IE860078L - Aminophenol derivatives - Google Patents

Description

This invention relates to aminophenol derivatives having a stimulant action at P 2~ ac* r ena rec ep t o rs , to processes for their preparation, to pharmaceutical compositions containing them and to their use in medic ine.

Aminophenol derivatives possessing a sulphonamido or ureido substituent in the phenol ring have previously been described as bronchodi lators having stimulant activity at P-adrenoreceptors.

Thus British Patent Specification No. 993584 describes compounds of the general structure represents inter alia hydroxy; Z represents inter alia -CH(OH)-; R2 and R3 each represent inter alia hydrogen; and R^ represents hydrogen, lower alkyl? or aralkyl or aryloxyalkyl in which the aryl ring may optionally be substituted by hydroxy, methoxy or methylenedioxy .

British Patent Specification No. 1286225 describes compounds of the general structure / w in which R 1 represents lower alkyl, phenyl or tolyl; X R 2 R ^HCON \ // \\ CH-CHNHR k 1 1 3 OH R 3 HO \ // in which R^ represents hydrogen, Ci-5 alkyl, phenyl, dimethylaminoethyl or dimethy1 aminopropy1; R2 and R3 each represent inter alia hydrogen; and R ** represents C 3_ 5 .R5 alkyl, C3-5 cycloalky 1 , C 3-6 cycloalky Imethy 1 or the group <® | ff -CH(CH3)CH2—» • where R5 and R6 each represent .==^R6 hydrogen, hydroxy or methoxy. 5 We have now found a novel group of aminophenol derivatives, which differ structurally from those described in British Patent Specifications Nos. 993584 and 1286225. and which have a desirable and useful profile of activity. 10 Thus, the present invention provides compounds of the general formula (I) QNH \ , *> R J- // \\ I HO—• • CHCH2NHCXCH20CH2YAr (I) *=• OH R2 wherein Ar represents a phenyl group optionally substituted by one 15 or more substituents selected from halogen atoms, or the groups Ci-galkyl. C^galkoxy, nitro, -(CH2)qR, [where R is hydroxy, -NR3R<+ (where R3 and R ** each represents a hydrogen atom, or a C alkyl group, or -NR 3R4 forms a saturated heterocyclic amino group which has 5-7 ring 20 members and optionally contains in the ring one or more atoms selected from -0- or -S- or a group -NH- or -N(CH 3)-), -NR 5COR6 (where R5 represents a hydrogen atom or a Ci-it alkyl group, and R6 represents a hydrogen atom or a C i-u alkyl? C alkoxy, phenyl or -NR3R!+ group), 25 -NR 5S0 2R7 (where R7 represents a C 4, alkyl, phenyl or -NR3R4 group), -CORa (where R9 represents hydroxy, C ^ alkoxy or -NR3R^), -SR9 (where R9 is a hydrogen atom, or a C^..^ alkyl or phenyl group), -SOR9, -S02R9, or -CN, and q 4. represents an integer from 0 to 3], -(CH2)rR10> [where R 10 is a C i-u alkoxy group and r represents an integer from 1 to 3], or [where R 11 represents a hydroxy or C x- 4- alkoxy group and t is 2 or 3], or Ar is a 5 phenyl group substituted by an alkylenedioxy group of formula -0(CH2)pO~, where p represents 1 or 2; R1 and R2 each represent a hydrogen atom or a C i-3 alkyl group with the proviso that the sum total of carbon atoms in R1 and R2 is not more than 4; 10 X represents a C x_ 7 alkylene, C 2-7 alkenylene or C 2- 7 alkynylene chain; Y represents a bond, or a C x- 5 alkylene, C 2- s alkenylene or C2-6 alkynylene chain with the proviso that the sum total of carbon atoms in X and Y is 2 to 10; 15 Q represents a group R12C0-, R12NHC0-, R12R13NS02- or R11*S02s where R12 and R13 each represent a hydrogen atom or a C 3 alkyl group, and R 1 ^ represents a C^u alkyl group; with the proviso that when X represents C7 alkylene, and Y represents a bond or Cx=5 alkylene. then 20 the group Ar does not represent an unsubstituted phenyl group or a phenyl group substituted by one or more substituents selected solely from halogen atoms or Cx-s alkyl or Cx-6 alkoxy groups or an alkylenedioxy group -0(CH2)pO~; and physiologically acceptable salts and 25 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- qroup and. when R1 and I OH R2 are different groups, the carbon atom to which these 30 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 OH •3c are preferred. 5 In the definition of general formula (I), the term alkenylene includes both c i s and trans structures.

In one aspect, the invention provides compounds of formula (I) in which R1-R11JXi,Y and Ar are as defined in 5 formula (I) and Q represents the group RL2C0-5 R12NHC0- or R^SOj- where R12 is as defined in formula (I) and R -4 represents a C3 alkyl group.

In the general formula (I), the chain X may for example contain 2 to 7 carbon atoms and may be for example 10 -(CH2)2~, — ( CH 2) 3 - . -(CH2)r. - ( C H 2) 5 - , -CH2C=C-, -(CH2) 2CH=CH-5 -C CH 2) 2C =C- 5 -CH = CHCH2-? -CH=CH(CH 2) 2- or -CH2C=CCH2-. The chain Y may be for example -CH2-? - ( CH 2) 2~ 1 -(CH2)3-, - ( CH 2) , -(CH2)5-f -(CH2)6-» -CH=CH~, -C=C-0 -CH2CH=CH-5 or ~CH2C=C~, 15 In general, the total number of carbon atoms in the chains X and Y is preferably 4 to 10 inclusive and may be for example 5. 6, 7 or 8. Compounds wherein the sum total of carbon atoms in the chains X and Y is 5, 6 or 7 are particularly preferred* 20 One preferred group of compounds of formula (I) is that in which X is Ci_ 7 alkylene, Y is C g alkylene and Q. Ar, R1 and R2 are as defined for formula (I)» Particularly interesting compounds of this type are those in which X is -(CH 2) 2"? -((^2)3-? -(^2)1+ or -(CH2)5-> 25 particularly — (CH 2) 3— or -(CH2)1+-, and Y is -CH2~, - ( CH 2) 2~ » -(CH 2) 3"? - ( C H 2) i+~ or - ( CH 2) 5-» particularly -CH2-S -(CH2)2- or -(CH2)3~.

Another preferred group of compounds of formula (I) is that in which X is -(CH2)2-» -(CH2)3-, -(CH2)4- or 30 —(CH2) 5-• particularly -(CH2)3~ or -(CH2)«t- and Y is a C 2- 3 alkenylene or C2-3 alkynylene group, particularly -CH2CH=CH- or -CH2C=C-.

A further preferred group of compounds of formula (I) is that in which X is a C3.it alkynylene group, particularly -CH2C=CCH2~, and Y is -CH2~, -(CH2)2-, -(CH2)3-, -(CH2)it- or -(CH2)s-, particularly —(CH2) 3—.

In the compounds of formula (I) R 1 and R2 may each be, for example, methyl, ethyl, propyl or isopropyl groups 5 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 R1 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 10 hydrogen atom or a methyl group.

A preferred group of compounds is that wherein R1 and R2 are both hydrogen atoms, or R 1 is a hydrogen atom and R is a C3 alkyl group, particularly a methyl group, or R1 is a methyl group and R2 is a methyl group. 15 In the group Q, R12 and R13 may each be for example, a hydrogen atom or a methyl,- ethyl, propyl or isopropyl group, and R14 may be for example a methyl. ethyl. propyl, isopropyl or butyl group. Preferably R12 represents hydrogen or methyl, R13 represents methyls and R14 20 represents methyl. Preferred meanings for the group Q are HCO-, CH3CO-, NH2C0-, (CH3)2NS02- and CH3S02-, more preferably HC0-, NH 2C0- or CH3SQ2~- Compounds in which Q represents R1^S02- where R11+ is methyl are particularly preferred. 25 When -NR3R1* in compounds of formula (I) represents a saturated heterocyclic amino group, this may have 5. 6 or 7 ring members and optionally contain in the ring a heteroatom selected from -0-, or -S-, or a group -NH- or -N(CH3)-. Examples of such -NR3RI+ groups are pyrrolidine, 30 piperidino, hexamethylenimino, piperazino, N-methylpiperazino„ morpholino, homomorpholino or thiamorpholino.

Ar may be for example a phenyl group. Examples of the optional substituents which may be present on the 35 phenyl group represented by Ar include chlorine, bromine, iodine, fluorine, methyl, ethyl, methoxy, ethoxy, ~(CH2)qR [where R is hydroxy, amino, methylaminOj ethylamino, dimethylamino, diethy1 amino, morpholinos piperidinOj, piperazino, N-methylpiper azino, -NHC0R6 (where R6 is hydrogen or a C ^ alkyl (e.q. methyl, ethyl, isopropyl or n-butylK C j__ ^ alkoxy (e.g. methoxy. ethoxy, 5 isopropoxy or n-butoxy), phenyl, amino or N,N-dimethylamino), -N(CH3)C0CH3. -NHS02CH3, -NHSO 2( CH 2) 3CH 3, -NR5S02R7j (where R5 represents a hydrogen atom or a methyl group and R7 represents phenyl).

-NHSO2NH2, -nhso 2N(ch 3) 2» -c00h, -cooch3, -c00ch 2ch 2ch 3s 10 -conh2, -con(ch3)2, -con(ch 2ch3) 2, -con(ch2ch2ch 3) 2, COrQ , -SR 9 (where R9 is methyl, ethyl or phenyl) -SOCH3, -S02CH3» or CN, and q is zero, 1, 2 or 3], -NO 2, -CH20CH3? - ( CH 2) 3O CH 3, -0(CH2)20H5 -0(CH2)30H, -0(CH2)20CH3, or -0(CH2)2OCH2CH3» The phenyl group represented by Ar may optionally contain one. two or three substituents, which may be present at the 2-, 3-, 4-, 5- or 6-positions on the phenyl ring.

Particular examples of a trisubstituted phenyl group 20 represented by Ar include phenyl substituted by an amino and two methyl groups (for example 3,5-dimethy1-4-amino-phenyl). an amino group and two chlorine atoms (for example 3,5-dichloro-4-aminopheny1), or three methoxy groups (for example 3 ,4 ,,5-trimethoxyphenyl) . Particular 25 examples of a disubstituted phenyl group represented by Ar include phenyl substituted by two hydroxyl qroups (for example 3,5-dihydroxyphenyl). a hydroxyl and methoxy group (for example 3-methoxy-4-hydroxypheny1), or two methyl groups (for example 3 ,4-dimethy1pheny1), 30 in general, when the substituent on the phenyl group represented by Ar is one of the groups -(CH2)qR? where R is -NR 3R4« -NR5C0R6, -NR5S02R7s -COR8, -SR9, -S0R9, -SO 2R 9 or -CN and q is an integer 1, 2 or 3, any additional substituent present on the phenyl group is desirably one 35 which is different from those substituents. 8 A preferred group of comoounds are those of formula (la) QNH * » R ^ // \\ i H0-«^ /-.'-CHCH2NH^XCH20CH2YAr (la) » * OH R 2 and physiologically acceptable salts and solvates thereof wherein X represents a Ci_7 alkylene. C 2-7 alkenylene or 5 C 2— 7 alkynylene chain, Y represents a bond or a Cg alkylene, C2-6 alkenylene or C2-6 alkynylene chain, and the sum total of carbon atoms in the chains X and Y is 5,6 or 7; R1 and R2 each represent a hydrogen atom or a methyl group? Q represents HC0-. NH2C0-, (CH3)2NS02- or CH 3S0 2-; 10 and Ar represents a phenyl group substituted by a group selected from amino, dimethylamino. nitro. morpholino, - (CH 2) qNHCOR6 (where R6 is C j-j, alkyl e.g. n-butyl and q is zero or more preferably 1), -NHS02R7 (where R7 is C^ alkyl e.g. butyl), -COR8 (where R8 is C 4 alkoxy, e.g. 15 propoxy, or -NR 3R 4 where R3 and R ** are both Cj. ^ alkyl e.g. ethyl or propyl, or NR3R^ forms a piperidino ring), -CH2C0NR3Rlt (where R3 and R4 are both C alkyl e.g. ethyl), -SR9 (where R9 is C^ alkyl e.g. methyl) or -(CH2)r R 10 (where r is 3 and R 10 is Ci-ij alkoxy e.g. 20 methoxy), or Ar is 3,5-dihydroxyphenyl or 3-methoxy-4-hydroxyphenyl, or when X and/or Y represent an alkenylene or alkynylene group then Ar may additionally represent a phenyl group optionally substituted by a fluorine atom. 25 A particularly preferred group of compounds of formula (la) are those in which X represents a C3_^ alkylene group and Y represents a C3 alkylene group, or X represents a C l+ alkynylene group (e.g. -CH2CeCCH2) and Y represents a C3 alkylene group, or X represents a C 3_ i+ 30 alkylene group and Y represents a C3 alkenylene or C3 alkynylene group (e.q. -CH2CH = CH- or -CH2C=C-). Most preferably X represents — (CH 2) i+— and Y represents -(CH2) 3-.

