IE59466B1 - Dichloroaniline derivatives - Google Patents

Abstract

Compounds of the formula (I> 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

This invention relates to dichloroani1ine derivatives having a stimulant action at β2~adrenoreceptors, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine.

Dihaloani1ine derivatives have previously been described as bronchodilators having stimulant activity at β-adrenoreceptors.

Thus British Patent Specification No. 1178191 describes compounds of the general structure NR^R in which the substituents Hal represent bromine or chlorine atoms; R1 represents hydrogen or hydroxyl; R2 and R3 each represent hydrogen or C | alkyl; and R ** and R $ each represent hydrogen, Ci-g alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, dialkylaminoalkyl, cycloalkyl, phenyl, benzyl or adamantyl, or NRUR5 forms a heterocylic ring optionally substituted by 0χ_3 alkyl groups.

We have now found a novel group of dichloroaniline derivatives, which differ structurally 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 of the general formula (I) Cl \ // h2n—·χ / Cl \\ I /.—(j?HCH 2NH(jXCH 2OCH 2ΥΑγ , OH R2 wherein (I) X represents a bond, C χ_ g alkylene, C2_6 alkenylene or C2-6 alkynylene chain and Y represents a bond, or a C1 _ alkylene, C 2 _ 4 alkenylene or C2-1+ 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 Cy—3 alkoxy, -NR3R4 (where R3 and R4 each represent a hydrogen atom, or a C y _ i+ alkyl 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)-), -NR5C0R6 (where R5 represents a hydrogen atom or a C1-4 alkyl group, and R6 represents a hydrogen atom or a Ci_4 alkyl, Cx_4 alkoxy or -NR3R4 group), and q represents an integer from 1 to 3], -(CH2)rR7 [where R7 represents -NR5SO2R8 (where R8 represents a C i_4 alkyl, phenyl or -NR3R4 group), -NR5C0CH2N(R5)2 (where each of the groups R5 represents a hydrogen atom or a Ci_4alkyl group), -COR9 (where R9 represents hydroxy, C i_4 alkoxy or NR3R4), -SR10 (where R10 is a hydrogen atom, or a Ci_4 alkyl group optionally substituted by hydroxy, C χ-4 alkoxy or NR3RU), -SORl°, -SO2R10, -CN, or -NRnR12 (where R11 2 and R represent a hydrogen atom or a C1-4 alkyl group, at least one of which is C2-4alkyl substituted by a hydroxy, C1-4 alkoxy or NR3R4 group), and r represents an integer from 0 to 3), -0(CH2)qC0R9 (where q and R9 are as defined above), or -0(CH2)tR^3 [where R 1 3 represents hydroxy, NR3R4, NRnR12 or a C1-4 alkoxy group optionally substituted by hydroxy, C1-4 alkoxy or NR3R4, and t is an integer 2 or 3 ] .

R and R each represents a hydrogen atom or a Cχ_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 or two asymmetric carbon atoms, namely the carbon atom of the -CH- group and, when R1 and OH 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 -CH- group is in the R configuration are preferred.

OH In the definition of general formula (I), the term alkenylene includes both cis and trans structures.

According to one aspect, the invention provides compounds of formula (I) in which R1, R2, X, Y and Ar are as defined for formula (I) and R7 represents -NR5SO2R8, -COR9, -SR10, -SOR10, -SO2R10, -CN or -NRnR12.

In the general formula (I), the chain X may be for example a bond, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)1+-, -(CH2)5-, -(ch2)6-, -ch2c=c-, -(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)t|-, -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 chains X and Y is 4, 5, 6 or 7 are particularly preferred.

One preferred group of compounds of formula (I) is that in which X represents a Ci-g alkylene chain and Y represents a Cj_i, alkylene chain. Particular compounds of this type are those wherein X represents -(CH2)3- or -(CH2)U- and Y is -CH2-, -(CH2)2- °r -(CH2)3-.

In the compounds of formula (I) R^ and R2 may each be, for example, methyl, ethyl, propyl or isopropyl groups except that if one of R1 and R2 is a propyl or isopropyl group, the other is a hydrogen atom or a methyl group.

Thus for example R* may be a hydrogen atom or a methyl, ethyl or propyl group. R2 may be, for example, a hydrogen atom or a methyl group. R1 and R2 are each preferably a hydrogen atom or a methyl group.

A preferred group of compounds are those wherein R1 and R2 are both hydrogen atoms, or R1 is a hydrogen atom and R is a Ci_3 alkyl group, particularly a methyl group .

When -NR3Rl* in compounds of formula (I) represents a saturated heterocyclic amino group, this may have 5, 6 or 7 ring members and optionally contains in the ring a heteroatom selected from -0- or -S-, or a group -NH- or — N(CH3)—. Examples of such -NR3Rt+ groups are pyrrolidino, piperidino, hexamethyleneimino, piperazino, N-methylpiperazino, morpholino, homomorpholino or thiamorpholino.

Ar may be for example a phenyl group substituted by -(CH2)qR [where R represents C1-3 alkoxy e.g. methoxy, d iC 4 al ky 1 am ino e.g. dimethylamino, morpholino, piperidino, piperazino, N-methylpiperazino, -NHCOR6 (where R6 is Cj^-μ alkyl e.g. methyl), and q is 1 or 2], -(0Η2)γ^7 [where R7 represents -NR5S02R8 (where R5 represents hydrogen or methyl, and R8 represents Cj_4 alkyl e.g. methyl), -NHCOCH2N(R5)2 (where both groups R5 represent Ci-i, alkyl e.g. methyl), -COR9 (where R9 represents Cy_4 alkoxy e.g. ethoxy, amino, diC 1-4alky1 amino e.g. dimethylamino, morpholino, piperidino, piperazino or N-methylpiperazino), -NR^R^2 (where one or both of R^1 and R12 represents a C 2-4 alkyl e.g. ethyl group substituted by a hydroxy or diC 1 -1+al ky 1 am ino e.g. dimethylamino group, and the other represents a hydrogen atom), and r is zero or 1], -OCH2COR9 (where R9 is diC 1-4alkylamino e.g. dimethylamino), or -0(CH2)2R13 (where R13 is diC 1-4alky1 amino e.g. dimethylamino). β A preferred group of compounds according to the invention are those of the formula (Ia) Cl \ // \ / (JHCH 2NHCH 2XCH 20CH 2YAr OH (Ia) Cl wherein X represents a C 3-4 alkylene chain and Y represents a Ci_3 alkylene chain with the proviso that the total number of carbon atoms in X and Y is 5 or 6; and Ar represents a phenyl group substituted by a group selected from Cx-4 alkoxymethyl (e.g. methoxymethyl), morpholinomethyl, diC χ_ i,al ky 1 amino C χ_ 2al kyl (θ·9· dimethylaminoethyl), -CH2NHC0R6 (where R6 is Cx-4 alkyl e.g. methyl), -NR5S02R8 (where R5 is hydrogen or methyl and R8 is Cj-ι, alkyl e.g. methyl), -NHCOCH2N(R5)2 (where both groups R5 represent Cχ_4 alkyl e.g. methyl), -COR9 (where R9 is hydroxy, Cx-4 alkoxy e.g. ethoxy, amino, diCχ_4alky1 amino e.g. dimethylamino, or morpholino), -CH2C0R9 (where R9 is amino or diC χ_ 4a]. kyl amino e.g. dimethylamino), -NR^R12 (where R11 and R12 both represent hydroxy C2_4 alkyl e.g. hydroxyethy1) , diCχ-4alkylaminoethylamino (e.g. dimethylaminoethylamino), -0CH2C0R9 (where R9 is diCχ-4alkylamino e.g. dimethylamino) or -O(CH2)2R13 (where R13 is diCχ_4alkylamino e.g. dimethylamino); and physiologically acceptable salts and solvates thereo f.

