MXPA06008966A - 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

COMBINATION OF AGRONISTS ADRENOCEPTORES OF BENZOTIAZOL-2-ONA BETA2 AND CORTICOSTEROIDES FOR THE TREATMENT OF RESPIRATORY DISEASES DESCRIPTION OF THE INVENTION This invention relates to organic compounds and their use as pharmaceuticals, in particular for the treatment of inflammatory or obstructive diseases of the respiratory tract. In one aspect, the present invention provides 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 -Ra-Y; Ar means a phenylene group optionally substituted by halo, hydroxy, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms-alkyl of 1 to 10 carbon atoms, phenyl, alkyl of 1 to 10 carbon atoms substituted by phenyl, alkoxy of 1 to 10 carbon atoms substituted by phenyl, alkyl of 1 to 10 carbon atoms-substituted phenyl or by alkoxy of 1 to 10 carbon atoms substituted phenyl; R1 and R2 are attached to the adjacent carbon atoms in AR, and either R1 is alkylene of 1 to 10 carbon atoms and R2 is hydrogen, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms. carbon or halogen, or R1 and R2, together with the carbon atoms in Ar to which they are attached, mean a cycloaliphatic ring of 5, 6 or 7 members; Ra is a bond or alkylene of 1 to 10 carbon atoms optionally substituted by hydroxy, alkoxy of 1 to 10 carbon atoms, aryl of 6 to 10 carbon atoms, or aralkyl of 7 to 14 carbon atoms; and Y is alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, or alkynyl of 2 to 10 carbon atoms optionally substituted by halo, cyano, hydroxy, alkyl from 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or haloalkyl of 1 to 10 carbon atoms; cycloalkyl of 3 to 10 carbon atoms optionally fused with one or more benzene rings, and optionally substituted by alkyl of 1 to 10 carbon atoms, alkoxyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, aralkyl of 7 to 14 carbon atoms, aralkyloxy of 7 to 14 carbon atoms, or aryl of 6 to 10 carbon atoms, wherein cycloalkyl of 3 to 10 carbon atoms, aralkyl of 7 to 14 carbon atoms, aralkyloxy of 7 to 14 carbon atoms, or aryl of 6 to 10 carbon atoms are optionally substituted by halo, hydroxy, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or haloalkyl of 1 to 10 carbon atoms; aryl of 6 to 10 carbon atoms optionally substituted by halo, hydroxy, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, haloalkyl of 1 to 10 carbon atoms, phenoxy, alkylthio of 1 to 10 carbon atoms, aryl of 6 to 10 carbon atoms, heterocyclic ring of 4 to 10 members having at least one nitrogen, oxygen or sulfur atom of the ring, or by NRbRc, wherein Rb and Rc are each independently alkyl of 1 to 10 carbon atoms optionally substituted by hydroxy, alkoxy of 1 to 10 carbon atoms, or phenyl, or Rb may additionally be hydrogen; phenoxy optionally substituted by alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or by phenyl optionally substituted by alkyl of 1 to 10 carbon atoms or alkoxy of 1 to 10 carbon atoms; a heterocyclic ring of 4 to 10 members having at least one nitrogen, oxygen, or sulfur atom of the ring, this heterocyclic ring being optionally substituted by halo, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 atoms of carbon, halo-alkyl of 1 to 10 carbon atoms, aryl of 6 to 10 carbon atoms, aralkyl of 7 to 14 carbon atoms, aralkyloxy of 7 to 14 carbon atoms, alkoxycarbonyl of 1 to 10 carbon atoms, or a heterocyclyl of 4 to 1 0 members-alkyl of 1 to 10 carbon atoms; -NRdRe, where Rd is hydrogen or alkyl of 1 to 10 carbon atoms and Re is alkyl of 1 to 10 carbon atoms optionally substituted by hydroxy, or Re is aryl of 6 to 10 carbon atoms optionally substituted by halo , or Re is a 4- to 10-membered heterocyclic ring having at least one nitrogen, oxygen or ring sulfur atom, which ring is optionally substituted by phenyl or phenyl substituted by halo, or Re is aryisulfonyl of 6 to 10 atoms carbon optionally substituted by alkylamino of 1 to 10 carbon atoms or di (amino) of 1 to 10 carbon atoms) amino; -SRf, wherein Rf is aryl of 6 to 10 carbon atoms or aralkyl of 7 to 14 carbon atoms optionally substituted by halo, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or haloalkyl of 1 to 10 carbon atoms; or -CONHR9, wherein R9 is alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, or aryl of 6 to 10 carbon atoms; and (B) a corticosteroid, for simultaneous, sequential, or separate administration in the treatment of an inflammatory or obstructive airway disease, the molar ratio being (A) to (B) from 1 00: 1 to 1: 300 In another aspect, the present invention provides a pharmaceutical composition comprising a mixture of effective amounts of (A) as defined hereinbefore, and (B) as defined hereinabove, optionally together with at least one carrier pharmaceutically acceptable.

