GB2182658A - Dichloroaniline derivatives - Google Patents

Abstract

Compounds of the formula (I> <IMAGE> wherein X represents a bond, C1-6 alkylene, C2-6 alkenylene or C2-6 alkynylene and Y represents a bond, C1-4 alkylene, C2-4 alkenylene or C2-4 alkynylene, the sum total of carbon atoms in X and Y being not more than 8; Ar represents a phenyl group substituted by one or more substituents selected from nitro, -(CH2)qR [where R is C1-3 alkoxy, -NR<3>R<4> (where R<3> and R<4> each represent a hydrogen atom, or a C1-4 alkyl group, or-NR<3>R<4> forms a saturated heterocyclic amino group which has 5-7 ring members), -NR<5>COR<6> (where R<5> represents a hydrogen atom or a C1-4alkyl group, and R<6> represents a hydrogen atom or a C1-4alkyl, C1-4alkoxy or-NR<3>R<4> group), and q is 1 to 3], -(CH2)rR<7> [where R<7> represents -NR<5>SO2R<8> (where R<8> represents a C1-4 alkyl, phenyl or -NR<3>R<4> group),- NR<5>COCH2N(R<5>)2 (where each of the groups R<5> represents a hydrogen atom or a C1-4 alkyl group), -COR<9 > (where R<9> represents hydroxy, C1-4 alkoxy or a NR<3>R<4>), -SR<10> (where R<10> is a hydrogen atom, or a C1-4 alkyl group optionally substituted by hydroxy, C1-4 alkoxy or NR<3>R<4>), -SOR<10>, -SO2R10, -CN, or -NR11R<12> (where R<11> and R<12> represent a hydrogen atom or a C1-4 alkyl group, at least one of which is C2-4 alkyl substituted by a hydroxy, C1-4 alkoxy or NR<3>R<4> group), and r is 0 to 3], -O(CH2)qCOR<9>, or -O(CH2)tR<13> [where R<13> represents hydroxy, NR<3>R<4>, NR<11>R<12> or a C1-4alkoxy group optionally substituted by hydroxy, C1-4 alkoxy or NR<3>R<4>,and t is 2 or 3]. R<1> and R<2> each represents a hydrogen atom or a C1-3 alkyl group, the sum total of carbon atoms in R<1> and R<2> being not more than 4; and physiologically acceptable salts and solvates (e.g. hydrates) thereof, have a stimulant action at a beta 2-adreno-receptors and may be used in the treatment of diseases associated with reversible airways obstruction such as asthma and chronic bronchitis.

Description

SPECIFICATION Dichloroaniline derivatives This invention relates to dichloroaniline derivatives having a stimulant action at (32-adrnnoreceptors, to pro cesses fortheir preparation, to pharmaceutical compositions containing them and totheir use in medicine.

Dihaloaniline derivatives have previously been described as bronchodilators having stimulant activity at -adrenoreceptors.

Thus British Patent Specification No. 1178191 describes compounds of the general structure

in which the substituents Hal represent bromine or chlorine atoms; R1 represents hydrogen or hydroxyl; R2 and R3 each represent hydrogen or C1.4 alkyl; and R4 and R5 each represent hydrogen, C1-6alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, dialkylaminoalkyl, cycloalkyl, phenyl, benzyl or adamantyl, or NR4R5forms a heterocyclic ring optionally substituted by C1 3 alkyl groups.

We have now found a novel group of dichloroaniline derivatives, which differ structually from those described in British Patent Specification No. 1178191, and which have a desirable and useful profile of activity.

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

wherein X represents a bond, C1-6 alkylene, C2.6 alkenylene or C2 6 alkynylene chain and Y represents a bond, ora C1 4 alkylene, C2 4 alkenylene orC2.4alkynylene chain with the provisothatthesum total of carbon atoms in X and Y is not more than 8;; Ar represents a phenyl group substituted by one or more substituents selected from nitro,-(CH2)qR [where R is C1-3alkoxy,-NR3R4 (where R3 and R4 each represent a hydrogen atom, ora C1-4alkyl group, or-NR3R4 forms a saturated heterocyclic amino group which has 5-7 ring members and optionally contains in the ring one or more atoms selected from -0-or-S- ora group -NH- or-N(CH3)-),-NR5COR6 (where R5 represents a hydrogen atom or a C1 4 alkyl group, and R6 represents a hydrogen atom or a C1 4 alkyl, C1 4 alkoxy or-NR3R4 group), and q represents an integer from 1 to 31],-(CH2)rR' [where R7 represents -NR5S02R8 (where R8 repre- sents a C1-4alkyl, phenyl or-NR3R4group),-NR5COCH2N(R5)2 (where each of the groups R5 represents a hydrogen atom or a C1 4 alkyl group),-COR9 (where R9 represents hydroxy, C1 4 alkoxy or NR3R4), -SR10 (where R is a hydrogen atom, ora C1 4 alkyl group optionally substituted by hydroxy, C1-4alkoxy or NR3R4),-SOR10, -SO2R10,-CN, or-NR11R12 (where R11 and R12 represent a hydrogen atom or a C1-4alkyl group, at least one of which is C2 4 alkyl substituted by a hydroxy, C1 4 alkoxy or NR3R4 group), and r represents an integer from Oto 3,-O(CH2)qCOR9 (where q and R9 are as defined above), or-O(CH2)tR13 [where R13 represents hydroxy, NR3R4, NR11R12ora C1 4 alkoxy group optionally substituted by hydroxy, C1.4alkoxy or NR3R4, andt is an integer 2 or 3].

R1 and R2 each represents a hydrogen atom or a C1 3 alkyl group, with the proviso that the sum total of carbon atoms in R1 and R2 is not more than 4; and physiologically acceptable salts and solvates (e.g. hydrates) thereof.

It will be appreciated that the compounds of general formula (I) possess one ortwo asymmetric carbon atoms, namelythecarbon atom ofthe

group and, when R1 and R2 are different groups, the carbon atom to which these are attached.

The compounds according to the invention thus include all enantiomers, diastereoisomers and mixtures thereof, including racemates. Compounds in which the carbon atom in the

group is in the R configuration are preferred.

In the definition of general formula (l),theterm alkenylene includes both cos and trans structures.

According to one aspect, the invention provides compounds offormula (I) in which R1, R2, X, Yand Arareas defined forformula (I) and R7 represents-NR5SO2R8,-COR9,-SR10,-SOR12,-SO2R10,-CN or-NR11R12.

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-, CH2C#C-,-(CH2)2CH=CH-, -(CH2)2C#C-,-CH=CHCH2-, -CH=CH(CH2)2- or -CH2CCCH2-. The chain Y may be for example a bond,-CH2-, -(CH2)2-,-(CH2)3-, -(CH2)4-,-CH=CH-, -C#C-,-CH2CH=CH-, or-CH2C#C-.

Preferably the total number of carbon atoms in the chains X and Y is 4 to 8 inclusive. Compounds wherein the sum total of carbon atoms in the chainsX and Y is4, 5,6 or7 are particularly preferred.

One preferred group of compounds offormula (I) is that in which X represents a C1.6 alkylene chain and Y represents a C1 4 alkylene chain. Particular compounds of thins type are those wherein X represents-(CH2)3- or -(CH2)4- and Y is-CH2-,-(CH2)2- or-(CH2)3-.

In the compounds offormula (I) R1 and R2 may each be,for example, methyl, ethyl, propyl orisopropyl groups exceptthat if one of R1 and R2 is a propyl or isopropyl group,the other is a hydrogen atom ora methyl group. Thus for example R1 may be a hydrogen atom ora methyl, ethyl or propyl group. R2 may be, for example, a hydrogen atom ora methyl group. R1 and R2 are each preferably a hydrogen atom ora methyl group.

A preferred group of compounds are those wherein R1 and R2 are both hydrogen atoms, or R1 is a hydrogen atom and R2 is a C1-3 alkyl group, particularly a methyl group.

When -NR3R4 in compounds offormula (I) represents a saturated heterocyclic amino group, this may have 5,6 or7 ring members and optionally contains in the ring a heteroatom selected from -O- or-S-, ora group -NH- or-N(CH3)-. Examples of such -NR3R4 groups are pyrrolidino, piperidino, hexamethyleneimino, piperazino, N-methylpiperazino, morpholino, homomorpholino orthiamorpholino.

Ar may be for example a phenyl group substituted by-(CH2)9R [where R represents C1-3 alkoxy e.g.

methoxy, diC1-4alkylamino e.g. dimethylamino, morpholino, piperidino, piperazino, N-methylpiperazino, -NHCOB6 (where R6 is C1 4 alkyl e.g. methyl), and q is 1 or 2], (CH2)rB7 [where R7 represents -NR5SO2R8 (where R5 represents hydrogen or methyl, and R8 represents C1-4 alkyl e.g. methyl), -NHCOCH2N(R5)2 (where both groups R5 represent C1 4 alkyl e.g. methyl), -COR9 (where R9 represents C1 4 alkoxy e.g. ethoxy, amino, diC1.4 alkylamino e.g. dimethylamino, morpholino, piperidino, piperazino or N-methylpiperazino),-NR11R12 (where one or both of R11 and R12 represents a C2-4 alkyl e.g. ethyl group substituted by a hydroxy or diC1-4alkylamino e.g. dimethylamino group, and the other represents a hydrogen atom), and riszero or 1],-OCH2COR9(where R9 is dC1.4 alklyamino e.g. dimethylamino), or -O(CH2)2R13 (where R13 is diC1-4alkylamino e.g. dimethylamino.

