Classifications

• • 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
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/08—Antiallergic agents
• • 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 compounds which are glucocorticoid receptor agonists 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.
• Androstane 17 ⁇ -carbonate compounds said to have anti-inflammatory activity are disclosed in U.S. patent 4,996,335.
• R 1 represents C 4 -C 7 branched chain alkyl
• C 3 -C 8 cycloalkyl optionally substituted by one or more groups independently selected from CrC 3 alkyl and methoxy,
• C 4 -C 6 cycloalkylmethyl optionally substituted by one or more groups selected from methyl or ethyl, or a bicycloalkyl group optionally substituted by one or more methyl groups;
• R 2 represents hydrogen, a methyl group, which may be in either the ⁇ or ⁇ configuration, or a methylene group
• R 3 and R 4 are the same or a different group and each independently represents hydrogen, halogen or a methyl group; and represents a single or a double bond; or a physiologically acceptable solvate thereof.
• solvates include hydrates.
• references hereinafter to a compound according to the invention includes both compounds of formula (I) and solvates thereof.
• R 1 represents C 4 -C 6 branched chain alkyl.
• C 4 -C 6 branched alkyl groups which R 1 may represent include a 1 ,1- dimethylethyl, 1 ,1-dimethylpropyl, 2-ethylbutyl, 1-ethyl-2-methylpropyl, 1 , 2- dimethylpropyl or a 1 ,2,2-trimethylpropyl Isomer A group.
• R 1 represents cyclohexyl optionally substituted by one or more groups independently selected from C 1 -C 3 alkyl and methoxy.
• R 1 represents cyclohexyl optionally substituted by one or more groups independently selected from methyl and methoxy.
• cyclohexyl groups which R 1 may represent include a (1/?, 2R)-2- (methyloxy)cyclohexyl, (1 S, 2S)-2-(methyloxy)cyclohexyl or a 3, 3-dimethylcyclohexyl Isomer A group.
• R 1 represents cyclopentylmethyl wherein the methyl group is optionally substituted by a group selected from methyl or ethyl.
• R 1 examples include a cyclopentylmethyl or a 1-cyclopentylethyl Isomer A group.
• R 1 represents a bicycloalkyl group optionally substituted by one or more methyl groups.
• bicycloalkyl groups which Ri may represent include 1 RS,2RS,4SR - bicyclo[2.2.1]hept-2-yl Isomer B, ⁇ RS,2SRASR bicyclo [2.2.1]hept-2-yl or a (1 R, 2R, 4S)-3, 3-dimethylbicyclo ⁇ 2.2.1]hept-2-yl group.
• R 2 represents a methyl group. In a further embodiment R 2 represents methyl in the ⁇ -configuration.
• R 3 and R 4 which can be the same or different, each represents hydrogen, methyl, fluorine or chlorine, for example hydrogen or fluorine. In one embodiment R 3 and R 4 are both fluorine.
• In one embodiment represents a double bond.
• Fluoromethyl (6 ⁇ ,1 1 ⁇ ,16 ⁇ ,17 ⁇ )-17-( ⁇ [(1 ,1-dimethylpropyl)oxy]carbonyl ⁇ oxy)-6,9- difluoro-11 -hydroxy-16-methyl-3-oxoandrosta-1 ,4-diene-17-carboxylate; Fluoromethyl (6 ⁇ , 1 1 ⁇ , 16 ⁇ , 17 ⁇ )-6,9-difluoro-11 -hydroxy-16-methyl-17-[( ⁇ [(1 R,2S,5R)- 5-methyl-2-(1 -methylethylJcyclohexylJoxyJcarbonyOoxyJ-S-oxoandrosta-i ,4-diene-17- carboxylate;
• Fluoromethyl (6 ⁇ , 11 ⁇ , 16 ⁇ , 17 ⁇ )-17-( ⁇ [(1 f?,2K,4S)-bicyclo[2.2.1 ]hept-2- yloxy]carbonyl ⁇ oxy)-6,9-difluoro-11 -hydroxy-16-methyl-3-oxoandrosta-1 ,4-diene-17- carboxylate; Fluoromethyl (6 ⁇ , 11 ⁇ , 16 ⁇ , 17 ⁇ )-17-( ⁇ [( 1 RS,2SR4Sf?)-bicyclo[2.2.1 ]hept-2- yloxy]carbonyl ⁇ oxy)-6,9-difluoro-11 -hydroxy-16-methyl-3-oxoandrosta-1 ,4-diene-17- carboxylate;
• Fluoromethyl (6 ⁇ ,1 1 ⁇ ,16 ⁇ ,17 ⁇ )-17- ⁇ [(cycloheptyloxy)carbonyl]oxy ⁇ -6,9-difluoro-11- hydroxy-16-methyl-3-oxoandrosta-1 ,4-diene-17-carboxylate; Fluoromethyl (6 ⁇ ,1 1 ⁇ ,16 ⁇ ,17 ⁇ )-17-( ⁇ [(cyclopentylmethyl)oxy]carbonyl ⁇ oxy)-6,9- difluoro-11 -hydroxy-16-methyl-3-oxoandrosta-1 ,4-diene-17-carboxylate;
• Fluoromethyl (6 ⁇ , 1 1 ⁇ , 16 ⁇ , 17 ⁇ )-17-( ⁇ [(1 -cyclopentylpropyOoxylcarbonylJoxyJ- ⁇ . ⁇ - difluoro-11 -hydroxy-16-methyl-3-oxoandrosta-1 ,4-diene-17-carboxylate; Fluoromethyl (6 ⁇ ,11 ⁇ ,16 ⁇ ,17 ⁇ )-17-( ⁇ [(1-cyclopentylethyl)oxy]carbonyl ⁇ oxy)-6,9- difluoro- 11 -hydroxy- 16-methyl-3-oxoandrosta-1 ,4-diene-17-carboxylate; Fluoromethyl (6 ⁇ ,1 1 ⁇ ,16 ⁇ ,17 ⁇ )-6,9-difluoro-1 1-hydroxy-16-methyl-3-oxo-17-( ⁇ [(1- propylbutyl)oxy]carbonyl ⁇ oxy)androsta-1 ,4-diene-17-carboxylate;
• Fluoromethyl (6 ⁇ ,1 1 ⁇ ,16 ⁇ ,17 ⁇ )-6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-( ⁇ [(1 ,2,2- trimethylpropyl)oxy]carbonyl ⁇ oxy)androsta-1 ,4-diene-17-carboxylate; Fluoromethyl (6 ⁇ , 11 ⁇ , 16 ⁇ , 17 ⁇ )-6,9-difluoro-11 -hydroxy-16-methyl-3-oxo-17-
• Fluoromethyl (6 ⁇ , 11 ⁇ , 16 ⁇ , 17 ⁇ )-6,9-difluoro-11 -hydroxy-16-methyl-17-[( ⁇ [1 -(1 - methylethyl)butyl]oxy ⁇ carbonyl)oxy]-3-oxoandrosta-1 ,4-diene-17-carboxylate; Fluoromethyl (6 ⁇ ,11 ⁇ ,16 ⁇ ,17 ⁇ )-6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-
• Fluoromethyl (6 ⁇ ,1 i ⁇ .i ⁇ . ⁇ V ⁇ - ⁇ cyclopentyloxyJcarbonylloxyJ- ⁇ . ⁇ -difluoro-i 1- hydroxy-16-methyl-3-oxoandrosta-1 ,4-diene-17-carboxylate; Fluoromethyl (6 ⁇ , 11 ⁇ ,16 ⁇ ,17 ⁇ )-6,9-difluoro-1 1 -hydroxy-16-methyl-17-[( ⁇ [(1 S,2R,5S)-
• Fluoromethyl (6 ⁇ ,11 ⁇ ,16 ⁇ ,17 ⁇ )-17-( ⁇ [(c/s-4-ethylcyclohexyl)oxy]carbonyl ⁇ oxy)-6,9- difluoro-1 1 -hydroxy-16-methyl-3-oxoandrosta-1 ,4-diene-17-carboxylate; Fluoromethyl (6 ⁇ ,11 ⁇ ,16 ⁇ ,17 ⁇ )-17-( ⁇ [( ⁇ rans-4-ethylcyclohexyl)oxy]carbonyl ⁇ oxy)-6,9- difluoro-11 -hydroxy-16-methyl-3-oxoandrosta-1 ,4-diene-17-carboxylate; and
• compounds of formula (I) include:
• Fluoromethyl (6 ⁇ ,11 ⁇ ,16 ⁇ ,17 ⁇ )-17-( ⁇ [(1 ,1-dimethylpropyl)oxy]carbonyl ⁇ oxy)-6,9- difluoro-1 1 -hydroxy-16-methyl-3-oxoandrosta-1 ,4-diene-17-carboxylate; Fluoromethyl (6 ⁇ ,11 ⁇ ,16 ⁇ ,17 ⁇ )-17-( ⁇ [(2-ethylbutyl)oxy]carbonyl ⁇ oxy)-6,9-difluoro-11- hydroxy-16-methyl-3-oxoandrosta-1 ,4-diene-17-carboxylate;
• Fluoromethyl (6 ⁇ ,1 1 ⁇ ,16 ⁇ ,17 ⁇ )-17-( ⁇ [(1 ,1-dimethylpropyl)oxy]carbonyl ⁇ oxy)-6,9- difluoro-11 -hydroxy-16-methyl-3-oxoandrosta-1 ,4-diene-17-carboxylate; Fluoromethyl (6 ⁇ J 1 ⁇ J6 ⁇ J 7 ⁇ )-17-( ⁇ [(1-ethyl-2-methylpropyl)oxy]carbonyl ⁇ oxy)-6,9- difluoro-11 -hydroxy-16-methyl-3-oxoandrosta-1 ,4-diene-17-carboxylate; Fluoromethyl (6 ⁇ ,11 ⁇ ,16 ⁇ ,17 ⁇ )-17-( ⁇ [(1 ,2-dimethylpropyl)oxy]carbonyl ⁇ oxy)-6,9- difluoro-11 -hydroxy-16-methyl-3-oxoandrosta-1 ,4-diene-17-carboxylate;
