WO2005028495A1 - Glucocorticoïdes anti-inflammatoires - Google Patents

Glucocorticoïdes anti-inflammatoires Download PDF

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Publication number
WO2005028495A1
WO2005028495A1 PCT/EP2004/010779 EP2004010779W WO2005028495A1 WO 2005028495 A1 WO2005028495 A1 WO 2005028495A1 EP 2004010779 W EP2004010779 W EP 2004010779W WO 2005028495 A1 WO2005028495 A1 WO 2005028495A1
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WIPO (PCT)
Prior art keywords
hydroxy
dodecahydro
hydroxyacetyl
naphtho
dioxol
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PCT/EP2004/010779
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English (en)
Inventor
Keith Biggadike
Gordon Gad Weingarten
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Glaxo Group Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Priority claimed from GB0322383A external-priority patent/GB0322383D0/en
Priority claimed from GB0322381A external-priority patent/GB0322381D0/en
Priority claimed from GB0322387A external-priority patent/GB0322387D0/en
Application filed by Glaxo Group Limited filed Critical Glaxo Group Limited
Publication of WO2005028495A1 publication Critical patent/WO2005028495A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
    • C07J71/0005—Oxygen-containing hetero ring
    • C07J71/0026—Oxygen-containing hetero ring cyclic ketals
    • C07J71/0031—Oxygen-containing hetero ring cyclic ketals at positions 16, 17
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring

Definitions

  • the present invention relates to novel anti-inflammatory and anti-allergic compounds of the glucocorticoid 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, rhinitis and rheumatoid arthritis.
  • Examples of glucocorticoids used clinically include Budesonide (4aR,4bS,5S,6aS,6bS,9a 10aS, 10bS)-5-hydroxy-6b-(hydroxyacetyl)- 4a,6a-dimethyl -8-propyl -4a,4b,5,6,6a,6b,9a,10,10a,10b,11 ,12-dodecahydro -2H- naphtho[2',1':4,5]indeno[1 ,2-c(][1 ,3]dioxol-2-one (i.e.
  • Ri and R 2 are the same or different and each represents hydrogen, halogen or a methyl group
  • R 3 represents H, CI, F, OH or OC(O)R 6 ;
  • R 4 represents hydrogen or methyl,
  • n represents 0,1 or 2;
  • m represents 0 or 1 ;
  • Cycl represents C 3-8 cycioalkyl or C 3 . 8 cycloalkenyl in which one or more ring carbon atoms may be replaced by an atom selected from O, N or S, and which C 3-8 cycioalkyl or C 3-8 cycloalkenyl group may optionally be substituted, the substituent optionally being at a hetero-atom present, by one or more groups selected from oxo, hydroxy, C 1-6 alkoxy, C 1-6 alkylthio, halo d. 6 alkoxy, amino, diCi.
  • Ar represents C 5-10 aryl or C 3-10 heteroaryl which may optionally be substituted, the substituent optionally being at a heteroatom present, by one or more groups selected from oxo, hydroxy, C 1-6 alkoxy, C 1-6 alkylthio, haloC L ⁇ alkoxy, amino, C ⁇ 6 alkylamino, diC 1-6 alkylamino, mercapto, cyano, nitro, acyl, carbamoyl, carboxamide, C 1-6 alkyl N-substituted carboxamide, sulphonamide, methylene, halogen, C ⁇ alkyl, C ⁇ .
  • R 6 represents H, C 1-8 alkyl or branched C 1-8 alkyl; and represents a single or a double bond; including pharmaceutically acceptable esters, amides and carbamates thereof, salts thereof, solvates thereof, and solvates of such pharmaceutically acceptable esters, amides, carbamates and salts.
  • R 3 represents OH or OC(0)R 6 .
  • Ri and R 2 may be the same or different and each preferably independently represents hydrogen or halogen. Amongst halogens there are preferred chloro and fluoro, especially fluoro. In a preferred embodiment, both Ri and R 2 are hydrogen; in an alternative embodiment, one of Ri and R 2 is hydrogen and the other is fluorine, for example Ri and is hydrogen and R 2 is fluorine. Preferably, R 2 is fluorine.
  • R 3 represents OH.
  • R 3 represents OC(0)R 6 and R 6 represents Ci. 8 alkyl or branched C ⁇ -8 alkyl.
  • Ri and R 2 are the same or different and each represents hydrogen, halogen or a methyl group
  • R 3 represents H, CI, F, OH or OC(O)R 6 ;
  • R 4 represents hydrogen or methyl,
  • Cycl represents C 3-8 cycioalkyl or C 3-8 cycloalkenyl in which one or more ring carbon atoms may be replaced by an atom selected from O, N or S, and which C 3-8 cycioalkyl or C 3-8 cycloalkenyl group may optionally be substituted, the substituent optionally being at a hetero-atom present, by one or more groups selected from oxo, hydroxy, C 1-6 alkoxy, C ⁇ -6 alkylthio, halo C 1-6 alkoxy, amino, C ⁇ . 6 alkylamino, did.
  • 6 alkenyl or phenyl substituent may be further substituted with one or more groups selected from C ⁇ -6 alkyl, C ⁇ -6 alkoxy or halogen; the C 3-8 cycioalkyl or C 3-8 cycloalkenyl group optionally being bridged; or else R 4 , R 5 and the carbon atom to which they are both joined, together form a C 3 -C 8 cycioalkyl group in which one or more ring carbon atoms may be replaced by an atom selected from O, N or S, which may optionally be substituted, the substituent optionally being at a hetero-atom present, by one or more groups selected from oxo, hydroxy, C ⁇ .
  • the C 3 . 8 cycioalkyl or C 3-8 cycloalkenyl group is substituted by one or more groups selected from oxo, hydroxy, d -6 alkoxy, C ⁇ -6 alkylthio, halo amino, mercapto, cyano, nitro, acyl, carbamoyl, carboxamide, methylene, halogen, C ⁇ alkyl, C 1-6 alkenyl or phenyl, which C 1-6 alkyl or phenyl substituent may be further substituted with one or more groups selected from Ci.6 alkyl, C 1-6 alkoxy or halogen.
