram (Torphy et al.. J. of Biol. Chem., Vol. 267, No. 3 pp1798-1804, 1992).
  • the assay was run for 1 hour at 30° C.
  • the reaction was terminated and bound ligand was separated from free ligand using a Brandel cell harvester. Competition for the high affinity binding site was assessed under conditions that were identical to those used for measuring low affinity PDE activity, expect that [ 3 H]-cAMP was not present.
  • PDE activity was assayed using a [ 3 H]cAMP SPA or [ 3 H]cGMP SPA enzyme assay as described by the supplier (Amersham Life Sciences).
  • the reactions were conducted in 96-well plates at room temperature, in 0.1 ml of reaction buffer containing (final concentrations): 50 mM Tris-HCI, pH 7.5, 8.3 mM MgCI 2 , 1.7 mM EGTA, [ 3 H]cAMP or [ 3 H] cGMP (approximately 2000 dpm/pmol), enzyme and various concentrations of the inhibitors.
  • the assay was allowed to proceed for 1 hr and was terminated by adding 50 ⁇ l of SPA yttrium silicate beads in the presence of zinc sulfate. The plates were shaken and allowed to stand at room temperature for 20 min. Radiolabeled product formation was assessed by scintillation spectrometry.
  • the assay was performed at 30°C for 1 hr in 0.5 ⁇ l buffer containing (final concentrations): 50 mM Tris-HCI, pH 7.5, 5 mM MgCI 2 , 0.05% bovine serum albumin, 2 nM [ H]R-rolipram (5.7 x 104 dpm/pmol) and various concentrations of non-radiolabeled inhibitors.
  • the reaction was stopped by the addition of 2.5 ml of ice-cold reaction buffer (without [ 3 H]-R-rolipram) and rapid vacuum filtration (Brandel Cell Harvester) through Whatman GF/B filters that had been soaked in 0.3% polyethylenimine. The filters were washed with an additional 7.5 ml of cold buffer, dried, and counted via liquid scintillation spectrometry.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a physiologically acceptable solvate thereof together with a PDE4 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.
  • a process according to the invention for preparing a compound of formula (I) comprises alkylation of a carboxylic acid of formula (II)
  • R 2 , R 3 , R 4 , R 5 and are as defined above, with a compound of formula R L wherein L represents a leaving group.
  • the compound of formula (II) may be reacted with a compound of formula R L wherein L represents a leaving group such as a 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 a 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.
  • 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 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 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.
  • 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 may need to be removed by reaction with an amine such as diethylamine or 1-methyl
  • 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.
  • Potassium carbonate (82mg, 0.59mmol) was added to a stirred solution of Intermediate 1 (250mg, 0.52mmol) in anhydrous DMF (5ml) and the mixture cooled to -25 °C.
  • Bromofluoromethane 160mg, 1.41 mmol was then added and the mixture stirred between -25 °C and -30 °C for 3h.
  • Diethylamine 49mg, 0.67mmol was added and the mixture stirred at -20 °C for 30min.
  • Methyl iodide (111 mg, 0.78mmol) was added to a stirred and cooled (ice) solution of Intermediate 2 (150mg, 0.29mmol) and sodium carbonate (62mg, 0.58mmol) in anhydrous DMF (5ml) under nitrogen. The mixture was allowed to warm to room temperature and stirred for 3h. Diethylamine (0.039ml) was added and the mixture was stirred for 20min and then poured into a mixture of 2M HCI (5.5ml) and water (25ml). Filtration yielded the title compound as an off-white solid (64mg): LCMS retention time 3.79min, m/z 535 MH + .
  • Example 4 was prepared from Intermediate 2 using a method similar to that described for Example 2. LCMS retention time 3.81 min, m/z 553 MH +
  • Example 5 9 -Chloro-6 ⁇ -fluoro-11 ⁇ -hvdroxy-16 ⁇ -methyl-3-oxo-17 ⁇ -(2.2.3.3- tetramethylcvclopropylcarbonvDoxy-androsta-1 ,4-diene-17 ⁇ -carboxylic acid methyl ester
  • Example 5 was prepared from Intermediate 3 using a method similar to that described for Example 1.
  • Example 6 was prepared from Intermediate 3 using a method similar to that described for Example 2. LCMS retention time 3.94min, m/z 569, 571 MH +
  • Example 7 6 ⁇ .9 -Difluoro-11 ⁇ -hvdroxy-16 ⁇ -methyl-3-oxo-17 ⁇ -(2.2.3.3- tetramethylcvclopropylcarbonvDoxy-androsta-1 ,4-diene-17 ⁇ -carboxylic acid chloromethyl ester
  • Chloroiodomethane (0.236ml, 3.24mmol) was added to a stirred and cooled (ice) mixture of Intermediate 2 (626mg, 1.2mmol) and sodium carbonate (1275mg, 12.02mmol) in anhydrous DMF (15ml) under nitrogen. The mixture was allowed to warm to room temperature and stirred for 2h. More sodium carbonate (255mg) was added and the mixture stirred for 2.5h when a further portion of sodium carbonate (255mg) was added and the mixture stirred for a further 18h. 2M Hydrochloric acid (20ml) was added dropwise, the mixture was diluted with water (25ml) and extracted with dichloromethane (2 x 25ml).
  • Example 8 9 ⁇ -Fluoro-11 ⁇ -hvdroxy-16 ⁇ -methyl-3-oxo-17oc-(2.2,3.3- tetramethylcvclopropylcarbonyl)oxy-androsta-1 ,4-diene-17 ⁇ -carboxylic acid methyl ester
  • Example 8 was prepared from Intermediate 4 using a method similar to that described for Example 3. LCMS retention time 3.81 min, m/z 517 MH +
  • Example 9 9 ⁇ -Fluoro-11 ⁇ -hvdroxy-16 ⁇ -methyl-3-oxo-17 ⁇ -(2.2.3.3- tetramethylcvclopropylcarbonyl)oxy-androsta-1 ,4-diene-17 ⁇ -carboxylic acid fluoromethyl ester
  • Example 9 was prepared from Intermediate 4 using a method similar to that described for Example 2.
