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WO2003064445A1 - 17-alpha-heterocyclic esters of androstane derivatives having anti-inflammatory activity - Google Patents

17-alpha-heterocyclic esters of androstane derivatives having anti-inflammatory activity Download PDF

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Publication number
WO2003064445A1
WO2003064445A1 PCT/GB2003/000379 GB0300379W WO03064445A1 WO 2003064445 A1 WO2003064445 A1 WO 2003064445A1 GB 0300379 W GB0300379 W GB 0300379W WO 03064445 A1 WO03064445 A1 WO 03064445A1
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Prior art keywords
methyl
compound
formula
carboxylic acid
androsta
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PCT/GB2003/000379
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French (fr)
Inventor
Keith Biggadike
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Glaxo Group Limited
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Publication of WO2003064445A1 publication Critical patent/WO2003064445A1/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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton

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 C 1-6 alkyl or d ⁇ haloalkyl
  • R 2 represents a 5 membered heterocyclic aromatic ring containing 1 -3 heteroatoms selected from O, N and S optionally substituted with one or more methyl groups and/or halogen atoms;
  • 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 salts and solvates thereof.
  • salts of compounds of formula (I) include physiologically acceptable salts which may be formed with basic compounds (such as when R 2 contains a basic nitrogen atom) eg. acetate, benzoate, citrate, succinate, lactate, tartrate, fumarate and maleate.
  • solvates include hydrates.
  • references hereinafter to a compound according to the invention includes both compounds of formula (I) and salts and solvates thereof, particularly pharmaceutically acceptable salts and solvates.
  • the absolute stereochemistry will be as shown in the representation of compounds of formula (I).
  • 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 to represent fluoromethyl, chloromethyl, bromomethyl or 2'-fluoroethyl, especially fluoromethyl.
  • heterocyclic aromatic rings that R may represent include thienyl (eg thien-2-yl or thien-3-yl), furanyl (eg furan-2-yl or furan-3-y), pyrrolyl (eg 1 H-pyrrol-2- yl), oxazolyl, thiadiazolyl (eg 1 ,2,3-thiadiazol-5-yl, 1 ,2,5-thiadiazol-3-yl or 1 ,2,3- thiadiazol-4-yl), thiazolyl (eg 1 ,3-thiazol-5-yl or 1 ,3-thiazol-4-yl), isoxazolyl (eg isoxazol-5-yl or isoxazol-4-yl), isothiazolyl (eg isothiazol-3-yl or isothiazol-5-yl), pyrazolyl (eg 1 H-pyrazol-5-yl) and imidazolyl (eg 1 H-
  • R 2 contains 2 or 3 heteroatoms, especially 2 heteroatoms.
  • R 2 contains 1 heteroatoms.
  • compounds wherein R contains 1 heteroatom are also of particular interest.
  • R 2 to represent a heterocyclic aromatic ring substituted by 1 or 2 substituents, especially 1 substituent.
  • R 2 to represent heterocyclic aromatic ring substituted by 1 or 2 methyl substituents, especially 1 methyl substituent.
  • at least one substituent is in a position ortho to the point of attachment of the heterocyclic ring to the CO moiety.
  • a substituent eg methyl
  • a further heteroatom may optionally be in position 4 (eg N).
  • Preferred groups R 2 include: furan-2-yl, 1 ,3-thiazol-5-yl and substituted derivatives thereof especially 3-methylfuran-2-yl and 4-methyl-1 ,3-thiazol-5-yl.
  • R 3 represents methyl, especially methyl in the cc 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: 6 ⁇ ,9 ⁇ -Difluoro-11 ⁇ -hydroxy-16 ⁇ -methyl-17 ⁇ -(3-methylfuran-2-ylcarbonyl)oxy-3-oxo- androsta-1 ,4-diene-17 ⁇ -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.
  • 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 compound of formula (I) or physiologically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of patients with inflammatory and/or allergic conditions.
  • 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 salt or solvate thereof.
  • the compounds according to the invention may be formulated for administration in any convenient way, and the invention therefore also includes within its scope pharmaceutical compositions comprising a compound of formula (I) or physiologically acceptable salt or solvate thereof together, if desirable, in admixture with one or more physiologically acceptable diluents or carriers.