  • substituents attached at a hetero-atom include N-acyl groups, N-suphonyl groups, N-carbamoyl groups.
  • substituted compounds include sulphoxides (SO), sulphones (SO 2 ) and sulphonamides (SO 2 NR 6 R 6 ).
  • Preferred halogen atoms are selected from bromine, chlorine and fluorine.
  • Examples of C ⁇ -6 alkyl substituents are methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, sec- butyl and tert-butyl, preferably methyl.
  • the Cycl group may have one methyl substituent; alternatively, there may, for example, be 2, 3 or 4 methyl substituents.
  • substituents it is preferred for substituents to be in the 4 position.
  • the Cycl group is 4,4 dimethylcyclohexyl.
  • the Cycl group is a C 3-8 cycioalkyl group.
  • cycioalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • the Cycl group is a C 3 . 8 cycloalkenyl group.
  • cycloalkenyl groups include cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.
  • a preferred group is cyclohexenyl, for example 1- cyclohexenyl.
  • the Cycl group is a bridged C 3 . 8 cycioalkyl or C 3-8 cycloalkenyl group.
  • bridged groups include norbornane and norbornene.
  • R 4 represents hydrogen or methyl
  • Preferred compounds of formula (I) include:
  • esters including pharmaceutically acceptable esters, amides and carbamates thereof, salts thereof, solvates thereof, and solvates of such pharmaceutically acceptable esters, amides, carbamates and salts.
  • Preferred examples are:
  • esters including pharmaceutically acceptable esters, amides and carbamates thereof, salts thereof, solvates thereof, and solvates of such pharmaceutically acceptable esters, amides, carbamates and salts.
  • esters including pharmaceutically acceptable esters, amides and carbamates thereof, salts thereof, solvates thereof, and solvates of such pharmaceutically acceptable esters, amides, carbamates and salts.
  • Ri and R 2 are the same or different and each represents hydrogen, halogen or a methyl group
  • R 3 represents H, CI, F, OH or OC(O)R 6 ;
  • R 4 represents hydrogen or methyl
  • Ar represents C 5-10 aryl or C 3- ⁇ 0 heteroaryl which may optionally be substituted, the substituent optionally being at a heteroatom present, by one or more groups selected from oxo, hydroxy, d -6 alkoxy, d. 6 alkylthio, halod. 6 alkoxy, amino, d.
  • aryl groups include phenyl, phenanthrene, naphthalene, anthracene and fluorene.
  • Preferred aryl groups include naphthalene.
  • heteroaryl groups include thiophene, pyrrole, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, 1 ,2,3-triazole, 1 ,2,4-triazole, 1 ,2,5- oxadiazole, tetrazole, benzofuran, isobenzofuran, benzothiophene, indole, benzoxazole, indazole, benzimidazole, benzotriazole, carbazole, 2-pyrone, 4-pyrone, pyridine, pyridazine, py midine, pyrazine, 1 ,3,5-triazine, coumarin, isocoumarin, chromone, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, 1 ,8- naphthyridine, acridine, purine and furan.
  • Prefered heterocyclic groups are thiophene, pyrrole, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, 1 ,2,3-triazole, 1 ,2,4-triazole, 1 ,2,5-oxadiazole, tetrazole, benzofuran, isobenzofuran, benzothiophene, indole, benzoxazole, indazole, benzimidazole, benzotriazole, carbazole, 2-pyrone, 4-pyrone, pyridine, pyridazine, pyrimidine, pyrazine, 1,3,5- triazine, coumarin, isocoumarin, chromone, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, 1 ,8-naphthyridine, acridine and purine.
  • substituents include oxo, hydroxy, d -6 alkoxy, C 1-6 alkylthio, haloC ⁇ -6 alkoxy, amino, d. 6 alkylamino, mercapto, cyano, acyl, carbamoyl, carboxamide, methylene, halogen, C ⁇ -6 alkyl, or phenyl, which C 1-6 alkyl, d. 6 alkenyl or phenyl substituent may be further substituted with one or more groups selected from C 1-6 alkyl, d ⁇ alkoxy or halogen.
  • Preferred halogen substituents are selected from bromine, chlorine and fluorine. Examples of C ⁇ . 6 alkyl substituents are methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, sec-butyl and tert-butyl, preferably methyl.
  • n may be 0, 1 or 2.
  • n is preferably 0, thus the Ar group may, for example, be joined to the acetal carbon by a direct bond, a methylene group or an ethyl group.
  • n is preferably 0.
  • Preferred compounds of formula (I) include:
  • esters including pharmaceutically acceptable esters, amides and carbamates thereof, salts thereof, solvates thereof, and solvates of such pharmaceutically acceptable esters, amides, carbamates and salts.
  • esters including pharmaceutically acceptable esters, amides and carbamates thereof, salts thereof, solvates thereof, and solvates of such pharmaceutically acceptable esters, amides, carbamates and salts.
  • esters including pharmaceutically acceptable esters, amides and carbamates thereof, salts thereof, solvates thereof, and solvates of such pharmaceutically acceptable esters, amides, carbamates and salts.
  • R T and R 2 are the same or different and each represents hydrogen, halogen or a methyl group
  • R 3 represents H, CI, F, OH or OC(0)R 6 ;
  • R 4 represents hydrogen;
  • R 5 represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl;
  • R 6 represents H, C ⁇ -8 alkyl or branched C 1-8 alkyl; and represents a single or a double bond; including pharmaceutically acceptable esters, amides and carbamates thereof, salts thereof, solvates thereof, and solvates of such pharmaceutically acceptable esters, amides, carbamates and salts; with the proviso that when R 5 is cyclohexyl, Ri is H, R 2 is F and r ⁇ rrz represents a double bond.
  • R 5 represents cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl or cyclooctyl.
  • Preferred compounds of formula (I) include:
  • esters including pharmaceutically acceptable esters, amides and carbamates thereof, salts thereof, solvates thereof, and solvates of such pharmaceutically acceptable esters, amides, carbamates and salts.