• 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 potentially useful in the treatment of inflammatory and/or allergic disorders.
• Examples of disease states in which the compounds of the invention may have utility include skin diseases such as eczema, psoriasis, allergic dermatitis neurodermatitis, pruhtis 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, pruhtis 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
• Compounds of the invention may also have use in the treatment of conjunctiva and conjunctivitis.
• compounds of formula (I) may be useful in human or veterinary medicine, in particular as anti-inflammatory and anti-allergic agents.
• a compound of formula (I) or a physiologically acceptable 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 solvate thereof.
• the compounds according to the invention may be formulated for administration in any convenient way, and the invention therefore also includes within its scope pharmaceutical compositions comprising a compound of formula (I) or physiologically acceptable solvate thereof together, if desirable, in admixture with one or more physiologically acceptable diluents or carriers.
• the compounds according to the invention may, for example, be formulated for nasal, 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.
• 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, sorbitan trioleate or lecithin and cosolvents e.g. ethanol.
• formulations of the invention may be buffered by the addition of suitable buffering agents.
• Powders for external application may be formed with the aid of any suitable powder base, for example, talc, lactose or starch. Suitable powders may be formulated with additional excipients, for example, cellobiose octo-acetate and magnesium stearate.
• 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 be given by internal administration in cases where systemic adreno-cortical therapy is indicated.
• preparations for internal administration may contain from 0.05 to 10% of the active ingredient dependent upon the type of preparation involved.
• the daily dose may vary from 0.1 mg to 60mg, e.g. 5-30mg, dependent on the condition being treated, and the duration of treatment desired.
• Slow release or enteric coated formulations may be advantageous, particularly for the treatment of inflammatory bowel disorders.
• the compound and pharmaceutical compositions according to the invention may be used in combination with or include one or more other therapeutic agents, for example selected from anti-inflammatory agents, anticholinergic agents (particularly an M 1 ZM 2 ZM 3 receptor antagonist), ⁇ 2 -adrenoreceptor agonists, antiinfective agents (e.g. antibiotics, antivirals), or antihistamines.
• other therapeutic agents for example selected from anti-inflammatory agents, anticholinergic agents (particularly an M 1 ZM 2 ZM 3 receptor antagonist), ⁇ 2 -adrenoreceptor agonists, antiinfective agents (e.g. antibiotics, antivirals), or antihistamines.
• the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with one or more other therapeutically active agents, for example selected from an anti-inflammatory agent (for example another corticosteroid or an NSAID), an anticholinergic agent, a ⁇ 2 -adrenoreceptor agonist, an antiinfective agent (e.g. an antibiotic or an antiviral), or an antihistamine.
• an anti-inflammatory agent for example another corticosteroid or an NSAID
• an anticholinergic agent for example another corticosteroid or an NSAID
• an anticholinergic agent for example another corticosteroid or an NSAID
• an anticholinergic agent for example another corticosteroid or an NSAID
• an anticholinergic agent for example another corticosteroid or an NSAID
• an anticholinergic agent for example another corticosteroid or an NSAID
• On embodiment of the invention encompasses combinations comprising a compound of formula (I) or a pharmaceutically acceptable solvate or physiologically functional derivative thereof together with a ⁇ 2 -adrenoreceptor agonist, and/or an anticholinergic, and/or a PDE-4 inhibitor, andZor antihistamine.
• One embodiment of the invention encompasses combinations comprising one or two other therapeutic agents.
• the other therapeutic ingredient(s) may be used in the form of salts, (e.g. as alkali metal or amine salts or as acid addition salts), or prodrugs, or as esters (e.g. lower alkyl esters), or as solvates (e.g. hydrates) to optimise the activity and/or stability and/or physical characteristics (e.g. solubility) of the therapeutic ingredient.
• the therapeutic ingredients may be used in optically pure form.
• the invention encompasses a combination comprising a compound of the invention together with a ⁇ 2 -adrenoreceptor agonist
• ⁇ 2 -adrenoreceptor agonists include salmeterol (e.g. as racemate or a single enantiomer such as the f?-enantiomer), salbutamol (e.g. as racemate or a single enantiomer such as the f?-enantiomer), formoterol (e.g.
• ⁇ 2 - adrenoreceptor agonists are long-acting ⁇ 2 -adrenoreceptor agonists, for example compounds which provide effective bronchodilation for about 12 hours or longer.
• ⁇ 2 -adrenoreceptor agonists include those described in WO 02/066422, WO
• ⁇ -adrenoreceptor agonists include compounds of formula (XX):
• R 26 and R 27 are independently selected from hydrogen, C 1-6 alkyl, C 3 - 7 cycloalkyl,
• R 26 and R 27 are each optionally substituted by one or two groups selected from halo, Ci -6 haloalkyl, d-galkoxy, hydroxy-substituted C 1-6 alkoxy, -CO 2 R 28 , -SO 2 NR 28 R 29 , -CONR 28 R 29 ,
• R 28 and R 29 are independently selected from hydrogen, C 1-6 alkyl, C 3-6 cycl oa Iky I, phenyl, and phenyl (C 1-4 alkyl)-; and p is an integer of from 0 to 6, preferably from 0 to 4;
• R 22 and R 23 are independently selected from hydrogen, d. 6 alkyl, Ci -6 alkoxy, halo, phenyl, and C 1-6 haloalkyl;
• R 24 and R 25 are independently selected from hydrogen and C ⁇ alkyl with the proviso that the total number of carbon atoms in R 24 and R 25 is not more than 4.