In a further aspect, the present invention provides a method for the treatment of an inflammatory or obstructive airway disease, which comprises administering to a subject in need of such treatment, effective amounts of (A) as defined above in present, and (B) as defined hereinbefore. The invention further provides the use of (A) as defined hereinbefore, and (B) as defined hereinbefore, in the preparation of a medicament for combination therapy, by simultaneous administration, in sequence, or separated from (A) and (B) in the treatment of an inflammatory or obstructive airway disease. The terms used in the specification have the following meanings: "Optionally substituted", as used herein, means that the referred group may be substituted in one or more positions by any or any combination of the radicals listed below. "Halo" or "halogen", as used herein, means an element belonging to group 17 (formerly group VII) of the Periodic Table of the Elements, which can be, for example, fluorine, chlorine, bromine or iodine. Preferably, halo or halogen is fluorine or chlorine. "Alkyl of 1 to 10 carbon atoms", as used herein, means straight or branched chain alkyl containing from 1 to 10 carbon atoms. Preferably, alkyl of 1 to 10 carbon atoms is alkyl of 1 to 4 carbon atoms. "Alkylene of 1 to 10 carbon atoms", as used herein, means a straight or branched chain alkylene containing from one to ten carbon atoms. Preferably, alkylene of 1 to 10 carbon atoms is alkylene of 1 to 4 carbon atoms, especially ethylene or methyl ethylene. "C 2 -C 10 alkenyl", as used herein, means straight or branched chain hydrocarbon chains containing 2 to 10 carbon atoms, and one or more carbon-carbon double bonds. Preferably, "alkenyl of 2 to 10 carbon atoms" is "alkenyl of 2 to 4 carbon atoms". "Alkynyl of 2 to 10 carbon atoms", as used herein, means straight or branched chain hydrocarbon chains containing from 2 to 10 carbon atoms, and one or more triple carbon-carbon bonds. Preferably "2 to 10 carbon atoms alkynyl" is "alkynyl of 2 to 4 carbon atoms". "Cycloalkyl of 3 to 10 carbon atoms", as used herein, means cycloalkyl having from 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 may be substituted by one or more, usually one or two alkyl groups of 1 to 4 carbon atoms, or a bicyclic group such as bicycloheptyl or bicyclooctyl. Preferably, cycloalkyl of 3 to 10 carbon atoms is cycloalkyl of 3 to 6 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. "Haloalkyl of 1 to 10 carbon atoms", as used herein, means alkyl of 1 to 10 carbon atoms as defined hereinbefore, substituted by one or more halogen atoms, preferably, two or three halogen atoms. "Alkylamino of 1 to 10 carbon atoms" and "di- (alkyl of 1 to 10 carbon atoms) -amino", as used herein, means amino substituted respectively by one or two alkyl groups of 1 to 10 atoms carbon as defined above herein, which may be the same or different. Preferably, alkylamino of 1 to 10 carbon atoms and di- (alkyl of 1 to 10 carbon atoms) -amino, are respectively alkylamino of 1 to 4 carbon atoms and di- (alkyl of 1 to 4 carbon atoms) -Not me. "Alkylthio of 1 to 10 carbon atoms", as used herein, means straight or branched chain alkylthio having from 1 to 10 carbon atoms. Preferably, alkylthio of 1 to 10 carbon atoms is alkylthio of 1 to 4 carbon atoms. "Alkoxy of 1 to 10 carbon atoms", as used herein, means straight or branched chain alkoxy containing from 1 to 10 carbon atoms. Preferably, alkoxy of 1 to 10 carbon atoms is alkoxy of 1 to 4 carbon atoms. "Alkoxy of 1 to 10 carbon atoms-alkyl of 1 to 10 carbon atoms", as used herein, means alkyl of 1 to 10 carbon atoms as defined hereinabove, substituted by alkoxy of 1 to 10 carbon atoms. Preferably, alkoxy of 1 to 10 carbon atoms-alkyl of 1 to 10 carbon atoms is alkoxy of 1 to 4 carbon atoms-alkyl of 1 to 4 carbon atoms. "Alkoxycarbonyl of 1 to 10 carbon atoms", as used herein, means alkoxy of 1 to 10 carbon atoms as defined hereinbefore, linked through an oxygen atom thereof with a carbonyl group. "Aryl of 6 to 10 carbon atoms", as used herein, means a monovalent carbocyclic aromatic group containing from 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, aryl of 6 to 10 carbon atoms is aryl of 6 to 8 carbon atoms, especially phenyl. "Aryiisulfonyl of 6 to 10 carbon atoms", as used herein, means aryl of 6 to 10 carbon atoms as defined hereinbefore, linked through a carbon atom thereof with a sulfonyl group. Preferably, arylsulfonyl of 6 to 10 carbon atoms is arylsulfonyl of 6 to 8 carbon atoms. "Aralkyl of 7 to 14 carbon atoms", as used herein, means alkyl, for example alkyl of 1 to 4 carbon atoms as defined hereinabove, substituted by aryl, eg aryl of 6 to 1. 0 carbon atoms as defined above in the present. Preferably, aralkyl of 7 to 14 carbon atoms is aralkyl of 7 to 10 carbon atoms, such as phenyl-alkyl of 1 to 4 carbon atoms, in particular benzyl or 2-phenylethyl. "Aralkyloxy of 7 to 14 carbon atoms", as used herein, means alkoxy, for example, alkoxy of 1 to 4 carbon atoms as defined hereinabove, substituted by aryl, for example aryl of 6 to 1. 0 carbon atoms. Preferably, aralkyloxy of 7 to 14 carbon atoms is aralkyloxy of 7 to 10 carbon atoms, such as phenyl-alkoxy of 1 to 4 carbon atoms, in particular 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, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms. carbon, alkoxy of 1 to 10 carbon atoms-alkyl of 1 to 10 carbon atoms, phenyl, or alkyl of 1 to 10 carbon atoms substituted by phenyl, alkoxy of 1 to 10 carbon atoms substituted by phenyl, 1 to 10 carbon atoms-substituted phenyl and alkoxy of 1 to 10 carbon atoms-substituted phenyl. Preferably, Ar is phenylene which is unsubstituted or substituted by one or two substituents selected from halogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms substituted by phenyl. Preferably, a substituent on Ar is para for R1, and the second and third optional substituents on Ar are meta for R. "4 to 10 membered heterocyclic ring having at least one nitrogen, oxygen, or ring sulfur atom", as used herein, may be, for example, pyrrolo, 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, azacicioheptane, and isoxazole. "Heterocyclyl of 4 to 10 members-alkyl of 1 to 10 carbon atoms" means alkyl, for example alkyl of 1 to 10 carbon atoms as defined hereinabove, substituted by a heterocyclic ring of 4 to 10 members as is defined above in the present. Preferably, 4- to 10-membered heterocyclyl-alkyl of 1 to 10 carbon atoms is alkyl of 1 to 4 carbon atoms substituted by a 4- to 8-membered heterocyclic ring having at least one nitrogen, oxygen, or sulfur atom of the ring. "C 1 -C 4 -alkylsulfonyl" means sulfonyl substituted by alkyl of 1 to 4 carbon atoms as defined hereinbefore. "Hydroxy-alkyl of 1 to 4 carbon atoms" means alkyl of 1 to 4 carbon atoms as defined hereinbefore, substituted by one or more, preferably one, two or three hydroxy groups. R1 and R2, together with the carbon atoms with which they are attached as a cycloaliphatic ring, can be, for example, a cyclopentane ring, optionally substituted by one or two alkyl groups of 1 to 4 carbon atoms; a cydohexane ring, optionally substituted by one or two alkyl groups of 1 to 4 carbon atoms; 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 -R1-Ar-R2 or -Ra-Y; Ar means a phenylene group optionally substituted by halo, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or by alkoxy of 1 to 10 carbon atoms substituted by phenyl; R1 and R2 are attached to the adjacent carbon atoms in Ar, and either R1 is alkylene of 1 to 10 carbon atoms and R2 is hydrogen, or R1 and R2, together with the carbon atoms in Ar with which they are united, they mean a cycloaliphatic ring of 5, 6 or 7 members; Ra is a bond or alkylene of 1 to 10 carbon atoms optionally substituted by hydroxy, aryl of 6 to 10 carbon atoms 0 aralkyl of 7 to 14 carbon atoms; and Y is alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or alkynyl of 2 to 10 carbon atoms; cycloalkyl of 3 to 10 carbon atoms optionally fused with one or more benzene rings, and optionally substituted with alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, aralkyl of 7 to 14 carbon atoms, aralkyloxy of 7 to 14 carbon atoms optionally substituted by halo, or aryl of 6 to 10 carbon atoms. carbon optionally substituted by alkyl of 1 to 10 carbon atoms or alkoxy of 1 to 10 carbon atoms; aryl of 6 to 10 carbon atoms optionally substituted by halo, hydroxy, alkyl of 1 to 10 carbon atoms, phenoxy, alkylthio of 1 to 10 carbon atoms, aryl of 6 to 10 carbon atoms, a heterocyclic ring of 4 to 10 members having at least one nitrogen atom of the ring, or by NRbRc, wherein Rb and Rc are each independently alkyl of 1 to 10 carbon atoms optionally substituted by hydroxy or phenyl, or Rb may additionally be hydrogen; phenoxy optionally substituted by alkoxy of 1 to 10 carbon atoms; a 4- to 10-membered heterocyclic ring having at least one nitrogen or oxygen atom of the ring, this heterocyclic ring being optionally substituted by alkyl of 1 to 10 carbon atoms, aryl of 6 to 10 carbon atoms, aralkyl of 7 to 14 carbon atoms, alkoxycarbonyl of 1 to 10 carbon atoms, or a heterocyclyl of 4 to 10 alkyl-members of 1 to 10 carbon atoms; -NRdRβ, wherein R is hydrogen or alkyl of 1 to 10 carbon atoms, and Re is alkyl of 1 to 10 carbon atoms, or Re is a 4 to 10 membered heterocyclic ring having at least one nitrogen atom or oxygen of the ring, which ring is optionally substituted by phenyl substituted by halo, or Re is arylsulfonyl of 6 to 10 carbon atoms optionally substituted by di- (alkyl of 1 to 10 carbon atoms) -amino; -SRf, wherein Rf is aryl of 6 to 10 carbon atoms or aralkyl of 7 to 14 carbon atoms optionally substituted by halo or haloalkyl of 1 to 10 carbon atoms; or -CONHR9, wherein R9 is cycloalkyl of 3 to 10 carbon atoms or aryl of 6 to 10 carbon atoms. Especially preferred compounds of formula I in free or salt or solvate form, include those wherein: X is -R1-Ar-R2 or -Ra-Y; Ar means a phenylene group optionally substituted by halo, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or by alkoxy of 1 to 4 carbon atoms substituted by phenyl; R1 and R2 are attached to the adjacent carbon atoms in Ar, and either R1 is alkylene of 1 to 4 carbon atoms and R2 is hydrogen, or R1 and R2, together with the carbon atoms in Ar with which they are joined, they mean a cycloaliphatic ring of 5, 6 or 7 members, especially a 5-membered cycloaliphatic ring; Ra is a bond or alkylene of 1 to 4 carbon atoms optionally substituted by hydroxy, aryl of 6 to 8 carbon atoms, or aralkyl of 7 to 10 carbon atoms; and Y is alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or alkynyl of 2 to 4 carbon atoms; cycloalkyl of 3 to 6 carbon atoms optionally fused to one or more benzene rings, and optionally substituted by alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aralkyl of 7 to 10 carbon atoms, aralkyloxy from 7 to 10 carbon atoms optionally substituted by halo, or by aryl of 6 to 8 carbon atoms optionally substituted by alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms; aryl of 6 to 8 carbon atoms optionally substituted by halo, hydroxy, alkyl of 1 to 4 carbon atoms, phenoxy, alkylthio of 1 to 4 carbon atoms, aryl of 6 to 8 carbon atoms, a heterocyclic ring of 4 to 8 members having at least one nitrogen atom of the ring, or by NRbRc, wherein Rb and RG are each independently alkyl of 1 to 4 carbon atoms optionally substituted by hydroxy or phenyl, or Rb may additionally be hydrogen; phenoxy optionally substituted by alkoxy of 1 to 4 carbon atoms; a 4- to 8-membered heterocyclic ring having at least one nitrogen atom or ring oxygen, this heterocyclic ring being optionally substituted by alkyl of 1 to 4 carbon atoms, aryl of 6 to 8 carbon atoms, aralkyl of 7 at 1 0 carbon atoms, alkoxycarbonyl of 1 to 4 carbon atoms, or a heterocyclyl of 4 to 8 members-alkyl of 1 to 4 carbon atoms; -NRdRe, where Rd is hydrogen or alkyl of 1 to 4 carbon atoms, and Re is alkyl of 1 to 4 carbon atoms, or Re is a 4 to 8 membered heterocyclic ring having at least one nitrogen atom or sulfur of the ring, which ring is optionally substituted by phenyl substituted by halo, or Re is aryisulfonyl of 6 to 8 carbon atoms optionally substituted by di- (alkyl of 1 to 10 carbon atoms) -amino; -SRf, wherein Rf is aryl of 6 to 8 carbon atoms or aralkyl of 7 to 10 carbon atoms optionally substituted by halogen or haloalkyl of 1 to 4 carbon atoms; or -CONHR9, wherein R9 is cycloalkyl of 3 to 6 carbon atoms or aryl of 6 to 8 carbon atoms. More especially preferred compounds of formula I in free or salt or solvate form include: 4-hydroxy-7- (1-hydroxy-2-. {2- 2- [4- (4-phenyl-butoxy) -phenyl] - ethylamino) -ethyl) -3H-benzo-tiazol-2-one; 7 - [(R) -2- (1,1-dimethyl-2-phenyl-ethyl-amino) -1-hydroxy-ethyl] -4-hydroxy-3H-benzothiazol-2-one; 4-hydroxy-7- formate. { (R) -1-Hydroxy-2- [2- (5,6,7,8-tetrahydro-naphthalen-2-yl) -ethylamino] -ethyl} -3H-benzothiazol-2-one; 7 - [(R) -2 - ((1S, 2S) -2-benzyloxy-cyclopentylamino) -1-hydroxy-ethy1-] -4-hydroxy-3H-benzothiazol-2-one; and 7 - [(R) -2 - ((1 S, 2R) -2-benzyloxy-cyclopentylamino) -1-hydroxy-ethyI] -4-hydroxy-3H-benzothiazol-2-one. In formula I, the alpha carbon atom for the phenolic ring carries a hydroxy group, and is thus asymmetric, so that the compound exists in individual optically active isomeric forms, or as mixtures thereof, for example as mixtures racemic or diastereomeric. The compounds of formula I encompass both the individual optically active R and S isomers and mixtures, for example racemic or diastereomeric mixtures thereof. The pharmaceutically acceptable acid addition salts of the compound of formula I include those of inorganic acids, for example hydrohalic acids, such as hydrophobic acid, hydrochloric acid, hydrobromic acid, or hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid; and organic acids, for example aliphatic monocarboxylic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, and butyric acid; aliphatic hydroxy acids, such as lactic acid, citric acid, tartaric acid, or malic acid; dicarboxylic acids, such as maleic acid or succinic acid; aromatic carboxylic acids, such as benzoic acid, p-chlorobenzoic acid, diphenylacetic acid, or triphenylacetic acid; aromatic hydroxy acids, such as o-hydroxybenzoic acid, p-hydroxybenzoic acid, 1-hydroxynaphthalene-2-carboxylic acid, or 3-hydroxynaphthalene-2-carboxylic acid; and sulfonic acids, such as methanesulfonic acid or benzenesulfonic acid. These salts can be prepared from the compounds of formula I by known salt formation methods. The pharmaceutically acceptable solvates are in general hydrates. The compounds of formula I in free or salt or solvate form can also be prepared by: (i) either (A) reacting a compound of formula II: wherein X is as defined hereinabove, and R7 signifies a protective group to replace R7 with hydrogen, or (B) react a compound of formula I11: wherein X and R7 are as defined hereinabove, and R8 and R9 each independently signify a protecting group, to convert the groups R7, R8 and R9 to hydrogen; and (ii) recovering the compound of formula I in free or salt or solvate form. When reference is made herein to protected functional groups or protecting groups, the protecting groups can be selected according to 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, whose reference also describes the proper procedures for the replacement of hydrogen protecting groups. The protecting group R7 can be, for example, a group selected from the known amine protecting groups.

Preferred R7 protecting groups include araliphatic groups, such as benzyl and trialkylsyl, for example trlmethylsilyl. The protecting groups R8 and R9 can be selected from the protective groups of phenolic hydroxy and hydroxy alcohol, respectively. Preferred groups R8 and R9 include alkyl groups of 1 to 4 carbon atoms, in particular branched groups, such as isopropyl and tert-butyl. The process variant (A) can be carried out, for example, using known procedures for the conversion of the amine protecting groups to hydrogen, or analogous processes. For example, when R7 is a benzyl group, it can be converted to hydrogen by hydrogenolysis of the compound of formula I I, for example with a carboxylic acid, such as formic acid, preferably in the presence of a palladium catalyst. This deprotection reaction can be carried out using the methods described hereinafter in the Examples, or analogous procedures. The process variant (B) can be carried out using known procedures for the conversion of hydroxy-to-hydrogen protecting groups, or analogous processes. For example, when R8 and R9 are alkyl groups, R8 and R9 can be converted to hydrogen by hydrogenolysis of the compounds of formula IV, for example with a carboxylic acid, such as formic acid, preferably in the presence of a palladium catalyst, example as described hereinabove for the conversion of R7 to hydrogen, or by its treatment with a single acid, such as formic acid, hydrochloric acid, or trifluoroacetic acid, the resulting compound being in any case 2-hydroxybenzothiazole in a tautomeric equilibrium with the benzothiazol-2-one form. The compounds of formula I I can be prepared by reducing a compound of formula IV: wherein X and R7 are as defined hereinabove. The reduction can be effected using known methods for the reduction of ketones to alcohols, or analogous methods, including asymmetric reductions. For example, the compounds of formula IV can be reacted with NaBH 4 in an inert solvent, such as an aliphatic alcohol. Suitable reaction temperatures are from -80 ° C to 100 ° C, conveniently from -5 ° C to 5 ° C. The reduction can be effected using known procedures, or in a manner analogous to that described hereinafter in the Examples. The compounds of formula I can be prepared by the reaction of a compound of formula V: wherein R8 and R9 are as defined hereinabove, with a compound of formula VI: wherein X and R7 are as defined hereinabove. The reaction of the compounds of formulas V and VI can be carried out using known procedures for the epoxide-amine reactions, or analogous procedures. The reaction is optionally carried out in an inert organic solvent, suitably an alcohol, such as n-butanol. Suitable reaction temperatures are, for example, from 0 ° C to the reflux temperature of the solvent. The reaction can be carried out in a convenient manner using a method as described hereinafter in the Examples, or in an analogous manner. The compounds of formula IV can be prepared by the reaction of a compound of formula VI: wherein X, R7, R8, and R9 are as described hereinabove, with concentrated hydrochloric or hydrobromic acid. The reaction is preferably carried out in an inert organic solvent, such as an aliphatic alcohol. The compounds of formulas V and VI can be prepared by known methods, or in an analogous manner, as described hereinafter in the Examples. The compounds of formula VII can be prepared by the reaction of a compound of formula VII: wherein Q is fluorine or chlorine, and R8 and R9 are as defined hereinbefore, with a strong base, such as an alkyl lithium, NaNH2, or potassium tert-butoxide, or a mixture of two or more thereof , and a compound of formula IX: wherein X and R7 are as defined hereinabove. The reaction is preferably carried out in an inert organic solvent, for example an ether, such as tetrahydrofuran (THF).

