EP1715860A1 - Combination of benzothiazol-2-one beta2 adrenoceptor agonists and corticosteroids for the treatment of respiratory diseases - Google Patents

Combination of benzothiazol-2-one beta2 adrenoceptor agonists and corticosteroids for the treatment of respiratory diseases

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Publication number
EP1715860A1
EP1715860A1 EP05707254A EP05707254A EP1715860A1 EP 1715860 A1 EP1715860 A1 EP 1715860A1 EP 05707254 A EP05707254 A EP 05707254A EP 05707254 A EP05707254 A EP 05707254A EP 1715860 A1 EP1715860 A1 EP 1715860A1
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EP
European Patent Office
Prior art keywords
alkyl
cio
optionally substituted
alkoxy
hydroxy
Prior art date
Legal status (The legal status 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 status listed.)
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Application number
EP05707254A
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German (de)
English (en)
French (fr)
Inventor
Robin Alec Fairhurst
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Novartis Pharma GmbH Austria
Novartis AG
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Novartis Pharma GmbH Austria
Novartis AG
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Publication of EP1715860A1 publication Critical patent/EP1715860A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention relates to organic compounds and their use as pharmaceuticals, in particular for the treatment of inflammatory or obstructive airways diseases.
  • the present invention provides a medicament comprising, separately or together (A) a compound of formula I
  • X is -R i -Ar-R 2 or -R a -Y;
  • Ar denotes a phenylene group optionally substituted by halo, hydroxy, Ci-Cio-alkyl, C1-C10- alkoxy, G-Go-alkoxy-Ci-Cio-alkyl, phenyl, Ci-Cio-alkyl substituted by phenyl, Ci-Cio-alkoxy substituted by phenyl, Ci-Cio-alkyl-substituted phenyl or by Ci-Cio-alkoxy-substituted phenyl;
  • R 1 and R 2 are attached to adjacent carbon atoms in Ar, and either R 1 is G-Cio-alkylene and R 2 is hydrogen, Ci-Go-alkyl, Ci-Cio-alkoxy or halogen or R 1 and R 2 together with the carbon atoms in Ar to which they are attached denote a 5-, 6- or 7-membered cycloaliphatic ring;
  • R a is a bond or G-Cio-alkylene optionally substituted by hydroxy, Ci-Go-alkoxy, C ⁇ -Cio-aryl or C -C ⁇ -aralkyl;
  • Y is G-Cio-alkyl, G-Go-alkoxy, C 2 -C ⁇ o-alkenyl or C 2 -Go-alkynyl optionally substituted by halo, cyano, hydroxy, Ci-Go-alkyl, Ci-Go-alkoxy or halo-G-Cio-alkyl; C 3 -C ⁇ o-cycloalkyl optionally fused to one or more benzene rings and optionally substituted by G-Go-alkyl, Ci-Cio-alkoxy, C 3 -C ⁇ o-cycloalkyl, C 7 -C ⁇ -aralkyl, C -C ⁇ - aralkyloxy or Cg-Go-aryl, where C 3 -C ⁇ 0 -cycloalkyl, C 7 -C ⁇ -aralkyl, C -C ⁇ -aralkyloxy or Cg-Cio-aryl are optionally substituted by halo, hydroxy
  • C6-C ⁇ o-aryl optionally substituted by halo, hydroxy, Ci-Go-alkyl, C ⁇ -C ⁇ 0 -alkoxy, G- Cio-haloalkyl, phenoxy, G-Cio-alkylthio, C ⁇ -Cio-aryl, 4- to 10- membered heterocyclic ring having at least one ring nitrogen, oxygen or sulphur atom, or by NR b R c where R b and R c are each independently Ci-Cio-alkyl optionally substituted by hydroxy, Ci-Go- alkoxy or phenyl or R b may additionally be hydrogen; phenoxy optionally substituted by Ci-Go-alkyl, Ci-Go-alkoxy or by phenyl optionally substituted by G-Go-alkyl or Ci-Cio-alkoxy; a 4- to 10-membered heterocyclic ring having at least one ring nitrogen, oxygen or sulphur atom, said heterocyclic ring being
  • R d is hydrogen or Ci-Cio-alkyl and R e is Ci-Cio-alkyl optionally substituted by hydroxy, or R e is Cg-Cio-aryl optionally substituted by halo, or R e is a 4- to 10-membered heterocyclic ring having at least one ring nitrogen, oxygen or sulphur atom which ring is optionally substituted by phenyl or halo-substituted phenyl or R e is Cg-Cio-arylsulfonyl optionally substituted by C ⁇ -C ⁇ o-alkylamino or di(C ⁇ -Go- alkyl)amino;
  • R f is Cg-Qo-aryl or C7-C ⁇ -aralkyl optionally substituted by halo, G-Cio- alkyl, Ci-Cio-alkoxy or C ⁇ -C ⁇ o-haloalkyl; or
  • R ⁇ is G-Cio-alkyl, C 3 -C ⁇ 0 -cycloalkyl or Cg-Cio-aryl;
  • (B) a corticosteroid, for simultaneous, sequential or separate administration in the treatment of an inflammatory or obstructive airways disease, the molar ratio of (A) to (B) being from 100:1 to 1:300.
  • the present invention provides a pharmaceutical composition comprising a mixture of effective amounts of (A) as hereinbefore defined and (B) as hereinbefore defined, optionally together with at least one pharmaceutically acceptable carrier.
  • the present invention provides a method of treating an inflammatory or obstructive airways disease which comprises administering to a subject in need of such treatment effective amounts of (A) as hereinbefore defined and (B) as hereinbefore defined.
  • the invention further provides the use of (A) as hereinbefore defined and (B) as hereinbefore defined in the preparation of a medicament for combination therapy by simultaneous, sequential or separate administration of (A) and (B) in the treatment of an inflammatory or obstructive airways disease.
  • Optionally substituted as used herein means the group referred to can be substituted at one or more positions by any one or any combination of the radicals listed thereafter.
  • Halo or halogen denotes a element belonging to group 17 (formerly group VII) of the Periodic Table of Elements, which may be, for example, fluorine, chlorine, bromine or iodine. Preferably halo or halogen is fluorine or chlorine.
  • Ci-Cio-alkyl denotes straight chain or branched alkyl that contains one to ten carbon atoms.
  • G-Cio-alkyl is C ⁇ -C -alkyl.
  • G-Cio-alkylene denotes a straight chain or branched alkylene that contains one to ten carbon atoms.
  • C ⁇ -C ⁇ o-alkylene is C ⁇ -C 4 alkylene, especially ethylene or methylethylene.
  • C 2 -C ⁇ o-alkenyl denotes straight chain or branched hydrocarbon chains that contain two to ten carbon atoms and one or more carbon-carbon double bonds.
  • C 2 -C ⁇ o-alkenyl is "C 2 -C 4 -alkenyl”.
  • C 2 -C ⁇ o-alkynyl denotes straight chain or branched hydrocarbon chains that contain two to ten carbon atoms and one or more carbon-carbon triple bonds.
  • C 2 - Cio-alkynyl is "C 2 -C 4 -alkynyl”.
  • C 3 -C ⁇ o-cycloalkyl denotes cycloalkyl having 3 to 10 ring carbon atoms, for example a monocyclic group such as a cyclopropyl, cyclobutyl, cyclopentyi, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, any of which can be substituted by one or more, usually one or two, C ⁇ -C -alkyl groups, or a bicyclic group such as bicycloheptyl or bicyclooctyl.
  • C 3 -C ⁇ o-cycloalkyl is C 3 -C6-cycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • Ci-Go-alkyl denotes Ci-Go-alkyl as hereinbefore defined substituted by one or more halogen atoms, preferably one, two or three halogen atoms.
  • C ⁇ -C ⁇ o-alkylamino and "di(C ⁇ -C ⁇ o-alkyl)amino" as used herein denote amino substituted respectively by one or two G-Cio-alkyl groups as hereinbefore defined, which may be the same or different.
  • C ⁇ -C ⁇ o-alkylamino and di(C ⁇ -C ⁇ o-alkyl)amino are respectively G-C - alkylamino and di(C ⁇ -C -alkyl)amino.
  • C ⁇ -C ⁇ o-alkylthio denotes straight chain or branched alkylthio having 1 to 10 carbon atoms.
  • C ⁇ -C ⁇ o-alkylthio is G-C -alkylthio.
  • Ci-Cio-alkoxy denotes straight chain or branched alkoxy that contains 1 to 10 carbon atoms.
