GB2230524A - Alpha-piperidine-2-yl- and alpha-pyrrolidin-2-yl benzyl alcohol derivatives - Google Patents

Abstract

Compounds are disclosed of formula (I> <IMAGE> and physiologically acceptable salts and solvates (e.g. hydrates) thereof, wherein Ar represents the group <IMAGE> (where Q<1> represents C1-3 alkylene), <IMAGE> (where Q<2> represents R<3>CO-, R<3>NHCO-, R<3>R<4>NSO2- or R<5>SO2-, where R<3> and R<4> are hydrogen or C1-3 alkyl, and R<5> is C1-3 alkyl), <IMAGE> X represents a bond, or a C1-7 alkylene, C2-7 alkenylene or C2-7 alkynylene chain, and Y represents a bond, or a C1-6 alkylene, C2-6 alkenylene or C2-6 alkynylene chain with the proviso that the sum total of carbon atoms in the chains X and Y is not more than 10; Z represents a bond or a -CH2- group; and Q represents an optionally substituted phenyl or pyridyl group. The compounds (i) have stimulant action at B2-adrenoreceptors and may be used in the treatment of conditions associated with reversible airways obstruction, such as asthma and bronchitis, and in the treatment of inflammatory and allergic skin diseases, congestive heart failure, depression, premature labour, glaucoma and gastric and peptic ulceration. Pharmaceutical compositions containing the compounds (I) as active ingredient are disclosed and also processes for the production of the compounds.

Description

CHEMICAL COMPOUNDS This invention relates to phenethanolamine derivatives having a stimulant action at p2 -adrenoreceptors, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine.

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

and physiologically acceptable salts and solvates (e.g. hydrates) thereof, wherein Ar represents the group

(where 91 represents a straight or branched C1.3 alkylene group),

(where Q2 represents a group R3CO-, R3NHCO-, R3R4NSO2- or R5S02-, where R3 and R4 each represent a hydrogen atom or a C1.3 alkyl group, and R5 represents a C1.3 alkyl group),

X represents a bond, or a C1.7 alkylene, C2.7 alkenylene or C2.7 alkynylene chain, and Y represents a bond, or a C1.6 alkylene, C2.6 alkenylene or C2.6 alkynylene chain with the proviso that the sum total of carbon atoms in the chains X and Y is not more than 10; Z represents a bond or a -CH2- group; and Q represents a phenyl group which may optionally be substituted by one or more groups selected from halogen atoms, C1.3 alkyl, C1.3 alkoxy or hydroxy groups, a group of formula -CONR3R4 or by an alkylenedioxy group of formula -O(CH2)pO- (where p is 1 or 2), or q represents a pyridyl group which may optionally be substituted by one or more groups selected from C1.4 alkyl, C1.4 alkoxy, hydroxy and halogen.

It will be appreciated that the compounds of general formula (I) possess at least three 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 definition of general formula (I), the term alkenylene includes both cia and trans structures.

In the general formula (I), the chain X may be for example a bond, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -CH2CEC-, -(CH2)2CH=CH-, -(CH2)2C--C-, -CH=CHCH2-, -CH=CH(CH2)2- or -CH2C=CCH2-. The chain Y may be for example a bond, -CH2-, -(CH2)2-, -(CH2)3., -(CH2)4-, -(CH2)5- -(CH2)6-, -CH=CH-, -CC-, -CH2CH=CH- or -CH2C=C-.

Preferably the total number of carbon atoms in the chains X and Y is 4 to 10 inclusive. Compounds wherein the sum total of carbon atoms in the chains X and Y is 4, 5, 6, 7, 8 or 9 are particularly preferred.

In the compounds of formula (I), 91 may be, for example, -CH2-, -CH(CH3)-, .(CH2)2- or -(CH2)3.. A preferred group of compounds are those in which Q1 represents -CH2-.

may represent for example HCO-, CH3CO-, H2NCO-, (CH3)2NSO2- or, more preferably, CH3SO2..

In the compounds of formula (I) q may be, for example, an unsubstituted pyridyl or phenyl group.