• ⁇ 2 -adrenoreceptor agonists include: 3-(4- ⁇ [6-( ⁇ (2f?)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl ⁇ amino) hexyl] oxy ⁇ butyl) benzenesulfonamide;
• the ⁇ 2 -adrenoreceptor agonist may be in the form of a salt formed with a pharmaceutically acceptable acid selected from sulphuric, hydrochloric, fumaric, hydroxynaphthoic (for example 1- or 3-hydroxy-2-naphthoic), cinnamic, substituted cinnamic, triphenylacetic, sulphamic, sulphanilic, naphthaleneacrylic, benzoic, 4-methoxybenzoic, 2- or 4-hydroxybenzoic, 4-chlorobenzoic and 4-phenylbenzoic acid.
• a pharmaceutically acceptable acid selected from sulphuric, hydrochloric, fumaric, hydroxynaphthoic (for example 1- or 3-hydroxy-2-naphthoic), cinnamic, substituted cinnamic, triphenylacetic, sulphamic, sulphanilic, naphthaleneacrylic, benzoic, 4-
• Suitable anti-inflammatory agents include corticosteroids.
• Suitable corticosteroids which may be used in combination with the compounds of the invention are those oral and inhaled corticosteroids and their pro-drugs which have anti-inflammatory activity. Examples include methyl prednisolone, prednisolone, dexamethasone, fluticasone propionate, 6 ⁇ ,9 ⁇ -difluoro-11 ⁇ -hydroxy-16 ⁇ -methyl-17 ⁇ -[(4-methyl-1 ,3- thiazole-5-carbonyl)oxy]-3-oxo-androsta-1 ,4-diene-17 ⁇ -carbothioic acid S- fluoromethyl ester, 6 ⁇ ,9 ⁇ -difluoro-17 ⁇ -[(2-furanylcarbonyl)oxy]-11 ⁇ -hydroxy-16 ⁇ - methyl-3-oxo-androsta-1 ,4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester (fluticasone furoate), 6 ⁇ ,9 ⁇ -
• the 17-propionate ester or the 17,21- dipropionate ester the 17-propionate ester or the 17,21- dipropionate ester
• budesonide flunisolide
• mometasone esters e.g. the furoate ester
• triamcinolone acetonide e.g. the furoate ester
• rofleponide triamcinolone acetonide
• ciclesonide (16 ⁇ ,17-[[(f?)- cyclohexylmethylene]bis(oxy)]-1 1 ⁇ ,21-dihydroxy-pregna-1 ,4-diene-3,20-dione
• butixocort propionate RPR-106541 , and ST-126.
• One embodiment of the invention encompasses corticosteroids including fluticasone propionate, 6 ⁇ ,9 ⁇ -difluoro-1 1 ⁇ - hydroxy-16 ⁇ -methyl-17 ⁇ -[(4-methyl-1 ,3-thiazole-5-carbonyl)oxy]-3-oxo-androsta-1 ,4- diene-17 ⁇ -carbothioic acid S-fluoromethyl ester, 6 ⁇ ,9 ⁇ -difluoro-17 ⁇ -[(2- furanylcarbonyl)oxy]-1 1 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-androsta-1 ,4-diene-17 ⁇ - carbothioic acid S-fluoromethyl ester, 6 ⁇ ,9 ⁇ -difluoro-11 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo- 17 ⁇ -(2,2,3,3- tetramethycyclopropylcarbony ⁇ oxy-androsta-i ,4-diene-17 ⁇ -carbothioic acid S-cyanomethyl ester, 6 ⁇
• the corticosteroid is 6 ⁇ ,9 ⁇ -difluoro-17 ⁇ -[(2- furanylcarbonyl)oxy]-11 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-androsta-1 ,4-diene-17 ⁇ - carbothioic acid S-fluoromethyl ester.
• Non-steroidal compounds having glucocorticoid agonism that may posess selectivity for transrepression over transactivation and that may be useful in combination therapy include those covered in the following patents: WO03/082827, WO01/10143, WO98/54159, WO04/005229, WO04/009016, WO04/009017, WO04/018429, WO03/104195, WO03/082787, WO03/082280, WO03/059899, WO03/101932, WO02/02565, WO01/16128, WO00/66590, WO03/086294, WO04/026248, WO03/061651 , WO03/08277.
• anti-inflammatory agents include non-steroidal anti-inflammatory drugs (NSAID's).
• NSAID's include sodium cromoglycate, nedocromil sodium, phosphodiesterase (PDE) inhibitors (e.g. theophylline, PDE4 inhibitors or mixed PDE3/PDE4 inhibitors), leukotriene antagonists, inhibitors of leukotriene synthesis (eg. montelukast), iNOS inhibitors, tryptase and elastase inhibitors, beta-2 integrin antagonists and adenosine receptor agonists or antagonists (e.g. adenosine 2a agonists), cytokine antagonists (e.g.
• chemokine antagonists such as a CCR3 antagonist
• inhibitors of cytokine synthesis or 5-lipoxygenase inhibitors.
• an iNOS inducible nitric oxide synthase inhibitor
• examples of iNOS inhibitors include those disclosed in WO93/13055, WO98/30537, WO02/50021 , WO95/34534 and WO99/62875.
• Examples CCR3 inhibitors include those disclosed in WO02/26722.
• the invention provides the use of the compounds of formula (I) in combination with a phosphodiesterase 4 (PDE4) inhibitor, for example in the case of a formulation adapted for inhalation.
• 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, such as PDE3 and PDE5, as well as PDE4.
• Compounds of interest include c/s-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].
• AWD-12-281 from Elbion (Hofgen, N. et al. 15th EFMC lnt Symp Med Chem (Sept 6-10, Edinburgh) 1998, Abst P.98; CAS reference No. 247584020-9); a 9-benzyladenine derivative nominated NCS-613 (INSERM); D- 4418 from Chiroscience and Schering-Plough; a benzodiazepine PDE4 inhibitor identified as CI-1018 (PD-168787) and attributed to Pfizer; a benzodioxole derivative disclosed by Kyowa Hakko in WO99/16766; K-34 from Kyowa Hakko; V-11294A from Napp (Landells, L.J.
• anticholinergic agents are those compounds that act as antagonists at the muscarinic receptors, in particular those compounds which are antagonists of the M 1 or M 3 receptors, dual antagonists of the M 1 ZM 3 or M 2 /M 3 , receptors or pan- antagonists of the M 1 ZM 2 ZM 3 receptors.
• exemplary compounds for administration via inhalation include ipratropium (e.g. as the bromide, CAS 22254-24-6, sold under the name Atrovent), oxitropium (e.g. as the bromide, CAS 30286-75-0) and tiotropium (e.g. as the bromide, CAS 136310-93-5, sold under the name Spiriva).
• revatropate e.g. as the hydrobromide, CAS 262586-79-8
• LAS- 34273 which is disclosed in WO01Z04118.
• Exemplary compounds for oral administration include pirenzepine (CAS 28797-61-7), darifenacin (CAS 133099-04- 4, or CAS 133099-07-7 for the hydrobromide sold under the name Enablex), oxybutynin (CAS 5633-20-5, sold under the name Ditropan), terodiline (CAS 15793- 40-5), tolterodine (CAS 124937-51-5, or CAS 124937-52-6 for the tartrate, sold under the name Detrol), otilonium (e.g.