  • 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, cetostearyf 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. (Senerall , 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 ondition 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, an anti-allergic or an anti-cholinergic.
  • ⁇ 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):
  • R 16 and R 17 are independently selected from hydrogen, C ⁇ - 6 alkyl, C 3 . 7 cycloalkyl,
  • R 16 and R 17 are each optionally substituted by one or two groups selected from halo, C ⁇ . 6 alkyl, C ⁇ . 6 haloalkyl,
  • R 18 and R 19 are independently selected from hydrogen, C ⁇ . 6 alkyl, C 3 . 6 cycloalkyl, phenyl, and phenyl (C ⁇ . 4 alkyl)-; and p is an integer of from 0 to 6, preferably from 0 to 4;
  • R 12 and R 13 are independently selected from hydrogen, C ⁇ alkyl, C ⁇ . 6 alkoxy, halo, phenyl, and C ⁇ - 6 haloalkyl;
  • R 14 and R 15 are independently selected from hydrogen and with the proviso that the total number of carbon atoms in R 14 and R 15 is not more than 4.
  • anti-histamines examples include methapyrilene or loratadine.
  • anti- allergies include cromoglycate (eg as sodium), ketotifen and nedocromil (as as sodium).
  • anti-cholinergics include ipratropium (eg as bromide), tiotropium, atropine or oxitropium. Any of the aforementioned substances may be employed in the form of alternative salts or solvates thereof.
  • 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.
  • 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 [ 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.
  • 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 al.
  • 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 [ ⁇ HjcAMP 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 (Torffhy 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 [ 3 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 salt or 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 reaction 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 t ase e.g. potassium carbonate.
  • R 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 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.
  • 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-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.
  • 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 salt and solvates thereof.
  • the advantages of compounds of formula (I) and/or solvates thereof include the fact that the substances 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.
  • LCMS 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% HCO 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 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).
  • Example 1 6 ⁇ ,9 ⁇ -Difluoro-11 ⁇ -hydroxy-16 ⁇ -methyl-17oc-(3-methylfuran-2- ylcarbonyl)oxy-3-oxo-androsta-1.4-diene-17 ⁇ -carboxylic acid methyl ester
  • Example 2 6 ⁇ .9 ⁇ -Difluoro-11 ⁇ -hvdroxy-16 ⁇ -methyl-3-oxo-17oc-(1.3-thiazol-5- ylcarbonyl)oxy-androsta-1 ,4-diene-17 ⁇ -carboxylic acid methyl ester
  • Example 2 was prepared from Intermediate 2 using a method analogous to that described for Example 1.
  • Example 3 6 ⁇ .9 ⁇ -Difluoro-11 ⁇ -hvdroxy-16 ⁇ -methyl-17 -(4-methyl-1 ,3-thiazol-5- ylcarbonyl)oxy-3-oxo-androsta-1.4-diene-17 ⁇ -carboxylic acid methyl ester
  • Example 3 was prepared from Intermediate 3 using a method analogous to that described for Example 1.
  • Example 4 6 ⁇ .9 ⁇ -Difluoro-11 ⁇ -hvdroxy-16 ⁇ -methyl-17 -(3-methylfuran-2- ylcarbonyl)oxy-3-oxo-androsta-1 ,4-diene-17 ⁇ -carboxylic acid fluoromethyl ester Potassium carbonate (62mg, 0.45mmol) was added to a stirred solution of Intermediate 1 (200mg, 0.4mmol) in anhydrous DMF (5ml) and the mixture cooled to -25 °C. Bromofluoromethane (123mg, 1.01 mmol) was then added and the mixture stirred between -25 °C and -30 °C for 3h.
  • Example 5 6 ⁇ .9 ⁇ -Difluoro-11 ⁇ -hvdroxy-16 ⁇ -methyl-3-oxo-17 ⁇ -(1 ,3-thiazol-5- ylcarbonyl)oxy-androsta-1.4-diene-17 ⁇ -carboxylic acid fluoromethyl ester
  • Example 5 was prepared from Intermediate 2 using a method analogous to that described for Example 4. LCMS retention time 3.35min, m/z 540 MHX
  • Example 6 6 ⁇ ,9 ⁇ -Difluoro-11 ⁇ -hvdroxy-16 ⁇ -methyl-17oc-(4-methyl-1 ,3-thiazol-5- ylcarbonyl)oxy-3-oxo-androsta-1 ,4-diene-17 ⁇ -carboxylic acid fluoromethyl ester
  • Example 6 was prepared from Intermediate 3 using a method analogous to that described for Example 4.