When Q represents an optionally substituted pyridyl group, this may be attached to the rest of the molecule at either the 2-, 3- or 4-position. 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 q represents a substituted phenyl group, this may contain one or more substituents which may be present at the 2-, 3-, 4-, 5- or 6-position(s) on the phenyl ring.

Examples of the optional substituents which may be present on the phenyl group represented by q include chlorine, bromine, iodine, fluorine, methyl, ethyl, methoxy, ethoxy, -CONH2, -CON(CH3)2, -CON(CH2CH3)2 or -CON(CH2CH2CH3)2.

A particularly preferred group of compounds of formula (I) is that in which Q represents a phenyl group optionally substituted by the group -CON(CH2CH3)2.

Preferred compounds according to the invention are 5-[hydroxy-[6-[4-(3-phenylpropoxy)butyl]-2-piperidinyl]methyl]- 1,3-benzenediol, 4-hydroxy-&alpha;-[6-[4-(3-phenylpropoxy)butyl)-2-piperidinyl]-1,3- benzenedimethanol, cis-N,N-diethyl 4-4-CCS-6-Chydroxy-4-hydroxy-3- [(methanesulphonyl)amino]phenyl]methyl]-2-piperidinyl]pentyl)oxy).

butylgbenzamide, 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, sulphates, phosphates, maleates, tartrates, citrates, benzoates, 4-methoxybenzoates, 2- or 4-hydroxybenzoates, 4-chlorobenzoates, benzenesulphonates, p-toluenesulphonates, naphthalenesulphonates, methanesulphonates, sulphamates, ascorbates, salicylates, acetates, diphenylacetates, triphenylacetates, adipates, fumarates, succinates, lactates, glutarates, gluconates, tricarball ylates, hydroxynaphthalenecarboxylates e.g. l-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 p2-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 PGF2a 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 allergic 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 physiologically acceptable salts and solvates for use in the therapy or prophylaxis of diseases associated with reversible airways obstruction in human or animal subjects.

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 formula (I) or a physiologically acceptable salt 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 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, 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 8 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 manner.

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 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 i 0.005mg to 20mg, for oral administration is 0.02mg to lOOmg, 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 a number of processes. In the following description, Ar, X, Y, Z and q are as defined for general formula (I) unless otherwise specified.

In the preparation of both intermediates and end-products the final step in the reaction may be the removal of a protecting group. Suitable protecting groups and their removal are described in general process (2) below.

In one general process (1) compounds of formula (I) may be prepared by reducing an intermediate of general formula (it): Ar~ X1-X2-XCH20CH2Y-Q (II) wherein at least one of X1, 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 a 2,6-linked piperidine or 2,5-linked pyrrolidine ring, and X and Y are as defined in formula (I), followed where necessary by removal of any protecting groups.

Suitable reducible groups include those wherein X1 is a group

X2 is a 2,6-linked pyridine ring or a 2,5-linked pyrrole ring, and/or Y represent alkenylene or alkynylene groups).

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

Thus, for example, when X1 in general formula (II) represents a

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 examples from 20 to 100C 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 dichloromethane.

When X2 in general formula (II) represents a 2,6-linked pyridine ring or a 2,5-linked pyrrole ring this may be reduced to a 2,6-linked piperidine or 2,5-linked pyrrolidine ring using hydrogen in the presence of a catalyst as described above, and, when X2 is pyridine, a strong acid such as concentrated hydrochloric acid.

When X represents C2.7alkenylene or C2.7alkynylene and/or Y represents C2,6alkenylene or C2,6alkynylene group(s), these may be reduced to X as C2.7 alkylene and/or Y as C2.6alkylene using hydrogen in the presence of a catalyst as described above.

Where it is desired to use a protected intermediate of general formula (II) it is particularly convenient to use a protecting group R6 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 groups 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 hydrogen and a catalyst in the preparation of products in which X and/or Y represent alkenylene or alkynylene groups, and where a hydride reducing agent is used and end-products are required in which Q2 represents the group R3CO-.

In a further process (2) compounds of formula (I) may be prepared by deprotecting an intermediate of general formula (III)

wherein R6 is a protecting group, and/or at least one of the hydroxy aroup(s) in AP I 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 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 (II) wherein a2 is pyrrole or pyridine for use in the reduction process (1) in which X1 is the group

be prepared by reaction of a compound of formula (III)

with a compound of formula (IV)

(wherein X2 is pyrrole or pyridine attached to the rest of the molecule (-XCH20CH2YQ) at the 2-position) in the presence of phosphoryl chloride.

