Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
• • 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
• • 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 a novel crystalline complex containing an anti- inflammatory and anti-allergic compound of the androstane series and to processes for its preparation.
• the present invention also relates to pharmaceutical formulations containing the complex and to therapeutic uses thereof, particularly for the treatment of inflammatory and allergic conditions.
• Glucocorticoids which have anti-inflammatory properties are known and are widely used for the treatment of inflammatory disorders or diseases such as asthma and rhinitis.
• US Patent 4335121 discloses 6 ⁇ , 9 ⁇ -Difluoro-17 ⁇ -(1- oxopropoxy)-11 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-androsta-1 ,4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester (known by the generic name of fluticasone propionate) and derivatives thereof.
• fluticasone propionate known by the generic name of fluticasone propionate
• glucocorticoids include suppression of the Hypothalamic- Pituitary-Adrenal (HPA) axis, effects on bone growth in children and on bone density in the elderly, ocular complications (cataract formation and glaucoma) and skin atrophy.
• HPA Hypothalamic- Pituitary-Adrenal
• Certain glucocorticoid compounds also have complex paths of metabolism wherein the production of active metabolites may make the pharmacodynamics and pharmacokinetics of such compounds difficult to understand. Whilst the modern steroids are very much safer than those originally introduced, it remains an object of research to produce new molecules which have excellent anti-inflammatory properties, with predictable pharmacokinetic and pharmacodynamic properties, with an attractive side effect profile, and with a convenient treatment regime.
• a crystalline complex comprising a compound of formula (I)
• the crystal lattice is stabilised by the presence of a guest molecule, characterised in that the crystalline complex is of space group P2 1 2 1 2 1 having unit cell dimensions of about 12.5 ⁇ 1.0 A, 15 ⁇ 1.0 A, and 16.2 ⁇ 1.0 A when determined at either 120K or 150K (hereinafter "a complex of the invention")
• XRPD X-ray powder diffraction
• the XRPD profiles of complexes of the invention when crystallographically pure also preferably exhibit one or more of the following 2 features when determined at ambient temperature (eg around 295K): (a) Absence of a peak at around 7 (eg around 6.8-7.4) which is associated with the profile of unsolvated Form 1 , 2 and 3 polymorphs and present at particularly high intensity in Forms 2 and 3;
• both features are exhibited.
• the chemical name of the compound of formula (I) is 6 ⁇ , 9 -Difluoro-17 ⁇ -[(2- furanylcarbonyl)oxy]-11 ⁇ -hydroxy-16 ⁇ methyl-3-oxo-androsta-1 ,4-diene-17 ⁇ - carbothioic acid S-fluoromethyl ester.
• the compound of formula (I) and compositions thereof have potentially beneficial anti-inflammatory or anti-allergic effects, particularly upon topical administration, demonstrated by, for example, its ability to bind to the glucocorticoid receptor and to illicit a response via that receptor, with long acting effect.
• the compound of formula (I) and compositions thereof is useful in the treatment of inflammatory and/or allergic disorders, especially in once-per-day therapy.
• Space group P2 1 2 1 2 1 is characterised by angles of 90° being present in each of the 3 axes.
• the compound of formula (I) can form a crystalline complex of characteristic space group, unit cell dimensions and crystalline structure as evidenced by X-ray diffraction with a very wide range of guest molecules.
• the guest molecule preferably has a relative molecular weight in the range 16 to 150, more preferably 16 to 100, especially 40 to 100.
• the guest molecule is a liquid at ambient temperature and pressure (eg 295K, 1.013 x 10 5 Pa).
• guest molecules which are a liquid under pressure may also be capable of acting as a guest molecule (especially under pressurised conditions).
• Substances which are solids at ambient temperature and pressure are also included.
• the guest molecule preferably contains a moiety capable of acting as a hydrogen bond acceptor.
• moieties capable of acting as a hydrogen bond acceptor include carbonyl, sulphoxide, ether, -OH and amine groups (whether primary, secondary or tertiary amine groups) which moieties may form part of a carboxylic acid, ester or amide group.
• Moieties thioether and -SH may also be contemplated but are less preferred. Crystallographic studies have shown that a hydrogen bond acceptor on the guest is capable of interacting with the hydrogen atom of the C11 hydroxy on the compound of formula (I) thereby assisting the stabilisation of the crystal lattice (see in particular Figure 2A and Figure 2B).
• a hydrogen bond donor on the guest eg the hydrogen atom of an -OH moiety
• Suitable guest molecules include solvents e.g.: amide moiety containing substances such as: dimethyl acetamide, dimethyl formamide, N-methyl-2-pyrrolidinone; amine moiety containing substances such as: cyclohexylamine, f-butylamine; carbonyl moiety containing substances such as: acetone, methylethylketone, cyclopentanone, cyclohexanone; sulphoxides such as dimethylsulphoxide; alcohols such as : ethanol, butan-1-ol, propan-1-ol, propan-2-ol; ethers such as: 1 ,4-dioxane, tetrahydrofuran; esters such as: ethylformate, methylacetate; carboxylic acids such as: acetic acid; heterocycles such as: pyridine; water.
• An example of a solid guest molecule is ⁇ -caprolactam.
• Preferred guest molecules are pharmaceutically acceptable substances and, as described below, complexes of the invention containing them may be used in therapy. However even if the guest molecule is not pharmaceutically acceptable then such complexes may be useful in the preparation of other complexes containing compound of formula (I), for example, other complexes of the invention containing guest molecules that are pharmaceutically acceptable or compound of formula (I) in unsolvated form.
• the complex is not an essentially stoichiometric complex containing as guest molecule one of the following: acetone, dimethylformamide, dimethylacetamide, tetrahydrofuran, N-methyl-2- pyrrolidinone, propan-2-ol (isopropanol) or methylethylketone, more particularly the complex is not a complex containing as guest molecule one of the aforementioned substances having stoichiometry of compound of formula (I) to solvent of 0.95:1 to 1.05:1.
• the complex is not a complex containing as guest molecule ethanol, water or methyl acetate, more particularly the complex is not an essentially stoichiometric complex containing as guest molecule one of the aforementioned substances, especially a complex having stoichiometry of compound of formula (I) to solvent of 0.95:1 to 1.05:1.
• guest molecules include: cyclopentanone, cyclohexanone, cyclohexylamine, f-butylamine, dimethylsulfoxide, ethanol, propan-1- ol, butan-1-ol, 1 ,4-dioxane, ethyl formate, methyl acetate, pyridine, water and acetic acid, particularly cyclopentanone, dimethylsulfoxide, propan-1-ol, 1,4-dioxane, ethyl formate, butan-1-ol and acetic acid.
• the guest molecule is propan-2-ol or acetone, more preferably propan-2-ol.
• the stoichiometry of the complex will usually be such that the ratio of compound to formula (I) to guest molecule, in molar terms, is 1:2.0 to - 1:0.3, more preferably 1:1.6 to 1 :0.6, especially 1 :1.2 to 1 :0.8.
• the complex of the invention has a crystal structure which is quite distinct from that of compound of formula (I) in the absence of a guest molecule, eg. the compound of formula (I) as unsolvated polymorph Form 1 which has a space group of P2-j (i.e. two of the axis angles are 90°) and cell dimensions of 7.6, 14.1 , 11. ⁇ A when determined at 150K.
• a threshold level which will differ from guest to guest
• the crystal structure of the complex starts to break down and converts to that of the structure of an unsolvated compound of formula (I), typically unsolvated polymorph Form 1.
• Figure 3 shows the evolution of the XRPD profile of the complex with acetone when subjected to heating, and its in conversion to unsolvated polymorph Form 1.
• the complexes with acetone, dimethylformamide, tetrahydrofuran, N-methyl-2- pyrrolidinone and acetic acid are particularly stable when subjected to heating, requiring a temperature in excess of 95 °C to cause substantial loss of guest from the crystal lattice.
• the complexes with acetone, dimethylformamide and acetic acid required a temperature in excess of 125 °C to cause substantial loss of guest.
• the unit cell dimensions are about 12.5 ⁇ 1.0 A, 15 ⁇ 1.0 A, and 16.2 ⁇ 1.0 A when determined at 120K. More preferably the unit cell dimensions are about 12.1 ⁇ 0.6 A, 14.9 ⁇ 0.7 A and 16.2 ⁇ 1.0 A when determined at either 120k or 150k. Usually the unit cell dimensions are about 12.1 ⁇ 0.4 A, 14.9 ⁇ 0.6 A, and 16.2 ⁇ 0.7 A when determined at either 120K or 150K, especially when determined at 120K.