Particularly preferred compounds of formula (Ia) are those in which X and Y are as defined for formula (la); and Ar represents a phenyl group substituted by a group selected from -CH2NHC0R6 (where R6 is methyl), -NHSO2R8 (where R8 is methyl), -COR9 (where R9 is hydroxy, ethoxy, amino or morpholino), or -CH2C0R9 (where R9 is amino or dimethylamino), and physiologically acceptable salts and solvates thereof.

Particularly important compounds of the invention are : 4-[3-[[6-[[2-(4-amino-3,5-dichlorophenyl)-2-hydroxyethyl]amino]hexyl]oxy]propyl]benzamide; .ethyl 4—[3—[[6—[[(4-amino-3,5-dichlorophenyl)-2-hydroxyethyl]amino]hexyl]oxy]propyl]benzoate; N-[[3-[3-[[6-[[2-(4-amino-3,5-dichlorophenyl)-2-hydroxyethyl]amino]hexyl]oxy]propyl]phenyl]methyl]acetamide; 4-[4-[5-[[2-(4-amino-3,5-dichlorophenyl)-2-hydroxyethyl)amino]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-hydroxyethyl]amino]hexyl]oxy]propyl]benzoyl]morpholine; N-[4-[3-[[6-[[2-(4-amino-3,5-dichlorophenyl)-2-hydroxyethyl]amino]hexyl]ox y]ethyl]phenyl]methanesulphonamide; [4-[3-[[6-[[2-(4-amino-3,5-dichlorophenyl)-2-hydroxyethyl]amino]hexyl]oxy]propyl]benzeneacetamide; and the physiologically acceptable salts and solvates thereof.

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, p-toluenesulphonates, methanesulphonates, sulphamates, ascorbates, salicylates, acetates, fumarates, succinates, lactates, glutarates, gluconates, tricarbal1y1 ates, hydroxy-naphthalenecarboxylates e.g. 1-hydroxy- or 3-hydroxy-2-naphthalenecarboxylates, or oleates. The compounds 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 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 PGF2a-induced contractions. Compounds 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 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 a metered amount.

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

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

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

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 ο 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 propel1 ant.

The compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glyceride.

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

A proposed daily dosage of active compound for the treatment of man is 0.005mg to 100mg, which may be conveniently administered in one or two doses. The precise dose employed will of course depend on the age and condition of the patient and on the route of administration. Thus a suitable dose for administration by inhalation is 0.005mg to 20mg, for oral administration is 0.02mg to 100mg, and for parenteral administration is 0.01mg to 2mg for administration by bolus injection and 0.01mg to 25mg for administration by infusion. j The compounds according to the invention may be prepared by a number of processes, as described in the following. In the following description of processes for 1 preparing compounds of formula (I) and intermediates 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 of the 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, either to use reagents which will not affect such groups, or to 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 may for example be protected by aralkyl groups such as benzyl, diphenylmethyl or triphenylmethyl, or as tetrahydropyranyl derivatives. Suitable amino protecting groups include aralkyl groups such as benzyl, α-methylbenzy1, diphenylmethyl or triphenylmethyl, and acyl groups such as acetyl, trichloroacetyl or trif1uoroacety1.

Conventional methods of deproteetion may be used.

Thus for example 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 2 mineral acid e.g. hydrochloric acid, or a base such as sodium hydroxide or potassium carbonate, or a group such as trich1oroacety1 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) Cl \ •_· H2N—. ·—(JHCH2NR 14r 15 (II) /·=. OH Cl (wherein R14 is a hydrogen atom or a 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 (ill): LCHXCH,OCH,YAr (III) 1 9 R2 (wherein L is a leaving group, for example a halogen atom such as chlorine, bromine or iodine, or a hydrocarbylsulphonyloxy group such as methanesulphonyloxy or p-toluenesulphonyloxy).

The alkylation is preferably effected in the presence of a suitable acid scavenger, for example, inorganic bases such as sodium or potassium carbonate, organic bases such as triethylamine, diisopropylethylamine or pyridine, or alkylene oxides such as ethylene oxide or propylene oxide. 3 The reaction is conveniently effected in a solvent such as acetonitrile or an ether e.g. tetrahydrofuran or dioxan, a ketone e.g. butanone or methyl isobutyl ketone, a substituted amide e.g. dimethylformamide or a chlorinated hydrocarbon e.g. chloroform at a temperature between ambient and the reflux temperature of the solvent.

According to another example (b) of an alkylation process, a compound of general formula (I) in which R1 represents a hydrogen atom may be prepared by alkylation of an amine of general formula (II), as previously defined except that R15 is a hydrogen atom or a group convertible thereto under the reaction conditions, with a compound of general formula (IV): R2C0XCH20CH2ΥΑγ (IV) in the presence of a reducing agent, followed when necessary by removal of any protecting groups.

Examples of suitable R15 groups convertible into a hydrogen atom are arylmethyl groups such as benzyl, α-methylbenzy1 and benzhydryl.

Suitable reducing agents include hydrogen in the presence of a catalyst such as platinum, platinum oxide, palladium, palladium oxide, Raney nickel or rhodium, on a support such as charcoal, using an alcohol, e.g. ethanol or methanol, or an ester e.g. ethyl acetate, or an ether e.g. tetrahydrofuran, or water, as reaction solvent, or a mixture of solvents, e.g. a mixture of two or more of those just described at normal or elevated temperature and pressure, for example from 20 to 100°C and from 1 to 10 atmospheres .

Alternatively when one or both of R114 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 for the reaction with these reducing 4 agents will depend on the particular hydride used, but will include alcohols such as methanol or ethanol, or ethers such as diethyl ether or tert-butyl methyl ether, or tetrahydrofuran.

When a compound of formula (II) where R1 ** and R15 are each hydrogen atoms is used, the intermediate imine of formula (V) may be formed: Cl \ //’~‘\\ . .

H2N—· /·—^HCH2N=(j:XCH20CH2YAr (V) .=. OH R2 / Cl 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 convenient to use hydrogen and a catalyst as described above with protecting group R1 ** which 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 α-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 (VI): Cl \ X**—/·—X !-X 2-X 3-CH20CH2Y-Ar · —· / Cl (VI) wherein at least one of X4, X1, X2, X3 and Y represents a reducible group and/or Ar contains a reducible group and the other(s) take the appropriate meaning as follows, which is X4 is -NH2, X1 is -CH(OH)-, X2 is -CH2NR14(wherein R14 is a hydrogen atom or a protecting group), X3 is -CR1R2X, and Ar and Y are as defined in formula (I), followed where necessary by removal of any protecting groups .

