PH26576A - Phenenthanolamine derivatives - Google Patents

Description

So o-

PHENETHANOLAMINE DERIVATIVES

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

Phenethanolamine derivatives of the general formula

Ar-GHEH NHR

OH in which Ar represents groupings of the type described hereinafter, and R represents inter alia an alkyl, arelkyl, aryloxyslkyl or an optionally substituted phenylalkyloxyalkyl group have previously been described as bronchodilators having stimulant activity at p-adrenoreceptors.

Thus, for example, British Patent Specification No. 1200886 describes phenethanolamine compounds of the general structure - < oz 2a

X R : 7 . \ I 08 ig *— CH , 2’ RE

To eo

HO—e e OH boo = © \ / | = — nh — vo © <7 ——— i - 8 E: te in which X represents inter alia a hydroxyC _ alkyl} group; tf Pe represents a hydrogen atom or an optionally branch C ,- 2lEV1 groupj’

R, represents inter alia a hydrogen atom; and R, represents a hydrogen atom or an optionally branched C,., alkyl group, optionally substituted by hydroxyl or emino groups or heterocyclic rings, or R represents a cycloalkyl, aralkyl or aryloxyalkyl group, optionally substituted by one or more alkoxy or hydroxyl groups.

UK Patent Specification No. 2140800 describes phenethanolamine compounds of the general structure

HOCH, — eo Ri 4 A

HO__e «CHCH NHC(CH ) och) Ar \ / | m n

PR on R2

INCOMPLETE DOCUMENT 2

BAD ORIGINAL ttt petite an imnd!

in which R! and RZ each represent hydrogen or C,_3 alkyl; m is an integer from 2 to B; n is an integer from 1 to 7; and Ar represents en optionally substituted phenyl ring.

We have now found a novel group of phenethanolamine derivatives : which differ in structure from those described previously (for example, British and UK Patent Specification Nos. 1200886 and 2140800), and have a desirable and potentially useful profile of activity.

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

Lod

Ar—CHCHNHE (CH) X(CH,) Y(CH,) Z-Q (1) k m n

OH R? and physiologically acceptable salts and solvates (e.g. hydrates) thereof, wherein

Ar represents the group

HoQ! \ . *—e

V4 \ (a) HO—-e -— \ / *-——e (where Q! represents a straight or branched C,-, alkylene group), 2 q NH, (b) — y \

HO—e -— \ / —— (where Q2 represents a group R3C0-, R3NHCO-, R¥R™NSO ~ or R>SO ,-, where R3 and R* each represent a hydrogen atom or a C,- 3 elkyl group, and R> represents a C,-3 alkyl group),

HO

\ [ J (c) 7 \ * oe ’ \ / [ J /

HO

Cl FC \ \ [ JE—— —_. (d) / \ (e) / \ d) HN - or e) H Neo —

TN ANY

So ST cL cl

R represents a hydrogen atom or a C-3 alkyl group;

R! and R2 each independently represent a hydrogen atom or a methyl or ethyl group; and k represents an integer from 1 to B; : m represents zero or an integer from 2 to 7, and; n represents an integer from 1 to 7 with the proviso that the sum total of k, m and n is 4 to 12;

X represents an oxygen Or sulphur atom, and;

Y and Z each represent a bond, or an oxygen OT sulphur atom with the proviso that when Y is a bond m is zero, or when Y represents an oxygen or sulphur atom m is an integer from 2 to 7, or when Y and Z each independently represent an oxygen or sulphur atom then n is an integer from 2 to 7;

Q represents a naphthalenyl group which may optionally be substituted by one or two groups selected from C,_, alkyl, C _, alkoxy, hydroxy and halogen.

It will be appreciated that the compounds of general formula (1) possess one or more asymmetric carbon atoms. The compounds according to the invention thus include all enantiomers, diastereoisomers and mixtures thereof, including racemates. Compounds in which the carbon atom in the -CH(OH)- group is in the R configuration are preferred.

In the general formula (I), the chain ~(CH,)y- may be for example a bond, -CH,—, -(cH,) , -(CH,) 4 -{CH,) fs -(CH,) -, -(CHp)g- or =(CH2)/-. The chains ~(CH2)p- and —-(CH2)y~ may be for example ~(CHy) y=, =(CH,) y=, =(CH,) =, —(CH,)6= or —(CH,) & or the chain ~(CH,)y~ may be a bond.

Preferably the total number of carbon atoms in the chains -(CHy y=, =(CH,)p~ and -(CH,)- is 6 to 12 inclusive. Compounds wherein the sum total of carbon atoms in the chains -(CH,)-, ~(CH,)y and -(CH,)n- is 6, 7, 8, 9, 10 or 11 are particularly preferred.

Examples of compounds of general formula (I) ere those wherein X represents an oxygen or sulphur atom and Y and Z each represent a bond. Further examples are those wherein X represents an oxygen or sulphur atom, Y represents a bond and Z represents an oxygen or sulphur atom. Still further examples of compounds of general formula (1) are those wherein X, Y and Z each represent oxygen or sulphur atoms.

A preferred group of compounds of general formula (I) are those in which X is an oxygen atom. Within this group of compounds Y preferably represents a bond or an oxygen atom and Z represents a bond or an oxygen or sulphur atom.

Preferred compounds from within this group are those wherein X is an oxygen atom, Y is a bond and 7 is a bond, or X is an oxygen atom, Y is a bond and Z is an oxygen or sulphur atom.

In the compounds of formula (I) R may be, for example, a methyl, ethyl, propyl or isopropyl group. R, R! and RZ are each preferably a hydrogen atom or a methyl group.

A preferred group of compounds are those in which R represents a hydrogen atom.

Another preferred group of compounds are those wherein RL! and RZ are both hydrogen atoms, or R! is a hydrogen atom and R% is a C _, alkyl group, particularly a methyl group, or R! is a methyl group and

RZ is a methyl group.