Intermediates of general formula (II) in which X1 is the group

may be reduced to the corresponding intermediate in which X1 is the group -CH(OH)- using for example a metal hydride such as sodium borohydride in a solvent e.g. ethanol, methanol and/or tetra; iydrofuran.

Intermediates of formula (II) for use in the reduction process (1) in which X2 is a pyridine or pyrrole group may be prepared by reaction of a compound of formula (V)

(wherein the group

is a pyridine or pyrrole group) with a compound of formula (VI) HC.=C-X '-CH20CH2 VAr (vI) (wherein X' is a bond or a C1.5 alkylene chain).

The reaction may be effected in a cold or hot solvent, for example acetonitrile, in the presence of a suitable catalyst such as bis(triphenylphosphin)palladium (III) chloride and copper (I) iodide, and preferably in the presence of a base such as N,N dicyclohexylamine or N,N-diisopropylethylamine.

Suitable methods for preparing intermediates of formulae (III), (IV), (v) and (VI) are described in UK Patent Specifications Nos.

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

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 (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 (Meroki9385). The following solvent system may be used: System A - toluene:ethanol: 0.88 ammonia. The following abbreviations are used : DMF - dimethylformamide, THF tetrahydrofuran, TAB - tetra-n-butylammonium hydrogen sulphate, BTPC bis(triphenylphosphine)palladium (II) chloride.

Intermediate 1 a-F3 .5.Bis( phenylmethoxy)phenyl).6.bromo-2.pyridinemethanol A stirred solution of 2,6-dibromopyridine (2.379) in dry ether (30mR) at -400 under nitrogen was treated dropwise with n-butyllithium (l.53 in hexane; 3.3mR), the mixture stirred at -400 for a further 5 min and allowed to warm up to -150. A solution of [3,5.bis(phenylmethoxy)phenyl]benzaldehyde (1.609) in dry THF (5ml distilled from calcium hydride) was added dropwise, the mixture allowed to warm to room temperature and stirring under nitrogen continued for 4h.The reaction was quenched by the addition of water (5ml), the THF was removed in vacuo at 400 and the residue partitioned between ether (loom) and water (25ml). Th organic layer was washed with further water (25ml), dried and concentrated to yield the crude product which was purified by FCC eluting with 3S ethyl acetate/ toluene affording the title compound as a pale yellow oil (1.79).

Analysis Found: C,65.6; H,4.7; N,2.8; Br,16.8.

C26H22BrN03 requires C,65.55; H,4.65; N,2.9; Br,16.8S.

Intermediate 2 C3-(3-Butynyl)oxylpropylbenzene A mixture of 3-butyn-l-ol (7.09), 3-bromo-1-phenylpropane (19.99), TAB (3.49) and 50S aqueous sodium hydroxides solution (160mR) was vigorously stirred at room temperature for 20h. The mixture was diluted with water (300rnz) and extracted with ether (2x300m). The organic phase was dried and concentrated in vacuo at 400 to yield the crude product which was purified by FCC eluting with ether/cyclohexane (1:2) affording the title compound as a colourless oil (15.6g), t.l.c. (Et20/hexane 1:10) Rf 0.60.

Intermediate 3 &alpha;-[3,5-bis(phenylmethoxy)phenyl]-6-[4-(3-phenylpropoxy )-1-butynyl]-2- pyridine methanol Copper (I) iodide (7mg) was added to a stirred mixture of &alpha;-[3,5-bis(phenylmethoxy)phenyl]-6-bromo-2-pyridinemethanol (0.5g), [3-[(3-butynyl)oxy]propyl]benzene (0.199) and BTPC (49mg) in N,Ndicyclohexylamine (5ml) and stirring under nitrogen continued for 20h.

