GB2230525A - 1-(Hydroxyphenyl)-2-aminoethanol derivatives - Google Patents

Abstract

Compounds are disclosed of formula (I> <IMAGE> and physiologically acceptable salts thereof, wherein W represents a group or <IMAGE> Z represents a group (CH2) qR<3> (where q is 0, 1 or 2 and R<3> is a hydroxy group or a group R<4>CONH-, R<4>NHCONH-, R<4>R<5>NSO2NH- or R<6>SO2NH); R<4> and R<5> represent hydrogen or a C1-3alkyl group; R<6> represents a C1-3alkyl group; R<1> and R<2> each independently represent hydrogen or a C1-3 alkyl group with the proviso that the sum total of carbon atoms in R<1> and R<2> is not more than 4; Q<1> and Q<2> each represent optionally substituted phenyl or pyridyl; X represents a bond or a C1-7alkylene, C2-7alkenylene or C2-7alkynylene group, and Y represents a bond or a C1-5 alkylene, C2-5alkenylene or C2-5alkynylene group with the proviso that the sum total of carbon atoms in X and Y is not more than 9.

Description

CHEMICAL COMPOUNDS This invention relates to phenethanolamine derivatives having a stimulant action at t -adrenoreceptors, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine.

Thus the present invention provides compounds of general formula (I)

and physiologically acceptable salts thereof, wherein W represents a group

Z represents a group (CH2)qR3 where q is 0, 1 or 2 and R3 is a group R4CONH-, R4NHCONH-, R4R5NSO2NH- or R6SO2NH; R4 and R5 each represent a hydrogen atom or a C1,3alkyl group; R6 represents a C1,3alkyl group; R1 and R2 each independently represent a hydrogen atom or a C1,3alkyl group with the proviso that the sum total of carbon atoms in R1 and R2 is not more than 4; Q1 and Q2 each independently represent a monocyclic aromatic group selected from phenyl and pyridyl;; when either of Q1 and Q2 represents a phenyl group, this may be unsubstituted or substituted by one or more substituents selected from halogen atoms, C1,4alkyl, C1,4alkoxy or hydroxy groups, or by an alkylenedioxy group of formula -O(CH2)pO- where p is 1 or 2; when either of Q1 and Q2 represents a pyridyl group, this may be unsubstituted or substituted by one or more substituents selected from halogen atoms, Cl~4alkyl, C1-elkoxy and hydroxy groups;; X represents a bond or a C1,7slkylene, C27alkenylene or C27alkynylene group, and Y represents a bond or a C1,selkylne, C25alkenylene or C25alkynylene group with the proviso that the sum total of carbon atoms in X and Y is not more than 9.

It will be appreciated that the compounds of general formula (I) possess at least one asymmetric carbon atom. The compounds according to the invention thus include all enantiomers, diastereomers and mixtures thereof, including racemates. Compounds in which the carbon atom in the -CH(OH)- group is in the R configuration are preferred.

As used herein the term alkenylene includes both cis and trans structures.

Conveniently R1 and R2 each represent a hydrogen atom or a methyl group. In particular, R1 and R2 conveniently both represent hydrogen atoms.

Z may conveniently represent, for example HOCH2-, HCONHCH2-, HCONH-, NH2CONH- or CH3S02NH-. In particular, Z conveniently represents HOCH2- or CH3 502 NH-.

Q1 and Q2 may each be, for example, an unsubstituted pyridyl or phenyl group.

When either of Q1 and Q2 represents a pyridyl group, this may be attached to the rest of the molecule at either the 2-, 3- or 4position. When the pyridyl group is substituted, the substituent(s) may be at the 2-, 3-, 4-, 5- or 6-position(s) in the ring.

When either of 91 and Q2 represents a subtituted phenyl group, the substituent(s) may be present at the 2-, 3-, 4-, 5- or 6-position(s) on the phenyl ring.

Examples of substituents which may be present on the aromatic rings represented by Q1 and Q2 include chlorine, bromine, iodine, fluorine atoms, methyl, ethyl, methoxy or ethoxy groups. Conveniently the aromatic rings represented by Q1 end Q2 are both unsubstituted.