Suitable reaction temperatures can be, for example, from -80 ° C to 80 ° C. The reaction can be carried out using a procedure as described hereinafter in the Examples, or analogous procedures. The compounds of the formulas VII, IX and IX can be prepared using known procedures, or in an analogous manner, as described hereinafter in the Examples. The compounds of formula I in free form can be converted into a salt form, and v / ceve, in a conventional manner. Compounds in free or salt form can be obtained in the form of hydrates or solvates containing a solvent used for crystallization. The compounds of formula I can be recovered from the reaction mixtures, and can be purified in a conventional manner. Isomers, such as enantiomers, can be obtained in a conventional manner, for example by fractional crystallization or asymmetric synthesis from the corresponding asymmetrically substituted, for example optically active starting materials. For example, the corticosteroid (B) can be a compound of formula X: or a 1,2-dihydro derivative thereof, wherein: Ra is alkyl of 1 to 4 carbon atoms optionally substituted by halogen (preferably chloro or fluoro), hydroxy, alkoxy 1 to 4 carbon atoms, acyloxy, or acylthio of 1 to 4 carbon atoms; or Ra is alkoxy of 1 to 4 carbon atoms or alkylthio of 1 to 4 carbon atoms optionally substituted by halogen; or Ra is heterocyclicthio of 5 to 6 members; or Ra is alkylthio of 1 to 4 carbon atoms optionally substituted by halogen (preferably chlorine or fluorine), whether Rb is acyloxy and Rc is hydrogen or alkyl of 1 to 4 carbon atoms, or Rb and Rc together mean a group of formula XI: wherein Rd is alkyl of 1 to 4 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, and Re is hydrogen or alkyl of 1 to 4 carbon atoms, Xa and Xb are each independently hydrogen, chlorine, 0 fluorine When Ra is alkyl of 1 to 4 carbon atoms substituted by acyloxy, the acyloxy group can be, for example, alkylcarbonyloxy of 1 to 20 carbon atoms, for example acetyloxy, n-propionyloxy, isopropionyloxy, or hexadecanoyloxy, or cycloalkylcarbonyloxy of 3 to 6 carbon atoms, for example cyclohexylcarbonyloxy. When Ra is alkyl of 1 to 4 carbon atoms substituted by acylthio, the acylthio group can be, for example, alkylcarbonylthio of 1 to 4 carbon atoms, for example acetylthio or n-propionylthio. When Ra is 5- or 6-membered heterocyclylide, the heterocyclyl group can be an O-heterocyclyl group, for example a furanonyl group. When Rb is acyloxy, it can be, for example, alkylcarbonyloxy of 1 to 4 carbon atoms, for example acetyloxy, n-propionyloxy, or n-butyroyloxy; cycloalkylcarbonyloxy having from 3 to 6 carbon atoms, for example cyclopropylcarbonyloxy, or 5- or 6-membered heterocyclylcarbonyloxy, for example furoyloxy; or when Rb is acyloxy, it can 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 heteroatoms selected from nitrogen, oxygen and sulfur. When R ° is alkyl of 1 to 4 carbon atoms, it may be in the alpha or beta conformation, more usually in the alpha conformation. When Rb and Rc together denote a group of formula XI, Rd as cycloalkyl of 3 to 6 carbon atoms can be, for example, cyclohexyl. The corticosteroids of formula X and its 1,2-dihydro derivatives include beclamethasone dipropionate, budesonide, fluticasone propionate, mometasone furoate, ciclesonide, triamcinolone acetonide, flunisolide, rhophyponide palmitate, butycocort propionate, icometasone enbutate, and as described in WO 03/042229, WO 03/035668, WO 02/100879, WO 02/088167. In the particularly preferred embodiments of the invention, the corticosteroid (B) is budesonide, futicasone propionate, mometasone furoate, or any of the following compounds: Budesonide, fluticasone propionate and mometasone furoate and their preparation are described in the specifications of US Pat. Nos. 3929768, US 4335121 and US 4472393, respectively. Corticosteroids of formula X, wherein Rb is -O-CO-T, are preferably compounds of formula XI I: XII wherein 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 heteroatoms selected from nitrogen, oxygen and sulfur. In one embodiment, T is a cycloaliphatic group having from 3 to 8 carbon atoms, for example cycloalkyl of 3 to 8 carbon atoms, such as cyclopropyl, methylcyclopropyl, cyclobutyl, methylcyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexyl, dimethylcyclohexyl or cycloheptyl, preferably cycloalkyl of 3 to 6 carbon atoms. In another embodiment, T is an at least partially saturated heterocyclic group having from 5 to 10 ring atoms, of which one or more are ring heteroatoms selected from nitrogen, oxygen, and sulfur, preferably having from 5 to 7 ring atoms, of which one or two are heteroatoms selected from nitrogen and oxygen, especially a 5-membered heterocyclic group having a ring heteroatom, such as a tetrahydrofuryl or oxotetrahydrofuryl group. In a further embodiment, T is a carbocyclic or heterocyclic aromatic group having from 5 to 15 atoms in the ring system. For example, T may be an aromatic group in which the ring system is unsubstituted or is substituted by one or more substituents selected from halogen, cyano, alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 atoms carbon, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, hydroxy, acyl of 1 to 4 carbon atoms, acyloxy of 1 to 4 carbon atoms, amino, alkylamine of 1 to 4 carbon atoms carbon, di- (alkyl of 1 to 4 carbon atoms) -amino, acylamino 1 to 4 carbon atoms, acyl of 1 to 4 carbon atoms- (alkyl of 1 to 4 carbon atoms) -amino, alkylsulfonyl of 1 to 4 carbon atoms- (alkyl of 1 to 4 carbon atoms) -amino, alkoxycarbonyl of 1 to 4 carbon atoms, or 5-membered heterocyclyl, usually N-heterocyclyl having one or two nitrogen atoms. A preferred class of these aromatic groups is phenyl or naphthyl optionally substituted by one or more, preferably one, two or three substituents selected from cyano, alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms , alkoxy of 1 to 4 carbon atoms, halogen, hydroxy, acyloxy of 1 to 4 carbon atoms, amino, alkylamino of 1 to 4 carbon atoms, di-alkylamino of 1 to 4 carbon atoms, acyl of 1 to 4 carbon-amino atoms, acyl of 1 to 4 carbon atoms- (alkyl of 1 to 4 carbon atoms) -amino, alkylsulfonyl of 1 to 4 carbon atoms- (alkyl of 1 to 4 carbon atoms) -amino, or alkoxycarbonyl of 1 to 4 carbon atoms, including these especially preferred aromatic groups to phenyl, cyanophenyl, tolyl, dimethylphenyl, ethylphenyl, (trifluoromethyl) -phenyl, dimethoxyphenyl, diethoxyphenyl, hydroxyphenyl, (methylamino) -phenyl, (methanesulfonylmethylamino) -phenyl, and (methoxycarbonyl) -phenyl. Another preferred class of these 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, hydroxy, acyloxy of 1 to 4 carbon atoms, amino, alkyl of 1 to 4 carbon atoms-amino, di- (alkyl of 1 to 4 carbon atoms) -amino, alkyl from 1 to 4 carbon atoms, hydroxy-alkyl of 1 to 4 carbon atomshaloalkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or alkylthio of 1 to 4 carbon atoms, and the heterocyclic ring optionally being fused to a benzene ring. Preferred 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 the pyridyl, pyrimidinyl and pyrazinyl groups, optionally substituted by one or two substituents selected from halogen (in particular chlorine) or alkyl of 1 to 4 carbon atoms (especially methyl or n-butyl). Another preferred class of these aromatic groups is a heterocyclic aromatic group having a 5-membered heterocyclic ring with one, two or three ring heteroatoms selected from nitrogen, oxygen, and sulfur, the heterocyclic ring being unsubstituted or substituted by one or two substituents selected from halogen, alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, cyano, or hydroxy -alkyl of 1 to 4 carbon atoms, and the heterocyclic ring optionally being fused with a benzene ring. Preferred heterocyclic aromatic groups include those in which the heterocyclic ring has a nitrogen, oxygen, or sulfur atom in the ring, or an oxygen atom and one or two nitrogen atoms in the ring, or a sulfur atom and one or two nitrogen atoms in the ring, especially a ring of pyrrolo, furan, thiophene, oxazole, isoxazole, imidazole, pyrazole, furazane, thiazole or thiadiazole. Especially preferred heterocyclic aromatic groups are the pyrrolyl, furyl and thienyl groups optionally substituted by one or two substituents selected from halogen (in particular chlorine or bromine), alkyl of 1 to 4 carbon atoms (in particular methyl or ethyl), haloalkyl of 1 to 4 carbon atoms (in particular trifluoromethyl), alkoxy of 1 to 4 carbon atoms (in particular methoxy), alkylthio of 1 to 4 carbon atoms (in particular methylthio), cyano or hydroxy -alkyl of 1 to 4 carbon atoms (in particular hydroxymethyl); isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, or thiadiazolyl groups optionally substituted by one or two alkyl groups of 1 to 4 carbon atoms; and benzofuryl, benzothienyl and benzofurazanyl groups. In the compounds of formula XI I, the methyl group indicated at position 16 of the corticosteroid ring system may be in the alpha or beta position. The 16-a-methyl compounds are preferred. Especially preferred compounds of formula XI I are those in which 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-dimethy-2-thienyl, 2,5-dimethyl-3-furyl, 4-methyl-2-furyl, - (dimethylamino) -phenyl, 4-methy1phenyl, 4-ethylphenyl, 2-pyridyl, 4-pyrimidyl, or 5-methyl-2-pyrazinyl, or the indicated 16-methyl group has the beta conformation and R is cyclopropyl. The compounds of formula XI I and their salts, wherein T contains a basic group, can be prepared using the procedures described in International Patent Application WO 02/00679. The corticosteroid (B), for example, can also be a non-steroidal glucocorticoid receptor agonist, such as those described in DE 1 0261874, WO 00/00531, WO 02/10143, WO 03/82280, WO 03 / 82787, WO 03/86294, WO 03/104195, WO 03/1 01 932, WO 04/05229, WO 04/1 8429, WO 04/19935 and WO 04/26248. The medicament of the present invention may additionally contain one or more AA2 agonists, A2B antagonists, antihistamines, caspase inhibitors, LTB4 antagonists, LTD4 antagonists, M3 antagonists, and PDE inhibitors, or anti-tussive drug substances. Suitable A2A agonists include those described in EP 409595A2, EP 1 052264, EP 1241 176, WO 94/17090, WO 96/02543, WO 96/02553, WO 98/28319, WO 99/24449, WO 99/24450 , WO 99/24451, WO 99/38877, WO 99/41267, WO 99/67263, WO 99/67264, WO 99/67265, WO 99/67266, WO 00/23457, WO 00/7701 8, WO 00 / 78774, WO 01/23999, WO 01/27130, WO 01/27131, WO 01/60835, WO 01/94368, WO 02/00676, WO 02/22630, WO 02/96462, WO 03/086408, WO 04 / 039762, WO 04/039766, WO 04/045618, and WO 04/046083. Suitable A2B antagonists include those described in WO 02/42298. Suitable antihistamine drug substances include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine, diphenhydramine and fexofenadine hydrochloride, activastin, astemizole, azelastine, ebastine, epinastine, mizolastine and tefenadine, as well as those given to know in JP 2004107299, WO 03/099807 and WO 04/026841. Suitable caspase inhibitors, including inhibitors of the interleukin-1 (ICE) converting enzyme P, include those disclosed in Canadian Patent Specification Number 21 09646, EP 519748, EP 547,699, EP 590,650, EP 628550 EP 644, 1 97; EP 6441 98, WO 93/05071, WO 93/14777, WO 93/1671 0, WO 94/00154, WO 94/03480, WO 94/21673, WO 95/05152, WO 95/35308, WO 97/2261 8, WO 97/2261 9, WO 98/41232, WO 99/06367, WO 99/65451, WO 01/1 19373, US 541 1985, US 5416013, US 5430128, US 5434248, US 5565430, US 5585357, US 5656627, US 5677283, US 6054487, US 6531474, US 20030096737, GB 2,278,276, as well as those described in international patent applications WO 98/10778, WO 98/1 1 109, WO 98/1 1 129 and WO 03/3291 8. Suitable LTB4 antagonists include those described in US 5451700. Suitable LTD4 antagonists include montelukast 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, WO 02/00652, WO 02 / 51841, WO 02/53564, WO 03/00840, WO 03/33495, WO 03/53966, WO 03/87094, WO 04/018422, WO 04/05285 and WO 04/96800, preferably the compounds of the examples of the same. The M3 antagonist is more preferably ipratropium bromide, oxitropium bromide, or a tiotropium salt. The M3 antagonist can also be a beta-2 adrenoceptor agonist / double 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-1294A (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plow), Arofylline (Almirall Prodesfarma), PD189659 / PD1 68787 (Parke-Davis), AWD-12-281 (Asta Medica), CDC-801 (Ceigene), SelCID (TM) CC-10004 (Celgene), VM554 / UM565 (Vernalis), T-440 (Tanabe), KW -4490 (Kyowa Hakko Kogyo), and those described 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 03/104205, WO 03/39544, WO 04/000814, WO 04/000839, WO 04/005258, WO 04/018450, WO 04/018451, WO 04/01 8457, WO 04/01 8465, WO 04/018431 , WO 04/018449, WO 04/018450, WO 04/018451, WO 04/018457, WO 04/018465, WO 04/019944, WO 04/019945, WO 04/045607 and WO 04/037805. Although the medicament of the invention contains a compound of formula I possessing a beta-2 adrenoceptor agonist activity, the medicament may additionally contain another beta-2 adrenoceptor agonist. Additional suitable beta-2 adrenoceptor agonists are albuterol (salbutamol), metaproterenol, terbutaline, salmeterol, fenoterol, procaterol, and especially, formoterol, carmoterol, and pharmaceutically acceptable salts thereof, and the compounds (in free or salt form) or solvate) of formula I of WO 00751 14, which document is incorporated herein by reference, preferably the compounds of the examples thereof, especially a compound of the formula: and pharmaceutically acceptable salts thereof, as well as the compounds of EP 1440966, JP 05025045, WO 93/1 8007, WO 99/64035, US 2002/0055651, WO 01/42193, WO 01/83462, WO 02/66422. , WO 02/70490, WO 02/76933, WO 03/24439, WO 03/42160, WO 03/42164, WO 03/72539, WO 03/91204, WO 03/99764, WO 04/16578, WO 04/22547. , WO 04/32921, WO 04/33412, WO 04/37768, WO 04/37773, WO 04/37807, WO 04/39762, WO 04/39766, WO 04/4561 8, WO 04/46083 and WO 04 / 80964 The administration of the medicament or the pharmaceutical composition as described hereinabove, ie, with (A) and (B) mixed or separately, is preferably by inhalation, ie, (A) and (B) are in an inhalable form. The inhalable form of the medicament can be, for example, a sprayable composition, such as an aerosol comprising the active ingredient, ie, (A) and (B) separately or mixed, 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 can 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 this medium, with a dispersion of (B) in this medium. An aerosol composition suitable for use as the inflatable form of the medicament may comprise the active ingredient in solution or dispersion in a propellant, which may be selected from any of the propellants known in the art. Known propellants include hydrocarbons, such as normal propane, normal butane, or sobutane, or mixtures of two or more of these hydrocarbons, and hydrocarbons substituted by halogen, for example methane, ethane, propane, butane, cyclopropane, or cyclobutane substituted by chlorine and / or fluorine, such as dichlorodifluoromethane (CFC-12), trichlorofluoromethane (CFC1 1), 1,2-dichloro-1,1, 2,2-tetrafluoroethane (CFC1 14), or in particular, 1, 1, 1 , 2-tetrafluoroethane (HFA134a) and 1, 1, 1, 2,3,3,3-heptafluoropropane (HFA227), or mixtures of two or more of these hydrocarbons substituted by halogen. When the active ingredient is present in suspension in the propellant, that is, when it is present in a particulate form dispersed in the propellant, the aerosol composition may also contain a lubricant and a surfactant, which may be selected from the lubricants and surfactants known in this field. Other suitable aerosol compositions include aerosol compositions devoid of surfactants or substantially devoid of surfactants. The aerosol composition can contain up to about 5 weight percent, for example from 0.0001 to 5 percent, from 0.001 to 5 percent, from 0.001 to 3 percent, from 0.001 to 2 percent, from 0.001 to 1 percent. percent, from 0.001 to 0.1 percent, or from 0.001 to 0.01 percent by weight of the active ingredient, based on the weight of the propellant. When present, the lubricant and the surfactant may be in an amount of up to 5 percent and 0.5 percent, respectively, by weight of the aerosol composition. The aerosol composition may also contain a co-solvent, such as ethanol, in an amount of up to 30 percent by weight of the composition, in particular to be administered from a pressurized 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 percent, usually from 0.001 to 1 per 100 percent by weight of the composition. In another embodiment of the invention, the inhalable form is a dry powder, ie, (A) and (B) are present in a dry powder comprising (A) and (B) finely divided, optionally together with at least one pharmaceutically acceptable particulate carrier, which may be one or more materials known as pharmaceutically acceptable carriers, preferably selected 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, mannitol, or sorbitol. A particularly preferred vehicle is lactose. The composition may also contain a compound that helps protect against