  • G-Go-alkoxy is C ⁇ -C -alkoxy.
  • Ci-Cio-alkoxy-C ⁇ -C ⁇ o-alkyl denotes C ⁇ -G o -alkyl as hereinbefore defined substituted by Ci-Cio-alkoxy.
  • Ci-Cio-alkoxy-Ci-Go-alkyl is G-C -alkoxy-C ⁇ -C - alkyl.
  • Ci-Cio-alkoxycarbonyl denotes G-Cio-alkoxy as hereinbefore defined linked through an oxygen atom thereof to a carbonyl group.
  • Cg-Cio-aryl denotes a monovalent carbocyclic aromatic group that contains 6 to 10 carbon atoms and which may be, for example, a monocyclic group such as phenyl or a bicyclic group such as naphthyl.
  • Cg-Cio-aryl is C6-C 8 -aryl, especially phenyl.
  • Cg-Cio-arylsulfonyl denotes Cg-Cio-aryl as hereinbefore defined linked through a carbon atom thereof to a sulfonyl group.
  • Cg-Cio-arylsulfonyl is Cg-Cs- arylsulfonyl.
  • C7-Ci4-aralkyl denotes alkyl, for example C ⁇ -C -alkyl as hereinbefore defined, substituted by aryl, for example C ⁇ -Cio-aryl as hereinbefore defined.
  • C 7 -G -aralkyl is C 7 -C ⁇ o-aralkyl such as phenyl-C ⁇ -C -alkyl, particularly benzyl or 2-phenylethyl.
  • C7-C ⁇ -aralkyloxy as used herein denotes alkoxy, for example G-C -alkoxy as hereinbefore defined, substituted by aryl, for example Cg-Cio-aryl.
  • C7-C ⁇ -aralkyloxy is C7-C10- aralkyloxy such as phenyl-C ⁇ -C -alkoxy, particularly benzyloxy or 2-phenylethoxy.
  • Ar as used herein may be, for example, phenylene which is unsubstituted or substituted by one or more substituents selected from halogen, hydroxy, Ci-Go-alkyl, Ci-Cio-alkoxy, C1-C10- alkoxy-C ⁇ -C ⁇ o-alkyl, phenyl, or Ci-Go-alkyl substituted by phenyl, G-Cio-alkoxy substituted by phenyl, G-Cio-alkyl-substituted phenyl and Ci-Cio-alkoxy-substituted phenyl.
  • Ar is phenylene which is unsubstituted or substituted by one or two substituents selected from halogen, G-C -alkyl, G-C -alkoxy, or G-C -alkoxy substituted by phenyl.
  • one substituent in Ar is para to R 1 and optional second and third substituents in Ar are meta to R 1 .
  • 4- to 10-membered heterocyclic ring having at least one ring nitrogen, oxygen or sulphur atom may be, for example, pyrrole, pyrrolidine, pyrazole, imidazole, triazole, tetrazole, thiadiazole, oxazole, isoxazole, thiophene, thiazole, isothiazole, oxadiazole, pyridine, pyrazine, pyridazine, pyrimidine, piperidine, piperazine, triazine, oxazine, morpholino, quinoline, isoquinoline, naphthyridine, indane or indene.
  • Preferred heterocyclic rings include thiazole, pyrrolidine, piperidine, azacycloheptane and isoxazole.
  • 4- to 10-membered heterocyclyl-C ⁇ -C ⁇ o-alkyl denotes alkyl, for example Ci-Go-alkyl as hereinbefore defined, substituted by a 4- to 10-membered heterocyclic ring as hereinbefore defined.
  • 4- to 10-membered heterocyclyl-C ⁇ -C ⁇ o-alkyl is G-C -alkyl substituted by a 4- to 8-membered heterocyclic ring having at least one ring nitrogen, oxygen or sulphur atom.
  • C ⁇ -C -alkylsulfonyl denotes sulfonyl substituted by G-C -alkyl as hereinbefore defined.
  • Haldroxy-C ⁇ -C -alkyl denotes C ⁇ -C 4 -alkyl as hereinbefore defined substituted by one or more, preferably one, two or three hydroxy groups.
  • R 1 and R 2 together with the carbon atoms to which they are attached as a cycloaliphatic ring may be, for example, a cyclopentane ring, optionally substituted by one or two C ⁇ -C 4 -alkyl groups, a cyclohexane ring, optionally substituted by one or two G-C -alkyl groups, or a cycloheptane ring, preferably a cyclopentane ring.
  • Preferred compounds of formula I in free or salt or solvate form include those wherein
  • X is -R i -Ar-R 2 or -R a -Y;
  • Ar denotes a phenylene group optionally substituted by halo, Ci-Cio-alkyl, Ci-Go-alkoxy or by
  • R 1 and R 2 are attached to adjacent carbon atoms in Ar, and either R 1 is Ci-Go-alkylene and R 2 is hydrogen, or R 1 and R 2 together with the carbon atoms in Ar to which they are attached denote a 5-, 6- or 7-membered cycloaliphatic ring;
  • R *1 is a bond or G-Go-alkylene optionally substituted by hydroxy, C ⁇ -Cio-aryl or C7-G - aralkyl;
  • Y is Ci-Cio-alkyl, Ci-Cio-alkoxy or C 2 -Go-alkynyl; C 3 -C ⁇ o-cycloalkyl optionally fused to one or more benzene rings and optionally substituted by G-Cio-alkyl, C 3 -Go-cycloalkyl, C 7 -C ⁇ 4 - aralkyl, C7-Ci4-aralkyloxy optionally substituted by halo, or by C ⁇ -Cio-aryl optionally substituted by Ci-Go-alkyl or G-Go-alkoxy; C ⁇ -Cio-aryl optionally substituted by halo, hydroxy, Ci-Cio-alkyl, phenoxy, G-Go-alkylthio, Cg-Go-aryl, a 4- to 10-membered heterocyclic ring having at least one ring nitrogen atom, or by NR b R c where R b and R c are each independently G
  • R e is C6-C ⁇ o-arylsulfonyl optionally substituted by di(G-C ⁇ o ⁇ alkyl)amino; -SR f where R f is Cg-
  • Especially preferred compounds of formula I in free or salt or solvate form include those wherein
  • X is -R i -Ar-R 2 or -R a -Y;
  • Ar denotes a phenylene group optionally substituted by halo, C ⁇ -C -alkyl, G-C -alkoxy or by
  • R 1 and R 2 are attached to adjacent carbon atoms in Ar, and either R 1 is Ci -C -alkylene and R 2 is hydrogen, or R 1 and R 2 together with the carbon atoms in Ar to which they are attached denote a 5-, 6- or 7-membered cycloaliphatic ring, especially a 5-membered cycloaliphatic ring; R a is a bond or G-C -alkylene optionally substituted by hydroxy, C6-C 8 -aryl or C7-C ⁇ o-aralkyl; and
  • Y is C ⁇ -C -alkyl, G-C -alkoxy or C 2 -C 4 -alkynyl; C 3 -C6-cycloalkyl optionally fused to one or more benzene rings and optionally substituted by Ci-Cg-alkyl, C 3 -Cg-cycloalkyl, CyCio-aralkyl, C7-C ⁇ o-aralkyloxy optionally substituted by halo, or by C6-C 8 -aryl optionally substituted by G- C -alkyl or C ⁇ -C 4 -alkoxy; Gs-Cs-aryl optionally substituted by halo, hydroxy, G-C4-alkyl, phenoxy, C ⁇ -C -alkylthio, Cg-C 8 -aryl, a 4- to 8-membered heterocyclic ring having at least one ring nitrogen atom, or by NR b R c where R b and R c are each
  • More especially preferred compounds of formula I in free or salt or solvate form include: 4-hydroxy-7-(l-hydroxy-2- ⁇ 2-[4-(4-phenyl-butoxy)-phenyl]-ethylamino ⁇ -ethyl)-3H-benzo- thiazol-2-one; 7-[(R)-2-(l,l-dimethyl-2-phenyl-ethylamino)-l-hydroxy-ethyl]-4-hydroxy-3H- benzothiazol-2-one; 4-hydroxy-7- ⁇ (R)-l-hydroxy-2-[2-(5,6,7,8-tetrahydro-naphthalen-2-yl)- ethylamino]-ethyl ⁇ -3H-benzothiazol-2-one formate; 7-[(R)-2-((lS,2S)-2-benzyloxy-cyclopentyl- amino)-l-hydroxy-ethyl]-4-hydroxy-3H-benzo-thiazol-2-one;
  • the carbon atom alpha to the phenolic ring carries a hydroxy group and so is asymmetric, so the compound exists in individual optically active isomeric forms or as mixtures thereof, e.g. as racemic or diastereomeric mixtures.