Suitable reducible groups include those wherein X4 is -N02, χΐ is a group >C = 0, X2 is a group -CH2NY'- (wherein Y' represents a group convertible to hydrogen by catalytic hydrogenation, for example an arylmethyl group such as benzyl, benzhydryl or α-methy1benzy1) , or an imine (-CH=N-) group or a group -CONH-, X3 is a group -COX- or a group CR1R2X (where X is C2_g alkenylene or C2_g alkynylene), or -X2-X3- is a group -CH2N=CR2X-, Y is C 2_ 4 alkenylene or alkynylene, and Ar is a phenyl group substituted by a group containing an amide linkage such as - (CH2)ς_χCONR3R4 or -NHC0R17 (where -NHC0R17 is reducible to the group NHR12).

The reduction may be effected using reducing agents conveniently employed for the reduction of ketones, imines, amides, protected amines, alkenes, alkynes and nitro groups. Thus, for example, when X4 in 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=0 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 or aluminium hydride. The reaction may be effected in a solvent, where appropriate an alcohol 6 e.g. methanol or ethanol, or an ether such as tetrahydrofuran, or a halogenated hydrocarbon such as diehloromethane.

When X2 in general formula (VI) represents a -CH2NY'group or the group -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 reducing agent and conditions as just described for the reduction of X1 when this represents a >C=0 group.

When X2 or X3 in general formula (VI) represents a -CONH- or -COX- group, or Ar is phenyl substituted by a gruop containing an amide linkage such as - ( CH 2 ) q-J.CONR 3R14 or -NHCOR17 (where R17 is as defined previously), this may be reduced to a group -CH2NH- or -CH2X-, or to phenyl substituted by the group - ( CH 2 ) qNR 3R14 or -NHR12, respectively, using a hydride such as diborane or a complex metal hydride such as lithium aluminium hydride or sodium bis(2-methoxyethoxy)aluminium hydride in a solvent such as an ether, e.g. tetrahydrofuran or diethyl ether.

When X3 represents a group CR2X where X 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 X is 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 ether at a low temperature e.g. 0®C.

In a further general process (3), a compound of general formula (I) may be prepared by deprotection of a protected intermediate of formula (VII) Cl R16HN—· \ // \ •—tpHCH 2NR 1 '♦(jxCH 20CH 2ΥΑγ OH R2 (VII) Cl where R1* and R16 each represent a hydrogen atom or a protecting group, and/or any hydroxy and/or amino substituent in the group Ar is protected, with the proviso that at least one of R14 and/or R16 represents a protecting group and/or Ar contains a protecting group.

Suitable protecting groups and their methods of removal are as described previously. Thus, for example, R11* may represent an 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 of formula (I) may also be prepared by a process comprising interconversion of one compound of general formula (I) to another.

Thus for example a compound of formula (I) in which Ar represents a phenyl group substituted by the group -(CH2)i-C0R9 where R9 is hydroxy may be prepared by hydrolysis of the corresponding compound of formula (I) in which R9 represents C^_4 alkoxy. The hydrolysis may for example be carried out under basic conditions using e.g. sodium hydroxide.

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 8 converted to the corresponding free acids 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 iso-propanol.

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. 9 Intermediate compounds of general formula (VI) for use in general process (2) may be prepared by a number of processes, analogous to those described in Patent Specification No. J?Λ'.

Thus for example intermediates of general formula (VI) in which X1 is a group /C=0 may be prepared from a haloketone of formula (VIII) Cl \ - —· // w 9N—. .—C0CH,Hal \ _ / 2 ♦ - / Cl (VIII) by reaction with an amine of general formula (IX) R1 Y'NHCXCH20CH2YAr (IX) R2 (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 or a ketone such as butanone or methylisobutylketone, or an ester, for example 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 X1 is a group yC=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 of formulae (II), (ill), (IV), (VIII) and (IX) are either known compounds or may be prepared by methods analogous to those described for the preparation of known compounds.

Suitable methods for preparing intermediates of formulae (III), (IV) and (IX) are described in Patent Specification Nos. , and in the exemplification included hereinafter. Ο The following examples illustrate the invention. Temperatures are in °C. 'Dried' refers to drying using magnesium sulphate or sodium sulphate except where otherwise stated. Thin layer chromatography (t.l.c.) was carried out over Si02, and flash column chromatography (FCC) was carried out on silica (Merck 9385) using, unless otherwise stated, one of the following solvent systems: A-toluene:ethanol:0.88 ammonia; B-toluene:ethanol:triethylamine; C-ethyl acetate:hexane: triethylamine; D-ethy1acetate:methanol:triethylamine; E-cyclohexane:ethyl acetate:triethylamine. The following abbreviations are used: THE - tetrahydrofuran; DMF-dimethylformamide; BTPC-bis(triphenylphosphine)palladium (II) chloride; DEAΝ,Ν-diisopropylethylamine.

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

Intermediate 2 (£)-N-[4-[3-[[6-[(PhenyImethyl)amino]hexyl]oxy]-l-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 temperature 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 (£)-N-[4-[3-[[6-[[2-(4-Amino-3,5-dichiorophenyl)-2-hydroxyethyl](phenylmethyl)amino]hexyl]oxy]-l-propenyl]phenyl]methanesulphonamide A suspension of Intermediate 1 (520mg), Intermediate 2 (850mg) and DEA (500mg) in THF (25ml) was stirred at room temperature overnight. After filtration, 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 1 organic phase was washed with water and brine, to a red oil which was purified by FCC eluting to give the title compound as a colourless oil (System E 75:25:1) Rf 0.09. dried and concentrated with System E (75:25:1) (540mg). T.l.c.

Intermediate 4 4-Iodo-N,N-dimethylbenzeneethanamine, hydrochloride 4-Bromo-N^N-dimethylbenzeneethanamine, hydrochloride (0.65g) was partitioned between ethyl acetate (10mA) and 894 sodium bicarbonate (10mA). The aqueous layer was extracted with ethyl acetate (10mA), o and the combined organic extracts were dried and concentrated to give the free base (0.57g). _n-Butyl lithium (1.6M in hexane, 1.72mA) was added to a solution of the free base (0.57g) in THF (10mA) at -78°, and the mixture was stirred under nitrogen for 30 min. A solution of iodine (0.63g) in THF (10mA) was added dropwise and after 10 min the reaction was quenched by addition of saturated ammonium chloride (10mA). The THF was evaporated and the aqueous residue was extracted with ethyl acetate (2x15mA). The organic extracts were washed with 1090 sodium thiosulphate (15mA) and brine (15mA), dried and concentrated to yield a brown oil. The oil in ether (10mA) and dichloromethane (2mA) 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 (0.54g).

Analysis Found: 0,38.77; H,4.87; N,4.39; 01,11.36; 1,40.67.

C10HlltIN.HCl requires 0,38,55; H,4.85; N,4.5; 01,11.38; 1,40.73%.