Preferably, both Q1 and Q2 represent unsubstituted phenyl groups.

According to another preference, one of Q1 and Q2 represents an unsubstituted phenyl group and the other group is an unsubstituted pyridyl ring attached to the rest of the molecule at the 2-position.

The chain X may be for example -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2 )5-, -(CH2)6-, (CH2)2CH:CH-, -(CH2)2CEC-, -CH=CHCH2-, -CH=CH(CH2)2- or -CH2CECCH2-.

The chain Y may be for example a bond, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -CH2CH=CH- or -CH2CEC-.

Preferably the sum total of carbon atoms in chains X and Y is 4 to 9 inclusive.

Preferred compounds according to the invention are those in which R1 and R2 each represent hydrogen and Z represents a group HOCH2- or CH3SO2NH-.

Also preferred are compounds of formula (I) in which R1 and R2 both represent hydrogen and the total number of carbon atoms in the chains X and Y is 4, 5, 6, 7, 8 or 9.

According to a further preference, compounds according to the invention have Z as HOCH2- or CH3SO2NH- and both Q1 and Q2 as unsubstituted phenyl groups.

According to a further preference, Z is HOCH2- or CH3S02NH- and one of Q1 and Q2 represents an unsubstituted phenyl group while the other represents an unsubstituted pyridyl group.

Preferred compounds according to the invention include a l-C 11-[[[6-(2,2-Diphenylethoxy)hexyl]amino]methyl]-4-hydroxy-1,3- benzenedimethanol, 4-Hydroxy 1[ [[6- [4-phenyl-4- (2-pyridinyl)butoxy]hexyl]amino] msthyl]-1,3-benzenedimethanol, N-[5-[[2-[[6-(2,2-Diphenylethoxy)hexyl]amino]-l-hydroxyethyl]-2- hydroxyphenyl) )methanesulphonamide; and their physiologically acceptable salts.

Suitable physiologically acceptable salts of the compounds of general formula (I) include acid addition salts derived from inorganic and organic acids, such as hydrochlorides, hydrobromids, sulphates, phosphates, maleates, tartrates, citrates, benzoates, 4-methoxy-benzoates, 2- or 4-hydroxybenzoates, 4-chlorobenzoates, benzenesulphonates, p-toluenesulphonates, naphthalenesulphostes, methanesulphonates, sulphamates, ascorbates, salicylates, acetates, diphenylacetates, triphenylacetates, adipates, fumarates, succinates, lactates, glutarates, gluconates, tricarballylates, hydroxynaphthalenecarboxylates e.g. 1-hydroxy or 3-hydroxy-2naphthalenecarboxylates, or oleates. The compounds may also form salts with suitable bases where appropriate.Examples of such salts are alkali metal (e.g. sodium and potassium) and alkaline earth metal (e.g. calcium or magnesium) salts, and salts with organic bases (e.g.

triethylamine).

The compounds according to the invention have a stimulant action at ss2-adrenoreceptors, which furthermore is of a particularly advantageous profile. The stimulant action was demonstrated in the isolated trachea of the guinea-pig, where compounds were shown to cause relaxation of contractions induced by PCF, a or electrical stimulation. A prolonged duration of action has also been observed.

The compounds according to the invention may be used in the therapy or prophylaxis of conditions susceptible to amelioration by a compound possessing selective stimulant action at b -adrenoreceptors, particularly of diseases associated with reversible airways obstruction such as asthma and chronic bronchitis. Further examples of conditions which may be alleviated by administration of a compound possessing selective b -stimulant activity are inflammatory and allergic skin diseases, congestive heart failure, depression, premature labour, glaucoma and conditions in which there is an advantage in lowering gastric acidity, particularly in gastric and peptic ulceration.

The invention thus further provides compounds of formula (I) and their physiologically acceptable salts for use as an active therapeutic agent in particular for the treatment of conditions subject to amelioration by a compound possessing selective stimulant action at b -adrenoreceptors, for example diseases associated with reversible airways obstruction.