  • Compounds of formula I embrace both individual optically active R and S isomers as well as mixtures, e.g. racemic or diastereomeric mixtures, thereof.
  • Pharmaceutically acceptable acid addition salts of the compound of formula I include those of inorganic acids, for example, hydrohalic acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid or hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid; and organic acids, for example aliphatic monocarboxylic acids such as formic acid, acetic acid, trifluoro- acetic acid, propionic acid and butyric acid, aliphatic hydroxy acids such as lactic acid, citric acid, tartaric acid or malic acid, dicarboxylic acids such as maleic acid or succinic acid, aromatic carboxylic acids such as benzoic acid, p-chlorobenzoic acid, diphenylacetic acid or triphenylacetic acid, aromatic hydroxy acids such as o-hydroxybenzoic acid, p-hydroxy- benzoic acid, l-hydrox naphthalene-2-carboxylic acid or 3-hydroxynaphthalene-2-carboxylic acid
  • R 8 and R 9 each independently denote a protecting group, to convert groups R 7 , R 8 and R 9 to hydrogen
  • the protecting groups may be chosen in accordance with the nature of the functional group, for example as described in Protective Groups in Organic Synthesis, T.W. Greene and P.G.M. Wuts, John Wiley & Sons Inc, Third Edition, 1999, which reference also describes procedures suitable for replacement of the protecting groups by hydrogen.
  • the protecting group R 7 may be, for example, a group chosen from known amine-protecting groups.
  • Preferred protecting groups R 7 include araliphatic groups such as benzyl and trialkylsilyl e.g. trimethylsilyl.
  • Protecting groups R 8 and R 9 may be chosen from known phenolic hydroxy - and alcoholic hydroxy-protecting groups respectively.
  • Preferred groups R 8 and R 9 include G-C -alkyl groups, particularly branched groups such as isopropyl and tert- butyl.
  • Process variant (A) may be effected, for example, using known procedures for conversion of amine-protecting groups to hydrogen or analogous procedures.
  • R 7 is a benzyl group it may be converted to hydrogen by hydrogenolysis of the compound of formula II, e.g. with a carboxylic acid such as formic acid, preferably in the presence of a palladium catalyst.
  • This de-protection reaction may be carried out using procedures as described hereinafter in the Examples or analogous procedures.
  • Process variant (B) may be effected using known procedures for conversion of hydroxy- protecting groups to hydrogen or analogous procedures.
  • R 8 and R 9 are alkyl groups
  • R 8 and R 9 may be converted to hydrogen by hydrogenolysis of the compounds of formula IN, e.g. with a carboxylic acid such as formic acid preferably in the presence of a palladium catalyst, for example as hereinbefore described for conversion of R 7 to hydrogen, or by treatment with an acid alone such as formic acid, hydrochloric acid or trifluoroacetic acid, in either case the resulting 2-hydroxybenzothiazole compound being in tautomeric equilibrium with the benzothiazol-2-one form.
  • a carboxylic acid such as formic acid preferably in the presence of a palladium catalyst, for example as hereinbefore described for conversion of R 7 to hydrogen
  • an acid alone such as formic acid, hydrochloric acid or trifluoroacetic acid
  • the reduction may be effected using known methods for reduction of ketones to alcohols, or analogous methods, including asymmetric reductions.
  • the compounds of formula IN may be reacted with ⁇ aBH 4 in an inert solvent such as an aliphatic alcohol. Suitable reaction temperatures are from -80° C to 100° C, conveniently from -5° C to 5° C.
  • the reduction may be effected using known procedures or analogously as described hereinafter in the Examples.
  • reaction of compounds of formulae V and VI may be effected using known procedures for epoxide-amine reactions or analogous procedures.
  • the reaction is optionally effected in an inert organic solvent, conveniently an alcohol such a n- butanol. Suitable reaction temperatures are, for example, from 0° C to solvent reflux temperature.
  • the reaction may be effected conveniently using a procedure as described hereinafter in the Examples, or analogously.
  • reaction is preferably effected in an inert organic solvent, for example an ether such as tetrahydrofuran (THF).
  • ether such as tetrahydrofuran
  • Suitable reaction temperatures may be, for example, from -80° C to 80° C.
  • the reaction may be effected using a procedure as described hereinafter in the Examples or analogous procedures.
  • Compounds of formula I in free form may be converted into salt form, and vice versa, in a conventional manner.
  • the compounds in free or salt form can be obtained in the form of hydrates or solvates containing a solvent used for crystallisation.
  • Compounds of formula I can be recovered from reaction mixtures and purified in a conventional manner.
  • Isomers, such as enantiomers may be obtained in a conventional manner, e.g. by fractional crystallisation or asymmetric synthesis from correspondingly asymmetrically substituted, e.g. optically active, starting materials.
  • the corticosteroid (B) may, for example, be a compound of formula X
  • R a is G-C -alkyl optionally substituted by halogen (preferably chlorine or fluorine), hydroxy,
  • G-C -alkoxy, acyloxy or by G-C -acylthio, or R a is C ⁇ -C 4 -alkoxy or G-C 4 -alkylthio
  • R a is 5-or 6-membered heterocyclylthio, or R a is G-C - alkylthio optionally substituted by halogen (preferably chlorine or fluorine), either R b is acyloxy and R c is hydrogen or C ⁇ -C -alkyl, or R b and R c together denote a group of formula XI
  • R d is G-C -alkyl or C 3 -C6-cycloalkyl and R e is hydrogen or G-C -alkyl
  • X a and X b are each independently hydrogen, chlorine or fluorine.
  • the acyloxy group may be, for example, G-C20- alkylcarbonyloxy, e.g. acetyloxy, n-propionyloxy, isopropionyloxy or hexadecanoyloxy, or C 3 - Cs-cycloalkylcarbonyloxy, e.g. cyclohexylcarbonyloxy.
  • the acylthio group may be, for example, G-C -alkylcarbonylthio, e.g.
  • the heterocyclyl group may be an O-heterocyclyl group, for example a furanonyl group.
  • R b is acyloxy
  • it may be, for example, G-C -alkylcarbonyloxy, e.g. acetyloxy, n- propionyloxy, or n-butyroyloxy, C.-Cg-cycloalkylcarbonyloxy e.g. cyclopropylcarbonyloxy, or 5-or 6-membered heterocyclylcarbonyloxy e.g. furoyloxy, or when R b is acyloxy it may be a group -O-CO-T where T is a monovalent cyclic organic group having from 3 to 15 atoms in the ring system.
  • T is a carbocyclic group or a heterocyclic group having one or more ring hetero atoms selected from nitrogen, oxygen and sulfur.
  • R c is G-C -alkyl it may be in the alpha or beta conformation, more usually in the alpha conformation.
  • R d as Q-Cg-cycloalkyl may be, for example, cyclohexyl.
  • Corticosteroids of formula X and their 1,2-dihydro derivatives include beclamethasone dipropionate, budesonide, fluticasone propionate, mometasone furoate, ciclesonide, triarhcinolone acetonide, flunisolide, rofleponide palmitate, butixocort propionate, icometasone enbutate and described in WO 03/042229, WO 03/035668, WO 02/100879, WO 02/088167.
  • the corticosteroid (B) is budesonide, fluticasone propionate, mometasone furoate or either of the following compounds:
  • Corticosteroids of formula X where R b is -O-CO-T are preferably compounds of formula XII
  • T is a monovalent cyclic organic group having from 3 to 15 atoms in the ring system.
  • T is a carbocyclic group or a heterocyclic group having one or more ring hetero atoms selected from nitrogen, oxygen and sulfur.
  • T is a cycloaliphatic group having 3 to 8 carbon atoms, for example C 3 - Cs-cycloalkyl such as cyclopropyl, methylcyclopropyl, cyclobutyl, methylcyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexyl, dimethylcyclohexyl or cycloheptyl, preferably C 3 - C ⁇ -cycloalkyL
  • T is an at least partially saturated heterocyclic group having 5 to 10 ring atoms, of which one or more are ring hetero atoms selected from nitrogen, oxygen and sulfur, preferably having 5 to 7 ring atoms, of which one or two are hetero atoms selected from nitrogen and oxygen, especially a 5-membered heterocyclic group having one ring hetero atom, such as a tetrahydrofuryl or oxotetrahydrofuryl group.