  • Example 7 6 ⁇ .9 ⁇ -Difluoro-17 ⁇ -(furan-2ylcarbonv0oxy-11 ⁇ -hvdroxy-16 ⁇ -methyl -3- oxo-androsta-1.4-diene-17 ⁇ -carboxylic acid fluoromethyl ester
  • Example 7 was prepared from Intermediate 4 using a method analogous to that described for Example 4.
  • 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,
  • the EC 50 for Examples 1 -7 was determined to be ⁇ 1 nM.

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Abstract

A compound of formula (I): wherein R1 represents C1-6 alkyl or C1-6 haloalkyl; R2 represents a 5 membered heterocyclic aromatic ring containing 1-3 heteroatoms selected from O, N and S optionally substituted with one or more methyl groups and/or halogen atoms; R3 represents methyl (which may be either the α or β configuration) or methylene; R4 and R5 are the same or different and each represents hydrogen or halogen; and (a) represents a single or a double bond; and salt and solvates thereof.

Description

17-ALPHA-HETEROCYCLIC ESTERS OF ANDROSTANE DERIVATIVES HAVING ANTI- INFLAMMATORY ACTIVITY
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 C1-6 alkyl or d^ haloalkyl; R2 represents a 5 membered heterocyclic aromatic ring containing 1 -3 heteroatoms selected from O, N and S optionally substituted with one or more methyl groups and/or halogen atoms;
R3 represents 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 salts and solvates thereof. Examples of salts of compounds of formula (I) include physiologically acceptable salts which may be formed with basic compounds (such as when R2 contains a basic nitrogen atom) eg. acetate, benzoate, citrate, succinate, lactate, tartrate, fumarate and maleate.
Examples of solvates include hydrates.
References hereinafter to a compound according to the invention includes both compounds of formula (I) and salts and solvates thereof, particularly pharmaceutically acceptable salts and solvates.
It will be appreciated that the invention includes within its scope all stereoisomers of the compounds of formula (I) and mixtures thereof.
Preferably, the absolute stereochemistry will be as shown in the representation of compounds of formula (I).
Examples of
Figure imgf000003_0001
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.
Examples of heterocyclic aromatic rings that R may represent include thienyl (eg thien-2-yl or thien-3-yl), furanyl (eg furan-2-yl or furan-3-y), pyrrolyl (eg 1 H-pyrrol-2- yl), oxazolyl, thiadiazolyl (eg 1 ,2,3-thiadiazol-5-yl, 1 ,2,5-thiadiazol-3-yl or 1 ,2,3- thiadiazol-4-yl), thiazolyl (eg 1 ,3-thiazol-5-yl or 1 ,3-thiazol-4-yl), isoxazolyl (eg isoxazol-5-yl or isoxazol-4-yl), isothiazolyl (eg isothiazol-3-yl or isothiazol-5-yl), pyrazolyl (eg 1 H-pyrazol-5-yl) and imidazolyl (eg 1 H-imidazol-5-yl).
We prefer that R2 contains 2 or 3 heteroatoms, especially 2 heteroatoms. However compounds wherein R contains 1 heteroatom are also of particular interest.
We prefer R2 to represent a heterocyclic aromatic ring substituted by 1 or 2 substituents, especially 1 substituent. We prefer R2 to represent heterocyclic aromatic ring substituted by 1 or 2 methyl substituents, especially 1 methyl substituent. Preferably at least one substituent is in a position ortho to the point of attachment of the heterocyclic ring to the CO moiety.
For example, in a heterocycle numbered with position 1 representing a first heteroatom (eg O or S), the point of attachment to the CO moiety may be at position 2, a substituent (eg methyl) may be in position 3 and a further heteroatom may optionally be in position 4 (eg N).
Preferred groups R2 include: furan-2-yl, 1 ,3-thiazol-5-yl and substituted derivatives thereof especially 3-methylfuran-2-yl and 4-methyl-1 ,3-thiazol-5-yl.