A preferred group of compounds according to the invention are those of the formula (la)

wherein X represents a C3.4 alkylene chain and Y represents a C1 3 alkylene chain with the proviso thatthetotal numberofcarbon atoms in X andY is5 or6; and Ar represents a phenyl group substituted bya groupselected from C1-4alkoxymethyl (e.g. methoxymethyl), morpholinomethyl, diC1-4alkylaminoC1-2alkyl (e.g.dimethyl- aminoethyl), -CH2NHCOR6 (where R6 is C1-4 alkyl e.g. methyl),-NR5SO2R6 (where R5 is hydrogen or methyl and R8 is C1-4alkyl e.g. methyl),-NHCOCH2N(R5)2 (where both groups R5 represent C1-4 alkyl e.g. methyl), -COR9 (where R9 is hydroxy, C1 4 alkoxy e.g. ethoxy, amino, diC1.4 alkylamino e.g. dimethylamino, or morpholino),-CH2COR9 (where R9 is amino ordiC1alkylamino e.g. dimethylamino),-NR11R12(where R11 and R12 both represent hydroxy C2 4 alkyl e.g. hydroxyethyl), diC1.4 alkylaminoethylamino (e.g. dimethylaminoethylamino),-OCH2COR9 (where R9 is diC1-4alkylamino e.g. dimethylamino) or-O(CH2)2R13 (where R13 is diC1-4 is diC1-4alkylamino e.g. dimethylamino); and physiologically acceptable salts and solvates thereof.

Particularly preferred compounds of formula (la) are those in which X and Y are as defined forformula (la); and Ar represents a phenyl group substituted by a group selected from -CH2NHCOR6 (where R6 is methyl), -NHSO2R8 (where R8 is methyl),-COR9 (where R9 is hydroxy, ethoxy, amino or morpholino), or-CH2COR9 (where R9 is amino ordimethylamino), and physiologicallyacceptablesalts and solvatesthereof.

Particularly important compounds ofthe invention are: 4-[3-[[6-[[2-(4-amino-3,5-dichlorophenyl)-2-hydroxy-ethyl]amino]hexyl]oxy]propyl]benzamide; ethyl 4-[3-[[6-[[(4-amino-3, 5-dichlorophenyl)-2-hydroxy-ethyl]amino]hexyl]oxy]propyl]benzoate; N-[[3-[3-[[6-[[2-(4-amino-3, 5-dichlorophenyl)-2-hydroxy- ethyl]amino]hexyljoxyjpropyl]phenyl]methyljacetamide; 4-[4-[5-[[2-(4-amino-3, 5.dichlorophenyl)-2-hydroxyethylj-aminojhexyl]oxyjpentyloxy]butyl].N, N dimethylbenzene-acetamide; 4-[3-[[6-[[2-(4-amino-3, 5.dichlorophenyl)-2-hydroxyethyljamino]hexyljoxy]propylbenzoic acid; 4-[4-[3-[[6-[[2-(4-amino-3, 5-dichlorophenyl)-2-hydroxy ethyl]amino]hexyl]oxy]proply]benzoyl]morpholine;; N-[4-[3-[[6-[[2-(4-amino-3, 5-dichlorophenyl)-2-hydroxy ethyl]aminojhexyl]oxy]ethyljphenyljmethanesulphonamide; [4-[3-[[6-[[2-(4-amino-3, 5.dichlorophenyl)-2-hydroxy-ethyl]aminojhexyl]oxy]propyl]benzeneacetamide; and the physiologically acceptable salts and solvates thereof.

Suitable physiologically acceptable salts ofthe compounds of general formula (I) include acid addition salts derived from inorganic and organic acids, such as hydrochlorides, hydrobromides, sulphates, phosph ates, maleates, tartrates, citrates, benzoates, 4-methoxy-benzoates, 2-or 4-hydroxybenzoates, 4 chlorobenzoates, p-toluenesulphonates, methanesulphonates, sulphamates, ascorbates, salicylates, acet ates, fumarates, succinates, lactates, gluta rates, gluconates, tricarballylates, hydroxy naphthalenecarboxylates e.g.I-hydroxy- or3-hydroxy-2-naphthalenecarboxylates, or oleates. The com pounds may also form salts with suitable bases. Examples of such salts are alkali metal (e.g. sodium and potassium), and alkaline earth metal (e.g. calcium or magnesium) salts.

The compounds according to the invention have a stimulant action at P2-adrenoreceptors, which further- more is of a particularly advantageous profile. The stimulant action was demonstrated in the isolated trachea ofthe guinea-pig, where compounds were shown to cause relaxation of PGF2a-induced contractions. Com pounds according to the invention have shown a particularly long duration of action in this test.

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 forthetreatmentofinflammatory and aliergic skin diseases, congestive heartfailure, 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 beformulated for administration in any convenientway.

The invention therefore includes within its scope pharmaceutical compositions comprising at least one com- pound offormula (I) ora physiologically acceptable saltorsolvatethereofformulatedforuse 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, orfor 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, orfrom 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 ofthe 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 inhalerorinsufflator.

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 administrationby bolus injection or continuous infusion. Formulations for injection may be presented in unitdosageform in ampoules, orin multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oilyoraqueousvehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder form for recon- stitution 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/orsolvents. For nasal application, the composition may takethe form of a spray, formulated forexample as an aqueous solution or suspension oras 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 tropical administration, these may be presented in a conventional manner associated with controlled release forms.

Aproposed daily dosage of active compound forthetreatment of man is 0.005mg to 100mg,which maybe conveniently administered in one or two doses. The precise dose employed will of course depend on the age and condition ofthe patient and on the route ofadministration.Thus a suitable dose for administration by inhalation is 0.005mg to 20mg, for oral administration is 0.02mg to 1 00mg, and for parenteral administration is O.Olmg to 2 mg for administration by bolus injection and 0.01 mg to 25 mg foradministration byinfusion.

The compounds according to the invention may be prepared by a number of processes, as described in the following. Inthefollowing description of processes for preparing compounds offormula (I) and inter- mediates which may be used in the preparation thereof, X, Y, Ar, R1 and R2 are as defined for general formula (I) unless otherwise specified. In addition, any substituent in the group Ar may be a precursor substituent which is convertible into the required substituent by conventional methods.

It will be appreciated that certain ofthe reactions described below are capable of affecting other groups in the starting material which are desired in the end product; this applies especially in the reduction processes described, particularly where hydrogen and a catalyst are used and when an ethylene or acetylene linkage is required in the compound of the invention. Care must therefore be taken in accordance with conventional practice, eitherto use reagents which will not affect such groups, orto perform the reaction as part of a sequence which avoids their use when such groups are present in the starting material.

In the preparation of both intermediates and end-products the final step in the reaction may be the removal of a protecting group. Conventional protecting groups may be used, as described for example in "Protective Groups in Organic Chemistry", Ed. J. F. W. McOmie (Plenum Press, 1973). Thus hydroxyl groups mayfor example be protected by aralkyl groups such as benzyl, diphenylmethyl ortriphenylmethyl, or as tetrahydropyranyl derivatives. Suitable amino protecting groups include aralkyl groups such as benzyl, oil methylbenzyl, diphenylmethyl ortriphenylmethyl, and acyl groups such as acetyl, trichloroacetyl ortrifluoroacetyl.

Conventional methods ofdeprotection may be used. Thusforexample aralkyl 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, or a group such as trichloroacetyl may be removed by reduction with, for example, zinc and acetic acid.

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 R1 is a hydrogen atom may be prepared by alkylation of an amine of general formula (II)

(wherein R14 is a hydrogen atom ora protecting group and R15 is a hydrogen atom)followed by removal of any protecting group where present.

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

(wherein Liy a leaving group,forexample a halogen atom such as chlorine, bromine or iodine, ora 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 astriethylamine, 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 ora chlorinated hydrocarbon e.g. chloroform at a temperature between ambient and reflux temperature of the solvent.

According to another example (b) of an alkylation process, a compound of general formula (I) in which R represents a hydrogen atom may be prepared by alkylation of an amine of general formula (II), as previously defined except that R'5 is a hydrogen atom ora group convertible thereto underthe reaction conditions, with a compound of general formula (IV): R2COXCH2OCH2YAr (lav) in the presence of a reducing agent, followed when necessary by removal of any protecting groups.

Examples of suitable B16 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. tetrahydrofu ran, orwater, as reaction solvent, ora mixture of solvents, e.g. a mixture of two or more ofthosejust described at normal or elevated temperature and pressure, for examplefrom 20to 100 Candfrom 1 to 10atmospheres.

Alternatively when one or both of R'4 and R15 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 forthe 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 etheror tert-butyl methyl ether, or tetra hydrofu ran.

When a compound of formula (II) where R'4 and R'5 are each hydrogen atoms is used, the intermediate imineofformula (V) maybeformed:

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).