  • T is a carbocyclic or heterocyclic aromatic group having 5 to 15 atoms in the ring system.
  • T may be such an aromatic group in which the ring system is unsubstituted or is substituted by one or more substituents selected from halogen, cyano, G-C -alkyl, halo-G-C -alkyl, G-C -alkoxy, C ⁇ -C -alkylthio, hydroxyl, G-C 4 -acyl, G- C -acyloxy, amino, G-Gt-alkylamino, di-(C ⁇ -C -alkyl)amino, G-C -acylamino, C ⁇ -C 4 -acyl(G- C -alkyl)-amino, C ⁇ -C -alkylsulfonyl(G-C -alkyl)amino, G-C -alkoxycarbonyl, or 5- membered heterocycly
  • aromatic groups is phenyl or naphthyl optionally substituted by one or more, preferably one, two or three, substituents selected from cyano, G-C -alkyl, halo-G-C - alkyl, G-C alkoxy, halogen, hydroxyl, C ⁇ -C 4 -acyloxy, amino, G-C -alkylamino, di-G-C - alkylamino, G-C 4 -acyl-amino, C ⁇ -C -acyl(G-C alkyl)amino, C ⁇ -C alkylsulfonyl(G-C alkyl)amino or G-C -alkoxy-carbonyl, especially preferred such aromatic groups including phenyl, cyanophenyl, tolyl, dimethylphenyl, ethylphenyl, (trifluoromethyl)phenyl, dimethoxy- phenyl, diethoxyphenyl, especially preferred such aromatic groups
  • heterocyclic aromatic group having a 6- membered heterocyclic ring with one, two or three ring heteroatoms, preferably nitrogen, the heterocyclic ring being unsubstituted or substituted by one or more, preferably one, two or three, substituents selected from halogen, cyano, hydroxyl, G-C -acyloxy, amino, G-C -alkyl- amino, di-(C ⁇ -C -alkyl)amino, G-C -alkyl, hydroxy-G-C -alkyl, halo-G-C -alkyl, Q-C - alkoxy, or G-C -alkylthio, and the heterocyclic ring being optionally fused to a benzene ring.
  • heterocyclic aromatic groups include those in which the heterocyclic group has one or two nitrogen atoms in the ring, especially a pyridine, pyrimidine, pyrazine or pyridazine ring.
  • Especially preferred heterocyclic aromatic groups are pyridyl, pyrimidinyl and pyrazinyl groups, optionally substituted by one or two substituents selected from halogen (particularly chlorine) or G-C -alkyl (especially methyl or n-butyl).
  • heterocyclic aromatic group having a 5- membered heterocyclic ring with one, two or three ring hetero atoms selected from nitrogen, oxygen and sulfur, the heterocyclic ring being unsubstituted or substituted by one or two substituents selected from halogen, G-C -alkyl, halo-G-C -alkyl, G-C -alkoxy, G-C -alkyl- thio, cyano or hydroxy-G-C -alkyl and the heterocyclic ring being optionally fused to a benzene ring.
  • heterocyclic aromatic groups include those in which the heterocyclic ring has one nitrogen, oxygen or sulfur atom in the ring or one oxygen and one or two nitrogen atoms in the ring, or one sulfur and one or two nitrogen atoms in the ring, especially a pyrrole, furan, thiophene, oxazole, isoxazole, imidazole, pyrazole, furazan, thiazole or thiadiazole ring.
  • Especially preferred heterocyclic aromatic groups are pyrrolyl, furyl and thienyl groups optionally substituted by one or two substituents selected from halogen (particularly chlorine or bromine), G-C -alkyl (particularly methyl or ethyl), halo-C ⁇ -C -alkyl (particularly trifluoro-methyl), G-C -alkoxy (particularly methoxy), G-C -alkylthio (particularly methylthio), cyano or hydroxy-G-C 4 -alkyl (particularly hydroxymethyl); isoxazolyl, imidazolyl, pyrazolyl, thiazolyl or thiadiazolyl groups optionally substituted by one or two G-C -alkyl groups; and benzofuryl, benzothienyl and benzofurazanyl groups.
  • substituents selected from halogen (particularly chlorine or bromine), G-C -alkyl (particularly methyl or ethyl), halo-
  • the indicated methyl group in the 16 position of the corticosteroid ring system may be in the alpha or beta conformation. 16- ⁇ -methyl compounds are preferred.
  • Especially preferred compounds of formula XII are those where the indicated 16-methyl group has the alpha conformation and T is 5-methyl-2-thienyl, N-methyl-2-pyrrolyl, cyclopropyl, 2- furyl, 3-methyl-2-furyl, 3-methyl-2-thienyl, 5-methyl-3 -isoxazolyl, 3,5-dimethyl-2-thienyl, 2,5- dimethyl-3 -furyl, 4-methyl-2-furyl, 4-(dimethylamino)phenyl, 4-methylphenyl, 4-ethylphenyl, 2-pyridyl, 4-pyrimidyl or 5-methyl-2-pyrazinyl or the indicated 16-methyl group has the beta conformation and R is cyclopropyl.
  • the compounds of formula XII and salts thereof where T contains a basic group may be prepared using the procedures described in international patent application WO 02/00679.
  • the corticosteroid (B) may, for example, also be a non-steroidal glucocorticoid receptor agonist, such as those described in DE 10261874, WO 00/00531, WO 02/10143, WO 03/82280, WO 03/82787, WO 03/86294, WO 03/104195, WO 03/101932, WO 04/05229, WO 04/18429, WO 04/19935 and WO 04/26248.
  • the medicament of the present invention may additionally contain one or more A 2 A agonists, A 2 B antagonists, antihistamines, caspase inhibitors, LTB4 antagonists, LTD4 antagonists, M3 antagonists and PDE inhibitors or anti-tussive drug substance.
  • Suitable A 2 A agonists include those described in EP 409595A2, EP 1052264, EP 1241176, WO 94/17090, WO 96/02543, WO 96/02553, WO 98/28319, WO 99/24449, WO 99/24450, WO 99/24451, WO 99/38 877, WO 99/41267, WO 99/67263, WO 99/67264, WO 99/67265, WO 99167266, WO 00/23457, WO 00/77018, WO 00/78774, WO 01/23399, WO 01/27130, WO 01/27131, WO 01/60835, WO 01/94368, WO 02/00676, WO 02/22630, WO 02/96462, WO 03/086408, WO 04/039762, WO 04/039766, WO 04/045618 and WO 04/046083.
  • Suitable A 2 B antagonists include those described in WO 02/42238.
  • Suitable antihistamine drug substances include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine, diphenhydramine and fexofenadine hydrochloride, activastine, astemizole, azelastine, ebastine, epinastine, mizolastine and tefenadine as well as those disclosed in JP 2004107299, WO 03/099807 and WO 04/026841.
  • Suitable caspase inhibitors include those that are disclosed in Canadian patent specification 2109646, EP 519748, EP 547 699, EP 590 650, EP 628550, EP 644 197, EP 644198, WO 93/05071, WO 93/14777, WO 93/16710, WO 94/00154, WO 94/03-480, WO 94/21673, WO 95/05152, WO 95/35308, WO 97/22618, WO 97/22619, WO 98/41232, WO 99/06367, WO 99/65451, WO 01/119373, US 5411985, US 5416013, US 5430128, US 5434248, US 5565430, US 5585357, US 5656627, US 5677283, US 6054487, US 6531474, US 20030096737, GB 2,278,276 as well as those disclosed in international patent
  • Suitable LXB4 antagonists include those described in US 5451700.
  • Suitable LTD4 antagonists include ontelukast and zafirlukast.
  • Suitable M3 antagonists include ipratropium bromide, oxitropium " bromide, tiotropium salts, CHF 4226 (Chiesi) and glycopyrrolate, but also those described in EP 424021, US 3714357, US 5171744, VO 02/00652, WO 02/51841, WO 02/53564, WO 03/00840, WO 03/33495, WO 03/53966, WO 03/87094, WO 04/018422, WO 04/0-5285 and WO 04/96800, preferably compounds of the Examples thereof.
  • the M3 antagonist is most preferably ipratropium bromide, oxitropium bromide or a tiotropium salt.
  • the M3 antagonist may also be a dual beta-2 adrenoceptor agonist / muscarinic antagonist such as those disclosed in US 2004/0167167, WO 04/74246 and WO 04/74812.