Another particularly preferred group of compounds of formula (la) are those in which Q represents CH3S02-.

A further particularly preferred group of compounds of formula (la) are those in which Ar represents a phenyl group optionally substituted by an amino, nitro, ch2nhc0(ch2)3ch3 or -con(ch2ch3)2 group, or by hydroxyl groups at the 3- and 5- positions. Most preferably Ar is a phenyl group containing a single substituent. preferably -con(ch2ch3) 2.

Particularly important compounds of the invention are : NsN-diethyl-4-[4-[[6-[[2-hydroxy-2-[4-hydroxy-3-[(methyl sulphonyl)amino]phenyl]ethyl]amino]hexyl]oxy]butyl] benzamide; N-[2-hydroxy-5-[l-hydroxy-2-[[6-[4-(3,5-dihydroxyphenyl) butoxy]hexyl]amino]ethyl]phenyl]methanesulphonamide; N-[2-hydroxy-5-[1-hydroxy-2-[[6-[4-(4-hydroxy-3-methoxyphenyl)butoxy]hexyl]amino]ethyl]phenyl]methane-sulphonamide; N-[2-hydroxy-5-[l-hydroxy-2-[[6-[4-(4-(methylthio) phenyl]butoxy]hexyl]amino]ethyl]phenyl]methane-sulpho nam ide; N-[2-hydroxy-5-[l-hydroxy-2-[[6-[4-(4-nitrophenyl)butoxy] hexyl]amino]ethyl]phenyl]methanesulphonamide; N-[5-[2-[[6-[4-(4-aminophenyl)butoxy]hexyl]amino-1- hydroxyethyl]-2-hydroxyphenyl]methanesulphonamide; propyl-4-[4-[[5-[C2-hydroxy-2-[4-hydroxy-3-[(methyl- sulphonyl)amino]phenyl]ethyl]amino]pentyl]oxy]butyl] benzoate; N-[[4-[4-[[6-[[2-hydroxy-2-[4-hydroxy-3-[(methyl- sulphonyl)amino]phenyl]ethyl]amino]hexyl]oxy]butyl] phenyl]methyl]pentanamide; N-[2-hydroxy-5-[l-hydroxy-2-[[5-[4-[4-(3-methoxyprooyl) phenyl]butoxy]pentyl]amino]ethyl]phenyl]formamide; N-[4-[4-[[6-[[2-[3-[(aminocarbonyl)amino]-4-hydroxyDhenyl] ethvl]amino]hexyl]oxy]butyl]phenyl]butanesulphonamide; 1 0 N-[2-hydroxy-5-[l-hydroxy-2-[[6-(4-phenylbutoxy)-3-hexynyl]amino]ethyl]phenyl]methanesulphonamide; (E)-N-[2-hydroxy-5-[1-hydroxy-2-[[6-[[4-(4-fluorophenyl) -3-butenyl]oxy]hexyl]amino]ethyl]phenyl]methane-sulphonam ide; 5 and their physiologically acceptable salts and hydrates.

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, 10 maleates, tartrates, citrates, benzoates, 4-methoxy- benzoates, 2- or 4-hydroxybenzoates, 4-chlorobenzoates, p-toluenesulphonates. methanesulphonates, sulphamates, ascorbates, salicylates, acetates, fumarates, succinates, lactates, glutarates, gluconates, tricarballylates, 15 • hydroxynaphthalenecarboxylates 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 20 magnesium) salts.

The compounds according to the invention have a selective stimulant action at (3 2-adrenorecep tors, which furthermore is of a particularly advantageous profile. The stimulant action was demonstrated in the isolated 25 trachea of the guinea-pig, where compounds were shown to cause relaxation of PGF2a-indueed 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 30 in the treatment of diseases associated with reversible airways obstruction such as asthma and chronic bronchitis.

The compounds according to the invention may also be used for the treatment of premature labour, depression and 35 congestive heart failure, and are also indicated as useful 1 i for the treatment of inflammatory and allergic skin diseases, glaucoma, and in the treatment of conditions in which there is an advantage in lowering gastric acidity, particularly in gastric an-d peptic ulceration. 5 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, 10 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 15 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. 20 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. 25 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 , dichloro-30 tetrafluoroethane, 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 35 insufflation, the compounds according to the invention may take the form of a dry powder composition, for example a i 2 10 20 25 30 powder mix of the compound and a suitable powder base such as lactose or starch. The powder composition may be presented in unit dosage form in for example capsules or cartridges of e.g. gelatin, or blister packs from which the powder may be administered with the aid of an inhaler or insufflator.

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

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

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

For topical administration the pharmaceutical composition may take the form of ointments, lotions or creams formulated in a conventional manner, with for example an aqueous or oily base, generally with the addition of suitable thickening agents and/or solvents. For nasal application, the composition may take the form of a spray, formulated for example as an aqueous solution or suspension or as an aerosol with the use of a suitable propel1 ant. 35 The compounds of the invention may also be formulated in rectal compositions such as suppositories or retention 1 3 enemas, e.q. 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 5 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 0.00 5mg to 1OOmg . which may be conveniently administered in one or two doses. The 10 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 15 0.01mg to 2mg for administration by bolus injection and 0.01mg to 25mg for administration by infusion.

The compounds according to the invention may be prepared by a number of processes, as described in the following wherein Q. X, Y, Ar. R1 and R2 are as defined 20 for general formula (I) unless otherwise specified. 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 25 processes described, particularly where a hydride reducing agent is used and end-products are required in which Q represents the group R12C0, and where hydrogen and a metal catalyst are used in the preparation of compounds containing an ethylene or acetylene linkage. 30 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 general 35 processes described below for the preparation of both intermediates and end-products the final step in the reaction may be the removal of a protecting group.

Suitable protecting groups and their removal are described in general process (2) below.

According to one general process (1). a compound of 5 general formula (I) may be prepared by alkylation. Conventional alkylation procedures may be used.

Thus, for example, in one process (a), a compound of general formula (I) in which R* is a hydrogen atom may be prepared by alkylation of an amine of general formula 10 (II) QNH \ ol5n \ 16 17 (ID R150 • CHCH2NR16R17 O «— 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 25 as triethy1 amine, diisopropy1ethy1 amine 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. tetrahydrofur an or dioxan, a ketone e.g. butanone or methyl isobutvl ketone, a 1 5 substituted amide e.g. dimethy1formamide 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 5 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 R17 is a hydrogen atom or a group convertible thereto under the reaction conditions, with a compound of 10 general formula (IV): R2C0XCH20CH2YAr (IV) in the presence of a reducing agent, followed when necessary by removal of any protecting groups.

Examples of suitable R17 groups convertible into a 15 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 20 support such as charcoal, using an alcohol, e.g. ethanol 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 25 pressure, for example from 20 to 100°C and from 1 to 10 atmospheres.

Alternatively when one or both of R1-6 and R17 are hydrogen atoms, the reducing agent may be a hydride such as diborane or a metal hydride such as sodium borohydride, 30 sodium cyanoborohydride or lithium aluminium hydride.

Suitable solvents for the reaction with these reducing agents will depend on the particular hydride used, but will include alcohols such as methanol or ethanol, or i-S ethers such as diethyl ether or tert-butyl methyl ether, or tetrahydrofuran .

When a compound of formula (II) where R*6 and R 17 are each hydrogen atoms is used, the intermediate imine of 5 formula (V) may be formed: QNH \ // \\ R150 * • CHCH ,N = CXCH ,0CH ,YAr (V) \ / I 2 I , 2 2 OH R 2 (wherein R15 is as defined for formula (II)).

Reduction of the imine using the conditions described above, followed, where necessary, by removal of any 10 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 15 protecting groups R15 and R16 which are 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 20 and a-methylbenzyl.

In another general process (2), a compound of general formula (I) may be obtained by deprotection of a protected intermediate of general formula (VI); QNH^ R 1 , C // W Rl50 • CHCH 2NR 16CXCH 20CH 2YAr (VI) OH R2 25 (where R 15 and R*6 are as defined in formula (II) except that at least one of R15 and R16 is a protecting group).

The protecting group may be any conventional protecting group, for example as described in "Protective 17 Groups in Organic Chemistry", Ed. 3.F.W. McOtnie (Plenum Press, 1973). Examples of suitable hydroxyl protecting groups represented by R15 are arylmethyl groups such as benzyl, diphenyImethyl or triphenyImethy1 and 5 tetrahydropyranyl. Examples of suitable amino protecting groups represented by R16 are arylmethyl groups such as benzyl, a-methylbenzyl, diphenylmethyl or triphenylmethyl and acyl groups such as trichloroacetyl or trifluoro-ac ety1 . 10 The deprotection to yield a compound of general formula (I) may be effected using conventional techniques. Thus for example, when R*5 and/or R1-6 is an arylmethyl group this may be cleaved by hydrogenolysis in the presence of a metal catalyst (e.g. palladium on 15 charcoal). When R15 is tetrahydropyranyl this may be cleaved by hydrolysis under acidic conditions. Acyl groups represented by R*6 may be removed by hydrolysis, for example with a base such as sodium hydroxide, or a group such as trichloroacetyl may be removed by reduction 20 with, for example, zinc and acetic acid.

In another general process (3), 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 (VII): QNH \ aii <» 25 R150 \ X 1-x 2-X 3-CH -OCH ,Y"Ar (VII) \ — / <■> "■ — i 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 the phenyl group Ar contains a nitro substituent, 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 (VII) 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), A1ternatively, 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 e.g. methanol or ethanol, or an ether such as tetrahydrofuran, or a halogenated hydrocarbon such as dichloromethane. 35 0 When X in general formula (VII) represents a -CHjNY*- group or the group -CH=N-, or X2-X3 represents 20 25 30 18 -CH2N=CR2X- this may be reduced to a -CH2NH- or -CH2NHCHR2X- group using hydrogen in the presence of a catalyst as previously described for process (1) part (b). Alternatively, when X2 is the group -CH=N- or -X 2-X3- is 5 the group 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 (VII) represents a 10 -CONH- or -COX- group this may be reduced to a group -CH2NH- or -CH 2X- using a hydride such as diborane or a complex metal hydride such as lithium aluminium hydride or sodium bis(2-methoxyethoxy)alum inium hydride in a solvent such as an ether, e.g. tetrahydr0furan or diethyl ether. 15 When X3 in general formula (VII) represents a group 1 2 -CR R X- where X is C2-7 alkenylene or C2-7 alkynylene,•or Y represents C 2_ s alkenylene or C2-5 alkynylene, X and/or Y may be reduced to C2_7 alkylene using hydrogen in the presence of a catalyst as previously described for process 20 (1) part (b)„ Alternatively., when X and/or Y is C 2-7 alkynylene this may be reduced to C2-7 alkenylene 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 25 ether at a low temperature e.g. 0°C.

It is also possible to prepare a compound of general formula (I) by a process comprising interconversion of one compound of general formula I into another compound of general formula (I). 30 For example, a compound of formula (I) in which Ar is phenyl substituted by a nitro group may be converted to the corresponding compound in which Ar is phenyl substituted by an amino group by reduction. Conventional reducing agents may be used, for example hydrogen in the 35 presence of a catalyst such as platinum or palladium on a support such as charcoal, in a solvent such as an alcohol e.g. ethanol.

In another example, a compound of formula (I) in which Ar is phenyl substituted by -(CH 2) qCONR 3R ** (where 5 q is zero, 1 or 2) may be reduced to a compound of formula (I) in which Ar is phenyl substituted by -(CH2)qNR3R1+, where q is 1, 2 or 3. The reduction may be performed using a hydride such as diborane, or a complex metal hydride such as lithium aluminium hydride or sodium 10 bis(2-methoxyethoxy)aluminium hydride in a solvent such as an ether e.g. tetrahydrofuran or diethyl ether.

In another example, a compound of formula (I) in which X and/or Y is an alkenylene or alkynylene chain, may be reduced to a compound of formula (I) in which X and/or 15 Y is an alkylene chain using hydrogen in the presence of a metal catalyst as previously described for process (1) part (b) .

In a further example, a compound of formula (I) in which X and/or Y is an alkenylene chain may be prepared by 20 reduction of a corresponding compound in which X and/or Y is an alkynylene chain as previously described under pr ocess (3 ) .

In the general processes described above, the compound of formula (1) obtained may be in the form of a 25 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 of the compounds of 30 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 acetonitri1e, 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 35 21 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 5 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 10 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. 15 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 20 (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 25 derivatives e.g. salts which then can be separated by conventional means e.g. by fractional crystallisation.