Where it is desired to use a protected intermediate of general formula (II) it is particularly convenientto use hydrogen and a catalyst as described above with protecting group R14which is capable of being converted to a hydrogen atom under these reducing conditions, 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 another general process (2), a compound of general formula (I) may be prepared by reduction. Thus, for example, a compound of general formula (I) may be prepared by reducing an intermediate of general formula (Vl):

wherein at least one ofX4, X1, X2, X3 and Y represents a reducible group and/orAr contains a reducible group and the other(s) take the appropriate meaning asfollows,which isX4 is-NH2,X1 is-CH(OH)-,X2 is-CH2NR'4- (wherein R14 is a hydrogen atom or a protecting group), X3 is -CR1 B2X, andArand Yare as defined informula (I),followed where necessary by removal of any protecting groups.

Suitable reducible groups include those wherein X4 is-NO2, X1 is a group > C=O, X2 is a group-CH2NY'- (wherein Y' represents a group convertible to hydrogen by catalytic hydrogenation, for example an arylme thyl group such as benzyl, benzhydryl ora-methylbenzyl), oran imine (-CH=N-) group ora group-CONH-, X3 iS a group-COX- ora group CR'R2X (whereX is C2 6alkenylene or C2.6 alkynylene), or-X2-X3- is a group -CH2N =CR2X-, Y is C2 4 alkenylene or alkynylene, and Aries a phenyl group substituted buy a group containing an amide linkage such as-(CH2)q-,1CONR3R4 or-NHCOR17(where-NHCOR17 is reducible to the group NHR12).

The reduction may be effected using reducing agents conveniently empolyed for the reduction of ketones, imines, amides, protected amines, alkenes, alkynes and nitro groups. Thus, for example, when X4in general formula (VI) represents a nitro group, this may be reduced to an amino group using hydrogen in the presence of a catalyst as previously described for process (1) part (b).

When X1 in general formula (VI) represents a > C=O group this may be reduced to a-CH(OH)- group using hydrogen in the presence of a catalyst as previously described for process (1 ) part (b). 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 oraluminium hydride. The reaction may be effected in a solvent, where appropriate an alcohol e.g. methanol orethanol,or an ether such astetrahydrofuran, ora halogenated hydrocarbon such asdichloromethane.

When X2 in general formula (VI) represents a-CH2NY'- group orthe g roup-CH=N-, or-X2-X3- represents -CH2N=CR2X-this may be reduced to a-CH2NH- or-CH2NHCHR2X- group using hydrogen in the presence of a metal catalyst as previously described for process (1 ) part (b). Alternatively, when X2 or-X2-X3- is the group-CH=N- or-CH2N=CR2X- this may be reduced to a-CH2NH- or-CH2NHCHR2X- group using a reduc- ing agent and conditions asjust described forthe reduction of Xa when this represents a > C=Ogroup.

When X2 orX3 in general formula (VI) represents a-CONH- or-COX- group, orAr is phenyl substituted bya gruop containing an amide linkage such as-(CH2),1CONR3R4 or-NHCORr7 (where R17 is as defined pre viously), this may be reduced to a group -CH2NH- or-CH2X-, orto phenyl substituted by the group (CH2)qNR3B4 or-NHR12, respectively, using a hydride such as diborane or a complex metal hydride such as lithium aluminium hydride orsodium bis(2-methoxyethoxy) aluminium hydride in a solvent such as an ether, e.g. tetrahydrofuran or diethyl ether.

When X3 represents a group CR1 R2X where is C2.6 alkenylene or C2 6 alkynylene, or Y represents C2.4 alkenylene or C2 4 alkynylene, this may be reduced to C2 6 alkylene or C2 4 alkylene respectively using hydrogen in the presence of a catalyst as previously described for process (1 ) part (b). Alternatively, when Xis C2 6 alkynylene or Y is C2.4 alkynylene this may be reduced to C2 6 alkenylene or C2 4 alkenylene respectively 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 etherata lowtemperature e.g.00C.

In a further general process (3), a compound of general formula (I) may be prepared by deprotection of a protected intermediate offormula (VII)

where B14 and B16 each represent a hydrogen atom ora protecting group, and/or any hydroxy and/oramino substituent in the group Ar is protected, with the proviso that at least one of R14 and/or R'6 represents a protecting group and/orArcontains a protecting group.

Suitable protecting groups and their methods of removal are as described previously. Thus, for example, R14 may rnpresentan aralkyl group e.g. benzyl, which may be removed by hydrogenolysis in the presence of a metal catalyst (e.g. palladium on charcoal), and/or R16 may represent an acyl group which may be removed by boiling with a dilute mineral acid (e.g. hydrochloric acid).

Compounds offormula (I) may also be prepared by a process comprising interconversion ofonecom- pound of general formula (l)toanother.

Thus for example a compound offormula (I) in which Ar represents a phenyl group substituted by the group -(CH2)rCOR9 where R9 is hydroxy may be prepared by hydrolysis of the corresponding compound of formula (I) in which R9 represents C1.4alkoxy. The hydrolysis mayforexample be carried out under basic conditions using e.g. sodium hydroxide.

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

Physiologically acceptable salts ofthe 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 suitablesolventsuch as acetonitrile, acetone, chloroform, ethyl acetate or an alcohol, e.g. methanol, ethanol or iso-propanol.

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

When a specific enantiomerofa 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 ofthe general processes described herein.

Specific diastereoisomers of a compound offormula (I) may be obtained by conventional methods for example, by synthesis from an appropriate asymmetricstarting 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.

Intermediate compounds of general formula (Vl)for use in general process (2) may be prepared buy a number of processes, analogous to those described in UK Patent Specification No. 21 65542A.

Thusforexample intermediates of general formula (VI) in which X1 is a group /C=O may be prepared from a haloketone offormula (VIII)

by reaction with an amine of general formula (IX)

(wherein Y' is hydrogen 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, dimethylformamide, acetonitrile ora ketonesuch as butanone or methylisobutylketone, oran ester,forex- ample 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 X' is a group )C=O may be reduced to the corresponding intermediate in which X1 is a group -CH(OH)- using for example a metal hydride such as sodium borohydride in a solvent e.g. ethanol.

Intermediates offormulae (II), (III), (IV), (VIII) and (IX) are either known compounds or may be prepared by methods analogousto those described forthe preparation of known compounds.

Suitable methods for preparing intermediates offormulae (III), (IV) and (IX) are described in UK Patent Specifications Nos. 2140800A, 2159151A, 2165542A and in in the exemplification included hereinafter.

The following examples illustrate the invention. Temperatures are in 0C. 'Dried' refers two drying using magnesium sulphate orsodium sulphate exceptwhere otherwise stated. Thin layerchromatography(t.l.c.) was carried out over SiO2, and flash column chromatography (FCC) was carried out on silica (Merck 9385) using, unless otherwise stated, one ofthe following solvent systems: A-toluene:ethanol :0.88 ammonia; Btoluene:ethanol: triethylamine; C-ethyl acetate: hexa ne :triethylam ine; D-ethylacetate: methanol :triethylamine; E cyclohexane:ethyl acetate:triethylamine.The following abbreviations are used: THF -tetrahydrofuran; DMF- dimethylformamide; BTPC-bis(triphenylphosphine)palladium (Il) chloride; DEA-N,N-diisopropylethylamine.

Intermediate 1 is 1-(4-amino-3, 5-dichlorophenyl)-2-bromoethanone.

Intermediate 2 (Z)-N-[4-[3-[[6-[(Phenylmethyl)amino]hexyl]oxy]-1-propenyl]phenyl]-methanesulphonamide, hydrochloride (Z)-N-[4-[3-[(6-Bromohexyl)oxy]-1 -propenyl]phenyl]methanesulphonamide (2.0g) was added to benzylamine (6ml) at 125 , under nitrogen. The reaction mixture was stirred at 125 for 3h, cooled to room tem- perature and added to 2N hydrochloric acid (50ml) and water (20ml). The resultant white solid was collected by filtration, washed in turn with 2N hydrochloric acid, water and ether then dried in vacuo at 50 to give the title compound as a white powder (1.0g) m.p. 133-134 .

Intermediate 3 (Z)-N-[4-[3-[[6-[[2-(4-Amino-3,5-dichlorophenyl)-2-hydroxyethyl]-phenylmethyl)amino]hexyl]oxy]-1- propenyl]phenyljmethanesulphonamide Asuspension of Intermediate 1 (520mg), Intermediate 2 (850mg) and DEA (SOOmg) in THF (25ml)was stirred at room temperature overnight. Afterfiltration, the filtrate was concentrated to an oil which was dissolved in methanol (20ml) cooled in an ice-bath and treated with sodium borohydride (250mg). The pale yellow solution was stirred at room temperature overnight, the methanol was evaporated and the residue partitioned between water (25ml) and ethyl acetate (25ml).The organic phase was washed with water and brine, dried and concentrated to a red oil which was purified by FCC eluting with System E (75:25:1) to give the titlecompoundas a colourless oil (540mg). T.l.c.(System E 75:25:1 ) RfO.09.

Intermediate 4 4-lodo-N,N-dimethylbenzeneethanamine, hydrochloride 4-Bromo-N,N-dimethyl benzeneethanamine, hydrochloride (0.65g) was partitioned between ethyl acetate (10ml) and 8% sodium bicarbonate (10ml). The aqueous layer was extracted with ethyl acetate (10ml), and the combined organic extracts were dried and concentrated to give the free base (0.57g). n-Butyl lithium (1.6M in hexane, 1.72m4) was added to a solution of the free base (0.57g) in THF (1 OmC) at -78", and the mixture was stirred under nitrogen for 30 min. A solution of iodine (0.63g) in THF (10ml) was added dropwise and after 10 min the reaction was quenched by addition of saturated ammonium chloride (10ml).TheTHF was evaporated and the aqueous residue was extracted with ethyl acetate (2x1 Sm'). The organic extracts werewashed with IO%sodium thiosulphate (15mt) and brine (1SmC),dried and concentrated to yield a brown oil. The oil in ether(10mb) and dichloromethane (2ml) was treated with ethereal hydrogen chloride and the resultant precipitate was collected by filtration and dried to give the title compound as a white solid (0.549).