Intermediate 5 Ν-(4-1odophenyl)-N-methylmethanesulphonamide A mixture of N-(4-iodophenyl)methanesulphonamide (4.3g), 50% aqueous sodium hydroxide (25mA), iodomethane (5mA), dichloromethane (10mA) and tetrabutylammonium bisulphate (0.5g) was stirred vigorously for 2h.

Water (50mA) was added and the mixture was extracted with ether (3x50mA). The organic extracts were washed with water and brine, dried and concentrated to a solid which was triturated with hexane to give the title compound as white crystals (4.1g) m.p. 106-107°.

Intermediate 6 2-(4-1odophenoxy)-N,N-dimethylacetamide Dimethylamine (33?ό w/w in IMS, 5.85mA) was added dropwise to a suspension of [(4-iodophenoxy)acetyl chloride (9.49g) in triethylamine (50mA) at 0° under nitrogen. The suspension was stirred for 2h at 0° and partitioned between ethyl acetate (300mA) and 8% agueous sodium bicarbonate (300mA). 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-^,Ν-dimethylbenzeneacetamide 4-Iodophenylacetyl chloride (5.15g) was added portionwise to dimethylamine (0.90g) in triethylamine (25mA) at 0°. The suspension was stirred at 0° for 2h and chloroform (100mA) was added. The organic phase was washed with 8% agueous sodium bicarbonate (50mA), dried and concentrated to give a red solid (5.0g) which was purified by FCC eluting with ether followed by ethyl acetate to give the title compound as a yellow solid (2.58g) m.p. 75-77°.

Intermediate 8 ^,Ν-Pimethyl 4-[4-[5-[(phenylmethy1)amino]pentyloxy]butyljbenzeneacetamide Intermediate 16 (1.60g) was added dropwise to benzylamine (3.5mA) at 120° under nitrogen. The solution was stirred for 3h at 120° and poured into 0.8N aqueous hydrochloric acid (65mA). The aqueous mixture was extracted with ethyl acetate (3x30mA) and the combined extracts were washed with 8SS aqueous sodium bicarbonate (50mA) and brine (50mA), dried and concentrated to give an oil (0.56g). The combined aqueous phases were re-extracted with ethyl acetate (2x50mA), 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 compound as a pale yellow oil (1.00g), t.l.c. (Ethyl acetate-triethylamine 100:1) Rf 0.1. 2 Intermediate 9 N-((3-(3-((6-((Phenylmethyl)amino]hexyl]oxy]-1-propynyl]phenyl]methyl]acetamide A suspension of N-((3-iodophenyl)methyl]acetamide (3.91g), N-(6-((2-propynyl)oxy]hexyl]benzenemethanamine (3.48g), BTPC (lOOmg) and copper iodide (60mg) in diethylamine (75mJl) was stirred at room temperature under nitrogen for 20h. The reaction mixture was poured into diethyl ether (lOOmX) 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 (4.60g), t.l.c. (Ethyl acetate-triethylamine 100:1) Rf 0.12.

Intermediates 10-13 were prepared in a similar manner: Intermediate 10 N,Ν-Dimethy1-4-(3-((6-((phenylmethyl)amino]hexyl]oxy]-1 propynyl]benzamide From 4-iodo-N,N-dimethylbenzamide (2.5g) and N—(6—((2-propynyl)oxy]hexyllbenzenemethanamine (2.23g). FCC purification eluting with ethyl acetate-triethylamine (100:1) gave the title compound as an orange oil (2.96g), t.l.c. (Ethyl acetate + few drops triethylamine) Rf 0.15.

Intermediate 11 Ν,,Ν-Dimethy 1-2-(4-( 3-( (6-((phenylmethyl) amino]hexyl]oxy]-1-propynyl]phenoxy] acetamide From Intermediate 6 (3.91g) and N-(6-((2-propynyl)oxy]hexyl]benzenemethanamine (3.14g). FCC purification 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 eluant to give the title compound as an orange oil (1.44g), t.l.c. (Ethyl acetate + few drops triethylamine) Rf 0.3.

Intermediate 12 N-Methyl-N-[4-(3-[[6-((phenylmethy1)amino]hexyl]oxy]-1-propynyl]phenyl] methanesulphonamide From Intermediate 5 (1,8g) and N-(6-[(2-propynyl)oxy]hexyl]2 4 benzenemethanamine (1.5g), except that triethylamine/THF (1:1, 50mA)) was used instead of diethylamine. 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) Rf 0.13.

Intermediate 13 4-[3-[[6-[[2-(4-Amino-3,5-dichloropheny1)-2-hydroxyethylj(phenylmethyl ) amino] hexyl] oxy]- 1-propynyl] benzamide From Intermediate 24 (550mg) and 4-iodobenzamide (250mg), except that diethylamine/THF (4:1, 10ml) was used instead of diethylamine, and addition of the reaction mixture to ether followed by filtration was omitted. FCC purification of the concentrated reaction mixture eluting with System B (90:10:1) gave the title compound as a pale yellow oil (540mg), t.1 .c.(System B 90:10:1) Rf 0.35.

Intermediate 14 N-[4-[3-[[6-([2-(4-Amino-3,5-dichlorophenyl)-2-hydroxyethyl](phenylmethyl)amino]hexyl]oxy]-1-propynyl]phenyl]-2-(dimethylamino) acetamide A suspension of Intermediate 24 (1.0g), 2-(dimethylamino)-N-(4iodophenyl)acetamide (680mg), dicyclohexylamine (450mg), BTPC (50mg) and copper (I) iodide (10mg) in acetonitrile (15ml) was stirred under nitrogven 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 A 80:20:2) Rf 0.53.

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

Intermediate 16 4-[4-((5-Bromopenty1)oxy]butyl]-N N-dimethylbenzeneacetamide 'A mixture of Intermediate 7 (2.50g), 1-bromo-5-(3-butynyloxy)pentane . (1.90g), dicyclohexylamine (1.73g), BTPC (50mg) and copper iodide (10mg) was stirred in acetonitrile (30mA) under nitrogen for 2h.

Ether (80mA) was added, the mixture was filtered, the filtrate was concentrated and the residue was refluxed in ethanol (100mA) with charcoal and filtered (Hyflcf*). 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 (100:0+80:20) to give the title compound as a yellow oil (l.62g), t.l.c. (Ether) Rf 0.12.

Intermediate 17 (£) -N-[[3-[3-[[6-[[2-(4-Amino-3,5-dichlorophenyl)-2-hydroxyethyl](phenylmethy1) amino]hexy1]oxy]-1-propenyl]phenyl]methyl]acetamide A solution of Intermediate 1 (1.44g), Intermediate 9 (2.0g) and DEA (660mg) in THF (20mA) was left to stand for 20h at room temperature under nitrogen. The precipitate was removed by filtration and the filtrate was concentrated to give an oil which was dissolved in methanol (20mA) 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 (100mA) was added. The mixture was extracted with ethyl acetate (3x50mA) and the combined extracts were washed with water (50mA) and brine (50mA), dried and concentrated to give an oil which was purified by FCC eluting with System 8 (95:5:1) to give the title compound as a yellow oil (1.51g), t.l.c. (System 8 95:5:1) Rf 0.13.