  • esters including pharmaceutically acceptable esters, amides and carbamates thereof, salts thereof, solvates thereof, and solvates of such pharmaceutically acceptable esters, amides, carbamates and salts.
  • esters including pharmaceutically acceptable esters, amides and carbamates thereof, salts thereof, solvates thereof, and solvates of such pharmaceutically acceptable esters, amides, carbamates and salts.
  • solvates include hydrates.
  • References hereinafter to a compound according to the invention includes both compounds of formula (I) and solvates thereof.
  • the invention includes within its scope all stereoisomers of the compounds of formula (I) and mixtures thereof.
  • the stereochemistry at the 22 position it is preferable for the stereochemistry at the 22 position to be (R), i.e. for the higher priority substituent to be ⁇ relative to the steroid moiety; in other situations, it is preferable for the stereochemistry at the 22 position to be (S), i.e. for the higher priority substituent to be ⁇ relative to the steroid moiety.
  • the compounds of formula (I) have potentially beneficial anti-inflammatory or antiallergic effects, particularly upon topical administration, demonstrated by, for example, their ability to bind to the glucocorticoid receptor and to illicit a response via that receptor. Hence, the compounds of formula (I) are useful in the treatment of inflammatory and/or allergic disorders.
  • Examples of disease states in which the compounds of the invention have utility include skin diseases such as eczema, psoriasis, allergic dermatitis neurodermatitis, pruritis and hypersensitivity reactions; inflammatory conditions of the nose, throat or lungs such as asthma (including allergen-induced asthmatic reactions), rhinitis (including hayfever), nasal polyps, chronic obstructive pulmonary disease, interstitial lung disease, and fibrosis; inflammatory bowel conditions such as ulcerative colitis and Crohn's disease; and auto-immune diseases such as rheumatoid arthritis.
  • skin diseases such as eczema, psoriasis, allergic dermatitis neurodermatitis, pruritis and hypersensitivity reactions
  • inflammatory conditions of the nose, throat or lungs such as asthma (including allergen-induced asthmatic reactions), rhinitis (including hayfever), nasal polyps, chronic obstructive pulmonary disease, interstitial lung disease, and fibros
  • Compounds of the invention may also have use in the treatment of conjunctiva and conjunctivitis.
  • compounds of formula (I) are useful in human or veterinary medicine, in particular as anti-inflammatory and anti-allergic agents.
  • a compound of formula (I) or physiologically acceptable solvate thereof for the manufacture of a medicament for the treatment of an inflammatory and/or an allergic condition.
  • 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 a physiologically acceptable solvate thereof together, if desirable, in admixture with one or more physiologically acceptable diluents or carriers.
  • the compounds according to the invention may, for example, be formulated for oral, buccal, sublingual, parenteral, local or rectal administration.
  • Local administration includes administration by insufflation and inhalation.
  • a compound accorindg to the invention for administration by insufflation or inhalation is preferably a compound in which R 3 represents OC(0)R 6 .
  • preparations 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.
  • 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
  • liposome or microencapsulation preparations e.g. for the treatment of aph
  • Ointments, creams and gels may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agent and/or solvents.
  • bases may thus, for example, include water and/or an oil such as liquid paraffin or a vegetable oil such as arachis oil or castor oil, or a solvent such as polyethylene glycol.
  • Thickening agents and gelling agents which may be used according to the nature of the base include soft paraffin, aluminium stearate, cetostearyl alcohol, polyethylene glycols, woolfat, beeswax, carboxypolymethylene and cellulose derivatives, and/or glyceryl monostearate and/or non-ionic emulsifying agents.
  • Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents or thickening agents.
  • Powders for external application may be formed with the aid of any suitable powder base, for example, talc, lactose or starch.
  • Drops may be formulated with an aqueous or non-aqueous base also comprising one or more dispersing agents, solubilising agents, suspending agents or preservatives.
  • Spray compositions may for example be formulated as aqueous solutions or suspensions or as aerosols delivered from pressurised packs, such as a metered dose inhaler, with the use of a suitable liquefied propellant.
  • Aerosol compositions suitable for inhalation can be either a suspension or a solution and generally contain a compound of formula (I) and a suitable propellant such as a fluorocarbon or hydrogen-containing chlorofluorocarbon or mixtures thereof, particularly hydrofluoroalkanes, especially 1 ,1 ,1 ,2-tetrafluoroethane, 1 ,1 ,1 ,2,3,3,3-heptafluoro-n- propane or a mixture thereof.
  • the aerosol composition may optionally contain additional formulation excipients well known in the art such as surfactants e.g. oleic acid or lecithin and cosolvents e.g. ethanol.
  • formulations of the invention may be buffered by the addition of suitable buffering agents.
  • Capsules and cartridges for use in an inhaler or insufflator may be formulated containing a powder mix for inhalation of a compound of the invention and a suitable powder base, for example lactose or starch.
  • a powder mix for inhalation of a compound of the invention and a suitable powder base, for example 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, for example without 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 typically 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 typically be within the range 100 ⁇ g-10mg preferably, 200 ⁇ g- 2000 ⁇ g.
  • the overall daily dose and the metered dose delivered by capsules and cartridges in an inhaler or insufflator will generally be double those with aerosol formulations.
  • Topical preparations may be administered by one or more applications per day to the affected area; over skin areas occlusive dressings may advantageously be used. Continuous or prolonged delivery may be achieved by an adhesive reservoir system.
  • the compounds according to the invention may, for example, be formulated in conventional manner for oral, parenteral or rectal administration.
  • Formulations for oral administration include syrups, elixirs, powders, granules, tablets and capsules which typically contain conventional excipients such as binding agents, fillers, lubricants, disintegrants, wetting agents, suspending agents, emulsifying agents, preservatives, buffer salts, flavouring, colouring and/or sweetening agents as appropriate.
  • Dosage unit forms are, however, preferred as described below.
  • dosage unit forms i.e. tablets and capsules.
  • Such dosage unit forms contain from 0.1 mg to 20mg preferably from 2.5 to 10mg of the compounds of the invention.