Analysis Found: C,38.77; H,4.87; N,4.39; Cl, 11.36; 1,40.67.

C10H141N.HCI requires C,38,55; H,4.85; N,4.5; Cl,11.38; 1,40.73%.

Intermediate 5 N({4-Iodophenyl)-N-methylmethanesulphonamide A mixture of N-(4-iodophenyl)methanesulphonamide (4.3g),50% aqueous sodium hydroxide (25ml), iodomethane (5mf), dichloromethane (10ml) andtetrabutylammonium bisulphate (0.5g) was stirred vigorously for 2h. Water (50ml) was added and the mixture was extracted with ether (3x50ml). The organic extracts were washed with water and brine, dried and concentrated to a solid which was triturated with hexaneto give the title compound as white crystals (4.1 g) m.p. 106-107 .

Intermediate 6 2-(4-lodophenoxy)-N,N-dimethylacetamide Dimethylamine (33% w/w in IMS, 5.85m') was added dropwise to a suspension of [(4-iodophenoxy)acetyl chloride (9.49g) in triethylamine (50ml) at 0' under nitrogen. The suspension was stirred for 2h at 0 and partitioned between ethyl acetate (300ml) and 8% aqueous sodium bicarbonate (300ml). The organic layer was dried and the solvent was evaporated to leave an oil which was purified by FCC eluting with diethyl ether to give the title compound as a white solid (3.96g), m.p. 63-65 .

Intermediate 7 4-Iodo-N,N-dimethylhenzeneacetamide 4-lodophenylacetyl chloride (5.1 5g) was added portionwiseto dimethylamine (0,90g) in triethylamine (25ml ) at 0'. The suspension was stirred atO for2h and chloroform (100m) was added. The organic phase was washed with 8% aqueous sodium bicarbonate (50m'), dried and concentrated to give a red solid (5.0g) which was purified by FCC eluting with etherfollowed by ethyl acetate to give the title compound as a yellow solid (2.589) m.p. 75-77 .

Intermediate 8 N,N-Dimethyl4-[4-[5-[(phenylmethyl)amino]pentyloxylbutyl]benzeneacetamide Intermediate 16 (1.60g) was added dropwise to benzylamine (3.5ml) at 120 under nitrogen. The solution was stirred for 3h at 120' and poured into 0.8N aqueous hydrochloric acid (65ml). The aqueous mixturewas extracted with ethyl acetate (3x30mC) and the combined extracts were washed with 8% aqueous sodium bicarbonate (50ml) and brine (50ml), dried and concentrated to give an oil (0.56g). The combined aqueous phases were re-extracted with ethyl acetate (2x50me), dried and concentrated to give an oil (0.92g). The two oils were combined and purified by FCC eluting with ethyl acetate-triethylamine (100:1) to give the title compoundasa paleyellowoil (1.00g),t.l.c. (Ethyl acetate-triethylamine 100:1) Rf 0.1.

Intermediate 9 N-[[3-[3-[[6-[(Phenylmethyl)amino]hexyl]oxy]- I-prop yn yphen y-meth yl]acetamide A suspension of N-[(3-iodophenyl)methyl]acetamide (3.91 g), N-[6-[(2 propynyl)oxy]hexyl]benzenemethanamine (3.489), BTPC(100mg)and copper iodide (60mg) in diethylamine (75ml) was stirred at room temperature under nitrogen for 20h. The reaction mixture was poured into diethyl ether (100ml) and filtered. The filtrate was concentrated to give an oil (6.62g) which was purified by FCC eluting with System D (100:0:1- > 100:10:1) to give the title compound as a red oil (4.609), t.l.c. (Ethyl acetate triethylamine 100:1) Rf0.12.

Intermediates 10-13 were prepared in a similar manner: Intermediate 10 N,N-Dimethyl-4-[3-[[6-[[phenylmethyl)amino o]hexyl]oxy]-1-propynyl]benzamide From 4-iodo-N,N-dimethylbenzamide (2.5g) and N-[6-[(2-propynyl)oxy]-hexyl]benzenemethanamine (2.23g). FCC purification eluting with ethyl acetate-triethylamine (100:1) gave the title compound as a orange oil (2.96g), t.l.c. (Ethyl acetate + few drops triethylamine) Rf 0.15.

Intermediate 11 N,N-Dimethyl-2-[4-[3-[[6-[phenylmethyl)amino]hexylyoxyl-1-propynyl]-phenoxylacetamide From Intermediate 6(3.91 g) and N-[6-[(2-propynyl )oxy]hexyl]-benzenemethanamine (3.1 4g). FCC purifica- tion eluting with System C(83:17:1) gave a product (3.87g) which was re-columned as previously but using ethyl acetate-triethylamine (100:1) as the eluantto give the titlecompoundas an orange oil (1.44g),t.l.c. (Ethyl acetate fewdropstriethylamine) Rf 0.3.

Intermediate 12 N-Methyl-N-[4-[3-[[6-[(phenylmethyl)amino]hexyl)oxy]-1-propynyl]-phenyl]methanesulphonamide From Intermediate 5 (1 .8g) and N-[6-[(2-propynyl)oxy]hexyl]-benzenemethanamine (1.5g), except that triethylamine/THF (1:1, 1,50ml ) was used instead ofdiethylamine. FCC purification eluting with System B(95:5:1) gave the title compound as an orange oil (2.0g),t.l.c. (System B 95:5:1) Rf0.13.

Intermediate 13 4-3-[[6-[[2-(4-Amino-3, 5-dichlorophenyl)-2-hydroxyethyl](phenyl-methyl)amino]hexyl]oxy]-1- propynyl)benzamide From Intermediate 24 (550mg) and 4-iodobenzamide (2509), exceptthat diethylamine/THF (4:1,1 Oml)was used instead of diethylamine, and addition of the reaction mixtureto etherfollowed by filtration was omitted.

FCC purification of the concentrated reaction mixture eluting with System B (90:10:1) gave the title compoundasa pale yellow oil (540mg),t.l.c. (System B90:10:1) Rf 0.35.

Intermediate 14 N-[4-[3-[[6-[[2-(4-Amino-3,5-dichlorophenyl)-2-hydroxyethyl]phenyl-methyl)amino]hexyl]oxy-1- propynyl]phenyl]-2-(dimethylamino)acetamide A suspension of Intermediate 24(1.09), 2-(dimethylamino)-N-(4-iodophenyl)acetamide (680mg), dicyclohexylamine (450mg), BTPC(50mg) and copper(l) iodide (10mg) in acetonitrile (15ml)was stirred undernitrogven for 3hr. Ether (25ml) was added, the precipitate was removed by filtration, the solvent was evaporated and the residue purified by FCC eluting with System C (50:50:1) to give the title compound as a yellow oil (800mg),t.l.c. (System A80:20:2) Rf 0.53.

Intermediate 15 4-[4-[3-[[6-[(Phenylmethyl)amino]hexyl]oxy]-1-propynyl]benzoyl]-morpholine 4-(4-lodobenzoyl)mo rpholine (4.0g) and N-[6-[(2-propynyl )oxy]-hexyl] benzenemetha nam ine (3.09g) were reacted according to the method of Intermediate 14. FCC purification eluting with ethyl acetate-triethylamine (100:1) gave the titlecompoundas a yellow oil (2.21g),t.l.c. (Ethyl acetate-triethylamine 100:1) Rf 0.2.

Intermediate 16 4-[4-[(5-Bromopentyl)oxy]butyl]-N,N-dimethylbenzeneacetamide A mixture of Intermediate 7 (2.50g), 1 -bromo-5-(3-butynyloxy) pentane (1.90g), dicyclohexylamine(l .739), BTPC (50mg)and copper iodide(lOmg)was stirred in acetonitrile (30m) under nitrogen for2h. Ether (80mC) was added, the mixture was filtered, the filtrate was concentrated and the residue was refluxed in ethanol (100mf )with charcoal and filtered (hyflo).The solution was hydrogenated over 10% palladium on charcoal (50% paste in water; 1 .0g) for 48h, filtered (hyflo) and concentrated to give a residue which was purified by FCC eluting with ether-ethyl acetate (1 00:80:20) to give the title compound as a yellow oil (1.62g),t.l.c.

(Ether) Rf0.12.

Intermediate 17 lz/-N-[[3-[3-[[6-[2-(4-A mino-3, 5-dichlorophenyl-2-hydroxyethyl]-(phenylmethyl)amino]hexyl]oxy]-1- propenyl]phenyljmethyljacetamide A solution of Intermediate 1(1.44g), Intermediate 9(2.0g) and DEA (660mg) in THF (20m) was left to stand for 20h at room temperature under nitrogen.The precipitate was removed by filtration and thefiltratewas concentrated to give an oil which was dissolved in methanol (20ml) cooled in an ice-bath, and treated portionwise with sodium borohydride (750mg). The reaction mixture was stirred at room temperature under nitrogen for 2h and concentrated to give an oil to which water (100ml) was added.The mixture was extracted with ethyl acetate (3x50ml) and the combined extracts were washed with water (50ml) and brine (50ml), dried and concentrated to give an oil which was purified by FCC eluting with System B (95:5:1 )to give the title compoundas ayellowoil (1.S1g),t.l.c. (System B9S:S:1) Rf0.13.