• anticholinergic agents include compounds of formula (XXI), which are disclosed in US patent application 60Z487981 : in which the preferred orientation of the alkyl chain attached to the tropane ring is endo;
• R 31 and R 32 are, independently, selected from the group consisting of straight or branched chain lower alkyl groups having preferably from 1 to 6 carbon atoms, cycloalkyl groups having from 5 to 6 carbon atoms, cycloalkyl-alkyl having 6 to 10 carbon atoms, 2-thienyl, 2-pyridyl, phenyl, phenyl substituted with an alkyl group having not in excess of 4 carbon atoms and phenyl substituted with an alkoxy group having not in excess of 4 carbon atoms;
• X " represents an anion associated with the positive charge of the N atom.
• X " may be but is not limited to chloride, bromide, iodide, sulfate, benzene sulfonate, and toluene sulfonate, including, for example:
• anticholinergic agents include compounds of formula (XXII) or (XXIII), which are disclosed in US patent application 60/51 1009:
• R 41 represents an anion associated with the positive charge of the N atom.
• R 41 may be but is not limited to chloride, bromide, iodide, sulfate, benzene sulfonate and toluene sulfonate;
• R 42 and R 43 are independently selected from the group consisting of straight or branched chain lower alkyl groups (having preferably from 1 to 6 carbon atoms), cycloalkyl groups (having from 5 to 6 carbon atoms), cycloalkyl-alkyl (having 6 to 10 carbon atoms), heterocycloalkyl (having 5 to 6 carbon atoms) and N or O as the heteroatom, heterocycloalkyl-alkyl (having 6 to10 carbon atoms) and N or O as the heteroatom, aryl, optionally substituted aryl, heteroaryl, and optionally substituted heteroaryl;
• R 44 is sleeted from the group consisting of (d-C 6 )alkyl, (C 3 -Ci 2 )cycloalkyl, (C 3 - C 7 )heterocycloalkyl, (d-C 6 )alkyl(C 3 -C 12 )cycloalkyl, (C 1 -C 6 )alkyl(C 3 -
• R 45 is selected from the group consisting of (C 1 -C 6 JaIkVl, (d-C 6 )alkyl(C 3 -
• R 46 is selected from the group consisting of (C 1 -C 6 JaIKyI 1 (C 3 -C 12 )cycloalkyl, (C 3 -
• R 47 and R 48 are, independently, selected from the group consisting of H, (C 1 -C 6 )alkyl,
• H1 -receptor antagonists examples include any one or more of the numerous antagonists known which inhibit H 1 -receptors, and are safe for human use.
• First generation antagonists include derivatives of ethanolamines, ethylenediamines, and alkylamines, e.g diphenylhydramine, pyrilamine, clemastine, chloropheniramine.
• Second generation antagonists which are non-sedating, include loratidine, desloratidine,terfenadine,astemizole,acrivastine, azelastine, levocetirizine fexofenadine and cetirizine.
• the antihistamines include loratidine, desloratidine, fexofenadine and cetirizine.
• Further examples include, without limitation, amelexanox, astemizole, azatadine, azelastine, acrivastine, brompheniramine, cetirizine, levocetirizine, efletirizine, chlorpheniramine, clemastine, cyclizine, carebastine, cyproheptadine, carbinoxamine, descarboethoxyloratadine, doxylamine, dimethindene, ebastine, epinastine, efletirizine, fexofenadine, hydroxyzine, ketotifen, loratadine, levocabastine, mizolastine, mequitazine, mianserin, noberastine, meclizine, norastemizole, olopatadine, picumast, pyrilamine, promethazine, terfenadine, tripelennamine, warmthlastine, trim
• the invention provides a combination comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof together with an H3 antagonist (and/or inverse agonist).
• H3 antagonists include, for example, those compounds disclosed in WO2004/035556 and in WO2006/045416.
• Other histamine receptor antagonists which may be used in combination with the compounds of the present invention include antagonists (and/or inverse agonists) of the H4 receptor, for example, the compounds disclosed in Jablonowski et al., J. Med. Chem. 46:3957-3960 (2003).
• the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with a PDE4 inhibitor.
• the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with a ⁇ 2 -adrenorecptor agonist.
• the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with an anticholinergic.
• the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with an antihistamine.
• the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with a PDE4 inhibitor and a ⁇ 2 - adrenoreceptor agonist.
• the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with an anticholinergic and a PDE-4 inhibitor.
• compositions comprising a combination as defined above together with a pharmaceutically acceptable diluent or carrier represent a further aspect of the invention.
• the individual compounds of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations. Preferably the individual compounds of such combinations may be administered simultaneously in a combined pharmaceutical combination. 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 1 , R 2 , R 3 , R 4 and are as defined above, with a compound of formula L-CH 2 -F wherein L represents a leaving group.
• the compound of formula (II) may be reacted with a compound of formula L-CH 2 -F wherein L represents a leaving group such as halogen atom or a tosyl or mesyl group or the like, under standard conditions.
• L represents a leaving group such as halogen atom or a tosyl or mesyl group or the like
• the reaction may be performed in an inert polar organic solvent e.g. N,N-dimethylformamide in the presence of a base e.g. potassium carbonate, sodium carbonate.
• R 2 , R 3 , R 4 and are as defined above, using for example, methodology similar to that described by G. H. Phillipps et a/., to prepare 17 ⁇ carboxylate esters (Journal of Medicinal Chemistry, (1994), 37, 3717- 3729) and by Druzgala et ai, to prepare the 17 ⁇ carbonate ester loteprednol etabonate (Journal of Steroid Chemistry and Molecular Biology, (1991 ), 38, 149- 154).
• the step typically comprises the reaction of the hydoxyacid (III) with a chloroformate RiOCOCI in the presence of a mild base e.g. triethylamine in a suitable solvent e.g. dichloromethane.
• a mild base e.g. triethylamine
• a suitable solvent e.g. dichloromethane.
• R 1 groups anhydrides (R 1 OCO) 2 O may be preferred to the
• chloroformate or anhydride would be employed in at least 2 times molar quantity relative to the compound of formula (III).
• the second mole of chloroformate or anhydride tends to react with the carboxylic acid moiety in the compound of formula (III) and would need to be removed by reaction with an amine such as diethylamine or 1-methylpiperazine.
• the chloroformates are either commercially available or are readily prepared by standard methodology e.g. by reaction of the corresponding alcohol R 1 OH with phosgene or more preferably triphosgene in the presence of a base e.g. pyridine in a suitable solvent e.g. dichloromethane.
• reaction of the 17 ⁇ -hydroxyl derivative (III) with the chloroformate R 1 OCOCI or anhydride (R 1 OCO) 2 O in pyridine solution often affords the 17 ⁇ carbonate (II) directly.
• Compounds of formula (I) and/or solvates thereof may demonstrate good antiinflammatory properties, with predictable pharmacokinetic and pharmacodynamic behaviour. They also may 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 likely to be compatible with a convenient regime of treatment in human patients.
• the following non-limiting Examples illustrate the invention:
• Chromatographic purification was performed using pre-packed Bond Elut silica gel cartridges available commercially from Varian.
• Autopreparative HPLC was carried out using a Waters 600 gradient pump, Waters 2767 inject/collector, Waters Reagent Manager, Micromass ZMD mass spectrometer, Gilson Aspec waste collector and Gilson 115 post-fraction UV detector.
• the column used was typically a Supelco LCABZ++ column with dimension of 20mm internal diameter by 100mm in length.
• the stationary phase particle size is 5 ⁇ m.
• the flow rate was 20ml/min and the runtime was 15 minutes, which comprises a 10-minute gradient followed by a 5 minute column flush and re-equilibration step.
• the LCMS system used was as follows:
• Solvents A: 0.1 % Formic Acid + IOmMolar Ammonium Acetate.