In the compounds of formula (I), Q! may be, for example, -CH,-, —CH(CH3)-, -(CH,),- or -(CH,);-. A preferred group of compounds are those in which Q! represents -CH ,-.

Q2 may represent for example HCO-, CH CO-, HNCO-, (CH ,) NSO o~ Or

CH3S02-

QZ preferably represents HCO- or, more particularly, CH S50 ,-.

The group Q is attached to the rest of the molecule through any available position on the naphthalenyl moiety. Any substituent(s) in the group Q may be attached to either the same or different rings of the naphthalenyl moiety. When the group Q is substituted by one or two halogen atoms, these may be chlorine, fluorine or bromine.

A preferred group of compounds of general formula (1) are those wherein Q is an unsubstituted naphthslenyl moiety attached to the remainder of the molecule at the 1- or 2- position.

A further group of preferred compounds of formula (I) are those in which the group Q is substituted by a single substituent, for example, a methoxy group.

In one preferred group of compounds of general formula (I) Ar represents group (a) wherein Q' represents -CH ~-, or group (b) wherein

Q? represents CH,S0,-, or group (c) or group (d); R represents a hydrogen atom; R! represents & hydrogen atom or a methyl group; R? represents a hydrogen atom; X represents an oxygen atom; Y represents a bond; Z represents a bond or an oxygen or sulphur atom; and k is 5, m is zero and n is an integer from 1 to 4.

Preferred compounds according to the invention are 4-hydroxy-a’- [[[6-[2-(2-naphthalenyl)ethoxylhexy]aminolmethyl]-1,3-benzenedi- methanol, 4-amino-3, 5-dichloro-a-[ [[6-[3-(6-methoxy-2-naphthalenyl)propoxyl- hexyllaminolmethyllbenzenemethanol, 5_[1-hydroxy-2-[[6-[ (2-naphthalenyl)ethoxyhexyl]aminolethyl]-1,3- benzenediol,

N-[2-hydroxy-5-[1-hydroxy-2-[[6-[4-[ (2-nephthalenyl)oxyJbutexylhexyl]- aminoJethyllphenyllmethanesulphonamide, and 4-hydroxy-a -[[[6-[2-(1-naphthalenyl)ethoxyhexyl]aminolmethyl]- 1,3-benzenedimethanol, and their physiologically acceptable salts and solvates.

Suitable physiologically acceptable salts of the compounds of general formula (I) include acid addition salts derived from inorganic and organic acids, such as hydrochlorides, hydrobromides, sulphatres, phosphates, maleates, tartrates, citrates, benzoates, 4-methoxy- benzoates, 2- or 4-hydroxybenzoates, 4-chlorobenzoates, benzene- sulphonates, p-toluenesulphonates, naphthalenesulphonates, methane- sulphonates, sulphamates, ascorbates, salicylates, acetates, diphenylacetates, triphenylacetates, edipates, fumarates, succinates, lactates, glutarates, gluconates, tricarballylates, hydroxynephthalenecarboxylates e.g. l-hydroxy- or 3-hydroxy-2- naphthalenecarboxylates, 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 B,-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 PGF ,a or electrical stimulation. A prolonged duration of action has also been observed.

The compounds according to the invention may be used in the treatment of diseases associated with reversible airways obstruction such as asthma and chronic bronchitis.

The compounds according to the invention are also indicated as useful for the treatment of inflammatory and ellergic skin diseases, congestive heart failure, depression, premature labour, glaucoma, and in the treatment of conditions in which there is an advantage in lowering gastric acidity, particularly in gastric and peptic ulceration.

The invention accordingly further provides compounds of formula (I) and their physiologicelly acceptable salts and solvates for use in the therapy or prophylaxis of diseases associated with reversible airways obstruction in human or animal subjects. . 35 The compounds according to the invention may be formulated for administration in any convenient way. The invention therefore includes within its scope pharmaceutical compositions comprising at least one compound of formule (1) or a physiologically acceptable selt or solvate thereof formulated for use in human or veterinary medicine.

Such compositions may be presented for use with physiologically acceptable carriers or excipients, optionally with supplementary medicinal agents.

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

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, dichlorotetrafluoroethane, 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 and a suitable powder base such as lactose or starch. The powder composition may be 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 conventional menner.

The compounds of the invention may be formulated for parenteral administration by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form in ampoules, or in multi-dose containers with en added preservative. The compositions

- 8B - 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 Lo formulated for example as an aqueous solution or suspension or as an aerosol with the use of a suitable propellent.

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 100mg, 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 100mg, and for parenteral administration is 0.0lmg to 2mg for administration by bolus injection and 0.0lmg to 25mg for administration by infusion.

The compounds according to the invention may be prepared by a number of processes. In the following description, Ar, k, m, n, X, Y,

Z, Q, R, R! and R? are as defined for general formula (I) unless otherwise specified. In the preparation of both intermediates and end-products the final step in the rcaction may be the removal of a protecting group. Suitable protecting groups and their removal are described in general process (3) below.

In one general process (1), a compound of general formula (I) 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 R! is a hydrogen atom may be prepared by alkylation of an emine of general formula (11)

R

Ar CHEHNR 6R/ (11) bi (wherein R® is a ryebagen atom or a protecting group and R/ is a hydrogen atom) followed by removal of any protecting group where present.

The alkylation (a) may be effected using an alkylating agent of - 15 general formula (III):

LOH(CH,) X (City) V(CH,) 2-8 (111)

RZ

(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 or dioxan, a ketone e.g. butanone or methyl isobutyl ketone, a substituted amide e.g. dimethylformamide or a chlorinated hydrocarbon e.g. chloroform, at a temperature between ambient end the reflux temperature of the solvent.

According to another example (b) of an alkylation process, a compound of genersl formula (1) in which R! represents a hydrogen atom may be prepared by alkylation of an amine of general formula (11), es previously defined except that R/ is a hydrogen atom or a group convertible thereto under the reaction conditions, with a compound of general formula (IV):

R2CO(CH,) X(CH,) ¥(CH,) Z-Q (Iv) > in the presence of a reducing agent, followed when necessary by removal of any protecting groups.