Intermediates 18-24 were prepared in a similar manner: Intermediate 18 4-[4-[5-[[2-(4-Amino-3,5-dichlorophenyl)-2-hydroxyethyl)(phenylmethyl)amino)pentyloxy]butyl]-N,N- dimethylbenzeneacetamide From Intermediate 1 (690mg) and Intermediate 8 (1.01g). The sodium borohydride/methanol reaction was continuedfor24h. FCC purification eluting with System C (50:50:1) gave the title compound as a yellow toil (1.1 2g), t.l.c. (Ethyl acetate-hexane (1:1) + few drops triethylamine) Ref 0.1.

Intermediate 19 (Z)-2-[4-[3-[[6-[[2-(4-Amino-3, 5-dichlorophenyl)-2-hydroxyethyl]-(phenylmethyl)amino]hexyl]oxy]-1- propenyl]phenoxy]-N,N-dimethylacetamide From Intermediate 1 (951 mg) and Intermediate 11 (1.429). FCC purification eluting with System B (97:3:1) gave the title compound as a yellow oil (1.1 1g),t.l.c. (System B 95:5:1) Rf 0.31.

Intermediate 20 N-[4-[2-[[6-[[2-1-Amino-3,5-dichloropheny-2- hydroxyethyl](phenylmethyl)amino]hexyl]oxy]ethyl]phenyl]methanesulphonamide From Intermediate 1 (0.7g) and N-[4-[2-[[6-[(phenylmethyl)amino] hexyl]oxy]ethyl]phenyl]methanesulphonamide (1 g). FCC purification eluting with System B (98:2:1) gave the title compound as a yellow oil (1 .2g), t.l.c. (System A 80:20:1) Rf 0.47.

Intermediate 21 N-[4-[3-[[6-[[2-(4-Amino-3,5-dichlorophenyl)-2-hydroxyethyl](phenylmethylhexyl]oxy]-1- 1- propynyl]phenyl]-N-methylmethane-sulphonamide From Intermediate 1 (660mg) and Intermediate 12(1 .0g). The sodium borohydride/methanol reaction was continued for 1 8h. FCC purification eluting with System C (33:66:1- > 150:50:1) gave the title compound as a pale yellow oil (320mg),t.l.c. (hexane-ether-triethylam i ne 50:50:1) Rf 0.04.

Intermediate 22 (Z)-4-[3-[[6-[[2-(4-Amino-3, 5-dichlorophenyl)-2-hydroxyethyl](phenylmethyl)amino]hexyl]oxyl- 1propenyl]-N,N-dimethylbenzamide From Intermediate 1 (1.0g) and Intermediate 10(1.39g). FCC purification eluting with System B (97:3:1) gavethe title compoundas a yellow oil (0.93g), t.l.c. (System B 95:5:1) Bf 0.3.

Intermediate 23 4-[4-[3-[[6-[[2-(4-Amino-3, 5-dichlorophenyl)-2-hydroxyethyl][phenylmethyl)amino]hexyl]oxy]-1- propynyljbenzoyl]morphollne From Intermediate 1 (1.0g) and Intermediate 15(1.53g). The sodium borohydride/methanol reaction was continuedfor60h. FCC purification eluting with System B (97:3:1) gave the titlecompoundas an orange oil (1.54g),t.l.c. (System B 95:5:1) Rf0.25.

Intermediate 24 4-A mino-3, 5-dichloro-&alpha;-[[(phenylmethyl)[6-[(2-propynyl)oxy]hexyl]amino]methyl]benzenemethanol From Intermediate 1(1.0g)and N-[6-[(2-propynyl)oxy]hexyl]benzenemethanamine(870mg), carrying out the first stage ofthe reaction for only 25 min. FCC purification eluting with System C (20:80:1) gave the title compound as a colourless oil (1 .27g), t.l.c. (System C 20:80:1) Rf 0.33.

Intermediate 25 N,N-Bis[2-ph en ylm ethoxyleth yl]-4-iodobenzeneamine A mixture of 2,2'-(4-iodophenylimino)bis-ethanol (2g), benzyl bromide (2.3g), tetra-n-butylammonium bi sulphate (0.4g) and 50% sodium hydroxide (20ml) was stirred vigorously for 5h. The mixture was diluted with water (20ml), extracted with ethyl acetate (2x20ml) and the combined extracts were washed consecutively with water (some) and brine (50ml), dried and evaporated. Purification by FCC eluting with hexane-ether (19:19:1) gave the title compoundas a pale yellow oil (2.1 g),t.l.c. (hexane-ether 1:1) Rf 0.7.

Intermediate 26 4-A min o-3, 5-dichloro-ol[[[6-[[3-[4-bis[2-lph en ylmeth oxylethyamin o]-phen yl]-2- propynyljoxyjhexylj(phenylmethyl)aminojmethyilbenzenemethanol Asolution of Intermediate 24 (1.9g), Intermediate 25 (1.75g), BTPC (90mg) and copper (I) iodide (9mg) in diethylamine/tetrahydrofuran (4: 1,30ml) was stirred at room temperature under nitrogen for 2 days. The solvent was evaporated and the residue was purified by FCC eluting with System C (20:80:1- > 30:70:1) to give the tftlecompoundas an orange oil (1.75g),t.l.c. (System C 20:80:1)Rf 0.17.

Intermediate 27 4-Amin o-3, 5-dichloro-&alpha;-[[6-[[3-[4-[2-(dimethylamino)ethoxy]phenyl]-2- propynyl)oxyjhexylj(phenylmethyl)aminojmethyljbenzenemethanol A solution of 2-(4-iodophenoxy)-N, N-dimethylethanamine' (1 .57g), Intermediate 24 (2.94g), BTPC (1 00mg) and copper iodide (1 Omg) in diethylamine (30ml) and acetonitrile (10ml) was stirred at room temperature under nitrogen for 16h. The solvent was evaporated and the residue was purified by FCC eluting with System B (95:5:1)to give the title compound as a red oil (3.57g),t.l.c. (System B 95:5:1) Rf0.26.

Example 1 4-[3-[[6-[[2-(4-Amino-3, 5-dichlorophenyl)-2-hydroxyethyl]amino]hexyl]-oxy]propylybenzamide Intermediate 13(1.3g) was hydrogenated over 10% palladium oxide on carbon (50% aqueous paste, 280mg) in ethanol (15ml)containing hydrochloric acid (conc. HCl/EtOH, 1:9 v/v, 2m). The catalyst was removed by filtration through hyflo, the solventwas evaporated and the residue was partitioned between 8% sodium bicarbonate (25ml) and ethyl acetate (25m:).The aqueous layer ways re-extracted with ethyl acetate (25ml) and the combined organic extracts were washed with 8% sodium bicarbonate and brine, dried and concentrated to a semi-solid which was triturated with ether/ethyl acetate (~4:1)two give the title compoundas an off-white solid (240mg, 22%) m.p.91-94 ,t.l.c. (System A80:20:2) Rf 0.25.

Examples 2-9 were prepared in a similar manner: Example 2 N-[4-[3-[[6-[[2-(4-Amino-3, 5-dichlorophenyl)-2-hydroxyethyl]amino]- hexyl]oxy]propyl]phenyl]methanesulphonamide From Intermediate 3 (500mg). Evaporation of the ethyl acetate extracts gave an oil which was purified by FCC eluting with System B (95:5:1) followed by trituration with dry ether to give the title compound as a white powder (1 00mg) m.p. 62-64".

Analaysis Found C,54,82;H,7.26;N,7.36 C24H35Cl2N304S.O.3SC4H10O requires C,54.63; H,6.95; N,7.52% Example 3 Ethy/4-[3-[6-[[(4-amino-3, 5-dichlorophenyl)-2-hydroxyethyl]aminohexyl]oxy]propyl]benzoate From ethyl 4-[3-[[6-[[(4-amino-3,5-dichlorophenyl)-2-hydroxyethyl]-(phenylmethyl)amino]heXyl]oxy]1- propynyl]benzoate (500mg), using pre-reduced 10% palladium on charcoal (50% paste in water, 60mg) as the catalyst for hydrogenation. The residue obtained by evaporation ofthe ethyl acetate extract was purified by FCC eluting with System C (50:50:1) to give the title compound as a white solid (97mg) m.p.66-68 . T.l.c.

(System C50:50:1) Rf 0.05.

Example4 N-[4-[3-[[6-[[2-(4-Amino-3, 5-dichlorophenyl )-2-hydroxyethyl]am ino]-hexyl]oxy] propyl]phenyl]-2- (dimethylamino)acetamide, (E)-butenedioate (salt) (1:1) From Intermediate 14 (750mg), using conc. HCl/EtOH, 1:9 v/v, 2.2ml. The yellow oil (520mg) obtained after concentration of the ethyl acetate extracts was dissolved in methanol (5 ml) and treated with a solution of fumaric acid (120mg) in methanol (2ml), the methanol was evaporated and the residue was triturated with ether to give a yellow solid (610mg) which was recrystallised from isopropanol (15ml) to give the titlecom- pound as a white solid (100mg) m.p. 106-110 .