  • Suitable PDE4 inhibitors include (Ariflo® GSK), Roflumilast (Byk Gulden),V- 11294A (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plough), Arofylline (Almirall Prodesfarma), PD189659 / PD168787 (Parke-Davis), AWD-12-281 (Asta Medica), CDC-801 (Celgene), SelCID(TM) CC-10004 (Celgene), VM554/UM565 (Nernalis), T-440 (Tanabe), KW-4490 (Kyowa Hakko Kogyo), and those disclosed in WO 92/19594, WO 93/1 749, WO 93/19750, WO 93/19751, WO 98/18796, WO 99/16766, WO 01/13953, WO 03/104204, WO 03/104205,
  • the medicament of the invention contains a compound of formula I that posseses beta-2 adrenoceptor agonist activity the medicament may additionally contain another beta-2 adrenoceptor agonist. Suitable additional such beta-2 adrenoceptor agonists albuterol
  • the inhalable form of the medicament may be, for example, an atomizable composition such as an aerosol comprising the active ingredient, i.e. (A) and (B) separately or in admixture, in solution or dispersion in a propellant, or a nebulizable composition comprising a solution or dispersion of the active ingredient in an aqueous, organic or aqueous/organic medium.
  • an atomizable composition such as an aerosol comprising the active ingredient, i.e. (A) and (B) separately or in admixture, in solution or dispersion in a propellant, or a nebulizable composition comprising a solution or dispersion of the active ingredient in an aqueous, organic or aqueous/organic medium.
  • the inhalable form of the medicament may be an aerosol comprising a mixture of (A) and (B) in solution or dispersion in a propellant, or a combination of an aerosol containing (A) in solution or dispersion in a propellant with an aerosol containing (B) in solution or dispersion in a propellant.
  • the inhalable form is a nebulizable composition comprising a dispersion of (A.) and (B) in an aqueous, organic or aqueous/organic medium, or a combination of a dispersion of (A) in such a medium with a dispersion of (B) in such a medium.
  • An aerosol composition suitable for use as the inhalable form of the medicament may comprise the active ingredient in solution or dispersion in a propellant, which may be chosen from any of the propellants known in the art.
  • propellants include hydrocarbons such as n- propane, n-butane or isobutane or mixtures of two or more such hydrocarbons, and halogen- substituted hydrocarbons, for example chlorine and/or fluorine-substituted methanes, ethanes, propanes, butanes, cyclopropanes or cyclobutanes, such as dichlorodifluoromethane (CFC 12), trichlorofluoromethane (CFC11), l,2-dichloro-l,l,2,2 -tetrafluoroethane (CFC114) or, particularly, 1,1,1,2-tetrafluoroethane (HFAl34a) and 1,1, 1,2,3,3, 3-heptafluoropropane (HFA
  • the aerosol composition may also contain a lubricant and a surfactant, which may be chosen from those lubricants and surfactants known in the art.
  • a surfactant which may be chosen from those lubricants and surfactants known in the art.
  • suitable aerosol compositions include surfactant-free or substantially surfactant-free aerosol compositions.
  • the aerosol composition may contain up to about 5% by weight, for example 0.0001 to 5%, 0.001 to 5%, 0.001 to 3%, 0.001 to 2%, 0.001 to 1%, 0.001 to 0.1%, or 0.001 to 0.01% by weight of the active ingredient, based on the weight of the propellant.
  • the lubricant and surfactant may be in an amount up to 5% and 0.5% respectively by weight of the aerosol composition.
  • the aerosol composition may also contain a co-solvent such as ethanol in an amount up to 30% by weight of the composition, particularly for administration from a pressurised metered dose inhalation device.
  • the aerosol composition may further contain a bulking agent, for example a sugar such as lactose, sucrose, dextrose, mannitol or sorbitol, in an amount, for example, of up to 20%, usually 0.001 to 1%, by weight of the composition.
  • the inhalable form is a dry powder, i.e.
  • (A) and (B) are present in a dry powder comprising finely divided (A) and (B) optionally together with at least one particulate pharmaceutically acceptable carrier, which may be one or more materials known as pharmaceutically acceptable carriers, preferably chosen from materials known as carriers in dry powder inhalation compositions, for example saccharides, including monosaccharides, disaccharides, polysaccharides and sugar alcohols such as arabinose, glucose, fructose, ribose, mannose, sucrose, trehalose, lactose, maltose, starches, dextran, rnannitol or sorbitol.
  • An especially preferred carrier is lactose.
  • the compostion may also contain a compound that helps to protect against product performance deterioration due to moisture e.g. magnesium stearate.
  • the dry powder may be contained as unit doses in capsules of, for example, gelatin or plastic, or in blisters (e.g. of aluminium or plastic), for use in a dry powder inhalation device, which may be a single dose or multiple dose device, preferably in dosage units of (A) and (B) together with the carrier in amounts to bring the total weight of powder per capsule to from 5 mg to 50 mg.
  • a dry powder inhalation device which may be a single dose or multiple dose device, preferably in dosage units of (A) and (B) together with the carrier in amounts to bring the total weight of powder per capsule to from 5 mg to 50 mg.
  • the dry powder may be contained in a reservoir in a multi-dose dry powder inhalation device adapted to deliver, for example, 3-25mg of dry powder per actuation.
  • the active ingredient may have an average particle diameter of up to about 10 ⁇ m, for example 0.1 to 5 ⁇ m, preferably 1 to 5 ⁇ m.
  • the particulate carrier where present, generally has a maximum particle diameter up to 300 ⁇ m, preferably up to 212 ⁇ m, and conveniently has a mean particle diameter of 40 to 100 ⁇ m, e.g. 50 to 75 ⁇ m.
  • the particle size of the active ingredient, and that of a particulate carrier where present in dry powder compositions, can be reduced to the desired level by conventional methods, for example by grinding in an air-jet mill, ball mill or vibrator mill, sieving, micro- precipitation, spray-drying, lyophilisation or controlled crystallisation from conventional solvents or from supercritical media.
  • the inhalable medicament may be administered using an inhalation device suitable for the inhalable form, such devices being well known in the art.
  • the invention also provides a pharmaceutical product comprising a medicament or pharmaceutical composition as hereinbefore described in inhalable form as hereinbefore described in association with one or more inhalation devices.
  • the invention provides an inhalation device, or a pack of two or more inhalation devices, containing a medicament or pharmaceutical composition as hereinbefore described in inhalable form as hereinbefore described.
  • the inhalation device may be an aerosol vial provided with a valve adapted to deliver a metered dose, such as 10 to 100 ⁇ l, e.g. 25 to 50 ⁇ l, of the composition, i.e. a device known as a metered dose inhaler.
  • a metered dose such as 10 to 100 ⁇ l, e.g. 25 to 50 ⁇ l
  • Suitable such aerosol vials and procedures for containing within them aerosol compositions under pressure are well known to those skilled in the art of inhalation therapy.
  • an aerosol composition may be administered from a coated can, for example as described in EP 0642992 A.
  • the inhalation device may be a known nebulizer, for example a conventional pneumatic nebulizer such as an air jet nebulizer, or an ultrasonic nebulizer, which may contain, for example, from 1 to 50 ml, commonly 1 to 10 ml, of the dispersion; or a hand-held nebulizer, sometimes referred to as a soft mist or soft spray inhaler, for example an electronically controlled device such as an AERx (Aradigm, OS) or Aerodose (Aerogen), or a mechanical device such as a RESPIMAT (Boehringer Ingelheim) nebulizer which allows much smaller nebulized volumes, e.g.
  • a conventional pneumatic nebulizer such as an air jet nebulizer, or an ultrasonic nebulizer, which may contain, for example, from 1 to 50 ml, commonly 1 to 10 ml, of the dispersion
  • a hand-held nebulizer sometimes
  • the inhalation device may be, for example, a dry powder inhalation device adapted to deliver dry powder from a capsule or blister containing a dry powder comprising a dosage unit of (A) and (B) or a multidose dry powder inhalation (MDPI) device adapted to deliver, for example, 3-25 mg of dry powder comprising a dosage unit of (A) and (B) per actuation.
  • MDPI multidose dry powder inhalation
  • Suitable such dry powder inhalation devices are well known.
  • a suitable device for delivery of dry powder in encapsulated form is that described in US 3991761, while a suitable MDPI device is that described in WO 97/20589.
  • the medicament of the invention is preferably a pharmaceutical composition comprising a mixture of (A) as hereinbefore defined and (B) as hereinbefore defined, preferably together with at least one pharmaceutically acceptable carrier as hereinbefore described.