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 (l.01g). The sodium borohydride/methanol reaction was continued for 24h. FCC purification *(Registered Trade Mark) 6 eluting with System C (50:50:1) gave the title compound as a yellow oil (l.12g), t.l.c. (Ethyl acetate-hexane (1:1) + few drops triethylamine) Rf 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,Ν-dimethylacetamide From Intermediate 1 (951mg) and Intermediate 11 (l.42g). FCC purification eluting with System 8 (97:3:1) gave the title compound as a yellow oil (l.11g), t.l.c. (System B 95:5:1) Rf 0.31.

Intermediate 20 N-[4-[2-[[6-[[2-(4-Amino-3,5-dichlorophenyl)-2-hydroxyethyl](phenylmethyl ) amino] hexyl] oxy] ethyl] phenyl jmethanesulphonamide From Intermediate 1 (0.7g) and N-[4-[2-[[6-[(phenylmethyl)amino]hexyl]oxy]ethyl]phenyl]methanesulphonamide (1g). 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](phenylmethyl) amino] hexyl]oxy]-1-propynyl]phenyl]-N-methylmethanesulphonamide From Intermediate 1 (660mg) and Intermediate 12 (1.0g). The sodium borohydride/methanol reaction was continued for 18h. FCC purification eluting with System C (33:66:1+50:50:1) gave the title compound as a pale yellow oil (320mg), t.l.c. (hexane-ether-triethylamine 50:50:1) Rf 0.04.

Intermediate 22 (Z)-4-[3-[[6-[[2-(4-Amino-3,5-dichlorophenyl )-2-hydroxyethyl](phenylmethyl ) amino]hexyl]oxy]-1-propenyl]-N,Ν-dimethylbenzamide From Intermediate 1 (1.0g) and Intermediate 10 (1.39g). FCC purification eluting with System B (97:3:1) gave the title compound as a yellow oil (0.93g), t.l.c. (System B 95:5:1) Rf 0.3. 7 Intermediate 23 4-(4-(3-((6-((2-(4-Amino-3,5-dichlorophenyl)-2-hydroxyethy13(phenylmethyl) amino] hexy1]oxy]-1-propynyl]benzoyljmorpholine From Intermediate 1 (l.Og) and Intermediate 15 (1.53g). The sodium borohydride/methanol reaction was continued for 60h. FCC purification eluting with System B (97:3:1) gave the title compound as an orange oil (1.54g), t.l.c. (System B 95:5:1) Rf 0.25.

Intermediate 24 4-Amino-3,5-dichloro-a-[[(phenylmethyl)[6-((2-propynyl)oxy]hexyl] amino]methyl]benzenemethanol From Intermediate 1 (1 .Og) and _N-[6-[(2-propynyl)oxy]hexyl]benzenemethanamine (870mg), carrying out the first stage of the 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-phenylmethoxy)ethyl]-4-iodobenzeneamine A mixture of 2,2'-(4-iodophenylimino)bis-ethanol (2g), benzyl bromide (2.3g), tetra-n-butylammonium bisulphate (0.4g) and 50?ό 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 (50ml) and brine (50ml), dried and evaporated. Purification by FCC eluting with hexane-ether (19:1+9:1) gave the title compound as a pale yellow oil (2.1g), t.l.c. (hexane-ether 1:1) Rf 0.7.

Intermediate 26 4-Amino-3,5-dichloro-a-[[[6-([3-[4-bis[2-(phenylmethoxy)ethyl]amino]phenyl]-2-propynyl]oxy]hexyl](phenylmethyl)amino]methyl]benzenemethanol A solution of Intermediate 24 (1.9g), Intermediate 25 (l.75g), BTPC (90mg) and copper (I) iodide (9mg) in diethylamine/tetrahydrofuran (4:1, 30ml) was stirred at room temperature under nitrogen for 2 days. 8 The solvent was evaporated and the residue was purified by FCC eluting with System C (20:80:1+30:70:1) to give the title compound as an orange oil (1.75g), t.l.c. (System C 20:80:1) Rf 0.17.

Intermediate 27 4-Amino-3 ,5-dichloro-a-[[6-[[3-[4-[2-(dimethylamino)ethoxy]phenyl]2-propynyl)oxy]hexyl](phenylmethy1) amino]methyl]benzenemethanol A solution of 2-(4-iodophenoxy)-N,N-dimethylethanamine' (1.57g), Intermediate 24 (2.94g), BTPC (lOOmg) and copper iodide (lOmg) 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) Rf 0.26.

Example 1 4-[3-[[6-[[2-(4-Amino-3,5-dichlorophenyl)-2-hydroxyethyl]amino]hexyl]oxy]propyl]benzamide Intermediate 13 (1.3g) was hydrogenated over 10% palladium oxide on carbon (50% aqueous paste, 280mg) in ethanol (15mA) containing hydrochloric acid (cone. HCl/EtOH, 1:9 v/v, 2mA). The catalyst was removed by filtration through hyflo, the solvent was evaporated and the residue was partitioned between 8% sodium bicarbonate (25mA) and ethyl acetate (25mA). The aqueous layer was re-extracted with ethyl acetate (25mA) 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) to give the title compound as an off-white solid (240mg, 22%) m.p. 91-94°, t.l.c.

(System A 80:20:2) 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]hexy1]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) 9 followed by trituration with dry ether to give the title compound as a white powder (100mg) m.p. 62-64°.

Analaysis Found: C, 54.82 ;Η, 7.26;Ν, 7.36 C2uH35C12N3°us·O.35C4H1oO rquires C,54.63;H,6.95;N,7.52?i Example 3 Ethyl 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]l-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 of the 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 C 50:50:1) Rf 0.05.

Example 4 ^-(4-(3-( [6-[[2-(4-Amino-3,5-dichlorophenyl)-2-hydroxyethyl]amino]hexy1]oxy]propy1]phenyl]-2-(dimethylamino)acetamide, (E)-butenedioate (salt) (1:1) From Intermediate 14 (750mg), using cone. HCl/EtOH, 1:9 v/v, 2.2ml.

The yellow oil (520mg) obtained after concentration of the ethyl acetate extracts was dissolved in methanol (5ml) 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 title compound as a white solid (100mg) m.p. 106-110°.

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

C27HUOC12NU°3-CUH404 reQuires 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]propy1]-N,N-dimethylbenzamide, (E)-butenedioate (salt) (2:1 ) From Intermediate 22 (0.82g) using pre-reduced 10% palladium on charcoal (50% aqueous paste, lOOmg) as the catalyst for hydrogenation. 0 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;Ci,12.6.

Example 6 4-[4-[3-[ [6-[[2-(4-Amino-3,5-dichlorophenyl)-2-hydroxyethyl]amino]hexyl]oxy3-propyl]benzoyl]morphoiine From Intermediate 23 (0.70g) using pre-reduced 10% palladium on charcoal (50% aqueous paste, 80mg) at the catalyst for hydrogenation. Evaporation of the 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 (391mg). A solution of the title compound (390mg) in methanol (2ml) was treated with (E)-butenedioic acid (41.1mg) 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) of the title compound as a white solid (40mg), m.p. 114-116°.