deterioration of product performance due to moisture, for example magnesium stearate. The dry powder may be contained as unit doses in capsules, for example, gelatin or plastic, or in ampoules (for example aluminum or plastic), for use in a dry powder inhalation device, which can be a single dose or multiple dose device, preferably in dosage units of (A) and (B) together with the vehicle in amounts to bring the total weight of the powder per capsule up to 5 milligrams to 50 milligrams Alternatively, the dry powder may be contained in a reservoir of a multi-dose dry powder inhalation device adapted to supply, for example, 3 to 25 milligrams of dry powder per drive. In the form of finely divided particles of the medicament, and in the aerosol composition wherein the active ingredient is present in a particulate form, the active ingredient can have an average particle diameter of up to about 10 microns, for example 0.1 to 10 microns, preferably from 1 to 5 microns. The particulate vehicle, when present, generally has a maximum particle diameter of up to 300 microns, preferably up to 212 microns, and in a convenient manner, has an average particle diameter of 40 to 100 microns, for example 50 to 75 microns. The size of the particles of the active ingredient, and that of a particulate carrier that is present in the dry powder compositions, can be reduced to the desired level by conventional methods, for example by grinding in an air injection mill, in a ball mill, or in a vibrating mill, sieving, microprecipitation, spray drying, lyophilization, or controlled crystallization from conventional solvents or from supercritical media. The inhalable medicament can be administered using an inhalation device suitable for the inhalable form, these devices being well known in the art. Accordingly, the invention also provides a pharmaceutical product comprising a medicament or a pharmaceutical composition as described hereinabove, in an inhalable form as described hereinabove, in association with one or more inhalation devices. . In a further aspect, the invention provides an inhalation device, or a package of two or more inhalation devices, containing a medicament or a pharmaceutical composition as described hereinabove, in an inhalable form as described above in the I presented. When the inhalable form of the active ingredient is an aerosol composition, the inhalation device may be an aerosol canister provided with a valve adapted to deliver a metered dose, such as 10 to 1000 microliters, for example, 25 to 50 microliters. of the composition, i.e., a device known as a metered dose inhaler. Suitable aerosol flasks and methods for containing aerosol compositions therein under pressure are well known to those skilled in the art of inhalation therapy. For example, an aerosol composition can be administered from a coated can, for example as described in EP 0642992. When the inhalable form of the active ingredient is an aqueous, organic, or aqueous / nebulizable organic dispersion, the device Inhalation can be a known nebulizer, for example a conventional pneumatic nebulizer, such as an air injection nebulizer, or an ultrasonic nebulizer, which may contain, for example, from 1 to 50 milliliters, commonly from 1 to 10 milliliters of the dispersion; or a manual nebulizer, sometimes referred to as a soft mist or soft mist inhaler, for example an electronically controlled device, such as an AERx (Aradigm, USA) or Aerodose (Aerogen), or a mechanical device such as a RESPIMAT nebulizer (Boehringer Ingelheim), which allows to have much smaller nebulized volumes, for example 10 to 100 microliters, than conventional nebulizers. When the inhalable form of the active ingredient is the form of finely divided particles, the inhalation device can be, for example, a dry powder inhalation device adapted to deliver the dry powder from a capsule or ampoule containing a dry powder comprising a dosage unit of (A) and (B), or a multi-dose dry powder inhalation device (MDPI) adapted to deliver, for example, 3 to 25 milligrams of dry powder comprising a unit dose of (A) ) and (B) by actuation. Suitable dry powder inhalation devices are well known. For example, a suitable device for the delivery of the dry powder in an encapsulated form is that described in US 3991761, while a suitable multi-dose dry powder inhalation device is that described in WO 97/20589. The medicament of the invention is preferably a pharmaceutical composition comprising a mixture of (A) as defined hereinabove, and (B) as defined hereinabove, preferably together with at least one pharmaceutically acceptable carrier as described hereinabove. The molar ratio of the compound (A) to the steroid (B) can be, in general, from 100: 1 to 1: 300, for example from 50: 1 to 1: 1 00, or from 20: 1 to 1: 50, preferably from 10: 1 to 1: 20, more preferably from 5: 1 to 1: 10, from 3: 1 to 1: 7, or from 2: 1 to 1: 2. The compound (A) and the steroid (B) can be administered separately in the same proportion. A suitable daily dose of the compound (A), in particular as the maleate or trifluoroacetate salt, for inhalation, can be from 10 micrograms to 2,000 micrograms, for example 10 to 1,500 micrograms, from 10 to 1, 000 micrograms, preferably 20 to 800 micrograms, for example 20 to 600 micrograms or 20 to 500 micrograms. A suitable daily dose of the steroid (B) for Inhalation can be from 20 micrograms to 5,000 micrograms, for example from 20 to 4,000 micrograms, from 50 to 3,000 micrograms, from 50 to 2,000 micrograms, from 50 to 1,000 micrograms, from 50 at 500 micrograms, 50 to 400 micrograms, 50 to 300 micrograms, 50 to 200 micrograms, or 50 to 100 micrograms. When (B) is budesonide, a suitable daily dose may be from 25 to 4,800 micrograms, for example from 25 to 4,000 micrograms, from 25 to 3,200 micrograms, from 25 to 2,400 micrograms, from 25 to 1, 600 micrograms, from 50 to 4,800 micrograms, from 50 to 4,000 micrograms, from 50 to 3,200 micrograms, from 50 to 2,400 micrograms, from 50 to 1,600 micrograms, from 1,000 to 4,000 micrograms, from 100 to 3,200 micrograms, from 100 to 2,400 micrograms, from 1 00 to 1, 600 micrograms, from 1 00 to 800 micrograms, from 1 00 to 400 micrograms, from 200 to 4,000 micrograms, from 200 to 1, 600 micrograms, from 200 to 800 micrograms, from 200 to 400 micrograms, with 100 preferred at 1, 600 micrograms. When (B) is mometasone furoate, a suitable daily dose can be from 50 micrograms to 2,000 micrograms, for example from 100 to 200 micrograms, from 1 00 to 1, 600 micrograms, from 100 to 1,000 micrograms, or from 100 micrograms. to 800 micrograms, preferably 200 to 500 micrograms, for example 200 to 400 micrograms. When (B) is fluticasone propionate, a suitable daily dose for inhalation can be from 25 to 2,000 micrograms, for example from 25 to 1,500 micrograms, from 25 to 1,000 micrograms, from 25 to 500 micrograms, from 25 to 250 micrograms, from 50 to 1, 500 micrograms, from 50 to 1,000 micrograms, from 50 to 500 micrograms, from 50 to 250 micrograms, from 1,000 to 1,500 micrograms, from 1,000 to 1,000 micrograms, from 100 to 500 micrograms, from 1 00 to 250 micrograms, from 200 to 1, 500 micrograms, from 200 to 1,000 micrograms, or from 200 to 500 micrograms, with 100 to 1,000 micrograms preferred. A suitable unit dose of the compound (A), in particular as the maleate or trifluoroacetate salt, can be from 1 to 2,000 micrograms, for example from 10 to 1,500 micrograms, from 10 to 1,000 micrograms, preferably from 20 to 800 micrograms, from 20 to 600 micrograms, or 20 to 500 micrograms. An appropriate unit dose of budesonide can be from 25 to 2,400 micrograms, for example from 50 to 2,400 micrograms, from 50 to 2,000 micrograms, from 50 to 1,600 micrograms, from 50 to 800 micrograms, from 50 to 400 micrograms, from 50 at 200 micrograms, from 100 to 1, 600 micrograms, from 100 to 800 micrograms, from 100 to 400 micrograms, from 100 to 200 micrograms, from 200 to 1, 600 micrograms, from 200 to 800 micrograms, or from 200 to 400 micrograms , preferring 100 to 400 micrograms. An appropriate unit dose of mometasone furoate for inhalation may be from 25 to 2,000 micrograms, for example 50 micrograms to 1,500 micrograms, 50 to 1,000 micrograms, 50 to 800 micrograms, 50 to 400 micrograms, 50 to 200 micrograms, 50 to 1000 micrograms, 100 to 800 micrograms, 100 to 400 micrograms, or 100 to 200 micrograms, with 100 to 400 micrograms preferred. An appropriate unit dose of fluticasone propionate for inhalation may be from 25 to 1,000 micrograms, for example from 25 to 500 micrograms, from 25 to 250 micrograms, from 25 to 200 micrograms, from 50 to 1,000 micrograms, from 50 at 500 micrograms, 50 to 250 micrograms, 50 to 200 micrograms, 100 to 1,000 micrograms, 100 to 500 micrograms, 100 to 250 micrograms, 100 to 200 micrograms, 150 to 500 micrograms, or 150 to 250 micrograms, with 100 to 500 micrograms preferred. These unit doses can be administered once or twice a day, according to the daily doses mentioned hereinabove. Of course, the precise unit and the daily dose used will depend on the condition to be treated, the patient, and the efficiency of the inhalation device. In a 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), for example as described hereinabove, and a unit dose of (B), for example as described hereinabove, together with a pharmaceutically acceptable carrier as described herein above, in an amount to bring the total weight of the dry powder per capsule to between 5 milligrams and 50 milligrams, for example up to 5 milligrams, 10 milligrams, 15 milligrams, 20 milligrams, 25 milligrams, 30 milligrams, 35 milligrams , 40 milligrams, 45 milligrams, or 50 milligrams. In another preferred embodiment of the invention, the medicament of the invention is a pharmaceutical composition that is a dry powder to be administered from a reservoir of a multi-dose dry powder inhaler adapted to deliver, for example, 3 milligrams to 25 milligrams. of the powder containing a unit dose of (A) and (B), for example wherein (A) is in the form of the maleate salt, the powder comprising, by weight, from 20 to 2,000 parts, for example 60 to 1, 000 parts, from 100 to 500 parts, or from 100 to 300 parts of (A); from 25 to 800 parts, from 25 to 500 parts, from 50 to 400 parts, or from 100 to 400 parts of (B); and from 2,000 to 25,000 parts, for example from 4,000 to ,000 parts or from 4,000 to 1,000,000 parts of a pharmaceutically acceptable vehicle, as described hereinabove. 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), for example, in a proportion as described hereinabove, in a propellant such as is described hereinbefore, optionally together with a surfactant and / or a bulk agent and / or a co-solvent, such as ethanol as described hereinabove, to be administered from a metered dose inhaler adapted to supply a 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 unit dose of (B) per actuation. Therefore, for example, if the Inhaler supplies half of the unit doses of (A) and (B) per drive, the unit doses can be administered by two drives of the inhaler. In accordance with the above, the invention also provides a pharmaceutical kit comprising (A) and (B) as defined hereinbefore, in separate unit dosage forms, these forms being suitable for the administration of (A) and ( B) in effective amounts. These kits suitably further comprise one or two inhalation devices for the 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 multi-dose dry powder inhalation device containing in its reservoir a dry powder comprising (A), and an inhalation device of dry powder in multiple doses containing in its deposit a dry powder comprising (B). In a further example, the kit may comprise a metered dose inhaler containing an aerosol comprising (A) in a propellant, and a metered dose inhaler containing an aerosol comprising (B) in a propellant. The medicaments of the invention are suitable in the treatment of inflammatory or obstructive diseases of the respiratory tract, exhibiting highly effective bronchodilator and anti-inflammatory properties. For example, it is possible to use the combination therapy of the invention to reduce the dosages of a corticosteroid (B) required for a given therapeutic effect, compared to those required using corticosteroid alone, thereby minimizing possible side effects. undesirable. In particular, these combinations, in particular when (A) and (B) are in the same composition, facilitate the reach of a high anti-inflammatory effect, in such a way that the amount of corticosteroid necessary for an anti-inflammatory effect can be reduced. Inflammatory given when used mixed with a compound of formula I, thereby reducing the risk of undesirable side effects, by repeated exposure to the steroid involved in the treatment of inflammatory or obstructive airways diseases. Additionally, using the combinations of the invention, in particular using the compositions containing (A) and (B), drugs can be prepared that have a rapid action setting and a long duration of action. Furthermore, using this combination therapy, drugs can be prepared that result in a significant improvement in lung function. In another aspect, using the combination therapy of the invention, drugs can be prepared that provide effective control of obstructive or inflammatory diseases of the respiratory tract, or a reduction in exacerbations of such diseases. In a further aspect, using the compositions of the invention containing (A) and (B), drugs can be prepared that reduce or eliminate the need for treatment with short acting rescue drugs, such as salbutamol or terbutaline.; therefore, the compositions of the invention containing (A) and (B), facilitate the treatment of an obstructive or inflammatory disease of the respiratory tract with a single medicament. The treatment of inflammatory or obstructive diseases of the respiratory tract according to the invention can be a symptomatic or prophylactic treatment. Inflammatory or obstructive airways diseases to which the present invention is applicable, include asthma of any type or genesis, including both intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitic asthma, asthma induced by exercise, occupational asthma, and asthma induced immediately after bacterial infection. It should also be understood that asthma treatment encompasses the treatment of subjects, for example less than 4 or 5 years of age, who exhibit symptoms of wheezing and are diagnosed or diagnosed as "panting babies", a well-established patient category. Medical concern and now frequently identified as early stage or early stage asthmatics. (For convenience, this particular asthmatic condition is referred to as "panting baby syndrome"). The prophylactic efficacy in the treatment of asthma will be evidenced by a reduced frequency or severity of the symptomatic attack, for example of asthmatic attack or acute bronchoconstrictor, an improvement in lung function, or a better hyperreactivity of the respiratory tract. In addition, it can be evidenced by a reduced requirement of another symptomatic therapy, that is, a therapy for, or intended to, restrict or abort the symptomatic attack when it occurs, for example anti-inflammatory (for example with corticosteroid) or bronchodilator. The prophylactic benefit in asthma may be apparent in particular in subjects susceptible to "morning drowning". "Morning drowning" is a recognized asthmatic syndrome, common to a substantial percentage of asthmatics, and characterized by asthma attack, for example between 4 and 6 o'clock in the morning, ie, in a time usually substantially distant from any symptomatic asthma therapy previously administered. Other inflammatory or obstructive airways diseases and conditions to which the present invention is applicable include acute / adult lung injury (ALI), acute / adult respiratory distress syndrome (ARDS), cystic fibrosis, chronic pulmonary obstructive disease, of the respiratory tract, or of the lung (COPD, COAD, or COLD), including chronic bronchitis and emphysema, bronchiectasis, and exacerbation of airway hyperreactivity as a result of other drug therapy, particularly other inhaled drug therapy. Other inflammatory or obstructive airways diseases to which the present invention is applicable include neu oconiosis (an inflammatory, commonly occupational, disease of the lungs, often accompanied by airway obstruction, either chronic or acute, and caused by repeated inhalation of powders) of any type or genesis, including, for example, aluminosis, anthracosis, asbestosis, calicosis, ptilosis, siderosis, silicosis, tabacosis, 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] -ethylamino} -ethyl) - 3H-benzothiazol-2-one. Palladium black (0.2 grams) is added in portions to a solution of 7- [2- (benzyl- {2- [4- (4-phenyl-butoxy) -phenyl] -ethyl} -amino) - 1-hydroxy-ethyl] -4-hydroxy-3H-benzothiazol-2-one (0.29 grams) in formic acid (10 milliliters) at room temperature. After 1 hour, the catalyst is removed by filtration, and the filtrate is partitioned between CH3C02CH2CH3 and aqueous NaHCO3. Evaporation of the CH3C02CH2CH3 layers and recrystallization from hexane / CH3C02CH2CH3 give the title compound. MS (ES +) 479.