• Table 1 shows the unit cell dimensions and peak positions for a number of example complexes :
• Inhaled steroids are also absorbed through the lung and this route of absorption makes a significant contribution to systemic exposure. Reduced lung absorption could therefore provide an improved safety profile.
• Studies with compound (I) have shown significantly lower exposure to compound (I) than with fluticasone propionate after dry powder delivery to the lungs of anaesthetised pigs.
• the compound of Formula (I) shows a significantly longer mean absorption time (MAT) than fluticasone propionate n man. Measurements have shown that the compound of Formula (I) has a mean absorption time of an average of 12 hours while fluticasone propionate has a MAT of an average of 2.1 hours. Mathematical deconvolution of the plasma concentration time data shows that the time taken for 90% of lung dose to be absorbed is on average, 21 hours for compounds of Formula (I) compared with 11 hours for fluticasone propionate. It has been shown that oral bioavailability of the compound of Formula (I) is very low, and therefore systemic exposure is predominantly the result of absorption from the lung. This would suggest that the compound of Formula (I) has a significantly longer residence time in the lung than fluticasone propionate.
• MAT mean absorption time
• a longer residence time in the lung may lead to a longer duration of action and the lower daily systemic exposure may lead to an improved safety profile which, it is believed, allows the compound of formula (I) to demonstrate the desired anti- inflammatory effects when administered once-per day.
• Once-per-day dosing is considered to be significantly more convenient to patients than the twice-per day dosing regime that is normally employed for fluticasone propionate.
• Examples of disease states in which the compound of formula (I) and compositions thereof 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.
• the compound of formula (I) may also have use in the treatment of conjunctiva and conjunctivitis.
• the complex of the invention is expected to be most useful in the treatment of inflammatory disorders of the respiratory tract e.g. asthma, COPD and rhinitis particularly asthma and rhinitis.
• the complex of the invention is useful in human or veterinary medicine, in particular as an anti-inflammatory and anti-allergic agent.
• the complex of the invention for use in human or veterinary medicine, particularly in the treatment of patients with inflammatory and/or allergic conditions, especially for treatment once- per-day.
• the complex of the invention for the manufacture of a medicament for the treatment of patients with inflammatory and/or allergic conditions, especially for treatment once-per-day.
• 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 the complex of the invention, especially for administration once-per-day.
• the complex of the invention may be formulated for administration in any convenient way, and the invention therefore also includes within its scope pharmaceutical compositions comprising the complex of the invention together, if desirable, in admixture with one or more physiologically acceptable diluents or carriers.
• pharmaceutical compositions suitable for once-per-day administration are of particular interest. Further, there is provided a process for the preparation of such pharmaceutical compositions which comprises mixing the ingredients.
• the complex of 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.
• compositions for topical administration to the lung include dry powder compositions and spray compositions.
• Dry powder compositions for topical delivery to the lung by inhalation may, for example, be presented in capsules and cartridges for use in an inhaler or insufflator of, for example, gelatine.
• Formulations generally contain a powder mix for inhalation of the compound of the invention and a suitable powder base (carrier substance) such as lactose or starch. Use of lactose is preferred.
• a suitable powder base such as lactose or starch.
• lactose is preferred.
• Each capsule or cartridge may generally contain between 20 ⁇ g-10mg of the compound of formula (I) in a pharmaceutical composition of the invention optionally in combination with another therapeutically active ingredient.
• the pharmaceutical composition of the invention may be presented without excipients.
• Packaging of the formulation may be suitable for unit dose or multi-dose delivery.
• the formulation can be pre-metered (e.g. as in Diskus, see GB 2242134 or Diskhaler, see GB 2178965, 2129691 and 2169265) or metered in use (e.g. as in Turbuhaler, see EP 69715).
• An example of a unit-dose device is Rotahaler (see GB 2064336).
• the Diskus inhalation device comprises an elongate strip formed from a base sheet having a plurality of recesses spaced along its length and a lid sheet hermetically but peelably sealed thereto to define a plurality of containers, each container having therein an inhalable formulation containing a pharmaceutical composition of the invention preferably combined with lactose.
• the strip is sufficiently flexible to be wound into a roll.
• the lid sheet and base sheet will preferably have leading end portions which are not sealed to one another and at least one of the said leading end portions is constructed to be attached to a winding means. Also, preferably the hermetic seal between the base and lid sheets extends over their whole width.
• the lid sheet may preferably be peeled from the base sheet in a longitudinal direction from a first end of the said base sheet.
• compositions which are non-pressurised and adapted to be administered as a dry powder topically to the lung via the buccai cavity (especially those which are free of excipient or are formulated with a diluent or carrier such as lactose or starch, most especially lactose) are of particular interest.
• Spray compositions for topical delivery to the lung by inhalation may for example be formulated as aqueous solutions or suspensions or as aerosols delivered from pressurised packs, such as a metered dose inhaler, with the use of a suitable liquefied propellant.
• Aerosol compositions suitable for inhalation can be either a suspension or a solution and generally contain the complex of the invention optionally in combination with another therapeutically active ingredient 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.
• 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
• 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.
• additional formulation excipients well known in the art such as surfactants e.g. oleic acid or lecithin and cosolvents e.g. ethanol.
• One example formulation is excipient free and consists essentially of (e.g. consists of) complex of the invention (optionally together with a further active ingredient) and a propellant selected from 1,1,1,2-tetrafluoroethane, 1 ,1 ,1,2,3,3,3-heptafiuoro-n-propane and mixture thereof.
• Another example formulation comprises particulate complex of the invention, a propellant selected from 1 ,1 ,1 ,2-tetrafluoroethane, 1 ,1 ,1 ,2,3,3,3- heptafluoro-n-propane and mixture thereof and a suspending agent which is soluble in the propellant e.g. an oligolactic acid or derivative thereof as described in WO94/21229.
• the preferred propellant is 1 ,1,1,2-tetrafluoroethane.
• Pressurised formulations will generally be retained in a canister (e.g. an aluminium canister) closed with a valve (e.g. a metering valve) and fitted into an actuator provided with a mouthpiece.
• Medicaments for administration by inhalation desirably have a controlled particle size.
• the optimum particle size for inhalation into the bronchial system is usually 1-1 O ⁇ m, preferably 2-5 ⁇ m. Particles having a size above 20 ⁇ m are generally too large when inhaled to reach the small airways.
• the particles of the complex of the invention as produced may be size reduced by conventional means e.g. by micronisation. The desired fraction may be separated out by air classification or sieving.
• the particles will be crystalline, prepared for example by a process which comprises mixing in a continuous flow cell in the presence of ultrasonic radiation a flowing solution of compound of formula (l)as medicament in a liquid solvent with a flowing liquid antisolvent for said medicament (e.g. as described in International Patent Application PCT/GB99/04368) or else by a process which comprises admitting a stream of solution of the substance in a liquid solvent and a stream of liquid antisolvent for said substance tangentially into a cylindrical mixing chamber having an axial outlet port such that said streams are thereby intimately mixed through formation of a vortex and precipitation of crystalline particles of the substance is thereby caused (e.g. as described in International Patent Application PCT/GB00/04327).
• the particle size of the excipient will be much greater than the inhaled medicament within the present invention.
• the excipient is lactose it will typically be present as milled lactose, wherein not more than 85% of lactose particles will have a MMD of 60-90 ⁇ m and not less than 15% will have a MMD of less than 15 ⁇ m.
• Formulations for administration topically to the nose include pressurised aerosol formulations and aqueous formulations administered to the nose by pressurised pump. Formulations which are non-pressurised and adapted to be administered topically to the nasal cavity are of particular interest.
• the formulation preferably contains water as the diluent or carrier for this purpose.
• Aqueous formulations for administration to the lung or nose may be provided with conventional excipients such as buffering agents, tonicity modifying agents and the like. Aqueous formulations may also be administered to the nose by nebulisation.
• Other possible presentations include the following:
• Ointments, creams and gels may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agent and/or solvents.
• bases may thus, for example, include water and/or an oil such as liquid paraffin or a vegetable oil such as arachis oil or castor oil, or a solvent such as polyethylene glycol.
• Thickening agents and gelling agents which may be used according to the nature of the base include soft paraffin, aluminium stearate, cetostearyl alcohol, polyethylene glycols, woolfat, beeswax, carboxypolymethylene and cellulose derivatives, and/or glyceryl monostearate and/or non-ionic emulsifying agents.
• Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents or thickening agents.