Analysis Found: o/ /0 Example 7 N-[[3-[3-[[6-[[2-(4-Amino-3,5-dichlorophenyl)-2-hydroxyethyljamino]hexyljoxy] propy1]phenylJmethyl3 acetamide From Intermediate 17 (1.40g) using pre-reduced 10% palladium on charcoal (50% aqueous paste, 170mg) 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;C1,13.9. 0/ /0 « 1 Example 8 2-[4-[3-[[6-[[2-(4-Amino-3,5-dichlorophenyl)-2-hydroxyethyl]amino]hexyl]oxy] propyljphenoxy], Ν,Ν-dimethylacetamide (E)-butenedioate (salt) (2:1) From Intermediate 19 (0.99g) using pre-reduced 10% palladium on charcoal (50% aqueous paste, 115mg) as the catalyst for hydrogenation. Concentration of the ethyl acetate extract gave an oil. The oil (0.70g) in methanol (2mA) was treated with (E)-butenedioic acid (75.5mg) in methanol (2mA) and the solution was concentrated. The residue was triturated with diethyl ether to give the title compound as a buff solid (0.63g), 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-hydroxyethyl]amino]hexyljoxy]propyl]phenyl]-N-methylmethanesuIphonamide hydrochloride From Intermediate 21 (250mg) using pre-reduced 10% palladium oxide on carbon (50% aqueous paste, 50mg) as the catalyst for 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 (5mA) 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) Rf 0.56.

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

C25H37C12N3°4S’HC1 requires C,51.50;H,6.57;N,7.21;C1,18.24;S,5.5O%.

Example 10 4-Amino-3,5-dichloro-ot-[[[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 (2.94g), BTPC (100mg) and copper (I) iodide (10mg) in diethylamine (30mA) and acetonitrile (10mA) was stirred under nitrogen for 18h.

The solution 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 (20mA) containing hydrochloric acid (cone. HCl/EtOH; 1:9 v/v, 6.9mA). The catalyst was removed by filtration through hyflo, the ethanol was evaporated and the residue was partitioned between 8% sodium bicarbonate (20mA) and ethyl acetate (20mA). The aqueous layer was re-extracted with ethyl acetate (20mA) and the combined organic extracts were washed with sodium bicarbonate (20mA) and brine (20mA), 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 (l.2g) which was triturated with hexane to give the title compound as a white solid (1.1g) m.p. .5-43.5.

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

C27HuoC12N3O2 requires C,63.64;H,7.91;N,8.25;C1,13.92%.

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 (20mA) containing hydrochloric acid (cone. HCl/EtOH, 1:9 v/v, 1.48mA) was hydrogenated over pre-reduced 10% palladium on charcoal (l50mg, 50% paste in water). The reaction mixture was filtered (hyflo) and the filtrate was concentrated. The residue was partitioned between ethyl acetate (100mA) and 8% aqueous sodium bicarbonate (2x50mA). 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 give the title compound as a yellow oil (0.69g). The title compound (469mg) in methanol (2ml) was treated with (E)-butenedioic acid (51.9mg) in methanol (2ml). The solution was concentrated to give an oil which was triturated with diethyl ether to give the (E)-butenedioate salt (2:1) of the title compound (407mg), m.p. 107-110°.

Analysis Found: C,59.9;H,7.4;N,7.0;Cl,12.0 C27H39C12N303-°-5C\H*t04 requires C,59.8;H,7.1;N,7.2;C1,12.2% Example 12 N-[4-[3-[[6-[[2-(4-Amino-3 >5-dichlorophenyl)-2-hydroxyethyl]amino]hexyl]oxy]ethyl]phenyllmethanesulphonamide Intermediate 20 (1.2g) was hydrogenated as in Example 11, 3 using pre-reduced 10% palladium oxide on carbon (50% aqueous paste, 150mg) 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.

C23H33CI2N3O4S requires C,53.28; H,6.42; N,8.10; Cl,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 of 4-amino-a-(aminomethyl)-3,5-dichlorobenzenemethanol (900mg) and DEA (650mg) in DMF (10mA) at 100° under nitrogen. After 1h the solvent was evaporated and the residue was partitioned between 8% sodium bicarbonate (20ml) and ethyl acetate (20mA). 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;Η,7.35;N,8.11;Cl,13.83 C25H35C12N3°3 requires C,60.48;H,7.11;N,8.46;C1,14.28% Example 14 4-Amino-3,5-dichloro-a-[[[6-[3-[4-(methoxymethyl)phenyl]propoxy] hexyl]amino]methyl]benzenemethanol, (E)-butenedioate (2:1) (salt) —[3—[(6-Bromohexyl)oxy]propyl]-4-(methoxymethyl).benzene (1.0g) and 4-amino-a-(aminomethyl)-3,5-dichlorobenzenemethanol (1.0g) were reacted according to the method of Example 13. Concentration of the 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 (5mA) was treated with a hot solution of fumaric acid (20mg) in isopropanol (2mA) and after 1h 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 4 as a pale yellow powder (550mg) m.p. 110-112°, t.l.c. (System A 80:20:2) Rf 0.43.

Analysis Found: C,59.33;H.6.87;N,4.88;C1,13.31.

C25H36C12N2°3-°-5CuH4°U requires C,59.89;Η,7.07;Ν,5.17;Cl,13.09%.

Example 15 4—[3—[[6—[C 2—(4-Amino-3,5-dichlorophenyl)-2-hydroxyethyl]amino]hexyl]~ oxy]propyl]benzoic acid The product according to Example 3 (600mg) in ethanol (8ml) was treated with 2N sodium hydroxide (4ml) and stirred at reflux for lh. 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 10min. 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.

C2i»H32C12N2^4 requires C,59.63;H6.67;N,5.79;C1,14.67%.

Example 1 6 4-Amino-3,5-dichloro-a-[[[6-[3-[4-[(4-morpholinyl)methyl]phenyl]propoxy]hexyl]amino]methyl]benzenemethanol The product according to Example 6 (0.67g) in benzene (10mA) was added dropwise to lithium aluminium hydride (300mg) in dry diethyl ether (15mA) at room temperature under nitrogen. The suspension was stirred for 18h at room temperature and treatment with water (0.3mA), 2N aqueous sodicm hydroxide (0.6mA) and water (0.6mA) qave a precipitate which was filtered off (hyflo). The filtrate was concentrated to qive an oil which was purified by FCC elutinq with System B (95:5:1) to give the title compound 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-g-[[[6-[3-[4- [[2-(dimethylamino)ethyl]amino] phenyl]propoxy]hexy1]amino]methy1]benzenemethanol-(E)-butenedioate (2:3) (salt) 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 (1mA), 2N aqueous sodium hydroxide (2mA) and water (1mA) were added successively, the precipitate being removed by filtration through hyflo and the ether was evaporated to leave a brown oil. A solution of the oil (320mg) and fumaric acid (78mg) in methanol (3mA) 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,7.3O;C1,9.61.