Suitable methods for preparing the intermediate compounds used in the above general processes are described below. In the following discussion, Ar, R1, R2, 30 R15, R16, R17, Q , X, Y, X1, X2, X3, Y1, and L are as defined above except where otherwise indicated. "Hal" represents a halogen atom. Where an intermediate with protected hydroxyl and/or amino groups is desired, this may be obtained using conventional protection methods, for 35 example those described by McOmie (see process (2) above). In addition, any substituent in Ar may be a £4 e*a precursor substituent which is convertible into the required substituent, far example as described above for the interconversion of compounds of formula (I)„ Intermediate compounds of general formula (VII) for 5 use in general process (3) may be prepared by a number of processes.

Thus for example intermediates of general formula (VII) in which X is a group ^C = 0 may be prepared from a haloketone of formula (IX): QNH \ # 3 r15q / \ C0CH2Hal (IX) by reaction with an amine of general formula (X): R 1 R 16NH^XCH20CH2YAr (X) R 2 (where R16 is a hydrogen atom or a group convertible thereto by catalytic hydrogenation) .

The reaction may be effected in a cold or hot solvent, for example tetrahydrofuran, tert-buty1 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 diisopropy1ethy1 amine, sodium carbonate or other acid scavenger such as propylene oxide.

The intermediates of formulae (II) and (IX) are either known compounds or may be prepared according to the methods described by Kaiser et al in J. Med. Chem., 1974, 17, 49, and Larsen et al in J. Med. Chem„, 1 967, 1Q, 462.

Intermediates of general formula (VII) in which X* is a group ^C=0 may be reduced to the corresponding 15 20 25 ■5> "^1 4^2 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.

Iminoketones of general formula (VII). in which X2 is 5 a group - C H = N - may be obtained from a phenylglyoxal derivative of formula (XI): QNH \ ' ->< <# using an ester or an activated derivative of an acid of 20 formula (XIII): ArVCH 20CH 2XCO 2H (XIII) Suitable activated derivatives include the acid chloride, an anhydride or imidazolide. The reaction may be optionally carried out in a solvent such as 25 tetrahydrofuran, benzene or chloroform, optionally in the presence of a base such as pyridine or triethylamine. The 2 4 acids (XIII) may be used directly if a coupling agent such as dicyclohexylcarbodiimide is added.

Acids of formula (XIII) may be obtained by treatment of an alcohol of general formula (XIV) 5 ArYCH 20CH 2XCH 20H (XIV) with a suitable oxidising agent, for example pyridinium dichromate in a solvent such as dimethylformamide.

Intermediates of formula (VII) in which -X2-X3- represents -CH2N = CR2X- may be obtained by reaction of an 10 amine of formula (XII) in which R*6 is a hydrogen atom with a compound of formula (IV) in a solvent such as acetonitrile.

Intermediates of formula (VII) in which X2 is -CONH-may be prepared by reaction of an amine of formula (X) in 15 which R1^ is a hydrogen atom with an acid of formula (xv ) : QNH^ ■' i a) R 150 * ^ X iCO -H (XV) \ / in the presence of a coupling agent such as dieyclohexyl-carbodiimide. The acids of formula (XV) may be prepared by methods analogous to conventional methods for the preparation of a-keto- and a-hydroxy carboxylic acids.

Intermediates of formulae (III), (IV), (X) and (XIV) are either known compounds or may be prepared by methods analagous to those described for the preparation of known compounds. Suitable methods are described in UK Specification No. 21&0800A and in the exemplification included hereinafter.

In addition, for the preparation of ketones of formula (IV) (in which R2 represents an alkyl group), a halide ArYCH20CH2XHal (where X represents a bond, Cg alkylene, C 2- 6 alkenylene or C 2-6 alkynylene) may be 20 25 30 25 reacted with an appropriate P-ketoester or p-diketone under basic conditions to give an alkylated derivative, which on hydrolysis affords a ketone of formula (IV). 28 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. Flash column chromatography (FCC) 5 was carried out on silica (Merck 9335). The following abbreviations are used: THF - tetrahydrofuran; EA - ethyl acetate, ER - diethyl ether; CX - cyclohexane; H-hexane; DMF - dimethyl formamide; T -toluene; ET - ethanol; MC - methylene chloride; CF - chloroform; DEA -diisopropylethylamine; BTPC - bis(triphenylphosphine)palladium (II) 10 chloride; A - 0.88 Ammonia solution; DCC - dicyclohexylcarbodiimide; TAB - tetra-n-butylammonium sulphate; PT-C platinun on charcoal; PD-C palladium on charcoal; PTO-C platinum oxide on carbon; PDO-C palladium oxide on carbon.

Intermediate 1 15 [4-(3-Butynyloxy)butyl]benzene A mixture of 3-butyn-l-ol (5.0q), (4-bromobutyl)benzene (I5.0g), aqueous sodium hydroxide (30ml. 50% w/v)5 and TAB (0.6q) was stirred vigorously for 3 days? treated with water (100ml) and extracted with ER (2x200ml). The dried extract was evaporated and the residue was 20 purified by FCC eluting with CX-ER 19:1 to give the title compound as a colourless oil (9.5g). T.l.c. (CX-ER 9:1) Rf 0.45.

Similarly were prepared Intermediates 2-9 Intermediate 2 (E)-1 - [[4-(6-Bromohexyl)oxy]-2-butenyl]-4-fluorobenzene as a yellow 25 oil (8.49g). T.l.c. (CX-EA) Rf 0.34, From Intermediate 24 (5.73g), 1,6-dibromohexane (25.2g). TAB (1.5g) and 40" NaOH (45 ml) except that the mixture was purified by FCC eluting with CX-EA (10:0 *9:1). e> t Intermediate 3 l-[4-[ (6-Bromohexyl)oxv]butvl]-4-nitrobenzene as a colourless liquid (1.92g) Analysis Found: C.54.05;H,6.95;N,4.15;8r.22.4 5 Ci^gHj^BrNOj requires C,53,65;H,6.75;N.3.9;Br,22.3% From 4-nitrobenzenebutanol (2.00g), 1,6-dibromohexane (4.73ml), TAB (459mg) and aq. sodium hydroxide (15.6ml, 12.5M) except that the mixture was purified by FCC eluting with CX-ER (3:200-*-1:19).

Intermediate 4 10 3,5-Bis(phenylmethoxy)-1-[4-[(6-bromohexyl)oxv]-3-butenvl]benzene as a colourless oil (1„1g).

Analysis Found: C.68.95;H,6.75.

C33s8r03 requires C.68.8;H,f6.7%.

From Intermediate 30 (1.25g). TAB (0»5g), 1,6-dibromohexane (2.54g) 15 and 50% sodium hydroxide solution (10ml) except that the mixture was purified by FCC eluting with CX and then CX-EA (9:1).

Intermediate 5 1-Bromo-6-[(3-butynyl)oxy]hexane as a colourless oil (27.Og). T.I.c. (CX-ER 19:1) Rf 0.3 20 From 3-butyn-1-ol (20.Og), 1 .,6-dibromohexane (209a), aqueous sodium hydroxide (40% w/v; 100mA) and TAB (2.0g) except that the product was purified by FCC eluting with CX and then CX-ER (24:1).

Intermediate 6 1 -[4-[ (6-Bromohexvl)oxy]butyl]-4-(methvlthio)benzene as a colourless 25 oil (2.7g). T.I.c. (CX-ER 19:1) Rf 0.3.

From 4-(methylthio)benzenebutanol (5.6g), 1,6-dibromohexane (18.3g), TAB (0.5g) and aqueous sodium hydroxide (50% w/v. 20ml).

Intermediate 7 1-Bromo-5-[(3-butynyl)oxv]pentane as a colourless oil (43.5a). T.I.c. 30 (CX-ER 9:1) Rf 0.65 Z 8 From 3-butyn-1-ol (50.Og), 1,5-dibromopentane (414g), aqueous sodium hydroxide (50% w/v; 250ml) and TAB (5.0g) except that the product was purified by FCC eluting with CX and then CX-ER (9:1).

Intermediate 8 5 (E)-i-[4-[(6-Bromohexyl)oxv]-1-butenyl]-3-methoxv-4- (methoxymethoxy)-benzene as a colourless oil (1.55g). T.I.c. (CX-EA 3:1) Rf 0.50.

From Intermediate 32 (1 .40g). 1.6-dibromohexane (6.,13g), 50% aqueous sodium hydroxide (10ml) and TAB (0.21g) except that the mixture was extracted with EA (2 x 30ml) and purified by FCC eluting with EA-H 10 (1:19) followed by EA-H (1:4).

Intermediate 9 4-[4-[4-[(4-Bromobutoxy)3butyl]phenyl]morpholine as a colourless solid m.p. 33-35°.

From Intermediate 34 (6.0g), 1,4-dibromobutane (22.1g). 50% aqueous 15 sodium hydroxide (40ml) and TAB (0.85g) except that the reaction mixture was stirred under nitrogen For 20h, and the product was purified by FCC eluting with CX and then ER-CX (1:3).

Intermediate 10 H-[4-[4-[[[6-(Phenylmethyl)amino]hexvl]oxy]butyl]phenyl] 20 butanesulohonamide Intermediate 16 (1 „50g) was added dropwise over 5 min to stirred benzylamine (l„79g) at 120° under nitrogen. The solution was stirred at 120° under nitrogen for 2h. then diluted with EA (50mA) and washed with 2N hydrochloric acid (30mJt). The aqueous phase was re-extracted 25 with EA (3x30mA) and the combined organic extracts washed with 8% sodium bicarbonate solution (100mJL)s dried and evaporated in vacuo to give the title compound as a yellow oil (1.32g). T.I.c. (T-ET-A 39:10:1) Rf 0.49.

Intermediate 11 30 (E)-N-[6-[4-[(4-Hvdroxy-3-methoxyphenyl)-3-butenvl]oxv]hexvl] benzenemethanamine as a brown oil (0.93g) t.l.c. (T-ET-A 39:10:1) Rf 0.51 was prepared from Intermediate 29 (1a) and benzylamine 2 9 (1 .5g)" following the method of Intermediate 10, except that MC was used for extraction instead of EA.

Intermediate 12 N-[5-[4-[4-(3-Methoxyoropvl)phenvl]butoxy]pentvl]benzenemethanamine 2 Intermediate 18 (1 -25g) was added dropwise over 10 min to benzylamine (10mA) stirred at 120° under nitrogen and stirring continued for a further 2h. The mixture was cooled, poured into 2N hydrochloric acid (150mA) and extracted with EA (1x75mA;, 1x50mA), The combined organic layers were washed with 2N hydrochloric acid (50mA), 8% sodium 10 bicarbonate solution (100mA), dried and concentrated in vacuo at 40° to afford the title compound as a pale yellow oil (1»Q6g). T.l.c. (ER) Rf 0.38.

Intermediate 13 4-[4-[(6-Bromohexyl)oxy]-1 -butynvl]-N ,N-diethvlbenzamide 15 A mixture of Intermediate 20 (10.0g)s Intermediate 5 (8.0g) BTPC (0.5g), cuprous iodide (0.059g), DEA (50mA) and THF (25mA) was stirred at room temperature for 18h. diluted with ER (100mA)? filtered and evaporated. The residue was purified by FCC eluting with CX-ER (1:1) to give the title compound as a yellow oil (12.5g). T.l.c. (CX-ER 20 1:1) Rf 0.3.

Similarly were prepared intermediates 14-15 Intermediate 14 N-[4-[4-[(6-Bromohexyl)oxy]-l-butynyljphenyl]butanesulohonamide as a red oil (4.4g). T.l.c. (H-EA 4:1) Rf 0.22. 25 From Intermediate 19 (5g), Intermediate 5 (3.61g), BTPC (300mq), Cul (30mg) and DEA (25ml) except that purification was by FCC eluting with H-EA (9:1). 30 Intermediate 15 Propyl 4—[4-[(5-bromooentvl)oxv]-1 -butvnyl]benzoate as a colourless oil (5.8g). T.l.c. (CX-ER 19:1) Rf 0.3. 3 0 From Intermediate 25 (10.Og), Intermediate 7 (7.7a), BTPC (0.35q), Cul (0.035q) and DEA (50ml) except that the FCC eluting solvent was CX-ER (19:1).

Intermediate 16 5 N-[4-[4-[ (6-BromohexyDoxy]butyl]phenyl]butanesulohonamide Intermediate 14 (4.3g) was hydrogenated in ET (40ml) over pre-reduced 10% PDO-C (500mg) and 5% PT-C (500mg). The catalyst was removed by filtration through hyflo and the solvent was evaporated to give the title compound as a pale yellow oil (3.65g). T.l.c. (H-EA 4:1) Rf 10 0°2Q Similarly prepared were Intermediate 17-18 Intermediate 17 4-[4-[(6-Bromohexyl)oxy]butyl]-N,N-diethylbenzamide as a colourless oil (7.5g).. T.l.c. (ER-CX 1:1) Rf 0.3. 15 From Intermediate 13 (12.Og). 108 .PD-C (2g) and 5% PT-C (2g), purifying the product by FCC eluting with ER-CX (1:1).