In a further or alternative aspect there is provided a method for the treatment of a disease associated with reversible airways obstruction in a mammal including man comprlsing administration of an effect amount of a compound of formula (I) or a physiologically acceptable salt thereof.

There is also provided in a further or alternative aspect use of a compound of formula (I) or a physiologically acceptable salt thereof for the manufacture of a medicament for the treatment of a condition which may be ameliorated by a compound having selective ss2-adrenoreceptor stimulant activity.

It will be appreciated by those skilled in the art that reference herein to treatment extends to prophylaxis as well as the treatment of established symptoms.

It is possible that a compound of the invention may be administered to a patient as the raw chemical, but it is preferable to present the active ingredient as a pharmaceutical formulation.

The invention accordingly provides a pharmaceutical formulation comprising a compound of formula (I) or a physiologically acceptable salt thereof together with one or more physiologically acceptable carriers and, optionally, other therapeutic and/or prophylactic ingredients. The carriers) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

The compounds may be formulated in a form suitable for administration by inhalation or insufflation, or for oral, buccal, parenteral, topical (including nasal) or rectal administration.

Administration by inhalation or insufflation is preferred.

For administration by inhalation the compounds according to the invention are conveniently delivered in the form of an aerosol spray presentation from pressurised packs, with the use of a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetraflurorethane, carbon dioxide or other suitable gas, or from a nebuliser. In the case of a pressurised aerosol the dosage unit may be determined by providing a valve to deliver a metered amount.

Alternatively, for administration by inhalation or insufflation, the compounds according to the invention may take the form of a dry powder composition, for example a powder mix of the compound an a suitable powder base such as lactose or starch. The powder composition may b presented in unit dosage form in for example capsules or cartridges of e.g. gelatin, or blister packs from which the powder may be administered with the aid of an inhaler or insufflator.

For oral administration, the pharmaceutical composition may take the form of, for example, tablets, capsules, powders, solutions, syrups or suspensions prepared by conventional means with acceptable excipients.

For buccal administration the composition may take the form of tablets, drops or lozenges formulated in the conventional manner.

The compounds of the invention may be formulated for parenteral administration by bolus injection or continuous infusion. Formulation for injection may be presented in unit dosage form in ampoules, or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.

For topical administration the pharmaceutical composition may take the form of ointments, lotions or creams formulated in a conventional manner, with for example an aqueous or oily base, generally with the addition of suitable thickening agents and/or solvents. For nasal application, the composition may take the form of a spray, formulated for example as an aqueous solution or suspension or as an aerosol with the use of a suitable propellant.

The compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g.

containing conventional suppository bases such as cocoa butter or other glyceride.

Where pharmaceutical compositions are described above for oral, buccal, rectal or topical administration, these may be presented in a conventional manner associated with controlled release forms.

A proposed daily dosage of active compound for the treatment of man is 0.005mg to lOOmg, which may be conveniently administered in one or two doses. The precise dose employed will of course depend on the age and condition of the patient and on the route of administration.

Thus a suitable dose for administration by inhalation is 0.005mg to 20mg, for oral administration is 0.02mg to loom, and for parenteral administration is O.Olmg to 2mg for administration by bolus injection and O.Olmg to 25mg for administration by infusion.

The compounds according to the invention may be prepared by any process known in the art for the preparation of compounds of analogous structure. In the following description, R1, R2, X, Y, Z, Ql and Q2 are as defined for general formula (I) unless otherwise specified.

In one general process (A), a compound of general formula (I) in which R1 is a hydrogen atom may be prepared by alkylation.

Conventional alkylation procedures may be used.

Thus, for example, in one process (a), a compound of general formula (I) in which R1 is a hydrogen atom may bs prepared by alkylation of an amine of general formula (Il)

(wherein R8 represents a hydrogen atom or a protecting group and R9 represents a hydrogen atom) followed by removal of any protecting groups where present.

The alkylation (a) may be effected using an alkylating agent of general formula (III)

(wherein L is a leaving group, for example a halogen atom such as chlorine, bromine or iodine, or a hydrocarbylsulphonyloxy group such as methanesulphonyloxy or p-toluenesulphonyloxy).