  • Example 10 9 ⁇ -Fluoro-11 ⁇ -hvdroxy-16 ⁇ -methyl-3-oxo-17 ⁇ -(2.2.3.3- tetramethylcvclopropylcarbonyl)oxy-androsta-1 ,4-diene-17 ⁇ -carboxylic acid chloromethyl ester
  • Example 10 was prepared from Intermediate 4 using a method similar to that described for Example 7. LCMS retention time 3.93min, m/z 551 , 553 MH +
  • Examplel 1 17 ⁇ -(Cvclopentylcarbonyl)oxy-6 ⁇ ,9 ⁇ -difluoro-11 ⁇ -hydroxy-16 ⁇ -methyl- 3-oxo-androsta-1.4-diene-17 ⁇ -carboxylic acid fluoromethyl ester
  • Example 11 was prepared from Intermediate 5 using a method similar to that described for Example 2. LCMS retention time 3.69min, m/z 525 MH +
  • Example 12 17 ⁇ -(Cvclohexylcarbonyl)oxy-6 ⁇ ,9 ⁇ -difluoro-11 ⁇ -hvdroxy-16 ⁇ -methyl- 3-oxo-androsta-1 ,4-diene-17 ⁇ -carboxylic acid methyl ester
  • Example 12 was prepared from Intermediate 6 using a method similar to that described for Example 3. LCMS retention time 3.68min, m/z 521 MH +
  • Example 13 17 ⁇ -(Cvclohexylcarbonyl)oxy-6 ⁇ .9 ⁇ -difluoro-11 ⁇ -hydroxy-16 ⁇ -methyl- 3-oxo-androsta-1 ,4-diene-17 ⁇ -carboxylic acid fluoromethyl ester
  • Example 13 was prepared from Intermediate 6 using a method similar to that described for Example 2. LCMS retention time 3.81 min, m/z 539 MH +
  • Example 14 17 ⁇ -(Cyclohexylcarbonyl)oxy-6 ⁇ .9 ⁇ -difluoro-11 ⁇ -hydroxy-16 ⁇ -methyl- 3-oxo-androsta-1 ,4-diene-17 ⁇ -carboxylic acid chloromethyl ester
  • Example 14 was prepared from Intermediate 6 using a method similar to that described for Example 7. LCMS retention time 3.94min, m/z 555, 557 MH +
  • Example 15 was prepared from Intermediate 7 using a method similar to that described for Example 2. LCMS retention time 3.87min, m/z 555, 557 MH +
  • Example 16 was prepared from Intermediate 7 using a method similar to that described for Example 7. LCMS retention time 4.05min, m/z 571 ,573 MH +
  • 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., (1997) Biochem J. 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 50 values may be estimated.
  • the functional assay based on that described by R.J.H. Austin et al., (2002) Eur Resp J., 20,1386-1392 measures the ability of compounds directly to 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): wherein R1 represents C1-6 alkyl or C1-6 haloalkyl;R2 represents C3-8 cycloalkyl or C3-8 cycloalkenyl either of which may be optionally substituted by one or more groups selected from C1-6 alkyl, oxo, methylene, halogen or phenyl, which phenyl substituent may be further substituted with one or more groups selected from C1-6 alkyl, C1-6 alkoxy or halogen; 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 represent hydrogen or halogen; and (Α) represents a single or a double bond; and solvates thereof.

Description

. ALPHA . -CYCLOALKYL/CYCLOALKENYL ESTERS OF ALKYL-OR HAL0ALKYL-ANDR0ST-4-EN- -ON- 11 . BETA . , 17 . ALPHA . -DIOL 17 . BETA . -CARBOXYLATES AS ANTI -INFLAMMATORY AGENTS
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
Ri represents represents C^.6 alkyl or C^ haloalkyl;
R2 represents C3-β cycloalkyl or C3.8 cycloalkenyl either of which may be optionally substituted by one or more groups selected from Ci-e alkyl, oxo, methylene, halogen or phenyl, which phenyl substituent may be further substituted with one or more groups selected from C^ alkyl, Ci-e alkoxy or halogen;
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 represent hydrogen or halogen; 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^e haloalkyl that R^ may represent include Cι-6 alkyl substituted by 1-3 halogen atoms, preferably 1 halogen atom. Preferred halogen atoms are selected from bromine, chlorine and fluorine. Examples of d-β alkyl that R may represent include methyl. We prefer Ri to represent fluoromethyl, chloromethyl, bromomethyl or 2'-fluoroethyl, especially fluoromethyl or chloromethyl.
Examples of C3.8 cycloalkyl groups that R2 may represent include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl and substituted derivatives such as methylcyclopropyl (eg 1-methylcyclopropyl), exomethylenecyclobutyl (eg 3- exomethylenecyclobutyl) and tetramethylcyclopropyl (eg 2,2,3,3- tetramethylcyclopropyl).
Examples of C3.8 cycloalkenyl groups that R2 may represent include alkenyl groups containing 1 or more double bonds (not being aromatic groups) such as cyclohexenyl (eg cyclohex-2,3-enyl).
We prefer R2 to represent C3.8 cycloalkyl optionally substituted by one or more methyl and/or halogen groups. We particularly prefer R2 to represent C3.6 cycloalkyl, more preferably C3.-, cycloalkyl, optionally substituted by one or more methyl or chlorine groups. We particularly prefer R2 to represent 2,2,3,3- tetramethylcyclopropyl. Another preference is for R2 to represent 1- methylcyclopropyl, cyclopentyl and cyclohexyl.