Intermediate 18 1-[4-[(5-Bromopentyl)oxy]butyl]-4-(3-methoxypropyl)benzene as a colourless oil (l.40g)„ T.l.c. (ER-H 1:8) Rf 0.41. 20 From Intermediate 27 (3.0g) and pre-reduced 10% PDO-C (1g), purifying the product by FCC eluting with CX-ER (10:1).

Intermediate 19 N-(4-Iodoohenyl)butanesulphonamide Butanesulphonyl chloride (7.8g) was added dropwise to a stirred 25 solution of 4-iodobenzeneamine (10g) in pyridine (50ml) at 0°. The bright red mixture was stirred at room temperature for 1hs then concentrated to an oil which was partitioned between 2N hydrochloric acid (100ml) and EA (100ml). The organic layer was washed with 2N hydrochloric acid, water and brine, dried (MgS0i+) and concentrated to 30 a pale brown solid which was recrystallised from CX to give the title compound as white flakes (10.5g) m.p. 80-81°. 31 Intermediate 20 N ,N-Diethvl-4-iodobenzamide 4-Iodobenzoyl chloride (10.Og) was added portionwise to diethvlamine (2.92g) in triethylamine (40mA) at 20°. The resulting slurry was 5 stirred at room temperature for 1h, diluted with ER (150mA). filtered and evaporated to give the title compound as an orange solid (10.2g) m.p. 68-70°.

Intermediate 21 N»N-Dipropyl-4-iodobenzarnide as an orange oil (11.51g) t.l.c. (ER) Rf ]_0 0.48 was prepared from 4-iodobenzoyl chloride (10.0a) and dipropylamine (4.10g) according to the method of Intermediate 20.

Intermediate 22 N_[(4-Iodoohenyl)methyl]pentanamide Valeric anhydride (3.7g) was added dropwise to 4-iodobenzene 15 methanamine (4.2g) and pyridine (3.2g) in MC (50mA) at 0°. The solution was stirred at 0° for 10min and at room temperature for 2h, washed with aqueous sodium bicarbonate, dried and evaporated. The residue was crystallised from ER at -78° to give the title compound as a white solid (3.7g) m.p. 80-81°. 20 Intermediate 23 I-Iodo-4-(3-methoxy-l-propynyl)benzene (i) 3-(4-Iodophenyl)-2-propyn-1-ol A mixture of 1.4-diiodobenzene (24.7g), propargyl alcohol (1.68g), BTPC (0.21g) and Cul (28mg) in diethylamine (180mA) was stirred at 25 room temperature under nitrogen for 18h. The solvent was evaporated in vacuo at 35°, the residual solid taken up in MC (200mA) and the solution washed with 2N hydrochloric acid (150mA). The aqueous phase was extracted with further MC (75mA), the organic layers combined, dried and purified by FCC eluting with EA-CX (1 :6) and then EA-CX 30 (1:3) to yield the title compound as a fawn crystalline solid (4.9g) m.p. 101-102°. 3 2 (ii) 1 -Iodo-4-(3-methoxy-1 -propvnvDbenzene Dimethylsulphate (2.2g) was added dropwise over 5 min to a vigorously stirred mixture of the product of stage (i) (3.0g), TAB (0.15g) 50% w/v aqueous sodium hydroxide (2.8mA) in H (10mA) and MC (5mA) and 5 stirring was continued for a further 2.5h, Concentrated ammonium hydroxide solution (5mA) was added and the mixture was stirred for 30 min to destroy the excess dimethylsulphate. Water (50mA) was added, the mixture extracted with ER (2x35mA), the organic layer dried and concentrated in vacuo at 35° to afford a brown oil. This was 10 purified by FCC eluting with ER-CX (1:10) yielding the title compound as a cream crystalline solid (2.91g) m.p. ca20°. T.l.c. (ER-H 1:8) Rf 0.44.

Intermediate 24 (E)-4-[4-Fluorophenvl]-3-buten-1-ol 15 n-8utyllithium (1.6M in H, 100mA) was added dropwise to a stirred suspension of (3-hydroxypropyl)triphenylphosphonium bromide (32.1g) in dry THF (200mA) cooled to 0°C under nitrogen. A solution of 4-fluorobenzaldehyde (9.93g) in dry THF (100mA) was added dropwise and the mixture stirred under nitrogen at 0°C for 30 min and at room 20 temperature for a further 1.5h. The mixture was carefully diluted with water (25mA), the solvent evaporated in vacuo at 40° and the residue partitioned between EA (200mA) and water (200mA). The aqueous phase was re-extracted with EA (200mA), the organic phases combined, dried and evaporated in vacuo to give a brown oil. Purification by 25 FCC eluting with CX-ER (1:1) gave the title compound as a colourless oil (6.33g). T.l.c. (CX-ER 1:1) Rf 0.13 Intermediate 25 Propyl 4-iodobenzoate DCC (13.4a) was added in one portion to 4-iodobenzoic acid (15.0g), 30 n-propanol (7.2g) and 4-(dimethylamino)pyridine (0.6g) in MC (50mA) at 0° under nitrogen. The mixture was stirred at 0° for 10 min and at room temperature for 3h, diluted with ER (50mA), filtered and evaporated. The residue was treated with CX (50mA), filtered and the 3 3 filtrate evaporated to give the title compound as a pale yellow oil (16.Zg). T.l.c. (CX-ER 3:1) Rf 0.8.

Intermediate 26 [6-[(6-Bromo-3-hexvnvl)oxv]butvl]benzene 5 ( i) 6-(4-Phenvlbutoxy)-3-hexyn-1-oi Bromoethane (3.82a) in THF (20ml) was added dropwise to magnesium (0.85g) under nitrogen at a rate to maintain gentle reflux. Intermediate 1 (7.0a) in THF (10ml) was added dropwise to the cloudy solution and the mixture was heated at 50-60° for 1h. Ethylene oxide 10 (3.52g) was added to the solution at 0° and the mixture was stirred at 0° for lOmin, at room temperature for 1h. and at reflux for 3h, treated with saturated aqueous ammonium chloride (100ml) and extracted with ER (2x100ml). The dried (MgSO^) extract was evaporated and the residue was purified by FCC eluting with CX-ER (20:7) to give a 15 colourless oil (4.8g)„ Distillation gave the title compound as a colourless oil (4.0g) b.p. 165-170°/0.3mm Hg T.l.c. (CX-ER 1:1) Rf 0.35 (ii) [4-[(6-Bromo-3-hexynyl)oxy]butyl]benzene Triphenylphosphine (4.5g) in dry MC (20ml) was added dropwise to the 20 product of stage (i) (3„8g) and carbon tetrabromide (5„8g) in dry MC (50ml) at 0°. The solution was stirred at 0° for lh and MC was evaporated. The residue was treated with ER (100ml). filtered and the filtrate was evaporated. The residue was purified by FCC eluting with CX followed by CX-ER (4:1) to give the title compound as a colourless 25 oil (4.2g). T.l.c. (CX-ER 9:1) Rf 0,4.

Intermediate 27 1-[4-[ (5-Bromooentyl)oxy]-1 -butynyl]-4-(3-methoxy-1 -propynyl) benzene Cul (I9mg) was added to a stirred solution of Intermediate 23 (2.72g), Intermediate 7 (2,19g), and BTPC (0.14g) in a mixture of THF (15mA) 30 and DEA (15mA) „ The mixture was stirred at room temperature under nitrogen for 18h» the solvents evaporated at 500 in vacuo and the residual oil was partitioned between EA (100mA) and 2N hydrochloric acid (100mA). The organic layer was washed with further 2N 3 4 hydrochloric acid (100mA), dried and concentrated to afford a product which was purified by FCC eluting with ER-CX (1:9) providing the title compound as a dark red oil (3.16g). T.l.c. (ER-H 1:8) Rf 0.30 = Intermediate 28 5 N-[[4-[4-[ [6-[ (Phenvlmethvl)amino]hexvl]oxy j-1 -butvnvl]phenyl j-methyl]pen tanamide A mixture of Intermediate 22 (3.5a), Intermediate 31 (2.85a), BTPC (0.2g). Cul (Q.02g), and diethylamine (50mA) was stirred at roam temperature under nitrogen for 18h and evaporated. The residue was 3_0 partitioned between aqueous sodium bicarbonate (1M; 50mA) and EA (2x100mA)« and the dried organic phase was evaporated. The residue was purified by FCC eluting with EA to give the title compound as a yellow solid (2.3g) m.p. 66-67°.

Intermediate 29 15 (E)-4-[4-[ (6-Bromohexyl )oxy]-l-butenyl]-2-methoxyphenol A solution of Intermediate 8 (4.05g) and 4-toluenesulphonic acid (2.34g) in a mixture of THF (80ml) and water (10ml) was heated under reflux for 2.5h and then the solvent evaporated in vacuo at 40° to yield a viscous oil. This was taken up in EA (100ml) and the solution 2o washed with 82o NaHC03 solution (2x75ml), driedf concentrated and purified by FCC eluting with EA-H (1:3) to give the title compound (3.60g). T.l.c. (EA-CX 1:3) Rf 0.44.

Intermediate 30 4-[[3 .5-Bis(phenylmethoxv) jphenyl]-3-buten~1 -ol 25 A stirred suspension of [3-(1-methoxy-1-methylethoxy)propyl]- (triphenylphosphonium)bromide (4g) in dry THF (25ml) at 0°C was heated with butyl lithium (5.28ml) and the mixture stirred at 0 °C for lOmin. 3,5-Bis(phenylmethoxy)benzaldehyde (2.24g) in dry THF (15ml) was added 3 5 and the mixture stirred for a further 45min at room temperature under nitrogen, diluted with ER (100ml) and filtered through silica (20a) twice. The filtrate was evaporated in vacuo to give a yellow oil which was dissolved in a mixture of THF (50ml), water (5ml) and 2M 5 hydrochloric acid (1ml) and left at room temperature for 30min. The mixture was basified with sodium bicarbonate solution and extracted with ER (200ml). The organic phase was washed with water (150ml), brine (100ml), dried and evaporated in vacuo to give a yeilow oil. Purification by FCC eluting with ER-CX (3:2) gave a colourless oil 10 (1.48g). T.l.c. (ER-CX 3:1) Rf 0.26 Intermediate 31 (3-Butynyl)oxy]hexyl]benzenemethanamine Intermediate 5 (43.3g) was added over 20 min to benzylamine (147mA) at 120° under nitrogen. The reaction mixture was stirred at 120° for 2h, 15 the benzylamine was removed by distillation (70°H3.1torr) and ER (1 A) was added to the residue. The resultant precipitate was removed by filtration and the filtrate was concentrated to an oil which was purified by FCC eluting with CX-ER (2:1 ■* ER) to give the title compound as a yellow oil (25.5g). T.l.c. (EA-triethylamine 99:1) Rf 20 0.38.