  • the compounds according to the invention may in general may be given by internal administration in cases where systemic adreno-cortical therapy is indicated.
  • preparations for internal administration may contain from 0.05 to 10% of the active ingredient dependent upon the type of preparation involved.
  • the daily dose may vary from 0.1 mg to 60mg, e.g. 5-30mg, dependent on the condition being treated, and the duration of treatment desired.
  • Slow release or enteric coated formulations may be advantageous, particularly for the treatment of inflammatory bowel disorders.
  • the compounds and pharmaceutical formulations according to the invention may be used in combination with or include one or more other therapeutic agents, for example selected from anti-inflammatory agents, anticholinergic agents (particularly an Mi, M 2 , M ⁇ /M 2 or M 3 receptor antagonist), bronchodilators, for example ⁇ 2 - adrenoreceptor agonists, antiinfective agents (e.g. antibiotics, antivirals), or antihistamines.
  • anti-inflammatory agents particularly an Mi, M 2 , M ⁇ /M 2 or M 3 receptor antagonist
  • bronchodilators for example ⁇ 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 bronchodilator, for a example ⁇ 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 a example ⁇ 2 -adrenoreceptor agonist
  • an antiinfective agent e.g. an antibiotic or an antiviral
  • an antihistamine e.g. an antibiotic or an antiviral
  • Preferred combinations are those comprising one or two other therapeutic agents.
  • the other therapeutic ingredient(s) may be used in the form of salts, (e.g. as alkali metal or amine salts or as acid addition salts), or prodrugs, or as esters (e.g. lower alkyl esters), or as solvates (e.g. hydrates) to optimise the activity and/or stability and/or physical characteristics (e.g. solubility) of the therapeutic ingredient.
  • the therapeutic ingredients may be used in optically pure form.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a physiologically acceptable salt or solvate thereof together with another therapeutically active agent, for example, a bronchodilator, for example a ⁇ 2 -adrenoreceptor agonist, an anti-histamine or an anti-allergic.
  • a bronchodilator for example a ⁇ 2 -adrenoreceptor agonist, an anti-histamine or an anti-allergic.
  • a combination comprising of compound of formula (I) or a physiologically acceptable salt or solvate thereof together with a ⁇ 2 -adrenoreceptor agonist is particularly preferred.
  • bronchodilators for example ⁇ 2 -adrenoreceptor agonists, include bronchodilators, e.g., albuterol (eg as free base or sulphate), salmeterol (eg as xinafoate), ephedrine, adrenaline, fenoterol (eg as hydrobromide), formoterol (eg as fumarate), isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol (eg as acetate), reproterol (eg as hydrochloride), rimiterol, terbutaline (eg as sulphate), isoetharine, tulobuterol or 4-hydroxy-7-[2-[[2-[
  • Preferred long acting ⁇ 2 -adrenoreceptor agonists include those described in
  • Suitable anti-inflammatory agents include NSAIDs.
  • Suitable NSAIDs include sodium cromoglycate, nedocromil sodium, phosphodiesterase (PDE) inhibitors (e.g. theophylline, PDE4 inhibitors or mixed PDE3/PDE4 inhibitors), leukotriene antagonists, inhibitors of leukotriene synthesis, iNOS inhibitors, tryptase and elastase inhibitors, beta-2 integrin antagonists and adenosine receptor agonists or antagonists (e.g. adenosine 2a agonists), cytokine antagonists (e.g. chemokine antagonists) or inhibitors of cytokine synthesis.
  • PDE phosphodiesterase
  • leukotriene antagonists e.g. theophylline, PDE4 inhibitors or mixed PDE3/PDE4 inhibitors
  • leukotriene antagonists inhibitors of leukotriene synthesis
  • iNOS inhibitors
  • the PDE4-specific inhibitor useful in this aspect of the invention may be any compound that is known to inhibit the PDE4 enzyme or which is discovered to act as a PDE4 inhibitor, and which are selective PDE4 inhibitors, not compounds which inhibit other members of the PDE family as well as PDE4 to a significant extent.
  • a PDE4 inhibitor which has an IC50 ratio of about 0.1 or greater as regards the IC50 for the PDE4 catalytic form which binds rolipram with a high affinity divided by the IC50 for the form which binds rolipram with a low affinity.
  • the cAMP catalytic site which binds R and S rolipram with a low affinity is denominated the "low affinity” binding site (LPDE 4) and the other form of this catalytic site which binds rolipram with a high affinity is denominated the "high affinity” binding site (HPDE 4).
  • LPDE 4 low affinity binding site
  • HPDE 4 high affinity binding site
  • the preferred PDE4 inhibitors of use in this invention will be those compounds which have a salutary therapeutic ratio, i.e., compounds which preferentially inhibit cAMP catalytic activity where the enzyme is in the form that binds rolipram with a low affinity, thereby reducing the side effects which apparently are linked to inhibiting the form which binds rolipram with a high affinity.
  • a salutary therapeutic ratio i.e., compounds which preferentially inhibit cAMP catalytic activity where the enzyme is in the form that binds rolipram with a low affinity, thereby reducing the side effects which apparently are linked to inhibiting the form which binds rolipram with a high affinity.
  • Another way to state this is that the preferred compounds will have an IC50 ratio of about 0.1 or greater as regards the
  • a further refinement of this standard is that of one wherein the PDE4 inhibitor has an IC50 ratio of about 0.1 or greater; said ratio is the ratio of the IC50 value for competing with the binding of 1nM of [ ⁇ HjR-rolipram to a form of PDE4 which binds rolipram with a high affinity over the IC50 value for inhibiting the PDE4 catalytic activity of a form which binds rolipram with a low affinity using 1 ⁇ M[3H]-cAMP as the substrate.
  • PDE4 inhibitors which have an IC50 ratio of greater than
  • Preferred compounds are cis 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1- carboxylic acid, 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4- difluoromethoxyphenyl)cyclohexan-1-one and c/s-[4-cyano-4-(3-cyclopropylmethoxy- 4-difluoromethoxyphenyl)cyclohexan-1-ol]; these are examples of compounds which bind preferentially to the low affinity binding site and which have an IC50 ratio of 0.1 or greater.
