CA2552938A1 - Combination of benzothiazol-2-one beta2 adrenoceptor agonists and corticosteroids for the treatment of respiratory diseases - Google Patents

Abstract

A medicament comprising, separately or together, (A) a compound of Formula (I) in free or salt or solvate form, wherein X has the meaning as indicated in the specification; and (B) a corticosteroid, for simultaneous, sequential or separate administration in the treatment of an inflammatory obstructive airways disease, the molar ratio of (A) to (B) being from 100:1 to 1:300.

Description

CORTICOSTEROIDS FOR THE TREATMENT OF RESPIRATORY DISEASES
This invention relates to organic compounds and their use as pharmaceuticals, in particular for the treatment of inflammatory or obstructive airways diseases.
In one aspect, the present invention provides a medicament comprising, separately or together (A) a compound of formula I
H
in free or salt or solvate form, wherein X is -R1-Ar-R2 or -R~-Y;
Ar denotes a phenylene group optionally substituted by halo, hydroxy, Ci-Cio-alkyl, CmCio-alkoxy, Ci-Cio-alkoxy-Ci-Cio-alkyl, phenyl, Ci-Cso-alkyl substituted by phenyl, Ci-Cio-alkoxy substituted by phenyl, Ci-Cio-alkyl-substituted phenyl or by Ci-Cio-alkoxy-substituted phenyl;
R1 and RZ are attached to adjacent carbon atoms in Ar, and either R1 is Ci-Cso-alkylene and R2 is hydrogen, Ci-Cio-alkyl, Cs-Cio-alkoxy or halogen or R1 and R2 together with the carbon atoms in Ar to which they are attached denote a 5-, 6-or 7-membered cycloaliphatic ring;
Ra is a bond or Ci-Cio-alkylene optionally substituted by hydroxy, Cs-C1o-alkoxy, Cs-Cio-aryl or C~-Ci4-aralkyl; and Y is Ci-C1o-alkyl, Ci-Cio-alkoxy, Cz-Cio-alkenyl or Ca-C1o-alkynyl optionally substituted by halo, cyano, hydroxy, Cs-Cio-alkyl, Ci-CZO-alkoxy or halo-Ci-C1o-alkyl;
Ca-Cio-cycloalkyl optionally fused to one or more benzene rings and optionally substituted by Ci-Cio-alkyl, Ci-Clo-alkoxy, Cs-Cso-cycloalkyl, C~-Ci4-aralkyl, C7-Cia.-aralkyloxy or C~-Cio-aryl, where Cs-Cio-cycloalkyl, C~-Ci4-aralkyl, C~-Ci4-aralkyloxy or Cs-Cio-aryl are optionally substituted by halo, hydroxy, Cl-Cio-alkyl, Ci-Cso-alkoxy or halo-Ci-Cio-alkyl;
Cs-Cio-aryl optionally substituted by halo, hydroxy, Ci-Cio-alkyl, Ci-Cso-alkoxy, C1-Cso-haloalkyl, phenoxy, CZ-Cio-alkylthio, Cs-Cio-aryl, 4- to 10- membered heterocyclic ring having at least one ring nitrogen, oxygen or sulphur atom, or by NRbR~
where Rb and R~ are each independently Ci-Cio-alkyl optionally substituted by hydroxy, Cs-Cio-alkoxy or phenyl or R~ may additionally be hydrogen;
phenoxy optionally substituted by Ci-Cio-alkyl, Cl-Cio-alkoxy or by phenyl optionally substituted by Ci-Cio-alkyl or Ci-CZO-alkoxy;
a 4- to 10-membered heterocyclic ring having at least one ring nitrogen, oxygen or sulphur atom, said heterocyclic ring being optionally substituted by halo, Ci-Cio-alkyl, Ci-Cio-alkoxy, halo-Ci-Cio-alkyl, Cs-Cio-aryl, C~-C24-aralkyl, C~-Ci4-aralkyloxy, C1-Cio-alkoxycarbonyl or a 4- to 10-membered heterocyclyl-Ci-Cio-alkyl;
-NRdR° where Rd is hydrogen or Ci-Cio-alkyl and Re is Ci-Cio-alkyl optionally substituted by hydroxy, or Re is Cs-Cio-aryl optionally substituted by halo, or Re 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 Re is Cs-Cso-arylsulfonyl optionally substituted by Ci-Cio-alkylamino or di(C1-Cio-alkyl)amino;
-SRfwhere Rf is Cs-CZO-aryl or C~-Cia-aralkyl optionally substituted by halo, Ci-Cio-alkyl, C1-Cio-alleoxy or Ci-Cio-haloalkyl; or -CONHRg where Rg is CZ-Clo-alkyl, Cs-Cio-cycloalkyl or Cs-Cio-aryl; and (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.
In another aspect, 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.

In a further aspect, 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.
Terms used in the specification have the following meanings:
"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" as used herein 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" as used herein denotes straight chain or branched alkyl that contains one to ten carbon atoms. Preferably, Ci-Cio-alkyl is Ci-Ca-alkyl.
"Cs-Cio-alkylene" as used herein denotes a straight chain or branched alkylene that contains one to ten carbon atoms. Preferably Ci-Cio-alkylene is Ci-C4 alkylene, especially ethylene or methylethylene.
"Cz-Cio-alkenyl" as used herein denotes straight chain or branched hydrocarbon chains that contain two to ten carbon atoms and one or more carbon-carbon double bonds.
Preferably "Cz-Cio-alkenyl" is "Cz-Ca-alkenyl".
"Cz-Cio-alkynyl" as used herein denotes straight chain or branched hydrocarbon chains that contain two to ten carbon atoms and one or more carbon-carbon triple bonds.
Preferably "Cz-Cio-alkynyl" is "Cz-C4-alkynyl".
"Cs-Cio-cycloalkyl" as used herein denotes cycloalkyl having 3 to 10 ring carbon atoms, for example a monocyclic group such as a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, any of which can be substituted by one or WO 2005/074924 . PCT/EP2005/001241 more, usually one or two, Cs-Ca-alkyl groups, or a bicyclic group such as bicycloheptyl or bicyclooctyl. Preferably C3-Clo-cycloalkyl is Cs-C6-cycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
"Ci-Cio-haloalkyl" as used herein denotes Cs-Cio-alkyl as hereinbefore defined substituted by one or more halogen atoms, preferably one, two or three halogen atoms.
"Ci-Cio-alkylamino" and "di(Ci-Clo-alkyl)amino" as used herein denote amino substituted respectively by one or two Ci-Cio-alkyl groups as hereinbefore defined, which may be the same or different. Preferably Ci-Cio-alkylamino and di(Ci-Cio-alkyl)amino are respectively C1-C4-alkylamino and di(Ci-C4-alkyl)amino.
"Ci-Cio-alkylthio" as used herein denotes straight chain or branched alkylthio having 1 to 10 carbon atoms. Preferably, Ci-Cio-alkylthio is Ci-C4-alkylthio.
"Ci-Cio-alkoxy" as used herein denotes straight chain or branched alkoxy that contains 1 to carbon atoms. Preferably, Ci-Cio-alkoxy is Ci-C4-alkoxy.
"C1-Cio-alkoxy-Ci-Cso-alkyl" as used herein denotes Ci-Cio-alkyl as hereinbefore defined substituted by Ci-Cio-alkoxy. Preferably, Ci-Cio-alkoxy-Ci-Cio-alkyl is Ci-C4-alkoxy-Cl-C4-alkyl.
"Ci-Cio-alkoxycarbonyl" as used herein denotes CmCio-alkoxy as hereinbefore defined linked through an oxygen atom thereof to a carbonyl group.
"Cs-Cio-aryl" as used herein 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. Preferably C6-C1o-aryl is Cs-Cs-aryl, especially phenyl.
"C~-Clo-arylsulfonyl" as used herein denotes Cs-Cio-aryl as hereinbefore defined linked through a carbon atom thereof to a sulfonyl group. Preferably Cs-Cso-arylsulfonyl is Cs-Cs-arylsulfonyl.
"C~-Cia.-aralkyl" as used herein denotes alkyl, for example CZ-C4-alkyl as hereinbefore defined, substituted by aryl, for example C6-Cio-aryl as hereinbefore defined.
Preferably, C~-Ci4-aralkyl is C~-C1o-aralkyl such as phenyl-Cl-C4-alkyl, particularly benzyl or 2-phenylethyl.

"CrCi4-aralkyloxy" as used herein denotes alkoxy, for example Cl-C~-alkoxy as hereinbefore defined, substituted by aryl, for example Cs-Cio-aryl. Preferably, C~-Ci4-aralkyloxy is C~-Cio-aralkyloxy such as phenyl-Ci-C4-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-C1o-alkyl, Ci-Cio-alkoxy, Ci-C1o-alkoxy-Ci-Cio-alkyl, phenyl, or Cs-Cio-alkyl substituted by phenyl, Ci-Cio-alkoxy substituted by phenyl, Ci-Cio-alkyl-substituted phenyl and Ci-Cio-alkoxy-substituted phenyl. Preferably Ar is phenylene which is unsubstituted or substituted by one or two substituents selected from halogen, Ci-C4-alkyl, Cs-C4-alkoxy, or Cs-C4-alkoxy substituted by phenyl.
Preferably one substituent in Ar is para to R1 and optional second and third substituents in Ar are meta to R1.
"4- to 10-membered heterocyclic ring having at least one ring nitrogen, oxygen or sulphur atom" as used herein 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-Cs-C1o-alkyl" denotes alkyl, for example Ci-Cio-alkyl as hereinbefore defined, substituted by a 4- to 10-membered heterocyclic ring as hereinbefore defined. Preferably, 4- to 10-membered heterocyclyl-Ci-Cio-alkyl is Ci-C4-alkyl substituted by a 4- to $-membered heterocyclic ring having at least one ring nitrogen, oxygen or sulphur atom.
"Ci-Ca-alkylsulfonyl" denotes sulfonyl substituted by Cs-C4-alkyl as hereinbefore defined.
"Hydroxy-Ci-C4-alkyl" denotes Ci-C4-alkyl as hereinbefore defined substituted by one or more, preferably one, two or three hydroxy groups.
R1 and RZ together with the carbon atoms to which they are attached as a cycloaliphatic ring rnay be, for example, a cyclopentane ring, optionally substituted by one or two Cl-C4-alkyl groups, a cyclohexane ring, optionally substituted by one or two Ci-Ca-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 -Ri-Ar-RZ or -Ra-Y;
Ar denotes a phenylene group optionally substituted by halo, Ci-Cio-alkyl, Cs-Cio-alkoxy or by Ci-CZO-alkoxy substituted by phenyl;
R~ and Rz are attached to adjacent carbon atoms in Ar, and either Rl is C~-Cio-alkylene and R2 is hydrogen, or Rl and RZ together with the carbon atoms in Ar to which they are attached denote a S-, 6-or 7-membered cycloaliphatic ring;
Ra is a bond or Ci-Cio-alkylene optionally substituted by hydroxy, C6-Cio-aryl or C~-Clø-aralkyl; and Y is Ci-Cio-alkyl, Ci-Cio-alkoxy or CZ-Cio-alkynyl; Cs-Cio-cycloalkyl optionally fused to one or more benzene rings and optionally substituted by Ci-CZO-alkyl, C3-CZO-cycloalkyl, C~-C14-aralkyl, C~-Cm-aralkyloxy optionally substituted by halo, or by Cs-Cio-aryl optionally substituted by C1-C1o-alkyl or C1-C10-alkOxy; Cs-Cio-aryl optionally substituted by halo, hydroxy, Ci-Cio-alkyl, phenoxy, Cs-Cio-alkylthio, Cs-Cio-aryl, a 4- to 10-membered heterocyclic ring having at least one ring nitrogen atom, or by NRbR°
where Rb and R~ are each independently Ci-Cio-alkyl optionally substituted by hydroxy or phenyl or Rb may additionally be hydrogen; phenoxy optionally substituted by Ci-Cio-alkoxy; a 4- to 10-membered heterocyclic ring having at least one ring nitrogen or oxygen atom, said heterocyclic ring being optionally substituted by Ci-Clo-alkyl, C6-Clo-aryl, C~-CZa-aralkyl, Ci-Clo-alkoxycarbonyl or by a 4- to 10-rnembered heterocyclyl-Cs-Cio-alkyl; -NRdRe where Rd is hydrogen or C2-Cio-alkyl and Re is Ci-Cio-alkyl, or Re is a 4- to 10-membered heterocyclic ring having at least one ring nitrogen or oxygen atom which ring is optionally substituted by halo-substituted phenyl or Re is Cs-Cio-arylsulfonyl optionally substituted by di(C1-Cio-alkyl)amino; -SRS where RE is C6-Cio-aryl or C~-Ci4-aralkyl optionally substituted by halo or Cs-Cio-haloalkyl;
or -CONHRg where Rg is C3-Cio-cycloalkyl or Cs-Cio-aryl.
Especially preferred compounds of formula I in free or salt or solvate form include those wherein X is -Rl-Ar-Rz or -Ra-Y;
Ar denotes a phenylene group optionally substituted by halo, Ci-Cø-alkyl, Ci-C4-alkoxy or by Ci-C4-alkoxy substituted by phenyl;
Rl and Rz are attached to adjacent carbon atoms in Ar, and either Rl is Ci-C4-alkylene and Ra is hydrogen, or Rl and RZ together with the carbon atoms in Ar to which they are attached denote a S-, 6-or 7-membered cycloaliphatic ring, especially a S-membered cycloaliphatic ring;