The alkylation is preferably effected in the presence of a suitable acid scavenger, for example inorganic bases such as sodium or potassium carbonate, organic bases such as triethylamine, diisopropylethylamine or pyridine, or alkylene oxides such as ethylene oxide or propylene oxide. The reaction is conveniently effected in a solvent such as acetonitrile or an ether e.g. tetrahydrofuran, a ketone e.g. butanone, a substituted amide e.g. dimethylformamide or 8 chlorinated hydrocarbon e.g. chloroform, at a temperature between ambient and the reflux temperature of the solvent.

According to another example (b) of an alkylation process, a compound of general formula (I) in which R1 represents a hydrogen atom may be prepared by alkylation of an amine of general formula (II), as previously defined except that R9 is a hydrogen atom or a group convertible thereto under the reaction conditions, with a compound of general formula (ivy) :

in the presence of a reducing agent, followed when necessary by removal of any protecting groups.

Examples of suitable R9 groups convertible into a hydrogen atom are arylmethyl groups such as benzyl, a-methylbenzyl and benzhydryl.

Suitable reducing agents include hydrogen in the presence of a catalyst such as platinum, platinum oxide, palladium, palladium oxide, Raney nickel or rhodium, on a support such as charcoal, using an alcohol, e.g. ethanol or methanol, or an ester, e.g. ethyl acetate, or an ether, e.g. tetrahydrofuran, or water, as reaction solvent, or a mixture of solvents, e.g. a mixture of two or more of those just described, at normal or elevated temperature and pressure, for example from 20 to 10d C and from 1 to 10 atmospheres.

Alternatively when one or both of R8 and R9 are hydrogen atoms, the reducing agent may be a hydride such as diborane or a metal hydride such as sodium borohydride, sodium cyanoborohydride or lithium aluminium hydride. Suitable solvents for the reaction with these reducing agents will depend on the particular hydride used, but will include alcohols such as methanol or ethanol, or ethers such as diethyl ether or tetrahydrofuran.

When a compound of formula (II) where R8 and R9 are each hydrogen atoms is used, the intermediate imine of formula (V) may b formed

Reduction of the imine using the conditions described above, followed, where necessary, by removal of any protecting groups gives a compound of general formula (I).

In another general process (B) compounds of formula (I) may be prepared by reducing an intermediate of general formula (VI)

wherein at least one of Xl, X2, X and Y represents a reducible group and the other(s) take the appropriate meaning as follows, which is X1 is -CH(OH)-, X2 is -CH2NR8- (where R8 represents a hydrogen atom or a protecting group), and X and Y are as defined in formula (I), followed where necessary by the removal of any protecting groups.

Suitable reducible groups include those wherein X1 is a group/ C=O, X2 is a group -CH2NR10- (wherein R10 represents a group convertible to hydrogen by catalytic hydrogenation, for example an arylmethyl group such as benzyl, benzylhydryl or a-methylbenzyl), or -CONH-, X is an alkenylene or alkynylene group, Y is an alkenylene or alkynylene group.

The reduction may be effected using reducing agents conveniently employed for the reduction of ketones, amides, protected amines, alkenes and alkynes.

Thus, for example, when X1 in general formula (Il) represents a C:0 group this may be reduced to a -CH(OH)- group using hydrogen in the presence of a catalyst such as platinum, platinum oxide, palladium palladium oxide, Raney nickel or rhodium, on a support such as charcoal, using an alcohol e.g. ethanol, an ester e.g. ethyl acetate, an ether e.g. tetrahydrofuran, or water, as reaction solvent, or a mixture of solvents, e.g. a mixture of two or more of those just described, at normal or elevated temperature and pressure, for example from 20 to 100C and from 1 to 10 atmospheres. Alternatively, the reducing agent may be, for example, a hydride such a diborane or a metal hydride such as lithium aluminium hydride, sodium bis(2methoxyethoxy) aluminium hydride, sodium borohydride or aluminium hydride.The reaction may be effected in an appropriate solvent, such as an alcohol e.g. methanol or ethanol, or an ether such as tetrahydrofuran, or a halogenated hydrocarbon such as dichloromethane.