  • AWD-12-281 from elbion (Hofgen, N. etal. 15th EFMC Int Symp Med Chem (Sept 6- 10, Edinburgh) 1998, Abst P.98; CAS reference No. 247584020-9); a 9- benzyladenine derivative nominated NCS-613 (INSERM); D-4418 from Chiroscience and Schering-Plough; a benzodiazepine PDE4 inhibitor identified as CI-1018 (PD- 168787) and attributed to Pfizer; a benzodioxole derivative disclosed by Kyowa Hakko in WO99/16766; K-34 from Kyowa Hakko; V-11294A from Napp (Landells, L.J.
  • PDE-4 and mixed PDE3/PDE4 inhibitors include those listed in WO01/13953, the disclosure of which is hereby incorporated by reference.
  • Suitable anticholinergic agents are those compounds that act as antagonists at the muscahnic receptor, in particular those compounds which are antagonists of the M and M 2 receptors.
  • Exemplary compounds include the alkaloids of the belladonna plants as illustrated by the likes of atropine, scopolamine, homatropine, hyoscyamine; those compounds are normally administered as a salt, being tertiary amines.
  • drugs particularly the salt forms
  • Atropine - CAS-51-55-8 or CAS-51-48-1 anhydrous form
  • atropine sulfate - CAS- 5908-99-6 atropine oxide - CAS-4438-22-6 or its HCI salt - CAS-4574-60-1 and methylatropine nitrate - CAS-52-88-0.
  • Preferred anticholinergics include ipratropium (e.g. as the bromide), sold under the name Atrovent, oxitropium (e.g. as the bromide) and tiotropium (e.g. as the bromide) (CAS-139404-48-1 ).
  • methantheline CAS-53-46-3
  • propantheline bromide CAS- 50-34-9
  • anisotropine methyl bromide or Valpin 50 CAS- 80-50-2
  • clidinium bromide Quarzan, CAS-3485-62-9
  • copyrrolate Robotul
  • isopropamide iodide CAS-71-81-8
  • mepenzolate bromide U.S.
  • Suitable antihistamines include any one or more of the numerous antagonists known which inhibit Hi-receptors, and are safe for human use. All are reversible, competitive inhibitors of the interaction of histamine with Hi-receptors. The majority of these inhibitors, mostly first generation antagonists, have a core structure, which can be represented by the following formula:
  • This generalized structure represents three types of antihistamines generally available: ethanolamines, ethylenediamines, and alkylamines.
  • first generation antihistamines include those which can be characterized as based on piperizine and phenothiazines.
  • Second generation antagonists which are non- sedating, have a similar structure-activity relationship in that they retain the core ethylene group (the alkylamines) or mimic the tertiary amine group with piperizine or piperidine.
  • Exemplary antagonists are as follows:
  • Ethanolamines carbinoxamine maleate, clemastine fumarate, diphenylhydramine hydrochloride, and dimenhydrinate.
  • Ethylenediamines pyrilamine amleate, tripelennamine HCI, and tripelennamine citrate.
  • Alkylamines chlropheniramine and its salts such as the maleate salt, and ac vastine.
  • Piperazines hydroxyzine HCI, hydroxyzine pamoate, cyclizine HCI, cyclizine lactate, meclizine HCI, and cetirizine HCI.
  • Piperidines Astemizole, levocabastine HCI, loratadine or its descarboethoxy analogue, and terfenadine and fexofenadine hydrochloride or another pharmaceutically acceptable salt.
  • Azelastine hydrochloride is yet another Hi receptor antagonist which may be used in combination with a corticosteroid.
  • Examples of preferred anti-histamines include methapyrilene and loratadine.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with a PDE4 inhibitor.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with a ⁇ 2 -adrenorecptor agonist.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with an anticholinergic.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with an antihistamine.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with a PDE4 inhibitor and a ⁇ 2 - adrenoreceptor agonist.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof together with an anticholinergic and a PDE-4 inhibitor.
  • compositions comprising a combination as defined above together with a pharmaceutically acceptable diluent or carrier represent a further aspect of the invention.
  • the individual compounds of such combinations may be administered separately, sequentially or simultaneously and they may be provided in separate or combined pharmaceutical formulations. Appropriate doses of known therapeutic agents will be readily appreciated by those skilled in the art.
  • the compounds of formula (I) and solvates thereof may be prepared by the methodology described hereinafter, constituting a further aspect of this invention.
  • the invention accordingly further provides a process for the preparation of a compound of formula (I) as defined above, which process comprises reacting a compound of formula (II):
  • R ⁇ R 2 , R 3 , R 6 and are as defined above and R 7 and R 8 independently represent H, C 1-6 acyl or R 7 and R 8 are joined together to form a 5- to 8-membered cyclic acetal or ketal, with a compound of formula R 4 C(O)R 5 , wherein R 4 and R 5 are as defined above, in the presence of a suitable catalyst.
  • R 7 and R 8 both represent H.
  • R 7 and R 8 are joined together so as to form a cyclic acetal or ketal, for example a dimethyl- dioxalane ring.
  • Suitable catalysts include acid catalysts.
  • the catalyst may be p-toluene sulfonic acid, perchloric acid or hydrochloric acid or mixtures thereof.
  • the preparation of compounds of formula (I) is performed in an anhydrous solvent, for example dichloromethane, tetrahydrofuran, toluene or 1 ,4-dioxane.
  • anhydrous solvent for example dichloromethane, tetrahydrofuran, toluene or 1 ,4-dioxane.
  • a preferred solvent for use with p-toluene sulfonic acid is dichloromethane.
  • the aldehyde or ketone reagent itself may serve as solvent.
  • a preferred solvent for use with perchloric acid is 1 ,4-dioxane.
  • Solvates of compounds of formula (I) which are not physiologically acceptable may be useful as intermediates in the preparation of compounds of formula (I) or physiologically acceptable solvates thereof.