Ra is a bond or Ci-Ca-alkylene optionally substituted by hydroxy, Cs-Cs-aryl or C~-Cio-aralkyl;
and Y is Ci-C4-alkyl, Ci-C4-alkoxy or Ca-C4-alkynyl; Cs-C6-cycloalkyl optionally fused to one or more benzene rings and optionally substituted by Cl-C6-alkyl, Cs-Cs-cycloalkyl, C~-Cio-aralkyl, CrCio-aralkyloxy optionally substituted by halo, or by C6-Cs-aryl optionally substituted by Cl-C4-alkyl or Ci-C4-alkoxy; Cg-Cs-aryl optionally substituted by halo, hydroxy, Ci-Ca.-alkyl, phenoxy, Ci-Ca-alkylthio, Cs-Cs-aryl, a 4- to 8-membered heterocydic ring having at least one ring nitrogen atom, or by NRbR~ where Rb and R~ are each independently Ci-C4-alkyl optionally substituted by hydroxy or phenyl or Rb may additionally be hydrogen; phenoxy optionally substituted by Cs-C4-alkoxy; a 4- to 8-membered heterocyclic ring having at least one ring nitrogen or oxygen atom, said heterocyclic ring being optionally substituted by Cl-C4-alkyl, Cs-Cs-aryl, C~-Cio-aralkyl, Ci-Ca-alkoxycarbonyl or by a 4- to 8-membered heterocyclyl-Ci-C4-alkyl; -NRdR° where Rd is hydrogen or Ci-C4-alkyl and Re is Ci-C4-alkyl, or Re is a 4- to 8-membered heterocyclic ring having at least one ring nitrogen or sulphur atom which ring is optionally substituted by halo-substituted phenyl or Re is C6-Cs-arylsulfonyl optionally substituted by di(Cl-C4-alkyl)amino; -SRfwhere Rf is C6-Cs-aryl or C~-Cio-aralkyl optionally substituted by halo or Ci-Ca-haloalkyl; or -CONHRg where Rg is C3-C6-cycloalkyl or C6-Cs-aryl.
More especially preferred compounds of formula I in free or salt or solvate form include:
4-hydroxy-7-( 1-hydroxy-2-{2-[4-(4-phenyl-butoxy)-phenyl]-ethylamino}-ethyl)-3H-benzo-thiazol-2-one; 7-[(R)-2-(1,1-dimethyl-2-phenyl-ethylamino)-1-hydroxy-ethyl]-4-hydroxy-3H-benzothiazol-2-one; 4-hydroxy-7-{(R)-1-hydroxy-2-[2-(5,6,7,8-tetrahydro-naphthalen-2-yl)-ethylaminol-ethyl}-3H-benzothiazol-2-one formate; 7-[(R)-2-((1S,2S)-2-benzyloxy-cyclopentyl-amino)-1-hydroxy-ethyl]-4-hydroxy-3H-benzo-thiazol-2-one; and 7-[(R)-2-((1S,2R)-2-benzyloxy-cyclopentylamino)-1-hydroxy-ethyl]-4-hydroxy-3H-benzothiazol-2-one.
In formula I 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, WO 2005/074924 g PCT/EP2005/001241 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 malefic 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, 1-hydroxynaphthalene-2,-carboxylic acid or 3-hydroxynaphthalene-2-carboxylic acid, and sulfonic acids such as methanesulfonic acid or benzenesulfonic acid.
These salts may be prepared from compounds of formula I by lenown salt-forming procedures.
Pharmaceutically acceptable solvates are generally hydrates.
Compounds of formula I in free or salt or solvate form may also be prepared by:
(i) either (A) reacting a compound of formula II
R'-N-X
HO
S\
/ ,,.
O II
where X is as hereinbefore defined and R~ denotes a protecting group to replace R~ by hydrogen, or (B) reacting a compound of formula III
F

where X and R'' are as hereinbefore defined and R8 and R9 each independently denote a protecting group, to convert groups R~, R8 and R9 to hydrogen; and (ii) recovering the compound of formula I in free or salt or solvate form.

Where reference is made herein to protected functional groups or to protecting groups, 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~ may be, for example, a group chosen from known amine-protecting groups. Preferred protecting groups R~ include araliphatic groups such as benzyl and trialkylsilyl e.g. trimethylsilyl. Protecting groups R$ and R9 may be chosen from known phenolic hydroxy - and alcoholic hydroxy-protecting groups respectively.
Preferred groups R8 and R9 include C1-C4-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. For example, where R~ 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. For example, where, Rg and R9 are alkyl groups, R8 and R9 rnay be converted to hydrogen by hydrogenolysis of the compounds of formula IV, 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~
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.
Compounds of formula II may be prepared by reduction of a compound of formula IV
IV

WO 2005/074924 1o PCT/EP2005/001241 where X and R~ are as hereinbefore defined. The reduction may be effected using known methods for reduction of ketones to alcohols, or analogous methods, including asymmetric reductions. For example, the compounds of formula IV may be reacted with NaBH4 in an inert solvent such as an aliphatic alcohol. Suitable reaction temperatures are from -80° C to 100° C, conveniently from -S° C to 5° C. The reduction may be effected using known procedures or analogously as described hereinafter in the Examples.
Compounds of formula III may be prepared by reacting a compound of formula V

where R$ and R9 are as hereinbefore defined, with a compound of formula VI
R' ~N-X VI
H
where X and R~ are as hereinbefore defined. The 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.
Compounds of formula IV may be prepared by reacting a compound of formula VII
R' N-X
O
C
S
~>--O-R9 VII
'N
R8,0 where X, R~ , R$ and R9 are as hereinbefore described, with concentrated hydrochloric or hydrobromic acid. The reaction is preferably carried out in an inert organic solvent such as an aliphatic alcohol.

Compounds of formula V and VI rnay be prepared by known methods or analogously such as hereinafter described in the Examples.
Compounds of formula VII may be prepared by reaction of a compound of formula VIII
Q
S
/ ~ IC-O-R9 VII
~N
H
Rs, O
where Q is fluorine or chlorine and R8 and R9 are as hereinbefore defined, with a strong base, such as an alkyllithium, NaNHa or potassium tert-butoxide or a mixture of two or more thereof, and a compound of formula IX
R' N-X
O
IX
N
H3C~ ~OCH3 where N and R~ are as hereinbefore defined. The reaction is preferably effected in an inert organic solvent, for example an ether such as tetrahydrofuran (THF). 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 formulae VIII and I~ may be prepared using known procedures or analogously, such as described hereinafter in the Examples.
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

,.,a ~c X
Xb or a 1,2-dihydro derivative thereof, where Ra is Ci-Ca-alkyl optionally substituted by halogen (preferably chlorine or fluorine), hydroxy, Cz-C4-alkoxy, acyloxy or by Ci-C4-acylthio, or Ra is C1-C4-alkoxy or Ci-C4-alkylthio optionally substituted by halogen, or R$ is 5-or 6-membered heterocyclylthio, or Ra is C1-C4-alkylthio optionally substituted by halogen (preferably chlorine or fluorine), either Rb is acyloxy and R~ is hydrogen or Ci-C4-alkyl, or Rb and R~ together denote a group of formula XI
,,~~~0/~Re XI
.,~»O Ra where Rd is CmC4-alkyl or Cs-C6-cycloalkyl and Re is hydrogen or Ci-C4-alkyl, Xa and Xb are each independently hydrogen, chlorine or fluorine.
,When Ra is acyloxy-substituted CmC4-alkyl, the acyloxy group may be, for example, C1-Cao-alkylcarbonyloxy, e.g. acetyloxy, n-propionyloxy, isopropionyloxy or hexadecanoyloxy, or C3-Cs-cycloalkylcarbonyloxy, e.g. cyclohexylcarbonyloxy. When Ra is acylthio-substituted C1-C4-alkyl, the acylthio group may be, for example, Ci-Ca-alkylcarbonylthio, e.g.
acetylthio or n-propionylthio. When Ra is 5-or-6-membered heterocyclylthio, the heterocyclyl group may be an O-heterocyclyl group, for example a furanonyl group.
When Rb is acyloxy, it may be, for example, Ci-Ca-alkylcarbonyloxy, e.g.
acetyloxy, n-propionyloxy, or n-butyroyloxy, Cs-Cs-cycloalkylcarbonyloxy e.g.
cyclopropylcarbonyloxy, or 5-or 6-membered heterocyclylcarbonyloxy e.g. furoyloxy, or when Rb 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. Preferably T is a carbocyclic group or a heterocyclic group having one or more ring hetero atoms selected from nitrogen, oxygen and sulfur.

When R~ is C1-C4-alkyl it may be in the alpha or beta conformation, more usually in the alpha conformation.
When Rb and R° together denote a group of formula XI, Ra as Ca-Cs-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, triamcinolone acetonide, flunisolide, rofleponide palmitate, butixocort propionate, icometasone enbutate and described in WO 03/042229, WO 03/035668, WO
02/100879, WO
02/088167.
In particularly preferred embodiments of the invention, the corticosteroid (B) is budesonide, fluticasone propionate, mometasone furoate or either of the following compounds:
G
O \ F~ '~N
S

nCH~ nCH~
O O
F F
Budesonide, fluticasone propionate and mometasone furoate and their preparation are described in United States patent specifications US 3929768, US 4335121 and US

respectively.
Corticosteroids of formula X where Rb is -O-CO-T are preferably compounds of formula XII

O
O
HO CH3 , O
O
CH3 "~~~~~ CH3 / XII
w/
O
F
where T is a monovalent cyclic organic group having from 3 to 15 atoms in the ring system.