We prefer R3 to represent methyl, especially methyl in the cc 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: 6α,9α-Difluoro-11 β-hydroxy-16α-methyl-17α-(3-methylfuran-2-ylcarbonyl)oxy-3-oxo- androsta-1 ,4-diene-17β-carboxylic acid methyl ester
6α,9α-Difluoro-11 β-hydroxy-16α-methyl-3-oxo-17α-(1 ,3-thiazol-5-ylcarbonyl)oxy- androsta-1 ,4-diene-17β-carboxylic acid methyl ester
6α,9α-Difluoro-11 β-hydroxy-16α-methyl-17α-(4-methyl-1 ,3-thiazol-5-ylcarbonyl)oxy- 3-oxo-androsta-1 ,4-diene-17β-carboxylic acid methyl ester
6α,9α-Difluoro-1 1 β-hydroxy-16α-methyl-17α-(3-methylfuran-2-ylcarbonyl)oxy-3-oxo- androsta-1 ,4-diene-17β-carboxylic acid fluoromethyl ester
6α,9α-Difluoro-11 β-hydroxy-16cc-methyl-3-oxo-17α-(1 ,3-thiazol-5-ylcarbonyl)oxy- androsta-1 ,4-diene-17β-carboxylic acid fluoromethyl ester 6α,9α-Difluoro-11 β-hydroxy-16α-methyl-17α-(4-methyl-1 ,3-thiazol-5-ylcarbo ϊyl)oxy- 3-oxo-androsta-1 ,4-diene-17β-carboxylic acid fluoromethyl ester, and 6α,9α-Dif luoro-17α-(f uran-2ylcarbonyl)oxy-11 β-hydroxy-16α-methyl -3-oxo-androsta- 1 ,4-diene-17β-carboxylic acid fluoromethyl 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 salt or solvate thereof for use in human or veterinary medicine, particularly in the treatment of patients with inflammatory and/or allergic conditions.
According to another aspect of the invention, there is provided the use of a compound of formula (I) or physiologically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of patients with inflammatory and/or allergic conditions.
In a further or alternative aspect, there is provided a method for the treatment of a human or animal subject with an inflammatory and/or allergic condition, which method comprises administering to said human or animal subject an effective amount of a compound of formula (I) or physiologically acceptable salt or solvate thereof.
The compounds according to the invention may be formulated for administration in any convenient way, and the invention therefore also includes within its scope pharmaceutical compositions comprising a compound of formula (I) or physiologically acceptable salt or solvate thereof together, if desirable, in admixture with one or more physiologically acceptable diluents or carriers.
Further, there is provided a process for the preparation of such pharmaceutical compositions which comprises mixing the ingredients.
The compounds according to the invention may, for example, be formulated for oral, buccal, sublingual, parenteral, local or rectal administration, especially local administration.
Local administration as used herein, includes administration by insufflation and inhalation. Examples of various types of preparation for local administration include ointments, lotions, creams, gels, foams, preparations for delivery by transdermal patches, powders, sprays, aerosols, capsules or cartridges for use in an inhaler or insufflator or drops (e.g. eye or nose drops), solutions/suspensions for nebulisation, suppositories, pessaries, retention enemas and chewable or suckable tablets or pellets (e.g. for the treatment of aphthous ulcers) or liposome or microencapsulation preparations.
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, cetostearyf 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. (Senerall , 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 ondition 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, an anti-allergic or an anti-cholinergic.
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 imgf000009_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, Cι-6alkyl, 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, Cι.6alkyl, Cι.6haloalkyl,
C^alkoxy, hydroxy-substituted d-ealkoxy, -CO2R18, -SO2NR18R19, -CONR18R19, -
NR18C(O)R19, or a 5-, 6- or 7-membered heterocylic ring;
R18and R19are independently selected from hydrogen, Cι.6alkyl, C3.6cycloalkyl, phenyl, and phenyl (Cι.4alkyl)-; and p is an integer of from 0 to 6, preferably from 0 to 4;
R12 and R13 are independently selected from hydrogen, C^alkyl, Cι.6alkoxy, halo, phenyl, and Cι-6haloalkyl; and
R14 and R15 are independently selected from hydrogen and
Figure imgf000010_0001
with the proviso that the total number of carbon atoms in R14 and R15 is not more than 4.