• Example 1 Fluoromethyl (6 ⁇ ,11 B.16 ⁇ .17 ⁇ )-17- ⁇ f(1.1- dimethylethv ⁇ oxylcarbonvDoxyV ⁇ .g-difluoro-H-hvdroxy-i ⁇ -methyl-S-oxoandrosta- 1.4-diene-17-carboxylate
• Bromofluoromethane (96 ⁇ l, 1.7mmol) was added and the reaction stirred at -3O 0 C to -2O 0 C for 2 hours before being allowed to warm to room temperature overnight.
• the reaction was then treated with diethylamine (500 ⁇ l, 7.56mmol) and added dropwise to 6M hydrochloric acid (30ml).
• the resulting precipitate was collected by filtration, washed with 2M hydrochloric acid (10ml) followed by water (3 x 10ml) and dried in vacuo at 5O 0 C.
• Example 2 Fluoromethyl f6 ⁇ .11 ⁇ .16 ⁇ .17 ⁇ )-17- ⁇ rf1.1- dimethylpropy ⁇ oxyicarbonvDoxyV ⁇ .g-difluoro-H-hvdroxy-i ⁇ -methyl-S-oxoandrosta- 1.4-diene-17-carboxylate
• Example 3 was prepared from (6 ⁇ ,11 ⁇ ,16 ⁇ ,17 ⁇ )-6,9-difluoro-1 1-hydroxy-16-methyl- 17-[( ⁇ [(1R,2S,5f?)-5-methyl-2-(1-methylethyl)cyclohexyl]oxy ⁇ carbonyl)oxy]-3- oxoandrosta-i ⁇ -diene- ⁇ -carboxylic acid (Intermediate 3) using a method similar to that described for Example 1.
• LCMS retention time 4.07 min, m/z 611 MH +
• Bromofluoromethane (45 ⁇ l, 0.79mmol) was added and the reaction stirred at -25 to - 35 0 C for 2 hours. Further bromofluoromethane (45 ⁇ l, 0.79mmol) was added and the reaction allowed to warm to room temperature overnight. The reaction was then treated with diethylamine (87 ⁇ l, 1.29mmol) and added dropwise to 2M hydrochloric acid. The resulting precipitate was extracted into ethyl acetate which was dried over anhydrous magnesium sulphate, filtered and evaporated in vacuo.
• Example 5 was prepared from (6 ⁇ ,11 ⁇ ,16 ⁇ ,17 ⁇ )-6,9-difluoro-11-hydroxy-16-methyl- 17-[( ⁇ [2-methyl-1 -(1 -methylethyOpropylJoxyJcarbonyOoxyJ-S-oxoandrosta-i ,4-diene- 17-carboxylic acid (Intermediate 5) using a method similar to that described for Example 4.
• the crude product was purified on a 5g silica Bond Elut cartridge using 1 :1 diethylether : cyclohexane to give the title compound: LCMS retention time 3.76 min, m/z 571 MH +
• Example 7 Fluoromethyl r ⁇ .1 1 B.16 ⁇ .17 ⁇ V17-(fff2.2- dimethylpropy ⁇ oxyicarbonvDoxyV ⁇ .g-difluoro-H-hvdroxy-i ⁇ -methyl-S-oxoandrosta- 1 ,4-diene-17-carboxylate
• Example 7 was prepared from (6 ⁇ ,1 1 ⁇ ,16 ⁇ ,17 ⁇ )-17-( ⁇ [(2,2- dimethylpropyl)oxy]carbonyl ⁇ oxy)-6,9-difluoro-1 1 -hydroxy-16-methyl-3-oxoandrosta- 1 ,4-diene-17-carboxylic acid (Intermediate 7) using a method similar to that described for Example 4. The crude product was purified on a 10g silica Bond Elut cartridge eluted using 0-100% diethylether in cyclohexane gradient over 40 minutes to give the title compound: LCMS retention time 3.61 min, m/z 543 MH +
• Example 8 Fluoromethyl (6 ⁇ .11 ⁇ .16o..17ct)-17-(ff(1-ethyl-2- methyl propyl )oxy1carbon yl)oxy)-6 , 9-d if I uoro- 1 1 -h yd roxy- 16-meth yl-3-oxoand rosta- 1 ,4-diene-17-carboxvlate
• Example 9 was prepared as a mixture of diastereomers from (6 ⁇ ,1 1 ⁇ ,16 ⁇ ,17 ⁇ )-17- ( ⁇ [(1 ,2-dimethylpropyl)oxy]carbonyl ⁇ oxy)-6,9-difluoro-1 1-hydroxy-16-methyl-3- oxoandrosta-1 ,4-diene-17-carboxylic acid (Intermediate 9) using a method similar to that described for Example 2.
• the crude product was purified on a 1Og silica Bond Elut cartridge eluted using a 0-100% diethylether in cyclohexane gradient over 40 minutes to give the title compound: LCMS retention time 3.58 min, m/z 543 MH +
• Example 1 OA: LCMS retention time 3.80 min, m/z 569 MH + .
• Example 10B LCMS retention time 3.80 min, m/z 569 MH + .
• 1 H-NMR (DMSO-d 6 , 400 MHz) 17 ⁇ fluoromethylene protons ⁇ 5.85 (dd, 50.5, 2Hz) and ⁇ 5.74 (dd, 50.5, 2Hz)
• Example 1 1 Fluoromethyl (6 ⁇ , 11 ⁇ .16 ⁇ .17 ⁇ )-6,9-difluoro-11 -hvdroxy-16-methyl-17- F((f4-(1 -methylethvPcyclohexylloxylcarbonvDoxyl-S-oxoandrosta-i .4-diene-17- carboxylate
• Example 1 1 A (minor isomer) LCMS retention time 3.90 min, m/z 597 MH +
• Example 11 B (major isomer) LCMS retention time 3.97 min, m/z 597 MH +
• Example 12 Fluoromethyl (6 ⁇ ,11 ⁇ .16 ⁇ .17 ⁇ )-17-((f(1/?S.2f?S,4S/?)- bicyclor2.2.1lhept-2-yloxy1carbonyl)oxy)-6.9-difluoro-1 1 -hvdroxy-16-methyl-3- oxoandrosta-1 ,4-diene-17-carboxylate
• Example 12 was prepared as a mixture of diastereomers from (6 ⁇ ,11 ⁇ ,16 ⁇ ,17 ⁇ )-17- ( ⁇ [(1 f?S,2 «S,4Sf?)-bicyclo[2.2.1]hept-2-yloxy]carbonyl ⁇ oxy)-6,9-difluoro-11-hydroxy- 16-methyl-3-oxoandrosta-1 ,4-diene-17-carboxylic acid (Intermediate 12) using a method similar to that described for Example 10.
• the diastereomers were then separated using a 2 x 25cm Chiralpak AD column eluting with 10% isopropyl alcohol in heptane with a flow rate of 20ml/min.