Preferably T is a carbocyclic group or a heterocyclic group having one or more ring hetero atoms selected from nitrogen, oxygen and sulfur.
In one embodiment, T is a cycloaliphatic group having 3 to ~ carbon atoms, for example C3-Cs-cycloalkyl such as cyclopropyl, methylcyclopropyl, cyclobutyl, methylcyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexyl, dimethylcyclohexyl or cycloheptyl, preferably Cs-Cs-cycloalkyl.
In another embodiment, 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.
In a further embodiment, T is a carbocyclic or heterocyclic aromatic group having S to 15 atoms in the ring system. For example, 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, Ci-C4-alkyl, halo-Ci-C4-alkyl, Ci-C4-alkoxy, Ci-C4-alkylthio, hydroxyl, Ci-C4-acyl, C1-C4-acyloxy, amino, CrCøalkylarnino, di-(C1-C4-alkyl)amino, Ci-Ca-acylamino, Cs-C4-acyl(C1-C4-alkyl)-amino, Cs-C4-alkylsulfonyl(CrC4-alkyl)amino, Cs-C4-alkoxycarbonyl, or 5-membered heterocyclyl, usually N-heterocyclyl having one or two nitrogen atoms. One preferred class of such aromatic groups is phenyl or naphthyl optionally substituted by one or rr~ore, preferably one, two or three, substituents selected from cyano, Ci-Ca.-alkyl, halo-C1-C4-alkyl, Ci-C4 alkoxy, halogen, hydroxyl, Ci-C4-acyloxy, amino, Ci-C4-alkylamino, di-Ci-C4-alkylamino, Ci-C4-acyl-amino, Ci-C4-acyl(Ci-C4 alkyl)amino, C2-C4 alkylsulfonyl(C1-C4 alkyl)amino or Ci-C4-alkoxy-carbonyl, especially preferred such aromatic groups including phenyl, cyanophenyl, tolyl, dimethylphenyl, ethylphenyl, (trifluoromethyl)phenyl, dimethoxy-phenyl, diethoxyphenyl, hydroxyphenyl, (methylarnino)phenyl, (methanesulfonylmethylamino)-phenyl and (methoxy-carbonyl)phenyl.
Another preferred class of such aromatic groups is a 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, Ci-C4-acyloxy, amino, Ci-C4-alkyl-amino, di-(C1-C4-alkyl)amino, Cs-C4-alkyl, hydroxy-Ci-C4-alkyl, halo-Cs-C4-alkyl, C1-Ca-alkoxy, or Ci-C4-alkylthio, and the heterocyclic ring being optionally fused to a benzene ring.

Preferred such 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 Ci-C4-alkyl (especially methyl or n-butyl).
Another preferred class of such aromatic groups is a heterocyclic aromatic group having a S-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, Ci-C4-alkyl, halo-Ci-C4-alkyl, Ci-Ca-alkoxy, Ci-Ca.-alkyl-thio, cyano or hydroxy-Ci-C4-alkyl and the heterocyclic ring being optionally fused to a benzene ring. Preferred such 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), Ci-C4-alkyl (particularly methyl or ethyl), halo-Ci-C4-alkyl (particularly trifluoro-methyl), Ci-C4-alkoxy (particularly methoxy), C2-C4-alkylthio (particularly methylthio), cyano or hydroxy-Ci-C4-alkyl (particularly hydroxymethyl);
isoxazolyl, imidazolyl, pyrazolyl, thiazolyl or thiadiazolyl groups optionally substituted by one or two Ci-C4-alkyl groups; and benzofuryl, benzothienyl and benzofurazanyl groups.
In compounds of formula XII, the indicated methyl group in the 16 position of the cortico-steroid ring system may be in the alpha or beta conformation. 16-a-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 S-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 S-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-steroids!
glucocorticoid receptor agonist, such as those described in DE 10261874, WO 00/00531, WO 02/10143, WO
03/82280, WO 03/82'787, 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 tlae present invention may additionally contain one or more AzA agonists, Azs antagonists, antihistamines, caspase inhibitors, LTB4 antagonists, LTD4 antagonists, M3 antagonists and PDE inhibitors or anti-tussive drug substance.
Suitable AzA agonists include those described in EP 409595A2, BP 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 99138 877, WO 99/41267, WO 99/67263, WO 99/67264, WO 99/67265, WO
99/67266, WO 00/2,3457, WO 00/77018, WO 00/78774, WO 01/23399, WO 01/27130, WO 01127131, WO O 1/60835, WO 01/94368, WO 02/00676, WO 02122630, WO 02/96462, WO 03/086408, WO 04/039762, WO 04/039766, WO 041045618 and WO 041046083.
Suitable Azs antagonists include those described in WO 02/42298. Suitable antihistamine drug substances include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratid3ne, desloratidine, diphenhydramine and fexofenadine hydrochloride, activastine, astemizole, azelastine, ebastine, epinastine, mizolastine and tefenadine as well as those disclosed in JP 2.004107299, WO 03/099807 and WO 0/026841. Suitable caspase inhibitors, including interleukin-I P converting enzyme (ICE) inhibitors, include those that are disclosed in Canadian patent specification 2109646, EP 519748, EP 547 699, EP
590 650, EP
628550, EP 644197, EP 644198, WO 93/05071, WO 93/14777, WO 93/16710, WO
94/00154, WO 94/03480, WO 94/21673, WO 95/05152, WO 95/35308, WO 97/22618, WO
97/22619, WO 981412,32, WO 99/06367, WO 99/65451, WO 01/119373, US 5411985, US
5416013, US 5430125, US 5434248, US 5565430, US 558535?, US 5656627, US
5677283, US
6054487, US 6531474, US 20030096737, GB 2,278,276 as well as those disclosed in international patent applications WO 98/10778, WO 98/11109, WO 98/11129 and WO
03/32918. Suitable LTB4 antagonists include those described in US 5451700.
Suitable LTD4 antagonists include m 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, TWO 02/00652, WO
02/51841, WO 02/53564, WO O 3/00840, WO 03/33495, WO 03/53966, WO 03/87094, WO
04/018422, WO 04/05285 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 l WO 2005/074924 1,~ PCT/EP2005/001241 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 (Nappy, BAY19-8004 (Bayer), SCH-351591 (Schering-Plough), Arofylline (Almirall Prodesfarma), PD1896S9 / PD168787 (Parke-Davis), AWD-12-281 (Asta Medica), CDC-(Celgene), SeICID(TM) CC-10004 (Celgene), VMSS4/UMS6S (Vernalis), T-440 (Tanabe), KW-4490 (Kyowa Hakko Kogyo), and those disclosed in WO 92/19594, WO 93/19749, WO
93/19750, WO 93/19751, WO 98/18796, WO 99/16766, WO 01/13953, WO 03/104204, WO 031104205, WO 03/39544, WO 041000814, WO 04/000839, WO 04/005258, WO
04/018450, WO 041018451, WO 041018457, WO 04/018465, ~l0 04/018431, WO
04/018449, WO 04/018450, WO 04/018451, WO 04/018457, W O 04/018465, WO
04/019944, WO 041019945, WO 04/045607 and WO 04/037805.
Although 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 (salbutamol), metaproterenol, terbutaline, salmeterol fenoterol, procaterol, and especially, formoterol, carmoterol and pharmaceutically acceptable salts thereof, and compounds (in free or salt or solvate form) of formula I of WO 0075114, which document is incorporated herein by reference, preferably compounds of the Examples thereof, especially a compound of formula HO
N
H
OH
and pharmaceutically acceptable salts thereof, as well as compounds of EP
1440966, JP
05025045, WO 93/18007, WO 99/64035, US 2002/0055651, WO 01/42193, WO 01/83462, WO 02/66422, WO 02/ 70490, WO 02/76933, WO 03/24439, ~O 03/42160, WO 03/42164, WO 03/72539, WO 03/91204, WO 03/99764, WO 04/16578, WO 04/22547, WO 04/32,921, WO 04/33412, WO 04/37768, WO 04/37773, WO 04/37807, WO 04/39762, WO 04/39766, WO 04/45618 WO 04/46083 and WO 04/80964.
Administration of the medicament or pharmaceutical composition as hereinbefore described, i.e. with (A) and (B) in admixture or separate, is preferably by inhalation, i.e. (A) and (B) are in inhalable form. The inhalable form of the medicament may be, for example, an atomizable WO 2005/074924 1g PCT/EP2005/001241 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. For example, 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. In another example, 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. Suitable such 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 urethanes, ethanes, propanes, butanes, cyclopropanes or cyclobutanes, such as dichlorodifluoromethane (CFC 12), trichlorofluoromethane (CFC11), 1,2-dichloro-1,1,2,2 -tetrafluoroethane (CFC114) or, particularly, 1,1,1,2-tetrafluoroethane (HFA134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFA227), or mixtures of two or more such halogen-substituted hydrocarbons.
D~here the active ingredient is present in suspension in the propellant, i.e. where it is present in particulate form dispersed in the propellant, the aerosol composition may also contain a lubricant and a surfactant, which may be chosen from those lubricants and surfactants known in the art.
Other suitable aerosol compositions include surfactant-free or substantially surfactant-free aerosol compositions. The aerosol composition may contain up to about S% 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. Where present, 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.

In another embodiment of the invention, 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 S mg to 50 mg. Alternatively, 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.
In the finely divided particulate form of the medicament, and in the aerosol composition where the active ingredient is present in particulate form, the active ingredient may have an average particle diameter of up to about 10 p.m, for example 0.1 to 5 p.m, preferably 1 to S pm. The particulate carrier, where present, generally has a maximum particle diameter up to 300 p,m, preferably up to 212, p,m, and conveniently has a mean particle diameter of 40 to 100 p,m, e.g.
50 to 75 pm. 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. Accordingly, 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. In a further aspect, 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.
Where the inhalable form of the active ingredient is an aerosol composition, the inha..lation device may be an aerosol vial provided with a valve adapted to deliver a metered dose, such as 10 to 100 p,l, e.g. 25 to 50 p.l, of the composition, i.e. a device known as a metered dose inhaler. 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.
For example, an aerosol composition may be administered from a coated can, for example as described in EP 0642992 A. Where the inhalable form of the active ingredient is a nebulizable aqueous, organic or aqueous/organic dispersion, the inhalation device may be a known nebulizer, for example a conventional pneumatic nebulizer such as an airjet 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, US) or Aerodose (Aerogen), or a mechanical device such as a RESPIMAT (Boehringer Ingelheim) nebulizer which allows much smaller nebulized volumes, e.g. 10 to 100 pl, than conventional nebulizers. Where the inhalable form of the active ingredient is the finely divided particulate form, 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.
Suitable such dry powder inhalation devices are well known. For example, 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 97/20559.
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 2,0:1 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~ the maleate or trifluoroacetate salt, for inhalation may be from 10 ~,g to 2000 p,g, for example from 10 to 1500 p,g, frorn 10 to 1000 p,g, preferably from 20 to 800 p,g, e.g. from 20 to 600 p,g or from 20 to 500 E,~,g. A
suitable daily dose of steroid (B) for inhalation may be from 20 p,g to 5000 pg, for example from 20 to 4000 fig, from 50 to 3000 fig, from 50 to 20r00 p.g, from 50 to 1000 ~t.g, from SO
to 500 ~.g, from 50 to 400 p.g, from 50 to 300 pg, frorr~ SO to 200 ~g or from 50 to 100 pg.
Where (B) is budesonide, a suitable daily dose may be from 25 to 4800 p.g, for example from 25 to 4000 p,g, from 25 to 3200 p.g, from 25 to 2400 pg, from 25 to 1600 fig, from 50 to 4800 pg, from 50 to 4000 pg, from 50 to 3200 p,g, from SO to 2400 p.g, from 50 to 1600 ~,g, from 100 to 4000 p,g, from 100 to 3200 p,g, from 100 to 2400 pg, from 100 to 1600 pg, from 100 to 800 p.g, from 100 to 400 p.g, from 200 to 4000 pg, from 200 to 1600 p,g, from 200 to 800 p,g or from 200 to 400 ~,g, 100 to 1600 p,g being preferred. Where (B) is mometasone furoate, a suitable daily dose may be from SO ~g to 2000 p,g, for example from 100 to 200 fig, from 100 to 1600 pg, from 100 to 1000 p,g or from 100 to 800pg, preferably from 200 to 500 pg, for instance from 200 to 400 pg. Where (B) is fluticasone propionate, a suitable daily dose may be for inhalation may be from 25 to 2000 p,g, for example from 25 to 1500 fig, from 25 to 100 0 ~.g, from 25 to 500 p.g, from 25 to 250 pg, from 50 to 1S 00 pg, from 50 to 1000 pg, from 54 to 500 ~,g, from SO to 250 pg, from 100 to 1500 p,g, from 100 to 1000 wg, from 100 to 500 pg, from 100 to 250 fig, from 200 to 1500 p.g, from 200 -to 1000 p,g or from 200 to 500 p,g, 100 to 1000 pg being preferred.
A suitable unit dose of compound (A), particularly as the maleate or trifluoroacetate salt, may be from 10 to 2000 p,g, for example from 10 to 1500 p,g, from 10 to 1000 pg, preferably from 20 to 800 p,g, from 20 to 600 pg or from 20 to 500 p.g. Pi suitable unit dose of budesonide may be from 25 to 2400 ~,g, for example from 50 to 2400 pg, from SO to 2000 p,g, from SO to 1600 pg, from SO to 800 ~,g, from SO to 400 pg, from 50 to 200 pg, from 100 to 1600 p,g, from 100 to 800 pg, from 100 to 400 p,g, from 100 to 200 p,g, from 200 to 1600 pg, from 200 to 800 p,g or from 200 to 400 p.g, 100 to 400 p,g being preferred. A suitable unit dose of mometasone furoate for inhalation may be from 25 to 2(>00 pg, for example from 50 p,g to 1500 p.g, from 50 to 1000 p,g, from 50 to 800 pg, from 5 0 to 400 p.g, from SO
to 200 p,g, from 50 to 100 p,g, from 100 to 800 ~.g, from 100 to 400 pg or from 100 to 200 p,g, 100 to 400 ~.i.g being preferred. A suitable unit dose of fluticasone propionate for inhalation may be from 25 to 1000 p,g, fox example from 25 to 500 p,g, from 25 to 250 pg, from 25 to 200 p,g, from SO to 1000 p,g, from 50 to 500 p,g, from 50 to 250 p,g, from SO to 200 pg, from 100 to 1000 pg, from 100 to 500 p,g, frorn 100 to 250 p,g, from 100 to 200 p,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.
In one preferred embodiment of the invention, 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, 2,0 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg or 50 mg.
In another preferred embodiment of the invention, the medicament of the invention is a pharmaceutical composition which is a dry powder for administration from a reservoir of a mufti-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.
In a further preferred embodiment of the invention, 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. Thus if, for example, 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.