  • Compounds of formula (I) and/or solvates thereof demonstrate good anti- inflammatory properties, with predictable pharmacokinetic and pharmacodynamic behaviour. They also have an attractive side-effect profile.
  • Chromatographic purification was performed on a Waters Spherisorb S5W 20x250mm preparative HPLC column, eluting with 45% to 70% ethyl acetate/methanol/ 0.880 ammonia (60:0.5:0.5) : 30 to 55% heptane mixtures and a flow rate of 20ml/min. Appropriate fractions were combined and evaporated to provide purified product.
  • LCMS for Examples 1 to 18 was conducted on a Luna C18 (2) 2x150mm 3um column eluting with water (solvent A), acetonitile (solvent B) and 2% TFA in water (solvent C) using the following elution gradient 0 min 70%A, 25%B and 5%C to 20 min 35%A, 60%B and 5%C at a flow rate of 0.3 ml/min and a column temperature of 30°C. An injection volume of 5 ⁇ l was used and UV detection was at 245nm.
  • LCMS was conducted on an ABZ+PLUS 3.3cm x 4.6mm ID, 3um Column with a flow rate of 3 ml/min and the column at room temperature, eluting with 0.1% Formic Acid + 10mMolar Ammonium Acetate (solvent A) and 95% Acetonitrile + 0.05% Formic Acid (solvent B) using the following elution gradient:
  • the injection volume was 5 ⁇ l and the UV Detection Range was 215 to 330nm. Mass spectra were recorded on a Fisons VG Platform spectrometer using electrospray positive and negative mode (ES+ve and ES-ve).
  • Compound 7 is a spiroacetal. That compound was purified by crystallisation from ethyl acetate and hexane.
  • Example 19 (4a , S,4b'R,5 , S,6a'S,6b'S,9a'R,10a'S,10b'S,12 , S)-4b , ,12 , -difluoro-5 , -hydroxy-6b'- (hydrOxyacetylHa'. ⁇ a'-dimethyMa' ⁇ b'.S'. ⁇ '. ⁇ a'.
  • Bis-formate A ((6 ⁇ , 11 ⁇ ,16 ⁇ )-6, 9-difluoro-11 ,17-dihydroxy-3,20-dioxopregna-1 , 4- diene-16,21-diyl diformate) was prepared as follows: A solution of (4aS,4bR,5S,6aS,6bS,9aR,10aS,10bS,12S)-4b,12-difluoro-5-hydroxy-6b- (hydroxyacetyl)-4a,6a,8,8-tetramethyl-4a,4b,5,6,6a,6b,9a, 10, 10a, 10b, 11 , 12- dodecahydro-2H-naphtho[2',1':4,5]indeno[1 ,2-d][1 ,3]dioxol-2-one (2g) (Commercially available or synthesisable according to Rolland, Guy I.; Mantica, Leonardo; Ciceri, Roberto.
  • Chromatographic purification was performed on a Waters Spherisorb S5W 20x250mm preparative HPLC column, eluting with 45% to 70% ethyl acetate/methanol/ 0.880 ammonia (60:0.5:0.5) : 30 to 55% heptane mixtures and a flow rate of 20ml/min. Appropriate fractions were combined and evaporated to provide purified product.
  • LCMS was conducted on a Luna C18 (2) 2x150mm 3um column eluting with water (solvent A), acetonitile (solvent B) and 2% TFA in water (solvent C) using the following elution gradient 0 min 70%A, 25%B and 5%C to 20 min 35%A, 60%B and 5%C at a flow rate of 0.3 ml/min and a column temperature of 30°C. An injection volume of 5 ⁇ l was used and UV detection was at 245nm. The mass spectra were recorded on a Fisons VG Platform spectrometer using electrospray positive and negative mode (ES+ve and ES-ve).
  • R ⁇ (I) wherein R 5 represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl;
  • General Chromatographic purification was performed on a Waters Spherisorb S5W 20x250mm preparative HPLC column, eluting with 45% to 70% ethyl acetate/methanol/ 0.880 ammonia (60:0.5:0.5) : 30 to 55% heptane mixtures and a flow rate of 20ml/min. Appropriate fractions were combined and evaporated to provide purified product.
  • LCMS was conducted on a Luna C18 (2) 2x150mm 3um column eluting with water (solvent A), acetonitile (solvent B) and 2% TFA in water (solvent C) using the following elution gradient 0 min 70%A, 25%B and 5%C to 20 min 35%A, 60%B and 5%C at a flow rate of 0.3 ml/min and a column temperature of 30°C. An injection volume of 5 ⁇ l was used and UV detection was at 245nm. The mass spectra were recorded on a Fisons VG Platform spectrometer using electrospray positive and negative mode (ES+ve and ES-ve).
  • chromatography conditions were a 50- 70% gradient of ethyl acetate /methanol / 0.880 ammonia (60:0.5:0.5) : heptane over 20min, held at 70% for 10min.
  • Pharmacological Activity may be assessed in functional in vitro assays of glucocorticoid agonist activity.
  • the functional assay based on that described by K.P.Ray et al.. Biochem J. (1997), 328, 707-715 provides a measure of transrepressive activity of a glucocorticoid agonist.
  • A549 cells stably transfected with a reporter gene containing the NF- ⁇ B responsive elements from the ELAM gene promoter coupled to sPAP (secreted alkaline phosphatase) are treated with test compounds at appropriate doses for 1 hour at 37°C.
  • the cells are then stimulated with tumour necrosis factor (TNF, 10ng/ml) for 16 hours, at which time the amount of alkaline phosphatase produced is measured by a standard colourimetric assay.
  • TNF tumour necrosis factor
  • Dose response curves are constructed from which IC 50 values may be estimated.
  • IC- 50 values for compounds of Examples 1 to 57 were ⁇ 100nM.