• Example 12A On analytical chiral HPLC (25 x 0.46cm Chiralpak AD column, 10% isopropyl alcohol in heptane with a flow rate of 1 ml/min) showed a retention time 17.2min. LCMS retention time 3.74 min, m/z 567 MH +
• Example 12B On analytical chiral HPLC (25 x 0.46cm Chiralpak AD column, 10% isopropyl alcohol in heptane with a flow rate of 1 ml/min) showed a retention time 21.8min. LCMS retention time 3.73 min, m/z 567 MH +
• Example 13 Fluoromethyl f6 ⁇ .1 1 B.16 ⁇ .17 ⁇ )-17-((f(1 /?S.2SR4Sffl- bicvclo[2.2.1lhept-2-yloxylcarbonyl ⁇ oxy)-6.9-difluoro-11-hvdroxy-16-methyl-3- oxoandrosta-1 ,4-diene-17-carboxvlate
• Example 13 was prepared as a mixture of diastereomers from (6 ⁇ ,1 1 ⁇ ,16 ⁇ ,17 ⁇ )-17- ( ⁇ [(IRS ⁇ SR ⁇ SRJ-bicyclo ⁇ .ilhept ⁇ -yloxylcarbonylJoxy ⁇ . ⁇ -difluoro-H-hydroxy- 16-methyl-3-oxoandrosta-1 ,4-diene-17-carboxylic acid (Intermediate 13) using a method similar to that described for Example 10. LCMS retention time 3.77 min, m/z 567 MH +
• Example 14 Fluoromethyl (6 ⁇ ,11 ⁇ .16 ⁇ ,17 ⁇ )-17- ⁇ f(cvcloheptyloxy)carbonylloxy ⁇ -6.9- difluoro-11-hvdroxy-16-methyl-3-oxoandrosta-1 ,4-diene-17-carboxylate
• Example 15 was prepared from (6 ⁇ ,1 1 ⁇ ,16 ⁇ ,17 ⁇ )-17-
• Example 16 Fluoromethyl (6 ⁇ ,11 ⁇ .16 ⁇ ,17 ⁇ )-17-(r(cvclooctyloxy)carbonv ⁇ oxy)-6,9- difluoro-11-hvdroxy-16-methyl-3-oxoandrosta-1.4-diene-17-carboxylate
• Example 16 was prepared from (6 ⁇ ,11 ⁇ ,16 ⁇ ,17 ⁇ )-17- ⁇ [(cyclooctyloxy)carbonyl]oxy ⁇ -
• Example 17 Fluoromethyl (6 ⁇ .11 ⁇ .16 ⁇ .17 ⁇ )-17-r ⁇ r(1 S.3R5SK3.5- dimethylcvclohexylloxylcarbonvDoxyl-e.g-difluoro-i 1 -hydroxy- 16-methyl-3- oxoandrosta-1 ,4-diene-17-carboxvlate
• Example 17 was prepared from (6 ⁇ ,11 ⁇ ,16 ⁇ ,17 ⁇ )-17-[( ⁇ [(1 S,3R,5S)-3,5- Dimethylcyclohexylloxyjcarbonyljoxyl- ⁇ . ⁇ -difluoro-i 1 -hydroxy- 16-methyl-3- oxoandrosta-1 ,4-diene-17-carboxylic acid (Intermediate 17) using a method similar to that described for Example 11. The crude product was purified on a silica biotage cartridge eluted using 25% ethyl acetate in cyclohexane to give the title compound: LCMS retention time 3.90 min, m/z 583 MH +
• Example 18 Fluoromethyl (6 ⁇ .11 ⁇ .16 ⁇ .17 ⁇ )-6,9-difluoro-11-hvdroxy-16-methyl-17- r( ⁇ f(1f?S.2/?S)-2-(methyloxy)cvclohexyllo ⁇ y ⁇ carbonyl)oxy1-3-oxoandrosta-1.4-diene- 17-carboxylate
• Example 18 was prepared as a ca 1 :1 mixture of diastereomers from (6 ⁇ , 11 ⁇ , 16 ⁇ , 17 ⁇ )-6,9-difluoro-1 1 -hydroxy-16-methyl-17-[( ⁇ [(1 RS,2RS)-2- (methyloxyJcyclohexylJoxyJcarbonyOoxyl-S-oxoandrosta-i ,4-diene-17-carboxylic acid (Intermediate 18) using a method similar to that described for Example 11.
• Example 18A LCMS retention time 3.51 min, m/z 585 MH + .
• Example 18B LCMS retention time 3.56 min, m/z 585 MH + .
• Example 19A LCMS retention time 3.88 min, m/z 583 MH + .
• Example 19B LCMS retention time 3.89 min, m/z 583 MH + .
• Example 20 Fluoromethyl (6 ⁇ .11 ⁇ .16 ⁇ .17 ⁇ )-17-((r(1- cvclopentylpropyl)oxylcarbonyl)oxy)-6,9-difluoro-11 -hydroxy- 16-methyl-3- oxoandrosta-1 ,4-diene-17-carboxylate
• Example 20 was prepared as a mixture of diastereomers from (6 ⁇ ,11 ⁇ ,16 ⁇ ,17 ⁇ )-17- ( ⁇ [(1 -cyclopentylpropyl)oxy]carbonyl ⁇ oxy)-6,9-difluoro-1 1 -hydroxy-16-methyl-3- oxoandrosta-1 ,4-diene-17-carboxylic acid (Intermediate 20) using a method similar to that described for Example 4.
• the crude product was purified on a 5g silica Bond Elut cartridge eluted using 0-100% diethylether in cyclohexane gradient over 30 minutes to give the title compound:
• Example 2OA LCMS retention time 3.82 min, m/z 583 MH + .
• Example 2OB LCMS retention time 3.84 min, m/z 583 MH + .
• Example 21 Fluoromethyl (6 ⁇ .11 ⁇ ,16 ⁇ .17 ⁇ )-17-((r(1- cvclopentylethyl)oxy1carbonyl)oxy)-6,9-difluoro-11 -hydroxy-16-methyl-3-oxoandrosta- 1 ,4-diene-17-carboxylate
• Example 21 was prepared as a mixture of diastereomers from (6 ⁇ ,11 ⁇ ,16 ⁇ ,17 ⁇ )-17- ( ⁇ [( 1 -Cyclopentylethyl )oxy] carbonyl ⁇ oxy)-6 , 9-d if I uoro- 11 -hyd roxy- 16-methyl-3- oxoandrosta-1 ,4-diene-17-carboxylic acid (Intermediate 21 ) using a method similar to that described for Example 4. The crude product was purified on a 5g silica Bond Elut cartridge eluted using 0-100% diethylether in cyclohexane gradient over 30 minutes to give the title compound:
• Example 21A LCMS retention time 3.72 min, m/z 570 MH + .
• Example 21 B LCMS retention time 3.75 min, m/z 570 MH + .
• Example 22 Fluoromethyl (6 ⁇ .11 ⁇ .16 ⁇ ,17 ⁇ )-6.9-difluoro-1 1-hydroxy-16-methyl-3- oxo-17-((r(1-propylbutyl)oxy1carbonyl ⁇ oxy)androsta-1 ,4-diene-17-carboxvlate
• Example 22 was prepared from (6 ⁇ ,11 ⁇ ,16 ⁇ ,17 ⁇ )-6,9-difluoro-11-hydroxy-16-methyl- 3-0X0-17-( ⁇ [(1-propylbutyl)oxy]carbonyl ⁇ oxy)androsta-1 ,4-diene-17-carboxylic acid (Intermediate 22) using a method similar to that described for Example 4.
• the crude product was purified on a 5g silica Bond Elut cartridge using 1 :1 diethylether : cyclohexane to give the title compound: LCMS retention time 3.82 min, m/z 571 MH +
• Example 23 Fluoromethyl (6 ⁇ .11 ⁇ .16 ⁇ .17 ⁇ )-6,9-difluoro-11-hvdroxy-16-methyl-3- oxo-17-(([(1.2.2-trimethylpropyl)oxylcarbonyl)oxy)androsta-1 ,4-diene-17-carboxylate
• Example 23 was prepared as a mixture of diastereomers from (6 ⁇ ,1 1 ⁇ ,16 ⁇ ,17 ⁇ )-6,9- Difluoro-11 -hydroxy-16-methyl-3-oxo-17-( ⁇ [(1 ,2,2- trimethylpropyl)oxy]carbonyl ⁇ oxy)androsta-1 ,4-diene-17-carboxylic acid (Intermediate 23) using a method similar to that described for Example 2.
• the crude product was purified on a 5g silica Bond Elut cartridge using a 0-100% ethyl acetate in cyclohexane gradient over 60 minutes to give the title compound:
• Example 23A LCMS retention time 3.77 min, m/z 557 MH + .