In accordance with the above, 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. Such a kit suitably further comprises one or more inhalation devices for administration of (A) and (B). For example, 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). In another example, 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 device containing in the reservoir thereof a dry powder comprising (B). In a further example, 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 minianising possibly undesirable side effects. In particular, these combinations, particularly where (.A) and (B) are in the same composition, 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 risk of undesirable side effects from the repeated exposure to the steroid involved in the treatment of inflammatory or obstructive airways diseases. Furthermore, 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. Moreover, using such combination therapy, medicaments which result in a significant improvement in lung function may be prepared. In another aspect, using the combination therapy of the invention, medicaments which provide effective control of obstructive or inflammatory airways diseases, or a reduction in exacerbations of such diseases, may be prepared. In a further aspect, using compositions of the invention containing (A) and (B), medicaments which reduce or eliminate the need for treatment with short-acting rescue medicaments such as salbutamo<I or terbutaline, may be prepared; thus compositions of the invention containing (A) and (P>) 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 "wheezy infants", an established patient category of major medical concern and now often identified as incipient or early-phase asthmatics. (For convenience this particular asthmatic condition is referred to as "wheezy-infant syndrome".) 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.
Other 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 CARDS), 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. Further inflammatory or obstructive airways diseases to which the present invention is applicable include 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) of whatever type or genesis, including, for example, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tobacosis and byssinosis.
The invention is illustrated by the following Examples.