Example of Preparation 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-benzothiazoI-7-yl) -2- (1,1-dimethyl-2-phenylisethylamino) -ethanol in formic acid ( 10 milliliters) is stirred at room temperature. The reaction is shown to be complete by LCMS after 48 hours. Evaporation of formic acid and purification by reverse phase chromatography (ISOLUTE FLASH C18, 0-50 percent methyl cyanide in water (0.1 percent trifluoroacetic acid)) gives the title compound. MS (ES +) m / e 359 (MH +).

Preparation Example 3: Compound E3 4-hydroxy-7- formate. { (R) -1-Hydroxy-2- [2- (5,6,7,8-tetrahydro-naphthalen-2-yl) -ethylamino] -ethyl} -3H-benzothiazol-2-one. Black palladium (0.4 grams) is added in portions to a solution of (R) -2-. { benzyl- [2- (5,6,7,8-tetrahydro-naphthalen-2-yl) -etiI] -amino} -1- (4-tert-butoxy-2-isopropoxy-benzothiazol-7-yl) -ethanol (0.40 grams) in formic acid (5 milliliters) at room temperature. After 24 hours, the catalyst is removed by filtration. Evaporation of formic acid and purification by reverse phase chromatography (ISOLUTE FLASH C1 8, 0-50 percent methyl cyanide in water (0.1 percent formic acid)) gives the title compound. MS (ES +) m / e 385 (MH +).

Example of Preparation 4: Compound E4 7 - [(R) -2 - ((1 S, 2S) -2-benzyloxy-cyclopentylamino) -1-hydroxy-ethyl] -4-hydroxy-3H-benzothiazol-2-one . Dissolve (R) -2 - ((1 S, 2S) -2-benzyloxy-cyclopentylamino) -1 - (4-tert-butoxy-2-isopropoxy-benzothiazol-7-yl) -ethanol (10 grams, 20 mmol) ) in isopropanol (1000 milliliters). 1 M HCl (50 milliliters) 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 (50 milliliters) and saturated NaHCO 3. The organic layer is washed with brine (50 milliliters), dried over MgSO, filtered and the solvent removed in vacuo. The title compound is purified by crystallization from ethanol. MS (ES +) m / e 401 (MH +).

Preparation Example 5: Compound E5 Example 154: 7 - [(R) -2 - ((1 S, 2R) -2-benzyloxy-cyclopentylamino) -1-hydroxy-ethyl] -4-hydroxy-3H-benzothiazole-2 -one Dissolve (R) -2 - ((1 S, 2R) -2-benzyloxy-cyclopentylamino) -1 - (4-tert-butoxy-2-isopropoxy-benzothiazol-7-yl) -ethanol (460 milligrams, 0.92 mmol) ) in isopropanol (5 milliliters). 1 M HCl (2.5 milliliters) 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 (50 milliliters) and saturated NaHCO3. The organic layer is washed with brine (50 milliliters), dried over MgSO4, filtered, and the solvent removed in vacuo to give the title compound. MS (ES +) m / e 401 (MH +).

Preparation of Intermediate Compounds Certain compounds that are used to prepare the compounds of the Examples, which are not readily available commercially, are prepared as follows: Terc-butoxy-5-f luoro-f enylamine A suspension of platinum oxide (17 grams) in a solution of 1-tert-butoxy-4-fluoro-2-nitro-benzene (225 grams, prepared by the TF method) Woiwode et al., J. Org. Chem. 1998, 63, 9594) in CH 3 OH (1.5 liters) is stirred under a hydrogen atmosphere for 18 hours. Filtration through a Celite ™ filter material and evaporation give the title compound. 19 F NMR (CDCIs, 376 MHz); -43.4. 1 - . 1 - . 1-tert-butoxy-4-fluoro-2-isothiocyanato-benzene Carbon disulfide (38.6 milliliters) is added to a solution of 2-tert-butoxy-5-fluoro-phenylamine (58.8 grams) and triethylamine (89.5 milliliters) in toluene (66 milliliters), and the reaction mixture is stirred at room temperature for 1 8 hours, and then evaporated. Chloroform (200 milliliters) and triethylamine (44.9 milliliters) are added to the residue, and this is cooled before the addition of ethyl chloroformate (30.8 milliliters). After 15 minutes at 0 ° C, the reaction mixture is washed sequentially with aqueous 3N HCl, saturated brine, saturated NaHCO3, and saturated brine, and then evaporated to give the title compound. 1 H NMR (CDCl 3, 400 MHz); 7.1 0-7.03 (m, 1 H), 6.93-6.87 (m, 1 H), 6.86-6.80 (m, 1 H), 1.43 (s, 9H).

O-Isopropyl ester of (2-tert-butoxy-5-fluoro-phenyl) -thio-carbamic acid A solution of 1-tert-butoxy-4-fluoro-2-isothiocyanato-benzene (50.0 grams) and triethylamine (31 milliliters) in isopropanol (170 milliliters) is refluxed for 48 hours. Evaporation of the reaction mixture, followed by flash column chromatography with silica gel, eluent of 20: 1 hexane: CH 3 CO 2 CH 2 CH 3, give the title compound. 1 H NMR (CDCl 3, 400 MHz); 8.60 (broad s, 1 H), 7.38 (broad s, 1 H), 7.50-6.87 (m, 1 H), 6.67-6.58 (m, 1 H), 5.64-5.50 (m, 1 H), 1.43- 1.32 (m, 6H), 1.32-1.25 (s, 9H). 2- (benzyl- {2.4"4- (4-phenyl-butoxy) -pheniH-ethyl) -amino) -1 - (4-tert-butoxy-2-isopropoxy-benzothiazol-7-yl) ) -etanone A solution of tert-butyl lithium in pentane (12.3 milliliters, 1.7 M) is added to a solution of (2-tert-butoxy-5-fluoro-phenyl) -thiocarbamic acid O-isopropyl ester (3.20) grams) in tetrahydrofuran (1.0 milliliters) at -78 ° C, the solution is heated to -20 ° C for 1 hour, and then cooled again to -78 ° C, and a solution of 2- (benzyl) is added. - { 2- [4- (4-phenyl-butoxy) -phenyl] -ethyl} -amino) -N-methoxy-N-methyl-acetamide in tetrahydrofuran (1.0 milliliter) at -78 ° C. The reaction mixture is warmed to room temperature and partitioned between NH4CI and CH3C02CH2CH3 The evaporation of the CH3CO2CH2CH3 layers and the silica gel column chromatography, eluent of 4: 1 hexane: CH3C02CH2CH3, give the title compound MS (ES +) 665. 7-r (benzyl- (2-f4- (4-phenyl-butoxy) -phenin-ethyl) -amino) -acetyl-4-hydroxy-3H-benzothiazol-2-one A solution of 2- (benzyl- {. 2- [4- (4-phenyl-butoxy) -phenyl] -ethyl} -amino) -1 - (4-tert-butoxy-2-isopropoxy-benzothiazo-7-yl) -ethanone (2.49 grams) in isopropanol (20 milliliters) and concentrated hydrobromic acid (20 milliliters) is heated at 50 ° C. After 3 hours, the reaction mixture is partitioned between CH3CO2CH2CH3 and water, and the CH3CO2CH2CH3 layer is washed with aqueous NaHCO3 and then brine. Evaporation of the CH3CO2CH2CH3 layers and column chromatography on silica gel, eluent of 4: 1 hexane: CH3CO2CH2CH3, give the title compound. MS (ES +) 567. 7-r2-benzyl-. { 2-r4- (4-phenyl-butoxy) -phenin-ethyl) -amino) -1-hydroxy-etn-4-hydroxy-3H-benzothiazol-2-one NaBH4 is added in portions ( 2.67 grams) to a solution of 7 - [(benzyl- {2- [4- (4-phenyl] -butoxy) -phenyl] -ethyl} -amino) -acetyl] -4-hydroxyl- 3H-benzothiazol-2-one (0.40 grams) in CH3OH (15 milliliters) at 0 ° C. After 30 minutes, the reaction mixture is partitioned between CH3CO2CH2CH3, and water. Evaporation of the CH3C02CH2CH3 layers, and column chromatography on silica gel, eluent of 1: 1 hexane: CH3C02CH2CH3, give the title compound. MS (ES +) 569. 1- (4-tert-butoxy-2-isopropoxy-benzothiazol-7-yl) -2-chloro-ethanone Tert-butyl-lithium (22.7 milliliters, 1.7 mg in pentane) is added dropwise to a solution of O-isopropyl - (2-tert-butoxy-5-fluoro-phenyl) -thiocarbamic acid ester (5.00 grams) in tetrahydrofuran (20 milliliters) at -78 ° C. This solution is then allowed to warm to -20 ° C, and a dry mixture of lithium chloride (2.12 grams) and copper (I) cyanide (2.24 grams) in tetrahydrofuran (50 milliliters) is added. After minutes, chloroacetyl chloride (4.36 grams) is added, and the reaction mixture is 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 NH CI (5 milliliters). The reaction mixture is partitioned between ethyl acetate (250 milliliters) and water (250 milliliters). The organic layer is washed with water (250 milliliters) and brine (250 milliliters), dried over MgSO, filtered, and the solvent removed in vacuo. The title compound is obtained by flash column chromatography (silica, isohexane / ethyl acetate, 10: 1). MS (ES +) m / e 341 (MH +).