• Powders for external application may be formed with the aid of any suitable powder base, for example, talc, lactose or starch.
• Drops may be formulated with an aqueous or non-aqueous base also comprising one or more dispersing agents, solubilising agents, suspending agents or preservatives.
• formulations of the invention may be buffered by the addition of suitable buffering agents.
• the proportion of the complex of the invention in the pharmaceutical compositions according to the invention depends on the precise type of formulation to be prepared but will generally be within the range of from 0.001 to 10% by weight. Generally, however for most types of preparations advantageously the proportion used will be within the range of from 0.005 to 1% and preferably 0.01 to 0.5%. However, in powders for inhalation or insufflation the proportion used will usually be within the range of from 0.1 to 5%.
• Aerosol formulations are preferably arranged so that each metered dose or "puff' of aerosol contains 1 ⁇ g-2000 ⁇ g e.g. 20 ⁇ g-2000 ⁇ g, preferably about 20 ⁇ g-500 ⁇ g of the complex of the invention optionally in combination with another therapeutically active ingredient.
• 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 pharmaceutical composition of the invention is delivered once or twice daily.
• the overall daily dose with an aerosol will typically be within the range 10 ⁇ g-10mg e.g. 100 ⁇ g-10mg preferably, 200 ⁇ g-2000 ⁇ g.
• 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 complex 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 complex of the invention .
• the complex according to the invention may in general may be given by internal administration in cases where systemic adreno-cortical therapy is indicated.
• preparations for internal administration may contain from 0.05 to 10% of the active ingredient dependent upon the type of preparation involved.
• the daily dose may vary from 0.1 mg to 60mg, e.g. 5-30mg, dependent on the condition being treated, and the duration of treatment desired.
• Slow release or enteric coated formulations may be advantageous, particularly for the treatment of inflammatory bowel disorders.
• the pharmaceutical composition of the invention will be delivered once-per-day and the dose will be selected so that the compound has a therapeutic effect in the treatment of respiratory disorders (e.g. asthma or COPD, particularly asthma) over 24 hours or more.
• respiratory disorders e.g. asthma or COPD, particularly asthma
• 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 exmaple a ⁇ 2 -adrenoreceptor agonist, an anti- histamine or an anti-allergic.
• ⁇ 2 -adrenoreceptor agonists examples include salmeterol (e.g. 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 agonist are preferred, especially those having a therapeutic effect over a 24 hour period.
• 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):
• n is an integer of from 3 to 11 , with the proviso that m + n is 5 to 19,
• R 11 is -XSO 2 NR 16 R 17 wherein X is -(CH 2 ) P - or C 2 . 6 alkenylene; R 16 and R 17 are independently selected from hydrogen, C 1-6 alkyl, C 3-7 cycloalkyI,
• R 16 and R 17 are each optionally substituted by one or two groups selected from halo, C 1-6 alkyl, C,. 6 haloalkyl, C 1-e alkoxy, hydroxy- substituted C 1-6 alkoxy, -CO 2 R 18 , -SO 2 NR 18 R 19 , -CONR 18 R 19 , -NR 18 C(O)R 19 , or a 5-, 6- or 7-membered heterocylic ring;
• R 18 and R 9 are independently selected from hydrogen, C,. 6 alkyl,
• R 12 and R 13 are independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halo, phenyl, and C 1-6 haloalkyl;
• R 14 and R 15 are independently selected from hydrogen and C ⁇ alkyl with the proviso that the total number of carbon atoms in R 14 and R 15 is not more than 4.
• the pharmaceutical composition comprising the complex of the invention and the long-acting ⁇ 2 - adrenoreceptor agonists will be delivered once-per-day and the dose of each will be selected so that the pharmaceutical composition has a therapeutic effect in the treatment of respiratory disorders effect (e.g. in the treatment of asthma or COPD, particularly asthma) over 24 hours or more.
• respiratory disorders effect e.g. in the treatment of asthma or COPD, particularly asthma
• anti-histamines examples include methapyrilene or loratadine.
• NSAIDs e.g. sodium cromoglycate, nedocromil sodium, PDE4 inhibitors, leukotriene antagonists, iNOS inhibitors, tryptase and elastase inhibitors, beta-2 integrin antagonists and adenosine 2a agonists
• antiinfective agents e.g. antibiotics, antivirals
• PDE4 phosphodiesterase 4
• compositions comprising a combination as defined above together with a physiologically acceptable diluent or carrier represent a further aspect of the invention.
• the complex according to the invention in combination with another therapeutically active ingredient as described above may be formulated for administration in any convenient way, and the invention therefore also includes within its scope pharmaceutical formulations comprising the complex of the invention in combination with another therapeutically active ingredient together, if desirable, in admixture with one or more physiologically acceptable diluents or carriers.
• the preferred route of administration for inflammatory disorders of the respiratory tract will generally be administration by inhalation.
• Therapeutic agent combinations may be in any form, for example combinations may comprise a single dose containing separate particles of individual therapeutics, and optionally excipient material(s), alternatively, multiple therapeutics may be formed into individual multicomponent particles, formed for example by coprecipitation, and optionally containing excipient material(s).
• the individual compounds of such combinations may be administered either sequentially in separate pharmaceutical compositions as well as simultaneously in combined pharmaceutical formulations. Appropriate doses of known therapeutic agents will be readily appreciated by those skilled in the art.
• the complex of the invention may be prepared by the methodology described hereinafter, constituting a further aspect of this invention.
• a first process for preparing a complex of the invention comprises crystallising the complex from a solution containing a compound of formula (I) and the guest molecule.
• the solution containing the guest molecule could be the guest itself when this a liquid, or could be the guest dissolved in another liquid substance which substance does not act as a guest molecule in the process.
• the crystallisation process may be assisted by seeding with crystals of the complex of the invention.
• the seed crystals of the complex of the invention need not contain the same guest molecule.
• a second process for preparing a complex of the invention comprises contacting the compound of formula (I) or a complex thereof in solid form with a liquid containing the guest molecule (for example by slurrying) and obtaining the complex therefrom.
• the liquid containing the guest molecule could be the guest itself when thisis a liquid, or could be the guest dissolved in another liquid substance which substance does not act as a guest molecule in the process.
• a third process for preparing a complex of the invention comprises contacting a compound of formula (I) or a complex thereof in solid form with a vapour containing the guest molecule. This process is suitable when the guest has acceptable volatility e.g. when the guest is a solvent.
• the compound of formula (I) may be employed in the form of a complex with a guest molecule or in a form without a guest molecule (eg as unsolvated polymorph Form 1 , 2 or 3).
• the compound of formula (I) or a complex according to the invention may be dissolved in the solution or prepared in situ.
• the input compound of formula (I) in the first, second and third processes is in the form of a substantially amorphous solid.
• the compound of formula (I) in the form of a substantially amorphous solid is preferably in the form of substantially amorphous particles.
• the compound of formula (I) in the form of substantially amorphous particles may be obtained by spray drying a solution containing the compound of formula (I).
• Any solvent that will dissolve the compound of formula (I) that can be evaporated safely in a spray drying process may be used.
• Suitable solvents for forming the solution include, but are not limited to, methyl acetate, ethyl acetate, isopropyl acetate, acetone, 2-butanone, 3-pentanone, 4-methyl-2-pentanone, ethanol, methanol, 1-propanol, propan-2-ol, acetonitrile, chloroform, dichloromethane especially methylethylketone (2-butanone).
• Solution concentration will typically be 0.5-50% specifically 10-40% eg 20-30%. Lower concentrations may be more suitable for preparing smaller particle sizes especially 2-4% e.g. 3.5-4%.
• the concentration that may be employed will be limited by the dissolution power of the solvent. Methylethylketone is preferred since it dissolves compound of formula (I) at a relatively high concentration which results in production advantages.
• the compound of formula (I) may be employed in non-solvated form or in the form of a complex of the invention (e.g. with acetone). Preferably it is employed as the non- solvated Form 1 polymorph.
• Spray drying maybe performed, for example, using apparatus supplied by Buchi or Niro.
• a pneumatic spray nozzle orifice of e.g. 0.04 inches is suitable, although alternate atomization methods such as rotary and pressure nozzles can be used.
• Solution flow rate may typically be in the range 1-100 ml/min, especially 15-30ml/min.
• the inlet temperature and flow rate combination should be suitable to evaporate the solvent completely to minimize the risk of solvent trapped in the particle expediting an amorphous to crystalline transition.