Preparation Example 1~ Compound E1 4-hydroxy-7-( 1-hydroxy-2-{2-[4-(4-phenyl-butoxy)-phenyl]-ethylar~ino}-ethyl)-benzothiazol-2-one Palladium black (0.2 g) is added portion-wise to a solution of 7-[2-~benzyl-{2-[4-(4-phenyl-butoxy)-phenyl]-ethyl}-amino)-1-hydroxy-ethyl]-4-hydroxy-3H-be~zothiazol-2-one (0.29 g) in formic acid (10 ml) at room temperature. After 1 hour the catalyst 3s removed by filtration and the filtrate partitioned between CHaCOaCHzCH3 and aqueous NaI~C03. Evaporation of the CHsCOaCHzCHs layers and recrystallisation from hexane l CH3COzCHaCH3 gives the title compound. MS (ES+) 479.
Preparation Example 2~ Compound E2 7-[(R)-2-(1,1-Dimethyl-2-phenyl-ethylamino)-1-hydroxy-ethyl]-4-hydroxy-3H-benzothiazol-2-one A solution of (R)-1-(4-tert-Butoxy-2-isopropoxy-benzothiazol-7-yl)-2-(l,ldimethyl-2-phenyl-ethylamino)-ethanol in formic acid (10 ml) is stirred at room temperature. The reaction is shown to be complete by LCMS after 48 hours. Evaporation of the formic acid and purification by reverse phase chromatography (ISOLUTE FLASH C 18, 0-SO%
methylcyanide in water (0.1% TFA)) gives the title compound. MS (ES+) rule 359 (MH+).
Preparation Example 3~ Compound E3 4-Hydroxy-7-{ (R)-1-hydroxy-2-[2-(5,6,7,8-tetrahydro-naphthalen-2. -yl)-ethylamino]-ethyl}-3H-benzothiazol-2-one formate Palladium black (0.4 g) is added portion-wise to a solution of (R)-2-{benzyl-[2-(5,6,7,8-tetrahydro-naphthalen-2-yl)-ethyl]-amino}-1-(4-tert-butoxy-2-isoprQpoxy-benzothiazol-7-yl)-ethanol (0.40 g) in formic acid (5 ml) at room temperature. After 2~- hours the catalyst is removed by filtration. Evaporation of the formic acid and purification by reverse phase chromatography (ISOLUTE FLASH C18, 0-50% methylcyanide in water (0.1% formic acid)) gives the title compound. MS (ES+) mle 385 (MH+).
Preparation Example 4~ Compound E4 7-[(R)-2-( ( 1 S,2 S )-2-B enzyloxy-cyclop entylamino )-1-hydroxy-ethyl]-4-hydroxy-3 H-benzo-thiazol-2-one (R)-2-( ( 1 S,2S)-2-Benzyloxy-cyclopentylamino)-1-(4-tert-butoxy-2-isopropoxy-benzothiazol-7-yl)-ethanol (10 g, 20 mmol) is dissolved in isopropanol (100 ml). 1M HCl (SO
ml) is added and the reaction mixture is heated at 80°C for 24 hours. The isopropanol is removed in vacuo and the residue is partitioned between ethyl acetate (SO ml) and sat. NaHCOs. The organic layer is washed with brine (50 ml), dried over MgSOa, filtered and the solvent removed i~ vacuo. The title compound is purified by crystallisation from ethanol. MS (ES+) mle 401 (MH+).
Preparation Example 5: Compound ES
Example 154: 7-[(R)-2-((1S,2R)-2-Benzyloxy-cyclopentylamino)-1-hydroxy-ethyl-4-hydroxy-3H-benzothiazol-2-one (R)-2-((1S,2R)-2-Benzyloxy-cyclopentylamino)-1-(4-tert-butoxy-2-isopropoxy-benzothiazol-7-yl)-ethanol (460 mg, 0.92 mmol) is dissolved in isopropanol (5 ml). 1M HCl (2.SmL) is added and the reaction mixture is heated at 80°C for 24 hours. The isopropanol is removed i~z vacuo and the residue is partitioned between ethyl acetate (50 ml) and sat. NaHC03.
Tie organic layer is washed with brine (50 ml), dried over MgS04, filtered and the solvent removed in vacuo to give the title compound. MS (ES+) mle 401 (MH+).
Preparation of intermediate compounds Certain compounds that are used to prepare compounds of the Examples that are not readily commercially available are prepared as follows:
Tert-butoxy-5-fluoro-phenylamine A suspension of platinum oxide (17 g) in a solution of 1-tert-butoxy-4-fluoro-2-riitro-benzene (225 g, prepared by procedure T. F. Woiwode et al J. (7rg. Chew. 1998, 63, 9594.) in CHsOH
(1.5 1) is stirred under an atmosphere of hydrogen for 18 hours. Filtration through CeliteTM
filter material and evaporation gives the title compound. 19F nmr (CDCIs, 376 M~~iz); -43.4.
1-Tert-butox~~-4-fluoro-2-isothiocyanato-benzene Carbon disulphide (38.6 ml) is added to a solution of 2-tert-butoxy-5-fluoro-phenylamine (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) and trietl-~ylamine (44.9 ml) are added to the residue, which is cooled before the addition of ethyl chloro~ormate (30.8 ml). After 15 minutes at 0°C, the reaction mixture is washed sequentially with aqueous 3N
HCI, saturated brine, saturated NaHCOs and saturated brine, then evaporated to give the title compound. 1H nmr (CDCIs, 400 MHz); 7.10-7.03 (m, 1H), 6.93-6.87 (m, 1H), x.86-6.80 (m, 1H), 1.43 (s, 9H).
f 2-Tert-butoxy-5-fluoro-phenyl)-thiocarbamic acid O-isopropyl ester A solution of 1-tert-butoxy-4-fluoro-2-isothiocyanato-benzene (50.0 g) and triethylamine (31 ml) in isopropanol (170 ml) is refluxed for 48 hours. Evaporation of the reaction mixture followed by silica gel flash column chromatography, eluent 20:1 hexane:
CH3CO2CHaCH3 gives the title compound. 1H nmr (CDC13, 400 MHz); 8.60 (br s, 1H), 7.38 (br s, 1H), 7.50-6.87 (m, 1H), 6.67-6.58 (m, 1H), 5.64-5.50 (m, 1H), 1.43-1.32 (m, 6H), 1.32-1.25 (s, 9H).
~benz~{2-[~4-phenyl-butoxYl-phen l~l-ether?-aminoLl~4-tert-butox, -~pro~ox~
benzothiazol-7-,~)-ethanone A solution of tert. butyl lithium in pentane (12.3 ml, 1.7 M) is added to a solution of (2-tert-butoxy-5-fluoro-phenyl)-thiocarbamic acid O-isopropyl ester (3.20 g) in tetrahydrofuran (10 ml) at -78° C, the solution warmed to -20° C over 1 hour then re-cooled -78° C and a solution of 2-(benzyl-{2-[4-(4-phenyl-butoxy)-phenyl]-ethyl}-amino)-N-methoxy-N-methyl-acetamide in tetrahydrofuran (10 ml) added at -78° C. The reaction mixture is warmed to room temperature and partitioned between aqueous NH4C1 and CHsCOzCHaCHs.
Evaporation of the CHaCO2CHzCHa layers and silica gel column chromatography, eluent 4:1 hexane:
CH3COzCHzCH3, gives the title compound. MS (ES+) 665.
7-.f(benz~l-{2-[~4-phenyl-butoxYLphen~]-ether}-amino -acet~]-4-h dery-3H-benzothiazol-2-one A solution of 2-(benzyl-{2-[4-(4-phenyl-butoxy)-phenyl]-ethyl}-amino)-1-(4-tert-butoxy-2-isopropoxy-benzothiazol-7-yl)-ethanone (2.49 g) in isopropanol (20 ml) and concentrated hydrobromic acid (20 ml) is heated at 50° C. After 3 hours the reaction mixture is partitioned between CHsCO2CH2CHs and water, and the CHsCOzCHaCHs layer washed with aqueous NaHCO3 then brine. Evaporation of the CH3CO2CH2CH3 layers and silica gel column chromatography, eluent 4:1 hexane: CHsCOzCHzCHs, gives the title compd. MS
(ES+) 567.
7-f2-(benz r~{2-[4-(4-phen~~l-butoxY~phen~)-eth~~-amino -~ d~ -~~]-4-h drop benzothiazol-2-one NaBHa (2.67 g) is added portion-wise to a solution of 7-[(benzyl-{2-[4-(4-phenyl-butoxy)-phenyl]-ethyl}-amino)-acetyl]-4-hydroxy-3H-benzothiazol-2-one (0.40 g) in CHaOH (15 ml) at 0° C. After 30 minutes the reaction mixture is partitioned between CHsCOaCHzCHs and water. Evaporation of the CHaCOaCHzCH3 layers and silica gel column chromatography, eluent 1:1 hexane: CH3COzCHzCH3, gives the title compound. MS (ES+) 569.
~4-Tert.butox~ -2-isopropoxy-benzothiazol-7-Xl)-2-chloro-ethanone Tert. butyllithium (22.7 ml, 1.7 M in pentane) is added dropwise to a solution of (2-tert. -butoxy-S-fluoro-phenyl)-thiocarbamic acid O-isopropyl ester (5.00 g) in THF
(20 ml) at -7~ °
C. This solution is then allowed to warm to -20~ C and a dried mixture of lithium chloride (2.12 g) and copper (I) cyanide (2.24 g) in THF (50 ml) is added. After 15 minutes chloroacetyl chloride (4.36 g) is added and the reaction mixture allowed to warm to 0~ C.
This temperature is maintained for 1 hour and then the reaction mixture is quenched by the addition of saturated aqueous NH4C1 (5 ml). The reaction mixture is partitioned between ethyl acetate (250 ml) and water (250 ml). The organic layer is washed with water (250 ml) and brine (25 0 ml), dried over MgS04, filtered and the solvent removed in vacuo. The title compound is obtained by flash column chromatography (silica, iso-hexane / ethyl acetate 10:1). MS (ES+~
mle 341 (MH+).
(R)-1-(4-Tert-butox -2-isopropoxy-benzothiazol-7-' 1)-2-chloro ethanol Borane-THF complex, (14.64 ml, 1M in THF) is added dropwise to a solution of (1R, 2S)-(+ )-1-amino-2-indanol (0.22 g) in THF (50 ml) and the solution is stirred at room temperature for 15 minutes. A solution of 1-(4-tert.butoxy-2-isopropoxy-benzothiazol-7-yl)-2-chloro-ethanorse (5.00 g) in THF (50 ml) is then added dropwise over a period of 1 hour. The reaction mixture is stirred at room temperature for a further 15 minutes and then quenched by the addition of 0.2M HaS04 (5 ml). The reaction mixture is partitioned between ethyl acetate (200 ml) and 0.2M H2SO4 (200 ml). The organic layer is washed with water (200 ml) and brine (2,00 ml), dried over MgS04, filtered and the solvent removed in vacuo to give the title compound. MS
(ES+) m/e 344 (MH+).
4-Tert.butox -2-isopropoxy-~R -oxiranyl-benzothiazole A mixture of (R)-1-(4-tert.butoxy-2-isopropoxy-benzothiazol-7-yl)-2-chloro-ethanol (4.70 g) and potassium carbonate (7.48 g) in acetone (250 ml) is refluxed for 48 hours.
The reaction mixture is allowed to cool, filtered and the solvent removed in vacuo to give the title compound. MS (ES+) m/e 308 (MH+).
IRl-2-lBenzyl-f2-(S 6 7 8-tetrahydro-naphthalen-2-vl -ether] aminol 1 (4 tert butox,~2 isopropoxy-benzothiazol-7-,~Tl)-ethanol A solution of 4-tert.butoxy-2-isopropoxy-7-(R)-oxiranyl-benzothiazole (3.50 g) and benzyl-[2 -(S,f,7,8-tetrahydro-naphthalen-2-yl)-ethyl]-amine (3.03 g) in 1-butanol (25 ml) is stirred at 110° C. The reaction is shown to be complete by TLC after 18 hours. The title compound is obtained after purification by flash column chromatography (silica, iso-hexane / ethyl acetate 10:1). 1H nmr (CDCl3, 400 MHz); 7.35-7.20 (m, SH), 7.00-6.95 (m, 3H), 6.90-6.80 (m, 2H) , 5.45 (m, 1H), 4.70 (m, 1H), 3.95 (d, 1H), 3.55 (d, 1H), 2.85 (m, 6H), 2.70 (m, 4H), 1.75 (m, 4H), 1.45 (m, 6H), 1.35 (s, 9H).
f R)-~4-tert-Butox -~-isopropoxy-benzothiazol-7-~)-2 ~(1 ldimethyl-2-phen~
lamino~
ethanol A solution of phentermine (0.728 g, 4.89 mmol) and N,O-bis(trimethylsilyl)acetamide (0:496 g, 2.44 mmol) in dry DMF (1 ml) is stirred at room temperature for 30 minutes.
A solution of 4-tert.butoxy-2-isopropoxy-7-(R)-oxiranyl-benzothiazole (0.75 g, 2.44 mmol) in dry DMF (1 ml) is added and the reaction mixture is stirred at 80° C. The reaction is shown to be complete by TLC after 18 hours. The title compound is obtained after purification by flash column chromatography (silica, iso-hexane / ethyl acetate 1:1). MS (ES+) hale 457 (MH+).
(R)-2-(jlS,2S -2-Benz~~yclopentylamino~4-tert-butox -y 2isopropoxy-benzothiazol-7-1 -ethanol 4-tert.butoxy-2-isopropoxy-7-(R)-oxiranyl-benzothiazole (13.2 g, 42.94 mmol) and (1S,2S)-2-Benzyloxy-cyclopentylamine (10.f8 g, 55.82 mmol) are placed in a flask with Diglyme (40 ml) and the reaction mixture is heated at 115°C. The reaction is shown to be complete by TLC
after 17 hours. The reaction mixture is cooled and partitioned between heptane (200 ml) and water (200 ml). The organic layer is dried over MgSOa., filtered and the solvent removed in vac~o. The title compound is purified by crystallisation from isopropanol. MS
(ES+) mle 499 (MH+).
~1R.'2S)-2-Aminoc,~pentanol hydrochloride The title compound is prepared from by the procedure of Schaus, Scott E.;
Larrow, Jay F.;
Jacobsen, Eric N. Practical Synthesis of Enantiopure Cyclic 1,2-Amino Alcohols via Catalytic Asymmetric Ring Opening of Meso Epoxides. Journal of Organic Chemistry (1997), 62,(12), 4197-4199.
llS,2R)-2-(2-H, d~,~ roxY-c,~pent,~}-isoindole-1,3-dione (1R,2S)-2-Aminocyclopentanol hydrochloride (10 g, 72.73 mmol), phthalic anhydride (10.76 g, 72.73 mmol) and diisopropylamine (11.26 g, 87.27 mmol) are placed in a flask and heated to 130°C. The reaction is shown to be complete by TLC after 2 hours.
The reaction mixture is allowed to cool and is partitioned between ethyl acetate (200 ml) and 2M
hydrochloric acid (200 ml). The organic layer is washed with water (1000 ml), sat. NaHC03 (100 ml) and brine (100 ml), dried over MgS04, filtered and the solvent removed in vacuo. The title compound is obtained after purification by flash column chromatography (silica, iso-hexane / ethyl acetate 3~ PCT/EP2005/001241 1:1). 1H nmr (CDCl3, 400 MHz); 7.85 (m, 2H), 7.70 (m, 2H), 4.50 (m, 1H), 4.30 (rn, 1H), 2.95 (d, 1H), 2.45 (m, 1H), 2.00 (m, 3H), 1.85 (m, 1H), 1.60 (m, 1H).
jlS.2R -~2-(2-Benz~~~~clopent~)-isoindole-1,3-dione (1S,2R)-2-(2-Hydroxy-cyclopentyl)-isoindole-1,3-dione (7.50 g, 32.47 mmol) is dissolved in dry DMF (15 ml) under an atmosphere of argon. The solution is cooled to 0°C and sodium hydride (0.78 g, 32.47 mmol) is added. The reaction mixture is stirred at room temperature for 30 minutes and then cooled on ice. Benzyl bromide (6.11 g, 35.71 mmol) is added dropwise and the reaction mixture is stirred at room temperature for 18 hours. The reaction is shown to be complete by TLC. 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 MgSO4, 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). 2H nmr (CDCIs, 400 MHz);
7.80 (m, 2H), 7.65 (m, 2H), 7.10 (m, SH), 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).
jlS, R)-2-Benz,~~,~pentylamine (1S,2R)-2-(2-Benzyloxy-cyclopentyl)-isoindole-1,3-dione S.SO g, 17.13 mmol) is dissolved in EtOH (17S ml). Acetic acid (3.08 g, 51.40 mmol) and hydrazine monohydrate (2.57 g, 51.40 mmol) are added and the reaction mixture is refluxed for 2 hours, allowed to cool, any solids are filtered off and the solvent removed iv ~racuo. The residue is partitioned between ethyl acetate (100 ml) and 2M hydrochloric acid (100 ml). The aqueous layer is basified to pHl2 with 2M NaOH and extracted with ethyl acetate (3 x SO ml). The organic layer is washed with brine (100 ml), dried over MgS04, filtered and the solvent removed in vacuo to give the title compound.1H nmr (CDCIs, 400 MHz); 7.80 (m, 2H), 7.65 (m, 2H), 7.10 (m, SH), 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).
~R~((1S,2R -2-Benz~~~pentylamino~4-tert-butox -2-isopropoxy-benzothiazol-7-1 -ethanol This compound is prepared from (R)-1-(4-tert-butoxy-2-isopropoxybenzothiazol-7-yl)-2-chloro-ethanol and (1S,2R)-2-Benzyloxy-cyclopentylamine using procedures analogous to those used to prepare 4-tert.butoxy-2-isopropoxy-7-(R)-oxiranyl-benzothiazole MS
(ES+) mle 499 (MH+).

Examples 1-60 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 E1 and budesonide which have been ground to a mean particle diameter of 1 to S
~m and lactose monohydrate having a particle diameter below 212 Vim, the amounts being as shown in the table below:
Example Compound E1 Budesonide Lactose Parts _ Parts Parts _ ' 16 20 100 24880 38 ~ 180 ~ 200 Examples 61-90 Examples 1-60 are repeated, but replacing budesonide with mometasone furoate, and using amounts as shown in the following table:
Example Compound E1 MF Lactose Parts Parts Parts 66 _ 100 _ .140 - 24760 _. 68 _ ~ 8p- 100 24720 - - -79 ~ 100 ~ 200 14700 81 140 _ 14660 88 500 ' 200 14300 Examples 91-135 A dry powder suitable for delivery from the reservoir of the mufti-dose inhaler described in WO
97/20589 is prepared by mixing Compound E1 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 Vim, the amounts being as shown in the table below:
Example Compound E1 FP Lactose Parts Parts Parts 110 ' 120 200 9680 119 _1000 200 8800 121 2.0 250 14730 _125 120 250 14630 Examples 13t~-180 A dry powder suitable for delivery from the reservoir of the mufti-dose inhaler described in WO
97/2,0589 is prepared by mixing Compound E1 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 Vim, the amounts being as shown in the table directly above but also containing 0.5 % magnesium stearate by weight.
Examples 181-208 Aerosol formulations are prepared by dispensing micronised active ingredients, Compound E1 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:
Ex. Cpd.E1 MF HFA134a HFA227 Ethanol OA Lactose P arts Parts Parts Parts Parts Parts Parts 182 4 10 3410 6340 230 0.3 -184 10 10 30500 67000 2500 0.5 100 186 14 10 3700 6_050 250 0.8 -187 16 10 3800 5900 230 0.4 -193 2 20 30000 67000 2250 0.2 90 194 10 20 3500 6200 250 0.5 -196 18 20 3100 6200 225 0.8 -198 24 20 30000 60000 2000 0.8 -Ex. Cpd.E1 FP HFA134a HFA227 Ethanol OA Lactose Parts Parts Parts Parts Parts Parts Parts 199 4 10 34000 63000 2250 0.3 50 200 8 10 92000 - 2500 0.5 70 202 16 10 2500 5000 200 0.3 -203 20 10 2000 3000 150 0.2 -204 30 10 2000 2000 150 0.2 -205 8 20 20000 25000 1500 0.2 -206 12 20 2500 2500 200 0.2 -207 20 20 2000 2000 150 0.2 -208 30 20 20000 20000 1500 0.2 -Examples 209-244 The procedure of Examples 91-135 is repeated, but replacing fluticasone propionate by mometasone furoate, and using amounts as shown in the following table:
Example Compound E1 MF ~ Lactose Parts Parts Parts 221 400 _ 200 4400 222 500 __ 200 4300 ~