(R) -1 (4-tert-butoxy-2-isopropoxy-benzothiazol-7-yl) -2-chloro-ethanol A borane-tetrahydrofuran complex is added dropwise (14.64 milliliters, 1M in tetrahydrofuran) to a solution of (1 R, 2S) - (+) - 1-amino-2-indanol (0.22 grams) in tetrahydrofuran (50 milliliters), and the solution is stirred at room temperature during 15 minutes. Then a solution of 1- (4-tert-butoxy-2-isopropoxy-benzothiazol-7-yl) -2-chloro-ethanone (5.00 grams) in tetrahydrofuran (50 milliliters) is added dropwise over a period of 1 hour. hour. The reaction mixture is stirred at room temperature for an additional 15 minutes, and then quenched by the addition of 0.2M H2SO4 (5 milliliters). The reaction mixture is divided between ethyl acetate (200 milliliters) and 0.2 M H2SO (200 milliliters). The organic layer is washed with water (200 milliliters) and brine (200 milliliters), dried over MgSO4, filtered, and the solvent removed in vacuo to give the title compound. MS (ES +) m / e 344 (MH +). 4-tert-butoxy-2-isopropoxy-7- (R) -oxiran-1-benzothiazole A mixture of (R) -1 - (4-tert-butoxy-2-isopropoxy-benzothiazole-7-yl) -2-chloro-ethanol (4.70 grams) and potassium carbonate (7.48 grams) in acetone (250 milliliters), 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 +).

(R) -2- (benzyl-r2- (5,6,7,8-tetrahydro-naphthalen-2-yl) -eti-amino). -1- (4-tert-butoxy-2-isopropoxy-benzothiazole) -7-yl) -ethanol A solution of 4-tert-butoxy-2-isopropoxy-7- (R) -oxiranyl-benzothiazole (3.50 grams) and benzyl- [2- (5,6,7,8-tetrahydro- Naphthalen-2-yl) -ethyl-amine (3.03 grams) in 1-butane (25 milliliters), is stirred at 10 ° C. The reaction is shown to be complete by thin layer chromatography after 18 hours. The title is obtained after purification by flash column chromatography (silica, isohexane / ethyl acetate, 10: 1), 1 H NMR (CDCl 3, 400 MHz), 7.35-7.20 (m, 5H), 7.00-6.95 (m , 3H), 6.90-6.80 (m, 2H), 5.45 (m, 1 H), 4.70 (m, 1 H), 3.95 (d, 1 H), 3.55 (d, 1 H), 2.85 (m, 6H) ), 2.70 (m, 4H), 1.75 (m, 4H), 1.45 (m, 6H), 1.35 (s, 9H).

(R) -1 - (4-tert-butoxy-2-isopropoxy-benzothiazol-7-yl) -2- (1,1-dimethyl-2-phenyl-ethylamino) -ethanol A solution of phentermine (0.728 grams, 4.89 millimoles) and N, O-bis- (trimethyl-silyl) -acetamide (0.496 grams, 2.44 mmol) in dry dimethylformamide (1 milliliter) is stirred at room temperature for 30 minutes. A solution of 4-tert-butoxy-2-isopropoxy-7- (R) -oxiranyl-benzothiazole (0.75 grams, 2.44 mmol) in dry dimethylformamide (1 milliliter) is added, and the reaction mixture is stirred at 80 ° C. The reaction is shown to be complete by thin layer chromatography after 18 hours. The title compound is obtained after purification by flash column chromatography (silica, isohexane / ethyl acetate, 1: 1). MS (ES +) m / e 457 (MH +).

(R) -2 - ((1 S, 2S) -2-benzyloxy-cyclopentylamino) -1 - (4-tert-butoxy-2-isopropoxy-benzothiazol-7-yl) -ethanol 4-tert-butoxy-2 -isopropoxy-7- (R) -oxiranyl-benzo-thiazole (13.2 grams, 42.94 mmol) and (1 S, 2 S) -2-benzyloxy-cyclopentyl-amine (1 0.68 grams, 55.82 mmol) are placed in a flask with Digly (40 milliliters), and the reaction mixture is heated to 1 1 5 ° C. The reaction is shown to be complete by thin layer chromatography after 1.7 hours. The reaction mixture is cooled and partitioned between heptane (200 milliliters) and water (200 milliliters). The organic layer is dried over MgSO 4, filtered, and the solvent is removed in vacuo. The title compound is purified by crystallization from isopropanol. MS (ES +) m / e 499 (MH +). (1 R.2S) -2-amino-cyclopentanol hydrochloride The title compound is prepared by the method 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), 4197-41 99. (1 S, 2R) -2- (2-hydroxy-cyclopentyl) -soindole-1,3-dione. Hydrochloride of (1R, 2S) -2-amino-cyclopentanol (1.0) is placed in a flask. grams, 72.73 millimoles), phthalic anhydride (10.76 grams, 72.73 millimoles), and di-isopropyl-amine (1.26 grams, 87.27 millimoles), and are heated to 130 ° C. The reaction is shown to be complete by thin layer chromatography after 2 hours. The reaction mixture is allowed to cool and is partitioned between ethyl acetate (200 milliliters) and 2M hydrochloric acid (200 milliliters). The organic layer is washed with water (1000 milliliters), saturated NaHCO3 (1000 milliliters), and brine (1000 milliliters), dried over MgSO4, filtered, and the solvent removed in vacuo. The title compound is obtained after purification by flash column chromatography (silica, isohexane / ethyl acetate, 1: 1). 1 H NMR (CDCl 3, 400 MHz); 7.85 (m, 2H), 7.70 (m, 2H), 4.50 (m, 1 H), 4.30 (m, 1 H), 2.95 (d, 1 H), 2.45 (m, 1 H), 2.00 (m, 3H), 1.85 (m, 1 H), 1.60 (m, 1 H). (1 S, 2R) -2- (2-benzyloxy-cyclopentyl) -isondole-1,3-dione It is dissolved (1 S, 2R) -2- (2-hydroxy-cyclopentyl) -isoindole-1 , 3-dione (7.50 grams, 32.47 millimoles) in dry dimethylformamide (15 milliliters) under an argon atmosphere. The solution is cooled to 0 ° C, and sodium hydride (0.78 grams, 32.47 millimoles) is added. The reaction mixture is stirred at room temperature for 30 minutes, and then cooled on ice. Benzyl bromide (6.1 1 gram, 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 thin layer chromatography. The reaction mixture is divided between ethyl acetate (200 milliliters) and water (200 milliliters). The organic layer is washed with brine (1000 milliliters), dried over MgSO, filtered, and the solvent removed in vacuo. The title compound is obtained after purification by flash column chromatography (silica, isohexane / ethyl acetate, 10: 1). 1 H NMR (CDCl 3, 400 MHz); 7.80 (m, 2H), 7.65 (m, 2H), 7.1 0 (m, 5H), 4.65 (q, 1 H), 4.50 (d, 1 H), 4.35 (d, 1 H), 4.00 (q, 1 H), 2.70 (m, 1 H), 2.00 (m, 4H), 1.50 (m, 1 H). (1 S, 2R) -2-benzyloxy-cyclopentyl-amine Dissolve (1 S, 2R) -benzyloxy-cyclopentyl) -isoindole-1,3-dione (5.50 grams, 1 7.1 3 mmol) in EtOH (175 milliliters) . Acetic acid (3.08 grams, 51.40 millimoles) and hydrazine monohydrate (2.57 grams, 51.40 millimoles) are added, and the reaction mixture is refluxed for 2 hours, allowed to cool, the solids are filtered, and The solvent is removed in vacuo. The residue is partitioned between ethyl acetate (100 milliliters) and 2M hydrochloric acid (100 milliliters). The aqueous layer is basified to a pH of 12 with 2M NaOH, and extracted with ethyl acetate (50 milliliters, three times). The organic layer is washed with brine (1000 milliliters), dried over MgSO4, filtered, and the solvent removed in vacuo to give the title compound. 1 H NMR (CDCl 3, 400 MHz); 7.80 (m, 2H), 7.65 (m, 2H), 7.10 (m, 5H), 4.65 (q, 1 H), 4.50 (d, 1 H), 4.35 (d, 1 H), 4.00 (q, 1) H), 2.70 (m, 1 H), 2.00 (m, 4H), 1.50 (m, 1 H).

(R) -2 - ((1 S, 2R) -2-benzyloxy-cyclopentylamino) -1 - (4-tert-butoxy-2-isopropoxy-benzothiazol-7-yl) -ethanol This compound is prepared from ( R) -1- (4-tert-butoxy-2-iopropoxybenzothiazole-7-ll) -2-cyclo-ethanol and (1 S, 2R) -2-benzyloxy-cyclopentyl-amine, using procedures analogous to those used for prepare 4-tert-butoxy-2-isopropoxy-7- (R) -oxiranyl-benzothiazole. MS (ES +) m / e 499 (MH +).

Examples 1 to 60 Gelatin capsules suitable for use in a capsule inhaler are prepared, such as that described in U.S. Patent No. US 3991761 or in European Patent Number EP 1270034, each capsule containing a dry powder obtained by mixing Compound E1 and budesonide, which have been milled to an average particle diameter of 1 to 5 microns, and lactose monohydrate having a particle diameter of less than 212 microns, the amounts being as shown in the following table : Examples 61 to 90 Examples 1 to 60 are repeated, but replacing budesonide with mometasone furoate, and using the amounts shown in the following table: Examples 91 to 1 A suitable dry powder is prepared for delivery from the multi-dose inhaler reservoir described in International Publication Number WO 97/20589, by mixing Compound E1 and fluticasone propionate, which have been milled to a particle diameter average of 1 to 5 microns, and lactose monohydrate having a particle diameter less than 212 microns, the quantities being as shown in the following table: Examples 136 to 180 A dry powder suitable for delivery from the multi-dose inhaler reservoir described in International Publication Number WO 97/20589 is prepared by mixing Compound E1 and fluticasone propionate, which have been milled to a particle diameter average of 1 to 5 microns, and lactose monohydrate having a particle diameter less than 212 microns, the amounts being as shown in the table directly above, but also containing 0.5 weight percent magnesium stearate.

Examples 181 to 208 Aerosol formulations are prepared by the dosing of micronized active ingredients, Compound E1, and mometasone furoate / fluticasone propionate, and if required, lactose as bulking agent in a flask; The vial is sealed with a metering valve, the previously mixed ethanol / propellant is injected and the optional surfactant in the bottle through the valve, and the bottle is subjected to ultrasonic energy to disperse the solid particles. The components and quantities used are shown in the following tables: Examples 209 to 244 The procedure of Examples 91 to 135 is repeated, but replacing fluticasone propionate with mometasone furoate, and using the amounts shown in the following table: Examples 245 to 280 The procedure of Examples 91 to 1 35 is repeated, but replacing the fluticasone proplonate with mometasone furoate, using the amounts shown in the table directly above, and including 0.5 weight percent magnesium stearate.