C27H42C12N*+02-1-5CuH404 retires C,56.66;Η,6.91;Ν,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-a-[[[6-[3-[4-[bis(2-hydroxyethyl)amino]phenyl]propoxy]hexyl]amino]methyl]benzenemethanol From Intermediate 26 (402mg), using cone. HCl/EtOH 1:9 v/v, 0.9ml. Evaporation of the ethyl acetate extracts 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 A 80:20:2) Rf 0.33. δ (CDC13) 1.2-1.63 and 1.84 (-CH2-)·, 3.4 (-0CH2); 3.54 and 3.81, 8H, (-CH2CH20H)2*, 6.62 and 7.04, 4H, (CH of phenyl ring); 7.17, 2H, (CJH of dichloroaniline ring).

Example 19 4-Amino-3,5-dichloro-a-[[[6-[3-[4-[2-(dimethylamino)ethoxy]pheny1]propoxy]hexyl]amino]methyl]benzenemethanol 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 (cone. 3Ό HCl/EtOH 1:9 v/v, 10.1ml). 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 (5ml) were treated with (E)-butenedioic acid (l09mg) in methanol (5ml). The solution was concentrated and the residual foam was triturated with diethyl ether to give the title compound as a pale yellow foam (0.361g), t.l.c. (System A 80:20:2) Rf 0.5.

Analysis Found C,56.1;H,7.2;N,6.2;C1,11.0 C27HU1C12N3°3·1 «250,^0,,. 0.8H20 requires C,56.0;H,7.0;N,6.1;Cl,10.3% The following are examples of suitable formulation of compounds of the invention. The term 'active ingredient' is used herein to represent a compound of the invention.

Tablets (Direct Compression) mg/tablet Active ingredient 2.0 Microcrystalline Cellulose USP 196.5 Magnesium Stearate BP 1 .5 Compression weight 200.0 The active ingredient is sieved through a suitable sieve, blended with the excipients and compressed using 7mm diameter punches.

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

The tablets may be film coated with suitable film forming materials, such as hydroxypropylmethylcellulose, using standard techniques. Alternatively the tablets may be sugar coated. 7 Syrup (Sucrose-free) Active ingredient Hydroxypropyl methylcellulose USP (viscosity type 4000) mg/5ml dose 2.0mg 22.5mg Buffer ) Flavour ) Colour ) Preservative ) Sweetener ) as required Purified Water BP to .0ml The hydroxypropyl methylcellulose is dispersed in hot water, 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 by filtration.

Metered Dose Pressurised Aerosol A. Suspension Aerosol mg/metered dose Per can Active ingredient micronised 0.100 26.40mg Oleic Acid BP 0.100 2.64mg Trichlorofluoromethane BP 23.64 5.67g Dichlorodifluoromethane BP 61.25 14.70g The active ingredient is micronised in a fluid energy mill to a fine particle size range. The oleic acid is mixed with the trichlorofluoromethane at a temperature of 10-15 °C and the micronised drug is mixed into the solution with a high shear mixer. The suspension is metered into aluminium aerosol cans and suitable metering valves delivering 85mg of suspension are crimped onto the cans and the dichlorodifluoromethane is pressure filled into the cans through the valves. 8 B. Solution Aerosol mg/metered dose Per can Active ingredient 0.055 13.20mg Ethanol BP 11.100 2.66g Dichlorotetrafluoroethane BP 25.160 6.04g Dichlorodifluoromethane BP 37.740 9.06g 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 mg/ml Active ingredient Sodium Chloride BP Water for Injection BP to 0.5mg as required 1.0ml Sodium chloride may be added to adjust the tonicity of the solution and the pH may be adjusted, using acid or alkali, to that of optimum stability and/or facilitate solution of the active ingredient. Alternatively suitable buffer salts may be used.

The solution is prepared, clarified and filled into appropriate size ampoules sealed by fusion of the glass. The injection is sterilised by heating in an autoclave using one of the 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 or other suitable gas.

*(Registered Trade Mark) Inhalation Cartridges mg/cartridge Active ingredient micronised 0.200 Lactose BP to 25.0 The active ingredient is micronised in a fluid energy mill to a fine particle size range prior to blending with normal tabletting grade lactose in a high energy mixer. The powder blend is filled into No. 3 hard gelatin capsules on a suitable encapsulating machine. The contents of the cartridges are administered using a powder inhaler such as the Glaxo Rotahaler (Registered Trade Mark).

Claims (14)

1. Compounds of the general formula (I) 1 CHCH o NHCXCH o 0CH o YAr ι Ζ ι 2 2 wherein X represents a bond, or a C 1 _g alkylene, C 2 _ g alkenylene or 0 2 _θ alkynylene chain and Y represents a bond, or a C 1-4 alkylene, C 2 _ 4 alkenylene or ^2-4 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, -(CH 2 )qR [where R is C^_ 2 alkoxy, -NR 8 R 1 * * 4 (where R 8 and R 4 each represent a hydrogen atom, or a C^_ 4 alkyl 3 4 group, or -NR R 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(CHg)-), -NR°COR 5 (where R represents a hydrogen atom or a θ alkyl group, and R° represents a hydrogen atom ,3„4 or 1 c 1_4 alkyl, c 1_ 4 alkoxy or -NR R group), and q represents an integer from 1 to 3 ], -(CH^^R [where R 7 represents -NR 5 * SO 2 R 8 (where R 8 represents a C 1-4 alkyl,phenyl or NR 8 R 4 group), -NR 8 COCH2N(R 5 )2 (where each of the groups R represents a hydrogen 4 1 9 9 atom or a alkyl group), -COR (where R represents 3 4 10 1(1 hydroxy, c ^_ 4 alkoxy or NR R ), -SR (where R x is a hydrogen atom, or a C^_ 4 a lkyl group optionally 3 4 substituted by hydroxy, c i_4 alkoxy or NR R ), -SOR 10 , -SO 2 R 10 , -CN, or -NR 1X R 12 (where R 11 and R represent a hydrogen atom or a C^-4 a lkyl group, at least one of which is c 2-4 alk y! substituted 3 4 by a hydroxy, C y_4 alkoxy or NR R group), and r represents an integer from 0 to 3], -0(CH o ) COR° 2. q 9 13 (where q and R are as defined above), or -0(CH„) R [where R 13 represents hydroxy, NR^R* 1 , NR X1 R 12 or a C^_ 4 alkoxy group optionally substituted by hydroxy, 3. 4 C^_ 4 alkoxy or NR R , and t is an integer 2 or 1 2 3]; and R and R each represents a hydrogen atom or a C 1 _ 3 alkyl group, with the proviso that the 1 2 sum total of carbon atoms in R and R 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- is 4, 5, 6 or 7.

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

4. Compounds as claimed in any of claims 1 1 2 to 3 in which R and R are both hydrogen atoms or 4 2 1 2 R is a hydrogen atom and R is a C 4 _ 3 alkyl group.