We also prefer R2 to represent C3-6 cycloalkyl substituted by methylene. We prefer R3 to represent methyl. In some preferred embodiments methyl is in the α configuration. In other preferred embodiments, R3 represents methyl in the β 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 R4 and R5 are both fluorine. Compounds where R4 is chlorine and R5 is fluorine, and where R4 is fluorine and R5 is hydrogen are also preferred. 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:
6α,9α-Difluoro-11 β-hydroxy-16α-methyl-17α-(1-methylcyclopropylcarbonyl)oxy-3- oxo-androsta-1 ,4-diene-17β-carboxylic acid methyl ester,
6α,9α-Difluoro-11 β-hydroxy-16α-methyl-17α-(1 -methylcyclopropylcarbonyl)oxy-3- oxo-androsta-1 ,4-diene-17β-carboxylic acid fluoromethyl ester, 6α,9α-Difluoro-11 β-hydroxy-16α-methyl-3-oxo-17α-(2, 2,3,3- tetramethylcyclopropylcarbonyl)oxy-androsta-1 ,4-diene-17β-carboxylic acid methyl ester,
6α,9α-Difluoro-11 β-hydroxy-16α-methyl-3-oxo-17α-(2, 2,3,3- tetramethylcyclopropylcarbonyl)oxy-androsta-1 ,4-diene-17β-carboxylic acid fluoromethyl ester,
9α-Chloro-6α-fluoro-11 β-hydroxy-16α-methyl-3-oxo-17α-(2,2,3,3- tetramethylcyclopropylcarbonyl)oxy-androsta-1 ,4-diene-17β-carboxylic acid methyl ester,
9α-Chloro-6α-fluoro-11 β-hydroxy-16α-methyl-3-oxo-17α-(2,2,3,3- tetramethylcyclopropylcarbonyl)oxy-androsta-1 ,4-diene-17β-carboxylic acid fluoromethyl ester
6α,9α-Difluoro-11 β-hydroxy-16α-methyl-3-oxo-17α-(2,2,3,3- tetramethylcyclopropylcarbonyl)oxy-androsta-1 ,4-diene-17β-carboxylic acid chloromethyl ester 9α-Fluoro-11 β-hydroxy-16β-methyl-3-oxo-17α-(2,2,3,3- tetramethylcyclopropylcarbonyl)oxy-androsta-1 ,4-diene-17β-carboxylic acid methyl ester
9α-Fluoro-11 β-hydroxy-16β-methyl-3-oxo-17α-(2,2,3,3- tetramethylcyclopropylcarbonyl)oxy-androsta-1 ,4-diene-17β-carboxylic acid fluoromethyl ester
9α-Fluoro-11 β-hydroxy-16β-methyl-3-oxo-17α-(2,2,3,3- tetramethylcyclopropylcarbonyl)oxy-androsta-1 ,4-diene-17β-carboxylic acid chloromethyl ester 17α-(Cyclopentylcarbonyl)oxy-6α,9α-difluoro-11 β-hydroxy-16α-methyl-3-oxo- androsta-1 ,4-diene-17β-carboxylic acid fluoromethyl ester
17α-(Cyclohexylcarbonyl)oxy-6α,9α-difluoro-11 β-hydroxy-16α-methyl-3-oxo- androsta-1 ,4-diene-17β-carboxylic acid methyl ester
17α-(Cyclohexylcarbonyl)oxy-6α,9α-difluoro-11 β-hydroxy-16 -methyl-3-oxo- androsta-1 ,4-diene-17β-carboxylic acid fluoromethyl ester
17α-(Cyclohexylcarbonyl)oxy-6α,9α-difluoro-11 β-hydroxy-16α-methyl-3-oxo- androsta-1 ,4-diene-17β-carboxylic acid chloromethyl ester
9α-Chloro-17α-(cyclohexylcarbonyl)oxy-6α-fluoro-11 β-hydroxy-16α-methyl-3-oxo- androsta-1 ,4-diene-17β-carboxylic acid fluoromethyl ester, and 9α-Chloro-17α-(cyclohexylcarbonyl)oxy-6α-fluoro-11 β-hydroxy-16α-methyl-3-oxo- androsta-1 ,4-diene-17β-carboxylic acid chloromethyl 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 pharmaceutical compositions according to the invention may also be used in combination with another therapeutically active agent, for example, a β2 adrenoreceptor agonist, an anti-histamine or an anti-allergic. The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a physiologically acceptable salt or solvate thereof together with another therapeutically active agent, for example, a β2-adrenoreceptor agonist, an anti- histamine or an anti-allergic.
Examples of β2-adrenoreceptor agonists include salmeterol (eg as racemate or a single enantiomer such as the R-enantiomer), salbutamol, formoterol, salmefamol, fenoterol or terbutaline and salts thereof, for example the xinafoate salt of salmeterol, 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 β2-adrenoreceptor agonists include those described in WO 02066422, WO02070490 and WO02076933.
Especially preferred long-acting β2-adrenoreceptor agonists include compounds of formula(X):
Figure imgf000010_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, d-ealkyl, C3-7cycloalkyl,
C(O)NR18R19, phenyl, and phenyl (C^alkyl)-, or R16 and R17, together with the nitrogen to which they are bonded, form a 5-, 6-, or
7- membered nitrogen containing ring, and R16 and R17are each optionally substituted by one or two groups selected from halo, d-ealkyl, d-ehaloalkyl,
Cealkoxy, hydroxy-substituted d-ealkoxy, -CO2R18, -SO2NR 8R19, -CONR18R19, -
NR18C(O)R19, or a 5-, 6- or 7-membered heterocylic ring;
R18 and R19are independently selected from hydrogen, Chalky!,
C3.6cycloalkyl, phenyl, and phenyl (C^alkyl)-; and p is an integer of from 0 to 6, preferably from 0 to 4;
R 2 and R13 are independently selected from hydrogen, Chalky!, d.6alkoxy, halo, phenyl, and Cι-6haloalkyl; and
R R1144 aanndd RR1155 aarree iinnddeeppeennddeennttllyy s < elected from hydrogen and d^alkyl with the proviso that the total number of carbon atoms in R1" and R'° is not more than 4.