Examples 281 to 317 The procedure of Examples 181 to 208 is repeated, but using the amounts shown in the following table, the ethanol being omitted in some of the Examples: Examples 31 8 to 326 The procedure of Examples 1 to 208 is repeated, but using sorbitan trioleate (ST) as a surfactant instead of oleic acid, the amounts of the ingredients being as shown in the following table: Examples 327 to 386 Gelatin capsules suitable for use in a capsule inhaler are prepared, such as that described in US 3991761 or EP 1270034, each capsule containing a dry powder obtained by mixing Compound E2 and budesonide , which have been ground to an average particle diameter of 1 to 5 microns, and lactose monohydrate having a particle diameter of less than 212 microns, the amounts being as shown in the following table: Examples 387 to 416 Examples 327 to 386 are repeated, but replacing budesonide with mometasone furoate, and using the amounts shown in the following table: Examples 417 to 461 A dry powder suitable for delivery from the multi-dose inhaler reservoir described in WO 97/20589 is prepared by mixing Compound E2 and fluticasone propionate, which have been milled to an average particle diameter from 1 to 5 microns, and lactose monohydrate having a particle diameter of less than 212 microns, the amounts being as shown in the following table: Examples 462 to 506 A dry powder suitable for delivery from the multi-dose inhaler reservoir described in WO 97/20589 is prepared by mixing Compound E2 and fluticasone propionate, which have been ground to an average particle diameter from 1 to 5 microns, and lactose monohydrate having a particle diameter less than 212 microns, the amounts being as shown in the table directly above, but also containing magnesium stearate at 1.0 percent by weight.

Examples 507 to 534 Aerosol formulations are prepared by the dosing of micronized active ingredients, Compound E2, and mometasone furoate / fluticasone propionate, and if required, lactose as a bulking agent in a bottle; The vial is sealed with a metering valve, the previously mixed ethanol / propellant is injected and the optional surfactant in the bottle through the valve, and the bottle is subjected to ultrasonic energy to disperse the solid particles. The components and quantities used are shown below: Examples 535 to 570 The procedure of Examples 417 to 461 is repeated, but replacing fluticasone propionate with mometasone furoate, and using the amounts shown in the following table: Examples 571 to 606 The procedure of Examples 417 to 461 is repeated, but replacing the fluticasone proplonate with mometasone furoate, using the amounts shown in the table directly above, and including magnesium stearate at 1.0 weight percent.

Examples 607 to 643 The procedures of Examples 507-534 are repeated, but using the amounts shown in the following table, the ethanol being omitted in some of the Examples: Examples 644 to 652 The procedure of Examples 507 to 534 is repeated, but using sorbitan trioleate (ST) as a surfactant instead of oleic acid, the amounts of the ingredients being as shown in the following table: Examples 653 to 712 Gelatin capsules suitable for use in a capsule inhaler such as that described in US Pat. No. 3991761 or in European Patent Number EP 1270034 are prepared, each capsule containing a dry powder. obtained by mixing Compound E3 and budesonide, which have been milled to an average particle diameter of 1 to 5 microns, and lactose monohydrate having a particle diameter of less than 212 microns, the amounts being as shown in the following table: Examples 713 to 742 Examples 1 to 70 are repeated, but replacing budesonide with mometasone furoate, and using the amounts shown in the following table: Examples 743 to 787 A dry powder suitable for delivery from the multi-dose inhaler reservoir described in International Publication Number WO 97/20589 is prepared by mixing Compound E3 and fluticasone propionate, which have been milled to an average particle diameter from 1 to 5 microns, and lactose monohydrate having a particle diameter of less than 212 microns, the amounts being as shown in the following table: Examples 788 to 832 A dry powder suitable for delivery from the multi-dose inhaler reservoir described in WO 97/20589 is prepared by mixing Compound E3 and fluticasone propionate, which have been milled to an average particle diameter of 1. at 5 microns, and lactose monohydrate having a particle diameter less than 212 microns, the amounts being as shown in the table directly above, but also containing 0.5 weight percent magnesium stearate.

Examples 833 to 860 Aerosol formulations are prepared by the dosing of micronized active ingredients, Compound E3, and mometasone furoate / fluticasone propionate, and if required, lactose as bulking agent in a flask; the vial is sealed with a metering valve, the previously mixed ethanol / propellant is injected and the optional surfactant through the valve, and the bottle is subjected to ultrasonic energy to disperse the solid particles. The components and quantities used are shown in the following tables: Examples 861 to 896 The procedure of Examples 743 to 787 is repeated, but replacing fluticasone propionate with mometasone furoate, and using the amounts shown in the following table: Examples 897 to 932 The procedure of Examples 743 to 787 is repeated, but replacing fluticasone propionate with mometasone furoate, using the amounts shown in the table directly above, and including 0.5 weight percent magnesium stearate.

Examples 933 to 969 The procedures of Examples 136 to 163 are repeated, but using the amounts shown in the following table, the ethanol being omitted in some of the examples: Examples 970 to 978 The procedure of Examples 833 to 860 is repeated, but using sorbitan trioleate (ST) as a surfactant instead of oleic acid, the amounts of the ingredients being as shown in the following table: Examples 979 to 1038 Gelatin capsules suitable for use in a capsule inhaler such as the one described in the document are prepared.

US 3991761 or EP 1270034, each capsule containing a dry powder obtained by mixing Compound E4 and budesonide, which have been milled to an average particle diameter of 1 to 5 microns, and lactose monohydrate having a particle diameter less than 212 microns, the quantities being as shown in the following table: Examples 1039 to 1068 Examples 979 to 1038 are repeated, but replacing budesonide with mometasone furoate, and using the amounts shown in the following table: Examples 1069 to 1 1 13 A dry powder suitable for delivery from the multi-dose inhaler reservoir described in WO 97/20589 is prepared by mixing Compound E4 and fluticasone propionate, which have been milled to an average particle diameter from 1 to 5 microns, and lactose monohydrate having a particle diameter of less than 212 microns, the amounts being as shown in the following table: Examples 1 1 14 to 1 158 A dry powder suitable for delivery from the multi-dose inhaler reservoir described in WO 97/20589 is prepared by mixing Compound E4 and fluticasone propionate, which have been milled to a particle diameter average of 1 to 5 microns, and lactose monohydrate having a particle diameter of less than 212 microns, the amounts being as shown in the table directly above, but also containing 1.0 weight percent magnesium stearate.

Examples 1 159 to 1 1 86 Aerosol formulations are prepared by the dosing of micronized active ingredients, Compound E4 and mometasone furoate / fluticasone propionate, and if required, lactose as bulking agent in a bottle; The vial is sealed with a metering valve, the previously mixed ethanol / propellant is injected and the optional surfactant in the bottle through the valve and the bottle is subjected to ultrasonic energy to disperse the solid particles. The components and quantities used are shown in the following tables: Examples 1187 to 1222 The procedure of Examples 1069 to 1113 is repeated, but replacing fluticasone propionate with mometasone furoate, and using the amounts shown in the following table: Examples 1223 to 1258 The procedure of Examples 1069 to 1113 is repeated, but replacing fluticasone propionate with mometasone furoate, using the amounts shown in the table directly above, and including magnesium stearate at 1.0 percent by weight. weight.

Examples 1259 to 1295 The procedures of Examples 1 159 to 1186 are repeated, but using the amounts shown in the following table, the ethanol being omitted in some of the Examples: Examples 1296 to 1304 The procedure of Examples 1 159 to 1186 is repeated, but using sorbitan trioleate (ST) as a surfactant instead of oleic acid, the amounts of the ingredients being as shown in the following table: Examples 1305 to 1364 Gelatin capsules suitable for use in a capsule inhaler are prepared, such as that described in US 3991761 or in EP 1270034, each capsule containing a dry powder obtained by mixing Compound E5 and budesonide, which have been ground to an average particle diameter of 1 to 5 microns, and lactose monohydrate having a particle diameter of less than 212 microns, the amounts being as shown in the following table: Examples 1365 to 1394 Examples 1 305 to 1 364 are repeated, but replacing budesonide with mometasone furoate, and using the amounts shown in the following table: Examples 1395 to 1439 A dry powder suitable for delivery from the multi-dose inhaler reservoir described in International Publication Number WO 97/20589 is prepared by mixing Compound E5 and fluticasone propionate, which have been milled to an average particle diameter from 1 to 5 microns, and lactose monohydrate having a particle diameter less than 212 microns, the amounts being as shown in the following table: Examples 1440 to 1484 A suitable dry powder is prepared to be delivered from the reservoir of the multiple doses described in WO 97/20589, by mixing Compound E5 and fluticasone propionate, which have been milled to an average particle diameter of 1 to 5 microns, and lactose monohydrate having a particle diameter of less than 212 microns , the amounts being as shown in the table directly above, but also containing magnesium stearate at 0.5 percent by weight or. Examples 1485 to 151 2 Aerosol formulations are prepared by the dosage of micronized active ingredients, Compound E5, and mometasone furoate / fluticasone propionate, and if required, lactose as bulking agent in a flask; the vial is sealed with a valve, measuring device, the previously mixed ethanol / propellant is injected and the optional surfactant in the bottle through the valve, and the bottle is subjected to ultrasonic energy to disperse the solid particles. The components and quantities used are shown in the following tables: Examples 1513 to 1548 The procedure of Examples 1395 to 1439 is repeated, but replacing fluticasone propionate with mometasone furoate, and using the amounts shown in the following table: Examples 1549 to 1584 The procedure of Examples 1395 to 1439 is repeated, but replacing fluticasone propionate with mometasone furoate, using the amounts shown in the table directly above, and including 0.5 weight percent magnesium stearate.

Examples 1585 to 1621 The procedures of Examples 1485 to 1512 are repeated, but using the amounts shown in the following table, the ethanol being omitted in some of the Examples: Examples 1622 to 1630 The procedure of Examples 1485 to 1512 is repeated, but using sorbitan trioleate (ST) as a surfactant instead of oleic acid, the amounts of the ingredients being as shown in the following table:

Claims (20)