Intermediate 32 (E)-4-[3-Methaxv-4-(methoxvmethoxy)phenyl]-3-buten-1-ol n-Butyllithium (1.6M in hexane, 25mA) was added dropwise to a stirred suspension of (3-hydroxypropyl)triphenylphosphonium bromide (8.03g) in 25 dry THF (50mA) cooled to 0° under nitrogen. The resulting blood-red solution was stirred at 0° for 10min and then 3-methoxy-4-(methoxymethoxy)-benzaldehyde (3.60g) in dry THF (10mA) was added dropwise over 5min. The mixture was allowed to warm to room temperature, stirred for 4h,, water (10mA) was added and the majority 30 of the solvent was removed in vacuo at 40°. A solution of the residual oil in ER (200mA) was washed with water (150mA), dried, treated with charcoal, concentrated and purified by FCC eluting with EA-H (1:1) to give the title compound (1.55g). T.l.c. (EA-H 1:1) Rf 0.30. 3 6 Intermediate 33 7-[2-[4-Methvlthio)phenvl]ethoxv]-2-heptanone (i) 1-[2-[(5-Bromooentvl)oxv]ethvl]-4-(methylthio)benzene 4-(Methylthio)benzeneethanol (7.44g) and 1,5 dibromopentane (30.48g) 5 were stirred rapidly at room temperature with TAB (l.Og) and 12.5M aqueous sodium hydroxide (35mA) for 64h. The mixture was diluted with water (170mA). extracted with ER (3x200mA) and the combined organic extracts were washed consecutively with water (170mA) and brine (170mA), dried and evaporated. The residual oil (29»29g) was purified 1° by FCC eluting with ER-CX (0:100*3:97) to give the title compound as a colourless oil (10,68g), T.l.c. (ER-CX 1:79) Rf 0.08. (ii) 7-[2-[4-»( Methyl thio)phenvl]ethoxy]-2-heptanone The product of stage (i) (5,00g) in ER (7.0mA) was added dropwise to magnesium turnings (0.384g) with one crystal of iodine at room temperature under nitrogen with stirring. The stirred mixture was heated to reflux for 3h under nitrogen and the solution of Grignard reagent was added slowly to a stirred solution of acetic anhydride (2.86g) in ER (70mA) over a period of 1h maintaining the temperature between -60 and -70°. After a further 2h at -60 to -70°, the reaction mixture was allowed to warm to -10° and treated with a saturated aqueous ammonium chloride solution (20mA). The ER layer was separated and the aqueous phase was extracted with ER (3x40mA). The combined extracts were washed with 2N sodium hydroxide (30mA) and brine (30mA). The washings were extracted with ER (3x40mA) and these extracts, combined with the previous extracts were dried and evaporated. The residual oil (3.73g) was purified by FCC eluting with ER-H (1:14 •* 1:7) followed by ER - CX (1:7 to give the title compound (2,17g). Analysis Found: C,69.9; H,9.2; 5,11.05 ^16^2^2^ requires C,68.55; H,8.65; S,11.458 30 Intermediate 34 4-(4-Morpholinyl)benzenebutanol A mixture of 4-aminobenzenebutanol (7.5), 2-chloroethyl ether (6.5q, 5.32mA), DEA (11.74g) and finely ground potassium iodide (15.Og) was stirred in DMF (500mA) at 100° under nitrogen for 65h. The mixture was 15 20 25 3 7 cooled, the solvent removed in vacuo at 55° and the residue partitioned between EA (250mA.) and water (100mA). The aqueous layer was extracted with further EA (100mA), the combined organic solutions washed with brine (150mA), dried and evaporated onto FCC silica (15g). 5 The impregnated material was applied to an FCC column, elution with ER-CX (2:1) affording the title compound as a waxy cream solid (6.13g) m.p, 51-52°.

Intermediate 35 10 t ,1-Dimethyl-5-[4-[4-(4-moroholinvl) phenylIbutoxy Jpentanamine (i) 2 ,2-Dimethyl-6-[4- [4-(4-morpholinvl) phenyl]butoxy]hexanoic acid A solution of lithium diisopropylamide was prepared by treating diisopropylamine (5.32g) in dry THF (20mA) with n-butyllithium (1.53M in hexane: 34.4mA) at -40° under nitrogen. The solution was stirred at 15 0° for 15 min. isobutyric acid (2„32g) was added and the mixture stirred at room temperature for 3h„ Intermediate 9 (6.0g) was added, the mixture stirred at room temperature for 20h under nitrogen and then the solvents evaporated in vacuo at 40°. The viscous residue was triturated with water (250mA), the pH adjusted to 6 by the addition of 20 2N hydrochloric acid and the mixture extracted with EA (2x200mA), The organic layer was dried and concentrated in vacuo to afford the title compound as a pale brown oil (5.75g). T.,l„c. (ER) Rf 0.6. (ii) (Phenylmethyl) 1?1-dimethyl-5-[4-[4-(4-morpholinyl)phenyl] butoxy]pentylcarbamate 25 Ethyl chloroformate (1 .66g) in acetone (5mA) was added dropwise to a solution of the product of stage (i) (5„5g) and triethylamine (2.13mA) in acetone (50mA) and water (5mA) stirred at 0°. The mixture was stirred at 0° for 40 min and sodium azide (1g) in water (10mA) was added dropwise. The resulting suspension was stirred at room 30 temperature for 45 min, diluted with water (100mA) and extracted with T (2x100mA). The dried extract was heated at 75-80° for 2h under nitrogen and evaporated in vacuo at 40°. The residual oil was dissolved in benzyl alcohol (10mA) and the solution stirred at 70-75 ° for 60h under nitrogen and then the excess alcohol removed in vacuo at 35 95°. The resulting oil was purified by FCC eluting with ER-CX (1:2) to 3 8 afford the title compound as a pale yellow oil (5.34g). T.l.c. (ER-CX 1:2) Rf 0.23. (iii) 1 ,1 -Dime thy 1-5-[4-[4-(4-morpholinvl)phenvl]butoxv]pent3namine A solution of the product of stage (ii) (4.60g) in absolute ethanol (75mA) was hydrogenated at room temperature and atmospheric pressure over a pre-reduced 10£ palladium oxide on carbon catalyst (1g, 50% paste in water) in absolute ethanol (25mA). The catalyst was removed by filtration through 'hyflo' and the solvent evaporated in vacuo at 40° to yield the title compound as a colourless oil (3.0g). T.l.c. (T-ET-A 39:10:1) Rf 0.32.

Intermediate 36 N-N-Dipropyl-4-[4-[[6-(phenvlmethyl) amino]hexyl]oxy]-1-butynyl] benzamide Copper (I) iodide (10mg) was added to a stirred solution of Intermediate 21 (2g) , Intermediate 31 (1 .57g) and BTPC (70mg) in diethylamine (30mA) under nitrogen, and the mixture stirred under nitrogen overnight. The solution was evaporated in vacuo, the residue dissolved in MC (50mA) and the solution evaporated onto FCC silica. Purification by FCC eluting with ER gave the title compound as an orange oil (1„2g).

Analysis Found: C.77.6; H,9.4; N,6.3.

C3oH2^2^2 requires C.77.9; H.9.2; N,6.1SS.

Intermediate 37 N-[4-[4-[ [6-[ [2-[3-[ (Aminocarbonvl) amino]-4-( phenylmethoxy)phenyl ]-2-oxoethyl] (pheny lmethvl) amino] hexyl]oxy] butyl] phenyl] but anesulphon-amide N_-[5-Bromoacetyl-2-[phenylmethoxy)phenyl]urea (0.96g), Intermediate 10 (1.25g) and DEA (0.68g) in THF (50mA) were stirred at room temperature under nitrogen for 20h. The mixture was diluted with water (100mA), extracted with EA (2 x 100mA), dried and evaporated in vacuo to give an oil. Purification by FCC eluting with EA-CX (3:1) gave the title compound as a white foam (0.90g). T.l.c. (EA-CX 3:1) Rf 0.27 3 9 Intermediate 38 (E)-NI-[5-[ 2-[[6-[ [4-(4—Hvdroxv-3—rneti~ioxvohenvl)-3-butenvl]oxy]hexvl] (phenvlme thvl) amino ]-1-oxoe th v 1 ]-2-( phenv Ime thoxv) phenyl] me thane sulohonamide 5 A solution of N-[5-bromoacetyl-2-(phenylmethoxy)phenyl]methane- sulphonamide (0.6g)« Intermediate 11 (0.48g) and DEA (0.39g) in THF (10mA) was left to stand for 48 hours. The precipitated DEA hydrobromide was filtered off and the filtrate evaporated in vacuo to give an oil. This was pre-absorbed onto FCC silica (5g) and purified ]_0 by FCC (80g) eluting with CX-EA (3:2) providing the title compound as a yellow oil (0.38g). T.l.c. (CX-EA 3:2) Rf 0.20 Intermediate 39 N-[5-[2-[[5-[4-[4-(3-Methoxv propyl) phenyl] butoxy ]pentyl] (phenvl-15 methyl) amino ]-1 -oxoethyl]-2-(phenyImethoxy) phenyl] formamide A solution of N-[5-bromoacetyl-2-(phenylmethoxy)phenyl]formamide (0o70g)j, Intermediate 12 (0.80g) and DEA (0.52g) in DMF (10mA) was allowed to stand at room temperature for 3h. The solvent was removed in vacuo at 55°, the residual oil was taken up in EA (50mA) and the 2o solution washed with water (50mA). The aqueous phase was extracted with further EA (50mA), the combined organic layers dried and concentrated to yield an orange oil which was purified by FCC eluting with EA-CX (1:2) to afford the title compound as colourless oil (0.89a) . T.l.c. (EA-H 1:1) Rf 0.45. 25 Intermediate 40 4-[4-[ [6-[ [2-[3-[ [ (Dimethylamino)sulphonyl ]amino]-4-(phenvImethoxy )phe nyl]-2-oxoethyl] (phenyImethyl)amino]hexvl]oxvj-1 -butynyl]-NI ,N-dipropyl benzamide as a yellow oil (0.47g) t.l.c. (T-EA 5:1) Rf 0.289 was prepared from NT-5-[bromoacetyl-2-(phenylmethoxy)phenyl]-N_,N-30 dimethylsulphamide (0.7q), Intermediate 36 (0.76g), and DEA (0.23g) according to the method of Intermediate 39, except that the reaction mixture was stirred under nitrogen for 4h, and T-EA (7:1) was used as eluant for the FCC purification. 4 © Intermediate 41 (E)N-[2-Hydroxv-5-[l-hydroxv-2-[[6-[[4-[3 .5-bis(phenvImethoxv)phenyl]-■ 3-butenvl] oxy ]hexvl] amino ] e th vl ] phenyl ]methanesulohonamide Intermediate 4 (2.13g) was added dropwise to a stirred solution of Intermediate 43 C1 -5g) and DEA (0.57g) in DMF (25mA) at 70° under nitrogen. The solution was stirred at 70° for 6h, diluted with water (100mA), extracted with EA (2x100ml)«, washed with water (100m A), dried and evaporated in vacuo to give a brown oil. Purification by FCC eluting with EA-ME (9:2) gave the title compound as a brown oil (0.79g). T.l.c. (T-ET-A 39:10:1) Rf 0.22 Intermediate 42 N_-[ 5—[ 1 -Hydroxy-2-[ [ 1 ,1 -dimethyl-5-[ 4-[4-(4-morpholinyl) phenyl ]butoxy j pent yl] amino] ethyl]-2-(phenylmethoxy) phen vl] methanesulphonamide A mixture of Nk[5-(oxoacetyl)-2-(phenylmethoxy) phenyl] methanesulphonamide hydrate (0„74g) and Intermediate 35 (0.70g) 2.0mmol) in benzene (20mA) was stirred and heated under reflux in a Dean-Stark apparatus for 0.5h when water ceased to be collected. The solvent was removed in vacuo at 40°, the residual oil was dissolved in methanol (25mA) and the solution stirred at 00 under nitrogen. Sodium borohydride (0.75g) was added portionwise over 0.5h? the mixture stirred at 0° for 15 min and then allowed to stand at room temperature for 20h„ The solution was acidified (pH2) with 2N hydrochloric acid, the majority of the methanol evaporated in vacuo at 40° and the residual oil partitioned between EA (75mA) and 8% sodium bicarbonate solution. The aqueous phase was extracted with further EA (50mA). the combined organic solutions were dried and concentrated to yield a product which was purified by FCC eluting with T-ET-A (39:10:1) to yield the title compound as a pale brown viscous gum. T.l.c. (T-ET-A 39:10:1) Rf 0.42.

Intermediate 43 is N^[5-(2-amino-1-hydroxyethyl)-2-hydroxyphenyl] methanesulphonamide.

Intermediate 44 N-(4-Iodobenzoyl)piperidine 4-IodobenzoyI chloride (10.Og) was added portionwise to piperidine (3.53q) in triethy1 amine (40mA) at 0° and the suspension was stirred at room temperature under nitroqen for 1h. The reaction mixture was poured into 2N aqueous hydrochloric acid (200mA) and extracted with EA (3x100mA). The combined extracts were washed with water (100mA), 88 aqueous sodium bicarbonate (100mA) and water (10mA), dried and concentrated. The resultant solid (10.25g) was purified by FCC eluting with ER-H (1:2->1:1) to give the title compound as a white solid (9.33q) m.p. 126-127°.

Intermediate 45 N,N~Diethyl-4-iodobenzeneacet amide 4-Iodobenzeneacetyl chloride (10.62g) was added portionwise to diethylamine (3„0g) in triethylamine (40mA) and washed in with MC (5mA) at 0° under nitroqen and the suspension was stirred at room temperature for 2h„ ER (150mA) was added;, the mixture was filtered and the filtrate was concentrated to give a residue (7.94g) which was purified by FCC eluting with ER-H (2:1) to give the title compound as a yellow oil (4„72g). T.l.c. (ER) Rf 0.31 .