• Inlet temperatures can range from 50 - 250°C, typically
• Form 1 Peak at around 18.9 degrees
• 2 Peaks at around 18.4 and 21.5 degrees
• 3 Peaks at around 18.6 and 19.2 degrees 2Theta.
• a process for preparing a compound of formula (I) as crystalline unsolvated Form 1 polymorph comprises dissolving compound of formula (I) in methylisobutylketone or ethyl acetate and producing compound of formula (I) as unsolvated Form 1 by addition of an anti-solvent such as iso-octane or toluene.
• the compound of formula (I) may be dissolved in ethyl acetate and compound of formula (I) as unsolvated Form 1 polymorph may be obtained by addition of toluene as anti-solvent.
• the ethyl acetate solution is hot and once the toluene has been added the mixture is distilled to reduce the content of ethyl acetate.
• the compound of formula (I) may be dissolved in methylisobutylketone and compound of formula (I) as crystalline unsolvated Form 1 polymorph may be obtained by addition of isooctane as anti-solvent.
• a process for preparing a compound of formula (I) as unsolvated Form 2 polymorph comprises dissolving compound of formula (I) in unsolvated form in methanol or dry dichloromethane and recrystallising the compound of formula (I) as unsolvated Form 2 polymorph.
• the compound of formula (I) will be dissolved in hot in methanol or dry dichloromethane and allowed to cool.
• a process for preparing a preparing a compound of formula (I) as unsolvated Form 3 polymorph comprises dissolving compound of formula (I) in particular as the complex with acetone in dichloromethane in the presence of water (typically 1-3% water by volume) and recrystallising the compound of formula (I) as unsolvated Form 3 polymorph.
• complexes of the invention may also find use as manufacturing intermediates in the preparation of compound of formula (I) in unsolvated form, or in the preparation of other complexes of the invention, or in pharmaceutical compositions thereof.
• a process for preparation of compound of formula (I) in unsolvated form comprises removing the guest molecule from a complex of the invention.
• the methodology described herein for preparing complexes of the invention may also be useful in preparing complexes of the invention of defined crystal habit and also for preparing compounds of formula (I) in unsolvated form (typically unsolvated polymorph Form 1) of defined crystal habit.
• the complexes of the invention with acetone are particularly advantageous since when prepared according to the method substantially as described in Example 1, second alternative method they are produced in the form of equant or substantially equant particles (typically elongated tetragonal bipyramidal crystals) which are readily micronised with high efficiency.
• the complexes of the invention with propan-2-ol are also particularly advantageous since when prepared according to the method substantially as described in Example 3, second and third alternative method they are produced in the form of equant or substantially equant particles (typically tetragonal bipyramidal crystals) which are also readily micronised with high efficiency. If these complexes of the invention are converted to unsolvated form (typically unsolvated Form 1 ) by removal of the guest molecule (eg on heating, typically to around 100-110 eg 105°C) then the unsolvated form is prepared in the corresponding advantageous crystal habit.
• unsolvated form typically unsolvated Form 1
• Unsolvated polymorph Form 1 when prepared by this method either from complexes of the invention with a acetone or complexes of the invention with propan-2-ol are much more readily micronised than the needle shaped crystals prepared by the method described above involving recrystallisation from ethylacetate and toluene.
• the different shaped particles are shown in Figures 6 to 8.
• Equant and substantially equant particles may be single crystals or agglomerations of crystals.
• Equant particles have dimensions in each of the three axes of measurement which are approximately the same, for example they have dimensions in the three axes such that the difference between the largest and the smallest measurement is not more than approximately 50% of the smallest.
• Particles which are single crystals are typically equant.
• Particles which are agglomerations of crystals are typically substantially equant such that the particles have dimensions in the three axes such that the difference between the largest and the smallest measurement is not more than approximately 100% of the smallest, particularly not more than 50% of the smallest.
• crystalline complex of the invention comprises equant or substantially equant particles.
• the guest molecule to be acetone or propan-2-ol.
• step (a) preferably the complex is a complex with propan-2-ol or acetone as guest molecule.
• a process for preparing a compound of formula (I) comprises alkylation of a thioacid of formula (II)
• the compound of formula (II) may be reacted with a compound of formula FCH 2 L wherein L represents a leaving group (e.g. a halogen atom, a mesyl or tosyl group or the like) for example, an appropriate fluoromethyl halide under standard conditions.
• the fluoromethyl halide reagent is bromofluoromethane.
• the compound of formula (II) is employed as a salt, particularly the salt with diisopropylethylamine.
• the compound of formula (II) or a salt thereof is treated with bromofluoromethane optionally in the presence of a phase transfer catalyst.
• a preferred solvent is methylacetate, or more preferably ethylacetate, optionally in the presence of water.
• the presence of water improves solubility of both starting material and product and the use of a phase transfer catalyst results in an increased rate of reaction.
• phase transfer catalysts include (but are not restricted to) tetrabutylammonium bromide, tetrabutylammonium chloride, benzyltributylammonium bromide, benzyltributylammonium chloride, benzyltriethylammonium bromide, methyltributylammonium chloride and methyltrioctylammonium chloride.
• THF has also successfully been employed as solvent for the reaction wherein the presence of a phase transfer catalyst again provides a significantly faster reaction rate.
• a phase transfer catalyst again provides a significantly faster reaction rate.
• the product present in an organic phase is washed firstly with aqueous acid e.g. dilute HCI in order to remove amine compounds such as triethylamine and diisopropylethylamine and then with aqueous base e.g. sodium bicarbonate in order to remove any unreacted precursor compound of formula (II).
• aqueous acid e.g. dilute HCI
• aqueous base e.g. sodium bicarbonate
• the step typically comprises the addition of a reagent suitable for performing the esterification e.g. an activated derivative of 2-furoic acid such as an activated ester or preferably a 2-furoyl halide e.g. 2-furoyl chloride (employed in at least 2 times molar quantity relative to the compound of formula (III)) in the presence of an organic base e.g. triethylamine.
• a reagent suitable for performing the esterification e.g. an activated derivative of 2-furoic acid such as an activated ester or preferably a 2-furoyl halide e.g. 2-furoyl chloride (employed in at least 2 times molar quantity relative to the compound of formula (III)) in the presence of an organic base e.g. triethylamine.
• the second mole of 2-furoyl chloride reacts with the thioacid moiety in the compound of formula (III) and needs to be removed e.g. by reaction with an
• step (b) removal of the sulphur-linked 2-furoyl moiety from compound of formula (IIA) by reaction of the product of step (a) with an organic primary or secondary amine base capable of forming a water soluble 2-furoyl amide.
• the activated derivative of 2-furoic acid may be an activated ester of 2-furoic acid, but is more preferably a 2-furoyl halide, especially 2-furoyl chloride.
• a suitable solvent for this reaction is ethylacetate or methylacetate
• step (d ) may be followed
• acetone when step (d ) may be followed
• step (c2) may be followed).
• an organic base e.g. triethylamine will be present.
• the organic base is diethanolamine.
• the base may suitably be dissolved in a solvent e.g. methanol.
• steps (a) and (b) will be performed at reduced temperature e.g. between 0 and 5 °C.
• the aqueous wash may be water, however the use of brine results in higher yields and is therefore preferred.
• the aqueous medium is for example a dilute aqueous acid such as dilute
• the activated derivative of 2-furoic acid may be an activated ester of 2-furoic acid, but is more preferably a 2-furoyl halide, especially 2-furoyl chloride.
• a suitable solvent for his step is acetone. Normally an organic base e.g. triethylamine will be present.
• a suitable solvent is DMF or dimethylacetamide. Normally an organic base e.g. triethylamine will be present.
• steps (a) and (b) will be performed at reduced temperature e.g. between 0 and 5°C.
• the product may be isolated by treatment with acid and washing with water.
• the compound of formula (II) may advantageously be isolated in the form of a solid crystalline salt.
• the preferred salt is a salt formed with a base such as triethylamine, 2,4,6-trimethylpyridine, diisopropylethylamine or N-ethylpiperidine.
• Such salt forms of compound of formula (II) are more stable, more readily filtered and dried and can be isolated in higher purity than the free thioacid.
• the most preferred salt is the salt formed with diisopropylethylamine.
• the triethylamine salt is also of interest.
• Step (a) comprises oxidation of a solution containing the compound of formula (V).
• step (a) will be performed in the presence of a solvent comprising methanol, water, tetrahydrofuran, dioxan or diethylene glygol dimethylether.
• a solvent comprising methanol, water, tetrahydrofuran, dioxan or diethylene glygol dimethylether.