Examples of anti-histamines include methapyrilene or loratadine. Examples of anti- allergies include cromoglycate (eg as sodium), ketotifen and nedocromil (as as sodium). Examples of anti-cholinergics include ipratropium (eg as bromide), tiotropium, atropine or oxitropium. Any of the aforementioned substances may be employed in the form of alternative salts or solvates thereof.
Other suitable combinations include, for example, other anti-inflammatory agents eg. NSAIDs (eg. 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 1nM 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 al. 15th EFMC Int Symp Med Chem (Sept 6- 10, Edinburgh) 1998, Abst P.98); a 9-benzyladenine derivative nominated NCS-613 (INSERM); D-4418 from Chiroscience and Schering-Plough; a benzodiazepine PDE4 inhibitor identified as CI-1018 (PD-168787; Parke-Davis/Warner-Lambert); a benzodioxole derivative Kyowa Hakko disclosed in WO 9916766; V-11294A from Napp (Landells, L.J. et al. Eur Resp J [Annu Cong Eur Resp Soc (Sept 19-23, Geneva) 1998] 1998, 12(Suppl. 28): Abst P2393); roflumilast (CAS reference No 162401-32-3) and a pthalazinone (WO 9947505) from Byk-Gulden; or a compound identified as T-440 (Tanabe Seiyaku; Fuji, K. et al. J Pharmacol Exp Ther,1998, 284(1): 162).
Phosphodiesterase and Rolipram Binding Assays
Assay method 1A
Isolated human monocyte PDE4 and hrPDE (human recombinant PDE4) was determined to exist primarily in the low affinity form. Hence, the activity of test compounds against the low affinity form of PDE4 can be assessed using standard assays for PDE4 catalytic activity employing 1 μM [^HjcAMP 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 (Torffhy 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.
f3H1R-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 [3H]R-rolipram (5.7 x 104 dpm/pmol) and various concentrations of non-radiolabeled inhibitors. The reaction was stopped by the addition of 2.5 ml of ice-cold reaction buffer (without [3H]-R-rolipram) and rapid vacuum filtration (Brandel Cell Harvester) through Whatman GF/B filters that had been soaked in 0.3% polyethylenimine. The filters were washed with an additional 7.5 ml of cold buffer, dried, and counted via liquid scintillation spectrometry. The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a physiologically acceptable salt or solvate thereof together with a PDE4 inhibitor.
The 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 salts and solvates thereof may be prepared by the methodology described hereinafter, constituting a further aspect of this invention.
A process according to the invention for preparing a compound of formula (I) comprises reaction of a carboxylic acid of formula (II)
Figure imgf000014_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 t ase e.g. potassium carbonate.
Compounds of formula (II) may conveniently be employed as salts when such salts may be prepared in crystalline form.
When R, 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 17cc-hydroxyl derivative of formula (III):
Figure imgf000015_0001
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 salt and solvates thereof.
The advantages of compounds of formula (I) and/or solvates thereof include the fact that the substances 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% HCO H 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).
Intermediate 1 : 6α.9α-Dif luoro-11 β-hydroxy-16α-methyl-17α-(3-methylf uran-2- ylcarbonyl)oxy-3-oxo-androsta-1.4-diene-17β-carboxylic acid A solution of 3-methylfuran-2-carbonyl chloride (474mg, 3.28mmole) in anydrous dichloromethane (5ml) was added to a stirred and cooled (ice) solution of 6α,9α- difluoro-11 β,17α-dihydroxy-16α-methyl-3-oxo-androsta-1 ,4-diene-17β-carbσxylic acid (G. H. Phillipps et al.. (1994) Journal of Medicinal Chemistry, 37, 3717-3729) (500mg, 1.26mmol) and triethylamine (0.453ml, 3.28mmol) in anhydrous dichloromethane (15ml). The mixture was stirred under nitrogen for 3h and then diluted with dichloromethane (30ml) and washed successively with aqueous sodium bicarbonate (20ml), 1 M hydrochloric acid (20ml), water (20ml) and dried through a hydrophobic frit and evaporated. The residual solid was dissolved in dioxane (20ml), 1-methylpiperazine (0.532ml, 4.8mmol) was added and the reaction left to stand at room temperature for 3h. The mixture was then added portionwise over 5min to a vigorously stirred solution of 2M hydrochloric acid (25ml) and ice (25ml). The resulting precipitate was filtered off, washed with water and dried to yield the title compound as a white solid (563mg): LCMS retention time 3.31 min.