Examples of anti-histamines include methapyrilene or loratadine. Other suitable combinations include, for example, other anti-inflammatory agents eg. NSAIDs (eg. PDE4 inhibitors, leukotriene antagonists, iNOS inhibitors, tryptase and elastase inhibitors, beta-2 integrin antagonists and adenosine 2a agonists)) or antiinfective agents (eg. antibiotics, antivirals).
Of particular interest is use of the compounds of formula (I) in combination with a phosphodiesterase 4 (PDE4) inhibitor. The PDE4-specific inhibitor useful in this aspect of the invention may be any compound that is known to inhibit the PDE4 enzyme or which is discovered to act as a PDE4 inhibitor, and which are only PDE4 inhibitors, not compounds which inhibit other members of the PDE family as well as PDE4. Generally it is preferred to use a PDE4 inhibitor which has an 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.
Initial experiments were conducted to establish and validate a [3H]-rolipram binding assay. Details of this work are given in the Binding Assays described in detail below.
The preferred PDE4 inhibitors of use in this invention will be those compounds which have a salutary therapeutic ratio, i.e., compounds which preferentially inhibit cAMP catalytic activity where the enzyme is in the form that binds rolipram with a low affinity, thereby reducing the side effects which apparently are linked to inhibiting the form which binds rolipram with a high affinity. Another way to state this is that the preferred compounds will have an IC50 ratio of about 0.1 or greater as regards the IC50 for the PDE4 catalytic form which binds rolipram with a high affinity divided by the IC50 for the form which binds rolipram with a low affinity.
A further refinement of this standard is that of one wherein the PDE4 inhibitor has an
IC50 ratio of about 0.1 or greater; said ratio is the ratio of the IC50 value for competing with the binding of 1 nM of [3H]R-rolipram to a form of PDE4 which binds rolipram with a high affinity over the IC50 value for inhibiting the PDE4 catalytic activity of a form which binds rolipram with a low affinity using 1 μM[3H]-cAMP as the substrate.
Examples of useful PDE4 inhibitors are: (R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone; (R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone; 3-(cyclopentyloxy-4-methoxyphenyl)-1-(4-N'-[N2-cyano-S-methyl- isothioureido]benzyl)-2-pyrrolidone; cis 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylic acid]; cis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol];
(R)-(+)-ethyl [4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidine-2-ylidene]acetate; and (S)-(-)-ethyl [4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidine-2-ylidene]acetate.
Most preferred are those PDE4 inhibitors which have an IC50 ratio of greater than 0.5, and particularly those compounds having a ratio of greater than 1.0. Preferred compounds are cis 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1- carboxylic acid, 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4- difluoromethoxyphenyl)cyclohexan-1-one and c/s-[4-cyano-4-(3-cyclopropylmethoxy- 4-difluoromethoxyphenyl)cyclohexan-1-ol]; these are examples of compounds which bind preferentially to the low affinity binding site and which have an IC50 ratio of 0.1 or greater.
Other compounds of interest include:
Compounds set out in U.S. patent 5,552,438 issued 03 September, 1996; this patent and the compounds it discloses are incorporated herein in full by reference. The compound of particular interest, which is disclosed in U.S. patent 5,552,438, is c/s-4- cyano-4-[3- (cyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxylic acid (also known as cilomalast) and its salts, esters, pro-drugs or physical forms;
AWD-12-281 from Astra (Hofgen, N. et_§ 15th EFMC Int Symp Med Chem (Sept 6- 10, Edinburgh) 1998, Abst P.98); a 9-benzyladenine derivative nominated NCS-613 (INSERM); D-4418 from Chiroscience and Schering-Plough; a benzodiazepine PDE4 inhibitor identified as CI-1018 (PD-168787; Parke-Davis/Wamer-Lambert); a benzodioxole derivative Kyowa Hakko disclosed in WO 9916766; V-11294A from Napp (Landells, L.J. et al. Eur Resp J [Annu Cong Eur Resp Soc (Sept 19-23, Geneva) 1998] 1998, 12(Suppl. 28): Abst P2393); roflumilast (CAS reference No 162401-32-3) and a pthalazinone (WO 9947505) from Byk-Gulden; or a compound identified as T-440 (Tanabe Seiyaku; Fuji, K. et al. J Pharmacol Exp Ther,1998, 284(1 ): 162).
Phosphodiesterase and Rolipram Binding Assays
Assay method 1 A
Isolated human monocyte PDE4 and hrPDE (human recombinant PDE4) was determined to exist primarily in the low affinity form. Hence, the activity of test compounds against the low affinity form of PDE4 can be assessed using standard assays for PDE4 catalytic activity employing 1 μM [ H]cAMP as a substrate (Torphy et al.. J. of Biol. Chem., Vol. 267, No. 3 pp1798-1804, 1992). Rat brain high speed supernatants were used as a source of protein and both enantiomers of [3H]-rolipram were prepared to a specific activity of 25.6 Ci/mmol. Standard assay conditions were modified from the published procedure to be identical to the PDE assay conditions, except for the last of the cAMP: 50mM Tris HCI (pH 7.5), 5 mM MgCI2, 50 μM 5'-AMP and 1 nM of [3H]-rolipram (Torphy et al.. J. of Biol. Chem., Vol. 267, No. 3 pp1798-1804, 1992). The assay was run for 1 hour at 30° C. The reaction was terminated and bound ligand was separated from free ligand using a Brandel cell harvester. Competition for the high affinity binding site was assessed under conditions that were identical to those used for measuring low affinity PDE activity, expect that [3H]-cAMP was not present.