The mixture was diluted with ethyl acetate (25mR) and poured into 2N hydrochloric acid (50ml). The precipitated dicyclohexylamine hydrochloride was filtered off, washed with further ethyl acetate (2x25mR) and the organic layer separated from the filtrate. The solution was dried and concentrated to afford the crude product which was purified by FCC eluting with ethyl acetate/cyclohexane (1:2) affording the title compound as a pale yellow oil (0.499), t.l.c.

(EtOAc/hexane - 1:2) Rf 0.32.

Intermediate 4 5-[Hydroxy[6-[4-(3-phenylpropoxy)butyl]-2-pyridinyl]methyl]-1,3- benzenediol A solution of a.3, 5-bis(phenylmethoxy)phenyl].6.4.(3.phenylpropoxy).

1-butynyl]-2-pyridinemethanol (0.389) in a mixture of absolute ethanol (lOmQ) and THF (tome) was hydrogenated at room temperature and atmospheric pressure over a pre-reduced 10S palladium oxide on carbon catalyst (0.259, 50S paste in ,O). The catalyst was removed by filtration through 'hyflo'jand the solvent evaporated to yield the crude product which was purified by FCC eluting with System A (39:10:1) affording the title compound as an off-white foam (105mg), t.l.c. (System A 39:10:1) Rf 0.36.

Intermediate 5 4-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-3-[[[(1,1-dimethylethyl) dimethylsilyl]oxy]methyl]benzaldehyde Tert.butyldimethylsilyl chloride (6.329) was added to a solution of 4-hydroxy-3-hydroxymethylbenzaldehyde (2.839) and imidazole (2.7595 in DMF (27ml) at 0-50 and stirred at 0-50 for lh and ambient temp.

for lh. The solvent was evaporated in vacuo and the residue partitioned between water (50ml) and ethyl acetate (60mR). The aqueous phase was further extracted with ethyl acetate (60mR) and the combined organic phases washed with water (2x50ml) and brine (40ml), dried and evaporated in vacuo to afford the title compound as a brown syrup (6.88g), t.l.c. (Et20) Rf 0.66.

Intermediate 6 a-(6-Bromo-2-pyridinyl)-4-hydroxy-1,3-benzenedimethanol n-Butyllithium in hexane (1.43M, 8.5mR) was added dropwise to a suspension of 2,6-dibromopyridine (5.529) in ether (75mR) and THF (15ml) at -400 under nitrogen over 2min (final temp. -300). After 5min the dark mixture was re-cooled to -400 and a solution of 4- (l,1.dimethylethyl)dimethylsilyl]oxy].3.(l,l.

dimethylethyl)dimethylsilyl]oxy]methyl]benzaldehyde (4.449) in ether (20mR) was added over 2min. (temp -400 to -200). The dark solution was allowed to warm to 200 over lh, then quenched with brine (40ml) and the organic phase dried and evaporated in vacuo. The residue was purified by FCC with toluene eluant followed by toluene-ethyl acetate (49:1-19:1) to give the intermediate silylated product. This was dissolved in THF (50mR) and a 1M solution of tetra-n-butylammonium fluoride in THF (24ml) added. The solution was allowed to stand for 2h, then evaporated in vacuo, and the residue partitioned between water (45mR) and ethyl acetate (4 x 50ml).The combined organic extracts were dried, evaporated in vacuo, and the dark residue purified by FCC with toluene-ethyl acetate (100:0- 75:25) eluant to remove silicon residues. Toluene-ethyl acetate (1:1) elution gave firstly an impurity, then crude product. Trituration with ether afforded the title compound as a colourless powder (0.939), m.p. 84-880.

Intermediate 7 4-Hydroxy-&alpha;-[6-[4-(3-phenylpropoxy)-1-butynyl]-2-pyridinyl]-1,3- benzenedimethanol BTPC (60mg) and copper (I) iodide (5mg) were added to a solution of a-(6-bromo-2-pyridinyl)-4-hydroxy-1,3-benzenedimethanol (1.369), [3. (3.butynyl).oxy]propyl]benzene, (0.93g) and N, N,-dicyclohexylamine (lmQ) in acetonitrile (35me) and stirred at room temperature for 20h.

The mixture was diluted with ethyl acetate (50mR), filtered and evaporated in vacuo to a gum which was purified by FCC with toluene and toluene-ethanol (49:1-19:1) eluants to remove impurities. Elution with System A (89:10:1) afforded the title compound as a viscous gum (1.349).