The following intermediates were prepared by an analogous method to Intermediate 1 :
Intermediate 2: 6α.9α-Dif luoro-11 β-hydroχy-16α-methyl-3-oxo-17 -(1 ,3-thiazol-5- ylcarbonyl)oxy-androsta-1 ,4-diene-17β-carboxylic acid LCMS retention time 3.13min.
Intermediate 3: 6 ,9α-Difluoro-11 β-hydroxy-16α-methyl-17α-(4-methyl-1 ,3-thiazol-5- ylcarbonyl)oxy-3-oxo-androsta-1 ,4-diene-17β-carboxylic acid LCMS retention time 3.17min.
Intermediate 4: 6α.9α-Difluoro-17α-(furan-2ylcarbonyl)oxy-11 β-hvdroxy-16α-methyl - 3-oxo-androsta-1 ,4-diene-17β-carboxylic acid LCMS retention time 3.28min.
Example 1 : 6α,9α-Difluoro-11 β-hydroxy-16α-methyl-17oc-(3-methylfuran-2- ylcarbonyl)oxy-3-oxo-androsta-1.4-diene-17β-carboxylic acid methyl ester
Potassium carbonate (50mg, 0.36mmol) was added to a solution of Intermediate 1 (200mg, 0.4mmol) and methyl iodide (84mg, 0.59mmol) in anhydrous DMF (5ml) and the mixture stirred under nitrogen for 4h. The reaction mixture was diluted with dichloromethane (10ml) and applied to a Bond Elut cartridge (10g) and eluted with dichloromethane followed by ether to yield the title compound as a white solid (152mg): LCMS retention time 3.47min, m/z 519 MHX Example 2: 6α.9α-Difluoro-11 β-hvdroxy-16α-methyl-3-oxo-17oc-(1.3-thiazol-5- ylcarbonyl)oxy-androsta-1 ,4-diene-17β-carboxylic acid methyl ester Example 2 was prepared from Intermediate 2 using a method analogous to that described for Example 1.
LCMS retention time 3.27min, m/z 522 MHX
Example 3: 6α.9α-Difluoro-11 β-hvdroxy-16α-methyl-17 -(4-methyl-1 ,3-thiazol-5- ylcarbonyl)oxy-3-oxo-androsta-1.4-diene-17β-carboxylic acid methyl ester Example 3 was prepared from Intermediate 3 using a method analogous to that described for Example 1. LCMS retention time 3.34min, m/z 536 MHX
Example 4: 6α.9α-Difluoro-11 β-hvdroxy-16α-methyl-17 -(3-methylfuran-2- ylcarbonyl)oxy-3-oxo-androsta-1 ,4-diene-17β-carboxylic acid fluoromethyl ester Potassium carbonate (62mg, 0.45mmol) was added to a stirred solution of Intermediate 1 (200mg, 0.4mmol) in anhydrous DMF (5ml) and the mixture cooled to -25 °C. Bromofluoromethane (123mg, 1.01 mmol) was then added and the mixture stirred between -25 °C and -30 °C for 3h. Diethylamine (37mg, 0.51 mmol) was added and the mixture stirred at -20 °C for 30min. The temperature was then allowed to rise to 0 °C, 2M hydrochloric acid (7.6ml) was added and the mixture was stirred at 0 °C for 30 min and then poured into water (25ml) with vigorous stirring. The resulting precipitate was filtered off, washed well with water and dried. This material was then dissolved in dichloromethane (20ml) and applied to a Bond Elut cartridge (1 Og) and eluted with dichloromethane followed by ether to yield the title compound as a white solid (100mg): LCMS retention time 3.53min, m/z 536 MHX
Example 5: 6α.9α-Difluoro-11 β-hvdroxy-16α-methyl-3-oxo-17α-(1 ,3-thiazol-5- ylcarbonyl)oxy-androsta-1.4-diene-17β-carboxylic acid fluoromethyl ester Example 5 was prepared from Intermediate 2 using a method analogous to that described for Example 4. LCMS retention time 3.35min, m/z 540 MHX
Example 6: 6α,9α-Difluoro-11 β-hvdroxy-16α-methyl-17oc-(4-methyl-1 ,3-thiazol-5- ylcarbonyl)oxy-3-oxo-androsta-1 ,4-diene-17β-carboxylic acid fluoromethyl ester Example 6 was prepared from Intermediate 3 using a method analogous to that described for Example 4.