• preferred solvents are methanol, water or tetrahydrofuran, and more preferably are water or tetrahydrofuran, especially water and tetrahydrofuran as solvent.
• Dioxan and diethylene glygol dimethylether are also preferred solvents which may optionally (and preferably) be employed together with water.
• the solvent will be present in an amount of between 3 and 10vol relative to the amount of the starting material (1wt.), more preferably between 4 and 6 vol., especially 5 vol.
• the oxidising agent is present in an amount of 1-9 molar equivalents relative to the amount of the starting material.
• the oxidising agent may be present in an amount of between 1.1 and 10wt. relative to the amount of the starting material (1wt), more preferably between 1.1 and 3wt., especially 1.3wt.
• the oxidation step will comprise the use of a chemical oxidising agent.
• the oxidising agent will be periodic acid or iodic acid or a salt thereof. Most preferably, the oxidising agent will be periodic acid or sodium periodate, especially periodic acid.
• the oxidation step may comprise any suitable oxidation reaction, e.g. one which utilises air and/or oxygen. When the oxidation reaction utilises air and/or oxygen, the solvent used in said reaction will preferably be methanol.
• step (a) will involve incubating the reagents at room temperature or a little warmer, say around 25 °C e.g. for 2 hours.
• the compound of formula (IV) may be isolated by recrystallisation from the reaction mixture by addition of an anti-solvent.
• a suitable anti-solvent for compound of formula (IV) is water.
• anti-solvent e.g. water.
• the recrystallisation is performed using chilled water (e.g. water/ice mixture at a temperature of 0-5°C) although better anti-solvent properties may be expected we have found that the crystalline product produced is very voluminous, resembles a soft gel and is very difficult to filter. Without being limited by theory we believe that this low density product contains a large amount of solvated solvent within the crystal lattice. By contrast when conditions of around 10°C or higher are used (e.g.
• crystallisation typically commences after around 1 hour and is typically completed within a few hours (e.g. 2 hours). Without being limited by theory we believe that this granular product contains little or no solvated solvent within the crystal lattice.
• Step (b) will typically comprise the addition of a reagent suitable for converting a carboxylic acid to a carbothioic acid e.g. using hydrogen sulphide gas together with a suitable coupling agent e.g. carbonyldiimidazole (CDI) in the presence of a suitable solvent e.g. dimethylformamide.
• a suitable coupling agent e.g. carbonyldiimidazole (CDI)
• CDI carbonyldiimidazole
• the advantages of the complex comprising a compound of formula (I) together with a guest compound according to the invention may include the fact that the substance appears to demonstrate excellent anti-inflammatory properties, with predictable pharmacokinetic and pharmacodynamic behaviour, with an attractive side-effect profile, long duration of action, and is compatible with a convenient regime of treatment in human patients, in particular being amenable to once-per day dosing. Further advantages may include the fact that the substance has desirable physical and chemical properties which allow for ready manufacture and storage. Alternatively it may serve as a useful intermediate in the preparation of other forms of the compound of formula (I) or complexes thereof.
• Figure 1 Figure showing the spacial arrangement of 4 steroid and 4 guest molecules in the unit cell of complexes of the invention with THF (upper figure) and DMF (lower figure) (guest molecule darkened).
• Figure 2A Figure showing detail of the spacial arrangement of steroid and guest molecules in complexes of the invention with THF.
• Figure 2B Figure showing detail of the spacial arrangement of steroid and guest molecules in complexes of the invention with DMF.
• Figure 3 Figure showing the evolution of the XRPD profile of the complex of the invention with acetone on heating, in particular showing its conversion to compound of formula (I) as unsolvated Form 1
• Figure 4 XRPD profiles for a range of complexes according to the invention (refer to
• Figure 5 Comparison of XRPD profiles of Form1, Form 2 and Form 3 polymorphs of unsolvated compound of formula (I).
• Figure 6 Scanning Electron Microscopy (SEM) study of crystals of unsolvated polymorph Form 1.
• Figure 9 Raman spectrum of complexes of the invention with butan-1 -ol
• Figure 10 Raman spectrum of complexes of the invention with methyl acetate
• Figure 11 Raman spectrum of complexes of the invention with acetic acid
• Figure 12 Raman spectrum of complexes of the invention with propan-1-ol
• Figure 13 Raman spectrum of complexes of the invention with ethanol
• Figure 14 Raman spectrum of complexes of the invention with ethyl formate
• Figure 15 Raman spectrum of complexes of the invention with 1 ,4-dioxane
• Figure 16 Raman spectrum of complexes of the invention with dimethylsulphoxide
• Figure 17 Enlarged XRPD profile of complexes of the invention with acetone
• Figure 18 Enlarged XRPD profile of complexes of the invention with methylethylketone
• Figure 20 Enlarged XRPD profile of complexes of the invention with tetrahydrofuran
• Figure 21 Enlarged XRPD profile of complexes of the invention with dimethylformamide
• Figure 22 Enlarged XRPD profile of complexes of the invention with butan-1 -ol
• Figure 23 Enlarged XRPD profile of complexes of the invention with methyl acetate
• Figure 24 Enlarged XRPD profile of complexes of the invention with acetic acid
• Figure 25 Enlarged XRPD profile of complexes of the invention with propan-1-ol
• Figure 26 Enlarged XRPD profile of complexes of the invention with ethanol
• Figure 27 Enlarged XRPD profile of complexes of the invention with ethyl formate
• Figure 28 Enlarged XRPD profile of complexes of the invention with 1 ,4-dioxane
• Figure 29 Enlarged XRPD profile of complexes of the invention with dimethylsulphoxide
• Figure 30 Enlarged XRPD profile of complexes of the invention with N-methyl-2- pyrrolidinone
• Figure 31 Enlarged XRPD profile of complexes of the invention with dimethylacetamide
• Figure 32 Enlarged XRPD profile of complexes of the invention with water
• Figure 33 Enlarged XRPD profile of complexes of the invention with cyclopentanone
• Figure 34 Enlarged XRPD profile of complexes of the invention with ⁇ -caprolactam.
• Figure 35 Enlarged XRPD profile of complexes of the invention with f-butylamine.
• ⁇ H-nmr spectra were recorded at 400 MHz and the chemical shifts are expressed in ppm relative to tetramethylsilane.
• the following abbreviations are used to describe the multiplicities of the signals: s (singlet), d (doublet), t (triplet), q (quartet), m
• Biotage refers to prepacked silica gel cartridges containing
• the XRPD analyses shown in the figures were performed on either a) a Phillips X'pert MPD powder diffractometer, serial number DY667. The pattern was recorded using the following acquisition conditions'. Tube anode: Cu, Start angle: 2.0 °2 ⁇ , End angle: 45.0 °2 ⁇ , Step size: 0.02 °2 ⁇ , Time per step: 1 second. XRPD profiles were collected at ambient temperature (295K) unless otherwise indicated, or b) a Philips PW1710 powder diffractometer. The pattern was recorded using the following acquisition conditions: Tube anode: Cu, Start angle: 3.5 °2 ⁇ , End angle: 35.0 °2 ⁇ , Step size: 0.02 °2 ⁇ , Time per step: 2.3 seconds. XRPD profiles were collected at ambient temperature (295K).
• the diffractometer used in each case can be determined by the end angle in the figure.
• Raman spectra were recorded with the sample in an NMR tube using a Nicolet 960 E.S.P. FT-Raman spectrometer, at 4 cm-1 resolution with excitation from a Nd:V04 laser (1064 nm) with a power output of 400mW.
• 2-Furoyl chloride 25ml is added and the mixture stirred at 0-5°C for 1 hour.
• a solution of diethanolamine (52.8g) in methanol (50ml) is added and the mixture stirred at 0-5°C for at least 2 hours.
• Dilute hydrochloric acid approximately 1 M, 550ml is added maintaining a reaction temperature below 15°C and the mixture stirred at 15°C.
• the organic phase is separated and the aqueous phase is back extracted with methyl acetate (2x250ml). All of the organic phases are combined, washed sequentially with brine (5 x 250m! and treated with di-isopropylethylamine (30ml).
• reaction mixture is concentrated by distillation at atmospheric pressure to an approximate volume of 250ml and cooled to 25-30°C (crystallisation of the desired product normally occurs during distillation/subsequent cooling).
• Tertiary butyl methyl ether (TBME) 500ml is added, the slurry further cooled and aged at 0-5°C for at least 10 minutes.