  • the molar ratio of the compound (A) to the steroid (B) may be, in general, from 100: 1 to 1:300, for example from 50:1 to 1:100 or from 20:1 to 1:50, preferably from 10:1 to 1:20, more preferably from 5:1 to 1:10, from 3:1 to 1:7 or from 2:1 to 1:2.
  • the compound (A) and the steroid (B) may be administered separately in the same ratio.
  • a suitable daily dose of the compound (A), particularly a-s the maleate or trifluoroacetate salt, for inhalation may be from 10 ⁇ g to 2000 ⁇ g, for example from 10 to 1500 ⁇ g, from 10 to 1000 ⁇ g, preferably from 20 to 800 ⁇ g, e.g.
  • a suitable daily dose of steroid (B) for inhalation may be from 20 ⁇ g to 5000 ⁇ g, for example from 20 to 4000 ⁇ g, from 50 to 3000 ⁇ g, from 50 to 20 00 ⁇ g, from 50 to 1000 ⁇ g, from 50 to 500 ⁇ g, from 50 to 400 ⁇ g, from 50 to 300 ⁇ g, from. 50 to 200 ⁇ g or from 50 to 100 ⁇ g.
  • a suitable daily dose may be from 25 to 4800 ⁇ g, for example from 25 to 4000 ⁇ g, from 25 to 3200 ⁇ g, from 25 to 2400 ⁇ g, from 25 to 1600 ⁇ g, from 50 to 4800 ⁇ g, from 50 to 4000 ⁇ g, from 50 to 3200 ⁇ g, from 50 to 2400 ⁇ g, from 50 to 1600 ⁇ g, from 100 to 4000 ⁇ g, from 100 to 3200 ⁇ g, from 100 to 2400 ⁇ g, from 100 to 1600 ⁇ g, from 10O to 800 ⁇ g, from 100 to 400 ⁇ g, from 200 to 4000 ⁇ g, from 200 to 1600 ⁇ g, from 200 to 80O ⁇ g or from 200 to 400 ⁇ g, 100 to 1600 ⁇ g being preferred.
  • a suitable daily dose may be from 50 ⁇ g to 2000 ⁇ g, for example from 100 to 200 ⁇ g, from 1O0 to 1600 ⁇ g, from 100 to 1000 ⁇ g or from 100 to 800 ⁇ g, preferably from 200 to 500 ⁇ g, for instance from 200 to 400 ⁇ g.
  • a suitable daily dose may be for inhalation may be from 25 to 2000 ⁇ g, for example fr/om 25 to 1500 ⁇ g, from 25 to 1000 ⁇ g, from 25 to 500 ⁇ g, from 25 to 250 ⁇ g, from 50 to 15 00 ⁇ g, from 50 to 1000 ⁇ g, from 50 to 500 ⁇ g, from 50 to 250 ⁇ g, from 100 to 1500 ⁇ g, from 100 to 1000 ⁇ g, from 100 to 500 ⁇ g, from 100 to 250 ⁇ g, from 200 to 1500 ⁇ g, from 200 to 1000 ⁇ g or from 200 to 500 ⁇ g, 100 to 1000 ⁇ g being preferred.
  • a suitable unit dose of compound (A), particularly as the maleate or trifluoroacetate salt may be from 10 to 2000 ⁇ g, for example from 10 to 1500 ⁇ g, from 10 to 1000 ⁇ g, preferably from 20 to 800 ⁇ g, from 20 to 600 ⁇ g or from 20 to 500 ⁇ g.
  • a suitable unit dose of budesonide may be from 25 to 2400 ⁇ g, for example from 50 to 240O ⁇ g, from 50 to 2000 ⁇ g, from 50 to 1600 ⁇ g, from 50 to 800 ⁇ g, from 50 to 400 ⁇ g, from 50 to 200 ⁇ g, from 100 to 1600 ⁇ g, from 100 to 800 ⁇ g, from 100 to 400 ⁇ g, from 100 to 2O0 ⁇ g, from 200 to 1600 ⁇ g, from 2O0 to 800 ⁇ g or from 200 to 400 ⁇ g, 100 to 400 ⁇ g being preferred.
  • a suitable unit dose of mometasone furoate for inhalation may be from 25 to 2O00 ⁇ g, for example from 50 ⁇ g to 1500 ⁇ g, from 50 to 1000 ⁇ g, from 50 to 800 ⁇ g, from 5 0 to 400 ⁇ g, from 50 to 200 ⁇ g, from 50 to 100 ⁇ g, from 100 to 800 ⁇ g, from 100 to 400 ⁇ g or from 100 to 200 ⁇ g, 100 to 400 ⁇ g being preferred.
  • a suitable unit dose of fluticasone propionate for inhalation may be from 25 to 1000 ⁇ g, for example from 25 to 500 ⁇ g, from 25 to 2.50 ⁇ g, from 25 to 200 ⁇ g, from 50 to 1000 ⁇ g, from 50 to 500 ⁇ g, from 50 to 250 ⁇ g, from 50 to 200 ⁇ g, from 100 to 1000 ⁇ g, from 100 to 500 ⁇ g, from 100 to 250 ⁇ g, from 100 to 200 ⁇ g, from 150 to 500 ⁇ g or from 150 to 250 ⁇ g, 100 to 500 ⁇ g being preferred.
  • These unit doses may be administered once or twice daily in accordance with the daily doses mentioned hereinbefore. The precise unit and daily dose used will of course depend on the condition to be treated, the patient and the efficiency of the inhalation device.
  • the medicament of the invention is a pharmaceutical composition which is a dry powder in a capsule containing a unit dose of (A) and (B), for example for inhalation from a single capsule inhaler, the capsule suitably containing a unit dose of (A) e.g. as hereinbefore described, and a unit dose of (B), e.g. as hereinbefore described, together with a pharmaceutically acceptable carrier as hereinbefore described in an amount to bring the total weight of dry powder per capsule to between 5 mg and 50 mg, for example 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg or 50 mg.
  • the medicament of the invention is a pharmaceutical composition which is a dry powder for administration from a reservoir of a multi-dose dry powder inhaler adapted to deliver, for example, 3 mg to 25 mg of powder containing a unit dose of (A) and (B) per actuation, for example, where (A) is in the form of the maleate salt, a powder comprising, by weight, 20 to 2000 parts, for example 60 to 1000 parts, 100 to 500 parts, or 100 to 300 parts of (A); 25 to 800 parts, e.g. 25 to 500 parts, 50 to 400 parts, or 100 to 400 parts of (B); and 2000 to 25000 parts, e.g. 4000 to 15000 parts or 4000 to 10000 parts of a pharmaceutically acceptable carrier as hereinbefore described.
  • a powder comprising, by weight, 20 to 2000 parts, for example 60 to 1000 parts, 100 to 500 parts, or 100 to 300 parts of (A); 25 to 800 parts, e.g. 25 to 500 parts, 50 to 400 parts, or 100 to 400 parts of (B); and 2000
  • the medicament of the invention is a pharmaceutical composition which is an aerosol comprising (A) and (B) e.g. in a ratio as hereinbefore described, in a propellant as hereinbefore described, optionally together with a surfactant and/or a bulking agent and/or a co-solvent such as ethanol as hereinbefore described, for administration from a metered dose inhaler adapted to deliver an amount of aerosol containing a unit dose of (A) and a unit dose of (B), or a known fraction of a unit dose of (A) and a known fraction of a unit dose of (B), per actuation.
  • a metered dose inhaler adapted to deliver an amount of aerosol containing a unit dose of (A) and a unit dose of (B), or a known fraction of a unit dose of (A) and a known fraction of a unit dose of (B), per actuation.
  • the inhaler delivers half of the unit doses of (A) and (B) per actuation
  • the unit doses can be administered by two actuations of the inhaler.
  • the invention also provides a pharmaceutical kit comprising (A) and (B) as hereinbefore defined in separate unit dosage forms, said forms being suitable for administration of (A) and (B) in effective amounts.
  • a kit suitably further comprises one or more inhalation devices for administration of (A) and (B).
  • the kit may comprise one or more dry powder inhalation devices adapted to deliver dry powder from a capsule, together with capsules containing a dry powder comprising a dosage unit of (A) and capsules containing a dry powder comprising a dosage unit of (B).
  • the kit may comprise a multidose dry powder inhalation device containing in the reservoir thereof a dry powder comprising (A) and a multidose dry powder inhalation de"vice containing in the reservoir thereof a dry powder comprising (B).