LCMS retention time 3.41 min, m/z 554 MHX
Example 7: 6α.9α-Difluoro-17α-(furan-2ylcarbonv0oxy-11 β-hvdroxy-16α-methyl -3- oxo-androsta-1.4-diene-17β-carboxylic acid fluoromethyl ester
Example 7 was prepared from Intermediate 4 using a method analogous to that described for Example 4.
LCMS retention time 3.38min, m/z 522 MHX
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 EC50 values may be estimated.
The EC50 for Examples 1 -7 was determined to be <1 nM.
Throughout the specification and the claims which follow, unless the context requires otherwise, the word 'comprise', and variations such as 'comprises' and ' 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 imgf000021_0001
wherein
RT represents represents
Figure imgf000021_0002
alkyl or C1-6 haloalkyl;
R2 represents a 5 membered heterocyclic aromatic ring containing 1 -3 heteroatoms selected from O, N and S optionally substituted with one or more methyl groups and/or halogen atoms;
R3 represents 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 salt and solvates thereof.
2. A compound as claimed in claim 1 wherein R, represents C^ haloalkyl.
3. A compound as claimed in claim 2 wherein RT represents fluoromethyl.
4. A compound as claimed in any one of the preceding claims wherein R2 is furan-2-yl, 1 ,3-thiazol-5-yl or substituted derivatives thereof especially 3-methylfuran- 2-yl and 4-methyl-1 ,3-thiazol-5-yl.
5. A compound as claimed in any one of the proceding claims wherein R3 is methyl in the α configuration.
6. A compound as claimed in any one of the preceding claims wherein the compound is: 6α,9α-Difluoro-11 β-hydroxy-16α-methyl-17α-(3-methylfuran-2-ylcarbonyl)oxy-3-oxo- androsta-1 ,4-diene-17β-carboxylic acid methyl ester
6α,9α-Difluoro-1 1 β-hydroxy-16α-methyl-3-oxo-17α-(1 ,3-thiazol-5-ylcarbonyl)oxy- androsta-1 ,4-diene-17β-carboxylic acid methyl ester 6α,9α-Difluoro-1 1 β-hydroxy-16α-methyl-17c -(4-methyl-1 ,3-thiazol-5-ylcarbonyl)oxy-
3-oxo-androsta-1 ,4-diene-17β-carboxylic acid methyl ester
6α,9α-Difluoro-11 β-hydroxy-16α-methyl-17α-(3-methylfuran-2-ylcarbonyl)oxy-3-oxo- androsta-1 ,4-diene-17β-carboxylic acid fluoromethyl ester
6α,9α-Difluoro-11 β-hydroxy-16α-methyl-3-oxo-17α-(1 ,3-thiazol-5-ylcarbonyl)oxy- androsta-1 ,4-diene-17β-carboxylic acid fluoromethyl ester
6α,9α-Difluoro-11 β-hydroxy-16α-methyl-17α-(4-methyl-1 ,3-thiazol-5-ylcarbonyl)oxy-
3-oxo-androsta-1 ,4-diene-17β-carboxylic acid fluoromethyl ester, or
6 ,9α-Difluoro-17α-(furan-2ylcarbonyl)oxy-11 β-hydroxy-16α-methyl -3-oxo-androsta-
1 ,4-diene-17β-carboxylic acid fluoromethyl ester.
7. A compound of formula (I) as defined in any one of claims 1 to 6 or a physiologically acceptable salt or 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 salt or 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 salt or 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 salt or 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 10 which further comprises another therapeutically active agent.
12. A pharmaceutical composition according to claim 11 in which saicl 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 6or a physiologically acceptable salt or solvate thereof.
14. A compound of formula (II)
Figure imgf000023_0001
or a salt thereof wherein R2> R3, R4, R5and are as defined in any one of claims 1 to 6.
PCT/GB2003/000379 2002-01-31 2003-01-28 17-alpha-heterocyclic esters of androstane derivatives having anti-inflammatory activity WO2003064445A1 (en)

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