Assay method 1 B Measurement of Phosphodiesterase Activity
PDE activity was assayed using a [3H]cAMP SPA or [3H]cGMP SPA enzyme assay as described by the supplier (Amersham Life Sciences). The reactions were conducted in 96-well plates at room temperature, in 0.1 ml of reaction buffer containing (final concentrations): 50 mM Tris-HCI, pH 7.5, 8.3 mM MgCI2, 1.7 mM EGTA, [3H]cAMP or [3H] cGMP (approximately 2000 dpm/pmol), enzyme and various concentrations of the inhibitors. The assay was allowed to proceed for 1 hr and was terminated by adding 50 μl of SPA yttrium silicate beads in the presence of zinc sulfate. The plates were shaken and allowed to stand at room temperature for 20 min. Radiolabeled product formation was assessed by scintillation spectrometry.
f HlR-rolipram binding assay The [ H]R-rolipram binding assay was performed by modification of the method of Schneider and co-workers, see Nicholson, et al.. Trends Pharmacol. Sci., Vol. 12, pp.19-27 (1991 ) and McHale et al.. Mol. Pharmacol., Vol. 39, 109-113 (1991 ). R- Rolipram binds to the catalytic site of PDE4 see Torphy et al.. Mol. Pharmacol., Vol. 39, pp. 376-384 (1991 ). Consequently, competition for [3H]R-rolipram binding provides an independent confirmation of the PDE4 inhibitor potencies of unlabeled competitors. The assay was performed at 30°C for 1 hr in 0.5 μl buffer containing (final concentrations): 50 mM Tris-HCI, pH 7.5, 5 mM MgCI2, 0.05% bovine serum albumin, 2 nM [ H]R-rolipram (5.7 x 104 dpm/pmol) and various concentrations of non-radiolabeled inhibitors. The reaction was stopped by the addition of 2.5 ml of ice-cold reaction buffer (without [3H]-R-rolipram) and rapid vacuum filtration (Brandel Cell Harvester) through Whatman GF/B filters that had been soaked in 0.3% polyethylenimine. The filters were washed with an additional 7.5 ml of cold buffer, dried, and counted via liquid scintillation spectrometry.
The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a physiologically acceptable solvate thereof together with a PDE4 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.
A process according to the invention for preparing a compound of formula (I) comprises alkylation of a carboxylic acid of formula (II)
Figure imgf000015_0001
wherein R2, R3, R4, R5and are as defined above, with a compound of formula R L wherein L represents a leaving group.
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 a 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.
Compounds of formula (II) may conveniently be employed as salts when such salts may be prepared in crystalline form.
When Ri represents fluoromethyl, the preferred haloalkyl halide reagent is bromofluoromethane.
Compounds of formula Ri-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 imgf000015_0002
wherein 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 R2COOH 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 may 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.
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. 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 100%B, 5.3-5.5 min 0%B at a flow rate of 3 ml/min. The mass spectra were recorded on a Fisons VG Platform spectrometer using electrospray positive and negative mode (ES+ve and ES-ve).
Intermediates
Intermediate 1 : 6α.9α-Difluoro-11 β-hvdroxy-16α-methyl-17α-(1- methylcvclopropylcarbonyl)oxy-3-oxo-androsta-1 ,4-diene-17β-carboxylic acid To a stirred and cooled (ice) solution of 6α,9α-difluoro-11 β,17α-dihydroxy-16α- methyl-3-oxo-androsta-1 ,4-diene-17β-carboxylic acid (G. H. Phillipps et al.. (1994) Journal of Medicinal Chemistry, 37, 3717-3729) (1.0g, 2.52mmol) and tnethylamine (664mg, 6.6mmol) in anhydrous dichloromethane (30ml) was added a solution of 1- methylcyclopropanecarbonyl chloride (783mg, 6.6mmol) in anhydrous dichloromethane (10ml). The mixture was stirred under nitrogen for 3h and then diluted with dichloromethane (50ml) and washed successively with aqueous sodium bicarbonate (1x100ml), 1 M hydrochloric acid (1x100ml), water (1x100ml) and dried through a hydrophobic frit and evaporated. The residual solid was dissolved in dioxane (40ml) and acetone (5ml), 1-methylpiperazine (960mg, 9.6mmol) was added and the reaction left to stand at room temperature for 4h. The mixture was then added portionwise over 5min to a vigorously stirred solution of 2M hydrochloric acid (55ml) and ice (55ml). The resulting precipitate was filtered off and dried to yield the title compound as a white solid (1.05g): LCMS retention time 3.29 min.
Intermediate 2: 6α.9α-Difluoro-11 β-hvdroxy-16α-methyl-3-oxo-17α-(2.2.3.3- tetramethylcvclopropylcarbonyl)oxy-androsta-1 ,4-diene-17β-carboxylic acid Prepared using methods similar to that described for Intermediate 1. LCMS retention time 3.59 min.