  • the kit may comprise a metered dose inhaler containing an aerosol comprising comprising (A) in a propellant and a metered dose inhaler containing an aerosol comprising (B) in a propellant.
  • the medicaments of the invention are advantageous in the treatment of inflammatory or obstructive airways disease, exhibiting highly effective bronchodilatory and anti-inflammatory properties. For instance, it is possible using the combination therapy of the invention to reduce the dosages of a corticosteroid (B) required for a given therapeutic effect compared with those required using treatment with a corticosteroid alone, thereby minimising possibly undesirable side effects.
  • a corticosteroid (B) required for a given therapeutic effect compared with those required using treatment with a corticosteroid alone, thereby minimising possibly undesirable side effects.
  • these combinations facilitate achievement of a high anti-inflammatory effect, such that the amount of corticosteroid needed for a given anti-inflammatory effect may be reduced when used in admixture with a compound of formula I, thereby reducing the ris J of undesirable side effects from the repeated exposure to the steroid involved in the treatment of inflammatory or obstructive airways diseases.
  • using the combinations of the invention particularly using compositions containing (A) and (B), medicaments which have a rapid onset of action and a long duration of action may be prepared.
  • medicaments which result in a significant improvement in lung function may be prepared.
  • medicaments which provide effective control of obstructive or inflammatory airways diseases, or a reduction in exacerbations of such diseases may be prepared.
  • medicaments which reduce of eliminate the need for treatment with short-acting rescue medicaments such as salbutamo-1 or terbutaline, may be prepared; thus compositions of the invention containing (A) and (Bv) facilitate the treatment of an obstructive or inflammatory airways disease with a single medicament.
  • Treatment of inflammatory or obstructive airways diseases in accordance with the invention may be symptomatic or prophylactic treatment.
  • Inflammatory or obstructive airways diseases to which the present invention is applicable include asthma of whatever type or genesis including both intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitic asthma, exercise-induced asthma, occupational asthma and asthma induced following bacterial infection.
  • Treatment of asthma is also to be understood as embracing treatment of subjects, e.g. of less than 4 or 5 years of age, exhibiting wheezing symptoms and diagnosed or diagnosable as "whezing symptoms and diagnosed or diagnosable as "whezing symptoms and diagnosed or diagnosable as "whezing symptoms and diagnosed or diagnosable as "whezing symptoms and diagnosed or diagnosable as "whezing symptoms and diagnosed or diagnosable as "whezing symptoms and diagnosed or diagnosable as "whezing symptoms and diagnosed or diagnosable as "whezing symptoms and diagnosed or diagnosable as "whezing symptoms and diagnosed or diagnosable as "whezing symptoms and diagnosed or diagnosable as "whezing symptoms and diagnosed
  • Prophylactic efficacy in the treatment of asthma will be evidenced by reduced frequency or severity of symptomatic attack, e.g. of acute asthmatic or bronchoconstrictor attack, improvement in lung function or improved airways hyperreactivity. It may further be evidenced by reduced requirement for other, symptomatic therapy, i.e. therapy for or intended to restrict or abort symptomatic attack when it occurs, for example anti-inflammatory (e.g. corticosteroid) or bronchodilatory.
  • Prophylactic benefit in asthma may in particular be apparent in subjects prone to "morning dipping". "Morning dipping" is a recognised asthmatic syndrome, common to a substantial percentage of asthmatics and characterised by asthma attack, e.g. between the hours of about 4 to 6 am, i.e. at a time normally substantially distant form any previously administered symptomatic asthma therapy.
  • inflammatory or obstructive airways diseases and conditions to which the present invention is applicable include acute/adult lung injury (ALI), adult/acute respiratory distress syndrome (ARDS), cystic fibrosis, chronic obstructive pulmonary, airways or lung disease (COPD, COAD or COLD), including chronic bronchitis and emphysema, bronchiectasis and exacerbation of airways hyperreactivity consequent to other drug therapy, in particular other inhaled drug therapy.
  • ALI acute/adult lung injury
  • ARDS adult/acute respiratory distress syndrome
  • cystic fibrosis cystic fibrosis
  • COAD or COLD chronic obstructive pulmonary, airways or lung disease
  • chronic bronchitis and emphysema bronchiectasis and exacerbation of airways hyperreactivity consequent to other drug therapy, in particular other inhaled drug therapy.
  • pneumoconiosis an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts
  • pneumoconiosis an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts
  • aluminosis an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts
  • aluminosis anthracosis
  • asbestosis chalicosis
  • ptilosis ptilosis
  • siderosis silicosis
  • tobacosis and byssinosis.
  • Palladium black (0.2 g) is added portion-wise to a solution of 7-[2- ⁇ benzyl- ⁇ 2-[4-(4-phenyl- butoxy)-phenyl]-ethyl ⁇ -amino)-l-hydroxy-ethyl]-4-hydroxy-3H-ben_zothiazol-2-one (0.29 g) in formic acid (10 ml) at room temperature. After 1 hour the catalyst as removed by filtration and the filtrate partitioned between CH 3 CO 2 CH CH 3 and aqueous Naf-3CO 3 . Evaporation of the CH 3 CO 2 CH 2 CH 3 layers and recrystallisation from hexane / CH 3 C0 2 CH 2 CH 3 gives the title compound. MS (ES+) 479.
  • Carbon disulphide 38.6 ml is added to a solution of 2-tert-butoxy-5-fluoro-phex ⁇ ylamine (58.8 g) and triethylamine (89.5 ml) in toluene (66 ml) and the reaction mixture stirred at room temperature for 18 hours, then evaporated.
  • Chloroform 200 ml
  • triethylamine 44.9 ml are added to the residue, which is cooled before the addition of ethyl chlorofrormate (30.8 ml). After 15 minutes at 0°C, the reaction mixture is washed sequentially with aqueous 3N HCl, saturated brine, saturated NaHCO 3 and saturated brine, then evaporated to give the title compound.
  • ⁇ nmr (CDC1 3 , 400 MHz); 7.10-7.03 (m, 1H), 6.93-6.87 (m, 1H), ⁇ .86-6.80 (m, 1H), 1.43 (s, 9H).
  • the title compound is prepared from by the procedure of Schaus, Scott E.; Larrow, Jay F.;
  • the reaction mixture is partitioned between ethyl acetate (200 ml) and water (200 ml). The organic layer is washed with brine (100 ml), dried over MgSO 4 , filtered and the solvent removed in vacuo.
  • the title compound is obtained after purification by flash column chromatography (silica, iso-hexane / ethyl acetate 10:1).
  • aqueous layer is basified to pH12 with 2M NaOH and extracted with ethyl acetate (3 x 50 ml). The organic layer is washed with brine (100 ml), dried over MgSO , filtered and the solvent removed in vacuo to give the title compound.
  • ⁇ nmr (CDC1 3 , 400 MHz); 7.80 (m, 2H), 7.65 (m, 2H), 7.10 (m, 5H), 4.65 (q, 1H), 4.50 (d, 1H), 4.35 (d, 1H), 4.00 (q, 1H), 2.70 (m, 1H), 2.00 (m, 4H), 1.50 (m, 1H). '
  • This compound is prepared from (R)-l-(4-tert-butoxy-2-isopropoxybenzothiazol-7-yl)-2- chloro-ethanol and (lS,2R)-2-Benzyloxy-cyclopentylamine using procedures analogous to those used to prepare 4-tert.butoxy-2-isopropoxy-7-(R)-oxiranyl-benzothiazole MS (ES+) m/e 499
  • Gelatin capsules suitable for use in a capsule inhaler such as that described in US 3991761 or EP 1270034 are prepared, each capsule containing a dry powder obtained by mixing Compound El and budesonide which have been ground to a mean particle diameter of 1 to 5 ⁇ m and lactose monohydrate having a particle diameter below 212 ⁇ m, the amounts being as shown in the table below:
  • Examples 1-60 are repeated, but replacing budesonide with mometasone furoate, and using amounts as shown in the following table:
  • a dry powder suitable for delivery from the reservoir of the multi-dose inhaler described in W0 97/20589 is prepared by mixing Compound El and fluticasone propionate which have been ground to a mean particle diameter of 1-5 ⁇ m and lactose monohydrate having a particle diameter below 212 ⁇ m, the amounts being as shown in the table below:
  • a dry powder suitable for delivery from the reservoir of the multi-dose inhaler described in W0 97/20589 is prepared by mixing Compound El and fluticasone propionate which have been ground to a mean particle diameter of 1-5 ⁇ m and lactose monohydrate having a particle diameter below 212 ⁇ m, the amounts being as shown in the table directly above but also containing 0.5% magnesium stearate by weight.