Examples of suitable R/ groups convertible into a hydrogen atom are arylmethyl groups such as benzyl, a-methylbenzyl and benzhydryl. lo Suitable reducing agents include hydrogen in the presence of a catalyst such as platinum, platinum oxifer 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 1s 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 100°C and from 1 to 10 atmospheres.

Alternatively when one or both of Ré and R/ 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 particuler hydride used, but will include alcohols such as methanol or ethanol, or ethers such as diethyl ether or tert-butyl methyl ether, or tetrahydrofuran.

When a compound of formula (II) where R® and R/ are each 2 hydrogen atoms is used, the intermediate imine of formula (V) may be formed:

R

I LIECRY (Ch,) v(CH,) 1-0 (v)

OH R?

Reduction of the imine using the conditions described above, followed, where necessary, by removal of any protecting groups, gives compound of general formula (1.

In another general process (2) compounds of formula (I) may be prepared by reducing an intermediate of general formula (VI):

~ 11 -

R!

An 1X (01), X01) Y(CH,) 7-Q (v1) na m n wherein at least one of X! and X2 represents a reducible group and the 3 other{s) take the appropriate meaning as follows, which is x!is _CH(OH)- and X2 is -CHRNRS- (where R® represents a hydrogen atom or a protecting group), followed where necessary by removal of any protecting groups.

Suitable reducible groups include those wherein X! is a, group

Ye=0 and X2 is a group -CHRNRS- (wherein R® represents a ovol convertible to hydrogen by catalytic hydrogenation, for example an arylmethyl group such as benzyl, benzhydryl or a-methylbenzyl).

The reduction may be effected using reducing agents conveniently employed for the reduction of ketones or protected amines.

Thus, for example, when X! in general formula (VI) represents a

Je=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, Reney 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 100°C and from 1 to 10 atmospheres. Alternatively, the reducing agent may be, for example, a hydride such as diborane or a metal hydride such as lithium aluminium hydride, sodium bis (2-methoxyethoxy) 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 20 dichloromethane.

When X2 in general formula (VI) represents a -CHRNR 8 group this may be reduced to a -CHRNH- group using hydrogen in the presence of a ’ catalyst as described above. ¥

Where it is desired to use a protected intermediate of general formula (VI) it is particularly convenient to use a protecting group

R® which is 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 yroups of this type } include arylmethyl groups such as benzyl, benzhydryl and a-methylbenzyl.

In the above reduction process, and also in the preparation of intermediates, care must be taken when using a hydride reducing agent and end-products are required in which Q% represents the group R %CO-.

In a further process (3) compounds of formula (I) may be prepared by deprotecting an intermediate of general formula (VII)

R Ri pe CHCHIRS C= (C11) X(OH,) YC) 2 (vi) ol R? wherein R® is a protecting group, and/or at least one of the hydroxy group(s) in Ar is protected, and/or the group Q contains a protecting group. }

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 as acetyl, or as tetrahydropyranyl derivatives. Examples of suitable amino protecting groups include 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 a miners) 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 ascetic acid.

Intermediates of formula (VI) for use in the reduction process (2) in which X! is the group See may be prepared by reaction of a haloketone of formula (VIII)

R

Ar__COCHIal (VIII) (where Hal represents a halogen atom e.g. bromine) with an amine of formula (IX) rl

RONH-L- (CH) X(CH,) Y(CH,) Z-Q (Ix) 1a k m n (where R® 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, tert-butyl methyl ether, dioxan, chloroform, dichloromethane, dimethylformsmide, acetonitrile, a ketone such as butanone or methylisobutylketone, 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.

Intermediates of general formula (VI) in which Xx! js the group

Je=0 may be reduced to the corresponding intermediate in which X! is the group —CH(DH)~- using for example & metal hydride such as sodium borohydride in a solvent e.g. ethanol, methanol and/or tetrahydrofuran.

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

Intermediates of formula (III) may be prepared from the corresponding alcohols of formula (X) using methods capable of effecting the conversion gene YE (x)

For example compounds of formula (III) where L represents a halogen atom may be prepared by reaction of the compounds of formula > (X) with a halogenating agent such as a triphenylphosphine- tetrahalogenomethane adduct (conveniently formed in situ e.g. by the reaction of triphenylphosphine and carbon tetrabromide). The reaction may take place in the presence of a solvent such as a chlorinated hydrocarbon (e.g. dichloromethane) at a temperature range of 0-30VY.

Alcohols of formula (X) may be prepared by reacting a compound of formula (XI)

L-(cH,) Y(cH,) 7-Q (XI) m n (where L is as defined above) with a compound of formula (XII)

HO-CH- (CH) XH (X11)

RZ

The reaction may take place optionally in a solvent such as an ether (e.g. tetrahydrofuran or 1,2-dimethoxyethane), an alcohol (e.g. methanol) or an amide (e.g. dimethylformamide) at a temperature up to the boiling point of the solvent. The reaction may be effected by first generating the anion of the compound of general formula (XII) by adding for example sodium, sodium hydride, potassium hydroxide or sodium hydroxide.

Compounds of formula (XI) may be prepared from the corresponding compounds of formula (XIII)

HO-(CH,) Y(CH,) 2-0 (XIII) using methods capable of effecting the conversion. For example when L in general formula (XI) represents a hydrocarbylsulphonyloxy group (e.g. methanesulphonyloxy) such compounds may be prepared by reacting the compounds of formula (XIII) with methanesulphonyl chloride in the presence of a base (e.g. triethylamine). The reaction conveniently takes place in the presence of a solvent such as a halogenated hydrocarbon (e.g- dichloromethene) at a temperature ranging from 0-259. ‘ Compounds of formula (XIII) in which Y represents an oxygen or sulphur atom may be prepared by reacting a compound of formula (XIV) with a compound of formula (XV)

L-(CH,) 7-Q (XIV) Ho(cH ,) YH (XV) n m under conditions as described for the preparation of compounds of formula (X) above.