5. Compounds as claimed in any of claims 1 to 4 in which Ar represents a phenyl group substituted by -(CH 2 )qR [where R represents C-^_ 3 alkoxy, diC^_ 4 alkylamino, morpholino, piperidino, piperazino, N-methyl6 6 piperazino, -NHCOR (where R is alkyl), and q is 1 or 2], -(CH 2 ) r R^ [where R? represents -NR^SO 2 R^ 5 8 (where R represents hydrogen or methyl, and R represents C^_ 4 alkyl -NHCOCH 2 N(R^) 2 (where both 5 9 9 groups R represent C^_ 4 alkyl), -COR (where R represents C^_ 4 alkoxy, amino diC^_ 4 alkylamino, morpholino, piperidino, piperazino or N-methylpiperazino), -NR^R 12 (where one or both of R 11 and 12 R represents a C 2 -4 a l k yl group substituted by a hydroxy or diC^_ 4 alkylamino group and the other represents a hydrogen atom), and r is zero or 1], -OCHgCOR® (where R^ is diC^_ 4 alkylamino), or -O(CH 2 ) 2 R 13 (where R is diC^_ 4 alkylamino).

6. Compounds of the general formula (la) CHCH 2 NHCH 2 XCH 2 OCH 2 YAr OH (la) wherein X represents a C 3 _ 4 alkylene chain and Y represents a alkylene chain, with the proviso that the total number of carbon atoms in X and Y is 5 or 6; and 4 3 Ar represents a phenyl group substituted by a group selected from C^_ 4 alkoxymethyl, morpholinomethyl, Λ* Λ* diC^_ 4 alkylaminoC^_ 2 alkyl, -CH 2 NHCOR° (where R is alkyl), NR 5 S0 2 R 8 (where R 8 is hydrogen or methyl, and R 8 is C^_4 alkyl), -NHCOCH2N(R 5 )2 (where both 5 9 9 groups R represent C^_ 4 alkyl), -COR (where R is hydroxy, θι_ 4 alkoxy, amino diC^_ 4 alkylamino, 9 9 or morpholino), -CH 2 COR (where R is amino or diC^_ 4 alkylamino), -NrHr12 (where R^ and R^ 8 both represent 9 q hydroxy C 2 _ 4 alkyl), diC^alkylaminoethylamino, -OCHgCOR (where R 13 13 is diC ^alkylamino); or-0(CH 2 ) 2 R where R is diC ^alkylamino; 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 selected from -CH 2 NHC0R 8 (where R 8 is methyl) -NHSOgR 8 8. 9 9 (where R is methyl), -COR (where R is hydroxy, g ethoxy, amino or morpholino, or -CHgCORg (where R is amino or dimethylamino).

8. The compounds: 4-[3-[[6-[[ 2-(4-amino-3,5-dichlorophenyl)-2-hydroxyethy1jamino]hexyl]oxy jpropyl]benzamide; ethyl 4-[3-[[6-[[(4-amino-3,5-dichlorophenyl)-2-hydroxyethyl jaminojhexyl]oxyjpropyljbenzoate; N-[[3—[3—[[6-[[2-(4-amino-3,5-dichlorophenyl)-2-hydroxyethyljamino]hexyl]oxyjpropyl]phenyljmethyl]acetamide; 4-[4-[5-[[2-(4-amino-3,5-dichlorophenyl)-2-hydroxyethyl]amino] pentyloxy]butyl]-N,N-dimethylbenzeneacetamide; 4 4 4-[3-[[6-[[2-(4-amino-3,5-dichlorophenyl)-2-hydroxyethyl] amino]hexyl ]oxy Jpropyl] benzoic acid ; 4-[4-[3-[[6-[[2-(4-amino-3,5-dichlorophenyl)-2-hydroxyethyl ]amino]hexyl]oxy]propyl]benzoylJmorpholine; 5 N-[4-[3-[[6-[[2-(4-amino-3,5-dichlorophenyl)-2-hydroxyethyl]amino]hexyl]oxy]ethylJphenyljmethanesulphonamide; [4- [ 3- [ [ 6- [ [2-(4-amino-3,5-dichlorophenyl)-2-hydroxyethylJaminoJhexylJoxyJpropylJbenzeneacetamide; and physiologically acceptable salts and solvates 10 thereof.

9. A process for the preparation of compounds as claimed in any of claims 1 to 8 or a physiologically acceptable salt or solvate thereof which comprises: (la) for the preparation of a compound of formula 15 (I) in which R 1 is a hydrogen atom, alkylating an amine of general formula (II) OH 14 15 CHCHgNR- 1 R ±o (II) (wherein R is a hydrogen atom or a protecting group 15 and R is a hydrogen atom) with an alkylating agent 20 of formula (III) LCHXCH o 0CH o YAr (HI) (wherein L is a leaving group and R , X, Y and Ar are as defined in claim 1) followed, if necessary, 4 5 by removal of any protecting group present; or (lb) for the preparation of a compound of formula (I) in which R 1 is a hydrogen atom, alkylating an amine of general formula (II) as defined above except that 15 5 R is a hydrogen atom or a group convertible thereto under the reaction conditions, with a compound of general formula (IV) R 2 COXCH 2 OCH 2 YAr (IV) o (wherein R , X, Y and Ar are as defined in claim 10 l) in the presence of a reducing agent followed, if necessary, by removal of any protecting groups present; or of general formula (VI) - X 2 - X 3 - CH 2 OCH 2 Y-Ar (VI) 15 wherein X 1 is -CH(OH)- or a group convertible thereto by reduction; 2 14 14 X is -CH 2 NR - (wherein R is a hydrogen atom or a protecting group) or a group convertible thereto 20 by reduction; 3 12 X is -CR R X- or a group convertible thereto by 1 2 reduction (wherein R and R are as defined in claim 4 α D; X is _ ΝΗ 2 or a group convertible thereto by reduction; and Y and Ar are as defined in claim 1 or are groups convertible thereto by reduction; at least one of 12 3 4 X , X , X and X representing a reducible group and/or Y representing a reducible group and/or Ar containing a reducible group, followed, if necessary, by removal of any protecting group present; or (3) deprotecting a protected intermediate of general formula (VII) CHCH„NR 14 CXCH„0CH o YAr I i 2 OH R (VII) 1 2 wherein R , R , X, Y and Ar are as defined in claim 1, R 14 and R^ 8 each represent a hydrogen atom or a protecting group and/or any hydroxy and/or amino substituent in the group Ar is protected, with the proviso that at least one of R 14 and R 18 represents a protecting group or Ar contains a protecting group; or (4) for the preparation of a compound of formula (I) in which Ar represents a phenyl group substituted g by the group -(CH O ) COR where r is as defined in Q claim 1 and R is hydroxy, hydrolysing the corresponding g compound of formula (I) in which R represents C^_ 4 alkoxy; and if desired, converting the resulting compound of general formula (I) or a salt thereof into a physiologically acceptable salt or solvate thereof.

10. A pharmaceutical composition comprising at least one compound of general formula (I) as defined in any of claims 1 to 8 or a physiologically acceptable salt or solvate thereof, together with a physiologically acceptable carrier or excipient.

11. A compound of the general formula (I) as claimed in claim 1 or a physiologically acceptable salt or solvate thereof, substantially as hereinbefore described and exemplified.

12. A process for the preparation of a compound of the general formula (I) as claimed in claim 1 or a physiologically acceptable salt or solvate thereof, substantially as hereinbefore described and exemplified.

13. A compound of the general formula (I) as claimed in claim 1 or a physiologically acceptable salt or solvate thereof, whenever prepared by a process claimed in a preceding claim.

14. A pharmaceutical composition according to claim 10, substantially as hereinbefore described and exemplified.