Intermediate 3: 9α-Chloro-6α-fluoro-11 β-hydroxy-16α-methyl-3-oxo-17α-(2,2,3.3- tetramethylcvclopropylcarbonyl)oxy-androsta-1 ,4-diene-17β-carboxylic acid Prepared using methods similar to that described for Intermediate 1. LCMS retention time 3.82 min. Intermediate 4: 9α-Fluoro-11 β-hvdroxy-16β-methyl-3-oxo-17α-(2,2.3.3- tetramethylcvclopropylcarbonvPoxy-androsta-1 ,4-diene-17β-carboxylic acid Oxalyl chloride (0.553ml, 6.34mmol) was added to a solution of 2,2,3,3- tetramethylcyclopropyl carboxylic acid (300mg, 2.114mmol) in dry dichloromethane (8ml) containing diethylformamide (1drop) and the mixture stirred for 1h. The solvent was evaporated and a portion (203mg) of the residual acid chloride was added to a stirred and cooled (ice) solution of 11 β,17α-dihydroxy-9α-fluoro-16β-methyl-3-oxo- androsta-1 ,4-diene-17β-carboxylic acid (G. H. Phillipps et al.. (1994) Journal of Medicinal Chemistry, 37, 3717-3729) (400mg, 1.06mmol) in pyhdine (5 ml). The mixture was allowed to warm to room temperature and after 2h more acid chloride (85mg) was added. After a further 2h more acid chloride (50mg) was added and the mixture stirred for 18h and then poured into 5M hydrochloric acid and extracted three times with dichloromethane. The combined organic extracts were washed successively with 5M hydrochloric acid and brine, dried through a hydrophobic frit and evaporated to yield the title compound as a cream solid (625mg): LCMS retention time 3.75 min.
Intermediate 5: 17α-(Cvclopentylcarbonyl)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 3.48 min.
Intermediate 6: 17α-(Cvclohexylcarbonyl)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 3.61 min.
Intermediate 7: 9α-Chloro-17α-(cvclohexylcarbonyl)oxy-6α-fluoro-11 β-hydroxy-16α- methyl-3-oxo-androsta-1 ,4-diene-17β-carboxylic acid
Prepared using methods similar to that described for Intermediate 4. LCMS retention time 3.80 min.
Examples X Example 1: 6α.9α-Difluoro-11 β-hvdroxy-16α-methyl-17α-(1- methylcvclopropylcarbonyl)oxy-3-oxo-androsta-1.4-diene-17β-carboχylic acid methyl ester
Potassium carbonate (65mg, 0.47mmol) was added to a solution of Intermediate 1 (250mg, 0.52mmol) and methyl iodide (111mg, 0.78mmol) in anhydrous DMF (6ml) and the mixture stirred under nitrogen for 4h. The reaction mixture was then poured into water (30ml) and extracted with ethyl acetate (3x20ml) and the combined organic layers washed with water (2x25ml), brine (25ml), dried through a hydrophobic frit and evaporated. The residue was chromatographed on a Bond Elut cartridge (10g) eluting with dichloromethane followed by ether to yield the title compound as a white solid (180mg): LCMS retention time 3.46min, m/z 493 MH+.
Example 2: 6α,9α-Difluoro-11 β-hvdroxy-16α-methyl-17α-(1- methylcvclopropylcarbonyl)oxy-3-oxo-androsta-1 ,4-diene-17β-carboxylic acid fluoromethyl ester
Potassium carbonate (82mg, 0.59mmol) was added to a stirred solution of Intermediate 1 (250mg, 0.52mmol) in anhydrous DMF (5ml) and the mixture cooled to -25 °C. Bromofluoromethane (160mg, 1.41 mmol) was then added and the mixture stirred between -25 °C and -30 °C for 3h. Diethylamine (49mg, 0.67mmol) was added and the mixture stirred at -20 °C for 30min. The temperature was then allowed to rise to 0 °C, 2M hydrochloric acid (9.9ml) was added and the mixture was stirred at 0 °C for 30 min and then poured into water with vigorous stirring.The resulting precipitate was filtered off and washed well with water to give the title compound as an off-white solid (68mg): LCMS retention time 3.55min, m/z 511 MH+.
Example 3: 6α.9α-Difluoro-11 β-hvdroxy-16α-methyl-3-oxo-17α-(2.2.3.3- tetramethylcvclopropylcarbonyl)oxy-androsta-1 ,4-diene-17β-carboxylic acid methyl ester
Methyl iodide (111 mg, 0.78mmol) was added to a stirred and cooled (ice) solution of Intermediate 2 (150mg, 0.29mmol) and sodium carbonate (62mg, 0.58mmol) in anhydrous DMF (5ml) under nitrogen. The mixture was allowed to warm to room temperature and stirred for 3h. Diethylamine (0.039ml) was added and the mixture was stirred for 20min and then poured into a mixture of 2M HCI (5.5ml) and water (25ml). Filtration yielded the title compound as an off-white solid (64mg): LCMS retention time 3.79min, m/z 535 MH+. Example 4: 6α.9 -Difluoro-11 β-hydroxy-16α-methyl-3-oxo-17α-(2.2,3.3- tetramethylcvclopropylcarbonyl)oxy-androsta-1 ,4-diene-17β-carboxylic acid fluoromethyl ester
Example 4 was prepared from Intermediate 2 using a method similar to that described for Example 2. LCMS retention time 3.81 min, m/z 553 MH+
Example 5: 9 -Chloro-6α-fluoro-11 β-hvdroxy-16α-methyl-3-oxo-17α-(2.2.3.3- tetramethylcvclopropylcarbonvDoxy-androsta-1 ,4-diene-17β-carboxylic acid methyl ester Example 5 was prepared from Intermediate 3 using a method similar to that described for Example 1. LCMS retention time 3.92min, m/z 551 , 553 MH+
Example 6: 9α-Chloro-6α-fluoro-11β-hvdroxy-16α-methyl-3-oxo-17α-(2.2.3.3- tetramethylcvclopropylcarbonyl)oxy-androsta-1 ,4-diene-17β-carboxylic acid fluoromethyl ester
Example 6 was prepared from Intermediate 3 using a method similar to that described for Example 2. LCMS retention time 3.94min, m/z 569, 571 MH+