Assay Found: C,72.3; H,6.7; N,3.3; C26H27N04.0.8H20 requires C,72.3; H,6.7; N,3.2.

Intermediate 8 4-Hydroxye -[6-[4-(3-phenylpropoxy)butyl]-2-pyridinyl]-1,3- benzenedimethanol A solution of 4-h ydroxy-a. 6- 4. (3.phenylpropoxy).1-butynyl].2.

pyridinyl].1,3.benzenedimethanol (1.049) in ethanol (25ml) was added to a pre-hydrogenated suspension of 10S palladium on charcoal (50S paste, lg) in ethanol (20ml) and hydrogenated at room temperature and pressure for 10 min. The mixture was filtered through hyflo and evaporated in vacuo to furnish the title compound as e viscous brown gum (0.949).

Analysis Found: C,72.5; H,7.75; N,3.5.

C26H31NO4.0.5H20 requires C,72.5; H,7.5; N,3.25 .

Intermediate 9 N,N-Diethyl 4.[4-[(4-pentynyl)oxy]butyl]benzamide A solution of 4-pentyn-1-ol (2.179) in DMF (30mR) was added slowly to a suspension of sodium hydride (80S, 0.779) in DMF (130mR) under nitrogen. The mixture was stirred at room temperature under nitrogen until evolution of hydrogen ceased (1.5h), then treated with a solution of N,N-diethyl 4-[4-[(methanesulphonyl)oxy]butyl]benzamide (6.589) in DMF (50ml) and stirred at 500 for 2h, and room temperature for 17h. The resulting dark solution was poured into water (500ml) and extracted with ethyl acetate (400ml). The organic phase was washed with water (3x200mi), brine (50ml), dried and evaporated in vacuo. The residue was purified by FCC with toluene eluant to remove paraffin residues (from sodium hydride).Elution with toluene-ether (1:1) and ether afforded the title compound as a colourless liquid (3.989), t.l.c. (Et20) Rf 0.51.

Intermediate 10 N-[5-[(6-Bromo-2-pyridinyl)hydroxymethyl]-2-(phenylmethoxy)phenyl].

methanesulphonamide n-Butyllithium/hexane (25me) was added dropwise at .300 over 6 min to a solution of 2,6-dibromopyridine (13.59) in ether (250mR) was cooled to -400 under nitrogen. The dark mixture was stirred at -300 for lOmin., a solution of N.[5.formyl.2.(phenylmethoxy)phenyl].

methanesulphonamide (3.859) in THF (100ml) was added dropwise at -300 over lOmin. (temp increased from -300 to -230), and allowed to warm to 210 over lh. The mixture was quenched with brine (50mR) and pH 6.5 phosphate buffer (70ml) and the dried organic phase was evaporated in vacuo. The residue was purified by FCC with toluene and toluene-ethyl acetate (17:3.3:1) eluants to afford the title compound as a brown foam (2.829) t.l.c. (System A 240:20:1) Rf 0.20.

Intermediate 11 N,N-Diethyl 4-[4-[[5-[6-[hydroxy[3-[((methanesulphonyl)amino)-4- (phenylmethoxy)phenyl]methyl]-2-pyridinyl]-1-pentynyl]oxy]butyl] benzamide A mixture of N-[5-[(6-bromo-2-pyridinyl)hydroxymethyl]-2-(phenyl methoxy)phenyl]methanesulphonamide (2.949), N,N-diethyl 4-[4-[(4- pentynyl)oxy]butyl]benzamide (2.019), N,N-dicyclohexylamine (2.3ml), BTPC, (114mg) and copper (I) iodide (15mg) in acetonitrile (40mR) was stirred at 220 under nitrogen for 20h. The mixture was diluted with ether (100iuz) filtered, and the filtrate evaporated in vacuo.A solution of the residue in ethyl acetate (200mR), was washed with 2N hydrochloric acid (40ml), filtered through hyflo and the organic layer of the filtrate washed with water (20ml) followed by 8S sodium bicarbonate (sota), dried and evaporated in vacuo. The residue was purified by FCC with dichloromethane-ether (4:1-2:1) eluants removing impurities. Elution with ether gave a further impurity. Elution with ether-methanol-triethylamine (94:5:1) afforded the title compound as a foam (1.31g), t.l.c. (System A 39:10:1) Rf 0.54.