• the product is filtered off, washed with chilled TBME (2x200ml) and dried under vacuum at approximately 40-50°C (75.3g, 98.7%).
• the suspension is stirred overnight, allowing to warm to 17°C.
• the aqueous layer is separated and the organic phase is sequentially washed with 1M HCI (50ml), 1 %w/v NaHCO 3 solution (3x50ml) and water (2x50ml).
• the ethylacetate solution is distilled at atmospheric pressure until the distillate reaches a temperature of approximately 73°C at which point toluene (150ml) is added. Distillation is continued at atmospheric pressure until all remaining EtOAc has been removed (approximate distillate temperature 103°C).
• the resultant suspension is cooled and aged at ⁇ 10°C and filtered off.
• reaction mixture is stirred for at least 30minutes and diluted with water (10vol) maintaining a reaction temperature in the range 0-5°C.
• the resultant precipitate is collected by filtration and washed sequentially with acetone/water (50/50 2vol) and water (2x2vol).
• a portion of the product (0.56g) is mixed with 6 ⁇ , 9 ⁇ -difluoro-11 ⁇ , 17 ⁇ -dihydroxy-16 ⁇ -methyl-3- oxo-androsta-1 ,4-diene-17 ⁇ -carbothioic acid (0.41 g) in a 1:1 molar ratio in DMF (1 Ovolumes wrt total steroid input).
• the reaction mixture is treated with triethylamine (approximately 2.1 equivalents) and the mixture is stirred at approximately 20°C for approximately 6 hours.
• Water (50vol) containing excess cone HCI (0.5vol) is added to the reaction mixture and the resultant precipitate collected by filtration.
• the bed is washed with water (2x5vol) and dried in vacuo at approximately 55°C overnight to leave the title compound as a white solid (0.99g,102%).
• Solution flow rate 30ml/min using Isco 260D syringe pump (Isco Inc, Lincoln, NE,
• Atomisation Pressure 2 Bar Particle collection was achieved in the conventional manner using a Fisher Kleinman XQ120-1.375 high efficiency cyclone (Fisher-Klosterman Inc, Louisville, KY, USA). A white powder was recovered. The spray drying process was successful at producing smooth, spherical particles of amorphous 6 ⁇ , 9 ⁇ -Difluoro-17 ⁇ -[(2- furanylcarbonyl)oxy]-11 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-androsta-1 ,4-diene-17 ⁇ - carbothioic acid S-fluoromethyl ester. System yield was 61 %
• a white powder was recovered from the cyclone and collection vessel, yield 37%.
• the spray drying process was successful at producing smooth, spherical particles of amorphous 6 ⁇ , 9 ⁇ -Difluoro-17 ⁇ -[(2-furanylcarbonyl)oxy]-11 ⁇ -hydroxy-16 ⁇ -methyl-3- oxo-androsta-1 ,4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester.
• the majority of the particles were between 0.5 and 4 ⁇ m.
• Pharmacological activity was assessed in a functional in vitro assay of glucocorticoid agonist activity which is generally predictive of anti-inflammatory or anti-allergic activity in vivo.
• the functional assay was based on that described by K.P.Ray et al., Biochem J. (1997), 328, 707-715.
• A549 cells stably transfected with a reporter gene containing the NF-KB responsive elements from the ELAM gene promoter coupled to sPAP (secreted alkaline phosphatase) were treated with test compounds at appropriate doses for 1 hour at 37°C.
• the cells were then stimulated with tumour necrosis factor (TNF, 10ng/ml) for 16 hours, at which time the amount of alkaline phosphatase produced is measured by a standard colourimetric assay.
• TNF tumour necrosis factor
• the glucocorticoid receptor can function in at least two distinct mechanisms, by upregulating gene expression through the direct binding of GR to specific sequences in gene promotors, and by downregulating gene expression that is being driven by other transcription factors (such as NFKB or AP-1) through their direct interaction with GR.
• the first cell line contains the firefly luciferase reporter gene under the control of a synthetic promoter that specifically responds to activation of the transcription factor NFKB when stimulated with TNF ⁇ .
• the second cell line contains the renilla luciferase reporter gene under the control of a synthetic promotor that comprises 3 copies of the consensus glucocorticoid response element, and which responds to direct stimulation by glucocorticoids.
• Anaesthetised pigs (2) were dosed intra-tracheally with a homogenous mixture of compound (I) (1mg) and fluticasone propionate (1mg) as a dry powder blend in lactose (10% w/w). Serial blood samples were taken for up to 8h following dosing. Plasma levels of compound (I) and fluticasone propionate were determined following extraction and analysis using LC-MS/MS methodology, the lower limits of quantitation of the methods were 10 and 20pg/mL for compound (I) and fluticasone propionate respectively. Using these methods compound (I) was quantifiable up to 2 hours after dosing and fluticasone propionate was quantifiable up to 8 hours after dosing.
• Plasma half-life data obtained from IV dosing (0.1 mg/kg) was used to calculate AUC (0-inf) values for compound (I). This compensates for the plasma profile of Compound (I) only being defined up to 2 hours after an IT dose and removes any bias due to limited data between compound (I) and fluticasone propionate.
• Example 1 6 ⁇ . 9 ⁇ -Difluoro-17 ⁇ -r(2-furanylcarbonyl)oxyl-11 ⁇ -hvdroxy-16 ⁇ -methyl-3- oxo-androsta-1 ,4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester crystalline complex with acetone
• the filter cake (the 6 ⁇ , 9 ⁇ -Difluoro-17 ⁇ -[(2-furanyIcarbonyl)oxy]-11 ⁇ -hydroxy-16 ⁇ -methyI-3- oxo-androsta-1,4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester complex with DMF) is washed with water (4x4vol) and the product is pulled dry on the filter.
• the damp cake is returned to the vessel, acetone (5.75vol) added and heated at reflux for 2h.
• the mixture is cooled to 52+3°C and water (5.75vol) added, keeping temperature at 52 ⁇ 3°C.
• Example 1 6 ⁇ . 9 ⁇ -Difluoro-17 ⁇ -[(2-furanylcarbonyl)oxyl-11 ⁇ -hvdroxy-16 ⁇ -methyl-3- oxo-androsta-1.4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester crystalline complex with acetone (alternative method)
• Example 1 6 ⁇ . 9 ⁇ -Difluoro-17 ⁇ -f(2-furanylcarbonyl)oxyl-11 ⁇ -hvdroxy-16 ⁇ -methyl-3- oxo-androsta-1.4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester crystalline complex with acetone (second alternative method)
• Example 2 6 ⁇ . 9 ⁇ -Difluoro-17 ⁇ -f(2-furanylcarbonyl)oxy1-11 ⁇ -hvdroxy-16 ⁇ -methyl-3- oxo-androsta-1.4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester crystalline complex with methylethylketone A suspension of Intermediate 2 (400mg) in methylethylketone (3.2ml) is heated to reflux giving a clear solution.
• Example 3 6 ⁇ . 9 ⁇ -Difluoro-17 ⁇ -r(2-furanylcarbonyPoxyl-11 ⁇ -hvdroxy-16 ⁇ -methyl-3- oxo-androsta-1 ,4-diene-17 ⁇ -carbothioic acid S-fluoromethyl este crystalline complex with propanol-2-ol
• Example 3 6 ⁇ . 9 ⁇ -Difluoro-17 ⁇ -[(2-furanylcarbonyl)oxy]-11 ⁇ -hvdroxy-16 ⁇ -methyl-3- oxo-androsta-1 ,4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester crystalline complex with propan-2-ol (alternative method)
• a sample of Intermediate 2 (1.0 g) was dissolved in approximately 80 volumes of propan-2-ol (80 mL) at reflux. The solvent level was reduced at reflux until crystallisation began before the flask was cooled to 21 °C over approximately 30 minutes. The white precipitate was recovered by filtration and dried on the filter under vacuum for 30 minutes to afford the title complex as a white solid.
• Example 3 6 ⁇ . 9 ⁇ -Difluoro-17 ⁇ -r(2-furanylcarbonv ⁇ oxy1-11 ⁇ -hydroxy-16 ⁇ -methyl-3- oxo-androsta-1.4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester crystalline complex n with propan-2-ol (second alternative method)
• a sample of Intermediate 2 (82 g) was dissolved in a mixture of propan-2-ol (900ml mL) and ethyl acetate (900ml) at reflux. The solvent level was reduced by distillation at atmospheric distillation to approximately 12 volumes (985ml) and the mixture seeded with authentic crystals of the desired product (ie complex with propan-2-ol, approximately 100mg).