When X2 in general formula (VI) represents a -CH2NR10- group this may be reduced to a -CH2NH- group using hydrogen in the presence of a catalyst as described above.

When X2 in general formula (VI) represents a -CONH- group, tbis may be reduced to a group -CH2NH2- using a hydride such a diborane or a complex metal hydride such as lithium aluminium hydride in a solvent such as an ether e.g. tetrahydrofuran or diethyl ether.

When X and/or Y in general formula (VI) represents an alkenylene or alkynylene group, this may be reduced to an alkylene group using hydrogen in the presence of a catalyst as described above.

Alternatively, when X and/or Y represents an alkynylene group, this may be converted to an alkenylene group, using for example hydrogen and a lead-poisoned palladium on calcium carbonate catalyst in a solvent such as pyridine, or lithium aluminium hydride in a solvent such as diethyl ether at low temperature.

Where it is desired to use a protected intermediate of general formula (VI) it is particularly convenient to use protecting groups which are capable of being removed under the reducing conditions, for example hydrogen and a catalyst, thus avoiding the need for a separate deprotection step. Suitable protecting groups of this type include arylmethyl groups such as benzyl, benzhydryl anda-methylbenzyl.

In the above reduction process, and also in the preparation of intermediates, care must be taken to avoid the use of hydrogen and a catalyst when products are required in which X and/or Y represent alkenylene or alkynylene groups.

In a further process (C) compounds of formula (I) may be prepared by deprotecting an intermediate of general formula (VII)

wherein R8 is a protecting group andtor at least one of W, Q1 and Q2 contains a protecting group(s).

The protecting group may be any conventional protecting group as described for example in "Protective Groups in Organic Synthesis", by Theodora Greene (John Wiley and Sons Inc, 1981). Thus, for example, hydroxyl groups may be protected by arylmethyl groups such as benzyl, diphenylmethyl or triphenylmethyl, by acyl groups such a acetyl, or as tetrahydropyranyl derivatives. Examples of suitable amino protecting groups inculde arylmethyl groups such as benzyl, a-methylbenzyl, diphenylmethyl or triphenylmethyl, and acyl groups such as acetyl, trichloroacetyl or trifluoroacetyl.

The deprotection to yield a compound of general formula (I) may be effected using conventional techniques. Thus for example arylmethyl groups may be removed by hydrogenolysis in the presence of a metal catalyst (e.g. palladium on charcoal). Tetrahydropyranyl groups may be cleaved by hydrolysis under acidic conditions. Acyl groups may be removed by hydrolysis with an acid such as mineral acid e.g. hydrochloric acid, or a base such as sodium hydroxide or potassium carbonate, and a group such as trichloroacetyl may be removed by reduction with, for example, zinc and acetic acid.

Intermediates of formula (VI) for use in the reduction process (B) in which X1 is the group ) C=O may be prepared by reaction of a haloketone of formula (VIII) W--COCH2Hal (VIII) (where Hal represents a halogen atom e.g. bromine) with an amine of formula (IX)

(where R8 is a hydrogen atom or a group convertible thereto by catalytic hydrogenation).

The reaction may be effected in a cold or hot solvent, for example tetrahydrofuran, dioxan, chloroform, dichloromethane, dimethylformamide, acetonitrile, a ketone such as butanone or an ester such as ethyl acetate, preferably in the presence of a base such as diisopropylethylamine, sodium carbonate or other acid scavenger such as propylene oxide.

It is convenient not to purify the intermediates of formula (VI) formed by reaction of a haloketone of formula (VIII) with an amine of formula (IX), but to reduce the crude reaction product to give a compound of formula (I).

Amines of formula (II) and haloketones of formula (VIII) are either known compounds or may be prepared by methods analogous to those described for the preparation of known compounds.

Suitable methods for preparing intermediates of formula (iii), (IV), (V) and (VI) are described in UK Patent Specification Nos.