Example 7: 6α.9 -Difluoro-11 β-hvdroxy-16α-methyl-3-oxo-17α-(2.2.3.3- tetramethylcvclopropylcarbonvDoxy-androsta-1 ,4-diene-17β-carboxylic acid chloromethyl ester
Chloroiodomethane (0.236ml, 3.24mmol) was added to a stirred and cooled (ice) mixture of Intermediate 2 (626mg, 1.2mmol) and sodium carbonate (1275mg, 12.02mmol) in anhydrous DMF (15ml) under nitrogen. The mixture was allowed to warm to room temperature and stirred for 2h. More sodium carbonate (255mg) was added and the mixture stirred for 2.5h when a further portion of sodium carbonate (255mg) was added and the mixture stirred for a further 18h. 2M Hydrochloric acid (20ml) was added dropwise, the mixture was diluted with water (25ml) and extracted with dichloromethane (2 x 25ml). The combined organic extracts were washed successively with aqueous sodium bicarbonate and brine, dried through a hydrophobic frit and and evaporated to a dark brown oil. This crude product was chromatographed on a Bond Elut cartridge (10g) eluting with cyclohexane followed by cyclohexane/ethyl acetate to yield the title compound as a white solid (459mg): LCMS retention time 3.94min, m/z 569, 571 MH+. Example 8: 9α-Fluoro-11 β-hvdroxy-16β-methyl-3-oxo-17oc-(2.2,3.3- tetramethylcvclopropylcarbonyl)oxy-androsta-1 ,4-diene-17β-carboxylic acid methyl ester
Example 8 was prepared from Intermediate 4 using a method similar to that described for Example 3. LCMS retention time 3.81 min, m/z 517 MH+
Example 9: 9α-Fluoro-11 β-hvdroxy-16β-methyl-3-oxo-17α-(2.2.3.3- tetramethylcvclopropylcarbonyl)oxy-androsta-1 ,4-diene-17β-carboxylic acid fluoromethyl ester Example 9 was prepared from Intermediate 4 using a method similar to that described for Example 2. LCMS retention time 3.99min, m/z 535 MH+
Example 10: 9α-Fluoro-11 β-hvdroxy-16β-methyl-3-oxo-17α-(2.2.3.3- tetramethylcvclopropylcarbonyl)oxy-androsta-1 ,4-diene-17β-carboxylic acid chloromethyl ester
Example 10 was prepared from Intermediate 4 using a method similar to that described for Example 7. LCMS retention time 3.93min, m/z 551 , 553 MH+
Examplel 1 : 17α-(Cvclopentylcarbonyl)oxy-6α,9α-difluoro-11 β-hydroxy-16α-methyl- 3-oxo-androsta-1.4-diene-17β-carboxylic acid fluoromethyl ester
Example 11 was prepared from Intermediate 5 using a method similar to that described for Example 2. LCMS retention time 3.69min, m/z 525 MH+
Example 12: 17α-(Cvclohexylcarbonyl)oxy-6α,9α-difluoro-11 β-hvdroxy-16α-methyl- 3-oxo-androsta-1 ,4-diene-17β-carboxylic acid methyl ester
Example 12 was prepared from Intermediate 6 using a method similar to that described for Example 3. LCMS retention time 3.68min, m/z 521 MH+
Example 13: 17α-(Cvclohexylcarbonyl)oxy-6α.9α-difluoro-11 β-hydroxy-16α-methyl- 3-oxo-androsta-1 ,4-diene-17β-carboxylic acid fluoromethyl ester
Example 13 was prepared from Intermediate 6 using a method similar to that described for Example 2. LCMS retention time 3.81 min, m/z 539 MH+
Example 14: 17α-(Cyclohexylcarbonyl)oxy-6α.9α-difluoro-11 β-hydroxy-16α-methyl- 3-oxo-androsta-1 ,4-diene-17β-carboxylic acid chloromethyl ester Example 14 was prepared from Intermediate 6 using a method similar to that described for Example 7. LCMS retention time 3.94min, m/z 555, 557 MH+
Example 15: 9α-Chloro-17α-(cvclohexylcarbonyl)oxy-6α-luoro-11 β-hvdroxy-16α- methyl-3-oxo-androsta-1 ,4-diene-17β-carboxylic acid fluoromethyl ester
Example 15 was prepared from Intermediate 7 using a method similar to that described for Example 2. LCMS retention time 3.87min, m/z 555, 557 MH+
Example 16: 9α-Chloro-17α-(cvclohexylcarbonyl)oxy-6α-luoro-11 β-hydroxy-16α- methyl-3-oxo-androsta-1.4-diene-17β-carboxylic acid chloromethyl ester
Example 16 was prepared from Intermediate 7 using a method similar to that described for Example 7. LCMS retention time 4.05min, m/z 571 ,573 MH+
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., (1997) Biochem J. 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. Dose response curves are constructed from which EC50 values may be estimated.
The EC50 values for Examples 1 to 16 in this assay were determined to be <1nM.
The functional assay based on that described by R.J.H. Austin et al., (2002) Eur Resp J., 20,1386-1392 measures the ability of compounds directly to 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%).
Examples 3 to 7, 9 and 10 showed maximal responses of <15 % 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

A compound of formula (I):
Figure imgf000024_0001
wherein
RT represents represents d-6 alkyl or d-6 haloalkyl;
R2 represents C3-a cycloalkyl or C3-8 cycloalkenyl either of which may be optionally substituted by one or more groups selected from d-e alkyl, oxo, methylene, halogen or phenyl, which phenyl substituent may be further substituted with one or more groups selected from d-e alkyl, d-6 alkoxy or halogen;
R3 represents methyl, which may be in either the α or β configuration or methylene;
R4 and R5are the same or different and each represent hydrogen or halogen; and represents a single or a double bond; and solvates thereof.