• Example 23B LCMS retention time 3.78 min, m/z 557 MH + .
• Example 24 was prepared from (6 ⁇ ,1 1 ⁇ ,16 ⁇ ,17 ⁇ )-6,9-difluoro-11-hydroxy-16-methyl- 3-OXO-17-[( ⁇ [(2, 2,3, S-tetramethylcyclopropyOmethylloxyJcarbonylJoxylandrosta-i , 4- diene-17-carboxylic acid (Intermediate 24) using a method similar to that described for Example 2.
• the crude product was purified on a 2g silica Bond Elut cartridge using a 0-20% ethyl acetate in cyclohexane gradient to give the title compound: LCMS retention time 3.89 min, m/z 583 MH +
• Example 25 Fluoromethyl (6 ⁇ ,11 ⁇ .16 ⁇ .17 ⁇ )-6.9-difluoro-11-hvdroxy-16-methyl-17- f((f1-(1-methvletr ⁇ vl)butvnoxv)carbonvl)oxv1-3-oxoandrosta-1.4-diene-17-carboxvlate
• Example 25 was prepared as a mixture of diastereomers from (6 ⁇ ,1 1 ⁇ ,16 ⁇ ,17 ⁇ )-6,9- difluoro-11-hydroxy-16-methyl-17-[( ⁇ [1-(1-methylethyl)butyl]oxy ⁇ carbonyl)oxy]-3- oxoandrosta-1 ,4-diene-17-carboxylic acid (Intermediate 25) using a method similar to that described for Example 2. The crude product was purified on a 10g silica Bond Elut cartridge using a 0-100% diethylether in cyclohexane gradient over 40 minutes to give the title compound: LCMS retention time 3.84 min, m/z 571 MH +
• Example 26 Fluoromethyl (6 ⁇ ,11 ⁇ ,16 ⁇ .17 ⁇ )-6.9-difluoro-11-hvdroxy-16-methyl-3- oxo-17-( ⁇ r(2,2,3,3-tetramethylcvclopropyl)oxylcarbonyl)oxy)androsta-1 ,4-diene-17- carboxylate
• Example 26 was prepared from (6 ⁇ ,11 ⁇ ,16 ⁇ ,17 ⁇ )-6,9-Difluoro-11-hydroxy-16- methyl-3-oxo-17-( ⁇ [(2,2,3,3-tetramethylcyclopropyl)oxy]carbonyl ⁇ oxy)androsta-1 ,4- diene-17-carboxylic acid (Intermediate 26) using a method similar to that described for Example 8.
• the crude reaction mixture was applied to silica Bond Elut cartridges but this failed to give pure material.
• the crude reaction mixture was therefore purified by mass-directed autopreparation to give the title compound: LCMS retention time 3.82 min, m/z 569 MH +
• Example 27 Fluoromethyl (6 ⁇ ,11 ⁇ ,16 ⁇ ,17 ⁇ )-6,9-difluoro-11-hvdroxy-16-methyl-3- oxo-17-r ⁇ rf1 S.2R4S)-1.7.7-trimethylbicvcloF2.2.nhept-2- ylloxy)carbonyl)oxy1androsta-1 ,4-diene-17-carboxvlate
• Example 27 was prepared from (6 ⁇ ,1 1 ⁇ ,16 ⁇ ,17 ⁇ )-6,9-Difluoro-1 1-hydroxy-16- methyl-3-oxo-17-[( ⁇ [(1 S,2R4S)-1 I 7 l 7-trimethylbicyclo[2.2.1]hept-2- yl]oxy ⁇ carbonyl)oxy]androsta-1 ,4-diene-17-carboxylic acid (Intermediate 27) using a method similar to that described for Example 10. The crude product was purified on a 10g silica Bond Elut cartridge using a 0-100% ethyl acetate in cyclohexane gradient over 20 minutes to give the title compound: LCMS retention time 3.95 min, m/z 609 MH +
• Example 28 Fluoromethyl (6 ⁇ .11 ⁇ ,16 ⁇ .17 ⁇ )-6.9-difluoro-11-hvdroxy-16-methyl-3- oxo-17-r((f(1 f?,2S.4f?)-1.7.7-trimethylbicvclor2.2.1lhept-2- y ⁇ oxy)carbonyl)oxylandrosta-1 ,4-diene-17-carboxvlate
• Example 28 was prepared from (6 ⁇ ,11 ⁇ ,16 ⁇ ,17 ⁇ )-6,9-Difluoro-11-hydroxy-16- methyl-3-oxo-17-[( ⁇ [(1R,2S,4R)-1 ,7,7-trimethylbicyclo[2.2.1]hept-2- yl]oxy ⁇ carbonyl)oxy]androsta-1 ,4-diene-17-carboxylic acid (Intermediate 28) using a method similar to that described for Example 10. The crude product was purified on a 10g silica Bond Elut cartridge using a 0-100% ethyl acetate in cyclohexane gradient over 20 minutes to give the title compound: LCMS retention time 3.95 min, m/z 609 MH +
• Example 29 Fluoromethyl (6 ⁇ ,11 ⁇ .16 ⁇ .17 ⁇ )-6,9-difluoro-11-hvdroxy-16-methyl-3- oxo-17-r ⁇ r(1f?.2R,4f?)-1.7.7-trimethylbicvclor2.2.1lhept-2- ylloxy)carbonyl)oxylandrosta-1 ,4-diene-17-carboxylate
• Example 29 was prepared as a mixture of diastereomers from (6 ⁇ ,11 ⁇ ,16 ⁇ ,17 ⁇ )-6,9- difluoro-1 1 -hydroxy-16-methyl-3-oxo-17-[( ⁇ [(1 RS,2RS,ARS)- ⁇ JJ- trimethylbicyclo[2.2.1]hept-2-yl]oxy ⁇ carbonyl)oxy]androsta-1 ,4-diene-17-carboxylic acid (Intermediate 29) using a method similar to that described for Example 10.
• Example 29A LCMS retention time 4.00 min, m/z 609 MH + .
• Example 29B LCMS retention time 4.00 min, m/z 609 MH + .