Intermediate 12 cis N,N-Diethyl 4-[4-[[5-[6-[hydroxy[4-hydroxy-3-(methanesulphonyl)- amino] phenyl) methyl].2. pyridinyl] pentyl] oxy] butyl] benzamide A solution of N, N.Diethyl 4-[4-[[5-[6-[hydroxy[(3-[(methanesulphonyl)- amino]-4-(phenylmethoxy)phenyl]methyl]-2-pyridinyl]-1-pentynyl]oxy]- butyl]benzamide (1.259) in ethanol (80ml) was added to a pre-hydrogenated suspension of 10S palladium on carbon (50S aqueous paste 1.40g) in ethanol (50me) and hydrogenated at room temperature and pressure for 3h. The mixture was filtered through hyflo and evaporated in vacuo to a gum.The gum was purified by FCC with ethyl acetate to afford the title compound as a colourless viscous gum (0.6769), t.l.c. (System A 40:10:1) Rf 0.20.

Example 1 cis 5.(Hydroxy6.4.(3.phenylpropoxy)butyl].2.piperidinyl]methyl].l ,3.

benzenediol, (E)-butenedioate salt (2:1) A solution of 5.hydroxy6.4.(3.phenylpropoxy)butyl].2.pyridinyl] methyl].1,3-benzenediol (0.569) in ethanol (20ml) containing conc.

hydrochloric acid-ethanol (1:9, 1.27ml) was added to a pre-hydrogenated suspension of platinum oxide (177mg) in ethanol (30ml) and hydrogenated at room temperature and pressure for 1.75h.

The mixture was filtered through hyflo and evaporated in vacuo to an oil. The residue was taken up in ethyl acetate (60mR) and washed with 8S sodium hydrogen carbonate solution (20ml), dried and evaporated in vacuo. The gummy residue was purified by FCC with System A (89:10:1-39:10:1) eluant which afforded the crude product (0.59). The crude product in isopropanol (lOmQ) was treated with fumaric acid (70mg) and concentrated to 1.5ml total volume. Dry ether (25ml) was added and the gum triturated to afford the title compound as a grey powder (420mg) m.p. 115-1170 (dried at 400/2mmHg for 8h).

Assay Found: C,66.3; H,8.3; N,2.8.

C25H35NO4.O.5C4H4O4.H2O requires C,66.2; H,8.0; N,2.9%.

Example 2 c.is 4-Hydroxy- -[6[4-(3-phenylpropoxy)butyl]-2-piperidinyl]-1,3- benzenedimethanol, (E).butenedioate salt (2:1) A solution of 4-hydroxy-&alpha;-[6-[4-(3.phenylpropoxy)butyl]-2- pyridinyl]-1,3-benzene dimethanol (0.369) in ethanol (30mR) was treated with conc. hydrochloric acid-ethanol (1:9, 0.79ml) and added to a pre-hydrogenated suspension of platinium oxide (202mg) in ethanol (lOmi) and hydrogenated et room temperature and pressure for 2h. The mixture was filtered through hyflo and evaporated in vacuo, and the residue partitioned between 8S sodium hydrogen carbonate solution (15mR) and ethyl acetate (60ml).The organic phase was dried and evaporated in vacuo to a gum (360mg). A solution of the gum in methanol (6mR) was treated with fumaric acid (52mg) and evaporated in vacuo. Trituration with ether-hexane (2:1) gave the title compound as an off-white solid foam (246mg), m.p. 80-880.

Assay Found: C,67.5; H,8.1; N,2.75; C26H37N04.0.65 C4H404.0.3H20 requires C,67.6; H,8.0; N,2.8%.