Compounds of formula (XIV) are either known compounds or may be prepared from the corresponding alcohols as described for the preparation of compounds of formula (IIL) above.

Compounds of formulae (XII) and (XV) are either known compounds or may be prepared by methods analogous to those used for the preparation of known compounds.

In addition, suitable methods for preparing intermediates of formulae (111), (IV), (IX), (XI), (XIII) end (XIV) are described in UK

Patent Specifications Nos. 2140800A and 2159151A and in the exemplification included hereinafter. oo In the general processes described above, the compound of formula (I) obtained may be 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 (1) with an eppropriate acid or base in the presence of a suitable solvent such as acetonitrile, acetone, chloroform, ethyl acetate or an 10 alcohol, e.g. methanol, ethanol or isopropanol.

Physiologically acceptable salts may also be prepared from other salts, including other physiologicelly acceptable salts, of the compounds of general formula (I), using conventional methods. when a specific enantiomer of a compound of general formula (1) 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 en appropriate optically active acid may be used to form salts with the racemate of a compound of general formula (1). 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 YC. 'Dried' refers to drying using magnesium sulphate or sodium sulphate. Unless otherwise stated, thin layer chromatography (t.1.c.) was carried out on silica and flash column chromatography (FCC) on silica (Merck 9385) using one of the following solvent systems: A-ethyl acetate:methanol:triethylamine, B - toluene:ethanol: 0.88 ammonia, C - toluene:ethanol:triethylamine. The following abbreviations are used : DMF - dimethylformamide, TAB - tetra-n- butylammonium hydrogen sulphate, DEA - N,N-diisopropylethylamine.

Intermediate 1 2-[2-[ (6-Bromohexyl)oxylethyl]naphthalene 2-Naphthaleneethanol (3g), 1,6-dibromohexane (8ml), TAB (0.5g) end sodium hydroxide (8g) in 16ml water) were stirred at room temperature under nitrogen for 26h Water (80ml) was added and the mixture extracted with diethyl ether (3x100ml). The combined extracts were v washed with water (80ml), brine (80ml), dried and evaporated to give a colourless oil (13g). The oil was purified by FCC eluting with cyclohexane (22) and then cyclohexane-ethyl acetate (40:1) to give the title compound, (4.23g), as a colourless oil, t.1.c. (cyclohexane- ethyl acetate; 5:1) Rf 0.45.

Intermediate 2 1-[2-[ (6-Bromohexyl)oxy Jethyl naphthalene 1-Naphthaleneethanol (3.00g) end 1,6-dibromohexane (12.73g) were treated according to the method of Intermediate 1. FCC eluting with | cyclohexane followed by ethyl acetate-cyclohexane (1:20, then 1:4) gave the title compound (4.329) as a colourless oil.

Analysis Found: C,64.5; H,6.65; Br,23.75.

C,eH,,Br0 requires C,64.5; H,6.9; Br,23.85%.

Intermediate 3 1-[[ (5-Bromopentyl)oxy methyl Inaphthalene 1-Naphthalenemethanol (6.00g) and 1,5-dibromopentane (11.5ml1) were . treated according to the method of Intermediate 1. FCC eluting with ether-cyclohexane (1:4952:48) gave the title compound as a colourless oil (B.4lg), t.l.c. (Cyclohexane-ether 19:1) Rf 0.22;

Intermediate 4 7-[ (1-Naphthalenyl)methoxy]-2-heptanone 1-[[ (5-Bromopentyl)oxyJmethyl]naphthalene (9.969) in dry ether (40m1) was added to magnesium turnings (0.94g) and iodine (one small crystal) under nitrogen with stirring at a rate which maintained a gentle reflux. The mixture was stirred at reflux for 30min, cooled to ambient temperature and added over 2.5h to acetic anhydride (7.67ml) in ether (15ml) at -78Y under nitrogen with vigorous stirring. After 2h at -789, the mixture was allowed to warm to -10Y and treated with aqueous saturated ammonium chloride (50ml). Ether (50ml) was added, the aqueous layer was separated and the ethereal layer was washed with 1M-aqueous sodium hydroxide (100ml). The combined aqueous washings were extracted with ether (100ml) and this extract was combined with 40 the ethereal layer sbove. The dried ethereal solution was evaporated and the residual oil purified FCC. Flution with ether-cyclohexane

(1:4) gave, after Kugelrohr distillation, the title compound es a colourless oil (3.39g), b.p. 190%9/0.3 Torr (Kugelrohr).

Intermediate 5

N-[6-[[3-[6-Methoxy-2-naphthalenyl]-2-propynylJoxyJhexyl] benzenemethanamine

Nitrogen was bubbled through a mixture of N-[6-[(2-propynyl)oxyl- hexyl]benzenemethanamine (4.149), 2-bromo-6-methoxynaphthalene (4.0g) and dicyclohexylamine (5.82g) in acetonitrile (60m%) for 15 min.

Bis(triphenylphosphine)palladium (11) chloride (120mg) and copper (I) iodide (10mg) hi added and the mixture was stirred at reflux under nitrogen for 4h, cooled, diluted with ether (100m%), filtered and the filtrate evaporated in vacuo. Purification by FCC eluting with System

B (90:10:1) gave the title compound as a brown oil (1.18g), t.l.c. (System B 40:10:1) Rf 0.19.