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Abstract

La présente invention a trait à un composé de formule (I), dans laquelle : R1 et R2, identiques ou différents, représentent chacun hydrogène, halogène ou un groupe méthyle ; R3 représente H, Cl, F, OH OR OC(O)R6; R4 représente hydrogène ou méthyle ; R5 représente -(CH2)n-CH=CH)m-Cycl ou -(CH2)n-(CH=CH)m-Ar ou cyclopropyle, cyclobutyle, cyclopentyle, cyclohexyle, cycloheptyle or cyclooctyle; n représente 0, 1 ou 2 ; m représente 0 ou 1 ; R6 représente H, alkyle en C1-C8; et formule (b) représente une liaison simple ou double ainsi qu'à des esters, amides, carbamates, sels, solvates pharmaceutiquement acceptables dudit composé et des solvates de tels esters, amides carbamates et sels pharmaceutiquement acceptables.
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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1893220A1 (fr) * 2005-06-14 2008-03-05 Gilead Sciences, Inc. Phenylphosphates substitues utilises en tant que promedicaments mutuels constitues de steroides et de beta-agonistes pour le traitement d'inflammation pulmonaire et de bronchoconstriction
WO2009069032A2 (fr) * 2007-11-30 2009-06-04 Pfizer Limited Nouveaux agonistes des récepteurs des glucocorticoïdes
WO2009108118A1 (fr) * 2008-02-27 2009-09-03 Astrazeneca Ab Dérivés de glucocorticostéroïdes de 16 alpha, 17 alpha-acétal et leur utilisation
WO2011029547A3 (fr) * 2009-09-11 2011-08-18 Chiesi Farmaceutici S.P.A. Dérivés d'isoxazolidine
US8163724B2 (en) 2007-10-04 2012-04-24 Astrazeneca Ab Glucocorticosteroids, processes for their preparation, pharmaceutical compositions containing them and their use in therapy
US8338587B2 (en) 2009-04-03 2012-12-25 Astrazeneca Ab Compounds
WO2012123493A3 (fr) * 2011-03-15 2013-01-10 Chiesi Farmaceutici S.P.A. Dérivés d'isoxazolidine
WO2012123482A3 (fr) * 2011-03-15 2013-02-07 Chiesi Farmaceutici S.P.A. Dérivés d'isoxazolidine
JP2015533801A (ja) * 2012-09-13 2015-11-26 シエシー ファルマセウティチィ ソシエタ ペル アチオニ イソキサゾリジン誘導体
US10668167B2 (en) 2016-06-02 2020-06-02 Abbvie Inc. Glucocorticoid receptor agonist and immunoconjugates thereof
US10772970B2 (en) 2017-12-01 2020-09-15 Abbvie Inc. Glucocorticoid receptor agonist and immunoconjugates thereof
WO2022166779A1 (fr) * 2021-02-04 2022-08-11 上海森辉医药有限公司 Conjugué médicamenteux d'agoniste du récepteur de glucocorticoïde et son utilisation en médecine
WO2023040793A1 (fr) * 2021-09-14 2023-03-23 映恩生物制药（苏州）有限公司 Composé anti-inflammatoire et son utilisation
WO2024020164A3 (fr) * 2022-07-21 2024-02-22 Firefly Bio, Inc. Agonistes du récepteur des glucocorticoïdes et leurs conjugués

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1131213B (de) * 1958-06-13 1962-06-14 Syntex Sa Verfahren zur Herstellung neuer Pregnanverbindungen
GB933867A (en) * 1958-12-08 1963-08-14 American Cyanamid Co Fluorinated steroids
US3197469A (en) * 1958-08-06 1965-07-27 Pharmaceutical Res Products In 16, 17-acetals and ketals of 6-halo-16, 17-dihydroxy steroids of the pregnane seriesand intermediates therefor
US3716529A (en) * 1970-05-14 1973-02-13 Syntex Corp Novel c-16,17 spiro-orthoester steroids and preparation
US3867528A (en) * 1973-10-11 1975-02-18 American Cyanamid Co Steroidal topical cream base
GB1469575A (en) * 1974-05-17 1977-04-06 Lark Spa Preparation of 16,17-cyclic acetals and ketals of 9alpha-halo steroids
US4158055A (en) * 1973-08-17 1979-06-12 American Cyanamid Company Administration of 16α,17α-cyclopentylidenedioxy-9α-fluor O-11β,21-dihydroxy-1,4-pregnadiene-3,20-dione 21-acetate
ES483720A3 (es) * 1979-08-29 1980-05-16 Espanola Esteroide Procedimiento de obtencion de los 21 esteres de los cetales ciclicos de los 6-halogeno corticoides
JPH0873491A (ja) * 1994-09-05 1996-03-19 Nissin Food Prod Co Ltd トリアムシノロン誘導体

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1131213B (de) * 1958-06-13 1962-06-14 Syntex Sa Verfahren zur Herstellung neuer Pregnanverbindungen
US3197469A (en) * 1958-08-06 1965-07-27 Pharmaceutical Res Products In 16, 17-acetals and ketals of 6-halo-16, 17-dihydroxy steroids of the pregnane seriesand intermediates therefor
GB933867A (en) * 1958-12-08 1963-08-14 American Cyanamid Co Fluorinated steroids
US3716529A (en) * 1970-05-14 1973-02-13 Syntex Corp Novel c-16,17 spiro-orthoester steroids and preparation
US4158055A (en) * 1973-08-17 1979-06-12 American Cyanamid Company Administration of 16α,17α-cyclopentylidenedioxy-9α-fluor O-11β,21-dihydroxy-1,4-pregnadiene-3,20-dione 21-acetate
US3867528A (en) * 1973-10-11 1975-02-18 American Cyanamid Co Steroidal topical cream base