2140800A and 2159151A and in the exemplification included hereinafter.

In the general processes described above, the compound of formula (I) obtained may b in the form of a salt, conveniently in the form of a physiologically acceptable salt. Where desired, such salts may be converted to the corresponding free bases using conventional methods.

Physiologically acceptable salts of the compounds of general formula (I) may be prepared by reacting a compound of general formula (I) with an appropriate acid or base in the presence of a suitable solvent such as acetonitrile, acetone, chloroform, ethyl acetate or an alcohol, e.g. methanol, ethanol or isopropanol.

Physiologically acceptable salts may also be prepared from other salts, including other physiologically acceptable salts, of the compounds of general formula (I), using conventional methods.

When a specific enantiomer of a compound of general formula (I) is required, this may be obtained by resolution of a corresponding racemate of a compound of general formula (I) using conventional methods.

Thus, in one example an appropriate optically active acid may be used to form salts with the racemate of a compound of general formula (I). The resulting mixture of isomeric salts may be separated for example by fractional crystallisation, into the diastereoisomeric salts from which the required enantiomer of a compound of general formula (I) may be isolated by conversion into the required free base.

Alternatively, enantiomers of a compound of general formula (I) may be synthesised from the appropriate optically active intermediates using any of the general processes described herein.

Specific diastereoisomers of a compound of formula (I) may be obtained by conventional methods for example, by synthesis from an appropriate asymmetric starting material using any of the processes described herein, or by conversion of a mixture of isomers of a compound of general formula (I) into appropriate diastereoisomeric derivatives e.g. salts which then can be separated by conventional means e.g. by fractional crystallisation.

The following examples illustrate the invention. Temperatures are in OC. 'Dried' refers to drying using magnesium sulphate or sodium sulphate. Unless otherwise stated, thin layer chromatography (t.l.c.) was carried out on. silica and flash column chromatography (FCC) on silica (Mercki9385). The following solvent systems may be used : System A - toluene:ethanol:0.88 ammonia (90:10:1); System B toluene:ethanol:0.88 ammonia (80:20:1); System C - toluene:ethanol: triethylamine (95:5:1). The following abbreviations are used : THF tetrahydrofuran, TAB - tetra-n-butylammonium hydrogen sulphate.

Example 1 &alpha;1 [[[6-(2,2-Diphenylethoxy)hexyl]amino]methyl]-4-hydroxy-1,3- benzenedimethanol Ci) 1 ,1-(2-( (6-Bromohexyl)oxy]ethylidene]bis(benzene] A mixture of 2,2-diphenylethanol (59), 1,6-dibromohexane (11.6ml), TAB (314mg) and sodium hydroxide solution (50S w/v, 12.5ml) was stirred at room temperature for 6h. The mixture was diluted with water (125ml) and extracted with ether (3 x 125ml). The extracts were dried and evaporated. The residue was purified by FCC, eluting with hexane:ether, 19:1, to give (i) (4.59), t.l.c. (hexane:ether, 19:1) Rf 0.47.

(ii) N-[6-C2,2-Diphenylethoxy)hexyl)benzenemethanamine A mixture of ( C4.5g) and benzylamine (13.5ml) was heated at 10d C for 3h. Excess benzylamine was removed by distillation. The residue was dissolved in 8% sodium hydrogen carbonate solution (50ml) and extracted with ethyl acetate (3 x 50ml). The extracts were dried and evaporated. The residue was purified by FCC eluting with System A to give (ii)(4.6g), t.l.c. (System B) Rf 0.64.

(iii) &alpha;-[[[6-(2,2-Diphenylethoxy]hexyl]amino]methyl]-4-hydroxy-1,3- benzenedimethanol A solution of (ii) (1.59), 2-bromo-1-[4-hydroxy-3-(hydroxymethyl) phenyl]ethanone (1.059) and N,N-diisopropylethylamine (0.81m1) in THF (50ml) was stirred st room temperature under nitrogen for 24h. The solvent was evaporated and the residue dissolved in ethanol (50m1) and hydrogenated over a mixture of 5S platinum (250mg) and 5% palladium (250mg) on charcoal catalysts. The catalysts were removed by filtration and the filtrate evaporated. Purification of the residue by FCC, eluting with System A, gave a brown oil (1.049) which was triturated with hexane:ether, 9:1, to give the title compound as a white powder m.p. 78 C.