• the propan-2-ol can be removed by the following process:
• Example 3 6 ⁇ . 9 ⁇ -Difluoro-17 ⁇ -[(2-furanylcarbonyl)oxy]-11 ⁇ -hydroxy-16 ⁇ -methyl-3- oxo-androsta-1.4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester crystalline complex n with propan-2-ol (third alternative method)
• the suspension is adjusted to 50+ 5 ° and aged for ca 5 mins (until crystallisation is established).
• the suspension is concentrated once again to ca 10vols. Further propan-2-ol (10vols) is added and the suspension concentrated to ca 10vols for a third time (note: pot temp at this point ca80°).
• the suspension is cooled to 0-5°C over ca 120mins and aged for at least 60mins.
• the white precipitate is isolated by vacuum filtration washing the filter cake with chilled propan-2-ol and dried in vacuo to afford the propan-2-ol solvate of 6 ⁇ , 9 ⁇ - Difluoro-17 ⁇ -[(2-furanylcarbonyl)oxy]-11 ⁇ -hydroxy- 6 ⁇ -methyl-3-oxo-androsta-1 ,4- diene-17 ⁇ -carbothioic acid S-fluoromethyl ester as tetrogonal bipyramidal particles an off-white to grey solid.
• Example 4 6 ⁇ , 9 ⁇ -Difluoro-17 ⁇ -r(2-furanylcarbonv0oxyl-11 ⁇ -hydroxy-16 ⁇ -methyl-3- oxo-androsta-1 ,4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester crystalline complex with tetrahydrofuran
• Example 4 6 ⁇ . 9 ⁇ -Difluoro-17 ⁇ -f(2-furanylcarbonyl)oxy "
• a mobile suspension of Intermediate 5 (1.2g) in THF (10ml) is treated with a phase transfer catalyst (tetrabutylammonium bromide, typically between 8 and 14mol%), cooled to approximately 3°C and treated with bromofluoromethane (0.98 equivalents). The suspension is stirred for between 2 and 5 hours, allowing to warm to 17°C.
• a phase transfer catalyst tetrabutylammonium bromide, typically between 8 and 14mol%
• reaction mixture is poured into water (30vol), stirred at approximately 10°C for 30 minutes and filtered off.
• the collected solid is washed with water (4x3vol) and the product oven dried under vacuum at 60°C overnight to give the title complex as a white solid (0.85g, 87%).
• Example 4 6 ⁇ . 9 ⁇ -Difluoro-17 ⁇ -r(2-furanylcarbonyl)oxyl-11 ⁇ -hydroxy-16 ⁇ -methyl-3- oxo-androsta-1.4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester crystalline complex with tetrahydrofuran (second alternative method)
• Example 5 6 ⁇ . 9 ⁇ -Difluoro-17 ⁇ -[(2-furanylcarbonyl)oxy]-11 ⁇ -hydroxy-16 ⁇ -methyl-3- oxo-androsta-1.4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester crystalline complex with dimethylformamide
• Example 6 6 ⁇ . 9 ⁇ -Difluoro-17 ⁇ -r(2-furanylcarbonyl)oxy1-11 ⁇ -hydroxy-16 ⁇ -methyl-3- oxo-androsta-1 ,4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester cyrstalline complex with butan-1 -ol A mixture of Intermediate 4A (400 mg) and butan-1 -ol (4 mL) was slurried at 21 °C for
• Example 7 6 ⁇ . 9 ⁇ -Difluoro-17 ⁇ -r(2-furanylcarbonyl)oxy]-11 ⁇ -hvdroxy-16 ⁇ -methyl-3- oxo-androsta-1.4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester crystalline complex with methyl acetate
• Example 7 6 ⁇ , 9 ⁇ -Difluoro-17 ⁇ -[Y2-furanylcarbonyl)oxy]-11 ⁇ -hydro ⁇ y-16 ⁇ -methyl-3- oxo-androsta-1.4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester crystalline complex with methyl acetate (alternative method)
• Example 8 6 ⁇ . 9 ⁇ -Difluoro-17 ⁇ -[T2-furanylcarbonyl)o ⁇ y
• Example 9 6 ⁇ . 9 ⁇ -Difluoro-17 ⁇ -f(2-furanylcarbonyl)oxy]-11 ⁇ -hvdroxy-16 ⁇ -methyl-3- oxo-androsta-1,4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester crystalline complex with propan-1-ol
• Example 10 6 ⁇ . 9 ⁇ -Difluoro-17 ⁇ -[(2-furanylcarbonyl)oxy1-11 ⁇ -hydroxy-16 ⁇ -methyl- 3-oxo-androsta-1.4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester crystalline complex with ethanol
• the product of Example 3 (500 mg) was slurried in ethanol (5 mL) under vacuum at 21 °C for a total of 16 hours, replacing the ethanol as necessary. The solid was collected by filtration and dried on the filter for 2 hours to give thetitie complex as a white solid (438 mg).
• Example 11 6 ⁇ . 9 ⁇ -Difluoro-17 ⁇ -f (2-furanylcarbonyl)oxy]-11 ⁇ -hydroxy-16 ⁇ -methyl- 3-oxo-androsta-1.4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester crystalline complex with ethyl formate Intermediate 4A (400 mg) was slurried in ethyl formate (2 mL) for 16 hours at 21 °C. The solid was recovered by filtration and dried on the filter for 20 minutes to afford the title complex (396 mg).
• Example 12 6, 9-Difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methyl-3-oxo- androsta-1,4-diene-17-carbothioic acid S-fluoromethyl ester crystalline complex with 1 ,4-dioxane
• Example 12 6, 9-Difluoro-17-[(2-furanylcarbonyl)oxyj-11-hydroxy-16-methyl-3-oxo- androsta-1 ,4-diene-17-carbothioic acid S-fluoromethyl ester crystalline complex with
• Example 15 6 ⁇ . 9 ⁇ -Difluoro-17 ⁇ -f(2-furanylcarbonyl)oxy1-11 ⁇ -hvdroxy-16 ⁇ -methyl- 3-oxo-androsta-1.4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester crystalline complex with dimethylacetamide
• Example 16 6 ⁇ . 9 ⁇ -Difluoro-17 ⁇ -[(2-furanylcarbonv ⁇ oxy]-11 ⁇ -hvdroxy-16 ⁇ -methyl- 3-oxo-androsta-1.4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester crystalline complex with water
• Example 17 6 ⁇ , 9 ⁇ -Difluoro-17 ⁇ -[(2-furanylcarbonyl)oxyl-11 ⁇ -hvdroxy-16 ⁇ -methyl- 3-oxo-androsta-1.4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester crystalline complex with f-butylamine
• Example 18 6 ⁇ . 9 ⁇ -Difluoro-17 ⁇ -[(2-furanylcarbonyl)oxy1-11 ⁇ -hvdroxy-16 ⁇ -methyl- 3-oxo-androsta-1.4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester crystalline complex with D-caprolactam ⁇ -Caprolactam (50mg) (Aldrich) was heated in a glass vial to 80°C where the solid had melted. Intermediate 4A (200 mg) was added and the mixture was agitated using a small magnetic stirrer bar. The mixture was stirred at 80°C for 1 hour before the resulting mixture was allowed to cool to 21 °C and the solid was recovered to afford the title complex.
• Example 20 6 ⁇ . 9 ⁇ -Difluoro-17 ⁇ -f(2-furanylcarbonyl)oxy1-11 ⁇ -hvdroxy-16 ⁇ -methyl-
• Example A Dry powder composition containing 6 ⁇ . 9 ⁇ -Difluoro-17 ⁇ -f(2- furanylcarbonvQoxyl-11 ⁇ -hvdro ⁇ y-16 ⁇ -methyl-3-oxo-androsta-1 ,4-diene-17 ⁇ - carbothioic acid S-fluoromethyl ester complex with acetone
• a dry powder formulation may be prepared as follows:
• milled lactose (wherein not greater than 85% of particles have a MMD of 60-90 ⁇ m, and not less than 15% of particles have a MMD of less than 15 ⁇ m): 12mg
• a peelable blister strip containing 60 blisters each filled with a formulation as just described may be prepared.