Analysis Found C,56.32; H,6.97; N,7.94; Cl, 11.32.

C27H40Cl2N4O3.C4H4O4requires C,56.79; H, 6.76; N, 8.55; Cl,10.82%.

Example 5 4-[3-[[6-[[2-(4-Amino-3, 5-dichlorophenyl)-2-hydroxyethyl]amino]-hexyl]oxy]propyl]-N,N- dimethylbenzamide, {E)-butenedioate (salt) (2:1) From Intermediate 22 (0.82g) using pre-reduced 10% palladium on charcoal (50% aqueous paste, 1 00mg) as the catalyst for hydrogenation. Evaporation of the ethyl acetate extracts gave an oil which was purified by FCC eluting with System B (95:5:1) to give an oil. The oil (0.42g) in methanol (2ml) was treated with (E)butenedioic acid (47.6mg) in methanol (2ml) and the solution was concentrated. The residue was triturated with diethyl ether to give the title compound as a white solid (0.47g) m.p. 107-109" Analysis Found C,59.0; H,7.2; N, 7.2; Cl, 12.6.

C26H37Cl2N303.0.5C4H4O4 requires C,59.2; H, 6.9; N,7.4; Cl,12.5% Example 6 4-[4-[3-[[6-[[2-(4-Amino-3, 5-dichlorophenyl)-2-hydroxyethyl]amino]-hexyl]oxy]- prop yl]benzoyUmorphollne From Intermediate 23 (0.70g) using pre-reduced 10% palladium on charcoal (50% aqueous paste, 80mg) at the catalyst for hydrogenation. Evaporation ofthe ethyl acetate extract gave an oil which was purified by FCC eluting with System B (95:5:1 to give the title compound as a yellow oil (391 mg).A solution ofthetitle compound (390mg) in methanol (2ml) was treated with (E)-butenedioicacid (41.1 mg) in methanol (2ml), and the solvent was evaporated to give an oil which, on trituration with diethyl ether, gave the (E)-butenedioate salt (2:1) ofthe titlecompound as a white solid (40mg), m.p. 114-116" Analysis Found: C,58.7; H, 6.0; N, 6.7; Cl,11.9.

(C28H39C12N3O4)2.C4H4O4 requires C, 59.0; H, 6.8; N, 6.9; Cl,11.6% Example 7 N-[[3-[3-[[6-[[2-(4-Amino-3, 5-dichlorophenyl)-2-hydroxyethylyamino]- hexyljoxyjpropyljphenyljmethyljacetamide From Intermediate 17(1.40g) using pre-reduced 10% palladium on charcoal (50% aqueous paste, 170 mg) as the catalyst for hydrogenation. The solid obtained from the ethyl acetate extracts was triturated with diethyl ether to give the title compound as a white solid (0.76g) m.p. 91 -94", t.l.c. (System A 80:20:2) Rf 0.45.

Analysis Found: C, 60.7; H, 7.5; N,7.9; Cl, 13.9.

C26H37C12N303 requires C,61.2; H, 7.3; N, 8.2; Cl,13.9%.

Example 8 2-[4-[3-[[6-[[2-(4-Amino-3, 5-dichlorophenyl)-2-hydroxyethyl]amino]hexy]oxy]propyl]phenoxyl],N,N- dimethylacetamide hE)-butenedioate (salt) (2:1) From Intermediate 19 (0.99g) using pre-reduced 10% palladium on charcoal (50% aqueous paste, 11 Smg) as the catalyst for hydrogenation. Concentration of the ethyl acetate extract gave an oil. The oil (0.70g) in meth anol (2ml) was treated with (E)-butenedioic acid (75.5mg) in methanol (2ml) and the solution was concentrated. The residue was triturated with diethyl ether to give the title compound as a buff solid (0.639), m.p.

116-118 ,t.l.c.(System B 95:5:1) Rf 0.17.

Example 9 N-[4-[3-[[6-[[2-(4-Amino-3,5-dichlorophenyl)-2-hydroxyl]amino]-hexyl]oxy]propyl]-N- ylj-N- methylmethanesulphonamide hydrochloride From Intermediate 21 (250mg) using pre-reduced 10% palladium oxide on carbon (50% aqueous paste, 50 mg) as the catalystfor hydrogenation. Concentration of the ethyl acetate extract gave an oil which was purified by FCC eluting with System B (99:1 :1 < 95:5: 1) to give a yellow oil (130mg). The oil in ether (5mf)was treated with ethereal hydrogen chloride and the resultant oil was triturated with dry ether to give the title compound as a yellow solid (90mg), t.l.c. (System B 95:5:1) Rf0.56.

Analysis Found: C, 51.14; H,7.02; N, 6.87; Cl, 17.82; S, 5.00.

C25H37CI2N304S.HCI requires C, 51.50; H, 6.57; N, 7.21; Cl, 18.24; S, 5.50%.

Example 10 4-A mino-3, 5-dichloro-&alpha;-[[[6-[3-[4-[2-(dimethylamino)ethyl]phenyl]-propoxy]hexyl]amino]methyl]- benzenemethanol A solution of Intermediate 4 as its free base (1.54g) Intermediate 24 (2.949), BTPC (100mg) and copper(l) iodide (10mg) in diethylamine (30ml) and acetonitrile (10ml) was stirred under nitrogen for 18h. Thesolution was concentrated in vacuo to give a brown oil which was purified by FCC eluting with System B (95:5:1) to give a yellow oil (2.4g). The oil (2.3g) was hydrogenated over 10% palladium oxide on carbon (50% aqueous paste,500mg) in ethanol (20ml) containing hydrochloric acid (conc. HCI/EtOH; 1.9 v/v, 6.9ml). The catalyst was removed by filtration through hyflo, the ethanol was evaporated and the residue was partitioned between 8% sodium bicarbonate (20ml) and ethyl acetate (20ml).The acqueous layer ways re-extracted with ethyl acetate (20ml) and the combined organic extracts were washed with sodium bicarbonate (20ml) and brine (20ml), dried and concentrated to give a yellow oil. The oil was purified by FCC eluting with System B (98:2:1 )to give a pale yellow oil (1.2g) which was triturated with hexaneto give the title compoundas a white solid (1.19) m.p.41.5-43.5.

Analysis Found: C, 63.23; H, 8.37; N, 8.10; Cl, 13.69.

C27H40C12N302 requires C, 63.64; H, 7.91; N, 8.25; Cl,13.92%.

Example 11 4-[4-[5-[[2-(4-Amino-3, 5-dichlorophenyl)-2-hydroxyethyl]-amino]-pentyloxy]butyl]-N,N- dimethylbenzeneacetamide Intermediate 18 (1.00g) in ethanol (20ml) containing hydrochloric acid (conc. HCI/EtOH, 1:9 v/v, 1.48ml) was hydrogenated over pre-reduced 10% palladium on charcoal 1150mg,50% paste in water). The reaction mixture was filtered (hyflo) and the filtrate was concentrated. The residue was partitioned between ethyl acetate (100ml) and 8% aqueous sodium bicarbonate (2x50mf). The dried organic layer was concentrated and the residual oil was purified by FCC eluting with System D (100:0:1- > 90:10:1)to givethetitlecompound as a yellow oil (0.69g). The title compound (469mg) in methanol (2ml) was treated with (E)-butenedioicacid (51.9mg) in methanol (2ml). The solution was concentrated to give an oil which wastriturated with diethyl ether to give the (E)-butenedioate salt (2:1) ofthe title compound(407mg), m.p. 107-110".

Analysis Found: C, 59.9; H, 7.4; N, 7.0; Cl, 12.0.

C27H39CI2N303.0.5C4H4O4 requires C, 59.8; H, 7.1; N, 7.2; Cl,12.2%.

Example 12 N-[4-[3-[[6-[[2-(4-Amino-3, 5-dichlorophenyl)-2-hydroxyethyl]amino]-hexyl]oxy]ethyl]phenyl]- methanesulphonamide Intermediate 20 (1.2g) was hydrogenated as in Example 11, using pre-reduced 10% palladium oxide on carbon (50% aqueous paste, 1 50mg) as the catalyst. Evaporation of the ethyl acetate extract gave a yellow oil which was purified by FCC eluting with System B (92:8:1) to give a pale yellow oil which when triturated with ether gave the title compound as a white solid (445mg), m.p. 62-65".

Analysis Found: C, 52.94; H, 6.40; N, 7.79; Cl, 13.96; S, 6.17.

C23H33C12N3O4S requires C, 53.28; H, 6.42; N, 8.10; CI, 13.68; S, 6.18%.

Example 13 4-[3-[[6-[[2-(4-Amino-3, 5-dichlorophenyl)-2-hydroxyethyl]amino]hexyl]oxy]propyl]benzeneacetamide 4-[3-[(6-Bromohexyl-oxy]propyl]benzeneacetamide (950mg) was added to a stirred solution of4-aminoa- (aminomethyl)-3, 5-dichlorobenzenemethanol (900mg) and DEA (650mg) in DMF (10m4) at 100"underni- trogen.After 1 h the solvent was evaporated and the residue was partitioned between 8% sodium bicarbonate (20ml) and ethyl acetate (20m). The organic layer was washed with water and brine, dried and concentrated in vacuo to give a yellow solid which was triturated with ether to give the title compound as an off-white powder(510mg) m.p. 104-106".