Intermediate 6 (2)-N-[5-[1-Hydroxy-2-[[6~[3-(6-methoxy-2-naphthalenyl)-2-propenyloxy] hexyl] (phenylmethyl)aminolethy1]-2-(pheny methoxy) phenyl]methane- sulphonamide

A solution of N-[5-(bromoacetyl)-2-(phenylmethoxy)phenyl]methane- sulphonamide (0.96g), N-[6-[3-(6-methoxy-2-naphthalenyl)-2- propynyloxy Jhexyllbenzenemethanamine (1.38g) and DEA (0.47g) in dichloromethane (22m2) was stirred at room temperature under nitrogen for 22h, diluted with water (100m%) end extracted with dichloromethane (2x100m2). The combined orgenic extracts were dried and evaporated in vacuo to give an oil. The oil was dissolved in methanol (20mg) and dichloromethane (20m2) and sodium borohydride (0.25g) were added portionwise to the solution at 00°C under nitrogen. The solution was stirred at room temperature for lh, cooled to 0% and a further portion of sodium borohydride (0.lg) added. The solution was stirred at room temperature for 30 min and then carefully diluted with water (10m2) and evaporated in vacuo. The residue was partitioned between dichloromethane (100m%) and water (100mf). The aqueous phase was re-extracted with dichloromethane (100m) and the combined ergenic fractions dried and evaporated in vacuo to give an oil. Purification

~ 19 - by FCC eluting with System C (100:2:1) gave the title compound as a colourless oil (0.77g), t.l.c (System C 98:2:1) Rf 0.23.

Intermediate 7 4-Amino-3,5-dichloro-a-[[[6-[[3-[6-methoxy-2-naphthalenyl] —2-propyny1loxylhexyl] (phenylmethyl)amino]methyl]benzenemethanol

A solution of 1-(4-amino-3,5-dichloro)-2-bromoethanone (0.789),

N-[6-[ [3-[6-methoxy-2-naphthalenyl]-2-propyny1Joxy JhexylJbenzene- methanamine (1.1g) and DEA (0.399) in tetrahydrofuran (25m1) was stirred under nitrogen for 20h. he mixture was filtered and the filtrate evaporated jn vacuo to give an oil. The oil was dissolved in methanol (20ml) and dichloromethane (30ml) and sodium borohydride (0.28g) added portionwise to the solution at 09C under nitrogen. The solution was stirred at room temperature for 2h, cooled to 0UC and a further portion of sodium borohydride (0.14g) added. The solution was then stirred at room temperature for lh, carefully diluted with water (10ml) and evaporated in vacuo. The residue was partitioned between ethyl acetate (100ml), water (100ml), the aqueous phase was re—extracted with ethyl acetate (100ml) and the combined organic fractions dried and evaporated in vacuo to give an oil. Purification by FCC eluting with System C (100:1:1) gave the title compound as a colourless oil (1.18g), t.l.c (System C 98:2:1) Rf 0.53

Intermediate 8 4-[ (2-Naphthalenyl)oxyJbutanol

A mixture of 2-[(4-bromobutyl)oxylnaphthalene (5.5g), sodium acetate (13.1g), trioctylpropylammonjum chloride (1.21g) and water (19m2) was stirred at ca 100° for 2h. 2N sodium hydroxide solution (32m2) and ethanol (32mf) were added to the cooled mixture which was stirred for a further 10min at room temperature. The ethanol was evaporated in vacuo and the residue diluted with brine (150mg) and extracted with ether (2x100mg), which was dried and evaporated in vacuo to give a white solid. The solid was dissolved in ether and purified by FCC eluting with hexane-ether (2:1+1:2) to give the title : 35 compound as a white solid (1.369), m.p. 66.5-67.59.

Intermediate 9 2-[4-[ (6-Bromohexyl)oxy lbutoxy Inaphthalene

A mixture of 4-[ (2-naphthalenyl)oxylbutanol (2.4qg), 1,6-dibromohexane (5.3m2), TAB (lg) and 50% sodium hydroxide solution (24mf) was stirred at room temperature for 19h. The mixture was diluted with water (100m) end extracted with ether (2x150mf). The combined orgenic fractions were dried and evaporated in vacuo to give an oil.

Purification by FCC eluting with hexane followed by hexane-ether (19:1 + B:1) gave the title compound as a colourless oil, (2.34g), t.l.c. (ether-hexane 1:1) Rf 0.85.

Intermediate 10

N-[6-[4-[ (2-Naphthalenyl)oxy]butoxylhexyl]lbenzenemethanamine 2-[4-[ (6-Bromohexyl)oxylbutoxy naphthalene (2.25g) and benzylamine (3.88g) were stirred under nitrogen at ca. 125Y for 2h. The solution was diluted with 8% sodium bicarbonate (100m) and extracted with diethyl ether (2x100mf%), dried and evaporated in vacuo to give an oil.

Purification by FCC eluting with System C (98:2:1) gave the title compound as a yellow oil (2.3g), t.l.c. (System C 40:10:1) Rf 0.71.

Intermediate 11 2-[[2-[ (6-Bromohexyl)oxylethyl]thiolnaphthalene

A mixture of 1,6-dibromohexane (9m), 50% w/v sodium hydroxide (40mg), 2-(2-naphthalenyl)thioethanol (4g), TAB (0.8g) and hexane (30m%) was stirred vigorously at 20%, under nitrogen for 4h. Water (100m2) and ether (100m) were added and the mixture was further extracted with ether (100, 2x50m%). The combined, dried ether extracts were evaporated in vacuo to give a yellow oil. Purification by FCC eluting with light petroleum (b.p. 60-809):ether (30:1+1:1) gave the title compound as a white crystalline solid (5.7g), m.p. 38-400 (softens 360).

~ 21 -

Example 1 4-tlydroxy-a!-[[[6-[2-(2-naphthalenyl)ethoxylhexyl]aminolmethyll-1,3- benzenedimethanol «!- (Aminomethyl)-4-hydroxy-1,3-benzenedimethanol (1.31qg), 2-[2-[(6- bromohexyl)oxylethyl]naphthalene (2g) and DEA (D0.83mg) in DMF (dried over type 4A sieves, 20m) were stirred at 1000 under nitrogen for 2h.