• Example B Dry powder composition containing 6 ⁇ . 9 ⁇ -Difluoro-17 ⁇ -f(2- furanylcarbonyl)oxy1-11 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-androsta-1 ,4-diene-17 ⁇ - carbothioic acid S-fluoromethyl ester complex with acetone and a long acting pV adrenoreceptor agonist
• a dry powder formulation may be prepared as follows:
• milled lactose (wherein not greater than 85% of particles have a MMD of 60-90 ⁇ m, and not less than 15% of particles have a MMD of less than 15 ⁇ m): 12mg
• a peelable blister strip containing 60 blisters each filled with a formulation as just described may be prepared.
• Example C Aerosol formulation containing 6 ⁇ . 9 ⁇ -Difluoro-17 ⁇ -[(2- furanylcarbonyl)oxy1-1 ⁇ -hvdroxy-16 ⁇ -methyl-3-oxo-androsta-1 ,4-diene-17 ⁇ - carbothioic acid S-fluoromethyl ester complex with acetone prepared according to Example 1, MMD of 3 ⁇ m: An aluminium canister may be filled with a formulation as follows: 6a, 9 ⁇ -Difluoro-17 ⁇ -[(2-furanylcarbonyl)oxy]-11 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo- androsta-1 ,4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester complex with acetone prepared according to Example 1 , MMD of 3 ⁇ m:
• the canister may be fitted with a metering valve adapted to dispense 50 ⁇ l per actuation.
• Example D Aerosol formulation containing 6 ⁇ . 9 ⁇ -Pifluoro-17 ⁇ -f(2- furanylcarbonyl)oxy]-11 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-androsta-1 ,4-diene-17 ⁇ - carbothioic acid S-fluoromethyl ester complex with acetone and a long acting ⁇ V adrenoreceptor agonist
• An aluminium canister may be filled with a formulation as follows: 6 ⁇ , 9 ⁇ -Difluoro-17 ⁇ -[(2-furanylcarbonyl)oxy]-11 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo- androsta-1 ,4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester complex with acetone prepared according to Example 1, MMD of 3 ⁇ m:
• the canister may be fitted with a metering valve adapted to dispense 50 ⁇ l per actuation.
• Example E Nasal formulation containing 6 ⁇ . 9 ⁇ -Difluoro-17 ⁇ -[(2- furanylcarbonyl)oxy]-11 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-androsta-1 ,4-diene-17 ⁇ - carbothioic acid S-fluoromethyl ester complex with acetone
• a formulation for intranasal delivery may be prepared as follows:
• the formulation may be fitted into a spraypump capable of delivering a plurality of metered doses (Valois).
• Table 2 XRPD characteristic angles and relative intensities for 6 ⁇ , 9 ⁇ -Difluoro-17 ⁇ - [(2-furanylcarbonyl)oxy]-11 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-androsta-1 ,4-diene-17 ⁇ - carbothioic acid S-fluoromethyl ester, complex with acetone.
• Table 3 XRPD characteristic angles and relative intensities for 6 ⁇ , 9 ⁇ -Difluoro-17 ⁇ - [(2-furanylcarbonyl)oxy]-11 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-androsta-1 ,4-diene-17 ⁇ - carbothioic acid S-fluoromethyl ester, complex with methylethylketone.
• Table 4 XRPD characteristic angles and relative intensities for 6 ⁇ , 9 ⁇ -Difluoro-17 ⁇ - [(2-furanylcarbonyl)oxy]-11 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-androsta-1 ,4-diene-17 ⁇ - carbothioic acid S-fluoromethyl ester, complex with propan-2-ol.
• Table 5 XRPD characteristic angles and relative intensities for 6 ⁇ , 9 ⁇ -Difluoro-17 ⁇ - [(2-furanylcarbonyl)oxy]-11 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-androsta-1 ,4-diene-17 ⁇ - carbothioic acid S-fluoromethyl ester, complex with tetrahydrofuran.
• Table 6 XRPD characteristic angles and relative intensities for 6 ⁇ , 9 ⁇ -Difluoro-17 ⁇ - [(2-furanylcarbonyl)oxy]-11 ⁇ hydroxy-16 ⁇ -methyl-3-oxo-androsta-1 ,4-diene-17 ⁇ - carbothioic acid S-fluoromethyl ester, complex with dimethylformamide.
• Table 7 XRPD characteristic angles and relative intensities for 6 ⁇ , 9 ⁇ -Difluoro-17 ⁇ - [(2-furanylcarbonyl)oxy]-11 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-androsta-1 ,4-diene-17 ⁇ - carbothioic acid S-fluoromethyl ester, complex with butan-1 -ol.
• Table 8 XRPD characteristic angles and relative intensities for 6 ⁇ , 9 ⁇ -Difluoro-17 ⁇ - [(2-furanylcarbonyl)oxy]-11 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-androsta-1 ,4-diene-17 ⁇ - carbothioic acid S-fluoromethyl ester, complex with methyl acetate.
• Table 9 XRPD characteristic angles and relative intensities for 6 ⁇ , 9 ⁇ -Difluoro-17 ⁇ - [(2-furanylcarbonyl)oxy]-11 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-androsta-1 ,4-diene-17 ⁇ - carbothioic acid S-fluoromethyl ester, complex with acetic acid.
• Table 10 XRPD characteristic angles and relative intensities for 6 ⁇ , 9 ⁇ -Difluoro- 17 ⁇ -[(2-furanylcarbonyI)oxy]-11 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-androsta-1 ,4-diene-17 ⁇ - carbothioic acid S-fluoromethyl ester, complex with propan-1-ol.
• Table 11 XRPD characteristic angles and relative intensities for 6 ⁇ , 9 ⁇ -Difluoro- 17 ⁇ -[(2-furanylcarbonyl)oxy]-11 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-androsta-1 ,4-diene-17 ⁇ - carbothioic acid S-fluoromethyl ester, complex with ethanol.
• Table 12 XRPD characteristic angles and relative intensities for 6 ⁇ , 9 ⁇ -Difluoro- 17 ⁇ -[(2-furanylcarbonyl)oxy]-11 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-androsta-1,4-diene-17 ⁇ - carbothioic acid S-fluoromethyl ester, complex with ethyl formate.
• Table 13 XRPD characteristic angles and relative intensities for ⁇ , 9 ⁇ -Difluoro- 17 ⁇ -[(2-furanylcarbonyl)oxy]-11 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-androsta-1 ,4-diene-17 ⁇ - carbothioic acid S-fluoromethyl ester, complex with 1 ,4-dioxane.
• Table 14 XRPD characteristic angles and relative intensities for 6 ⁇ , 9 ⁇ -Difluoro- 17 ⁇ -[(2-furanylcarbonyl)oxy]-11 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-androsta-1 ,4-diene-17 ⁇ - carbothioic acid S-fluoromethyl ester, complex with dimethylsulfoxide.
• Table 15 XRPD characteristic angles and relative intensities for 6 ⁇ , 9 ⁇ -Difluoro- 17 ⁇ -[(2-furanylcarbonyl)oxy]-11 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-androsta-1 ,4-diene-17 ⁇ - carbothioic acid S-fluoromethyl ester, complex with N-methyl-2-pyrrolidinone.
• Table 16 XRPD characteristic angles and relative intensities for 6 ⁇ , 9 ⁇ -Difluoro- 17 ⁇ -[(2-furanylcarbonyl)oxy]-11 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-androsta-1 ,4-diene-17 ⁇ - carbothioic acid S-fluoromethyl ester, complex with dimethyl acetamide.
• Table 17 XRPD characteristic angles and relative intensities for 6 ⁇ , 9 ⁇ -Difluoro- 17 ⁇ -[(2-furanylcarbonyl)oxy]-11 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-androsta-1 ,4-diene-17 ⁇ - carbothioic acid S-fluoromethyl ester, complex with water.
• Table 18 XRPD characteristic angles and relative intensities for 6 ⁇ , 9 ⁇ -Difluoro- 17 ⁇ -[(2-furanylcarbonyl)oxy]-11 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-androsta-1 ,4-diene-17 ⁇ - carbothioic acid S-fluoromethyl ester.complex with cyclopentanone.
• Table 19 XRPD characteristic angles and relative intensities for 6 ⁇ , 9 ⁇ -Difluoro- 17 ⁇ -[(2-furanylcarbonyl)oxy]-11 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-androsta-1 ,4-diene-17 ⁇ - carbothioic acid S-fluoromethyl ester, complex with f-butylamine.
• Table 20 XRPD characteristic angles and relative intensities for 6 ⁇ , 9 ⁇ -Difluoro- 17 ⁇ -[(2-furanylcarbonyl)oxy]-11 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-androsta-1 ,4-diene-17 ⁇ - carbothioic acid S-fluoromethyl ester, complex with ⁇ -caprolactam.

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