Analysis Found: C, 60.58; H, 7.35; N, 8.11; Cl, 13.83 C25H35C12N3O3 requires C, 60.48; H,7.11; N, 8.46; Cl,14.28%.

Example 14 4-A mino-3, 5-dichloro -a-fff6-f3-f4- (m ethoxym eth yl)ph en Wiprop oxyihexyliaminoimeth yli benzenemethanol, FE)-butenedioate (2:1) (salt) 1 -[3-[(6-Bromohexyl(oxy-propyl]-4-(methoxymethyl)benzene (1.0g)and 4-amino-a-(aminomethyl)-3, 5- dichlorobenzenemethanol (1.0g) were reacted accordingtothe method of Example 13. Concentration ofthe ethyl acetate extract gave an oil which was purified by FCC eluting with System B (90:10:1) to give a yellow oil (620mg).The oil in isopropanol (5ml) was treated with a hot solution offumaric acid (20mg) in isopropanol (2ml) and after 1 h the two phase system was stirred vigorously to leave a pale yellow precipitate which was collected by filtration and dried in vacuo to give the title compound as a pale yellow powder (550mg) m.p.

110-1 12",t.l.c. (System A80:20:2) Rf 0.43.

Analysis Found: C, 59.33; H. 6.87; N,4.88; Cl, 13.31.

C25H36Cl2N2O3.0.5C4H4O4 requires C, 59.89; H, 7.07; N, 5.17; Cl,13.09%.

Example 15 4-[3-[[6-[[2-(4-Amino-3, 5-dichlorophenyl)-2-hydroxyethylyamino exyli-oxyiprop ylibenzoic acid The product according to Example 3 (600mg) in ethanol (8ml) was treated with 2N sodium hydroxide (4ml) and stirred at refluxfor 1 h. The ethanol was evaporated,water (20ml) was added to the residue and the mixture was neutralised using 2N hydrochloric acid. Ethyl acetate (25ml) was added and the two phase mixture was vigorously stirred for 10 min. The resulting precipitate was collected by filtration, washed with ethyl acetate and dried to give a cream solid (450mg),which was triturated with warm methanol (10ml) and filtered to give the title compound as a white powder (290mg) m.p. 190-191".

Analysis Found: C, 59.22, H6.82; N, 5.62; C1,14.40.

C24H32Cl2N2O4 requires C, 59.63; H6.67; N, 5.79; Cl,14.67%.

Example 16 4-A mino-3, 5-dichloro-&alpha;-[[[6-[3-[4-[(4-morpholinyl)methyl]phenyl]propoxy]hexyl]amino]- methylibenzenemethanol The product according to Example 6 (0.67g) in benzene (10m) was added dropwiseto lithium aluminium hydride (300mg) in dry diethyl ether (15mf) at room temperature under nitrogen. The suspension was stirred for 18h at room temperature with water (0.3ml), 2N aqueous sodium hydroxide (0.6ml) and water(0.6ml) gave a precipitate which was filtered off (hyflo). The filtrate was concentrated to give an oil which was purified by FCC eluting with System B (95:5:1) to give the titlecompound as a white solid (318mg) m.p. 57-59",t.l.c.

(System B 95:5:1)Rf 0.22.

Example 17 4-Amino-3, 5-dichloro-&alpha;-[[[6[3-[-4[[2-(dimethylamino)ethyl]amino]phenyl]propoxy]hexyl]amino]methyl]- benzenemethanol-(El-butenedioate (2:3) salts The product according to Example 4 as its free base (440mg) was treated with lithium aluminium hydride (420mg) following the method of Example 16. After 7 days, water (1 ml), 2N aqueous sodium hydroxide (2me) and water (1 ml) were added successively, the precipitate being removed by filtration through hyflo and the etherwas evaporated to leave a brown oil. Asolution ofthe oil (320mg) amd fumaric acid (78mg) in methanol (3ml) was concentrated to an oil which was triturated with ether to give the title compound as a brown solid (230mg), m.p. 41-45 .

Analysis Found: C, 56.59; H,7.35; N,7.30; C1,9.61.

C27H42Cl2N4O2.1.5C4H4O4 requires C, 56.66; H, 6.91; N, 8.01, Cl,10.13%.

Examples 18 and 19 were prepared according to the method of Example 1: Example 18 4-Amino-3, 5-dichloro-(&alpha;-[[[6-[3-[4-[bis(2-hydroxyethyl)amino]phenyl)propoxyl]hexyl]aminoj- methylibenzenemethanol From Intermediate26(402 mg), using conc. HCI/EtOH 1:9 v/v, 0.9ml. Evaporation of the ethyl acetate ex- tracts gave a brown oil which was purified by FCC eluting with System B (95:5:1- > 80:20: 1) to give the title compound as a pale yellow oil (85mg), t.l.c. (System A80:20:2) Rf 0.33.8 (CDCl3) 1.2-1.63 and 1.84 (-CH2-); 3.4 (-OCH2-); 3.54 and 3.81,8H, (-CH2CH20H)2; 6.62 and 7.04,4H, (CHof phenyl ring); 7.17,2H,(CH of dichioroa- niline ring).

Example 19 4-Amino-3, 5-dichloro-&alpha;-[[[6-[3-[4-[2-(dimethylamino)ethoxy]phenyl]-propoxy]hexyl]amino]- methyljbenzenemethanol From Intermediate 27 (3.42g), using pre-reduced 10% palladium on charcoal (50% paste in water,750mg) as the catalyst for hydrogenation, in ethanol (30ml) containing hydrochloric acid (conc. HCl/EtOH 1:9 v/v, 10.1 ml). The oil obtained by evaporation of the ethyl acetate extracts was purified by FCC eluting with System A (80:20:2) followed by further FCC chromatography of the impure fractions eluting with System B (95:5:1).

The combined oils obtained (493mg) in methanol (5m I) were treated with (E)-butenedioic acid (109mg) i n methanol (5ml). The solution was concentrated and the residual foam was triturated with diethyl ether to give the title compoundas a pale yellowfoam (0.361 g), tl.c. (System A 80:20:2) Rf 0.5.

Analysis Found: C,56.1; H, 7.2; N, 6.2; Cl, 11.0 C27H41Cl2N3O3. 1 .25C4H4O4.0.8H2O requires C,56.0; H, 7.0; N, 6.1; Cl,10.3% The following are examples of suitable formulation of compounds ofthe invention. The term 'active ingredient' is used herein to represent a compound ofthe invention.

Tablets (Direct Compression) mgltablet 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 orthe compression weight and using punches to suit.

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

Syrup (Sucrosefree) mg/5ml dose Active ingredient 2.0mg Hydroxypropyl methylcellulose USP (viscosity type 4000) 22.5mg Buffer ) Flavour ) Colour ) as required Preservative ) Sweetener ) Purified Water BP to 5.0ml The hydroxypropyl methylcellulose is dispersed in hotwater, cooled and then mixed with an aqueous solution containing the active ingredient and the other components of the formulation. The resultant solution is adjusted to volume and mixed. The syrup is clarified byfiltration.

Metered dose pressurised aerosol A. Suspension Aerosol mgimetered dose Per can Active ingredient micronised 0.100 26.40mg OleicAcidBP 0.100 2.64mg Trichlorofluoromethane BP 23.64 5.679 Dichlorodifluoromethane BP 61.25 14.709 The active ingredient is micronised in a fluid energy mill to a fine particle size range. The oleic acid is mixed with thetrichlorofluoromethane at a temperature of 10-15"C and the micronised drug is mixed into the sol- ution 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 pres surefilled into the cans through the valves.

B. Solution Aerosol mgimetered dose Per can Active ingredient 0.055 13.20mg Ethanol BP 11.100 2.66g Dichlorotetrafluoroethane BP 25.160 6.049 Dichlorodifluoromethane BP 37.740 9.069 Oleic acid BP, or a suitable surfactant e.g. Span 85 (sorbitan trioleate )may also be included.

The active ingredient is dissolved in the ethanol together with the oleic acid or surfactant if used. The alcoholic solution is metered into suitable aerosol containers followed by the dichlorotetrafluoroethane.

Suitable metering valves are crimped onto the containers and dichlorodifluoromethane is pressure filled into them through the valves.

Injection for intravenous administration mgiml Active ingredient 0.5mg Sodium Chloride BP as required Waterforlnjection BPto 1.0ml Sodium chloride may be added to adjust the tonicity ofthe solution and the pH may be adjusted, using acid oralkali, to that of optimum stability and/orfacilitatesolution ofthe active ingredient. Alternatively suitable buffer salts may be used.

The solution is prepared, clarified and filled into appropriate size ampoules sealed by fusion ofthe glass.

The injection is sterilised by heating in an autoclave using one ofthe acceptable cycles. Alternatively the solution may be sterilised by filtration and filled into sterile ampoules under aseptic conditions. The solution may be packed under an inert atmosphere of nitrogen orothersuitablegas.

Inhalation cartridges mgicartridge Active ingredient micronised 0.200 Lactose BPto 25.0 The active ingredient is micronised in a fluid energy mill to fine particle size range priorto 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 contents ofthe cartridge are administered using a powder inhalersuch as the Glaxo Rotahaler.