Example 3 cia-N ,N.Diethyl 4-[4-[[5-[6-[hydroxy[4-hydroxy-3-[(methanesulphonyl) amino]phenyl]methyl]-2-piperidinyl]pentyl]oxy]butyl]benzamide, (E) butenedioate salt (2:1) A solution of N,N-diethyl 4-[4-[[5-[6-[hydroxy]4-hydroxy-3- (methanesulphonyl)amino]phenyl]methyl].2.pyridin yl]pentyl]oxy] butyl]benzamide (633mg) in ethanol (45ml) was treated with conc.

hydrochloric acid-ethanol (1:9, 0.95ml) and added to pre-hydrogenated platinum oxide (280mg) in ethanol (20mR) and hydrogenated at room temperature and pressure for 2h. The mixture was filtered through hyflo and evaporated in vacuo. The residue was partitioned between 8% sodium hydrogen carbonate (some) and ethyl acetate (150mR) and the organic phase dried and evaporated in vacuo to a gum which was purified by FCC with System A (89:10:1-39:10:1) eluant. A solution of the product in methanol (15ml) was treated with fumaric acid (42mg) and evaporated in vacuo to a gum. Trituration with dry ether afforded the title compound as a solid foam (380mg), m.p. 1100.

Analysis Found: C,60.4; H,8.0; N,5.75.

C33H51N3O6S.O.5C4H4O4.H2O requires C,60.6; H,8.0; N,6.1S.

Claims (11)

CLAIMS:

1. Compounds of the general formula (I)

wherein Ar represents the group

(where Q1 represents a straight-or branched C1.3 alkylene group),

(where Q2 represents a group R3CO-, R3NHCO-, R3R4NSo2- or R5S02-, where R3 and R4 each represents a hydrogen atom or a C1.3 alkyl group, and R5 represents a C1~3 alkyl group),

X represents a direct bond, or a C1.7 alkylene, C2.7 alkenylene or C2.7 alkynylene chain, and Y represents a direct bond, or a C16 alkylene, C2.6 alkenylene or C2.6 alkynylene chain with the proviso that the sum total of carbon atoms in the chains X and Y is not more than 10; Z represents a direct bond or a -CH2- group; and Q represents a phenyl group which may be unsubstituted or substituted by one or more groups selected from halogen atoms, C13 alkyl, C1.3 alkoxy and hydroxy groups, a group of formula -CONR3R4 and an alkylenedioxy group of formula -O(CH2)pO- (where p is 1 or 2), or Q represents a pyridyl group which may be unsubstituted or substituted by one or more groups selected from C14 alkyl, C1.4 alkoxy, hydroxy and halogen, and physiologically acceptable salts and solvates thereof.

2. Compounds according to claim 1, wherein, in the general formula (I), Ar represents the group (a), (b) or (c) as defined in claim 1.

3. Compounds according to claim 1 or 2, wherein, in the general formula (I), the sum total of carbon atoms in the chains X and Y is 4, 5, 6, 7, 8 or 9.

4. Compounds according to any of claims 1 to 3, wherein, in the general formula (I), Q1 represents -CH2-.

5. Compounds according to any of claims 1 to 3, wherein, in the general formula (I), Q2 represents CH3SO2-.

6. Compounds according to any of claims 1 to 5, wherein, in the general formula (I), Q represents a phenyl group.

7. Compounds according to claim 6, wherein, in the general formula (I), Q represents a phenyl group substituted by the group .CON(CH2CH3)2.

8. Compounds according to claim 1 selected from 5-[hydroxy-[6-[4-(3-phenylpropoxy)butyl]-2- piperidinyl]methyl]-1,3 -benzenediol, 4-hydroxy-a. [ 6- [ 4- (3-phenylpropoxy) butyl) -2-piperidinyl)- 1,3 -benzenedimethanol, cis-N,N-diethyl 4-(4-([5-[6-[hydroxy-(4-hydroxy-3.

[(methanesulphonyl)amino)phenyl)methyl)-2- piperidinyl)pentyl)oxy)butyl)benzamide, and the physiologically acceptable salts and solvates thereof.

9. A pharmaceutical composition comprising, as active ingredient, a compound of general formula (I) as defined in claim 1 or a physiologically acceptable salt thereof together with one or more physiologically acceptable carriers or excipients therefor.

10. A pharmaceutical composition according to claim 9, formulated for administration by inhalation or insufflation.

11. A pharmaceutical composition according to claim 10, formulated in unit dosage form containing 0.005mg to 20mg active ingredient.