Examples 245-280 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 O.S%
magnesium stearate by weight.
Examples 281-317 The procedures of Examples 181-208 is repeated, but using the amounts shown in the following table, the ethanol being omitted in some of the Examples:
Ex. Cpd.E1 MF HFA134a HFA227 Ethanol OA Lactose Parts Parts Parts Parts Parts Parts Parts 281 20 20 5000 - 200 O.S -284 20 20 3600 6150 225 - O.S

I 286 14 ~ 20 ~ 3200 ~ 6500 ~ 1500 - ~ 4 I ( WO 2005/074924 3~ PCT/EP2005/001241 287_ 20 20 3150 6100 1500 4 -288 10 20 4700 5050 500 - 0.2 291 60 20 10000 10000 - 0.5 -293 40 20 5000 15000 500 0.5 0.5 294 50 20 9000 11000 400 0.8 0.2 295 20 20 4600 5000 400 0.4 0.2 Ex. Cpd.E1 FP HFA134a HFA227 Ethanol OA Lactose Parts Parts Parts jParts Parts Parts Parts 301 30 10 3200 6800 100 0.5 0.5 303 40 20 8300 6700 200 0.5 -306 50 20 1600 3400 500 2 0.5 Ex. Cpd.E1 Bud HFA134a FA227 Ethanol OA Lactose Parts H Parts Parts Parts Parts Parts Parts _310 20 20 3800 6100 100 0.5 -311 15 20 3300 6600 100 0.5 0.5 314 30 10 3100 6800 100 0.2 0.5 315 40 10 1400 3100 500 0.2 -317 80 ~ 10 30000 70000 - - -( Example 318 - 326 The procedure of Examples 181-208 is repeated, but using sorbitan trioleate (ST) as surfactant in place of oleic acid, the amounts of the ingredients being as shown in the following table:
Ex. Cpd.E1 MF HFA134a HFA227 Ethanol ST Lactose Parts Parts Parts Parts Parts Parts Parts 319 60 20 ~ 8000 12000 200 8 -321 40 20 5000 5000 600 2.5 1 322_ 30 20 3500 6500 - 4 2 326 15 5 1550 3450 200 0.5 1 Examples 327-386 Gelatin capsules suitable for use in a capsule inhaler such as that described in IJS 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 Sam and lactose monohydrate having a particle diameter below 212 Vim, the amounts being as shown in the table below:
Example Compound E2 Budesonide Lactose Parts Parts Parts 373 8. 200 24760 Examples 3 87-41 G
Examples 327-386 are repeated, but replacing budesonide with mometasone furoate, and using amounts as shown in the following table:
Example Compound E2 MF Lactose Parts Parts Parts 404 16 ___ 200 14720 ~

405 20 _ 14700 Examples 417-461 A dry powder suitable for delivery from the reservoir of the mufti-dose inhaler described in ~0 97/20589 is prepared by mixing Compound E2 and fluticasone propionate which have been ground to a mean particle diameter of 1-S~m and lactose monohydrate having a particle diameter below 212~m, the amounts being as shown in the table below Example Compound E2 FP Lactose Parts Parts Parts 417 4 __ ~~ 4880 435 ~ 20 200 9700 443 60 200 ~ 9500 __ 461 ~ 400 250 12750 Examgles 462-506 A dry powder suitable for delivery from the reservoir of the mufti-dose inhaler described in WO
97/20589 is prepared by mixing Compound E2 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.
Examples 507-534 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:
Ex. Cpd.E2 MF HFA134a FA227 Ethanol OA ~ Lactose H

Parts Parts Parts _ Parts Parts Parts Parts 507 0.5 10 36500 60750 2500 - 70 508 1 10 3410 6340 230 0.3 -510 2.S 10 30500 67000 2500 O.S 100 S12 3.S 10 3700 6050 250 0.8 -S13 4 10 3800 5900 230 0.4 -S14 4.S 10 4700 SOSO 250 1 -S16 S.S 20 3500 6200 230 1 -518 6.S 20 3900 5900 250 1 -S19 0.S 20 30000 67000 2250 0.2 90 520 2.S 20 3500 6200 250 O.S -521 3.S 20 3200 6500 230 1 -S22 4.S 20 3100 6200 225 0.8 -524 S.S 20 30000 X0000 2000 0 8 -~ ~

Ex. Cpd.E2 FP HFA134a FA227 Ethanol OA Lactose Parts H Parts Parts Parts Parts Parts Parts S2S 1 10 34000 63000 2250 0.3 SO

526 2 10 _92000 - 2500 O.S 70 S28 4 10 2500 5000 200 0.3 -S29 S 10 2000 3000 150 0.2 S30 6 10 2000 2000 150 0.2 -S31 2 ' 20 20000 25000 1500 0.2 -S32 3 20 2500 2500 200 0.2 -S33 S 20 2000 2000 150 0.2 -534 6 ~ 20 20000 20000 1500 0 2 -~

Examples 535-570 The procedure of Examples 417-461 is repeated, but replacing fluticasone propionate by mometasone furoate, and using amounts as shown in the following table.
Example Compound E2 MF Lactose Parts Parts Parts _ 546 60 200 _ 552 ~ 240 200 3600 558 120 . 400 4000 S6~ ~0 200 9500 Examples 571-606 The procedure of Examples 417-461 is repeated, but replacing fluticasone propionate by mometasone furoate, using amounts as shown in the table directly above and including 1.0%
magnesium stearate by weight.
Examyles 607-643 The procedures of Examples 507-534 is repeated, but using the amounts shown in the following table, the ethanol being omitted in some of the Examples:
Ex. Cpd.E2 MF HFA134a HFA227 Ethanol OA Lactose Parts Parts Parts Parts Parts Parts Parts 607 S 20 5000 - 200 O.S -~ 608 8 ~ 2 2500 2500 - -~

609 19 2S 1500 3500 _ 500 - 1 610 S 20 _ 6150 225 - O.S

61_1 O.S 20 30000 67000 - - -612 3.S 20 3200 6500 1500 - 4 614 2.S 20 4700 SOSO 500 - 0.2 617 1S 20 10000 10000 - O.S -618 7.S 20 8000 12000 - 1 1 619 10 20 5000 15000 500 O.S O.S

620 12.5 20 9000 11000 400 0.8 0.2 621 S 20 4600 5000 400 0.4 0.2 622 7.S 10 20000 25000 - -624 1S ~ 10 ~ 35000 65000 - ~ -~ ~ ~

Ex. Cpd.E2 FP HFA134a HFA227 Ethanol OA Lactose Parts Parts, Parts Parts Parts Parts Parts 626 2.S 10 3650 6350 - - 1 627_ 7.S 10 3200 6800 100 O.S O.S

628 7.S 20 7400 7600 100 - -629 10 20 8300 6700 200 O.S -631 2.S 10 8000 12000 - - -632 12.5 20 1600 3400 500 2 O.S

Ex. Cpd.E2 Bud HFA134a HFA227 ~ EthanolOA Lactose Parts Parts Parts Parts Parts Parts Parts 633 2.S 20 SS00 4500 - - -634 O.S 20 3500 6500 - - 1 635 0.25 20 2500 7500 - - 1 636 S 20 3800 6100 - .100 O.S -637 3.75 20 3300 6600 100 O.S O.S

638 7.S 20 3600 5900 500 4 -640 7.S 10 3100 6800 100 0.2 O.S

641 10 10 1400 3100 500 0.2 -Example 644 - 652 The procedure of Examples 507-534 is repeated, but using sorbitan trioleate (ST) as surfactant in place of oleic acid, the amounts of the ingredients being as shown in the following table:

Ex. Cpd.E2 MF ~ HFA134a FA227 Ethanol ST Lactose Parts H Parts Parts Parts Parts Parts Parts 646 12.5 20 12000 8000 400 10 -647 10 20 5000 5000 600 2.5 1 648 7.S 20 3500 6500 - 4 2 650 2.S 20 4500 SS00 100 2 1 652 3.75 5 ~ 1550 ~ 3450 ~ 200 0 5 1 ~ ~

Examples 653-712 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 S~m and lactose monohydrate having a particle diameter below 212 Vim, the amounts being as shown in the table below:
Example Compound E3 Budesonide Lactose Parts Parts Parts . 658 140 100 19760 674 ( 160 ~ 100 _ WO 2005/074924 4~ PCT/EP2005/001241 678 2,40 100 24660 &80 500 100 24400 687 ~ 120 200 14680 Examples 713-742 Examples 1-60 are repeated, but replacing budesonide with mometasone furoate, and using amounts as shovcrn in the following table:
Example Compound E3 M F Lactose Parts Parts ,Parts WO 2005/074924 4g PCT/EP2005/001241 714 40 100 ~ 24860 Examples 743-787 A dry powder suitable for delivery from the reservoir of the mufti-dose inhaler described in WO
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 Vim, the amounts being as shown in the table below Example Compound E3 FP Lactose Parts Parts Parts 749 ~ 160 ~ 100 4740 Examples 788-832 A dry powder suitable for delivery from the reservoir of the mufti-dose inhaler described in WO
97/20589 is prepared by mixing Compound E3 and fluticasone propionate which have been ground to a mean particle diameter of 1-S ~m and lactose monohydrate having a particle diameter below 212 Vim, the amounts being as shown in the table directly above but also containing O.S% magnesium stearate by weight.

5~ PCT/EP2005/001241 Examples 833-860 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 yvith 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:
Ex. Cpd.E3 MF HFA134a HFA227 Ethanol OA Lactose P arts Parts Parts Parts Parts Parts Parts 834 4 10 3410 6340 230 0.3 -836 10 10 30500 67000 2500 O.S 100 838 14 10 3700 6050 250 0.8 -839 16 10 3800 5900 230 0.4 -84S 2 20 30000 67000 2250 0.2 90 846 10 20 3500 6200 250 O.S -848 18 20 3100 6200 225 0.8 -8S0 24 20 30000 60000 2000 0.8 -Ex. Cpd.E3 FP HFA134a HFA227 Ethanol OA Lactose Parts Parts Parts Parts Parts Parts Parts 851 4 10 34000 63000 2250 0.3 SO