Intermediate 46 l-Bromo-6-[(2-propynyl)oxy]hexane A mixture of propargyl alcohol (5„6g) 1.6-dibromohexane (73.2q), TAB (0.5g). and aqueous sodium hydroxide (508 w/v, 25ml) was stirred at room temperature for 20h, diluted with water (50ml), and extracted with ER (2x100ml). The dried extract was evaporated and the residue was purified by FCC eluting with CX fallowed by CX-ER (19s1) to give the title compound as a colourless oil (15. Og). T.l.c. (CX-ER 9:1) Rf 0.4. 42 Intermediate 47 2-[4-[(6-Bromohexyl)oxy]butyl]-N,N-diethylbenzamide A mixture of Cul (20mg). l-bromo-6-t(3-butynyl)oxy] hexane (3.04gK N_,N-diethv 1-2-iodabenzamide (3.95g), BTPC (200mg)., N^N-dieye1ohexy1 amine (2.60g) and acetonitrile (20mA) was stirred under nitrogen at room temperature for 4.5h, diluted with ether (200mA) and filtered. The filtrate was evaporated in vacuo, the residue in ethanol (100mA) was treated with charcoal and the solvent evaporated in vacuo. The residual oil (5.32g) in absolute ethanol (190mA) was hydrogenated over pre-reduced 10S PDO-C (508 paste in water, 1.25g) in absolute ethanol (20mA). filtered through hyflo and evaporated in vacuo to give an oil. Purification by FCC eluting with T-EA -triethylamine (95j5:1) followed by FCC eluting with CX-EA (2:1) gave the title compound as a yellow oil (2. 04g). T.l.c. (T-ET-A - 40:10:1) Rf 0.14.

Similarly were prepared Intermediates 48-51 Intermediate 48 4-[4-[(5-Bromopentyl)oxy]butyl]-N,N-diethylbenzamide as a light brown oil (5.81g), t.l.c. (ER) Rf 0.37. from Cul (25mg), jM;N-diethyl-4-iodobenzamide (6.06g). Intermediate 2 (4.38g). BTPC (250mg) and dicyclohexylamine (4.0g) in acetonitrile (30ml)„ reaction time 2h, followed by hydrogenation using 10% PD-C (508 agueous paste) as catalyst. Purification of product was carried out usinq Merck 7734 silica, eluting with H-ER (1:1) and ER.

Intermediate 49 N-[4-[4-[(6-Bromohexyl)oxy]butyl]benzoyl]piperidine as a dark brown oil (7.55g), t.l.c. (ER-H 2:1) Rf 0.25, from Intermediate 44 (9.30g), 1-bromo-6- [(3-butyny1)oxy]hexane (6.46g) N.N-dicyclohexy1 amine (5.90g)„ BTPC (150mq) and uyl Cul (30mg) in acetonitrile (90mA), reaction time 20h„ 10% PD-C was used as catalyst for hydrogenation, and ER-H (2:1) and CF as eluents for FCC purification Intermediate 50 4-[4-[(6-Bromohexyl)oxy]butyl]°N,,N-diethylbenzeneacetamide as a dark brown oil (3.51g), t.l.c. (ER-H 2:1) Rf 0.18,, from Intermediate 45 (4„65g) 1-bromo-6-[ ( 3-buty ny 1) oxy ]hexane (3.22g), j^.N-dicyclohexylamine (2.94g), BTPC (75mg) and Cul (15mg) in acetonitrile (30mA), with reaction time,, hydrogenation catalyst and FCC purification as in Intermediate 49.

Intermediate 51 3°[4-[(6-Bromohexyl)oxy]butyl]-N,N-diethylben2aiT)ide as a brown oil (5„91g), t.l.c. (H-ER 1:1) Rf 0.175. from N^,N_-diethy 1-3-iodobenzamide (8.49g) 1-bromo-6-[(3-butyny1)oxy]hexane (6„99g), BTPC (350mg), Cul (250mg) and dicyclohexylamine (6»45g) in acetonitrile (35mJl).

After stirring at room temperature for 2 days, the solvent was evaporated and the residue partitioned between water (100mA) and EA (100mA),, The phases were separated, charcoal (5g) was added to the organic layer which was then dried and concentrated to an oil. Ethanol (100mA) was added to the oil. the resulting fine brown precipitate was removed by filtration and the filtrate was hydrogenated using 10% PD-C as a catalyst. ER-CX (1:2) was used as eluent for FCC purification.

Intermediate 52 4-[3-[[6-[(Phenylmethyl)amino]hexyl]oxy3propyl]-N,N-dipropylbenzamide A suspension of Intermediate 21 (6.62g)5 Intermediate 46 (4„40q). dicyclohexylamine (4.0q), BTPC (250mq) and Cul (25mg) in acetonitrile (40mA) was treated as in Intermediate 25, followed by hydrogenation using 44 pre-reduced 108 PD-C as catalyst, with FCC purification using H-ER (2:1) as eluent, The resultant orange oil (5.1g) was added to benzylamine (15mA) at 140° under nitrogen. After 2h the reaction mixture was added to 2N 5 hydrochloric acid (200mA) and ice (100mA). The aqueous mixture was extracted with EA (3x100mA) and the combined organic extracts were washed with 2N sodium carbonate (2x100mA), water and brine, dried and concentrated to a dark oil which was purified by FCC eluting with 10 T-ER-triethy 1 amine (95:5:1 -*■ 90:10:1) to give the title compound as a pale yellow oil (2.4q) t.l.c. T-ET-triethylamine (90:10:1) Rf 0.36.

Intermediate 53 ^-[6-[2-[4-(N.N-Dimethylamino)phenyl]ethoxy]hexyl] 15 benzenemethanamine A mixture of 1 ,6-dibromohexane (73.84g) 4-(_N,_N-dimethy1 amino)benzeneethanol (10g)„ 508 w/v sodium hydroxide solution (200mA) and TAB (3„4g) was vigorously stirred at room temperature for 72h5 diluted with water 20 (500mA) and extracted with ER (2x100mA)„ The dried extracts were evaporated to give a yellow oil which was purified by FCC eluting with H then H-EA (9:1) to give 4 —[2 — [(6-bromohexyl)oxy] ethyl]-N,N-dimethylbenzeneamine as a yellow oil. The benzeneamine (15g) was added to 25 benzylamine (65mA) with stirring at 140° under nitrogen and stirring continued for 2h„ The benzylamine was removed in vacuo at 90°, the solution was partitioned between sodium bicarbonate (150mA) and EA (2x100mA) and the combined organic layers dried and concentrated to give 30 a product which was ourified by FCC elutinq with ER-H (1:1 -*-ER) to give the title compound as a yellow oil (11.1g) t.l.c. (T-ET-A 95:4:1) Rf 0.62. 4 5 Example 1 (a) N,Nl-Diethvl-4-[4- [[6-[[2-hvdroxv-2-[4-hydroxv-3-[ (methvl-sulphonvl)amino]phenyl]ethvl] amino]hexvl]oxy]butyl]benzamide, benzoate (salt) 5 Intermediate 17 (1.Og) in DMF (2ml) was added dropwise to a solution of Intermediate 43 (1.2g) and DEA (1.3g) in DMF (20mA) at 75°. The solution was heated at 75-80° for 90min and evaporated under reduced pressure. The residue was purified by FCC eluting with T-ET-A (80:20:1) to give a colourless gum. The qum in CF (10mA) was treated 1° with benzoic acid (0.3g) in CF (5mA) and CF was evaporated. The residue was triturated with ER (2x25mA) to give the title compound as a white solid (0„55g) m.p. 90-92°„ Analysis Found: C?63„3: H,7.55; N,5.9 ^29^4-8^3^6^-CyHgO2 requires C.62.8; H.7.9; N,6.1S 15 Similarly prepared were: (b) Propyl 4-[4-[[5-[[2-hydroxy-2-[4-hydroxv-3-[(methylsulphonyl)-amino]pheny1]ethyl]aminoJpentyl]oxy]-1-butvnyl]benzoate as a white solid (0.26g) m.p. 88-90°.

Analysis Found: C.61.0; H,7.0; N,5»0. 20 C28^38'^2O7S requires C.61.5; H.7.0| N,5,18.

From Intermediate 43 (1 ,0g) , Intermediate 15 (1.43g) and DEA (l.Og) after a reaction time of 2hs and omitting treatment with benzoic acid in CF. (c) N-[2-Hydroxy-5-[l-hydroxv-2-[[6-[&-[4-(methylthio)phenyl]- 25 butoxy]hexyl]amino]ethyl]phenyl]methanesulphonamide as a beige solid (0.3g) m.p. 92-93°.

Analysis Found: C,59.0; H,7.9: N,5.4.

C26^40N2^5^2-2H20 requires C,59.1; Hs8.4: N,5.3S.

From Intermediate 43 (0.8g), Intermediate 6 (1 .3g) and DEA (1.0a) 30 after a reaction time of 3h, and omitting treatment with benzoic acid in CF. (d) N-[2-Hvdroxv-5-[ 1 -hvdroxv-2-[[6-[4-(4-nitrophenvl)butoxv]hexvl]-amino]ethyl]phenyl]methanesulphonamide as a beige solid (1.15g) m.p. 77-80°.

Analysis Found: C,57.0; H,7.1 ; N,7.85» ^ 25^37'^3^7^ requires C.57.3; H.7.1; N.8.0K.

From Intermediate 43 (2.5g)? Intermediate 3 (3.6g) and DEA (2.6g) after a reaction time of 2h? and omitting treatment with benzoic acid in CF.

Example 2 10 (a) (E)-N-[2-Hydroxv-5-[l-hvdroxy-2-[[6-[[4-(4-fluoroohenvl)-3-butenvl]oxy]hexyl]amino]ethvl]phenyl]methanesulphonamide Intermediate 2 (1 ,34g) was added to a stirred solution of Intermediate 43 (1«50g) and DEA (0*57g) in DMF (25mA) at 70° under nitrogen. The solution was stirred at 70° for 5h, diluted with water (100mA) and 15 extracted with EA (2x100mA). The organic phase was washed with water (100mA), dried and evaporated in vacuo to give a brown oil which was purified by FCC eluting with EA-ME (9:1) to give a brown foam. Trituration with ER gave the title compound as a white solid (0.47g) m.p. 79-80° 20 Analysis Found: C,59-6;H.7.15;N,5.6.

C25H35FN205S.0.5H20 requires C,59.6;H,7.2;N,5.6SS.

Similarly prepared was: (b) N-[2-Hydroxy-5-[1-hydroxv-2-[[6-(4-phenylbutoxy)-3-hexvnyl]amino]-ethyl]phenyl]methanesulphonamide as a yellow foam (159mg). T.l.c. 25 (T-ET-A. 39:10:1) Rf 0.22 Analysis Found: C,61.6;H,7.3;N,5.7.

C232^5*^^2^ requires C.62.1 ;H,7.3;N,5.8!o.

From Intermediate 43 (0.8g), Intermediate 26 (lg) and DEA (0.45g) after a reaction time of 2h. 30 Example 3 (a) Propyl 4-[4-[[5-[[2-hvdroxy-2-[4-hvdroxy-3-[(methylsulphonyl) A amino]phenyl]ethyl]amino]pentvl]oxy]butvl]benzoate A solution of Example 1(b) (0„2a) in ET (20ml) was hydrogenated over 108 PD-C (0.05a), filtered through hyflo and evaporated. The residue was triturated with ER (20ml) to give the title compound as an 5 off-white solid (0.19g) m.p. 74-76°.

Analysis Founds C,60.6;H,7.4;N,5.0.

C28Hl+2^2^7^ requires C,61.1 ;H,7.7;N,5.18.

Similarly prepared were: (b) N-[2-Hydroxy-5-[1-hvdroxv-2-C[6-[&-(3,5-dihydroxyphenyl)butoxv]-10 hexyl]amino]ethyl]phenvl]methanesulphonamide as a beige solid (0.27g) m.p. 73-74° (dec) Analysis Found: C,56.3;HS7.6;N.5.2.

C25H38N2O7S.IH2O requires C.56.8:H,7.6;N.5.38.

From Intermediate 41 (0.5g), pre-reduced 108 PD-C (40mg) and 58 PT-C 15 (30mg). (c) N-[4-[4-[[6-[[2-[3-[(Aminocarbonyl)amino]-4-hydroxyphenyl]ethyl]-amino]hexyl]oxv]butyl]phenyl]butanesulphonamide as a beige foam (0.45g). T.l.c. (T-ET-A 39:10:1) Rf 0.16 Analysis Found: C.58,3;H,7_75;N?8.9. 20 C^H^gN^OgS.I-^O requires C.58.4;H?8.1 jN,9.48.

From Intermediate 37 (0.8g), pre-reduced 108 PD-C (200mg) and 58 PT-C (200mg). (d) N—C5—[2—C[6-[4-(4-Aminophenyl)butoxy]hexyl]amino]-1-hydroxyethy1]-2-hvdroxyphenyl]methanesulphonamide as a beige solid (0.3g) m.p. 25 57-60° Analysis Found: C,58.3; H,7„5; N,8.0.

C25^39N3O5S»H20 requires C.58.7; H.8.0; N,8.2S.