The cooled mixture was poured into aqueous saturated sodium bicarbonate (80m2) and extracted with ethyl acetate (3 x 100mg). The combined extracts were washed (water, 100m%), dried and evaporated to give a yellow tacky solid (3.5g). This solid was adsorbed onto silica (Merck 7734, 2g) from methanol and the resultant silica gel plug was applied to an FCC column. Elution with System A (89:10:1) gave a white solid (0.95g), which crystallised from ethyl acetate (20mg) to give the title compound (0.32g) as a white solid, m.p. 112-1149,

Analysis Found: C,73.3; H,8.2; 'N,3.1.

C, M3 NO, -0.201,0 requires C,73.5; H,8.1; N,3.2%.

Water analysis, 0.2 mole water

Example 2 4-Hydroxy-a'~[[[6-[2-(1-nephthalenyl)ethoxyJhexyllamino]methyl]-1,3- benzenedimethanol

A mixture of «l= (aminomethyl)-4-hydroxy-1,3-benzenedimethanol (0.75q), 1-[2-[ (6-bromohexy1)oxy Jethyl]naphthalene (1.00g), DEA (0.85m2) in DMF (6.5m) was heated at 800% for 2h. The clear brown solution was diluted with water (65m%), acidified to pH4 with 2N hydrochloric acid and then basified to pli8 with solid potassium bicarbonate. The mixture was extracted with ethyl acetate (2x65m%) and the combined extracts were washed with water (65m) and brine (30m%). The dried extracts were evaporated, the residue dissolved in ethyl acetate-methanol (1:1) and absorbed onto silica (Merck 7734, 5.00g).

The silica gel plug was applied to an FCC colunn and elution with

System A (90:10:1) gave the title compound (0.229) as a white solid m.p. 1059-107°.

Analysis Found: C,73.1; H,7.85; N,3.1.

C, Hy NO, 0.33H,0 requires C,73.1; H,8.1; N,3.1%.

Example 3 4-Nydroxy-a!~[[[1-methyl-6-[[ (1-naphthalenyl)methyl]oxylhexyl]amino]- methyl]-1,3- benzenedimethanol 7-1 (1-naphthalenyl)methoxy]-2-heptanone (1.00g) and a!-[[bis(phenyl methyl)aminolmethyl]-4-hydroxy-1,3-benzenedimethanol (1.34g) in ethanol (40ml) were hydrogenated over pre-reduced 10% palladium oxide-on-carbon (0.2g) snd 5% platinum oxide-on-carbon (0.2g) at room temperature and pressure. The catalyst was removed (hyflo) end the solution evaporated. The residual oil was purified by FCC, eluting with System A (94:5:1) to give a white solid (704mg). The white solid was further purified by repeating the chromatography procedure to give the title compound as a white solid (469mg) m.p. 99-1010

Analysis Found: C,73.7;1,8.5;N,3.15.

C,,H4,NO, requires C,74.1;H,8.05;N,3.2%.

Example 4

N-[2-Hydroxy-5-[1-hydroxy-2-[[6-[3-(6-methoxy-2-naphthalenyl)propoxy J- hexyLlamino]ethy Llpheny 11methanesulphonamide

A solution of Z-N-[5-[1-hydroxy-2-[6-[3-(6-methoxy-2-naphthalenyl)- 2-propenyloxy Jhexyl] (phenylmethyl)aminolmethyl]benzenemethanol (0.73g) in absolute ethanol (30m%) was hydrogenated over pre-reduced 10% palladium on charcoal catalyst {(0.4g) in absolute ethanol (10m). The mixture was filtered through hyflo and evaporated jn vacuo. The resultant solid was dissolved in dichloromethane (50m%) and washed wit 8% sodium bicarbonate (50m). The aqueous phase was re-extracted withh dichloromethane (50m) and the combined organic extracts dried and evaporated jin vacuo to give a solid. Trituration with diethyl ether gave the title compound as an off-white solid (0.25g), m.p. 87-89Y.

Analysis found: C,63.2; H,7.1; N,5.1.

CogHyyN,0,S5.0.25H,0 requires C,63.4; H,7.4; N,5.1%.

Example 5 4-Amino-3,5-dichloro-a-[[[6-[3-(6-methoxy-2-naphthalenyl )propoxy]- hexyl]aminolmethyl]benzenemethanol

A solution of 4-amino-3,5-dichloro-a-[[[6-[{3-[6-methoxy-2- naphthalenyl]-2-propynyl]oxylhexyl](phenylmethyl)aminolmethyllbenzene- methanol (1.11g) in absolute ethanol (50ml) was hydrogenated over pre-reduced 10% palladium on charcoal catalyst (0.4g) in sbsolute ethanol (10ml) containing hydrochloric acid (1:9 conc. hydrochloric acid/ethanol, 1.67ml). The mixture wes filtered through hyflo and evaporated in vacuo to give an oil. The oil was partitioned between dichloromethane (150ml) and 8% sodium bicarbonate (100ml). The aqueous phase was re-extracted with dichloromethane (100ml) and the combined organic extracts dried and evaporated in vacuo to give an oil.

Purification by FCC eluting with System C (95:5:1) gave the title compound as a white solid (513mg), m.p. 102.5 - 103.50.

Analysis Found: C,64.5;H,7.5; N,5.3; c1,13.9.

C,gl35CL N20; requires C,64.7; H,7.0; N,5.4; C1,13.6%

Example 6 5-[1-Hydroxy-2-[[6-[ (2-naphthalenyl)ethoxylhexyllaminolethyll-1,5= benzenediol, 4,4" ~methy lenebisl 3-hydroxy-2-nsphthalenecarboxylate] (2:1) salt.

A mixture of 5-(2-amino-1-hydroxyethyl)-1,3-benzenediol (1.029), 2-[3-[ (6-bromohexyl)oxylethyllnaphthalene (1.349) and DEA (1.74ml) in

DMF (25ml) was heated at 1009 for 3h under nitrogen. The solvent was removed in vacuo end the residue purified by FCC eluting with System B (80:20:1) to give the base as a solid pink glass (0.8g).