Analysis Found C,75.1; H,8.0; N,2.9.

C29H37N04 requires C,75.1; H,8.0; N,3.0% Example 2 4-Hydroxye 1-[[[6-(4-phenyl-4-C2-pyridinyl)butoxy]hexyl]amino]methyl]- 1,3-benzenedimethanol (E)-butenedioate (2:1) salt (i) 4-Phenyl-4-(2-pyridinyl)-3-buten-1-ol A solution of n-butyllithium in hexane (1.55M, 24ml) was added dropwise to a solution of 3-hydroxypropyltriphenylphosphonium bromide (7.3g) in THF (lOOml) at -100C under nitrogen. The solution was stirred at 00 for 0.75h and a solution of 2-benzoylpyridine (2.59) in THF (lOml) was added dropwise during 10 min. The solution was stirred at 0 for 2h and quenched with water (lOOml). The mixture was extracted with ethyl acetate (2 x SOml), the extracts dried and evaporated.Purification of the residue by FCC, eluting with ether:hexane (1:1 to 1:0), gave (i) (1.08g), t.l.c. (ether) Rf 0.3 (ii) 2-[4-[(6-Bromohexyl)oxy]-1-phenyl-1-butenyl]pyridine Prepared similarly to Example l(i) from Example 2(i) (l.û8g) and 1,6-dibromohexane (4.19). Purification by FCC, eluting wth hexane: ether (1:0 to 3:1), gave Example 2(ii) (730mg), t.l.c. (ether) Rf 0.6.

(iii) N-[6-[[4-Phenyl-4-(2-pyridinyl)-3-butenyl]oxy]hexyl] benzenemethanamine Prepared similarly to Example 1(it) from Example 2(ii) (730mg) and benzylamine (3ml). Purification by FCC, eluting with System C, gave Example 2(iii) (790mg), t.l.c. (System C) Rf 0.25.

(iv) 4-Hydroxy-a1 -[ [[6-[4- phenyl-4-( 2-pyridinyl) butoxy] hexyl] amino] methyl]-1,3-benzenedimethanol (E )-butenedioate (2:1) salt A solution of Example 2(iii) (790mg), 2-bromo-l-[4-hydroxy-3- (hydroxymethyl)phenyl]ethanone (461mug) and N,N-diisopropylethylamine (0.39ml) in THF (80ml) was stirred at room temperature under nitrogen for 24h. The solvent was evaporated. The residue was dissolved in ethanol (50ml) and hydrogenated over a mixture of pre-reduced 5 platinum oxide (250mg) and 10% palladium oxides (250mg) on charcoal.

The catalysts were removed by filtration and the filtrate evaporated.

The residue was purified by FCC, eluting with System A, to give a pale yellow gum. The gum was dissolved in methanol (lOml) and a solution of fumaric acid (54mg) in methanol (5ml) added. The solvent was evaporated to give the title compound as a pale yellow foam (47Omg), m.p.

Analysis Found C,67.4; H,7.7; N,4.9 C30H40N204.0.5C4H404.H20 requires C,67.6; H,7.8; N,4.9S Example 3 N-[5-[[2-[[6-(2,2-Diphenylethoxy)hexyl]amino]-1-hydroxyethyl]-2- hydroxyphenyl] )methanesulphonamide A solution of Example 1(ii) (2.29), N-(5-(bromoacetyl)-2- (phenylmethoxy)phenyl]methanesulphonamide (2.29) and N,Ndiisopropylethylamine (0.859) in dichloromethane (50ml) was stirred at room temperature under nitrogen for 24h. The mixture was diluted with water (150ml) and extracted with ether (2 x 150ml). The extracts were dried and evaporated. The residue was dissolved in ethanol/methanol (3:1, lOOml) and hydrogenated over a mixture of pre-reduced 5S platinum oxide (500mg) and 10S palladium oxide (500mg) on charcoal.