852 8 10 92000 - 2500 O.S 70 8S4 16 10 2500 5000 200 0.3 -8SS 20 10 2000 3000 150 0.2 -8S6 30 10 2000 2000 150 0.2 -8S7 8 20 20000 25000 1500 0.2 8S8 12 20 2500 2500 200 0.2 -8S9 20 20 2000 2000 150 0.2 -860 30 20 20000 20000 1500 0.2 -Examples 861-896 The procedure of Examples 743-787 is repeated, but replacing fluticasone propionate by mometasone furoate, and using amounts as shown in the following table:
Example Compound E3 MF Lactose Parts Parts Parts 896 ~ 500 200 9300 Examples 897-932 The procedure of Examples 743-787 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.
Examples 933-969 The procedures of Examples 136-163 is repeated, but using the amounts shown in the following table, the ethanol being omitted in some of the Examples:
Ex. Cpd.E3 MF HFA134a HFA227 Ethanol OA Lactose Parts Parts Parts Parts Parts Parts Parts 933 20 20 5000 - 200 0.5 -936 20 20 3600 6150 225 - 0.5 940 10 20 4700 5050 500 - 0.2 943 60 20 10000 10000 - 0.5 -945 40 20 5000 15000 500 0.5 0.5 946 50 20 9000 11000 400 0.8 0.2 947 20 20 4600 5000 400 0.4 0.2 Ex. Cpd.E3 FP HFA134a HFA227 Ethanol OA Lactose Parts Parts Parts Parts Parts Parts Parts 953 30 10 3200 6800 100 0.5 0.5 955 40 20 8300 6700 200 0.5 -958 SO 20 1600 3400 500 2 0.5 Ex. ~ Cpd.E3 ~ Bud ~ HFA134a ~ HFA227 ~ Ethanol ~ OA Lactose 962 20 20 3800 6100 100 0.5 -963 15 20 3300 6600 100 0.5 0.5 966 30 10 3100 6800 100 0.2 0.5 967 40 10 1400 3100 500 0.2 -Example 970 - 978 The procedure of Examples 833-860 is repeated, but using sorbitan trioleate (ST) as surfactant in place of oleic acid, the amounts of the ingredients being as shown in the following table:
Ex. Cpd.E3 MF HFA134a HFA227 Ethanol ST Lactose P arts Parts Parts Parts Parts Parts Parts 973 40 20 5000 5000 600 2.5 1 978 15 5 1550 3450 200 0.5 1 Examples 979-1038 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 S
~.m and lactose monohydrate having a particle diameter below 212 ~tm, the amounts being as shown in the table below:
Example Compound E4 Budesonide Lactose Parts Parts Parts 982 SO _ 100 19800 WO 2005/074924 5$ PCT/EP2005/001241 Examples 1039-1068 Examples 979-1038 are repeated, but replacing budesonide with mometasone furoate, and using amounts as shown in the following table:
Example Compound E4 MF Lactose Parts Parts Parts 1059 '70 200 14660 Examples 1069-1113 A dry powder suitable for delivery from the reservoir of the mufti-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 ~tm and lactose monohydrate having a particle diameter below 212 Vim, the amounts being as shown in the table below:
Example Compound E4 FP Lactose Parts Parts Parts Examples 1114-1158 A dry powder suitable for delivery from the reservoir of the mufti-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-S ~m and lactose monohydrate having a particle diameter below 212 ~tm, the amounts being as shown in the table directly above but also containing 1.0°1° magnesium stearate by weight.
Examples 1159-1186 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:
Ex. Cpd.E4 MF HFA134a~ HFA227 Ethanol OA Lactose Parts Parts Parts Parts Parts Parts Parts ~

1160 2 10 3410 6340 230 0.3 -1162 S 10 30500 67000 2500 O.S 100 1164 7 10 3700 6050 250 0.8 -1165 8 10 3800 5900 230 0.4 -1171 1 20 30000 67000 2250 0.2 90 1172 S 20 3500 6200 250 O.S -1174 9 20 3100 6200 225 0.8 -1176 12 20 30000 60000 2000 0.8 -Ex. Cpd.E4 FP HFA134a HFA227 Ethanol OA Lactose Parts Parts Parts Parts Parts Parts Parts _1_1772 10 34000 63000 2250 0.3 50 1178 4 10 92000 - 2500 0.5 70 _ 1179_ 6 10 3000 5500 200 - -1180 8 10 2500 5000 200 0.3 -1181 10 10 2000 3000 150 0.2 -1182 15 10 2000 2000 150 0.2 -1183 4 20 20000 25000 1500 0.2 -1184 6 20 2500 2500 200 0.2 -1185 10 20 2000 2000 150 0.2 -1186 15 20 20000 20000 1500 0.2 -Examples 1187-1222 The procedure of Examples 1069-1113 is repeated, but replacing fluticasone propionate by mometasone furoate, and using amounts as shown in the following table.
Example Compound E4 MF Lactose Parts Parts Parts Examples 1223-1258 The procedure of Examples 10f9-1113 is repeated, but replacing fluticasone propionate by mometasone furoate, using amounts as shown in the table directly above and including 1.0%
magnesium stearate by weight.
Examples 1259-1295 The procedures of Examples 1159-1186 is repeated, but using the amounts shown in the following table, the ethanol being omitted in some of the Examples:
Ex. Cpd.E4 MF HFA134a HFA227 Ethanol OA Lactose P arts Parts Parts Parts Parts Parts Parts 1259 10 20 5000 - 200 0.5 -1260 20 2 2500 2,500 - - -1262 10 20 3600 6150 225 - 0.5 1266 5 20 4700 5050 500 - 0.2 1269 30 20 10000 10000 - 0.5 -1271 20 20 5000 15000 500 0.5 0.5 1272 25 20 9000 11000 400 0.8 0.2 1273 10 20 4600 5000 400 0.4 0.2 6~ PCT/EP2005/001241 Ex. Cpd.E4 FP HFA134a HFA227 Ethanol OA Lactose Parts Parts Parts Parts Parts Parts Parts 1279 15 10 3200 6800 100 0.5 0.5 128_0 15 20 7400 7600 100 - -1281 20 20 8300 6700 200 0.5 -1284 25 20 1600 3400 500 2 0.5 Ex. Cpd.E4 Bud HFA134a HFA227 Ethanol OA Lactose P arts Parts Parts Parts Parts Parts f Parts 1287 0.5 20 2500 7500 - - 1 1288 10 20 3800 6100 100 0.5 -1289 7.5 20 3300 6600 100 0.5 0.5 1292 15 10 3100 6800 100 0.2 0.5 1293 20 10 1400 3100 500 0.2 -1295 40 ~ 10 ~ 30000 ~ 70000 - ~ - -~ ~

Example 1296 -1304 The procedure of Examples 1159-1186 is repeated, but using sorbitan trioleate (ST) as surfactant in place of oleic acid, the amounts of the ingredients being as shown in the following table:
Ex. Cpd.E4 MF HFA134a IIFA227 Ethanol ST Lactose - Parts Parts Parts Parts Parts Parts Parts 1299 20 20 5000 5000 600 2.5 1 1304 7.5 5 1550 3450 200 0.5 1 Examples 1305-1364 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 ES and budesonide which have been ground to a mean particle diameter of 1 to S~rn and lactose monohydrate having a particle diameter below 212 Vim, the amounts being as shown in the table below:
Example Compound ES Budesonide Lactose Parts Parts Parts Examples 1365-1394 Examples 1305-1364 are repeated, but replacing budesonide with mometasone furoate, and using amounts as shown in the following table:
Example Compound ES MF Lactose Parts Parts Parts 1391 ~ 300 200 14500 _ 1392 ~ - 500 200 14300 1393 1000 '200 _ Examples 1395-1439 A dry powder suitable for delivery from the reservoir of the mufti-dose inhaler described in WO
97/20589 is prepared by mixing Compound ES 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 Vim, the amounts being as shown in the table below:
Example Compound ES FP Lactose Parts Parts Parts Examples 1440-1484 A dry powder suitable for delivery from the reservoir of the multi-dose inhaler described in WO
97/20589 is prepared by mixing Compound ES and flutacasone propionate which have been ground to a mean particle diameter of 1-5 ~m and lactose monohydrate having a particle diameter below 212 pm, the amounts being as shown in the table directly above but also containing O.S% magnesium stearate by weight.
Examples 1485-1512 Aerosol formulations are prepared by dispensing micronised active ingredients, Compound ES
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:

Ex. Cpd.ES MF HFA134a HFA227 Ethanol OA Lactose P arts Parts Parts Parts Parts Parts Parts 1486 4 10 3410 6340 230 0.3 -1488 10 10 30500 67000 2500 0.5 100 1490 14 10 3700 6050 250 0.8 -1491 16 10 3800 5900 230 0.4 -1497 2 20 30000 67000 2250 0.2 90 1498 10 20 3500 6200 250 0.5 -1500 18 20 3100 6200 225 0.8 -1502 24 ~ 20 30000 60000 2000 0.8 -~

Ex. Cpd.ES FP HFA134a HFA227 Ethanol OA Lactose P arts Parts Parts Parts Parts Parts Parts 1503 4 10 34000 63000 2250 0.3 50 1504 8 10 92000 - 2500 0.5 70 1506 16 10 2500 5000 200 0.3 -1507 20 10 2000 3000 150 0.2 -1508 30 10 2000 2000 150 0.2 -1509 8 20 20000 25000 1500 0.2 -1510 12 20 2500 2500 200 0.2 -1511 20 20 2000 2000 150 0.2 -1512 30 20 20000 20000 1500 0.2 -Examples 1513-1548 The procedure of Examples 1395-1439 is repeated, but replacing fluticasone propionate by .
mometasone furoate, and using amounts as shown in the following table.
Example Compound ES MF Lactose Parts Parts Parts Examples 1549-1584 The procedure of Examples 1395-1439 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.
Examples 1585-1621 The procedures of Examples 1485-1512 is repeated, but using the amounts shown in the following table, the ethanol being omitted in some of the Examples:

WO 2005/074924 6~ PCT/EP2005/001241 Ex. Cpd.ES MF HFA134a HFA227 Ethanol OA Lactose Parts Parts Parts Parts Parts Parts Parts 1585 20 20 5000 - 200 0.5 -1588 20 20 3600 6150 225 - 0.5 1592 10 20 4700 5050 500 - 0.2 1595 60 20 10000 10000 - 0.5 -1597 40 20 5000 15000 500 0.5 0.5 1598 SO 20 9000 11000 400 0.8 0.2 1599 20 20 4600 5000 400 0.4 0.2 1602 6~ 10 35000 65000 - - -~

Ex. Cpd.ES FP HFA134a HFA227 Ethanol OA Lactose P arts Parts Parts Parts Parts Parts Parts 1605 30 10 3200 6800 100 0.5 0.5 1607 40 20 8300 6700 200 O.S -2610 50 20 1600 3400 500 2 0.5 Ex. Cpd.ES Bud HFA134a HFA227 Ethanol OA Lactose Parts Parts Parts Parts Parts Parts Parts 1614 20 20 3800 6100 100 0.5 -1615 15 20 3300 6600 100 0.5 0.5 1618 30 10 3100 6800 100 0.2 0.5 1619 40 10 1400 3100 500 0.2 -Example 1622 -1630 The procedure of Examples 1485-1512 is repeated, but using sorbitan trioleate (ST) as surfactant in place of oleic acid, the amounts of the ingredients being as shown in the following table:
Ex. Cpd.ES MF HFA134a HFA227 Ethanol ST Lactose P arts Parts Parts Parts Parts Parts Parts 1625 40 20 5000 5000 600 2.5 1 1630 15 5 1550 3450 200 0.5 1

Claims (20)

1. A medicament comprising, separately or together (A) a compound of formula I
in free or salt or solvate form, wherein X is -R1-Ar-R2 or -R a-Y;
Ar denotes a phenylene group optionally substituted by halo, hydroxy, C1-C10-alkyl, C1-C10-alkoxy, C1-C10-alkoxy-C1-C10-alkyl, phenyl, C1-C10-alkyl substituted by phenyl, C1-C10-alkoxy substituted by phenyl, C1-C10-alkyl-substituted phenyl or by C1-C10-alkoxy-substituted phenyl;
R1 and R2 are attached to adjacent carbon atoms in Ar, and either R1 is C1-C10-alkylene and R2 is hydrogen, C1-C10-alkyl, C1-C10-alkoxy or halogen or R1 and R2 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 C1-C10-alkylene optionally substituted by hydroxy, C1-C10-alkoxy, C6-C10-aryl or C7-C14-aralkyl; and Y is C1-C10-alkyl, C1-C10-alkoxy, C2-C10-alkenyl or C2-C10-alkynyl optionally substituted by halo, cyano, hydroxy, C1-C10-alkyl, C1-C10-alkoxy or halo-C1-C10-alkyl;
C3-C10-cycloalkyl optionally fused to one or more benzene rings and optionally substituted by C1-C10-alkyl, C1-C10-alkoxy, C3-C10-cycloalkyl, C7-C14-aralkyl, aralkyloxy or C6-C10-aryl, where C3-C10-cycloalkyl, C7-C14-aralkyl, C7-C14-aralkyloxy or C6-C10-aryl are optionally substituted by halo, hydroxy, C1-C10-alkyl, C1-C10-alkoxy or halo-C1-C10-alkyl;
C6-C10-aryl optionally substituted by halo, hydroxy, C1-C10-alkyl, C1-C10-alkoxy, C1-C10-haloalkyl, phenoxy, C1-C10-alkylthio, C6-C10-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 C1-C10-alkyl optionally substituted by hydroxy, alkoxy or phenyl or R b may additionally be hydrogen;
phenoxy optionally substituted by C1-C10-alkyl, C1-C10-alkoxy or by phenyl optionally substituted by C1-C10-alkyl or C1-C10-alkoxy;
a 4- to 10-membered heterocyclic ring having at least one ring nitrogen, oxygen or sulphur atom, said heterocyclic ring being optionally substituted by halo, C1-C10-alkyl, C1-C10-alkoxy, halo-C1-C10-alkyl, C6-C10-aryl, C7-C14-aralkyl, C7-C14-aralkyloxy, C1-C10-alkoxycarbonyl or a 4- to 10-membered heterocyclyl-C1-C10-alkyl;
-NR d R e where R d is hydrogen or C1-C10-alkyl and R e is C1-C10-alkyl optionally substituted by hydroxy, or R e is C6-C10-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 C6-C10-arylsulfonyl optionally substituted by C1-C10-alkylamino or di(C1-C10-alkyl)amino;
-SR f where R f is C6-C10-aryl or C7-C14-aralkyl optionally substituted by halo, C1-C10-alkyl, C1-C10-alkoxy or C1-C10-haloalkyl; or -CONHR g where R g is C1-C10-alkyl, C3-C10-cycloalkyl or C6-C10-aryl; and (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.