A mixture of the base (0.4g) and 4,4" -methylenebis[3- hydroxy-2-naphthalenecarboxylic acid] (0.18g) in methanol (30m) was heated under reflux for 30min. The methanol was removed in vacuo and the residue triturated under ether {20m2) to give the title compound as an off-white solid (0.52g), m.p. 105-110° (softens 1009).

Analysis found : C,70.2; H,6.9; N,2.1. (CHO) Colt (0-2-5010 requires C,70.35; H,6.85; N,2.2%.

Example 7

N-[ 2-Hydroxy-5-[1-hydroxy-2-[[6-[4-[ (2-naphthalenyl)oxylbutoxy J- hexyllaminolethyl]lphenyl]methanesulphonamide

A solution of N-[5-(bromoacetyl)-2-(phenylmethoxy)phenyllmethane- sulphonamide (1.96), N-[6-[4-[ (2-nephthalenyl)oxy Joutoxyl- hexyl]benzenemethanamine (2.04) and DEA (0.96g) in dichloromethane (45m2) was stirred under nitrogen at room temperature for 22h. The mixture was treated with water (100m2) and extracted with dichloromethane (2x150m2). The combined organic extracts were dried and evaporated in vacuo to give an oil which was dissolved in methanol (30m2) end dichloromethane (20m2) and cooled to 0-5% under nitrogen.

Sodium borohydride (0.50g) was added portionwise and the solution stirred at room temperature for 30min, then carefully diluted with water (20mf). The solvent was evaporated in vacuo, the residue partitioned between water (100m1) and dichloromethane (150m) end the aqueous phase re-extracted with dichloromethane (150m%), the combined organic extracts being dried and evaporated in vacuo to give an 0il which was purified by FCC eluting with System C (95:5:1). A solution of the oil (3.41g) in absolute ethanol (60mf) was hydrogenated over pre-reduced 10% palladium on charcoal catalyst (50% aqueous paste, 1.5g) in absolute ethanol (10mR) for 4.5h. The mixture was filtered through hyflo and evaporated in vacuo to give an oil which was purified by FCC eluting with System B (40:10:1) to give a cream solid. Trituration with diethyl ether gave the title compound as a white solid (1.23g), m.p. 99.5-100.59.

Analysis Found: C,64.1; H,7.3; N,5.2.

C,yHy N05 requires C,63.9; H,7.4; N,5.1%.

Example 8

N-[2-Hydroxy-5-[1-hydroxy-2-[[6-[4-[ (2-naphthalenyl)oxyJbutoxyJhexyl]- amino]ethy1]phenyllmethanesulphonamide, 4,4'-methylenebis- [3-hydroxy-2-naphthalenecarboxylate] salt (2:1)

A solution of N-[2-hydroxy-5-[2-hydroxy-2-[[6-[4-[ (2- naphthalenyl)- oxy ]butoxylhexyllaminolethyllphenyl]methanesulphonamide (449mg) in methanol (17mg) and 4,4 '-methylenebis[3-hydroxy-2- naphthalenecarboxylic acid] (160mg), was heated at reflux for lh, cooled, filtered and the filtrate evaporated in vacuo. The residue was triturated with dry ether to afford the title compound as an of f-white foam (413mg), m.p. 100-106".

Assay Found: C,65.0; H,6.6; N,3.7; S,4.2.

C,ogH,N,0,5.0.5C, H, 0,.0.5H.0 requires C,65.0; H,6.65 N,3.75; S,4.3%.

Example 9 4-tydroxy-a'-[[[6-[2-[ (2-nephthalenyl) thiolethoxylhexyl]aminolmethy L]- 1,3-benzenedimethanol

A solution of «!-(aminomethyl)-4-hydroxy-1,3-benzenedimethenol (1.09), 2-[[2-[ (6-bromohexyl)oxyJethyllthiolnaphthalene (1.01g) and

DEA (0.52g) in dry DMF (30m) was stirred at 100Y under nitrogen for 4h. The solvent was evaporated and the residue purified by FCC eluting with System B (39:10:1) to give a pale brown solid (0.769).

Trituration under ether (2x50m%) gave the title compound as a cream coloured solid (0.39g,), m.p. 101-27.

Analysis Found: €,68.9; H,7.65; N,3.03 S5,6.6.

C, H3,NO,S requires C,69.05; H,7.5; N,3.0; S5,6.8%.

The following are examples of suitable formulations of compounds of the invention. The term 'active ingredient' is used herein to represent a compound of the invention.

Tablets (Direct Compression) mg/tablet

Active ingredient 2.0

Microcrystalline cellulose usp 196.5

Magnesium Stearate BP 1.5 —_—

Compression weight 200.0

The active ingredient is sieved through a suitable sieve, blended with the excipients and compressed using 7mm diameter punches.

Tablets of other strengths may be prepared by altering the ratio of active ingredient to microcrystalline cellulose or the compression weight and using punches to suit.

The tablets may be film coated with suitable film forming materials, such as hydroxypropylmethylcellulose, using standard techniques. Alternatively, the tablets may be sugar coated.

- 26 =

Metered Dose Pressurised Aerosol (Suspension Aerosol) mg/metered dose Per can

Active ingredient micronised 0.100 26.40mg

Oleic Acid BP 0.100 2.64mg

Trichlorofluoromethane BP 23.64 5.679

Dichlorodifluoromethane BP 61.25 14.70g

The active ingredient is micronised in a fluid energy mill to a fine particle size range. The oleic acid is mixed with the {x ichlorof Luorome thane at a temperature of 10-15% and the micronised drug is mixed into the solution with a high shear mixer. The suspension is metered into aluminium aerosol cans and suitable metering valves delivering 85mg of suspension are crimped onto the cans and the dichlorodifluoromethane is pressure filled into the cans through the valves.