1. CLAIMS 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 -Ra-Y; Ar means a phenylene group optionally substituted by halo, hydroxy, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms-alkyl of 1 to 10 carbon atoms, phenyl , alkyl of 1 to 10 carbon atoms substituted by phenyl, alkoxy of 1 to 10 carbon atoms substituted by phenyl, alkyl of 1 to 10 carbon atoms-substituted phenyl, or alkoxy of 1 to 10 carbon atoms-substituted phenyl; R1 and R2 are attached to the adjacent carbon atoms in AR, and either R1 is alkylene of 1 to 10 carbon atoms and R2 is hydrogen, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms or halogen, or R1 and R2, together with the carbon atoms in Ar to which they are attached, mean a cycloaliphatic ring of 5, 6, or 7 members; Ra is a bond or alkylene of 1 to 10 carbon atoms optionally substituted by hydroxy, alkoxy of 1 to 10 carbon atoms, aryl of 6 to 10 carbon atoms, or aralkyl of 7 to 14 carbon atoms; and Y is alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, or alkynyl of 2 to 10 carbon atoms optionally substituted by halo, cyano, hydroxy, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or haloalkyl of 1 to 10 carbon atoms; cycloalkyl of 3 to 10 carbon atoms optionally fused with one or more benzene rings, and optionally substituted by alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, aralkyl of 7 to 14 carbon atoms, aralkyloxy of 7 to 14 carbon atoms, or aryl of 6 to 10 carbon atoms, wherein cycloalkyl of 3 to 10 carbon atoms, aralkyl of 7 to 14 carbon atoms, aralkyloxy of 7 to 14 carbon atoms, or aryl of 6 to 10 carbon atoms are optionally substituted by halo, hydroxy, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or haloalkyl of 1 to 10 carbon atoms; aryl of 6 to 10 carbon atoms optionally substituted by halo, hydroxy, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, haloalkyl of 1 to 10 carbon atoms, phenoxy, alkylthio of 1 to 1 0 carbon atoms, aryl of 6 to 10 carbon atoms, heterocyclic ring of 4 to 10 members having at least one nitrogen, oxygen or sulfur atom of the ring, or by NRbRc, wherein Rb and Rc are each independently alkyl of 1 to 10 carbon atoms optionally substituted by hydroxy, alkoxy of 1 to 10 carbon atoms, or phenyl, or Rb may additionally be hydrogen; phenoxy optionally substituted by alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or by phenyl optionally substituted by alkyl of 1 to 10 carbon atoms or alkoxy of 1 to 10 carbon atoms; a 4 to 10 membered heterocyclic ring having at least one nitrogen, oxygen, or ring sulfur atom, this heterocyclic ring being optionally substituted by halo, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 atoms carbon, haloalkyl of 1 to 10 carbon atoms, aryl of 6 to 10 carbon atoms, aralkyl of 7 to 14 carbon atoms, aralkyloxy of 7 to 14 carbon atoms, alkoxycarbonyl of 1 to 10 carbon atoms carbon, or a 4- to 10-membered heterocyclyl-alkyl of 1 to 10 carbon atoms; -NRdRe, where Rd is hydrogen or alkyl of 1 to 10 carbon atoms, and Re is alkyl of 1 to 10 carbon atoms optionally substituted by hydroxy, or Re is aryl of 6 to 10 carbon atoms optionally substituted by halo, or Re is a 4- to 10-membered heterocyclic ring having at least one nitrogen, oxygen or sulfur atom of the ring, which ring is optionally substituted by phenyl or by substituted halo-phenyl, or Re is aryisulfonyl from 6 to 10. carbon atoms optionally substituted by alkylamino of 1 to 10 carbon atoms or di- (alkyl of 1 to 10 carbon atoms) -amino; -SRf, wherein Rf is aryl of 6 to 10 carbon atoms or aralkyl of 7 to 14 carbon atoms optionally substituted by halo, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or haloalkyl of 1 to 10 carbon atoms; or -CONHR9, wherein R9 is alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, or aryl of 6 to 10 carbon atoms; and (B) a corticosteroid, for simultaneous, sequential, or separate administration in the treatment of an inflammatory or obstructive airway disease, with the molar ratio of (A) to (B) being from 1 00: 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, wherein (A) is a compound of formula I in free or salt or solvate form, wherein: X is -R1-Ar-R2 or -Ra-Y; Ar means a phenylene group optionally substituted by halo, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms substituted by phenyl; R1 and R2 are attached to the adjacent carbon atoms in Ar, and either R1 is alkylene of 1 to 10 carbon atoms and R2 is hydrogen, or R1 and R2, together with the carbon atoms in Ar with which they are joined, they mean a cycloaliphatic ring of 5, 6, or 7 members; Ra is a bond or alkylene of 1 to 10 carbon atoms optionally substituted by hydroxy, aryl of 6 to 10 carbon atoms or aralkyl of 7 to 14 carbon atoms; and Y is alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or alkynyl of 2 to 10 carbon atoms; cycloalkyl of 3 to 10 carbon atoms optionally fused to one or more benzene rings, and optionally substituted by alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, aralkyl of 7 to 14 carbon atoms, aralkyloxy from 7 to 14 carbon atoms optionally substituted by halo, or by aryl of 6 to 10 carbon atoms optionally substituted by alkyl of 1 to 10 carbon atoms or alkoxy of 1 to 10 carbon atoms; aryl of 6 to 10 carbon atoms optionally substituted by halo, hydroxy, alkyl of 1 to 10 carbon atoms, phenoxy, alkylthio of 1 to 10 carbon atoms, aryl of 6 to 10 carbon atoms, a heterocyclic ring of 4 to 10 members having at least one nitrogen atom of the ring, or by NRbRc, wherein Rb and Rc are each independently alkyl of 1 to 10 carbon atoms optionally substituted by hydroxy or phenyl, or Rb may additionally be hydrogen; phenoxy optionally substituted by alkoxy of 1 to 10 carbon atoms; a 4 to 10 membered heterocyclic ring having at least one nitrogen or oxygen atom of the ring, this heterocyclic ring being optionally substituted by alkyl of 1 to 10 carbon atoms, aryl of 6 to 10 carbon atoms, aralkyl from 7 to 14 carbon atoms, alkoxycarbonyl of 1 to 10 carbon atoms, or a heterocyclyl of 4 to 10 alkyl-members of 1 to 10 carbon atoms; -NRdRe, where Rd is hydrogen or alkyl of 1 to 10 carbon atoms, and Re is alkyl of 1 to 10 carbon atoms, or Rβ is a 4 to 10 membered heterocyclic ring having at least one nitrogen atom or oxygen of the ring, which ring is optionally substituted by substituted halo-phenyl, or Re is arylsulfonyl of 6 to 10 carbon atoms optionally substituted by di- (alkyl of 1 to 10 carbon atoms) -amino; -SRf, wherein Rf is aryl of 6 to 10 carbon atoms or aralkyl of 7 to 14 carbon atoms optionally substituted by halogen or haloalkyl of 1 to 10 carbon atoms; or -CONHR9, wherein R9 is cycloalkyl of 3 to 10 carbon atoms or aryl of 6 to 10 carbon atoms. 4. A medicament according to any of the preceding claims, wherein (A) is a compound of formula I in free or salt or solvate form, wherein: X is -R1-Ar-R2 or -Ra-Y; Ar means a phenylene group optionally substituted by halo, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or by alkoxy of 1 to 4 carbon atoms substituted by phenyl; R1 and R2 are attached to the adjacent carbon atoms in Ar, and either R1 is alkylene of 1 to 4 carbon atoms and R2 is hydrogen, or R1 and R2, together with the carbon atoms in Ar with which they are joined, they mean a cycloaliphatic ring of 5, 6, or 7 members, especially a 5-membered cycloaliphatic ring; Ra is a bond or alkylene of 1 to 4 carbon atoms optionally substituted by hydroxy, aryl of 6 to 8 carbon atoms, or aralkyl of 7 to 10 carbon atoms; and Y is alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or alkynyl of 2 to 4 carbon atoms; cycloalkyl of 3 to 6 carbon atoms optionally fused to one or more benzene rings, and optionally substituted by alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aralkyl of 7 to 10 carbon atoms, aralkyloxy from 7 to 10 carbon atoms optionally substituted by halo, or by aryl of 6 to 8 carbon atoms optionally substituted by alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms; aryl of 6 to 8 carbon atoms optionally substituted by halo, hydroxy, alkyl of 1 to 4 carbon atoms, phenoxy, alkylthio of 1 to 4 carbon atoms, aryl of 6 to 8 carbon atoms, a heterocyclic ring of 4 to 8 members having at least one nitrogen atom of the ring, or by NRbRc, wherein Rb and R ° are each independently alkyl of 1 to 4 carbon atoms optionally substituted by hydroxy or phenyl, or Rb may additionally be hydrogen; phenoxy optionally substituted by alkoxy of 1 to 4 carbon atoms; a 4- to 8-membered heterocyclic ring having at least one nitrogen atom or ring oxygen, this heterocyclic ring being optionally substituted by alkyl of 1 to 4 carbon atoms, aryl of 6 to 8 carbon atoms, aralkyl of 7 at 1 0 carbon atoms, alkoxycarbonyl of 1 to 4 carbon atoms, or a heterocyclyl of 4 to 8 members-alkyl of 1 to 4 carbon atoms; -NRdRe, where Rd is hydrogen or alkyl of 1 to 4 carbon atoms, and Re is alkyl of 1 to 4 carbon atoms, or Re is a 4 to 8 membered heterocyclic ring having at least one nitrogen atom or ring sulfur, which ring is optionally substituted by substituted halo-phenyl, or Re is arylsulfonyl of 6 to 8 carbon atoms optionally substituted by di- (1 to 10 carbon atoms) -amino; -SRf, wherein Rf is aryl of 6 to 8 carbon atoms or aralkyl of 7 to 10 carbon atoms optionally substituted by halo or haloalkyl of 1 to 4 carbon atoms; or -CONHR9, wherein R9 is cycloalkyl of 3 to 6 carbon atoms or aryl of 6 to 8 carbon atoms. A medicament according to any one of the preceding claims, wherein (A) is selected from the group consisting of 4-hydroxy-7- (1-hydroxy-2-. {2- 2- (4-phenyl) -butoxy) -phenyl] -ethylamino.}.-ethyl) -3H-benzo-thiazol-2-one; 7 - [(R) -2- (1,1-dimethyl-2-phenyl-eti-amino) -1-hydroxy-ethyl] -4-hydroxy-3H-benzothiazol-2-one; 4-hydroxy-7- formate. { (R) -1-Hydroxy-2- [2- (5,6,7,8-tetrahydro-naphthalen-2-yl) -ethylamino] -ethyl} -3H-benzothiazoI-2-one; 7 - [(R) -2 - ((1 S, 2 S) -2-benzyloxy-cyclo-pentylamino) -1-hydroxy-ethyl] -4-hydroxy-3 H -benzo-thiazol-2-one; and 7 - [(R) -2 - ((1 S, 2R) -2-benzyloxy-cyclopentylamino) -1-hydroxyethyl] -4-hydroxy-3H-benzothiazol-2-one. 6. A medicament according to any of the preceding claims, wherein (B) is a compound of formula X: or a 1,2-dihydro derivative thereof, wherein: Ra is alkyl of 1 to 4 carbon atoms optionally substituted by halogen (preferably chloro or fluoro), hydroxy, alkoxy of 1 to 4 carbon atoms, acyloxy, or by acylthio of 1 to 4 carbon atoms; or Ra is alkoxy of 1 to 4 carbon atoms or alkylthio of 1 to 4 carbon atoms optionally substituted by halogen; or Ra is heterocyclicthio of 5 to 6 members; or Ra is alkylthio of 1 to 4 carbon atoms optionally substituted by halogen (preferably chlorine or fluorine); either Rb is acyloxy and Rc is hydrogen or alkyl of 1 to 4 carbon atoms, or R and Rc together denote a group of formula XI: wherein Rd is alkyl of 1 to 4 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, and Re is hydrogen or alkyl of 1 to 4 carbon atoms, Xa and Xb are each independently hydrogen, chlorine or fluorine. A medicament according to any one of the preceding claims, wherein (B) is a compound selected from the group consisting of beclamethasone dipropionate, budesonide, fluticasone propionate, mometasone furoate, ciclesonide, triamsinolone acetonide, flunisolide, palmitate of rofleponide, butixocort propionate, icometasone enbutate, 8. A medicament according to any of claims 1 to 6, wherein (B) is a compound of formula XI I: wherein T is a monovalent cyclic organic group having from 3 to 15 atoms in the ring system. 9. A medicament according to claim 8, wherein T is a heterocyclic aromatic group having a 5-membered heterocyclic ring with one, two or three ring heteroatoms selected from nitrogen, oxygen, and sulfur, the ring being heterocyclic unsubstituted or substituted by one or two substituents selected from halogen, alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 atoms of carbon, cyano or hydroxy-alkyl of 1 to 4 carbon atoms, and the heterocyclic ring being optionally fused with a benzene ring. A medicament according to claim 8, wherein 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, hydroxy, acyloxy of 1 to 4 carbon atoms, amino, alkylamino of 1 to 4 carbon atoms, di- (alkyl of 1 to 4 carbon atoms) -amino, alkyl of 1 to 4 carbon atoms, hydroxy alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or alkylthio of 1 to 4 carbon atoms, and the heterocyclic ring optionally fused with a benzene ring. eleven . A medicament according to claim 8, wherein the indicated 6-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-methyI-2-thienyl, 5-methyl-3-isoxazolyl, 3,5-dimethyl-2-thienyl, 2,5-dimethyl-3-furyl, 4-methyl-2-furyl, - (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 of the preceding claims, which is in an 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 comprising (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 of claims 1 to 11, wherein (A) and / or (B) are present in an inhalable form as a dry powder comprising (A) and / or (B) finely divided , optionally together with at least one pharmaceutically acceptable particulate carrier. 14. A medicament according to claim 12 or 13, wherein (A) and / or (B) has an average particle diameter of up to 10 microns. 15. A medicament according to any of the preceding claims, wherein 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 the dry powder per capsule to between 5 milligrams and 50 milligrams; or a dry powder comprising, by weight, 20-2,000 parts of (A) in the form of the maleate salt, 25-800 parts of (B), and 2,000-25,000 parts of a pharmaceutically acceptable vehicle; or an aerosol comprising (A) and (B) in a proportion as specified hereinabove in claim 1 or 15, in a propellant, optionally together with a surfactant and / or a bulking agent and / or a co-agent. -suitable solvent to be administered 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 drive. The use of (A) as defined in any of the preceding claims, and of (B) as defined in any of the preceding claims, in the preparation of a medicament for combination therapy by simultaneous administration, in sequence , or separated from (A) and (B), in the treatment of an inflammatory or obstructive airway disease. 18. The use according to claim 17, wherein the inflammatory or obstructive airways disease is asthma or a chronic obstructive pulmonary disease. 19. A pharmaceutical kit comprising (A) as defined in any of claims 1, 3, 4 and 5 and (B) as defined in any of claims 1, 6, 7, 8, 9, 10 and 1 1, in separate unit dosage forms, these forms being suitable for the administration of (A) and (B) in effective amounts, together with one or more inhalation devices for the administration of (A) and (B). 20. A medication comprising, separately or together, (A) a compound of formula I as defined in the claim; and (B) a corticosteroid, for simultaneous, sequential, or separate administration in the treatment of an inflammatory or obstructive airway disease, substantially as described herein with reference to any of the Examples.