The catalysts were removed by filtration and the filtrate evaporated.

Purification of the residue by FCC, eluting with System A, gave a solid which was triturated with ether to give the title compound as a white solid (1.169), m.p. 147 .

Analysis Found C,66.0; H,7.3; N,5.2; S,6.0.

C29H38N205S requires C,66.1; H,7.3; N,5.3; 5.6.1S

Claims (11)

1. CLAIMS: 1. Compounds of general formula (I)

   wherein W represents a group

   Z represents a group (CH2)gR3 where q is 0, 1 or 2 and R3 is a hydroxy group or a group R4CONH-, R4NHCONH-, R4R5NSo2NH- or R6S02NH; R4 and R5 each represents a hydrogen atom or a C1,3alkyl group; R6 represents a C1-3alkyl group; R1 and R2 each independently represents a hydrogen atom or a C1-3alkyl group with the proviso that the sum total of carbon atoms in R1 and R2 is not more than 4;; Q1 and Q2 each independently represents a monocyclic aromatic group selected from phenyl and pyridyl wherein the phenyl group may be unsubstituted or substituted by one or more substituents selected from halogen atoms, C14alkyl, C1-4alkoxy or hydroxy groups, or by an alkylenedioxy group of formula -O(CH2)pO- where p is 1 or 2 and the pyridyl group may be unsubstituted or substituted by one or more substituents selected from halogen atoms, C14alkyl, C1-4alkoxy and hydroxy groups;; X represents a direct bond or a C1-7alkylene, C27alkenylene or C27alkynylene group, and Y represents a direct bond or a C1-5alkylene, C25alkenylene or C25alkynylene group with the proviso that the sum total of carbon atoms in X and Y is not more than 9 and physiologically acceptable salts thereof.
2. 2. Compounds according to claim 1, wherein, in the general formula (I), Q1 and Q2 each represents an unsubstituted phenyl group.
3. 3. Compounds according to claim 1, wherein, in the general formula (I), one of Q1 and Q2 represents an unsubstituted phenyl group and the other group is an unsubstituted pyridyl ring attached to the rest of the molecule at the 2-position.
4. 4. Compounds according to any of claims 1 to 3, wherein, in the general formula (I), the sum total of carbon atoms in chains X and Y is 4 to 9 inclusive.
5. 5. Compounds according to any of claims 1 to 4, wherein, in the general formula (I), R1 and R2 each represent hydrogen.
6. 6. Compounds according to claim 1, wherein, in the general formula (I), Z represents HOCH2- or CH3S02NHand Q1 and Q2 each represents an unsubstituted phenyl group.
7. 7. Compounds according to claim 1, wherein, in the general formula (I), Z represents HOCH2 or CH3SO2NH- and one of Q1 and Q2 represents an unsubstituted phenyl group while the qther represents an unsubstituted pyridyl group.
8. 8. Compounds according to claim 1, selected from &alpha;1- [[[6-(2,2-Diphenylethoxy)hexyl)amino]inethyl)- 4-hydroxy-l, 3-benzenedimethanol, 4-Hydroxy- &alpha;1-[[[6-[4-phenyl-4-(2- pyridinyl)butoxy]hexyl]amino]methyl]-1,3- benzenedimethanol, N-[5-[[2-[[6-(2,2-Diphenylethoxy)hexyl)amino]-l- hydroxyathyl]-2-hydroxyphenyl])methanesulphonamide; and the physiologically acceptable salts thereof.
9. 9. A pharmaceutical composition comprising, as active ingredient, or compound of general formula (I) as defined in claim 1 or a physiologically acceptable salt thereof together with one or more physiologically acceptable carriers therefor.
10. 10. A pharmaceutical composition according to claim 9, formulated for administration by inhalation or insufflation.
11. 11. A pharmaceutical composition according to claim 10, formulated in unit dosage form containing 0.005 mg to 20 mg active ingredient.