Inhalation Cartridges mg/cartridge

Active ingredient micronised 0.200

Lactose BP to 25.0

The active ingredient is micronised in a fluid energy mill to a fine particle size range prior to blending with normal tabletting grade lactose in a high energy mixer. The powder blend is filled into

No. 3 hard gelatin capsules on a suitable encapsulating machine. The i contents in the cartridges are administered using a powder inhaler such as the Glaxo Rotahaler.

Claims (14)

WE_CLAIM:

1. A compounds of formula (I) e > 2 ? 5 TE 1 & NO a) R R < 2 T z = IY al = : on ~C, -— HS Ar —— CHCHNHC(CH2) X(CH2) Y (CH3) 2-9" o (IY nm n : pa mel js iy - we OH R2 = fs \ Ww "ER or a physiologically acceptable salt or solvate thereof, wherein Ar represents the group HOQ! (a) HO _/ y— where Ql represents a straight or branched Cj.jalkylene group, Q2NH (b) HO — where Q2 represents a group rR3co-, R3INHCO-, R3IRANSO,- or R%505-, where R3 and R? each represent a hydrogen atom or a Cj-3alkyl group, and R?® represents a Cj-3alkyl group, HO (c) N-, — HO cl F3C (d) wd) , Or (e) wd) ; Cl Cl R represents a hydrogen atom or a Cj_jalkyl group: Rl and R? each independently represent a hydrogen atom or a methyl or ethyl group; and

. k represents an integer from 1 to 8: m represents zero or an integer from 2 to 7, and; n represents an integer from 1 to 7 with the proviso that the sum total of k, m and n is 4 to 12; X represents an oxygen or sulphur atom, and; Y and Z each represent a bond, or an oxygen or sulphur atom with the proviso that when Y¥ is a bond m is zero, or when Y represents an oxygen or sulphur atom m is an integer from 2 to 7, or when Y and Z each independently represent an oxygen or sulphur atom then n is an integer from 2 to 7; Q represents a naphthalenyl group which may optionally be substituted by one or two groups selected from Cj.galkyl, Ci-galkoxy, hydroxy and halogen.

2. A compound according to Claim 1 in which the sum total of carbon atoms in the chains - (CH), -, =(CH2) - and -(CHp) - is 6, 7, 8, 9, 10 or 11.

3. A compound according to Claim 1 in which X is an oxygen atom, Y is a bond and Z is a bond or X is an oxygen atom, Y¥ is a bond and Z is an oxygen or sulphur atom.

4, A compound according to Claim 1 in which R represents a hydrogen atom.

5. A compound according to claim 1 in which Rl is a hydrogen atom and R? is a hydrogen atom or a cjp-3alkyl group or RL is a methyl group and R2 is a methyl group.

6. A compound according to claim 1 in which ol represents -CHj-, -CH(CH3)=-, —(CHp)a- or -(CHp)3-.

7. A compound according to claim 1 in which 02 represents HCO-, CH3CO~-, HpNCO-, (CH3) 2NSO3- or CH3S0;,-.

8. A compound according to Claim 1 in which Q is an unsubstituted naphthalenyl moiety attached to the remainder of the molecule at the 1- or 2- position or Q is a naphthalenyl moiety substituted by a single methoxy group.

9. A compound according to claim 1 in which Ar represents group (a) wherein ol represents -CHp-, Or group (b) wherein 02 represents CH3SO-, Or group (c) or group (d); R represents a hydrogen atom; RL represents a hydrogen atom or a methyl group: RZ represents a hydrogen atom; X represents an oxygen atom; Y represents a bond; Zz represents a pond or an oxygen or sulphur atom; and k is 5, m is zero and n is an integer from 1 to 4.

10. A compound selected from: 4-hydroxy-«l-[[[6-[2-(2-naphthalenyl)ethoxylhexyl]- amino]methyl]-1,3-benzenedimethanol; 4—amino-3,5-dichloro-«-[[[6-[3-(6-methoxy-2-naphthalenyl)- propoxy Jhexyl]amino]methyl]benzenemethanol, 5-(l-hydroxy-2-[(6-[(2-naphthalenyl)ethoxyjhexyl]}= aminojethyl]-1,3-benzenediol;

N-[{2-hydroxy-5-[1-hydroxy-2-[(6-[4-([ (2-naphthalenyl)oxy]- butoxylhexyl]amino]ethyl]phenyl ]methanesulphonamide; 4-hydroxy-«l-[[[6-[2-(l-naphthalenyl)ethoxy]hexyl]- amino]methyl]~1,3~benzenedimethanol; and physiologically acceptable salts and solvates thereof.

11. A pharmaceutical composition for therapy or prophylaxis of a disease associated with reversible airways obstruction such as asthma or chronic bronchitis, which comprises an effective amount to alleviate said disease of at least one compound of formula (I) as defined in claim 1 or a physiologically acceptable salt or solvate thereof, together with a physiologically acceptable carrier or excipient. y

12. A pharmaceutical composition for the treatment of premature labour, depression, congestive heart failure, an inflammatory or allergic skin disease, glaucoma or a condition in which there is an advantage in lowering gastric acidity such as gastric or peptic ulceration, which comprises an effective amount to alleviate said condition of at least one compound of formula (I) as defined in claim 1 or a physiologically acceptable salt or solvate thereof, together with a physiologically acceptable carrier or excipient.

13. A method of therapy or prophylaxis of a disease associated with reversible airways obstruction such as asthma or chronic bronchitis in a patient, which comprises administering to said patient an effective amount to alleviate said disease of a compound of formula (I) as defined in claim 1 or a physiologically acceptable salt or solvate thereof. ¥

14. A method of treating a patient suffering from premature labour, depression, congestive heart failure, an inflammatory or allergic skin disease, glaucoma or a condition: in which there is an advantage in lowering gastric acidity such as gastric or peptic ulceration, which method comprises administering to said patient an effective amount to alleviate said condition of a compound of formula (I) as defined in claim 1 or a physiologically acceptable salt or solvate thereof. 5934/4 t