From Example 1(d) (0.5g), 108 PD-C (0.1g) and 58 PT-C (0,1g) Example 4 30 N-[2-Hydroxv-5-[ 1 -hvdroxy-2-[ [ 5-[ 4-[ 4-(3-methoxvpropvl) phenyl] butoxy] pentvl] amino]ethyl]phenvl]formamide, benzoate (salt) 4 8 A solution of Intermediate 39 (0 .85g) in absolute ET (25mA) was hydrogenated over pre-reduced 108 PDO-C (Q.5g) and 58 PTO-C (0.25g), The mixture was filtered through hyflo and the solvent removed to yield an oil which was purified by FCC eluting with T-ET-A (39:10:1) 5 to give the title compound free base as a viscous colourless oil (0.2g)« This was dissolved in ME (5mA), benzoic acid (50mg) was added and the solvent evaporated to give a viscous oil which on trituration with ER gave the title compound as a white powder (0„16g) m.p. 88-91° Analysis Found: C,68.21: H,7.75: N,4„54; 028^2^2^5•'-7^6^2'®-^HjO requires C?68.04: H?7.99: N.4.538 Example 5 N-[2-Hydroxy-5-[l-hydroxv-2-[[6-[4-(4-hydroxy-3-methoxyphenyl)butoxy]-hexyl]amino]ethyl]phenyl]methanesulphonamide 15 A solution of Intermediate 38 (0.36g) in absolute ethanol (20mA) was hydrogenated over pre-reduced 108 PD-C (40mg) and 58 PT-C (40mg) in absolute ET (5mA). The mixture was filtered through hyflo and evaporated to give a brown oil. Purification by FCC eluting with T-ET-A (39:10:1) gave a brown oil which on trituration with ER gave 20 the title compound as a brown foam (40mg) T.l.c. (T-ET-A 39:10:1) Rf 0,23.

Analysis Found: C.58.4;H,7.85;N,4.9.

C26^40^2®^7^*0.5 H20 requires C.58.5*,H.7.7:N ,5 „258» Example 6 25 N-[[4-[4-[[6-[[2-Hvdroxy-2-[4-hvdroxy-3-[(methylsulphonyl)amino]- phenv1]ethyl]amino]hexvl]oxv]butyl]phenyl]methvl]pentanamide. benzoate (salt) A solution of N-[5-(bromoacetyl)-2-(phenylmethoxy)phenyI]methane-sulphonamide (0.9g), Intermediate 28 (1.0g) and DEA (0„65g) in THF 30 (15mA) was left at room temperature for 20h. filtered, and evaporated. The residue was purified by FCC eluting with ER to give a yellow oil. The oil in ET (40mA) was hydrogenated over 108 PD-C (0.3g) and 58 PT-C (0.2g), filtered and evaporated. The residue was purified by FCC eluting with T-ET-A (80:20:1) to give a colourless gum. A solution of the gum (0.2g) in CF (15ml) was treated with benzoic acid (0.7g) and evaporated. The residue was triturated with ER (15ml) to give the title compound as a white solid (Q.2g) m.p. 88-89° Analysis Found: C«.63.□; H.7.7; N.5.8.

C3jH3OgS.C?HgO2 requires C,63.1; H57.8: N,5.88.

Example 7 4-[4-[[6-[[2-[5-[[(Dimethylamino)sulphonyl]amino3-4-hvdroxvphenvl3 2-hydroxyethyl]amino]hexyl]oxy]butyl]-N,N-dipropylbenzamide, (E)-2-butenedioate (salt) (1:1) A solution of Intermediate 40 (0.43g) in absolute ET (30ml) was hydrogenated over a mixture of pre-reduced 58 PTO-C (10Qmg) and 108 PDO-C (100g) in absolute ET (10ml). The mixture was filtered through 'hyflo' and evaporated in vacuo to give a yellow oil (0„27g) . Purification by FCC eluting with T-ET-A (39:10:1) gave a yellow oil (200mg) which was dissolved in methanol (2ml) and treated with fumar acid (40mg). The solution was evaporated in vacuo and the residue triturated with ER to give the title compound as a cream foam (0.2g) T.l.c. (T-ET-A 39:10:1) Rf 0.21.

Analysis Found: C,58.6; H,8.0; N,6.9.

C33H5ltNlt0gS.C!.H2Ok.0.2H20 requires C.58.9; H,7.8: N?7.48.

Example 8 N-[2-Hydroxy-5-[l-hvdroxv-2-[[1.1-dimethy1-5-[4-[4-(4-morpholinyl) pheny1]butoxy]pentyl]amino]ethyl]phenyl]methanesulphonamide A solution of Intermediate 42 (0.65g) in absolute ethanol (25ml) was hydrogenated at atmospheric pressure and room temperature over pre-reduced 108 PDO-C (0.5g, 508 paste in H20). The catalyst was removed by filtration through 'hyflo1- Purification by FCC eluting with T-ET-A (39:10:1) afforded the title compound as a fawn powder (128mg) m.p. 165-167°.

Analysis Found: C.62.22; H?8.37; IM.6.99.

C3oH,7N306S requires C.62.36; H,8.20; N,7.27%. 5 0 Example 9 N-[2-Hvdroxv-5-[l-hydroxv-2-[[l-methyl-6-[2-[4— (methylthio) phenyl] ethoxv]hexy1]amino]ethyl]phenyl]methanesulphonamide A solution of Intermediate 43 (0.62g), Intermediate 33 (0„7g) and 5 acetic acid (CL18g) in methanol (15mJ0 was treated with sodium cyanoborohydride (0.19g) under nitrogen and left at room temperature for 18h in the presence of molecular sieves (4A). Aqueous sodium bicarbonate (1M; 50ml) was added and the mixture was extracted with EA (2x100ml). The dried extract was evaporated and the residue was 10 purified by FCC eluting with T-ET-A (80:20:1) to give a semi-solid residue which was triturated with ER (50mi.) fco give the title compound as a white solid (0.45g) m.p. 133-138°.

Analysis Found: C?58.8; H,7„6; N,5.3. ^25H38^2^5^2 requires C.58.8; H.7.5; N.5.5X. 4 1 Jfi- Example 10 N,N-Dipropyl-4-[3-[[6-[[2-hydroxy-2-[4-hydroxy-3- 10 [(methylsulphonyl)amino]phenyl]ethyl]amino]hexyl] oxy]propy1]benzamide. benzoate (salt) A solution of N-[5-(bromoacetyl)-2-(phenylmethoxy ) phenylJmethanesulphonamide (1.93g), Intermediate 52 (2.10a), and DEA (0.68g) in dichloromethane (45mA) was stirred under nitrogen for 24h. The mixture was diluted with water (150mA). extracted with ether (200mA) and the organic phase washed with brine (50mA), dried and evaporated in vacuo. A solution of the resultant yellow oil (3.57g) in absolute ethanol (170mA) was hydrogenated over a mixture of pre-reduced 10% PDO-C (1.0q) and 5% PTO-C (l.2g) catalysts in absolute ethanol (20mA), filtered through hyflo and evaporated in vacuo to qive an oil. Purification by FCC eluting with T-ET-A (40;20s1) gave an oil which on trituration with ER gave the free base of the title compound as a white foam (1„40g)? t.l.c. (T-ET-A 40^10:1) Rf 0.16. A portion (0.60g) was dissolved 20 in methanol (10mA) and treated with benzoic acid (0.14g) to give the title compound as a white solid (0„54g) m.p. 100.5 - 101 .5 °.

Analysis Found: C?62.2;H„7„8? N,5.7.

C 3 iH 30 6S .C ?H 60 2»H 20 requires C,62,3; H.7.8? N,5.73S. 25 Example 11 N-[2-Hydroxy-5-[l-hydroxy-2-[[6-[2-[4-(dimethylamino) phenyl3ethoxy]hexyl]amino]ethyl3phenyl]methane sulphonamide The title compound was prepared as a light brown solid 30 (450mg) m.p. 45-50° Analysis Found: C,59.27;H.,8.05|Ny8.18; C 25H 3 gN 3O 5S .0 .7H 20 requires C , 59 .31 ; H , 8 .04 ; N , 8 .29 ; 5 , 6 . 33 . From N — [5 — (bromoacetyl)-2-(phenylmethoxy)phenyl]methane sulphonamide (4q), Intermediate 53 (3.54g) and DEA (2.1q) 35 according to the method of Example 10, except that 108 5 2 PD-C (1 .5q) and 5% PT-C (1.5q) was used as the hydroqenation catalyst, T-ET-A (80:20:1) was used as the eluant for FCC, and treatment with benzoic acid has omitted . 5 Examples 12-16 were prepared according to the method of Example 1(a): Example 12 j[gN-Diethyl-4-[4-[[5-[[2-hydroxy-2-[4~hydroxy-3-[(methylsulphonylamino]phenyl]ethyl]amino]pentyl]-10 oxy]buty11benzamide, benzoate salt, as a solid (1„35g) m.p. 92-105°. t.l.c. (T-ET-A 38:10:2) Rf 0.19.

Analysis Found; C,61.88; H.7.58; N,5.99So„ ^29^45^ 7^ 6^ 2^ requires C,61.98; H.7.64: Ns6.27£. 15 From Intermediate 43 (2„5g)s DEA (0„89g) and Intermediate 48 (2.7g), after a reaction time of 3-4 h. T-ET-A (78 :20 :2 then 73:25:2) was used as eluent for FCC, and methanol as the solvent for treatment with benzoic acid (0„45g).

Example 13 20 N-[2-Hydroxy-5-[1-hydroxy-2-[[6-[4~[4-(1-piperidinyl- carbonyl)phenyl]butoxy] hexyl]amino]ethyl]phenyl] methanesulphonamide hydrobromide From Intermediate 43 (1.0g), Intermediate 49 (l.15q) and DEA (0.38g), after a reaction time of 4h. T-ET-A (80:20:2) 25 was used as eluent for FCC, and the resulting foam (0.28g) in methanol (2ml) was treated with hydrogen bromide in methanol (1M. 0.4ml). The solution was concentrated and the residue triturated with ER to give the title compound as a yellow foam (0*22q) t.l.c. (T-ET-A 80:20:2) Rf 30 0.16.

Analysis Found: C„53.3; H?7.0; N.5.7: S,4.6; 8r,12„0. ^ 3 1^ 47^ 3^ 6^ • ^Br • ^ 2^ requires C , 5 3 . 4 ; H ? 7 .2 ; Ns6.0; S,4.6; Br,11.55S.

Example 14 N^N-Diethyl-2-[4-[[6-[[2-hydroxy-2-[4-hydroxy-3-[(methylsulphonyl)amino]phenyl]ethyl]amino]hexyl] oxy]buty1]benzamide acetate (salt) From Intermediate 43 (1.70g), Intermediate 47 (1.9g) and DEA (0.66g). After a reaction time of 3h the solvent was evaporated in vacuo and the residue dissolved in methanol (30mA) and pre-absorbed onto FCC silica. Purification by FCC eluting with T-ET-A (40:10:1) gave a foam (0.56g).

This was dissolved in methanol (10mA) and treated with glacial acetic acid (0.06mA) to give the title compound as a buff foam (0.40g)s t.l.c. (T-ET-A 40:10:1) Rf 0.09. Analysis Found; C,58.5; H„7„5; N,6.0. 3 0^1+7^ 3^ 6^ • C 2^ 1,0 2»H 20 requires C.58.6: H , 8 .1 : N?6.4%.

Example 15 N?N-Diethv1-4-[4-[[6-[[2-[4-hydroxy-3-[(methyl sulphonyl) amino]phenyl]ethyl]amino]hexyl]oxy]butyl]benzene acetamide, benzoate (salt) as a cream solid (80mg) m.p. 114-116 °.

Analysis Found: C »6 2 »7 : H„7.7^ N , 5.5; S.

CsiH^gNsOgS.I .25C7H 60 2»H20 requires C,62.6; H.7.7: N,5.5; S,4.2%.

From Intermediate 43 (2»0g)? Intermediate 50 (2.29g) and DEA (0„76q), after a reaction time of 3h. Following FCC, the resulting foam (0.7g) was partitioned between EA (50ml) and 8% aqueous sodium bicarbonate (50ml) , and the dried organic layer concentrated to qive a foam (0.20g) which was then treated with benzoic acid (80mg) in chloro form. .54 Example 16 N,N-Diethyl-3-[4-[ [ 6 — [[2-hydroxy-2-[4-hydroxy-3-[(methyl sulphonyl)amino)phenyl]ethyl]amino]hexyl3oxy]butyl) benzamide, as a sticky pink foam (1.2g), t.l.c. (T-ET-A 80 s 20:2) Rf 0.1.

Analysis Found C.62 .27;H,8.25;N .7 .03 ; S .5 .61 . c 30h i*7n 3° 6s requires; C , 62 . 36 ; H , 8 . 20 ; N , 7 .27 ; 0 ,5 »558 From Intermediate 51 (3»0g). Intermediate 43 (2„9g) and DEA (3.6g), at a reaction temperature of 100°, and using T-ET-A (80:20 :2)*T-methanol-A (50 :50 - 2) as the FCC eluent.