• Example 30 Fluoromethyl (6 ⁇ .11 B.16 ⁇ .17 ⁇ )-17-r(fff1R2R4S)-3.3- dimethylbicvclor2.2.1lhept-2-yl1oxy)carbonyl)oxyl-6,9-difluoro-11-hvdroxy-16-methyl- 3-oxoandrosta-1 ,4-diene-17-carboxylate
• Example 30 was prepared from (6 ⁇ ,11 ⁇ ,16 ⁇ ,17 ⁇ )-17-[( ⁇ [(1 R,2R,4S)-3,3- dimethylbicyclo ⁇ .ilhept ⁇ -ylJoxyJcarbonyOoxyl- ⁇ . ⁇ -difluoro-H-hydroxy-i ⁇ -methyl- 3-oxoandrosta-1 ,4-diene-17-carboxylic acid (Intermediate 30) using a method similar to that described for Example 4. The crude product was purified on a 10g silica Bond Elut cartridge using a 0-100% diethylether in cyclohexane gradient over 40 minutes to give the title compound: LCMS retention time 3.88 min, m/z 595 MH +
• Example 32 Fluoromethyl (6 ⁇ .1 1 ⁇ ,16 ⁇ ,17 ⁇ )-6.9-difluoro-1 1 -hvdroxy-16-methyl-17- rdrd S ⁇ R ⁇ SVS-methyl ⁇ -d-methylethvDcvclohexynoxylcarbonvDoxyi-S- oxoandrosta-1 ,4-diene-17-carboxvlate
• Example 32 was prepared from (6 ⁇ ,11 ⁇ ,16 ⁇ ,17 ⁇ )-6,9-difluoro-11-hydroxy-16-methyl- 17-[( ⁇ [(1 S,2R5S)-5-methyl-2-(1 -methylethyl)cyclohexyl]oxy ⁇ carbonyl)oxy]-3- oxoandrosta-1 ,4-diene-17-carboxylic acid (Intermediate 32) using a method similar to that described for Example 1. LCMS retention time 4.08 min, m/z 611 MH +
• Example 33 Fluoromethyl (6 ⁇ ,11 ⁇ .16 ⁇ .17 ⁇ )-6,9-difluoro-1 1-hvdroxy-16-methyl-3- oxo-17-rfffM R2R4S)-1.3.3-trimethylbicvclor2.2.nheDt-2- yl1oxy)carbonyl)oxylandrosta-1 ,4-diene-17-carboxylate
• Example 33 was prepared from (6 ⁇ ,11 ⁇ ,16 ⁇ ,17 ⁇ )-6,9-difluoro-11-hydroxy-16-methyl- 3-OXO-17-[( ⁇ [(1R2R4S)-1 ,3,3-trimethylbicyclo[2.2.1 ]hept-2- ylJoxyJcarbonyOoxyJandrosta-i ⁇ -diene- ⁇ -carboxylic acid (Intermediate 33) using a method similar to that described for Example 10. The crude product was purified on a 1Og silica Bond Elut cartridge using a 0-100% ethyl acetate in cyclohexane gradient over 20 minutes to give the title compound: LCMS retention time 4.00 min, m/z 609 MH +
• Example 34 Fluoromethyl (6 ⁇ .1 1 ⁇ .16 ⁇ ,17 ⁇ )-6,9-difluoro-11-hvdroxy-16-methyl-3- oxo-17-rfffM R2R3R5S)-2.6.6-trimethylbicvclor3.1.nhept-3- yl1oxy)carbonyl)oxylandrosta-1 ,4-diene-17-carboxylate
• Example 34 was prepared from (6 ⁇ ,11 ⁇ ,16 ⁇ ,17 ⁇ )-6,9-Difluoro-11-hydroxy-16- methyl-S-oxo-I Z-mKI R ⁇ R.SR.SS ⁇ . ⁇ . ⁇ -trimethylbicyclofS.i .ilhept-S- ylJoxyJcarbonyOoxyJandrosta-I ⁇ -diene-IZ-carboxylic acid (Intermediate 34) using a method similar to that described for Example 10. The crude product was purified on a 10g silica Bond Elut cartridge using a 0-100% ethyl acetate in cyclohexane gradient over 20 minutes to give the title compound: LCMS retention time 4.00 min, m/z 609 MH +
• Example 35 Fluoromethyl (6 ⁇ ,11 ⁇ .16 ⁇ ,17 ⁇ )-6.9-difluoro-11-hvdroxy-16-methyl-3- oxo-IZ-r ⁇ rd S ⁇ S.SS. ⁇ ffl ⁇ .e.e-trimethylbicvclorS.i .ilhept-S- y ⁇ oxy)carbonvQoxy1androsta-1 ,4-diene-17-carboxylate
• Example 35 was prepared from (6 ⁇ ,11 ⁇ ,16 ⁇ ,17 ⁇ )-6,9-Difluoro-11-hydroxy-16- methyl-a-oxo-IZ-IttKI S ⁇ S.aS.SR ⁇ . ⁇ . ⁇ -trimethylbicyclop.i .ilhept-S- yl]oxy ⁇ carbonyl)oxy]androsta-1 ,4-diene-17-carboxylic acid (Intermediate 35) using a method similar to that described for Example 10.
• Example 36 Fluoromethyl (6 ⁇ .1 1 ⁇ .16 ⁇ .17 ⁇ )-17-((r(c/s-4- ethylcvclohexyDoxylcarbonvDoxyVe.g-difluoro-H-hvdroxy-ie-methyl-S-oxoandrosta- 1 ,4-diene-17-carboxylate
• Example 36 was prepared from (6 ⁇ ,11 ⁇ ,16 ⁇ ,17 ⁇ )-17-( ⁇ [(c/s-4- ethylcyclohexyOoxylcarbonylJoxyJ- ⁇ . ⁇ -difluoro-H-hydroxy-i ⁇ -methyl-S-oxoandrosta- 1 ,4-diene-17-carboxylic acid (Intermediate 36) using a method similar to that described for Example 19.
• the crude product was purified on a 1g silica Bond Elut cartridge eluting with 1 :1 diethylether.cyclohexane to give the title compound: LCMS retention time 3.92 min, m/z 583 MH +
• Example 37 Fluoromethyl (6 ⁇ ,1 1 ⁇ .16 ⁇ .17 ⁇ )-17- ⁇ f(frans-4- ethylcvclohexyDoxylcarbonvDoxyVe.g-difluoro-H-hvdroxy-ie-methyl-S-oxoandrosta- 1 ,4-diene-17-carboxylate
• Example 37 was prepared from (6 ⁇ ,11 ⁇ ,16 ⁇ ,17 ⁇ )-17-( ⁇ [( ⁇ ans-4- ethylcyclohexyOoxylcarbonylJoxyJ- ⁇ . ⁇ -difluoro-i 1 -hydroxy-16-methyl-3-oxoandrosta- 1 ,4-diene-17-carboxylic acid (Intermediate 37) using a method similar to that described for Example 19.
• the crude product was purified on a 1g silica Bond Elut cartridge eluting with 1:1 diethylethercyclohexane to give the title compound: LCMS retention time 3.97 min, m/z 583 MH +
• Example 38 Fluoromethyl (6 ⁇ ,11 ⁇ .16 ⁇ .17 ⁇ )-17-( ⁇ r(1-ethyl-2.2- dimethylpropyDoxylcarbonvDoxyV ⁇ .Q-difluoro-i i-hvdroxy-i ⁇ -methyl-S-oxoandrosta- 1 ,4-diene-17-carboxylate
• Example 38 was prepared as a mixture of diastereomers from (6 ⁇ ,11 ⁇ ,16 ⁇ ,17 ⁇ )-17- ( ⁇ [(i-Ethyl ⁇ -dimethylpropyOoxyJcarbonylJoxyV ⁇ . ⁇ -difluoro-H-hydroxy-i ⁇ -methyl-S- oxoandrosta-1 ,4-diene-17-carboxylic acid (Intermediate 38) using a method similar to that described for Example 2. The crude product was purified on a 1Og silica Bond Elut cartridge eluted using a 0-100% diethylether in cyclohexane gradient over 40 minutes to give the title compound: LCMS retention time 3.82 min, m/z 571 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., 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 0 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 were constructed from which EC 50 values were estimated.
• the PlC 50 values for compounds of Examples 1 to 38 were > 8.0 in this assay.
• the plC 50 values for compounds of Examples 1 to 11 A, 12A to 2OA, 21A to 23A, 24 to 31 and 33 to 38 were > 9.0 in this assay.
• the functional assay based on that described by R. J. H. Austin et al., Eur Resp J. (2002), 20,1386-1392 measures the ability of compounds to directly transactivate gene expression.
• A549 cells stably transfected with a reporter gene containing the glucocorticoid responsive region of the mouse mammary tumour virus long terminal repeat (MMTV-LTR) coupled to renilla luciferase were treated with test compounds at appropriate doses for 6 hour at 37°C.
• the amount of luciferase activity present within the cells is then determined by measuring the light emitted following incubation with a suitable substrate. Dose response curves were constructed from which EC 50 values were estimated and from which maximal responses are calculated relative to Dexamethasone (100%).
• a T225 flask of CV-1 cells at a density of 80% confluency was washed with PBS, detached from the flask using 0.25% trypsin and counted using a Sysmex KX-21N.

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