2. A medicament according to claim 1 which is a pharmaceutical composition comprising a mixture of effective amounts of (A) and (B) optionally together with at least one pharmaceutically acceptable carrier.

3. A medicament according to claim 1 or 2, in which (A) is a compound of formula I in free or salt or solvate form wherein X is -R1-Ar-R2 or -R a-Y;

Ar denotes a phenylene group optionally substituted by halo, C1-C10-alkyl, C1-C10-alkoxy or by C1-C10-alkoxy substituted by phenyl;
R1 and R2 are attached to adjacent carbon atoms in Ar, and either R1 is C1-C10-alkylene and R2 is hydrogen, or R1 and R2 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 C1-C10-alkylene optionally substituted by hydroxy, C6-C10-aryl or C7-C14-aralkyl; and Y is C1-C10-alkyl, C1-C10-alkoxy or C2-C10-alkynyl; C3-C10-cycloalkyl optionally fused to one or more benzene rings and optionally substituted by C1-C10-alkyl, C3-C10-cycloalkyl, C7-C14-aralkyl, C7-C14-aralkyloxy optionally substituted by halo, or by C6-C10-aryl optionally substituted by C1-C10-alkyl or C1-C10-alkoxy; C6-C10-aryl optionally substituted by halo, hydroxy, C1-C10-alkyl, phenoxy, C1-C10-alkylthio, C6-C10-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 C1-C10-alkyl optionally substituted by hydroxy or phenyl or R b may additionally be hydrogen; phenoxy optionally substituted by C1-C10-alkoxy; a 4- to 10-membered heterocyclic ring having at least one ring nitrogen or oxygen atom, said heterocyclic ring being optionally substituted by C1-C10-alkyl, C6-C10-aryl, C7-C14-aralkyl, C1-C10-alkoxycarbonyl or by a 4- to 10-membered heterocyclyl-C1-C10-alkyl; -NR d R e where R d is hydrogen or C1-C10-alkyl and R e is C1-C10-alkyl, or R e is a 4- to 10-membered heterocyclic ring having at least one ring nitrogen or oxygen atom which ring is optionally substituted by halo-substituted phenyl or R e is C6-C10-arylsulfonyl optionally substituted by di(C1-C10-alkyl)amino; -SR f where R f is C6-C10-aryl or C7-C14-aralkyl optionally substituted by halo or C1-C10-haloalkyl;
or -CONHR g where R g is C3-C10-cycloalkyl or C6-C10-aryl.

4. A medicament according to any preceding claim, in which (A) is a compound of formula I
in free or salt or solvate form wherein X is -R1-Ar-R2 or -R a-Y;
Ar denotes a phenylene group optionally substituted by halo, C1-C4-alkyl, C1-C4-alkoxy or by C1-C4-alkoxy substituted by phenyl;
R1 and R2 are attached to adjacent carbon atoms in Ar, and either R1 is C1-C4-alkylene and R2 is hydrogen, or R1 and R2 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 C1-C4-alkylene optionally substituted by hydroxy, C6-C8-aryl or C7-C10-aralkyl;
and Y is C1-C4-alkyl, C1-C4-alkoxy or C2-C4-alkynyl; C3-C6-cycloalkyl optionally fused to one or more benzene rings and optionally substituted by C1-C6-alkyl, C3-C6-cycloalkyl, C7-C10-aralkyl, C7-C10-aralkyloxy optionally substituted by halo, or by C6-C8-aryl optionally substituted by C1-C4-alkyl or C1-C4-alkoxy; C6-C8-aryl optionally substituted by halo, hydroxy, C1-C4-alkyl, phenoxy, C1-C4-alkylthio, C6-C8-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 independently C1-C4-alkyl optionally substituted by hydroxy or phenyl or R b may additionally be hydrogen; phenoxy optionally substituted by C1-C4-alkoxy; a 4- to 8-membered heterocyclic ring having at least one ring nitrogen or oxygen atom, said heterocyclic ring being optionally substituted by C1-C4-alkyl, C6-C8-aryl, C7-C10-aralkyl, C1-C4-alkoxycarbonyl or by a 4- to 8-membered heterocyclyl-C1-C4-alkyl; -NR d R e where R d is hydrogen or C1-C4-alkyl and R e is C1-C4-alkyl, or R e is a 4- to 8-membered heterocyclic ring having at least one ring nitrogen or sulphur atom which ring is optionally substituted by halo-substituted phenyl or R e is C6-C8-arylsulfonyl optionally substituted by di(C1-C4-alkyl)amino; -SR f where R f is C6-C7-aryl or C7-C10-aralkyl optionally substituted by halo or C1-C4-haloalkyl; or -CONHR g where R g is C3-C6-cycloalkyl or C6-C8-aryl.

5. A medicament according to any preceding claim, in which (A) is selected from the group consisting of 4-hydroxy-7-(1-hydroxy-2-{2-[4-(4-phenyl-butoxy)-phenyl]-ethylamino}-ethyl)-3H-benzothiazol-2-one; 7-[(R)-2-(1,1-dimethyl-2-phenyl-ethylamino)-1-hydroxy-ethyl]-4-hydroxy-3H-benzo-thiazol-2-one; 4-hydroxy-7-{(R)-1-hydroxy-2-[2-(5,6,7,8-tetrahydro-naphthalen-2-yl)-ethyl-amino]-ethyl}-3H-benzothiazol-2-one formate; 7-[(R)-2-((1S,2S)-2-benzyloxy-cyclopentyl-amino)-1-hydroxy-ethyl]-4-hydroxy-3H-benzo-thiazol-2-one; and 7-[(R)-2-((1S,2R)-2-benzyloxy-cyclopentylamino)-1-hydroxy-ethyl]-4-hydroxy-3H-benzothiazol-2-one.

6. A medicament according to any preceding claim, in which (B) is a compound of formula X
or a 1,2-dihydro derivative thereof, where R a is C1-C4-alkyl optionally substituted by halogen (preferably chlorine or fluorine), hydroxy, C1-C4-alkoxy, acyloxy or by C1-C4-acylthio, or R a is C1-C4-alkoxy or C1-C4-alkylthio optionally substituted by halogen, or R a is 5-or 6-membered heterocyclylthio, or R a is C1-C4-alkylthio optionally substituted by halogen (preferably chlorine or fluorine), either R b is acyloxy and R c is hydrogen or C1-C4-alkyl, or R b and R c together denote a group of formula XI

where R d is C1-C4-alkyl or C3-C6-cycloalkyl and R e is hydrogen or C1-C4-alkyl, X a and X b are each independently hydrogen, chlorine or fluorine.

7. A medicament according to any preceding claim, in which (B) is a compound selected from the group consisting of beclamethasone dipropionate, budesonide, fluticasone propionate, mometasone furoate, ciclesonide, triamcinolone acetonide, flunisolide, rofleponide palmitate, butixocort propionate, icometasone enbutate,

8. A medicament according to any one of claims 1 to 6, in which (B) is a compound of formula XII

where T is a monovalent cyclic organic group having from 3 to 15 atoms in the ring system.

9. A medicament according to claim 8, in which T is a 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, C1-C4-alkyl, halo-C1-C4-alkyl, Cl-C4-alkoxy, C1-C4-alkylthio, cyano or hydroxy-C1-C4-alkyl, and the heterocyclic ring being optionally fused to a benzene ring.

10. A medicament according to claim 8, in which T is a heterocyclic aromatic group having a 6-membered heterocyclic ring with one or two ring nitrogen atoms, the heterocyclic ring being unsubstituted or substituted by one or two substituents selected from halogen, cyano, hydroxyl, C1-C4-acyloxy, amino, C1-C4 alkylamino, di-(C1-C4-alkyl)amino, C1-C4-alkyl, hydroxy-C1-C4-alkyl, halo-C1-C4-alkyl C1-C4-alkoxy, or C1-C4-alkylthio and the heterocyclic ring being optionally fused to a benzene ring.

11. A medicament according to claim 8 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.

12. A medicament according to any preceding claim, which is in inhalable form and is (i) an aerosol comprising a mixture of (A) and (B) in solution or dispersion in a propellant; or (ii) 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; or (iii) a nebulizable composition comprising a dispersion of (A) and (B) in an aqueous, organic or aqueous/organic medium; or (iv) a combination of a dispersion of (A) in an aqueous, organic or aqueous/organic medium with a dispersion of (B) in an aqueous, organic or aqueous/organic medium.

13. A medicament according to any one of claims 1 to 11, in which (A) and/or (B) are present in inhalable form as a dry powder comprising finely divided (A) and/or (B) optionally together with at least one particulate pharmaceutically acceptable carrier.

14. A medicament according to claim 12 or 13, in which (A) and/or (B) has an average particle diameter up to 10 µm.

15. A medicament according to any one of the preceding claims, in which the molar ratio of (A) to (B) is from 5:1 to 1:10.

16. A medicament according to claim 2, which is a dry powder in a capsule, the capsule containing a unit dose of (A), a unit dose of (B) and a pharmaceutically acceptable carrier in an amount to bring the total weight of dry powder per capsule to between 5 mg and 50 mg; or a dry powder comprising, by weight, from 20-2000 parts of (A) in the form of the maleate salt, from 25-800 parts of (B) and 2000-25000 parts of a pharmaceutically acceptable carrier; or an aerosol comprising (A) and (B) in a ratio as hereinbefore specified in claim 1 or 15, in a propellant, optionally together with a surfactant and/or a bulking agent and/or a co-solvent suitable 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.

17. The use of (A) as defined in any preceding claim and (B) as defined in any preceding claim 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.

18. The use according to claim 17, in which the inflammatory or obstructive airways disease is asthma or chronic obstructive pulmonary disease.

19. A pharmaceutical kit comprising (A) as defined in any one of claims 1, 3, 4 and 5 and (B) as defined in any one of claims 1, 6, 7, 8, 9, 10 and 11 in separate unit dosage forms, said forms being suitable for administration of (A) and (B) in effective amounts, together with one or more inhalation devices for administration of (A) and (B).

20. A medicament comprising, separately or together, (A) a compound of formula I as defined in claim; and (B) a corticosteroid, for simultaneous, sequential or separate administration in the treatment of an inflammatory or obstructive airways disease, substantially as herein described with reference to any one of the Examples.