The following are examples of suitable pharmaceutical compositions according to the invention. The term "active ingredient" is used herein to refer to a compound of the invention.

Tablets (Direct Compression) mq/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.

Syrup (Sucrose-free) mq/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 hot water, cooled and then mixed with an aqueous solution containing the active ingredient and the other components of the formulation. The resultant 5 6 solution is adjusted to volume and mixed. The syrup is clarified by filtration.

Metered Dose Pressurised Aerosol A. Suspension Aerosol 5 mq/metered dose Per can Active ingredient micronised 0.100 26.40mg Oleic Acid BP 0.100 2.64mg Trichlorofluoromethane BP 23.64 5.67g 10 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 15 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.

B. Solution Aerosol 20 mq/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 25 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 30 dichlorotetrafluoroethane. Suitable metering valves are crimped onto 57 the containers and dichlorodifluoromethane is pressure filled into them through the valves.

Injection for Intravenous Administration mg/ml 5 Active ingredient 0.5mg Sodium Chloride BP as required Water for Injection BP to 1.0ml Sodium chloride may be added to adjust the tonicity of the solution and the pH may be adjusted, using acid or 10 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 15 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.

Inhalation Cartridges 20 mq/cartridqe 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 25 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. -5 3

Claims (18)

CLAIMS:

1. Compounds of the general formula (I) QNH R1 OH R i 2 CHCH2NHCXCH2OCH2YAr (I) wherein 5 Ar represents a phenyl group optionally substituted by one or more substituents selected from halogen atoms, or the groups C^_galkyl, C^galkoxy, nitro, ~(CH2)^R, [where R is 3 4 3 4 hydroxy, -NR R (where R and R each represents a hydrogen 3 4 atom, or a C1-4 alkyl group or -NR R~ forms a saturated 10 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 C1-4 alkyl group, 0 and R represents a hydrogen atom or a C^_4 alkyl, C^_4 15 alkoxy, phenyl or -NR^R^ group), -NR^S02R7 (where R7 3 4 8 represents a C^_4 alkyl, phenyl or -NR R group), -COR 8 3 4 9 (where R represents hydroxy, C1-4 alkoxy or -NR R ), -SR 9 (where R is a hydrogen atom, or a C^_^ alkyl or phenyl 9 9 group), -SOR , ~S02R , or -CN, and q represents an integer 20 from 0 to 3], -(CH2)rR10, [where R10 is a C1-4 alkoxy group and r represents an integer from 1 to 3], or -0(CH2) [where R11 represents a hydroxy or alkoxy group and t is 2 or 3], or Ar is a phenyl group substituted by an alkylenedioxy group of formula -0(CHo) 0-, where p repre- P sents 1 or 2; 1 2 R and R each represent a hydrogen atom or a alkyl group with the proviso that the sum total of carbon atoms 1 2 in R and R is not more than 4; X represents a C^_7 alkylene, C2_7 alkenylene or C2_7 alkynylene chain; Y represents a bond, or a alkylene, C2_g alkenylene or C2__6 alkynylene chain with the proviso that the sum total of carbon atoms in X and Y is 2 to 10; 19 19 191? Q represents a group R CO-, R NHCO-, R R NS02~ or 14 12 13 R S02, where R and R each represent a hydrogen atom 14 or a C^^g alkyl group, and R represents a C^_4 alkyl group; with the proviso that when X represents C^_7 alkylene, and Y represents a bond or C^_g alkylene, then the group Ar does not represent an unsubstituted phenyl group or a phenyl group substituted by one or more substituents selected solely from halogen atoms or C^_g alkyl or C^_g alkoxy groups or an alkylenedioxy group -0(CH9) 0-; 6 P and physiologically acceptable salts and solvates thereof.

2. Compounds as claimed in claim 1 in which -X- is -(CH2)2-, -(CH2)3-, -CCH2)4-, -(CH2)5-, -CH2C*C~, -(CH2)2CH=CH-, -(CH2)2C=C, -CH=CHCH2", -CH=CH(CH2)2- or 6 '0 -CH2C=CCH2- and -Y- is -CHg-, -(CH^-, -(CH2)3-, -(CH^-, -(CH2)--, -(CH2)g-,-CH=CH-, -CHC-, -CH2CH=CH-, or -CH2C=C-.

3. Compounds as claimed in claim 1 or 2 in which R"1" and 2 R independently represent a hydrogen atom or a methyl group.

4. Compounds as claimed in any of claims 1 to 3 in which Q is HC0-, CHgCO-, NHgCO-, (CH3)2NSC>2- or CH3S02~.

5. Compounds as claimed in Claim 4 in which Q is CHgSOg-.

6. Compounds as claimed in any of claims 1 to 5 in which Ar is phenyl; or Ar is phenyl substituted by one or more substituents selected from chlorine, bromine, iodine, fluorine, methyl, ethyl, methoxy, ethoxy, -(CH0) R [where R ^ q is hydroxy, amino, methylamino, ethylamino, dimethylamino, diethylamino, morpholino, piperidino, piperazino, N-methyl-piperazino, -NHCOR (where R is hydrogen or C^_4 alkyl, C1_4 alkoxy, phenyl, amino or N,N-dimethylamino), -N(CH3)COCH3, -NHS02CH3, -NHS02(CH2)3CH3, -NR5S02R7 (where R5 represents a 7 hydrogen atom or a methyl group and R represents phenyl), -nhso2nh2, -nhso2n(ch3)2, -cooh, -cooch3, -cooch2ch2ch3, -C0NH2, -C0N(CH3)2, -C0N(CH2CH3)2, -CON(CH2CH2CH3)2,-CON^), -SR9 [where R^ is methyl, ethyl or phenyl), -S0CH3, -S02CH3, or -CN and q is zero, 1, 2 or 3], ~NC>2, -CH20CH3, ~(CH2)3OCH3> -0(CH2)20H, -0(CH2)30H, -0(CH2)20CH3 or -0(CH2)20CH2CH3.

7. Compounds as claimed in claim 6 in which Ar is a phenyl group containing a single substituent which is -CON(CH2CH3)2.

8. . Compounds of the general formula (la) QNH HO > CHCHoNHCXCHo0CHoYAr l 1 \o 1 * OH R~ R 1 (la) and physiologically acceptable salts and solvates thereof wherein X represents a C^_7 alkylene, ^2-7 a^kenylene or C2-7 alkynylene chain; Y represents a bond, or a C1_g alkylene, Cg_g alkenylene or C2_g alkynylene chain with the proviso that the sum total of carbon atoms in the chains X and Y is 5, 6 or 7; 1 2 R and R each independently represent a hydrogen atom or a methyl group; Q represents HCO-, NE2CO~, (CH3)2NS02~ or CH^SOg-; and Ar represents a phenyl group substituted by a group selected from amino, dimethylamino, nitro, morpholino, (CH„) NHCOR z q 6 7 (where R is alkyl and q is zero or 1), -NHS02R (where R7 is , -COR^ (where R^ is 3 4 3 4 alkoxy, or -NR R where R and R are both C^_^ alkyl or NR3R4 forms a piperidino ring), -CH2C0NR3R4 (where R3 and R4 are both alkyl), -SR9 (where R9 is C^_4 alkyl) or -(CH2)r R3"0 (where r is 3 and R10 is C^_4 alkoxy), or Ar is 3,5-dihydroxyphenyl or 3-methoxy-4- hydroxyphenyl, or, when X and/or Y represent an alkenylene or alkynylene group, Ar may additionally represent a phenyl group optionally substituted by a fluorine atom.

9. Compounds as claimed in claim 8 in which Q represents CH^SC^-.

10. Compounds as claimed in claim 8 in which Ar is a phenyl group containing a single substituent 5 which is -CON(CH2CH3)2.

11. N, N-Diethyl-4-[4-[[6-[[2-hydroxy-2-[4-hydroxy-3-[(methylsulphonyl)amino]phenyl]ethyl]amino]hexyl]oxy]butyl] benzamide and physiologically acceptable salts and hydrates thereof. 10

12. The compounds: N-[ 2-hydroxy-5-[l-hydroxy-2- [ [6-[4-(3,5-dihydroxypheny1) butoxy]hexyl]amino]ethyl]phenylJmethanesulphonamide; N-[2-hydroxy-5-[X-hydroxy-2-[[6-[4-(4~hydroxy-3-methoxy-phenyl)butoxy J hexylJamino]ethyl]phenylJmethanesulphonamide; 15 N-[2-hydroxy-5-[l-hydroxy-2-[[6-[4-(4-(methylthio)phenyl J butoxy J hexyl Jamino] ethyl J phenyl Jmethanesulphonamide. N-[2-hydroxy-5-[l-hydroxy-2-[[6-[4-(4-nitrophenyl)butoxy] hexylJamino]ethyl]phenylJmethanesulphonamide; N- [ 5-[2-[[6-[4-(4-ami nophenyl)butoxy J hexylJ amino-l-hydroxy-20 ethylJ-2-hydroxyphenylJmethanesulphonamide ; propyl 4-[4-[[5-[[2-hydroxy-2~[4-hydroxy-3-[(methylsulphonyl) amino J phenyl JethylJamino]pentvl]oxy]butylJbenzoate; N—[[4—[4—[[6—[[2-hydroxy-2-[4-hydroxy-3-[(methylsulphonyl) amino]phenyl]ethyl]amino]hexyl]oxy J butyl J phenylJmethylJ 25 pentanarnide; N-[2-hydroxy-5-[l-hydroxy-2-[ [5-[4-[4-(3-methoxypropyl) phenyl]butoxy]pentylJamino]ethyl]phenyl J formamide; N-[4-[4-[[6-[[2—[3—[(aminocarbonyl)amino]-4-hydroxypheny] ethyl]amino]hexyl]oxv]butyl]phenylJbutanesulphonamide; 63 N-[2-hydroxy-5-[l-hydroxy-2-[ [6-(4-phenylbutoxy)-3-hexynyl] amino]ethyl]phenylJmethanesulphonamide; (E)-N-[2-hydroxy-5-[l-hydroxy-2-[[6-[[4-(4-fluorophenyl)-3-butenylJoxyJhexylJaminoJethylJphenylJmethanesulphonamide; 5 and physiologically acceptable salts and hydrates thereof.

13. A process for the preparation of compounds as claimed in any of claims 1 to 12 or a physiologically acceptable salt or solvate thereof which comprises: (la) for the preparation of a compound of formula 1 (I) in which R is a hydrogen atom, alkylating an amine of general formula (II) QNH CHCH0NR16R17 (II) i ^ OH (where each of R15 and R16 is a hydrogen atom or a protecting 17 group and R is a hydrogen atom) with an alkylating agent of general formula (III) LCHXCH„0CHoYAr (III) I o ^ ^ RZ (wherein L represents a leaving group) followed, if necessary, by removal of any protecting group present; or @4 (lb) for the preparation of a compound of formula (I) in which R"*" is a hydrogen atom, alkylating an amine of 17 general formula (II) as defined above except that R is a hydrogen atom or a group convertible thereto under the 5 reaction conditions, with a compound of general formula (IV) in the presence of a reducing agent followed, if necessary, by removal of any protecting group present; or (2) deprotection of a protected intermediate of 10 general formula (VI) QNH R2C0XCH20CH2YAr (IV) (VI) ^ r «4 /* (where each of R and R is a hydrogen atom or a protecting group, except that at least one of R and R is a protecting group); or 15 (3) reducing an intermediate of general formula (VII) QNH (VII) 85 (wherein Rl0 is a hydrogen atom or a protecting group, 1 X~ is -CH(OH) or a group convertible thereto by reduction, X" is -CHgNR"" or a group convertible thereto by i g reduction (where R"*" is a hydrogen atom or a protecting group), 3 1 9 X is -CR R'"X or a group convertible thereto by reduction at least one of X , X", X° representing a reducible group and/or Y and/or Ar containing a reducible group) followed, if necessary, by removal of any protecting group present; an if desired, converting the resulting compound of general formula (I) or a salt thereof into a physiologically acceptable salt or solvate thereof.

14. a pharmaceutical composition comprising at least one compound of general formula (I) as defined in any of claims 1 to 12 or a physiologically acceptable salt or solvate thereof, together v;ith a physiologically acceptable carrier or excipient.

15. A compound according to Claim le substantially as hereinbefore described with particular reference to Examples 1-16 of the accompanying Examples.

16. ™ A process for the preparation of a compound according to Claim If, substantially as hereinbefore described and exemplified-

17. A compound according to Claim 1f whenever prepared by a process claimed in a preceding claim-

18. A pharmaceutical composition according to Claim 14, substantially as hereinbefore described and exemplified., F. R. KELLY & CO., AGENTS FOR THE APPLICANTS.