GB1469575A (en) * 1974-05-17 1977-04-06 Lark Spa Preparation of 16,17-cyclic acetals and ketals of 9alpha-halo steroids
ES483720A3 (es) * 1979-08-29 1980-05-16 Espanola Esteroide Procedimiento de obtencion de los 21 esteres de los cetales ciclicos de los 6-halogeno corticoides
JPH0873491A (ja) * 1994-09-05 1996-03-19 Nissin Food Prod Co Ltd トリアムシノロン誘導体

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
A.I.TEREKHINA ET AL.: "Synthesis and Pharmacological Activity of 16alpha-Oxyprednisolone 16alpha,17alpha-acetals", PHARM.CHEM.J., vol. 27, no. 3, 1993, pages 188 - 192, XP009032187 *
E.M.W.KOCH ET AL.: "Altersbedingte Unterschiede der pharmakologischen Wirkung von Kortikosteroid-Externa", ARZNEIM.-FORSCH., vol. 36, no. 10, 1986, pages 1540 - 1544, XP001204958 *
J.FRIED ET AL.: "Cyclic 16alpha,17alpha-Ketals and Acetals of 9alpha-Fluoro-16alpha-hydroxy-Cortisol and Prednisolone", JACS, vol. 80, 1958, pages 2338 - 2339, XP002316130 *

Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1893220A4 (fr) * 2005-06-14 2011-06-15 Gilead Sciences Inc Phenylphosphates substitues utilises en tant que promedicaments mutuels constitues de steroides et de beta-agonistes pour le traitement d'inflammation pulmonaire et de bronchoconstriction
JP2008546694A (ja) * 2005-06-14 2008-12-25 コラス・フアーマ・インコーポレイテツド 肺炎及び気管支の治療のためのステロイド及びβ−アゴニストの相互プロドラッグとしての置換されたフェニルホスファート
EP1893220A1 (fr) * 2005-06-14 2008-03-05 Gilead Sciences, Inc. Phenylphosphates substitues utilises en tant que promedicaments mutuels constitues de steroides et de beta-agonistes pour le traitement d'inflammation pulmonaire et de bronchoconstriction
US8163724B2 (en) 2007-10-04 2012-04-24 Astrazeneca Ab Glucocorticosteroids, processes for their preparation, pharmaceutical compositions containing them and their use in therapy
KR101295998B1 (ko) * 2007-11-30 2013-08-13 화이자 리미티드 신규한 글루코코티코이드 수용체 작용제
WO2009069032A2 (fr) * 2007-11-30 2009-06-04 Pfizer Limited Nouveaux agonistes des récepteurs des glucocorticoïdes
JP4686650B2 (ja) * 2007-11-30 2011-05-25 ファイザー・リミテッド 新規なグルココルチコイド受容体アゴニスト
JP2011505350A (ja) * 2007-11-30 2011-02-24 ファイザー・リミテッド 新規なグルココルチコイド受容体アゴニスト
WO2009069032A3 (fr) * 2007-11-30 2009-08-06 Pfizer Ltd Nouveaux agonistes des récepteurs des glucocorticoïdes
US8822439B2 (en) 2007-11-30 2014-09-02 Pfizer Inc. Glucocorticoid receptor agonists
AU2008331187B2 (en) * 2007-11-30 2014-04-03 Pfizer Limited Novel glucocorticoid receptor agonists
CN101878221B (zh) * 2007-11-30 2014-04-02 辉瑞有限公司 糖皮质激素受体激动剂
WO2009108118A1 (fr) * 2008-02-27 2009-09-03 Astrazeneca Ab Dérivés de glucocorticostéroïdes de 16 alpha, 17 alpha-acétal et leur utilisation
US8338587B2 (en) 2009-04-03 2012-12-25 Astrazeneca Ab Compounds
AU2010294598B2 (en) * 2009-09-11 2016-09-01 Chiesi Farmaceutici S.P.A. Pregnane derivatives condensed in the 16, 17 position with an n-substituted isoxazolidine ring as anti-inflammatory agents
WO2011029547A3 (fr) * 2009-09-11 2011-08-18 Chiesi Farmaceutici S.P.A. Dérivés d'isoxazolidine
US8637662B2 (en) 2009-09-11 2014-01-28 Chiesi Farmaceutici S.P.A. Isoxazolidine derivatives
EA025191B1 (ru) * 2009-09-11 2016-11-30 КЬЕЗИ ФАРМАЧЕУТИЧИ С.п.А. Производные прегнана, конденсированные по положению 16,17 с n-замещенным изоксалидиновым кольцом, в качестве противовоспалительных агентов
JP2013504524A (ja) * 2009-09-11 2013-02-07 シエシー ファルマセウティチィ ソシエタ ペル アチオニ イソオキサゾリジン誘導体
JP2014508181A (ja) * 2011-03-15 2014-04-03 シエシー ファルマセウティチィ ソシエタ ペル アチオニ イソオキサゾリジン誘導体
WO2012123493A3 (fr) * 2011-03-15 2013-01-10 Chiesi Farmaceutici S.P.A. Dérivés d'isoxazolidine
US8835412B2 (en) 2011-03-15 2014-09-16 Chiesi Farmaceutici S.P.A. Isoxazolidine derivatives
CN103380142A (zh) * 2011-03-15 2013-10-30 奇斯药制品公司 异噁唑烷衍生物
WO2012123482A3 (fr) * 2011-03-15 2013-02-07 Chiesi Farmaceutici S.P.A. Dérivés d'isoxazolidine
EA028904B1 (ru) * 2011-03-15 2018-01-31 КЬЕЗИ ФАРМАЧЕУТИЧИ С.п.А. Изоксазолидиновые производные
JP2015533801A (ja) * 2012-09-13 2015-11-26 シエシー ファルマセウティチィ ソシエタ ペル アチオニ イソキサゾリジン誘導体
US10668167B2 (en) 2016-06-02 2020-06-02 Abbvie Inc. Glucocorticoid receptor agonist and immunoconjugates thereof
US10772970B2 (en) 2017-12-01 2020-09-15 Abbvie Inc. Glucocorticoid receptor agonist and immunoconjugates thereof
WO2022166779A1 (fr) * 2021-02-04 2022-08-11 上海森辉医药有限公司 Conjugué médicamenteux d'agoniste du récepteur de glucocorticoïde et son utilisation en médecine
WO2023040793A1 (fr) * 2021-09-14 2023-03-23 映恩生物制药（苏州）有限公司 Composé anti-inflammatoire et son utilisation
WO2024020164A3 (fr) * 2022-07-21 2024-02-22 Firefly Bio, Inc. Agonistes du récepteur des glucocorticoïdes et leurs conjugués

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