Claims (10)

1. Compounds of the general formula (I)

wherein X represents a bond, or a C1 6 alkylene, C2-6 alkenylene or C2-6 alkynylene chain and Y represents a bond, ora C1-4 alkylene, C2.4alkenylene or C2.4 alkynylene chain with the proviso that the sum total of carbon atoms in X and Y is not more than 8;; Ar represents a phenyl group substituted by one or more substituents selected from nitro,-(CH2)qR [where R is C1-3 alkoxy,-NR3R4 (where R3 and R4 each represent a hydrogen atom, ora C1.4alkyl group, or-NR3R4 forms a saturated heterocyclic amino group which has 5-7 ring members and optionally contains in the ring one or more atoms selected from -0-or-S-or a group -NH- or-N(CH3)-), -NR5CoR6 (where R5 represents a hydrogen atom or a C1 4 alkyl group, and R6 represents a hydrogen atom or a C1-4 alkyl, C1 4 alkoxy or-NR3R4 group), and q represents an integer from 1 to 3],-(CH2)rR7 [where R7 represents-NR5SO2R8 (where R8repre- sents a C1 4 alkyl, phenyl or NR3R4 group),-NR6COCH2N(R5)2 (where each ofthe groups R5 represents a hydrogen atom ora C1.4 alkyl group),-COR9(where R9 represents hydroxy, C1.4 alkoxy or NR3R4),-SR10(where R10 is a hydrogen atom, ora C1.4alkyl group optionally substituted by hydroxy, C1.4alkoxy or NR3R4),-SOR10, -SO2R10,-CN,or-NR11B12(where R11 and R12 represent a hydrogen atom ora C1-4alkyl group, at least one of which is C2A alkyl substituted by a hydroxy, C1 4 alkoxy or NR3R4 group), and r represents an integer from O to 3],-O(CH2)qCOR9 (where q and R9 are as defined above), or-O(CH2)tR13 [where R13 represents hydroxy, NR3R4, NR11R12ora C1 4 alkoxy group optionally substituted by hydroxy, C1.4alkoxy or NB3R4, and t is an integer2 or 3]; and B1 and R2 each represent a hydrogen atom ora C1-3 alkyl group, with the proviso that the sum total of carbon atoms in R1 and R2 is not more than 4; and physiologically acceptable salts and solvates (e.g. hydrates) thereof.

2. Compounds as claimed in claim 1 in which the sum total of carbon atoms in the chains-X- and -Y- is4, 5,60r7.

3. Compounds as claimed in claim 1 or 2 in which X represents -(CH2)3- or-(CH2)4-, and Y represents -CH2-,-(CH2)2- or-(CH2)3-.

4. Compounds as claimed in any of claims 1 to 3 in which R1 and R2 are both hydrogen atoms or R1 is a hydrogen atom and R2 is a C1-3 alkyl group.

5. Compounds as claimed in any of claims 1 to 4 in which Ar represents a phenyl group substituted by -(CH2)qR [where R represents C1 3 alkoxy, diC1-4alkylamino, morpholino, piperidino, piperazino, Nmethylpiperazino,-NHCOR6 (where R6 is C1 4 alkyl), and q is 1 or2],-(CH2)rR7 (where R7 represents-NB6SO2R8 (where R5 represents hydrogen or methyl, and R8 represents C1-4 alkyl-NHCOCH2N(R5)2 (where both groups R5 represent C1.4 alkyl),-COR9 (where R9 represents C1.4alkoxy,amino diC1-4alkylamino, morpholino, piperidino, piperazino or N-methyl-piperazino),-NR11R12 (where one or both of R11 and R12 represents a C2.4alkyl group substituted bya hydroxyordiC1.4alkylamino group and the other represents a hydrogen atom), and ris zero or 1],-OCH2COR9 (where R9 is diC1-4alkylamino), or-O(CH2)2R13 (where B13 is diC1.4alkylamino).

6. Compounds ofthegeneralformula (la)

wherein X represents a C3 4 alkylene chain and Y represents a C1 3 alkylenechain,with the proviso thatthetotal number of carbon atoms in Xand y is 5 or6; and Ar represents a phenyl group substituted by a group selected from C1-4alkoxymethyl, morpholinomethyl, diC1-4 alkylamino C1-4alkyl,-CH2NHCOR6 is C1-4alkyl), NR5SO2R8 (where R5 is hydrogen or methyl, and B8is C, 4 alkyl),-NHCOCH2N(B5)2 (where both groups R5 represent C1 4 alkyl), -COR9 (where R9 is hydroxy, C1-4 alkoxy, amino diC1-4alkylamino, ormorpholino),-CH2COR9 (where R9 is amino or diC1.4alkylamino),-NR11R12 (where R11 and R12 both represent hydroxy C2-4 alkyl), diC1.4 alkylaminoethylamino,-OCH2COR9 (where R9 is diC1-4alkylamino); or-O(CH2)2R13where R13 is diC1-4alkylamino; and physiologically acceptable salts and solvates thereof.

7. Compounds as claimed in claim 6 in which Ar represents a phenyl group substituted by a group selec- ted from -CH2NHCOR6 (where R6 is methyl) -NHSO2R8 (where R8 is methyl), -COR9 (where R9 is hydroxy, ethoxy, amino morpholino, or-CH2CORg (where R9 is amino or dimethylamino.

8. The compounds: 4-[3-[[6-[[2-(4-amino-3, 5-dichlorophenyl)-2-hydroxy-ethyljamino]hexyl]oxy]- propyl]benzamide; ethyl 4-[3-[[6-[[(4-amino-3, 5-dichlorophenyl)-2-hydroxy-ethyljamino]hexyl]oxy]- propyl]benzoate; N-[[3-[[6-[[2-(4-amino-3, 5-dichlorophenyl)-2-hydroxy- ethyl]amino]hexyl]oxy]propyl]phenyl]methyl]acetamide; 4-[4-[5-[[2-(4-amino-3, 5-dichlorophenyl)-2-hydroxyethyl]-amino]hexyl]pentyloxy]butyl]-N,N- dimethylbenzeneacetamide; 4-[3-[[6-[[2-(4-amino-3, 5-dichlorophenyl)-2-hydroxyethyl]amino]hexyl]oxy]propylbenzoic acid; 4-[4-[3-[[6-[[2-(4-amino-3, 5-dichlorophenyl)-2-hydroxy-ethyl]aminojhexyl]oxyjpropyl]- benzoyl]morpholine;; N-[4-[3-[[6-[[2-(4-amino-3, S-dichlorophenyl)-2-hydroxy-ethyl]amino]hexyl]oxyjethylj- phenyl]methanesulphonamide; [4-[3-[[6-[[2-(4-amino-3, 5-dichlorophenyl)-2-hydroxy-ethyljaminojhexyljoxyjpropyl]benzeneacetamide; and physiologically acceptable salts and solvates thereof.

9. A process forthe preparation of compounds as claimed in any of claims 1 to 8 ora physiologically acceptable salt or solvate there of which comprises: (1 a) forthe preparation of a compound offormula (I) in which R1 is a hydrogen atom, alkylating an amine of general formula (II)

(wherein B14 is a hydrogen atom or a protecting group and B16 isa hydrogen atom) with an alkylating agent of formula (III)

(wherein Lisa leaving group and R2, X, Y and Ar are as defined in claim 1) followed, if necessary, by removal ofany protecting group present;; or (1 b)forthe preparation of compound offormula (I) in which R1 isa hydrogen atom, alkylating an amine of general formula (II) as defined above exceptthat R15 is a hydrogen atom ora group convertible thereto underthe reaction conditions, with a compound of general formula (IV) R2COXCH20CH2YAr (IV) (wherein R2, X, Y and Ar are as defined in claim 1) in the presence of a reducing agent followed, if necessary, by removal of any protecting groups present; or (2) reducing an intermediate of general formula (VI)

wherein X1 is-CH(OH)- or a group convertible there to by reduction; X2 is-CH2NR14- (wherein B14 is a hydrogen atom ora protecting group) ora group convertible thereto by reduction; X3 is-CR1R2X- ora group convertible thereto by reduction (wherein R1 and R2 are as defined in claim 1); X4 is-N H2 or a group convertible thereto by reduction; and Yand Ar are as defined in Claim 1 or are groups convertible thereto by reduction; at least one ofX1,X2,X3 and X4 representing a reducible group and/orY representing a reducible group and/or Ar containing a redu cible group, followed, if necessary, by removal of any protecting group present; or (3) deprotecting a protected intermediate of general formula (VII)

wherein R1, R2, X, Y and Ar are as defined in claim 1, R14 and R15 each represent a hydrogen atom ora protecting group and/or any hydroxy and/or amino substituent in the group Ar is protected, with the proviso that at leastone ofR14and R16 represents a protecting group orArcontainsa protecting group; or (4) for the preparation of a compound of formula (I) in which Ar represents a phenyl group substituted by the group-(CH2)rCOB9 where r is as defined in claim 1 and R9 is hydroxy, hydrolysing the corresponding compound offormula (I) in which R9 represents C1-4alkoxy; and if desired, converting the resulting com pound of general formula (I) or a saltthereof into a physiologically acceptable salt orsolvatethereof.

10. Apharmaceutical composition comprising at least one compound of general formula (I) as defined in any of claims 1 to 8 of a physiologically acceptable salt orsolvate thereof,togetherwith a physioiogically acceptable carrier or excipient.