2. A compound as claimed in claim 1 wherein R^ represents d-6 haloalkyl.
3. A compound as claimed in claim 2 wherein R^ represents fluoromethyl or chloromethyl.
4. A compound as claimed in any one of claims 1 to 3 wherein R2 represents a 2,2,3,3-tetramethyl cyclopropyl group.
5. A compound asclaimed in any one of claimsl to 4 wherein R4 and R5 both represent fluorine atoms.
6. A compound as claimed in any one of the preceding claims wherein the compound is: 6α,9α-Difluoro-1 1 β-hydroxy-16α-methyl-17α-(1 -methylcyclopropylcarbonyl)oxy-3- oxo-androsta-1 ,4-diene-17β-carboxylic acid methyl ester,
6α,9α-Difluoro-11 β-hydroxy-16α-methyl-17α-(1-methylcyclopropylcarbonyl)oxy-3- oxo-androsta-1 ,4-diene-17β-carboxylic acid fluoromethyl ester, 6α,9α-Difluoro-1 1 β-hydroxy-16α-methyl-3-oxo-17α-(2, 2,3,3- tetramethylcyclopropylcarbonyl)oxy-androsta-1 ,4-diene-17β-carboxylic acid methyl ester,
6 ,9α-Difluoro-1 1 β-hydroxy-16α-methyl-3-oxo-17α-(2, 2,3,3- tetramethylcyclopropylcarbonyl)oxy-androsta-1 ,4-diene-17β-carboxylic acid fluoromethyl ester,
9α-Chloro-6α-fluoro-11 β-hydroxy-16α-methyl-3-oxo-17α-(2,2,3,3- tetramethylcyclopropylcarbonyl)oxy-androsta-1 ,4-diene-17β-carboxylic acid methyl ester,
9α-Chloro-6α-fluoro-11 β-hydroxy-16 -methyl-3-oxo-17α-(2, 2,3,3- tetramethylcyclopropylcarbonyl)oxy-androsta-1 ,4-diene-17β-carboxylic acid fluoromethyl ester
6α,9α-Difluoro-1 1 β-hydroxy-16α-methyl-3-oxo-17α-(2, 2,3,3- tetramethylcyclopropylcarbonyl)oxy-androsta-1 ,4-diene-17β-carboxylic acid chloromethyl ester 9α-Fluoro-11 β-hydroxy-16β-methyl-3-oxo-17α-(2,2,3,3- tetramethylcyclopropylcarbonyl)oxy-androsta-1 ,4-diene-17β-carboxylic acid methyl ester
9α-Fluoro-11 β-hydroxy-16β-methyl-3-oxo-17α-(2,2,3,3- tetramethylcyclopropylcarbonyl)oxy-androsta-1 ,4-diene-17β-carboxylic acid fluoromethyl ester
9α-Fluoro-11 β-hydroxy-16β-methyl-3-oxo-17α-(2,2,3,3- tetramethylcyclopropylcarbonyl)oxy-androsta-1 ,4-diene-17β-carboxylic acid chloromethyl ester
17α-(Cyclopentylcarbonyl)oxy-6α,9α-difluoro-1 1 β-hydroxy-16α-methyl-3-oxo- androsta-1 ,4-diene-17β-carboxylic acid fluoromethyl ester
17α-(Cyclohexylcarbonyl)oxy-6α,9α-difluoro-11 β-hydroxy-16α-methyl-3-oxo- androsta-1 ,4-diene-17β-carboxylic acid methyl ester
17α-(Cyclohexylcarbonyl)oxy-6α,9α-difluoro-11 β-hydroxy-16α-methyl-3-oxo- androsta-1 ,4-diene-17β-carboxylic acid fluoromethyl ester 17α-(Cyclohexylcarbonyl)oxy-6α,9α-difluoro-11 β-hydroxy-16α-methyl-3-oxo- androsta-1 ,4-diene-17β-carboxylic acid chloromethyl ester
9α-Chloro-17α-(cyclohexylcarbonyl)oxy-6α-fluoro-11 β-hydroxy-16α-methyl-3-oxo- androsta-1 ,4-diene-17β-carboxylic acid fluoromethyl ester, or
9α-Chloro-17α-(cyclohexylcarbonyl)oxy-6α-fluoro-11 β-hydroxy-16α-methyl-3-oxo- androsta-1 ,4-diene-17β-carboxylic acid chloromethyl ester.
7. A compound of formula (I) as defined in any one of claims 1 to 6, or a physiologically acceptable solvate thereof for use in veterinary or human medicine.
8. Use of a compound of formula (I) as defined in any one of claims 1 to 6, or a physiologically acceptable solvate thereof for the manufacture of a medicament for the treatment of inflammatory and/or allergic conditions.
9. A pharmaceutical composition comprising a compound of formula (I) as defined in any one of claims 1 to 6, or a physiologically acceptable solvate thereof together, if desirable, in admixture with one or more physiologically acceptable diluents or carriers.
10. A pharmaceutical aerosol formulation comprising a compound of formula (I) as defined in any one of claims 1 to 6 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.
11. A pharmaceutical composition according to claim 9 or claim 10 which further comprises another therapeutically active agent.
12. A pharmaceutical composition according to claim 11 in which said another therapeutically active agent is a β2-adrenoreceptor agonist.
13. 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 6, or a physiologically acceptable solvate thereof.
14. A compound of formula (II)
Figure imgf000027_0001
wherein R2, R3, R4, R5and are as defined in any one of claims 1 to 6.
PCT/GB2003/000183 2002-01-15 2003-01-15 17.alpha-cycloalkyl/cycloylkenyl esters of alkyl-or haloalkyl-androst-4-en-3-on-11.beta.,17.alpha.-diol 17.beta.-carboxylates as anti-inflammatory agents WO2003072592A1 (en)

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