  • Aerosol formulations are prepared by dispensing micronised active ingredients, Compound El and mometasone furoate/ fluticasone propionate, and if required, lactose as bulking agent into a vial, sealing the vial with a metering valve, injecting the premixed ethanol/propellant and optional surfactant into the vial through the valve and subjecting the vial to ultrasonic energy to disperse the solid particles.
  • the components and amounts used are shown in the following tables:
  • Examples 91-135 The procedure of Examples 91-135 is repeated, but replacing fluticasone propionate by mometasone furoate, using amounts as shown in the table directly above and including 0.5% magnesium stearate by weight.
  • Gelatin capsules suitable for use in a capsule inhaler such as that described in US 3991761 or EP 1270034 are prepared, each capsule containing a dry powder obtained by mixing Compound E2 and budesonide which have been ground to a mean particle diameter of 1 to 5 ⁇ m and lactose monohydrate having a particle diameter below 212 ⁇ m, the amounts being as shown in the table below:
  • Examples 327-386 are repeated, but replacing budesonide with mometasone furoate, and using amounts as shown in the following table:
  • a dry powder suitable for delivery from the reservoir of the multi-dose inhaler described in W0 97/20589 is prepared by mixing Compound E2 and fluticasone propionate which have been ground to a mean particle diameter of l-5 ⁇ m and lactose monohydrate having a particle diameter below 212 ⁇ m, the amounts being as shown in the table below
  • a dry powder suitable for delivery from the reservoir of the multi-dose inhaler described in W0 97/20589 is prepared by mixing Compound E2 and fluticasone propionate which have been ground to a mean particle diameter of l-5 ⁇ m and lactose monohydrate having a particle diameter below 212 ⁇ m, the amounts being as shown in the table directly above but also containing 1.0% magnesium stearate by weight.
  • Aerosol formulations are prepared by dispensing micronised active ingredients, Compound E2 and mometasone furoate/ fluticasone propionate, and if required, lactose as bulking agent into a vial, sealing the vial with a metering valve, injecting the premixed ethanol/propellant and optional surfactant into the vial through the valve and subjecting the vial to ultrasonic energy to disperse the solid particles.
  • the components and amounts used are shown as follows:
  • Gelatin capsules suitable for use in a capsule inhaler such as that described in US 3991761 or EP 1270034 are prepared, each capsule containing a dry powder obtained by mixing Compound E3 and budesonide which have been ground to a mean particle diameter of 1 to 5 ⁇ m and lactose monohydrate having a particle diameter below 212 ⁇ m, the amounts being as shown in the table below:
  • Examples 1-60 are repeated, but replacing budesonide with mometasone furoate, and using amounts as shown in the following table:
  • a dry powder suitable for delivery from the reservoir of the multi-dose inhaler described in W0 97/2058 is prepared by mixing Compound E3 and fluticasone propionate which have been ground to a mean particle diameter of 1-5 ⁇ m and lactose monohydrate having a particle diameter below 212 ⁇ m, the amounts being as shown in the table below
  • a dry powder suitable for delivery from the reservoir of the multi-dose inhaler described in W0 97/20589 is prepared by mixing Compound E3 and fluticasone propionate which have been ground to a mean particle diameter of 1-5 ⁇ m and lactose monohydrate having a particle diameter below 212 ⁇ m, the amounts being as shown in the table directly above but also containing 0.5% magnesium stearate by weight.
  • Aerosol formulations are prepared by dispensing micronised active ingredients, Compound E3 and mometasone furoate/ fluticasone propionate, and if required, lactose as bulking agent into a vial, sealing the vial with a metering valve, injecting the premixed ethanol/propellant and optional surfactant into the vial through the valve and subjecting the vial to ultrasonic energy to disperse the solid particles.
  • the components and amounts used are shown in the following tables:
  • Gelatin capsules suitable for use in a capsule inhaler such as that described in US 3991761 or EP 1270034 are prepared, each capsule containing a dry powder obtained by mixing Compound E4 and budesonide which have been ground to a mean particle diameter of 1 to 5 ⁇ m and lactose monohydrate having a particle diameter below 212 ⁇ m, the amounts being as shown in the table below:
  • Examples 979-1038 are repeated, but replacing budesonide with mometasone furoate, and using amounts as shown in the following table:
  • a dry powder suitable for delivery from the reservoir of the multi-dose inhaler described in WO 97/20589 is prepared by mixing Compound E4 and fluticasone propionate which have been ground to a mean particle diameter of 1-5 ⁇ m and lactose monohydrate having a particle diameter below 212 ⁇ m, the amounts being as shown in the table below:
  • a dry powder suitable for delivery from the reservoir of the multi-dose inhaler described in W0 97/20589 is prepared by mixing Compound E4 and fluticasone propionate which have been ground to a mean particle diameter of 1-5 ⁇ m and lactose monohydrate having a particle diameter below 212 ⁇ m, the amounts being as shown in the table directly above but also containing 1.0% magnesium stearate by weight.
  • Aerosol formulations are prepared by dispensing micronised active ingredients, Compound E4 and mometasone furoate/ fluticasone propionate, and if required, lactose as bulking agent into a vial, sealing the vial with a metering valve, injecting the premixed ethanol/propellant and optional surfactant into the vial through the valve and subjecting the vial to ultrasonic energy to disperse the solid particles.
  • the components and amounts used are shown in the following tables:
  • Gelatin capsules suitable for use in a capsule inhaler such as that described in US 3991761 or EP 1270034 are prepared, each capsule containing a dry powder obtained by mixing Compound E5 and budesonide which have been ground to a mean particle diameter of 1 to 5 ⁇ m and lactose monohydrate having a particle diameter below 212 ⁇ m, the amounts being as shown in the table below:
  • Examples 1305-1364 are repeated, but replacing budesonide with mometasone furoate, and using amounts as shown in the following table:
  • a dry powder suitable for delivery from the reservoir of the multi-dose inhaler described in W0 97/20589 is prepared by mixing Compound E5 and fluticasone propionate which have been ground to a mean particle diameter of 1-5 ⁇ m and lactose monohydrate having a particle diameter below 212 ⁇ m, the amounts being as shown in the table below:
  • a dry powder suitable for delivery from the reservoir of the multi-dose inhaler described in W0 97/20589 is prepared by mixing Compound E5 and fluticasone propionate which have been ground to a mean particle diameter of 1-5 ⁇ m and lactose monohydrate having a particle diameter below 212 ⁇ m, the amounts being as shown in the table directly above but also containing 0.5% magnesium stearate by weight.
  • Aerosol formulations are prepared by dispensing micronised active ingredients, Compound E5 and mometasone furoate/ fluticasone propionate, and if required, lactose as bulking agent into a vial, sealing the vial with a metering valve, injecting trie premixed ethanol/propellant and optional surfactant into the vial through the valve and subjecting the vial to ultrasonic energy to disperse the solid particles.
  • the components and amounts used are shown in the following tables:

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EP05707254A 2004-02-09 2005-02-08 Combination of benzothiazol-2-one beta2 adrenoceptor agonists and corticosteroids for the treatment of respiratory diseases Withdrawn EP1715860A1 (en)

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AU2006315657B2 (en) 2005-11-10 2011-12-01 Shell Internationale Research Maatschappij B.V. Soft anticholinergic esters
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EP2011534A1 (en) * 2007-07-03 2009-01-07 CHIESI FARMACEUTICI S.p.A. Metered dose inhaler actuator
WO2009069032A2 (en) 2007-11-30 2009-06-04 Pfizer Limited Novel glucocorticoid receptor agonists
JP5570996B2 (ja) 2007-12-14 2014-08-13 エアロデザインズ インコーポレイテッド エアロゾル化可能な食料品の送達
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UY31905A (es) 2008-06-18 2010-01-29 Astrazeneca Ab Derivados de benzoxazinona, procesos de preparación, composiciones farmacéuticas conteniéndolos y aplicaciones.
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MY194619A (en) 2016-06-02 2022-12-07 Abbvie Inc Glucocorticoid receptor agonist and immunoconjugates thereof
BR112020010694A2 (pt) 2017-12-01 2020-11-10 Abbvie Inc. agonista de receptor de glicocorticoides e imunoconjugados do mesmo

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